Method for predicting skin sensitizing activity of compounds
Quinoline- and isoquinoline-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, methods of using compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions comprising compounds exhibiting ATP-utilizing enzyme inhibitory activity, are disclosed.
1 . A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein:
Ar is chosen from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
A is —N— and B is —CH—, or A is —CH— and B is —N—;
L is chosen from NR 1 and 0;
R 1 is chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
X and Y are independently chosen from CH and N;
G is chosen from a covalent bond and NR 6 ;
R 6 is chosen from hydrogen and optionally substituted alkyl; and
R is chosen from optionally substituted heterocycloalkyl,
with the proviso that when Ar is phenyl, A is —N—, B is —CH—, L is NR 1 , R 1 is H, X is CH, Y is CH, and G is a covalent bond, then R is not 4-methylpiperazin-1-yl.
2 - 39 . (canceled)
40 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 1 .
41 . The pharmaceutical composition of claim 40 , wherein the at least one chemical entity is present in an amount effective for the treatment in a patient of a disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
42 . The pharmaceutical composition of claim 41 , wherein inflammation is chosen from Crohn's disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
43 . A method of treating a disease regulated by at least one ATP-utilizing enzyme in a subject in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 1 .
44 . The method according to claim 43 , wherein the disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
45 . The method of claim 44 , wherein inflammation is chosen from Crohn's disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
46 . A method of inhibiting at least one ATP-utilizing enzyme in a subject comprising administering to the subject at least one compound according to claim 1 .
47 . The method of claim 46 , where the ATP-utilizing enzyme is chosen from a human protein kinase.
48 . The method of claim 47 , wherein the human protein kinase is chosen from ABL1, AKT1, AKT2, AKT3, AURORA-A, BMX, c-TAK1, CDK1, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK2, CSK, DAPK1, DYRK2, FLT-3, FYN, GSK3-α, GSK3-β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK2, MAPKAPK3, MSK1, MSK2, NEK2, p38-α, p38-β, p38-δ, p38-γ, P70S6K1, PAK2, PDGFR-α, PAKI, PKA, PRAK, ROCK2, SGK1, SRC, SYK, PIM-1-kinase, PDK1, and RSK2.
49 . The method of claim 48 , wherein the human protein kinase is chosen from MAPKAPK2.
50 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 1 .
51 . The method of claim 50 , where the ATP-utilizing enzyme is chosen from a human protein kinase.
52 . The method of claim 51 , wherein human protein kinase is chosen from ABL1, AKT1, AKT2, AKT3, AURORA-A, BMX, c-TAK1, CDK1, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK2, CSK, DAPK1, DYRK2, FLT-3, FYN, GSK3-α, GSK3-β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK2, MAPKAPK3, MSK1, MSK2, NEK2, p38-α, p38-β, p38-δ, p38-γ, P70S6K1, PAK2, PDGFR-α, PAKI, PKA, PRAK, ROCK2, SGK1, SRC, SYK, PIM-1-kinase, PDK1, and RSK2.
53 . The method of claim 52 , wherein the human protein kinase is chosen from MAPKAPK2.
54 - 55 . (canceled)