Pyrazole compounds as CRTH2 antagonists

1. A pyrazole compound of formula (Ia) or (Ib) and pharmaceutically acceptable salts thereof,

wherein:

R a and R b are each independently hydrogen, hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, or C 3 -C 8 -cycloalkyl, or R a and R b together with the carbon atom they are bound to form a carbonyl group, or R a and R b together with the carbon atom they are bound to form a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as a ring member and wherein the ring members of the ring are optionally independently substituted by hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, or C 3 -C 8 -cycloalkyl;

R c and R d are each independently hydrogen, hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, or C 3 -C 8 -cycloalkyl, or R c and R d together with the carbon atom they are bound to form a carbonyl group, or R c and R d together with the carbon atom they are bound to form a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as a ring member and wherein the ring members of the ring are optionally independently substituted by hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, or C 3 -C 8 -cycloalkyl;

Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently N or CR y , wherein each R y is independently H, hydroxy, halogen, cyano, nitro, SF 5 , C(O)NR f R g , C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 8 -cycloalkoxy, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylsulfonyl, phenyl, phenoxy, 5- or 6-membered heterocyclyl, or 5- or 6-membered heterocyclyloxy;

Z is O, S, or NR z , wherein R z is H, C 1 -C 6 -alkyl, or benzyl;

R 1 and R 2 are each independently H, halogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, —NR f R g , C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl-C 2 -C 6 -alkenyl, C 3 -C 8 -cycloalkenyl, C 3 -C 8 -cycloalkenyl-C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkenyl-C 2 -C 6 -alkenyl, phenyl, phenyl-C 1 -C 6 -alkyl, phenyl-C 2 -C 6 -alkenyl, naphthyl, naphthyl-C 1 -C 6 -alkyl, naphthyl-C 2 -C 6 -alkenyl, heterocyclyl, heterocyclyl-C 1 -C 6 -alkyl, or heterocyclyl-C 2 -C 6 -alkenyl, wherein

the C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl moieties in R 1 and R 2 are unsubstituted or carry at least one substituent selected from hydroxy, halogen, cyano, nitro, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylamino, di C 1 -C 6 -alkylamino, and C 1 -C 6 -alkylsulfonyl, and/or

wherein two radicals bound to the same carbon atom of the C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl moieties in R 1 and R 2 together with the carbon atom optionally form a carbonyl group, and wherein

the C 3 -C 8 -cycloalkyl, cycloalkenyl, phenyl, naphthyl, and heterocyclyl moieties in R 1 and R 2 are unsubstituted or carry at least one substituent selected from hydroxy, halogen, cyano, nitro, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylsulfonyl, phenyl, and 5- or 6-membered hetaryl and/or

wherein two radicals bound to the same carbon atom of the C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl and heterocyclyl moieties of R 1 and R 2 together with the carbon atom optionally form a carbonyl group;

R f and R g are each independently H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, or 5- or 6-membered heterocyclyl, or R f and R g together with the nitrogen atom to which they are bound form a cyclic amine optionally comprising a further heteroatom selected from O, N, and S as a ring member;

n is 0, 1, 2, or 3; and

R 3 are each independently halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, or C 3 -C 8 -cycloalkyl.

2. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein R a and R b are both hydrogen.

3. The pyrazole compounds of formula (Ia) or (Ib) according to claim 1 , wherein R c and R d are both hydrogen.

4. The pyrazole compounds of formula (Ia) or (Ib) according to claim 2 , wherein R c and R d are both hydrogen.

5. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein Y 1 is CR y1 and R y1 is independently selected from R y as defined in claim 1 .

6. The pyrazole compound of formula (Ia) or (Ib) according to claim 5 , wherein R y1 is H, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, or C 1 -C 6 -haloalkyl.

7. The pyrazole compound of formula (Ia) or (Ib) according to claim 5 , wherein Y 2 is CR y2 , Y 3 is CR y3 , Y 4 is CR y4 , and Y 5 is CR y5 , wherein R y2 , R y3 , R y4 and R y5 are each independently selected from R y .

8. The pyrazole compound of formula (Ia) or (Ib) according to claim 7 , wherein R y2 , R y3 , R y4 , and R y5 are each independently H, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, or C 1 -C 6 -haloalkoxy.

9. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein Z is O.

10. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein Z is S.

11. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein Z is NR z .

12. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein R 1 and R 2 are each independently H, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, or naphthyl.

13. The pyrazole compound of formula (Ia) or (Ib) according to claim 12 , wherein R 1 and R 2 are each independently H, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, or phenyl.

14. The pyrazole compound of formula (Ia) or (Ib) according to claim 13 , wherein R 1 and R 2 are each independently C 1 -C 4 -alkyl.

15. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein n is 0 or 1.

16. The pyrazole compound of formula (Ia) or (Ib) according to claim 1 , wherein R 3 are each independently halogen.

17. The pyrazole compound of formula (Ia) according to claim 7 , wherein the pyrazole compound is a compound of formula (Ia′)

and n is 0 or 1.

18. The pyrazole compound of formula (Ib) according to claim 7 , wherein the pyrazole compound is a compound of formula (Ib′)

and n is 0 or 1.

19. A method of treating a disease that can be treated by inhibition of CRTH2 receptor in a patient in need thereof, the method comprising administering an effective amount of a pyrazole compound of formula (Ia) or (Ib) according to claim 1 to the patient.

20. A pharmaceutical formulation comprising a pyrazole compound of formula (Ia) and/or (Ib) according to claim 1 and a pharmaceutical excipient.

21. The pharmaceutical formulation of claim 20 , further comprising a betamimetic, anticholinergic, corticosteroid, PDE4 inhibitor, LTD4 antagonist, EGFR inhibitor, CCR3 antagonist, CCR5 antagonist, CCR9 antagonist, 5-LO inhibitor, histamine-receptor antagonist, SYK inhibitor, or sulfonamide.

22. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

23. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(benzofuran-2-carbonyl)aminol-2-chlorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

24. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4- [(5-methoxybenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid or a pharmaceutically acceptable salt thereof.

25. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(7-fluoro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

26. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{[(5-chlorobenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

27. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4- [(7-methoxybenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

28. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-chlorobenzofuran-2-carbonyl)amino]benzyl}-3,5-diethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

29. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(benzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4yl)acetic acid or a pharmaceutically acceptable salt thereof.

30. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-fluoro-3-methylbenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

31. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4- [(7-chloro-3-methylbenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

32. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(3-ethyl-7-fluorobenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

33. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5,7-difluoro-3-ethylbenzofuran-2-carbonyl)amino]benzyl}3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

34. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4- [(6-chlorobenzofuran-2-carbonyl)amino]benzyl}3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

35. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4- [(7-chloro-3-methylbenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl) acetic acid or a pharmaceutically acceptable salt thereof.

36. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(3-ethyl-7-fluorobenzofuran- 2 -carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

37. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(6-chlorobenzofuran-2-carbonyl)amino]-2-fluorobenzy}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

38. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(methoxymethyl)benzofuran-2-carbonyl)amino]-2-fluorobenzyl}3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

39. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-chloro-3-methylbenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

40. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-bromo-3-methylbenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

41. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(3-ethyl-5-fluorobenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

42. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(3-ethyl-5-Fluorobenzofuran-2-carbonyl)amino]benzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

43. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-methoxy-3-methylbenzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

44. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(7-fluoro-3-methylbenzofuran-2-carbonyl)aminol]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.

45. The pyrazole compound according to claim 9 , wherein the pyrazole compound is (1-{4-[(5-fluoro-3-(n-propyl)benzofuran-2-carbonyl)amino]-2-fluorobenzyl}-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid or a pharmaceutically acceptable salt thereof.