Combination therapy with glutaminase inhibitors

Abstract

The invention relates to methods of treating cancer or myeloproliferative diseaseswith a combination of a glutaminase inhibitor and an anticancer agent selected from cabozantinib, crizotinib, and axitinib. The invention further relates to methods of treating cancer or myeloproliferative diseases that are resistant to one or more anticancer agents.

1 . A method of treating or preventing cancer or a myeloproliferative disease, comprising conjointly administering a glutaminase inhibitor and an anticancer agent selected from cabozantinib, axitinib, and an ALK inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the anticancer agent is selected from cabozantinib, crizotinib, and axitinib. 
     
     
         3 - 8 . (canceled) 
     
     
         9 . The method of  claim 2 , wherein the anticancer agent is crizotinib. 
     
     
         10 . The method of  claim 2 , wherein the anticancer agent is axitinib. 
     
     
         11 . The method of  claim 1 , wherein the glutaminase inhibitor is a compound of formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 , CH 2 S, SCH 2 , CH 2 NHCH 2 , CH═CH, or 
       
         
           
           
               
               
           
         
       
       wherein any hydrogen atom of a CH or CH 2  unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH 2  unit of CH 2 CH 2 , CH 2 CH 2 CH 2  or CH 2  may be replaced by hydroxy;
 X, independently for each occurrence, represents S, O or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; 
 Y, independently for each occurrence, represents H or CH 2 O(CO)R 7 , 
 R 7 , independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, or heterocyclylalkoxy; 
 Z represents H or R 3 (CO); 
 R 1  and R 2  each independently represent H, alkyl, alkoxy or hydroxy; 
 R 3 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R 5 )(R 9 )(R 10 ), N(R 4 )(R 5 ) or OR 6 , wherein any free hydroxyl group may be acylated to form C(O)R 7 , 
 R 4  and R 5  each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; 
 R 6 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; and 
 R 8 , R 9  and R 10  each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R 5  and R 9  together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R 7 , and wherein at least two of R 8 , R 9 , and R 10  are not H. 
 
     
     
         12 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the glutaminase inhibitor is a compound of formula Ia, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 , CH 2 S, SCH 2 , CH 2 NHCH 2 , CH═CH, or 
       
         
           
           
               
               
           
         
       
       preferably CH 2 CH 2 , wherein any hydrogen atom of a CH or CH 2  unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH 2  unit of CH 2 CH 2 , CH 2 CH 2 CH 2  or CH 2  may be replaced by hydroxy;
 X represents S, O or CH═CH, preferably S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; 
 Y, independently for each occurrence, represents H or CH 2 O(CO)R 7 , 
 R 7 , independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or heterocyclylalkoxy; 
 Z represents H or R 3 (CO); 
 R 1  and R 2  each independently represent H, alkyl, alkoxy or hydroxy, preferably H; 
 R 3  represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R 5 )(R 9 )(R 10 ), N(R 4 )(R 5 ) or OR 6 , wherein any free hydroxyl group may be acylated to form C(O)R 7 ; 
 R 4  and R 5  each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; 
 R 6 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; and 
 R 8 , R 9  and R 10  each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R 5  and R 9  together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R 7 , and wherein at least two of R 8 , R 9  and R 10  are not H; 
 R 11  represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or C(R 12 )(R 13 )(R 14 ), N(R 4 )(R 14 ) or OR 14 , wherein any free hydroxyl group may be acylated to form C(O)R 7 ; 
 R 12  and R 13  each independently respresent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 , and wherein both of R 12  and R 13  are not H; and 
 R 14  represents substituted or unsubstituted aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl. 
 
     
     
         35 . The method of  claim 34 , wherein R 11  represents substituted or unsubstituted arylalkyl. 
     
     
         36 . The method of  claim 34 , wherein R 11  represents substituted or unsubstituted benzyl. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 34 , wherein one or more of (a) through (e) applies:
 (a) L represents CH 2 CH 2 ;   (b) Y represents H;   (c) X represents S;   (d) Z represents R 3 (CO); and   (e) R 1  and R 2  each represent H.   
     
     
         39 - 44 . (canceled) 
     
     
         45 . The method of  claim 34 , wherein R 3  represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. 
     
     
         46 . The method of  claim 34 , wherein R 3  represents substituted or unsubstituted heteroarylalkyl. 
     
     
         47 - 58 . (canceled) 
     
     
         59 . The method of  claim 34 , wherein the glutaminase inhibitor is a compound having the structure of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         60 . (canceled) 
     
     
         61 . The method of  claim 1 , for treating or preventing cancer, wherein the cancer is selected from brain tumor, breast cancer, hepatocellular cancer, lung cancer including non-small cell lung cancer and small cell lung cancer, melanoma, ovarian cancer, prostate cancer, and renal cell cancer. 
     
     
         62 . The method of  claim 61 , wherein the cancer is non-small cell lung cancer. 
     
     
         63 . The method of  claim 61 , wherein the cancer is renal cell cancer. 
     
     
         64 . The method of  claim 60 , wherein the cancer is resistant to an anticancer agent selected from cabozantinib, crizotinib, and axitinib. 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 1 , further comprising conjointly administering one or more additional chemotherapeutic agents. 
     
     
         67 - 73 . (canceled) 
     
     
         74 . The method of  claim 9 , wherein the glutaminase inhibitor is a compound of formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         75 . The method of  claim 74 , wherein the cancer is non-small cell lung cancer. 
     
     
         76 . The method of  claim 10 , wherein the glutaminase inhibitor is a compound of formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         77 . The method of  claim 76 , wherein the cancer is renal cell carcinoma. 
     
     
         78 . A pharmaceutical composition comprising a glutaminase inhibitor and an anticancer agent selected from cabozantinib, crizotinib, and axitinib. 
     
     
         79 - 81 . (canceled)