Compositions useful as inhibitors of protein kinases

1. A compound of formula (II)-A:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 and R 2 are each independently selected from hydrogen, or (U) p —R 5 , wherein p is 0 or 1, U is an optionally substituted C 1 –C 6 alkylidene chain wherein up to two non-adjacent methylene units of U are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR, and R 5 is an optionally substituted group selected from optionally substituted C 1-10 aliphatic, an aryl group selected from a 5–6 membered monocyclic or an 8–10 membered bicyclic ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3–8-membered saturated or partially unsaturated monocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10-membered saturated or partially unsaturated bicyclic ring system having 0–5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R 1 and R 2 taken together with the nitrogen atom form an optionally substituted 5–8 membered heterocyclyl or heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein R 1 and R 2 are each independently optionally substituted with up to five substituents selected from Q–R X ; wherein Q is a bond or is an optionally substituted C 1 –C 6 alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR; and each occurrence of R X is independently selected from R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′C(O)R′, NR′C(O)N(R′) 2 , NR′CO 2 R′, C(O)R′, CO 2 R′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , C(O)C(O)R′, or C(O)CH 2 C(O)R′;

each occurrence of R 3 and R 4 is independently selected from R, halogen, CN, OR, N(R) 2 , SR, C(═O)R, CO 2 R, CONR 2 , NRC(═O)R, NRCO 2 (C 1-6 aliphatic), OC(═O)R, SO 2 R, S(═O)R, SO 2 NR 2 , or NRSO 2 (C 1-6 aliphatic);

n is 0, 1, 2;

m is 0, 1, 2 or 3;

T is an optionally substituted C 1-4 alkylidene chain wherein one methylene unit of T is optionally replaced by O, NR, NRCO, NRCONR, NRCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O); q is 0 or 1;

R Z is R, CN, halogen, or Cy;

Cy is an optionally substituted aryl or heteroaryl group selected from a 5–6 membered monocyclic or an 8–10 membered bicyclic ring having 0–5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or is an optionally substituted group selected from a 3–8-membered saturated or partially unsaturated monocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10-membered saturated or partially unsaturated bicyclic ring system having 0–5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy is optionally substituted with up to five substituents selected from Z-R Y ; wherein Z is a bond or is a C 1 –C 6 alkylidene chain non-adjacent methylene units of Q are optionally replaced by CO, CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR; and each occurrence of R Y is independently selected from R′, halogen, NO 2 , CN, OR′, SR′, N(R′) 2 , NR′C(O)R′, NR′C(O)N(R) 2 , NR′CO 2 R′, C(O)R′, CO 2 R′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , SOR′, SO 2 R′, SO 2 N(R′) 2 , NR′SO 2 R′, NR′SO 2 N(R′) 2 , C(O)C(O)R′, or C(O)CH 2 C(O)R′;

each occurrence of R is independently selected from hydrogen or an optionally substituted C 1-8 aliphatic group, or two R on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5–8 membered heterocyclyl or heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R′ is independently selected from hydrogen or an optionally substituted group selected from C 1-8 aliphatic, C 6-10 aryl, a heteroaryl ring having 5–10 ring atoms, or a heterocyclyl ring having 3–10 ring atoms, or wherein two R′ on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5–8 membered heterocyclyl or heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

provided that when R Z is Cy, and Cy is an optionally substituted 5–6 membered monocyclic or an 8–10 membered bicyclic aryl ring having 0 heteroatoms, then q is 1.

2. The compound of claim 1 , wherein one of R 1 or R 2 is (U) p —R 5 , and R 5 is an optionally substituted aryl or heteroaryl group selected from:

wherein x is 0–5.

3. The compound of claim 2 , wherein R 1 is (U) p —R 5 ; R 5 is any one of a-i through z-i; and R 2 is hydrogen.

4. The compound of claim 2 , wherein R 2 is hydrogen; R 1 is (U) p —R 5 ; and R 5 is any one of:

5. The compound of claim 2 , wherein R 2 is hydrogen, and R 1 is (U) p —R 5 , wherein U and p are as defined generally above and herein, and R 5 is a-i, b-i, e-i, or f-i.

6. The compound of claim 2 , wherein R 2 is hydrogen; R 1 is (U) p —R 5 ; and R 5 is a-i.

7. The compound of claim 1 , wherein p is 0 and R 5 is directly attached to the ring system.

8. The compound of claim 1 , wherein p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—.

9. The compound of claim 1 , wherein p is 1, U is —CH 2 —, —CO—, —CO(CH 2 )O—, —CO(CH 2 ) 2 —, CO(NH)— or —CO(O)—.

10. The compound of claim 1 , wherein R Z is Cy, and Cy is an optionally substituted group selected from:

wherein y is 0–5.

11. The compound of claim 10 , wherein Cy is a-ii, b-ii, c-ii, e-ii, f-ii, g-ii, or oo-ii.

12. The compound of claim 10 , wherein Cy is any one of i-ii, j-ii, k-ii, l-ii, m-ii, n-ii, o-ii, p-ii, q-ii, r-ii, s-ii, t-ii, u-ii, v-ii, x-ii, y-ii, z-ii, aa-ii, bb-ii, cc-ii, dd-ii, ee-ii, ff-ii, gg-ii, hh-ii, ii-ii, jj-ii, kk-ii, ll-ii, mm-ii, nn-ii, oo-ii, pp-ii, qq-ii, or rr-ii.

13. The compound of claim 1 , wherein q is 0 and T is absent.

14. The compound of claim 1 , wherein q is 1 and T is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —C≡C—, —C═C—, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—.

15. The compound of claim 1 , wherein QR X and ZR Y groups are each independently halogen, CN, NO 2 , or an optionally substituted group selected from C 1-4 alkyl, aryl, aralkyl, —N(R′) 2 , CH 2 N(R′) 2 , —OR′, CH 2 OR′, —SR′, CH 2 SR′,COOR′, or —S(O) 2 N(R′) 2 .

16. The compound of claim 1 , wherein QR X and ZR Y groups are each independently Cl,Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

17. The compound of claim 1 , wherein R 3 is selected from hydrogen or a C 1-4 alkyl group.

18. The compound of claim 1 , wherein each occurrence of R 3 is hydrogen.

19. The compound of claim 1 , wherein each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group.

20. The compound of claim 1 , wherein each occurrence of R 4 is hydrogen.

21. The compound of claim 1 , wherein R Z is Cy, and Cy is an optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-pyrimdinyl, 5-pyrimidinyl, or tetrahydrofuranyl group and the compounds have one of the general formulae:

22. The compound of claim 21 , wherein:

a) R 2 is hydrogen; R 1 is (U) p —R , wherein p is 0, or p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and R 5 is any one of:

b) n is 0, 1, or 2, and each occurrence of R 3 is selected from hydrogen or a C 1-4 alkyl group;

c) m is 0, 1, 2, or 3, and each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group;

d) q is 0, or q is 1 and T groups, when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and

e) x is 0, 1, or 2, and y is 0, 1, or 2, and each occurrence of QR X and ZR Y is independently Cl, Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

23. The compound of claim 21 , wherein:

a) R 2 is hydrogen, and R 1 is (U) p —R 5 , wherein p is 0, or p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and R 5 is a-i, b-i, e-i, or f-i;

b) n is 0, 1, or 2, and each occurrence of R 3 is selected from hydrogen or a C 1-4 alkyl group;

c) m is 0, 1, 2, or 3, and each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group;

d) q is 0, or q is 1 and T groups, when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —,—CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and

e) x is 0, 1, or 2, and y is 0, 1, or 2, and each occurrence of QR X and ZR Y is independently Cl, Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

24. The compound of claim 21 , wherein:

a) R 2 is hydrogen; R 1 is (U) p —R 5 , wherein R 2 is hydrogen; R 1 is (U) p —R 5 , wherein p is 0, or p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 —, NH—; and R 5 is a-i;

b) n is 0, 1, or 2, and each occurrence of R 3 is selected from hydrogen or a C 1-4 alkyl group;

c) m is 0, 1, 2, or 3, and each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group;

d) q is 0, or q is 1 and T groups, when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 NH—; and

e) x is 0, 1, or 2, and y is 0, 1, or 2, and each occurrence of QR X and ZR Y is independently Cl, Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

25. The compound of claim 10 , wherein

a) R Z is Cy, and Cy is any one of b-ii, c-ii, d-ii, e-ii, f-ii, g-ii, h-ii, i-ii, j-ii, k-ii, l-ii, m-ii, n-ii, o-ii, p-ii, q-ii, r-ii, s-ii, t-ii, u-ii, v-ii, x-ii, y-ii, z-ii, aa-ii, bb-ii, cc-ii, dd-ii, ee-ii, ff-ii, gg-ii, hh-ii, ii-ii, jj-ii, kk-ii, ll-ii, mm-ii, nn-ii, oo-ii, pp-ii, qq-ii, or rr-ii;

b) R 2 is hydrogen; R 1 is (U) p —R 5 , wherein p is 0, or p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and R 5 is any one of:

c) n is 0, 1, or 2, and each occurrence of R 3 is selected from hydrogen or a C 1-4 alkyl group;

d) m is 0, 1, 2, or 3, and each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group;

e) q is 0, or q is 1 and T groups, when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and

f) x is 0, 1, or 2, and y is 0, 1, or 2, and each occurrence of QR X and ZR Y is independently Cl, Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

26. The compound of claim 1 , wherein

a) R Z is Cy, and Cy is any one of i-ii, j-ii, k-ii, l-ii, m-ii, n-ii, o-ii, p-ii, q-ii, r-ii, s-ii, t-ii, u-ii, v-ii, x-ii, y-ii, z-ii, aa-ii, bb-ii, cc-ii, dd-ii, ee-ii, ff-ii, gg-ii, hh-ii, ii-ii, jj-ii, kk-ii, ll-ii, mm-ii, nn-ii, oo-ii, pp-ii, qq-ii, or rr-ii;

b) R 2 is hydrogen; R 1 is (U) p —R 5 , wherein p is 0, or p is 1 and U is selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and R 5 is any one of:

c) n is 0, 1, or 2, and each occurrence of R 3 is selected from hydrogen or a C 1-4 alkyl group;

d) m is 0, 1, 2, or 3, and each occurrence of R 4 is selected from hydrogen, halo, O(C 1-4 alkyl), or a C 1-4 alkyl group;

e) q is 0, or q is 1 and T groups, when present, are selected from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CO(CH 2 ) 0-2 —, —CO(CH 2 ) 0-2 O—, —CONH(CH 2 ) 0-2 —, or —CO(CH 2 ) 0-2 NH—; and

f) x is 0, 1, or 2, and y is 0, 1, or 2, and each occurrence of QR X and ZR Y is independently Cl, Br, F, CN, COOH, —N(CH 3 ) 2 , —OH, CH 2 OH, SO 2 NH 2 , or an optionally substituted group selected from C 1-4 alkoxy, phenyl, phenyloxy, benzyl, or benzyloxy.

27. The compound of claim 1 , selected from:

28. A composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.

29. The composition of claim 28 , additionally comprising a therapeutic agent selected from an anti-flammatory agent, an immunomodulatory or immunosuppressive agent, or an agent for treating asthma.

30. A method of treating or lessening the severity of a disease or condition selected from rheumatoid arthritis, allergic or type I hypersensitivity reaction, asthma, transplant rejection or familial amyotrophic lateral selerosis (FALS), comprising the step of administering to a patient in need thereof

a) a composition of claim 28 ; or

b) a compound of claim 1 .

31. The method of claim 30 , comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, or an agent for treating asthma, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.