Methods of modulating the activity of the MC5 receptor and treatment of conditions related to this receptor

摘要

The present invention provides compounds of Formula (I) that are useful for modulating the biological activity of the melanocortin-5 receptor (MC5R). Compounds of this invention can be used to treat diseases and/or conditions in which downregulation of MC5R is beneficial. Such diseases and/or conditions include, but are not limited to, acne, seborrhea, seborrheic dermatitis, cancer, and inflammatory diseases.;

主权项

1. A method of treating or controlling a melanocortin 5 receptor (MC5R)-associated condition selected from one or more conditions of the group consisting of acne, seborrhea, and seborrheic dermatitis, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (Ib):wherein
Y is CH2; X is —C(═O)—; Z is —(CH2)q—; r is 0 or 1; q is 1, 2, 3, or 4; R1 is selected from the group consisting of (a) optionally substituted C6-C18 aryl wherein the C6-C18 aryl is phenyl, biphenyl, or naphthyl; (b) optionally substituted C1-C18 heteroaryl wherein the C1-C18 heteroaryl is indol-2-yl, indol-3-yl, quinolin-2-yl, quinolin-3-yl, isoquinolin-3-yl, quinoxaline-2-yl, benzo[b]furan-2-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-5-yl, thiazole-4-yl, benzimidazole-5-yl, benzotriazol-5-yl, furan-2-yl, benzo[d]thiazole-6-yl, pyrazole-1-yl, pyrazole-4-yl or thiophen-2-yl; and (c) optionally substituted alkenyl of the formula:wherein R1c is optionally substituted C6-C18 aryl wherein the C6-C18 aryl is selected from phenyl and naphthyl;
R2 is H or C1-C6 alkyl; R3 is H or C1-C6 alkyl; R4 is selected from the group consisting of H, C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6 aryl, OR20, and OCR17R18R20; R5a and R5b are each H; R6 and R8 are each independently H, methyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, isopropenyl, propyl, 2-ethyl-propyl, 3,3-dimethylpropyl, butyl, 2-methylbutyl, isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, optionally substituted phenyl, optionally substituted C1-C5 heteroaryl, wherein the C1-C5 heteroaryl is thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, or tetrazole; R7 is H; each of R17, R18, and R20 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, and phenyl, or a halogenated derivative thereof; and wherein each optional substituent is independently selected from the group consisting of F, Cl, Br, I, CH3, CH2CH3, OH, OCH3, CF3, OCF3, NO2, NH2, and CN; or a pharmaceutically acceptable salt thereof.