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CN-114773314-B - Biaryl aminoguanidine derivative

CN114773314BCN 114773314 BCN114773314 BCN 114773314BCN-114773314-B

Abstract

The present disclosure relates to biaryl aminoguanidine derivatives represented by formula II or pharmaceutically acceptable salts thereof, and methods of preparing the same. The disclosure also relates to the use of such biaryl aminoguanidine derivatives for the treatment of diseases involving the melanocortin receptor or related systems such as melanocyte stimulating hormone.

Inventors

  • LI YUNFEI
  • ZHU GUODONG
  • PANG XIAMING
  • ZHANG FANG

Assignees

  • 上海拓界生物医药科技有限公司

Dates

Publication Date
20260508
Application Date
20220120
Priority Date
20210121

Claims (5)

  1. 1. A compound of the formula or a pharmaceutically acceptable salt thereof, 。
  2. 2. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  3. 3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, in the manufacture of a medicament for the prevention and/or treatment of a disorder associated with the melanocortin receptor.
  4. 4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for the manufacture of a medicament for the prevention and/or treatment of inflammation, diabetes, insulin resistance, sexual dysfunction, eating disorders, coronavirus disease 19 (COVID-19) infection, nephrotic syndrome, respiratory distress syndrome.
  5. 5. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, in the manufacture of a medicament for the prevention and/or treatment of psoriatic arthritis, rheumatoid arthritis, membranous glomerulonephritis.

Description

Biaryl aminoguanidine derivative Technical Field The present disclosure belongs to the field of medicine, and relates to biaryl aminoguanidine derivatives. Background Melanocortin peptide (melanocortin melanocortin) is a natural peptide hormone that binds to the MC-receptor and stimulates it in animals and humans. One family of melanocortin receptor types and subtypes has been identified, including the melanocortin 1 receptor (MC 1-R) expressed in normal human melanocytes and melanoma cells, the melanocortin 2 receptor (MC 2-R) of corticotropin (ACTH) expressed in adrenal cells, the melanocortin 3 and melanocortin 4 receptors (MC 3-R and MC 4-R) expressed primarily in hypothalamus, midbrain and brain stem cells, and the melanocortin 5 receptor (MC 5-R) expressed in widely distributed tissues. Examples of melanocortins are alpha-MSH (melanocyte stimulating hormone), beta-MSH, gamma-MSH, ACTH (adrenocorticotropic hormone) and peptide fragments thereof. MSH is known to have primarily the ability to regulate peripheral pigmentation, while ACTH induces steroidogenesis. Melanocortins also mediate many other physiological effects. They are reported to affect exercise, learning, memory, behavior, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, natriuresis, cerebral blood flow, nerve growth and repair, placental development, aldehyde sterol synthesis and release, thyroxine release, semen production, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, sexual capacity, penile erection, blood glucose levels, intrauterine fetal growth, food stimulating behavior, and other childbirth-related events. Disclosure of Invention The present disclosure (The disclosure) provides a compound represented by formula I or a pharmaceutically acceptable salt thereof Wherein: A is selected from the group consisting of a fused ring of a 5-12 membered heteroaryl, a phenyl group with a 5-10 membered heteroaryl, a fused ring of a 5-10 membered heteroaryl with a 5-10 membered heteroaryl, said fused ring of a 5-12 membered heteroaryl, a phenyl group with a 5-10 membered heteroaryl, a fused ring of a 5-10 membered heteroaryl with a 5-10 membered heteroaryl optionally substituted with one or more deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, amido, acyl, nitro, carboxyl, hydroxyl, mercapto, sulfinyl, sulfonyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 cycloalkoxy, 3-20 membered heterocycloalkoxy or C 3-20 cycloalkenyloxy, said C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 cycloalkoxy, 3-20 membered heterocycloalkoxy or C 3-20 cycloalkoxy optionally substituted with one or more R 6a; B is selected from C 6-10 aryl, 5-12 membered heteroaryl, condensed ring formed by C 6-10 aryl and 5-10 membered heteroaryl, condensed ring formed by C 6-10 aryl and C 5-12 cycloalkyl, wherein the C 6-10 aryl, The fused ring formed by the 5-12 membered heteroaryl, the C 6-10 aryl and the 5-10 membered heteroaryl, the fused ring formed by the C 6-10 aryl and the C 5-12 cycloalkyl is optionally substituted with one or more deuterium, halogen, C 1-6 alkyl, Substituted by C 1-6 alkoxy, amino, cyano, oxo, amido, acyl, nitro, carboxyl, hydroxy, mercapto, sulfinyl, sulfonyl, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 cycloalkoxy, 3-20 membered heterocycloalkoxy or C 3-20 cycloalkenyloxy, said C 1-6 alkyl, C 1-6 alkoxy, C 3-20 cycloalkyl, 3-20 membered heterocycloalkyl, C 3-20 cycloalkoxy, 3-20 membered heterocycloalkoxy, or C 3-20 cycloalkenyloxy optionally substituted with one or more R 6b; R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 4-6 dienyl, C 2-6 alkynyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 6-10 aryl, C 6-10 -aryloxycarbonyl, C 6-10 -arylcarbonyl, 5-10-membered heteroaryl, 5-10-membered heteroaryloxycarbonyl, 5-10-membered heteroarylcarbonyl, aminocarbonyl, said C 1-6 -alkyl, C 2-6 -alkenyl, C 4-6 dienyl, C 2-6 alkynyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyl, C 6-10 aryl, C 6-10 -aryloxycarbonyl, C 6-10 -arylcarbonyl, 5-10 membered heteroaryl, 5-10 membered heteroaryloxycarbonyl, 5-10 membered heteroarylcarbonyl optionally substituted with one or more deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, Amino, cyano, oxo, amido, acyl, nitro, carboxyl, hydroxyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocycloalkoxy or C 3-10 cycloalkenyloxy; or R 3 and R 4 may together form a five or six membered nitrogen containing ring, optionally substituted with one or more R 6c; n is an integer from 0 to 8; When a is pyrrolyl, B is not selected from phenyl; r 6a is independently selected from hydrogen, halogen, deuterium, hydroxy, oxo, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, said C 1-6 alkyl, C 1-6 alkoxy optionally substituted with one or more groups selected f