Combination compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds and methods of use thereof

Abstract

The present invention provides compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds, including compounds of Formula (I) or prodrugs thereof; in combination with an additional cancer therapeutic agent, and methods of use thereof for treating diseases and disorders such as cancer.

1 - 30 . (canceled) 
     
     
         31 . A composition comprising one or more compounds represented by the structure of Formula (I): 
       
         
           
           
               
               
           
         
         and/or at least one salt thereof, wherein: 
         R 1  is —CH 2 CF 3  or —CH 2 CH 2 CF 3 ; 
         R 2  is —CH 2 CF 3 , —CH 2 CH 2 CF 3 , or —CH 2 CH 2 CH 2 CF 3 ; 
         R 3  is H, —CH 3  or Rx; 
         R 4  is H or R y ; 
         R x    
         is: —CH 2 OC(O)CH(CH 3 )NH 2 , —CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , —CH 2 OC(O)CH((C H(CH 3 ) 2 )NHC(O)CH(NH 2 )CH(CH 3 ) 2 , 
       
       
         
           
           
               
               
           
         
         R y  is: —SCH 2 CH(NH 2 )C(O)OH, —SCH 2 CH(NH 2 )C(O)OH 3 , 
         or —SCH 2 CH(NH 2 )C(O)OC(CH 3 ) 3 ; 
         Ring A is phenyl or pyridinyl; 
         each R a  is independently F, Cl, —CN, —OCH 3 , C 1-3  alkyl, —CH 2 OH, —CF 3 , cyclopropyl, —OCH 3 , —O(cyclopropyl) and/or —NHCH 2 CH 2 OCH 3 ; 
         each R b  is independently F, Cl, —CH 3 , —CH 2 OH, —CF 3 , cyclopropyl, and/or —OCH 3 ; 
         y is zero, 1 or 2; and 
         z is zero, 1, or 2, 
         in combination with a composition comprising Venclexta, a tyrosine kinase inhibitor, a retinoic acid derivative, an anti-PD1 antibody, an EGFR inhibitor, or a combination thereof. 
       
     
     
         32 . The composition of  claim 31 , wherein the compound of Formula (I) is represented by the structure of Compound (1): 
       
         
           
           
               
               
           
         
       
     
     
         33 . The composition of  claim 31 , wherein the compound of Formula (I) is represented by the structure of Compound (2): 
       
         
           
           
               
               
           
         
       
     
     
         34 . The composition of  claim 31 , wherein the compound of Formula (I) is represented by the structure of Compound (22): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The composition of  claim 31 , wherein said anti-PD1 antibody comprises Pembrolizumab. 
     
     
         36 . The composition of  claim 31 , wherein said tyrosine kinase inhibitor comprises Sorafenib. 
     
     
         37 . A method of treating, suppressing or inhibiting a proliferative disease in a subject comprising the step of administering to said subject a first composition comprising a first composition comprising one or more compounds represented by the structure of Formula (I): 
       
         
           
           
               
               
           
         
         and/or at least one salt thereof, wherein: 
         R 1  is —CH 2 CF 3  or —CH 2 CH 2 CF 3 ; 
         R 2  is —CH 2 CF 3 , —CH 2 CH 2 CF 3 , or —CH 2 CH 2 CH 2 CF 3 ; 
         R 3  is H, —CH 3  or Rx; 
         R 4  is H or R y ; 
         R x    
         is: —CH 2 OC(O)CH(CH 3 )NH 2 , —CH 2 OC(O)CH(NH 2 )CH(CH 3 ) 2 , —CH 2 OC(O)CH((C H(CH 3 ) 2 )NHC(O)CH(NH 2 )CH(CH 3 ) 2 , 
       
       
         
           
           
               
               
           
         
         R y  is: —SCH 2 CH(NH 2 )C(O)OH, —SCH 2 CH(NH 2 )C(O)OH 3 , 
         or —SCH 2 CH(NH 2 )C(O)OC(CH 3 ) 3 ; 
         Ring A is phenyl or pyridinyl; 
         each R a  is independently F, Cl, —CN, —OCH 3 , C 1-3  alkyl, —CH 2 OH, —CF 3 , cyclopropyl, —OCH 3 , —O(cyclopropyl) and/or —NHCH 2 CH 2 OCH 3 ; 
         each R b  is independently F, Cl, —CH 3 , —CH 2 OH, —CF 3 , cyclopropyl, and/or —OCH 3 ; 
         y is zero, 1 or 2; and 
         z is zero, 1, or 2 
         and a second composition comprising Venclexta, a tyrosine kinase inhibitor, a retinoic acid derivative, an anti-PD1 antibody, an EGFR inhibitor, or a combination thereof. 
       
     
     
         38 . The method of  claim 37 , wherein said proliferative disease is a pre-cancerous condition or a benign proliferative disorder. 
     
     
         39 . The method of  claim 37 , wherein said proliferative disease is a cancer. 
     
     
         40 . The method of  claim 39 , wherein said cancer comprises Adenoid Cystic Carcinoma (ACC). 
     
     
         41 . The method of  claim 39 , wherein said cancer comprises a Desmoid tumor. 
     
     
         42 . The method of  claim 39 , wherein said cancer comprises breast cancer, endometrial cancer, non-small cell lung cancer (NSCLC), multiple myeloma, leukemia, a lymphoma or a combination thereof. 
     
     
         43 . The method of  claim 41 , wherein said breast cancer comprises triple negative breast cancer. 
     
     
         44 . The method of  claim 41 , wherein said leukemia comprises T-cell acute lymphoblastic leukemia (T-ALL) or T-lymphoblastic leukemia/lymphoma (TLL). 
     
     
         45 . The method of  claim 39 , wherein said cancer comprises a Notch-activating mutation. 
     
     
         46 . The method of  claim 37 , wherein said first composition and/or said second composition is intravenously or orally administered to said subject. 
     
     
         47 . The method of  claim 37 , wherein the compound of Formula (I) comprises: 
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 37 , wherein the compound of Formula (I) comprises: 
       
         
           
           
               
               
           
         
       
     
     
         49 . The method of  claim 37 , wherein said anti-PD1 antibody comprises Pembrolizumab. 
     
     
         50 . The method of  claim 37 , wherein said tyrosine kinase inhibitor comprises Sorafenib.