Compositions and methods for inhibition of the JAK pathway

1. A compound of formula I:

or salt thereof, wherein:

X and Y are each independently O, S, S(O), SO 2 or NR 1 ;

each R 1 is independently for each occurrence H, optionally substituted C 1-6 alkyl, C(O)—C 1-6 alkyl, CO 2 —C 1-6 alkyl or R 50 ;

each R 50 is —C(R 9 ) 2 —O—R 10 or —C(R 9 ) 2 —S—R 10 ; each R 9 is independently for each occurrence H, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl or optionally substituted C 7-16 arylalkyl; or alternatively, two R 9 , together with the carbon to which they are attached, form an optionally substituted C 3-8 cycloalkyl group or an optionally substituted 3-8 membered heteroalicyclyl; R 10 is R a or —P(O)(OR 11 ) 2 ; each R 11 is independently for each occurrence R a or a monovalent cationic group; or two R 11 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two R 11 together represent a divalent cationic group;

ring A is a C 6-10 aryl or a 5-10 membered heteroaryl;

each R 2 is independently for each occurrence H, R e , R b , R e substituted with one or more of the same or different R a and/or R b , —OR e substituted with one or more of the same or different R a and/or R b , —SR e substituted with one or more of the same or different R a and/or R b , —C(O)R e substituted with one or more of the same or different R a and/or R b , —N(R a )R e where R e is substituted with one or more of the same or different R a and/or R b , —S(O) 2 R e substituted with one or more of the same or different R a and/or R b , —N(R a )—S(O) 2 R e where R e is substituted with one or more of the same or different R a and/or R b , —B(OR a ) 2 , —B(N(R c ) 2 ) 2 , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2 or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b ;

each R a is independently for each occurrence H, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

each R b is independently for each occurrence ═O, —OR a , —O—(C(R a ) 2 ) m —OR a , haloC 1-3 alkyloxy, ═S, —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O)N(R c ) 2 , —S(O) 2 N(R c ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R c ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —C(NR a )—N(R c ) 2 , —C(NOH)—R a , —C(NOH)—N(R c ) 2 , —OC(O)R a , —OC(O)OR a , —OC(O)N(R c ) 2 , —OC(NH)—N(R c ) 2 , —OC(NR a )—N(R c ) 2 , —N(R a )—S(O) 2 H, —[N(R a )C(O)] n R a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R c ) 2 or —[N(R a )C(NR a )] n —N(R c ) 2 ;

each R c is independently for each occurrence R a , or, alternatively, two R c are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different R a and/or R d groups;

each R d is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , ═NR a , ═NOR a , —N(R a ) 2 , halo, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 , —N 3 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O)N(R a ) 2 , —S(O) 2 N(R a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OSO 3 R a , —OS(O) 2 N(R a ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —C(NR a )N(R a ) 2 , —C(NOH)R a , —C(NOH)N(R a ) 2 , —OCO 2 R a , —OC(O)N(R a ) 2 , —OC(NR a )N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —N(R a )—S(O) 2 R a , —C(O)—C 1-6 halo alkyl, —S(O) 2 C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )C 1-6 haloalkyl, —P(O)(OR a ) 2 , —N(R a )—(C(R a ) 2 ) m —OR a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R a ) 2 , —[N(R a )C(NR a )] n N(R a ) 2 or —N(R a )C(O)C 1-6 haloalkyl; or two R d , taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a ;

each R e is independently for each occurrence C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;

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

each m is 1, 2 or 3;

each n is 0, 1, 2 or 3;

or two R 2 groups, taken together with the atom or atoms to which they are attached, combine to form a 4-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b ;

Z 1 and Z 2 are each independently CH, CR 2 or N;

R 3 is H, optionally substituted C 1-6 alkyl or R 50 ;

R 4 is H, optionally substituted C 1-6 alkyl or R 50 ; and

R 5 is halo, —CN, optionally substituted C 1-6 alkyl, alkynyl, hydroxy, optionally substituted C 1-6 alkoxy, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .

2. The compound of claim 1 , according to formula IA:

wherein:

X and Y are each independently O or NR 1 ;

each R 1 is H, optionally substituted C 1-6 alkyl or R 50 ;

each of R 2a , R 2b , R 2c and R 2d is independently for each occurrence as defined for R 2 ; and

R 5 is halo, —CN, optionally substituted C 1-6 alkyl, nitro, —N(R a ) 2 , —C(O)N(R a ) 2 , —CO 2 R a or —C(O)R a .

3. The compound of claim 2 , wherein one of X and Y is O and the other is NR 1 .

4. The compound of claim 3 , according to formula IA1:

wherein R 2d is H; R 5 is halo or C 1-6 alkyl; Z 1 is CH, C-halo or C-optionally substituted C 1-6 alkyl; and Z 2 is CH.

5. The compound of claim 4 , wherein R 5 is F or CH 3 .

6. The compound of claim 5 , wherein each of R 2a , R 2b and R 2c is independently for each occurrence C 1-6 alkyl, —OR a , —OCF 3 , —SR a , —N(R c ) 2 , halo, —OCH 2 F, —OCF 2 H, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 1e, —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —(C(R a ) 2 ) m —R b , —N(R a )—S(O) 2 R a or —[N(R a )C(O)] n R a .

7. The compound of claim 6 , wherein R 2a , R 2b and R 2c are each independently C 1-6 alkyl, —OR a , —OCF 3 , halo, —CF 3 or —CN.

8. The compound of claim 7 , wherein R 2a is CH 3 ; R 2b is halo; and R 2c is CH 3 .

9. The compound of claim 7 , wherein R 2a is CH 3 ; R 2b is CH 3 ; and R 2c is halo.

10. The compound of claim 7 , wherein R 2a is CH 3 ; R 2b is CH 3 ; and R 2c is CH 3 .

11. The compound of claim 4 , wherein R 2b is H; and R 5 is F or CH 3 .

12. The compound of claim 11 , wherein each of R 2a and R 2c is independently for each occurrence H, C 1-6 alkyl, —OR a , —OCF 3 , —SR a , —N(R c ) 2 , halo, —OCF 2 H, —OCH 2 F, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 R a , —C(R a ) 2 —N(R c ) 2 or —[N(R a )C(O)] n R a ; and one of R 2a and R 2c is not H.

13. The compound of claim 12 , wherein each of R 2a and R 2c is independently for each occurrence H, C 1-6 alkyl, —OR a , —OCF 3 , halo, —CF 3 , —C(R a ) 2 —N(R c ) 2 or —CN.

14. The compound of claim 13 , wherein R 2a is —CF 3 or —CH 3 ; and R 2c is halo or —CH 3 .

15. The compound of claim 13 , wherein R 2a is H, —CH 3 , —CF 3 , —OR a or —OCF 3 ; and R 2c is —C(R a ) 2 —N(R c ) 2 .

16. The compound of claim 4 , wherein R 2c is H; and R 5 is F or CH 3 .

17. The compound of claim 16 , wherein each of R 2a and R 2b is H, C 1-6 alkyl, —OR a , —OCF 2 H, —OCF 3 , —OCH 2 F, —SR a , —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 R a , —C(R a ) 2 —N(R c ) 2 or —[N(R a )C(O)] n R a ; and one of R 2a and R 2b is not H.

18. The compound of claim 17 , wherein each of R 2a and R 2b is H, C 1-6 alkyl, —OR a , —OCF 3 , halo, —N(R c ) 2 , —CF 3 , —C(R a ) 2 —N(R c ) 2 or —CN.

19. The compound of claim 18 , wherein R 2b is —CF 3 or —CH 3 ; and R 2a is halo or —CH 3 .

20. The compound of claim 18 , wherein R 2a is H, —CH 3 , —CF 3 , —OR a or —OCF 3 ; and R 2b is —N(R c ) 2 or —C(R a ) 2 —N(R c ) 2 .

21. The compound of claim 18 , wherein R 2a is —N(R c ) 2 or —C(R a ) 2 —N(R c ) 2 ; and R 2b is H, —CH 3 , —CF 3 , —OR a or —OCF 3 .

22. The compound of claim 16 , wherein R 2a and R 2b are taken together with the carbons to which they are attached to form a 4-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b .

23. The compound of claim 22 , wherein R 2a and R 2b are taken together with the carbons to which they are attached to form a 5 membered partially or fully saturated monocyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b .

24. The compound of claim 23 , wherein the 5 membered partially or fully saturated monocyclic ring is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine or tetrahydrofuran; optionally substituted with one or more R a and/or R b .

25. The compound of claim 24 , according to formula IA3

wherein R b is OH, C 1-6 alkyl, —CO 2 C 1-6 alkyl, —C(O)C 1-6 alkyl or —S(O) 2 C 1-6 alkyl.

26. The compound of claim 22 , wherein R 2a and R 2b are taken together with the carbons to which they are attached to form a 6 membered partially or fully saturated monocyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b .

27. The compound of claim 26 , wherein the 6 membered partially or fully saturated monocyclic ring is cyclohexane, morpholine, piperidine, dioxane, oxathiazinane or piperazine; optionally substituted with one or more R a and/or R b .

28. The compound of claim 22 , wherein R 2a and R 2b are taken together with the carbons to which they are attached to form a 7 membered partially or fully saturated monocyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b .

29. The compound of claim 28 , wherein the 7 membered partially or fully saturated monocyclic ring is cycloheptane, cycloheptene, azepane, tetrahydroazepine or diazepane; optionally substituted with one or more R a and/or R b .

30. The compound of claim 22 , wherein R 2a and R 2b are taken together with the carbons to which they are attached to form a 8 membered partially or fully saturated monocyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a and/or R b .

31. The compound of claim 30 , wherein the 8 membered partially or fully saturated monocyclic ring is cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane or hexahydrodiazocine; optionally substituted with one or more R a and/or R b .

32. The compound of claim 1 , according to formula IB1:

wherein each of R 2a , R 2b , R 2c and R 2d is independently for each occurrence as defined for R 2 .

33. The compound of claim 32 , wherein X is O and Y is NR 1 .

34. The compound of claim 33 , wherein R 5 is halo or C 1-6 alkyl; Z 1 is CH, C-Halo or C-optionally substituted C 1-6 alkyl; and Z 2 is CH.

35. The compound of claim 34 , wherein R 2a and R 2d are H; and R 5 is F or CH 3 .

36. The compound of claim 35 , wherein each of R 2b and R 2c is independently for each occurrence H, C 1-6 alkyl, —OR a , —OCF 3 , —SR a , —N(R c ) 2 , halo, —OCF 2 H, —OCH 2 F, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —N(R a )—S(O) 2 R a , —C(R a ) 2 —N(R c ) 2 or —[N(R a )C(O)] n R a ; and one of R 2b and R 2c is not H.

37. The compound of claim 35 , wherein each of R 2b and R 2c is independently for each occurrence H, C 1-6 alkyl, —N(R c ) 2 , halo, —CF 3 , —CN, —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —C(R a ) 2 —N(R c ) 2 or —N(R a )—S(O) 2 R a .

38. The compound of claim 37 , wherein R 2b is H, halo, —CF 3 , —CN or —CH 3 ; and R 2c is —N(R c ) 2 , —S(O) 2 N(R c ) 2 , —S(O) 2 R a , —C(O)N(R c ) 2 or —C(R a ) 2 —N(R c ) 2 .

39. The compound of claim 38 , wherein R 2b is H, halo, —CF 3 , —CN or —CH 3 ; and R 2c is —N(R c ) 2 or —C(R a ) 2 —N(R c ) 2 .

40. The compound of claim 6 , wherein one of R 2a ,R 2b and R 2c is:

optionally substituted with one or more of the same or different R a and/or R b groups.

41. The compound of claim 40 , wherein R 1 is H or R 50 ; R 50 is —CH 2 OP(O)(OR 11 ) 2 ; and each R 11 is independently for each occurrence R a or a monovalent cationic group; or two R 11 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two R 11 together represent a divalent cationic group.

42. The compound of claim 41 , wherein each R 11 is independently for each occurrence H, t-butyl, HOCH 2 CH 2 N(CH 3 ) 3 + , Na + , Li + or K + .

43. The compound of claim 6 , wherein one of R 2a ,R 2b and R 2c is —C(R a ) 2 —N(R c ) 2 , where —C(R a ) 2 —N(R c ) 2 is:

optionally substituted with one or more of the same or different R a and/or R b groups.

44. The compound of claim 43 , wherein R 1 is H or R 50 ; R 50 is —CH 2 OP(O)(OR 11 ) 2 ; and each R 11 is independently for each occurrence R a or a monovalent cationic group; or two R 11 , together with the atoms to which they are attached, form a 4-8 membered cyclic phosphate group, or two R 11 together represent a divalent cationic group.

45. The compound of claim 44 , wherein each R 11 is independently for each occurrence H, t-butyl, HOCH 2 CH 2 N(CH 3 ) 3 + , Na + , Na + , Li + or K + .

46. A pharmaceutical composition comprising the compound according to claim 1 .