CA2636077A1 - Thiazole compounds as protein kinase b (pkb) inhibitors - Google Patents
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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Abstract
The invention relates to thiazole compounds of Formula (I) and Formula (II) and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein. The invention also relates to the therapeutic use of such thiazole compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
Claims (81)
1. A compound of Formula I
wherein:
A is or aryl;
Y is -N(R5)R6 or -OR6;
X is O, S, or N(R7);
R1 is R8, -CHR11-N(H)-R8, -CHR11-O-R8, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, or -C.ident.N;
R2 is aryl or heteroaryl;
R3 is -H, C1-C6 alkyl which may be interrupted by one or more hetero atoms, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl);
R4 is C1-C6 alkyl which may be interrupted by one or more hetero atoms, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl), or R3 and R4, together with the carbon atom to which they are both attached, join to form a C3-C10 heterocyclic or carbocyclic ring system, or R4 and R7 join to form a C3-C10 heterocyclic ring;
R5 is -H, C1-C8 alkyl, -C(O)(CR9R10)t)N(R7)2, -C(O)(CR9R10)t, -C(O)2(CR9R10)t, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl), or R4 and R5 join to form a C3-C10 heterocyclic ring;
R6 and R7 are independently selected from -H, C1-C8 alkyl, -(C1-C6 alkyl)aryl, or -C(O)(C1-C6 alkyl), or R6 and R7, together with the atoms to which they are linked, join to form a 5 to 6-membered heterocyclic ring, or R5 and R6, together with the nitrogen atom to which they are linked, join to form a 5 to 6-membered heterocyclic or heteroaryl ring;
R8 is -H, C1-C6 alkyl, -(C1-C6 alkyl)aryl, aryl, or heteroaryl; and R9, R10, and R11 are independently selected from -H, C1-C6 alkyl, or aryl;
wherein n is an integer from 1 to 6; m is an integer from 0 to 2; and each t is independently an integer from 0 to 3;
wherein each of the above alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties and heterocyclic and carbocyclic rings are optionally and independently substituted by 1-3 substituents selected from amino, aryl, heteroaryl, cycloalkyl, or heterocyclyl optionally substituted by 1-5 substituents selected from C1-C6 alkoxy, C1-C6 alkyl optionally substituted by halo, aryl, halo, hydroxyl, heteroaryl, C1-C6 hydroxyalkyl, or NHS(O)2-(C1-C6 alkyl);
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms, cyano, halo, hydroxyl, nitro, or -O-aryl;
or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
wherein:
A is or aryl;
Y is -N(R5)R6 or -OR6;
X is O, S, or N(R7);
R1 is R8, -CHR11-N(H)-R8, -CHR11-O-R8, C2-C6 alkynyl, C2-C6 hydroxyalkynyl, or -C.ident.N;
R2 is aryl or heteroaryl;
R3 is -H, C1-C6 alkyl which may be interrupted by one or more hetero atoms, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl);
R4 is C1-C6 alkyl which may be interrupted by one or more hetero atoms, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl), or R3 and R4, together with the carbon atom to which they are both attached, join to form a C3-C10 heterocyclic or carbocyclic ring system, or R4 and R7 join to form a C3-C10 heterocyclic ring;
R5 is -H, C1-C8 alkyl, -C(O)(CR9R10)t)N(R7)2, -C(O)(CR9R10)t, -C(O)2(CR9R10)t, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl), or R4 and R5 join to form a C3-C10 heterocyclic ring;
R6 and R7 are independently selected from -H, C1-C8 alkyl, -(C1-C6 alkyl)aryl, or -C(O)(C1-C6 alkyl), or R6 and R7, together with the atoms to which they are linked, join to form a 5 to 6-membered heterocyclic ring, or R5 and R6, together with the nitrogen atom to which they are linked, join to form a 5 to 6-membered heterocyclic or heteroaryl ring;
R8 is -H, C1-C6 alkyl, -(C1-C6 alkyl)aryl, aryl, or heteroaryl; and R9, R10, and R11 are independently selected from -H, C1-C6 alkyl, or aryl;
wherein n is an integer from 1 to 6; m is an integer from 0 to 2; and each t is independently an integer from 0 to 3;
wherein each of the above alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties and heterocyclic and carbocyclic rings are optionally and independently substituted by 1-3 substituents selected from amino, aryl, heteroaryl, cycloalkyl, or heterocyclyl optionally substituted by 1-5 substituents selected from C1-C6 alkoxy, C1-C6 alkyl optionally substituted by halo, aryl, halo, hydroxyl, heteroaryl, C1-C6 hydroxyalkyl, or NHS(O)2-(C1-C6 alkyl);
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 alkoxy, C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms, cyano, halo, hydroxyl, nitro, or -O-aryl;
or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
2. The compound of claim 1, wherein A is
3. The compound of claim 2, wherein m, n, and t are 1.
4. The compound of claim 1, wherein A is X is -N(R7), Y is -N(R5)(R6), and m, n, and t are 1.
5. The compound of claim 1, wherein A is X is -N(R7), Y is -N(R5)(R6), R2 is heteroaryl, R3 is -H, R4 is -(CR9R10)t(aryl) or -(CR9R10)t(heteroaryl), and m, n, and t are 1, wherein R5, R6, and R7 are -H, and R9 and R10 are independently selected from H or C1-C3 alkyl.
6. The compound of claim 5, wherein R2 is a bicyclic heteroaryl, R4 is -(CR9R10)t(monocyclic aryl) or -(CR9R10)t(bicyclic heteroaryl), and R5, R6, R7, R9 and R10 are -H.
7. The compound of claim 6, wherein the bicyclic heteroaryl group of R2 is isoquinolinyl, 1H-indazolyl, thiazolo[5,4-c]pyridinyl, benzo[d]thiazole-2(3H)-onyl, phthalazinyl, indolin-2-onyl, 3,4-dihydroquinolin-2(1H)-onyl, benzo[d]isoxazolyl, benzo[d]oxazol-2(3H)-onyl, benzo[d]imidazol-2(3H)-onyl, or 1,6-naphthyridinyl;
and the monocyclic aryl group of R4 is phenyl, chlorophenyl, (trifluoromethyl)phenyl, or (C1-C6)alkoxyphenyl, or the bicyclic heteroaryl group of R4 is 1H-indolyl.
and the monocyclic aryl group of R4 is phenyl, chlorophenyl, (trifluoromethyl)phenyl, or (C1-C6)alkoxyphenyl, or the bicyclic heteroaryl group of R4 is 1H-indolyl.
8. The compound of claim 7, wherein the bicyclic heteroaryl group of R2 is isoquinolin-6-yl, 3-aminoisoquinolin-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 3-amino-1H-indazol-5-yl, 3-amino-1H-indazol-6-yl, 3-amino-1-methyl-1H-indazol-6-yl, 3-methylamino-1H-indazol-5-yl, 3-methyl-1H-indazol-5-yl, thiazolo[5,4-c]pyridin-2-yl, benzo[d]thiazole-2(3H)-on-6-yl, 1-hydroxyphthalazin-6-yl, phthalazin-6-yl, indolin-2-on-5-yl, 3-methylindolin-2-on-5-yl, 3-(furan-2-ylmethylene)indolin-2-on-5-yl, 3-(1H-imidazol-5-ylmethylene)indolin-2-on-5-yl, 3,3-difluoroindolin-2-on-5-yl, 3,4-dihydroquinolin-2(1H)-on-6-yl, benzo[d]isoxazol-5-yl, 3-aminobenzo[d]isoxazol-5-yl, benzo[d]oxazol-2(3H)-on-6-yl, 1-methyl-1H-benzo[d]imidazol-2(3H)-on-6-yl, or 1,6-naphthyridin-2-yl; and the monocyclic aryl group of R4 is phenyl, 3-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3-(trifluoromethyl)phenyl, or 4-(trifluoromethyl)phenyl, or the bicyclic heteroaryl group of R4 is 1H-indol-3-yl.
9. The compound of claim 1, wherein A is X is -N(R7), Y is -N(R5)(R6), R2 is a bicyclic heteroaryl, R3 is -H, R4 is -(CR9R10)t(monocyclic aryl), and m, n, and t are 1, wherein R5, R6, R7, R9 and R10 are -H, the bicyclic heteroaryl group of R2 is isoquinolin-6-yl, 3-aminoisoquinolin-6-yl, 1H-indazol-5-yl, 3-methyl-1H-indazol-5-yl, thiazolo[5,4-c]pyridin-2-yl, benzo[d]oxazol-2(3H)-on-6-yl, or 1,6-naphthyridin-2-yl, and the monocyclic aryl group of R4 is 4-chlorophenyl, 3-(trifluoromethyl)phenyl, or 4-(trifluoromethyl)phenyl.
10. The compound of any one of claims 1-9, wherein R1 is -H, -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OH, -CH2OCH2CF3, -CH2N(H)CH3, -CH(CH3)OCH3, furanyl, phenyl, pyridyl, or -C.ident.N.
11. The compound of claim 10, wherein R1 is -CH3, -CH2CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OH, -CH2OCH2CF3, -CH2N(H)CH3, -CH(CH3)OCH3, furanyl, phenyl, pyridyl, or -C.ident.N.
12. The compound of claim 10, wherein R1 is -H, -CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OH, or furanyl.
13. The compound of claim 10, wherein R1 is -CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OH, or furanyl.
14. The compound of any one of claims 1-9, wherein R1 is -(C1-C6 alkyl), -(C1-alkyl)aryl, aryl, heteroaryl, -CHR11-N(H)-R8, -CHR11-O-R8, or -C.ident.N.
15. The compound of claim 14, wherein R1 is -(C1-C6 alkyl), heteroaryl, or -O-R8.
16. The compound of claim 1, wherein A is aryl, X is -N(R7), R2 is heteroaryl, and m is 1.
17. The compound of claim 16, wherein R2 is a bicyclic heteroaryl and R7 is -H.
18. The compound of claim 16, wherein A is a monocyclic aryl, R1 is H, R2 is thiazolo[5,4-c]pyridin-2-yl, and R7 is -H.
19. A compound selected from N-((S)-2-amino-3-phenylpropyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-chlorophenyl)propyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-chlorophenyl)propyl)-5-(1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-5-(isoquinolin-6-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)thiazol-2-amine, N-((S)-2-amino-3-phenylpropyl)-4-methyl-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-phenylpropyl)-5-(1H-indazol-5-yl)-4-methylthiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-(furan-2-yl)-5-(isoquinolin-6-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-4-phenylthiazol-2-amine, (2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(isoquinolin-6-yl)thiazol-4-yl)methanol, (2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(3-methyl-1H-indazol-5-yl)thiazol-4-yl)methanol, (2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(1H-indazol-5-yl)thiazol-4-yl)methanol, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-4-(methoxymethyl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(1H-indazol-5-yl)-4-(methoxymethyl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-(methoxymethyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-4-(1-methoxyethyl)thiazol-2-amine, N-((S)-2-amino-3-(3-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide, N-((S)-2-amino-3-(3-chlorophenyl)propyl)-4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-chlorophenyl)propyl)-4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(3-chlorophenyl)propyl)-5-(thiazolo[5,4-c]pyridin-2-yl)-4-((2,2,2-trifluoroethoxy)methyl)thiazol-2-amine, N-((S)-2-amino-3-(4-chlorophenyl)propyl)-4-(ethoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-ethyl-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-methyl-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-chlorophenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)acetamide, N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-benzyl-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3 -(3-(trifluoromethyl)phenyl)propyl)-N-benzyl-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-N-benzyl-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, N-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propyl)-5-(thiazolo[5,4-c]pyridin-yl)thiazol-2-amine, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(thiazolo[5,4-c]pyridin-yl)thiazol-2-amine, N-(4-(methoxymethyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-yl)-N-((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)acetamide, 4-(methoxymethyl)-N-((S)-2-(2-morpholinoethylamino)-3-(4-(trifluoromethyl)phenyl)propyl)-5-(thiazolo[5,4-c]pyridin-2-yl)thiazol-2-amine, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-3,4-dihydroquinolin-2(1H)-one, 6-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)benzo[d]thiazol-2(3H)-one, 5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)-1H-indazol-3-amine, 5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amine, 6-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-3,3-difluoroindolin-2-one, 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)indolin-2-one, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)benzo[d]thiazol-2(3H)-one, 5-(2-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)indolin-2-one, 5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)-N-methyl-1H-indazol-3-amine), 6-(2-((S)-2-amino-3-(3-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-3-methylindolin-2-one, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(1H-indazol-6-yl)thiazol-amine, (S)-4-(2-(2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)benzamide, 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1H-indazol-3-amine, 5-(2-((S)-2-amino-3 -(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)benzo[d]isoxazol-3-amine, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1H-indazol-3-amine, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1-methyl-1H-indazol-3-amine, 5-(2-((S)-2-Amino-3-(4-chlorophenyl)propylamino)thiazol-5-yl)indolin-2-one, 6-(2-((S)-2-amino-3-(4-chlorophenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, N-((S)-2-amino-3 -(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)-4-((methylamino)methyl)thiazol-2-amine, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-4-(methoxymethyl)thiazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-4-(methoxymethyl)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, 2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(2-oxoindolin-5-yl)thiazole-4-carbonitrile, 2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thiazole-4-carbonitrile, 2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(isoquinolin-6-yl)thiazole-4-carbonitrile, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(phthalazin-6-yl)thiazol-amine, 6-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)phthalazin-1-ol, N-((S)-2-amino-3 -(3-chlorophenyl)propyl)-5-(isoquinolin-6-yl)thiazol-2-amine, 5-(2-((S)-2-amino-3-(4-methoxyphenyl)propylamino)thiazol-5-yl)indolin-2-one, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(1,6-naphthyridin-2-yl)thiazol-2-amine, 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-4-(methoxymethyl)thiazol-5-yl)indolin-2-one, 5-(2-((S)-2-amino-3-phenylpropylamino)thiazol-5-yl)-3-methylindolin-2-one, N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-4-(methoxymethyl)-5-(1,6-naphthyridin-2-yl)thiazol-2-amine, (E)-5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)-3-(furan-2-ylmethylene)indolin-2-one ditrifluoroacetates, (Z)-5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)-3-(furan-2-ylmethylene)indolin-2-one ditrifluoroacetates, (E)-3-((1H-imidazol-5-yl)methylene)-6-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)indolin-2-one, 5-(2-((S)-2-amino-3-(1H-indol-3-yl)propylamino)thiazol-5-yl)indolin-2-one, 6-(2-((S)-2-Amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)isoquinolin-3-amine, 6-(2-((S)-2-amino-3-(4-chlorophenyl)propylamino)thiazol-5-yl)isoquinolin-3-amine, 6-(2-((S)-2-amino-3-(4-methoxyphenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one, or 4-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)-5-(isoquinolin-6-yl)thiazole-4-yl)-2-methylbut-3-yn-2-ol, or a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof.
20. A pharmaceutical composition, comprising: a pharmaceutically-acceptable carrier and the compound of any one of claim 1-18.
21. The composition of claim 20, further comprising at least one additional therapeutic agent.
22. A method for treating a kinase-mediated disorder in a mammal in need thereof, comprising: administering to the mammal a therapeutically effective amount of the compound of any one of claims 1-18, or the compound of claim 19.
23. The method of claim 22, wherein the disorder is mediated by IGF-1R, Insulin Receptor, KDR, Tie2, EGFR, PKA, PKB, PKC, FKHR, TSC1/2, SGK, LCK, BTK, Erk, MSK, MK2, MSK, p38, P70S6K, PIM1, PIM2, ROCK2, GSK3, or a CDK complex.
24. The method of claim 22, wherein the disorder is mediated by PKB.
25. The method of claim 23, wherein the method comprises selective inhibition of PKB.
26. The method of claim 22, wherein the disorder is cancer.
27. A method of treating a proliferation-related disorder in a mammal in need thereof, comprising: administering to the mammal a therapeutically effective amount of the compound of any one of claims 1-18, or the compound of claim 19.
28. The method of claim 27, wherein the disorder is abnormal cell growth.
29. The method of claim 27, wherein the disorder is inflammation or an inflammation-related disorder.
30. The method of claim 27, wherein the disorder is a metabolic disease.
31. The method of claim 30, wherein the metabolic disease is diabetes.
32. The method of claim 27, wherein the disorder is cancer.
33. A compound of Formula II
wherein:
R1 is -H, halo, -OR8, C1-C6 alkyl, -(C1-C6 alkyl)-O-R8, -(C1-C6 haloalkyl)-O-R8, -(C2-C6 alkenyl)-O-R8, -(C1-C6 alkyl)N(R7)2, -(C1-C6 alkyl)aryl, -C(O)R8, -C(O)O-R8, -C(O)N(R7)2, -CHR11-N(H)-R8, -CHR11-O-R8, C2-C6 alkynyl, (C2-C6 alkynyl)-O-R8, -C.ident.N, -(C2-C6 alkynyl)(C3-C8 cycloalkyl), -(C2-C6 alkynyl)(C5-C8 cycloalkenyl), -(C2-C6 alkynyl)-N(R7)S(O)2-R8, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
R2 is a carbocyclic ring system or is a heterocyclic ring system;
R5 is -H, C1-C8 alkyl, -C(O)(CR9R10)t)N(R7)2, -C(O)(CR9R10)t, -C(O)2(CR9R10)t, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl);
R6 and R7, in each instance, are independently selected from -H, C1-C8 alkyl, -(C1-C6 alkyl)aryl, or -C(O)(C1-C6 alkyl);
R8 is selected from -H, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkyl)aryl, aryl, heteroaryl, C1-C6 hydroxyalkyl, or -(C1-C6 alkyl)-O-(C1-C6 alkyl), cycloalkyl, or heterocyclyl;
R9 and R10, in each instance, and R11 are independently selected from -H, C1-C6 alkyl, or aryl;
R12 is -H, -OR8, -O-(C1-C6 alkyl)-O-R8, C1-C6 alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8;
R13 is -H, or C1-C6 alkyl;
R14 is -H, -OR8, -O-(C1-C6 alkyl)-O-R8, C1-C6 alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8;
each t is independently selected from 0, 1, 2, or 3; and Z is aryl or heteroaryl;
wherein each of the above alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties and heterocyclic and carbocyclic rings are optionally and independently substituted by 1-3 substituents selected from amino, aryl, heteroaryl, cycloalkyl, or heterocyclyl optionally substituted by 1-5 substituents selected from C1-C6 alkoxy, C1-C6 alkyl optionally substituted by halo, aryl, halo, hydroxyl, heteroaryl, C1-C6 hydroxyalkyl, or -NHS(O)2-(C1-C6 alkyl);
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkoxy,C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms, cyano, halo, hydroxyl, nitro, oxo, -NH(CO)-O-(C1-C6 alkyl)aryl, -NH(CO)-O-(C1-C6 alkyl), -N(C1-C6 alkyl)(CO)-O-(C1-C6 alkyl)aryl, -N(C1-C6 alkyl)(CO)-O-(C1-C6 alkyl), -C(O)OH, -C(O)O(C1-C6 alkyl), -C(O)NH2, -C(O)N(H)-(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C2-C4 alkenyl)heterocyclyl, or -(C2-C4 alkenyl)cycloalkyl, or -O-aryl;
or a pharmaceutically acceptable salt, hydrate, stereoisomer, or mixture thereof.
wherein:
R1 is -H, halo, -OR8, C1-C6 alkyl, -(C1-C6 alkyl)-O-R8, -(C1-C6 haloalkyl)-O-R8, -(C2-C6 alkenyl)-O-R8, -(C1-C6 alkyl)N(R7)2, -(C1-C6 alkyl)aryl, -C(O)R8, -C(O)O-R8, -C(O)N(R7)2, -CHR11-N(H)-R8, -CHR11-O-R8, C2-C6 alkynyl, (C2-C6 alkynyl)-O-R8, -C.ident.N, -(C2-C6 alkynyl)(C3-C8 cycloalkyl), -(C2-C6 alkynyl)(C5-C8 cycloalkenyl), -(C2-C6 alkynyl)-N(R7)S(O)2-R8, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
R2 is a carbocyclic ring system or is a heterocyclic ring system;
R5 is -H, C1-C8 alkyl, -C(O)(CR9R10)t)N(R7)2, -C(O)(CR9R10)t, -C(O)2(CR9R10)t, -(CR9R10)t(aryl), -(CR9R10)t(heteroaryl), -(CR9R10)t(cycloalkyl), or -(CR9R10)t(heterocyclyl);
R6 and R7, in each instance, are independently selected from -H, C1-C8 alkyl, -(C1-C6 alkyl)aryl, or -C(O)(C1-C6 alkyl);
R8 is selected from -H, C1-C6 alkyl, C1-C6 haloalkyl, -(C1-C6 alkyl)aryl, aryl, heteroaryl, C1-C6 hydroxyalkyl, or -(C1-C6 alkyl)-O-(C1-C6 alkyl), cycloalkyl, or heterocyclyl;
R9 and R10, in each instance, and R11 are independently selected from -H, C1-C6 alkyl, or aryl;
R12 is -H, -OR8, -O-(C1-C6 alkyl)-O-R8, C1-C6 alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8;
R13 is -H, or C1-C6 alkyl;
R14 is -H, -OR8, -O-(C1-C6 alkyl)-O-R8, C1-C6 alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8;
each t is independently selected from 0, 1, 2, or 3; and Z is aryl or heteroaryl;
wherein each of the above alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties and heterocyclic and carbocyclic rings are optionally and independently substituted by 1-3 substituents selected from amino, aryl, heteroaryl, cycloalkyl, or heterocyclyl optionally substituted by 1-5 substituents selected from C1-C6 alkoxy, C1-C6 alkyl optionally substituted by halo, aryl, halo, hydroxyl, heteroaryl, C1-C6 hydroxyalkyl, or -NHS(O)2-(C1-C6 alkyl);
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkoxy,C1-C6 alkylamino, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms, cyano, halo, hydroxyl, nitro, oxo, -NH(CO)-O-(C1-C6 alkyl)aryl, -NH(CO)-O-(C1-C6 alkyl), -N(C1-C6 alkyl)(CO)-O-(C1-C6 alkyl)aryl, -N(C1-C6 alkyl)(CO)-O-(C1-C6 alkyl), -C(O)OH, -C(O)O(C1-C6 alkyl), -C(O)NH2, -C(O)N(H)-(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(C2-C4 alkenyl)heterocyclyl, or -(C2-C4 alkenyl)cycloalkyl, or -O-aryl;
or a pharmaceutically acceptable salt, hydrate, stereoisomer, or mixture thereof.
34. The compound of claim 33, wherein the compound of Formula II has the Formula IIA
35. The compound of claim 33, wherein the compound of Formula II has the Formula IIB
36. The compound of claim 33, wherein the compound of Formula II has the Formula IIC
37. The compound of claim 33, wherein the compound of Formula II has the Formula IID
38. The compound of claim 33, wherein the compound of Formula II has the Formula IIE
39. The compound of claim 33, wherein R1 is -H.
40. The compound of claim 33, wherein R12 is -H or C1-C6 alkyl.
41. The compound of claim 40, wherein R12 is -H or methyl.
42. The compound of claim 33, wherein R13 is -H.
43. The compound of claim 33, wherein R14 is -H.
44. The compound of claim 33, wherein R14 is -OR8, -O-(C1-C6 alkyl)-O-R8, C1-alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8.
45. The compound of claim 33, wherein R14 is selected from -H, methyl, ethyl, propyl, ethenyl, propenyl, hydroxymethyl, methoxymethyl, -CH2-O-C(O)-(C1-C6 alkyl), 1-hydroxyethyl,or methoxymethoxy.
46. The compound of claim 33, wherein Z is selected from optionally substituted phenyl, optionally substituted indolyl, optionally substituted naphthyl, optionally substituted pyridyl, or optionally substituted thiophenyl.
47. The compound of claim 46, wherein Z is selected from phenyl, indolyl, naphthyl, pyridyl, or thiophenyl, each of which is optionally substituted with 1-3 substituents selected from -Cl, -F, -CF3, -OH, -O-(C1-C6 alkyl), -O-(C1-C6 alkyl)-Cl, -O-(C1-C6 alkyl)-OH, -C1-C6 alkyl, -OCF3, -NH(CO)-O-(C1-C6 alkyl)aryl, or -NH(CO)-O-(C1-alkyl).
48. The compound of claim 47, wherein Z is selected from phenyl, indolyl, naphthyl, pyridyl, thiophenyl, 4-chlorophenyl, 4-trifluormethylphenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, 3-fluoro-4-trifluoromethylphenyl, 4-chloro-3-fluorophenyl, 4-(3-chloropropoxy)phenyl, 4-(3-hydroxypropoxy)phenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 3,4-difluorophenyl, 3-fluoro-4-methoxyphenyl, 3,5-difluorophenyl, 6-trifluoromethylpyridin-3-yl, 5-methoxy-6-trifluoromethylpyridin-3-yl, 2-fluoro-4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2,3-difluoro-4-trifluoromethylphenyl, 4-hydroxyphenyl, methoxy-4-trifluoromethylphenyl, 3-hydroxy-4-trifluoromethylphenyl, 5-chlorothiophen-2-yl, 3-fluoro-4-hydroxyphenyl, or a phenyl substituted in the 4 position with -NH-C(O)-O-CH2-phenyl.
49. The compound of claim 33, wherein R7 is H.
50. The compound of claim 33, wherein R5 and R6 are each H.
51. The compound of claim 33, wherein R12 is -H or C1-C6 alkyl, R13 is H, and is -H, -OR8, -O-(C1-C6 alkyl)-O-R8, C1-C6 alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8.
52. The compound of claim 51, wherein R14 is -OR8, -O-(C1-C6 alkyl)-O-R8, C1-alkyl, C1-C6 alkenyl, -(C1-C6 alkyl)-O-R8, or -(C1-C6 alkyl)-O-C(O)-R8.
53. The compound of claim 52, wherein R5, R6, and R7 are all H.
54. The compound of claim 33, wherein the carbocyclic ring system or the heterocyclic ring system of R2 comprises at least one aromatic ring.
55. The compound of claim 33, wherein R2 is selected from optionally substituted phenyl, pyridyl, indazolyl, isoquinolinyl, thiazolopyridinyl, benzothiazolonyl, dihydroquinolinonyl, benzoisoxazolyl, benzooxazolonyl, indolinonyl, benzoimidazolonyl, phthalazinyl, naphthyridinyl, thienopyridinyl, benzodioxolyl, isoindolinonyl, quinazolinyl, or cinnolinyl.
56. The compound of claim 33, wherein R2 is selected from one of the following groups which may optionally be substituted and where the wavy line indicates the point of attachment to the thiazole:
57. The compound of claim 33, wherein R2 is selected from one of the following groups, where the wavy line indicates the point of attachment to the thiazole:
58. The compound of claim 33, wherein R' is selected from -H, -C.ident.N, -Br, -Cl, -OH, -CF3, -CH3, -CH2CH3, -CH2CH2OH, -C(H)(CH3)OCH3, -CH2OCH2CF3, -CH2N(H)CH3, -CH2N(CH3)2, -CF2CH2OH, cyclopropyl, furanyl, tetrahydrofuranyl, phenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, pyridyl, oxazolyl, hydroxymethyl, methoxymethyl, ethoxymethyl, -C(O)OMe, -C(O)N(H)CH2CH2OH, -C(O)N(H)CH3, -C(O)NH2, -C(O)N(CH3)2, or a group selected from one of the following groups where the wavy line indicates the point of attachment to the thiazole:
59. A pharmaceutical composition, comprising: a pharmaceutically-acceptable carrier and the compound of any one of claim 33-58.
60. The composition of claim 59, further comprising at least one additional therapeutic agent.
61. A method for treating a kinase-mediated disorder in a mammal in need thereof, comprising: administering to the mammal a therapeutically effective amount of the compound of any one of claims 33-58.
62. The method of claim 61, wherein the disorder is mediated by IGF-1R, Insulin Receptor, KDR, Tie2, EGFR, PKA, PKB, PKC, FKHR, TSC1/2, SGK, LCK, BTK, Erk, MSK, MK2, MSK, p38, P70S6K, PIM1, PIM2, ROCK2, GSK3, or a CDK complex.
63. The method of claim 61, wherein the disorder is mediated by PKB.
64. The method of claim 63, wherein the method comprises selective inhibition of PKB.
65. The method of claim 61, wherein the method comprises selective inhibition of PKB .alpha..
66. The method of claim 61, wherein the disorder is cancer.
67. A method of treating a proliferation-related disorder in a mammal in need thereof, comprising: administering to the mammal a therapeutically effective amount of the compound of any one of claims 33-58.
68. The method of claim 67, wherein the disorder is abnormal cell growth.
69. The method of claim 67, wherein the disorder is inflammation or an inflammation-related disorder.
70. The method of claim 67, wherein the disorder is a metabolic disease.
71. The method of claim 70, wherein the metabolic disease is diabetes.
72. The method of claim 67, wherein the disorder is cancer.
73. The method of claim 72, wherein the cancer is a solid tumor.
74. The use of the compound of any one of claims 1-18, or 19 in the preparation of a medicament for treating a disease mediated by PKB.
75. The use of claim 74, wherein the disease is mediated by PKB.alpha..
76. The use of claim 74, wherein the disease is cancer.
77. The use of claim 76, wherein the cancer is a solid tumor.
78. The use of the compound of any one of claims 33-58 in the preparation of a medicament for treating a disease mediated by PKB.
79. The use of claim 78, wherein the disease is mediated by PKB.alpha..
80. The use of claim 78, wherein the disease is cancer.
81. The use of claim 80, wherein the cancer is a solid tumor.
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| US75954606P | 2006-01-18 | 2006-01-18 | |
| US60/759,546 | 2006-01-18 | ||
| PCT/US2007/000871 WO2007084391A2 (en) | 2006-01-18 | 2007-01-11 | Thiazole compounds as protein kinase b ( pkb) inhibitors |
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| EP (1) | EP1981884B1 (en) |
| JP (1) | JP5199885B2 (en) |
| KR (1) | KR20080091369A (en) |
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| CA (1) | CA2636077C (en) |
| CR (1) | CR10211A (en) |
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| US8084479B2 (en) | 2011-12-27 |
| EP1981884A2 (en) | 2008-10-22 |
| UA91895C2 (en) | 2010-09-10 |
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