Imidazole compounds as modulators of FSHR and uses thereof

Patent metadata

Field	Value
Publication number	US-10138233-B2
Application number	US-201414900215-A
Country	US
Kind code	B2
Filing date	Jun 24, 2014
Priority date	Jun 24, 2013
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention relates to imidazole compounds, and pharmaceutically acceptable compositions thereof, useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR).

First claim

We claim:

1. A compound of formula I,

X is CR 2 , or O;
Y is O, S, or NR;
Z is N;
each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
Ring A is a fused C 3-10 aryl, a fused 3-8 membered saturated or partially unsaturated carbocyclic ring, a fused 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a fused 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 1 is —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 2 is —R, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 3 is C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R 3 is halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R 4 is independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
R 5 is C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
R 6 is hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
or R 5 and R 6 , together with the atom to which each is attached, form a 3-8 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3-8 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
n is 0, 1, or 2; and
p is 1.

2. The compound of claim 1 , wherein X is CR 2 .

3. The compound of claim 1 , wherein Y is O.

4. The compound of claim 1 , wherein Ring A is phenyl.

5. The compound of claim 1 , wherein R 1 is —OCH 3 or —OCD 3 .

6. The compound of claim 1 , wherein R 2 is —OCH 3 ,

7. The compound of claim 1 , wherein R3 is —Br,

8. The compound of claim 1 , wherein R 5 is methyl, t-butyl, —CD 3 ,

9. The compound of claim 1 , wherein Z is N and the ring formed by Z, R 5 and R 6 is

10. The compound of claim 1 , wherein R 6 is hydrogen, methyl, t-butyl, or —CD 3 .

11. The compound of claim 1 , of formula I-b:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , of formula I-d:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , wherein R 1 is —OCH 3 or —OCD 3 ; and R 2 is —OR or 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted.

14. The compound of claim 1 , selected from

Assignees

• Merck Patent Gmbh
• Yu Henry
• Richardson Thomas E
• Donnelly Marianne
• Nguyen Ngan
• Jiang Xuliang

Inventors

• Yu Henry
• Richardson Thomas E
• Donnelly Marianne
• Nguyen Ngan
• Jiang Xuliang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• A61P15/08

  for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D471/02

  in which the condensed system contains two hetero rings · CPC title