Compounds having anti-androgen receptor activity and their use

Abstract

The present invention provides a compound represented by formula I, its racemate, stereoisomer, tautomer, solvate, crystalline polymorph, or a pharma- ceutically acceptable salt thereof. The compound has good prostate tumor cell proliferation inhibitory activity and anti-AR activity. In addition, the compound has good in vivo metabolism, and has AUC and C max The compounds of the present invention have good hair growth promoting effect and can effectively increase the number of hair follicles and the length of hair growth. [Formula 1] JPEG2025515508000061.jpg30169

Description

Detailed description of the invention

[0001] This application claims priority to a prior application filed with the China National Intellectual Property Administration on April 29, 2022, patent application number 202210476508.3, with the title of the invention "Compounds Having Anti-Androgen Receptor Activity and Uses Thereof." The aforementioned prior application is incorporated into this application by reference in its entirety.

[0002] [Technical Field] This invention belongs to the field of pharmaceutical technology and specifically relates to compounds having anti-androgen receptor activity and their use.

[0003] [Background technology] The androgen receptor (AR) is a member of the ligand-related transcription factor family, which is also known as the steroid receptor superfamily. The androgen receptor is a steroid hormone receptor that has a ligand-binding domain, a DNA-binding domain, and multiple phosphorylation sites. After binding to the ligand androgen in the body, AR forms an AR dimer, is further phosphorylated, and translocates from the cytoplasm to the cell nucleus, where it mediates the transcription and activation of various pathways.

[0004] AR is widely distributed in many parts and organs of the human body and plays an important role in the progression of many androgen-related diseases, such as cancer, alopecia, and acne.

[0005] Androgens and ARs have been reported in the literature to play important roles in the normal growth of the prostate and prostate cancer, and anti-androgen drugs are already widely used in the treatment of prostate cancer. Furthermore, high serum androgen levels are associated with acne and androgenic alopecia, and anti-androgen therapy has a potential impact on acne and androgenic alopecia. However, androgens are involved in many biological processes, and blocking or inhibiting the binding of androgens to their corresponding receptors can lead to an effective increase in androgen levels in the surrounding environment. This increase in androgen levels in the surrounding environment can affect other androgen-related biological processes and cause undesirable side effects. Currently, inhibiting androgen receptor production is a hot spot in research, and compounds with anti-androgen receptor activity are considered potential therapies for androgen receptor-related diseases.

[0006] Chinese patent application CN03808650.6 discloses curcumin analogs that have activity to inhibit androgen receptor production and can effectively inhibit androgen receptor production in cells, many of which are oily or have less than ideal activity.

[0007] Mental illnesses such as low self-esteem and depression often trouble patients with alopecia, skin diseases, and other conditions, placing a serious psychological burden on them. Therefore, there is an urgent need for novel compounds with good drug discovery potential and other properties such as biological activity.

[0008] [Summary of the Invention] The present invention provides a curcumin derivative that has high bioavailability, good biological activity, acts rapidly, and can maintain a stable physiological concentration in the body for a long period of time.

[0009] The present invention further aims to provide a composition containing the above curcumin derivatives and the use of the above curcumin derivatives in the manufacture of a drug for treating, preventing or ameliorating symptoms or diseases caused by androgen-related disorders.

[0010] The object of the present invention is achieved by the following technical solutions, According to a first aspect, the present invention provides a compound represented by the following formula I, its racemate, stereoisomer, tautomer, solvate, crystal polymorph or pharmaceutically acceptable salt thereof,

[0011]

Chemical formula

[0012] Among them, R1, R2, R3, and R4 are the same or different and are independently of each other an unsubstituted or optionally substituted C 1-12 alkyl group or deuterated C 1-12 alkyl group,

[0013]

Chemical formula

[0014] is an unsubstituted or optionally substituted C 3-20 cycloalkyl group, C 4-20 cycloalkenyl group, 3- to 20-membered heterocyclyl group, C 3-20 cycloalkyl group and C 3-20 a spiro ring formed by linking cycloalkyl groups, C 3-20 a spiro ring formed by linking a cycloalkyl group and a 3- to 20-membered heterocyclyl group, a spiro ring formed by linking two 3- to 20-membered heterocyclyl groups, Ra are the same or different and are independently of each other halogen, =O, hydroxy group, amino group, C 1-12 alkyl group, C 1-12 alkoxy group, Rb is homologous or different, and each is independently deuterated, halogenated, =O, hydroxyl group, amino group, unsubstituted, or optionally substituted with one, two, or more Rc. 1-12 Alkyl alkyl group, C 1-12 Alkoxy group, C 3-20 Cycloalkyl group, 3-20 membered heterocyclyl group, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl(2),-NHCOC 1-12 Alkyl, -CONHC 1-12 Alkyl alkyl, -NHC 3-20 Cycloalkyl groups, -NHCOC 3-20 Cycloalkyl groups, -CONHC 3-20 Cycloalkyl groups, -S(O)2C 1-12 Alkyl group, -COOC 1-12 Two Rb groups, selected from an alkyl group or linked to the same carbon atom, are linked together with the carbon atom, either unsubstituted or optionally substituted with one, two, or more Rc groups. 3-20 It forms a ring system consisting of a cycloalkyl group and a 3-20 membered heterocyclyl group. The above Rc is a halogen, hydroxyl group, amino group, C 1-12 Alkyl alkyl group, C 1-12 Alkoxy group, C 3-20 Selected from cycloalkyl groups, 3-20 membered heterocyclyl groups, and 5-20 membered heteroaryl groups.

[0015] According to embodiments of the present invention, R1, R2, R3, and R4 are homologous or different, and are independent of each other. 1-6 Alkyl or deuterated C 1-6 Selected from alkyl groups, According to embodiments of the present invention,

[0016] [ka]

[0017] C is either unsubstituted or optionally substituted with one, two, or more (e.g., 1, 2, 3, 4, or 5) Rb.3-12 Cycloalkyl groups, C 4-12 Cycloalkenyl group, 3-12 membered heterocyclyl group, C 3-12 Cycloalkyl groups and C 3-12 A spiro ring formed by linking cycloalkyl groups, C 3-12 This represents a ring system consisting of a spiro ring formed by linking a cycloalkyl group and a 3-12 membered heterocyclyl group, and a spiro ring formed by linking two 3-12 membered heterocyclyl groups. According to embodiments of the present invention, Rb is homologous or homologous and is independently substituted with deuterated, halogenated, =O, hydroxyl group, amino group, unsubstituted, or optionally one, two, or more (e.g., 1, 2, 3, 4, or 5) Rc C. 3-12 Cycloalkyl group, 3-12 member heterocyclyl group, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2,-NHCOC 1-6 Alkyl alkyl, -NHC 3-12 Cycloalkyl groups, -S(O)2C 1-6 Alkyl group, -COOC 1-6 Selected from the group called alkyl, In some embodiments of the present invention, the above Rc is a halogen, a hydroxyl group, C 3-12 Selected from cycloalkyl groups, 3-12 membered heterocyclyl groups, and 5-12 membered heteroaryl groups.

[0018] In some embodiments of the present invention, the 3- to 20-membered heterocyclyl group may be a nitrogen-containing heterocyclyl group, an oxygen-containing heterocyclyl group, or the like, such as a piperidinyl group, piperazinyl group, morpholinyl group, or dioxanyl group.

[0019] In some embodiments of the present invention,

[0020] [ka]

[0021] C is either unsubstituted or optionally substituted with one, two, or more Rb. 3-10 Monocycloalkyl group, C 3-10 Monocycloalkenyl group, oxa C 2-10 Monocycloalkyl groups, Aza C 2-10 Monocycloalkyl groups, spirocycloC 6-16 Alkyl alkyl groups, oxapirocyclo C 6-16 The ring system may also be an alkyl group, for example, a spirocyclohexane group, a spirocycloheptane group, a spirocyclooctane group, a spirocyclononane group, a spirocyclodecane group, pyrrolidine, piperidine, hexamethyleneimine, an oxapirocyclohexane group, an oxapirocycloheptane group, an oxapirocyclooctane group, an oxapirocyclononane group, or an oxapirocyclodecane group.

[0022] In some embodiments of the present invention,

[0023] [ka]

[0024] This may be a ring system consisting of an unsubstituted or optionally substituted cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclohexenyl group, spiro[2,3]hexane group, 1,3-dioxacyclohexane group, piperidine group, or 1,4-dioxaspiro[4,5]decane group, either substituted or optionally substituted with one, two, or more Rb groups. In some embodiments of the present invention, Rb is deuterated, F, Cl, Br, I, =O, hydroxyl group, amino group, tert-butoxycarbonyl group, -S(O)2CH3, -COOC(CH3)3,

[0025] [ka]

[0026] Selected from, In some embodiments of the present invention, R1, R2, R3, and R4 are homologous or different, and are independent of each other. 1-3 Alkyl or deuterated C 1-3 Selected from alkyl groups, for example, a methyl group or a deuterated methyl group. In some embodiments of the present invention, the compound represented by formula I is

[0027] [ka]

[0028] It has the following structure, Of these, R1, R2, R3, and R4 have the definitions described above. R5 is a halogen, and R6 is a C with a hydroxyl group, an amino group, unsubstituted, or optionally substituted with one, two, or more Rc groups. 1-12 Alkyl alkyl group, C 1-12 Alkoxy group, C 3-20 Cycloalkyl group, 3-20 membered heterocyclyl group, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl(2),-NHCOC 1-12 Alkyl, -CONHC 1-12 Alkyl alkyl, -NHC 3-20 Cycloalkyl groups, -S(O)2C 1-12 Alkyl group, -COOC 1-12 It is an alkyl group, In some embodiments of the present invention,

[0029] [ka]

[0030] is =O, halogen,

[0031] [ka]

[0032] Alternatively, it represents a cyclohexyl group substituted with -N(C2H5)2.

[0033] In one embodiment of the present invention,

[0034] [ka]

[0035] represents a cyclohexyl group substituted with =O or a halogen, for example,

[0036] [ka]

[0037] That is the case.

[0038] In some preferred embodiments of the present invention, the compound represented by formula I is

[0039] [ka]

[0040] They are selected from among them.

[0041] In some specific embodiments of the present invention, the compound represented by formula I is

[0042] [ka]

[0043] They are selected from among them.

[0044] In some preferred embodiments of the present invention, the compound represented by formula I is

[0045] [ka]

[0046] They are selected from among them.

[0047] If the compound of the present invention can exist in the form of a tautomer, the present invention includes all tautomer forms.

[0048] The compounds of the present invention can exist in the form of stereoisomers (enantiomers, diastereoisomers). Accordingly, the present invention includes enantiomers or diastereoisomers and mixtures thereof. From this mixture of enantiomers and / or diastereoisomers, a homogeneous component of stereoisomers can be separated by known methods.

[0049] In some embodiments of the present invention, pharmaceutically acceptable salts of the compounds represented by formula I are their hydrochloride salts, for example, the hydrochloride salts of compound 12, compound 14, compound 16, compound 18, compound 19, and compound 23.

[0050] The present invention further provides a method for producing the compound described in Formula I above, and includes the following steps.

[0051] [ka]

[0052] Of these, R1 to 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, for example, bromine. Compound I is obtained by reacting the compound of formula SM-A with the compound of formula SM-B. Furthermore, different substituents can be introduced to the A ring of the compound of formula I by conventional chemical synthesis methods. For example, several compounds of formula I can be produced by the following method, which is: This includes reacting the compound of formula (I-1) with R5-L to obtain the compound of formula (I-2),

[0053] [ka]

[0054] Of these, R1, R2, R3, R4, and R5 have the definitions described above, and L is a leaving group.

[0055] Alternatively, the method includes reacting the compound of formula (I-1) with R6-L to obtain the compound of formula (I-3),

[0056] [ka]

[0057] Of these, R1, R2, R3, R4, and R6 have the definitions described above, and L is a leaving group.

[0058] In some embodiments, n is an integer from 0 to 9, for example, 0, 1, 2, 3, 4, 5.

[0059] In some embodiments, m is an integer between 0 and 10, for example, an integer between 0 and 5, for example, 0, 1, 2, 3, 4.

[0060] The present invention further provides a pharmaceutical composition comprising at least one of the compounds represented by formula I, their racemates, stereoisomers, tautomers, solvates, crystalline polymorphs, or pharmaceutically acceptable salts thereof.

[0061] According to the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable adjuvants.

[0062] Preferred routes of administration for the pharmaceutical composition of the present invention include, but are not limited to, oral, rectal, topical, oral, parenteral, intramuscular, intradermal, intravenous, and transdermal administration.

[0063] According to the present invention, the above-mentioned pharmaceutical composition is used for oral administration, and the pharmaceutical composition may be in the form of tablets, pills, lozenges, sugar-coated preparations, capsules, etc.

[0064] According to the present invention, the above-mentioned pharmaceutical composition is for topical application, and the pharmaceutical composition may be an ointment, cream, paste, tincture, hard ointment, gel, smeared film, application agent, aerosol, spray, foam, microsponge, etc.

[0065] The pharmaceutical compositions of the present invention can be manufactured by employing methods well known in the art, such as conventional mixing methods, granulation methods, sugar-coated pill manufacturing methods, polishing methods, melting methods, emulsification methods, and dissolution methods. For example, solid oral compositions can be manufactured by conventional mixing, filling, or tableting methods, and topical preparations can be obtained by conventional dissolution, mixing, and stirring methods. For example, an active compound can be mixed with a solid auxiliary agent, the resulting mixture can be optionally pulverized, other suitable auxiliaries can be added as needed, and then the mixture can be processed into granules to obtain the core of a tablet or sugar-coated preparation. Suitable auxiliaries include, but are not limited to, binders, diluents, disintegrants, lubricants, flow promoters, sweeteners, or flavoring agents. For example, a cream can be manufactured by emulsification, 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, and then adding the aqueous phase to the oil phase while stirring until condensation occurs to obtain an ointment. Suitable adjuvants include, but are not limited to, substrates, pH adjusters, and transdermal absorption enhancers.

[0066] The present invention provides for the use of the compound represented by Formula I above, its racemic mixture, stereoisomer, tautomer, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention, in the manufacture of drugs for treating, preventing or improving symptoms or diseases of androgen-related disorders.

[0067] According to the present invention, non-limiting examples of the symptoms or diseases of androgen-related disorders include wounds (the compounds of the present invention can help heal wounds), acne, atopic dermatitis, rheumatoid arthritis, androgen-related inflammation including psoriasis and rosacea, Kennedy disease (spinal and medullary muscular atrophy or SBMA), polyglutamine-mediated motor neuron diseases, androgen-related cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma of the liver, central nervous system cancers, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer and pancreatic cancer, alopecia including androgen-related alopecia, acne and hirsutism.

[0068] The present invention further provides a method for treating, preventing or improving symptoms or diseases of androgen-related disorders, which includes providing an effective amount of a compound represented by Formula I of the present invention, its racemates, stereoisomers, tautomers, solvates, crystalline polymorphs or pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the present invention, to an individual in need thereof.

[0069] According to the present invention, non-limiting examples of the symptoms or diseases of androgen-related disorders include wounds (the compounds of the present invention can help heal wounds), acne, atopic dermatitis, rheumatoid arthritis, psoriasis and rosacea, androgen-related inflammation, polyglutamine-mediated motor neuron disease, Kennedy disease (spinal and medullary muscular atrophy or SBMA), androgen-related cancers such as prostate cancer, bladder cancer, breast cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, hepatocellular carcinoma of the liver, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer and pancreatic cancer, alopecia including androgen-related alopecia, acne and hirsutism.

[0070] In all administration methods of the compound shown in Formula I described herein, the daily dose is 0.01 to 200 mg / kg body weight.

[0071] According to the present invention, the administration plan can be adjusted to provide the optimal desired response. For example, it may be administered as a single oral dose, as divided doses over time, or the dose may be proportionally reduced or increased as indicated by the needs of the treatment situation. It should be noted that the dose values ​​may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. Furthermore, it should be understood that for any particular individual, the specific administration plan should be adjusted over time based on the individual's needs and the professional judgment of the person administering or managing the administration of the composition.

[0072] Definition and Description Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as those commonly understood by those skilled in the art. All patents and published works relating to this invention are incorporated collectively by reference.

[0073] Unless otherwise specified, the following definitions used herein shall apply. Where a trade name is mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0074] The terms “including,” “incorporating,” “possessing,” “containing,” or “related to” as used herein, and other variations thereof, are inclusive or non-exclusive and do not exclude other unlisted elements or method steps.

[0075] In this specification, the term “optionally” indicates whether or not a described feature has two possible outcomes, meaning that the event described thereafter may or may not occur, and thus includes both the case where the event occurs and the case where it does not. For example, “optionally alkyl-substituted heterocyclyl group” means that the alkyl group may or may not be present, and thus includes both the case where the heterocyclyl group is alkyl-substituted and the case where the heterocyclyl group is not alkyl-substituted.

[0076] In this specification, the term "halogen" refers to fluorine, chlorine, bromine, and / or iodine. Accordingly, the term "halogenation" refers to fluoro, chloro, bromo, and / or iodine. Within the scope of this specification, when an atom, residue, group, or part is halogenated, the atom at the halogenation site may be monosubstituted, disubstituted, or polysubstituted, up to total substitution by a halogen atom.

[0077] In this application, "*" indicates a bonding site.

[0078] "C 1-12 The term "alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably C 1-6 It should be understood that it is an alkyl group. 1-6 It should be understood that the alkyl group preferably refers to a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, a methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isoamyl group, 2-methylbutyl group, 1-methylbutyl group, 1-ethylpropyl group, 1,2-dimethylpropyl group, neopentyl group, 1,1-dimethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 2-ethylbutyl group, 1-ethylbutyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, or 1,2-dimethylbutyl group or its isomers. In particular, the group has 1, 2, or 3 carbon atoms ("C 1-3 It has an alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.

[0079] "C 3-20 The term "cycloalkyl group" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3-12 It should be understood as a "cycloalkyl group". 3-12 The term "cycloalkyl group" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. 3-12 The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, or cyclodecyl group, or it may be a bicyclic hydrocarbon group such as a decahydronaphthalene ring.

[0080] "C 4-20 The term "cycloalkenyl group" should be understood to refer to an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 4 to 20 carbon atoms and containing at least one unsaturated double bond, for example, 1, 2, or 3 unsaturated double bonds. Preferably "C 4-12 It is a "cycloalkenyl group". 4-12 The term "cycloalkenyl group" should be understood to refer to 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. 4-12 A cycloalkyl group is, for example, a cyclohexenyl group.

[0081] The term "3-20 membered heterocyclyl group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5 heteroatoms independently selected from N, O, and S, and is preferably a "3-12 membered heterocyclyl group." A "3-12 membered heterocyclyl group" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1 to 5, preferably 1 to 3, heteroatoms selected from N, O, and S. The heterocyclyl group can be linked to the rest of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, the heterocyclyl group may include, but is not limited to, a four-membered ring such as an azetidinyl group or an oxetanyl group, a five-membered ring such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a six-membered ring such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group, or a trithianyl group, or a seven-membered ring such as a diazepanyl group. Optionally, the heterocyclyl group may be benzo-condensed. The heterocyclyl group may also be bicyclic, for example, a five-, five-membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a five-, six-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring, but is not limited to these. The nitrogen atom-containing ring may be partially unsaturated, that is, it may contain one or more double bonds, for example, a 2,5-dihydro-1H-pyrrolyl group, a 4H-[1,3,4]thiadiazinyl group, a 4,5-dihydroxazolyl group, or a 4H-[1,4]thiadinyl group, but is not limited thereto, or it may be benzo-condensed, for example, a dihydroisoquinolinyl group, but is not limited thereto. According to the present invention, the heterocyclyl group is non-aromatic.

[0082] "C 3-20 Cycloalkyl groups and C 3-20 The term "spiro ring composed of a cycloalkyl group" is C 3-20 The definition of a cycloalkyl group is the same as above, with two C 3-20This refers to a spiro ring, which is composed of cycloalkyl groups sharing one carbon atom.

[0083] "C 3-20 The term "spiro ring composed of a cycloalkyl group and a 3-20 membered heterocyclyl group" is C 3-20 The definitions of cycloalkyl groups and 3-20 membered heterocyclyl groups are the same as above, and one C 3-20 This refers to a spiro ring, which is composed of a cycloalkyl group and one 3-20 membered heterocyclyl group sharing one carbon atom.

[0084] The term "spiro ring composed of two 3-20 membered heterocyclyl groups" refers to a spiro ring in which two 3-20 membered heterocyclyl groups share one carbon atom, with the definition of a 3-20 membered heterocyclyl group being the same as above.

[0085] The term "5-20 membered heteroaryl group" should be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5-20 ring atoms and containing 1-5 heteroatoms independently selected from N, O, and S, for example, a "5-12 membered heteroaryl group." The term "5-12 membered heteroaryl group" should be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, and which may be benzo-condensed in each case. In particular, heteroaryl groups include thienyl, furan, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and their benzo derivatives, such as benzofuran, benzothienyl, benzooxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, and isoindolyl groups. Alternatively, selected from pyridinyl groups, pyridadinyl groups, pyrimidinyl groups, pyrazinyl groups, triazinyl groups, etc. and their benzo derivatives, such as quinoline groups, quinazolinyl groups, isoquinoline groups, etc., or azosin groups, indolidinyl groups, purine groups, etc. and their benzo derivatives, or sinnolinyl groups, phthalazinyl groups, quinazolinyl groups, quinoxalinyl groups, naphthilidinyl groups, pteridinyl groups, carbazolyl groups, acridinyl groups, phenadinyl groups, phenothiazinyl groups, phenoxadinyl groups, etc.

[0086] The term "prevention or treatment" means administering the compounds or formulations described in the present invention to prevent, improve, or eliminate a disease or one or more symptoms associated with the disease, and (i) In cases where mammals are particularly susceptible to a disease condition but have not yet been diagnosed with that condition, to prevent the occurrence of the disease or disease condition in those mammals, (ii) Suppressing the disease or disease state, that is, suppressing its progression, (iii) To alleviate the disease or disease state, that is, to eliminate the disease or disease state, Includes.

[0087] The term “therapeutic dose” means an amount of the compound of the present invention that (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder as described herein. The amount of the compound of the present invention constituting a “therapeutic dose” varies depending on the compound, the disease state and its severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by a person skilled in the art based on their knowledge and the content of this disclosure.

[0088] The term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, within the bounds of reliable medical judgment, is suitable for use in contact with human and animal tissues, is free from excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit-to-hazard ratio.

[0089] The pharmaceutically acceptable salts of the compounds of the present invention include salts formed from them with a pharmaceutically acceptable acid, and salts formed from them with a pharmaceutically acceptable base.

[0090] As used herein, the term “pharmaceutically acceptable acid” means a pharmaceutically acceptable acid, for example, 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, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 1,5-naphthalenedisulfonic acid, This refers to 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, goji citric acid, malic acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pamoic acid, niacin, orotic acid, methyl sulfate, dodecyl sulfate, glutamic acid, aspartic acid, gluconic acid, glucuronic acid, or any combination thereof.

[0091] As used herein, the term “pharmaceutically acceptable base” refers to a pharmaceutically acceptable base, such as an inorganic base (e.g., alkali metal hydroxide or alkaline earth metal hydroxide) or an organic base (e.g., an amine (primary, secondary, or tertiary amine)). Examples of suitable salts include, but are not limited to, organic salts obtained from amino acids, ammonia, primary, secondary, tertiary amines, and cyclic amines (e.g., diethylamine salt, piperidine salt, morpholine salt, piperazine salt, choline salt, meglumine salt, trometamine salt, etc.), and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0092] The term "solvate" refers to a formulation formed by the coordination of the compound of the present invention with a solvent molecule in its solid or liquid state. A hydrate is a specific form of solvate in which the coordination occurs with water.

[0093] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present invention or salts thereof and pharmaceutically acceptable adjuvants. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present invention to organisms.

[0094] The compounds of the present invention may be manufactured into tablets, pills, lozenges, sugar-coated preparations, capsules, etc., for oral administration to patients. The compounds of the present invention may also be manufactured into ointments, creams, pastes, tinctures, hard ointments, gels, smeared films, ointments, aerosols, sprays, foams, microsponges, etc., for topical administration to patients.

[0095] The term "pharmaceutically acceptable adjuvants" refers to adjuvants that do not cause apparent irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable adjuvants are those well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water.

[0096] The pharmaceutical compositions of the present application can be manufactured by combining the compounds of the present application with appropriate pharmaceutically acceptable adjuvants, and can be manufactured in the form of solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microballs, and aerosols.

[0097] Typical routes for administering the compound of this application, its pharmaceutically acceptable salt, or its pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, nasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration, with oral administration exhibiting even better patient compliance than intravenous administration.

[0098] The pharmaceutical composition of this application can be manufactured by employing methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill manufacturing methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0099] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with pharmaceutically acceptable adjuvants well known in the art. These adjuvants allow the compound of the application to be prepared for oral administration to patients in the form of tablets, pills, lozenges, sugar-coated preparations, capsules, liquids, gels, slurries, suspensions, etc. For example, a solid oral composition can be prepared by conventional mixing, filling, or tableting methods. For example, it can be prepared by mixing the active compound with a solid adjuvant, optionally grinding the resulting mixture, adding other suitable adjuvants as needed, then processing the mixture into granules to obtain the core of a tablet or sugar-coated preparation. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, flow enhancers, sweeteners, or flavoring agents.

[0100] The pharmaceutical compositions of the present invention may also be applied to topical administration, for example, in appropriate unit dosage forms such as creams, gels, foams, or tinctures. Topical preparations can be produced by conventional dissolution, mixing, and stirring methods. For example, creams can be produced by emulsification, where oily and oil-soluble components are heated and melted to obtain an oil phase, water-soluble components are dissolved in water and heated to obtain an aqueous phase, and the aqueous phase is added to the oil phase while stirring until condensation occurs to obtain an ointment. Suitable adjuvants include, but are not limited to, substrates, pH adjusters, and transdermal absorption enhancers.

[0101] The term "androgen" refers to male hormones such as testicular hormones and dihydrotestosterone (DHT). DHT is a product of testicular hormones transformed with 5-α-reductase. Androgens stimulate or regulate the development and maintenance of male characteristics and other physiological functions in vertebrates by binding to androgen receptors and subsequently to androgen / AR regulatory genes (DNA), thereby maintaining, activating, or regulating genes.

[0102] The term "androgen receptor" or "AR" refers to an intracellular receptor that specifically binds to androgens, including testicular hormones and dihydrotestosterone (DHT). ARs include all mammalian androgen receptor conjugates, binding mutants, and crystalline polymorphs.

[0103] The human term "androgenetic alopecia" refers to hair loss symptoms and conditions associated with androgen levels in vivo. Generally, androgenetic alopecia is thought to be caused by the sensitivity of hair follicles or surrounding tissues to androgens, a sensitivity that is hereditary and tends to occur within families. Androgenetic alopecia is associated with several other medical conditions in men, including coronary heart disease, benign prostatic hyperplasia, prostate cancer, insulin resistance disorders (e.g., diabetes and obesity), and hypertension. In women, alopecia may correlate with an increased risk of polycystic ovary syndrome (PCOS), characterized by hormonal imbalances that can lead to menstrual irregularities, acne, excessive body hair (hirsutism), and weight gain. Alopecia is often associated with androgen accumulation or elevated androgen levels in women. Androgenetic alopecia is the most common form of hair loss in men, and this condition is commonly referred to as androgenetic alopecia. Hair loss is clearly noticeable from both temples. Over time, the hairline recedes into a typical "M" shape. Hair also thins at the crown, often resulting in partial or complete baldness. In women, the hair thins further in various parts of the scalp, and the hairline does not recede. Androgenic alopecia in women rarely causes complete hair loss.

[0104] The term "anti-AR activity" refers to the ability of the compound of the present invention to reduce AR expression in human prostate cancer cells (LNCaP). In this invention, the ability of the compound to reduce AR expression is expressed as the percentage of AR reduction (%). The greater the reduction in AR expression, the stronger the anti-AR activity of the compound; that is, the larger the value of the percentage of AR reduction (%), the stronger the anti-AR activity. The formula for calculating the percentage of AR reduction (%) is: Percentage of AR reduction (%) = (DHT group AR / GAPDH value - test compound group AR / GAPDH value) / DHT group AR / GAPDH value × 100%.

[0105] As used herein, “individual” includes humans and non-human animals. An exemplary human individual includes a human individual suffering from a disease (e.g., a disease described herein) (referred to as a patient) or a healthy individual. “Non-human animals” in the present invention include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, dairy cows, pigs, etc.).

[0106] Beneficial effects The present invention provides a curcumin derivative represented by formula I, which has good prostate tumor cell proliferation inhibitory activity and anti-AR activity. Furthermore, the curcumin derivative of the present invention has good metabolic activity in the body, with AUC and C max All of these factors are relatively high, indicating good drug discovery potential, and they can be used for the prevention and / or treatment of androgen-related disorders. Furthermore, the curcumin derivatives of the present invention also have a good hair growth promoting effect and can effectively increase the number of hair follicles and the length of hair growth.

[0107] [Brief explanation of the drawing] [Figure 1] Western blot diagram showing the reduction in AR protein expression in LNCaP cells by different concentrations of the compound of the present invention. [Figure 2] This shows the pharmacokinetic curves of each compound in male rat plasma after oral administration of the compounds of the present invention. [Figure 3] These are photographs of hair growth and representative HE-stained pathological images of skin tissue from each group of mice in the hair growth promotion test of Measurement Example 4 on day 18 of the experiment.

[0108] [Modes for carrying out the invention] The compounds of the general formula of the present invention, their manufacturing methods, and applications will be described in more detail below, in accordance with specific examples. The following examples are merely illustrative and should not be interpreted as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0109] The intermediate compounds according to the present invention can be produced by several synthesis methods well known to those skilled in the art, including specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0110] The chemical reactions of specific embodiments of the present invention are completed in a suitable solvent, which must be suitable for the chemical changes of the present invention and the necessary reagents and materials. To obtain the compounds of the present invention, those skilled in the art may need to modify or select synthesis steps or reaction processes based on existing embodiments.

[0111] The present invention will be specifically described below with reference to examples, but these examples are not intended to limit the present invention.

[0112] In the following examples, experimental methods for which specific conditions are not explicitly stated generally follow conventional conditions or conditions suggested by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight, and all raw materials and reagents used in the following examples are either commercially available or can be manufactured by known methods.

[0113] This invention adopts the following abbreviations: DHT represents dihydrotestosterone, cluscoterone (purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.) is a commercially available chemical drug whose target indications include androgenetic alopecia, acne, etc. Its mechanism of action is to achieve anti-androgenic effects by competitively inhibiting the binding of DHT and AR, and dimethylcurcumin (purchased from Nanjing Kangmanlin Chemical Industry Co., Ltd.) has the structural formula of raw material A.

[0114] [ka]

[0115] The structural formula of raw material B is

[0116] [ka]

[0117] The structural formula of raw material C is

[0118] [ka]

[0119] The structural formula of raw material D is

[0120] [ka]

[0121] (Ingredients B-D were all purchased from Nanjing Jiming Biopharmaceutical Co., Ltd.)

[0122] Example 1 Synthesis of Compound 1

[0123] [ka]

[0124] In a reaction flask, 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) were added 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 the DMF was washed away with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 39 mg of a pale yellow solid.

[0125] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 15.8 Hz, 2H), 7.30 (d, J = 2.0 Hz, 2H), 7.24 (dd, J = 8.4, 2.1 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 15.7 Hz, 2H), 1.54 (brs, 4H). MS m / z: 435.14 [M+H] + .

[0126] Example 2 Synthesis of Compound 2

[0127] [ka]

[0128] In a reaction flask, 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) were added 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 the DMF was washed away with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 90 mg of a pale yellow solid.

[0129] 1 H NMR (400 MHz,CDCl3) δ 7.57 (d, J = 15.6 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 7.20 - 6.91 (m, 6H), 6.84 (d, J = 8.2 Hz, 1H), 6.79 (d, J = 8.2 MS m / z: 449.22 [M+H] + .

[0130] Example 3 Synthesis of Compound 3

[0131] [ka]

[0132] In a reaction flask, 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) were added 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 the DMF was washed away with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 87 mg of a pale yellow solid.

[0133] 1 H NMR (400 MHz, DMSO- d6) δ 7.55 (d, J = 15.6 Hz, 2H), 7.32 - 7.18 (m, 4H), 6.96 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 15.7 Hz, 2H), 2.31 - 2.15 (m, 4H), 1.67 - 1.50 (m, 4H). MS m / z: 463.20 [M+H]+ .

[0134] Example 4 Synthesis of Compound 4

[0135] [ka]

[0136] In a reaction flask, 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) were added 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 the DMF was washed away with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1-2:1) yielded 92 mg of a pale yellow solid.

[0137] 1 H NMR (400 MHz, DMSO- d6) δ 7.56 (d, J = 15.5 Hz, 2H), 7.37 - 7.18 (m, 4H), 7.03 (d, J = 15.5 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 2.21 - 1.96 (m, 4H), 1.60 - 1.28 (m, 6H). MS m / z: 477.23 [M+H] + .

[0138] Example 5 Synthesis of Compound 5

[0139] [ka]

[0140] 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 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 the DMF was washed away with saturated brine. 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.

[0141] 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 15.8 Hz, 1H), 7.56 (d, J = 15.6 Hz, 1H), 7.33 (d, J = 16.1 Hz, 1H), 7.24 - 6.79 (m, 6H), 6.72 (d, J = 15.5 Hz, 1H), 3.92 (s, 12H), 1.63 (brs, 4H), 0.70 (brs, 4H). MS m / z: 463.16 [M+H] + .

[0142] Example 6 Synthesis of Compound 6

[0143] [ka]

[0144] Raw 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) were added to a reaction flask, and the mixture was stirred at 50 °C for 20 hours. After completion of the reaction, water (50 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, and the DMF was washed away with saturated brine. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate 10:1 - 2:1) afforded 30 mg of a pale yellow solid.

[0145] 1 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 15.8 Hz, 2H), 7.12 (dd, J = 8.3, 2.1 Hz, 2H), 7.00 (d, J = 2.0 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 15.7 Hz, 2H). MS m / z: 439.18 [M+H] + .

[0146] Example 7 Synthesis of Compound 7

[0147] [Chemical formula]

[0148] 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 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 the DMF was washed away with saturated brine. 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.

[0149] 1 H NMR (400 MHz, CDCl3) 7.75 (d, J = 15.5 Hz, 2H), 7.15 (dd, J = 8.4, 2.0 Hz, 2H), 7.02 (d, J = 2.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 15.4 Hz, 2H), 3.91 (s, 12H), 2.56 - 2.40 (m, 8H). MS m / z: 479.29 [M+H] + .

[0150] Example 8 Synthesis of Compound 8

[0151] [ka]

[0152] Under nitrogen gas protection, compound 7 (2.0 g, 4.18 mmol), dichloromethane (20 mL), and one drop of pyridine hydrogen fluoride were added to the reaction flask. The mixture was stirred and cooled to 0°C. 4-tert-butyl-2,6-dimethylphenyl sulfur trifluoride (2.1 g, 8.36 mmol) was added all at once, and the reaction was carried out at 10-15°C for 6 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and the crude product was obtained by column chromatography (petroleum ether / ethyl acetate 10:1-2:1). Preparative HPLC (acetonitrile / water 10:90-80:20) yielded 150 mg of a pale yellow solid.

[0153] 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 15.4 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 7.09 - 6.96 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 15.4 Hz, 2H), 3.91 (s, 12H), 2.45 - 2.18 (m, 4H), 2.12 - 1.91 (m, 4H). 19 F NMR (376 MHz, CDCl3) δ -97.28 . MS m / z: 501.27 [M+H] + .

[0154] Example 9 Synthesis of Compound 9

[0155] [ka]

[0156] Step (1) Synthesis of Intermediate 9-1 Dimethyl curcumin (2.00 g, 5.0 mmol) and tetrahydrofuran (16 mL) were sequentially added to a reaction flask and stirred to dissolve. The reaction temperature was controlled between -1 and 0 °C, and an aqueous formaldehyde solution (37 - 40%, 860 mg, 10.6 mmol) and a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (93 mg) were sequentially added. Then, the reaction was carried out at 0 - 10 °C for 1 - 2 hours and concentrated by rotary evaporation at room temperature. 900 mg of a yellow solid was obtained by column chromatography (MeOH / CH2Cl2 1:100 - 1:50).

[0157] 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.4 Hz, 2H), 7.15 (dd, J = 8.3, 2.1 Hz, 2H), 7.01 (d, J = 2.1 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 15.4 Hz, 2H), 4.34 (d, J = 8.0 Hz, 4H), 3.90 (s, 12H), 2.97 (t, J = 8.0 Hz, 2H).

[0158] Synthesis of compound 9 in step (2) Under nitrogen gas 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 stirred to cool to -70 °C. A solution of bis(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 and dried over anhydrous sodium sulfate, and then 210 mg of a pale yellow solid was obtained by column chromatography (petroleum ether / ethyl acetate 10:1 - 2:1). MS m / z: 483.35 [M+H] + .

[0159] Example 10 Synthesis of compound 10

[0160]

Chemical formula

[0161] 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 a reaction flask and 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 the DMF was washed away with saturated brine. 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.

[0162] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 15.5 Hz, 2H), 7.12 (dd, J = 8.3, 1.9 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 15.4 Hz, 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] + .

[0163] Example 11 Synthesis of Compound 11

[0164] [ka]

[0165] 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 stirred at 25°C for 20 hours. After the reaction was complete, the reaction solution was diluted with 50 mL of ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, concentrated, and obtained 420 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1-2:1).

[0166] 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 15.5 Hz, 2H), 7.12 (dd, J = 8.3, 2.0 Hz, 2H), 7.00 (d, J = 1.9 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 15.4 Hz, 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] + .

[0167] Example 12 Synthesis of Compound 12 and its hydrochloride salt

[0168] [ka]

[0169] 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 hours. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution. It was dried over sodium sulfate and concentrated. Preparative TLC (petroleum ether / ethyl acetate 1:1) yielded 30 mg of a pale yellow solid.

[0170] 1 H NMR (400 MHz, CDCl3) 7.68 (d, J = 15.5 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.16 - 7.09 (m, 2H), 7.03 - 6.98 (m, 2H), 6.83 (dd, J = 8.4, 3.1 Hz, 2H), 6.75 (d, J = 15.5 Hz, 1H), 6.69 (d, J = 15.5 Hz, 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] + .

[0171] Synthesis of the hydrochloride salt of compound 12: 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 vacuum-dried to obtain 120 mg of a pale yellow solid.

[0172] 1 H NMR (400 MHz, CDCl3) δ 12.96 (brs, 1H), 7.72 (d, J = 15.2 Hz, 1H), 7.69 (d, J = 15.3 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.03 - 6.96 (m, 2H), 6.84 (dd, J = 8.4, 3.5 Hz, 2H), 6.71 (d, J = 15.4 Hz, 1H), 6.62 (d, J = 15.4 Hz, 1H), 4.56 - 4.29 (m, 2H), 4.05 - 3.80 (m, 2H), 3.91 (s, 12H), 3.34 - 2.88 (m, MS m / z: 550.48 [M+H] + .

[0173] Example 13 Synthesis of Compound 13

[0174] [ka]

[0175] 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 hours. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution. It was dried over sodium sulfate and concentrated. Preparative TLC (petroleum ether / ethyl acetate 2:1) yielded 20 mg of a pale yellow solid.

[0176] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 15.5 Hz, 1H), 7.66 (d, J = 15.5 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.03 - 6.99 (m, 2H), 6.83 (dd, J = 8.3, 2.6 Hz, 2H), 6.76 (d, J = 15.4 Hz, 1H), 6.73 (d, J = 15.5 Hz, 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] + .

[0177] Example 14 Synthesis of Compound 14 and its hydrochloride salt

[0178] [ka]

[0179] Under nitrogen gas protection, compound 7 (300 mg, 0.63 mmol), ammonium trifluoroacetate (160 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to the reaction flask. The mixture was stirred at 25°C for 30 minutes, after which sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added. 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 mixture was dried over sodium sulfate and concentrated to obtain a yellow oily substance. Preparative HPLC (acetonitrile / water 10:90-80:20) yielded yellow solid compound 14 (MS m / z: 480.26. [M+H]). + Ethyl acetate (7 mL) and methanol (0.1 mL) were added, and the mixture was stirred at room temperature to dissolve. Ethyl acetate hydrochloride (0.5 N / 1.2 mL) was added dropwise. The mixture was filtered and vacuum-dried at 40°C to obtain 20 mg of the hydrochloride salt of yellow solid compound 14.

[0180] 1 H NMR (400 MHz, CDCl3) δ 8.39 (brs, 3H), 7.68 (d, J = 15.4 Hz, 1H), 7.66 (d, J = 15.4 Hz, 1H), 7.18 - 7.06 (m, 2H), 7.05 - 6.95 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 15.5 Hz, 1H), 6.68 (d, J = 15.5 Hz, 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). MS m / z: 480.26. [M+H] + .

[0181] Example 15 Synthesis of Compound 16 and its Hydrochloride Salt

[0182] [ka]

[0183] Under nitrogen gas protection, compound 7 (300 mg, 0.63 mmol), diethylamine (9 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to the reaction flask. The mixture was stirred at 25°C for 30 minutes, after which sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added. 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 mixture was dried over sodium sulfate and concentrated to obtain a yellow oily compound. TLC preparative fractionation (petroleum ether / ethyl acetate 1:1) yielded pale yellow solid compound 16 (MS m / z: 536.44 [M+H]). + Ethyl acetate (12 mL) and methanol (0.2 mL) were added, and the mixture was stirred at room temperature to dissolve. Ethyl acetate hydrochloride (0.5 N / 1.2 mL) was added dropwise. The mixture was filtered and vacuum-dried at 40°C to obtain 160 mg of a yellow solid as the hydrochloride salt of compound 16.

[0184] 1 H NMR (400 MHz, CDCl3) δ 11.95 (brs, 1H), 7.72 (d, J = 15.1 Hz, 1H), 7.69 (d, J = 14.8 Hz, 1H), 7.14 (dd, J = 8.3, 1.9 Hz, 2H), 7.04 - 6.96 (m, 2H), 6.85 (dd, J = 8.4, 2.7 Hz, 2H), 6.71 (d, J = 15.4 Hz, 1H), 6.63 (d, J = 15.4 Hz, 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 = 7.2 Hz, 6H). MS m / z: 536.44 [M+H] + .

[0185] Example 16 Synthesis of Compound 18

[0186] [ka]

[0187] Under nitrogen gas 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 the reaction flask. The mixture was stirred at 25°C for 30 minutes, after which sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added. The reaction was allowed to proceed at room temperature for 2 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 mixture was dried over anhydrous sodium sulfate and concentrated. Preparative 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] + .

[0188] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 15.5 Hz, 1H), 7.65 (d, J = 15.5 Hz, 1H), 7.17 - 7.06 (m, 2H), 7.01 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.4, 3.4 Hz, 2H), 6.76 (d, J = 15.5 Hz, 1H), 6.70 (d, J = 15.5 Hz, 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). 19 F NMR (376 MHz, CDCl3) δ -97.80.

[0189] Example 17 Synthesis of Compound 19 and its hydrochloride salt

[0190] [Chemical formula]

[0191] Under nitrogen gas protection, compound 7 (300 mg, 0.63 mmol), piperidine (110 mg, 1.25 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask. It was stirred at 25 °C for 30 minutes, and then sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added. The reaction was carried out at room temperature for 3 h, and ethyl acetate (30 mL) and dilute hydrochloric acid (0.2 N / 30 mL) were added. The layers were separated, and the organic phase was washed with purified water. It was dried over sodium sulfate and concentrated to obtain a yellow oily compound, and by preparative TLC (petroleum ether / ethyl acetate 1:1), pale yellow solid compound 19 was obtained (MS m / z: 548.45 [M+H] + ). Ethyl acetate (12 mL) and methanol (0.2 mL) were added, stirred and dissolved at room temperature, and hydrochloric acid ethyl acetate (0.5 N / 1.2 mL) was added dropwise. It was filtered and dried in vacuo at 40 °C to obtain 120 mg of hydrochloride of yellow solid compound 19.

[0192] 1 H NMR (400 MHz, CDCl3) δ 11.95 (brs, 1H), 7.71 (d, J = 15.4 Hz, 1H), 7.68 (d, J = 15.4 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 2H), 7.05 - 6.96 (m, 2H), 6.84 (dd, J = 8.4, 3.3 Hz, 2H), 6.71 (d, J = 15.4 Hz, 1H), 6.63 (d, J = 15.4 Hz, 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] + .

[0193] Example 18 Synthesis of Compound 22

[0194] [ka]

[0195] Under nitrogen gas protection, compound 7 (1.00 g, 2.09 mmol) and dichloromethane (20 mL) were added to the reaction flask. The mixture was stirred at 0°C for 10 minutes, and diethylaminosulfur trifluoride (0.40 g, 2.51 mmol) was added dropwise. The mixture was then allowed to react overnight at room temperature, and saturated sodium bicarbonate aqueous solution was added. The mixture was separated, the aqueous phase was extracted with dichloromethane, and after concentration, 320 mg of the crude product was obtained by column chromatography (petroleum ether / ethyl acetate 10:1-2:1). Preparative HPLC (acetonitrile / water 10:90-80:20) yielded 0.10 g of a pale yellow solid.

[0196] 1 H NMR (400 MHz, CDCl3) δ 7.704 (d, J = 15.4 Hz, 2H), 7.138 (dd, J = 8.3, 1.9 Hz, 2H), 7.013 (d, J = 1.9 Hz, 2H), 6.842 (d, J = 8.3 Hz, 2H), 6.727 (d, J = 15.4 Hz, 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). 19 F NMR (377 MHz, CDCl3) δ -102.82. MS m / z: 481.99 [M+H] + .

[0197] Example 19 Synthesis of Compound 23 and its hydrochloride salt

[0198] [ka]

[0199] Under nitrogen gas 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, then sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added, and the mixture was reacted at room temperature for 2 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 anhydrous sodium sulfate, and concentrated to obtain the yellow oily compound 23 (MS m / z: 570.43 [M+H]). + Ethyl acetate (15 mL) and methanol (0.3 mL) were added, and the mixture was stirred at room temperature to dissolve. Ethyl acetate hydrochloride (0.5 N / 1.2 mL) was added dropwise. The mixture was filtered and vacuum-dried at 40°C to obtain 120 mg of the hydrochloride salt of yellow solid compound 23.

[0200] 1 H NMR (400 MHz, CDCl3) δ 10.26 (brs, 2H), 7.71 (d, J = 15.4 Hz, 1H), 7.67 (d, J = 15.4 Hz, 1H), 7.18 - 7.06 (m, 2H), 7.03 - 6.97 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 15.4 Hz, 1H), 6.69 (d, J = 15.5 Hz, 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] + .

[0201] Example 20 Synthesis of Compound 24

[0202] [ka]

[0203] 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 a reaction flask and 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). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 20 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1-2:1). MS m / z: 544.42 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 15.4 Hz, 2H), 7.15 (dd, J = 8.4, 2.0 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 6.69 (d, J = 15.4 Hz, 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] [ka]

[0206] Dimethyl curcumin (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 stirred at 50 °C for 20 h. After completion of the reaction, water (50 mL) and ethyl acetate (20 mL) were added, and the layers were 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 purified by column chromatography (petroleum ether / ethyl acetate 10:1 - 2:1) to obtain 90 mg of a pale yellow solid.

[0207] MS m / z: 566.47 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 15.4 Hz, 2H), 7.13 (dd, J = 8.4, 2.0 Hz, 2H), 7.00 (d, J = 2.0 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 15.5 Hz, 2H), 3.90 (s, 12H), 3.54 - 3.26 (m, 4H), 2.30 - 2.10 (m, 4H), 1.44 (s, 9H).

[0208] Example 22 Synthesis of Compound 26

[0209]

Chemical Structure

[0210] 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 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). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 50 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1-2:1).

[0211] 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 7.13 (dd, J = 8.3, 1.9 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 15.5 MS m / z: 491.42 [M+H] + .

[0212] Example 23 Synthesis of Compound 27

[0213] [ka]

[0214] In a reaction flask, 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) were added 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). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 30 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1~2:1).

[0215] 1 H NMR (400 MHz, CDCl3) δ 7.707 (d, J = 15.5 Hz, 2H), 7.139 (dd, J = 8.3, 2.0 Hz, 2H), 7.009 (d, J = 2.0 Hz, 2H), 6.840 (dd, J = 8.4, 2.4 Hz, MS m / z: 504.44 [M+H] + .

[0216] Example 24 Synthesis of Compound 28

[0217] [ka]

[0218] The starting materials 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) were added to a reaction flask and 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). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 35 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1~2:1).

[0219] 1 H NMR (400 MHz, CDCl3) δ 7.709 (d, J = 15.4 Hz, 2H), 7.140 (dd, J = 8.3, 2.0 Hz, 2H), 7.027 - 6.982 (m, 2H), 6.843 (dd, J = 8.4, 2.5 Hz, 2H), 6.722 (d, J = 15.4 Hz, 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] + .

[0220] Example 25 Synthesis of Compound 29

[0221] [ka]

[0222] In a reaction flask, starting materials 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) were added 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). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 25 mg of a pale yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1~2:1).

[0223] 1 H NMR (400 MHz, CDCl3) δ 7.704 (d, J = 15.4 Hz, 2H), 7.136 (dd, J = 8.4, 2.0 Hz, 2H), 7.007 (d, J = 2.0 Hz, 2H), 6.834 (d, J = 8.3 Hz, 2H), 6.720 (d, J = 15.4 Hz, 2H), 3.904 (s, 6H), 2.366 - 2.227 (m, 4H), 2.117 - 1.939 (m, 4H). MS m / z: 507.51 [M+H] + .

[0224] Example 26 Synthesis of Compound 30 and its Hydrochloride Salt

[0225] [ka]

[0226] Step 1 Synthesis of Intermediate 30-1 In a reaction flask, starting materials 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) were added and the mixture was stirred at 50°C for 20 hours. After the reaction was complete, water (70 mL) and ethyl acetate (40 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (400 mL). DMF was washed away from the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, and obtained 600 mg of a yellow solid by column chromatography (petroleum ether / ethyl acetate 10:1-2:1).

[0227] Step 2 Synthesis of Compound 30 and its hydrochloride salt Under nitrogen gas protection, intermediate 30-1 (300 mg, 0.62 mmol), diethylamine (9 mg, 1.25 mmol), and tetrahydrofuran (10 mL) were added to the reaction flask and stirred at 25°C for 30 minutes. Then sodium triacetoxyborohydride (270 mg, 1.25 mmol) was added and the reaction was allowed to proceed 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. Preparative TLC (petroleum ether / ethyl acetate 1:1) yielded pale yellow solid compound 30 (MS m / z: 542.57 [M+H]). + Ethyl acetate (12 mL) and methanol (0.2 mL) were added, and the mixture was stirred at room temperature to dissolve. Ethyl acetate hydrochloride (0.5 N / 1.2 mL) was added dropwise. The mixture was filtered and vacuum-dried at 40°C to obtain 60 mg of the hydrochloride salt of yellow solid compound 30.

[0228] 1H NMR (400 MHz, CDCl3) δ 11.83 (brs, 1H), 7.77 - 7.60 (m, 2H), 7.14 (d, J = 8.2 Hz, 2H), 7.01 (dd, J = 4.2, 1.8 Hz, 2H), 6.84 (dd, J = 8.3, 2.7 Hz, 2H), 6.72 (d, J = 15.4 Hz, 1H), 6.63 (d, J = 15.4 Hz, 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] + .

[0229] Measurement Example 1: Inhibition test of cell viability of the compound of the present invention against human prostate cancer cells. Human prostate cancer cells LNCaP and human prostate cancer cells 22Rvl are present in the bodies of prostate cancer patients, and the androgen DHT can promote the growth of human prostate cancer cells LNCaP. The purpose of using the above cell model was to study the inhibitory effect of the compounds 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.

[0230] Test materials: Measurement compound (obtained by the method of the present 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, Biolohivsl Industries, Cat. No. 04-204-1A), penicillin and streptomycin mixture (Solarbio, Cat No: P1400), CellTiter-Glo (CTG) reagent (Promega, Cat#G7573).

[0231] Test Method Human prostate cancer cells LNCaP and 22Rvl in the exponential growth phase were placed under a microscope, and their proliferation status was observed to be good. The culture medium in the culture dish was discarded, 5 mL of trypsin was added, and digestion was carried out for approximately 3 minutes. 10 mL of fresh medium was added to complete the digestion, the cells were thoroughly blown out, and the cells were transferred to a 15 mL centrifuge tube. Centrifugation was performed at 1000 rpm for 5 minutes to collect the cells. The collected cells were resuspended in 11 mL of fresh medium, and 1 mL was measured and counted to check cell viability. An appropriate amount of medium was added to increase the cell density to 1 × 10⁶. 4 The cells were adjusted to cells / mL, inoculated into 96-well plates at 200 μL / well, and incubated overnight in a cell incubator.

[0232] After the cells adhered to the cell wall, the human prostate cancer cell LNCaP group was incubated in 96-well plates with the test compounds (0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM, 30 μM) and DHT (1 nM, which induces AR expression) for 5 days. The human prostate cancer cell 22Rvl group was incubated in 96-well plates with the test compounds (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 observed under a microscope to ensure there were no abnormalities in the cell condition. The 96-well plates were then equilibrated at room temperature for 30 minutes.

[0233] Cell activity was measured using the CTG method. Before measurement, CellTiter-Glo® Buffer and its primers (collectively referred to as CTG reagents) were thawed and equilibrated at room temperature. Then, 100 mL of Buffer was carefully and uniformly mixed with the primers to form a homogeneous solution. This solution was added to a 96-well plate at a rate of 100 μL / well, incubated in a shaker for 15 minutes, and the fluorescence value of each well was measured. The method for measuring the fluorescence value of each well was as follows: After adding the CTG reagent, fluorescence detection (integration time: 500 ms) was performed using a multimode plate reader (M200Pro, TECAN) of the appropriate instrument according to the supplier's manual to quantify the effect of the inhibitor on cell activity. For data analysis, the test background value was subtracted from all data points. This value was measured in wells containing culture medium but no cells. The data was processed using XLfit software (XLfit 5.2, IDBS, UK) to obtain the IC for each test compound. 50 The values ​​were calculated, and the IC20 was determined for human prostate cancer cells LNCaP and human prostate cancer cells 22Rvl, and for typical compounds of the present invention. 50 The values ​​are shown in Table 1 below.

[0234] [Table 1]

[0235] As can be seen from the test data in the table above, the compound of the present invention has good prostate cancer cell proliferation inhibitory activity and can effectively inhibit the proliferation of prostate cancer cells.

[0236] Measurement Example 2: Measurement test of the effect of the compound of the present invention on the expression of AR protein in human prostate cancer cells (LNCaP). AR is a key factor that modulates the androgen response of prostate cancer cells, and is also a key factor in the androgen response of hair follicles or perifollicular tissues. Reducing AR content can not only downregulate the growth of prostate cancer cells but also inhibit androgenic alopecia. This measurement example measures the effect of the compound of the present invention on the reduction of AR protein expression in human prostate cancer cells (LNCaP) in the presence of DHT. The anti-AR activity of the compound of the present invention in human prostate cancer cells (LNCaP) was analyzed by measuring the reduction of AR protein using Western blotting.

[0237] Test materials: Compound to be measured (obtained by the method of the present 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, Biolohivsl Industries, Cat. No. 04-204-1A), BCA protein quantification reagent kit (Thermo, Cat. No. 23225), Color prestained protein marker (Biyuntian, Cat. No. P0069), GAPDH antibody (Millipore, Cat. No. MAB374), AR antibody (CST, Cat. No. 5153).

[0238] Test method: Human prostate cancer cells LNCaP were divided into 4 × 10⁶ cells. 5Cells / mL were inoculated into 6-well plates, with each well containing 2 mL of cells. The plates were incubated overnight in a cell incubator. DMSO and dihydrotestosterone (DHT, 1 nM) were used as control groups. The tests were performed in the presence of DHT (1 nM). After culturing cells in the target compound for a predetermined period, they were collected and lysed using Western blotting techniques known in biochemistry. During the test, separate 6-well plates were set up for the DMSO group, DHT group (1 nM), and target compound group (containing 1 nM DHT). DMSO and DHT (1 nM DHT) were added to the corresponding 6-well plates for the DMSO group and DHT group, respectively. DHT (1 nM) and the target compound (0.6 μM, 1.2 μM, 2.5 μM, 5 μM, 10 μM) were added to the corresponding 6-well plate for the target compound group. After incubating the control and target compound groups for 48 hours, the cells were collected and lysed. Protein concentrations were quantified using a BCA reagent kit, and the samples were stored for use.

[0239] Western blotting was used to measure the AR protein content in each group, with a loading amount of 30 μg for each group's sample. Western blotting analysis is already disclosed in the prior art. Specifically, cells were collected in 2x sodium dodecyl sulfate / polyacrylamide gel electrophoresis buffer, or in radioimmunoprecipitation assay (RIPA) buffer enhanced with 10 μg / mL benzamidine, 10 μg / mL trypsin inhibitor, and 1 mM phenylmethylsulfonyl fluoride. Total protein samples (approximately 40 μg) from each cell lysate were separated by electrophoresis onto SDS / PAGE gels. After electrophoretic separation, proteins were delivered from the gel to a nitrocellulose membrane according to standard procedures. Subsequently, the membranes were cultured for 1 hour in phosphate-buffered water supplemented with 0.1% Tween 20 (PBST) with 10% skim milk, and then cultured overnight at 4°C with primary human AR-specific antibody (purchased from BD-Harlingen). After culturing, the membrane was washed three times with PBST buffer for 10 minutes each time, and then alkaline phosphatase-conjugated secondary antibody was added and incubated at room temperature for 1 hour. After secondary culture, the membrane was washed again with PBST, and then alkaline phosphatase medium, bromochloroindolyl phosphate, and nitrotetrazole were added to the membrane to bring out the AR protein signal. To ensure the analysis of equal amounts of protein in each sample, a specific antibody for controlling the protein GAPDH (SantaCruz Biotechnology) was retained in a portion of the membrane, and the GAPDH signal was displayed using the second antibody described above. The protein signal intensity (as shown by the bands on the membrane) was measured by hydrometer and analyzed using NIH ImageJ software (NIH1.33). The AR protein signal (relative to GAPDH) in each sample was normalized, and the data is shown as the ratio of the AR grayscale value to the GAPDH grayscale value, specifically shown in Figure 1.

[0240] The above experiments measured the ability of some of the 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 at multiple concentrations against the DHT group and the DMSO group. The relative efficacy of the anti-AR activity of the compounds of the present invention is shown as the percentage reduction in AR after 48 hours of incubation with the compound at concentrations of 2.5 μM, 5 μM, and 10 μM (containing 1 nM DHT), and the evaluation index is as shown in Table 2 below.

[0241] [Table 2]

[0242] The formula for calculating the percentage reduction in AR (%) is: Percentage reduction in AR (%) = (AR / GAPDH value of the DHT group - AR / GAPDH value of the test compound group) / AR / GAPDH value of the DHT group × 100%.

[0243] The ability of the compounds of the present invention to reduce AR expression in human prostate cancer cells (LNCaP), i.e., their anti-AR activity, is shown in Table 3. The values ​​in Table 3 represent the percentage reduction in AR (%), the concentrations in Table 3 represent the concentrations of the measured compounds, and the more "+" signs there are in the relative efficacy column in Table 3, the better the anti-AR activity of the compound.

[0244] [Table 3]

[0245] In conclusion, DHT can upregulate the expression of AR protein in human prostate cancer cells (LNCaP), and all of the compounds of the present invention can dose-dependently inhibit the expression of AR protein in human prostate cancer cells (LNCaP), i.e., the compounds of the present invention have anti-AR activity. Considering the relative potency as a whole, the compounds of the present invention, in particular compound 7, compound 8, compound 12 hydrochloride, compound 16 hydrochloride, and compound 19 hydrochloride, have remarkable anti-AR activity.

[0246] Measurement Example 3: Study of Pharmacokinetic Properties This measurement example aims to study the single oral administration of each compound solution of the present invention to SD rats, detect the concentration of the active ingredient in plasma, and evaluate the pharmacokinetic (PK) characteristics of the drug in the body of the SD rats.

[0247] Experimental materials: Male SD rats (body weight 180 - 220 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016 - 0006), experimental compounds (manufactured according to the method of the examples of the present invention), purified water (self - made).

[0248] Experimental method: Male SD rats were randomly grouped (3 rats / group), allowed to freely ingest water during the test period, fasted for more than 12 hours before administration, and fed 4 hours after administration. Oral gavage was performed, and a 0.5% suspension aqueous solution of the experimental compound (calculated by the amount of the experimental compound) at a dose of 50 mg / kg was administered to each group of SD rats. The suspension aqueous solution contained 0.5% test compound, 1% CMCNa, 0.5% Tween 80, and 98% purified water.

[0249] Blood samples were collected into K2EDTA anticoagulant tubes at 0 min before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h after administration, and temporarily stored on ice until centrifugation.

[0250] Plasma must be centrifuged within 60 min after blood collection (centrifuged at 8000 rpm for 5 min under the condition of 2 - 8 °C). After centrifugation, the plasma was transferred to a 96 - well plate or a centrifuge tube, transferred in an ice case, and stored at ≤ - 15 °C until LC - MS / MS detection. The LC - MS / MS biological analysis method was adopted to detect the drug concentration in the plasma of SD rats. The non - compartmental model was adopted, and the blood drug concentration - time data were analyzed by WinNonlinTM (Version 8.3, Certara, USA) to evaluate the pharmacokinetic (PK) characteristics of the drug in the body of the SD rats. The data are shown in Table 4, and the pharmacokinetic curve is shown in Figure 2.

[0251]

Table 4

[0252] From the drug-time curve in Figure 2, compound 10 is shown to be C in rats. max At least, AUC last This is the minimum, and compounds 7 and 8 are C max Although they are similar, compound 8 has a different AUC. last This shows that compound 10 is higher than compound 7. These results suggest that when each compound is administered intragastricly to SD rats at the same dose, compound 10 may have the lowest exposure in the rat body and the worst therapeutic effect, followed by compound 7, and compound 8 is C max and AUC last All of these factors show a significant increase, suggesting that the drug's effects may be the most pronounced.

[0253] As shown by the above results, the compounds of the present invention have significantly improved pharmacokinetic properties. In particular, after administration of the compounds of the present invention, AUC and C max All of these improvements were remarkably significant. Therefore, the compounds of the present invention have good drug discovery potential, and even better therapeutic effects can be obtained at lower doses.

[0254] Measurement Example 4: Hair growth promotion test of the compound of the present invention in alopecia mice Test Objective: The hair growth promoting effect of the compound of the present invention on a mouse model of alopecia was measured.

[0255] Test materials: C57BL / 6 mice (purchased from Beijing SPF Biotechnology Co., Ltd., production license number: SCXK(Beijing) 2019-0010), test compounds (obtained by manufacturing according to the method of the present invention), rosin (Shanghai Yuanye Bio-Technology Co., Ltd., lot number: Y18M10C83144), liquid paraffin (Shanghai Yuanye Bio-Technology Co., Ltd., lot number: Z22S11Y125555), chloral hydrate (Sinopharm Chemical Reagent Co., Ltd., lot number: 20190823, prepared into a 2% chloral hydrate solution with 0.9% sodium chloride solution during use), testosterone propionate (Shanghai Aladdin Reagent Co., Ltd., lot number: T101368, prepared into a 0.5% testosterone propionate solution with soybean oil for injection during use), soybean oil for injection (Tieling Beiya Pharmaceutical Oil Co., Ltd., lot number:国药准字H21024303), paraformaldehyde (Xilong Scientific Co., Ltd., lot number: 1705022), 0.9% sodium chloride solution (Jiangsu Shuanghe Pharmaceutical Co., Ltd., lot number: 210322-3C), electronic balance (Beijing Sartorius Instrument Et System Engineering Co., Ltd., model number: BS224 S, GZX-9140MBE), digital display electric constant temperature forced air dryer (Shanghai Boxun Industry Co., Ltd.).

[0256] Test method: Select 8-week-old male C57BL / 6 mice, intraperitoneally inject 2% chloral hydrate (400 mg / kg) to anesthetize them, weigh equal amounts of rosin and paraffin, heat and mix them evenly, apply them to an area of about 2 cm×2.5 cm on the back of the mouse. After the mixture cools and hardens, gently peel off the coagulated hair with tweezers. From this study, animals found to have a deep skin color after hair removal were excluded, among which the above deep skin color indicates that these animals are in the hair growth stage with active hair follicle growth.

[0257] Approved C57BL / 6 mice (3 mice / group) were randomly assigned to a blank group, a model group, a positive control group (7.5% class coterone group), and a test group (including 8 groups of 0.3% compounds and 7 groups of 0.3% compounds). In the blank group, 0.1 mL of physiological saline was applied to the hair loss area once daily in the morning for 17 consecutive days. In the model group, 0.1 mL of 0.5% testosterone propionate solution was applied to the hair loss area once daily in the morning (from the first day for 17 consecutive days), and 0.5 mL of the control solvent was applied to the hair loss area once daily in the afternoon (from the next day for 16 consecutive days). In the positive control group, 0.1 mL of 0.5% testosterone propionate solution was applied to the hair loss area once daily in the morning (from the first day for 17 consecutive days), and 0.5 mL of 7.5% clascoterone solution was applied to the hair loss area once daily in the afternoon (from the next day for 16 consecutive days). In the test group, 0.1 mL of 0.5% testosterone propionate solution was applied to the hair loss area once daily in the morning (from the first day for 17 consecutive days), and 0.5 mL of the control solvent was applied to the hair loss area once daily in the afternoon. A 0.3% test compound solution was applied once daily for 16 consecutive days starting the following day. The test compound solution consisted of 0.3% test compound, 40% DMSO, 30% ethanol, and the remainder being water. The control solvent consisted of 40% DMSO, 30% ethanol, and the remainder being water. The positive control group consisted of 7.5% clascoterone, 40% DMSO, 30% ethanol, and the remainder being water. Hair regrowth in the alopecia areas of mice in each group was observed, and photographs were taken 16 days after the start of topical administration of the test compound solution.

[0258] On day 18 of the experiment, five newly grown hairs were extracted from the bald area on the back of each mouse in each group, and the length of the hairs was measured with calipers. The hair lengths of the mice in each group were statistically analyzed, skin was excised from the bald area of ​​each mouse in each group, and hematoxylin-eosin staining (HE staining) was performed. The morphology of the hair follicles was observed under a microscope, and six fields (×100) were randomly selected from each sample for observation. The average number of hair follicles within each field was calculated. The software used for data statistics was GraphPad 8.0, and the data for each group are all shown as mean ± standard difference (X ± SD), specifically as shown in Table 5 below. Representative photographs of hair growth status and representative HE-stained sections of skin tissue from each group on day 18 are shown in Figure 3.

[0259] [Table 5]

[0260] As shown in Figure 3, the mice in the model group showed poorer hair growth and significantly fewer hair follicles compared to the blank group, demonstrating that a mouse model of alopecia can be formed by applying a 0.5% testosterone propionate solution. Compared to the model group, the mice in the positive control group showed significantly increased hair growth and a remarkable increase in hair follicle count, demonstrating the reliability of the alopecia mouse model. Compounds 7 and 8 of the present invention showed even better hair and hair follicle growth than the positive control group when administered at a daily dose of 1.5 mg, indicating that low doses of the compounds of the present invention have even better alopecia treatment efficacy than high doses of the positive control.

[0261] From the above test data, it can be seen that the compound of the present invention, when administered in relatively small doses, can significantly increase both the hair length and the number of hair follicles in the test group mice, can promote the generation of hair follicles and hair growth in alopecia mice, and has a good hair growth promoting effect.

[0262] Embodiments of the present invention have been described above. However, the present invention is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention are also included within the scope of the claims of the present invention. [Brief explanation of the drawing]

[0263] [Figure 1] This is a Western blot diagram showing the reduction in AR protein expression in LNCaP cells by different concentrations of the compound of the present invention. [Figure 2] These are the pharmacokinetic curves of each compound in male rat plasma after oral administration of the compounds of the present invention. [Figure 3] These are photographs of hair growth and representative HE-stained pathological images of skin tissue from mice in each group during the hair growth promotion test in Measurement Example 4, on day 18 of the experiment.

Claims

1. Compounds represented by formula I, their racemates, stereoisomers, tautomers, solvates, crystalline polymorphs, or pharmaceutically acceptable salts thereof, 【Chemistry 1】 Eventually, R1, R2, R3, and R4 are homologous or different, and are independently selected from C1-3 alkyl groups or deuterated C1-3 alkyl groups. 【Chemistry 2】 This represents a ring system consisting of a C3-10 monocycloalkyl group, a C3-10 monocycloalkenyl group, an oxa C2-10 monocycloalkyl group, or an aza C2-10 monocycloalkyl group substituted with one, two, or more Rb groups, or 【Transformation 3】 These are spirocyclo C6-16 alkyl groups and oxaspirocyclo C6-16 alkyl groups. Rb is homologous or homologous, and independently selected from halogens, =O, hydroxyl groups, amino groups, unsubstituted, or optionally substituted with one, two, or more Rc groups, C3-12 cycloalkyl groups, 3-12 member heterocyclyl groups, -NHC1-6 alkyl groups, -N(C1-6 alkyl)2, -NHCOC1-6 alkyl groups, -NHC3-12 cycloalkyl groups, -S(O)2 C1-6 alkyl groups, and -COOC1-6 alkyl groups. The aforementioned Rc is characterized by being selected from halogens, hydroxyl groups, and 5-12 membered heteroaryl groups. Compounds represented by formula I, their racemates, stereoisomers, tautomers, solvates, crystalline polymorphs, or pharmaceutically acceptable salts thereof.

2. The compound represented by formula I is 【Chemistry 4】 It has the following structure, Of these, R1, R2, R3, and R4 have the definitions described in claim 1. R 5 is a halogen, R 6 is a hydroxyl group, an amino group, unsubstituted, or optionally substituted with one, two, or more Rc groups, a C 3-12 cycloalkyl group, a 3- to 12-membered heterocyclyl group, an -NHC 1-6 alkyl group, -N(C 1-6 alkyl group) 2, -NHCOC 1-6 alkyl group, -NHC 3-12 cycloalkyl group, -S(O) 2 C 1-6 alkyl group, or -COOC 1-6 alkyl group. Rc has the definition described in claim 1. The compound described in feature 1 or a pharmaceutically acceptable salt thereof. 【Request Item 3】 【Chemistry 5】 is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or cyclohexenyl group substituted with one, two, or more Rb groups, or 【Transformation 6】 These are a spiro[2,3]hexane group, a 1,3-dioxacyclohexane group, and a 1,4-dioxaspiro[4,5]decane group, Rb is F, Cl, Br, I, =O, hydroxyl group, amino group, tert-butoxycarbonyl group, -S(O) 2 CH 3 , -COOC(CH 3 ) 3 , 【Transformation 7】 Selected from, R 1 、R 2 、R 3 、R 4 are the same or different and are independently of each other C 1-3 alkyl group or deuterated C 1-3 alkyl group, characterized in that it is selected from The compound according to claim 1.

4. The compound shown in formula I is 【Transformation 8】 The compound according to claim 1, characterized by being selected from among.

5. The compound shown in formula I is 【Chemistry 9】 The compound according to claim 1, characterized by being selected from among.

6. The compound according to claim 1, characterized in that the pharmaceutically acceptable salt of the compound shown in formula I is its hydrochloride salt.

7. A compound represented by formula I as described in any one of claims 1 to 6, comprising at least one of the racemic mixture, stereoisomer, tautomer, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof, Pharmaceutical composition.

8. Further comprising one or more pharmaceutically acceptable adjuvants, The pharmaceutical composition according to feature 7.

9. Preferred routes of administration of the pharmaceutical composition include oral, rectal, topical, oral, parenteral, intramuscular, intradermal, intravenous and transdermal administration. The pharmaceutical composition according to feature 7.

10. The pharmaceutical composition is for topical application, and is characterized in that it is an ointment, cream, paste, tincture, hard ointment, gel, smeared film, application agent, aerosol, spray, foam, or microsponge agent. The pharmaceutical composition according to claim 7.

11. Use in the manufacture of a drug for treating, preventing or improving symptoms or diseases of androgen-related disorders of a compound represented by formula I as described in any one of claims 1 to 6, a racemate, stereoisomer, tautomer, solvate, crystalline polymorph, or pharmaceutically acceptable salt thereof.

12. The use according to claim 11, characterized in that the symptoms or diseases of androgen-related disorders are selected from androgen-related inflammation, polyglutamine-mediated motor neuron disease, Kennedy disease, androgen-related cancer, alopecia, acne, and hirsutism.

13. The use according to claim 12, characterized in that the symptoms or diseases of androgen-related disorders are selected from wounds, acne, atopic dermatitis, rheumatoid arthritis, psoriasis, rosacea, spinal cord and medullary muscular atrophy, prostate cancer, bladder cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, central nervous system cancer, skin cancer, lymphoma, leukemia, esophageal cancer, gastric cancer, colon cancer and pancreatic cancer, and androgenetic alopecia.

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