Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies

Abstract

The present invention relates to methods for the treatment of hematological malignancies. In particular, the invention provides methods for treatment of hematological malignancies by administering Aurora kinase inhibitors in combination with anti-CD20 antibodies.

1 . A method of treating a patient suffering from a hematological malignancy, comprising administering to the subject a therapeutically effective amount of an Aurora kinase inhibitor simultaneously with or consecutively with an anti-CD20 antibody. 
   
   
       2 . The method of  claim 1 , wherein the hematological malignancy is selected from the group consisting of lymphoma, leukemia and multiple myeloma. 
   
   
       3 . The method of  claim 2 , wherein the lymphoma is selected from the group consisting of B-cell lymphoma, Non-Hodgkin's lymphoma and mantle cell lymphoma. 
   
   
       4 . The method of  claim 1 , wherein the anti-CD20 antibody is rituximab. 
   
   
       5 . The method of  claim 4 , wherein the patient was treated previously with an anti-CD20 antibody. 
   
   
       6 . The method of  claim 1 , wherein the Aurora kinase inhibitor is an Aurora A kinase specific inhibitor. 
   
   
       7 . The method of  claim 6 , wherein the Aurora A kinase specific inhibitor is characterized by formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein: 
       Ring A is a substituted or unsubstituted 5- or 6-membered aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring; 
       Ring B is a substituted or unsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring; 
       Ring C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; 
       R e  is hydrogen, —OR 5 , —N(R 4 ) 2 , —SR 5 , or a C 1-3  aliphatic optionally substituted with R 3  or R 7 ; 
       each of R x  and R y  independently is hydrogen, fluoro, or an optionally substituted C 1-6  aliphatic; or R x  and R y , taken together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloaliphatic ring; 
       each R 3  independently is selected from the group consisting of -halo, —OH, —O(C 1-3  alkyl), —CN, —N(R 4 ) 2 , —C(O)(C 1-3  alkyl), —CO 2 H, —CO 2 (C 1-3  alkyl), —C(O)NH 2 , and —C(O)NH(C 1-3  alkyl); 
       each R 4  independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S; 
       each R 5  independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and 
       each R 7  independently is an optionally substituted aryl, heterocyclyl, or heteroaryl group. 
     
   
   
       8 . The method of  claim 6 , wherein the Aurora A kinase specific inhibitor is characterized by formula (III): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein: 
       R a  is selected from the group consisting of C 1-3  aliphatic, C 1-3  fluoroaliphatic, —R 2 , and -T-R 2 ; 
       T is a C 1-3  alkylene chain optionally substituted with fluoro; 
       R 1  is an optionally substituted aryl, heteroaryl, or heterocyclyl group; 
       R 2  is selected from the group consisting of halo, —C═C—R 3 , —CH═CH—R 3 , —N(R 4 ) 2 , and —OR 5 ; 
       R 3  is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; 
       each R 4  independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R 4  on the same nitrogen atom, taken together with the nitrogen atom form an optionally substituted 5- to 6-membered heteroaryl or 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S; 
       R 5  is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group; and 
       R b  is selected from the group consisting of fluoro, chloro, —CH S , —CF 3 , —OH, —OCH 3 , —OCF 3 , —OCH 2 CH 3 , and —OCH 2 CF 3 . 
     
   
   
       9 . The method of  claim 6 , wherein the Aurora A kinase specific inhibitor is 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid.