Combination of catalytic mtorc 1/2 inhibitors and selective inhibitors of aurora a kinase

Abstract

Disclosed are methods for the treatment of proliferative disorders. Disclosed in particular, are methods for treatment of proliferative disorders such as cancer, by administering an mTORC1/2 inhibitor in combination with a selective inhibitor of Aurora A kinase. Preferred MTORC1/2 inhibitors include MLN0128 and the preferred Aurora A kinase inhibitor of the combination is ML-N8237.

1 . A method of treating a patient suffering from cancer, wherein the cancer is colon cancer, breast cancer, ovarian cancer, renal cell carcinoma, SCLC, Diffuse large B cell lymphoma, mantle cell lymphoma, or neuroblastoma, comprising administering to the patient an mTORC1/2 inhibitor in combination with a selective inhibitor of Aurora A kinase, wherein the amounts of each inhibitor are therapeutically effective when used in combination. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the mTORC1/2 inhibitor is represented by formula I-C1a: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 E 2  is —H; X 1  is CH and X 2  is N; 
 R 1  is -L-C 1-10 alkyl, -L-C 3-8 cycloalkyl, -L-C 1-10 alkylheterocyclyl, or -L-heterocyclyl, each of which is unsubstituted or is substituted by one or more independent R 3 ; 
 L is absent, —(C═O)—, —C(═O)O—, —C(═O) N(R 31 )—, —S—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 31 )—, or —N(R 31 )—; 
 R 3  is hydrogen, —OH, —OR 31 , —NR 31 R 32 , —C(O)R 31 , —C(═O)NR 31 R 32 , —C(═O)NR 34 R 35 , aryl, heteroaryl, C 1-4 alkyl, C 1-10 alkyl, C 3-8 cycloalkyl, or heterocyclyl, wherein each of said aryl or heteroaryl moiety is unsubstituted or is substituted with one or more independent alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 R 32 , —C(═O)NR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , —NR 31 C(═O)R 32 , —NR 31 C(═O)OR 32 , —NR 31 C(═O)NR 32 R 33 , —NR 31 S(O) 0-2 R 32 , —C(═S)OR 31 , —C(═O)SR 31 , —NR 31 C(═NR 32 )NR 33 R 32 , —NR 31 C(═NR 32 )OR 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)OR 31 , —P(O)OR 31 OR 32 , or —SC(═O)NR 31 R 32 , and wherein each of said alkyl, cycloalkyl, or heterocyclyl moiety is unsubstituted or is substituted with one or more alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —O-aryl, —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 34 R 35 , or —C(═O)NR 31 R 32 ; —(W 2 ) k — is —NH—, —N(H)C(O)— or —N(H)S(O) 2 —; 
 R 2  is hydrogen, halogen, —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 R 32 , —C(═O)NR 34 R 35 , —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , bicyclic aryl, substituted monocyclic aryl, heteroaryl, C 1-10 alkyl, C 3-8 cycloalkyl, C 1-10 alkyl-C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-10 alkyl, C 2-10 alkyl-monocyclic aryl, monocyclic aryl-C 2-10 alkyl, C 1-10 alkylbicycloaryl, bicycloaryl-C 1-10 alkyl, substituted C 1-10 alkylaryl, substituted aryl-C 1-10 alkyl, C 1-10 alkylheteroaryl, C 1-10 alkylheterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, heterocyclyl, heterocyclyl C 1-10 alkyl, heterocyclyl-C 2-10 alkenyl, heterocyclyl-C 2-10 alkynyl, aryl-heterocyclyl, heteroaryl-C 1-10 alkyl, heteroaryl-heteroalkyl, or heteroaryl-heterocyclyl, wherein each of said bicyclic aryl or heteroaryl moiety is unsubstituted, or wherein each of bicyclic aryl, heteroaryl moiety or monocyclic aryl moiety is substituted with one or more independent halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 31 R 32 , —C(═O)NR 34 R 35 , —NO 2 , —CN, —S(O) 0-2 R 31 , —SO 2 NR 31 R 32 , —SO 2 NR 34 R 35 , —NR 31 C(═O)R 32 , —NR 31 C(═O)OR 32 , —NR 31 C(═O)NR 32 R 33 , —NR 31 S(O) 0-2 R 32 , —C(═S)OR 31 , —C(═O)SR 31 , —NR 31 C(═NR 32 )NR 33 R 32 , —NR 31 C(═NR 32 )OR 33 , —NR 31 C(═NR 32 )SR 33 , —OC(═O)OR 33 , —OC(═O)NR 31 R 32 , —OC(═O)SR 31 , —SC(═O)OR 31 , —P(O)OR 31 OR 32 , or —SC(═O)NR 31 R 32 , and wherein each of said alkyl, cycloalkyl, heterocyclyl, or heteroalkyl moiety is unsubstituted or is substituted with one or more halo, —OH, —R 31 , —CF 3 , —OCF 3 , —OR 31 , —O-aryl, —NR 31 R 32 , —NR 34 R 35 , —C(O)R 31 , —CO 2 R 31 , —C(═O)NR 34 R 35 , or —C(═O)NR 31 R 32 ; 
 R 31 , R 32 , and R 33 , in each instance, are independently H or C 1-10 alkyl, wherein the C 1-10 alkyl is unsubstituted; and 
 R 34  and R 35  in —NR 34 R 35 , —C(═O)NR 34 R 35 , or —SO 2 NR 34 R 35 , are taken together with the nitrogen atom to which they are attached to form a 3-10 membered saturated or unsaturated ring; wherein said ring is independently unsubstituted or is substituted by one or more —NR 31 R 32 , hydroxyl, halogen, oxo, aryl, heteroaryl, C 1-6 alkyl, or O-aryl, and wherein said 3-10 membered saturated or unsaturated ring independently contains 0, 1, or 2 more heteroatoms in addition to the nitrogen. 
 
     
     
         4 . The method of  claim 3 , wherein the mTORC1/2 inhibitor is represented by subclass 1a: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein the mTORC1/2 inhibitor is 3-(2-amino-1,3-benzoxazol-5-yl)-1-(propan-2-yl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 1 , wherein the selective inhibitor of Aurora A kinase is represented by formula (V): 
       
         
           
           
               
               
           
         
         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 1 , -T-R 1 , —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 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —OCH 2 CH 3 , and —OCH 2 CF 3 . 
 
       
     
     
         7 . The method of  claim 6 , wherein the selective inhibitor of Aurora A kinase is 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , wherein the pharmaceutically acceptable salt is sodium 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate.