Pharmaceutical combinations for the treatment of cancer

Abstract

The disclosure herein provides combination therapies for the treatment of cancers such as Leukemia, lymphoma and triple negative breast cancer. The disclosure provides combination therapies of CDK inhibitors, e.g., a CDK inhibitor represented by Formula (I): or a pharmaceutically acceptable salt thereof together with a BCL-2 inhibitor or proteasome inhibitor for the treatment of cancer.

1 - 24 . (canceled) 
     
     
         25 . A method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a CDK inhibitor represented by Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is optionally substituted phenyl; 
 R 2  and R 3  are each independently selected from hydroxy and OR 8 , wherein R 8  is optionally substituted C 1 -C 10 -alkyl; 
 R 4  is optionally substituted C 1 -C 4 -alkyl; and 
 R 9  is hydrogen or optionally substituted C 1 -C 4 -alkyl; 
 
       and a therapeutically effective amount of a proteasome inhibitor. 
     
     
         26 . The method of  claim 25 , wherein the compound or salt of Formula I is represented by Formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 25 , wherein R 1  is optionally substituted with one or more substituents independently selected from hydroxy, cyano, halo, amino, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -haloalkyl, and nitro. 
     
     
         28 . The method of  claim 27 , wherein R 1  is substituted with one or more substituents independently selected from halo and C 1 -C 4 -haloalkyl. 
     
     
         29 . The method of  claim 28 , wherein R 1  is 2-chloro-4-trifluoromethylphenyl. 
     
     
         30 . The method of  claim 25 , wherein R 2  and R 3  are each independently selected from hydroxy and OR 8 , wherein R 8  is C 1 -C 10 -alkyl optionally substituted with one or more substituents independently selected from hydroxy, cyano, halo, amino, ═O, ═S, C 1 -C 4 -alkoxy, and nitro. 
     
     
         31 . The method of  claim 30 , wherein R 2  and R 3  are each hydroxy. 
     
     
         32 . The method of  claim 25 , wherein R 4  is C 1 -C 4 -alkyl substituted with one or more substituents selected from hydroxy, cyano, halo, amino, ═O, ═S, C 1 -C 4 -alkoxy, and nitro. 
     
     
         33 . The method of  claim 32 , wherein R 4  is C 1 -C 4 -alkyl substituted with one or more substituents selected from hydroxy, cyano, halo, amino, ═O, ═S, C 1 -C 4 -alkoxy, and nitro. 
     
     
         34 . The method of  claim 33 , wherein R 4  is 2-hydroxymethyl. 
     
     
         35 . The method of  claim 25 , wherein R 9  is C 1 -C 4 -alkyl optionally substituted with hydroxy, cyano, halo, amino, ═O, ═S, C 1 -C 4 -alkoxy, and nitro. 
     
     
         36 . The method of  claim 35 , wherein R 9  is methyl. 
     
     
         37 . The method of  claim 25 , wherein the compound of Formula I is represented by formula Ib: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 25 , wherein the proteasome inhibitor is selected from bortezomib, marizomib, ixazomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfilzomib, ONX 0912, CEP-18770, MLN9708, epoxomicin, MG132 and a pharmaceutically acceptable salt of any one thereof. 
     
     
         39 . The method of  claim 38 , wherein the proteasome inhibitor is selected from bortezomib, marizomib, ixazomib, and a pharmaceutically acceptable salt of any one thereof. 
     
     
         40 . The method of  claim 25 , wherein the cancer is a blood cancer. 
     
     
         41 . The method of  claim 40 , wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphomia (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas, extranodal marginal zone B-cell lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma. 
     
     
         42 . The method of  claim 41 , wherein the blood cancer is diffuse large B-cell lymphoma, acute myeloid leukemia or chronic lymphocytic leukemia. 
     
     
         43 . The method of  claim 25 , wherein the cancer is triple negative breast cancer (TNBC). 
     
     
         44 . The method of  claim 25 , wherein the CDK inhibitor and the proteasome inhibitor are administered concurrently. 
     
     
         45 . The method of  claim 25 , wherein the CDK inhibitor and the proteasome inhibitor are administered sequentially within about 12 hours of each other. 
     
     
         46 . The method of  claim 45 , wherein the CDK inhibitor and the proteasome inhibitor are administered sequentially within about 5 hours of each other. 
     
     
         47 . The method of  claim 25 , wherein the CDK inhibitor and the proteasome inhibitor are co-formulated in a pharmaceutical composition. 
     
     
         48 . The method of  claim 25 , wherein the CDK inhibitor and the proteasome inhibitor are administered daily, every other day or every third day. 
     
     
         49 - 66 . (canceled)