Heterocyclic compounds and uses thereof

Abstract

The invention provides compounds having the imidazole, oxazole, or thiazole skeleton and uses thereof. The compounds described herein bind to phosphodiesterase 6D. The compounds disclosed herein can be used to modulate the activity of phosphodiesterase 6. The invention provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects. Kits comprising the compounds of the invention are also provided.

1 . A method of treating a disease comprising administering to a subject in need thereof an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 R 1  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl and R 2  and R 3  can optionally form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms; and  
 R 4  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl and R 3  and R 4  together can optionally form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms:  
 
     
     
         2 . The method of  claim 1  wherein the compound is at least one of a compound selected from the compounds 782132, 782158, 782340, 782288, 782626, 782756, 782808, 782990, 783094, 783068, 783198, 783224, 783250, 783276, 783302, 783328, 783458, 783432, 783406, 783380, 783354, 783484, 783510, 783536, and 783562.  
     
     
         3 . A method of treating a disease comprising administering to a subject in need thereof an effective amount of a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 R 1  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl or R 2  and R 3  can form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms.  
 
     
     
         4 . The method of  claim 1  wherein the compound is at least one of a compound selected from the compounds 782262, 782106, 782418, 782444, 782470, 782496, 782548, 782522, 782704, 782782, 782886, 782860, 782834, 782938, 782730, and 782678.  
     
     
         5 . A method of treating a disease comprising administering to a subject in need thereof an effective amount of a compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 R 1  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl or R 2  and R 3  can form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms.  
 
     
     
         6 . The method of  claim 1  wherein the compound is at least one of a compound selected from the compounds 783822, 782600, 782574, 782314, 782652, 782392, 783848, 782912, 782652, and 783822.  
     
     
         7 . The method of  claim 1 ,  3 , or  5  wherein said disease is a PDE6-related condition.  
     
     
         8 . The method of  claim 1 ,  3 , or  5  wherein said disease is a condition wherein a beneficial effect is obtained by modulating PDE6 or any of its subunits.  
     
     
         9 . The method of  claim 1 ,  3 , or  5  wherein said disease is a condition wherein a beneficial effect is obtained by modulating PDE6D.  
     
     
         10 . The method of  claim 1 ,  3 , or  5  wherein said disease is related to an aberrant or undesired phosphodiesterase activity.  
     
     
         11 . The method of  claim 1  wherein said disease is stroke.  
     
     
         12 . The method of  claim 11  wherein said PDE6 modulating compound is acutely administered to a subject following a stroke.  
     
     
         13 . The method of  claim 11  wherein said PDE6 modulating compound is prophylactically administered to a subject to prevent a stroke.  
     
     
         14 . The method of  claim 1 ,  3 , or  5  wherein said disease is at least one of a disease selected from cancer, impaired vision, an oxidative stress disorder, inflammation, and multiple sclerosis.  
     
     
         15 . The method of  claim 1 ,  3 , or  5  wherein said disease is at least one of a disease selected from cerebrovascular accident, neurodegenerative disease, and cardiovascular disease  
     
     
         16 . The method of  claim 15  wherein said cerebrovascular accident is a stroke.  
     
     
         17 . The method of  claim 15  wherein treatment of said cardiovascular disease decreases the frequency and/or the severity of damage of myocardial infarction  
     
     
         18 . The method of  claim 15  wherein said neurodegenerative disease is at least one of an ischemic stroke, Alzheimer's disease, diabetic peripheral neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease and Parkinson's disease.  
     
     
         19 . The method of  claim 1 ,  3 , or  5  wherein said compound stimulates blood vessel growth, bone growth, or immune system.  
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 R 1  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl and R 2  and R 3  can optionally form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms; and  
 R 4  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl and heteroaryl and R 3  and R 4  together can optionally form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms.  
 
     
     
         21 . The pharmaceutical composition of  claim 20  wherein the compound is at least one of a compound selected from the compounds 782132, 782158, 782340, 782288, 782626, 782756, 782808, 782990, 783094, 783068, 783198, 783224, 783250, 783276, 783302, 783328, 783458, 783432, 783406, 783380, 783354, 783484, 783510, 783536, and 783562.  
     
     
         22 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula II  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 Ris selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl or R 2  and R 3  can form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms.  
 
     
     
         23 . The pharmaceutical composition of  claim 22  wherein the compound is at least one of a compound selected from the compounds 782262, 782106, 782418, 782444, 782470, 782496, 782548, 782522, 782704, 782782, 782886, 782860, 782834, 782938, 782730, and 782678.  
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula III  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein 
 X is a direct bond or a linking group selected from unsubstituted or substituted carbon, N, O or S;  
 R 1  is selected from the group consisting of H, alkyl, cycloalkyl, aryl, heteroaryl, alkaryl and alkheteroaryl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, aryl, and heteroaryl or R 2  and R 3  can form a 3, 4, 5, 6, or 7 membered ring optionally having one or more substituents or heteroatoms.  
 
     
     
         25 . The pharmaceutical composition of  claim 24  wherein the compound is at least one of a compound selected from the compounds 783822, 782600, 782574, 782314, 782652, 782392, 783848, 782912, 782652, and 783822.