Certain chemical entities, compositions and methods

Abstract

Certain substituted urea derivatives selectively modulate the cardiac sarcomere, for example by potentiating cardiac myosin, and are useful in the treatment of systolic heart failure including congestive heart failure.

1 . A method of increasing extent but not velocity of cardiac contraction comprising administering at least one chemical entity chosen from compounds of Formula I  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein  
       W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;  
       n is one, two, or three;  
       R 1  is optionally substituted amino or optionally substituted heterocycloalkyl;  
       R 2  is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,  
       R 3  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3  is absent when W is —N═;  
       R 4  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4  is absent when Y is —N═;  
       R 5  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5  is absent when X is —N═;  
       R 13  is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13  is absent when Z is —N═;  
       R 6  and R 7  are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6  and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring; and  
       R 18  and R 19  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.  
     
   
   
       2 . A method of treating heart disease in a mammal comprising administering to a mammal in need thereof, in an amount effective for increasing extent but not velocity of cardiac contraction, at least one chemical entity chosen from compounds of Formula I  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein  
       W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;  
       n is one, two, or three;  
       R 1  is optionally substituted amino or optionally substituted heterocycloalkyl;  
       R 2  is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,  
       R 3  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3  is absent when W is —N═;  
       R 4  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4  is absent when Y is —N═;  
       R 5  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5  is absent when X is —N═;  
       R 13  is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13  is absent when Z is —N═;  
       R 6  and R 7  are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6  and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring; and  
       R 18  and R 19  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.  
     
   
   
       3 . A method of increasing extent of contraction but not ±dP/dt comprising administering at least one chemical entity chosen from compounds of Formula I  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein  
       W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;  
       n is one, two, or three;  
       R 1  is optionally substituted amino or optionally substituted heterocycloalkyl;  
       R 2  is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,  
       R 3  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3  is absent when W is —N═;  
       R 4  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4  is absent when Y is —N═;  
       R 5  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5  is absent when X is —N═;  
       R 13  is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13  is absent when Z is —N═;  
       R 6  and R 7  are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6  and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring; and  
       R 18  and R 19  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.  
     
   
   
       4 . A method of treating heart disease in a mammal comprising administering to a mammal in need thereof, in an amount effective for increasing extent of contraction but not ±dP/dt, at least one chemical entity chosen from compounds of Formula I  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein  
       W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;  
       n is one, two, or three;  
       R 1  is optionally substituted amino or optionally substituted heterocycloalkyl;  
       R 2  is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,  
       R 3  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3  is absent when W is —N═;  
       R 4  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is C═, and R 4  is absent when Y is —N═;  
       R 5  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5  is absent when X is —N═;  
       R 13  is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13  is absent when Z is —N═;  
       R 6  and R 7  are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6  and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring; and  
       R 18  and R 19  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.  
     
   
   
       5 . The method of  claim 2  wherein the heart disease is heart failure.  
   
   
       6 . The method of  claim 5  wherein the heart failure is congestive heart failure  
   
   
       7 . The method of  claim 6  wherein the heart failure is systolic heart failure.  
   
   
       8 . At least one chemical entity chosen from 
 N-(3-{[4-(azetidinylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)(4-pyridylamino)carboxamide;    N-(2-fluoro-3-{[4-(methylsulfonyl)piperazinyl]methyl}phenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-(ethylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    methyl 4-[(2-fluoro-3-{[(2-methyl(4-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-[2-fluoro-3-({4-[(methylethyl)sulfonyl]piperazinyl}methyl)phenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(propylsulfonyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[4-(cyclopropylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[(2-chloro-5-{[4-(methylsulfonyl)piperazinyl]methyl}phenyl)methyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-[(2-chloro-5-{[4-(ethylsulfonyl)piperazinyl]methyl}phenyl)methyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[4-(azetidinylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-(azetidinylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)(4-pyridylamino)carboxamide;    N-[2-fluoro-3-({4-[(methylethyl)sulfonyl]piperazinyl}methyl)phenyl][(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-(cyclopropylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    methyl 4-{[2-fluoro-3-({[6-(hydroxyethyl)(3-pyridyl)]amino}carbonylamino)phenyl]methyl}piperazinecarboxylate;    methyl 4-{[2-fluoro-3-({[6-(methoxyethyl)(3-pyridyl)]amino}carbonylamino)phenyl]methyl}piperazinecarboxylate;    methyl 4-[(2-fluoro-3-{[(6-vinyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-methoxyethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-(2-fluoro-3-{[4-(2-methoxyacetyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[(4-cyanopiperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl}-2-oxoethyl acetate;    N-(3-{[4-((1Z)-1-azetidinyl-2-cyano-2-azavinyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl 4-{[2-fluoro-3-({[6-(1-hydroxy-isopropyl)(3-pyridyl)]amino}carbonylamino)phenyl]methyl}piperazinecarboxylate;    methyl 4-({2-fluoro-3-[(pyrimidin-4-ylamino)carbonylamino]phenyl}methyl)piperazinecarboxylate;    N-(3-{[4-(ethylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)(pyrimidin-4-ylamino)carboxamide;    N-(2-fluoro-3-{[4-(methylsulfonyl)piperazinyl]methyl}phenyl)(pyrimidin-4-ylamino)carboxamide;    N-(3-{[4-(azetidinylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(2-hydroxyacetyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(morpholin-4-ylcarbonyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[2-fluoro-3-({4-[(4-methylpiperazinyl)carbonyl]piperazinyl}methyl)phenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(morpholin-4-ylcarbonyl)piperazinyl]methyl}phenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-[2-fluoro-3-({4-[(4-methylpiperazinyl)carbonyl]piperazinyl}methyl)phenyl][(2-methyl(4-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(2-methoxyacetyl)piperazinyl]methyl}phenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    2-methoxyethyl 4-[(2-fluoro-3-{[(2-methyl(4-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-{4-[(2-fluoro-3-{[N-(6-methyl(3-pyridyl))carbamoyl]amino}phenyl)methyl]piperazinyl}-2-oxoethyl 2,2-dimethylpropanoate;    2-hydroxyethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    2-methoxyethyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    N-(3-{[(3S)-4-(ethylsulfonyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    ethyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    N-(2-fluoro-3-{[4-(2-hydroxyacetyl)piperazinyl]methyl}phenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-((1E)-2-cyano-1-morpholin-4-yl-2-azavinyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-[3-({4-[(1Z)-2-cyano-1-(4-methylpiperazinyl)-2-azavinyl]piperazinyl}methyl)-2-fluorophenyl][(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-((1Z)-1-azetidinyl-2-cyano-2-azavinyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(morpholin-4-ylsulfonyl)piperazinyl]methyl}phenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-(3-{[4-((1E)-2-cyano-1-morpholin-4-yl-2-azavinyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[3-({4-[(1Z)-2-cyano-1-(4-methylpiperazinyl)-2-azavinyl]piperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(morpholin-4-ylsulfonyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl 4-[1-(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)-isopropyl]piperazinecarboxylate;    methyl 2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetate;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}ethyl acetate;    N-[2-fluoro-3-({4-[(7-methoxy-2-oxochromen-3-yl)carbonyl]piperazinyl}methyl)phenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-{2-fluoro-3-[(4-{[2-(methylamino)phenyl]carbonyl}piperazinyl)methyl]phenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-(2-fluoro-3-{[4-(2-oxo-2-phenylacetyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}ethyl propanoate;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}ethyl 2-methylpropanoate;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}ethyl 2,2-dimethylpropanoate;    ethyl 2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetate;    2-methylpropyl 2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetate;    2-methoxy-1-(methoxymethyl)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-hydroxyethyl 4-[(2-fluoro-3-{[(2-methyl(4-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-(3-{[4-((1Z)-2-cyano-1-pyrrolidinyl-2-azavinyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    2-(dimethylamino)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    tert-butyl 2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetate;    2H-3,4,5,6-tetrahydropyran-4-yl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methylethyl 2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetate;    3-methoxypropyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-(3-{[(3R)-4-(ethylsulfonyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    ethyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    2-methoxyethyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    N-(3-{(1S)-1-[4-(methylsulfonyl)piperazinyl]ethyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{(1S)-1-[4-(ethylsulfonyl)piperazinyl]ethyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl)-2-oxoethyl 2-methylpropanoate;    2-(methoxy-N-methylcarbonylamino)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-[N-methyl(methylethoxy)carbonylamino]ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-(N-methylacetylamino)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-(N-methylpropanoylamino)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    2-(2,N-dimethylpropanoylamino)ethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-(3-{[(3R)-4-(azetidinylsulfonyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[3-(((3R)-4-[(dimethylamino)sulfonyl]-3-methylpiperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-4-(cyclopropylsulfonyl)-3-methylpiperazinyl]methyl)-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxycarbonyl)piperazinecarboxylate;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxycarbonyl)piperazinecarboxylate;    N-{2-fluoro-3-[(4-{[3-(phenylcarbonyl)phenyl]carbonyl}piperazinyl)methyl]phenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-{2-fluoro-3-[(4-{[4-(phenylcarbonyl)phenyl]carbonyl}piperazinyl)methyl]phenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    methyl 4-[(1R)-1-(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)ethyl]piperazinecarboxylate;    N-(3-{(1R)-1-[4-(methylsulfonyl)piperazinyl]ethyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{(1R)-1-[4-(ethylsulfonyl)piperazinyl]ethyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[(1R)-1-(4-acetylpiperazinyl)ethyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinylcarbonyloxy}acetic acid;    N-[2-fluoro-3-({4-[N-(2-methoxyethyl)-N-methylcarbamoyl]piperazinyl}methyl)phenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-3-methyl-4-(methylsulfonyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-(methylsulfonyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl 4-{[2-fluoro-3-({[6-(methoxymethyl)(3-pyridyl)]amino}carbonylamino)phenyl]methyl}piperazinecarboxylate;    ethyl 4-[(1R)-1-(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)ethyl]piperazinecarboxylate;    N-(3-{[4-(ethylsulfonyl)piperazinyl]methyl)-2-fluorophenyl){[6-(methoxymethyl)(3-pyridyl)]amino}carboxamide;    N-{3-[(4-{N-[2-(dimethylamino)ethyl]-N-methylcarbamoyl}piperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-2-(azetidinylcarbonyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-[2-({4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl}-N-methylcarbonylamino)ethyl]methoxy-N-methylcarboxamide;    N-[2-({4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl}-N-methylcarbonylamino)ethyl]-N-methylacetamide;    (2R)-2-methoxy-2-phenylethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    (2S)-2-methoxy-2-phenylethyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    (1S)-2-methoxy-isopropyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    (2S)-2-methoxypropyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-[2-((4-[(4-acetylpiperazinyl)carbonyl]piperazinyl}methyl)benzoxazol-4-yl][(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-[(methylethyl)oxycarbonyl]piperazinecarboxylate;    N-(3-{(1S)-1-[4-(N,N-dimethylcarbamoyl)piperazinyl]ethyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[3-((1S)-1-{4-[(dimethylamino)sulfonyl]piperazinyl}ethyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-benzylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-1-(ethylsulfonyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    methyl (2S)-4-[(2-fluoro-3-([(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-1-(methylsulfonyl)piperazine-2-carboxylate;    methyl (2S)-1-acetyl-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    3-methoxy-2-(methoxymethyl)propyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methylethyl (2S)-1-(N,N-dimethylcarbamoyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    N-(3-{[(3R)-4-(N,N-dimethylcarbamoyl)-3-(N-methylcarbamoyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(N,N-dimethylcarbamoyl)-3-(N-methylcarbamoyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-[(methylethyl)oxycarbonyl]piperazinecarboxylate;    methyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(N-methylcarbamoyl)piperazinecarboxylate;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(N-methylcarbamoyl)piperazinecarboxylate;    N-{3-[((3R)-4-acetyl-3-methylpiperazinyl)methyl]-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    {(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N,N-dimethylcarboxamide;    N-{3-[((3S)-4-acetyl-3-methylpiperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    {(2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N,N-dimethylcarboxamide;    N-[3-({(3S)-4-[(dimethylamino)sulfonyl]-3-methylpiperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    (N,N-dimethylcarbamoyl)methyl 4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methyl (2S)-2-(ethoxycarbonyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    ethyl (2S)-1-[(dimethylamino)sulfonyl]-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    ethyl (2S)-1-(N,N-dimethylcarbamoyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    ethyl (2S)-1-(ethylsulfonyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    ethyl (2S)-2-(ethoxycarbonyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    N-(3-([4-(N,N-dimethylcarbamoyl)piperazinyl]methyl}-2-fluorophenyl)[(2-methyl(4-pyridyl))amino]carboxamide;    N-[3-({4-[(dimethylamino)sulfonyl]piperazinyl}methyl)-2-fluorophenyl][(2-methyl(4-pyridyl))amino]carboxamide;    methyl 4-[(2-fluoro-3-{[(2-fluoro-3-{[4-(methoxycarbonyl)piperazinyl]methyl}phenyl)amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    ethyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-1-(methylsulfonyl)piperazine-2-carboxylate;    (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-1-(methoxycarbonyl)piperazine-2-carboxylic acid;    tert-butyl (2S)-2-(N,N-dimethylcarbamoyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinecarboxylate;    N-(3-{[(3S)-3-(N,N-dimethylcarbamoyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-2-(N,N-dimethylcarbamoyl)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    methyl 2-{(2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxycarbonyl)piperazinyl}acetate;    N-(2-fluoro-3-{[4-benzylpiperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-1-[(dimethylamino)sulfonyl]-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazine-2-carboxylate;    N-(2-fluoro-3-{[4-(2,2,2-trifluoroethyl)piperazinyl]methyl}phenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{2-fluoro-3-[(4-methylpiperazinyl)methyl]phenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    2-{4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl}-N,N-dimethylacetamide;    {(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N-methylcarboxamide;    {(2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N-methylcarboxamide;    N-{3-[((3S)-3-methyl-4-sulfamoylpiperazinyl)methyl]-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[((3R)-3-methyl-4-sulfamoylpiperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[((1R)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    tert-butyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinecarboxylate;    N-(3-{[(3S)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-[3-({(3S)-4-[(dimethylamino)sulfonyl]-3-(methoxymethyl)piperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    {(2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinyl}-N,N-dimethylcarboxamide;    (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxamide;    (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxamide;    2-{(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N,N-dimethylacetamide;    N-{3-[((3R)-3-methylpiperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[((3S)-3-methylpiperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-[2-fluoro-3-({4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinyl}methyl)phenyl][(6-methyl(3-pyridyl))amino]carboxamide;    methyl 4-[(2-fluoro-3-{[(2-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]piperazinecarboxylate;    tert-butyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinecarboxylate;    N-[3-({(3R)-3-methyl-4-[(methylamino)sulfonyl]piperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-acetyl-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[((1S)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-(2,2,2-trifluoroethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-([(3R)-4-(2-methoxyethyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-4-(azetidinylcarbonyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinecarboxylat;    N-[3-({(3S)-3-methyl-4-[(methylamino)sulfonyl]piperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(azetidinylcarbonyl)-3-methylpiperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(ethylsulfonyl)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    ethyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(methoxymethyl)piperazinecarboxylate;    N-[3-({(3R)-4-[(dimethylamino)sulfonyl]-3-(methoxymethyl)piperazinyl}methyl)-2-fluorophenyl][(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-(methoxymethyl)-4-(methylsulfonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(azetidinylcarbonyl)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(azetidinylsulfonyl)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3S)-4-(cyclopropylsulfonyl)-3-(methoxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[((1S)-9,9-dimethyl-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(hydroxymethyl)piperazinecarboxylate;    ethyl (2S)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-(hydroxymethyl)piperazinecarboxylate;    N-(3-{[(3S)-4-(ethylsulfonyl)-3-(hydroxymethyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-(pyrrolidinylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-(piperidylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    N-(3-{[(3R)-3-methyl-4-(morpholin-4-ylcarbonyl)piperazinyl]methyl}-2-fluorophenyl)[(6-methyl(3-pyridyl))amino]carboxamide;    4-({(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}carbonylamino)butanoic acid;    3-({(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}carbonylamino)propanoic acid;    {(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N-(3-hydroxypropyl)carboxamide;    {(2R)-4-[(2-fluoro-3-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinyl}-N-(4-hydroxybutyl)carboxamide;    N-{3-[((1R)-9,9-dimethyl-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[(4-{[7-(diethylamino)-2-oxochromen-3-yl]carbonyl}piperazinyl)methyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    methyl (2R)-4-({2-fluoro-3-[(3-pyridylamino)carbonylamino]phenyl}methyl)-2-methylpiperazinecarboxylate;    methyl (2R)-4-[(2-fluoro-3-{[(2-methyl(4-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    methyl (2R)-4-[(3-fluoro-5-{[(6-methyl(3-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    methyl (2R)-4-({3-fluoro-5-[(3-pyridylamino)carbonylamino]phenyl}methyl)-2-methylpiperazinecarboxylate;    methyl (2R)-4-[(3-fluoro-5-{[(2-methyl(4-pyridyl))amino]carbonylamino}phenyl)methyl]-2-methylpiperazinecarboxylate;    [(4-chlorophenyl)amino]-N-{2-fluoro-3-[(4-{[3-(phenylcarbonyl)phenyl]carbonyl}piperazinyl)methyl]phenyl}carboxamide;    [(6-chloro(3-pyridyl))amino]-N-{2-fluoro-3-[(4-{[3-(phenylcarbonyl)phenyl]carbonyl}piperazinyl)methyl]phenyl}carboxamide;    N-{3-[(1S)-1-((1S)-9,9-dimethyl-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)ethyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide;    N-{3-[(1R)-1-((1S)-9,9-dimethyl-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)ethyl]-2-fluorophenyl}[(6-methyl(3-pyridyl))amino]carboxamide,    Methyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate;    1-(3-((4-(Ethylsulfonyl)piperazin-1-yl)methyl)-2-fluorophenyl)-3-(2-methylpyridin-4-yl)urea;    Methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate;    Tetrahydro-2H-pyran-4-yl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate;    (R)-1-(3-((4-(Azetidine-1-carbonyl)-3-methylpiperazin-1-yl)methyl)-2-fluorophenyl)-3-(6-methylpyridin-3-yl)urea; and    (R)-Methyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)-2-methylpiperazine-1-carboxylate;    and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.    
   
   
       9 . At least one chemical entity chosen from compounds of Formula I  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein  
       W, X, Y, and Z are independently —C═ or —N═, provided that no more than two of W, X, Y, and Z are —N═;  
       n is one, two, or three;  
       R 1  is optionally substituted amino or optionally substituted heterocycloalkyl;  
       R 2  is optionally substituted aryl, optionally substituted aralkyl; optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl or optionally substituted heterocycloalkyl,  
       R 3  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when W is —C═, and R 3  is absent when W is —N═;  
       R 4  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Y is —C═, and R 4  is absent when Y is —N═; and  
       R 5  is hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when X is —C═, and R 5  is absent when X is —N═;  
       R 13  is hydrogen, halo, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl when Z is —C═, and R 13  is absent when Z is —N═;  
       R 6  and R 7  are independently hydrogen, aminocarbonyl, alkoxycarbonyl, optionally substituted alkyl or optionally substituted alkoxy, or R 6  and R 7 , taken together with the carbon to which they are attached, form an optionally substituted 3- to 7-membered ring which optionally incorporates one or two additional heteroatoms, selected from N, O, and S in the ring; and  
       R 18  and R 19  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, provided that  
       at least one of R 18  and R 19  is not hydrogen.  
     
   
   
       10 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one chemical entity of  claim 8 .  
   
   
       11 . A pharmaceutical composition of  claim 10  wherein the composition is formulated in a form chosen from injectable fluids, aerosols, tablets, pills, capsules, syrups, creams, gels, and transdermal patches.  
   
   
       12 . A packaged pharmaceutical composition, comprising a pharmaceutical composition of  claim 10  and instructions for using the composition to treat a patient suffering from a heart disease.  
   
   
       13 . The packaged pharmaceutical composition of  claim 2  wherein the heart disease is heart failure.  
   
   
       14 . A method of treating heart disease in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity of  claim 8  or a pharmaceutical composition thereof.  
   
   
       15 . The method of  claim 14  wherein the therapeutically effective amount is an amount effective for increasing extent but not velocity of cardiac contraction.  
   
   
       16 . The method of  claim 14  wherein the therapeutically effective amount is an amount effective for increasing extent of contraction but not ±dP/dt.  
   
   
       17 . The method of  claim 14  wherein the heart disease is heart failure.  
   
   
       18 . The method of  claim 17  wherein the heart failure is congestive heart failure  
   
   
       19 . The method of  claim 17  wherein the heart failure is systolic heart failure.  
   
   
       20 - 21 . (canceled)  
   
   
       22 . A method for modulating the cardiac sarcomere in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity of  claim 8  or  9  or a pharmaceutical composition thereof.  
   
   
       23 . A method for potentiating cardiac myosin in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity of  claim 8  or  9 .  
   
   
       24 - 27 . (canceled)  
   
   
       28 . A packaged pharmaceutical composition, comprising a pharmaceutical composition of  claim 11  and instructions for using the composition to treat a patient suffering from a heart disease.  
   
   
       29 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or adjuvant and at least one chemical entity of  claim 9 .  
   
   
       30 . A pharmaceutical composition of  claim 29  wherein the composition is formulated in a form chosen from injectable fluids, aerosols, tablets, pills, capsules, syrups, creams, gels, and transdermal patches.  
   
   
       31 . A packaged pharmaceutical composition, comprising a pharmaceutical composition of  claim 29  and instructions for using the composition to treat a patient suffering from a heart disease.  
   
   
       32 . A packaged pharmaceutical composition, comprising a pharmaceutical composition of  claim 30  and instructions for using the composition to treat a patient suffering from a heart disease.  
   
   
       33 . A method of treating heart disease in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity of  claim 9  or a pharmaceutical composition thereof.  
   
   
       34 . The method of  claim 33  wherein the therapeutically effective amount is an amount effective for increasing extent but not velocity of cardiac contraction.  
   
   
       35 . The method of  claim 33  wherein the therapeutically effective amount is an amount effective for increasing extent of contraction but not ±dP/dt.  
   
   
       36 . The method of  claim 33  wherein the heart disease is heart failure.  
   
   
       37 . The method of  claim 36  wherein the heart failure is congestive heart failure  
   
   
       38 . The method of  claim 36  wherein the heart failure is systolic heart failure.  
   
   
       39 . The method of  claim 4  wherein the heart disease is heart failure.  
   
   
       40 . The method of  claim 39  wherein the heart failure is congestive heart failure  
   
   
       41 . The method of  claim 40  wherein the heart failure is systolic heart failure.