A local acting androgen receptor antagonist and its application

Abstract

The present invention discloses a locally acting androgen receptor antagonist and its application, wherein the androgen receptor antagonist is a compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; the compound provided by the present invention has good skin stability, slow metabolism, and exerts an anti-androgenic alopecia effect, but has extremely poor stability in plasma, and can be directed and rapidly metabolized into an inactive metabolite, enzalutamide, to avoid systemic androgen antagonism side effects caused by systemic distribution. At the same time, the provided compound exhibits a hair growth promoting effect in a mouse alopecia model by transdermal administration.

Description

Technical Field

[0001] The present invention relates to novel substituted thioimidazolidinone compounds as topically acting androgen receptor antagonists, and pharmaceutical compositions comprising such compounds for the treatment of androgen receptor-related diseases or conditions, such as androgenic alopecia and acne. Background Art

[0002] Androgenic alopecia (AGA), also known as seborrheic alopecia and premature baldness, is divided into male pattern alopecia and female pattern alopecia. It is the most common non-scarring hair loss in clinical practice. AGA mainly occurs in late adolescence and is characterized by atrophy between hair follicles. The disease is mainly manifested by a receding hairline or a decrease and thinning of hair on the top of the head in male patients; female patients are mainly manifested by a decrease and thinning of hair on the top of the head. A few patients show diffuse thinning of hair without affecting the hairline. The 2010 epidemiological survey showed that the prevalence of AGA in men in my country was 21.3% and 6.0% in women, of which 29.7% of men had a family history and 19.2% of women. The incidence of male hair loss in China is increasing, and there is a trend of younger age. Young and middle-aged people have become the main force of the "hair loss army". 60% of men begin to lose their hair before the age of 25, and the proportion of those who begin to lose their hair before the age of 30 is nearly 84%. Qi J, Ho CH et al. reported that 50% of men and women are suffering from AGA to varying degrees. Androgenic alopecia often occurs in young men aged 17 to 20, with the peak incidence at around 30 years old. As age increases, the incidence decreases, but the symptoms worsen, and eventually turn into total baldness. Although AGA does not affect the patient's physical health, it affects the patient's mental health and quality of life. In severe cases, it can cause depression, anxiety, tension in interpersonal relationships, and sensitivity.

[0003] Androgenic alopecia is an androgen-dependent polygenic hereditary disease. Since Hamilton Norwood first proposed in 1942 that the occurrence of AGA is related to androgens, domestic and foreign scholars have focused their research on AGA on androgens and their metabolic enzymes in the scalp. However, the exact cause and pathogenesis of this disease have not yet been clarified. Some scholars have found that the incidence of the disease is also related to factors such as race, ethnicity, age, gender, living environment, living habits, mental and psychological factors, and bacterial infection (pityrosporum, Corynebacterium acnes, etc.). In recent years, the incidence of AGA has continued to increase and has shown a younger age. Therefore, treatment is urgently needed.

[0004] Male androgens are mainly synthesized by the testicles, including testosterone, dihydrotestosterone (DHT), androstenedione (DHEA) and dehydroepiandrosterone (ASD). Female androgens are mainly derived from the adrenal cortex. Testosterone and androstenedione can be reduced to DHT by 5α-reductase, and the affinity of DHT for androgen receptor (AR) is 5+ times that of testosterone. There are two 5α-reductase isozymes in the human body: 5α-reductase I and 5α-reductase II. Among them, 5α-reductase I is mainly distributed in the sebaceous glands and liver; 5α-reductase II is mainly distributed in the scalp hair follicles, epididymis, vas deferens, seminal vesicles, prostate and fetal genital skin. Studies have shown that scalp hair follicles are one of the target organs of androgens. Hair biopsy specimens of male AGA patients were taken, and it was found that the activity of 5α-reductase in the hair loss area on the top of the head was significantly higher than that in the non-hair loss area on the occipital part. In addition, studies have shown that AR is highly expressed in the hair follicles in the hair loss area on the top of the head, thereby accelerating hair loss in this area. DHT has a strong affinity for AR. After binding to AR, it enters the cell nucleus, inhibits the adenylate cyclase of the hair follicles, reduces the synthesis of cyclic nucleotides and related proteins, and causes the hair to enter the resting phase early. It also inhibits the growth of hair follicles, shrinks them, stimulates the proliferation of sebaceous glands and oil secretion, further reduces the volume of hair follicles and gradually disappears, thereby promoting hair shedding.

[0005] There are many AGA patients at present, but there are still few drugs for AGA. Currently, only finasteride and minoxidil are approved for the treatment of AGA, and most other drugs are used off-label. Existing AGA therapies are effective, but they also bring many side effects, such as male sexual dysfunction caused by finasteride, propylene glycol allergy and orthostatic hypotension caused by minoxidil. These side effects limit the clinical use of the corresponding drugs. Therefore, there is still an urgent need for AGA drugs that are locally effective, avoid systemic distribution, have low side effects, and are easy to use. Summary of the invention

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

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

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

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

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

[0011]

[0012] in:

[0013] R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C 10 Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH2) n -cycloalkyl, substituted or unsubstituted-(CH2) n -heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5~C 10 Alkyl, substituted alkenyl, substituted alkynyl, substituted -(CH2) n -cycloalkyl, substituted-(CH2) n -heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5);

[0014] R4, R5, R7, and R8 are each independently selected from hydrogen or C1-C8 alkyl;

[0015] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0016] R2 and R3 are each independently selected from cyano, nitro, alkyl, haloalkyl, hydroxyl, mercapto, halogen, C1-C8 alkoxy or C1-C8 haloalkoxy;

[0017] X and Y independently select N or CR6;

[0018] R6 is selected from hydrogen, halogen, C1-C8 alkyl, cycloalkyl or heterocyclic group.

[0019] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted -(CH2) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5 to C8 alkyl, substituted C2 to C8 alkenyl, substituted C2 to C8 alkynyl, substituted -(CH2) n -3- to 8-membered cycloalkyl, substituted -(CH2) n -3-8 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0020] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted -(CH2) n-3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0021] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0022] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n-3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, halogen, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0023] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted The substituted ethyl group is substituted by one or more hydroxyl groups, halogen groups, C1-C4 alkoxy groups, 3-6-membered cycloalkyl groups, 3-6-membered heterocycloalkyl groups or NR4(R5); the substituted n-propyl group, substituted n-butyl group, substituted isobutyl group, substituted sec-butyl group, substituted cyclopropyl group, substituted Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced or replaced wherein the substitution is one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0024] In some embodiments, R1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,

[0025]

[0026] In some embodiments, R1 is selected from

[0027]

[0028] In some embodiments, R7 and R8 are each independently selected from hydrogen or C1-C6 alkyl.

[0029] In some embodiments, R7 and R8 are each independently selected from hydrogen or C1-C4 alkyl.

[0030] In some embodiments, R7, R8 are each independently selected from hydrogen, methyl, ethyl or isopropyl.

[0031] In some embodiments, R7 is selected from hydrogen, methyl, or isopropyl.

[0032] In some embodiments, R8 is selected from methyl, ethyl or isopropyl.

[0033] In some embodiments, n is selected from 0, 1, 2, 3, or 4.

[0034] In some embodiments, n is selected from 0, 1 or 2.

[0035] In some embodiments, R4 and R5 are each independently selected from hydrogen or C1-C6 alkyl.

[0036] In some embodiments, R4 and R5 are each independently selected from hydrogen or C1-C4 alkyl.

[0037] In some embodiments, R4, R5 are each independently selected from hydrogen, methyl or ethyl.

[0038] In some embodiments, R2 and R3 are each independently selected from cyano, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, hydroxyl, thiol, halogen, C1-C4 alkoxy or halogenated C1-C4 alkoxy.

[0039] In some embodiments, R2 and R3 are each independently selected from C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, thiol, cyano, and halogen.

[0040] In some embodiments, R2, R3 are each independently selected from cyano, methyl, trifluoromethyl, fluoro or chloro.

[0041] In some embodiments, R2, R3 are each independently selected from cyano, trifluoromethyl, fluoro or chloro.

[0042] In some embodiments, R2 is selected from cyano and R3 is selected from trifluoromethyl.

[0043] In some embodiments, X and Y are each independently selected from N or CR6.

[0044] In some embodiments, X and Y are both selected from CR6.

[0045] In some embodiments, R6 is selected from hydrogen, halogen, C1-C8 alkyl, cycloalkyl or heterocyclyl; in some embodiments, R6 is selected from hydrogen, halogen, C1-C4 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl; in some embodiments, R6 is selected from hydrogen or halogen; in some embodiments, R6 is selected from hydrogen, fluorine or chlorine; in some embodiments, R6 is selected from hydrogen or fluorine.

[0046] In some embodiments, X is selected from CH.

[0047] In some embodiments, Y is selected from CF.

[0048] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II),

[0049]

[0050] in:

[0051] R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C 10 Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH2) n -cycloalkyl, substituted or unsubstituted-(CH2) n-heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5~C 10 Alkyl, substituted alkenyl, substituted alkynyl, substituted -(CH2) n -cycloalkyl, substituted-(CH2) n -heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5);

[0052] R4, R5, R7, and R8 are each independently selected from hydrogen or C1-C8 alkyl;

[0053] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0054] R2 and R3 are each independently selected from cyano, nitro, alkyl, haloalkyl, hydroxyl, mercapto, halogen, C1-C8 alkoxy or C1-C8 haloalkoxy;

[0055] R6 is selected from hydrogen, halogen, C1-C8 alkyl, cycloalkyl or heterocyclic group.

[0056] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted -(CH2) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5 to C8 alkyl, substituted C2 to C8 alkenyl, substituted C2 to C8 alkynyl, substituted -(CH2) n -3- to 8-membered cycloalkyl, substituted -(CH2) n-3-8 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0057] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0058] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n-3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0059] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, halogen, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0060] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted The substituted ethyl group is substituted by one or more hydroxyl groups, halogen groups, C1-C4 alkoxy groups, 3-6-membered cycloalkyl groups, 3-6-membered heterocycloalkyl groups or NR4(R5); the substituted n-propyl group, substituted n-butyl group, substituted isobutyl group, substituted sec-butyl group, substituted cyclopropyl group, substituted Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced or replaced wherein the substitution is one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0061] In some embodiments, R1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,

[0062]

[0063]

[0064] In some embodiments, R1 is selected from

[0065]

[0066] In some embodiments, R7 and R8 are each independently selected from hydrogen or C1-C6 alkyl.

[0067] In some embodiments, R7 and R8 are each independently selected from hydrogen or C1-C4 alkyl.

[0068] In some embodiments, R7, R8 are each independently selected from hydrogen, methyl, ethyl or isopropyl.

[0069] In some embodiments, R7 is selected from hydrogen, methyl, or isopropyl.

[0070] In some embodiments, R8 is selected from methyl, ethyl or isopropyl.

[0071] In some embodiments, n is selected from 0, 1, 2, 3, or 4.

[0072] In some embodiments, n is selected from 0, 1 or 2.

[0073] In some embodiments, R4 and R5 are each independently selected from hydrogen or C1-C6 alkyl.

[0074] In some embodiments, R4 and R5 are each independently selected from hydrogen or C1-C4 alkyl.

[0075] In some embodiments, R4, R5 are each independently selected from hydrogen, methyl or ethyl.

[0076] In some embodiments, R2 and R3 are each independently selected from cyano, nitro, C1-C4 alkyl, halogenated C1-C4 alkyl, hydroxyl, thiol, halogen, C1-C4 alkoxy or halogenated C1-C4 alkoxy.

[0077] In some embodiments, R2 and R3 are each independently selected from C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, thiol, cyano, and halogen.

[0078] In some embodiments, R2, R3 are each independently selected from cyano, methyl, trifluoromethyl, fluoro or chloro.

[0079] In some embodiments, R2, R3 are each independently selected from cyano, trifluoromethyl, fluoro or chloro.

[0080] In some embodiments, R2 is selected from cyano and R3 is selected from trifluoromethyl.

[0081] In some embodiments, R6 is selected from hydrogen, halogen, C1-C8 alkyl, cycloalkyl or heterocyclyl.

[0082] In some embodiments, R6 is selected from hydrogen, halogen, C1-C4 alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl.

[0083] In some embodiments, R6 is selected from hydrogen or halogen; in some embodiments, R6 is selected from hydrogen, fluorine, or chlorine.

[0084] In some embodiments, R6 is selected from hydrogen or fluoro.

[0085] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III),

[0086]

[0087] in:

[0088] R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C 10 Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted -(CH2) n -cycloalkyl, substituted or unsubstituted-(CH2) n -heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5~C 10 Alkyl, substituted alkenyl, substituted alkynyl, substituted -(CH2) n -cycloalkyl, substituted-(CH2) n -heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); R4, R5, R7, R8 are each independently selected from hydrogen or C1~C8 alkyl; n is selected from 0, 1, 2, 3, 4, 5 or 6.

[0089] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted -(CH2) n -3 to 8 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3 to 8 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5 to C8 alkyl, substituted C2 to C8 alkenyl, substituted C2 to C8 alkynyl, substituted -(CH2) n -3- to 8-membered cycloalkyl, substituted -(CH2) n -3-8 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0090] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n-3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0091] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n -3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, mercapto, cyano, halogen, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, alkyl, alkoxy, cycloalkyl, heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0092] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted C5-C6 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted -(CH2) n -3-6 membered cycloalkyl, substituted or unsubstituted -(CH2) n-3-6 membered heterocycloalkyl, substituted or unsubstituted -CH(R7)OC(O)OR8 or substituted or unsubstituted -CH(R7)OC(O)NH(R8); wherein the substituted ethyl is substituted by one or more hydroxyl, halogen, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); the substituted n-propyl, substituted n-butyl, substituted isobutyl, substituted sec-butyl, substituted C5-C6 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted -(CH2) n -3-6 membered cycloalkyl, substituted -(CH2) n -3-6 membered heterocycloalkyl, substituted -CH(R7)OC(O)OR8 or substituted -CH(R7)OC(O)NH(R8), wherein the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R7, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0093] In some embodiments, R1 is selected from substituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted allyl, substituted or unsubstituted propargyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted Substituted or unsubstituted The substituted ethyl group is substituted by one or more hydroxyl groups, halogen groups, C1-C4 alkoxy groups, 3-6-membered cycloalkyl groups, 3-6-membered heterocycloalkyl groups or NR4(R5); the substituted n-propyl group, substituted n-butyl group, substituted isobutyl group, substituted sec-butyl group, substituted cyclopropyl group, substituted Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced Replaced or replaced wherein the substitution is one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or NR4(R5); wherein R4, R5, R8 are each independently selected from hydrogen or C1-C8 alkyl.

[0094] In some embodiments, R1 is selected from n-propyl, n-butyl, isobutyl, allyl, propargyl, cyclopropyl,

[0095]

[0096] In some embodiments, R1 is selected from

[0097]

[0098] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0099]

[0100] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0101]

[0102] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0103]

[0104] In some embodiments, the compound represented by formula (I) is selected from the following compounds:

[0105]

[0106] In order to solve the above-mentioned second technical problem, the present invention discloses a pharmaceutical composition, which comprises (i) a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in the above-mentioned first technical problem, and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0107] In order to solve the third technical problem mentioned above, the present invention discloses the use of the compound of formula (I) or its stereoisomer, or its pharmaceutically acceptable salt, described in the first technical problem, or the pharmaceutical composition described in the second technical problem in the preparation of a drug for preventing diseases or conditions mediated by androgen or androgen receptor activity, reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity, or treating diseases or conditions mediated by androgen or androgen receptor activity.

[0108] In some embodiments, the disease or condition mediated by androgen or androgen receptor activity is selected from prostate cancer, acne, or alopecia.

[0109] In order to solve the fourth technical problem mentioned above, the present invention discloses a method for preventing diseases or conditions mediated by androgen or androgen receptor activity in mammals, reducing the progression of diseases or conditions mediated by androgen or androgen receptor activity in mammals, and treating diseases or conditions mediated by androgen or androgen receptor in mammals, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula (I) or its stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second technical problem, as described in the first technical problem mentioned above.

[0110] In some embodiments, the mammal is a human.

[0111] Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0112] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence state of the particular atom is normal and the compound after the substitution is stable.

[0113] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0114] In this article, C n ~C m, means that the moiety has an integer number of carbon atoms in a given range. For example, "C1-C6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, C1-C3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

[0115] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0116] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a covalent bond.

[0117] When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a covalent bond, it means that the structure is actually AZ.

[0118] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

[0119] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0120] The term "hydroxy" refers to an -OH group.

[0121] The term "mercapto" refers to a -SH group.

[0122] The term "amino" refers to a -NH2 group.

[0123] The term "cyano" refers to a -CN group.

[0124] The term "nitro" refers to a -NO2 group.

[0125] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1- "C6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above. For another example, the term "C 1-The term "C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms (eg, methyl, ethyl, propyl and isopropyl).

[0126] The term "alkoxy" refers to an alkyl group as described above with a specific number of carbon atoms connected by an oxygen bridge. C1-C6 alkoxy groups include C1, C2, C3, C4, C5 and C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.

[0127] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0128] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡CC≡CH), etc.

[0129] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, bicyclo [1.1.1] penta-1-yl, etc. For example, C3 to C4 cycloalkyl includes cyclopropyl and cyclobutyl.

[0130] The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 10 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen, or a 4 to 6 ring. Non-limiting examples of heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, 3,4-dihydropyranyl, 3,6-dihydropyranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.3] heptane etc.

[0131] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 10-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen, or a 4 to 6-membered ring. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiene, thiazolinyl, and oxetanyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, and tetrahydrofuranyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferably, the monocyclic heterocycloalkyl has 5 or 6 ring atoms.

[0132] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0133] i. To inhibit a disease or disease state, i.e. to curb its development;

[0134] ii. To alleviate a disease or condition, even if the disease or condition regresses.

[0135] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0136] The term "therapeutically effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0137] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" refers to salts of compounds of the present application, prepared from compounds with specific substituents found in the present application and relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compounds with a suitable base. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compounds with a suitable acid. Certain specific compounds of the present application contain basic and acidic functional groups, and thus can be converted into either base or acid addition salts.

[0139] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0140] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0141] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0142] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0143] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0144] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0145] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

[0146] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0147] The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen, such as d3-methyl, which means that all three hydrogen atoms on the methyl group are replaced by deuterium atoms. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described later may but does not necessarily occur, and the description includes the situation in which the event or situation occurs and the situation in which the event or situation does not occur.

[0148] The present application also includes isotope-labeled compounds of the present application that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I, and 36Cl, etc.

[0149] Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H and 14C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15O, 13N, 11C, and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present invention can generally be prepared by replacing an isotopically labeled reagent with an isotopically labeled reagent by the following procedures similar to those disclosed in the schemes and / or embodiments below.

[0150] In addition, the use of heavier isotopes such as deuterium (i.e. 2 H)) substitution may provide certain therapeutic advantages arising from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.

[0151] The compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be separated in optically pure form or racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0152] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0153] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0154] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0155] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0156] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0157] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0158] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0159] The compounds of the present application, their stereoisomers and pharmaceutically acceptable salts thereof are locally acting androgen antagonists. At the same time, the compounds have good skin stability, slow metabolism, and play an anti-androgenic alopecia effect, but have extremely poor stability in plasma and can be directed and rapidly metabolized to an inactive metabolite, enzalutamide (CAS: 1242137-15-0), avoiding systemic androgen antagonism side effects caused by systemic distribution. The provided compounds are administered transdermally and show a hair growth promoting effect in a mouse alopecia model. BRIEF DESCRIPTION OF THE DRAWINGS

[0160] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0161] Figure 1 C57BL / 6 mice were scored for hair growth.

[0162] Figure 2 This is the hair growth condition of mice (Application Example 5).

[0163] Figure 3 The figure is a graph of hair growth of mice on day 26 and a curve of changes in body weight and hair coverage (Application Example 6). DETAILED DESCRIPTION

[0164] For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present application. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. All reagents used in the present application are commercially available and can be used without further purification.

[0165] Example 1: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid propyl ester (Compound 1)

[0166]

[0167] Step 1: Synthesis of compound 1-1

[0168] Add 150mL N,N-dimethylformamide and 15mL water to a 250mL three-necked flask, and add 10g 2-fluoro-4-bromobenzoic acid, 7.25g 2-methylalanine, 15.8g potassium carbonate, 1.7g cuprous iodide, 1.2g 2-acetylcyclohexanone and 0.8g triethylamine in sequence. Heat and stir at 110℃ for 6h, add 500mL water to dilute, and adjust the pH to 3-4 with citric acid. Extract with ethyl acetate 3 times, combine the organic phases, and wash with saturated brine 3 times. The organic phase is dried over anhydrous sodium sulfate and concentrated, and 50mL dichloromethane is added to the obtained solid crude product. Stir at room temperature for 1h and filter, and the filter cake is washed with dichloromethane. Collect and dry the filter cake to obtain 9.3g compound 1-1.

[0169] Step 2: Synthesis of compound 1-2

[0170] Add 100mL of methanol and 13g of compound 1-1 prepared in step 1 above to a 250mL three-necked flask, stir to dissolve and cool in an ice bath. Slowly add 25.6g of thionyl chloride dropwise under ice bath conditions, and heat to reflux for reaction after the addition is complete. After the reaction is complete, turn off the heating, add 50mL of toluene after cooling to room temperature, and concentrate under reduced pressure. The resulting residue is redissolved with 300mL of ethyl acetate, washed once with saturated brine, and then washed 3 times with saturated sodium bicarbonate aqueous solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain 11.3g of compound 1-2.

[0171] Step 3: Synthesis of Compound 1-3

[0172] 5 mL of dimethyl sulfoxide, 10 mL of isopropyl acetate, 5 g of compound 1-2 prepared in step 2 above and 8.9 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile were added to a 50 mL three-necked flask in sequence, and the mixture was heated and stirred at 90 ° C for 20 h. Turn off the heating, cool to room temperature naturally, add 50 mL of water to dilute the reaction solution, and extract with ethyl acetate 3 times. Combine the organic phases, wash 3 times with saturated brine, and concentrate the organic phase after drying over anhydrous sodium sulfate. Add 35 mL of methanol to the resulting oil and stir at room temperature for 2 h. Filter, collect the filter cake and dry it, and obtain 5.8 g of compound 1-3.

[0173] Step 4: Synthesis of Compound 1-4

[0174] 3.8 g of compound 1-3 prepared in step 3 above was dissolved in 15 mL of tetrahydrofuran, and 15 mL of an aqueous solution containing 0.68 g of sodium hydroxide was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 50 mL of water was added for dilution, the pH was adjusted to 3-4 with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, and the organic phases were concentrated to obtain 3.0 g of compound 1-4.

[0175] Step 5: Synthesis of compound 1

[0176] 0.2 g of compound 1-4 prepared in step 4 above and 5 mL of n-propanol were added to a 25 mL round-bottom flask, and 0.158 g of thionyl chloride was added dropwise under ice bath conditions. After the addition was complete, the ice bath was removed, and the mixture was heated to 45 ° C and stirred for 6 h. The mixture was concentrated under reduced pressure, and the obtained oil was redissolved in 30 mL of ethyl acetate and washed 3 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography to obtain 0.18 g of a white solid.

[0177] 1 H NMR(400MHz,Chloroform-d)δ8.15(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(s,1H),7.85(d,J=8.3H z,1H),7.25–7.15(m,2H),4.37(t,J=6.6Hz,2H),1.90–1.77(m,2H),1.64(s,6H),1.07(t,J=7.4Hz,3H).

[0178] MS (ESI, [M+H] + )m / z:494.2.

[0179] Example 2: Preparation of butyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoate (Compound 2)

[0180]

[0181] Referring to the method of step 5 of example 1, compound 2 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with n-butanol.

[0182] 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(s,1H),7.85(dd,J=8.3,1.7Hz,1H) ,7.26–7.15(m,2H),4.41(t,J=6.6Hz,2H),1.86–1.73(m,2H),1.64(s,6H),1.56–1.47(m,2H),1.01(t,J=7.4Hz,3H).

[0183] MS (ESI, [M+H] + )m / z:508.7.

[0184] Example 3: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid isobutyl ester (Compound 3)

[0185]

[0186] Referring to the method of step 5 of example 1, compound 3 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with neobutanol.

[0187] 1 H NMR(400MHz,Chloroform-d)δ8.15(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.98(s,1H),7.86(d,J=8.1H z,1H),7.27–7.15(m,2H),4.19(d,J=6.4Hz,2H),2.19–2.06(m,1H),1.64(s,6H),1.06(d,J=6.7Hz,6H).

[0188] MS (ESI, [M+H] + )m / z:508.2.

[0189] Example 4: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid cyclopropylmethyl ester (Compound 4)

[0190]

[0191] Referring to the method of step 5 of example 1, compound 4 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with cyclopropylmethanol.

[0192] 1 H NMR(400MHz,Chloroform-d)δ8.16(t,J=8.0Hz,1H),8.03–7.96(m,2H),7.85(d,J=8.1Hz,1H),7.27–7.15( m,2H),4.25(d,J=7.2Hz,2H),1.66(s,6H),1.35-1.30(m,1H),0.67(d,J=7.9Hz,2H),0.42(d,J=5.0Hz,2H).

[0193] MS (ESI, [M+H] + )m / z:506.1.

[0194] Example 5: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid cyclopropyl ester (Compound 5)

[0195]

[0196] Referring to the method of step 5 of example 1, compound 5 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with cyclopropanol.

[0197] 1 H NMR(400MHz,Chloroform-d)δ8.11(t,J=8.0Hz,1H),8.01(d,J=8.3Hz,1H),7.97(s,1H),7. 85(d,J=8.2Hz,1H),7.25–7.13(m,2H),4.51–4.40(m,1H),1.63(s,6H),0.93–0.81(m,4H).

[0198] MS (ESI, [M+H] + )m / z:492.3.

[0199] Example 6: Preparation of (R)-2,3-dihydroxypropyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxyimidazolidin-1-yl)-2-fluorobenzoate (Compound 6)

[0200]

[0201] Step 1: Preparation of compound 6-1

[0202] 5 mL of isopropyl acetate, 0.15 g of compound 1-4 obtained in step 4 of Example 1, and 1 mL of thionyl chloride were added to a 25 mL round-bottom flask, heated and stirred at 80 ° C for 2 h, and the heating was stopped. The reaction solution was cooled to room temperature and concentrated, and the residue was redissolved with 5 mL of isopropyl acetate, 0.19 g of diisopropylethylamine and 0.08 g of (S)-glyceryl acetone were added, and the reaction was stirred at room temperature overnight. After the reaction was completed, 20 mL of ethyl acetate was added to dilute and washed 3 times with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated, and the resulting crude oil was purified by column chromatography to obtain 0.13 g of compound 6-1.

[0203] MS (ESI, [M+H] + )m / z:566.2.

[0204] Step 2: Preparation of compound 6

[0205] 0.13 g of compound 6-1 obtained in step 1 above, 5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid were added to a 25 mL round-bottom flask and stirred at room temperature for 2 h. The reaction solution was concentrated and the obtained oil was purified by column chromatography to obtain 97 mg of compound 6.

[0206] 1 H NMR (400MHz, Chloroform-d) δ8.17(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(s,1H),7.85(d,J=7.8Hz,1H),7.27–7.15(m,2H),4.54(dd,J =11.5,4.5Hz,1H),4.47(dd,J=11.5,6.0Hz,1H),4.17–4.09(m,1H),3.85(dd,J=11.4,3.8Hz,1H),3.76(dd,J=11.3,5.7Hz,1H),1.64(s,6H).

[0207] MS (ESI, [M+H] + )m / z:526.4.

[0208] Example 7: Preparation of (S)-2,3-dihydroxypropyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-sulfoxyimidazolidin-1-yl)-2-fluorobenzoate (Compound 7)

[0209]

[0210] Step 1: Preparation of compound 7-1

[0211] Referring to the method of step 1 of example 6, compound 1-4 obtained in step 4 of example 1 was reacted with (R)-glycerol acetonide to prepare compound 7-1.

[0212] MS (ESI, [M+H] + )m / z:566.2.

[0213] Step 2: Preparation of compound 7

[0214] Referring to the method of step 1 of Example 6, compound 7 was prepared by reacting compound 7-1 obtained in step 1 with trifluoroacetic acid.

[0215] 1H NMR (400MHz, Chloroform-d) δ8.17(t,J=8.0Hz,1H),8.02(d,J=8.4Hz,1H),7.97(s,1H),7.85(d,J=8.3Hz,1H),7.27–7.16(m,2H),4.54(dd,J =11.5,4.4Hz,1H),4.47(dd,J=11.3,6.2Hz,1H),4.22–4.07(m,1H),3.85(dd,J=11.4,3.6Hz,1H),3.76(dd,J=11.2,5.6Hz,1H),1.65(s,6H).

[0216] MS (ESI, [M+H] + )m / z:526.6.

[0217] Example 8: Preparation of 2-(dimethylamino)ethyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxyimidazolidin-1-yl)-2-fluorobenzoate (Compound 8)

[0218]

[0219] Referring to the method of step 1 of Example 6, compound 8 was prepared by reacting compound 1-4 obtained in step 4 of Example 1 with N,N-dimethylethanolamine.

[0220] 1 H NMR (400MHz, Chloroform-d) δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=1.9Hz,1H),7.85(dd,J =8.3,2.0Hz,1H),7.24–7.14(m,2H),4.50(t,J=5.7Hz,2H),2.75(t,J=5.7Hz,2H),2.36(s,6H),1.63(s,6H).

[0221] MS (ESI, [M+H] + )m / z:523.3.

[0222] Example 9: Preparation of 2-(diethylamino)ethyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxyimidazolidin-1-yl)-2-fluorobenzoate (Compound 9)

[0223]

[0224] Referring to the method of step 1 of example 6, compound 9 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with N,N-diethylethanolamine.

[0225] 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.0Hz,1H ),7.26–7.13(m,2H),4.46(t,J=6.2Hz,2H),2.88(t,J=6.2Hz,2H),2.66(q,J=7.1Hz,4H),1.64(s,6H),1.09(t,J=7.1Hz,6H).

[0226] MS (ESI, [M+H] + )m / z:551.2.

[0227] Example 10: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxyimidazol-1-yl)-2-fluorobenzoic acid 2-morpholinoethyl ester (Compound 10)

[0228]

[0229] Referring to the method of step 1 of example 6, compound 10 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with N-hydroxyethylmorpholine.

[0230] 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(s,1H),7.85(dd,J=8.3,2.0Hz,1H),7. 25–7.12(m,2H),4.54(t,J=5.7Hz,2H),3.75(t,J=4.7Hz,4H),2.80(t,J=5.7Hz,2H),2.60(t,J=4.6Hz,4H),1.64(s,6H).

[0231] MS (ESI, [M+H] + )m / z:565.1.

[0232] Example 11: Preparation of (S)-tetrahydrofuran-3-yl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 11)

[0233]

[0234] Referring to the method of step 5 of example 1, compound 1-4 obtained in step 4 of example 1 was reacted with (S)-3-hydroxytetrahydrofuran to prepare compound 11.

[0235] 1 H NMR (400MHz, Chloroform-d) δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2. 1Hz,1H),7.26–7.14(m,2H),5.69–5.55(m,1H),4.13–3.90(m,4H),2.42–2.26(m,1H),2.25–2.15(m,1H),1.64(s,6H).

[0236] MS (ESI, [M+H] + )m / z:522.3.

[0237] Example 12: Preparation of (R)-tetrahydrofuran-3-yl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 12)

[0238]

[0239] Referring to the method of step 5 of example 1, compound 1-4 obtained in step 4 of example 1 was reacted with (R)-3-hydroxytetrahydrofuran to prepare compound 12.

[0240] 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz,1H) ,7.26–7.10(m,2H),5.62(ddt,J=6.4,4.2,1.9Hz,1H),4.10–3.91(m,4H),2.40–2.26(m,1H),2.26–2.14(m,1H),1.64(s,6H).

[0241] MS (ESI, [M+H] + )m / z:522.3

[0242] Example 13: Preparation of oxetane-3-yl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 13)

[0243]

[0244] Referring to the method of step 5 of example 1, compound 13 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-hydroxyoxetane.

[0245] 1 H NMR(400MHz,Chloroform-d)δ8.18(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.8 5(dd,J=8.3,2.1Hz,1H),7.24(m,2H),5.80–5.69(m,1H),5.04(m,2H),4.88–4.78(m,2H),1.65(s,6H).

[0246] MS (ESI, [M+H] + )m / z:508.6

[0247] Example 14: Preparation of (oxetane-3-yl)methyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 14)

[0248]

[0249] Referring to the method of step 5 of example 1, compound 14 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-hydroxymethyloxetane.

[0250] 1 H NMR (400MHz, Chloroform-d) δ8.16(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8. 2,2.1Hz,1H),7.25–7.13(m,2H),4.90(dd,J=7.9,6.3Hz,2H),4.69–4.55(m,4H),3.55–3.39(m,1H),1.64(s,6H).

[0251] MS (ESI, [M+H] + )m / z:522.4

[0252] Example 15: Preparation of tetrahydropyran-4-yl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxyimidazolidin-1-yl)-2-fluorobenzoate (Compound 15)

[0253]

[0254] Referring to the method of step 5 of example 1, compound 15 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with tetrahydropyran-4-ol.

[0255] 1 H NMR(400MHz,Chloroform-d)δ8.15(t,J=8.0Hz,1H),8.02(d,J=8.2Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.2,2.1Hz,1H), 7.25-7.17(m,2H),5.39–5.21(m,1H),4.09–3.92(m,2H),3.74–3.61(m,2H),2.15–2.02(m,2H),1.94–1.79(m,2H),1.64(s,6H).

[0256] MS (ESI, [M+H] + )m / z:536.1

[0257] Example 16: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester (Compound 16)

[0258]

[0259] 0.2 g of compound 1-4 obtained in step 4 of Example 1, 5 mL of N,N-dimethylformamide, 0.25 g of 2-iodobutane and 0.15 g of potassium carbonate were added to a 25 mL round-bottom flask in sequence, and the mixture was heated at 60°C for overnight reaction. After the reaction was completed, the heating was removed, the mixture was cooled to room temperature, and 25 mL of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (15 mL × 3), the organic phases were combined, and washed with saturated brine (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to obtain 0.34 g of a white solid.

[0260] 1H NMR(400MHz,Chloroform-d)δ8.13(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz ,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J=6.3Hz,3H),1.02(t,J=7.5Hz,3H).

[0261] MS (ESI, [M+H] + )m / z:508.4.

[0262] Example 17: Preparation of (R)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester (Compound 17)

[0263]

[0264] Referring to the method of step 5 of example 1, compound 1-4 obtained in step 4 of example 1 was reacted with (R)-2-butanol to prepare compound 17.

[0265] 1 H NMR(400MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.2,2.1Hz ,1H),7.25–7.11(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.65(s,6H),1.38(d,J=6.4Hz,3H),1.01(t,J=7.3Hz,3H).

[0266] MS (ESI, [M+H] + )m / z:508.3.

[0267] Example 18: Preparation of (S)-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoic acid sec-butyl ester (Compound 18)

[0268]

[0269] Referring to the method of step 5 of example 1, compound 18 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with (S)-2-butanol.

[0270] 1 H NMR(400MHz,Chloroform-d)δ8.13(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz ,1H),7.25–7.10(m,2H),5.25–5.11(m,1H),1.85–1.67(m,2H),1.64(s,6H),1.39(d,J=6.3Hz,3H),1.02(t,J=7.5Hz,3H).

[0271] MS (ESI, [M+H] + )m / z:508.3.

[0272] Example 20: Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoic acid pentyl-3-yl ester (Compound 20)

[0273]

[0274] Referring to the method of step 5 of example 1, compound 20 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-pentanol.

[0275] 1 H NMR(600MHz,Chloroform-d)δ8.14(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(s,1H),7.88–7.82(m ,1H),7.25–7.14(m,2H),5.10(p,J=6.3Hz,1H),1.81–1.70(m,4H),1.64(s,6H),1.00(t,J=7.4Hz,6H).

[0276] MS (ESI, [M+H] + )m / z:522.4.

[0277] Example 21: Preparation of 2-methylbutyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 21)

[0278]

[0279] Step 1:

[0280] Add 0.5g of compound 1-4 obtained in step 4 of Example 1 and 4mL of thionyl chloride to a 25mL round-bottom flask, and heat to reflux for 2h. After concentration, redissolve in 2mL of anhydrous tetrahydrofuran, and dropwise add to 3mL of anhydrous tetrahydrofuran solution containing 0.29g of 2-methyl-2-butanol and 0.34g of triethylamine under ice-water bath conditions. After the addition is complete, stir at room temperature for 1h. Add 30mL of ethyl acetate and wash 3 times with saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated, and the resulting yellow oil is purified by column chromatography to obtain 0.43g of the target product as a white solid.

[0281] 1 H NMR(600MHz,Chloroform-d)δ8.07(t,J=8.0Hz,1H),8.01(d,J=8.3Hz,1H),7.97(s,1H),7.85(d,J=8.3Hz,1H),7.1 9(d,J=8.4Hz,1H),7.15(d,J=10.3Hz,1H),1.95(q,J=7.4Hz,2H),1.63(s,6H),1.61(s,6H),1.01(t,J=7.5Hz,3H).

[0282] MS (ESI, [M+H] + )m / z:522.6.

[0283] Example 22: Preparation of 3-methylpentyl-3-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 22)

[0284]

[0285] Referring to the method of step 1 of Example 21, compound 22 was prepared by reacting compound 1-4 obtained in step 4 of Example 1 with 3-methyl-3-pentanol.

[0286] 1H NMR (400MHz, Chloroform-d) δ8.07(t,J=8.1Hz,1H),8.01(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2 .1Hz,1H),7.22–7.12(m,2H),2.12–2.00(m,2H),1.99–1.86(m,2H),1.63(s,6H),1.57(s,3H),0.98(t,J=7.5Hz,6H).

[0287] MS (ESI, [M+H] + )m / z:536.1.

[0288] Example 23: Preparation of 3-ethylpentyl-3-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 23)

[0289]

[0290] Referring to the method of step 1 of example 21, compound 23 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 3-ethyl-3-pentanol.

[0291] 1 H NMR(400MHz,Chloroform-d)δ8.06(t,J=8.0Hz,1H),8.02(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.8 6(dd,J=8.2,1.9Hz,1H),7.22–7.11(m,2H),2.01(q,J=7.5Hz,6H),1.64(s,6H),0.94(t,J=7.5Hz,9H).

[0292] MS (ESI, [M+H] + )m / z:550.4.

[0293] Example 24: Preparation of 1-methylcyclobutyl 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 24)

[0294]

[0295] Referring to the method of step 1 of example 21, compound 24 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 1-methylcyclobutanol.

[0296] 1 H NMR (400MHz, Chloroform-d) δ8.11(t,J=8.0Hz,1H),8.01(d,J=8.3Hz,1H),7.97(d,J=2.0Hz,1H),7.85(dd,J=8.3,2.1Hz,1H ),7.24–7.13(m,2H),2.55–2.43(m,2H),2.35–2.25(m,2H),1.97–1.86(m,1H),1.83–1.73(m,1H),1.71(s,3H),1.63(s,6H).

[0297] MS (ESI, [M+H] + )m / z:520.4.

[0298] Example 25: Preparation of 1-methylcyclopentyl-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 25)

[0299]

[0300] Referring to the method of step 1 of example 21, compound 25 was prepared by reacting compound 1-4 obtained in step 4 of example 1 with 1-methylcyclopentanol.

[0301] 1 H NMR(400MHz,Chloroform-d)δ8.08(t,J=8.1Hz,1H),8.01(d,J=8.2Hz,1H),7.97(d,J=2.0Hz,1H),7.85(d d,J=8.3,2.1Hz,1H),7.17(m,2H),2.37–2.25(m,2H),1.89–1.78(m,4H),1.74(s,5H),1.65–1.60(m,6H).

[0302] MS (ESI, [M+H] + )m / z:534.1.

[0303] Example 26: Preparation of 2-methylbutyl 4-(3-(4-cyano-3-chlorophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolin-1-yl)-2-fluorobenzoate (Compound 26)

[0304]

[0305] Step 1: Synthesis of compound 26-1

[0306] Referring to the method of step 3 of Example 1, compound 26-1 was prepared by reacting compound 1-2 obtained in step 2 of Example 1 with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile.

[0307] Step 2: Synthesis of compound 26-2

[0308] Referring to the method of step 4 of Example 1, compound 26-2 was obtained by using compound 26-1 prepared in the previous step.

[0309] Step 3: Synthesis of compound 26

[0310] Referring to the method of step 1 of Example 21, compound 26 was prepared by reacting compound 26-2 obtained in the previous step with 2-methyl-2-butanol.

[0311] 1 H NMR(400MHz,Chloroform-d)δ8.07(t,J=8.1Hz,1H),7.84(d,J=8.4Hz,1H),7.70(d,J=1.9Hz,1H),7.53(d d,J=8.4,2.0Hz,1H),7.21–7.11(m,2H),1.94(q,J=7.5Hz,2H),1.62–1.59(m,12H),1.01(t,J=7.5Hz,3H).

[0312] MS (ESI, [M+H] + )m / z:488.4.

[0313] Application Experimental Example 1: Antagonistic activity of compounds on androgen receptor

[0314] 1) All test compounds were dissolved in DMSO to prepare a 15 mM solution, and then serially diluted 3-fold 10 times to prepare 15 mM, 5 mM, 1.6667 mM, 0.5576 mM, 0.1852 mM, 0.0617 mM, 0.0206 mM, 0.0069 mM, 0.0023 mM and 0.0008 mM solutions.

[0315] 2) HEK293T cells (ATCC, CRL-3216) were cultured according to ATCC recommendations (https: / / www.atcc.org / ). Cells were tested when they were in the exponential growth phase.

[0316] 3) Remove the culture medium from the dish, rinse the cells with phosphate buffered saline, add trypsin solution to the dish to detach the cells. Wash the cells once with complete culture medium.

[0317] 4) Wash the cells twice with phosphate buffered saline to remove phenol red and resuspend them in culture medium to an appropriate concentration.

[0318] 5) 6*10 6 HEK293T cells were seeded into 100-mm culture dishes (only cells with a viability greater than 90% were used for analysis) and cultured at 37°C, 5% CO2 for 16 h.

[0319] 6) Plasmids (pGL4.36[luc2P / MMTV / Hygro], Promega, E1360; pBIND-AR Vector, Pharmaron; LTX&Plus Reagent, Invitrogen, 15338-100) was transfected into HEK293T cells and cultured at 37°C and 5% CO2 for 5-6 h.

[0320] 7) Use a non-contact nanoliter acoustic pipetting system (Labcyte, Echo550) to transfer 50 nl of compound dilutions into a 384-well assay plate.

[0321] 8) The transfected HEK293T cells were seeded into a 384-well assay plate (25 μl) at 15,000 cells / well and a final concentration of 1 nM DHT (MCE, HY-A0120).

[0322] 9) The cells were cultured at 37°C and 5% CO2 for 18-20 hours.

[0323] 10) Add 25 μl of luciferase assay reagent (britelite plus, PerkinElmer, 6066769) to each well of a 384-well assay plate.

[0324] 11) Use an ELISA reader (Envision 2105, PerkinElmer) to record the luminescence value and calculate the IC 50 .

[0325] Table 1. Antagonistic activity of compounds on androgen receptor

[0326] Example <![CDATA[IC 50 (μM)]]> 1 2.375 2 1.695 3 1.784 4 3.041 5 7.416 6 7.473 7 >10 8 >10 9 >10 10 >10 11 1.282 12 0.873 13 4.240 14 2.011 15 0.790 16 0.778 17 1.032 18 0.508 19 1.527 20 1.238 21 0.871 22 1.236 23 2.141 24 1.185 25 0.819 26 0.904 Enzalutamide 0.776 Enzalutamide >30

[0327] The results show that the compounds of the present invention have androgen receptor antagonist activity.

[0328] Wherein, the compound 19 is

[0329] Application Experiment 2: Chemical Stability

[0330] Preparation of incubation solution: 10 mL of 0.02 M phosphate buffered saline (PBS) with a pH of 7.4 was added to 9.8 mL of DMSO, cooled in an ice bath, and then vortexed for 30 seconds to prepare the incubation solution.

[0331] The test compound was prepared into a 10mM stock solution with DMSO. The test compound was diluted to 2mM with DMSO. 15μL of 2mM test compound solution was added to 1485μL incubation solution, vortexed for 30s and left to stand at room temperature. At 0h, 2h, 4h, 6h, and 8h, 300μL of sample was taken, centrifuged at 14400rpm for 3min, 200μL of supernatant was taken, HPLC was used for detection, and the concentration was calculated according to the formula T 1 / 2 =-0.693 / k to calculate the half-life.

[0332] Table 2. Chemical stability

[0333] Example half life 1 <![CDATA[NA a ]]> 2 NA 3 NA 4 NA 5 NA 6 231h 10 77h 11 NA 12 NA 13 11.6h 14 57h 15 NA 16 NA 17 NA 18 NA 19 NA 20 NA 21 NA 22 NA 23 NA 24 NA 25 NA Enzalutamide NA

[0334] a No obvious degradation was observed after 8 hours, and the half-life could not be calculated.

[0335] The results showed that the compound of the present invention had good stability under pH 7.4.

[0336] Application Experiment 3: Rat Plasma Stability

[0337] The test compound was prepared into a 10mM storage solution with DMSO. The test compound was diluted to a 2mM working solution with DMSO. 10μL of 2mM working solution was added to 990μL rat plasma, vortexed for 5s, and configured into a reaction system with an initial concentration of 20μM. The reaction was incubated at 37°C, and 80μL of plasma samples were taken at 0min, 10min, 20min, 30min, 1h, 2h, 4h and 6h. 240μL of methanol was added to the plasma sample, vortexed for 3min, and centrifuged at 14400rpm for 3min. 200μL of supernatant was taken, and HPLC was used for detection. The concentration was calculated and the concentration was calculated according to the formula T 1 / 2 =-0.693 / k to calculate the half-life. The results are shown in Table 3.

[0338] Table 3. Rat plasma half-life and degradation products

[0339]

[0340]

[0341] a No obvious degradation was observed after 6 hours, and the half-life could not be calculated.

[0342] The results showed that the compounds provided by the present invention were extremely unstable in plasma. Most of the compounds could be almost completely degraded into inactive metabolites - enzalutamide acid within 5 minutes of plasma incubation, and the prototype compounds could not be detected at all after 15 minutes. Therefore, the compounds of the present invention were rapidly inactivated after entering the blood and could not be distributed throughout the body, thus unable to cause systemic androgen antagonism, and would not cause side effects such as decreased libido, reduced sperm production, and ED. It could effectively solve the problems of systemic distribution of existing drugs such as finasteride, which led to systemic androgen inhibition and caused side effects such as decreased libido, reduced sperm production, and ED.

[0343] Application Experimental Example 4: Stability of 10% Skin Homogenate of Mice

[0344] 1) The compound to be tested was prepared into a 10 mM stock solution with DMSO. Take 20 μL of the stock solution of the compound to be tested and add it to 80 μL of DMSO, vortex for 10 s to prepare a 2 mM working solution.

[0345] 2) The backs of C57BL / 6 male mice (license number SCXK(Yu)2020 - 0005) were depilated with depilatory cream.

[0346] 3) Under anesthesia, the back skin was dissected, blood vessels, subcutaneous tissue and fat were removed, and it was rinsed thoroughly with pre - cooled physiological saline.

[0347] 4) Take 2.3 g of skin, add it to 23 mL of pre - cooled physiological saline, and homogenize it thoroughly under ice - bath conditions (homogenize for 15 s each time and pause for 10 s), centrifuge at 5000 rpm for 5 min, aspirate the supernatant, which is the skin tissue homogenate, and place it on ice for later use.

[0348] 5) Take 990 μL of the skin tissue homogenate, add 10 μL of the 2 mM working solution of the compound to be tested, vortex for 5 s, and place it in a 37 °C water bath for incubation. Samples of 80 μL were taken at 0 min, 5 min, 10 min, 15 min, 30 min, 1 h, and 2 h respectively, and 240 μL of methanol was added.

[0349] 6) After vortexing for 3 min, centrifuge at 13000 rpm for 5 min.

[0350] 7) Aspirate 200 μL of the supernatant, analyze it by HPLC injection, calculate the concentration, and calculate the half - life according to the formula T 1 / 2 =-0.693 / k. The results are shown in Table 4.

[0351] Table 4. Stability and Degradation Products of 10% Skin Homogenate of Mice

[0352]

[0353]

[0354] a No obvious degradation was observed after 2 hours, and the half-life could not be calculated.

[0355] Some compounds of the present invention have a long half-life and good stability in skin homogenate and are slowly degraded into inactive metabolites such as enzalutamide.

[0356] Application Experiment 5: C57BL / 6 Mouse Hair Growth Model

[0357] Male C57BL / 6 mice aged 6 to 7 weeks were purchased and kept in group cages under standard conditions for one week. The lower back was shaved with an electric shaver under mild anesthesia, and then the back hair was removed with a depilatory cream, leaving about 2 cm × 2 cm of bare skin. The next day, mice with no damage to the back skin and pink skin color were selected and randomly divided into: blank control group and model combination treatment group.

[0358] Blank control group: soybean oil was intraperitoneally injected every 2 days, and 20 μL of acetone was applied to the hair removal area twice a day;

[0359] Model group: dihydrotestosterone soybean oil solution was intraperitoneally injected every 2 days at a dose of 1 mg / kg, and 20 μL of acetone was applied to the hair removal area twice a day;

[0360] Treatment group: dihydrotestosterone soybean oil solution was intraperitoneally injected every 2 days at a dose of 1 mg / kg, and 20 μL of 5% (w / v) acetone solution of Example 16 was applied to the hair removal area twice a day.

[0361] Hair growth scores were recorded every two days.

[0362] The scoring system used for mouse hair growth is:

[0363] a) 0: no hair growth, pink skin color;

[0364] b) 1: The skin color of the shaved area changes from pink to gray with no visible hair growth, indicating the initiation of the anagen phase;

[0365] c)2: The skin color of the shaved area is dark with tiny hairs;

[0366] d)3: short black hair in shaved areas;

[0367] e) 4: The hair in the shaved area is almost close to the surrounding area.

[0368] Hair score Figure 1 The hair growth of mice is shown in Figure 2The results show that after 12 days of treatment, Example 16 has the effect of promoting hair growth.

[0369] Application Experiment 6: C57BL / 6 Mouse Hair Growth Model 2

[0370] Male C57BL / 6 mice aged 6 to 7 weeks were purchased and kept in group cages under standard conditions for one week. The lower back was shaved with an electric shaver under mild anesthesia, and then the back hair was removed with a depilatory cream, leaving about 2 cm × 2 cm of bare skin. The next day, mice with no damage to the back skin and pink skin color were selected and randomly divided into: blank control group and model combination treatment group, 6 mice in each group.

[0371] Blank control group: subcutaneously injected with a mixed solvent of DMSO: glycerol = 1:1 (v / v) every day, with a dose of 100 μL per 20 g body weight, and applied 20 μL of a mixed solvent of ethanol: DMSO = 75:25 to the hair removal area twice a day;

[0372] Model group: dihydrotestosterone solution (6 mg / mL, solvent DMSO: glycerol = 1:1 (v / v)) was subcutaneously injected daily at a dose of 30 mg / kg, and 20 μL of a mixed solvent of ethanol: DMSO = 75:25 was applied to the hair removal area twice a day;

[0373] Treatment group: daily subcutaneous injection of dihydrotestosterone solution (6 mg / mL, solvent is DMSO: glycerol = 1: 1 (v / v)), the dose is 30 mg / kg, and twice a day, 20 μL of 5% (w / v) solution of Example 16 (solvent is a mixed solvent of ethanol: DMSO = 75:25) is applied to the hair removal area

[0374] Weigh the body weight every 2-3 days, take photos, and calculate the hair coverage using Image J. Use Graphpad to create a curve of body weight change and hair coverage. The results are shown in Figure 3 shown.

[0375] The present invention provides a locally acting androgen receptor antagonist and its application ideas and methods. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: R1 is selected from substituted or unsubstituted sec-butyl, In the substituted sec-butyl group, the substitution is by one or more hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy.

2. The compound of formula (I) according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The compound represented by formula (I) is selected from:

3. A pharmaceutical composition, characterized in that The invention comprises (i) a compound of formula (I) according to claim 1 or 2 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

4. The compound of formula (I) according to claim 1 or 2, or its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 3 for preparing a drug for preventing a disease or condition mediated by androgen or androgen receptor activity, reducing the progression of a disease or condition mediated by androgen or androgen receptor activity, or treating a disease or condition mediated by androgen or androgen receptor activity.

5. The use according to claim 4, characterized in that The disease or condition mediated by androgen or androgen receptor activity is selected from prostate cancer, acne or alopecia.

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