Imidazole compounds as modulators of fshr and uses thereof

Patent metadata

Field	Value
Publication number	US-2016152609-A1
Application number	US-201414900215-A
Country	US
Kind code	A1
Filing date	Jun 24, 2014
Priority date	Jun 24, 2013
Publication date	Jun 2, 2016
Grant date	—

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

1 . A compound of formula I,

X is CR 2 , O, S, SO, SO 2 , or NR;
Y is O, S, or NR;
Z is O, S, SO, SO 2 , or N; wherein when Z is O, S, SO, or SO 2 , then p is 0;
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, 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 3 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 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 0 or 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 Z is N.

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

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

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

8 . The compound of claim 14 , wherein R 3 is —Br,

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

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

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

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

14 . The compound of claim 1 , selected from Table 1.

15 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

16 . (canceled)

17 . A method for treating a FSHR-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 .

18 . A method for treating fertility disorders in a subject, comprising the step of administering to said subject a compound of claim 1 or a physiologically acceptable salt thereof.

19 . (canceled)

20 . (canceled)

21 . The compound of claim 1 , of formula I-e:

or a pharmaceutically acceptable salt thereof.

22 . The compound of claim 21 , 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.

23 . The compound of claim 13 , 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.

Assignees

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

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/02

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