Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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 R 1a , R 1b , R 1c , R 1d , R 2 , R 2a , 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.
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 R 4 ;
R 1a is H, halogen, C 1-4 alkyl, alkoxy or trifluoromethyl;
R 1b and R 1c are the same or different and are independently H, halogen, hydroxy, haloC 1-4 alkyl, —C 1-6 alkyl-(R 5 ) p , —O—C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p , —NR 7 —C 1-6 alkyl-(R 5 ) p , or —S(O) m —C 1-6 alkyl-(R 5 ) p ;
R 1d is Cl, F, methyl, or CF 3 ;
R 2 is —C 1-4 alkyl-(R 5 ) p ;
R 2a is phenyl substituted with 0-4 R 3 , heteroaryl substituted with 0-4 R 3 , aryl-C 1-4 alkyl substituted with 0-4 R 3 , or heteroaryl-C 1-4 alkyl substituted with 0-4 R 3 , wherein heteroaryl is an aromatic heterocyclic ring of 5-10 members containing at least one heteroatom selected from N, O, and S;
R 3 at each occurrence is independently halogen, cyano, halo-C 1-4 alkyl, R 5 , —C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p , —O—C 1-6 alkyl-(R 5 ) p , —NR 7 —C 1-6 alkyl-(R 5 ) p , —S(O) m —C 1-6 alkyl-(R 5 ) p , —O—C 1-6 alkyl-NR 7 —C 1-6 alkyl-(R 5 ) p , heterocycle-(R 5 ) p ;
R 4 at each occurrence is independently halogen, C 1-6 alkyl, haloC 1-4 alkyl, C 1-6 alkoxy, hydroxy, cyano, thioC 1-6 alkyl, —C(O)NR 7 R 8 or 5 member heteroaryl containing at least one heteroatom selected from N, O, and S;
R 5 at each occurrence is independently H, hydroxy, —OC(O)—C 1-6 alkyl, —OC(O)O—C 1-6 alkyl, —OC(O)—C 1-6 alkyl-NR 7 R 8 , —COOR 6 , —C(O)NR 7 R 8 , —NR 7 C(O)NR 7 R 8 , —S(O) 2 NR 9 R 9 , —S(O) m —C 1-4 alkyl, —NR 7 R 8 , C 1-6 alkoxy, —O-heterocycle, or heterocycle wherein said heterocycle and said —O-heterocycle are substituted with 0-4 groups selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, hydroxy, oxo, thio, —NH 2 , —S(O) 2 C 1-4 alkyl and —COOH;
R 6 at each occurrence is independently H, C 1-4 alkyl, C 1-4 alkyl-O—C(O)—C 1-6 alkyl, or C 1-4 alkyl-O—C(O)—O—C 1-6 alkyl;
R 7 at each occurrence is independently H, C 1-4 alkyl, hydroxy, or heterocycle where said heterocycle is substituted with 0-4 groups selected from halogen, C 1-6 alkyl, hydroxy, keto, —NH 2 and —COOH;
R 8 at each occurrence is independently H, C 1-4 alkyl, haloC 1-4 alkyl, —C(O)—C 1-4 alkyl, —C(O)-haloC 1-4 alkyl, —S(O) m -haloC 1-4 alkyl or —S(O) m —C 1-4 alkyl;
R 9 at each occurrence is independently H, C 1-4 alkyl, or —C(O)C 1-4 alkyl;
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; and
p at each occurrence is independently 1-3.
2. The compound of claim 1 having the following structure (Ia):
or a stereoisomer, or a pharmaceutically acceptable salt thereof,
wherein:
A is pyridyl or phenyl, wherein the pyridyl or phenyl is substituted with 0-4 R 4 ;
R 1a is H, halogen, C 1-4 alkyl, alkoxy or trifluoromethyl;
R 1b and R 1c are the same or different and are independently H, halogen, hydroxy, haloC 1-4 alkyl, —C 1-6 alkyl-(R 5 ) p , —O—C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p , —NR 7 —C 1-6 alkyl-(R 5 ) p , or —S(O) m —C 1-6 alkyl-(R 5 ) p ;
R 1d is Cl, methyl, or CF 3 ;
R 2 is C 1-4 alkyl-(R 5 ) p ;
R 3 at each occurrence is independently halogen, haloC 1-4 alkyl, hydroxy, —C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p , —O—C 1-6 alkyl-(R 5 ) p , —NR 7 —C 1-6 alkyl-(R 5 ) p , —S(O) m —C 1-6 alkyl-(R 5 ) p , —CO 2 R 6 , —C(O)NR 7 R 8 ;
R 4 at each occurrence is independently halogen, C 1-6 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, hydroxy, cyano, thioC 1-4 alkyl, —C(O)NR 7 R 8 or 5 member heteroaryl containing at least one heteroatom selected from N, O, and S;
R 5 at each occurrence is independently H, hydroxy, —OC(O)—C 1-6 alkyl, —OC(O)O—C 1-6 alkyl, —OC(O)—C 1-6 alkyl-NR 7 R 8 , —COOR 6 , —C(O)NR 7 R 8 , —S(O) 2 NR 9 R 9 , —S(O) m C 1-4 alkyl, —NR 7 R 8 , C 1-6 alkoxy, or a heterocycle selected from the group consisting of
R 6 at each occurrence is independently H, C 1-4 alkyl, C 1-4 alkyl-O—C(O)—C 1-6 alkyl, or C 1-4 alkyl-O—C(O)—O—C 1-6 alkyl;
R 7 is H, C 1-4 alkyl or hydroxy;
R 8 is H, C 1-4 alkyl, —C(O)—C 1-4 alkyl, or —S(O) m —C 1-4 alkyl;
R 9 at each occurrence is independently H, C 1-4 alkyl, or —C(O)C 1-4 alkyl;
m is 0-2;
n is 0-4; and
p at each occurrence is independently 1-3.
3. The compound of claim 2 wherein A is pyridyl substituted with 0-4 R 4 .
4. The compound of claim 3 wherein A is 2-pyridyl substituted with 0-4 R 4 .
5. The compound of claim 3 wherein A is 3-pyridyl substituted with 0-4 R 4 .
6. The compound of claim 1 wherein A is 3-pyridyl substituted with 0-4 R 4 .
7. The compound of claim 1 wherein R 1a and R 1c are H.
8. The compound of claim 1 wherein R 1b is —C 1-6 alkyl-(R 5 ) p or —O—C 1-6 alkyl-(R 5 ) p , p is 1, and R 5 is H, hydroxy or —COOR 6 .
9. The compound of claim 2 wherein one of R 3 is —O—C 1-6 alkyl-(R 5 ) p , p is 1, and R 5 is H, hydroxy, or —COOR 6 .
10. The compound of claim 1 wherein one of R 3 is —C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p or —O—C 1-6 alkyl-(R 5 ) p .
11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
12. The compound of claim 4 wherein R 4 at each occurrence is independently halogen, C 1-6 alkyl, haloC 1-4 alkyl, or cyano.
13. The compound of claim 12 wherein one of R 3 is —O—C 1-6 alkyl-(R 5 ) p , p is 1, and R 5 is H, hydroxy, or —COOR 6 .
14. The compound of claim 5 wherein R 4 at each occurrence is independently halogen, C 1-6 alkyl, haloC 1-4 alkyl, or cyano.
15. The compound of claim 14 wherein one of R 14 is —O—C 1-6 alkyl-(R) p , p is 1, and R 5 is H, hydroxy, or —COOR 6 .
16. The compound of claim 3 wherein R 1a and R 1c are H, R 1d is Cl, one of R 3 is —C 1-6 alkyl-(R 5 ) p , —C 1-6 alkyl-O—C 1-6 alkyl-(R 5 ) p or —O—C 1-6 alkyl-(R 5 ) p and R 4 at each occurrence is independently halogen, C 1-6 alkyl, haloC 1-4 alkyl, or cyano.