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US 7,612,065 B2Granted
Inhibitors of c-JUN N-terminal kinases (JNK)
AssigneeVertex Pharmaceuticals Incorporated
InventorsJeremy Green, Susanne Wilke, Francesco Salituro, Edmund Harrington, Jingrong Cao, Guy Bemis, Huai Gao
Life of this patent
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Abstract
The present invention relates to inhibitors of JNK, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Claims22
A compound of the formula:
- or a pharmaceutically acceptable salt thereof;
- wherein
- Y is selected from —(CH2)-Q1;
- —(CO)-Q1;
- —(CO)NH-Q1;
- —(CO)—O-Q1;
- —(SO2)-Q1 or —(SO2)NH-Q1;
- Q1 is a C1-C6 straight chain or branched alkyl or alkenyl group;
- a 5-7 membered aromatic or non-aromatic heterocyclic ring;
- or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system, wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NH—R, N(R)2, NO2, OH, OR, CF3, halo, CN, CO2H, C(O)—NH2, C(O)—NH—R, C(O)—N(R)2, C(O)—R, SR, S(O)—R, S(O)2—R, S(O)2—NH—R or —R;
- W is N;
- R8 is a lone pair of electrons;
- A1 is CR1;
- A2 is CR2;
- A3 is CR3;
- A4 is CR4;
- R1 is —NHR5, —OR5, —SR5, or —R5;
- R2, R3, and R4 are independently selected from —(CO)NH2, —(CO)NHR, —(CO)N(R)2, —NHR5, —NHCH2R5, —OR5, —SR5, —R5, —NH(CO)—R6, —NH(CO)—NHR6, —NH(CO)—NH(CO)R6, —NH(CO)—OR6, —NH(SO2)—R6, —NH(SO2)—NHR6, —C(O)OH, —C(O)OR, —(CO)-Q1, —(CO)NH-Q1, —(CO)NR-Q1, —(CO)—O-Q1, —(SO2)-Q1 or —(SO2)NH-Q1;
- R5 and R6 are each independently selected from H;
- N(R)2, NHOH, NO2, C(O)OR or halo;
- a C1-C6 straight chain or branched alkyl, alkenyl or alkynyl group;
- a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring;
- or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring;
- wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NHR, NHC(O)OR, N(R)2, NO2, OH, OR, CF3, halo, CN, Si(R)3, CO2H, COOR, CONH2, CONHR, CON(R)2, COR, SR, S(O)R, S(O)2R, S(O)2NHR or R;
- R is a C1-C6 straight chain or branched alkyl or alkenyl group, a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a 9-10 membered bicyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system.
22 more elements
A compound of the formula:
- or a pharmaceutically acceptable salt thereof;
- wherein
- Y is —(CH2)-Q1;
- Q1 is benzodioxanyl, a substituted phenyl group, a substituted 5-7 membered aromatic heterocyclic ring, a 10-membered heterocyclic bicyclic ring, or a straight chain alkyl group substituted with phenyl or a heterocyclic monocyclic or bicyclic ring, wherein said phenyl or heterocyclic ring is substituted with one to four substituents, each of which is independently selected from NH2, NH—R, N(R)2, NO2, OH, OR, CF3, halo, CN, CO2H, C(O)—NH2, C(O)—NH—R, C(O)—N(R)2, C(O)—R, SR, S(O)—R, S(O)2—R, S(O)2—NH—R or —R;
- R1 is R5;
- R2 is OCF3, NH2, R5, NH(CO)—R6, NH(SO2)—R6, —NHCH2R5, CO-Q1 or CONH-Q1;
- R3 is NH(CO)—R6, NH(SO2)—R6, CONH-Q1, H, halo, methyl, CF3, substituted or unsubstituted phenyl, a substituted or unsubstituted aromatic heterocyclic ring, an aromatic bicyclic ring, NO2 or NH2;
- R4 is R5;
- R5 and R6 are each independently selected from H;
- N(R)2, NHOH, NO2, C(O)OR or halo;
- a C1-C6 straight chain or branched alkyl, alkenyl or alkynyl group;
- a 5-7 membered aromatic or non-aromatic carbocyclic or heterocyclic ring;
- or a 9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring;
- wherein said alkyl, alkenyl, ring or ring system is optionally substituted with one to four substituents, each of which is independently selected from NH2, NHR, NHC(O)OR, N(R)2, NO2, OH, OR, CF3, halo, CN, Si(R)3, CO2H, COOR, CONH2, CONHR, CON(R)2, COR, SR, S(O)R, S(O)2R, S(O)2NHR or R;
- and
- R is a C1-C6 straight chain or branched alkyl or alkenyl group, a 5-7 membered aromaticor non-aromatic carbocyclic or heterocyclic ring, or a 9-10 membered bicyclic aromatic or non-aromatic carbocyclic or heterocyclic ring system.
13 more elements
Dependencies are inferred from the claim text.