Aryl sulfonyl (hydroxy) piperidines as CCR6 inhibitors

1. A compound having formula (Ia):

or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form, or rotamer thereof,

wherein

each R 1 is independently selected from the group consisting of halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR a , and —NR a R b ;

each R a and R b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 3-6 cycloalkyl;

Ar 2 is selected from the group consisting of:

i) monocyclic 5- or 6-membered aromatic or heteroaromatic ring having 0 to 3 heteroatoms as ring vertices selected from N, O and S, and which is substituted with 0 to 5 R 2 ; and

ii) bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring having 0 to 4 heteroatoms as ring vertices selected from N, O and S, and which is substituted with 0 to 5 R 2 ;

each R 2 is independently selected from the group consisting of halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR c , —SR c , —COR c , —CO 2 R c , —NR c R d , —CONR c R d , —CO(NR c ) 2 COR d , —SO 2 R c , —SO 2 NR c R d , —X 2 —CONR c R d , —X 2 —NR c SO 2 R d , —X 2 —NR c CO 2 R d , —X 2 —P(═O)(OR d ) 2 , —X 2 —O—P(═O)(OR d ) 2 , —N(R c )—R d —X 2 —NR c R d , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl and 5- or 6-membered heteroaryl; and wherein the heterocyclyl, spiroheterocyclyl and heteroaryl rings of R 2 have from 1 to 3 heteroatoms selected from N, O, and S, and are each unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 hydroxalkyl, and C 1-4 haloalkyl; and wherein two R 2 groups attached to the same carbon atom are optionally combined to form a 3- to 6-membered spirocyclic ring or a 3- to 6-membered spiroheterocyclic ring having from 1 to 3 heteroatoms selected from N, O, and S;

R c is independently selected from the group consisting of hydrogen, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl;

R d is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; and wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl rings of R d have from 1 to 3 heteroatoms selected from N, O, and S, and are each unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 hydroxalkyl, and C 1-4 haloalkyl;

or R c and R d , when attached to the same nitrogen atom are joined to form a 4- to 7-membered heterocyclic ring having from 0 to 2 additional heteroatoms as ring vertices selected from O, S, S(O), S(O) 2 , NH, and N(C 1-4 alkyl); and

X 2 is C 1-4 alkylene.

2. A compound having formula (Ia):

or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, optically enriched form, or rotamer thereof,

wherein

each R 1 is independently selected from the group consisting of halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR′, and —NR a R b ;

each R a and R b is independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, and C 3-6 cycloalkyl;

Ar 2 is selected from the group consisting of:

i) monocyclic 5- or 6-membered aromatic or heteroaromatic ring having 0 to 3 heteroatoms as ring vertices selected from N, O and S, and which is substituted with 0 to 5 R 2 ; and

ii) bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring having 0 to 4 heteroatoms as ring vertices selected from N, O and S, and which is substituted with 0 to 5 R 2 ;

each R 2 is independently selected from the group consisting of halogen, CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, —OR c , —SR c , —COR c , —CO 2 R c , —NR c R d , —CONR c R d , —CO(NR c ) 2 COR d , —SO 2 R c , —SO 2 NR c R d , —X 2 —CONR c R d , —X 2 —NR c SO 2 R d , —X 2 —NR c CO 2 R d , —X 2 —P(═O)(OR d ) 2 , —X 2 —O—P(═O)(OR d ) 2 , —NR c R d —X 2 —NR c R d , oxo, 4- to 6-membered heterocyclyl, 7- to 10-membered spiroheterocyclyl and 5- or 6-membered heteroaryl; and wherein the heterocyclyl, spiroheterocyclyl and heteroaryl rings of R 2 are each unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 hydroxalkyl, and C 1-4 haloalkyl; and wherein two R 2 groups attached to the same carbon atom are optionally combined to form a 3- to 6-membered spirocyclic ring;

R c is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl;

R d is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl; and wherein the C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, and 5- or 6-membered heteroaryl rings of R d are each unsubstituted or substituted with one or two members independently selected from the group consisting of halogen, hydroxyl, oxo, C 1-4 alkyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 1-4 hydroxalkyl, and C 1-4 haloalkyl;

or R c and R d , when attached to the same nitrogen atom are joined to form a 4- to 7-membered heterocyclic ring having from 0 to 2 additional heteroatoms as ring vertices selected from O, S, S(O), S(O) 2 , NH, and N(C 1-4 alkyl); and

X 2 is C 1-4 alkylene.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof, wherein Ar 2 is a bicyclic 9- or 10-membered fused aromatic or heteroaromatic ring that is substituted with 0 to 5 R 2 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof, wherein Ar 2 is a monocyclic 5- or 6-membered aromatic or heteroaromatic ring that is substituted with 0 to 5 R 2 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of

each of which is substituted with from 0-3 R 2 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of

each of which is substituted with from 0-3 R 2 , and wherein R 2a is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —C(O)NH 2 , —C(O)N(H)C 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —S(O) 2 C 1-4 alkyl, —S(O) 2 N(H)C 1-4 alkyl, —C(O)OC 1-4 alkyl, and —C(O)C 1-4 alkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is substituted with from 0-3 R 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is pyridyl, which is substituted with from 0-3 R 2 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is thiazolyl, which is substituted with from 0-2 R 2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is 1,3,4-oxadiazolyl, which is substituted with from 0-1 R 2 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 imidazolyl, which is substituted with from 0-2 R 2 .

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

or a pharmaceutically acceptable salt thereof, wherein R 1 is —CN or —CF 3 .

13. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof, wherein R 1 is —CN or —CF 3 ; and Ar 2 is selected from the group consisting of

each of which is substituted with from 0-3 R 2 .

14. The compound of claim 1 ,

or a pharmaceutically acceptable salt thereof, wherein R 1 is —CN or —CF 3 ; and Ar 2 is selected from the group consisting of

each of which is substituted with from 0-3 R 2 , and wherein R 2a is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —C(O)NH 2 , —C(O)N(H)C 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —S(O) 2 C 1-4 alkyl, —S(O) 2 N(H)C 1-4 alkyl, —C(O)OC 1-4 alkyl, and —C(O)C 1-4 alkyl.

15. The compound of claim 1 ,

or a pharmaceutically acceptable salt thereof, wherein R 1 is —CN or —CF 3 ; and Ar 2 is selected from the group consisting of phenyl, pyridyl, thiazolyl, oxadiazolyl, imidazolyl, pyridazinyl, and oxazolyl, each of which is substituted with from 0-2 R 2 .

16. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of

each of which is substituted with from 0-2 R 2 , and wherein R 2b is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of

each of which is substituted with from 0-2 R 2 .

18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is selected from the group consisting of

each of which is substituted with from 0-1 R 2 ; and wherein R 2b is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 hydroxyalkyl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 1 is CF 3 ; and

R 2 is CN, —CH 3 , —OH, —NH 2 , —N(CH 3 ) 2 , —C(O)NH 2 , —C(O)N(H)(CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —S(O) 2 NH 2 , Cl, F, —N(CH 3 ) 2 , —OCH 3 , —CH 2 OH, —N(H)R d , piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, wherein the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl and azetidinyl groups can be optionally substituted with 1 or 2 substituents selected from the group consisting of —CH 3 , C(CH 3 ) 2 OH, OH, —OCH 3 , —NH 2 , and —N(CH 3 ) 2 .

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CN, —CH 3 , —OH, —NH 2 , —N(CH 3 ) 2 , —C(O)NH 2 , —C(O)N(H)(CH 3 ), —C(O)N(CH 3 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —S(O) 2 NH 2 , Cl, F, —N(CH 3 ) 2 , —OCH 3 , —N(H)R d , or —CH 2 OH.

21. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 2 is piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl, or azetidinyl, wherein the the piperazinyl, piperidinyl, morpholinyl, triazolyl, 1,3,4-oxadiazolyl, pyrrolidinyl and azetidinyl groups can be optionally substituted with 1 or 2 substituents selected from the group consisting of —CH 3 , C(CH 3 ) 2 OH, OH, —OCH 3 , —NH 2 , and —N(CH 3 ) 2 .

22. A compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof, with a pharmaceutically acceptable excipient.

24. A method of treating a disease or condition modulated at least in part by CCR6, comprising administering to a subject in need thereof, a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof.

25. The method in accordance with claim 24 , wherein said disease or condition is an inflammatory disease or condition.

26. The method in accordance with claim 24 , wherein said disease or condition is atopic dermatitis, scleroderma, lumbar disk disease, psoriasis, pustular psoriasis, rheumatoid arthritis, psoratic arthritis, arthritis associated with systemic lupus erythematosus, endometriosis, or periodontitis.

27. The method in accordance with claim 24 , wherein said disease or condition is psoriasis, or pustular psoriasis.

28. A method of treating a disease or condition modulated at least in part by CCR6, comprising administering to a subject in need thereof, a compound of claim 22 , or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer thereof.

29. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

38. The compound of claim 1 , having the formula

or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of claim 1 ; or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

41. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

43. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

45. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

46. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

47. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

48. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

49. The pharmaceutical composition of claim 39 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

50. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

51. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

52. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

53. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

54. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

55. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

56. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

57. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

58. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

59. The method of treating a disease or condition of claim 26 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.