Preparation and use of 1,5,6,7-tetrahydropyrrolo[3,2-C]pyridine derivatives for the treatment of obesity

Abstract

This invention relates to 1,5,6,7-tetrahydropynolo[3,2-c]pyridine derivatives which have been found to suppress appetite and induce weight loss. The invention also provides methods for synthesis of the compounds, pharmaceutical compositions comprising the compounds, and methods of using such compositions for inducing weight loss and treating obesity and obesity-related disorders.

1 . A compound of Formula (I)  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, trifluoromethyl, trifluoromethoxy, carboxyl, amino, cyano, nitro, (C 1 -C 6 )alkyl-carbonyl-amino, (C 1 -C 6 )alkyl-amino-carbonyl-amino, or phenyl optionally substituted with one or more halogen;  
 R 2  is a hydrogen, 
 halogen,  
 (C 1 -C 9 )alkyl optionally substituted with (C 1 -C 6 )alkoxy, trifluoromethyl, or with one or more fluorine,  
 phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-thio, trifluoromethyl, trifluoromethoxy, carboxyl, amino, cyano, nitro, (C 1 -C 6 )alkyl-carbonyl-amino, (C 1 -C 6 )alkyl-amino-carbonyl-amino, or phenyl, or  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro;  
 
 R 3  is hydrogen, (C 1 -C 6 )alkyl, or benzyl;  
 X is CH 2 ;  
 R 4  is 
 (C 2 -C 6 )alkyl group,  
 cyclic (C 3 -C 7 )alkyl group which is optionally substituted with one or more (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or fluorine,  
 2-hydroxy-1-propyl group, substituted at the 3-position with a (C 1 -C 6 )alkoxy, benzyloxy, phenoxy, pyridinyloxy, or furylmethoxy group; in which the benzyloxy, phenoxy, pyridinyloxy, or furylmethoxy group is optionally substituted on the phenyl, pyridinyl, or furyl ring with one or more halogen, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl,  
 benzyl group which is substituted on the phenyl ring with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 )alkyl-carbonyl-amino, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-amino, bis[(C 1 -C 6 )alkyl]-amino, or —NR 5 R 6 , 
 in which R 5  and R 6  of the —NR 5 R 6  moiety, together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, or fluorine,  
 
 phenyl substituted with one or more halogen, cyano, nitro, trifluoromethyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-amino-carbonyl, (C 1 -C 6 )alkyl-amino sulfonyl, (C 1 -C 6 )alkyl-sulfonyl, or a phenyl group,  
 piperidin-4-yl, piperidin-3-yl, or pyrrolidin-3-yl, unsubstituted or substituted on the nitrogen atom of the piperidine or pyrrolidine ring with (C 1 -C 6 )alkyl, hydroxy-substituted (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy-substituted (C 1 -C 3 )alkyl, benzyl, or a phenyl that is optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, or cyano,  
 —(C═O)—R 7 , 
 where R 7  is 
 (C 1 -C 9 )alkyl optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, fluorine, benzyloxy, or phenoxy, in which the benzyloxy or phenoxy group may optionally be substituted on the phenyl ring with one or more halogen,  
 (C 1 -C 6 )alkoxy, benzyloxy, or phenoxy, each of which may optionally be substituted with one or more (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, or fluorine,  
 phenyl, optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, hydroxy-substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, bis[(C 1 -C 6 )alkyl]-amino, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-sulfonyl-amino, (C 1 -C 6 )alkyl-carbonyl-amino, or (C 1 -C 6 )alkyl-amino-carbonyl-amino,  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical, each of which may be optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or nitro,  
 
 
 —(C═O)NR 8 R 9 , where R 8  and R 9  are each independently 
 hydrogen,  
 (C 1 -C 9 )alkyl optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, benzyloxy, trifluoromethyl, cyano, or fluorine,  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or nitro,  
 phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro, or  
 R 8  and R 9  may, together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical which is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, hydroxy-substituted (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy-substituted (C 1 -C 3 )alkyl, benzyl, phenyl, or fluorine, or  
 
 —SO 2 R 10 , where R 10  is 
 (C 1 -C 9 )alkyl optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, benzyloxy, trifluoromethyl, cyano, or fluorine,  
 benzyl in which the phenyl ring is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, or halogen,  
 phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro,  
 1- or 2-naphthyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, bis[(C 1 -C 6 )alkyl]-amino, or (C 1 -C 6 )alkyl-amino, or  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical, optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or nitro;  
 and pharmaceutical salts and esters thereof.  
 
 
 
   
   
       2 . (canceled)  
   
   
       3 . (canceled)  
   
   
       4 . The compound of  claim 1 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, or amino;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 (C 2 -C 6 )alkyl group,  
 cyclic (C 3 -C 7 )alkyl group which is optionally substituted with one or more (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or fluorine, or  
 2-hydroxy-1-propyl group, substituted at the 3-position with (C 1 -C 6 )alkoxy, benzyloxy, phenoxy, pyridinyloxy, or furylmethoxy group; in which the benzyloxy, phenoxy, pyridinyloxy, or furylmethoxy group is optionally substituted on the phenyl, pyridinyl, or furyl ring with one or more halogen, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;  
 and pharmaceutical salts and esters thereof.  
   
   
   
       5 . The compound of  claim 4 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 (C 2 -C 6 )alkyl group,  
 cyclopentyl or cyclohexyl, optionally substituted with one or more hydroxy or fluorine, or  
 2-hydroxy-1-propyl group, substituted at the 3-position with (C 1 -C 6 )alkoxy, benzyloxy, or phenoxy group; in which the benzyloxy or phenoxy group is optionally substituted on the phenyl ring with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;  
 and pharmaceutical salts and esters thereof.  
   
   
   
       6 . The compound of  claim 5 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 cyclopentyl or cyclohexyl, optionally substituted at the 2-position with hydroxy, or  
 2-hydroxy-1-propyl group, substituted at the 3-position with (C 1 -C 6 )alkoxy, benzyloxy, or phenoxy group; in which the benzyloxy or phenoxy group is optionally substituted on the phenyl ring with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;  
 and pharmaceutical salts and esters thereof.  
   
   
   
       7 . The compound of  claim 1 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, or amino;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 benzyl group which is substituted on the phenyl ring with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, trifluoromethyl, cyano, nitro, (C 1 -C 6 )alkyl-carbonyl-amino, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-amino, bis[(C 1 -C 6 )alkyl]-amino,  
 or —NR 5 R 6 , 
 in which R 5  and R 6  of the —NR 5 R 6  moiety, together with the nitrogen atom to which they are attached, form a 5- to 10-membered saturated or unsaturated heterocyclic radical optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, or fluorine;  
 and pharmaceutical salts and esters thereof.  
 
   
   
   
       8 . The compound of  claim 7 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 benzyl group which is substituted on the phenyl ring with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, (C 1 -C 6 )alkyl-carbonyl-amino, bis[(C 1 -C 6 )alkyl]-amino, or 1-pyrrolidinyl;  
 and pharmaceutical salts and esters thereof.  
   
   
   
       9 . The compound of  claim 1 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, or amino;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 —(C═O)—R 7 , 
 where R 7  is 
 (C 1 -C 9 )alkyl optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, fluorine, benzyloxy, or phenoxy, in which the benzyloxy or phenoxy group may optionally be substituted on the phenyl ring with one or more halogen,  
 (C 1 -C 6 )alkoxy, benzyloxy, or phenoxy, each of which may optionally be substituted with one or more (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy, trifluoromethyl, or fluorine,  
 phenyl, optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, hydroxy-substituted (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, bis[(C 1 -C 6 )alkyl]-amino, (C 1 -C 6 )alkyl-sulfonyl, (C 1 -C 6 )alkyl-sulfonyl-amino, (C 1 -C 6 )alkyl-carbonyl-amino, or (C 1 -C 6 )alkyl-amino-carbonyl-amino, or  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical, each of which may be optionally substituted with one or more of a halogen atom, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or nitro;  
 and pharmaceutical salts and esters thereof.  
 
 
   
   
   
       10 . The compound of  claim 9 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 —(C═O)—R 7 , 
 where R 7  is 
 (C 1 -C 9 )alkyl,  
 phenyl, optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, or cyano, or  
 3-pyridinyl or 4-pyridinyl;  
 and pharmaceutical salts and esters thereof.  
 
 
   
   
   
       11 . The compound of  claim 1 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, or amino;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 —SO 2 R 10 , where R 10  is 
 (C 1 -C 9 )alkyl optionally substituted with one or more hydroxy, (C 1 -C 6 )alkoxy, benzyloxy, trifluoromethyl, cyano, or fluorine,  
 benzyl in which the phenyl ring is optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, or halogen,  
 phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro,  
 1- or 2-naphthyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, bis[(C 1 -C 6 )alkyl]-amino, or (C 1 -C 6 )alkyl-amino, or  
 a 5- to 10-membered aromatic monocyclic or bicyclic heterocyclic radical, optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, cyano, or nitro;  
 and pharmaceutical salts and esters thereof.  
 
   
   
   
       12 . The compound of  claim 11 , wherein 
 R 1  is phenyl optionally substituted with one or more halogen or (C 1 -C 6 )alkyl;    R 2  is phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or trifluoromethyl;    R 3  is hydrogen or (C 1 -C 6 )alkyl;    X is CH 2 ;    R 4  is 
 —SO 2 R 10 , where R 10  is 
 (C 1 -C 9 )alkyl, or  
 phenyl optionally substituted with one or more halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, trifluoromethoxy, or cyano;  
 and pharmaceutical salts and esters thereof.  
 
   
   
   
       13 . (canceled)  
   
   
       14 . (canceled)  
   
   
       15 . (canceled)  
   
   
       16 . (canceled)  
   
   
       17 . (canceled)  
   
   
       18 . The compound of  claim 1  selected from the group consisting of: 
 1-(2-chlorophenyl)-2-(4-chlorophenyl)-5-cyclohexyl-3-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine hydrochloride;    1-(2-chlorophenyl)-2-(4-chlorophenyl)-5-cyclohexyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine hydrochloride;    1-(2-chlorophenyl)-2-(4-methoxyphenyl)-5-[4-(trifluoromethyl)benzoyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine;    1-(2-chlorophenyl)-5-(4-fluorobenzyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine hydrochloride;    (1S,2S)-2-[1-(2-chlorophenyl)-2-(4-chlorophenyl)-3-methyl-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]cyclohexanol hydrochloride; and    (1S,2S)-2-[1-(2-chlorophenyl)-2-(4-chlorophenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]cyclohexanol hydrochloride.    
   
   
       19 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier.  
   
   
       20 . A pharmaceutical composition comprising an effective amount of a compound of  claim 18 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier.  
   
   
       21 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more hypoglycemic agents.  
   
   
       22 . The pharmaceutical composition of  claim 21 , wherein said hypoglycemic agent is selected from the group consisting of insulin, biguanidines, sulfonylureas, insulin secretagogues, α-glycosidase inhibitors, and O 3 -adrenoreceptor agonists.  
   
   
       23 . A pharmaceutical composition comprising an effective amount of a compound of  claim 18 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more hypoglycemic agents.  
   
   
       24 . The pharmaceutical composition of  claim 23 , wherein said hypoglycemic agent is selected from the group consisting of insulin, biguanidines, sulfonylureas, insulin secretagogues, α-glycosidase inhibitors, and P 3 -adrenoreceptor agonists.  
   
   
       25 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more agents selected from the group consisting of HMG CoA reductase inhibitor, bile acid binding agent, fibric acid derivative, and agent that regulates hypertension.  
   
   
       26 . A pharmaceutical composition comprising an effective amount of a compound of  claim 18 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more agents selected from the group consisting of HMG CoA reductase inhibitor, bile acid binding agent, fibric acid derivative, and agent that regulates hypertension.  
   
   
       27 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more agents selected from the group consisting of agents that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety.  
   
   
       28 . A pharmaceutical composition comprising an effective amount of a compound of  claim 18 , or a pharmaceutically acceptable salt or ester thereof, in combination with a pharmaceutically acceptable carrier and one or more agents selected from the group consisting of agents that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety.  
   
   
       29 . A composition comprising an effective amount of a compound of  claim 1 , or a salt or ester thereof, in combination with an inert carrier.  
   
   
       30 . A composition comprising an effective amount of a compound of  claim 18 , or a salt or ester thereof, in combination with an inert carrier.  
   
   
       31 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       32 . The method of  claim 31 , wherein said obesity-related disorders include dyslipidemia, hypertriglyceridemia, hypertension, diabetes, Syndrome X, atherosclerotic disease, cardiovascular disease, cerebrovascular disease, peripheral vessel disease, cholesterol gallstones, cancer, menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis, and sleep apnea.  
   
   
       33 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18 .  
   
   
       34 . The method of  claim 33 , wherein said obesity-related disorders include dyslipidemia, hypertriglyceridemia, hypertension, diabetes, Syndrome X, atherosclerotic disease, cardiovascular disease, cerebrovascular disease, peripheral vessel disease, cholesterol gallstones, cancer, menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis, and sleep apnea.  
   
   
       35 . A method of regulating appetite and food intake comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       36 . A method of regulating appetite and food intake comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18 .  
   
   
       37 . A method of treating bulimia comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       38 . A method of treating bulimia comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18 .  
   
   
       39 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1  in combination with one or more hypoglycemic agents.  
   
   
       40 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18  in combination with one or more hypoglycemic agents.  
   
   
       41 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1  in combination with one or more agents that modulate digestion and/or metabolism.  
   
   
       42 . The method of  claim 41 , wherein said agents that modulate digestion and/or metabolism include agents that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety.  
   
   
       43 . The method of  claim 41 , wherein said agents that modulate digestion and/or metabolism include β 3 -adrenoreceptor agents.  
   
   
       44 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18  in combination with one or more agents that modulate digestion and/or metabolism.  
   
   
       45 . The method of  claim 44 , wherein said agents that modulate digestion and/or metabolism include agents that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety.  
   
   
       46 . The method of  claim 44 , wherein said agents that modulate digestion and/or metabolism include β 3 -adrenoreceptor agents.  
   
   
       47 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1  in combination with one or more agents selected from the group consisting of HMG CoA reductase inhibitor, bile acid binding agent, fibric acid derivative, and agent that regulates hypertension.  
   
   
       48 . A method of treating obesity and obesity-related disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18  in combination with one or more agents selected from the group consisting of HMG CoA reductase inhibitor, bile acid binding agent, fibric acid derivative, and agent that regulates hypertension.  
   
   
       49 . A method of treating CNS disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       50 . A method of treating cognition and memory disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       51 . A method of treating substance or behavioral addiction comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 1 .  
   
   
       52 . A method of treating CNS disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18 .  
   
   
       53 . A method of treating cognition and memory disorders comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18 .  
   
   
       54 . A method of treating substance or behavioral addiction comprising the step of administering to a patient in need thereof a pharmaceutically effective amount of a compound of  claim 18.