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CN-121986088-A - Amide compounds

CN121986088ACN 121986088 ACN121986088 ACN 121986088ACN-121986088-A

Abstract

There is provided a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing them and their use as Androgen Receptor (AR) antagonists in the treatment or prophylaxis of androgen receptor mediated diseases, preferably in the treatment of androgen receptor mediated hair loss, such as androgenic hair loss.

Inventors

  • ZHANG YAN
  • WANG FENG
  • JIAO YU
  • HUANG LIANCHENG
  • ZHAO SIQI
  • TANG FENG
  • LIU LE
  • CHEN YADONG
  • LU TAO
  • PENG SHAOPING

Assignees

  • 中国药科大学
  • 江苏先声药业有限公司

Dates

Publication Date
20260505
Application Date
20240927
Priority Date
20230928

Claims (19)

  1. A compound represented by the formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Wherein, the X is selected from CH or N; Y is selected from OH, COOH, -CONH 2 、-COOR 3 or-CONR 3' R 3 ; R 1 is selected from OH or-O-C 1 -C 6 alkyl; R 2 is selected from H, deuterium, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, or C 1 -C 6 haloalkyl; R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, or 5-10 membered heteroaryl optionally substituted with R 3a ; R 3a is selected from halogen 、OH、CN、NH 2 、-COR 3b 、-COOR 3b 、-NHCOR 3b 、-CONHR 3b 、-O-C 1 -C 6 alkyl, C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, said C 1 -C 6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 3c ; R 3b is selected from H or C 1 -C 6 alkyl; R 3c is selected from halogen, OH, C 1 -C 6 alkyl or-O-C 1 -C 6 alkyl; R 3' is selected from H or C 1 -C 6 alkyl; r 4 is selected from NO 2 , CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or-O-C 1 -C 6 alkyl; R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COOC 1 -C 6 alkyl, -S-C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -Se-C 1 -C 6 alkyl, -S (O) -C 1 -C 6 alkyl or-S (O) 2 -C 1 -C 6 alkyl; R 6 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or-O-C 1 -C 6 alkyl; n is selected from 1,2,3,4, 5, 6, 7, 8 or 9; With the proviso that when Y is selected from OH, n is selected from 1,2 or 3.
  2. A compound of formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein Y is selected from COOH, -CONH 2 、-COOR 3 or-CONR 3' R 3 ; Or Y is selected from CONH 2 、-COOR 3 or-CONR 3' R 3 ; Or Y is selected from-COOR 3 or-CONR 3' R 3 ; Or Y is-COOR 3 ; Or Y is selected from OH、COOH、-COOCH 2 CH 3 、-COOCH 3 、-COOCH(CH 3 ) 2 、-COOC(CH 3 ) 3 、-CONHCH 3 or-CONH 2 ; Or Y is selected from -COOCH 2 CH 3 、-COOCH 3 、-COOCH(CH 3 ) 2 、-COOC(CH 3 ) 3 、 or-CONHCH 3 ; Or Y is selected from-COOCH 2 CH 3 、-COOCH 3 、-COOCH(CH 3 ) 2 or-COO (CH 3 ) 3 ).
  3. A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein R 1 is OH.
  4. A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-3, wherein R 2 is selected from H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, or R 2 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, or C 1 -C 6 haloalkyl; Or R 2 is selected from C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; Or R 2 is selected from H, CH 3 or CF 3 ; Or R 2 is selected from CH 3 or CF 3 .
  5. A compound of formula (I) according to any one of claims 1-4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl, or 5-6 membered heteroaryl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 10 aryl, or 5-6 membered heteroaryl being optionally substituted with R 3a ; Or R 3 is selected from C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl, said C 1 -C 6 alkyl optionally substituted with R 3a ; or R 3 is unsubstituted C 1 -C 6 alkyl; Or R 3 is selected from unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl or unsubstituted tert-butyl.
  6. A compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein R 3a is selected from halogen 、OH、CN、NH 2 、-COR 3b 、-COOR 3b 、-NHCOR 3b 、-CONHR 3b 、-O-C 1 -C 6 alkyl or C 1 -C 6 alkyl, the C 1 -C 6 alkyl being optionally substituted by R 3c .
  7. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 3' is H or C 1 -C 4 alkyl, or R 3' is H.
  8. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 4 is selected from halogen or CN, or R 4 is selected from F, cl or CN, or R 4 is CN.
  9. A compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -COOC 1 -C 6 alkyl, -S-C 1 -C 6 alkyl or-O-C 1 -C 6 alkyl; Or R 5 is selected from C 1 -C 6 haloalkyl, -S-C 1 -C 6 alkyl, -O-C 1 -C 6 alkyl, -Se-C 1 -C 6 alkyl, -S (O) -C 1 -C 6 alkyl, or-S (O) 2 -C 1 -C 6 alkyl; Or R 5 is selected from C 1 -C 3 haloalkyl, -S-C 1 -C 3 alkyl, -O-C 1 -C 3 alkyl or-Se-C 1 -C 3 alkyl; Or R 5 is selected from C 1 -C 6 haloalkyl, -S-C 1 -C 6 alkyl or-O-C 1 -C 6 alkyl; or R 5 is selected from CF 3 、-S-CH 3 、-O-CH 3 、-Se-CH 3 、-S(O)-CH 3 or-S (O) 2 -CH 3 ; Or R 5 is selected from CF 3 、-S-CH 3 、-O-CH 3 or-Se-CH 3 .
  10. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 6 is selected from H or halogen, or R 6 is H.
  11. A compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein n is selected from 1,2 or 3; Or n is selected from 1 or 2; Or n is 2.
  12. A compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein X is N.
  13. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (II) or a stereoisomer or a pharmaceutically acceptable salt thereof, Wherein X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , n are as defined in any one of claims 1 to 12.
  14. The compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  15. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 14 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  16. Use of a compound of formula (I) as defined in any one of claims 1 to 14 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 15, in the manufacture of a medicament for the prophylaxis or treatment of androgen receptor mediated diseases.
  17. A method of preventing or treating androgen receptor mediated diseases in a mammal, comprising administering to a mammal, preferably a human being, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 15.
  18. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 15, for use in the prevention or treatment of a disorder mediated by the androgen receptor in a mammal.
  19. The use according to claim 16 or the method according to claim 17 or the compound of formula (I) according to claim 18 or a stereoisomer thereof or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the androgen receptor mediated disease is selected from androgenic alopecia.

Description

Amide compounds Cross Reference to Related Applications The present disclosure claims priority and rights to chinese patent application No. 202311282820.X submitted by month 28 of 2023, chinese patent application No. 202410900706.7 submitted by month 07 of 2024. The entire contents of the above-mentioned patent application are incorporated herein by reference in their entirety. Technical Field The present disclosure relates to the field of pharmaceutical chemistry, and in particular to a class of amide compounds or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as Androgen Receptor (AR) antagonists. Background Androgen receptor (Androgen receptor, AR) is one of the nuclear receptor family members, AR comprises four major regions, an N-terminal active transcription control region (NTD), a DNA binding region (DNA binding domain, DBD), a hinge region, and a C-terminal ligand binding region (Ligand binding domain, LBD). Its activation is closely related to the occurrence of benign prostatic hyperplasia, prostate cancer, seborrhea, acne, premenstrual syndrome, lung cancer, ovarian polycystic syndrome, hirsutism, alopecia, etc. Therefore, androgen receptors are important targets in a number of fields of drug discovery. Androgenetic alopecia (androgenitic alopecia, AGA) is currently one of the most clinically common types of alopecia, but its specific pathogenesis is still not completely understood, and most researchers believe that it is related to androgen metabolism. Studies have shown that increased androgen action on susceptible hair follicles results from increased androgen receptor gene expression and/or increased expression of type II 5α reductase gene in hair follicles in the bald area. For androgenetic alopecia, the dermis component cells in the susceptible hair follicle contain specific type II 5 alpha reductase, which can convert androgen testosterone circulating to the area in blood into dihydrotestosterone, and a series of reactions are caused by binding with androgen receptors in the cells, so that progressive miniaturization and alopecia of the hair follicle can occur until alopecia. Currently, only minoxidil and finasteride are approved by the FDA for the treatment of androgenic alopecia. Minoxidil is a potassium channel opener, the exact mechanism of its effectiveness in androgenetic alopecia is not fully understood, and it is applied as a topical medicine to the affected area. But has long onset time and adverse effects such as itching, contact dermatitis, aggravation of alopecia after stopping drug administration, etc. Finasteride is a type II 5-alpha reductase inhibitor that reduces serum and scalp dihydrotestosterone levels for use in the treatment of male AGA. However, male erectile dysfunction and ejaculation dysfunction caused by long-term administration of finasteride, decreased libido, and the like, can make the patient suffering from alopecia prohibitive. Therefore, the research of the antagonistic activity of the novel molecule on AR is of great significance to the research of androgenetic alopecia. Disclosure of Invention In one aspect, the present disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, Wherein, the X is selected from CH or N; Y is selected from OH, COOH, -CONH 2、-COOR3 or-CONR 3'R3; R 1 is selected from OH or-O-C 1-C6 alkyl; R 2 is selected from H, deuterium, C 1-C6 alkyl, C 1-C6 deuterated alkyl, or C 1-C6 haloalkyl; R 3 is selected from C 1-C6 alkyl, C 1-C6 deuterated alkyl, C 3-C6 cycloalkyl, 4-10 membered heterocyclyl, C 6-C10 aryl, or 5-10 membered heteroaryl, said C 1-C6 alkyl, C 3-C6 cycloalkyl, 4-10 membered heterocyclyl, C 6-C10 aryl, or 5-10 membered heteroaryl optionally substituted with R 3a; R 3a is selected from halogen 、OH、CN、NH2、-COR3b、-COOR3b、-NHCOR3b、-CONHR3b、-O-C1-C6 alkyl, C 1-C6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, said C 1-C6 alkyl, phenyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 3c; R 3b is selected from H or C 1-C6 alkyl; R 3c is selected from halogen, OH, C 1-C6 alkyl or-O-C 1-C6 alkyl; R 3' is selected from H or C 1-C6 alkyl; r 4 is selected from NO 2, CN, halogen, C 1-C6 alkyl, C 1-C6 haloalkyl or-O-C 1-C6 alkyl; R 5 is selected from halogen, C 1-C6 alkyl, C 1-C6 haloalkyl, -COOC 1-C6 alkyl, -S-C 1-C6 alkyl, -O-C 1-C6 alkyl, -Se-C 1-C6 alkyl, -S (O) -C 1-C6 alkyl or-S (O) 2-C1-C6 alkyl; R 6 is selected from H, halogen, C 1-C6 alkyl, C 1-C6 haloalkyl or-O-C 1-C6 alkyl; n is selected from 1,2,3,4, 5, 6, 7, 8 or 9; With the proviso that when Y is selected from OH, n is selected from 1,2 or 3. In another aspect, the present disclosure provides pharmaceutical compositions comprising the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant. In yet another