Tetrahydro-benzoimidazolyl modulators of TGR5

Patent metadata

Field	Value
Publication number	US-10077241-B2
Application number	US-201515303746-A
Country	US
Kind code	B2
Filing date	Apr 14, 2015
Priority date	Apr 15, 2014
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

The present invention comprises compounds of Formula (I).

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Z 1 and Z 2 are defined in the specification.

First claim

What is claimed is:

1. A compound of Formula (I) wherein:

wherein:
R 1 is

R a is H, F, Br, or Cl;
R b is H, F, Cl, Br, CF 3 , OCH 3 , —CN, or NO 2 ;
R c is H, F, OH, or (OCH 2 CH 2 ) n N(CH 3 ) 2 ;
R d is H, —CN, Br, SO 2 NH 2 , SO 2 NHSO 2 CH 3 , C (2-3) alkylOH, C (2-3) alkylN(CH 3 ) 2 , CH 2 CH 2 -tetrazolyl, CH 2 CH 2 CO 2 CH 2 CH 3 , CH 2 CH 2 CO 2 H, OCH 2 CN, OCH 2 CO 2 H, OCH 2 -tetrazolyl, (OCH 2 CH 2 ) n N(CH 3 ) 2 , (OCH 2 CH 2 ) n -pyrrolidinyl, (OCH 2 CH 2 ) n Cl, (OCH 2 CH 2 ) n OH, (OCH 2 CH 2 ) n OCH 3 , CO 2 H, C(O)NH 2 , C(O)NHCH 3 , C(O)N(CH 3 ) 2 , C(O)NHCH 2 CH 2 N(CH 3 ) 3 + (CF 3 CO 2 ) − , SO 2 NH(CH 2 ) 3 N(CH 3 ) 3 + (CF 3 CO 2 ) − , C(O)NHCH 2 CH 2 (OCH 2 CH 2 ) n OH, C(O)NHCH 2 CH 2 (OCH 2 CH 2 ) n OCH 3 , C(O)-morpholinyl, CH 2 CH 2 -morpholinyl, CH 2 CH 2 CN, CH 2 CH 2 C(O)NH 2 ,

 or tetrazolyl;
n is 0, 1, 2, 3, or 4;
R 2 is H, CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 F, or CH═O;
R 3 is H or Br;
R 4 is H or Br;
R 5 is Cl, H, F, or OCH 3 ;
R 6 is OCH 3 , or Cl, or R 6 and R 5 may be taken together with their attached phenyl to form the fused ring system

R 7 is phenyl, wherein said phenyl is optionally substituted with one substituent selected from the group consisting of F, CH 3 , Cl, CF 3 , and OCH 3 , and further optionally substituted with up to two additional fluorine atoms;
R 8 is H or CH 3 ;
X is O or CH 2 ; and
Z 1 and Z 2 are H, or Z 1 and Z 2 may be taken together with their attached carbon to form a

 group;
and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein:
X is CH 2 ;
Z 1 and Z 2 are H;
and pharmaceutically acceptable salts thereof.

3. A compound of claim 2 , wherein:
R 5 is Cl;
R 6 is OCH 3 ;
and pharmaceutically acceptable salts thereof.

4. A compound of claim 3 , wherein:
R 7 is

and pharmaceutically acceptable salts thereof.

5. A compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

8. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A method comprising of treating a syndrome, disease or disorder selected from the group consisting of: (a) obesity, (b) type II diabetes, (c) Syndrome X (also known as metabolic syndrome), (d) insulin resistance, (e) inadequate glucose tolerance, (f) impaired glucose metabolism, (g) antherosclerosis, (h) fatty liver disease, and (i) nonalcoholic steatohepatitis, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or a form, composition or medicament thereof.

10. The method of claim 9 , wherein the disease is obesity.

11. The method of claim 9 , wherein the disease is type II diabetes.

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Zhang Xuqing
• Wall Mark J
• Sui Zhihua

Classifications

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D235/02 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/12

  Ketones · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title