Patent NZ-505845-A (NZ)
Title: Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
Inventor: DUMAS JACQUES
IPC: A61K31/4155
Filed: 1998-12-22
Abstract: A compound of formula I where: -A is a compound of formula II, where wherein R1 is selected from the group consisting of C3-C10 alkyl, C3-C10 cycloalkyl, up to per-halosubstituted C1-C10 alkyl and up to per halosubstituted C3-C10 cycloalkyl. - B is a substituted or unsubstituted, up to tricyclic, aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 5-or 6-member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. If B is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of halogen, up to per-halosubstitution, and Xn. -Xn comprises of n is 0-3 and each X is independently selected from the group consisting -CO2R5, -C(O)NR5R5',- C(O)R5,-NO2,-OR5,-SR5,-NR5R5',-CN, C1-C10alkyl, C2-C10 alkenyl, C1-C10 alkoxy, C3-C10 cycloalkyl, C6-C14 aryl, C7- C24 alkaryl, C3-CI3 heteroaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C2-10 alkenyl, substituted C1-C10 alkoxyl, substituted C3-C10 cycloalkyl, up to per halosubstituted C6-C14aryl, up to per halosubstituted C3-C13 heteroaryl, substituted C4-C23 alkheteroaryl and-Y-Ar; -Where X is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R4, -C(O)R5, -C (O)NR5R5', -OR5, - SR5, -NR5R5', -NO2, -NR5C(O)R5', -NR5C(O)OR5' and halogen up to per-halosubstitution; -R5 and R5' are independently selected from H, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1- C10 alkyl, up to per halosubstituted C2-C10 alkenyl, up to perhalosubstituted C3-C10 cycloalkyl, up to perhalosubstituted C6-C14 aryl and up to per-halosubstituted C3-C13 heteroaryl. -Y is -O-, -S-, -N (R5)-, - (CH2)m-, -C(O)-, -CH(OH)-, - (CH2)mO-, -C(O)-, -CH(OH)-, -(CH2)mS-, -(CH2)mN(R5)-, - O(CH2)m-, -CHXa-, -CXa2-, -S-(CH2)m- and -N(R5)(CH2)m. -m = 1-3, and Xa is halogen. -Ar is a 5-10 member aromatic structure containing 0-2 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by Zn1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of-CN, -C(O)NR5,-CO2R5, -C(O)NR5', -NO2-, OR5, -SR5, -NR5R5', -NR5C(O)OR5', -NR5C(O)R5', - NR5C(O)NR5', C1-C10 alkyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl, C7-CC24 alkaryl and substituted C4-C23 alkheteroaryl. -Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of -CN, -CO2R5, -C(O)NR5R5', -OR5, -SR5, -NO2, - NR5R5', -NR5C(O)R5' and-NR5C(O)OR5'. -R2 is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of halogen, up to perhalosubstitution, and Vn, wherein n = 0-3 and each V is independently selected from the group consisting -CO2R5,-C(O)NR5R5',-OR5,-SR5,-NR5R5',- C(O)R5,-CN, -SO2R5,-SOR5,-NR5C(O)R5',-NO2,C1-C10 alkyl, C3- OC(O)NR5R5', -NR5C(O)OR5', C6-C14 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C24 alkheteroaryl, C10 cycloalkyl, substituted substituted C3-C10 cycloalkyl,substituted C6-C14 aryl, substituted C3-C13 heteroaryl, substituted C7-C24 alkheteroaryl. V is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of halogen, up to per -CO2R5,- C(O)R5,halosubstitution,-CN, -OR5,-SR5,-NR5R5', and-NO2;- NR5C(O)R5',-NR5C(O)OR5' wherein R5 and R5' are each independently as defined above. Used in the treatment of diseases mediated by raf-kinase.