Ion channel modulators

Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of ion channel function, and treatment of disease and disease symptoms, particularly those mediated by certain calcium channel subtype targets.

1 - 12 . (canceled)  
     
     
         13 . A method for treating a disease or disease symptom in a subject in need of such treatment comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
         wherein,  
         Ar 1  is cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl haloalkoxy, and alkanoyl;  
         R 1  is Ar 2  or lower alkyl optionally substituted with Ar 2 ;  
         Ar 2  is independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl, each of which may be optionally substituted with one or more substituents selected from the group consisting of H, halogen, amino, hydroxy, cyano, nitro, carboxylate, alkyl, alkenyl, alkynyl, cycloalkyl, cyclohexyl, alkoxy, mono and di-alkyl amino, phenyl, carboxamide, haloalkyl, haloalkoxy, and alkanoyl;  
         q is 0, 1, or 2;  
         each R 2  is independently selected from (CH 2 ) m CO 2 R 3 , (CH 2 ) m COAr 3 , (CH 2 ) m CONR 3 R 4 , (CH 2 ) m Ar 3 , (CH 2 ) 3 Ar 3 , (CH 2 ) n NR 3 R 4  or (CH 2 ) n OR 4 ;  
         each R 3  is independently selected from H, or lower alkyl;  
         each R 4  is independently selected from H, lower alkyl or (CH 2 ) p Ar 3 ;  
         each Ar 3  is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more substituents, with the proviso that Ar 3  is not piperidinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;  
         each m is 1 or 2;  
         each n is 2 or 3;  
         each p is 0 or 1;  
         each substituent for Ar 1 , Ar 2  and Ar 3  is independently selected from halogen, CN, NO 2 , OR 5 , SR 5 , S(O) 2 OR 5 , NR 5 R 6 , cycloalkyl, C 1 -C 2  perfluoroalkyl, C 1 -C 2  perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 5 , C(O)NR 5 R 6 , OC(O)NR 5 R 6 , NR 5 C(O)NR 5 R 6 , C(NR 6 )NR 5 R 6 , NR 5 C(NR 6 )NR 5 R 6 , S(O) 2 NR 5 R 6 , R 7 , C(O)R 7 , NR 5 C(O)R 7 , S(O)R 7 , or S(O) 2 R 7 ;  
         each R 5  is independently selected from hydrogen or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl;  
         each R 6  is independently selected from hydrogen, (CH 2 ) p Ar 4 , or lower alkyl optionally substituted with one or more substituent substituents independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl;  
         each R 7  is independently selected from (CH 2 ) p Ar 4  or lower alkyl optionally substituted with one or more substituents independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or C 3 -C 6  cycloalkyl; and  
         each Ar 4  is independently selected from C 3 -C 6  cycloalkyl, aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from halogen, OH, C 1 -C 4  alkoxy, NH 2 , C 1 -C 4  alkylamino, C 1 -C 4  dialkylamino or 1,2-methylenedioxy.  
       
     
     
         14 . The method of  claim 13 , wherein the disease or disease symptom is angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, stroke, pain, traumatic brain injury, or a neuronal disorder.  
     
     
         15 . The method of  claim 13 , wherein the disease or disease symptom is modulated by calcium channel Ca v 2.  
     
     
         16 . The method of  claim 15 , wherein the disease or disease symptom is modulated by calcium channel Ca v 2.2.  
     
     
         17 . A method of modulating calcium channel activity comprising contacting a calcium channel with a compound of formula I or pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
         wherein,  
         Ar 1 , R 1 , R 2 , and q are as defined in  claim 13 .  
       
     
     
         18 - 19 . (canceled)  
     
     
         20 . A method of modulating ion channel activity in a subject in need of such treatment, comprising administering an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
         wherein  
         Ar 1 , R 1 , R 2 , and q are as defined in  claim 13.