Heterocyclic inhibitors of ERK2 and uses thereof
Described herein are compounds that are useful as protein kinase inhibitors having the formula: wherein Z 1 and Z 2 are each independently nitrogen or CH and Ring A, T m R 1 , QR 2 , U n R 3 , and Sp are as described in the specification. The compounds are especially useful as inhibitors of ERK2 and for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, diabetes, and cardiovascular disease.
1 . A method of treating a cancer selected from melanoma, colon cancer, lung cancer, kidney carcinoma, ovarian cancer, pancreatic cancer, or prostate cancer, which method comprises administering to said patient a compound of formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;
Z 1 and Z 2 are each independently selected from N or CH;
T is a linker group selected from —NH—, —CH 2 —, —CO—;
Q is —CO 2 —, —C(O)NR 7 —, or —S(O) 2 NR 7 —;
U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, —CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;
m and n are each independently selected from zero or one;
R 1 is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;
R 2 is selected from —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , —N(R 4 ) 2 , or —NR 4 (CH 2 ) y N(R 4 ) 2 ;
y is 0-6;
R 3 is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;
each R is independently selected from an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
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 independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;
each R 6 is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 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 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
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.
2 . (canceled)
3 . The method according to claim 1 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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;
(c) Q is —CO 2 —, —CONH—, or —SO 2 NH;
(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 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;
(f) R 4 is R, R 7 , or —(CH 2 ) y CH(R 5 ) 2 ; and
(g) R 5 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
4 . The method according to claim 3 , wherein:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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;
(c) Q is —CO 2 —, —CONH—, or —SO 2 NH;
(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 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;
(f) R 4 is R, R 7 ; or —(CH 2 ) y CH(R 5 ) 2 ; and
(g) R 5 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
5 . The method according to claim 3 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(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 ;
(c) Q is —CO—, —CONH—, or —SO 2 NH—;
(d) R 2 is —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , wherein R 8 is OH or CH 2 OH; and
(e) R is —CH 2 OH, —(CH 2 ) 2 OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.
6 . The method according to claim 5 , wherein:
(a) R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(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 ;
(c) Q is —CONH— or —SO 2 NH—;
(d) R 2 is —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , wherein R 8 is OH or CH 2 OH; and
(e) R 5 is —CH 2 OH, —(CH 2 ) 2 OH, isopropyl, or an optionally substituted group selected from pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, 4-methyldiazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl, pyridin-4-yl, imidazolyl, furan-2-yl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl, phenyl, or benzyl.
7 - 9 . (canceled)
10 . A method of inhibiting ERK-2 activity in a biological sample, which method comprises contacting said sample with a compound of formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;
Z 1 and Z 2 are each independently selected from N or CH;
T is a linker group selected from —NH—, —CH 2 —, —CO—;
Q is —CO 2 —, —C(O)NR 7 —, or —S(O) 2 NR 7 —;
U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, ——CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;
m and n are each independently selected from zero or one;
R 1 is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;
R 2 is selected from —(CH 2 ) y R 5 , —(CH 2 ) y CH(R 5 ) 2 , —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , —N(R 4 ) 2 , or —NR 4 (CH 2 ) y N(R 4 ) 2 ;
y is 0-6;
R 3 is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;
each R is independently selected from an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
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 independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, SO 2 N(R 7 ) 2 ;
each R 6 is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 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 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
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 - 19 . (canceled)
20 . A compound of formula I′:
or a pharmaceutically acceptable derivative thereof, wherein:
Sp is a 5-membered heteroaromatic ring selected from pyrrole, imidazole, pyrazole, triazole, oxazole, isoxazole, 1,3-thiazole, 1,2-thiazole, furan or thiophene, wherein Ring A and QR 2 are attached to Sp at non-adjacent positions; and wherein Sp has up to two R 6 substituents, provided that two substitutable carbon ring atoms in Sp are not simultaneously substituted by R 6 ;
Z 1 and Z 2 are each independently selected from N or CH;
T is a linker group selected from —NH—, —CH 2 —, —CO—;
Q′ is selected from —CO 2 —, —C(O)NR 7 — or —SO 2 NR 7 —;
U is selected from —NR 7 —, —NR 7 CO—, —NR 7 CONR 7 —, —NR 7 CO 2 —, —O—, —CONR 7 —, —CO—, —CO 2 —, —OC(O)—, —NR 7 SO 2 —, —SO 2 NR 7 —, —NR 7 SO 2 NR 7 —, or —SO 2 —;
m and n are each independently selected from zero or one;
R 1 is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;
R 2′ is selected from —(CH 2 ) y CH(R 5 ) 2 or —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 ;
y is 0-6;
R 3 is selected from R 7 , R, —(CH 2 ) y CH(R 8 )R, CN, —(CH 2 ) y CH(R 8 )CH(R 5 ) 2 , or —(CH 2 ) y CH(R 8 )N(R 4 ) 2 ;
each R is independently selected from an optionally substituted group selected from C 1-6 aliphatic, C 6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 3-10 ring atoms;
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 independently selected from R, OR, CO 2 R, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 7 , CN, or SO 2 N(R 7 ) 2 ;
each R 6 is independently selected from R 7 , F, Cl, (CH 2 ) y N(R 7 ) 2 , N(R 7 ) 2 , OR 7 , SR 7 , NR 7 COR 7 , NR 7 CON(R 7 ) 2 , CON(R 7 ) 2 , SO 2 R 7 , NR 7 SO 2 R 7 , COR 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 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
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.
21 . (canceled)
22 . The compound according to claim 20 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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 OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
23 . The compound according to claim 22 , wherein:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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 OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
24 . The compound according to claim 22 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(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, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q′ is —C(O)NH—.
25 . The compound according to claim 24 , wherein:
(a) R 3 is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, isopropyl, —CH(CH 2 OH)phenyl, —CH(CH 2 OH)ethyl, —CH(CH 2 OH) 2 , —CH(CH 2 OH)isopropyl, —CH(CH 2 OH)CH 2 cyclopropyl, or an optionally substituted phenyl, benzyl, or isoxazolyl group;
(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, CH 2 OH, carbocyclic, or an optionally substituted phenyl or pyridyl ring, and Q′ is —C(O)NH—.
26 . The compound according to claim 20 , wherein said compound is of formula I″:
or a pharmaceutically acceptable derivative thereof.
27 . The compound according to claim 26 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) T m R 1 is hydrogen, N(R 4 ) 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.
28 . The compound according to claim 27 , wherein:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring;
(b) T m R 1 is hydrogen, N(R 4 ) 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.
29 . The compound according to claim 20 , wherein said compound is of formula I o :
or a pharmaceutically acceptable derivative thereof.
30 . The compound according to claim 29 , wherein said compound has one or more features selected from the group consisting of:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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 OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
31 . The compound according to claim 30 , wherein:
(a) R 3 is hydrogen, carbocyclyl, —CH(R 8 )R, or an optionally substituted group selected from C 1-4 aliphatic, 3-6 membered heterocyclic, or a 5-6 membered aryl or heteroaryl 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 OR 7 , wherein R is carbocyclic, or an optionally substituted 5 or 6-membered aryl or heteroaryl ring.
32 - 40 . (canceled)
41 . A composition comprising a compound according to claim 20 and a pharmaceutically acceptable carrier.
42 . The composition according to claim 41 , further comprising an additional therapeutic agent selected from a chemotherapeutic agent or anti-proliferative agent.
43 . A method of treating a cancer selected from melanoma, colon cancer, lung cancer, kidney carcinoma, ovarian cancer, pancreatic cancer, or prostate cancer in a patient comprising the step of administering to said patient a therapeutically effective amount of the composition according to claim 41 .
44 - 70 . (canceled)