Omega-carboxyarl substituted diphenyl ureas as raf kinase inhibitors

Abstract

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

1 . Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a compound of Formula I:
   A-D-B  (I)
   
       or a pharmaceutically acceptable salt thereof, wherein
 D is —NH—C(O)—NH—, 
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 5 or 6 membered cyclic structure bound directly to D, L 1  comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L 1  contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and 
 B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, 
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y )R z , 
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, 
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen,
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or 
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; 
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, 
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen; and 
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 , with R 7  as defined above. 
 
     
     
         2 . A method as in  claim 1  wherein:
 R y  is hydrogen, C 1-10  alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatoms, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 7-24  aralkyl, C 7-24  alkaryl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 3-10  cycloalkyl having 0-3 heteroatoms selected from N, S and O, substituted C 6 -C 14  aryl, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24  alkaryl or substituted C 7 -C 24  aralkyl, where R y  is a substituted group, it is substituted by halogen up to per halo, 
 R z  is hydrogen, C 1-10  alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatom, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3 -C 12  hetaryl having 1-3 heteroatoms selected from, S, N and O, C 7-24  alkaryl, C 7-24  aralkyl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 6 -C 14  aryl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from S, N and O, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from S, N and O, substituted C 7-24  alkaryl or substituted C 7 -C 24  aralkyl where R z  is a substituted group, it is substituted by halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl up to per halo cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo substituted C 3 -C 12  hetaryl up to per halo hetaryl having 1-3 heteroatoms selected from O, N and S, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , 
 R a  and R b  are, 
 a) independently hydrogen,
 a carbon based moiety selected from to group consisting of C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 3-10  cycloalkyl, C 2-10  alkenyl, C 1-10  alkenoyl, C 6-12  aryl, C 3-12  hetaryl having 1-3 heteroatoms selected from O, N and S, C 3-12  cycloalkyl having 0-3 heteroatoms selected from N, S and O, C 7-24  aralkyl, C 7 -C 24  alkaryl, substituted C 1-10  alkyl, substituted C 1-10  alkoxy, substituted C 3-10  cycloalkyl, having 0-3 heteroatoms selected from N, S and O, substituted C 6-12  aryl, substituted C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, substituted C 7-24  aralkyl, substituted C 7-24  alkaryl, where R a  and R b  are a substituted group, they are substituted by halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteroaryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g ; or 
 —OSi(R f ) 3  where R f  is hydrogen, C 1-10  alkyl, C 1-10  alkoxy, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 6-12  aryl, C 3 -C 12  hetaryl having 1-3 heteroatoms selected from O, S and N, C 7-24  aralkyl, substituted C 1-10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 3 -C 12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, substituted C 3 -C 12  heteroaryl having 1-3 heteroatoms selected from O, S, and N, substituted C 6-12  aryl, and substituted C 7-24  alkaryl, where R f  is a substituted group it is substituted halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteroaryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , 
 
 or 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O with substituents selected from the group consisting of halogen up to per halo, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, halo substituted C 1-6  alkyl up to per halo alkyl, halo substituted C 6 -C 12  aryl up to per halo aryl, halo substituted C 3 -C 12  cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteroaryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , 
 or 
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, 
 wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, C 1-10  alkyl, C 3-12  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 3-12  hetaryl having 1-3 heteroatoms selected from N, S and O, C 1-10  alkoxy, C 6-12  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 1-6  halo substituted alkyl up to per halo alkyl, C 6 -C 12  halo substituted aryl up to per halo aryl, C 3 -C 12  halo substituted cycloalkyl having 0-3 heteroatoms selected from N, S and O, up to per halo cycloalkyl, halo substituted C 3 -C 12  hetaryl up to per halo heteroaryl, halo substituted C 7 -C 24  aralkyl up to per halo aralkyl, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and —C(O)R g , 
 where R g  is C 1-10  alkyl; —CN, —CO 2 R d , —OR d , —SR d , —NO 2 , —C(O)R e , —NR d R e , —NR d C(O)OR e  and —NR d C(O)R e , and R d  and R e  are independently selected from the group consisting of hydrogen, C 1-10 , alkyl, C 1-10  alkoxy, C 3-10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6-12  aryl, C 3 -C 12  hetaryl with 1-3 heteroatoms selected from O, N and S and C 7 -C 24  aralkyl, C 7 -C 24  alkaryl, up to per halo substituted C 1 -C 10  alkyl, up to per halo substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per halo substituted C 6 -C 14  aryl, up to per halo substituted C 3 -C 12  hetaryl having 1-3 heteroatoms selected from O, N, and S, halo substituted C 7 -C 24  alkaryl up to per halo alkaryl, and up to per halo substituted C 7 -C 24  aralkyl, 
 W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 6 -C 14  aryl, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 3 -C 12  heteroaryl having 1-3 heteroatoms selected from O, N and S, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C 1 -C 10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 2 -C 10  alkenyl, substituted C 1 -C 10  alkenoyl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C 6 -C 12  aryl, substituted C 3 -C 12  hetaryl having 1-3 heteroatoms selected from O, N and S, substituted C 7 -C 24  aralkyl, substituted C 7 -C 24  alkaryl, substituted C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and -Q-Ar; 
 R 7  is independently selected from H, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, S and N, C 6 -C 14  aryl, C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, C 7 -C 14  alkaryl, C 7 -C 24  aralkyl, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 1 -C 10  alkyl, up to per-halosubstituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 6 -C 14  aryl, up to per-halosubstituted C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, up to per-halosubstituted C 7 -C 24  aralkyl, up to per-halosubstituted C 7 -C 24  alkaryl, and up to per-halosubstituted C 4 -C 23  alkheteroaryl; and 
 each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , C 1 -C 10  alkyl, C 1 -C 10  alkoxy, C 2 -C 10  alkenyl, C 1 -C 10  alkenoyl, C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, C 6 -C 14  aryl, C 3 -C 13  hetaryl having 1-3 heteroatoms selected from O, N and S, C 7 -C 24  alkaryl, C 7 -C 24  aralkyl, C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S, substituted C 1 -C 10  alkyl, substituted C 1 -C 10  alkoxy, substituted C 2 -C 10  alkenyl, substituted C 1 -C 10  alkenoyl, substituted C 3 -C 10  cycloalkyl having 0-3 heteroatoms selected from O, N and S, substituted C 6 -C 12  aryl, substituted C 7 -C 24  alkaryl, substituted C 7 -C 24  aralkyl and substituted C 4 -C 23  alkheteroaryl having 1-3 heteroatoms selected from O, N and S; wherein if Z is a substituted group, the one or more substituents are selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 . 
 
     
     
         3 - 28 . (canceled) 
     
     
         29 - 38 . (canceled) 
     
     
         39 . Method for the treatment of cancerous cell growth mediated by raf kinase comprising administering a urea of Formula I:
   A-D-B  (I)
   
       or a pharmaceutically acceptable salt thereof, wherein
 D is —NH—C(O)—NH—, 
 A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a substituted or unsubstituted phenyl or peritoneal moiety bound directly to D, L 1  comprises a substituted phenyl, peritoneal or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and 
 B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, 
 wherein L 1  is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x  and —C(NR y )R z , 
 R y  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo, and; 
 R z  is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 R x  is R z  or NR a R b  where R a  and R b  are 
 a) independently hydrogen,
 a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or 
 —OSi(R f ) 3  where R f  is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 
 b) R a  and R b  together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or 
 c) one of R a  or R b  is —C(O)—, a C 1 -C 5  divalent alkylene group or a substituted C 1 -C 5  divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C 1 -C 5  divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; 
 where B is substituted, L is substituted or L 1  is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; 
 wherein each W is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)NR 7 R 7 , —C(O)—R 7 , —NO 2 , —OR 7 , —SR 7 , —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NR 7 R 7 , —NO 2 , —NR 7 C(O)R 7 , —NR 7 C(O)OR 7  and halogen up to per-halo; with each R 7  independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, 
 wherein Q is —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, and X a  is halogen; 
 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z n1 , wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO 2 R 7 , —C(O)R 7 , —C(O)NR 7 R 7 , —NO 2 , —OR 7 , —SR 7 —NR 7 R 7 , —NR 7 C(O)OR 7 , —NR 7 C(O)R 7 , and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO 2 R 7 , —COR 7 , —C(O)NR 7 R 7 , —OR 7 , —SR 7 , —NO 2 , —NR 7 R 7 , —NR 7 C(O)R 7 , and —NR 7 C(O)OR 7 ; and 
 wherein M is one or more bridging groups selected from the group consisting of —O—, —S—, —N(R 7 )—, —(CH 2 ) m —, —C(O)—, —CH(OH)—, —(CH 2 ) m O—, —(CH 2 ) m S—, —(CH 2 ) m N(R 7 )—, —O(CH 2 ) m —CHX a —, —CX a   2 —, —S—(CH 2 ) m — and —N(R 7 )(CH 2 ) m —, where m=1-3, X a  is halogen. 
 
     
     
         40 - 46 . (canceled) 
     
     
         47 . A method of  claim 39  wherein L 1  is substituted by C(O)R x . 
     
     
         48 . (canceled) 
     
     
         49 . A method of  claim 47  wherein R x  is NR a R b  and R a  and R b  are independently hydrogen and a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen. 
     
     
         50 . A method of  claim 1  wherein the compound of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of
 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and 
 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 
 
     
     
         51 - 53 . (canceled) 
     
     
         54 . A method of  claim 39  wherein the urea of formula I is a pharmaceutically acceptable salt of a compound of formula I selected from the group consisting of
 a) basic salts of organic acids and inorganic acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluorosulphonic acid, benzenesulfonic acid, p-toluene sulphonic acid (tosylate salt), 1-napthalene sulfonic acid, 2-napthalene sulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid; and 
 b) acid salts of organic and inorganic bases containing cations selected from the group consisting of alkaline cations, alkaline earth cations, the ammonium cation, aliphatic substituted ammonium cations and aromatic substituted ammonium cations. 
 
     
     
         55 - 66 . (canceled) 
     
     
         67 . A method for the treatment of a cancerous cell growth mediated by raf kinase, comprising administrating a compound selected from the group consisting of
 N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea.