Imidazolopyridine compounds useful for the treatment of degenerative and inflammatory diseases

1. A compound according to formula III:

wherein CY—R 1 is

 the subscript n1 is 1, 2, 3, or 4; and each R 1b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, OCF 3 , cyano, and halo;

and R 1 is -L-R 1a ; and

wherein

L is selected from a single bond, alkylene, —CO—, and —SO 2 —;

R 1a is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl,

cycloalkyl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 haloalkoxy, CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, or halo,

aryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo,

heterocycloalkyl unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, C 1 -C 6 haloalkoxy, CN, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, or halo,

heteroaryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo,

amino, unsubstituted or substituted with C 1 -C 6 alkyl,

aralkyl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, or halo,

heteroarylalkyl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, or halo, and

aminoalkyl;

or R 1 is -L-R 1a ; and

L is —CO—, and —SO 2 —; and

R 1a is amino, alkylamino, dialkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, aralkylamino, heteroarylamino, and heteroarylalkylamino;

R 2 is selected from

aryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo, and

heteroaryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo; and

R 3 , R 4 , R 5 , and R 6 are independently selected from H, OH, OMe, OC 2 H 5 , F, Cl, Me, Et, SO 2 Me, CF 3 and OCF 3 .

2. A compound according to formula III:

wherein

R 1 represents H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, CF 3 , CN,

heterocycloalkyl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, carboxamido, cyano, or halo,

cycloalkyl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, carboxamido, cyano, or halo,

monocyclic aryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, carboxamido, cyano, or halo,

monocyclic heteroaryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, carboxamido, cyano, or halo,

C(═NH)NR a R b , —COR a , —OR a , —OC(O)—C 1 -C 6 alkyl, (CH 2 ) a COOR a , C(O)NR a R b , S(O) 2 (CH 2 ) a N(R a R b ), SR a , SO(CH 2 ) a NR a R b , S(O) 2 —R a , SOR a , (CH 2 ) a NR a R b , (CH 2 ) a N(R a )S(O) 2 —C 1 -C 6 alkyl, (CH 2 ) a NR a S(O)—C 1 -C 6 alkyl, NR a CO—R b , and NH—CO—CO—OR a ; each of which may be optionally substituted with one or more groups selected from H, halogen, OH, C 1 -C 6 alkyl, NH 2 , N(C 1 -C 6 alkyl)(C 1 -C 6 -alkyl), heterocycloalkyl, cycloalkyl and CF 3 ;

R 2 is selected from aryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo, and heteroaryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo;

R 3 , R 4 , R 5 and R 6 are independently selected from H, OH, OMe, OC 2 H 5 , F, Cl, Me, Et, SO 2 Me, CF 3 and OCF 3 ;

CY—R 1 is

 the subscript n1 is 1, 2, 3, or 4; and each R ib is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo;

R a and R b each independently represent H, halogen, C 1 -C 6 alkyl, (CH 2 ) a —N(C 1 -C 6 alkyl)(C 1 -C 6 -alkyl), (CH 2 ) a -monocyclic aryl, (CH 2 ) a -monocyclic heteroaryl, (CH 2 ) a -cycloalkyl or (CH 2 ) a -heterocycloalkyl, each of which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , NR c COR d , heteroaryl, heterocycloalkyl, or —CF 3 ; or R a and R b may, if joined to the same atom, represent together with the nitrogen to which they are attached a heterocycloalkyl group which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , —NR c COR d , —C(O)NR c R d , aryl, aralkyl, heteroaryl, cycloalkyl or —CF 3 ;

R c and R d each independently represent H, or C 1 -C 6 alkyl; and

“a” is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt, stereoisomers, or tautomers thereof.

3. The compound according to claim 2 , wherein CY is selected from unsubstituted phenyl, unsubstituted pyridyl, and unsubstituted pyrimidine.

4. The compound according to claim 2 , wherein each of R 3 , R 4 and R 5 is H.

5. The compound according to claim 1 , wherein the compound is according to formula IIIa, IIIb, IIIc or IIId:

wherein L, R 1a , and R 2 are as defined in claim 1 , the subscript n1 is 1, 2, 3 or 4; and

each R 1b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo.

6. The compound according to claim 5 , wherein L is —CO— or SO 2 —; and R 1a is amino.

7. The compound according to claim 5 , wherein L is —CO— or SO 2 —; and R 1a is alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, heteroarylamino, and heteroarylalkylamino.

8. The compound according to claim 5 , wherein L is a single bond, —CO—, SO 2 , and —(CH 2 ) m1 —; the subscript m1 is selected from 1, 2, 3, or 4; and R 1a is

and wherein the ring P is heterocycloalkyl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, or halo.

9. The compound according to claim 5 , wherein L is a single bond.

10. The compound according to claim 5 , wherein L is —CO—.

11. The compound according to claim 2 , wherein the compound is according to formula Va, Vb or Vc:

and wherein R 2 is as in claim 14 , Ya is C or N, Yb is C—R 1c , O, S, SO 2 or N—R 1c ; each R 1b is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 and OCF 3 ; R 1c is hydrogen, alkyl, cycloalkyl or heterocycloalkyl; each R 1d is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 and OCF 3 ; and each n1 and n2 is independently 1 or 2.

12. A compound according to formula VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj, VIk, or VIl:

and wherein R 2 is selected from

aryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo, and

heteroaryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo; each R ib is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 ; R 1c is selected from hydrogen, alkyl or substituted or unsubstituted cycloalkyl or heterocycloalkyl; each R id is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 or OCF 3 ; and each n1 and n2 is independently 1 or 2.

13. The compound according to claim 2 , wherein the compound is according to formula IXa or IXb:

and wherein R 1b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo; n1 is 1, 2, 3 or 4; R 2 is selected from aryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo, heteroaryl, unsubstituted, or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, or halo;

and;

R a and R b each independently represent H, halogen, C 1 -C 6 alkyl, (CH 2 ) a —N(C 1 -C 6 alkyl)(C 1 -C 6 -alkyl), (CH 2 ) a -monocyclic aryl, (CH 2 ) a -monocyclic heteroaryl, (CH 2 ) a -cycloalkyl or (CH 2 ) a -heterocycloalkyl, each of which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , NR c COR d , heteroaryl, heterocycloalkyl, or —CF 3 ; or R a and R b may, if joined to the same atom, represent together with the nitrogen to which they are attached a heterocycloalkyl group which may be optionally substituted with one or more groups selected from halogen, —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —NR c R d , —NR c COR d , —C(O)NR c R d , aryl, aralkyl, heteroaryl, cycloalkyl or —CF 3 ;

R c and R d each independently represent H, or C 1 -C 6 alkyl; and

“a” is 0, 1, 2 or 3.

14. The compound according to claim 1 , wherein R 2 is selected from heteroaryl.

15. The compound according to claim 1 , wherein R 2 is selected from phenyl, pyridyl, indolyl, isoindolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl.

16. The compound according to claim 1 , wherein R 2 is

17. The compound according to claim 1 , wherein R 2 is

18. A compound according to formula XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh, XIi, XIj, XIk or XIl

and wherein R 1c is hydrogen, alkyl, cycloalkyl, or heterocycloalkyl; each R 1b is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 and OCF 3 ; each R 1d is independently selected from H, Me, Et, n-Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 and OCF 3 ; and each n1 and n2 is independently selected 1 or 2.

19. The compound according to either of claim 12 or 18 , with respect to compounds of formulae VId-VIl, and XIa-XIl wherein R 1c is Me, Et, Pr, i-Pr, t-Bu, i-Bu, i-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or piperidinyl.

20. The compound according to claim 1 , wherein the compound is according to formula XIVa, or XIVb:

and wherein R 1b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, cyano, and halo; n1 is 1, 2, 3 or 4; each R a and R b is independently selected from hydrogen, C 1 -C 6 alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and cycloalkylalkyl.

21. The compound according to claim 13 , wherein R a is H, and R b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, i-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cyclopropylmethyl.

22. A compound selected from:

23. A compound selected from any one of:

24. A pharmaceutical composition comprising an effective therapeutically effective amount of a compound according to claim 1 , in admixture with a pharmaceutically acceptable carrier.

25. The compound according to claim 1 , wherein each R 1b is H.

26. The compound according to claim 1 , wherein n1 is 1 or 2; and each R 1b is independently selected from Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, OEt, CF 3 , CF 2 CF 3 and OCF 3 .

27. The compound according to claim 1 , wherein n1 is 1 or 2; and each R 1b is independently selected from Me, F, Cl and CF 3 .

28. The compound according to claim 18 wherein each R 1d is H.

29. The compound according to claim 20 , wherein R a is H; and R b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, i-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, phenyl, benzyl, or pyridylmethyl.

30. A compound according to claim 1 , wherein L is —CH 2 .

31. A compound according to formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe, VIIIf, VIIIg, VIIIh, or VIIIi:

and wherein R 2 is selected from aryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo, and

heteroaryl, unsubstituted or substituted with C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, hydroxy, cyano, carboxamido, or halo; A is CH or N; and R ic is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted cycloalkyl.

32. A compound according to formula XXIIa, XXIIb, XXIIc, XXIId, XXIIe, or XXIIf:

and wherein each R 1f and R 1g is hydrogen or F.

33. A compound according to claim 1 , wherein R 2 is