Heterocyclic inhibitors of ERK2 and uses thereof
AssigneeVertex Pharmaceuticals Incorporated
InventorsMichael Robin Hale, Francois Maltais, Qing Tang, Judith Straub, Alexander Aronov
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Abstract
Described herein are compounds that are useful as protein kinase inhibitors having the formula: wherein A1, A2, TmR1, X, R2, R3, R9, R12, and R13 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.
Claims22
A compound of general formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- A1 is N;
- A2 is CR11;
- T is selected from —C(R7)2—, —C(O)—, —C(O)C(O)—, —C(O)NR7—, —C(O)NR7NR7—, —CO2—, —OC(O)—, —NR7CO2—, —O—, —NR7C(O)NR7—, —OC(O)NR7—, —NR7NR7—, —NR7C(O)—, —S—, —SO—, —SO2—, —NR7—, —SO2NR7—, —NR7SO2—, or —NR7SO2NR7—;
- m is selected from zero or one;
- R1 is selected from:
- (a) hydrogen, CN, halogen, R, N(R7)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)NR7 —, —NR7C(O)—, —NR7SO2—, —SO2NR7—, —S(O)—, or —SO2—;
- R2 is selected from —(CH2)yR5, —(CH2)yCH(R5)2, —(CH2)yCH(R8)(R5), —(CH2)yCH(R8)CH(R5)2, —N(R4)2, —NR4(CH2)yN(R4)2, —ON(R7)2, or —NR7OR6;
- y is 0-6;
- R3 is selected from —R, —OR6, —S(O)R6, or —ON(R7)2;
- R6 is selected from hydrogen or —R;
- each R is independently selected from an optionally substituted group selected from C1-6 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 R4 is independently selected from —R, —R7, —COR7, —CO2R, —CON(R7)2, —SO2R7, —(CH2)yR5, or —(CH2)yCH(R5)2;
- each R5 is independcntly selected from —R, —OR, —CO2R, —(CH2)yN(R7)2, —N(R7)2, —OR7, —SR7, —NR7C(O)R7, —NR7CON(R7)2, —C(O)N(R7)2, —SO2R7, —NR7SO2R7, —C(O)R7, —CN, or —SO2N(R7)2;
- each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 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;
- R8 is selected from —R, —(CH2)wOR7, —(CH2)wN(R4)2, or —(CH2)wSR7;
- each w is independently selected from 0-4;
- R9 is selected from hydrogen, an optionally substituted C1-6 aliphatic group, C(O)R7, C(O)OR7, or SO2R7;
- R11 is selected from R7, halogen, CN, NO2, OR7, SR7, N(R7)2, C(O)R7, or CO2R7;
- and
- each of R12 and R13 is hydrogen.
Dependencies are inferred from the claim text.