Certain chemical entities, compositions and methods

Abstract

Provided are certain chemical entities, and methods of use to modulate skeletal myosin, skeletal actin, skeletal tropomyosin, skeletal troponin C, skeletal troponin I, skeletal troponin T, and skeletal muscle, including fragments and isoforms thereof, as well as the skeletal sarcomere, and methods of use in the treatment of neuromuscular disorders, conditions having muscle wasting, claudication, frailty, metabolic syndrome, muscle atrophy associated with disuse, and muscle fatigue, and other indications.

1 . At least one chemical entity selected from compounds of Formula I: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and tautomers thereof, wherein
 R 3  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl; 
 R 4  is optionally substituted aryl; 
 R 5  is selected from hydrogen, halo, hydroxy, optionally substituted alkyl, optionally substituted amino, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, sulfanyl, and sulfinyl; and 
 R 6  is selected from hydrogen, halo, hydroxy, lower alkyl, and lower haloalkyl. 
 
     
     
         2 . At least one chemical entity of  claim 1  wherein R 4  is optionally substituted phenyl. 
     
     
         3 . (canceled) 
     
     
         4 . At least one chemical entity of  claim 1  wherein R 4  is phenyl,
 optionally substituted with one or two groups independently chosen from optionally substituted lower alkyl, halo, cyano, sulfonyl, 
 optionally substituted lower alkoxy, aminocarbonyl, optionally substituted amino, alkoxycarbonyl, and acyl. 
 
     
     
         5 - 7 . (canceled) 
     
     
         8 . At least one chemical entity of  claim 1  wherein the compound of Formula I is chosen from compounds of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein
 R 8  and R 12  are independently selected from hydrogen, halo, optionally substituted lower alkyl, cyano, and acyl; 
 R 9  and R 11  are independently selected from hydrogen, halo, acyl, lower alkoxy, cyano, lower alkoxy carbonyl, and optionally substituted lower alkyl; and 
 R 10  is selected from hydrogen, halo, hydroxy, cyano, optionally substituted lower alkyl, sulfonyl, aminocarbonyl, and optionally substituted lower alkoxy. 
 
     
     
         9 . (canceled) 
     
     
         10 . At least one chemical entity of  claim 8  wherein R 10  is selected from hydrogen, halo, methoxy, trifluoromethoxy, trifluoromethyl, methyl, and cyano. 
     
     
         11 . At least one chemical entity of  claim 10  wherein R 10  is selected from hydrogen, chloro, and fluoro. 
     
     
         12 . At least one chemical entity of  claim 8  wherein R 11  is hydrogen. 
     
     
         13 . At least one chemical entity of  claim 8  wherein R 9  is selected from hydrogen, lower alkyl, and halo. 
     
     
         14 . (canceled) 
     
     
         15 . At least one chemical entity of  claim 13  wherein R 9  is selected from fluoro and hydrogen. 
     
     
         16 . At least one chemical entity of  claim 8  wherein R 12  is hydrogen. 
     
     
         17 . (canceled) 
     
     
         18 . At least one chemical entity of  claim 8  wherein R 8  is selected from hydrogen, fluoro, chloro, trifluoromethyl, methoxy, methyl, and cyano. 
     
     
         19 . At least one chemical entity of  claim 18  wherein R 8  is selected from hydrogen and fluoro. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . At least one chemical entity of  claim 1  wherein R 6  is hydrogen. 
     
     
         23 . (canceled) 
     
     
         24 . At least one chemical entity of  claim 1  wherein R 5  is selected from hydrogen, halo, and optionally substituted alkynyl. 
     
     
         25 . (canceled) 
     
     
         26 . At least one chemical entity of  claim 24  wherein R 5  is chloro. 
     
     
         27 . (canceled) 
     
     
         28 . At least one chemical entity of  claim 1  wherein R 3  is lower alkyl optionally substituted with one or more groups chosen from optionally substituted phenyl, hydroxy, optionally substituted alkoxy, optionally substituted amino, optionally substituted heteroaryl, halo, and optionally substituted heterocycloalkyl. 
     
     
         29 . At least one chemical entity of  claim 28  wherein R 3  is selected from alkenyl, pentyl, cyclopropyl, butyl, propyl, ethyl, and methyl, each of which is optionally substituted with one or more groups chosen from optionally substituted phenyl, hydroxy, optionally substituted alkoxy, optionally substituted amino, and optionally substituted heterocycloalkyl. 
     
     
         30 . At least one chemical entity of  claim 29  wherein R 3  is selected from 3-pentyl, isopropyl, tert-butyl, 1-ethyl-2-hydroxyethyl, 1-ethyl-2-hydroxyethyl, 1-methyl-2-hydroxethyl, 1-methyl-2-hydroxethyl, 1-methyl-2-hydroxyethyl, 1-ethyl-3-hydroxypropyl, 1-hydroxymethylpropyl, 3-hydroxypropyl, 2-hydroxyethyl, isopropyl, 1-hydroxymethyl-3-methylbutyl, 1-(methoxymethyl)propyl, 1-ethyl-2-hydroxy-2-methylpropyl, 2-hydroxy-tert-buyl, 1-ethyl-2-hydroxy-2-methylpropyl, and 2-hydroxy-1-(2-methylpropyl)ethyl. 
     
     
         31 . At least one chemical entity of  claim 30  wherein R 3  is selected from 3-pentyl, isopropyl, 1-ethyl-2-hydroxyethyl, 1-methyl-2-hydroxethyl, tert-butyl, 1-ethyl-3-hydroxypropyl, 1-hydroxymethyl-3-methylbutyl, 1-(methoxymethyl)propyl, 1-ethyl-2-hydroxy-2-methylpropyl, 2-hydroxy-tert-buyl, and (S)-1-hydroxy-pentan-3-yl, and (S)-1-hydroxy-butan-2-yl. 
     
     
         32 . At least one chemical entity of  claim 31  wherein R 3  is selected from 3-pentyl, isopropyl, (S)-1-hydroxy-pentan-3-yl, (S)-1-hydroxy-butan-2-yl and methylpropyl. 
     
     
         33 . (canceled) 
     
     
         34 . At least one chemical entity of  claim 1  wherein the compound of Formula I is chosen from:
 6-chloro-1-(ethylpropyl)-7-phenylimidazol[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-chlorophenyl)-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(3-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-(ethylpropyl)-7-phenylimidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(3-chlorophenyl)-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzenecarbonitrile; 
 3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzenecarbonitrile; 
 6-chloro-1-(ethylpropyl)-7-(4-methylphenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]-4-(methylsulfonyl)benzene; 
 4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzamide; 
 6-chloro-1-(ethylpropyl)-7-[3-(hydroxymethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[4-(methoxymethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(4-methoxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]-3-(methylsulfonyl)benzene; 
 6-chloro-1-(ethylpropyl)-7-(4-hydroxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[4-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 {3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}-N,N-dimethylcarboxamide; 
 6-chloro-1-(ethylpropyl)-7-(3-methoxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzamide; 
 6-chloro-1-(ethylpropyl)-7-[3-(methoxymethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 {4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}-N,N-dimethylcarboxamide; 
 6-chloro-1-(ethylpropyl)-7-(2-methylphenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(2-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[3-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(3-hydroxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 N-{4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}acetamide; 
 7-(3,4-difluorophenyl)-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(3-methylphenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[4-(trifluoromethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 7-[4-(aminomethyl)phenyl]-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-chloro-3-fluorophenyl)-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(4-morpholin-4-ylphenyl)imidazo[4,5-b]pyridin-2-ol; 
 {4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}(methylsulfonyl)amine; 
 6-chloro-1-(ethylpropyl)-7-[4-(hydroxymethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 methyl 3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzoate; 
 3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzoic acid; 
 6-chloro-1-(ethylpropyl)-7-[4-(1-hydroxy-isopropyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 2-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzoic acid; 
 6-chloro-1-(ethylpropyl)-7-[3-(1-hydroxy-isopropyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-chlorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-chlorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 4-(6-chloro-2-hydroxy-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-7-yl)-2-fluorobenzonitrile; 
 7-[3-(aminomethyl)phenyl]-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[2-(methoxymethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-(3-fluoro-4-methoxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 N-({4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}methyl)acetamide; 
 7-{4-[(dimethylamino)methyl]phenyl}-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 (tert-butoxy)-N-{4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}-N-methylcarboxamide; 
 6-chloro-1-(ethylpropyl)-7-(2-fluoro-4-methoxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 4-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzoic acid; 
 1-(1S)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(ethylpropyl)-7-[4-(hydroxyethyl)phenyl]imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-methylimidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-prop-2-enylimidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-(methylethyl)imidazo[4,5-b]pyridin-2-ol; 
 2-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzenecarbonitrile; 
 7-{3-[(dimethylamino)methyl]phenyl}-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 7-{2-[(dimethylamino)methyl]phenyl}-6-chloro-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 2-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzaldehyde; 
 3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzaldehyde; 
 N-({3-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]phenyl}methyl)acetamide; 
 2-[6-chloro-1-(ethylpropyl)-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzamide; 
 6-chloro-7-(2-chloro-4-methylphenyl)-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(2-chloro-4-methoxyphenyl)-1-(ethylpropyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-2-hydroxy-isopropyl)-6-chloro-7-(4-chlorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-2-hydroxy-isopropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 1-((1S)-1-ethyl-2-hydroxyethyl)-6-chloro-7-phenylimidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-2-hydroxy-isopropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]propane-1,3-diol; 
 1-(tert-butyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-(2-hydroxyethyl)-7-phenylimidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-3-hydroxypropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-3-hydroxypropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-7-(3,4-difluorophenyl)-6-chloroimidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-(3-hydroxypropyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-3-hydroxy-1-methylpropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 (2S)-2-[7-(3,4-difluorophenyl)-6-chloro-2-hydroxyimidazo[4,5-b]pyridinyl]butyl (2S)-2amino-3-methylbutanoate; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-methoxyphenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-methylphenyl)imidazo[4,5-b]pyridin-2-ol; 
 4-[1-((1S)-1-ethyl-2-hydroxyethyl)-6-chloro-2-hydroxyimidazo[4,5-b]pyridin-7-yl]benzenecarbonitrile; 
 2-[7-(3,4-difluorophenyl)-6-chloro-2-hydroxyimidazo[4,5-b]pyridinyl]butyl dihydrogen phosphate; 
 (2S)-2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]butyl dihydrogen phosphate; 
 (2S)-2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]butyl (2S)-2-amino-3-methylbutanoate; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-6,7-bis(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-[2-hydroxy-1-(2-methylpropyl)ethyl]imidazo[4, 5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-2-hydroxyethyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-[(1S)-1-(methoxymethyl)propyl]-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-2-hydroxyethyl)-7-(3,4-difluorophenyl)-6-chloroimidazo[4,5-b]pyridin-2-ol; 
 1-[(1R)-1-(methoxymethyl)propyl]-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-2-hydroxy-2-methylpropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-7-(4-fluorophenyl)-1-(2-hydroxy-tert-butyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1S)-1-ethyl-2-hydroxyethyl)-7-(4-chlorophenyl)-6-fluoroimidazol[4,5-b]pyridin-2ol; 
 1-((1S)-1-ethyl-2hydroxyethyl)-6-fluoro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-2-hydroxy-2-methylpropyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 (2S)-2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]butyl acetate; 
 1-[(1S)-2-hydroxy-1-(2-methylpropyl)ethyl]-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 6-chloro-1-cyclopentyl-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-2-amino-1-ethylethyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2ol; and 
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
     
     
         35 . At least one chemical entity of  claim 1  wherein the compound of Formula I is chosen from:
 N-{(2S)-2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]butyl}acetamide; 
 1-((1S)-2-amino-1-ethylethyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 N-{(2R)-2-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]butyl}acetamide; 
 1-((1S)-1-ethyl-3-hydroxy-3-methylbutyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5-b]pyridin-2-ol; 
 1-((1R)-1-ethyl-3-hydroxy-3-methylbutyl)-6-chloro-7-(4-fluorophenyl)imidazo[4,5b]pyridin-2-ol; 
 2-{(1S)-1-[6-chloro-7-(4-fluorophenyl)-2-hydroxyimidazo[4,5-b]pyridinyl]propyl}propane-1,3-diol; 
 or a pharmaceutically acceptable salt or tautomer thereof. 
 
     
     
         36 . A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and at least one chemical entity of  claim 1 . 
     
     
         37 . A pharmaceutical composition of  claim 36 , wherein the composition is formulated in a form chosen from a tablet, capsule, powder, liquid suspension, suppository and aerosol. 
     
     
         38 - 39 . (canceled) 
     
     
         40 . A method for treating a patient having a condition chosen from neuromuscular disorders, conditions having muscle wasting, claudication, frailty, metabolic syndrome, muscle atrophy associated with disuse and muscle fatigue comprising administering to the patient a therapeutically effective amount of at least one chemical entity of  claim 1 . 
     
     
         41 - 46 . (canceled)