Substituted arylamine derivatives and methods of use

Abstract

Selected 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. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

What is claimed is:  
     
         1 . Compound of Formula IV  
       
         
           
           
               
               
           
         
         wherein R 2  is selected from unsubstituted or substituted phenyl, and 9-10 membered bicyclic and 11-14 membered tricyclic unsaturated or partially unsaturated heterocyclyl,  
         wherein substituted R 2  is optionally 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 phenyloxy, optionally substituted 4-6 membered heterocyclyl-C 1 -C 6 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 2 -C 4 -alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted 4-6 membered heterocyclyloxy, optionally substituted 4-6 membered heterocyclyl-C 1-4 -alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally substituted 4-6 membered heterocyclylcarbonyl, optionally substituted 4-6 membered heterocyclyl-C 1-4 -alkylcarbonyl, optionally substituted 4-6 membered heterocyclylcarbonyl-C 1-4 -alkyl, optionally substituted 4-6 membered heterocyclyl-C 1-4 -alkylcarbonylamino, optionally substituted 4-6 membered heterocyclyl-oxycarbonylamino, C 1-2 -haloalkyl, C 1-4 -aminoalkyl, nitro, amino, C 1-3 -alkylsulfonylamino, hydroxy, cyano, aminosulfonyl, C 1-2 -alkylsulfonyl, halosulfonyl, C 1-4 -alkylcarbonyl, amino-C 1-4 -alkylcarbonyl, C 1-3 -alkylamino-C 1-4 -alkylcarbonyl, C 1-3 -alkylamino-C 1-4 -alkylcarbonylamino, C 1-4 -alkoxycarbonyl-C 1-4 -alkyl, 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 1-3 -alkylsulfonylamino-C 1-3 -alkoxy, C 1-4 -hydroxyalkyl,  
         
           
             
             
                 
                 
             
           
         
         and C 1-4 -alkoxy;  
         wherein R e  and R f  are independently selected from H and C 1-2 -haloalkyl;  
         wherein R g  is selected from H, C 1-3 -alkyl, optionally substituted phenyl-C 1-3 -alkyl, 4-6 membered heterocyclyl, and 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  
         wherein R 8  is one or more substituents independently selected from halo, amino, nitro, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 1-6 -aminoalkyl, C 1-6 -hydroxyalkyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl-C 1-6 -alkoxy, aminosulfonyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino, C 1-6 -alkylamino-C 1-6 -alkyl, 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;  
         and pharmaceutically acceptable isomers and derivatives thereof;  
         provided R 2  is not 3-trifluoromethylphenyl when R 8  is 4-hydroxy or 3-hydroxy.  
       
     
     
         2 . Compound of  claim 1  wherein R 2  is selected from phenyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1′,2′-dihydro-spiro[cyclopropane-1,3′-[3H]indol]-6′-yl, isoquinolyl, quinolyl, indolyl, isoindolyl, 2,3-dihydro-1H-indolyl, naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, dihydrobenzo[1,4]oxaxinyl, quinozalinyl, benzo[d]isothiazolyl, 3,4-dihydro-quinazolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, tetrahydroquinolinyl, indazolyl, 2,1,3-benzothiadiazolyl, benzodioxanyl, benzothienyl, benzofuryl, benzimidazolyl, dihydro-benzimidazolyl, benzoxazolyl and benzthiazolyl, where R 2  is unsubstituted or substituted with one or more substituents selected from bromo, chloro, fluoro, iodo, nitro, amino, cyano, Boc-aminoethyl, hydroxy, oxo, fluorosulfonyl, methylsulfonyl, aminosulfonyl, 4-methylpiperazinylsulfonyl, cyclohexyl, phenyl, phenylmethyl, 4-pyridylmethyl, 4-morpholinylmethyl, 1-methylpiperazin-4-ylmethyl, 1-methylpiperazin-4-ylpropyl, morpholinylpropyl, piperidin-1-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-methyl-2-(1-methylpiperidin-4-yl)ethyl, 2-methyl-2-(4-pyrimidinyl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, 2-methyl-2-(pyrazol-5-yl)ethyl, 2-methyl-2-(1-ethoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl, morpholinylethyl, 1-(4-morpholinyl)-2,2-dimethylpropyl, 1-(4-morpholinyl)-2,2-dimethylethyl, piperidin-4-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-1-ylethyl, 1-Boc-piperidin-4-ylethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-ylmethyl, piperidin-4-ylpropyl, 1-Boc-piperidin-4-ylpropyl, piperidin-1-ylpropyl, pyrrolidin-1-ylpropyl, pyrrolidin-2-ylpropyl, 1-Boc-pyrrolidin-2-ylpropyl, 1-(pyrrolidin-1-yl)-2-methylpropyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-ylmethyl, 1-Boc-pyrrolidin-2-ylmethyl, 2-methyl-2-(pyrrolidin-1-yl)ethyl, pyrrolidinylpropenyl, pyrrolidinylbutenyl, methylcarbonyl, Boc, piperidin-1-ylmethylcarbonyl, pyrrolidin-1-yl-carbonyl, pyrrolidin-2-yl-carbonyl, 4-pyridylcarbonyl, 4-methylpiperazin-1-ylcarbonylethyl, CH 3 O—C(═O) —CH 2 —, methoxycarbonyl, aminomethylcarbonyl, dimethylaminomethylcarbonyl, methylsulfonylamino, dimethylaminomethylcarbonylamino, 1-pyrrolidinyl-CH 2 —C(═O)—NH—, 4-morpholinyl-CH 2 —C(═O)—NH—, 3-tetrahydrofuryl-O—C(═O)—NH—, cyclohexyl-N(CH 3 )—, (4-pyrimidinyl)amino, (2-methylthio-4-pyrimidinyl)amino, 3-ethoxycarbonyl-2-methyl-fur-5-yl, 4-methylpiperazin-1-yl, 4-methyl-1-piperidyl, 1-Boc-4-piperidyl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-methyl-(1,2,3,6-tetrahydropyridyl), imidazolyl, morpholinyl, 4-trifluoromethyl-1-piperidinyl, hydroxybutyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, trifluoromethyl, pentafluoroethyl, nonafluorobutyl, dimethylaminopropyl, 1,1-di(trifluoromethyl)-1-hydroxymethyl, 1,1-di(trifluoromethyl)-1-(piperidinylethoxy)methyl, 1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl, 1,1-di(trifluoromethyl)-1-(methoxyethoxyethoxy)methyl, 1-hydroxyethyl, 2-hydroxyethyl, trifluoromethoxy, 1-aminoethyl, 2-aminoethyl, 1-(N-isopropylamino)ethyl, 2-(N-isopropylamino)ethyl, 3-tetrahydrofuryloxy, dimethylaminoethoxy, 4-chlorophenoxy, phenyloxy, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, 3-tetrahydrofurylmethoxy, pyrrolidin-2-ylmethoxy, 1-methylcarbonyl-pyrrolidin-2-ylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy, pyrrolidin-1-ylmethoxy, 1-methyl-pyrrolidin-2-ylmethoxy, 1-isopropyl-pyrrolidin-2-ylmethoxy, 1-Boc-piperdin-4-ylmethoxy, (1-pyrrolidinyl)ethoxy, piperdin-4-ylmethoxy, piperdin-3-ylmethoxy, 1-methylpiperdin-4-yloxy, methylsulfonylaminoethoxy, isopropoxy, methoxy and ethoxy; and pharmaceutically acceptable isomers and derivatives thereof.  
     
     
         3 . Compound of  claim 1  wherein R 8  is one or more substituents independently selected from chloro, fluoro, bromo, hydroxy, methoxy, ethoxy, —O—CH 2 —O—, trifluoromethoxy, 1-methylpiperidinylmethoxy, dimethylaminoethoxy, amino, dimethylamino, dimethylaminopropyl, diethylamino, aminosulfonyl, cyclohexyl, dimethylaminopropynyl, 3-(4-morpholinyl)propyn-1-yl, dimethylaminoethoxyethoxy, 3-(4-morpholinyl)propylamino, optionally substituted piperidinyl, morpholinyl, optionally substituted piperazinyl, optionally substituted phenyl, methyl, ethyl, propyl, cyano, hydroxymethyl, aminomethyl and trifluoromethyl; and pharmaceutically acceptable derivatives thereof.  
     
     
         4 . Compound of  claim 2  wherein R 2  is selected from 
 1,2,3,4-tetrahydro-isoquinolyl optionally substituted with one or more substituents selected from methyl, and Boc,  
 1,2,3,4-tetrahydro-quinolyl optionally substituted with one or more substituents selected from methyl, Boc and oxo,  
 2,3-dihydro-1H-indolyl optionally substituted with one or more substituents selected from methyl, methylsulfonyl, 1-Boc-piperidin-4-ylmethyl, piperidin-4-ylmethyl, 1-Boc-piperidin-4-yl, piperidin-4-yl, 1-methyl-piperidin-4-ylmethyl, 1-methyl-piperidin-4-yl, pyrrolidin-1-yl-carbonyl, dimethylaminomethylcarbonyl, aminomethylcarbonyl, methylcarbonyl, pyrrolidin-2-ylmethyl, and 1-Boc-pyrrolidin-2-ylmethyl, and  
 3,4-dihydro-2H-benzo[1,4]oxazinyl optionally substituted with one or more substituents selected from methyl, and methylcarbonyl; and pharmaceutically acceptable derivatives thereof.  
 
     
     
         5 . Compound of  claim 4  wherein R 2  is 3,3-dimethyl-2,3-dihydro-1H-indolyl optionally substituted with a substituent selected from pyrrolidin-1-yl-carbonyl, methylcarbonyl, and methylsulfonyl; and pharmaceutically acceptable derivatives thereof.  
     
     
         6 . Compound of  claim 4  wherein R 2  is 4,4-dimethyl-1,2,3,4-tetrahydro-1H-isoquinolinyl.  
     
     
         7 . Compound of  claim 3  wherein R 8  is one or more substituents independently selected from fluoro, hydroxy, amino, and nitro; and pharmaceutically acceptable derivatives thereof.  
     
     
         8 . Compound of  claim 3  wherein R 8  is 4-fluoro; and pharmaceutically acceptable derivatives thereof.  
     
     
         9 . Compound of  claim 1  wherein R 2  is selected from phenyl substituted with one or more substituents selected from chloro, tert-butyl, azetidin-3-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy, dimethylaminomethylcarbonylamino, 1,1-di(trifluoromethyl)-1-(pyrrolidin-2-ylmethoxy)methyl, trifluoromethyl, 2-methyl-2-(morpholin-4-yl)ethyl, 2-methyl-2-(pyrrolidin-1-yl)ethyl, 2-methyl-2-(5-methyloxadiazol-2-yl)ethyl, methylsulfonylamino, 1-methyl-pyrrolidin-2-ylmethoxy, and isopropyl; and pharmaceutically acceptable derivatives thereof.  
     
     
         10 . A compound and pharmaceutically acceptable salts thereof selected from: 
 N-(3,3-Dimethyl-1-(methylsulfonyl)-2,3-dihydro-1H-indol-6-yl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;    N-(4-(1,1-dimethylethyl)-3-((N,N-dimethylglycyl)amino)phenyl)-2-(((4-fluorophenyl)methyl)amino)-3-pyridinecarboxamide;    N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-2-((3-(1,3-oxazol-5-yl)phenyl)amino)-3-pyridinecarboxamide;    2-(((4-fluorophenyl)methyl)amino)-N-(3-((((2R)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;    2-(((4-fluorophenyl)methyl)amino)-N-(3-((methylsulfonyl)amino)-5-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;    2-((3-(1,3-oxazol-5-yl)phenyl)amino)-N-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;    2-(((4-fluorophenyl)methyl)amino)-N-(4-(1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)phenyl)-3-pyridinecarboxamide;    3-(2-Chloro-5-{[2-(4-fluoro-benzylamino)-pyridine-3-carbonyl]-amino}-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester;    N-[3-(Azetidin-3-ylmethoxy)-4-chloro-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide;    6-Chloro-3-(4-fluoro-benzylamino)-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide;    3-(4-Fluoro-benzylamino)-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide;    2-(4-Hydroxy-3-amino-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;    2-(4-Hydroxy-3-nitro-benzylamino)-N-(4-isopropyl-phenyl)-nicotinamide;    3-(4-Fluoro-benzylamino)-1,2,5,6-tetrahydro-pyridazine-4-carboxylic acid (4-tert-butyl-phenyl)-amide; and    N-[3-(Azetidin-3-ylmethoxy)-5-trifluoromethyl-phenyl]-2-(4-fluoro-benzylamino)-nicotinamide.    
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound as in any of claims  1 - 10 .  
     
     
         12 . A method of treating cancer in a subject, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         13 . The method of  claim 12  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.  
     
     
         14 . A method of treating angiogenesis in a subject, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         15 . A compound as in any of claims  1 - 10  for use in a method of therapeutic treatment for the human or animal body.  
     
     
         16 . A method of treating KDR-related disorders in a mammal, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         17 . A method of treating proliferation-related disorders in a mammal, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         18 . A method of reducing blood flow in a tumor in a subject, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         19 . A method of reducing tumor size in a subject, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .  
     
     
         20 . A method of treating diabetic retinopathy in a subject, said method comprising administering an effective amount of a compound as in any of claims  1 - 10 .