Bicyclic agonists of GPR131 and uses thereof

Patent metadata

Field	Value
Publication number	US-9593109-B2
Application number	US-201213594598-A
Country	US
Kind code	B2
Filing date	Aug 24, 2012
Priority date	Aug 26, 2011
Publication date	Mar 14, 2017
Grant date	Mar 14, 2017

Abstract

The present disclosure relates to compounds that act as agonists of, or otherwise modulate the activity of, GPR131 and to their use in the treatment of various diseases. In particular embodiments, the structure of the compounds is given by Formula I:

wherein the variables are as described herein. Related compositions, formulations and methods for the preparation of compounds of formula I are also described.

First claim

What is claimed is:

1. A compound of formula (I)

or a derivative thereof, wherein
A is an optionally substituted aryl or heteroaryl;
D 1 and D 2 are each independently C or N; and D 3 , D 4 , and D 5 are each independently CR 2 , N, NR 8 , or O, wherein D 1 , D 2 , D 3 , D 4 , and D 5 together form Het 2 , which is an optionally substituted 5-membered heteroaryl;
E is alkyl, aryl, arylalkyl, cycloalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, each of which may be optionally substituted,

is selected from the group consisting of

and
R 2 is independently H, alkoxy, optionally substituted C 1-6 alkyl, amido, amino, cyano, halo, hydroxyl, sulfonyl, or sulfonamido; and
R 8 is H or optionally substituted C 1-6 alkyl.

2. The compound of claim 1 , wherein A is an optionally substituted phenyl or heteroaryl.

3. The compound of claim 2 , wherein A is phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, amido, amino, an optionally substituted C 1-6 alkyl, carboxylate, cyano, halo, and hydroxyl.

4. The compound of claim 1 , wherein Het 2 is selected from the group consisting of imidazole, triazole and tetrazole.

5. The compound of claim 1 , wherein D 2 is carbon.

6. The compound of claim 1 , wherein E is an optionally substituted aryl or heteroaryl.

7. A compound represented by Formula (Ib2)

or a derivative thereof, wherein
A is an optionally substituted aryl or heteroaryl;
D 4 and D 5 are each independently CR 2 , or N, wherein D 4 and D 5 together with the two nitrogen attached thereto Het 2 , which is an optionally substituted 5-membered heteroaryl;
E is aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, each of which may be optionally substituted, or E is an unsubstituted alkyl; and
R 2 is independently H, alkoxy, optionally substituted C 1-6 alkyl, amido, amino, cyano, halo, hydroxyl, sulfonyl, or sulfonamido.

8. A compound represented by Formula (Ib3)

or a derivative thereof, wherein
A is an optionally substituted aryl or heteroaryl;
D 3 and D 5 are each independently CR 2 or N, wherein D 3 and D 5 together with the two nitrogen attached thereto Het 2 , which is an optionally substituted 5-membered heteroaryl;
E is aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, each of which may be optionally substituted, or E is an unsubstituted alkyl; and
R 2 is independently H, alkoxy, optionally substituted C 1-6 alkyl, amido, amino, cyano, halo, hydroxyl, sulfonyl, or sulfonamido.

9. A compound selected from the group consisting of:
2-(2-Chlorophenyl)-3-(1-(4-chlorophenyl)-1H-tetrazol-5-yl)imidazo[1,2-a]pyridine;
2-(2-Chlorophenyl)-3-(4-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
3-(4-Cyclohexyl-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
2-(2-Chlorophenyl)-3-(1-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyridine;
3-(1-(4-Chlorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
3-(4-(4-Chlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
3-(1-(4-Chlorophenyl)-1H-imidazol-2-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
3-(1-(4-Chlorophenyl)-1H-imidazol-5-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-isopropyl-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-N,N-dimethylaniline;
4-(4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)phenyl)morpholine;
2-(2,5-Dichlorophenyl)-3-(4-(4-(methylsulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(4-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
5-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indazole;
4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)benzonitrile;
6-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indazole;
6-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-benzo[d]imidazole;
5-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole;
5-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-indazole;
6-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-indazole;
5-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-benzo[d]imidazole;
6-(3-(2-(2-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indazole;
3-(4-(1H-Indazol-6-yl)-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-b]pyridazine;
3-(4-(4-Chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine;
4-(4-Chlorophenyl)-3-(2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-1H-1,2,4-triazol-5 (4H)-one;
4-(4-Chlorophenyl)-3-(2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-1H-1,2,4-triazole-5 (4H)-thione;
3-(4-(4-Chlorophenyl)-5-methoxy-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
3-(4-(4-Chlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(4-ethylphenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(4-isopropylphenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
3-(4-([1,1′-Biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
Ethyl 4-(3-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine-3-yl)-4H-1,2,4-triazol-4-yl)benzoate;
2-(2,5-Dichlorophenyl)-3-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
2-(2,5-Dichlorophenyl)-3-(4-(4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridine-3-yl)-4H-1,2,4-triazol-4-yl)-3,5-dimethylisoxazole;
N-(4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)phenyl)-N-methylacetamide;
2-(2,5-Dichlorophenyl)-3-(4-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)imidazo[1,2-a]pyridine;
6-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)quinoline;
N-(2-Chloro-4-(3-(2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)phenyl)acetamide;
3-(4-(4-Chlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-(2,5-dichlorophenyl)imidazo[1,2-a]pyridine;
4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indazole;
4-(3-(2-(2,5-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-indazole;
2-(2,5-Dichlorophenyl)-3-(4-(4-(4-methylpiperazin-1-yl)phenyl)-4H-1,2,4-triazol-3-

Assignees

• Song Jiangao
• Pham Phuongly
• Ma Jingyuan
• Novack Aaron Robert
• Nashashibi Imad
• Wone David W G
• Shi Dong-Fang
• Chen Xin
• Cymabay Therapeutics Inc

Inventors

• Song Jiangao
• Pham Phuongly
• Ma Jingyuan
• Novack Aaron Robert
• Nashashibi Imad
• Wone David W G
• Shi Dong-Fang
• Chen Xin

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title