Fused 2-aminothiazole compounds
The present application relates to therapeutic organic compounds of formula (I), wherein Q, R1, R2, R3, and R4 are defined herein. The invention also relates to pharmaceutical compositions comprising an effective amount of a therapeutic organic compound; and methods for treating and preventing disease such as cancer comprising administering and effective amount of a therapeutic organic compound to a subject in need thereof.
1. A compound of the Formula I:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof;
wherein
Q is CH or N;
R 1 is H, C(O)—C 3-6 -cycloalkyl, aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycle, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, C 3-6 -cycloalkyl, or C(O)—C 1-6 -alkyl-heterocycle, wherein the aryl, heterocycle, or heteroaryl groups can be substituted or unsubstituted;
R 2 is H, C 1-6 -alkyl, C 1-6 -alkoxy, or halogen;
R 3 is H, C(O)—N(H)-aryl, C(O)—N(H)—C 1-6 -alkyl-heterocycle, C(O)—N(H)—C 1-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted; and
R 4 is H, C(O)N(H)-aryl, N(H)C(O)N(H)-aryl, C(O)N(H)—C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)N(H)—C 1-6 -alkyl-heteroaryl, N(H)CO 2 —C 1-6 -alkyl, N(H)C(O)aryl, or N(H)C(O)N(H)—C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted, and wherein at least one of R 3 and R 4 is not H.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein the aryl, heteroaryl and heterocycle groups of R 1 , R 3 and R 4 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 1 is H, C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C(O)—C 1-6 -alkyl, C 3-6 -cycloalkyl, pyridine, phenyl, C(O)-phenyl, C(O)—C 1-6 -alkyl-piperazine, or C(O)-oxazolidinone;
wherein the pyrimidine, piperidine, pyridine, and phenyl groups of R 1 can be optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 3 is H, C(O)—N(H)-phenyl, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole;
wherein the morpholino, imidazole, and phenyl groups of R 3 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 4 is H, C(O)N(H)Ph, N(H)C(O)N(H)Ph, C(O)N(H)—C 1-6 -alkyl-morpholino, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)—N(H)—C 1-6 -alkyl-imidazole, N(H)CO 2 C 1-6 -alkyl, N(H)C(O)N(H)—C 1-6 -alkyl-morpholino, or N(H)C(O)Ph;
wherein the morpholino, imidazole, and phenyl groups of R 4 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 1 is C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C(O)C 1-6 -alkyl, H, C 3-6 -cycloalkyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-C 1-6 -alkyl, C(O)—C 1-6 -alkyl-piperazine, Ph-piperazine-C 1-6 -alkyl, C(O)-oxazolidinone-C 1-6 -alkyl-morpholino, wherein the pyrimidine group is optionally independently substituted one or more times with C 1-6 -alkyl or piperazine, wherein the piperazine is optionally substituted with C 1-6 -alkyl-OH; and wherein C(O)—C 1-6 -alkyl-piperazine is optionally substituted with C(O)C 1-6 -alkyl;
R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole, wherein Ph is optionally substituted one or more times with CF 3 , C 1-6 -alkyl-piperazine-C 1-6 -alkyl, or imidazole-C 1-6 -alkyl; and
R 4 is H, C(O)N(H)Ph, N(H)C(O)N(H)Ph, C(O)N(H)—C 1-6 -alkyl-morpholino, CO 2 —C 1-6 -alkyl, CO 2 H, N(H)CO 2 —C 1-6 -alkyl, or N(H)C(O)N(H)—C 1-6 -alkyl-morpholino, wherein the Ph group is optionally independently substituted one or more times with CF 3 , C 1-6 -alkyl-piperazine-C 1-6 -alkyl, imidazole-C 1-6 -alkyl, imidazole, tetrazole, pyrazole, piperazine, C 1-6 -alkyl-piperazine-C 1-6 -alkyl, morpholino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-imidazole, C 1-6 -alkyl-morpholino, C 1-6 -alkyl-piperidine-OH, C 1-6 -alkyl-piperazine-C 1-6 -alkyl), imidazole-C 1-6 -alkyl, piperazine-C 1-6 -alkyl-OH, or O-piperidine-C 1-6 -alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 1 is C(O)-cyclopropyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C(O)CH 3 , H, cyclopropyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-CH 2 CH 3 , C(O)—(CH 2 ) 2 -piperazine, Ph-piperazine-CH 3 , or C(O)-oxazolidinone-(CH 2 ) 3 -morpholino, wherein the pyrimidine is substituted with CH 3 and piperazine that is optionally substituted with (CH 2 ) 2 OH, and wherein the piperazine of the C(O)—(CH 2 ) 2 -piperazine group is optionally substituted with C(O)CH 3 ;
R 2 is H, CH 3 , F or Cl;
R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—(CH 2 ) 3 -morpholino, or C(O)—N(H)—(CH 2 ) 3 -imidazole, wherein Ph is substituted with CF 3 and CH 2 -piperazine-CH 2 CH 3 , or CF 3 and imidazole-CH 3 ; and
R 4 is H, C(O)N(H)Ph-CF 3 , N(H)C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), C(O)N(H)(CH 2 ) 2 -morpholino, C(O)N(H)(CH 2 ) 3 -morpholino, CO 2 CH 2 CH 3 , C(O)N(H)Ph-imidazole, C(O)N(H)Ph-tetrazole, C(O)N(H)Ph-pyrazole, C(O)N(H)Ph(CF 3 )(piperazine), CO 2 H, C(O)N(H)Ph-CH 2 -piperazine-CH 2 CH 3 , C(O)—N(H)Ph-morpholino, C(O)—N(H)Ph-t-butyl, —C(O)N(H)Ph(OCH 2 CH 3 )(morpholino), C(O)N(H)Ph(OCH 3 )(morpholino), C(O)N(H)Ph(OCH 3 ) 2 , C(O)—N(H)—(CH 2 ) 3 -imidazole, N(H)CO 2 -t-butyl, N(H)C(O)Ph(CF 3 )(CH 2 -piperidine-OH), N(H)C(O)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), N(H)C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), N(H)C(O)N(H)—(CH 2 ) 2 -morpholino, N(H)C(O)N(H)—(CH 2 ) 3 -morpholino, N(H)C(O)Ph(CF 3 )(piperazine-(CH 2 ) 2 OH), or N(H)C(O)Ph(CF 3 )(O-piperidine-CH 3 ).
8. The compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein Formula I is represented by the Formula II:
wherein
Q is CH;
R 1 is C(O)—C 3-6 -cycloalkyl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-aryl, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, C 3-6 -cycloalkyl, or C(O)—C 1-6 -alkyl-heterocycle;
R 2 and R 3 are H; and
R 4 is C(O)N(H)-aryl, N(H)C(O)N(H)-aryl, C(O)N(H)—C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)N(H)—C 1-6 -alkyl-heteroaryl, N(H)CO 2 —C 1-6 -alkyl, N(H)C(O)aryl, or N(H)C(O)N(H)—C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted.
9. The compound of claim 8 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 1 is C(O)—C 3-6 -cycloalkyl;
R 4 is C(O)N(H)Ph, wherein the Ph group is optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen, wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein Ph is optionally independently substituted one or more times with CF 3 , piperazine, C 1-6 -alkyl-piperazine, C 1-6 -alkyl-piperazine-C 1-6 -alkyl, CH 2 CH 3 , imidazole, or imidazole-C 1-6 -alkyl.
11. A compound of Formula III:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof;
wherein
G is N or CR 10 ;
R 1 is H, C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C(O)—C 1-6 -alkyl, C 3-6 -cycloalkyl, pyridine, phenyl, C(O)-phenyl, C(O)—C 1-6 -alkyl-piperazine, or C(O)-oxazolidinone,
wherein the pyrimidine, piperidine, pyridine, and phenyl groups of R 1 can be optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl,
R 10 is H or C 1-3 alkyl;
R 12 is H, C 1-6 -alkyl, C 1-6 -alkoxy, or halogen;
R 13 is H, C(O)—N(R 28 )-aryl, C(O)—N(R 29 )—C 1-6 -alkyl-heterocycle, C(O)—N(R 30 )—C 1-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl or heterocycle groups are optionally substituted with one or more of OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
R 14 is H, C(O)NR 15 -aryl, NR 16 C(O)NR 17 -aryl, C(O)NR 20 —C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)NR 21 —C 1-6 -alkyl-heteroaryl, NR 22 CO 2 —C 1-6 -alkyl, NR 25 C(O)aryl or NR 26 C(O)NR 27 —C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups are optionally substituted with one or more of OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein one of R 13 and R 14 is not H; and
R 15 , R 16 , R 17 , R 20 , R 21 , R 22 , R 25 , R 26 , R 27 , R 28 , R 29 , and R 30 are C 1-6 -alkyl, halogen, or H.
12. The compound of claim 11 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 12 is H, CH 3 , F or Cl;
R 13 is H, C(O)—N(H)-Ph, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—(CH 2 ) 3 -morpholino, or C(O)—N(H)—(CH 2 ) 3 -imidazole, wherein Ph is substituted with CF 3 and CH 2 -piperazine-CH 2 CH 3 , or CF 3 and imidazole-CH 3 ; and
R 14 is H, C(O)N(H)Ph-CF 3 , N(H)C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), C(O)N(H)(CH 2 ) 2 -morpholino, C(O)N(H)(CH 2 ) 3 -morpholino, CO 2 CH 2 CH 3 , C(O)N(H)Ph-imidazole, C(O)N(H)Ph-tetrazole, C(O)N(H)Ph-pyrazole, C(O)N(H)Ph(CF 3 )(piperazine), CO 2 H, C(O)N(H)Ph-CH 2 -piperazine-CH 2 CH 3 , C(O)—N(H)Ph-morpholino, C(O)—N(H)Ph-t-butyl, —C(O)N(H)Ph(OCH 2 CH 3 )(morpholino), C(O)N(H)Ph(OCH 3 )(morpholino), C(O)N(H)Ph(OCH 3 ) 2 , C(O)—N(H)—(CH 2 ) 3 -imidazole, N(H)CO 2 -t-butyl, N(H)C(O)Ph(CF 3 )(CH 2 -piperidine-OH), N(H)C(O)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), N(H)C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), N(H)C(O)N(H)—(CH 2 ) 2 -morpholino, N(H)C(O)N(H)—(CH 2 ) 3 -morpholino, N(H)C(O)Ph(CF 3 )(piperazine-(CH 2 ) 2 OH), or N(H)C(O)Ph(CF 3 )(O-piperidine-CH 3 ).
13. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof.
14. A compound of the Formula I:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof;
wherein Q is CH or N;
R 1 is H, C(O)—C 3-6 -cycloalkyl, aryl, heteroaryl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-heterocycle, C(O)-aryl, CO 2 —C 1-6 -alkyl, C 3-6 -cycloalkyl, or C(O)—C 1-6 -alkyl-heterocycle, wherein the aryl, heterocycle, or heteroaryl groups can be substituted or unsubstituted;
R 2 is H, C 1-6 -alkyl, C 1-6 -alkoxy, or halogen;
R 3 is H, C(O)—N(H)-aryl, C(O)—N(H)—C 1-6 -alkyl-heterocycle, C(O)—N(H)—C 1-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted; and
R 4 is H, C(O)N(H)-aryl, N(H)C(O)N(H)-aryl, C(O)N(H)—C 1-6 -alkoxy, C(O)—N(H)—C 3-6 -cycloalkyl, C(O)N(H)—C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)N(H)—C 1-6 -alkyl-heteroaryl, N(H)CO 2 —C 1-6 -alkyl, NH 2 , N(H)C(O)aryl, or N(H)C(O)N(H)—C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted, and wherein at least one of R 3 and R 4 is not H.
15. The compound of claim 14 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof, wherein the aryl, heteroaryl, and heterocycle groups of R 1 , R 3 and R 4 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen.
16. The compound of claim 14 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof, wherein
R 1 is H, C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C 3-6 -cycloalkyl, pyridine, phenyl, C(O)-phenyl, C(O)—C 1-6 -alkyl-piperazine, or C(O)-oxazolidinone; wherein the pyrimidine, piperidine, pyridine, and phenyl groups of R 1 can be optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl;
R 3 is H, C(O)—N(H)-phenyl, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole; wherein the morpholino, imidazole, and phenyl groups of R 3 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl; and
R 4 is H, C(O)N(H)Ph, N(H)C(O)N(H)Ph, C(O)N(H)—C 1-6 -alkoxy, C(O)—N(H)—C 3-6 -cycloalkyl, C(O)N(H)—C 1-6 -alkyl-morpholino, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)—N(H)—C 1-6 -alkyl-imidazole, N(H)CO 2 C 1-6 -alkyl, NH 2 , N(H)C(O)Ph, or N(H)C(O)N(H)—C 1-6 -alkyl-morpholino; wherein the morpholino, imidazole, and phenyl groups of R 4 can optionally be independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
17. The compound of claim 14 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof, wherein
R 1 is C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, H, C 3-6 -cycloalkyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-C 1-6 -alkyl, C(O)—C 1-6 -alkyl-piperazine, Ph-piperazine-C 1-6 -alkyl, C(O)-oxazolidinone-C 1-6 -alkyl-morpholino, wherein the pyrimidine group is optionally independently substituted one or more times with C 1-6 -alkyl or piperazine, wherein the piperazine is optionally substituted with C 1-6 -alkyl-OH; and wherein C(O)—C 1-6 -alkyl-piperazine is optionally substituted with C(O)C 1-6 -alkyl;
R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—C 1-6 -alkyl-morpholino, or C(O)—N(H)—C 1-6 -alkyl-imidazole, wherein Ph is optionally substituted one or more times with CF 3 , C 1-6 -alkyl-piperazine-C 1-6 -alkyl, or imidazole-C 1-6 -alkyl; and
R 4 is H, C(O)N(H)Ph, N(H)C(O)N(H)Ph, C(O)N(H)C 1-6 -alkoxy, C(O)—N(H)—C 3-6 -cycloalkyl, C(O)N(H)—C 1-6 -alkyl-morpholino, CO 2 —C 1-6 -alkyl, CO 2 H, N(H)CO 2 —C 1-6 -alkyl, NH 2 , or N(H)C(O)N(H)—C 1-6 -alkyl-morpholino, wherein the Ph group is optionally independently substituted one or more times with CF 3 , C 1-6 -alkyl-piperazine-C 1-6 -alkyl, imidazole-C 1-6 -alkyl, imidazole, tetrazole, pyrazole, piperazine, C 1-6 -alkyl-piperazine-C 1-6 -alkyl, morpholino, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-imidazole, C 1-6 -alkyl-morpholino, C 1-6 -alkyl-piperidine-OH, C 1-6 -alkyl-piperazine-C 1-6 -alkyl), imidazole-C 1-6 -alkyl, piperazine-C 1-6 -alkyl-OH, or O-piperidine-C 1-6 -alkyl.
18. The compound of claim 14 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof wherein
R 1 is C(O)-cyclopropyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, H, cyclopropyl, pyridine, Ph-SO 2 -piperazine, C(O)-PhCH 2 -piperazine-CH 2 CH 3 , C(O)—(CH 2 ) 2 -piperazine, Ph-piperazine-CH 3 , or C(O)-oxazolidinone-(CH 2 ) 3 -morpholino, wherein the pyrimidine is substituted with CH 3 and piperazine that is optionally substituted with (CH 2 ) 2 OH, and wherein the piperazine of the C(O)—(CH 2 ) 2 -piperazine group is optionally substituted with C(O)CH 3 ;
R 2 is H, CH 3 , F or Cl;
R 3 is H, C(O)—N(H)-Ph, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—(CH 2 ) 3 -morpholino, or C(O)—N(H)—(CH 2 ) 3 -imidazole, wherein Ph is substituted with CF 3 and CH 2 -piperazine-CH 2 CH 3 , or CF 3 and imidazole-CH 3 ; and
R 4 is H, C(O)N(H)Ph-CF 3 , N(H)C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)OCH 3 , C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), C(O)—N(H)-cyclopropyl, C(O)N(H)(CH 2 ) 2 -morpholino, C(O)N(H)(CH 2 ) 3 -morpholino, CO 2 CH 2 CH 3 , C(O)N(H)Ph-imidazole, C(O)N(H)Ph-tetrazole, C(O)N(H)Ph-pyrazole, C(O)N(H)Ph(CF 3 )(piperazine), CO 2 H, C(O)N(H)Ph-CH 2 -piperazine-CH 2 CH 3 , C(O)—N(H)Ph-morpholino, C(O)—N(H)Ph-t-butyl, —C(O)N(H)Ph(OCH 2 CH 3 )(morpholino), C(O)N(H)Ph(OCH 3 )(morpholino), C(O)N(H)Ph(OCH 3 ) 2 , C(O)—N(H)—(CH 2 ) 3 -imidazole, N(H)CO 2 -t-butyl, NH 2 , N(H)C(O)Ph(CF 3 )(CH 2 -piperidine-OH), N(H)C(O)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), N(H)C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), N(H)C(O)N(H)—(CH 2 ) 2 -morpholino, N(H)C(O)N(H)—(CH 2 ) 3 -morpholino, N(H)C(O)Ph(CF 3 )(piperazine-(CH 2 ) 2 OH), or N(H)C(O)Ph(CF 3 )(O-piperidine-CH 3 ).
19. The compound of claim 14 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof wherein Formula I is represented by the Formula II:
wherein Q is CH;
R 1 is C(O)—C 3-6 -cycloalkyl, C(O)N(H)-heteroaryl, C(O)-heteroaryl, C(O)-aryl, CO 2 —C 1-6 -alkyl, or C 3-6 -cycloalkyl;
R 2 and R 3 are H; and
R 4 is C(O)N(H)-aryl, N(H)C(O)N(H)-aryl, C(O)N(H)—C 1-6 -alkoxy, C(O)—N(H)—C 3-6 -cycloalkyl, C(O)N(H)—C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)N(H)—C 1-6 -alkyl-heteroaryl, N(H)CO 2 —C 1-6 -alkyl, NH 2 , N(H)C(O)aryl, or N(H)C(O)N(H)—C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups can be substituted or unsubstituted.
20. The compound of claim 19 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof wherein
R 1 is C(O)—C 3-6 -cycloalkyl;
R 4 is C(O)N(H)Ph, wherein the Ph group is optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen, wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl.
21. The compound of claim 20 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof wherein the Ph is optionally independently substituted one or more times with CF 3 , piperazine, C 1-6 -alkyl-piperazine, C 1-6 -alkyl-piperazine-C 1-6 -alkyl, CH 2 CH 3 , imidazole, or imidazole-C 1-6 -alkyl.
22. A compound of Formula III:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof;
wherein
G is N or CR 10 ;
R 1 is H, C(O)—C 3-6 -cycloalkyl, pyrimidine, C(O)N(H)-piperidine, C(O)-piperidine, C 3-6 -cycloalkyl, pyridine, phenyl, C(O)-phenyl, C(O)—C 1-6 -alkyl-piperazine, or C(O)-oxazolidinone,
wherein the pyrimidine, piperidine, pyridine, and phenyl groups of R 1 can be optionally independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and wherein the substituent aryl, heteroaryl and heterocycle groups can optionally be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-OH, or C(O)—C 1-6 -alkyl,
R 10 is H or C 1-3 alkyl;
R 12 is H, C 1-6 -alkyl, C 1-6 -alkoxy, or halogen;
R 13 is H, C(O)—N(R 28 )-aryl, C(O)—N(R 29 )—C 1-6 -alkyl-heterocycle, C(O)—N(R 30 )—C 1-6 -alkyl-heteroaryl, wherein the aryl, heteroaryl or heterocycle groups are optionally substituted with one or more of OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen; and
R 14 is H, C(O)NR 15 -aryl, NR 16 C(O)NR 17 -aryl, C(O)—NR 18 —C 1-6 -alkoxy, C(O)—NR 19 —C 3-6 -cycloalkyl, C(O)NR 20 —C 1-6 -alkyl-heterocycle, CO 2 —C 1-6 -alkyl, CO 2 H, C(O)NR 21 —C 1-6 -alkyl-heteroaryl, NR 22 CO 2 —C 1-6 -alkyl, NR 23 R 24 , NR 25 C(O)aryl or NR 26 C(O)NR 27 —C 1-6 -alkyl-heterocycle, wherein the aryl, heteroaryl or heterocycle groups are optionally substituted with one or more of OH, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkyl-heterocycle, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein the substituent aryl, heteroaryl and heterocycle groups can be further independently substituted one or more times with OH, C 1-6 -alkyl, C 1-6 -alkoxy, C(O)—C 1-6 -alkyl, CO 2 —C 1-6 -alkyl, aryl, heteroaryl, heterocycle, SO 2 -heterocycle, SO 2 -aryl, SO 2 -heteroaryl, C 1-6 -alkyl-heterocycle, C 1-6 -alkyl-aryl, C 1-6 -alkyl-heteroaryl, CF 3 , or halogen;
wherein one of R 13 and R 14 is not H; and
R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , and R 30 are C 1-6 -alkyl, halogen, or H.
23. The compound of claim 22 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer or racemate thereof, wherein
R 12 is H, CH 3 , F or Cl;
R 13 is H, C(O)—N(H)-Ph, C(O)—N(H)—(CH 2 ) 2 -morpholino, C(O)—N(H)—(CH 2 ) 3 -morpholino, or C(O)—N(H)—(CH 2 ) 3 -imidazole, wherein Ph is substituted with CF 3 and CH 2 -piperazine-CH 2 CH 3 , or CF 3 and imidazole-CH 3 ; and
R 14 is H, C(O)N(H)Ph-CF 3 , N(H)C(O)N(H)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H) Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), C(O)N(H)OCH 3 , C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), C(O)—N(H)-cyclopropyl, C(O)N(H)(CH 2 ) 2 -morpholino, C(O)N(H)(CH 2 ) 3 -morpholino, NH 2 , CO 2 CH 2 CH 3 , C(O)N(H)Ph-imidazole, C(O)N(H)Ph-tetrazole, C(O)N(H)Ph-pyrazole, C(O)N(H)Ph(CF 3 )(piperazine), CO 2 H, C(O)N(H)Ph-CH 2 -piperazine-CH 2 CH 3 , C(O)—N(H)Ph-morpholino, C(O)—N(H)Ph-t-butyl, —C(O)N(H)Ph(OCH 2 CH 3 )(morpholino), C(O)N(H)Ph(OCH 3 )(morpholino), C(O)N(H)Ph(OCH 3 ) 2 , C(O)—N(H)—(CH 2 ) 3 -imidazole, N(H)CO 2 -t-butyl, N(H)C(O)Ph(CF 3 )(CH 2 -piperidine-OH), N(H)C(O)Ph(CF 3 )(CH 2 -piperazine-CH 2 CH 3 ), N(H)C(O)N(H)Ph(CF 3 )(imidazole-CH 3 ), N(H)C(O)N(H)—(CH 2 ) 2 -morpholino, N(H)C(O)N(H)—(CH 2 ) 3 -morpholino, N(H)C(O)Ph(CF 3 )(piperazine-(CH 2 ) 2 OH), or N(H)C(O)Ph(CF 3 )(O-piperidine-CH 3 ).
24. A method of treating cancer, wherein the cancer etiology or progression is at least partially mediated by the activity of Abl kinase, BCR-Abl kinase, c-kit kinase, Src kinase, or PDGFR kinase, comprising administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof.
25. The method of claim 24 , wherein the cancer is selected from the group consisting of multiple myeloma, chronic myelogenous leukemia, pancreatic cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, prostate cancer, malignant melanoma, non-melanoma skin cancers, gastrointestinal stromal tumors, hematologic tumors, hematologic malignancies, childhood leukemia, childhood lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic origin, lymphomas of cutaneous origin, acute leukemia, chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.
26. The method of claim 24 , wherein the cancer is non-small cell lung cancer.
27. The method of claim 24 , wherein the cancer is resistant to treatment with imatinib.
28. The method of claim 27 , wherein treatment-resistance is due to one or more point-mutations in an Abl kinase, a BCR-Abl kinase domain, a c-kit kinase, an Src kinase or a PDGFR kinase.
29. A method of inhibiting the activity of a kinase in a cell, comprising contacting the cell with the compound of claim 1 .
30. The method of claim 29 , wherein the kinase is selected from Abl, Abl (T 315 l), BCR-Abl, BRAF, CDK 11 , CDK 5 , CDK 2 , CDK 3 , CDK 7 , DDR 1 , FLT 1 , FLT 3 , FLT 4 , HIPK 1 , kit, LOK, p 38 -gamma, PDGFRA, PDGFRB, and Src.
31. A method of treating a disease in a subject, wherein the disease etiology or progression is at least partially mediated by the activity of Abl kinase, BCR-Abl kinase, c-kit kinase, Src kinase, or PDGFR kinase, comprising administering to the subject a compound of claim 1 , or a pharmaceutically acceptable salt, enantiomer, stereoisomer, rotamer, tautomer, diastereomer, or racemate thereof.