2,6-Substituted chroman derivatives useful as beta-3 adrenoreceptor agonists

Abstract

This invention relates to novel 2,6-substituted chroman derivatives which are useful in the treatment of beta-3 adrenoreceptor-mediated conditions.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       wherein, 
 R is independently 
 hydroxy,  
 oxo,  
 halo,  
 cyano,  
 nitro,  
 C 1 -C 10  alkyl,  
 C 1 -C 10  haloalkyl,  
 CF 3 ,  
 NR 1 R 1 ,  
 SR 1 ,  
 OR 1 ,  
 SO 2 R 2 ,  
 OCOR 2 ,  
 NR 1 COR 2 ,  
 COR 2 ,  
 NR 1 SO 2 R 2 ,  
 phenyl, or  
 a 5- or 6-membered heterocycle with from 1 to 4 heteroatoms selected from O, S, and N;  
 each cyclic moiety being optionally substituted with 
 hydroxy,  
 R 1 ,  
 halo,  
 cyano,  
 NR 1 R 1 ,  
 SR 1 ,  
 CF 3 ,  
 OR 1 ,  
 C 3 -C 8  cycloalkyl,  
 NR 1 COR 2 ,  
 COR 2 ,  
 SO 2 R 2 ,  
 OCOR 2 ,  
 NR 1 SO 2 R 2    
 C 1 -C 10  alkyl, or  
 C 1 -C10 alkoxy;  
 
 
 R 1  is 
 hydrogen,  
 (CH 2 ) d —O—(CH 2 ) d R 5  where each d is selected independently, or  
 C 1 -C 10  alkyl optionally substituted with 1 to 4 substituents each independently selected from 
 hydroxy,  
 halo,  
 CO 2 C 1 -C 4 -alkyl,  
 CO 2 H,  
 C 1 -C 10  alkoxy,  
 S(O) b C 1 -C 10  alkyl,  
 S(O) b -phenyl optionally substituted with halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, SO 2 -C 1 -C 4 alkyl, or CO 2  C 1 -C 4 alkyl; or  
 phenyl optionally substituted with CO 2 C 1 -C 4 -alkyl, CO 2 H, halo, or C 1 -C 10  alkyl; or  
 
 C 3 -C 8  cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1 to 4 substituents each independently selected from halo, nitro, oxo, C 1 -C 10  alkyl, C 1 -C 10 alkoxy, C 1 -C 10  alkylthio, CO 2 C 1 -C 4 -alkyl, and CO 2 H, and  
 
 when two R 1  groups are attached to N as NR 1 R 1 , these R 1  groups may form together with the nitrogen to which they are attached, a heterocyclic ring containing 4 to 7 C atoms, 1 to 2 N atoms, and 0 to 1 O or S atoms;  
 R 2 is 
 R 1 ,  
 OR 1 ,  
 NR 1 R 1 ,  
 NHS(O) b phenyl optionally substituted with C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo or nitro;  
 NHS(O) b naphthyl,  
 NHS(O) b C 1 -C 10 alkyl optionally substituted with fluoro up to the perfluoro level, or  
 a 5- or 6-membered heterocycle with one or more heteroatoms selected from O, S, and N, said heterocyclic moiety being optionally substituted with R 1 ;  
 
 R 3  is hydrogen, C 1 -C 10  alkyl, or COR 2 ;  
 R 4  is hydrogen, C 1 -C 10  alkyl, C 1 -C 10  alkyl-phenyl, or C 1 -C 10  alkyl-pyridyl;  
 R 5  is hydrogen or COOH;  
 R 6  is 
 hydrogen,  
 C 1 -C 10  alkyl optionally substituted with 1 to 4 substituents each independently selected from halo, phenyl, or phenyl-COR 2 , or  
 C 1 -C 10  alkyl-S(O) b C 1 -C 10  alkyl optionally substituted with COR 2  or C 3 -C 8  cycloalkyl;  
 
 Ar is 
 phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or  
 a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;  
 
 Y is 
 halo,  
 NO 2 ,  
 R 6    
 SR 1 ,  
 S(O) b -phenyl-CO 2 R 1 ,  
                     
 where, when the two R 4  groups attached to the same C are both alkyl, they optionally may be joined so that, when taken together with the C to which they are attached, they form a Spiro ring of 3, 5, or 6 C atoms, or where the R 4  attached to N and one R 4  attached to the adjacent C are both alkyl, they optionally may be joined so that, taken together with the atoms to which they are attached, they form a 5- or 6-membered heterocyclic ring; 
 with the proviso that when e is 1, at least one R 4  group must be C 1 -C 10  alkyl-phenyl or C 1 -C 10  alkyl-pyridyl, or two R 4  groups must form one of said spiro or heterocyclic ring moieties;  
 
 a phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or  
 a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from  
 COR 2 ,  
 CONR 1 S(O) 2 R 9 ,  
 COCH 2 SO 2 -thiazolyl optionally substituted with alkyl or amino,  
 halo,  
 NO 2 ,  
 OR 1 ,  
 R 1 ,  
 SR 1 ,  
 O—C 1 -C 6 -alkyl substituted by C 3 -C 6 -cycloalkyl,  
 O-phenyl optionally substituted by SO 2 CH 3 ,  
 SO 2 NH 2 ,  
 SO 2 NR 1 R 7 ,  
 NR 1 R 1 ,  
 NR 1 COC 1 -C 6 alkyl,  
                     
 C 1 -C 10 COR 2 ,  
 phenyl optionally substituted with halo, C 1 -C 4  alkyl, or C 1 -C 4  alkoxy,  
 tetrazolo;  
 
 R 7  is 
 phenyl or heteroaryl containing 3-6 C and 1-3 O, N, or S atoms, each optionally substituted by C 1 -C 4  alkyl, CN, NO 2 , CO-C 1 -C 4 alkyl, C1-C 4  alkoxy, or C 1 -C 4  haloalkyl,  
 CO—R 8 ,  
                     
 
 R 8  is 
 C 1 -C 6  alkyl optionally substituted with C 1 -C 4  alkoxy, N(CH 3 ) 2 ,or one or two CF 3 ,  
 C 3 -C 6 -cycloalkyl,  
 phenyl optionally substituted with C 1 -C 4 alkoxy, halo, or C 1 -C 4 alkyl,  
 NH-phenyl optionally substituted with C 1 -C 4  alkyl, halo, C 1 -C 4  alkoxy, or C 1 -C 4  haloalkoxy,  
 NH-cyclohexyl;  
 
 R 9  is 
 C 3 -C 6 cycloalkyl,  
 thienyl optionally substituted with C 1 -C 4  alkyl or isoxazolyl,  
 pyridyl optionally substituted with —SO 2 —C 1 -C 4 alkyl,  
 pyrazolyl optionally substituted with halo or C 1 -C 4  alkyl,  
 isoxazolyl optionally substituted with C 1 -C 4  alkyl, or  
                     
 
 a is 0, 1, 2, 3, 4, or 5;  
 b is 0, 1, or 2;  
 d is 1, 2, or 3;  
 e is 1 or 2;  
 and pharmaceutically acceptable salts and esters thereof.  
 
     
     
         2 . The compound of  claim 1  wherein Y is 
 halo,    R 6 ,    SR 1 ,    S(O) b -phenyl-CO 2 R 1 ,    phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or    a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring,    each cyclic moiety being optionally substituted with one or more substituents independently selected from 
 COR 2 ,  
 halo,  
 NO 2 ,  
 OR 1 ,  
 R 1 ,  
 SR 1 ,  
 SO 2 NR 1 R 7 ,  
 NR 1 R 1 ,  
 NR 1 COC 1 -C 6 alkyl,  
 C 1 -C 10 COR 2 ,  
 phenyl,  
 tetrazolo;  
 and pharmaceutically acceptable salts and esters thereof.  
   
     
     
         3 . The compound of  claim 1  wherein Y is 
 phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or    a 5- or 6- membered heterocycle containing one or more heteroatoms each independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from 
 COR 2 ,  
 halo,  
 NO 2 ,  
 OR 1 ,  
 R 1 ,  
 SR 1 ,  
 SO 2 NR 1 R 7 ,  
 NR 1 R 1 ,  
 NR 1 COC 1 -C 6 alkyl,  
 C 1 -C 10 COR 2 ,  
 phenyl,  
 tetrazolo;  
 and d is 1or 2;  
 and pharmaceutically acceptable salts and esters thereof.  
   
     
     
         4 . The compound of  claim 1  wherein 
 Y is 
 phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or  
 a 5- or 6- membered heterocycle containing one or more heteroatoms each 
 independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from  
 COR 2 ,  
 halo,  
 NO 2 ,  
 OR 1 ,  
 R 1 ,  
 SR 1 ,  
 SO 2 NR 1 R 7 ,  
 NR 1 R 1 ,  
 C 1 -C 10 COR 2 ,  
 phenyl,  
 tetrazolo;  
 
   Ar is 
 phenyl optionally fused to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from O, S, and N, said bicyclic moiety being optionally fused to a phenyl, or  
 a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, optionally fused to phenyl;  
   and d is 1 or 2;    and pharmaceutically acceptable salts and esters thereof.    
     
     
         5 . The compound of  claim 1  wherein 
 Y is 
 phenyl optionally fused to one or two phenyl rings, or to a 5- or 6-membered heterocycle containing one or more heteroatoms each independently selected from N, S, and O, or  
 a 5- or 6- membered-heterocycle containing one or more heteroatoms each 
 independently selected from N, S and O, optionally fused to a phenyl ring, each cyclic moiety being optionally substituted with one or more substituents independently selected from  
 COR 2 ,  
 halo,  
 OR 1 ,  
 R 1 ,  
 NR 1 R 1 ,  
 
   Ar is 
 phenyl or  
 a 5- or 6-membered heterocycle containing one or more N atoms;  
   a is 0, 1, 2, or 3; and    d is 1;    and pharmaceutically acceptable salts and esters thereof.    
     
     
         6 . A compound selected from the group consisting of: 
 2-[4-(ethoxycarbonyl)phenoxy]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutylbenzoic acid;    N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-2-methylbenzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isobutoxybenzoic acid;    N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-4-methoxybenzenesulfonamide;    N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}-1-propanesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxybenzoyl)benzenesulfonamide;    N-(2-cyano-4-nitrophenyl)-3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    2-(4-chlorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    N-(4,6-dimethoxy-2-pyrimidinyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide;    2-(4-fluorophenoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-methoxybenzoyl)benzenesulfonamide;    4-fluoro-N-{3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoyl}benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methylphenoxy)benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-phenylethyl)benzoic acid;    3-chloro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    N-(4-fluorobenzoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methoxybenzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-phenoxybenzoic acid;    N-(4-cyanophenyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(trifluoromethoxy)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)-2-(trifluoromethoxy)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3,3,3-trifluoropropanoyl)benzenesulfonamide;    2-hydroxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    3-((1R)-2-{[((2R)-6-{4-[({[(4-fluorophenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;    N-benzoyl-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-propoxybenzoic acid;    N-({4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-pyridinyl}carbonyl)-4-methoxybenzenesulfonamide;    3-((1R)-1-hydroxy-2-{[((2R)-6-{4-[({[(4-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}ethyl)pyridine;    3-((1R)-2-{[((2R)-6-{4-[({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)sulfonyl]phenyl}-3,4-dihydro-2H-chromen-2-yl)methyl]amino}-1-hydroxyethyl)pyridine;    N-(ethoxyacetyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    N-(3,3-dimethylbutanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methyl-2-pyrimidinyl)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-[4-(methylsulfonyl)phenoxy]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-methylbenzoic acid;    4-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid;    N-(2,2-dimethylpropanoyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    3-[(1R)-2-({[(2R)-6-(4-{[(anilinocarbonyl)amino]sulfonyl}phenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-1-hydroxyethyl]pyridine;    2-ethoxy-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(4-methoxy-6-methyl-2-pyrimidinyl)benzenesulfonamide;    3-{(1R)-2-[({(2R)-6-[4-({[(cyclohexylamino)carbonyl]amino}sulfonyl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]-1-hydroxyethyl}pyridine;    N-(cyclopropylcarbonyl)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    2-chloro-5-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(4-[R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methylbenzoic acid;    2-fluoro-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-propoxybenzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-isopropoxybenzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(1,3-thiazol-2-yl)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(4-methoxyphenoxy)benzoic acid;    3-(cyclopropylmethoxy)-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzenesulfonamide;    5-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4′-methyl-1,1′-biphenyl-2-carboxylic acid;    N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(3-pyridinyl)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-methoxybenzoic acid;    4-chloro-N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-isobutoxybenzoic acid;    N-{6-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-3-pyridinyl}methanesulfonamide;    3-{2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]ethyl}benzoic acid;    3-[(1E)-1-hexenyl]-4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    3-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-N-(2-pyrimidinyl)benzenesulfonamide;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2-(2-methoxyethoxy)benzoic acid;    4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-2,6-dimethylbenzoic acid;    4-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    3-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid;    (1R)-1-(6-amino-3-pyridinyl)-2-[({(2R)-6-[4-(1H-tetraazol-5-yl)phenyl]-3,4-dihydro-2H-chromen-2-yl}methyl)amino]ethanol;    5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-phenyl-1,2I5,3I5,4-thiatriazole-2-carboxylic acid;    5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-furoic acid;    5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;    5-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-3-thiophenecarboxylic acid;    4-{4-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]phenyl}-2-thiophenecarboxylic acid;    6-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid;    5-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]nicotinic acid;    2-[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]-4-pyridinecarboxylic acid;    1-({[(2R)-2-({[(2R)-2-(6-amino-3-pyridinyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]carbonyl}amino)cyclopropanecarboxylic acid; and    4-[(2R)-2-({[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoic acid (Example 344).    
     
     
         7 . A method of treating a beta-3 adrenergic receptor-mediated condition comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         8 . A method of treating obesity comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         9 . A method of treating diabetes comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         10 . A method of treating a patient with impaired fasting glucose or impaired glucose tolerance comprising the step of administering to said patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         11 . A method of treating gastrointestinal disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         12 . A method of treating hypertriglyceridemia, hypercholesteolemia, atherosclerotic disorders, or cardiovascular disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         13 . A method for lowering high-density lipoprotein levels comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         14 . A method for treating urinary disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
     
     
         15 . The method of  claim 14 , wherein said urinary disorders is selected from the group consisting of pollakiuria and incontinence.  
     
     
         16 . A method of treating a beta-3 adrenergic receptor-mediated condition comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         17 . A method of treating obesity comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         18 . A method of treating diabetes comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         19 . A method of treating a patient with impaired fasting glucose or impaired glucose tolerance comprising the step of administering to said patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         20 . A method of treating gastrointestinal disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         21 . A method of treating hypertriglyceridemia, hypercholesteolemia, atherosclerotic disorders, or cardiovascular disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         22 . A method for lowering high-density lipoprotein levels comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         23 . A method for treating urinary disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 6 .  
     
     
         24 . The method of  claim 23 , wherein said urinary disorders is selected from the group consisting of pollakiuria and incontinence.  
     
     
         25 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt and esters thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         26 . A pharmaceutical composition for the treatment of obesity, diabetes, gastrointestinal disorders, hypertriglyceridaemia, hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or urinary disorders comprising an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt and ester thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         27 . A composition comprising an effective amount of a compound of  claim 1  or a salt and esters thereof in combination with an inert carrier.  
     
     
         28 . A pharmaceutical composition comprising an effective amount of a compound of  claim 6  or a pharmaceutically acceptable salt and esters thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         29 . A pharmaceutical composition for the treatment of obesity, diabetes, gastrointestinal disorders, hypertriglyceridaemia, hypercholesterolaemia, atherosclerosis, cardiovascular diseases, or urinary disorders comprising an effective amount of a compound of  claim 6  or a pharmaceutically acceptable salt and ester thereof in combination with a pharmaceutically acceptable carrier.  
     
     
         30 . A composition comprising an effective amount of a compound of  claim 6  or a salt and esters thereof in combination with an inert carrier.