Substituted alkylamine derivatives and methods of use

Abstract

Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like.

What is claimed is: 
     
         1 . A method of treating angiogenesis in a subject, said method comprising administering an effective amount of a compound as in any of Formula XI 
       
         
           
           
               
               
           
         
         wherein R is selected from
 a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and 
 b) unsubstituted or substituted 9- or 10-membered fused heteroaryl, 
 where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkylamino, optionally substituted heterocyclyl-C 1-6 -alkyl, C 1-6 -alkylamino-C 2-4 -alkynyl, C 1-6 -alkylamino-C 1-6 -alkoxy, C 1-6 -alkylamino-C 1-6 -alkoxy-C 1-6 -alkoxy, and optionally substituted heterocyclyl-C 2-4 -alkynyl; 
 
         wherein R 1  is a ring selected from unsubstituted or substituted
 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl, 
 9-10 membered saturated or partially un-saturated bicyclic heterocyclyl, and 
 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl, 
 
         wherein substituted R 1  is substituted with one or more substituents selected from halo, C 1-6 -alkyl, optionally substituted C 3-6 -cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C 1 -C 4 -alkylenyl, C 1-2 -haloalkoxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyclyl-C 1-4 -alkylcarbonyl, C 1-2 -haloalkyl, C 1-4 -aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C 1-2 -alkylsulfonyl, halosulfonyl, C 1-4 -alkylcarbonyl, C 1-3 -alkylamino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy-C 1-3 -alkoxy, C 1-4 -alkoxycarbonyl, C 1-4 -alkoxycarbonylamino-C 1-4 -alkyl, C 1-4 -hydroxyalkyl, 
       
       
         
           
           
               
               
           
         
          and C 1-4 -alkoxy; 
         wherein R 2  is one or more substituents independently selected from H, halo, hydroxy, amino, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-2 -alkylamino, aminosulfonyl, C 3-6 -cycloalkyl, cyano, C 1-2 -hydroxyalkyl, nitro, C 2-3 -alkenyl, C 2-3 -alkynyl, C 1-6 -haloalkoxy, C 1-6 -carboxyalkyl, 5-6-membered heterocyclyl-C 1-6 -alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 5-6 membered heterocyclyl; 
         wherein R 4  is selected from a direct bond, C 1-4 -alkyl, and 
       
       
         
           
           
               
               
           
         
         wherein R z  is selected from C 1-2 -alkyl, C 2-6 -branched alkyl, C 2-4 -branched haloalkyl, amino-C 1-4 -alkyl and C 1-2 -alkylamino-C 1-2 -alkyl; 
         wherein R e  and R f  are independently selected from H and C 1-2 -haloalkyl; and 
         wherein R 7  is selected from H, C 1-3 -alkyl, optionally substituted phenyl, optionally substituted phenyl-C 1-3 -alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C 1 -C 3 -alkyl, C 1-3 -alkoxy-C 1-2 -alkyl and C 1-3 -alkoxy-C 1-3 -alkoxy-C 1-3 -alkyl; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 . A method of treating KDR-related disorders in a mammal, said method comprising administering an effective amount of a compound of Formula XI 
       
         
           
           
               
               
           
         
         wherein R is selected from
 a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and 
 b) unsubstituted or substituted 9- or 10-membered fused heteroaryl, 
 where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkylamino, optionally substituted heterocyclyl-C 1-6 -alkyl, C 1-6 -alkylamino-C 2-4 -alkynyl, C 1-6 -alkylamino-C 1-6 -alkoxy, C 1-6 -alkylamino-C 1-6 -alkoxy-C 1-6 -alkoxy, and optionally substituted heterocyclyl-C 2-4 -alkynyl; 
 
         wherein R 1  is a ring selected from unsubstituted or substituted
 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl, 
 9-10 membered saturated or partially un-saturated bicyclic heterocyclyl, and 
 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl, 
 
         wherein substituted R 1  is substituted with one or more substituents selected from halo, C 1-6 -alkyl, optionally substituted C 3-6 -cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C 1 -C 4 -alkylenyl, C 1-2 -haloalkoxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyclyl-C 1-4 -alkylcarbonyl, C 1-2 -haloalkyl, C 1-4 -aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C 1-2 -alkylsulfonyl, halosulfonyl, C 1-4 -alkylcarbonyl, C 1-3 -alkylamino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy-C 1-3 -alkoxy, C 1-4 -alkoxycarbonyl, C 1-4 -alkoxycarbonylamino-C 1-4 -alkyl, C 1-4 -hydroxyalkyl, 
       
       
         
           
           
               
               
           
         
          and C 1-4 -alkoxy; 
         wherein R 2  is one or more substituents independently selected from H, halo, hydroxy, amino, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-2 -alkylamino, aminosulfonyl, C 3-6 -cycloalkyl, cyano, C 1-2 -hydroxyalkyl, nitro, C 2-3 -alkenyl, C 2-3 -alkynyl, C 1-6 -haloalkoxy, C 1-6 -carboxyalkyl, 5-6-membered heterocyclyl-C 1-6 -alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 5-6 membered heterocyclyl; 
         wherein R 4  is selected from a direct bond, C 1-4 -alkyl, and 
       
       
         
           
           
               
               
           
         
         wherein R z  is selected from C 1-2 -alkyl, C 2-6 -branched alkyl, C 2-4 -branched haloalkyl, amino-C 1-4 -alkyl and C 1-2 -alkylamino-C 1-2 -alkyl; 
         wherein R e  and R f  are independently selected from H and C 1-2 -haloalkyl; and 
         wherein R 7  is selected from H, C 1-3 -alkyl, optionally substituted phenyl, optionally substituted phenyl-C 1-3 -alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C 1 -C 3 -alkyl, C 1-3 -alkoxy-C 1-2 -alkyl and C 1-3 -alkoxy-C 1-3 -alkoxy-C 1-3 -alkyl; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . A method of treating proliferative disorders in a mammal, said method comprising administering an effective amount of a compound of Formula XI 
       
         
           
           
               
               
           
         
         wherein R is selected from
 a) unsubstituted or substituted 5- or 6-membered nitrogen-containing heteroaryl, and 
 b) unsubstituted or substituted 9- or 10-membered fused heteroaryl, 
 where substituted R is substituted with one or more substituents selected from halo, amino, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkoxy, optionally substituted heterocyclyl-C 1-6 -alkylamino, optionally substituted heterocyclyl-C 1-6 -alkyl, C 1-6 -alkylamino-C 2-4 -alkynyl, C 1-6 -alkylamino-C 1-6 -alkoxy, C 1-6 -alkylamino-C 1-6 -alkoxy-C 1-6 -alkoxy, and optionally substituted heterocyclyl-C 2-4 -alkynyl; 
 
         wherein R 1  is a ring selected from unsubstituted or substituted
 4-6 membered saturated or partially un-saturated monocyclic heterocyclyl, 
 9-10 membered saturated or partially un-saturated bicyclic heterocyclyl, and 
 13-14 membered saturated or partially un-saturated tricyclic heterocyclyl, 
 
         wherein substituted R 1  is substituted with one or more substituents selected from halo, C 1-6 -alkyl, optionally substituted C 3-6 -cycloalkyl, optionally substituted phenyl, optionally substituted phenyl-C 1 -C 4 -alkylenyl, C 1-2 -haloalkoxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 4 -alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 5-6 membered heterocyclyl-C 1-4 -alkylcarbonyl, C 1-2 -haloalkyl, C 1-4 -aminoalkyl, nitro, amino, hydroxy, oxo, cyano, aminosulfonyl, C 1-2 -alkylsulfonyl, halosulfonyl, C 1-4 -alkylcarbonyl, C 1-3 -alkylamino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkoxy, C 1-3 -alkylamino-C 1-3 -alkoxy-C 1-3 -alkoxy, C 1-4 -alkoxycarbonyl, C 1-4 -alkoxycarbonylamino-C 1-4 -alkyl, C 1-4 -hydroxyalkyl, 
       
       
         
           
           
               
               
           
         
          and C 1-4 -alkoxy; 
         wherein R 2  is one or more substituents independently selected from H, halo, hydroxy, amino, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-2 -alkylamino, aminosulfonyl, C 3-6 -cycloalkyl, cyano, C 1-2 -hydroxyalkyl, nitro, C 2-3 -alkenyl, C 2-3 -alkynyl, C 1-6 -haloalkoxy, C 1-6 -carboxyalkyl, 5-6-membered heterocyclyl-C 1-6 -alkylamino, unsubstituted or substituted phenyl and unsubstituted or substituted 5-6 membered heterocyclyl; 
         wherein R 4  is selected from a direct bond, C 1-4 -alkyl, and 
       
       
         
           
           
               
               
           
         
         wherein R z  is selected from C 1-2 -alkyl, C 2-6 -branched alkyl, C 2-4 -branched haloalkyl, amino-C 1-4 -alkyl and C 1-2 -alkylamino-C 1-2 -alkyl; 
         wherein R e  and R f  are independently selected from H and C 1-2 -haloalkyl; and 
         wherein R 7  is selected from H, C 1-3 -alkyl, optionally substituted phenyl, optionally substituted phenyl-C 1-3 -alkyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyl-C 1 -C 3 -alkyl, C 1-3 -alkoxy-C 1-2 -alkyl and C 1-3 -alkoxy-C 1-3 -alkoxy-C 1-3 -alkyl; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 1  wherein said compound is N-(3,3-dimethylindolin-6-yl) {2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide and pharmaceutically acceptable salts thereof. 
     
     
         5 . The method of  claim 1  comprising a combination with a compound selected from antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and miscellaneous agents.