Cell proliferation inhibitors and conjugates thereof

Abstract

Disclosed herein are immunoconjugates comprising an inhibitor of Eg5 linked to an antigen binding moiety such as an antibody, that are useful for treating cell proliferative disorders. Also disclosed are novel inhibitors of Eg5 that can be used either alone or as part of an immunoconjugate to treat cell proliferation disorders. The Eg5 inhibitors include compounds of this formula as described herein: The invention further provides pharmaceutical compositions comprising these compounds and immunoconjugates, and compositions comprising the immunoconjugates or compounds with a therapeutic co-agent, and methods to use these compounds, conjugates and compositions for treating cell proliferation disorders.

1 . An immunoconjugate of Formula (I):
     AbLX ) m ) n    (I)
   wherein Ab represents an antigen binding moiety;   L represents a linking group that connects X to Ab;   m is an integer from 1-4;   n is an integer from 1 to 16; and   X independently at each occurrence represents a group of Formula (II)   
       
         
           
           
               
               
           
         
       
       that is connected by L to Ab,
 wherein: 
 Z is N or CH; 
 Ar 1  is phenyl optionally substituted with up to three groups selected from halo, C 1-3  alkyl, and C 1-3  haloalkyl; 
 Ar 2  is phenyl or pyridinyl, and Ar 2  is optionally substituted with up to two groups selected from halo, CN, C 1-3  alkyl, hydroxyl, amino, and C 1-3  haloalkyl; 
 R 1  is C 1-6  alkyl, —(CH 2 ) 0-2 —C 3-6 cycloalkyl, or —(CH 2 ) 0-2 —C 4-7  heterocyclyl containing up to two heteroatoms selected from N, O and S as ring members, wherein each C 1-6  alkyl, C 3-6  cycloalkyl, or C 4-7  heterocyclyl is optionally substituted with up to three groups selected from halo, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted C 1-4  alkyl, amino-substituted C 1-4  alkyl, and COO(C 1-4  alkyl); 
 R 2  is H or C 1-4  alkyl; 
 T is (CH 2 ) 1-3 ; 
 Y is selected from C 1-3  aminoalkyl, C 4-6  heterocyclyl, and C 3-6  cycloalkyl, wherein C 1-3  aminoalkyl, C 4-6  heterocyclyl, and C 3-6  cycloalkyl are each optionally substituted with up to three groups selected from amino, oxo, halo, hydroxyl, C 1-4  alkyl, C 1-4  alkoxy, hydroxyl-substituted C 1-4  alkyl, amino-substituted C 1-4  alkyl, COOH, COO—(C 1-4  alkyl), —C(═O)NH(C 1-4  alkyl), —C(═O)N(C 1-4  alkyl) 2 , and C 1-4  haloalkyl; 
 A is NH, N(C 1-4  alkyl), or a bond between the carbonyl in Formula (II) and Q; 
 Q is selected from C 1-4  alkyl, —O—C 1-4 alkyl, —(CH 2 ) 0-2 —C 4-6 heterocyclyl, —(CH 2 ) 0-2 —C 3-6 cycloalkyl, —(CH 2 ) 0-2 —C 5-6 heteroaryl, and —(CH 2 ) 0-2 -phenyl, and is optionally substituted with up to three groups selected from halo, hydroxyl, amino, —SH, —R, —OR, —SR, —SO 2 R, —NHR, —O-glucuronate, and —NR 2 , where each R is C 1-6  alkyl optionally substituted with halo, —SH, —NH 2 , OMe, or —OH. 
 
     
     
         2 . The immunoconjugate of  claim 1 , wherein R 2  is H. 
     
     
         3 . The immunoconjugate of  claim 1 , wherein Z is CH. 
     
     
         4 . The immunoconjugate of  claim 1 , wherein Z is N. 
     
     
         5 . The immunoconjugate of  claim 1 , wherein R 1  is tetrahydropyran, and R 1  is optionally substituted with up to two groups selected from oxo and methyl. 
     
     
         6 . The immunoconjugate of  claim 1 , wherein Ar 1  is dihalophenyl. 
     
     
         7 . The immunoconjugate of  claim 1 , wherein the compound of Formula (II) has the formula: 
       
         
           
           
               
               
           
         
         wherein L is attached to Y, or to Q, or to R 1 . 
       
     
     
         8 . The immunoconjugate of  claim 1 , wherein R 1  is 4-tetrahydropyranyl. 
     
     
         9 . The immunoconjugate of  claim 1 , wherein Q is C 1-4  alkyl substituted with one or two groups selected from hydroxyl and amino. 
     
     
         10 . The immunoconjugate of  claim 1 , wherein Y is pyrrolidone optionally substituted with halo, amino, or hydroxy. 
     
     
         11 . The immunoconjugate of  claim 1 , wherein A is —NH—. 
     
     
         12 . The immunoconjugate of  claim 1 , wherein the linking group is cleavable. 
     
     
         13 . The immunoconjugate of  claim 1 , wherein the linking group is non-cleavable. 
     
     
         14 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Z is N or CH; 
 Ar 1  is phenyl optionally substituted with up to three groups selected from halo, C 1-3  alkyl, and C 1-3  haloalkyl; 
 Ar 2  is phenyl or pyridinyl, optionally substituted with up to two groups selected from halo, CN, C 1-3  alkyl, hydroxyl, amino, and C 1-3  haloalkyl; 
 R 1  is —(CH 2 ) 0-2 —C 4-7  heterocyclyl or —(CH 2 ) 0-2 —C 3-7  cycloalkyl, where the C 4-7  heterocyclyl contains up to two heteroatoms selected from N, O and S as ring members, and C 4-7  heterocyclyl and C 3-7  cycloalkyl are each optionally substituted with up to three groups selected from halo, C 1-4  alkyl, C 1-4  alkoxy, hydroxyl, amino, oxo, hydroxyl-substituted C 1-4  alkyl, amino-substituted C 1-4  alkyl, C 1-4  haloalkyl, and COO(C 1-4  alkyl); 
 R 2  is H or C 1-4  alkyl; 
 T is (CH 2 ) 1-3 ; 
 Y is selected from C 1-2  aminoalkyl, C 4-6  heterocyclyl, and C 3-6  cycloalkyl, wherein C 1-2  aminoalkyl, C 4-6  heterocyclyl, and C 3-6  cycloalkyl are each optionally substituted with up to three groups selected from amino, oxo, halo, hydroxyl, C 1-4  alkoxy, hydroxyl-substituted C 1-4  alkyl, amino-substituted C 1-4  alkyl, COOH, COO—(C 1-4  alkyl), CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , and C 1-3  haloalkyl; 
 A is NH, N(C 1-4  alkyl), or a bond between the carbonyl in Formula (III) and Q; 
 Q is selected from C 1-4  alkyl, —(CH 2 ) 0-2 —C 4-6 heterocyclyl, —(CH 2 ) 0-2 —C 5-6 heteroaryl, and —(CH 2 ) 0-2 -phenyl, and Q is optionally substituted with up to three groups selected from halo, hydroxyl, amino, —SH, —R, —OR, —SR, —SO 2 R, —NHR, and —NR 2 , where each R is C 1-6  alkyl optionally substituted with up to three groups selected from halo, —SH, —NH 2 , OMe, and —OH. 
 
     
     
         15 . The compound of  claim 14 , wherein R 1  is tetrahydropyranyl. 
     
     
         16 . A compound of Formula (IIA) or (IIB): 
       
         
           
           
               
               
           
         
       
       wherein Ar 1 , Ar 2 , Z, R 1 , R 2 , T, Q, Y, and A are as defined in  claim 1 ,
 Q* is selected from —CH 2 O—, —CH 2 S—, —CH 2 —NH—, —CH 2 —NMe-, —CH(Me)O—, —CH(OH)—CH 2 O—, —CH(CH 2 OH)—O—, —CH(OH)—CH 2 NH—, —CH(CH 2 OH)—NH—, —CH(CH 2 NH 2 )—O—, —CH(CH 2 OH)—NH—, —CH(Me)S—, —CH(Me)NH—, —CH 2 CH 2 O—, —CH 2 CH 2 NH—, —CH 2 CH 2 S—, —CH(Me)CH 2 O—, —CH(Me)CH 2 S—, —CH(Me)CH 2 NH—, 
 
       
         
           
           
               
               
           
         
         Y* is selected from —CH(CH 2 F)NH—, —CH 2 NH—, 
       
       
         
           
           
               
               
           
         
       
       where R 10  and R 11  are independently H, Me, OMe, F, CH 2 F, CH 2 OH, COOH, CONH(C 1-4  alkyl), CON(C 1-4 alkyl) 2 , COO(C 1-4 alkyl), or OH, 
       and W is a linking moiety that comprises one or more linker components and a reactive functional group. 
     
     
         17 . The compound of  claim 16 , wherein W comprises a reactive functional group selected from —SH, —NH 2 , —C(═O)H, —C(═O)Me, N-maleimide, —NHC(═O)—CH 2 -halo, —COOH, and —C(═O)—OR′, wherein halo is selected from Cl, Br and I, and —OR′ is the leaving group moiety of an activated ester. 
     
     
         18 . The compound of  claim 16 , wherein Ar 1  is dihalophenyl. 
     
     
         19 . The compound of  claim 16 , wherein Ar 2  is phenyl or halophenyl. 
     
     
         20 . The compound of  claim 16 , wherein Z is CH. 
     
     
         21 . The compound of  claim 16 , wherein Z is N. 
     
     
         22 . The compound of  claim 16 , wherein R 1  is 4-tetrahydropyranyl. 
     
     
         23 . The compound of  claim 16 , wherein R 2  is H. 
     
     
         24 . The compound of  claim 16 , wherein A is —NH—. 
     
     
         25 . The compound of  claim 16 , wherein A is a bond. 
     
     
         26 . The compound of  claim 16 , wherein T is CH 2  or CH 2 CH 2 . 
     
     
         27 . The compound of  claim 16 , wherein Y is selected from —CH(CH 2 F)NH 2 , 
       
         
           
           
               
               
           
         
       
       where R 10  and R 11  are independently H, Me, OMe, F, CH 2 F, CH 2 OH, COOH, COO(C 1-4  alkyl), or OH. 
     
     
         28 . The compound of  claim 16 , wherein Q is selected from —CH 2 OH, —CH 2 —NH 2 , —CH(Me)OH, —CH(OH)—CH 2 OH, —CH(OH)—CH 2 NH 2 , —CH(NH 2 )—CH 2 OH, —CH(NH 2 )—CH 2 OH, —CH(Me)SH, —CH(Me)NH 2 , —CH 2 CH 2 OH, —CH 2 CH 2 NH 2 , —CH 2 CH 2 SH, —CH(Me)CH 2 OH, —CH(Me)CH 2 SH, —CH(Me)CH 2 NH 2 , 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 14 , which is selected from the compounds in Table 1 and the pharmaceutically acceptable salts thereof. 
     
     
         30 . A pharmaceutical composition comprising a compound of  claim 15  or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. 
     
     
         31 . A combination comprising a therapeutically effective amount of a compound according to  claim 14  or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents. 
     
     
         32 . A method of treating a cell proliferation disorder, comprising administering to a subject in need thereof a therapeutically effective amount of an immunoconjugate of  claim 1 , or a pharmaceutically acceptable salt thereof.