Modulators of the beta-3 adrenergic receptor useful for the treatment or prevention of disorders related thereto

Abstract

The present invention relates to compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the beta-3 adrenergic receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a beta-3 adrenergic receptor-mediated disorder, such as, heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; LVEF≤35% by echocardiography or ventricular contrast angiography; and conditions related thereto.

This listing of claims replaces all prior versions and listings of claims in the application: 
     
         1 . A compound selected from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is —SO 2 —, —C(═O)—, or —CH 2 C(═O)—; 
 W is absent or C 1 -C 3  alkylene; 
 R 1  is aryl or heteroaryl, wherein each is optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkyl, amino, cyano, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, halogen, hydroxyl, oxo, and sulfamoyl; and wherein said C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl are each optionally substituted with one or more substituents selected from: amino, C 1 -C 6  alkoxy, C 1 -C 6  alkylcarboxamide, —Y—C 3 -C 7 -cycloalkyl, —Y—C 1 -C 6 -alkylene-Z, C 1 -C 6  alkylamino, C 1 -C 6  haloalkylamino, and heterocyclyl; 
 Y is independently selected from: —O—, —NH—, and —N—(C 1 -C 4  alkyl)-; 
 Z is independently selected from: hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, and C 2 -C 6  dialkylamino; 
 R 2  is selected from: C 2 -C 6  alkenyl, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, and C 1 -C 6  haloalkyl; each optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkylenehydroxyl, amino, aryl, C 3 -C 7  cycloalkyl, cyano, C 3 -C 7  halocycloalkyl, hydroxyl, and oxo; and 
 R 3a , R 3b , R 3c , and R 3d  are each independently H or halogen. 
 
     
     
         2 . The compound according to  claim 1 , wherein X is —SO 2 —. 
     
     
         3 . The compound according to  claim 1 , wherein W is absent. 
     
     
         4 . The compound according to  claim 1 , wherein Y is —NH—. 
     
     
         5 . The compound according to  claim 1 , wherein Z is C 1 -C 6  alkoxy. 
     
     
         6 . The compound according to  claim 1 , wherein:
 R 1  is aryl optionally substituted with one or more substituents selected from:   C 1 -C 6  alkoxy, C 1 -C 6  alkyl, cyano, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, halogen, and sulfamoyl; and wherein said C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl are each optionally substituted with one or more substituents selected from: amino, C 1 -C 6  alkylcarboxamide, —NH—C 3 -C 7 -cycloalkyl, —NH—C 1 -C 6 -alkylene-NH 2 , —NH—C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, C 1 -C 6  alkylamino, C 1 -C 6  haloalkylamino, and heterocyclyl.   
     
     
         7 . The compound according to  claim 1 , wherein:
 R 1  is selected from: 5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl; wherein each is optionally substituted with one or more substituents selected from:   2-methylpropan-2-yl, bromo, chloro, cyano, cyclopropyl, ethoxy, ethyl, fluoro, isopropoxy, methoxy, methyl, propan-2-yl, sulfamoyl, and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl, and propan-2-yl are each optionally substituted with one or more substituents selected from: 2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, methylamino, morpholino, propylamino, tert-butylamino, and tert-pentylamino.   
     
     
         8 . The compound according to  claim 1 , wherein:
 R 1  is selected from: 5,6,7,8-tetrahydronaphthalenyl, biphenyl, naphthalenyl, and phenyl; wherein each is optionally substituted with one or more substituents selected from:   (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin-1-ylmethyl, bromo, chloro, cyano, ethoxy, fluoro, isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl, and trifluoromethyl.   
     
     
         9 . The compound according to  claim 1 , wherein:
 R 1  is selected from: 5,6,7,8-tetrahydronaphthalen-2-yl, biphenyl-3-yl, biphenyl-4-yl, naphthalen-2-yl, and phenyl; wherein each is optionally substituted with one or more substituents selected from:   (2,2,2-trifluoroethylamino)methyl, (2-aminoethylamino)methyl, (2-methoxyethylamino)methyl, (3-aminopropylamino)methyl, (butylamino)methyl, (cyclobutylamino)methyl, (ethylamino)methyl, (isobutylamino)methyl, (isopropylamino)methyl, (methylamino)methyl, (propylamino)methyl, (tert-butylamino)methyl, (tert-pentylamino)methyl, 1-amino-2-methylpropan-2-yl, 1-aminocyclopropyl, 2-acetamidoethyl, 2-aminoethyl, 2-aminopropan-2-yl, aminomethyl, azetidin-1-ylmethyl, bromo, chloro, cyano, ethoxy, fluoro, isopropoxy, methoxy, methyl, morpholinomethyl, sulfamoyl, and trifluoromethyl.   
     
     
         10 . The compound according to  claim 1 , wherein R 1  is selected from:
 1-ethoxynaphthalen-2-yl, 3-(trifluoromethyl)phenyl, 3-bromo-2-methylphenyl, 3-bromo-4-methoxyphenyl, 3-bromophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-fluorophenyl, 3-methoxyphenyl, 4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4′-((2-aminoethylamino)methyl)biphenyl-3-yl, 4′-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4′-((3-aminopropylamino)methyl)biphenyl-3-yl, 4′-((butylamino)methyl)biphenyl-3-yl, 4′-((cyclobutylamino)methyl)biphenyl-3-yl, 4′-((ethylamino)methyl)biphenyl-3-yl, 4′-((isobutylamino)methyl)biphenyl-3-yl, 4′-((isopropylamino)methyl)biphenyl-3-yl, 4′-((methylamino)methyl)biphenyl-3-yl, 4′-((propylamino)methyl)biphenyl-3-yl, 4′-((tert-butylamino)methyl)biphenyl-3-yl, 4′-((tert-pentylamino)methyl)biphenyl-3-yl, 4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl, 4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl, 4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl, 4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl, 4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl, 4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4′-(1-aminocyclopropyl)biphenyl-3-yl, 4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl, 4′-(2-acetamidoethyl)-biphenyl-3-yl, 4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl, 4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl, 4′-(2-aminoethyl)biphenyl-3-yl, 4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-2-methoxybiphenyl-3-yl, 4′-(aminomethyl)-2-methylbiphenyl-3-yl, 4′-(aminomethyl)-3′-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-4-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4′-(aminomethyl)-5-methoxybiphenyl-3-yl, 4′-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-6-fluorobiphenyl-3-yl, 4′-(aminomethyl)-6-methoxybiphenyl-3-yl, 4′-(aminomethyl)biphenyl-3-yl, 4′-(aminomethyl)biphenyl-4-yl, 4′-(azetidin-1-ylmethyl)biphenyl-3-yl, 4′-(morpholinomethyl)biphenyl-3-yl, 4′-(sulfamoyl)biphenyl-3-yl, 4-bromo-3-methylphenyl, 4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl, 4′-methylbiphenyl-3-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 5-chloronaphthalen-2-yl, 6-chloronaphthalen-2-yl, m-tolyl, naphthalen-2-yl, and phenyl.   
     
     
         11 . The compound according to  claim 1 , wherein R 1  is heteroaryl optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkyl, amino, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, halogen, hydroxyl, and oxo; and wherein said C 1 -C 6  alkyl is optionally substituted with one or more substituents selected from: amino and C 1 -C 6  alkoxy. 
     
     
         12 . The compound according to  claim 1 , wherein R 1  is selected from:
 (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl;   wherein each is optionally substituted with one or more substituents selected from: amino, bromo, chloro, cyclopropyl, ethyl, fluoro, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl; and wherein said ethyl and methyl are each optionally substituted with one or more substituents selected from: amino and methoxy.   
     
     
         13 . The compound according to  claim 1 , wherein R 1  is selected from:
 (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, 1,2,3,4-tetrahydropyrido[3,2-b]pyrazinyl, 1,2-dihydroquinolinyl, 1,4-dihydroquinolinyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, 1H-indolyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-1H-imidazo[4,5-b]pyridinyl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrobenzofuranyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 3H-imidazo[4,5-b]pyridinyl, (phenyl)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazolyl, benzofuranyl, chromanyl, isoquinolinyl, isoxazolyl, phenylthiophenyl, pyridinyl, pyrrolo[1,2-a]pyrimidinyl, quinolinyl, and thiazolyl;   wherein each is optionally substituted with one or more substituents selected from: 2-methoxyethyl, amino, aminomethyl, bromo, chloro, cyclopropyl, ethyl, fluoro, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl.   
     
     
         14 . The compound according to  claim 1 , wherein R 1  is selected from:
 1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,2-dihydroquinolin-6-yl, 1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazol-4-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 2,3-dihydrobenzofuran-5-yl, 3-(1H-pyrazol-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 3H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-6-yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 5-(1H-pyrazol-4-yl)pyridin-3-yl, 5-(phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-phenylthiophen-2-yl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, benzo[c][1,2,5]oxadiazol-4-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, isoxazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, quinolin-7-yl, and thiazol-4-yl;   wherein each is optionally substituted with one or more substituents selected from: 2-methoxyethyl, amino, aminomethyl, bromo, chloro, cyclopropyl, ethyl, fluoro, hydroxy, methoxy, methyl, oxo, propan-1-yl, and trifluoromethyl.   
     
     
         15 . The compound according to  claim 1 , wherein R 1  is selected from:
 (R)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, (S)-1,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-(2-methoxyethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,3,3-trimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl, 1,4-dimethyl-1,2,3,4-tetrahydropyrido[3,2-b]pyrazin-7-yl, 1,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1,8-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-5-methyl-1H-pyrazol-4-yl, 1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-6-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-7-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-3-yl, 1-ethyl-8-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 1H-benzo[d]imidazol-5-yl, 1H-indazol-5-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 1-methyl-4-oxo-1,4-dihydroquinolin-3-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl, 2,3-dihydrobenzofuran-5-yl, 2-aminothiazol-4-yl, 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl, 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl, 3,5-dimethylisoxazol-4-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-5-yl, 3-methyl-3H-imidazo[4,5-b]pyridin-6-yl, 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4-hydroxy-6-methylquinolin-3-yl, 4-hydroxy-7-methylquinolin-3-yl, 4-hydroxy-8-methylquinolin-3-yl, 4-hydroxyquinolin-3-yl, 4-methoxyquinolin-3-yl, 4-methyl-2-oxo-1,2-dihydroquinolin-6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl, 4-oxo-1,4-dihydroquinolin-3-yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5-bromo-6-chloropyridin-3-yl, 5-bromopyridin-3-yl, 5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl, 5-phenylthiophen-2-yl, 6-fluoro-4-hydroxyquinolin-3-yl, 7-chlorobenzo[c][1,2,5]oxadiazol-4-yl, 7-fluoro-4-hydroxyquinolin-3-yl, 8-fluoro-4-hydroxyquinolin-3-yl, benzofuran-2-yl, benzofuran-5-yl, chroman-6-yl, chroman-7-yl, isoquinolin-5-yl, pyridin-2-yl, pyridin-3-yl, pyrrolo[1,2-a]pyrimidin-3-yl, quinolin-3-yl, quinolin-6-yl, and quinolin-7-yl.   
     
     
         16 . The compound according to  claim 1 , R 2  is selected from:
 1,1-difluoroethyl, 1-fluoroethyl, 2-methylpropan-2-yl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, azetidin-3-yl, cyclobutyl, cyclopentyl, cyclopropyl, ethyl, fluoromethyl, isobutyl, isopentyl, isopropyl, methyl, oxetan-3-yl, propan-1-yl, sec-butyl, and vinyl; each optionally substituted with one or more substituents selected from: 2,2-difluorocyclopropyl, amino, cyano, cyclobutyl, cyclohexyl, cyclopropyl, ethoxy, hydroxy, hydroxymethyl, methoxy, oxo, and phenyl.   
     
     
         17 . The compound according to  claim 1 , wherein R 2  is selected from:
 1-(hydroxymethyl)cyclobutyl, 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, 3-amino-3-oxopropyl, 3-hydroxypropyl, 3-methoxypropyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl, isobutyl, isopropyl, methoxymethyl, methyl, and propan-1-yl.   
     
     
         18 . The compound according to  claim 1 , wherein R 3a , R 3b , R 3c , and R 3d  are each independently H or F. 
     
     
         19 . The compound according to  claim 1 , wherein R 3a , R 3b , R 3c , and R 3d  are each H. 
     
     
         20 . The compound according to  claim 1 , selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar 1  and Ar 2  are independently 1H-pyrazolyl, phenyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each is optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkyl, amino, C 3 -C 7  cycloalkyl, C 1 -C 6  haloalkyl, halogen, and sulfamoyl; and wherein said C 1 -C 6  alkyl and C 3 -C 7  cycloalkyl are each optionally substituted with one or more substituents selected from: amino, C 1 -C 6  alkylcarboxamide, —NH—C 3 -C 7 -cycloalkyl, —NH—C 1 -C 6 -alkylene-NH 2 , —NH—C, —C 6 -alkylene-O—C 1 -C 5 -alkyl, C 1 -C 6  alkylamino, C 1 -C 6  haloalkylamino, and heterocyclyl; 
 R 2  is selected from: C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and C 1 -C 6  haloalkyl; each optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkylenehydroxyl, amino, hydroxyl, and oxo; and 
 R 3a , R 3b , R 3c , and R 3d  are each independently H or halogen. 
 
     
     
         21 . The compound according to  claim 1 , selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 Ar 1  and Ar 2  together form a group selected from: (1H-pyrazolyl)phenyl, (1H-pyrazolyl)pyridinyl, (phenyl)pyridinyl, (pyridinyl)phenyl, (pyrimidinyl)phenyl, biphenyl, and phenylthiophenyl, wherein each is optionally substituted with one or more substituents selected from: 2-methylpropan-2-yl, amino, cyclopropyl, ethoxy, ethyl, fluoro, isopropoxy, methoxy, methyl, n-propyl, propan-2-yl, sulfamoyl, and trifluoromethyl; and wherein said 2-methylpropan-2-yl, cyclopropyl, ethyl, methyl, and propan-2-yl are each optionally substituted with 2,2,2-trifluoroethylamino, 2-aminoethylamino, 2-methoxyethylamino, 3-aminopropylamino, acetamido, amino, azetidin-1-yl, butylamino, cyclobutylamino, ethylamino, isobutylamino, isopropylamino, isopropylamino, methylamino, morpholino, propylamino, tert-butylamino, and tert-pentylamino; 
 R 2  is selected from: 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, isopropyl, and methyl; each optionally substituted with one or more substituents selected from: amino, hydroxy, hydroxymethyl, methoxy, and oxo; and 
 R 3a , R 3b , R 3c , and R 3d  are each H. 
 
     
     
         22 . The compound according to  claim 1 , selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 A r  and Ar 2  together form a group selected from: 
 3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl, 3-(1-ethyl-1H-pyrazol-4-yl)phenyl, 3-(1H-pyrazol-4-yl)phenyl, 3-(1-methyl-1H-pyrazol-4-yl)phenyl, 3-(1-propyl-1H-pyrazol-4-yl)phenyl, 3-(2-methylpyridin-4-yl)phenyl, 3-(3-fluoropyridin-2-yl)phenyl, 3-(4-methylpyridin-2-yl)phenyl, 3-(5-methylpyridin-2-yl)phenyl, 3-(6-(trifluoromethyl)pyridin-2-yl)phenyl, 3-(6-aminopyridin-3-yl)phenyl, 3-(6-fluoropyridin-2-yl)phenyl, 3-(6-methylpyridin-2-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyrimidin-5-yl)phenyl, 4′-((2,2,2-trifluoroethylamino)methyl)biphenyl-3-yl, 4′-((2-aminoethylamino)methyl)biphenyl-3-yl, 4′-((2-methoxyethylamino)methyl)biphenyl-3-yl, 4′-((3-aminopropylamino)methyl)biphenyl-3-yl, 4′-((butylamino)methyl)biphenyl-3-yl, 4′-((cyclobutylamino)methyl)biphenyl-3-yl, 4′-((ethylamino)methyl)biphenyl-3-yl, 4′-((isobutylamino)methyl)biphenyl-3-yl, 4′-((isopropylamino)methyl)biphenyl-3-yl, 4′-((methylamino)methyl)biphenyl-3-yl, 4′-((propylamino)methyl)biphenyl-3-yl, 4′-((tert-butylamino)methyl)biphenyl-3-yl, 4′-((tert-pentylamino)methyl)biphenyl-3-yl, 4′-(1-amino-2-methylpropan-2-yl)-4-ethoxybiphenyl-3-yl, 4′-(1-amino-2-methylpropan-2-yl)biphenyl-3-yl, 4′-(1-aminocyclopropyl)-2-methylbiphenyl-3-yl, 4′-(1-aminocyclopropyl)-4-ethoxybiphenyl-3-yl, 4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-yl, 4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-yl, 4′-(1-aminocyclopropyl)biphenyl-3-yl, 4′-(2-acetamidoethyl)-4-ethoxy-biphenyl-3-yl, 4′-(2-acetamidoethyl)-biphenyl-3-yl, 4′-(2-aminoethyl)-4-ethoxybiphenyl-3-yl, 4′-(2-aminoethyl)-6-methoxybiphenyl-3-yl, 4′-(2-aminoethyl)biphenyl-3-yl, 4′-(2-aminopropan-2-yl)-4-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-2-methoxybiphenyl-3-yl, 4′-(aminomethyl)-2-methylbiphenyl-3-yl, 4′-(aminomethyl)-3′-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-4-fluorobiphenyl-3-yl, 4′-(aminomethyl)-4-isopropoxybiphenyl-3-yl, 4′-(aminomethyl)-5-methoxybiphenyl-3-yl, 4′-(aminomethyl)-6-ethoxybiphenyl-3-yl, 4′-(aminomethyl)-6-fluorobiphenyl-3-yl, 4′-(aminomethyl)-6-methoxybiphenyl-3-yl, 4′-(aminomethyl)biphenyl-3-yl, 4′-(aminomethyl)biphenyl-4-yl, 4′-(azetidin-1-ylmethyl)biphenyl-3-yl, 4′-(morpholinomethyl)biphenyl-3-yl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, 4-(pyridin-4-yl)phenyl, 4′-(sulfamoyl)biphenyl-3-yl, 4-ethoxy-4′-((isopropylamino)methyl)biphenyl-3-yl, 4′-methylbiphenyl-3-yl, 5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl, 5-(4-(aminomethyl)phenyl)pyridin-3-yl, and 5-phenylthiophen-2-yl; 
 R 2  is selected from: 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-hydroxy-2-methylpropan-2-yl, 2-amino-2-oxoethyl, 2-hydroxyethyl, cyclopropyl, ethyl, isopropyl, methoxymethyl, and methyl; and 
 R 3a , R 3b , R 3c , and R 3d  are each H. 
 
     
     
         23 . The compound according to  claim 1 , selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from: C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, and C 1 -C 6  haloalkyl; each optionally substituted with one or more substituents selected from: C 1 -C 6  alkoxy, C 1 -C 6  alkylenehydroxyl, and hydroxyl; 
 R 3a , R 3b , R 3c , and R 3d  are each independently H or halogen; 
 R 4  is H or C 1 -C 6  alkyl; and 
 R 5a , R 5b , R 5c , and R 5d  are independently selected from: H, C 1 -C 6  alkyl, and halogen. 
 
     
     
         24 . The compound according to  claim 1 , selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from: 1,1-difluoroethyl, 2-methylpropan-2-yl, cyclopropyl, ethyl, 1-fluoroethyl, isopropyl, and methyl; each optionally substituted with one or more substituents selected from: hydroxy, hydroxymethyl, and methoxy; 
 R 3a , R 3b , R 3c , and R 3d  are each H; 
 R 4  is selected from: H, methyl, and ethyl; and 
 R 5a , R 5b , R 5c , and R 5d  are independently selected from: H, methyl, and fluoro. 
 
     
     
         25 . The compound according to  claim 1 , selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, solvates, and hydrates thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is selected from: 1-(hydroxymethyl)cyclopropyl, 1,1-difluoro-2-hydroxyethyl, 1-fluoroethyl, 1-hydroxy-2-methylpropan-2-yl, cyclopropyl, isopropyl, methoxymethyl, and methyl; 
 R 3a , R 3b , R 3c , and R 3d  are each H; 
 R 4  is selected from: H, methyl, and ethyl; 
 R 5a , R 5b , and R 5C  are independently selected from: H, methyl, and fluoro; and 
 R 5d  is H. 
 
     
     
         26 . The compound according to  claim 1 , wherein the stereochemistry for the C(3) carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogen is (R) and the stereochemistry for the C(2) carbon of the propyl group bonded to the hydroxyl group is (S). 
     
     
         27 . The compound according to  claim 1 , wherein the stereochemistry for the C(3) carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogen is (R) and the stereochemistry for the C(2) carbon of the propyl group bonded to the hydroxyl group is (R). 
     
     
         28 . The compound according to  claim 1 , wherein the stereochemistry for the C(3) carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogen is (S) and the stereochemistry for the C(2) carbon of the propyl group bonded to the hydroxyl group is (S). 
     
     
         29 . The compound according to  claim 1 , wherein the stereochemistry for the C(3) carbon of the oxa-azaspiro[4.5]decanyl group bonded to the nitrogen is (S) and the stereochemistry for the C(2) carbon of the propyl group bonded to the hydroxyl group is (R). 
     
     
         30 . The compound according to  claim 1 , selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
 (2S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-(8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 5);   (S)-1-(3-(2-hydroxyethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 88);   2-(3-((S)-2-hydroxy-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propoxy)phenylsulfonyl)acetamide (Compound 123);   (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(quinolin-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 136);   (S)-1-(3-(cyclopropylsulfonyl)phenoxy)-3-((R)-8-(1-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 154);   (S)-1-((R)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol (Compound 161);   (S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 163);   (S)-1-((R)-8-(4′-(aminomethyl)-4-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 169);   (S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 199);   (S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1,1-difluoro-2-hydroxyethylsulfonyl)phenoxy)propan-2-ol (Compound 210);   (S)-1-((S)-8-(4′-(2-aminoethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl) phenoxy)propan-2-ol (Compound 211);   (S)-1-((R)-8-(4′-(1-aminocyclopropyl)-6-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 217);   (S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxy-3′-fluorobiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 220);   (S)-1-((S)-8-(4′-(1-aminocyclopropyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 225);   (S)-1-((S)-8-(4′-(aminomethyl)-6-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl) phenoxy)propan-2-ol (Compound 227);   (S)-1-((S)-8-(4′-(aminomethyl)-5-methoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl) phenoxy)propan-2-ol (Compound 229);   (S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methoxymethylsulfonyl)phenoxy)propan-2-ol (Compound 230);   (S)-1-((S)-8-(4′-(aminomethyl)-4-ethoxybiphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy) propan-2-ol (Compound 232);   (2S)-1-(3-(1-fluoroethylsulfonyl)phenoxy)-3-((R)-8-(quinolin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 234);   (S)-1-((S)-8-(4′-((tert-butylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 240);   (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((tert-pentylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 241);   (S)-1-((S)-8-(4′-(azetidin-1-ylmethyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 243);   (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((propylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 244);   (S)-1-((S)-8-(4′-((butylamino)methyl) biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 245);   (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((S)-8-(4′-((2-methoxyethylamino)methyl)biphenyl-3-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 247);   3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-1-ethylquinolin-4(1H)-one (Compound 297);   (S)-1-(3-(1-(hydroxymethyl)cyclopropylsulfonyl)phenoxy)-3-((R)-8-(naphthalen-2-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)propan-2-ol (Compound 300);   (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(cyclopropylsulfonyl)phenoxy)propan-2-ol (Compound 309);   1-ethyl-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl) phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 310);   (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(methylsulfonyl)phenoxy)propan-2-ol (Compound 320);   (S)-1-((R)-8-(1H-pyrrolo[3,2-b]pyridin-6-ylsulfonyl)-1-oxa-8-azaspiro[4.5]decan-3-ylamino)-3-(3-(isopropylsulfonyl)phenoxy)propan-2-ol (Compound 321);   1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(methylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 322);   3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 326);   3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-8-methylquinolin-4-ol (Compound 327);   3-((R)-3-((S)-3-(3-(cyclopropylsulfonyl)phenoxy)-2-hydroxypropylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)-7-fluoroquinolin-4-ol (Compound 329); and   1-ethyl-8-fluoro-3-((R)-3-((S)-2-hydroxy-3-(3-(isopropylsulfonyl)phenoxy)propylamino)-1-oxa-8-azaspiro[4.5]decan-8-ylsulfonyl)quinolin-4(1H)-one (Compound 331).   
     
     
         31 - 37 . (canceled) 
     
     
         38 . A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a compound according to  claim 1 . 
     
     
         39 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         40 . A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         41 . A method for treating or preventing a beta-3 adrenergic receptor-mediated disorder in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         42 . A method for treating or preventing a beta-3 adrenergic receptor-mediated disorder in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to  claim 1 ;
 wherein said beta-3 adrenergic receptor-mediated disorder is selected from the list consisting of:   heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; and LVEF≤35% by echocardiography or ventricular contrast angiography.   
     
     
         43 - 47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising a compound according to  claim 30 , and a pharmaceutically acceptable carrier. 
     
     
         49 . A method for preparing a pharmaceutical composition comprising the step of admixing a compound according to  claim 30 , and a pharmaceutically acceptable carrier. 
     
     
         50 . A method for treating or preventing a beta-3 adrenergic receptor-mediated disorder in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to  claim 30 . 
     
     
         51 . A method for treating or preventing a beta-3 adrenergic receptor-mediated disorder in an individual, comprising administering to said individual in need thereof, a therapeutically effective amount of a compound according to  claim 30 ;
 wherein said beta-3 adrenergic receptor-mediated disorder is selected from the list consisting of:   heart failure; cardiac performance in heart failure; mortality, reinfarction, and/or hospitalization in connection with heart failure; acute heart failure; acute decompensated heart failure; congestive heart failure; severe congestive heart failure; organ damage associated with heart failure (e.g., kidney damage or failure, heart valve problems, heart rhythm problems, and/or liver damage); heart failure due to left ventricular dysfunction; heart failure with normal ejection fraction; cardiovascular mortality following myocardial infarction; cardiovascular mortality in patients with left ventricular failure or left ventricular dysfunction; left ventricular failure; left ventricular dysfunction; class II heart failure using the New York Heart Association (NYHA) classification system; class III heart failure using the New York Heart Association (NYHA) classification system; class IV heart failure using the New York Heart Association (NYHA) classification system; LVEF<40% by radionuclide ventriculography; and LVEF≤35% by echocardiography or ventricular contrast angiography.