Chemical compounds

Abstract

Benzimidazole derivatives, which are useful as TIE-2 and/or VEGFR2 inhibitors are described herein. The described invention also includes methods of making such benzimidazole derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

1 . A compound of Formula (I):  
     
       
         
         
             
             
         
       
     
     or a salt or solvate thereof:  
     wherein: 
 E is aryl substituted by R 1  and R 2 , or R 1  and R 2  together with the atoms of E to which they are attached form a cycloalkyl, aryl, or heterocyclic ring fused to E;  
 A is aryl, heteroaryl, or heterocyclic;  
 X is S, O, S(O) 2 , S(O), C(H) 2 , C(H)(OH), or C(O);  
 Z is O or S;  
 p is 0 or 1;  
 q is 0 or 1;  
 the dotted line bonds “---” attached to Q and N′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond, and when q is 1 the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond; and  
 the dotted line within the 6 membered ring containing D, M, and T represents appropriate aromatic bonds;  
 D is CH, T is CR 8 , M is C and Q is N(R 7 ) p , wherein p is 0 and q is 1; or  
 D is CH, T is CR 8 , M is C and Q is N(R 7 ) p , wherein p is 1 and q is 0; or  
 R 1  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, aralkyl, aralkoxy, aryloxy, C 1 -C 6  alkylsulfanyl, C 1 -C 6  haloalkylsulfanyl, C 1 -C 6  alkylsulfenyl, C 1 -C 6  alkylsulfonyl, —NO 2 , —NR 4 R 5 , —C(O)OR 6 , —CN, —C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or cyanoalkyl;  
 R 2  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 1 -C 6  alkylsulfanyl, C 1 -C 6  haloalkylsulfanyl, C 1 -C 6  alkylsulfenyl, C 1 -C 6  alkylsulfonyl, oxo, hydroxy, —NO 2 , —NR 4 R 5 , —C(O)OR 6 , —CN, —C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or cyanoalkyl;  
 R 3  is hydrogen, C 1 -C 6  alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR 6 , —RNR 4 R 5 , —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)RR 6 , —C(O)RR′R 6 , —C(O)ROR′OR″O R 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —C(O)ORNR 4 R 5 , —S(O) 2 R 6 , or —S(O) 2 NR 4 R 5 ; or  
 R 3  is C 1 -C 6  alkylene or C 1 -C 6  alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;  
 R, R′, and R″, are each independently selected from C 1 -C 6  alkylene, arylene, heteroarylene, C 3 -C 7  cycloalkylene, or heterocyclylene;  
 R′″ is C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl, C 3 -C 7  cycloalkyl, or heterocyclic;  
 R 4  and R 5  are each independently selected from hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C 3 -C 7  cycloalkyl, —C(O)OR 6 , —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH 2 , or  
 —S(O) 2 NR′″R′″;  
 R 6  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C 3 -C 7  cycloalkyl;  
 R 7  is hydrogen, C 1 -C 6  alkyl, —S(O) 2 R 6 , —RNR 4 R 5 —RR 6 , or aralkyl; and  
 R 8  is hydrogen or halogen; and  
 when R 1  is Cl, R 2  is hydrogen or Cl, R 3  is —C(O)OCH 3 , E and A are phenyl, D is CH, T is CH, M is C, Q is N(R 7 ) p , where R 7  is H, wherein either p or q is 0 and the other is 1, and Z is O, then X is O, S(O), S(O) 2 , CH2, CH(OH), or C(O).  
 
   
   
       2 . A compound as claimed in  claim 1 , wherein the compound is a compound of formula (III):  
     
       
         
         
             
             
         
       
     
     or salt or solvate thereof.  
   
   
       3 . A compound as claimed in  claim 1 , wherein E is aryl substituted with R 1  and R 2 .  
   
   
       4 . A compound as claimed in  claim 1 , wherein E is phenyl substituted with R 1  and R 2 .  
   
   
       5 . A compound as claimed in  claim 1 , wherein E is phenyl and R 1  and R 2  together with the phenyl ring atoms with which they are attached form a cycloalkyl ring fused to E.  
   
   
       6 . A compound as claimed in  claim 10 , wherein the cycloalkyl ring is cyclopentyl.  
   
   
       7 . A compound as claimed in  claim 1 , wherein E is phenyl and R 1  and R 2  together with the phenyl ring atoms with which they are attached form an aryl ring fused to E.  
   
   
       8 . A compound as claimed in  claim 7 , wherein the aryl ring is phenyl.  
   
   
       9 . A compound as claimed in  claim 1 , wherein A is phenyl, 2-pyridyl or 3-pyridyl.  
   
   
       10 . A compound as claimed in  claim 1 , wherein A is phenyl.  
   
   
       11 . A compound as claimed in  claim 1 , wherein the group A is linked to the side chain —NHC(Z)NHE and to the linker group X of the benzimidazole core through a (−1,3-) or a (−1,4-) linkage.  
   
   
       12 . A compound as claimed in  claim 1 , wherein A is a phenyl group linked through a (−1,4-) or (−1,3-) linkage.  
   
   
       13 . A compound as claimed in  claim 1 , wherein X is C(O) or O.  
   
   
       14 . A compound as claimed in  claim 1 , wherein X is O.  
   
   
       15 . A compound as claimed in  claim 1 , wherein X is S.  
   
   
       16 . A compound as claimed in  claim 1 , wherein Z is O.  
   
   
       17 . A compound as claimed in  claim 1 , wherein Z is S.  
   
   
       18 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  alkyl, aryloxy, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkylsulfanyl, C 1 -C 6  alkylsulfanyl, —C(O)OR 6 , halogen, —CN, or —NO 2 .  
   
   
       19 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6 alkoxy, halogen, or —NO 2 .  
   
   
       20 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  haloalkyl.  
   
   
       21 . A compound as claimed in  claim 1 , wherein R 1  is —CF 3 .  
   
   
       22 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  alkyl.  
   
   
       23 . A compound as claimed in  claim 1 , wherein R 1  is —C(CH 3 ) 3 .  
   
   
       24 . A compound as claimed in  claim 1 , wherein R 2  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  haloalkyl.  
   
   
       25 . A compound as claimed in  claim 1 , wherein R 2  is hydrogen or halogen.  
   
   
       26 . A compound as claimed in  claim 1 , wherein R 2  is halogen.  
   
   
       27 . A compound as claimed in  claim 1 , wherein R 2  is fluorine.  
   
   
       28 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  alkyl, C 1 -C 6  alkoxy, aryloxy, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkylsulfanyl, C 1 -C 6  alkylsulfanyl, C(O)OR 6 , halogen, —CN, or —NO 2  and R 2  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, or C 1 -C 6  haloalkyl.  
   
   
       29 . A compound as claimed in  claim 1 , wherein R 1  is C 1 -C 6  haloalkyl and R 2  is hydrogen or halogen.  
   
   
       30 . A compound as claimed in  claim 1 , wherein R 1  is —CF 3  and R 2  is fluorine.  
   
   
       31 . A compound as claimed in  claim 1 , wherein D is CH, T is CR 8 , M is C and Q is N(R 7 ) p , wherein p is 0, q is 1, R 7  is hydrogen, methyl, or S(O) 2 R 6 .  
   
   
       32 . A compound as claimed in  claim 1 , wherein D is CH, T is CR 8 , wherein R 8  is hydrogen or —Br, M is C and Q is N(R 7 ) p , wherein p is 1, q is 0, R 7  is hydrogen, methyl, —S(O) 2 R 6 , —RNR 4 R 5 , —RR 6  or aralkyl.  
   
   
       33 . A compound as claimed in  claim 1 , wherein D is CH, T is CR 8 , wherein R 8  is hydrogen, M is C and Q is N(R 7 ) p , wherein either p or q is 0, the other is 1 and R 7  is hydrogen.  
   
   
       34 . A compound as claimed in  claim 1 , wherein D is CH, T is CR 8 , wherein R 8  is hydrogen or —Br, M is C and Q is S or O; wherein q is 0.  
   
   
       35 . A compound as claimed in  claim 1 , wherein R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR″OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .  
   
   
       36 . A compound as claimed in  claim 1 , wherein R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , or —C(O)OR 6 .  
   
   
       37 . A compound as claimed in  claim 1 , wherein R 3  is —C(O)OR 6 .  
   
   
       38 . A compound as claimed in  claim 1 , wherein R 3  is —C(O)OR 6  and R 6  is methyl.  
   
   
       39 . A compound as claimed in  claim 1 , wherein A is phenyl; X is O; Z is O; R 1  is C 1 -C 6 alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, or —NO 2 ; R 2  is hydrogen, halogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; and R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 —C(O)RC(O)OR 6 , —C(O)ROR′OR″OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .  
   
   
       40 . A compound as claimed in  claim 1 , wherein A is phenyl; X is O; Z is 0; R 1  is C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; R 2  is hydrogen or halogen; and R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , or —C(O)OR 6 .  
   
   
       41 . A compound as claimed in  claim 1 , wherein A is phenyl; X is O; Z is O; R 1  is C 1 -C 6  haloalkyl; R 2  is halogen; and R 3  is —C(O)OR 6 .  
   
   
       42 . A compound as claimed in  claim 1 , wherein A is phenyl; X is S; Z is O; R 1  is C 1 -C 6 alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, or —NO 2 ; R 2  is hydrogen, halogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; and R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 —C(O)RC(O)OR 6 , —C(O)ROR′OR″OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .  
   
   
       43 . A compound as claimed in  claim 1 , wherein A is phenyl; X is S; Z is O; R 1  is C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; R 2  is hydrogen or halogen; and R 3  is —C(O)R 6 , or —C(O)OR 6 .  
   
   
       44 . A compound as claimed in  claim 1 , wherein A is phenyl; X is S; Z is O; R 1  is C 1 -C 6  haloalkyl; R 2  is halogen; and R 3  is —C(O)OR 6 .  
   
   
       45 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is O; Z is O; R 1  is C 1 -C 6 alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, or —NO 2 ; R 2  is hydrogen, halogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; and R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR″OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .  
   
   
       46 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is O; Z is O; R 1  is C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; R 2  is hydrogen or halogen; and R 3  is —C(O)R 6 , or —C(O)OR 6 .  
   
   
       47 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is O; Z is O; R 1  is C 1 -C 6  haloalkyl; R 2  is halogen; and R 3  is —C(O)OR 6 .  
   
   
       48 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is S; Z is O; R 1  is C 1-6 alkyl, C 1 -C 6  alkoxy, C 1 -C 6  haloalkyl, or —NO 2 ; R 2  is hydrogen, halogen, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; and R 3  is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR″OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .  
   
   
       49 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is S; Z is O; R 1  is C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; R 2  is hydrogen or halogen; and R 3  is —C(O)R 6 , or —C(O)OR 6 .  
   
   
       50 . A compound as claimed in  claim 1 , wherein A is pyridyl; X is S; Z is O; R 1  is C 1 -C 6  haloalkyl; R 2  is halogen; and R 3  is —C(O)OR 6 .  
   
   
       51 . A compound as claimed in  claim 1 , selected from the group consisting of: 
 methyl N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H -benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;    methyl (5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate; 
 t-butyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;  
   methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;    (6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;    6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)cyclopentamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylpentamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-acetylamino)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-aminoacetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-methoxyacetamide;    3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionic acid;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;    N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1H -benzimidazol-2-yl)acetamide;    methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)acetamide; and    methyl N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    or a salt or solvate thereof.    
   
   
       52 . A compound as claimed in  claim 1 , selected from the group consisting of: 
 methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((4-chloro-3-trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;    methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate;    methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcarbonyl)-1H -benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;    2-(dimethylamino)ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate; 
 benzyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;  
   5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)methanesulfonamide;    5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylbenzenesulfonamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-5-benzimidazolecarboxamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(dimethylamino)butylamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-pyridinecarboxamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-tetrahydrofurancarboxamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-indole-3-carboxamide);    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-imidazole-4-carboxamide);    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)benzamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-thiophenecarboxamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide;    N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(dimethylamino)acetamide;    6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;    7-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;    2-(2-(4-methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;    2-(2-(dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;    2-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;    methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-3-benzyl-1H-benzimidazol-2-yl)acetamide;    methyl N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;    6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine; and    N-(6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide;    or a salt or solvate thereof.    
   
   
       53 . A compound as claimed in  claim 1 , selected from the group consisting of: 
 methyl N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;    1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea;    1-(5-(4-((2-fluoro-5-(trifluoromethy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea;    N-(5-(4-((5-carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;    methyl N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea;    methyl N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    methyl N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate; and    methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;    or a salt or solvate thereof.    
   
   
       54 . A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 1 , or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.  
   
   
       55 . A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 51 , or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.  
   
   
       56 . A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 52 , or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.  
   
   
       57 . A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in  claim 53 , or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.