Azaindole derivatives as CRTH2 receptor antagonists

1. A compound of the formula I:

or a pharmaceutically acceptable salt thereof, wherein:

one of X 1 , X 2 , X 3 and X 4 is N and the others are CH;

Y is selected from —C(R a )(R b )—, —C(R a )(R b )—C(R a )(R b )—, —C(R a )═C(R b )—, —OCH 2 —, —OCH(C 1-3 alkyl)-, —OC(C 1-3 alkyl) 2 -, —O(CH 2 ) 2-5 —, —SCH 2 —, —SCH(C 1-3 alkyl)-, —SC(C 1-3 alkyl) 2 - and —S(CH 2 ) 2-5 —;

Cy is aryl, heteroaryl or C 3-6 cycloalkyl optionally fused to a benzene, each of which is optionally substituted with 1 to 4 groups independently selected from R c ;

R 1 is selected from H, halogen, —C 1-6 alkyl and —OC 1-6 alkyl;

R 2 is selected from H, halogen, —C 1-6 alkyl, —OC 1-6 alkyl, —SC 1-6 alkyl, —S(O)C 1-6 alkyl, —S(O) 2 C 1-6 alkyl, —CN, aryl and heteroaryl;

R 3 is selected from H, C 1-6 alkyl and benzyl optionally substituted on the phenyl portion with 1 to 3 halogen;

R a and R b are independently H, aryl, heteroaryl, C 1-6 alkyl or haloC 1-6 alkyl; or

R a and R b together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl ring; or

R a and R b together with the adjacent carbon atoms to which they are attached form a C 3-6 cycloalkyl ring;

R c is selected from halogen, NR f R g , SO 2 NR f R g , CN, C 1-6 alkoxy, C 1-6 alkyl, haloC 1-6 alkoxy, and haloC 1-6 alkyl;

R d and R e are independently selected from hydrogen, C 1-6 alkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, hydroxy, C 1-6 alkoxy, aryl optionally substituted with 1 to 3 groups independently selected from R c , and NR f R g ; or

R d , R e together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl optionally having a ring heteroatom selected from —O—, —S—, —N(C(O)R f )— and —N(R f )—, and optionally substituted with 1 to 3 C 1-3 alkyl groups; and

R f and R g are independently selected from hydrogen and C 1-3 alkyl; or

R f , R g together with the atom to which they are both attached form a 3- to 6-membered ring.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Cy is phenyl optionally substituted with 1 to 3 groups independently selected from R c .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Y is —C(R a )(R b )—.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Cy is phenyl optionally substituted with 1 to 2 groups independently selected from halogen, C 1-6 alkyl, haloC 1-6 alkyl and C 1-6 alkoxy.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein the chiral carbon to which the —NR 3 —C(O)CR d R e -Cy moiety is attached has the (R)-configuration.

6. The compound of claim 1 I having the formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d and R e are as defined in claim 1 .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are each hydrogen.

8. The compound of claim 1 having the formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d and R e are as defined in claim 1 .

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are each hydrogen.

10. The compound of claim 1 having the formula Ic:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d and R e are as defined in claim 1 .

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are each hydrogen.

12. The compound of claim 1 having the formula Id:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R c , R d and R e are as defined in claim 1 .

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein R 1 and R 2 are each hydrogen.

14. The compound of claim 1 having the formula Ie:

or a pharmaceutically acceptable salt thereof, wherein R 1 and R 3 are as defined in claim 1 ; R c is a halogen; R c′ is hydrogen or a halogen; R d and R e are independently selected from hydrogen and C 1-3 alkyl, or R d and R e together with the carbon atom to which they are both attached form a C 3-6 cycloalkyl or tetrahydropyranyl, each of which is optionally substituted with 1 to 2 C 1-3 alkyl groups.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof wherein R 1 and R c′ are each hydrogen, R c is a fluorine, and R 3 is methyl.

16. A compound selected from the group consisting of:

((8R)-8-{methyl[(2R)-2-(4-fluorophenyl)propanoyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]-indolizin-5-yl)acetic acid;

((8R)-8-{methyl[(2S)-2-(4-fluorophenyl)propanoyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]-indolizin-5-yl)acetic acid;

{(8R)-8-[[2-(4-fluorophenyl)-3-methylbutanoyl](methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid;

{(8R)-8-[(diphenylacetyl)(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid;

{(8R)-8-[[2-(4-fluorophenyl)-2-methylpropanoyl](methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid;

{(8R)-8-[{[4-(4-fluorophenyl)tetrahydro-2H-pyran-4-yl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid;

{(8R)-8-[{[1-(4-fluorophenyl)-2,2-dimethylcyclopropyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid;

{(8R)-8-[{[1-(4-fluorophenyl)cyclobutyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid; and

{(8R)-8-[{[1-(4-fluorophenyl)cyclopentyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indolizin-5-yl}acetic acid;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 which is ((8R)-8-{methyl[(2R)-2-(4-fluorophenyl)propanoyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)acetic acid or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 which is ((8R)-8-{methyl[(2S)-2-(4-fluorophenyl)propanoyl]amino}-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)acetic acid or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 which is {(8R)-8-[[2-(4-fluorophenyl)-3-methyl-butanoyl](methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 which is {(8R)-8-[(diphenylacetyl)(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 which is {(8R)-8-[[2-(4-fluorophenyl)-2-methyl-propanoyl] (methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 which is {(8R)-8-[{[4-(4-fluorophenyl)-tetrahydro-2H-pyran-4-yl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 which is {(8R)-8-[{[1-(4-fluorophenyl)-2,2-dimethylcyclopropyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 which is {(8R)-8-[{[1-(4-fluorophenyl)-cyclobutyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 which is {(8R)-8-[{[1-(4-fluorophenyl)-cyclopentyl]carbonyl}(methyl)amino]-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl}acetic acid or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 26 comprising a second active ingredient selected from the group consisting of a leukotriene antagonist, a 5-lipooxygenase inhibitor and a FLAP inhibitor.