Tyrosine kinase inhibitors

Abstract

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises an indole-sulfonamide moiety. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.

1 . A compound of Formula I:  
     
       
         
         
             
             
         
       
       wherein:  
       R 1a  and R 1b  are independently selected from: 
 1) hydrogen,  
 2) unsubstituted or substituted C 1 -C 10  alkyl,  
 3) OR 3 ,  
 4) N(R 3 ) 2 ,  
 5) unsubstituted or substituted aryl,  
 6) unsubstituted or substituted heterocycle, and  
 7) unsubstituted or substituted C 3 -C 10  cycloalkyl;  
 
       R 1c  is independently selected from: 
 1) hydrogen,  
 2) C 1 -C 10  alkyl,  
 3) OR 3 ,  
 4) N(R 3 ) 2 ,  
 5) C 3 -C 10  cycloalkyl,  
 6) aryl, and  
 7) heterocycle;  
 
       said alkyl, cycloalkyl, aryl and heterocycle is optionally substituted with at least one substituent selected from R 7 ;  
       R 2  is independently selected from: 
 1) hydrogen,  
 2) unsubstituted or substituted C 1 -C 10  alkyl,  
 3) N(R 3 ) 2 ,  
 4) OR 3 ,  
 5) unsubstituted or substituted aryl, and  
 6) unsubstituted or substituted C 3 -C 10  cycloalkyl;  
 
       R 3  is independently selected from: 
 1) hydrogen,  
 2) C 1 -C 10  alkyl,  
 3) aryl,  
 4) heterocycle,  
 5) C 3 -C 10  cycloalkyl,  
 6) CF 3 ,  
 7) C 2 -C 6  alkenyl,  
 8) C 2 -C 6  alkynyl,  
 9) S(O) m R 6 , and  
 10) C(O)R 6 ;  
 
       said alkyl, cycloalkyl, aryl, heterocycle, alkynyl, and alkenyl is optionally substituted with at least one substituent selected from R 7 ;  
       R 5  is independently selected from: 
 1) hydrogen,  
 2) halogen,  
 3) —(CR 1c   2 ) n OR 3 ,  
 4) —(CR 1c   2 ) n R 6 ,  
 5) —C(O)OR 3 ,  
 6) —C(O)R 3 ,  
 7) —C≡CR 3 ,  
 8) —R 3 C═C(R 3 ) 2 ,  
 9) —OS(O) m R 6 ,  
 10) —NO 2 ,  
 11) —(CR 1c   2 ) n N(R 3 ) 2 ,  
 12) —N(R 3 )C(O)R 3 ,  
 13) —N(R 3 )S(O) m R 6 ,  
 14) —(CR 1c   2 ) n NR 3 (CR 1c   2 ) n C(O)NR 3   2 ,  
 15) —O(CR 1c   2 ) n C(O)N(R 3 ) 2 ,  
 16) —O(CR 1c   2 ) n C(O)OR 3 ,  
 17) —NR 3 (CR 1c   2 ) n N(R 3 ) 2 ,  
 18) —(CR 1c   2 ) n NR 3 R 6 OR 3 ,  
 19) —S(O) m R 6 ,  
 20) —S(O) m N(R 3 ) 2 ,  
 21) —CN,  
 22) —(CR 1c   2 ) n N(R 3 )(CR 1c   2 ) n R 6 , and  
 23) —(CR 1c   2 ) n C(O)N(R 3 ) 2 ;  
 
       R 6  is independently selected from: 
 1) C 1 -C 10  alkyl,  
 2) C 3 -C 10  cycloalkyl,  
 3) aryl, and  
 4) heterocycle;  
 
       said, alkyl, cycloalkyl, aryl and heterocycle is optionally substituted with at least one substituent selected from R 7 ;  
       R 7  is independently selected from: 
 1) hydrogen,  
 2) unsubstituted or substituted C 1 -C 10  alkyl,  
 3) unsubstituted or substituted C 3 -C 10  cycloalkyl,  
 4) unsubstituted or substituted aryl,  
 5) halogen,  
 6) OR 3 ,  
 7) CF 3 ,  
 8) unsubstituted or substituted heterocycle,  
 9) S(O) m N(R 3 ) 2 ,  
 10) C(O)OR 3 ,  
 11) C(O)R 3 ,  
 12) CN,  
 13) C(O)N(R 3 ) 2 ,  
 14) N(R 3 )C(O)R 3 ,  
 15) S(O) m R 6 , and  
 16) NO 2 ;  
 
       Y and Z are independently selected from: 
 1) hydrogen,  
 2) R 6 ,  
 3) OR 3 ,  
 4) N(R 3 ) 2 ,  
 5) C(O)OR 3 ,  
 6) C(O)N(R 3 ) 2 ,  
 7) C(O)R 3 ,  
 8) halogen,  
 9) N(R 3 )(CR 1c   2 ) n C(O)N(R 3 ) 2 ,  
 10) S(O) m N(R 3 ) 2 ,  
 11) N(R 3 )C(O)OR 3 ,  
 12) N(R 3 )S(O) m R 6 ,  
 13) N(R 3 )C(O)R 3 ,  
 14) N(R 3 )(CR 1c   2 ) n R 3 ,  
 15) S(O) m R 6 ,  
 16) R 6 S(O) m N(R 3 ) 2 ,  
 17) R 6 S(O) m R 6 ,  
 18) N(R 3 )S(O) m (CR 1c   2 ) n R 6 ,  
 19) N(R 3 )S(O) m R 6 OR 3 ,  
 20) N(R 3 )C(O)N(R 3 ) 2 ,  
 21) N(R 3 )C(O)R 6 OR 3 ,  
 22) N(R 3 )(CR 1c   2 ) n R 6 OR 3 ,  
 23) N(R 3 )OR 3 , and  
 24) N(R 3 )S(O) m R 6 NO 2 ;  
 
       m is independently 0, 1 or 2;  
       n is independently 0 to 6;  
       s is 0 to 6;  
       t is 0 to 6;  
       w is 0 to 4;  
       or a pharmaceutically acceptable salt or stereoisomer thereof.  
     
   
   
       2 . The compound according to  claim 1 , 
 wherein:    R 1a  and R 1b  are independently selected from: 
 1) hydrogen,  
 2) unsubstituted or substituted C 1 -C 10  alkyl,  
 3) unsubstituted or substituted aryl,  
 4) unsubstituted or substituted heterocycle, and  
 5) OR 3 ;  
   R 1c  is independently selected from: 
 1) hydrogen,  
 2) C 1 -C 10  alkyl,  
 3) OR 3 ,  
 4) N(R 3 ) 2 ,  
 5) aryl, and  
 6) heterocycle;  
   said alkyl, aryl and heterocycle is optionally substituted with at least one substituent selected from R 7 ;    R 2  is: 
 1) H,  
 2) unsubstituted or substituted alkyl,  
 3) OR 3 , or  
 4) N(R 3 ) 2 ;  
   R 3  is independently selected from: 
 1) hydrogen,  
 2) C 1 -C 10  alkyl,  
 3) aryl,  
 4) heterocycle,  
 5) C 3 -C 10  cycloalkyl,  
 6) CF 3 ,  
 7) S(O) m R 6 , and  
 8) C(O)R 6 ;  
   said alkyl, cycloalkyl, aryl and heterocycle is optionally substituted with at least one substituent selected from R 7 ;    R 5  is independently selected from: 
 1) hydrogen,  
 2) halogen,  
 3) —OR 3 ,  
 4) —C(O)OR 3 ,  
 5) —C(O)R 3 ,  
 6) —C≡CR 3 ,  
 7) —R 3 C═C(R 3 ) 2 ,  
 8) —OS(O) m R 6 ,  
 9) —NO 2 ,  
 10) —N(R 3 ) 2 ,  
 11) —N(R 3 )C(O)R 3 ,  
 12) —N(R 3 )S(O) m R 6 ,  
 13) —(CR 1c   2 ) n NR 3 (CR 1c   2 ) n C(O)NR 3   2 ,  
 14) —O(CR 1c   2 ) n C(O)N(R 3 ) 2 ,  
 15) —O(CR 1c   2 ) n C(O)OR 3 ,  
 16) —NR 3 (CR 1c   2 ) n N(R 3 ) 2 ,  
 17) —(CR 1c   2 ) n NR 3 R 6 OR 3 ,  
 18) —S(O) m R 6 ,  
 19) —S(O) m N(R 3 ) 2 ,  
 20) —CN, and  
 21) —(CR 1c   2 ) n N(R 3 )(CR 1c   2 ) n R 6 ;  
   or a pharmaceutically acceptable salt or stereoisomer thereof.    
   
   
       3 . The compound according to  claim 2 , 
 wherein:    R 1a  and R 1b  are independently selected from hydrogen, unsubstituted or substituted C 1 -C 10  alkyl, OR 3 , and unsubstituted or substituted aryl;    R 1c  is independently selected from: 
 1) hydrogen,  
 2) C 1 -C 10  alkyl,  
 3) OR 3 , and  
 4) aryl;  
   said alkyl and aryl is optionally substituted with at least one substituent selected from R 7 ;    R 2  is: 
 1) OR 3 , or  
 2) N(R 3 ) 2 ;  
   R 5  is independently selected from: 
 1) hydrogen,  
 2) (CR 1c   2 ) n R 6 ,  
 3) halogen,  
 4) —(CR 1c   2 ) n OR 3 ,  
 5) —C(O)OR 3 ,  
 6) —C(O)R 3 ,  
 7) —C≡CR 3 ,  
 8) —R 3 C═C(R 3 ) 2 ,  
 9) (CR 1c   2 ) n C(O)N(R 3 ) 2 , and  
 10) (CR 1c   2 ) n N(R 3 ) 2 ;  
   Y is: 
 1) hydrogen,  
 2) R 6 ,  
 3) OR 3 ,  
 4) C(O)R 3 ,  
 5) C(O)N(R 3 ) 2 , or  
 6) N(R 3 ) 2 ;  
   Z is: 
 1) hydrogen,  
 2) R 6 ,  
 3) OR 3 ,  
 4) N(R 3 ) 2 ,  
 5) C(O)OR 3 ,  
 6) C(O)N(R 3 ) 2 ,  
 7) C(O)R 3 ,  
 8) halogen,  
 9) N(R 3 )(CR 1c   2 ) n C(O)N(R 3 ) 2 ,  
 10) S(O) m N(R 3 ) 2 ,  
 11) N(R 3 )C(O)OR 3 ,  
 12) N(R 3 )S(O) m R 6 ,  
 13) N(R 3 )C(O)R 3 ,  
 14) N(R 3 )(CR 1c   2 ) n R 3 , or  
 15) S(O) m R 6 ;  
   n is independently 0 to 4;    or a pharmaceutically acceptable salt or stereoisomer thereof.    
   
   
       4 . A compound selected from: 
 5-Chloro-3-[(methylamino)sulfonyl]-1H-indole-2-carboxamide;    3-(Aminosulfonyl)-5-chloro-1H-indole-2-carboxamide;    5-Bromo-3-({methyl[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3yl)methyl]amino}sulfonyl)-1H-indole-2-carboxamide;    3-({[2-(Aminosulfonyl)ethyl]amino}sulfonyl)-5-iodo-1H-indole-2-carboxamide;    3-[(Dimethylamino)sulfonyl]-5-methoxy-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-phenethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-[(benzylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(cyclohexylamino)sulfonyl]-1H-indole-2-carboxamide    5-Chloro-3-[(1-naphthylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(3-phenylpropyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-[(ethylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(propylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(butylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(pentylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[ethyl(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-[(diethylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(iso-propylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(cyclobutylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(cyclopentylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(4-chlorophenyl)amino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(3-chlorophenyl)amino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-chlorophenyl)amino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(4-chlorophenyl)methylamino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(3-chlorophenyl)methylamino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-chlorophenyl)methylamino}sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(tert-butylamino)sulfonyl]-1H-indole-2-carboxamide;    (±)-5-Chloro-3-[(pyrrolidin-3-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(piperidin-4-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(1-methyl-1H-benzimidazol-2-yl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-[(benzamideamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(5-aminotetrazole)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(pyridin-4-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-[(pyridin-2-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-methyoxyethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-[(dimethylamino)sulfonyl]-1H-indole-2-carboxamide;    3-({[2-(Aminosulfonyl)ethyl]amino}sulfonyl)-5-chloro-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-hydroxyethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-morpholin-4-ylethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-methoxyethyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-[({[2-(2-acetamide)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    N-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}-N-methyl-β-alaninamide;    5-Bromo-3-[(methylamino)sulfonyl]-1H-indole-2-carboxamide;    Ethyl N-{[2-(aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}N-methyl-β-alaninate;    5-Bromo-3-{[cyclopropyl(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Bromo-3-{[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-({methyl[2-(1H-1,2,4-triazol-1-yl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-Bromo-3-{[methyl(tetrahydro-2H-pyran-4-yl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Bromo-3-{[(1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    3-({[4-(Aminosulfonyl)benzyl]amino}sulfonyl)-5-bromo-1H-indole-2-carboxamide;    5-Chloro-3-{[iso-propyl(2-methoxyethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    3-{[(2-Bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-hydroxy-1H-indole-2-carboxamide;    3-{[(2-Bromoethyl)(2-hydroxyethyl)amino]sulfonyl}-5-methoxy-1H-indole-2-carboxamide;    5-Chloro-3-{[methoxy(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Chloro-3-{[(2,3-dihydroxypropyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Chloro-3-{[(2-hydroxyethyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    N-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}-N-methylglycine;    N-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}-N-methylglycinamide;    5-Bromo-3-({[4-(methylsulfonyl)benzyl]amino}sulfonyl)-1H-indole-2-carboxamide;    3-[({2-[4-(Aminosulfonyl)phenyl]ethyl}amino)sulfonyl]-5-bromo-1H-indole-2-carboxamide;    3-{[(5-Amino-5-oxopentyl)amino]sulfonyl}-5-bromo-1H-indole-2-carboxamide;    3-({[2-(Aminosulfonyl)ethyl]amino}sulfonyl)-5-bromo-1H-indole-2-carboxamide;    tert-Butyl 2-({[2-(aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}amino)-ethylcarbamate;    3-{[(2-Aminoethyl)amino]sulfonyl}-5-bromo-1H-indole-2-carboxamide;    5-Bromo-3-[({ethylsulfonylamino}ethylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Iodo-3-{[(2-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1 H-indole-2-carboxamide;    5-Bromo-3-{[methoxy(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Fluoro-3-{[(2-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(4-nitrophenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-({[2-({[(4-methoxyphenyl)amino]carbonyl}amino)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-Bromo-3-[({3-[(4-chlorophenyl)thio]propyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[({3-[(4-chlorophenyl)thio]propyl}amino)sulfonyl]-1 H-indole-2-carboxamide;    5-Bromo-3-[({3-[(4-chlorophenyl)sulfonyl]propyl}amino)sulfonyl]-1 H-indole-2-carboxamide;    5-Bromo-3-[({propylsulfonylamino}ethylamino)sulfonyl]-1H-indole-2-carboxamide hydrochloride;    5-Bromo-3-{[(2-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(phenylsulfonyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(methylsulfonyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    3-[({2-[(Benzylsulfonyl)amino]ethyl}amino)sulfonyl]-5-bromo-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(3-methoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(2,5-dimethoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(5-bromo-2-methoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-({[2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]amino}sulfonyl)-1 H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(2-methoxy-5-methylphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(4-cyanophenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(4-chlorophenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(3,4-dimethoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-[({3-[(phenylsulfonyl)amino]propyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-{[(3-{[(4-methoxyphenyl)sulfonyl]amino}propyl)amino]sulfonyl}-1H-indole-2-carboxamide;    3-[({3-[(Benzylsulfonyl)amino]propyl}amino)sulfonyl]-5-bromo-1H-indole-2-carboxamide;    3-[({2-[(Aminocarbonyl)amino]ethyl}amino)sulfonyl]-5-bromo-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(4-bromophenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(thien-3-ylsulfonyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(3-chlorobenzyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-{[(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(4-methoxybenzoyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(4-methoxybenzyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(4-methoxyphenyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[({2-[(4-methoxyphenyl)(methylsulfonyl)amino]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    3-[({2-[Acetyl(4-methoxyphenyl)amino]ethyl}amino)sulfonyl]-5-bromo-1H-indole-2-carboxamide;    5-Iodo-3-{[cyclopropyl(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Iodo-3-[(cyclopropylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Bromo-3-[(cyclopropylamino)sulfonyl]-1H-indole-2-carboxamide;    5-Iodo-3-{[methoxy(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Chloro-3-{[(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Bromo-3-{[(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Iodo-3-{[(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Chloro-3-{[methyl(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Bromo-3-{[methyl(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    (±)-5-Iodo-3-{[methyl(tetrahydro-2H-pyran-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-Bromo-3-({[2-(tert-butylthio)ethyl]amino}sulfonyl)-1-H-indole-2-carboxamide;    5-chloro-3-{[methyl(tetrahydro-2H-pyran-4-yl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-chloro-3-({[1-(2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-[(tetrahydro-2H-pyran-4-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-chloro-3-{[(1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-chloro-3-({[(3-methyloxetan-3-yl)methyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-[(tetrahydrofuran-3-ylamino)sulfonyl]-1H-indole-2-carboxamide;    5-chloro-3-({[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-({[2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-({[2-(2-methoxyphenyl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-({[3-(trifluoromethyl)benzyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-({[2-(2,3-dihydro-1H-indol-1-yl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-({methyl[(1-methylpiperidin-3-yl)methyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-chloro-3-{[(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-{[(3-ethoxypropyl)amino]sulfonyl}-1H-indole-2-carboxamide;    3-[({[2-(aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}amino)methyl]-1-benzylpyrrolidine;    5-bromo3-({[(1-benzylpyrrolidin-3-yl)methyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-bromo-3-{[(3-pyridin-3-ylpropyl)amino]sulfonyl}-1H-indole-2-carboxamide;    1-[2-({[2-(aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}amino)ethyl]-4-phenylpiperidine;    5-bromo-3-{[(3-cyclohexylpropyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-{[(4,4-diphenylbutyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-{[(3-butoxypropyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-{[(6,7,8,9-tetrahydro-5H-benzo[a][7]annulen-7-ylmethyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-({[3-(3,5-dimethyl-1H-pyrazol-1-yl)propyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-bromo-3-({[3-(4-tert-butoxyphenyl)propyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-bromo-3-({[4-(4-tert-butoxyphenyl)butyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-bromo-3-{[(2-methoxy-1-methylethyl)amino]sulfonyl}-1 H-indole-2-carboxamide;    5-bromo-3-{[(4-phenylbutyl)amino]sulfonyl}-1H-indole-2-carboxamide;    5-bromo-3-[({2-[(2,6-dichlorobenzyl)thio]ethyl}amino)sulfonyl]-1H-indole-2-carboxamide;    5-bromo-3-({[2-(tert-butylthio)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide;    5-bromo-3-[({6-[(4-chlorobenzyl)amino]-6-oxohexyl}amino)sulfonyl]-1H-indole-2-carboxamide;    or a pharmaceutically acceptable salt or stereoisomer thereof.    
   
   
       5 . The compound according to  claim 4 , that is selected from: 
 5-Chloro-3-{[ethyl(methyl)amino]sulfonyl}-1H-indole-2-carboxamide                          (±)-5-Bromo-3-{[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}-1H-indole-2-carboxamide                          3-({[2-(Aminosulfonyl)ethyl]amino}sulfonyl)-5-bromo-1H-indole-2-carboxamide                          5-Bromo-3-{[(2-{[(4-methoxyphenyl)sulfonyl]amino}ethyl)amino]sulfonyl}-1H-indole-2-carboxamide                          5-bromo-3-{[(3-butoxypropyl)amino]sulfonyl}-1-H-indole-2-carboxamide                          5-bromo-3-({[3-(4-tert-butoxyphenyl)propyl]amino}sulfonyl)-1H-indole-2-carboxamide                          5-chloro-3-({[2-(3-phenyl-1H-1,2,4-triazol-5-yl)ethyl]amino}sulfonyl)-1H-indole-2-carboxamide                          or a pharmaceutically acceptable salt or stereoisomer thereof.    
   
   
       6 . A pharmaceutical composition which is comprised of a compound in accordance with  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       7 . A method of modulating the catalytic activity of protein kinases in a mammal in need thereof comprising contacting the protein kinase with a compound of  claim 1 .  
   
   
       8 . The method of  claim 7  wherein the protein kinase is an RTK.  
   
   
       9 . The method of  claim 8 , wherein the RTK is selected from IR, IGF-1R and IRR.  
   
   
       10 . A method of treating or preventing a PK-related disorder in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
   
   
       11 . A method of  claim 10 , wherein the PK-related disorder is an IGF-1R-related disorder selected from: 
 1) cancer,    2) diabetes,    3) an autoimmune disorder,    4) a hyperproliferation disorder,    5) aging,    6) acromegaly, and    7) Crohn's disease.    
   
   
       12 . A method of treating cancer in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
   
   
       13 . A method of treating retinal vascularization comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 1 .  
   
   
       14 . A method of treating cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  in combination with a second compound selected from: 
 1) an estrogen receptor modulator,    2) an androgen receptor modulator,    3) retinoid receptor modulator,    4) a cytotoxic agent,    5) an antiproliferative agent,    6) a prenyl-protein transferase inhibitor,    7) an HMG-CoA reductase inhibitor,    8) an HIV protease inhibitor,    9) a reverse transcriptase inhibitor, and    10) an angiogenesis inhibitor.    
   
   
       15 . The method of  claim 14 , wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.  
   
   
       16 . A method of treating cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  in combination with radiation therapy.  
   
   
       17 . The method of  claim 16  wherein radiation therapy is also administered.  
   
   
       18 . A method of treating cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  and paclitaxel or trastuzumab.  
   
   
       19 . A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of  claim 1  and a GPIIb/IIIa antagonist.  
   
   
       20 . (canceled)  
   
   
       21 . (canceled)  
   
   
       22 . A process for preparing an alkyl 5-iodo-1H-indole-2-carboxylate which comprises the steps of: 
 a) combining alkyl 1H-indole-2-carboxylate, iodine, sodium periodate and sulfuric acid in an alcohol, and heating to a temperature of about 50° C. to about 100° C. to obtain a product;    b) adding the product to a solution of organic solvent and aqueous solution to create a first biphasic mixture;    c) removing, drying, filtering and concentrating the organic layer;    d) dissolving the organic layer in an alcohol;    e) adding zinc and aqueous acid to produce a mixture;    f) combining the mixture with water to create a second biphasic mixture; and    g) extracting, drying and filtering the organic layer of the second biphasic mixture to obtain the alkyl 5-iodo-1H-indole-2-carboxylate.    
   
   
       23 . The process of  claim 22  wherein the alkyl 5-iodo-1H-indole-2-carboxylate is ethyl 5-iodo-1H-indole-2-carboxylate.