Heterocyclic inhibitors of ERK2 and uses thereof
Described herein are compounds that are useful as protein kinase inhibitors having the formula: wherein A 1 , A 2 , T m R 1 , X, R 2 , R 3 , R 9 , R 12 , and R 13 are as described in the specification. The compounds are especially useful as inhibitors of ERK2, Aurora2, GSK3, CDK2, AKT3, and ROCK protein kinases and for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, neurodegenerative disorders, inflammatory disorders, restenosis, diabetes, and cardiovascular disease.
1. A compound of general formula I:
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is N;
A 2 is CR 11 ;
T is selected from —C(R 7 ) 2 —, —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 —;
m is selected from zero or one;
R 1 is selected from: (a) hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH, wherein m is zero; or (b) hydrogen or R, wherein m is one;
X is selected from —C(O)—, —C(O)NR 7 —, —NR 7 C(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —S(O)—, or —SO 2 —;
R 2 is selected from —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )(R 5 ), —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , —N(R 4 ) 2 , —NR 4 (CH 2 ) y N(R 4 ) 2 , —ON(R 7 ) 2 , or —NR 7 OR 6 ;
y is 0-6;
R 3 is selected from —R, —OR 6 , —S(O)R 6 , or —ON(R 7 ) 2 ;
R 6 is selected from hydrogen or —R;
each R is independently selected from an optionally substituted group selected from C 1-6 aliphatic; 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having zero to three heteroatorns independently selected from nitrogen, sulfur, or oxygen; or an 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having zero to four hetero atoms independently selected from nitrogen, sulfur, or oxygen;
each R 4 is independently selected from —R, —R 7 , —COR 7 , —CO 2 R, —CON(R 7 ) 2 , —SO 2 R 7 , —(CH 2 ) y R 5 , or —(CH 2 ) y CH(R 5 ) 2 ;
each R 5 is independcntly selected from —R, —OR, —CO 2 R, —(CH 2 ) y N(R 7 ) 2 , —N(R 7 ) 2 , —OR 7 , —SR 7 , —NR 7 C(O)R 7 , —NR 7 CON(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 groups bound to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
R 8 is selected from —R, —(CH 2 ) w OR 7 , —(CH 2 ) w N(R 4 ) 2 , or —(CH 2 ) w SR 7 ;
each w is independently selected from 0-4;
R 9 is selected from hydrogen, an optionally substituted C 1-6 aliphatic group, C(O)R 7 , C(O)OR 7 , or SO 2 R 7 ;
R 11 is selected from R 7 , halogen, CN, NO 2 , OR 7 , SR 7 , N(R 7 ) 2 , C(O)R 7 , or CO 2 R 7 ; and
each of R 12 and R 13 is hydrogen.
2. The compound according to claim 1 wherein said compound has one or more features selected from the group consisting of:
(a) X is selected from —C(O)— or —C(O)NR 7 ;
(b) R 3 is —OH; —O(C 1-6 aliphatic); 3-6 membered carbocyclyl; or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;
(c) T m R 1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;
(d) R 2 is —NR 4 (CH 2 ) y N(R 4 ) 2 , —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )(R 5 ), or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;
(e) R 4 is R, R 7 , or —(CH 2 ) y CH(R 5 ) 2 ; and
(f) R 5 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, naphthyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
3. The compound according to claim 2 wherein said compound has one or more features selected front the group consisting of:
(a) X is selected from —C(O)— or —C(O)NR 7 ;
(b) R 3 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, OH, O-methyl, O-ethyl, or —CH 2 — morpholin-4-yl;
(c) T m R 1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ;
(d) R 2 is —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )(R 5 ), or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , wherein R 8 is OH, NH 2 , CH 2 OH, CH 2 NH 2 , or CH 2 CH 2 NH 2 ; and
(e) R 5 is —CH 2 OH, —(CH 2 ) 2 OH, isopropyl, or an optionally substituted group selected from pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, methyldiazepanyl, phenylpiperazineyl, pyridinyl, imidazolyl, furanyl, tetrahydroisoquinoline, tetrahydrofuranyl, cyclohexyl, phenyl, or benzyl.
4. The compound according to claim 1 wherein said compound is of formula I′:
or a pharmaceutically acceptable salt or derivative thereof, wherein:
R 2′ is selected from —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )(R 5 ), or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 .
5. The compound according to claim 4 wherein said compound has one or more features selected from the group consisting of:
(a) X is selected from —C(O)— or —C(O)NR 7 ;
(b) R 3 is —OH; —O(C 1-6 aliphatic); 3-6 membered carbocyclyl; or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;
(c) T m R 1 is hydrogen, amino, OH, 3-6 m y membered carbocyclyl, or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(d) R 5 is R, OR 7 , or N(R 7 ) 2 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
6. The compound according to claim 5 wherein said compound has one or more features selected from the group consisting of:
(a) X is selected from —C(O)— or —C(O)NR 7 ;
(b) R 3 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, OH, O-methyl, O-ethyl, or —CH 2 — morpholin-4-yl;
(c) T m R 1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ; and
(d) R 5 is OH, NH 2 , carbocyclic, or an optionally substituted phenyl or pyridyl ring.
7. The compound according to claim 1 wherein said compound is of formula I″:
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is —O(C 1-6 aliphatic); 3-6 membered carbocyclyl; or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;
(b) T m R 1 is hydrogen, N(R 7 ) 2 , OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R 5 is an optionally substituted 6-membered aryl, heteroaryl, or carbocyclic ring.
9. The compound according to claim 8 wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, OH, O-methyl, O-ethyl, or —CH 2 — morpholin-4-yl;
(b) T m R 1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ; and
(c) R 5 is cyclohexyl or an optionally substituted phenyl or pyridyl ring.
10. The compound according to claim 1 wherein said compound is of formula I o :
or a pharmaceutically salt thereof, wherein:
T is selected from —C(R 7 ) 2 —, —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 —;
m is selected from zero or one;
R 1 is selected from: (a) hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH, wherein m is zero; or (b) hydrogen or R, wherein m is one;
R 3 is selected from —R, —OR 6 , —S(O)R 6 , or —ON(R 7 ) 2 ;
R 6 is selected from hydrogen or —R;
each R is independently selected from an optionally substituted group selected from C 1-6 aliphatic; 3-7 membered saturated, partially saturated, or aromatic monocyclic ring having zero to three heteroatoms independently selected from nitrogen, sulfur, or oxygen; or an 8-10 membered saturated, partially saturated, or aromatic bicyclic ring having zero to four heteroatoms independently selected from nitrogen, sulfur, or oxygen;
each R 4 is independently selected from —R, —R 7 , —COR 7 , —CO 2 R, —CON(R 7 ) 2 , —SO 2 R 7 , —(CH 2 ) y R 5 , or —(CH 2 ) y CH(R 5 ) 2 ;
each R 5 is independcntly selected from —R, —OR, —CO 2 R, —(CH 2 ) y N(R 7 ) 2 , —N(R 7 ) 2 , —OR 7 , —SR 7 , —NR 7 C(O)R 7 , —NR 7 CON(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 hydroger or an optionally substituted C 1-6 aliphatic group, or two R 7 groups bound to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
R 8 is selected from —R, —(CH 2 ) w OR 7 , —(CH 2 ) w N(R 4 ) 2 , or —(CH 2 ) w SR 7 ; and
each w is independently selected from 0-4.
11. The compound according to claim 10 wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is —OH; —O(C 1-6 aliphatic); 3-6 membered carbocyclyl; or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl, heteroaryl, or heterocyclyl ring;
(b) T m R 1 is hydrogen, amino, OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring; and
(c) R 5 is R, OR 7 , or N(R 7 ) 2 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
12. The compound according to claim 11 wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, pyridinyl, morpholinyl, piperidinyl, piperazinyl, OH, O-methyl, O-ethyl, or —CH 2 — morpholin-4-yl;
(b) T m R 1 is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 ; and
(c) R 5 is OH, NH 2 , carbocyclic, or an optionally substituted phenyl or pyridyl ring.
13. The compound according to claim 1 of the formula I:
wherein X is —C(O)—, A 1 is N, A 2 is CH, R 9 is hydrogen, and R 12 and R 13 is hydrogen, selected from any of the following compounds:
No.
I-
R 3
T m R 1
R 2
1
Methyl
2
Methyl
3
Methyl
4
5
6
7
Methyl
8
9
10
11
12
13
14
15
16
17
18
Methyl
19
Methyl
21
Methyl
22
Methyl
23
Methyl
24
Methyl
25
methyl
methyl
26
Methyl
27
—CH 2 OH
28
Methyl
29
—CH 2 OH
30
—CH 2 OH
31
—CH 2 NH 2
32
Methyl
33
methyl
34
H
35
H
36
37
38
39
40
41
42
43
44
H
45
H
.
14. The compound according to claim 1 of the formula I:
wherein X is —C(O)—, and R 13 is hydrogen, selected from any one of the following compounds:
No.
I-
A 1
R 3
T m R 1
R 9
R 12
R 2
47
N
Methyl
H
H
48
N
Methyl
H
H
49
N
Methyl
Methyl
H
H
50
N
—OH
Methyl
H
H
53
N
Methyl
H
H
55
N
Methyl
H
H
58
N
Methyl
H
H
59
N
Methyl
H
H
.
15. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
16. The composition according to claim 15 , 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.
17. A method of treating or lessening the severity of a proliferative disorder, wherein said proliferative disorder is breast cancer, colon cancer, kidney carcinoma, lung cancer, melanoma, ovarian cancer, pancreatic cancer, or prostate cancer; diabetes; a cardiovascular disease, wherein said cardiovascular disease is stroke, atherosclerosis, cardiomegaly, restenosis, or myocardial infraction; allergic disorders; asthma; or a neurological disorder, wherein said neurological disorder is Alzheimer's disease, amyotrophic lateral sclerosis, or cerebral ischemia, comprising the step of administering to said patient a composition according to claim 15 .
18. The method according to claim 17 , wherein said method is used to treat or lessen the severity of breast cancer, colon cancer, kidney carcinoma, lung cancer, melanoma, ovarian cancer, pancreatic cancer, or prostate cancer.
19. The method according to claim 17 , wherein said method is used to treat or lessen the severity of a cardiovascular disease selected from stroke, restenosis, cardiomegaly, arteriosclerosis, or congestive heart failure.
20. The method according to claim 17 , wherein said method is used to treat or lessen the severity of a neurological disorder selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, or cerebral ischemia.
21. The method according to claim 17 , 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 date 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 pan of a multiple dosage form.
22. A composition for coating an implantable device comprising a compound according to claim 1 and a carrier suitable for coating said implantable device.