Pyrazole-derived kinase inhibitors and uses thereof

1. A compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein:

B is selected from a group consisting of C 6-10 aryl, heteroaryl having 5–10 ring atoms, or heterocyclyl having 3–10 ring atoms; wherein B has the substituent -L-A and 0–3 R 2 substituents; and wherein B is optionally furher substituted;

L is a bond or an optionally substituted C 1 –C 8 alkylidene chain, wherein up to 2 methylene units are optionally replaced by —O—, —C(O)—, —C(O)C(O)—, —C(O)N(R 8 )—, —C(O)N(R 8 )N(R 8 )—, —O 2 —, —OC(O)—, —N(R 8 )CO 2 —, —N(R 8 )C(O)N(R 8 )—, —OC(O)N(R 8 )—, —N(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CO—, —S—, —SO—, —SO 2 —, —SO 2 N(R 8 )—, —N(R 8 )SO 2 —, —N(R 8 )SO 2 N(R 8 )—, —N(R 8 )O—, or —ON(R 8 )—;

A is -het,

 het is an optionally substituted group selected from heteroaryl having 5–10 ring atoms, or heterocyclyl having 3–10 ring atoms;

Q is an optionally substituted C 1 –C 6 alkylidene chain; wherein up to two methylene units are replaced by —C(O)—, —C(O)C(O)—, —C(O)NR 7 —, —C(O)NR 7 NR 7 —, —CO 2 —, —OC(O)—, —NR 7 CO 2 —, —O—, —NR 7 C(O)NR 7 —, —OC(O)NR 7 —, —NR 7 NR 7 —, —NR 7 C(O)—, —S—, —SO—, —SO 2 —, —NR 7 —, —SO 2 NR 7 —, —NR 7 SO 2 —, or —NR 7 SO 2 NR 7 —;

n is zero or one;

R 1 is hydrogen, R, fluoro, N(R 7 ) 2 , OR 7 , NR 7 C(O)R 7 , NR 7 C(O)N(R 7 ) 2 , C(O)N(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , or SO 2 N(R 7 ) 2 ;

each R 2 is independently R, OH, OR, SN, SR, nitro, N(R 7 ) 2 , halogen, CF 3 , or cyano;

R 3 is hydrogen, R, OH, OR, N(R 7 ) 2 , fluoro, or CN;

R 4 selected from —(CH 2 ) y R 6 , —(CH 2 ) y R 10 , —(CH 2 ) y CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 ) 2 , —(CH 2 ) y CH(R 10 )CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 )(R 6 ), —N(R 5 ) 2 , or —NR 5 (CH 2 ) y N(R 5 ) 2 ;

each R is independently selected from an optionally substituted group selected from the group consisting of C 1-6 aliphatic, C 6-10 aryl, heteroaryl having 5–10 ring atoms, and heterocyclyl having 3–10 ring atoms;

each R 5 is independently selected from R, —(CH 2 ) y R 6 , —(CH 2 ) y CH(R 6 ) 2 , R 7 , —C(O)R 7 , —CO 2 R 7 , —C(O)N(R 7 ) 2 , or —SO 2 R 7 ;

each y is independently 0–6;

each R 6 is independently selected from hydrogen, R, —(CH 2 ) y R, —OH, —OR, —CO 2 R, —(CH 2 ) y N(R 7 ) 2 , —N(R 7 ) 2 , —OS 7 , —SR 7 , —NR 7 C(O)R 7 , —NR 7 C(O)N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —SO 2 R 7 , —NR 7 SO 2 R 7 , —C(O)R 7 , —CN, or —SO 2 N(R 7 ) 2 ,

each R 7 is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or two R 7 the same nitrogen are taken together with the nitrogen to optionaily form a 5–8 membered heterocydlic or heteroaryl ring;

each R 8 is independently selected from hydrogen, R, —(CH 2 ) y R 9 , —(CH 2 ) y CH(R 9 ) 2 , —C(O)R 9 , R 9 , or R 7 ;

each R 9 is as defined in R 6 ;

each R 10 is independently selected from R, —(CH 2 ) w OR 7 , —(CH 2 ) w N(R 5 ) 2 , or —(CH 2 ) w SR 7 ; and

each w is independently 0–4;

provided that when Q n -R 4 is

 R 1 is H, R 3 is H, B is phenyl, and R 2 is a meta substituent Cl, then -L-A is not a para substituent

2. The compound according to claim 1 wherein B is phenyl having -L-A and 0–3 R 2 substituents.

3. The compound according to claim 2 wherein said compound is selected from the following:

wherein

W is O or H 2 ;

Z is an optionally substituted C 1 –C 4 alkylidene chain; wherein 1 methylene unit is optionally replaced by —O—, —C(O)—, —C(O)C(O)—, —C(O)NH—, —C(O)NHNH—, —CO 2 —, —OC(O)—, —NHCO 2 —, —NHC(O)NH—, —OC(O)NH—, —NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO 2 —, —SO 2 NH—, —NHSO 2 —, or —NHSO 2 NH—; and

m is 0 or 1.

4. The compound according to claim 3 wherein said compound has one or more features selected from the group consisting of:

(a) Q is —CO—, —CO 2 —, or —CONH—;

(b) R 1 is hydrogen or NHR 7 ;

(c) R 2 a meta substituent on the phenyl ring;

(d) -L-A is a para substituent on the phenyl ring;

(e) R 4 is —NR 5 (CH 2 ) y N(R 5 ) 2 , —(CH 2 ) y R 6 , —(CH 2 ) y CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 )CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 )(R 6 ), —(CH 2 ) y CH(R 10 ), or —(CH 2 ) y CH(R 10 ) 2 ;

(f) R 5 is R, R 7 or —(CH 2 ) y CH(R 6 ); and

(g) each R 6 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5–6 membered heteroaryl, or 5–6 membered heterocyclyl.

5. The compound according claim 4 wherein said compound has one or more features selected from the group consisting of:

(a) R 2 is halogen, nitrile, or CF 3 ;

(b) one methylene unit of L is replaced; and

(c) L is replaced with —NH—, —NHC(O)—, or —C(O)NH—.

6. The compound according to claim 2 wherein said compound is selected from the following:

7. The compound according to claim 6 wherein said compound has one or more features selected from the group consisting of:

(a) Q is —CO—, —CO 2 —, or —CONH—;

(b) R 2 is a meta substituent on the phenyl ring;

(c) -L-A is a para substituent on the phenyl ring;

(d) R 4 is —NR 5 (CH 2 ) y N(R 5 ) 2 , —(CH 2 ) y R 6 , —(CH 2 ) y CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 )CH(R 6 ) 2 , —(CH 2 ) y CH(R 10 )(R 6 ), —(CH 2 ) y CH(R 10 ), or —(CH 2 ) y CH(R 10 ) 2 ;

(e) R 5 is R, R 7 or —(CH 2 ) y CH(R 6 ) 2 ; and

(f) each R 6 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5–6 membered heteroaryl, or 5–6 membered heterocyclyl.

8. The compound according to claim 7 wherein said compound has one or more features selected from the group consisting of:

(a) R 2 is halogen, nitrile, or CF 3 ;

(b) one methylene unit of L is replaced; and

(c) L is replaced with —NH—, —NHC(O)—, or —C(O)NH—.

9. The compound according to claim 2 wherein said compound is selected from the following:

10. The compound according to claim 2 wherein said compound is selected from the following:

11. The compound according to claim 1 wherein said compound has the formula:

wherein

each of R 2 , -L-A, and -Q n -R 4 is:

No.

R 2

—L—A

Q n —R 4

II-1

Cl

II-2

Cl

II-3

Cl

II-4

Cl

II-5

Cl

II-6

Cl

II-7

Cl

II-8

Cl

II-9

Cl

II-10

H

II-11

Cl

II-12

Cl

II-13

Cl

II-14

Cl

II-15

Cl

II-16

Cl

12. The compound according to claim 1 wherein said compound is selected from

13. A composition comprising a compound according to claim 1 in an amount to detectably inhibit ERK kinase activity and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

14. The composition according to claim 13 , additionally comprising 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.

15. A method of inhibiting ERK2 or AKT activity in a biological sample in vitro comprising the step of contacting said biological sample with: a)a compound according to claim 1 ; or b)a composition according to claim 13 .

16. A method of treating or lessening the severity of a cancer in a patient, wherein said cancer is selected from breast cancer; ovarian cancer; prostate cancer; a lung cancer selected from epidermoid carcinoma, large cell carcinoma, small cell carcinoma, adenocarcinoma; colon cancer, pancreatic cancer, melanoma; or kidney carcinoma, comprising the step of administering to said patient a composition according to claim 13 .

17. A method of treating or lessening the severity of cardiovascular disease in a patient, wherein said cardiovascular disease is selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure, comprising the step of administering to said patient a composition according to claim 13 .

18. A method of treating or lessening the severity of in a patient, wherein said neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or a neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, or hypoxia, comprising the step of administering to said patient a composition according to claim 13 .