Thiophene-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
Thiophene-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 . At least one compound of Formula (I):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
E is chosen from CN, halogen, —NO 2 , and —C(═X)YR 5 ; wherein
X is chosen from O, and S;
Y is chosen from —N(R 10 )—, O, S, and a direct bond; wherein
R 10 is chosen H, alkyl, and substituted alkyl; and
R 5 is chosen from H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, and when Y is —N(R 10 )—, or a direct bond, then R 5 is additionally chosen from aryl, substituted aryl, heteroaryl, substituted heteroaryl, —N(R 7 ) 2 , and —OR 9 ; wherein each R 7 is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, and H; and
R 9 is chosen from H, alkyl, and substituted alkyl;
or R 5 and R 10 together with the atoms to which R 5 and R 10 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
R 1 is chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, and substituted heteroalkyl;
R 2 is chosen from H, —CHO, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, alkylsulfonyl, substituted alkylsulfonyl, heteroalkylsulfonyl, substituted heteroalkylsulfonyl, and -ZR 6 , wherein
Z is chosen from carbonyl, —C(O)O—, aminosulfonyl, aminothiocarbonyl, —C(═O)NR 11 —, sulfonyl, and thiocarbonyl; wherein
R 11 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and H; and
R 6 is chosen from H, —COOH, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, and substituted bicycloheteroalkyl;
or R 1 and R 2 , together with the atoms to which R 1 and R 2 are attached, form a heterocycloalkyl, or substituted heterocycloalkyl ring;
R 3 is chosen from H, halogen, —NH 2 , acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, dialkylamino, and substituted dialkylamino; and
R 4 is chosen from H, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, or substituted bicycloheteroalkyl ring;
with the provisos that
when E is —CO 2 R 5 , then
R 3 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine; and
R 4 is not 2-aminopyrimidine, substituted 2-aminopyrimidine 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine;
when E is —CN, then
R 3 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine; and
R 4 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine;
when E is —CN, and R 2 is —C(═X)NH 2 , where X is O or S, then
R 3 is not unsubstituted phenyl, or a 5 to 7 member heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S; and
R 4 is not unsubstituted phenyl, or a 5 to 7 member heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S;
when E is —C(═O)NR 5 R 10 , and R 3 is H, and R 2 is C(═O)NR 12 R 11 , and R 11 is H, then R 12 is not alkyl or substituted alkyl; and
when E is —C(═O)NR 5 R 10 , and R 1 is H, and R 5 is H, then R 10 is not H;
and wherein the compound of Formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, exhibits ATP-utilizing enzyme inhibitory activity.
2 . At least one compound of Formula (II):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
E is chosen from —CN, halogen, —NO 2 , and —C(═X)YR 5 ; wherein
X is chosen from O, and S;
Y is chosen from —N(R 10 )—, O, S, and a direct bond; wherein
R 10 is chosen H, alkyl, and substituted alkyl; and
R 5 is chosen from H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl, substituted heteroarylalkyl, and when Y is —N(R 10 )—, or a direct bond, then R 5 is additionally chosen from aryl, substituted aryl, heteroaryl, substituted heteroaryl, —N(R 7 ) 2 , and —OR 9 ; wherein
each R 7 is independently chosen from alkyl, substituted alkyl, aryl, substituted aryl, and H; and
R 9 is chosen from H, alkyl, and substituted alkyl;
or, R 5 and R 10 together with the atoms to which R 5 and R 10 form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
R 2 is chosen from H, —CHO, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, alkylsulfonyl, substituted alkylsulfonyl, heteroalkylsulfonyl, substituted heteroalkylsulfonyl, and -ZR 6 , wherein
Z is chosen from carbonyl, —C(O)O—, aminosulfonyl, aminothiocarbonyl, —C(═O)NR 11 —, sulfonyl, and thiocarbonyl; wherein
R 11 is chosen from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and H; and
R 6 is chosen from H, —COOH, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, and substituted bicycloheteroalkyl;
or R 1 and R 2 , together with the atoms to which R 1 and R 2 are attached, form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
R 3 is chosen from H, halogen, —NH 2 , acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, dialkylamino, and substituted dialkylamino; and
R 4 is chosen from H, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, or substituted bicycloheteroalkyl ring;
with the provisos that
when E is —CO 2 R 5 , then
R 3 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine or substituted aminotriazine; and
R 4 is not 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine or substituted aminotriazine;
when E is —CN, then
R 3 is not 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine or substituted aminotriazine; and
R 4 is not 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine or substituted aminotriazine;
when E is —CN, and R 2 is —C(═X)NH 2 , then
R 3 is not unsubstituted phenyl or a 5 to 7 membered heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S; and
R 4 is not unsubstituted phenyl or a 5 to 7 membered heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S;
when E is —C(═O)NR 5 R 10 , and R 3 is H, and R 2 is —C(═O)NR 12 R 11 , and R 11 is H, then R 12 is not alkyl, or substituted alkyl; and
when E is —C(═O)NR 5 R 10 , and R 1 is H, and R 5 is H, then R 10 is not H;
and wherein the compound of Formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, exhibits ATP-utilizing enzyme inhibitory activity.
3 . The compound of claim 2 , wherein
Y is chosen from O, a direct bond, and —N(R 10 )— wherein R 10 is H; and
R 5 is chosen from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, and substituted arylalkyl.
4 . The compound of claim 3 , wherein R 5 is chosen from H, C 1-10 alkyl, substituted C 1-10 alkyl, C 3-12 aryl, substituted C 3-12 aryl, C 3-12 heteroaryl, substituted C 3-12 heteroaryl, C 4-18 arylalkyl, and substituted C 4-18 arylalkyl.
5 . The compound of claim 2 , wherein R 2 is chosen from H, and -ZR 6 , wherein
Z is chosen from carbonyl, and —C(═O)NH—, and
R 6 is chosen from H, —COOH, C 1-10 alkyl, substituted C 1-10 alkyl, C 5-12 aryl, substituted C 5-12 aryl, C 3-12 cycloalkyl, substituted C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, substituted C 3-12 heterocycloalkyl, C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 heteroarylalkyl, substituted C 6-18 heteroarylalkyl, C 4-18 cycloalkylalkyl, substituted C 4-18 cycloalkylalkyl, C 4-18 heterocycloalkylalkyl, substituted C 4-18 heterocycloalkylalkyl, C 6-18 arylalkyl, substituted C 6-18 arylalkyl, C 5-12 bicycloalkyl, substituted C 5-12 bicycloalkyl, C 5-12 bicycloheteroalkyl, and substituted C 5-12 bicycloheteroalkyl.
6 . The compound of claim 2 , wherein R 3 is chosen from H, halogen, —NH 2 , alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, and dialkylamino.
7 . The compound of claim 2 , wherein R 3 is chosen from H, halogen, —NH 2 , C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 acyl, substituted C 1-10 acyl, C 1-10 alkoxycarbonyl, substituted C 1-10 alkoxycarbonyl, C 1-10 aminocarbonyl, substituted C 1-10 aminocarbonyl, C 3-12 cycloalkyl, substituted C 3-12 cycloalkyl, C 3-12 heteroalkyl, substituted C 3-12 heteroalkyl, C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 arylalkyl, substituted C 6-18 arylalkyl, C 6-18 heteroarylalkyl, substituted C 6-18 heteroarylalkyl, and C 2-20 dialkylamino
8 . The compound of claim 2 , wherein R 4 is chosen from H, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl, heteroaryl, substituted heteroaryl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, heteroarylalkyl, and substituted heteroarylalkyl.
9 . The compound of claim 2 , wherein R 4 is chosen from H, halogen, C 1-10 acyl, substituted C 1-10 acyl, C 1-10 alkoxycarbonyl, substituted C 1-10 alkoxycarbonyl, C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 aminocarbonyl, substituted C 1-10 aminocarbonyl, C 5-12 aryl, substituted C 5-12 aryl, arylalkyl, and substituted arylalkyl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 4-18 heterocycloalkylalkyl, substituted C 4-18 heterocycloalkylalkyl, C 6-18 heteroarylalkyl, and substituted C 6-18 heteroarylalkyl.
10 . At least one compound of Formula (III):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
R 2 is chosen from H, and -ZR 6 , wherein
Z is carbonyl; and
R 6 is chosen from H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, heteroarylalkyl, and substituted heteroarylalkyl;
R 3 is chosen from H, —NH 2 , alkyl, and substituted alkyl; and
R 4 is chosen from H, halogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
with the provisos that
R 3 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine;
R 4 is not H, 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine; and
when R 2 is —C(═X)NH 2 , where X is O or S, then
R 3 is not unsubstituted phenyl, or a 5 to 7 membered heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S; and
R 4 is not unsubstituted phenyl, or a 5 to 7 membered heteroaromatic ring containing 1 to 3 heteroatoms chosen from O, N or S;
and wherein the compound of Formula (III), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, exhibits ATP-utilizing enzyme inhibitory activity.
11 . The compound of claim 10 , wherein R 4 is chosen from C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 heteroalkyl, substituted C 1-8 heteroalkyl, C 6-12 arylalkyl, substituted C 6-12 arylalkyl, C 6-12 heterocycloalkylalkyl, and substituted C 6-12 heterocycloalkylalkyl.
12 . The compound of claim 10 , wherein R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a C 5-10 cycloalkyl, substituted C 5-10 cycloalkyl, C 5-10 heterocycloalkyl, or substituted C 5-10 heterocycloalkyl ring.
13 . The compound of claim 12 , wherein the at least one substituent group is chosen from halogen, C 1-6 alkyl, and ═O.
14 . The compound of claim 10 , wherein R 4 is chosen from C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-10 arylalkyl, and substituted C 6-10 heterocycloalkylalkyl.
15 . The compound of claim 10 , wherein R 3 is chosen from —NH 2 , C 1-8 alkyl, and substituted C 1-8 alkyl.
16 . The compound of claim 10 , wherein R is chosen from H, and —C(O)R 6 wherein
R 6 is chosen from C 1-8 alkyl, substituted C 1-8 alkyl, C 1-8 heteroalkyl, substituted C 1-8 heteroalkyl, C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 heterocycloalkyl, substituted C 6-18 heterocycloalkyl, C 6-18 heterocycloalkylalkyl, substituted C 6-18 heterocycloalkylalkyl, C 6-18 heteroarylalkyl, and substituted C 6-18 heteroarylalkyl.
17 . The compound of claim 16 , wherein the at least one substituent group is chosen from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 5-8 aryl, substituted C 5-8 aryl, C 5-8 heteroaryl, substituted C 5-8 heteroaryl, ═O, ═S, —COOH, —CF 3 , and —OH.
18 . The compound of claim 10 , wherein the at least one compound has the structure of any of compounds 1.1 to 1.45:
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing.
19 . The compound of claim 10 , wherein the at least one ATP-utilizing enzyme is chosen from a human protein kinase.
20 . The compound of claim 19 , wherein the human protein kinase is chosen from AKT2, AURORA-A, CDK2/cyclinE, CHEK1, CHEK2, CK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LYNA, MAPK1, MAPKAPK-2, MAPKAPK-3, MSK2, NEK2, P38-α, PAK2, PDGFR-α, PDK1, PKA, PRAK, SYK, TRKB, and ZAP70.
21 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 10 .
22 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 18 .
23 . The pharmaceutical composition of claim 21 , wherein the at least one compound is present in an amount effective for the treatment in a patient of at least one disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
24 . The pharmaceutical composition of claim 23 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
25 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 10 .
26 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 18 .
27 . The method of claim 25 , wherein the at least one disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
28 . The method of claim 27 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
29 . 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 10 .
30 . 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 18 .
31 . The method of claim 29 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
32 . The method of claim 31 , wherein the human protein kinase is chosen from AKT2, AURORA-A, CDK2/cyclinE, CHEK1, CHEK2, CK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LYNA, MAPK1, MAPKAPK-2, MAPKAPK-3, MSK2, NEK2, P38-α, PAK2, PDGFR-α, PDK1, PKA, PRAK, SYK, TRKB, and ZAP70.
33 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 10 .
34 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 18 .
35 . The method of claim 33 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
36 . The method of claim 35 , wherein human protein kinase is chosen from AKT2, AURORA-A, CDK2/cyclinE, CHEK1, CHEK2, CK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LYNA, MAPK1, MAPKAPK-2, MAPKAPK-3, MSK2, NEK2, P38-α, PAK2, PDGFR-α, PDK1, PKA, PRAK, SYK, TRKB, and ZAP70.
37 . 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 subject a therapeutically effective amount of at least one compound according to claim 10 .
38 . 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 subject a therapeutically effective amount of at least one compound according to claim 18 .
39 . The method of claim 37 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
40 . The method of claim 39 , wherein the protein kinase is chosen from AKT2, AURORA-A, CDK2/cyclinE, CHEK1, CHEK2, CK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LYNA, MAPK1, MAPKAPK-2, MAPKAPK-3, MSK2, NEK2, P38-α, PAK2, PDGFR-α, PDK1, PKA, PRAK, SYK, TRKB, and ZAP70.
41 . At least one compound of Formula (IV):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
R 2 is chosen from H, —CHO, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, alkylsulfonyl, substituted alkylsulfonyl, and -ZR 6 , wherein
Z is carbonyl; and
R 6 is chosen from H, —COOH, alkyl, substituted alkyl, aryl, and substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, and substituted bicycloheteroalkyl;
R 3 is chosen from H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, and dialkylamino;
R 4 is chosen from H, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, heteroarylalkyl, and substituted heteroarylalkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, bicycloalkyl, substituted bicycloalkyl, bicycloheteroalkyl, or substituted bicycloheteroalkyl ring; and
R 5 is chosen from H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl;
with the provisos that
R 3 is not chosen from H, 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine; and
R 4 is not chosen from 2-aminopyrimidine, substituted 2-aminopyrimidine, 2-aminopyridine, substituted 2-aminopyridine, aminotriazine, or substituted aminotriazine;
and wherein the compound of Formula (IV), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, exhibits ATP-utilizing enzyme inhibitory activity.
42 . The compound of claim 41 , wherein R 3 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 heterocycloalkyl, substituted C 6-18 heterocycloalkyl, C 6-18 arylalkyl, substituted C 6-18 arylalkyl, C 2-6 dialkylamino, and substituted C 2-6 dialkylamino.
43 . The compound of claim 42 , wherein the at least one substituent group is chosen from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 5-12 aryl, substituted C 5-12 aryl, —OH, —CN, —NH 2 , —CF 3 , nitro, and —NHC(O)CH 3 .
44 . The compound of claim 41 , wherein R 5 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 6-18 arylalkyl, and substituted C 6-18 arylalkyl.
45 . The compound of claim 41 , wherein R 5 is chosen from H, C 1-6 alkyl, and C 6-10 arylalkyl.
46 . The compound of claim 41 , wherein R 4 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 aminocarbonyl, substituted C 1-6 aminocarbonyl, C 1-6 carbonyl, substituted C 1-6 carbonyl, C 1-6 alkoxycarbonyl, substituted C 1-6 alkoxycarbonyl, C 5-12 aryl, substituted C 5-12 aryl, C 6-18 heteroarylalkyl, and substituted C 6-18 heteroarylalkyl.
47 . The compound of claim 46 , wherein the at least one substituent group is chosen from halogen, ═O, C 1-6 alkoxy, and C 1-6 alkyl.
48 . The compound of claim 41 , wherein R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a C 5-12 cycloalkyl, substituted C 5-12 cycloalkyl, C 5- 12 heterocycloalkyl, substituted C 5-12 heterocycloalkyl, C 5-12 bicycloalkyl, substituted C 5-12 bicycloalkyl, C 5-12 bicycloheteroalkyl, or substituted C 5-12 bicycloheteroalkyl ring.
49 . The compound of claim 48 , wherein the at least one substituent group is chosen from C 1-6 alkoxy, halogen, C 1-6 alkyl, C 5-12 aryl, substituted C 5-12 aryl, C 1-6 alkoxycarbonyl, substituted C 1-6 alkoxycarbonyl, C 6-12 arylalkyl, substituted C 6-12 arylalkyl, ═O, and ═N—OH.
50 . The compound of claim 41 , wherein R 2 is chosen from H, —COOH, —CH═O, C 1-6 alkylsulfonyl, substituted C 1-6 alkylsulfonyl, C 6-12 heterocycloalkylalkyl, substituted C 6-12 heterocycloalkylalkyl, C 6-12 heteroarylalkyl, substituted C 6-12 heteroarylalkyl, and —COR 6 wherein,
R 6 is chosen from C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 3-12 cycloalkyl, substituted C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, substituted C 3-12 heterocycloalkyl, C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 cycloalkylalkyl, substituted C 6-18 cycloalkylalkyl, C 6-18 heterocycloalkylalkyl, substituted C 6-18 heterocycloalkylalkyl, C 6-18 arylalkyl, substituted C 6-18 arylalkyl, C 6-18 heteroarylalkyl, substituted C 6-18 heteroarylalkyl, C 5-12 bicycloalkyl, substituted C 5-12 bicycloalkyl, C 5-12 bicycloheteroalkyl, and substituted C 5-12 bicycloheteroalkyl.
51 . The compound of claim 50 , wherein the at least one substituent group is chosen from C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 substituted C 1-6 alkoxy, C 5-8 aryl, substituted C 5-8 aryl, C 5 -8 heteroaryl, substituted C 5-8 heteroaryl, C 5-8 cycloalkyl, substituted C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, substituted C 5-8 heterocycloalkyl, C 6-10 arylalkyl, substituted C 6-10 arylalkyl, C 6-10 heteroarylalkyl, substituted C 6-10 heteroarylalkyl, C 6-10 cycloalkylalkyl, substituted C 6-10 cycloalkylalkyl, C 6-10 heterocycloalkylalkyl, substituted C 6-10 heterocycloalkylalkyl, C 1-6 alkylsulfonyl, substituted C 1-6 alkylsulfonyl, halogen, —OH, ═O, nitro, —COOH, —CF 3 , ═NH, and —NH 2 .
52 . The compound of claim 41 , wherein the at least one compound has the structure of any of compounds 2.1 to 2.193:
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing.
53 . The compound of claim 41 , wherein the at least one ATP-utilizing enzyme is chosen from a human protein kinase.
54 . The compound of claim 53 , wherein the human protein kinase is chosen from ABL, ABL1, ABL-T315I, AKT1, AKT2, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-β, P38-γ, P38-δ, P70S6K1, PDGFR-Q, PDK1, PKA, ROCK2, SRC, SYK, TRKB, and ZAP70.
55 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 41 .
56 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 52 .
57 . The pharmaceutical composition of claim 55 , wherein the at least one compound is present in an amount effective for the treatment in a patient of at least one disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
58 . The pharmaceutical composition of claim 57 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
59 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 41 .
60 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 52 .
61 . The method of claim 59 , wherein the at least one disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
62 . The method of claim 61 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
63 . 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 41 .
64 . 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 52 .
65 . The method of claim 63 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
66 . The method of claim 65 , wherein the human protein kinase is chosen from ABL, ABL1, ABL-T315I, AKT1, AKT2, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-β, P38-γ, P38-δ, P70S6K1, PDGFR-α, PDK1, PKA, ROCK2, SRC, SYK, TRKB, and ZAP70.
67 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 41 .
68 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 52 .
69 . The method of claim 67 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
70 . The method of claim 69 , wherein human protein kinase is chosen from ABL, ABL1, ABL-T315I, AKT1, AKT2, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-β, P38-γ, P38-δ, P70S6K1, PDGFR-α, PDK1, PKA, ROCK2, SRC, SYK, TRKB, and ZAP70.
71 . 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 subject a therapeutically effective amount of at least one compound according to claim 41 .
72 . 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 subject a therapeutically effective amount of at least one compound according to claim 52 .
73 . The method of claim 71 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
74 . The method of claim 73 , wherein the protein kinase is chosen from ABL, ABL1, ABL-T315I, AKT1, AKT2, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-β, P38-γ, P38-δ, P70S6K1, PDGFR-α, PDK1, PKA, ROCK2, SRC, SYK, TRKB, and ZAP70.
75 . At least one compound of Formula (V):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
R 2 is chosen from H, and -ZR 6 wherein
Z is carbonyl; and
R 6 is chosen from alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkylalkyl, and substituted heterocycloalkylalkyl;
R 3 is chosen from H, halogen, alkyl, and substituted alkyl;
R 4 is chosen from H, halogen, alkyl, and substituted alkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl ring;
R 5 is chosen from H, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
and wherein the compound of Formula (V), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, exhibits ATP-utilizing enzyme inhibitory activity.
76 . The compound of claim 75 , wherein R 4 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl.
77 . The compound of claim 75 , wherein R 3 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl.
78 . The compound of claim 75 , wherein R 3 and R 4 together with the carbon atoms to which R 3 and R 4 are attached form a C 5-8 cycloalkyl or substituted C 5-8 cycloalkyl ring.
79 . The compound of claim 75 , wherein R 5 is chosen from C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, and substituted C 5-12 heteroaryl.
80 . The compound of claim 79 , where the at least one substituent group is chosen from halogen, C 1-6 alkyl, and C 1-6 alkoxy.
81 . The compound of claim 75 , wherein R 5 is chosen from C 5-6 aryl, substituted C 5-6 aryl, C 5-6 heteroaryl, and substituted C 5-6 heteroaryl.
82 . The compound of claim 81 , where the at least one substituent group is chosen from halogen, C 1-6 alkyl, and C 1-6 alkoxy.
83 . The compound of claim 75 , wherein R 2 is chosen from H, and —C(O)R 6 wherein R 6 is chosen from C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 5-12 aryl, substituted C 5-12 aryl, C 5-12 heteroaryl, substituted C 5-12 heteroaryl, C 6-18 heterocycloalkylalkyl, and substituted C 6-18 heterocycloalkylalkyl.
84 . The compound of claim 83 , wherein the at least one substituent group is chosen from halogen, —OH, and C 1-6 alkyl.
85 . The compound of claim 75 , wherein the at least one compound has the structure of any of compounds 3.1 to 3.21:
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing.
86 . The compound of claim 75 , wherein the at least one ATP-utilizing enzyme is chosen from a human protein kinase.
87 . The compound of claim 86 , wherein the human protein kinase is chosen from AURORA-A, CDK2/cyclinE, CK2, FLT-3, GSK-3α, GSK-3β, KIT, MAPKAPK-2, MSK1, P38-β, PDGFR-α, and TRKB.
88 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 75 .
89 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 85 .
90 . The pharmaceutical composition of claim 88 , wherein the at least one compound is present in an amount effective for the treatment in a patient of at least one disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
91 . The pharmaceutical composition of claim 88 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
92 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 75 .
93 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 85 .
94 . The method of claim 92 , wherein the at least one disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
95 . The method of claim 94 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
96 . 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 75 .
97 . 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 85 .
98 . The method of claim 96 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
99 . The method of claim 98 , wherein the human protein kinase is chosen from AURORA-A, CDK2/cyclinE, CK2, FLT-3, GSK-3α, GSK-3β, KIT, MAPKAPK-2, MSK1, P38-β, PDGFR-α, and TRKB.
100 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 75 .
101 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 85 .
102 . The method of claim 100 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
103 . The method of claim 102 , wherein human protein kinase is chosen from AURORA-A, CDK2/cyclinE, CK2, FLT-3, GSK-3α, GSK-3β, KIT, MAPKAPK-2MSK1, P38-β, PDGFR-α, and TRKB.
104 . 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 subject a therapeutically effective amount of at least one compound according to claim 75 .
105 . 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 subject a therapeutically effective amount of at least one compound according to claim 85 .
106 . The method of claim 104 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
107 . The method of claim 106 , wherein the protein kinase is chosen from AURORA-A, CDK2/cyclinE, CK2, FLT-3, GSK-3α, GSK-3β, KIT, MAPKAPK-2, MSK1, P38-β, PDGFR-α, and TRKB.
108 . At least one compound of Formula (VI):
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, wherein:
R 2 is chosen from H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, alkylsulfonyl, substituted, alkylsulfonyl, heteroalkylsulfonyl, substituted heteroalkylsulfonyl, and -ZR 6 , wherein
Z is carbonyl; and
R 6 is chosen from H, alkyl, substituted alkyl, aryl, and substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heteroalkyl;
R 3 is chosen from H, halogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aminocarbonyl, substituted aminocarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
R 4 is chosen from H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
or R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
R 5 is chosen from H, alkyl, substituted alkyl;
R 10 is chosen from H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroalkyl, and substituted heteroalkyl;
or, R 5 and R 10 together with the atoms to which R 5 and R 10 are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring; and
with the provisos that
when R 3 is H, and R 2 is —C(═O)NR 12 R 11 , and R 11 is H, then R 12 is not alkyl or substituted alkyl; and
when R 1 is H, and R 5 is H, then R 10 is not H;
and wherein the compound of Formula (VI), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing, is an inhibitor of at least one ATP-utilizing enzyme.
109 . The compound of claim 108 , wherein
R 2 is chosen from H, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkylsulfonyl, substituted, alkylsulfonyl, heteroalkylsulfonyl, substituted heteroalkylsulfonyl, and -ZR 6 , wherein
Z is carbonyl, and
R 6 is chosen from H, alkyl, substituted alkyl, aryl, and substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heterocycloalkylalkyl, substituted heterocycloalkylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heteroarylalkyl;
R 3 is chosen from alkyl, substituted alkyl, aryl, substituted aryl, and H;
R 4 is chosen from H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or
R 3 and R 4 together with the atoms to which R 3 and R 4 are attached, form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl ring;
R 5 is H; and
R 10 is chosen from H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
or R 5 and R 10 together with the atoms to which R 5 and R 10 are attached form a heterocycloalkyl or substituted heterocycloalkyl ring.
110 . The compound of claim 108 , wherein R 3 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 5-10 aryl, and substituted C 5-10 aryl.
111 . The compound of claim 108 , wherein R 3 is chosen from H, methyl, and phenyl.
112 . The compound of claim 108 , wherein R 5 is chosen from H, and R 10 is chosen from H, C 1-8 alkyl, substituted C 1-8 alkyl, C 1-12 heteroalkyl, substituted C 1-12 heteroalkyl, C 5-10 aryl, substituted C 5-10 aryl, C 6-12 arylalkyl, and substituted C 6-12 arylalkyl.
113 . The compound of claim 112 , wherein the at least one substituent group is chosen from halogen, C 1-6 alkyl, C 1-6 alkoxy, —OH, ═O, and —NH 2 .
114 . The compound of claim 108 , wherein R 5 and R 10 together with the atoms to which R 5 and R 10 are attached form a C 5-10 heterocycloalkyl or substituted C 5-10 heterocycloalkyl ring.
115 . The compound of claim 108 , wherein R 4 is chosen from H, C 1-6 alkyl, substituted C 1-6 alkyl, C 5-10 aryl, substituted C 5-10 aryl, C 6-12 arylalkyl, and substituted C 6-12 arylalkyl.
116 . The compound of claim 108 , wherein R 3 and R 4 together with the atoms to which R 3 and R 4 are attached form a C 5-8 cycloalkyl, substituted C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, or substituted C 5-8 heterocycloalkyl ring.
117 . The compound of claim 116 , wherein the at least one substituent group is chosen from halogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 6-10 arylalkyl, substituted C 6-10 arylalkyl, and ═O.
118 . The compound of claim 108 , wherein R 2 is chosen from H, C 5 -8 aryl, substituted C 5-8 aryl, C 5-8 heteroaryl, substituted C 5-8 heteroaryl, C 6-10 heterocycloalkyl, substituted C 6-10 heterocycloalkyl, C 6-10 heteroarylalkyl, substituted C 6-10 heteroarylalkyl, C 1-10 alkylsulfonyl, substituted C 1-10 alkylsulfonyl, and —C(O)R 6 wherein
R 6 is chosen from C 1-10 alkyl, substituted C 1-10 alkyl, C 1-10 heteroalkyl, substituted C 1-10 heteroalkyl, C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, substituted C 3-10 heterocycloalkyl, C 5-10 aryl, substituted C 5-10 aryl, C 5-10 heteroaryl, substituted C 5-110 heteroaryl, C 6-18 cycloalkylalkyl, substituted C 6-18 cycloalkylalkyl, C 6-18 heterocycloalkylalkyl, substituted C 6-18 heterocycloalkylalkyl, C 6-18 arylalkyl, substituted C 6-18 arylalkyl, C 6-18 heteroarylalkyl, and substituted C 6-18 heteroarylalkyl.
119 . The compound of claim 118 , wherein R 2 is chosen from —C(O)R 6 and the at least one substituent group is chosen from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, C 5-8 aryl, C 5-8 heterocycloalkyl, substituted C 5-8 heterocycloalkyl, C 5-8 heteroaryl, C 6-12 heterocycloalkylalkyl, substituted C 6-12 heterocycloalkylalkyl, C 6-12 heteroarylalkyl, substituted C 6-12 heteroarylalkyl, C 5-8 alkkylsulfonyl, ═O, ═S, —C(O)NH 2 , —OH, —CF 3 , nitro, —CN, —COOH, —OCF 3 , and —N(CH 3 ) 2 .
120 . The compound of claim 108 , wherein the at least one compound has the structure of any of compounds 4.1 to 4.285:
a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate of any of the foregoing.
121 . The compound of claim 108 , wherein the at least one ATP-utilizing enzyme is chosen from a human protein kinase.
122 . The compound of claim 121 , wherein the human protein kinase is chosen from ABL-1, ABL-T315I, AKT1, AKT2, AKT3, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-γ, P38-β, P38-δ, P70S6K1, PAK2, PDGFR-α, PDK1, PRAK, ROCK2, SGK1, SRC, SYK, TRKB, and ZAP70.
123 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 108 .
124 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to claim 120 .
125 . The pharmaceutical composition of claim 123 , wherein the at least one compound is present in an amount effective for the treatment in a patient of at least one disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
126 . The pharmaceutical composition of claim 125 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
127 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 108 .
128 . A method of treating a disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to claim 120 .
129 . The method of claim 127 , wherein the at least one disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer.
130 . The method of claim 129 , wherein cancer is chosen from at least one of glioblastoma, ovarian, breast, endometrial, hepatocellular carcinoma, melanoma, digestive tract, lung, renal-cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancer.
131 . 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 108 .
132 . 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 120 .
133 . The method of claim 131 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
134 . The method of claim 131 , wherein the human protein kinase is chosen from ABL-1, ABL-T315I, AKT1, AKT2, AKT3, AURORA-A, BMX, CDK, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-β, P38-β, P38-δ, P70S6K1, PAK2, PDGFR-α, PDK1, PRAK, ROCK2, SGK1, SRC, SYK, TRKB, and ZAP70.
135 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 108 .
136 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to claim 120 .
137 . The method of claim 135 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
138 . The method of claim 137 , wherein human protein kinase is chosen from ABL-1, ABL-T315I, AKT1, AKT2, AKT3, AURORA-A, BMX, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-γ, P38-β, P38-δ, P70S6K1, PAK2, PDGFR-α, PDK1, PRAK, ROCK2, SGK1, SRC, SYK, TRKB, and ZAP70.
139 . 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 subject a therapeutically effective amount of at least one compound according to claim 108 .
140 . 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 subject a therapeutically effective amount of at least one compound according to claim 120 .
141 . The method of claim 139 , wherein the ATP-utilizing enzyme is chosen from a human protein kinase.
142 . The method of claim 141 , wherein the protein kinase is chosen from ABL-1, ABL-T315I, AKT1, AKT2, AKT3, AURORA-A, BMX, CDK, CDK1, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK1, CK2, CSK, c-TAK1, DAPK1, DYRK2, FLT-3, FYN, GSK-3α, GSK-3β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK-2, MET, MSK1, MSK2, NEK2, P38-α, P38-γ, P38-β, P38-δ, P70S6K1, PAK2, PDGFR-α, PDK1, PRAK, ROCK2, SGK1, SRC, SYK, TRKB, and ZAP70.