Omega-Carboxyaryl 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 . 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 —C(O)R x    
 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    
 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 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)O)R 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 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  with R 7  as defined above. 
 
     
     
         2 . A compound as in  claim 1  wherein:
 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 ,   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 C6-C 12  aryl substituted C3-C 12  hetaryl having 1-3 heteroatoms selected from O, N and S, substituted 07-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 24  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 —ON, —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 . A compound as in  claim 1  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 and R 7  is as defined in  claim 1 . 
     
     
         4 . A compound as in  claim 1  wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen. 
     
     
         5 . (canceled) 
     
     
         6 . A compound of  claim 1  wherein B of Formula I is a substituted or unsubstituted six member aryl moiety or six member hetaryl moiety, said hetaryl moiety having 1 to 4 members selected from the group of hetaryl atoms consisting of nitrogen, oxygen and sulphur with the balance of the hetaryl moiety being carbon. 
     
     
         7 . A compound of  claim 1  wherein B of Formula I is an unsubstituted phenyl group, an unsubstituted pyridyl group, an unsubstituted pyrimidinyl, a phenyl group substituted by a substitutent selected from the group consisting of halogen and Wn wherein W and n are as defined in  claim 1 , a pyrimidinyl group substituted by a substituent selected from the group consisting of halogen and Wn whereas W and n are as defined in  claim 1 , or a substituted pyridyl group substituted by a substituent selected from the group consisting of halogen and Wn wherein W and n are as defined in  claim 1 . 
     
     
         8 . A compound of  claim 6  wherein B of Formula I is a substituted phenyl group or substituted pyrimidinyl group substituted pyrridyl group substituted 1 to 3 times by 1 or more substituents selected from the group consisting of —CN, halogen, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, —OH, up to per halo substituted C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkoxy or phenyl substituted by halogen up to per halo. 
     
     
         9 . A compound of  claim 1 , wherein L, the six member cyclic structure bound directly to D, is a substituted or unsubstituted 6 member aryl moiety or a substituted or unsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulphur with the balance of said hetaryl moiety being carbon, wherein the one or more substituents are selected from the group consisting of halogen and Wn wherein W and n are as defined in  claim 1 . 
     
     
         10 . A compound of  claim 8 , wherein L, the 6 member cyclic structure bound directly to D, is a substituted phenyl, unsubstituted phenyl, substituted pyrimidinyl unsubstituted pyrimidinyl, substituted pyridyl or unsubstituted pyridyl group. 
     
     
         11 . A compound of  claim 1 , wherein said substituted cyclic moiety L 1  comprises a 5 to 6 membered aryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1 to 4 members selected from the group of heteroatoms consisting of nitrogen, oxygen and sulphur. 
     
     
         12 . A compound of  claim 1 , wherein said substituted cyclic moiety L 1  is phenyl, peritoneal or pyrimidinyl. 
     
     
         13 . A compound of  claim 3 , wherein said substituted cyclic moiety L 1  is phenyl, peritoneal or pyrimidinyl. 
     
     
         14 . A compound of  claim 6 , wherein said substituted cyclic moiety L 1  is phenyl, pyridinyl or pyrimidinyl. 
     
     
         15 . A compound of  claim 8 , wherein said substituted cyclic moiety L 1  is phenyl, pyridinyl or pyrimidinyl. 
     
     
         16 . A compound of  claim 9 , wherein said substituted cyclic moiety L 1  is phenyl, pyridinyl or pyrimidinyl. 
     
     
         17 . A compound of  claim 10 , wherein said substituted cyclic moiety L 1  is phenyl, pyridinyl or pyrimidinyl. 
     
     
         18 . A compound of  claim 14 , 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)—, —(C 2 ) m O—, —(CH 2 )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 and R 7  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 up to per halo. 
     
     
         19 . A compound of  claim 15 , 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)—, —(C 2 ) m O—, —(CH 2 )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 and R 7  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 up to per halo. 
     
     
         20 . A compound of  claim 16 , 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)—, —(C 2 ) m O—, —(CH 2 )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 and R 7  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 up to per halo. 
     
     
         21 . A compound of  claim 17 , 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)—, —(C 2 ) m O—, —(CH 2 )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 and R 7  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 up to per halo. 
     
     
         22 . A compound of  claim 1  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         23 . A compound of  claim 13  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  allyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         24 . A compound of  claim 18  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         25 . A compound of  claim 19  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         26 . A compound of  claim 20  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         27 . A compound of  claim 21  wherein L 1  is additionally substituted 1 to 3 times by one or more substituents selected from the group consisting of C 1 -C 10  alkyl, up to per halo substituted C 1 -C 10  alkyl, —CN, —OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . 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 6 membered aryl moiety or a 6 membered hetaryl moiety 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 —C(O)R x    
 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; 
 Rx is Rz 
 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 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 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 x   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 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 ; 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. 
 
     
     
         39 . 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 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 —C(O)R x      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      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 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 —, —(CH 2 ) m S—, —(CH 2 )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 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 ; 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 . A compound as in  claim 38  wherein the cyclic structures of B and L bound directly to D is substituted in the ortho position by hydrogen. 
     
     
         41 . (canceled) 
     
     
         42 . A compound as in  claim 39  wherein the cyclic structures of B and L bound directly to D are substituted in the ortho position by hydrogen. 
     
     
         43 . (canceled) 
     
     
         44 . A compound as in  claim 38  wherein substituents for B and L and additional substituents for L 1 , are selected from the group consisting of C 1 -C 10  alkyl up to per halo substituted C 1 -C 10  alkyl, CN, OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         45 . A compound as in  claim 39  wherein substituents for B and L and additional substituents for L 1 , are selected from the group consisting of C 1 -C 10  alkyl up to per halo substituted C 1 -C 10  alkyl, CN, OH, halogen, C 1 -C 10  alkoxy and up to per halo substituted C 1 -C 10  alkoxy. 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . A compound of  claim 38  which 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, sulphonic acid, toluene sulphonic acid (tosylate salt), acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic 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.   
     
     
         54 . A compound of  claim 39  which 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, sulphonic acid, toluene sulphonic acid (tosylate salt), acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenyl acetic 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 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt of a compound of formula I, and a physiologically acceptable carrier. 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . A pharmaceutical composition comprising a compound of  claim 38  consistent with formula I or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. 
     
     
         59 . A pharmaceutical composition comprising a compound of  claim 1  consistent with formula I or a pharmaceutically acceptable salt thereof and a physiologically acceptable carrier. 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . A method for the inhibition of raf kinase in a host, comprising administering a compound of Formula I of  claim 1 . 
     
     
         63 . (canceled) 
     
     
         64 . A method for the inhibition of raf kinase in a host, comprising administering a compound of Formula I of  claim 38 . 
     
     
         65 . A method for the inhibition of raf kinase in a host, comprising administering a compound of Formula I of  claim 39 . 
     
     
         66 . (canceled) 
     
     
         67 . (canceled)