Heteroaryl compounds useful as inhibitors or protein kinases

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is CR x , wherein R x and U—R 1 are taken together to form an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or

two R on the same nitrogen atom are taken together with the nitrogen atom attached thereto to form a 4-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R y is independently selected from R, CN, NO 2 , halogen, N(R) 2 , SR, or OR;

R z is hydrogen, an optionally substituted C 1-6 aliphatic group, C(O)R, C(O)OR, or SO 2 R;

each y is independently 0-6;

each Ar is independently selected from an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Q is selected from a valence bond, —O—, —S—, —NR—, or a C 1-6 alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —S—, —SO—, —SO 2 —, —N(R)SO 2 —, —SO 2 N(R)—, —N(R)—, —CO—, —CO 2 —, —N(R)CO—, —N(R)C(O)O—, —N(R)CON(R)—, —N(R)SO 2 N(R)—, —N(R)N(R)—, —C(O)N(R)—, —OC(O)N(R)—, —C(R)═NN(R)—, or —C(R)═N—O—;

R 2 is selected from —(CH 2 ) y R 3 , —(CH 2 ) y CH(R 3 ) 2 , —(CH 2 ) y CH(R 5 )CH(R 3 ) 2 , —(CH 2 ) y N(R 6 ) 2 , or —NR 6 (CH 2 ) y N(R 6 ) 2 ;

each R 3 is independently selected from —CN, —R 4 , —OR 4 , —CO 2 R 4 , —(CH 2 ) y N(R 6 ) 2 , —SR 4 , —NRCOR 4 , —NRCON(R 6 ) 2 , —CON(R 6 ) 2 , —SO 2 R 4 , —NRSO 2 R 4 , —COR 4 , or —SO 2 N(R 6 ) 2 ;

each R 4 is independently selected from R or Ar;

R 5 is selected from R, (CH 2 ) w OR 4 , (CH 2 ) w N(R 4 ) 2 , or (CH 2 ) w SR 4 ;

each w is independently selected from 0-4; and

each R 6 is independently selected from R, Ar, —COR 4 , —CO 2 R 4 , —CON(R 4 ) 2 , —SO 2 R 4 , —(CH 2 ) y R 3 , or —(CH 2 ) y CH(R 3 ) 2 ; wherein

optional substituents on one or more unsaturated carbons of an aryl or heteroaryl group are selected from halogen, N 3 , —R o , —OR o , —SR o , 1,2-methylene-dioxy, 1,2-ethylenedioxy, acyloxy, phenyl, phenyl substituted with R o , —O(phenyl), —O(phenyl) substituted with R o , —CH 2 (phenyl), —CH 2 (phenyl) substituted with R o , —CH 2 CH 2 (phenyl), —CH 2 CH 2 (phenyl) substituted with R o , —NO 2 , —CN, —N(R o ) 2 , —NR o C(O)R o , —NR o C(O)N(R o ) 2 , —NR o CO 2 R o , —NR o NR o C(O)R o , —NR o NR o C(O)N(R o ) 2 , —NR o NR o CO 2 R o , —C(O)C(O)R o , —C(O)CH 2 C(O)R o , —CO 2 R o , —C(O)R o , —C(O)N(R o ) 2 , —OC(O)N(R o ) 2 , —S(O) 2 R o , —SO 2 N(R o ) 2 , —S(O)R o , —NR o SO 2 N(R o ) 2 , —NR o SO 2 R o , —C(═S)N(R o ) 2 , —C(═NH)—N(R o ) 2 , or —(CH 2 ) y NHC(O)R o , wherein each R o is independently selected from hydrogen, optionally substituted C 1-6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, —O(phenyl), or —CH 2 (phenyl)—CH 2 (phenyl), wherein substituents on the aliphatic group of R o are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O—(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), —O(halo C14 aliphatic), or halo C 1-4 aliphatic,

optional substituents on an aliphatic group or on a non-aromatic heterocyclic ring are selected from those defined above for the unsaturated carbon of an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═N—, ═NNHC(O)R*, ═NNHCO 2 (alkyl), ═NNHSO 2 (alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic, wherein substituents on the aliphatic group of R* are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O—(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), —O(halo C 1-4 aliphatic), or halo C 1-4 aliphatic, and

optional substituents on the nitrogen of a non-aromatic heterocyclic ring are selected from —R + , —N(R + ) 2 , —C(O)R + , —CO 2 R + , —C(O)C(O)R + , —C(O)CH 2 C(O)R + , —SO 2 R + , —SO 2 N(R + ) 2 , —C(═S)N(R 30 ) 2 , —C(═NH)—N(R + ) 2 , or —NR + SO 2 R + ; wherein R + is hydrogen, an optionally substituted C 1-6 aliphatic, optionally substituted phenyl (Ph), optionally substituted —O(Ph), optionally substituted —CH 2 (Ph), optionally substituted —CH 2 CH 2 (Ph), or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, wherein substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O—(C 1-4 aliphatic), NO 2 , CN, CO 2 H, CO 2 (C 1-4 aliphatic), —O(halo C 1-4 aliphatic), or halo C 1-4 aliphatic.

2. The compound according to claim 1 , wherein:

Q is a C 1-4 alkylidene chain wherein one methylene unit of Q is replaced by —C(O)—, —CO 2 —, —C(O)N(R)—, —SO 2 —, —SO 2 N(R)—, —OC(O)N(R)—, —C(O)ON(R)—, or —C(O)N(R)N(R)—; and

R 2 is —(CH 2 ) y R 3 , —(CH 2 ) y CH(R 3 ) 2 , —(CH 2 ) y CH(R 5 )CH(R 3 ) 2 , or —(CH 2 ) y N(R 6 ) 2 .

3. The compound according to claim 1 , wherein said compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein

R 2′ is selected from —(CH 2 ) y CH(R 3 ) 2 or —(CH 2 ) y CH(R 5 )CH(R 3 ) 2 .

4. The compound according to claim 3 , wherein said compound is of formula III:

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3 , wherein said compound is of formula IV:

or a pharmaceutically acceptable salt thereof.

6. The compound according to either of claims 4 or 5 wherein:

U—R 1 and R x are taken together to form an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R 3 is independently selected from R, OR 4 , Ar, CO 2 R 4 , —(CH 2 )N(R 6 ) 2 , or CN.

7. A compound according to claim 1 , wherein said compound is selected from the group consisting of:

8. A composition comprising an effective amount of a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

9. The composition according to claim 8 , additionally comprising a therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

10. A method for treating, or lessening the severity of, a disease or condition selected from cardiomyocyte hypertrophy, reperfusionlischemia, or stroke in a patient in need thereof, wherein said method comprises administering to said patient an effective amount of the composition according to claim 8 .

11. The method according to claim 10 , wherein said disease or condition is stroke.

12. A method for treating or lessening the severity of Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, multiple sclerosis, or schizophrenia in a patient in need thereof, wherein said method comprises administering to said patient an effective amount of the composition according to claim 8 .

13. A method for treating or lessening the severity of allergy or asthma in a patient in need thereof, wherein said method comprises administering to said patient an effective amount of the composition according to claim 8 .

14. A method for treating or lessening the severity of breast cancer, colon cancer, kidney carcinoma, lung cancer, melanoma, ovarian cancer, pancreatic cancer, or prostate cancer in a patient in need thereof, wherein said method comprises administering to said patient an effective amount of the composition according to claim 8 .

15. The method according to any one of claims 10 - 14 , comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, 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.

16. A method for treating or lessening the severity of diabetes in a patient in need thereof, wherein said method comprises administering to said patient an effective amount of the composition according to claim 8 .