Novel mch receptor antagonists

Abstract

The present invention relates to a melanin concentrating hormone antagonist compound of formula (I) wherein R 1 , R a , R b , R 2 , L 1 , R 3 , R 4 and R 5 are as defined, or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture of diasteromers thereof useful in the treatment, obesity and related diseases.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein: 
         “ ” is optionally a bond to form a double bond; 
         R 1  is independently selected from the group consisting of —CH 3 , halo, —CF 3 , —OCH 3 , —OCF 3 , —O—C 3 -C 4  cycloalkyl, —SO 7 CH 3 , and —N(CH 3 ) 2 ; 
         R a  and R b  are independently hydrogen, fluoro, chloro, or —OCH 3 ; 
         R 2  is hydrogen or —CH 3 ; 
         L 1  is selected from the group consisting of a bond, —OCH 2 CH 2 —, —OCH 2 CH 2 CH 2 —, —CF 2 CH 2 CH 2 —, —CHFCH 2 CH 2 —, —CH(OH)CH 2 CH 2 —, —NHC(O)CH 2 —, —C(O)CH 2 CH 2 —, —C(O)NHCH 2 CH 2 —, —NH(CO)CH 2 CH 2 CH 2 —, and —C(O)NHCH 2 CH 2 CH 2 ; 
         R 3  and R 4  combine together with the nitrogen atom to which they are attached to form an optionally substituted 4 to 7-member nitrogen containing heterocyclic ring; or one of R 3  and R 4  combine with L 1  at a position α, β, γ, or, δ to the nitrogen of NR 3 R 4  to form a 4 to 7-member nitrogen containing heterocyclic ring with L 1 ; wherein each 4 to 7-member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is optionally substituted with one or two groups independently selected from oxo, hydroxy, halo, —CH 3 , —C 3 -C 6  cycloalkyl, and —NR 6 R 6′ ; 
         R 5  is hydrogen, chloro, fluoro, cyano, methyl, or —OCH 3 ; 
         R 6  and R 6′  are independently selected from the group consisting of hydrogen, and —CH 3 ; 
         provided that when L 1  is a bond then “ ” does not optionally form a double bond; provided that the compound is not N-{4-[2-(4-chloro-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide, hydrochloride salt; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein:
 “ ” is optionally a bond to form a double bond; 
 R 1  is independently selected from the group consisting of —CH 3  halo, —OCH 3 , —OC 3 -C 4  cycloalkyl, and —CF 3 ; 
 R a  and R b  are independently hydrogen, or chloro; 
 R 2  is hydrogen; 
 L 1  is selected from the group consisting of a bond, —OCH 2 CH 2 —, —CF 2 CH 2 CH 2 —, —CHFCH 2 CH 2 —, —CH(OH)CH 2 CH 2 —, —OCH 2 CH 2 CH 2 , —NHC(O)CH 2 —, —C(O)CH 2 CH 2 —, —C(O)NHCH 2 CH 2 —, and —C(O)NHCH 2 CH 2 CH 2 —; 
 R 3  and R 4  combine together and with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 member nitrogen containing heterocyclic ring; or one of R 3  and R 4  combine with L 1  at a position α, β, γ, or, δ to the nitrogen of NR 3 R 4  to form a 4 to 7 member nitrogen containing heterocyclic ring with L 1 ; wherein each 4 to 7-member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is selected from the group consisting of azetidinyl, morpholino, pyrrolidinyl, imidazolyl, piperazinyl, and piperidinyl and each is optionally substituted with one or two groups independently selected from the group consisting of oxo, halo, hydroxy, —CH 3 , and —NR 6 R 6′ ; 
 R 5  is selected from the group consisting of —OCH 3 , chloro, and fluoro; 
 R 6  and R 6′  are independently selected from the group consisting of hydrogen and; —CH 3 ; 
 provided that when L 1  is a bond then   does not optionally form a double bond; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . (canceled) 
     
     
         4 . A compound according to  claim 1  wherein:
 R 1  is methyl, chloro, —OCH 3 , fluoro, trifluoromethyl, or cyclopropoxy; 
 R a  and R b  are independently hydrogen, fluoro, or —OCH 3 ; 
 R 2  is hydrogen; 
 L 1  is selected from the group consisting of a bond, —OCH 2 CH 2 —, —NHC(O)CH 2 —, —C(O)CH 2 CH 2 —, and —C(O)NHCH 2 CH 2 —; 
 R 3  and R 4  combine together and with the nitrogen atom to which they are attached form an optionally substituted 4 to 7 member nitrogen containing heterocyclic ring; or one of R 3  and R 4  combine with L 1  at a position α, β, or γ to the nitrogen of NR 3 R 4  to form a 4 to 7 member nitrogen containing heterocyclic ring with L 1 ; wherein each 4 to 7-member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is selected from the group consisting of pyrrolidinyl, morpholino, piperidinyl, piperazinyl, imidazolyl, and azetidinyl and each is optionally substituted with one or two groups independently selected from hydroxy, methyl, fluoro, —N-methylamine, —N,N-dimethylamine, oxo, cyclopropyl and cyclobutyl; 
 R 5  is hydrogen, —OCH 3 , cyano, fluoro, or chloro; 
 provided that when L 1  is a bond then “ ” does not optionally form a double bond; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . (canceled) 
     
     
         6 . A compound according to  claim 1  wherein:
 R 1  is chloro, trifluoromethyl, or methoxy; 
 R a  and R b  are independently selected from hydrogen, fluoro, and chloro; 
 R 2  is hydrogen; 
 L 1  is a bond —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —; 
 R 3  and R 4  combine together and with the nitrogen atom to which they are attached form a 4 to 7-member nitrogen containing heterocyclic ring selected from the group consisting of pyrrolidinyl, morpholino, piperidinyl, piperazinyl, imidazolyl, and azetidinyl wherein each 4 to 7 member nitrogen containing heterocyclic ring is optionally substituted with one or two groups selected from hydroxy, methyl, fluoro, —N-methylamine, N,N-dimethylamine, oxo, cyclopropyl and cyclobutyl; 
 R 5  is hydrogen, —OCH 3 , cyano, fluoro, or chloro; 
 provided that when L 1  is a bond then “ ” does not optionally form a double bond; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         7 . A compound according to  claim 1  wherein:
 R 1  is chloro, —OCH 3 , trifluoromethyl, or trifluoromethoxy; 
 R a  and R b  are both hydrogen; 
 R 2  is hydrogen; 
 L 1  is selected from the group consisting of —NHC(O)CH 2 —, —C(O)CH 2 CH 2 —, —C(O)NHCH 2 CH 2 , and —C(O)NHCH 2 CH 2 CH 2 —; 
 R 3  and R 4  combine together and with the nitrogen atom to which they are attached form an optionally substituted 4 to 7-member nitrogen containing heterocyclic ring; or one of R 3  and R 4  combine with L 1  at a position α, β, or γ to the nitrogen of NR 3 R 4  to form a 4 to 7 member nitrogen containing heterocyclic ring with L 1 ; wherein each 4 to 7-member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is selected from the group consisting of pyrrolidinyl, morpholino, piperidinyl, piperazinyl, imidazolyl, and azetidinyl and is optionally substituted with one or two groups independently selected from hydroxy, methyl, fluoro, —N-methylamine, N,N-dimethylamine, cyclobutyl, and oxo; 
 R 5  is selected from the group consisting of hydrogen, —OCH 3 , and chloro; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         8 . (canceled) 
     
     
         9 . A compound according to  claim 1  wherein:
 R 1  is chloro, fluoro, methoxy, trifluoromethyl, or trifluoromethoxy; 
 R a  and R b  are both hydrogen; 
 R 2  is hydrogen; 
 L 1  is —OCH 2 CH 2 —, —OCH 2 CH 2 CH 2 —; 
 R 3  and R 4  combine together to form a 4 to 7 member nitrogen containing heterocyclic ring selected from the group consisting of pyrrolidinyl, piperidinyl, diazepanyl, and morpholino and wherein each 4 to 7 member nitrogen containing heterocyclic ring is optionally substituted with a group consisting of —OH, —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , cyclobutyl, and fluoro; and 
 R 5  is hydrogen, methyl, methoxy, or cyano; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         10 . A compound according to  claim 1  wherein:
 R 1  is chloro, fluoro, —OCH 3 , trifluoromethyl or trifluoromethoxy; 
 R a  and R b  are independently selected from hydrogen, fluoro, and chloro; 
 R 2  is hydrogen; 
 L 1  is selected from the group consisting of —NHC(O)CH 2 —, —C(O)NHCH 2 CH 2 —, —NHC(O)CH 2 CH 2 CH 2 , and —C(O)NHCH 2 CH 2 CH 2 —; 
 R 3  and R 4  combine together and with the nitrogen atom to which they are attached form an optionally substituted 4 to 7-member nitrogen containing heterocyclic ring; or one of R 3  and R 4  combine with L 1  at a position α, β, or γ to the nitrogen of NR 3 R 4  to form a 4 to 7 member nitrogen containing heterocyclic ring with L 1 ; wherein each 4 to 7-member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is selected from the group consisting of pyrrolidinyl, piperidinyl, and morpholino and wherein each 4 to 7 member nitrogen containing heterocyclic ring formed by the combination of R 3  and R 4  or L 1  and either of R 3  and R 4  is optionally substituted with a group selected from the group consisting of —OH, —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , cyclobutyl, and fluoro; and 
 R 5  is hydrogen, chloro, fluoro, or —OCH 3 ; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         11 . A compound selected from the group consisting of:
 2-(4-Methoxy-phenyl)-6-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one, hydrochloride,   6-[3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-methoxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(2,4-Dichloro-phenyl)-6-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one,   6-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one, hydrochloride,   N-{4-[2-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide, hydrochloride,   2-(4-Chloro-phenyl)-6-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((R)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridine-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-(3-fluoro-4-piperazin-1-yl-phenyl)-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((S)-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((R)-pyrrolidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-(piperidin-4-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((R)-1-methyl-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((S)-1-methyl-piperidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-(1-methyl-azetidin-3-yloxy)-phenyl]-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-fluoro-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-(1-methyl-azetidin-3-yloxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-(3-methyl-3H-imidazol-4-ylmethoxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[4-((S)-3-dimethylamino-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((S)-3-methylamino-pyrrolidin-1-yl)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[4-((R)-3-dimethylamino-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[3-methoxy-4-((S)-4-methyl-5-oxo-morpholin-3-ylmethoxy)-phenyl]-6H-thieno[2,3-c]pyridin-7-one,   2-(4-Chloro-phenyl)-6-[4-(1-methyl-pyrrolidine-3-carbonyl)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   2-(4-Chloro-phenyl)-6-[4-(1-methyl-azetidine-3-carbonyl)-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   (±)-trans-2-(4-Chloro-phenyl)-6-[4-(4-hydroxy-1-methyl-pyrrolidin-3-yloxy)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride,   (±)-trans-2-(4-Chloro-phenyl)-6-[4-(4-hydroxy-pyrrolidin-3-yloxy)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride   (±)-1-Methyl-pyrrolidine-3-carboxylic acid {4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-phenyl}-amide, hydrochloride,   trans-2-(4-Chloro-phenyl)-6-[4-(4-hydroxy-1-methyl-pyrrolidin-3-yloxy)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride, Isomer 1, and   trans-2-(4-Chloro-phenyl)-6-[4-(4-hydroxy-1-methyl-pyrrolidin-3-yloxy)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one, hydrochloride, Isomer 2;   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . (canceled) 
     
     
         13 . The compound N-{4-[2-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide, hydrochloride salt. 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of treating obesity comprising administering a pharmaceutically effective amount of a compound according to  claim 1  to a patient in need thereof. 
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or diluent. 
     
     
         16 . Use of a compound according to  claim 1  as an appetite suppressant. 
     
     
         17 . Use of a compound according to  claim 1  for the treatment of obesity. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 13  that is N-{4-[4-(4-Chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenyl}-2-pyrrolidin-1-yl-acetamide.