Pyrazole compounds as CRTH2 antagonists
View Patent ↗The present invention relates to pyrazole compounds of formula (I) and pharmaceutically acceptable salts thereof having CRTH2-activity, wherein W, L 1 , L 2 , X, L 3 , Y, R 1 and R 2 are as defined in the specification and claims, to their use as medicaments and to pharmaceutical formulations, containing said compounds or containing a combination of said compounds with one or more active substances.
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from hydroxycarbonyl, —C(O)—NH—S(O) 2 —R a , tetrazol-5-yl, 1,2,4-oxadiazol-5(4H)-on-3-yl, and 1,3,4-oxadiazol-2(3H)-on-5-yl, wherein R a is selected from C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, cyclopropyl, phenyl, and tolyl;
L 1 is methylene, ethylene, ethenylene, or acetylene, wherein each carbon atom in the L 1 methylene or ethylene is unsubstituted or carries 1 or 2 radicals selected independently from hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, and C 3 -C 8 -cycloalkyl, and wherein two radicals bound to the same carbon atom of the L 1 methylene or ethylene together with the carbon atom optionally forms a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as 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, and C 3 -C 8 -cycloalkyl, and/or wherein two radicals bound to the same carbon atom of the L 1 methylene or ethylene together with the carbon atom optionally forms a carbonyl group;
L 2 is methylene or ethylene, wherein each carbon atom in L 2 methylene or ethylene is unsubstituted or carries 1 or 2 radicals selected independently from hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, and C 3 -C 8 -cycloalkyl and wherein two radicals bound to the same carbon atom of the L 2 methylene or ethylene together with the carbon atom optionally forms a carbonyl group and wherein two radicals bound to the same carbon atom of the L 2 methylene or ethylene together with the carbon atom optionally forms a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as 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;
X is a 6-membered carbocyclic or heterocyclic moiety selected from phen-1,4-ylene, pyridin-2,5-ylene, pyridazin-3,6-ylene, pyrimidin-2,5-ylene, and pyrazin-2,5-ylene, each optionally unsubstituted or substituted with 1, 2, or 3 radicals selected independently from hydroxy, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, and C 3 -C 8 -cycloalkyl;
L 3 is selected from —CH═CH—, —C≡C—, —CR b R c —CH(OH)—, —CR b R c —C(O)—, —CR b R c —O—, —CR b R c —NR d —, —CR b R c —S(O) m —, —CH(OH)—, —C(O)—, —C(O)—NR d —, —O—, —NR d —, —NR d —C(O)—, —NR d C(O)—O—, —NR d —C(O)—NR e —, —NR d —S(O) p —, —S(O) p —, and —S(O) q —NR d —, wherein m, n, and p are each independently 0, 1, or 2 and q is 1 or 2, and wherein R b and R c are independently selected from H, C 1 -C 6 -alkyl, and C 3 -C 8 -cycloalkyl and wherein two radicals R b and R c bound to the same carbon atom together with the carbon atom optionally form a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as 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, and C 3 -C 8 -cycloalkyl, and wherein R d and R e are each independently H or C 1 -C 6 -alkyl;
Y is selected from 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, 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, and heterocyclyl-C 2 -C 6 -alkenyl, wherein the C 1 -C 6 -alkyl and C 2 -C 6 -alkenyl moieties thereof 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 wherein two of the substituents bound to the same carbon atom of the C 1 -C 6 -alkyl moieties together with the carbon atom optionally forms a 3- to 8-membered ring, wherein the ring optionally contains 1 or 2 heteroatoms selected from O, N, and S as ring member, and wherein the C 3 -C 8 -cycloalkyl, phenyl, naphthyl, or heterocyclyl moieties thereof are unsubstituted or carry at least one substituent selected from 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, and 5- or 6-membered heterocyclyloxy, wherein R f and R g are independently selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl and 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, which optionally comprises a further heteroatom selected from O, N, and S as a ring member,
and/or wherein two radicals bound to the same carbon atom of the C 3 -C 8 -cycloalkyl or heterocyclyl moieties thereof together with the carbon atom optionally forms a carbonyl group, and/or
wherein the C 3 -C 8 -cycloalkyl, phenyl, naphthyl, or heterocyclyl moieties thereof optionally carry a fused carbocyclic or heterocyclic moiety, wherein the fused carbocyclic or heterocyclic moiety is unsubstituted or carries 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 fused carbocyclic or heterocyclic moiety together with the carbon atom optionally forms a carbonyl group; and
R 1 and R 2 are each independently selected from 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, and 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 forms a carbonyl group, and
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 forms a carbonyl group, and
R f and R g are independently selected from H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, and heterocyclyl, or
R f and R g together with the nitrogen atom to which they are bound form a cyclic amine, which optionally comprises a further heteroatom selected from O, N, and S as a ring member.
2. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is hydroxycarbonyl.
3. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is methylene.
4. The compound of formula (I) according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein L 1 is unsubstituted methylene.
5. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is methylene.
6. The compound of formula (I) according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein L 2 is unsubstituted methylene.
7. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is phen-1,4-ylene or pyridin-2,5-ylene.
8. The compound of formula (I) according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein X is phen-1,4-ylene.
9. The compound of formula (I) according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted phen-1,4-ylene.
10. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from —CH═CH—, —C≡C—, —CR b R c —O—, —CR b R c —S(O) m —, —CH(OH)—, —C(O)—, —C(O)—NR d —, —O—, —NR d —, —NR d —C(O)—, —NR d C(O)O—, —NR d —C(O)—NR e —, —NR d —S(O) p —, —S(O) p —, and —S(O) q —NR d —.
11. The compound of formula (I) according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from —CR b R c —O—, —C(O)—NR d —, —O—, —NR d —C(O)—, —NR d C(O)O—, —NR d C(O)—NR e —, —NR d —S(O) p —, and —S(O) q —NR d —.
12. The compound of formula (I) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein L 3 is —C(O)—NR d — and R d is H or C 1 -C 6 -alkyl.
13. The compound of formula (I) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein L 3 is —NR d —C(O)— and R d is H or C 1 -C 6 -alkyl.
14. The compound of formula (I) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein L 3 is —NR d C(O)O- and R d is H or C 1 -C 6 -alkyl.
15. The compound of formula (I) according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein L 3 is —S(O) 2 —NR d —.
16. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from phenyl, phenyl-C 1 -C 6 -alkyl, phenyl-C 2 -C 6 -alkenyl, naphthyl, naphthyl-C 1 -C 6 -alkyl, and naphthyl-C 2 -C 6 -alkenyl, wherein the phenyl or naphthyl moieties thereof are unsubstituted or carry at least one substituent selected from 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, and 5- or 6-membered heterocyclyloxy, and/or
wherein the phenyl or naphthyl moieties thereof optionally carry a fused carbocyclic or heterocyclic moiety, wherein the fused carbocyclic or heterocyclic moiety is unsubstituted or carries 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 fused carbocyclic or heterocyclic moiety together with the carbon atom optionally forms a carbonyl group.
17. The compound of formula (I) according to claim 16 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from phenyl, benzyl, phenethyl, phenethenyl, naphthyl, naphthylmethyl, naphthylethyl, and naphthylethenyl.
18. The compound of formula (I) according to claim 16 , or a pharmaceutically acceptable salt thereof, wherein Y is selected from phenyl and naphthyl.
19. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, phenyl, and naphthyl.
20. The compound of formula (I) according to claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, and phenyl.
21. The compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is C 1 -C 4 -alkyl.
22. A method of treating a CRTH2-activity disorder selected from a respiratory or gastrointestinal diseases; an inflammatory diseases of the joints; and an allergic diseases of the nasopharynx, eyes, and skin, the method comprising administering to a patient in need thereof of a pharmaceutically effective amount of the compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 , wherein the CRTH2-activity disorder is a respiratory or gastrointestinal disease.
24. A pharmaceutical formulation comprising the compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical formulation comprising the compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more active substances selected from among betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CCR3 antagonists, CCR5 antagonists, CCR9 antagonists, 5-LO inhibitors, histamine-receptor antagonists, SYK inhibitors, and sulfonamides.
26. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-trifluoromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
27. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-chloro-2-methylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
28. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(benzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
29. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-methylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
30. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-methoxybenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
31. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-chloromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
32. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-Dimethyl-1-[4-(naphtalene-2-carbonylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid or a pharmaceutically acceptable salt thereof.
33. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(3,4-dichloromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
34. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2-methyl-4-trifluoromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
35. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2,4-dimethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
36. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-tert-butylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
37. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-bromo-2-methylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
38. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-bromo-2,5-dimethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
39. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2,4-dichlorobenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
40. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-chloro-2-fluorobenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
41. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2-fluoro-4-methylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
42. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-methyl-2-trifluoromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
43. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2-fluoro-4-trifluoromethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
44. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(3-chloronaphtalene-2-carbonylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
45. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2,4,6-trimethylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
46. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(3-methylnaphtalene-2-carbonylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
47. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(1-methylnaphtalene-2-carbonylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
48. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(4-bromo-2-chlorobenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
49. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2-bromo-4-chlorobenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
50. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(1-bromonaphtalene-2-carbonylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.
51. The compound of formula (I) according to claim 1 , wherein the compound is {3,5-dimethyl-1-[4-(2-bromo-5-methylbenzoylamino)benzyl]-1H-pyrazol-4-yl}acetic acid or a pharmaceutically acceptable salt thereof.