Fused ring heterocycle kinase modulators
The present invention provides fused ring heterocycles as kinase modulators, pharmaceutical compositions containing these modulators, and methods of using these modulators to treat diseases mediated by kinase activity.
1. A compound of Formula (A), or an enantiomer, diastereomer, racemate, tautomer or pharmaceutically acceptable salt thereof:
wherein
A 1 is substituted or unsubstituted phenyl;
A 2 is a pyridinyl group;
X 1 is CR 4 ; wherein
R 4 is hydrogen, halogen, cyano, nitro, haloalkyl, or substituted or unsubstituted alkyl;
R 1 is hydrogen, lower alkyl or lower heteroalkyl;
R 2 is hydrogen, lower alkyl, halogen, hydroxy, —OR 8 , cyano, nitro, haloalkyl, —NR 6 R 7 ;
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOH, —NR 9 R 10 , —CH 2 NR 9 R 10 , —CONR 9 R 10 , —CH 2 CONR 9 R 10 or —OR 8 ; or
R 2 and R 3 together with the carbon atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted cycloalkyl;
each R 5 is independently halogen, cyano, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, —NR 11 R 12 , —CONR 11 R 12 , —OR 13 , —C(═Z)R 14 , or —S(O)R 15 , wherein n is independently an integer from 0 to 2;
y is 0, 1, 2, 3 or 4;
Z is independently O, S or N(R 16 );
R 6 and R 7 , R 9 and R 10 , and R 11 and R 12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl-NR 17 R 18 , substituted or unsubstituted alkyl-CONR 17 R 18 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or
one or more of R 6 and R 7 , R 9 and R 10 , and R 11 and R 12 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;
R 8 and R 13 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
a pair of R 13 , taken together with the oxygens to which they are attached, form a heterocycle;
R 14 is independently —OR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 15 is independently substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then R 15 is optionally —NR 19 R 20 or —OR 13 ;
R 16 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted heteroalkyl;
R 17 and R 18 , and R 19 and R 20 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; or one or more of R 17 and R 18 and R 19 and R 20 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; and
wherein any of the groups listed for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each optionally independently substituted with 1 to 3 groups, each group independently selected from halogen, hydroxyl, amino, aminomonoalkyl,aminomonohaloalkyl, aminodihaloalkyl, aminodialkyl, cyano, nitro, haloalkyl, alkyl, —O-alkyl, O-haloalkyl, S-haloalkyl and —S-alkyl
with the proviso that when R 1 and R 2 are both hydrogen, R 3 is not hydrogen, NR 9 R 10 , CONR 9 R 10 , or CHNH 2 CONR 9 R 10 and with the proviso that when R 1 and R 3 are both hydrogen, R 2 is not NR 6 R 7 .
2. The compound of claim 1 , wherein A 2 has the formula:
wherein any of the above groups are each independently optionally substituted with 1 to 4 R 5 groups.
3. The compound of claim 1 , wherein A 1 is substituted with one or more halogen, cyano, nitro, trifluoromethyl, difluoromethyl, —NR 11 R 12 , —N(R 11 )COR 12 , —CONR 11 R 12 , OR 13 , —SR 13 , —C(═Z)R 14 , —S(O) n R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or combination thereof.
4. The compound of claim 1 , wherein A 1 is:
wherein
x is an integer from 1 to 5; and
R 21 is independently halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, —NR 11 R 12 , —CONR 11 R 12 , —OR 13 , —SR 13 , —C(═Z)R 14 , —S(O) n R 15 , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
two adjacent R 21 groups together with the carbon atoms to which they are attached are combined to form a substituted or unsubstituted ring.
5. The compound of claim 1 , wherein R 1 is hydrogen or methyl.
6. The compound of claim 5 , wherein R 2 is hydroxy or methoxy.
7. The compound of claim 1 or claim 6 , wherein R 3 is —CH 2 CONR 9 R 10 or —CONR 9 R 10 .
8. The compound of claim 1 , wherein
A 1 is 2-methoxyphenyl.
9. The compound of claim 1 , having the formula:
10. The compound of claim 9 , wherein R 3 is —CONR 10 .
11. The compound of claim 1 , wherein
R 1 is hydrogen;
R 2 is —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —F, —CN, —CF, —OCH 3 , thiomorpholinyl sulfone, or piperazinyl; and
R 3 is
12. The compound of claim 1 wherein
R 1 is hydrogen;
R 2 is hydroxy; and
R 3 is —CONR 9 R 10 .
13. A compound of Formula (B), or an enantiomer, diastereomer, racemate, tautomer or pharmaceutically acceptable salt thereof:
wherein
A 1 is substituted or unsubstituted phenyl;
A 2 is a pyridinyl group;
X 1 is CR 4 ; wherein
R 4 is hydrogen, halogen, cyano, nitro, haloalkyl, or substituted or unsubstituted alkyl;
R 1 is hydrogen, lower alkyl or lower heteroalkyl;
R 2 is lower alkyl, halogen, hydroxy, —OR 8 , cyano, nitro, haloalkyl, —NR 6 R 7 ;
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, —COOH, —NR 9 R 10 , —CH 2 NR 9 R 10 , —CONR 9 R 10 , —CH 2 CONR 9 R 10 or —OR 8 ; or
R 2 and R 3 together with the carbon atom to which they are attached, form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted cycloalkyl; or
each R 5 is independently halogen, cyano, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, —NR 11 R 12 , —CONR 11 R 12 , —OR 13 , —C(═Z)R 14 , or —S(O) n R 15 , wherein n is independently an integer from 0 to 2;
y is 0, 1, 2, 3 or 4;
Z is independently O, S or N(R 16 );
R 6 and R 7 , R 9 and R 10 , and R 11 and R 12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl-NR 17 R 18 , substituted or unsubstituted alkyl-CONR 17 R 18 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl, or
one or more of R 6 and R 7 , R 9 and R 10 , and R 11 and R 12 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;
R 8 and R 13 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
a pair of R 13 , taken together with the oxygens to which they are attached, form a heterocycle;
R 14 is independently —OR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 15 is independently substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then R 15 is optionally —NR 19 R 20 or —OR 13 ;
R 16 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted heteroalkyl;
R 17 and R 18 , and R 19 and R 20 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (cycloalkyl)alkyl, substituted or unsubstituted (heterocycloalkyl)alkyl, substituted or unsubstituted arylalkyl, or substituted or unsubstituted heteroarylalkyl; or one or more of R 17 and R 18 or R 19 and R 20 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; and
wherein any of the groups listed for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 are each optionally independently substituted with 1 to 3 groups, each group independently selected from halogen, hydroxyl, amino, aminomonoalkyl, aminomonohaloalkyl, aminodihaloalkyl, aminodialkyl, cyano, nitro, haloalkyl, alkyl, —O-alkyl, O-haloalkyl, S-haloalkyl and —S-alkyl.
14. The compound of claim 13 , wherein
A 1 is 2-methoxyphenyl.
15. The compound of claim 13 , wherein
R 1 is hydrogen;
R 2 is —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , —F, —CN, —OCH 3 , thiomorpholinyl sulfone, or piperazinyl; and
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —COOH, —NR 9 R 10 , —CH 2 CONR 9 R 10 , —CONR 9 R 10 , —CH 2 CONR 9 R 10 or —OR 8 .
16. The compound of any of claims 13 wherein R 3 is
17. A compound of Formula (C), or an enantiomer, diastereomer, racemate, tautomer or pharmaceutically acceptable salt thereof:
wherein
A 1 is substituted or unsubstituted phenyl;
A 2 is a pyridinyl group;
X 1 is CR 4 ; wherein
R 4 is hydrogen, halogen, cyano, nitro, haloalkyl, or substituted or unsubstituted alkyl;
Q is O;
R 3 is substituted or unsubstituted C-attached heteroalkyl, substituted or unsubstituted C-attached heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C-attached heteroaryl, —COOR 8 , —CH 2 NR 9 R 10 , —CONR 9 R 10 , —CH 2 CONR 9 R 10 ;
each R 5 is independently halogen, cyano, nitro, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, —NR 11 R 12 , —CONR 11 R 12 , —OR 13 , —C(═Z)R 14 , or —S(O) n R 15 , wherein n is independently an integer from 0 to 2;
y is 0, 1, 2, 3 or 4;
Z is independently O, S or N(R 16 );
R 9 and R 10 , and R 11 and R 12 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl-NR 17 R 18 , substituted or unsubstituted alkyl-CONR 17 R 18 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
one or more of R 9 and R 10 , and R 12 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or substituted or unsubstituted heteroaryl;
R 8 and R 13 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
a pair of R 13 , taken together with the oxygens to which they are attached, form a heterocycle;
R 14 is independently —OR 13 , substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 15 is independently substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then R 15 is optionally —NR 19 R 20 or —OR 13 ;
R 16 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, or substituted or unsubstituted heteroalkyl;
R 17 and R 18 , and R 19 and R 20 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or =substituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or one or more of R 17 and R 18 or R 19 and R 20 are each independently joined together with the nitrogen to which they are attached, to form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; and
wherein any of the groups listed for R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each optionally independently substituted with 1 to 3 groups, each group independently selected from halogen, hydroxyl, amino, aminomonoalkyl, aminomonohaloalkyl, aminodihaloalkyl, aminodialkyl, cyano, nitro, haloalkyl, alkyl, —O-alkyl, O-haloalkyl, S-haloalkyl and —S-alkyl.
18. The compound of claim 17 , wherein
A 1 is 2-methoxyphenyl.
19. The compound of claim 17 , wherein
R 3 is —CH 2 NR 9 R 10 , —CONR 9 R 10 , —CH 2 CONR 9 R 10 .
20. The compound of claim 17 wherein R 3 is