Substituted heterocyclic compounds

Abstract

Disclosed are novel substituted heterocyclic derivatives having the structure of Formula I: The compounds are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, diabetes, and myocardial infarction.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen, lower alkyl, or —C(O)R, in which R is —OR 111  or —NR 11 R 12 , where R 11  and R 12  are independently hydrogen or lower alkyl; or 
 R 1  and R 2 , R 3  and R 4 , R 5  and R 6 , R 7  and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or 
 R 1  and R 5 , or R 1  and R 7 , or R 3  and R 5 , or R 3  and R 7 , when taken together form a bridging group —(CR 13 R 14 ) n —, in which n is 1, 2 or 3, and R 13  and R 14  are independently hydrogen or lower alkyl;
 with the provisos that
 i. the maximum number of carbonyl groups is 1, 
 ii. the maximum number of —C(O)NR 11 R 12  groups is 1, and 
 iii. the maximum number of bridging groups is 1; 
 
 
 R 9  and R 10  are independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, or optionally substituted heteroaryl; 
 T is —O—, —S—, —NHSO 2 —, —SO 2 NH—, or —CO—NH—; or 
 R 9  and T are taken together are optionally substituted heterocyclyl; 
 Q is —N< or —NH—CH<; 
 X is a covalent bond or an optionally substituted alkylene of 1-6 carbon atoms; 
 Y is optionally substituted alkylene of 1-3 carbon atoms; and 
 Z is a covalent bond, —O—, —S—, or —N(R 15 )—, wherein R 15  is hydrogen or C 1-4  alkyl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen or lower alkyl. 
     
     
         3 . The compound of  claim 2 , wherein Y is methylene. 
     
     
         4 . The compound of  claim 3 , wherein Z is —O—. 
     
     
         5 . The compound of  claim 4 , wherein R 10  is optionally substituted aryl or optionally substituted heteroaryl. 
     
     
         6 . The compound of  claim 5 , wherein Q is —N<. 
     
     
         7 . The compound of  claim 6 , wherein X is C 1-4  alkyl. 
     
     
         8 . The compound of  claim 7 , wherein T is —O—. 
     
     
         9 . The compound of  claim 8 , selected from the group consisting of: 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]propan-2-ol; 
       (2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]propan-2-ol 
       (2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl}propan-2-ol; 
       (2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethyl)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol; 
       -(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one; 
       ethyl 2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]acetate; 
       ethyl 3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoate; 
       2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]acetic acid; 
       (2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       ethyl 2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetate; 
       ethyl 2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoate; 
       2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]-2-methylpropanoic acid; 
       3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenyl]propanoic acid; 
       (2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyloxy)butyl)piperazinyl]propan-2-ol; 
       (2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butoxy)phenoxy]acetic acid; 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy]hexyl}piperazinyl)propan-2-ol; 
       (2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; 
       (2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol; and 
       (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohexyloxy]butyl}piperazinyl)propan-2-ol. 
     
     
         10 . The compound of  claim 9 , wherein T and R 9  together form an optionally substituted heterocyclyl. 
     
     
         11 . The compound of  claim 10 , wherein T and R 9  together form an optionally substituted pyrrolidin-2-one. 
     
     
         12 . The compound of  claim 11 , selected from the group consisting of: 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylpyrrolidin-2-one; 
       4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-methylphenyl)pyrrolidin-2-one; and 
       4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}piperazinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one. 
     
     
         13 . The compound of  claim 10 , wherein T and R 9  together form an optionally substituted azolidine-2,5-dionyl moiety. 
     
     
         14 . The compound of  claim 13 , selected from the group consisting of: 
       1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; 
       1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; 
       1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-vinylphenyl)azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-phenylazolidine-2,5-dione; 
       3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-phenylazolidine-2,5-dione; 
       3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-naphthylazolidine-2,5-dione; 
       3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; 
       1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; 
       3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; 
       1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; 
       1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; 
       1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; 
       1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-naphthylazolidine-2,5-dione; and 
       3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-1-(4-methylphenyl)azolidine-2,5-dione. 
     
     
         15 . The compound of  claim 10 , wherein T and R 9  together form an optionally substituted benzo[c]azolidine-1,3-dione moiety. 
     
     
         16 . The compound of  claim 15 , namely 2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azolidine-1,3-dione. 
     
     
         17 . The compound of  claim 6 , wherein T is —SO 2 NH—. 
     
     
         18 . The compound of  claim 17 , selected from the group consisting of: 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) (phenylsulfonyl)amine 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) [(4-methylphenyl)sulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) [4-chlorophenylsulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) [(4-trifluoromethoxy)phenylsulfonyl]amine; 
       (3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl) [(4-trifluoromethyl)phenylsulfonyl]amine; 
       (4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}butyl) [(4-trifluoromethyl)phenylsulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,5-dimethyl)phenylsulfonyl]amine; 
       {[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; 
       [(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl) [(3-methylphenyl)sulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine; 
       (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(naphthylsulfonyl)amine; 
       {[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; 
       [(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; and 
       {[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine. 
     
     
         19 . The compound of  claim 6 , wherein T is —NHSO 2 —. 
     
     
         20 . The compound of  claim 19 , selected from the group consisting of: 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]phenylamine 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(methyl)phenyl]amine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine; 
       [3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; 
       (4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]naphthylamine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine; 
       [(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}propyl)sulfonyl][4-(tertbutyl)phenyl]amine; 
       (2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; 
       (3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine; and 
       [(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine. 
     
     
         21 . The compound of  claim 6 , wherein T is —CO—NH—. 
     
     
         22 . The compound of  claim 21  selected from the group consisting of: 
       (2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide; 
       N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzamide; 
       (4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide; and 
       (4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide. 
     
     
         23 . The compound of  claim 5 , wherein Q is —NH—CH<. 
     
     
         24 . The compound of  claim 23  selected from the group consisting of: 
       (3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; 
       (3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; 
       3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-chlorophenyl)pyrrolidin-2-one; 
       (3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; 
       3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one; 
       3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-(2-fluorophenyl)pyrrolidin-2-one; 
       3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; 
       3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; 
       (3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}pyrrolidin-2-one; and 
       4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one. 
     
     
         25 . A method of treating a disease state chosen from diabetes, damage to skeletal muscles resulting from trauma or shock and a cardiovascular disease in a mammal by administration of a therapeutically effective dose of a compound of  claim 1 . 
     
     
         26 . The method of  claim 25 , wherein the cardiovascular disease is atrial arrhythmia, intermittent claudication, ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina, unstable angina, congestive heart failure, or myocardial infarction. 
     
     
         27 . The method of  claim 26 , wherein the disease state is diabetes. 
     
     
         28 . The method of  claim 26 , wherein the disease state is congestive heart failure. 
     
     
         29 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .