Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

摘要

GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure:;
wherein R1a, R1b, R1c, R1d, R2, R2a, and A are as defined herein, including stereoisomers, esters, solvates and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.

主权项

1. A compound having the following structure (I):or a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein:
A is pyridyl or phenyl, wherein the pyridyl or phenyl is substituted with 0-5 R4;R1a is H, halogen, C1-4alkyl, alkoxy or trifluoromethyl;R1b and R1c are the same or different and are independently H, halogen, hydroxy, haloC1-4alkyl, —C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, or —S(O)m—C1-6alkyl-(R5)p;R1d is Cl, F, methyl, or CF3;R2 is —C1-4alkyl-(R5)p;R2a is phenyl substituted with 0-4 R3, heteroaryl substituted with 0-4 R3, aryl-C1-4alkyl substituted with 0-4 R3, or heteroaryl-C1-4alkyl substituted with 0-4 R3, wherein heteroaryl is an aromatic heterocyclic ring of 5-10 members containing at least one heteroatom selected from N, O, and S;R3 at each occurrence is independently halogen, cyano, halo-C1-4alkyl, R5, —C1-6alkyl-(R5)p, —C1-6alkyl-O—C1-6alkyl-(R5)p, —O—C1-6alkyl-(R5)p, —NR7—C1-6alkyl-(R5)p, —S(O)m—C1-6alkyl-(R5)p, —O—C1-6alkyl-NR7—C1-6alkyl-(R5)p, heterocycle-(R5)p;R4 at each occurrence is independently halogen, C1-6alkyl, haloC1-4alkyl, C1-6alkoxy, hydroxy, cyano, thioC1-6alkyl, —C(O)NR7R8 or 5 member heteroaryl containing at least one heteroatom selected from N, O, and S;R5 at each occurrence is independently H, hydroxy, —OC(O)—C1-6alkyl, —OC(O)O—C1-6alkyl, —OC(O)—C1-6alkyl-NR7R8, —COOR6, —C(O)NR7R8, —NR7C(O)NR7R8, —S(O)2NR9R9, —S(O)m—C1-4alkyl, —NR7R8, C1-6alkoxy, —O-heterocycle, or heterocycle wherein said heterocycle and said —O-heterocycle are substituted with 0-4 groups selected from halogen, C1-6alkyl, C1-4haloalkyl, hydroxy, oxo, thio, —NH2, —S(O)2C1-4alkyl and —COOH;R6 at each occurrence is independently H, C1-4alkyl, C1-4alkyl-O—C(O)—C1-6alkyl, or C1-4alkyl-O—C(O)—O—C1-6alkyl;R7 at each occurrence is independently H, C1-4alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C1-6alkyl, hydroxy, keto, —NH2 and —COOH; R8 at each occurrence is independently H, C1-4alkyl, haloC1-4alkyl, —C(O)—C1-4alkyl, —C(O)-haloC1-4alkyl, —S(O)m-haloC1-4alkyl or —S(O)m—C1-4alkyl;
R9 at each occurrence is independently H, C1-4alkyl, or —C(O)C1-4alkyl;wherein heterocycle is a 5-7 member monomeric or 7-14 member polycyclic heterocyclic ring that is saturated, unsaturated, or aromatic and that contains 1-4 heteroatoms selected from N, O, and S;m is 0-2; andp at each occurrence is independently 1-3.