Propionamide androgen receptor antagonist, and preparation method therefor and use thereof

Abstract

The present invention relates to a propionamide androgen receptor antagonist and a use thereof. The present invention relates to a compound of formula I or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, metabolite or isotope derivative thereof, wherein R1, R2, R3, R4, R5, R6, R7, Z, and W are as defined in the description. The present invention further relates to a method for preparing the compound, a pharmaceutical composition comprising the compound, and a use of the compound and the pharmaceutical composition comprising the compound for preventing and / or treating a disease associated with the androgen level.

Description

Propionamide androgen receptor antagonist and its preparation method and use Technical Field

[0001] The present invention relates to propionamide compounds that can be used as androgen receptor antagonists. The present invention also relates to methods for preparing such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds and pharmaceutical compositions containing such compounds for preventing and / or treating diseases related to androgen levels. Background Art

[0002] The androgen receptor belongs to the nuclear receptor family and is a receptor for ligand-induced nuclear transcription factors. The androgen receptor is an important cellular regulatory protein that plays an important role in a series of physiological processes through endogenous androgens, including the development and maintenance of male secondary sexual characteristics, muscle and bone mass, male hair, prostate growth, and sperm development. Endogenous steroidal androgens are known as male sex hormones and include testosterone and dihydrotestosterone (DHT). Testosterone is the main steroidal androgen found in male serum and is mainly secreted by the testicles. In many peripheral tissues, such as the prostate and skin, testosterone can be converted to the more active androgen dihydrotestosterone by 5α-reductase.

[0003] Many diseases are related to androgen levels. As men age, androgen levels gradually decline, leading to muscle loss, osteoporosis, and decreased sexual function. Conversely, excessive androgen levels can also cause diseases such as benign prostatic hyperplasia (BPH), prostate cancer (including castration-resistant prostate cancer), other androgen receptor-expressing cancers such as breast, bladder, and ovarian cancers, uterine fibroids and abdominal aortic aneurysms, Kennedy's disease, amyotrophic lateral sclerosis (ALS), androgenic alopecia, or hyperandrogenic dermal disorders such as acne or hirsutism.

[0004] Because prostate cancer is hormone-dependent, endocrine therapy is the oldest, most established, and most effective treatment. As early as 1941, Huggins and Hodges discovered that surgical castration (i.e., surgical removal of both testicles to eliminate the source of testosterone) and estrogen could slow the progression of metastatic prostate cancer, and for the first time confirmed the responsiveness of prostate cancer to androgen ablation. However, clinical studies have shown that while simple testicular removal can reduce blood androgen levels, it cannot significantly reduce androgen levels in prostate tissue. This is because prostate tissue contains an enzyme system that synthesizes androgens from steroids secreted by the adrenal glands and converts the androgen testosterone into the more active androgen dihydrotestosterone. Therefore, even with castration therapy, anti-androgen drugs are essential.

[0005] The current standard treatment for prostate cancer is to use anti-androgen drugs (i.e., androgen antagonists) to competitively block the binding of androgens to androgen receptors on prostate cells. Anti-androgen drugs are also used to treat breast cancer and other diseases (J Hematol Oncol, 2022, 15, p. 12). Commonly used non-steroidal androgen receptor antagonists include:

[0006] 1. Flutamide is a first-generation nonsteroidal androgen receptor antagonist (Endocrinology, 1972, 91(2), pp. 427–437; Biochemical Society Transactions, 1979, 7, pp. 565–569; Journal of Steroid Biochemistry, 1975, 6(6), pp. 815–819). Its metabolite, 2-hydroxyflutamide, is the main active form and can bind to androgen receptors in target tissues, blocking the binding of dihydrotestosterone to androgen receptors and inhibiting the uptake of testosterone by target tissues, thereby exerting an anti-androgenic effect. Due to the large dosage, long-term use can cause male breast development, accompanied by tumors and tenderness, as well as nausea, vomiting, diarrhea, occasional skin reactions, metastatic hemoglobin anemia, and leukopenia and thrombocytopenia. In addition, flutamide is prone to anti-androgen withdrawal syndrome during treatment, and a small number of patients have liver toxicity and other problems.

[0007] 2. Bicalutamide, a second-generation nonsteroidal androgen receptor antagonist (Bicalutumide) (The Journal of Endocrinology, 1987, 113, R7–R9; Urologic Clinics of North America, 1991, 18, pp. 99–110). This drug is a racemic isomer, with the active ingredient being the L-isomer. Bicalutamide is more effective than flutamide and has 70% fewer side effects. Similar to flutamide, bicalutamide binds to androgen receptors in target tissues, blocking the binding of dihydrotestosterone to androgen receptors and inhibiting testosterone uptake by target tissues, thereby exerting an anti-androgenic effect. However, its disadvantage is that after a median treatment period (generally 18–24 months), almost all patients will develop hormone-resistant prostate cancer. Furthermore, bicalutamide treatment can also lead to problems such as anti-androgen withdrawal syndrome.

[0008] 3. Enzalutamide (trade name: Xtandi), a third-generation non-steroidal androgen receptor antagonist (Archives of Pharmacal Research, 2015, 38(11): pp. 2076–82). The US FDA approved the drug for marketing in 2012. It has a stronger androgen receptor antagonist effect, but its disadvantages are high price and the fact that it can also cause patients to develop hormone-resistant prostate cancer. In addition, enzalutamide has been found to have a side effect of causing convulsions in patients during treatment, so its application is subject to certain restrictions.

[0009] 4. Apalutamide (trade name: Erleada), similar to enzalutamide, is a nonsteroidal antiandrogen (NSAA) drug used to treat prostate cancer. The US FDA approved the drug for marketing in February 2018. It is particularly suitable for use in combination with castration to treat non-metastatic castration-resistant prostate cancer (NM-CRPC). However, its disadvantages are its high price and the potential for the development of hormone-resistant prostate cancer. In addition to side effects such as fatigue, nausea, abdominal pain, diarrhea, hypertension, rash, falls, fractures, and thyroid dysfunction, apalutamide can also cause seizures in patients, thus limiting its use.

[0010] In summary, existing anti-androgen drugs have problems such as high price, severe side effects, and easy resistance. There is still a need to develop new safe and effective anti-androgen drugs in this field to provide more treatment options.

[0011] Ostarine is a known selective androgen receptor modulator. During the process of structural modification to develop new androgen receptor agonists, the inventors unexpectedly discovered that by changing the substitution pattern of its A ring from disubstitution to trisubstitution, the activity of the compound was reversed, and it exhibited good androgen receptor antagonist activity, thereby completing the present invention.

[0012] Summary of the Invention

[0013] The purpose of the present invention is to provide new androgen receptor antagonists to meet the needs of the art.

[0014] The first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof:

[0015] in

[0016] R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano, nitro or C1-C6 haloalkyl;

[0017] R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0018] R5 is hydrogen, C1-C6 alkyl, -C(O)R or -S(O)2R;

[0019] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0020] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, nitro, -NR8R9, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R 10 )-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy;

[0021] R8, R9 and R 10 Each independently represents H or a C1-C6 alkyl group:

[0022] Z is -O-, -S-, -S(O)-, -S(O)2-, -N(R 10 )-, -CH2-, or a bond; and

[0023] W is CH or N.

[0024] In some embodiments, the compound has the following Formula Ia:

[0025] wherein R1, R2, R3, R4, R5, R6, R7, Z and W are as defined above for the compound of formula I.

[0026] In some embodiments, the compound has the following Formula II:

[0027] wherein R1, R2, R3, R5, R6, R7 and W are as defined above for the compound of formula I.

[0028] In some embodiments, the compound has the following Formula IIa:

[0029] wherein R1, R2, R3, R5, R6, R7 and W are as defined above for the compound of formula I.

[0030] A second aspect of the present invention relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0031] A third aspect of the present invention relates to a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers, for use in preventing and / or treating diseases associated with androgen levels.

[0032] A fourth aspect of the present invention relates to the use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers for preventing and / or treating diseases associated with androgen levels.

[0033] A fifth aspect of the present invention relates to the use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for preventing and / or treating diseases associated with androgen levels.

[0034] A sixth aspect of the present invention relates to a method for preventing and / or treating a disease associated with androgen levels in a subject in need thereof, the method comprising administering to the subject a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0035] In the third to sixth aspects above, the diseases associated with androgen levels are benign prostatic hyperplasia, prostate cancer, including castration-resistant prostate cancer, other androgen receptor-expressing cancers, such as breast cancer, bladder cancer, ovarian cancer, etc., uterine fibroids and abdominal aortic aneurysm, Kennedy's disease, amyotrophic lateral sclerosis (ALS), androgenic alopecia or hyperandrogenic dermal diseases, such as acne or hirsutism, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG1 shows the inhibition rate results of the compound of Example 1 in the proliferation inhibition experiment of PC-3 and DU-145 cell lines. DETAILED DESCRIPTION

[0037] definition

[0038] Unless otherwise stated, the following terms used in this specification and claims have the following meanings. It should be understood that, where not clearly defined herein, terms shall be given their meanings commonly known in the art. Further, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention in any way. Unless otherwise stated, when there is a discrepancy between the structural formula and the chemical name of the compound described herein, the structural formula shall prevail.

[0039] The group prefix "C x -C y " represents the range of carbon atoms contained in the group, wherein x and y are both integers. For example, C3-C8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, i.e., a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that "C3-C8" also includes any sub-range therein, such as C3-C7, C3-C6, C4-C7, C4-C6, C5-C6, etc.

[0040] As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon radical having a specified number of carbon atoms, whether straight or branched. Alkyl groups typically contain 1 to 6 carbon atoms ("C1-C6 alkyl"), preferably 1 to 5 carbon atoms ("C1-C5 alkyl"), more preferably 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), or 1 to 2 carbon atoms ("C1-C2 alkyl"). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0041] As used herein, the term "alkoxy" refers to an alkyl group attached to the parent molecular group through an oxygen atom (i.e., "-O-alkyl"), wherein alkyl is as defined above. Alkoxy groups typically contain 1 to 6 carbon atoms ("C1-C6 alkoxy"), more preferably 1 to 4 carbon atoms ("C1-C4 alkoxy"). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0042] The term "halogen" as used herein refers to fluorine, chlorine, bromine, iodine, with fluorine and chlorine being preferred.

[0043] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different, as defined above. For example, a "C1-C6 haloalkyl" refers to a "C1-C6 alkyl group" in which one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. Examples of C1-C6 haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, and dichloromethyl.

[0044] As used herein, the term "cyano" refers to a -CN group.

[0045] As used herein, the term "nitro" refers to a -NO2 group.

[0046] As used herein, the term "hydroxyl" refers to an -OH group.

[0047] As used herein, the term "trifluoromethyl" refers to a -CF3 group.

[0048] As used herein, the term "difluoromethyl" refers to a -CF2H group.

[0049] As used herein, the term "trichloromethyl" refers to a -CCl3 group.

[0050] As used herein, the term "dichloromethyl" refers to a -CCl2H group.

[0051] As used herein, the term "tribromomethyl" refers to a -CBr3 group.

[0052] As used herein, the term "dibromomethyl" refers to a -CBr2H group.

[0053] As used herein, the term "aryl" refers to a monovalent hydrocarbon radical derived from a monocyclic or fused bicyclic or polycyclic ring system having well-known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Fused aryl groups may include an aryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring or to another aryl or heteroaryl ring, provided that the point of attachment to the parent molecule on such a fused ring system is an atom of the aromatic portion of the ring system. Aryl groups typically contain 6-14 ("C6-C 14 aryl”), more preferably 6 to 10 carbon atoms (“C6-C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl.

[0054] As used herein, the term "cycloalkyl" refers to a monovalent hydrocarbon radical derived from a non-aromatic, saturated carbocyclic ring system containing a specified number of carbon atoms. Cycloalkyl groups typically contain 3 to 8 carbon atoms ("C3-C8 cycloalkyl"), preferably 3 to 7 carbon atoms ("C3-C7 cycloalkyl") or 3 to 6 carbon atoms ("C3-C6 cycloalkyl"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0055] As used herein, the term "heteroatom" refers to an N, O, or S atom.

[0056] The term "heterocyclyl" as used herein refers to a monovalent group derived from a saturated or partially unsaturated non-aromatic ring structure containing a specified number of ring atoms and including at least one heteroatom, preferably one to four heteroatoms as ring members. Heterocyclyl includes spirocycles, bridged rings or fused rings formed with one or more other heterocycles or carbocycles, provided that the point of attachment to the parent molecule is an atom of the heterocyclic portion of such a ring system. Heterocyclyl typically contains 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), preferably contains 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyl), and most preferably contains 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl). Examples of heterocyclic groups include, but are not limited to, aziridinyl, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl, and isoindolinyl.

[0057] As used herein, the term "heteroaryl" refers to a monovalent group derived from an aromatic ring structure containing the specified number of ring atoms and including at least one heteroatom, preferably one to four heteroatoms, as ring members. A heteroaryl group typically contains 5 to 12 ring atoms (a "5-12 membered heteroaryl"), preferably 5 to 10 ring atoms (a "5-10 membered heteroaryl"), and more preferably 5 or 6 ring atoms (a "5- or 6-membered heteroaryl"). A heteroaryl group may also be fused to another aryl or heteroaryl ring, or to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule on such a fused ring system is through an atom on the heteroaromatic portion of the ring system. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, Thiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl and phenothiazinyl.

[0058] The term "optionally" as used herein means that the situation described immediately after the term may occur, but may not occur. For example, "phenyl optionally substituted with halogen" encompasses both "phenyl not substituted with halogen" and "phenyl substituted with halogen".

[0059] As used herein, the term "stereoisomer" refers to an isomer resulting from a different arrangement of atoms in a molecule in space. When a compound has an asymmetric carbon atom, enantiomers are produced; when a compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers are produced. The scope of the present invention includes enantiomers, diastereomers, racemates, optical isomers, geometric isomers, epimers, and mixtures thereof of all compounds of Formula I. When the bond to a chiral carbon in a formula of the present invention is depicted as a straight line, it is understood that the (R) and (S) configurations of the chiral carbon and therefore both enantiomers and mixtures thereof are encompassed by the formula.

[0060] As used herein, the term "solvate" refers to a molecular complex comprising a compound of Formula I and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is employed.

[0061] As used herein, the term "prodrug" refers to a compound that is inactive or minimally active in vitro and releases a pharmacologically active compound in vivo through enzymatic or non-enzymatic conversion. The conversion can occur by various mechanisms, such as hydrolysis, oxidation, reduction, etc. Examples of prodrugs are, for example, compounds in which an amino group in the compound is acylated, alkylated, or phosphorylated, or in which a hydroxyl group is acylated, alkylated, phosphorylated, or in which a carboxyl group is esterified or amidated. The present invention includes prodrugs of compounds of Formula I, pharmaceutically acceptable salts thereof, or stereoisomers thereof. Specific examples of prodrugs are, for example:

[0062] wherein R' is an optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocyclic group, 5- to 12-membered heteroaryl group or dimethylamino group.

[0063] As used herein, the term "metabolite" refers to an active substance that is metabolized in vivo by a compound of Formula I. The present invention includes active metabolites of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, such as primary and / or secondary metabolites in vivo. Examples are as follows:

[0064] Primary metabolites in the body:

[0065] Secondary metabolites in the body:

[0066] Primary and secondary metabolites in the body:

[0067] As used herein, the term "isotopic derivative" refers to a compound that is isotopically labeled, i.e., one or more atoms in a compound of Formula I are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of suitable isotopes for incorporation into a compound include, but are not limited to, hydrogen (such as 2 H and 3 H), carbon (such as 11 C. 13 C and 14 C), chlorine (such as 36 Cl), fluorine (such as 18 F), iodine (such as 123 I. 124 I and 125 I), nitrogen (such as 13 N and 15 N), oxygen (such as 15 O. 17 O and 18 O), phosphorus (such as 32 P) and sulfur (such as 35S). Isotopically labeled compounds of the invention can be prepared without undue experimentation by conventional techniques known to those skilled in the art or by methods analogous to those described in the schemes and examples herein using appropriate isotopically labeled reagents and / or intermediates. The present invention particularly includes deuterated derivatives of compounds of formula I, examples of which are as follows:

[0068] As used herein, the term "pharmaceutically acceptable" refers to those substances or materials that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects, such as humans or other mammals, without excessive toxicity, irritation, allergic response, or other problems, and with a commensurate benefit / risk ratio.

[0069] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed by the reaction of a pharmaceutically non-toxic acid with the basic portion of the compound of formula I of the present invention, including, for example, hydrochloride, acetate, hydrobromide, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, hydrogen phosphate, oxalate, malonate, valerate, borate, p-toluenesulfonate, methanesulfonate, tartrate, benzoate, lactate, citrate, maleate, fumarate, malate, salicylate, mandelate, succinate, gluconate, lactobionate, etc. Such salts can be prepared by methods well known to those skilled in the art.

[0070] As used herein, the term "prevent" or "prevent" means to reduce or eliminate the likelihood of a disease.

[0071] As used herein, the term "treating" refers to the complete or partial elimination of a disease and / or its attendant symptoms.

[0072] The term "subject" as used herein refers to an animal, preferably a mammal, that is an individual for intended experiment or treatment, including but not limited to primates (e.g., monkeys and humans), equines (e.g., horses), canines (e.g., dogs), felines, domestic livestock (e.g., pigs, goats, sheep, etc.), as well as domestic pets and animals kept in zoos, preferably humans.

[0073] As used herein, the term "disease associated with androgen levels" refers to a disease that can be treated or prevented by reducing androgen levels.

[0074] Detailed description of the technical solution of the present invention

[0075] The first aspect of the present invention relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof:

[0076] in

[0077] R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano, nitro or C1-C6 haloalkyl;

[0078] R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0079] R5 is hydrogen, C1-C6 alkyl, -C(O)R or -S(O)2R;

[0080] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0081] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, nitro, -NR8R9, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R 10 )-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy;

[0082] R8, R9 and R 10 Each independently represents H or a C1-C6 alkyl group:

[0083] Z is -O-, -S-, -S(O)-, -S(O)2-, -N(R 10 )-, -CH2-, or a bond; and

[0084] W is CH or N.

[0085] In some embodiments, the compound has the following Formula Ia:

[0086] wherein R1, R2, R3, R4, R5, R6, R7, Z and W are as defined above for the compound of formula I.

[0087] In some embodiments, Z is -O-, -S-, -S(O)-, -S(O)2-, -NH-, -N(C1-C6 alkyl)-, or -CH2-. In some embodiments, Z is -O-. In some embodiments, Z is -S-. In some embodiments, Z is -S(O)-. In some embodiments, Z is -S(O)2-. In some embodiments, Z is -NH-. In some embodiments, Z is -N(C1-C6 alkyl)-, preferably -N(CH3)-. In some embodiments, Z is -CH2-.

[0088] In some embodiments, W is CH. In some embodiments, W is N.

[0089] In some embodiments, R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano, nitro or C1-C6 haloalkyl. In some embodiments, R1, R2 and R3 are each independently methyl, ethyl, fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, tribromomethyl or dibromomethyl.

[0090] In some embodiments, R1 is methyl, ethyl, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trichloromethyl, or dichloromethyl. In some embodiments, R1 is methyl, fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, or difluoromethyl. In some embodiments, R1 is fluorine, chlorine, or trifluoromethyl. In some embodiments, R1 is fluorine.

[0091] In some embodiments, R2 is methyl, ethyl, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trichloromethyl, or dichloromethyl. In some embodiments, R2 is methyl, fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl, or difluoromethyl. In some embodiments, R2 is fluorine, chlorine, or trifluoromethyl. In some embodiments, R2 is chlorine. In some embodiments, R2 is trifluoromethyl.

[0092] In some embodiments, R3 is methyl, ethyl, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, trichloromethyl or dichloromethyl. In some embodiments, R3 is methyl, fluorine, chlorine, bromine, cyano, nitro, trifluoromethyl or difluoromethyl. In some embodiments, R3 is fluorine, chlorine, cyano or trifluoromethyl. In some embodiments, R3 is cyano.

[0093] In some embodiments, R4 is hydrogen or C1-C6 alkyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is methyl, ethyl, propyl or butyl. In some embodiments, R4 is methyl.

[0094] In some embodiments, R5 is hydrogen, C1-C6 alkyl, -C(O)R, or -S(O)2R, wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 10 Aryl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms independently selected from N, O or S, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0095] In some embodiments, R5 is hydrogen.

[0096] In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R5 is methyl.

[0097] In some embodiments, R5 is -C(O)R and R is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3, or -C(O)CH(CH3)2, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)CH3.

[0098] In some embodiments, R5 is -C(O)R and R is C3-C8 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -C(O)R and R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -C(O)-cyclopentyl, which is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxy, cyano, -NH2, -NHCH3, and -N(CH3)2.

[0099] In some embodiments, R5 is -C(O)R and R is a 3- to 8-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)R and R is a 5- or 6-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)R and R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyrazolyl, alkyl), -Ci-C6 alkyl, -Ci-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 ...

[0100] In some embodiments, R5 is -C(O)R and R is C6-C 10 Aryl, wherein the aryl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -C(O)R and R is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -C(O)phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -NH2, -NHCH3 and -N(CH3)2.

[0101] In some embodiments, R5 is -C(O)R and R is a 5- to 12-membered heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)R and R is a 5- or 6-membered heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)R and R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, imidazole R5 is -C(O)-pyridinyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl). In some embodiments, R5 is -C(O)-pyridinyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -NH2, -NHCH3 and -N(CH3).

[0102] In some embodiments, R5 is -S(O)2R and R is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2CH2CH3, or -S(O)2-CH(CH3)2, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2-CH2CH2CH3.

[0103] In some embodiments, R5 is -S(O)2R and R is C3-C8 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -S(O)2R and R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -S(O)2-cyclopentyl, which is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxy, cyano, -NH2, -NHCH3, and -N(CH3)2.

[0104] In some embodiments, R5 is -S(O)2R and R is a 3- to 8-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2R and R is a 5- or 6-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2R and R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydro Pyridyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl or thiomorpholinyl, wherein the group is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0105] In some embodiments, R5 is -S(O)2R and R is C6-C 10Aryl, wherein the aryl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -S(O)2R and R is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R5 is -S(O)2phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -NH2, -NHCH3 and -N(CH3)2.

[0106] In some embodiments, R5 is -S(O)2R and R is a 5- to 12-membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2R and R is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2R and R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, imidazole R5 is -S(O)2-pyridyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2-pyridyl, which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxyl, cyano, -NH2, -NHCH3 and -N(CH3).

[0107] In some embodiments, R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)-C1-C6 haloalkyl, -N(C1-C6 alkyl)C(O)C1-C6 haloalkyl, -NHC(O)OC1-C6 alkyl, - N (C1-C6 alkyl) C (O) OC1-C6 alkyl, -S (O) 2-C1-C6 alkyl, -NH-S (O) 2-C1-C6 alkyl, -N (C1-C6 alkyl) -S (O) 2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy. In some embodiments, R6 and R7 are each independently hydrogen, halogen, cyano, C1-C6 haloalkyl, nitro, -NH2, -C (O) C1-C6 alkyl, -NHC (O) C1-C6 alkyl, -NHC (O) -C1-C6 haloalkyl, -S (O) 2-C1-C6 alkyl or -NH-S (O) 2-C1-C6 alkyl. In some embodiments, R6 is fluoro, chloro, bromo, iodo, trifluoromethyl, cyano, nitro, -NH2, -C(O)2CH3, -NHC(O)CH3, -NHC(O)CHF2, -S(O)2-CH2CH3, or -NH-S(O)2-CH2CH3. In some embodiments, R6 is cyano, fluoro, or chloro. In some embodiments, R7 is hydrogen, fluoro, chloro, bromo, or iodo. In some embodiments, R7 is hydrogen. In some embodiments, R7 is fluoro or chloro.

[0108] In some embodiments, Z is -O- and R4 is methyl, such that the compound has Formula II:

[0109] wherein R1, R2, R3, R5, R6, R7 and W are as defined above for the compound of formula I.

[0110] In some embodiments, the compound of Formula II has the following Formula IIa:

[0111] wherein R1, R2, R3, R5, R6, R7 and W are as defined above for the compound of formula I.

[0112] In some embodiments, R1, R2 and R3 are each independently halogen, C1-C6 haloalkyl or cyano. In some implementations, R1 is halogen, R2 is halogen or C1-C6 haloalkyl, and R3 is cyano. In some implementations, R1 is fluorine or chlorine, R2 is fluorine, chlorine or trifluoromethyl, and R3 is cyano. In some implementations, R1 is fluorine, R2 is chlorine, and R3 is cyano. In some implementations, R1 is fluorine, R2 is trifluoromethyl, and R3 is cyano.

[0113] In some embodiments, R4 is methyl, and R5 is hydrogen, -C(O)R, or -S(O)2R, wherein R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 10 Aryl or 5 to 12 membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms independently selected from N, O or S, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0114] In some embodiments, R4 is methyl and R5 is hydrogen.

[0115] In some embodiments, R4 is methyl, R5 is -C(O)R and R is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl and R5 is -C(O)CH3, -C(O)CH2CH3, -C(O)CH2CH2CH3 or -C(O)CH(CH3)2, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl and R5 is -C(O)CH3.

[0116] In some embodiments, R4 is methyl, R5 is -C(O)R and R is C3-C8 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl, R5 is -C(O)R and R is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl, R5 is -C(O)-cyclopentyl, and the cyclopentyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxy, cyano, -NH2, -NHCH3, and -N(CH3)2.

[0117] In some embodiments, R4 is methyl, R5 is -C(O)R and R is a 3- to 8-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R4 is methyl, R5 is -C(O)R and R is a 5- or 6-membered heterocyclyl, wherein the heterocyclyl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl).

[0118] In some embodiments, R4 is methyl, R5 is -C(O)R and R is C6-C 10Aryl, wherein the aryl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl, R5 is -C(O)R and R is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2. In some embodiments, R4 is methyl and R5 is -C(O)phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, -NH2, -NHCH3 and -N(CH3)2.

[0119] In some embodiments, R4 is methyl, R5 is -C(O)R and R is a 5- to 12-membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R4 is methyl, R5 is -C(O)R and R is a 5- or 6-membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R4 is methyl and R5 is -C(O)-pyridinyl, which is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, hydroxy, cyano, -NH2, -NHCH3 and -N(CH3)2.

[0120] In some embodiments, R4 is methyl, R5 is -S(O)2R and R is C1-C6 alkyl, wherein the alkyl is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R4 is methyl and R5 is -S(O)2-CH3, -S(O)2-CH2CH3, -S(O)2-CH2CH2CH3, or -S(O)2-CH(CH3)2, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkoxy, halogen, hydroxyl, cyano, -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl). In some embodiments, R5 is -S(O)2-CH2CH2CH3.

[0121] In some embodiments, R6 is halogen, cyano, C1-C6 haloalkyl, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -NHC(O)-C1-C6 haloalkyl, -N(C1-C6 alkyl)C(O)C1-C6 haloalkyl, -NHC(O)OC1-C6 alkyl, -N(C1-C6 alkyl)C(O)OC1-C6 alkyl C6 alkyl, -S(O)2-C1-C6 alkyl, -NH-S(O)2-C1-C6 alkyl, -N(C1-C6 alkyl)-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy, and R7 is hydrogen or halogen.

[0122] In some embodiments, R6 is halogen, cyano, C1-C6 haloalkyl, nitro, -NH2, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-C1-C6 haloalkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl, and R7 is hydrogen or halogen.

[0123] In some embodiments, R6 is fluoro, chloro, bromo, cyano, trifluoromethyl, nitro, -NH2, -C(O)CH3, -NHC(O)CH3, -NHC(O)CHF2, -S(O)2-CH2CH3, or -NH-S(O)2-CH2CH3, and R7 is hydrogen, fluoro, chloro, or bromo.

[0124] In some embodiments, R6 is cyano, fluoro, or chloro, and R7 is hydrogen, fluoro, or chloro.

[0125] In some embodiments, R6 is cyano and R7 is hydrogen.

[0126] In some embodiments, R6 is cyano and R7 is fluoro.

[0127] In some embodiments, R6 is fluoro or chloro and R7 is hydrogen.

[0128] In some embodiments, R6 is fluoro and R7 is chloro.

[0129] In some embodiments, R6 is chloro and R7 is fluoro.

[0130] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0131] R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano, nitro or C1-C6 haloalkyl;

[0132] R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0133] R5 is hydrogen, -C(O)R or -S(O)2R;

[0134] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0135] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, nitro, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl or -N(R 10 )-S(O)2-C1-C6 alkyl;

[0136] R8, R9 and R 10 Each independently represents H or a C1-C6 alkyl group:

[0137] Z is -O-, -S-, -S(O)-, -S(O)2-, -N(R 10 )- or -CH2-; and

[0138] W is CH or N.

[0139] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0140] R1, R2 and R3 are each independently halogen, cyano or C1-C6 haloalkyl;

[0141] R4 is a C1-C6 alkyl group;

[0142] R5 is hydrogen, -C(O)R or -S(O)2R;

[0143] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0144] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl or -N(R 10 )-S(O)2-C1-C6 alkyl;

[0145] R8, R9 and R 10 Each independently represents H or a C1-C6 alkyl group:

[0146] Z is -O-, -S-, -S(O)-, -S(O)2-, -NH-, or -CH2-; and

[0147] W is CH or N

[0148] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0149] R1, R2 and R3 are each independently halogen, cyano or C1-C6 haloalkyl;

[0150] R4 is a C1-C6 alkyl group;

[0151] R5 is hydrogen, -C(O)R or -S(O)2R;

[0152] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0153] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl or cyano;

[0154] R8 and R9 are each independently H or C1-C6 alkyl;

[0155] Z is -O-, -S-, -S(O)-, -S(O)2-, -NH-, or -CH2-; and

[0156] W is CH or N.

[0157] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0158] R1, R2 and R3 are each independently halogen, cyano or C1-C6 haloalkyl;

[0159] R4 is a C1-C6 alkyl group;

[0160] R5 is hydrogen or -C(O)R;

[0161] R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9;

[0162] R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl or cyano;

[0163] R8 and R9 are each independently hydrogen or C1-C6 alkyl.

[0164] Z is -O-; and

[0165] W is CH or N.

[0166] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0167] R1, R2 and R3 are each independently fluorine, chlorine, bromine, cyano, trifluoromethyl or difluoromethyl;

[0168] R4 is a methyl group;

[0169] R5 is hydrogen or -C(O)R,

[0170] R is C1-C4 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S;

[0171] R6 and R7 are each independently hydrogen, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl or cyano;

[0172] Z is -O-; and

[0173] W is CH or N.

[0174] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof is provided, wherein:

[0175] R1 is halogen;

[0176] R2 is halogen or trifluoromethyl;

[0177] R3 is a cyano group;

[0178] R4 is a methyl group;

[0179] R5 is hydrogen or -C(O)R,

[0180] R is C1-C4 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S;

[0181] R6 is halogen or cyano;

[0182] R7 is hydrogen or halogen;

[0183] Z is -O-; and

[0184] W is CH or N.

[0185] In some embodiments, provided is a compound selected from the group consisting of:

[0186] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0187] In some embodiments, the pharmaceutical composition comprises 0.1% to 99.5% by weight of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof as an active ingredient, preferably 0.5% to 99.5% by weight, more preferably 1% to 50% by weight, for example 1%, 1.5%, 2%, 5%, 10%, 15%, 20%, 25%, 30% or 50% by weight of the active ingredient. The remainder of the pharmaceutical composition is a pharmaceutically acceptable carrier.

[0188] In some embodiments, the pharmaceutical composition comprises two, three or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier includes conventional pharmaceutical carriers in the pharmaceutical field, such as diluents, fillers, adhesives, disintegrants, lubricants, wetting agents, solubilizers, solvents, colorants, spices, absorption promoters, surfactants, adsorption carriers, etc., examples of which include but are not limited to starch, pregelatinized starch, sodium carboxymethyl starch, powdered sugar, lactose, calcium phosphate, magnesium stearate, talc, micropowdered silica gel, dextrin, cellulose and its derivatives (such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, etc.), microcrystalline cellulose, mannitol, sorbitol, polysorbate 80, polyethylene glycol, water, water for injection, normal saline, glucose solution, etc. The pharmaceutical composition may also include various other commonly used additives, such as preservatives, emulsifiers, suspending agents, flavoring agents, etc.

[0189] The pharmaceutical composition can be prepared into any suitable pharmaceutically acceptable dosage form by any conventional technology in the art, including but not limited to tablets, capsules, pills, granules, syrups, injections, solutions, suspensions, powders (including sterile powders for injection), etc. The pharmaceutical composition of the present invention can be applied to a subject (such as a human or non-human mammal) by any route of administration, including, for example, oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, buccal, sublingual, rectal, etc. The effective amount of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof depends on a variety of factors, including but not limited to: the specific compound to be administered; the species, size, age and general health of the mammal; the severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the formulation administered; the selected dosage regimen; the use of other concomitant drugs, etc., which can usually be determined by the attending physician according to conventional practice. In general, the effective amount is usually in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg body weight / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, it may be necessary to use larger doses without causing any harmful side effects, with such larger doses generally being divided into several smaller doses for administration throughout the day.

[0190] The third aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers, for use in preventing and / or treating diseases associated with androgen levels.

[0191] A fourth aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers for use in preventing and / or treating diseases associated with androgen levels.

[0192] A fifth aspect of the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for preventing and / or treating diseases associated with androgen levels.

[0193] A sixth aspect of the present invention provides a method for preventing and / or treating a disease associated with androgen levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0194] In the above aspects 3 to 6, the diseases related to androgen levels are benign prostatic hyperplasia, prostate cancer, including castration-resistant prostate cancer, other androgen receptor-expressing cancers, such as breast cancer, bladder cancer, ovarian cancer, etc., uterine fibroids and abdominal aortic aneurysm, Kennedy's disease, amyotrophic lateral sclerosis (ALS), androgenic alopecia or hyperandrogenic dermal diseases, such as acne or hirsutism, etc.

[0195] The compounds or pharmaceutical compositions of the present invention can be administered to a subject (e.g., a human or non-human mammal) by any route of administration, including, for example, oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, buccal, sublingual, rectal, and the like.

[0196] The attending physician may adjust the dosage and frequency of administration of the compound of the present invention or pharmaceutical composition, taking into account factors such as the patient's age, general health, weight, and severity of the symptoms to be treated. In general, the total daily dose of the compound of the present invention or pharmaceutical composition is typically from about 0.1 to about 1000 mg of active ingredient / day, such as from about 1 to about 800 mg / day, from about 10 to about 600 mg / day, from about 50 to about 500 mg / day, administered in a single dose or 2, 3, or 4 divided doses.

[0197] The main beneficial effects of the compounds of the present invention include the following aspects:

[0198] (1) The compounds of the present invention have good ability to bind to androgen receptors;

[0199] (2) The compounds of the present invention have good androgen receptor antagonist ability, and some of them show a maximum inhibition rate on androgen receptor that is better than or equivalent to that of apalutamide. They are complete antagonists of androgen receptor, avoiding the side effects caused by androgen agonism, and are safer and more effective.

[0200] (3) The compound of the present invention exhibited an inhibition rate exceeding 90% in an in vitro prostate cancer cell proliferation inhibition test and has great potential for development as an effective therapeutic agent for prostate cancer.

[0201] General Methods for Preparing Compounds of the Invention

[0202] Compounds of Formula I can be prepared from commercially available or readily prepared starting materials according to synthesis and purification methods well known to those skilled in the art of organic synthesis. Exemplary methods for preparing compounds of Formula I are described in the following schemes and examples. It should be understood that these exemplary methods do not limit the present invention in any way, and those skilled in the art of organic synthesis will appreciate alternative synthetic routes.

[0203] Option 1

[0204] Scheme 1 illustrates a general method for preparing compounds of Formula I, wherein the variables R1, R2, R3, R4, R5, R6, R7, Z and W are as defined above for compounds of Formula I. The method comprises the following steps:

[0205] Step 1: reacting compound (III) with SOCl2 in the presence of a base at 0°C in an anhydrous solvent to obtain an acyl chloride compound (IV);

[0206] Step 2: In the presence of a base, compound (IV) is reacted with compound (V) in an anhydrous solvent at 0°C to obtain compound (VI);

[0207] Step 3: In the presence of a catalyst (copper bromide dimethyl sulfide (CuBr·S(Me)2)), a ligand (triphenylphosphine or tricyclohexylphosphine) and a base, compound (VI) and compound (VII) are reacted in an anhydrous solvent to obtain compound (VIII);

[0208] Step 4: Compound (VIII) is reacted with an acid anhydride compound (IX) (which may also be a carboxylic acid compound) in an anhydrous solvent to produce a compound of formula I.

[0209] The base used in the above steps 1-3 can be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide and potassium hydroxide, and the anhydrous solvent used can be selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide and N,N-dimethylacetamide.

[0210] Option 2

[0211] Scheme 2 illustrates an alternative method for preparing a compound of Formula I, wherein the variables R1, R2, R3, R4, R5, R6, R7, Z and W are as defined above for the compound of Formula I. The method comprises the following steps:

[0212] Step 1: Refluxing compound (X) with an acid anhydride compound (IX) in an anhydrous solvent to obtain compound (XI);

[0213] Step 2: removing the protecting group of compound (XI) to obtain compound (XII);

[0214] Step 3: reacting compound (XII) with SOCl2 in the presence of a base at 0°C in an anhydrous solvent to obtain compound (XIII);

[0215] Step 4: reacting compound (XIII) with compound (V) in the presence of a base in an anhydrous solvent at 0°C to produce compound (XIV);

[0216] Step 5: Compound (XIV) is reacted with compound (VII) in the presence of a base in an anhydrous solvent under reflux to obtain a compound of formula I.

[0217] The base used in the above steps 3-5 can be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, tripotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide and potassium hydroxide, and the anhydrous solvent used can be selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide and N,N-dimethylacetamide.

[0218] Option 3

[0219] Scheme 3 illustrates a general method for preparing compounds of Formula IIa, wherein the variables R1, R2, R3, R5, R6, R7 and W are as defined above for compounds of Formula I. The method comprises the following steps:

[0220] Step 1: Compound 1 reacts with SOCl2 in the presence of a base at 0°C in an anhydrous solvent to obtain compound 2;

[0221] Step 2: Compound 2 reacts with compound 3 at 0°C in an anhydrous solvent in the presence of a base to produce compound 4;

[0222] Step 3: Compound 4 is heated in an anhydrous solvent in the presence of a base to convert it into compound 5;

[0223] Step 4: Compound 5 reacts with compound 6 in the presence of a base in an anhydrous solvent to produce compound 7;

[0224] Step 5: Compound 7 is reacted with compound 8 in the presence of a base at 0°C in an anhydrous solvent to obtain a compound of formula II.

[0225] In each of the above reaction steps, the base is selected from sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, trimethylammonium hydroxide, guanidines, 1,4-diazabicyclo[2.2.2]octanediazabicyclo, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, etc., and the anhydrous solvent is selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0226] Option 4

[0227] Scheme 4 illustrates an alternative method for preparing a compound of Formula IIa, wherein the variables R1, R2, R3, R5, R6, R7 and W are as defined above for the compound of Formula I. The method comprises the following steps:

[0228] Step 1: Compound 9 reacts with compound 6 at 0°C in an anhydrous solvent in the presence of a base to produce compound 10;

[0229] Step 2: Compound 10 reacts in the presence of a base in an anhydrous solvent to produce compound 11;

[0230] Step 3: Compound 11 reacts with SOCl2 in an anhydrous solvent at 0°C in the presence of a base to obtain compound 12;

[0231] Step 4: Compound 12 reacts with compound 3 in the presence of a base at 0°C in an anhydrous solvent to obtain compound 7;

[0232] Step 5: Compound 7 is reacted with compound 8 in the presence of a base at 0°C in an anhydrous solvent to obtain a compound of formula II.

[0233] In each of the above reaction steps, the base is selected from sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, trimethylammonium hydroxide, guanidines, 1,4-diazabicyclo[2.2.2]octane, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, etc., and the anhydrous solvent is selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0234] Example

[0235] The present invention will be further specifically described below with reference to examples. It is apparent that the examples described are only a part of the present invention, rather than all of it. These examples are merely illustrative of the present invention and should not be construed as limiting the scope of protection of the present invention. Based on the examples of the present invention, all other technical solutions obtained by those skilled in the art without creative effort are intended to fall within the scope of protection of the present invention.

[0236] In the examples, the abbreviation THF stands for tetrahydrofuran, DMSO-d6 stands for deuterated dimethyl sulfoxide, DMSO stands for dimethyl sulfoxide, CDCl3 stands for deuterated chloroform, eq stands for equivalent, HPLC stands for high pressure liquid chromatography, PPh3 stands for triphenylphosphine, PCy3 stands for tricyclohexylphosphine, K3PO4 stands for tripotassium phosphate, DMF stands for dimethylformamide, Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium, and DME stands for ethylene glycol dimethyl ether.

[0237] 1 H NMR measurements were performed using a Bruker AVANCE II 400 MHz nuclear magnetic resonance instrument, where s represents a singlet, bs or brs represents a broad singlet, d represents a doublet, dd represents a doublet of doublets, and m represents a multiplet. Ar represents an aromatic group. Mass spectrometry was performed using a Bruker amaZon SL mass spectrometer. High-resolution mass spectrometry was performed using a Thermo TSQ. High-pressure liquid chromatography was performed using an Agilent 1260 Infinity II. Thin-layer chromatography was performed using Silica Gel 60F254 Plates (Merck).

[0238] I. Compound Preparation Examples

[0239] Example 1 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (SARM-30)

[0240] First and second step reactions

[0241] Under nitrogen, (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (2.7 mmol) was added to 10 mL of anhydrous THF. Then, thionyl chloride (3.28 mmol) was slowly added in an ice bath, maintaining the temperature in the reaction vessel below 0°C. The reaction solution was gradually warmed to room temperature and allowed to react for 1.5 hours. The reaction solution was returned to an ice bath, and triethylamine (3.55 mmol) was added dropwise, maintaining the temperature in the reaction vessel below 0°C. Subsequently, a THF solution (2 mL) of 4-amino-2-chloro-3-fluorobenzonitrile (2.7 mmol) was added dropwise, continuing to maintain the temperature in the reaction vessel below 0°C. After the additions were complete, the mixture was slowly warmed to room temperature, then heated to 50°C and allowed to react for 2 hours. TLC indicated the reaction was complete. The reaction solution, cooled to room temperature, was quenched with water, and extracted with 40 mL of ethyl acetate. The organic phase was washed with water and saturated brine. Anhydrous sodium sulfate was added for drying, filtered, and evaporated under reduced pressure to obtain compound (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide.

[0242] 1H NMR (400MHz, DMSO) δ9.72 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.7, 7.1 Hz, 1H), 7.91–7.73 (m, 1H), 3.80 (d, J = 10.4 Hz, 1H), 3.56 (d, J = 10.4 Hz, 1H), 1.47 (s, 3H).

[0243] The third step reaction

[0244] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-hydroxybenzonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 80-85°C, and the reaction was stirred for 3 hours. TLC indicated that the reaction was complete, and the K2CO3 was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained by distillation under reduced pressure, and the target compound was obtained after separation on a chromatographic column as a white powdery solid with a yield of 71%.

[0245] 1H NMR(400MHz,DMSO)δ9.81(s,1H,NH),8.10(dd,J=8.7,7.1Hz,1H,CH),7.82(dd,J=8.7,1.6Hz,1H,CH),7.82–7.65(m,2H,2*CH) ,7.17–7.00(m,2H,2*CH),6.56(s,1H,OH),4.30(d,J=9.9Hz,1H,1 / 2*CH2),4.08(d,J=10.0Hz,1H,1 / 2*CH2),1.43(s,3H,CH3).

[0246] LRMS(-ESI)m / z:372.0, 374.0, [(MH) - ,100 / 33%].

[0247] Example 2 Preparation of (S)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-41)

[0248] First and second step reactions

[0249] Under nitrogen protection, (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (2.7mmol) was added to 10mL of anhydrous THF, and then dichlorothionyl (3.28mmol) was slowly added under ice bath conditions while keeping the temperature in the reaction vessel below 0°C. The reaction solution was gradually warmed to room temperature and reacted for 1.5 hours. The reaction solution was placed back under ice bath conditions, triethylamine (3.55mmol) was added dropwise, and the temperature in the reaction vessel was kept below 0°C. Subsequently, a THF solution (2mL) of 4-amino-3-fluoro-2-(trifluoromethyl)benzonitrile (2.7mmol) was added dropwise, and the temperature in the reaction vessel was continued to be kept below 0°C. After the addition was complete, the mixture was slowly warmed to room temperature, then heated to 50°C and reacted for 2 hours. TLC showed that the reaction was complete, and the reaction solution cooled to room temperature was quenched with water and extracted with 40mL of ethyl acetate. The organic phase was washed with water and saturated brine. Anhydrous sodium sulfate was added for drying, filtered, and evaporated under reduced pressure to obtain compound (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide.

[0250] 1H NMR(400MHz,DMSO)δ9.82(d,J=2.3Hz,1H,NH),8.44(t,J=7.9Hz,1H,CH),8.00(d,J=8.6Hz,1H,CH),6 .66(s,1H,OH),3.83(d,J=10.5Hz,1H,1 / 2*CH2),3.59(d,J=10.5Hz,1H,1 / 2*CH2),1.50(s,3H,CH3).

[0251] The third step reaction

[0252] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-hydroxybenzonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (2.1 mmol) was added, and the temperature was controlled at 80-85°C with stirring for 3 hours. TLC indicated the reaction was complete, and the KCO was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the title compound was obtained after column chromatography as a white powdery solid in a 61% yield.

[0253] 1H NMR(400MHz,DMSO)δ9.90(s,1H,NH),8.45(t,J=7.9Hz,1H,CH),7.99(d,J=8.6Hz,1H,CH),7.80–7.71(m,2H,2*CH),7.15– 7.07(m,2H,2*CH),6.60(s,1H,OH),4.33(d,J=10.0Hz,1H,1 / 2*CH2),4.11(d,J=10.0Hz,1H,1 / 2*CH2),1.46(s,3H,CH3).

[0254] LRMS(-ESI)m / z:406.1,[(MH) - ,100%].

[0255] Example 3 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (SARM-31)

[0256] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 5-hydroxypyridinecarbonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 80-85°C, and the reaction was stirred for 3 hours. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 71% yield.

[0257] 1H NMR(400MHz,dmso)δ9.82(s,1H,NH),8.41(d,J=2.9Hz,1H,2*CH),8.13–7.95(m,2H,2*CH),7.83(dd,J=8.7,1.6Hz,1H,CH),7.61 (dd,J=8.7,2.9Hz,1H,CH),6.61(s,1H,OH),4.41(d,J=10.2Hz,1H,1 / 2*CH2),4.19(d,J=10.2Hz,1H,1 / 2*CH2),1.44(s,3H,CH3).

[0258] LRMS(-ESI)m / z:373.0, 375.0, [(MH) - ,100 / 33%].

[0259] Example 4 Preparation of (S)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (TNBC-42)

[0260] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 5-hydroxypicolinonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 80-85°C, and the reaction was stirred for 3 hours. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after chromatographic separation as a white powdery solid in a 77% yield.

[0261] 1H NMR(400MHz,DMSO)δ9.91(s,1H,NH),8.48–8.39(m,2H,2*CH),8.00(dd,J=8.7,2.9Hz,2H,2*CH),7.63(dd,J=8.7,2 .9Hz,1H*CH),6.65(s,1H,OH),4.44(d,J=10.2Hz,1H,1 / 2*CH2),4.22(d,J=10.2Hz,1H,1 / 2*CH2),1.47(s,3H,CH3).

[0262] LRMS(-ESI)m / z:407.0,[(MH) - ,100%].

[0263] Example 5 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-57)

[0264] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and p-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after chromatographic separation as a white powdery solid in a 27% yield.

[0265] 1H NMR (400MHz, DMSO) δ9.79 (s, 1H, NH), 8.16 (dd, J = 8.6, 7.0 Hz,1H,CH),7.85(dd,J=8.7,1.6Hz,1H,CH),7.10(t,J=8.8Hz,2H,2*CH),6.99–6.89(m,2H,2*CH), 6.51(s,1H,OH), 4.19(d,J=9.7Hz,1H,1 / 2*CH2), 3.97(d,J=9.7Hz,1H,1 / 2*CH2), 1.44(s,3H,CH3).

[0266] LRMS(-ESI)m / z:365.1[(MH) - ,100%].

[0267] Example 6 Preparation of (S)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-47)

[0268] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and p-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after chromatographic separation as a white powdery solid in a 15% yield.

[0269] 1H NMR(400MHz,DMSO)δ9.87(s,1H,NH),8.48(t,J=7.9Hz,1H,CH),7.99(d,J=8.6Hz,1H,CH),7.10(t,J=8.8Hz,2H,CH),6 .96–6.91(m,2H,CH),6.54(s,1H,OH),4.20(d,J=9.7Hz,1H,1 / 2*CH2),4.07–3.94(m,1H,1 / 2*CH2),1.44(s,3H,CH3).

[0270] LRMS(-ESI)m / z:399.1[(MH)-,100%].

[0271] Example 7 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-chlorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-58)

[0272] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and p-chlorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated the reaction was complete. The KCO was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the title compound as a white powdery solid in a 27% yield.

[0273] 1H NMR(400MHz,DMSO)δ9.79(s,1H,NH),8.15(dd,J=8.7,7.0Hz,1H,CH),7.84(dd,J=8.6,1.6Hz,1H,CH),7.35–7.26(m,2H,2*CH) ,7.00–6.91(m,2H,2*CH),6.53(s,1H,OH),4.21(d,J=9.8Hz,1H,1 / 2*CH2),3.99(d,J=9.8Hz,1H,1 / 2*CH2),1.44(s,3H,CH3).

[0274] LRMS(-ESI)m / z:381.0[(MH) - ,100%].

[0275] Example 8 Preparation of (S)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-3-(4-chlorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-52)

[0276] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and p-chlorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 15% yield.

[0277] 1H NMR (400MHz, DMSO) δ9.88(s,1H,NH),8.47(t,J=7.9Hz,1H,CH),7.99(d,J=8.6Hz,1H,CH),7.35–7.23(m,2H,2*CH),7.02–6 .92(m,2H,2*CH),6.56(s,1H,OH),4.22(d,J=9.8Hz,1H,1 / 2*CH2),4.01(t,J=10.5Hz,1H,1H,1 / 2*CH2),1.47(s,3H,CH3).

[0278] LRMS(-ESI)m / z:415.0,417.0[(MH) - ,100 / 33%].

[0279] Example 9 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(3-chloro-4-fluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-59)

[0280] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 3-chloro-4-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after chromatographic separation as a white powdery solid in a 75% yield.

[0281] 1H NMR (400MHz, DMSO) δ9.79(s,1H,NH),8.14(dd,J=8.7,7.0Hz,1H,CH),7.85(dd,J=8.7,1.6Hz,1H,CH),7.45(t,J=8.9Hz,1H,CH),7.08(dd,J=11.5,2 .8Hz,1H,CH),6.82(dd,J=8.9,2.8Hz,1H,CH),6.55(s,1H,OH),4.25(d,J=9.9Hz,1H,1 / 2*CH2),4.02(d,J=10.0Hz,1H,1 / 2*CH2),1.44(s,3H,CH3).

[0282] LRMS(-ESI)m / z:399.0[(MH) - ,100%].

[0283] Example 10 Preparation of (S)-3-(3-chloro-4-fluorophenoxy)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (TNBC-54)

[0284] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 3-chloro-4-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained by distillation under reduced pressure, and the target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 35%.

[0285] 1H NMR (400MHz, DMSO) δ9.87 (s, 1H, NH), 8.47 (t, J = 7.9Hz, 1H,CH),7.99(d,J=8.6Hz,1H,CH),7.45–7.11(m,2H,2*CH),7.09–6.90(m,1H,CH),6.55(s, 1H,OH), 4.25(d,J=9.9Hz,1H,1 / 2*CH2), 4.02(d,J=9.9Hz,1H,1 / 2*CH2), 1.44(s,3H,CH3).

[0286] LRMS(-ESI)m / z:433.0,435.0[(MH) - ,100 / 33%].

[0287] Example 11 Preparation of (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-60)

[0288] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 2-fluoro-4-hydroxybenzonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after chromatographic separation as a white powdery solid in a 56% yield.

[0289] 1H NMR(400MHz,DMSO)δ9.81(s,1H,NH),8.12(dd,J=8.6,7.0Hz,1H,CH),7.88–7.77(m,2H,2*CH),7.19(dd,J=11.9,2.4Hz,1H,CH),6. 97(dd,J=8.8,2.3Hz,1H,CH),6.61(s,1H,OH),4.36(d,J=10.1Hz,1H,1 / 2*CH2),4.13(d,J=10.1Hz,1H,1 / 2*CH2),1.45(s,3H,CH3).

[0290] LRMS(-ESI)m / z:390.1[(MH) - ,100%].

[0291] Example 12 Preparation of (S)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-3-(4-cyano-3-fluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-48)

[0292] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 2-fluoro-4-hydroxybenzonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (2.1 mmol) was added, and the temperature was controlled at 60°C and the reaction was stirred overnight. TLC indicated the reaction was complete. The KCO was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound as a white powdery solid in a 22% yield.

[0293] 1H NMR (400MHz, DMSO) δ9.89(s,1H,NH),8.44(t,J=7.9Hz,1H,CH),7.99(d,J=8.6Hz,1H,CH),7.81(t,J=8.3Hz,1H,CH),7.19(dd,J=11.9,2.4Hz, 1H,CH),6.97(dd,J=8.8,2.4Hz,1H,CH),6.63(s,1H,OH),4.37(d,J=10.1Hz,1H,1 / 2*CH2),4.14(d,J=10.1Hz,1H,1 / 2*CH2),1.46(s,3H,CH3).

[0294] LRMS(-ESI)m / z:424.0[(MH) - ,100%].

[0295] Example 13 Preparation of (S)-3-(4-chloro-3-fluorophenoxy)-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (TNBC-61)

[0296] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-chloro-3-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 36% yield.

[0297] 1H NMR(400MHz,DMSO)δ9.78(s,1H,NH),8.19–8.11(m,1H,CH),7.85(dd,J=8.7,1.4Hz,1H,CH),7.31(t,J=9.1Hz,1H,CH),7.19(dd,J=6.1,3.0Hz ,1H,CH),6.94(dt,J=9.2,3.5Hz,1H,CH),6.53(s,1H,OH),4.24(d,J=9.9Hz,1H,1 / 2*CH2),4.01(d,J=9.9Hz,1H,1 / 2*CH2),1.43(s,3H,CH3).

[0298] LRMS(-ESI)m / z:399.0[(MH) - ,100%].

[0299] Example 14 Preparation of (S)-3-(4-chloro-3-fluorophenoxy)-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (TNBC-53)

[0300] Under nitrogen, (R)-3-bromo-N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-chloro-3-fluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated that the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 34% yield.

[0301] 1H NMR (400MHz, DMSO) δ9.88(s,1H,NH),8.46(t,J=7.9Hz,1H,CH),7.99(d,J=8.6Hz,1H,CH),7.49–7.37(m,1H,CH),7.09(dd,J=11.5,2.8 Hz,1H,CH),6.93–6.79(m,1H,CH),6.58(s,1H,OH),4.26(d,J=9.9Hz,1H,1 / 2*CH2),4.03(d,J=9.9Hz,1H,1 / 2*CH2),1.45(s,3H,CH3).

[0302] LRMS(-ESI)m / z:433.0,435.0[(MH) - ,100 / 33%].

[0303] Example 15 Preparation of (S)-N-(4-cyano-2-fluoro-3-chlorophenyl)-3-(3,4-difluorophenoxy)-2-hydroxy-2-methylpropionamide (TNBC-62)

[0304] Under nitrogen, (R)-3-bromo-N-(3-chloro-4-cyano-2-fluorophenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 3,4-difluorophenol (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, the temperature was controlled at 60°C, and the reaction was stirred overnight. TLC indicated the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 36% yield.

[0305] 1H NMR (400MHz, DMSO) δ9.78(s,1H,NH),8.15(dd,J=8.6,7.0Hz,1H,CH),7.85(dd,J=8.7,1.6Hz,1H,CH),7.32(q,J=9.7Hz,1H,CH),7.08(ddd,J=12. 8,6.8,3.0Hz,1H,CH),6.81–6.72(m,1H,CH),6.54(s,1H,CH),4.22(d,J=9.8Hz,1H,1 / 2*CH2),3.99(d,J=9.9Hz,1H,1 / 2*CH2),1.44(s,3H,CH3).

[0306] LRMS(-ESI)m / z:383.0[(MH) - ,100%].

[0307] Example 16 Preparation of (S)-1-((3-chloro-4-cyano-2-fluorophenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl acetate (TNBC-63)

[0308] Under the protection of nitrogen, (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.3mmol), 4-dimethylaminopyridine (0.4mmol) and acetic anhydride (0.6mmol) were added to 5mL of pyridine and stirred to dissolve. The temperature was controlled at 80°C to 85°C and the reaction was stirred for 3 hours. TLC showed that the reaction was complete, the reaction solution was added to water, and 20mL of ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the above-mentioned target compound was obtained after separation by chromatographic column. White powdery solid, yield 56%.

[0309] 1H NMR(400MHz,DMSO)δ7.93(dd,J=8.5,1.5Hz,1H,CH),7.91–7.85(m,2H,2*CH),7.78(dd,J=8.6 ,6.9Hz,1H,CH),7.30–7.23(m,2H,2*CH),4.59(s,2H,CH),2.20(s,3H,CH3),1.80(s,3H,CH3).

[0310] LRMS(-ESI)m / z:414.0[(MH) - ,100%].

[0311] Example 17 Preparation of (S)-1-((3-chloro-4-cyano-2-fluorophenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxoprop-2-ylnicotinate (TNBC-64)

[0312] Under the protection of nitrogen, (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.3mmol), 4-dimethylaminopyridine (0.4mmol) and nicotinic anhydride (0.6mmol) were added to 5mL of pyridine and stirred to dissolve. The temperature was controlled at 80℃ to 85℃ and the reaction was stirred for 3 hours. TLC showed that the reaction was complete, and the reaction solution was added to water and extracted with 20mL of ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained after vacuum distillation, and the above-mentioned target compound was obtained after separation by chromatographic column. White powdery solid, yield 52%.

[0313] 1H NMR(400MHz,DMSO)δ10.26(s,1H,NH),9.10(d,J=2.2Hz,1H,CH),8.85(dd,J=4.9,1.7Hz,1H,CH),8.30(dt,J=8.0,2.0Hz,1H,CH),7.89–7.82(m,1H,CH), 7.82–7.78(m,2H,2*CH),7.73(dd,J=8.6,6.8Hz,1H,CH),7.60(dd,J=8.0,4 .8Hz,1H,CH),7.26–7.19(m,2H,2*CH),4.69(s,2H,2*CH),1.88(s,3H,CH3).

[0314] LRMS(-ESI)m / z:477.0[(MH) - ,100%]. LRMS(+ESI)m / z:479.1[(M+H)+,100%].

[0315] Example 18 Preparation of (S)-1-((3-chloro-4-cyano-2-fluorophenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylbenzoate (TNBC-65)

[0316] Under nitrogen, (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and benzoic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after column chromatography. It was a white powdery solid with a yield of 66%.

[0317] 1H NMR (400MHz, DMSO) δ10.22(s,1H,NH),7.97(d,J=7.6Hz,2H,2*CH),7.88–7.82(m,1H,CH),7.80(d,J=8.8Hz,2H,2*CH),7.77–7 .46(m,5H,5*CH),7.22(d,J=8.7Hz,2H,2*CH),4.73–4.62(m,2H,CH2),1.87(s,3H,CH3).LRMS(-ESI)m / z:476.1[(MH)-,100%].

[0318] LRMS (+ESI) m / z: 478.0 [(M+H) + ,100%].

[0319] Example 19 Preparation of (S)-1-((3-chloro-4-cyano-2-fluorophenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylcyclopentanecarboxylate (TNBC-66)

[0320] Under the protection of nitrogen, in an ice bath, (S)-N-(3-chloro-4-cyano-2-fluorophenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. Subsequently, 4-dimethylaminopyridine (3.8 mmol) and cyclopentanecarboxylic acid (1.6 mmol) were added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the above-mentioned target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 79%.

[0321] 1H NMR(400MHz,DMSO)δ9.96(s,1H,NH),7.85(d,J=8.7Hz,1H,CH),7.83–7.73(m,3H,3*CH),7.21–7.13(m,2H,2*CH),4.59–4.48(m ,2H,CH2),2.87(ddd,J=15.5,8.6,6.9Hz,1H,CH),1.83(q,J=8.5Hz,2H,CH2),1.72(s,5H,CH2,CH3),1.61–1.50(m,4H,2*CH2).

[0322] LRMS(-ESI)m / z:468.1[(MH) - ,100%].

[0323] II. Formulation Examples

[0324] Formulation Example A: Preparation of Injection

[0325] (1) Batch formula composition:

[0326] (2) Preparation method:

[0327] According to the formula, the compound of Example 15, polysorbate 80, and mannitol were added to 4000 mL of water for injection. After stirring to dissolve, water for injection was added to a total volume of 5000 mL. Stirring was continued, and the mixture was sterile filtered through a 0.22 μm microporous filter membrane. The filtrate was aseptically filled into 5 mL ampoules (specification: 25 mg / ampoule) at a volume of 5 mL per vial, sealed, and sterilized.

[0328] Formulation Example B: Preparation of Tablets

[0329] (1) Formula composition (dosage per 1000 tablets)

[0330] (2) Preparation process

[0331] The compound of Example 15, lactose, and part of the microcrystalline cellulose were micronized in a ratio of 200:100:40. The remaining microcrystalline cellulose, pregelatinized starch, micropowdered silica gel, and sodium carboxymethyl starch that had passed through an 80-mesh sieve were added according to the formula ratio and mixed evenly. An appropriate amount of 0.3% HPMC solution was added to prepare a soft material. The mixture was granulated with an 18-mesh sieve and dried at 60°C (the moisture content of the granules was controlled at approximately 3%). Magnesium stearate that had passed through an 80-mesh sieve was added and mixed evenly with the granules. The granules were sieved through a 16-mesh sieve, compressed into tablets, and packaged.

[0332] Formulation Example C: Preparation of Tablets

[0333] (1) Formula composition (dosage per 1000 tablets)

[0334] (2) Preparation process

[0335] Tablets of Formulation Example C were prepared similarly to Formulation Example B above.

[0336] Formulation Example D: Preparation of Tablets

[0337] (1) Formula composition (dosage per 1000 tablets)

[0338] (2) Preparation process

[0339] The compound of Example 15, lactose, and part of the microcrystalline cellulose were micronized in a ratio of 200:100:40. The remaining microcrystalline cellulose, pregelatinized starch, micropowdered silica gel, and sodium carboxymethyl starch that had passed through an 80-mesh sieve were added according to the formula ratio and mixed evenly. An appropriate amount of 0.3% HPMC solution was added to prepare a soft material. The mixture was granulated with an 18-mesh sieve and dried at 60°C (the moisture content of the granules was controlled at approximately 3%). Magnesium stearate that had passed through an 80-mesh sieve was added and mixed evenly with the granules. The granules were sieved through a 16-mesh sieve, compressed into tablets, and packaged.

[0340] III. Bioactivity Assay

[0341] 1. Small molecule and protein affinity (protein ligand coupling) experiment

[0342] (1) Experimental equipment

[0343] Biacore TM T200, from CM5 series chips (purchased from Catalog number: 29149604); human androgen receptor (AR) recombinant protein (CLOUD-CLONE CORP. WUHAN, RPB252Hu03, Ile673-His918 with an N-terminal His tag).

[0344] (2) Experimental process

[0345] 1) pH screening: Screen suitable ligand buffer pH from 10 mM sodium acetate at pH 5.5, 5.0, 4.5, and 4, with a ligand concentration of 10-100 μg / ml. Contact time = 180 s, flow rate = 5 μL / min, followed by surface regeneration with 50 mM NaOH.

[0346] 2) Ligand immobilization: Immobilize using amino-direct coupling. Activate and immobilize the ligand using EDC / NHS, then block with ethanolamine. Automated coupling is performed using the aim for immobilized level mode and a target level of 1000 RU. After coupling, the amount of coupling is measured using the response bound method.

[0347] 3) Surface Testing: Prepare 85 nM, 8.5 nM, and 0.85 nM β2-microglobulin solutions and glycine hydrochloride regeneration solution, respectively, and place them on the sample rack. Set the contact time to 180 seconds and the wait time to 60 seconds. Select the corresponding position for the regeneration solution and set the contact time to 30 seconds. Repeat the surface testing-regeneration process for the three samples. Use the sensorgram results of channel 2 subtracted from channel 1 to examine whether the analyte and ligand are bound, whether the injection dissociation time is appropriate, and estimate the KD value.

[0348] 4) Regeneration conditions: Glycine hydrochloride at different pH values ​​was used for regeneration. The regeneration solution flow rate was 30 μL / min.

[0349] 5) Set up a reasonable analyte concentration gradient based on previous experimental results and perform kinetic analysis. Select a kinetic / affinity calculation method. For kinetic analysis, the Rmax value should be less than 100 RU.

[0350] (3) Experimental results

[0351] The affinity test results of the compounds of the present invention as androgen receptor ligands to androgen receptor protein are shown in the table below, where Ostarine is a control compound:

[0352] Table 1. In vitro small molecule and protein affinity results of the compounds

[0353] Under the experimental conditions, the compounds of Examples 1 and 3 showed excellent affinity for the androgen receptor protein, suggesting that the compounds may be a class of potent androgen receptor antagonists / agonists. In contrast, the control compound Ostarine showed no affinity for the androgen receptor protein.

[0354] 2. Androgen receptor antagonism reporter gene test

[0355] 2.1 Experimental Overview

[0356] This experiment investigates the antagonistic ability of the compounds of the present invention on androgen receptors. The positive control compound used in the experiment is ARN509 (Apalutamide). The experiment mainly includes: HEK293T cells (ATCC, CRL-3216) transfected with plasmids are inoculated into well plates containing dilutions of corresponding concentrations of compounds, and the cells are detected by CellTiter-Fluor TM The fluorescence values ​​corresponding to different compounds were measured using a cell viability reagent (Promega, G6081) and a briteliteplus luciferase assay reagent (PerkinElmer, 6066769). The relative receptor antagonist activity of the compounds of the present invention was calculated using the formula with ARN509 as a positive control. At the same time, the EC was calculated by fitting the % activity value and the logarithm of the compound concentration to a nonlinear regression. 50 .

[0357] 2.2 Experimental Procedure

[0358] (1) Compound preparation

[0359] All test compounds were serially diluted 10 times in DMSO at a ratio of 1:3 from 10 mM to a final concentration of 0.000508053 mM, and each concentration was repeated 3 times. The positive control ARN509 was serially diluted 10 times in DMSO at a ratio of 1:3 from 0.1 mM to a final concentration of 5.08053 E -06 Prepare 1000× positive control (10 mM ARN509) and 1000× vehicle control (100% DMSO).

[0360] (2) Experimental operation

[0361] 1) HEK293T cells were cultured according to ATCC recommendations and assayed during the exponential growth phase;

[0362] 2) Remove the culture medium from the flask;

[0363] 3) Rinse cells with PBS;

[0364] 4) Add TrypLE solution to the flask and allow the cells to detach. Wash the cells once with complete growth medium.

[0365] 5) Pellet and wash the cells twice with PBS to remove phenol red, and resuspend them in culture medium to an appropriate concentration;

[0366] 6) Only cells with viability greater than 90% were used for the assay;

[0367] 7) 6*10 6 HEK293T cells were seeded into 100 mm culture dishes;

[0368] 8) Incubate cells at 37°C, 5% CO2 for 16 hours;

[0369] 9) Transfect the plasmid into cells and culture at 37°C, 5% CO2 for 5-6 hours;

[0370] 10) Use Echo655 to transfer 25 μL of compound dilution to a 384-well assay plate;

[0371] 11) HEK293T cells were seeded into a 384-well assay plate at 17,000 cells / well;

[0372] 12) Incubate cells at 37°C, 5% CO2 for 18-20 hours;

[0373] 13) Add 25 μL CellTiter-Fluor to each well of the 384-well plate. TM Cell viability reagent, and incubate cells at 37°C, 5% CO2 for 30 minutes;

[0374] 14) Read the values ​​using ex 380nm / em 510nm;

[0375] 15) Add 25 μL of britelite plus luciferase assay reagent to each well of a 384-well assay plate and record the luminescence value on an Envision plate reader.

[0376] (3) Data processing

[0377] Calculate the % inhibition rate according to the following formula:

[0378] % inhibition rate = 100-(Activated cmpd -Activated Ave_PC ) / (Activated Ave_VC -Activated Ave_PC )*100

[0379] in:

[0380] Activated cmpd : the activation average of compound signals in the whole plate;

[0381] Activated Ave_PC : Average activation value of positive control in the whole plate;

[0382] Activated Ave_VC : The average activation value of negative control in the whole plate.

[0383] IC was calculated by fitting the % inhibition and compound concentration logarithms to a nonlinear regression using Graphpad 8.0 using the following formula: 50 :

[0384] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0385] in:

[0386] X: logarithm of inhibitor concentration; Y: % inhibition rate; Bottom is the lowest platform value of the curve; Top is the highest platform value of the curve; Hillslope is the slope of the curve.

[0387] 2.3 Experimental Results

[0388] The androgen receptor antagonist ability test results of the control compound and some example compounds are shown in Table 2 below.

[0389] Table 2. Test results of androgen receptor antagonism ability of compounds

[0390] Based on the comparison of the results of the test example compound and the positive control group (apalutamide / ARN-509), the following conclusions can be drawn:

[0391] Compared with the positive control compound apalutamide / ARN-509 (E MAX =98.05), Example 1 (E MAX =88.07), Example 3 (E MAX =96.70), Example 5 (E MAX =100.0), Example 6 (E MAX =100.0), Example 7 (E MAX =100.0), Example 8 (E MAX =100.0), Example 9 (E MAX =100.0), Example 10 (E MAX = 100.0), Example 11 (E MAX =100.0), Example 13 (E MAX =100.0), Example 14 (E MAX =97.05), Example 15 (E MAX =85.95) showed superior or equivalent effects on androgen receptor compared to the positive control apalutamide / ARN-509 (E MAX =98.05) / E MAX , is a class of androgen receptor complete antagonists; Example 2 (EMAX =74.65), Example 4 (E MAX =71.01), Example 12 (E MAX =65.54) showed a certain inhibition rate on androgen receptor (E MAX >60), a type of partial androgen receptor antagonist.

[0392] The biological activity test results in the above table show that the compounds of the present invention are a class of effective androgen receptor antagonists (IC 50 <10 μM, E MAX >80).

[0393] 3. Androgen receptor agonist ability reporter gene test

[0394] 3.1 Experimental Overview

[0395] This experiment investigates the ability of the compounds of the present invention to stimulate androgen receptors. The positive control compound used in the experiment is dihydrotestosterone (DHT). The experiment mainly includes: HEK293T cells (ATCC, CRL-3216) after plasmid transfection are inoculated into a well plate containing dilutions of the corresponding concentrations of the compounds, and the cells are detected by CellTiter-Fluor TM The fluorescence values ​​corresponding to different compounds were measured using a cell viability reagent (Promega, G6081) and a britelite plus luciferase assay reagent (PerkinElmer, 6066769). The relative receptor agonist activity of the compounds of the present invention was calculated using the formula with DHT as a positive control. At the same time, the EC was calculated by fitting the % activity value and the logarithm of the compound concentration to a nonlinear regression. 50 .

[0396] 3.2 Experimental Procedure

[0397] (1) Compound preparation

[0398] All test compounds were serially diluted 10 times in DMSO at a ratio of 1:3 from 10 mM to a final concentration of 0.000508053 mM, and each concentration was repeated 3 times. The positive control, dihydrotestosterone, was serially diluted 10 times in DMSO at a ratio of 1:3 from 0.1 mM to a final concentration of 5.08053E -06 Prepare 1000× positive control (0.1 mM dihydrotestosterone) and 1000× vehicle control (100% DMSO).

[0399] (2) Experimental operation

[0400] 1) HEK293T cells were cultured according to ATCC recommendations and assayed during the exponential growth phase;

[0401] 2) Remove the culture medium from the flask;

[0402] 3) Rinse cells with PBS;

[0403] 4) Add TrypLE solution to the flask and allow the cells to detach. Wash the cells once with complete growth medium.

[0404] 5) Pellet and wash the cells twice with PBS to remove phenol red, and resuspend them in culture medium to an appropriate concentration;

[0405] 6) Only cells with viability greater than 90% were used for the assay;

[0406] 7) 6*10 6 HEK293T cells were seeded into 100 mm culture dishes;

[0407] 8) Incubate cells at 37°C, 5% CO2 for 16 hours;

[0408] 9) Transfect the plasmid into cells and culture at 37°C, 5% CO2 for 5-6 hours;

[0409] 10) Use Echo655 to transfer 25 μL of compound dilution to a 384-well assay plate;

[0410] 11) HEK293T cells were seeded into a 384-well assay plate at 17,000 cells / well;

[0411] 12) Incubate cells at 37°C, 5% CO2 for 18-20 hours;

[0412] 13) Add 25 μL CellTiter-Fluor to each well of the 384-well plate. TM Cell viability reagent, and incubate cells at 37°C, 5% CO2 for 30 minutes;

[0413] 14) Read the values ​​using ex 380nm / em 510nm;

[0414] 15) Add 25 μL of britelite plus luciferase assay reagent to each well of a 384-well assay plate and record the luminescence value on an Envision plate reader.

[0415] (3) Data processing

[0416] Calculate the % activity according to the following formula:

[0417] % active cmpd -Activated Ave_PC ) / (Activated Ave_VC -Activated Ave_PC )*100

[0418] in:

[0419] Activated cmpd : the activation average of compound signals in the whole plate;

[0420] Activated Ave_PC : Average activation value of positive control in the whole plate;

[0421] Activated Ave_VC : The average activation value of negative control in the whole plate.

[0422] Calculate EC according to the following formula 50 :

[0423] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*Hillslope))

[0424] in:

[0425] X is the logarithm of the activator concentration; Y is the activity percentage; Bottom is the lowest platform value of the curve; Top is the highest platform value of the curve; Hillslope is the slope of the curve.

[0426] 3.3 Experimental Results

[0427] The androgen receptor agonist ability test results of the control compound and some of the example compounds are shown in Table 3 below.

[0428] Table 3. Test results of androgen receptor agonist ability of compounds

[0429] The above experimental results show that the propionamide compounds of the present invention do not have any androgen receptor agonist ability and are complete androgen receptor antagonists. Therefore, compared with partial antagonists, there is no need to worry about the side effects of androgen receptor agonism, and they are safer and more effective.

[0430] 4. In vitro anti-prostate cancer cell experiment

[0431] 4.1 Experimental Overview

[0432] This experiment investigated the in vitro antiproliferative activity of compounds of this invention against prostate cancer cells. Compound preparation was as follows: 20 mg of the test compound was weighed and completely dissolved in 200 μL of DMSO to prepare a stock solution. This stock solution was then diluted with complete culture medium to the desired test concentration. The common prostate cancer cell lines PC-3 and DU-145 were used in this experiment.

[0433] 4.2 Experimental Procedure

[0434] 1) PC-3 or DU-145 cells were inoculated in DMEM containing 10% fetal bovine serum, supplemented with 100 μg / mL of penicillin and 100 μg / mL of streptomycin, and placed in a cell culture incubator at 37°C with 5% CO2.

[0435] 2) Change the medium every 1-2 days, digest with 0.25% trypsin, passage, and collect cells;

[0436] 3) Cells in the logarithmic growth phase were cultured with DMEM containing 10% fetal bovine serum to form 3*10 4 / mL concentration of cell suspension, 3000 cells per well (100 μL), each concentration set up 4 parallel wells;

[0437] 4) After 72 hours of incubation, the culture medium containing the test substance was discarded and 150 μL of 0.5 mg / mL MTT solution was added to each well;

[0438] 5) Incubate at 37°C for 4 hours, discard the fully reacted MTT solution, add 150 μL of DMEM to each well, and shake thoroughly to mix;

[0439] 6) Detect the absorbance (OD value) using a microplate reader with a detection wavelength of 570 nm and a reference wavelength of 450 nm.

[0440] 4.3 Experimental Results

[0441] The inhibition results of the compound of Example 1 on PC-3 and DU-145 cell lines are shown in Table 4 below. FIG1 shows a curve showing the change of cell inhibition rate with compound concentration.

[0442] Table 4 Test results of the compound of Example 1 in the PC-3 and DU-145 cell line proliferation inhibition experiment

[0443] The above experimental results demonstrate that the propanamide compounds of the present invention exhibit excellent anti-cancer cell proliferation effects in cell-based experiments. The compound of Example 1 achieved inhibition rates exceeding 90% in both PC-3 and DU-145 prostate cancer cell lines, with the inhibition rate reaching as high as 99.7% in the DU-145 cell line. This suggests that the compound has great potential for development as an effective prostate cancer therapeutic.

[0444] The present invention has been described through the above embodiments, but it should be understood that the above embodiments are for illustrative and illustrative purposes only and are not intended to limit the present invention to the scope of the described embodiments. Those skilled in the art will also understand that the present invention is not limited to the above embodiments and that various variations and modifications may be made based on the teachings of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof: in R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano, nitro or C1-C6 haloalkyl; R4 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; R5 is hydrogen, C1-C6 alkyl, -C(O)R or -S(O)2R; R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9; R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, nitro, -NR8R9, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R 10 )-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy; R8, R9 and R 10 Each independently represents H or a C1-C6 alkyl group: Z is -O-, -S-, -S(O)-, -S(O)2-, -N(R 10 )-, -CH2-, or a bond; and W is CH or N.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein the compound has the following formula Ia: wherein R1, R2, R3, R4, R5, R6, R7, Z and W are as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein Z is -O-.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein R1, R2 and R3 are each independently C1-C6 alkyl, halogen, cyano or C1-C6 haloalkyl, preferably methyl, fluorine, chlorine, cyano or trifluoromethyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein R4 is C1-C6 alkyl, preferably methyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein R5 is hydrogen.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein R5 is -C(O)R, and R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 10 aryl or 5- to 12-membered heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano and -NR8R9.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, -C(O)C1-C6 alkyl, -C(O)NH2, -NHC(O)C1-C6 alkyl, -NHC(O)-C1-C6 haloalkyl, -NHC(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein W is CH.

10. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein the compound has Formula II: wherein R1, R2, R3, R5, R6, R7 and W are as defined in claim 1.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein: R1, R2 and R3 are each independently halogen, cyano or C1-C6 haloalkyl; R4 is a C1-C6 alkyl group; R5 is hydrogen, -C(O)R or -S(O)2R; R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9; R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl, cyano, -C(O)C1-C6 alkyl, -C(O)NR8R9, -N(R 10 )C(O)C1-C6 alkyl, -N(R 10 )C(O)-C1-C6 haloalkyl, -N(R 10 )C(O)OC1-C6 alkyl, -S(O)2-C1-C6 alkyl or -N(R 10 )-S(O)2-C1-C6 alkyl; R8, R9 and R 10 Each independently is H or C1-C4 alkyl: Z is -O-, -S-, -S(O)-, -S(O)2-, -N(R 10 )- or -CH2-; and W is CH or N.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein: R1, R2 and R3 are each independently halogen, cyano or C1-C6 haloalkyl; R4 is a C1-C6 alkyl group; R5 is hydrogen or -C(O)R; R is C1-C6 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 10 Aryl or 5- to 12-membered heteroaryl, wherein the heterocyclyl and heteroaryl groups contain 1-3 heteroatoms independently selected from N, O, or S, and the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, and -NR8R9; R6 and R7 are each independently hydrogen, halogen, C1-C6 haloalkyl or cyano; R8 and R9 are each independently H or C1-C4 alkyl; Z is -O-; and W is CH or N.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

15. Use of the compound according to any one of claims 1 to 13 or its pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, metabolite or isotopic derivative, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating diseases related to androgen levels.

16. The use according to claim 15, wherein the disease is selected from benign prostatic hyperplasia, prostate cancer, breast cancer, bladder cancer, ovarian cancer, uterine fibroids, abdominal aortic aneurysm, Kennedy's disease, amyotrophic lateral sclerosis, androgenic alopecia, acne and hirsutism.

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