2-phenyl pyrimidines which are tubulin inhibitors
Compounds of general formula (I), (II) (III) and (V) are described for use in modulating microtubule polymerisation and in the treatment of associated disease states. Use of compounds (I), (III) and (V) in the treatment of kinase-associated disease states is also described. Further described are novel compounds of formula (II), (III) and (V).
1. A compound of the formula (V)
or a pharmaceutically acceptable salt, enantiomer, or diastereomer form thereof;
wherein X 1 and X 2 are N and X 3 and X 4 are C independently substituted with Y; wherein:
R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , where R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, or hetaryl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 7 ;
wherein R 7 is H or C 1-4 alkyl;
R 2 is selected from C 1-6 alkylOH, OC 2-6 alkylOH, C 1-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1 - 6 alkylNR 8 COR 9 , OC 2-6 alkylNR 8 COR 9 , C 1 - 6 alkylhetaryl, OC 2-6 alkylhetaryl, OCONR 8 R 9 , NR 8 COOR 9 , NR 10 CONR 8 R 9 , CONR 8 R 9 , and NR 8 COR 12 ;
wherein R 8 and R 9 are each independently H, C 1-4 alkyl, C 1-4 hetaryl, or cyclohetalkyl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 14 ;
wherein R 12 is C 2-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl, or cyclohetalkyl;
wherein R 11 and R 13 are each independently H, or C 1-4 alkyl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 14 ;
wherein R 14 is H or C 1-4 alkyl;
wherein R 10 is H or C 1-4 alkyl;
R 3 and R 4 are each independently H, halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 , or OCF 3 ;
Q is CH;
W is C 2-4 alkyl, or C 2-6 alkenyl; where C 2-4 alkyl or C 2-6 alkenyl may be optionally substituted with C 1-4 alkyl, OH, OC 1-4 alkyl or NR 15 R 16 ;
R 15 , and R 16 are each independently H or C 1-4 alkyl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 17 ;
A is aryl, or hetaryl optionally substituted with 0-2 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 , and NR 18 SO 2 R 19 ;
wherein R 18 and R 19 are each independently H, C 1-4 alkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, or C 1-4 alkyl hetaryl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 21 ;
wherein R 21 is H or C 1-4 alkyl;
wherein R 20 is H or C 1-4 alkyl;
Y is selected from H, C 1-4 alkyl and NR 22 R 23 ;
wherein R 22 R 23 are each independently H or C 1-4 alkyl.
2. The compound of claim 1 selected from:
or a pharmaceutically acceptable salt or enantiomer form thereof.
3. A composition comprising a carrier and at least one compound according to claim 1 .
4. A composition comprising a carrier and at least one compound according to claim 2 .
5. A tubulin inhibitor of the formula (V)
or a pharmaceutically acceptable salt, enantiomer, or diastereomer form thereof;
wherein X 1 and X 2 are N and X 3 and X 4 are C independently substituted with Y;
R 1 is H, C 1-6 alkyl, C 1-6 alkylNR 5 R 6 , C 1-6 alkylNR 5 COR 6 , C 1-6 alkylNR 5 SO 2 R 6 , C 1-6 alkylCO 2 R 5 , or C 1-6 alkylCONR 5 R 6 ,
wherein R 5 and R 6 are each independently H, C 1-4 alkyl, aryl, hetaryl, C 1-4 alkylaryl, or C 1-4 alkylhetaryl or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 7 ;
wherein R 7 is H or C 1-4 alkyl;
R 2 is selected from OH, C 1-6 alkylOH, OC 2-6 alkylOH, C 1-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1 - 6 alkylNR 8 COR 9 , OC 2-6 alkylNR 8 COR 9 , C 1 - 6 alkylhetaryl, OC 2-6 alkylhetaryl, OCONR 8 R 9 , NR 8 COOR 9 , NR 10 CONR 8 R 9 , CONR 8 R 9 , and NR 8 COR 12 ;
wherein R 8 and R 9 are each independently H, C 1-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl, or cyclohetalkyl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 14 ;
wherein R 12 is C 2-4 alkyl, C 1-4 alkylNR 11 R 13 , hetaryl, or cyclohetalkyl;
wherein R 11 and R 13 are each independently H, or C 1-4 alkyl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 14 ;
wherein R 14 is H or C 1-4 alkyl;
wherein R 10 is H or C 1-4 alkyl;
R 3 and R 4 are each independently H, halogen, C 1-4 alkyl, OH, OC 1-4 alkyl, CF 3 , or OCF 3 ;
Q is C 1-4 alkyl;
W is selected from C 1-4 alkyl, and 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, or NR 15 R 16 ;
wherein R 15 , and R 16 are each independently H, C 1-4 alkyl, C 1-4 alkyl cycloalkyl, C 1-4 alkyl cyclohetalkyl, aryl, or hetaryl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR' 17 ;
wherein R 17 is H, or C 1-4 alkyl;
A is aryl or hetaryl optionally substituted with 0-3 substituents independently selected from halogen, C 1-4 alkyl, CF 3 , aryl, hetaryl, OCF 3 , OC 1-4 alkyl, OC 2-5 alkylNR 18 R 19 , Oaryl, Ohetaryl, CO 2 R 18 , CONR 18 R 19 , NR 18 R 19 , C 1-4 alkylNR 18 R 19 , NR 20 C 1-4 alkylNR 18 R 19 , NR 18 COR 19 , NR 20 CONR 18 R 19 , and NR 18 SO 2 R 19 ;
wherein R 18 and R 19 are each independently H, C 1-4 alkyl, C 1-4 alkyl cyclohetalkyl, aryl, hetaryl, C 1-4 alkyl aryl, or C 1-4 alkyl hetaryl, or may be joined to form a 3-8 membered ring optionally containing one of O, S or NR 21 ;
wherein R 21 is H or C 1-4 alkyl;
wherein R 20 is H or C 1-4 alkyl;
Y is selected from H, C 1-4 alkyl, OH, and NR 22 R 23 ;
wherein R 22 and R 23 are each independently H or C 1-4 alkyl.
6. The tubulin inhibitor of claim 5 , wherein R 2 is selected from C 1-6 alkylOH, OC 2-6 alkylOH, C 1-6 alkylNR 8 R 9 , OC 2-6 alkylNR 8 R 9 , C 1-6 alkylNR 8 COR 9 , OC 2-6 alkylNR 8 COR 9 , C 1-6 alkylhetaryl, OC 2-6 alkylhetaryl, OCONR 8 R 9 , NR 8 COOR 9 , NR 10 CONR 8 R 9 , CONR 8 R 9 , and NR 8 COR 12 .
7. A composition comprising a carrier and at least one tubulin inhibitor according to claim 5 .
8. A composition comprising a carrier and at least one tubulin inhibitor according to claim 6 .
9. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or enantiomer form thereof.
10. A composition comprising a carrier and at least one compound according to claim 9 .
11. A compound of the formula:
or a pharmaceutically acceptable salt or enantiomer form thereof.
12. A composition comprising a carrier and at least one compound according to claim 11 .
13. A compound of the formula:
14. A composition comprising a carrier and at least one compound according to claim 13 .