Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Patent metadata

Field	Value
Publication number	US-9422310-B2
Application number	US-201514592690-A
Country	US
Kind code	B2
Filing date	Jan 8, 2015
Priority date	Apr 6, 2007
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

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.

First claim

We claim:

1. A method for treating a sex-hormone related condition of a subject in need thereof, comprising administering to the subject an effective amount of a compound having the following structure (I):

or a stereoisomeror pharmaceutically acceptable salt thereof,
wherein:
A is pyridyl, phenyl, quinolinyl, naphthyridinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl, wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl 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, CF 3 or cyano;
R 2 is —C 1-4 alkyl-(R) p ;
R 2a is phenyl substituted with 0-4 R 3 , heteroaryl substituted with 0-4 R 3 , C 1-6 alkyl 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 ;
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;
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;
m is 0-2; and
p at each occurrence is independently 1-3.

2. The method of claim 1 wherein the compound has the following structure (Ia):

or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
A is pyridyl, phenyl, quinolinyl, thienopyrimidinyl, or 2-oxo-pyrimidinyl, wherein the pyridyl, phenyl, quinolinyl, thienopyrimidinyl or 2-oxo-pyrimidinyl is substituted with 0-4 R 4 ;
R 1a is H, halogen, 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, CF 3 or cyano;
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, 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;
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 method of claim 1 wherein A is pyridyl substituted with 0-4 R 4 .

4. The method of claim 3 wherein A is 2-pyridyl substituted with 0-4R 4 .

5. The method of claim 3 wherein A is 3-pyridyl substituted with 0-4R 4 .

6. The method of claim 1 wherein A is phenyl substituted with 0-4 R 4 .

7. The method of claim 1 wherein A is quinolinyl substituted with 0-4 R 4 .

8. The method of claim 1 wherein A is thienopyrimidinyl substituted with 0-4 R 4 .

9. The method of claim 1 wherein A is 2-oxo-pyrimidinyl substituted with 0-4 R 4 .

10. The method of claim 1 wherein R 1a and R 1c are H.

11. The method 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 .

12. The method of claim 1 wherein R 2a is phenyl substituted with 1 or 2 R 3 , 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 .

13. The method of claim 1 wherein 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 .

14. The method of claim 1 wherein the compound is 3-(2-{[4-Chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-methyl-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 3-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-3-methyl-phenoxy)-propionic acid, 4-(2-{[4-Chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid, 2-{[4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoyl]-methyl-amino}-benzoic acid methyl ester, 4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-fluoro-6-methoxy-phenyl)-2-methoxy-N-methyl-benzamide, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 wherein the compound is 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid, 3-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-6-methyl-phenyl)-methyl-carbamoyl]-phenoxy}-propionic acid, 4-{5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenoxy}-butyric acid, 4-[5-Chloro-2-[(5-chloro-2-methoxy-phenyl)-methyl-carbamoyl]-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-phenoxy]-butyric acid, 2-{[2-(3-Carboxy-propoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-benzoic

Assignees

• Neurocrine Biosciences Inc

Inventors

• Beaton Graham
• Chen Mi
• Coon Timothy Richard
• Ewing Todd
• Jiang Wanlong
• Moree Willy
• Rowbottom Martin
• Wade Warren
• Zhao Liren
• Lowe Richard
• Smith Nicole
• Ashweek Neil
• Zhu Yun-Fei

Classifications

• A61P5/08

  for decreasing, blocking or antagonising the activity of the anterior pituitary hormones · CPC title

• A61P5/02

  of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/08

  of the prostate · CPC title