Protein kinase inhibitors
View Patent ↗A compound of the general formula: or pharmaceutically acceptable salts, hydrates, solvates, crystal forms of diastereomers thereof is described. A method of treating protein kinase-associated disease states using the compound of Formula I is also described.
1. A compound of the general formula
or pharmaceutically acceptable salts, hydrates, or diastereomers thereof, wherein:
R 1 is H, C 1-4 alkyl;
Q is a bond, or C 1-4 alkyl;
A is aryl, hetaryl optionally substituted with 0–3 substituents independently chosen from halogen, C 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , CN, aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 4 R 5 , O-aryl, O-heteroaryl, CO 2 R 4 , CONR 4 R 5 , nitro, NR 4 R 5 , C 1-4 alkylNR 4 R 5 , NR 6 C 1-4 alkylNR 4 R 5 , NR 4 COR 5 , NR 6 CONR 4 5 , NR 4 SO 2 R 5 ; and R 4 and R 5 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 7 ; and R 6 is selected from H, C 1-4 alkyl; and R 7 is selected H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl;
R 2 is 0–2 substituents independently selected from halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, C 1-4 alkylNR 8 R 9 , OC 1-4 alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 , NR 8 SO 2 R 9 ; and R 8 , R 9 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 11 ; and R 10 is selected from H, C 1-4 alkyl, aryl or hetaryl; and R 11 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl;
Y is halogen, OH, NR 12 R 13 , NR 12 COR 13 , NR 12 CONR 13 , NR 12 SO 2 R 13 ; and R 12 , and R 13 are each independently H, CH 2 F, CHF 2 , CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3–6 membered ring optionally containing an atom selected from O, S, NR 14 and R 14 is selected from H, C 1-4 alkyl;
n=0–4;
W is selected from H, C 1-4 alkyl, C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, NR 15 R 16 ; and R 15 and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 17 ; and R 17 is selected from H, C 1-4 alkyl;
when Y is OH or NHCOCH 3 then R 2 is 1–2 substituents; and
when Y is NH 2 and R 2 is absent then Y is in the para position.
2. A compound according to claim 1 selected from compounds of the general formula II:
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms or diastereomers thereof, wherein:
R1 is H, C 1-4 alkyl;
Q is a bond, or C 1-4 alkyl;
A is aryl, hetaryl optionally substituted with 0–3 substituents independently chosen from halogen, C 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , CN, aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 4 R 5 , O-aryl, O-heteroaryl, CO 2 R 4 , CONR 4 R 5 , NR 4 R 5 , C 1-4 alkylNR 4 R 5 , NR 6 C 1-4 alkylNR 4 R 5 , NR 4 COR 5 , NR 6 CONR 4 R 5 , NR 4 SO 2 R 5 ; and R 4 and R 5 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 7 ; and R 6 is selected from H, C 1-4 alkyl; and R 7 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl;
R 2 is 0–2 substituents independently selected from halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , OCF 3 , CN, C 1-4 alkylNR 8 R 9 , OC 1-4 alkylNR 8 R 9 , CO 2 R 8 , CONR 8 R 9 , NR 8 R 9 , NR 8 COR 9 , NR 10 CONR 8 R 9 , NR 8 SO 2 R 9 ; and R 8 , R 9 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 11 ; and R 10 is selected from H, C 1-4 alkyl, aryl or hetaryl; and R 11 is selected from H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkyl aryl, C 1-4 alkyl hetaryl;
Y is halogen, OH, NR 12 R 13 , NR 12 COR 13 , NR 12 CONR 13 , NR 12 SO 2 R 13 ; and R 12 , and R 13 are each independently H, CH 2 F, CHF 2 , CF 3 , CN, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may b joined to form an optionally substituted 3–6 membered ring optionally containing an atom selected from O, S, NR 14 and R 14 is selected from H, C 1-4 alkyl;
n=0–4;
W is selected from H, C 1-4 alkyl, C 2-6 alkenyl; where C 1-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl, NR 15 R 16 ; and R 15 and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3–8 membered ring optionally containing an atom selected from O, S, NR 17 ; and R 17 is selected from H, C 1-4 alkyl;
when Y is OH or NHCOCH 3 then R 2 is 1–2 substituents; and
when Y is NH 2 and R 2 is absent then Y is in the para position.
3. A compound according to claim 1 where W is C 1-4 alkyl wherein the compound possesses S chirality at the chiral carbon bearing W.
4. A compound according to claim 3 wherein the compound is a mixture of R and S isomers and the mixture comprises at least 70% of the S isomer.
5. A compound according to claim 4 wherein the compound comprises at least 80% of the S isomer.
6. A compound according to claim 4 wherein the compound comprises at least 90% of the S isomer.
7. A compound according to claim 4 wherein the compound comprises at least 95% of the S isomer.
8. A compound according to claim 4 wherein the compound comprises at least 99% of the S isomer.
9. A compound according to claim 1 wherein the compound is selected from the group consisting of:
and
10. A composition comprising a carrier and at least one compound according to claim 1 .
11. A pharmaceutical composition comprising at least one of the compounds according to claim 1 and a pharmaceutically acceptable vehicle or diluent.