Macrocyclic compounds as alk, fak and jak2 inhibitors

Abstract

The present invention provides compounds of Formula I or a pharmaceutically acceptable salt forms thereof, wherein R1, R2, R3, R4, R5, A and X are as defined herein, methods of treatment and uses thereof.

What is claimed is: 
     
         1 . A method of treating a subject suffering from an ALK-, FAK- or JAK2-mediated disorder or condition comprising administering to the subject a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein: 
         A is H, cyano, F, Cl, Br, CH 3  or CF 3 ; 
         R1 is H, heterocyclyl, heteroaryl, carbocyclyl, aryl, C 1-6 alkyl, C 1-6 alkoxy, carbocyclyloxy, or C 1-6 alkylamino, 
         where, when R1 is a nitrogen containing heterocyclyl, the nitrogen may be substituted with C 1-6 alkyl, hydroxy(C 2-3 )alkyl, dihydroxy (C 3 )alkyl, C 1-6 alkoxy(C 2-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 2-3 )alkyl, (C 1-6  alkyl)sulfonyl, amino(C 2-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl may be the same or different, heteroaryl or heterocyclyl, 
         and where, when R1 is heterocyclyl, heteroaryl, carbocyclyl, or aryl, such heterocyclyl, heteroaryl, carbocyclyl, or aryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 )alkylsulfonyl, fluorine, carboxy, amino(C 1-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl may be the same or different, and heterocyclyl, 
         and where, when R1 is C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, the alkyl groups of such C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino may be unsubstituted, or substituted with one, two or three substituents independently selected from the group consisting of heterocyclyl, heteroaryl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, 
       
       N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminosulfonyl, and C 1-6 alkylsulfonyl;
 R2 is H, heterocyclyl, heteroaryl, carbocyclyl, aryl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, 
 where, when R2 is a nitrogen containing heterocyclyl, the nitrogen may be substituted with H, C 1-6 alkyl, hydroxy(C 2-3 )alkyl, dihydroxy (C 3 )alkyl, C 1-6 alkoxy(C 2-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 2-3 )alkyl, (C 1-6  alkyl)sulfonyl, amino(C 2-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl may be the same or different, heteroaryl or heterocyclyl, 
 and where, when R2 is heterocyclyl, heteroaryl, carbocyclyl, or aryl, such heterocyclyl, heteroaryl, carbocyclyl, or aryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 )alkylsulfonyl, fluoro, carboxy, amino(C 1-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl may be the same or different, and heterocyclyl, 
 and where, when R2 is C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, the alkyl groups of such C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino may be unsubstituted, or substituted with one, two or three substituents independently selected from the group consisting of heterocyclyl, heteroaryl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, 
 
       N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminosulfonyl, and C 1-6 alkylsulfonyl; or
 R1 and R2, together with the phenyl ring to which they are attached, form a five- to eight-membered monocarbocyclic or monoheterocyclic ring, where the ring so formed by R1 and R2, may be unsubstituted, or substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, amino(C 1-3 )alkyl, N—(C 1-6 alkyl)amino(C 1-3 )alkyl, N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl may be the same or different, alkoxy(C 1-6 )alkyl, hydroxyl, hydroxy(C 1-6 )alkyl, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, heterocyclyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, and aminosulfonyl; 
 R3 is H, C 1-6 alkoxy, or Cl; 
 where at least one of R1 and R3 is other than H; 
 R4 and R5, independently, are H, C 1-6 alkoxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, (C 1-6 alkyl)sulfonyl, aminosulfonyl, N—(C 1-6 alkyl)aminosulfonyl, N,N-di-(C 1-6 alkyl)aminosulfonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminosulfonyl may be the same or different, N—[(C 1-6 alkyl)sulfonyl]amino, N—[(C 1-6 alkyl)sulfonyl]-N—(C 1-6 alkyl)amino, where the alkyl groups of N—[(C 1-6 alkyl)sulfonyl]-N—(C 1-6 alkyl)amino may be the same or different, (C 1-6 alkyl) 2 phosphinyl, where the alkyl groups of (C 1-6 alkyl) 2 phosphinyl may be the same or different, or heteroaryl, where, when R4 or R5 is heteroaryl, such heteroaryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 alkyl)sulfonyl, fluorine, carboxy, aminocarbonyl, N—(C 1-6 )alkylaminocarbonyl, and N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, 
 and where, when R4 or R5 is N—(C 1-6 alkyl)aminocarbonyl or C 1-6 alkoxy, the alkyl groups of such N—(C 1-6 alkyl)aminocarbonyl or C 1-6 alkoxy may be unsubstituted, or substituted by one, two or three substituents independently selected from the group consisting of heterocyclyl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, cyano, carboxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, or 
 R4 and R5, together with the phenyl ring to which the are attached, form a five- to eight-membered monoheterocyclic ring, where the ring so-formed by R4 and R5 may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, amino(C 1-3 )alkyl, N—(C 1-6 alkyl)amino(C 1-3 )alkyl, N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl may be the same or different, alkoxy(C 1-6 )alkyl, hydroxyl, hydroxy(C 1-6 )alkyl, (C 1-6 alkyl)sulfonyl, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, heterocyclyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, and aminosulfonyl; and 
 —X— is —CH═CH—, —CH 2 CH 2 —, —NH—CO—, —CONH— or —(CH(OH)) 2 —; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method of  claim 1  wherein the ALK-, FAK- or JAK2-mediated disorder or condition is cancer. 
     
     
         3 . The method of  claim 1  wherein the ALK-, FAK- or JAK2-mediated disorder or condition is selected from colon cancer, breast cancer, renal cancer, lung cancer, hemangioma, squamous cell myeloid leukemia, melanoma, glioblastoma, and astrocytoma. 
     
     
         4 . A method of treating a proliferative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         wherein: 
         A is H, cyano, F, Cl, Br, CH 3  or CF 3 ; 
         R1 is H, heterocyclyl, heteroaryl, carbocyclyl, aryl, C 1-6 alkyl, C 1-6 alkoxy, carbocyclyloxy, or C 1-6 alkylamino, 
         where, when R1 is a nitrogen containing heterocyclyl, the nitrogen may be substituted with C 1-6 alkyl, hydroxy(C 2-3 )alkyl, dihydroxy (C 3 )alkyl, C 1-6 alkoxy(C 2-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 2-3 )alkyl, (C 1-6  alkyl)sulfonyl, amino(C 2-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl may be the same or different, heteroaryl or heterocyclyl, 
         and where, when R1 is heterocyclyl, heteroaryl, carbocyclyl, or aryl, such heterocyclyl, heteroaryl, carbocyclyl, or aryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 )alkylsulfonyl, fluorine, carboxy, amino(C 1-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl may be the same or different, and heterocyclyl, 
         and where, when R1 is C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, the alkyl groups of such C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino may be unsubstituted, or substituted with one, two or three substituents independently selected from the group consisting of heterocyclyl, heteroaryl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, 
       
       N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminosulfonyl, and C 1-6 alkylsulfonyl;
 R2 is H, heterocyclyl, heteroaryl, carbocyclyl, aryl, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, 
 where, when R2 is a nitrogen containing heterocyclyl, the nitrogen may be substituted with H, C 1-6 alkyl, hydroxy(C 2-3 )alkyl, dihydroxy (C 3 )alkyl, C 1-6 alkoxy(C 2-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 2-3 )alkyl, (C 1-6  alkyl)sulfonyl, amino(C 2-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 2-3 )alkylcarbonyl may be the same or different, heteroaryl or heterocyclyl, 
 and where, when R2 is heterocyclyl, heteroaryl, carbocyclyl, or aryl, such heterocyclyl, heteroaryl, carbocyclyl, or aryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 )alkylsulfonyl, fluoro, carboxy, amino(C 1-3 )alkylcarbonyl, N—(C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl, where the alkyl groups of N,N-(di-C 1-6 alkyl)amino(C 1-3 )alkylcarbonyl may be the same or different, and heterocyclyl, 
 and where, when R2 is C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino, the alkyl groups of such C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino may be unsubstituted, or substituted with one, two or three substituents independently selected from the group consisting of heterocyclyl, heteroaryl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, 
 
       N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminosulfonyl, and C 1-6 alkylsulfonyl; or
 R1 and R2, together with the phenyl ring to which they are attached, form a five- to eight-membered monocarbocyclic or monoheterocyclic ring, where the ring so formed by R1 and R2, may be unsubstituted, or substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, amino(C 1-3 )alkyl, N—(C 1-6 alkyl)amino(C 1-3 )alkyl, N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl may be the same or different, alkoxy(C 1-6 )alkyl, hydroxyl, hydroxy(C 1-6 )alkyl, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, heterocyclyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, N—(C 1-6 )alkylaminocarbonyl, N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, and aminosulfonyl; 
 R3 is H, C 1-6 alkoxy, or Cl; 
 where at least one of R1 and R3 is other than H; 
 R4 and R5, independently, are H, C 1-6 alkoxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, (C 1-6 alkyl)sulfonyl, aminosulfonyl, N—(C 1-6 alkyl)aminosulfonyl, N,N-di-(C 1-6 alkyl)aminosulfonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminosulfonyl may be the same or different, N—[(C 1-6 alkyl)sulfonyl]amino, N—[(C 1-6 alkyl)sulfonyl]-N—(C 1-6 alkyl)amino, where the alkyl groups of N—[(C 1-6 alkyl)sulfonyl]-N—(C 1-6 alkyl)amino may be the same or different, (C 1-6 alkyl) 2 phosphinyl, where the alkyl groups of (C 1-6 alkyl) 2 phosphinyl may be the same or different, or heteroaryl, where, when R4 or R5 is heteroaryl, such heteroaryl may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, hydroxy(C 1-3 )alkyl, C 1-6 alkoxy, C 1-6 alkoxy(C 1-3 )alkyl, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, (C 1-6 alkyl)sulfonyl, fluorine, carboxy, aminocarbonyl, N—(C 1-6 )alkylaminocarbonyl, and N,N-di-(C 1-6 )alkylaminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl may be the same or different, 
 and where, when R4 or R5 is N—(C 1-6 alkyl)aminocarbonyl or C 1-6 alkoxy, the alkyl groups of such N—(C 1-6 alkyl)aminocarbonyl or C 1-6 alkoxy may be unsubstituted, or substituted by one, two or three substituents independently selected from the group consisting of heterocyclyl, hydroxyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, cyano, carboxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, or 
 R4 and R5, together with the phenyl ring to which the are attached, form a five- to eight-membered monoheterocyclic ring, where the ring so-formed by R4 and R5 may be unsubstituted, or substituted with one or two substituents independently selected from the group consisting of C 1-6 alkyl, amino(C 1-3 )alkyl, N—(C 1-6 alkyl)amino(C 1-3 )alkyl, N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)amino(C 1-3 )alkyl may be the same or different, alkoxy(C 1-6 )alkyl, hydroxyl, hydroxy(C 1-6 )alkyl, (C 1-6 alkyl)sulfonyl, (C 1-6 alkyl)sulfonyl(C 1-3 )alkyl, heterocyclyl, amino, (C 1-6 )alkylamino, di-(C 1-6 )alkylamino, where the alkyl groups of di-(C 1-6 )alkylamino may be the same or different, carboxy, aminocarbonyl, N—(C 1-6 alkyl)aminocarbonyl, N,N-di-(C 1-6 alkyl)aminocarbonyl, where the alkyl groups of N,N-di-(C 1-6 alkyl)aminocarbonyl may be the same or different, aminocarbonyl(C 1-3 )alkyl, N—(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl, where the (C 1-6 )alkyl groups of N,N-di-(C 1-6 )alkylaminocarbonyl(C 1-3 )alkyl may be the same or different, and aminosulfonyl; and 
 —X— is —CH═CH—, —CH 2 CH 2 —, —NH—CO—, —CONH— or —(CH(OH)) 2 —; or 
 a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . The method according to  claim 4  wherein the proliferative disorder is cancer. 
     
     
         6 . The method according to  claim 4  wherein the proliferative disorder is selected from colon cancer, breast cancer, renal cancer, lung cancer, hemangioma, squamous cell myeloid leukemia, melanoma, glioblastoma, and astrocytoma.