CRTH2 modulators

1. A compound having Formula I, or a pharmaceutically acceptable salt thereof;

with the proviso that the compound having Formula I is not a compound selected from 5[[6-methoxy-3-(4-methoxybenzoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl]methyl]-α,α-dimethyl-2H-Tetrazole-2-acetic acid [CAS Registry No. 1097838-63-5], 5-[[5-(benzoylamino)-2-thiazolyl]thio]-2H-tetrazole-2-acetic acid [CAS Registry No. 1099441-56-1], 2-butyl-1-[[4-[(2-carboxybenzoyl)amino]phenyl]methyl]-5-chloro-1H-imidazole-4-acetic acid [CAS Registry No. 114798-40-2], and 2-butyl-1-[[4-[(2-carboxybenzoyl)amino]phenyl]methyl]-5-chloro-1H-imidazole-4-acetic acid [CAS Registry No. 114773-45-4],

wherein:

ring A is a phenyl or pyrrolidinyl;

ring B is a phenyl;

ring D is an optionally substituted pyrrolyl; wherein

x 1 is N;

x 2 is C—R 2 ;

x 3 is C;

x 4 is C—R 4 ; and

x 5 is C—R 5 ;

R 2 is selected from —H, a halogen, —CN, a C 1-6 aliphatic radical, a C 1-6 alkoxy and a cyclopropyl ring, wherein R 2 is independently substituted with from 0 to 3 instances of R A ; wherein

each R A is independently selected from a halogen, —OH, a C 1-2 alkoxy and a C 1-2 haloalkoxy;

R 4 is selected from a halogen, —CN, —R 6 , —OR 6 , —C(O)R 6 , —C(O)OR 6 , —N(R 6 ) 2 ;

R 5 is selected from a halogen, —CN, —R 6 , —OR 6 , —C(O)R 6 , —N(R 6 ) 2 ;

p is an integer selected from 0, 1 and 2;

each R 6 is independently selected from —H, a C 1-6 aliphatic radical,

a 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, and a C 3-10 cycloaliphatic ring;

wherein

when R 6 is a C 1-6 aliphatic radical, it is independently substituted with from 0 to 6 instances of R 7 ,

when R 6 is a C 3-10 cycloaliphatic ring or a 5 or 6-membered heteroaryl, it is independently substituted with from 0 to 6 instances of R 8 , and

when R 6 is 6-membered aryl, it is independently substituted with from 0 to 6 instances of R 8′ ;

each R 7 is independently selected from a halogen, —CN, oxo, —OR 9 and —C(O)R 9 ;

each R 8 is independently selected from a halogen, —CN, oxo, a C 1-6 aliphatic radical, and —C(O)R 9 ;

each R 8′ is independently selected from a halogen, —CN, a C 1-6 aliphatic radical, and —C(O)R 9 ;

 each R 9 is independently selected from hydrogen, a C 1-6 aliphatic radical,

 a 6 membered aryl, a 5 or 6 membered heteroaryl, and a C 3-10 cycloaliphatic; wherein

 when R 9 is a C 1-6 aliphatic radical, it is independently substituted with from 0 to 6 instances of R 11 , and

 when R 9 is a 6-membered aryl, a 5 or 6-membered heteroaryl, or a C 3-10 cycloaliphatic ring, it is independently substituted with from 0 to 3 instances of R 12 ;

 each R 11 is independently selected from a halogen, —CN, —OH, a C 1-4 alkoxy and a C 1-4 haloalkoxy;

 each R 12 is independently selected from a halogen, —CN, —OH, a C 1-4 alkyl, a C 1-4 haloalkyl, a C 1-4 alkoxy and a C 1-4 haloalkoxy;

R 13 is selected from —H, a C 1-6 aliphatic radical, and a monocyclic or bicyclic ring, wherein the ring is selected from a 6 to 10-membered aryl, a 5 to 10-membered heteroaryl, a C 3-10 cycloaliphatic and a 4 to 10-membered heterocycle; wherein

when R 13 is a C 1-6 aliphatic radical, it is independently substituted with from 0 to 6 instances of R 14 ;

when R 13 is a non-aromatic ring or a heteroaryl, it is independently substituted with from 0 to 6 instances of R 15 ; and

when R 13 is an aryl, it is independently substituted with from 0 to 6 instances of R 15′ ;

each R 14 is independently selected from a halogen, —CN, oxo, —OR 9 , —R 10 , —C(O)R 9 , —C(O)OR 9 , —S(O) m R 9 , —N(R 9 ) 2 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 9 , —C(O)N(R 9 ) 2 and —NR 9 C(O)R 9 ;

each R 15 is independently selected from a halogen, —CN, —NO 2 , oxo, a C 1-6 aliphatic radical, —R 10 , —C(O)R 9 , —C(O)OR 9 , —OR 9 , —S(O) m R 9 , —N(R 9 ) 2 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 9 , —C(O)N(R 9 ) 2 and —NR 9 C(O)R 9 ; and

each R 15′ is independently selected from a halogen, —CN, —NO 2 , a C 1-6 aliphatic radical, —R 10 , —C(O)R 9 , —C(O)OR 9 , —OR 9 , —S(O) m R 9 , —N(R 9 ) 2 , —S(O) 2 N(R 9 ) 2 , —NR 9 S(O) 2 R 9 , —C(O)N(R 9 ) 2 and —NR 9 C(O)R 9 ;

R 16 and R 17 are each independently selected from —H, deuterium, a C 1-6 alkyl, a C 1-6 haloalkyl and a halogen, or

alternatively, R 16 and R 17 are independently selected from a C 1-6 alkyl and a C 1-6 haloalkyl, and R 16 and R 17 taken together with the atom to which they are attached form a cyclopropyl or halocyclopropyl ring;

L is a linker selected from a methylene, —O—, —S(O) m — and —NR 1 —; wherein

when L is a methylene, it is independently substituted with from 0 to 2 instances of R 18 ;

m is 0, 1 or 2;

R 1 is selected from —H, a C 1-6 aliphatic radical, a C 3-6 cycloaliphatic, —CO(C 1-6 aliphatic), —CO(C 3-6 cycloaliphatic), —CO—(phenyl), a benzyl and —CO—(benzyl); wherein

when R 1 is selected from a C 1-6 aliphatic radical, —CO—(phenyl), a benzyl and —CO—(benzyl), it is independently substituted with from 0 to 3 instances of R B ; wherein each R B is independently selected from a halogen, a C 1-2 alkyl and a C 1-2 alkoxy;

each R 18 is independently selected from a halogen, —CN, a C 1-6 aliphatic radical, a C 1-6 haloaliphatic radical, and a C 3-6 cycloaliphatic; or

alternatively, each R 18 is independently selected from a C 1-6 aliphatic radical and a C 1-6 haloaliphatic radical, and two R 18 groups, taken together with the atom to which they are attached form a cyclopropyl or halocyclopropyl ring;

o is an integer selected from 0, 1 and 2;

each J B is independently selected from a halogen, —NO 2 , —CN, —R 19 , —C(O)H, —C(O)OH, —C(O)NH 2 , —OH, —SH, —NH 2 , —C(O)R 19 , —C(O)OR 19 , —C(O)N(R 20 )R 19 , —N(R 20 )C(O)R 19 , —OR 19 , —SR 19 and —NR 19 R 20 ;

each R 20 is independently selected from a —H and a C 1-6 aliphatic radical;

each R 19 is independently selected from a C 1-6 aliphatic radical, a C 3-6 cycloaliphatic, a phenyl, a benzyl;

wherein

when R 19 is a C 1-6 aliphatic radical, it is independently substituted with from 0 to 3 instances of R C , wherein each R C is independently selected from a halogen, —CN, —OH, —NH 2 , a C 3-4 cycloalkyl, a C 3-4 halocycloalkyl, a —O (C 1-4 alkyl), a —O(C 3-4 cycloalkyl), a —O(C 3-4 halocycloalkyl), a —O(C 1-4 haloalkyl), a —NH(C 1-4 alkyl), and a —N(C 1-4 alkyl) 2 ; wherein

when R 19 is a phenyl, it is independently substituted with from 0 to 3 instances of R D , wherein each R D is independently selected from a halogen, a C 1-4 aliphatic radical, —CN, —OH, —NH 2 , a —O(C 1-4 alkyl), a —NH(C 1-4 alkyl) and a —N(C 1-4 alkyl) 2 ; and

when R 19 is a C 3-6 cycloaliphatic, it is independently substituted with from 0 to 3 instances of R D′ , wherein each R D′ is independently selected from a halogen, oxo, a C 1-4 aliphatic radical, —CN, —OH, —NH 2 , a —O(C 1-4 alkyl), a —NH(C 1-4 alkyl) and a —N(C 1-4 alkyl) 2 ;

L′ is a linker selected from —Y—SO 2 —, —NR 21 SO 2 —, —SO 2 NR 21 —, —Y—C(O)—, —NR 21 C(O)— and —C(O)NR 21 —; wherein

Y is selected from a single bond, a straight C 1-2 alkylene linker, and a branched C 2 alkylene linker, wherein the C 1-2 alkylene linker is independently substituted with from 0 to 3 halogen atoms;

R 21 is selected from hydrogen, a C 1-6 alkyl, and a C 1-6 haloalkyl; n is an integer selected from 0, 1, 2 and 3;

each J A is independently selected from a halogen, —CN, —R 22 , —C(O)H, —C(O)OH, —C(O)NH 2 , —OH, —SH and —NH 2 , —C(O)R 22 , —C(O)OR 22 , —C(O)N(R 23 )R 22 , —N(R 23 )C(O)R 22 , —OR 22 , —SR 22 and —NR 22 R 23 ;

each R 23 is independently selected from a —H and a C 1-6 aliphatic radical;

each R 22 is independently selected from a C 1-6 aliphatic radical, a C 3-6 cycloaliphatic ring, a phenyl, and a benzyl; wherein

when R 22 is a C 1-6 aliphatic radical, it is independently substituted with from 0 to 3 instances of R F , wherein each R F is independently selected from a halogen, —CN, —OH, —NH 2 , a C 3-4 cycloalkyl, a C 3-4 halocycloalkyl, a —O(C 1-4 alkyl), a —O(C 3-4 cycloalkyl), a —O(C 3-4 halocycloalkyl), a —O(C 1-4 haloalkyl), a —NH(C 1-4 alkyl), and a —N(C 1-4 alkyl) 2 ;

when R 22 is a C 3-4 cycloalkyl ring, it is independently substituted with from 0 to 3 instances of R G , wherein

 each R G is independently selected from a halogen, oxo, a C 1-4 aliphatic radical, —CN, —OH, —NH 2 , a —O(C 1-4 alkyl), a —NH(C 1-4 alkyl) and a —N(C 1-4 alkyl) 2 ; and

when R 22 is a phenyl, it is independently substituted with from 0 to 3 instances of R G′ , wherein

 each R G′ is independently selected from a halogen, a C 1-4 aliphatic radical, —CN, —OH, —NH 2 , —O(C 1-4 alkyl), —NH(C 1-4 alkyl) and —N(C 1-4 alkyl) 2 .

2. The compound of claim 1 , wherein R 16 and R 17 are each independently selected from —H and a methyl or, alternatively, R 16 and R 17 taken together with the carbon to which they are attached, form a cyclopropyl ring.

3. The compound according to claim 2 , wherein R 16 and R 17 are both —H.

4. The compound according to claim 1 , wherein the compound is selected from compounds having formula IA:

5. The compound according to claim 1 , wherein L is selected from a methylene, and —S—.

6. The compound according to claim 5 , wherein L is selected from a methylene and —S—.

7. The compound according to claim 6 , wherein the compound is selected from compounds having formula IIA or formula IIB:

8. The compound of claim 1 , wherein R 2 is selected from a halogen, —H, a cyclopropyl ring, a C 1-4 alkyl and a C 1-4 haloalkyl.

9. The compound according to claim 8 , wherein R 2 is selected from a C 1-4 alkyl and —H.

10. The compound according to claim 9 , wherein R 2 is a methyl.

11. The compound according to claim 10 , wherein the compound is selected from compounds having structural formula IIIA or structural formula IIIB:

12. The compound according to claim 1 , wherein L′ is selected from —SO 2 — and —CH 2 SO 2 —.

13. The compound according to claim 12 , wherein L′ is —SO 2 —.

14. The compound of claim 1 , wherein o is 0.

15. The compound according to claim 14 , wherein the compound is selected from compounds having structural formula IVA or structural formula IVB:

16. The compound of claim 1 , wherein ring A is phenyl.

17. The compound of claim 1 , wherein ring A is pyrrolidinyl.

18. The compound of claim 1 , wherein ring A is selected from a phenyl and an N-linked pyrrolidinyl.

19. The compound of claim 18 , wherein the compound is selected from compounds having structural formula VA, VC, VD or VF:

20. The compound of claim 1 , wherein R 4 is selected from a halogen, —CN, —R 6 , —OR 6 , —C(O)R 6 , —C(O)OR 6 , —N(R 6 ) 2 , —S(O) p R 6 , —S(O) 2 N(R 6 ) 2 , —NR 6 S(O) 2 R 6 , —C(O)N(R 6 ) 2 and —NR 6 C(O)R 6 .

21. The compound of claim 20 , wherein R 4 is selected from a —H, a halogen, —CN, a C 1-6 aliphatic radical, a C 3-6 cycloaliphatic ring, a C 1-6 haloaliphatic radical, a phenyl which is optionally substituted by R 8′ , a benzyl which is optionally substituted by R 8′ , —OR 6 and —C(O)R 6 .

22. The compound of claim 21 , wherein R 4 is selected from —H, a halogen, —CN, a C 1-4 alkyl, a C 1-4 haloalkyl, a C 3-6 cycloalkyl, a —O(C 1-4 alkyl), a —O(C 1-4 haloalkyl), a —O(C 3-6 cycloalkyl), a —O(phenyl), a —O(substituted phenyl), a —O(benzyl), a —O(substituted benzyl), a —C(O)(C 1-4 alkyl), a —C(O)(C 1-4 haloalkyl), a —C(O)(C 3-6 cycloalkyl), a —C(O)(phenyl), a —C(O)(substituted phenyl), a —C(O)(benzyl), —C(O)(substituted benzyl) and —C(O)H; wherein each of said substituted phenyl or benzyl rings, is substituted by from 0 to 4 instances of R 8′ .

23. The compound of claim 22 , wherein R 4 is selected from —H, a halogen, —CN, an ethyl, a methyl, a propyl, a trifluoroethyl, a trifluoromethyl, a cyclopropyl, a cyclopentyl, a cyclohexyl, a cyclopropyloxy, a cyclopentyloxy, a cyclohexyloxy, an ethoxy, a methoxy, a propyloxy, a trifluoromethoxy, a trifluoroethoxy, a benzoyl, a phenyl, a phenyloxy, a methylcarbonyl, an ethylcarbonyl, a trifluoromethylcarbonyl, a trifluoroethylcarbonyl, and —C(O)H; wherein each of said benzoyl, phenyl or phenyloxy is independently substituted by from 0 to 4 instances of R 8′ .

24. The compound of claim 23 , wherein R 4 is selected from a —H, a halogen, —CN, an ethyl, a methyl, a propyl, a trifluoroethyl, a trifluoromethyl, a cyclopropyl, a cyclopentyl, a cyclohexyl, phenyl, a benzoyl, a methylcarbonyl, an ethylcarbonyl, a trifluoromethylcarbonyl, a trifluoroethylcarbonyl and —C(O)H; wherein each of said phenyl and benzoyl groups is independently substituted by from 0 to 4 instances of R 8′ .

25. The compound of claim 24 , wherein R 4 is selected from a —H, iodo, —CN, methyl, 2,2,2-trifluoroethyl, benzoyl, methylcarbonyl, trifluoromethylcarbonyl, —C(O)H and phenyl; wherein said phenyl is independently substituted with from 0 to 2 instances of halogen.

26. The compound of claim 25 , wherein R 4 is a phenyl substituted with from 0 to 2 instances of halogen.

27. The compound of claim 26 , wherein R 4 is a phenyl substituted with from 0 to 2 instances of fluoro.

28. The compound of claim 25 , wherein R 4 is selected from a —H, —CN, a methyl, 2,2,2-trifluoroethyl, a benzoyl, a methylcarbonyl, a trifluoromethylcarbonyl, —C(O)H, a phenyl and a fluorophenyl; wherein said fluorophenyl is substituted with from 0 to 2 additional instances of fluoro.

29. The compound of claim 1 , wherein R 5 is selected from a halogen, —CN, a C 1-6 aliphatic radical independently substituted with from 0 to 4 instances of R 7 , a C 3-6 cycloaliphatic, a phenyl independently substituted with from 0 to 4 instances of R 8′ , and a 6-membered heteroaryl independently substituted with from 0 to 4 instances of R 8′ .

30. The compound of claim 29 , wherein R 5 is selected from a halogen, —CN, a C 1-6 alkyl independently substituted with from 0 to 4 instances of R 7 , a C 3-6 cycloaliphatic, a phenyl independently substituted by from 0 to 4 instances of R 8′ , and a 6-membered heteroaryl independently substituted by from 0 to 4 instances of R 8′ .

31. The compound of claim 30 , wherein R 5 is selected from the group consisting of: a halogen, —CN; a C 1-6 alkyl substituted with from 0 to 2 instances of a substituent independently selected from halogen and —OH; a 3-6 membered cycloalkyl, a phenyl and a 6-membered heteroaryl; wherein each of said phenyl and 6-membered heteroaryl rings is substituted by from 0 to 3 instances of a substituent independently selected from a halogen, a C 1-4 alkyl, a C 1-4 haloalkyl, a C 1-4 alkoxy, a C 1-4 haloalkoxy and —CN.

32. The compound of claim 31 , wherein R 5 is selected from a halogen, —CN, an ethyl, a methyl, a propyl, a 3-6 membered cycloalkyl, a phenyl, a pyridine and a pyrimidine; wherein each said methyl, ethyl and propyl is independently substituted with from 0 to 4 instances of a halogen or —OH; and wherein each said phenyl, pyridine and pyrimidine is substituted with from 0 to 4 instances of a substituent independently selected from a halogen, a C 1-2 alkyl, a C 1-2 haloalkyl, an C 1-2 alkoxy and a C 1-2 haloalkoxy.

33. The compound of claim 32 , wherein R 5 is selected from —CN, an ethyl, a methyl, a propyl, a cyclopropyl, a cyclopentyl, a cyclohexyl, a phenyl and a pyridine; wherein each said methyl, propyl and ethyl is independently substituted with from 0 to 2 instances of a halogen or —OH; wherein said phenyl is independently substituted by from 0 to 2 instances of halogen or —CF 3 ; and wherein said pyridine is substituted by from 0 to 4 instances of a substituent independently selected from a halogen, a C 1-2 alkoxy, a C 1-2 haloalkoxy and CF 3 .

34. The compound of claim 33 , wherein R 5 is selected from a —CN, a 2-hydroxyethyl, a methyl, a cyclopropyl, a cyclopentyl, a cyclohexyl, a phenyl and a pyridine; wherein said phenyl is independently substituted by from 0 to 2 instances of fluorine or —CF 3 ; and wherein said pyridine is independently substituted by from 0 to 1 instances of fluoro or chloro.

35. The compound of claim 34 , wherein R 5 is selected from —CN, a methyl, a cyclopropyl, a cyclopentyl, a cyclohexyl, a phenyl, pyridine, a 3-chloro-4-pyridinyl and a 3-chloro-2-pyridinyl; wherein said phenyl is independently substituted by from 0 to 2 instances of fluorine or from 0 to 1 instances of —CF 3 .

36. The compound of claim 1 , wherein R 13 is selected from a —H and a C 1-6 alkyl.

37. The compound of claim 36 , wherein R 13 is a —H.

38. The compound of claim 1 , wherein o is 1 or 2 and J B is a halogen.

39. A compound according to claim 1 selected from those depicted in Table 1.

40. A composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1 or 39 .

41. A composition comprising a compound according to claim 1 or 39 , in combination with one or more therapeutic agents seleted from: inactivating antibodies to interleukins; soluble chemokine receptors; a chemokine receptor modulators; histamine H1 receptor antagonists or antihistamines; leukotriene D4 receptor antagonists or leukotriene antagonists or a LTD4 antagonists; PGD2 receptor antagonists; VLA-4 antagonists; corticosteroids; immunosuppressants; non-steroidal anti-asthmatics, non-steroidal antiinflammatory agents (NSAIDs); cyclooxygenase-2 (COX-2) inhibitors; inhibitors of phosphodiesterase type IV (PDE-IV); opioid analgesics; antithrombotic agents; warfarin derivatives, β-blockers; β-adrenergic agonists; ACE inhibitors; vasodilators; anti-diabetic agents; preparations of interferon beta; gold compounds such as auranofin and aurothioglucose; TNF inhibitors; multiple sclerosis therapeutic agents; 5-aminosalicylic acid and prodrugs thereof; DNA-alkylating agents; antimetabolites; microtubule disruptors; DNA intercalators; DNA synthesis inhibitors; DNA cross-linking agents; hormone therapy; or cytostatic agents; and a pharmaceutically acceptable carrier.

42. The compound of claim 1 , having the following formula,

or a pharmaceutically acceptable salt thereof.