Bicycloheteroaryl compounds as P2X7 modulators and uses thereof

1. A bicycloheteroaryl compound having a formula:

wherein

A is CR 2a R 2b or CO; B and Y are independently selected from CR 2a and CR 2a R 2b ;

W, W′ and Z are independently selected from CR 4 and N, provided that all three of W, W′ and Z are not N at the same time;

L 1 is a bond, SO, SO 2 or substituted or unsubstituted C 1 -C 5 alkylene;

n is 0, 1, 2, 3 or 4;

R 1 is selected from a substituted or unsubstituted 3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl ring;

each of R 2a , R 2b , R 2′ and R 2″ is independently selected from hydrogen, halo, and substituted or unsubstituted C 1 -C 6 alkyl; or any of R 2′ and R 2″ join together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms;

R 3 is selected from hydrogen, a hydrogen bond donor group, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl, and substituted or unsubstituted bicycloheteroaryl;

R 4 is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted R 4 is independently selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted, dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, substituted or unsubstituted heteroalkyl, hydroxyl, nitro, and thio;

and the dotted bond is a single or double bond; or a stereoisomer, isotopic variant, or tautomer thereof; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1 wherein each of B and Y is CR 2a R 2b ; and the dotted bond is a single bond.

3. A compound according to claim 1 wherein each of B and Y is CH 2 ; and the dotted bond is a single bond.

4. A compound according to claim 1 wherein each of B and Y is CR 2a ; and the dotted bond is a double bond.

5. A compound according to claim 1 wherein each of B and Y is CH; and the dotted bond is a double bond.

6. A compound according to claim 1 wherein each of R 2′ and R 2″ is H.

7. A compound according to claim 1 wherein one of R 2′ and R 2″ is independently Me and the other is H.

8. A compound according to claim 1 wherein n is 0, 1, or 2.

9. A compound according to claim 1 wherein R 1 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinoline, substituted or unsubstituted benzodioxole, substituted or unsubstituted benzodioxane, substituted or unsubstituted benzofuran, substituted or unsubstituted benzothiophene, and substituted or unsubstituted benzodioxepine.

10. A compound according to claim 1 wherein the compound is according to formula II, III or IV:

wherein

W is CR 4 ; Z is CR 4 ;

L 1 , R 1 , R 2′ , R 2″ , R 3 and R 4 are as in claim 1 ;

R 5 is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;

or a stereoisomer, isotopic variant or tautomer thereof;

or a pharmaceutically acceptable salt, or solvate thereof.

11. A compound according to claim 10 wherein each of R 2′ and R 2″ is H.

12. A compound according to claim 10 wherein R 2′ is Cl or F; and R 2″ is H.

13. A compound according to claim 10 wherein R 2′ is Me; and R 2″ is H.

14. A compound according to claim 10 wherein R 1 is selected from substituted or unsubstituted phenyl.

15. A compound according to claim 10 wherein R 1 is selected from substituted or unsubstituted naphthalene.

16. A compound according to claim 1 wherein the compound is according to formula V, VI or VII:

wherein

W is CR 4 ; Z is CR 4 ;

L 1 , R 1 , R 2′ , R 2″ , R 3 and R 4 are as in claim 1 ;

R 5 is selected from H, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;

each R 4a is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, arloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyoloxy, amino, aryl, substituted aryl, arylalkyl, substituted or unsubstituted sulfoxide, substituted or unsubstituted sulfone, substituted or unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester, substituted or unsubstituted dihydroxyphosphoryl, substituted or unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstituted carbamoyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and thio;

and m is selected from 0-5; or a stereoisomer, isotopic variant, or tautomer thereof;

or a pharmaceutically acceptable salt, or solvate thereof.

17. A compound according to claim 16 wherein each of R 2′ and R 2″ is H.

18. A compound according to claim 16 wherein R 2′ is Cl; and R 2″ is H.

19. A compound according to claim 16 wherein R 2′ is Me; and R 2″ is H.

20. A compound according to claim 16 wherein R 2′ is F; and R 2″ is H.

21. A compound according to claim 16 wherein R 2′ is Et; and R 2″ is H.

22. A compound according to claim 1 wherein the compound is according to formula IX or X:

wherein

W is CR 4 ; Z is CR 4 ;

L 1 , R 3 and R 4 are as in claim 1 ; m, R 4a , and R 5 are as in claim 16 ; R 2′ is H or Me;

or a stereoisomer, isotopic variant or tautomer thereof;

or a pharmaceutically acceptable salt, or solvate thereof.

23. A compound according to either of claim 16 or 22 wherein m is 1, 2 or 3.

24. A compound according to either of claim 16 or 22 wherein each R 4a is independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 3 H, SO 3 Me, and pyridyl.

25. A compound according to claim 1 wherein L 1 is C 1 -C 5 alkylene group unsubstituted or substituted by one or more substituents selected from alkyl, oxo, aryl, hydroxyl, and hydroxyalkyl.

26. A compound according to claim 1 wherein L 1 is a C 1 -C 5 alkylene group substituted with two alkyl groups and wherein any two alkyl groups on the same carbon atom can join together to form a cycloalkyl or cycloheteroalkyl ring of 3-7 atoms.

27. A compound according to claim 1 wherein L 1 is CH 2 and R 3 is substituted or unsubstituted aryl or heteroaryl.

28. A compound according to claim 1 wherein L 1 is CH 2 and R 3 is phenyl or pyridyl substituted with one or more substituents independently selected from halo, hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and sulfonamide.

29. A compound according to claim 1 wherein L 1 is CH 2 and R 3 is phenyl or pyridyl substituted with one or more substituents independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 3 H, SO 3 Me, and pyridyl.

30. A compound according to claim 1 wherein R 3 is selected from hydroxyl, amino, alkylamino or carbamoyl.

31. A compound according to claim 1 wherein the group L 1 -R 3 is selected from

32. A compound according to claim 1 wherein the group L 1 -R 3 is selected from

33. A compound according to claim 1 wherein the group L 1 -R 3 is selected from

34. A compound according to claim 1 wherein R 2′ is Me.

35. A compound according to claim 1 wherein R 2′ is H.

36. A compound according to claim 1 wherein the compound is according to formula XIa, XIb, XIc, XId, XIe, XIf, XIg, XIh or XIj:

wherein m and R 4a are as in claim 16 ; and R 5 is H, alkyl, cycloalkyl or halo.

37. A compound according to claim 1 wherein the compound is according to formula XIIa, XIIb, or XIC:

wherein m and R 4a are as in claim 16 ; R 5 is H, alkyl, cycloalkyl or halo; and R 2d is selected from hydrogen, alkyl, hydroxyalkyl, and substituted or unsubstituted phenyl.

38. A compound according to claim 37 wherein R 2d is methyl, i-Pr or hydroxymethyl.

39. A compound according to claim 37 wherein R 2d is phenyl.

40. A compound according to claim 1 wherein the compound is according to formula XIIIa, XIIIb, XIIIc, or XIIId:

wherein m and R 4a are as in claim 16 ; R 5 is H, alkyl, cycloalkyl or halo.

41. A compound according to any one of claims 36 - 40 wherein m is 1 or 2; and each R 4a is independently selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CF 3 , CHF 2 , OCF 3 , i-Pr, i-Bu, t-Bu, SMe, CH═CH—CO 2 H, SOMe, SO 2 Me, SO 3 H, SO 3 Me, and pyridyl.

42. A compound according to any one of claims 36 - 40 wherein m is 1 and each R 4a is CF 3 .

43. A compound according to any one of claims 36 - 40 wherein m is 2 and each R 4a is F and CF 3 .

44. A compound according to any one of claims 36 - 40 wherein m is 2 and each R 4a is F and Cl.

45. A compound according to claim 1 wherein each of W and Z is independently CH.

46. A compound according to any one of claims 10 , 16 , 22 , and 36 - 40 wherein R 5 is Me, cyclopropyl, Cl, F, or CF 3 .

47. A compound according to claim 1 wherein the compound is selected from the compounds listed below:

2053

2058

2059

2060

2061

2066

2067

2068

2071

2072

2073

2074

2075

2076

2077

2078

2079

48. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .

49. The pharmaceutical composition of claim 48 , wherein the carrier is a parenteral carrier.

50. The pharmaceutical composition of claim 48 , wherein the carrier is an oral carrier.

51. The pharmaceutical composition of claim 48 , wherein the carrier is a topical carrier.