Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to GPR40

1. A compound of formula (I)

including salts thereof, wherein

t is 0, 1, 2, 3, or 4;

R 1 is alkyl, alkoxy, halogen, haloalkyl, nitro, cyano, or —NR 7 R 8 , where each of R 7 and R 8 independently are H or alkyl;

A is —OH, OR 9 where R 9 is alkyl or aryl, or —NR 2 R 3 ;

each of R 2 and R 3 independently is H or -(Q 1 ) n -R 4 ;

n is 0, 1 or 2;

Q 1 is alkylene;

each R 4 independently is alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxy, alkoxy, or aryloxy;

X 1 is —NH—;

X 2 is —C(R 5 ) 2 —;

each R 5 independently is H or alkyl;

Y is aryl or heteroaryl;

Z is -(Q 2 ) m -R 6 ;

m is 0 or 1;

Q 2 is —NR 5 —, —O—, —S—, —O(CH 2 ) p —, or —CH 2 —;

p is 1, 2, or 3; and

R 6 is aryl or heteroaryl.

2. The compound of claim 1 wherein X 2 is —CH 2 —.

3. The compound of claim 2 wherein X 1 is substituted para to the depicted cyclopropyl ring.

4. The compound of claim 1 wherein t is 0.

5. The compound of claim 1 wherein Y is aryl.

6. The compound of claim 5 wherein Y is phenyl.

7. The compound of claim 6 wherein said phenyl is unsubstituted or is optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, or C 1 -C 6 haloalkyl.

8. The compound of claim 1 wherein Y is heteroaryl.

9. The compound of claim 8 wherein Y is thiazolyl.

10. The compound of claim 9 wherein said thiazolyl is unsubstituted or is optionally substituted with C 1 -C 6 alkyl, aryl, or heteroaryl.

11. The compound of claim 1 wherein A is —OH.

12. The compound of claim 1 wherein Q 1 is unsubstituted alkylene.

13. The compound of claim 1 wherein Q 1 is optionally substituted alkylene.

14. The compound of claim 1 wherein Z is —O—R 6 .

15. The compound of claim 14 wherein R 6 is phenyl.

16. The compound of claim 15 wherein said phenyl is unsubstituted or is optionally substituted with halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

17. The compound of claim 1 wherein Z is —R 6 .

18. The compound of claim 17 wherein R 6 is phenyl.

19. The compound of claim 18 wherein said phenyl is unsubstituted or is optionally substituted with halogen, C 1 -C 6 haloalkyl, or C 1 -C 6 alkoxy.

20. The compound of claim 19 wherein R 6 is heteroaryl.

21. The compound of claim 1 wherein A is —OH, t is 0, X 1 is —NH—, X 2 is —CH 2 —, Y is phenyl, m is 1, Q 2 is —O—, and R 6 is phenyl.

22. The compound of claim 1 wherein A is —OH, t is 0, X 1 is —NH—, X 2 is —CH 2 —, Y is thiazolyl, m is 0, and R 6 is phenyl substituted with —CF 3 .

23. The compound of claim 1 wherein the compound is selected from:

Racemic-(trans)-2-[4-({[3-(phenyloxy)phenyl]methyl}ammonium)phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[(4-biphenylylmethyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-[4-({[4-(2-pyridinyl) phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({3-[(3,4-dichlorophenyl)oxy]phenyl}methyl)ammonium]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-(4-{[(3-{[4-(methyloxy)phenyl]oxy}phenyl)methyl]ammonium}phenyl)-cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({3-[(4-chlorophenyl)oxy]phenyl}methyl)ammonium]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-(4-{[(3-{[4-(1,1-dimethylethyl)phenyl]oxy}phenyl)methyl]ammonium}phenyl)cyclopropanecarbox ylic acid;

Racemic-(trans)-2-{4-[({3-[(3,5-dichlorophenyl)oxy]phenyl}methyl)ammonium]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-(4-{[(3-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]ammonium}-phenyl)cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({3-[(4-methylphenyl)oxy]phenyl}methyl)ammonium]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4[({3-[(phenylmethyl)oxy]phenyl}methyl)ammonium]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-[4-({[4-methyl-2-(phenyloxy)-1,3-thiazol -5-yl]methyl}ammonium)-phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({4-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-[4-({[5-(4-chlorophenyl)-2-furanyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({4-[(phenylmethyl)oxy]phenyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({2-[(3,4-difluorophenyl)oxy]-4-methyl-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({5-[4-(trifluoromethyl)phenyl]-2-furanyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({5-[4-(trifluoromethyl)phenyl]-2-thienyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({4-[4-(trifluoromethyl)phenyl]-2-furanyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-[4-({[3-(phenylmethyl)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({3-[(4-nitrophenyl)oxy]phenyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Racemic-(trans)-2-[4-({[3-(phenylthio)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[({3-[(4-aminophenyl)oxy]phenyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

(−)-(Trans)-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

(+)-(Trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid;

(+)-(Trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Enantiomerically enriched (trans)-ethyl-2-{4-[({3-[(3,4-dichlorophenyl)oxy]phenyl}methyl)amino]phenyl}-cyclopropanecarboxylate;

(+)-(Trans)-2-{4-[({3-[(3,4-dichlorophenyl)oxy]phenyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

(−)-(cis)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

Enantiomerically enriched-(trans)-ethyl-2-[2-chloro-4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate;

(+)-(Trans)-2-[2-chloro-4-({[3-(phenyloxy) phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

Enantiomerically enriched-(trans)-ethyl-2-[2,5-difluoro-4-({[3-(phenyloxy) phenyl]methyl}amino)phenyl]cyclopropanecarboxylate;

(+)-(trans)-2-[2,5-difluoro-4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylic acid;

(+)-(trans)-2-{4-[({3-[(3,5-dichlorophenyl)oxy]phenyl}methyl)amino]phenyl}cyclopropanecarboxylic acid;

(+)-(trans)-2-(4-{[(3-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]amino}phenyl)cyclopropanecarboxylic acid;

(+)-(trans)-2-{4-[({3-[(4-methylphenyl)oxy]phenyl}methyl)amino]phenyl}-cyclopropanecarboxylic acid;

Racemic-(trans)-2-{4-[(4-biphenylmethyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-2-[4-({[4-(2-pyridinyl)phenyl]methyl}amino)phenyl]cyclopropanecarboxamide;

Racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}-N-(4-pyridinylmethyl)cyclopropanecarboxamide;

Enantiomerically enriched (trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}-N-(4-pyridinylmethyl)cyclopropanecarboxamide;

Enantiomerically enriched (trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

Enantiomerically enriched (trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}-N-[(1S)-1-phenylethyl]cyclopropanecarboxamide;

Enantiomerically enriched (trans)-N-hydroxy-2-{4[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

Enantiomerically enriched (trans)-N-cyclobutyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

(+)-(trans)-N-(1-methylethyl)-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxamide;

Racemic-(trans)-N-isopropyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-N,N-dimethyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-2-[4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]-N-(4-pyridinylmethyl)cyclopropanecarboxamide;

Racemic-(trans)-N-(4-methoxybenzyl)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}-N-[4-(trifluoromethyl)benzyl]cyclopropanecarboxamide;

Racemic-(trans)-N-(2-morpholin-4-ylethyl)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxamide;

Racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}-N-(2,2,2-trifluoroethyl)cyclopropanecarboxamide;

Racemic-(trans)-N-isopropyl-2-{4-[({4-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide; and

Enantiomerically enriched N-isopropyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxamide; and

Enantiomerically enriched N-(cyclopropylmethyl)-2-{4[(3-phenoxybenzyl) amino]phenyl}cyclopropanecarboxamide, including salts thereof.

24. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.