Carbamoyl Compounds as DGAT1 Inhibitors 190

Abstract

DGAT-1 inhibitor compounds of formula (1), pharmaceutically-acceptable salts and pro-drugs thereof are described, together with pharmaceutical compositions, processes for making them and their use in treating, for example, obesity wherein, for example, Ring A is optionally substituted 2,6-pyrazindiyl; X is ═0; Ring B is optionally substituted 1,4-phenylene; Y 1 is a direct bond or —O—; Y 2 is —(CH 2 ) r — wherein r is 2 or 3; n is 0 or n is 1 when Y 1 is a direct bond between Ring B and Ring C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane; Ring C is optionally substituted (4-6C)cycloalkane, (7-10C)bicycloalkane, (8-12C)tricycloalkane, phenylene or pryidindiyl; L is a direct bond or —O—; p is 0, 1 or 2 and when p is 1 or 2 R A1 and R A2 are each independently hydrogen or (1-4C)alkyl; Z is carboxy or a mimic or bioisostere thereof.

1 . A compound of formula (I), or a pharmaceutically-acceptable salt, or pro-drug thereof, 
       
         
           
           
               
               
           
         
         wherein 
         Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each optionally substituted on an available carbon atom by one or two substituents independently selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano; 
         X is ═O or ═S; 
         Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links via the same or adjacent atoms) ring selected from pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionally substituted on an available carbon atom by one or two substituents independently selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; 
         Y 1  is a direct bond between Ring B and Ring C or Y 1  is —O—, —S— or —NRa— wherein Ra is hydrogen or (1-4C)alkyl; 
         Y 2  is —(CH 2 ) r — wherein r is 2 or 3, and Y 2  is linked at the same carbon atom as Y 1  in Ring C and Y 2  is linked at an adjacent carbon atom to Y 1  in Ring B; 
         n is 0 or n is 1 when Y 1  is a direct bond between Ring B and Ring C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or 6-membered spino-ring system is formed and Ring C is tri-linked; 
         Ring C is a di-linked (excluding links via the same or adjacent atoms) ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and (8-12C)tricycloalkane each optionally substituted on an available carbon atom, including the ring carbon atom bearing the Z-containing group, by one substituent selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; 
         or Ring C is a di-linked (excluding links via the same or adjacent atoms) ring selected from phenylene, pryidindiyl, piperidinediyl N-linked to Y 1 , piperazinediyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl, pyrazoldiyl and azabicyclo[3.1.0]hexanediyl; 
         each optionally substituted on an available carbon atom by up to four substituents independently selected from fluoro, chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl; 
         L is a direct bond to Ring C, —O—, —S— or —NH—; 
         p is 0 (when L is a direct bond), 1 or 2 and when p is 1 or 2 R AI  and R A2  are each independently hydrogen or (1-4C)alkyl or R A1  and R A2  are linked together to form a (3-6C)spiroalkyl ring; 
         Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRc wherein Rb and Rc are independently selected from hydrogen and (1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted by carboxy or a mimic or bioisostere thereof; 
         and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing group defined above may be optionally substituted by up to 3 fluoro atoms; with the proviso that the compound (4-(4-(6-carbamoyl-pyridin-2-yl)phenyl)cyclohexyl)acetic acid is excluded. 
       
     
     
         2 . A compound of formula (I), or a pharmaceutically-acceptable salt, or pro-drug thereof, as claimed in  claim 1 , wherein
 Ring A is 2,6-pyrazindiyl, 3,5-pyridindiyl or 2,6-pyridindiyl, each optionally substituted on an available carbon atom by one or two substituents independently selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano;   X is ═O or ═S;   Ring B is 1,4-phenylene or Ring B is a di-linked (excluding links via the same or adjacent atoms) ring selected from pyridindiyl, furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl; each optionally substituted on an available carbon atom by one or two substituents independently selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl;   Y 1  is a direct bond between Ring B and Ring C or Y 1  is —O—, —S— or —NRa— wherein Ra is hydrogen or (1-4C)alkyl;   Y 2  is —(CH 2 ) r — wherein r is 2 or 3, and Y 2  is linked at the same carbon atom as Y 1  in Ring C and Y 2  is linked at an adjacent carbon atom to Y 1  in Ring B;   n is 0 or n is 1 when Y 1  is a direct bond between Ring B and Ring C and when Ring B is 1,4-phenylene and Ring C is (4-6C)cycloalkane, so that a 5- or 6-membered spiro-ring system is formed;   Ring C is a di-linked (excluding links via the same or adjacent atoms) ring or ring system chosen from (4-6C)cycloalkane, (7-10C)bicycloalkane and (8-12C)tricycloalkane each optionally substituted on an available carbon atom, including the ring carbon atom bearing the Z-containing group, by one substituent selected from hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;   or Ring C is a di-linked (excluding links via the same or adjacent atoms) ring selected from phenylene, pryidindiyl, piperidinediyl N-linked to Y 1 , furandiyl, thiophendiyl, pyrroldiyl, oxazoldiyl, thiazoldiyl, imidazoldiyl, isoxazoldiyl, isothiazoldiyl and pyrazoldiyl;   each optionally substituted on an available carbon atom by up to four substituents independently selected from fluoro, chloro, bromo, cyano, (1-4C)alkyl, (1-4C)alkoxy and (1-4C)alkoxy(1-4C)alkyl;   L is a direct bond to Ring C, —O—, —S— or —NH—;   p is 0, 1 or 2 and when p is 1 R A1  and R A2  are each independently hydrogen or (1-4C)alkyl or R A1  and R A2  are linked together to form a (3-6C)spiroalkyl ring;   Z is carboxy or a mimic or bioisostere thereof, hydroxy or —CONRbRc wherein Rb and Rc are independently selected from hydrogen and (1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted by carboxy or a mimic or bioisostere thereof;   and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing group defined above may be optionally substituted by up to 3 fluoro atoms.   
     
     
         3 . A compound of formula (IA) as claimed in  claim 1  or  2 , or a pharmaceutically-acceptable salt, or pro-drug thereof, 
       
         
           
           
               
               
           
         
         wherein X, Ring A, Ring B, Y 1 , p, R AI , R A2  and Z are as defined in  claim 1  or  2 . 
       
     
     
         4 . A compound of formula (IB) as claimed in  claim 1  or  2 , or a pharmaceutically-acceptable salt, or pro-drug thereof, 
       
         
           
           
               
               
           
         
         wherein X, Ring A, Ring B, Y 1 , p, R A1 , R A2  and Z are as defined in  claim 1  or  2 . 
       
     
     
         5 . A compound as claimed in any one of  claims 1  to  4 , or a pharmaceutically-acceptable salt, or pro-drug thereof, wherein X is ═O;
 Ring A is 2,6-pyrazindiyl optionally substituted on an available carbon atom by one or two substituents independently selected from linear (1-3C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, methoxymethyl, amino and cyano; 
 Ring B is 1,4-phenylene optionally substituted on an available carbon atom by one or two substituents independently selected from halo, amino, cyano, (1-4C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-4C)alkoxy and (1-4C)alkoxy-(1-4C)alkyl; 
 Ring C is 1,4-cyclohexane; 
 n is 0 and Y 1  is a direct bond or Y 1  is —O—; 
 L is a direct bond; 
 p is 1 and R A1  and R A2  are each hydrogen; 
 Z is carboxy, a tetrazole group, —C(O)NHS(O) 2 Me, hydroxy or —CONRbRc wherein Rb and Rc are independently selected from hydrogen and (1-4C)alkyl, which (1-4C)alkyl group may be optionally substituted by carboxy; and wherein any carbon atom in a linear (1-3C)alkyl, (1-2C)alkoxy, (1-4C)alkyl or (1-4C)alkoxy containing group defined above may be optionally substituted by up to 3 fluoro atoms. 
 
     
     
         6 . A compound as claimed in any one of  claims 1  to  5 , or a pharmaceutically-acceptable salt, or pro-drug thereof, wherein Ring A is 2,6-pyrazindiyl optionally substituted on an available carbon atom by one or two linear (1-3C)alkyl substituents. 
     
     
         7 . A compound as claimed in  claim 1  or  2  selected from
 {trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetic acid; 
 3,5-Dimethyl-6-[4-(trans-4-{2-[(methylsulfonyl)amino]-2-oxoethyl}cyclohexyl)-phenyl]pyrazine-2-carboxamide; 
 6-{4-[trans-4-(2-Amino-2-oxoethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide; 
 N-({trans-4-[4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl]cyclohexyl}acetyl)-2-methylalanine; 
 6-{4-[trans-4-(2-Hydroxyethyl)cyclohexyl]phenyl}-3,5-dimethylpyrazine-2-carboxamide; 
 (trans-4-{4-[6-Carbamoyl-5-(difluoromethyl)-3-methylpyrazin-2-yl]phenyl}cyclohexyl)acetic acid; 
 {trans-4-[4-(6-Carbamoyl-3-ethyl-5-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic acid; 
 {trans-4-[4-(6-Carbamoyl-5-ethyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic acid 
 and {trans-4-[4-(6-Carbamoyl-3-methylpyrazin-2-yl)phenyl]cyclohexyl}acetic acid; 
 2-((1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-yl)acetic acid; 
 (1r,4s)-5′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2′,3′-dihydrospiro[cyclohexane-1,1′-indene]-4-carboxylic acid; 
 2-((1r,4r)-4-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)cyclohexyl)-2-methylpropanoic acid 
 2-(1-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)pyrrolidin-3-yl)acetic acid; 
 (1R,5S,6r)-3-(4-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid; 
 6-(4-((1r,4r)-4-((1H-Tetrazol-5-yl)methyl)cyclohexyl)phenyl)-3,5-dimethylpyrazine-2-carboxamide; 
 4′-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)biphenyl-4-carboxylic acid; 
 Methyl trans-4-{4-[6-(aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}-cyclohexanecarboxylate; 
 trans-4-{4-[6-(Aminocarbonyl)-3-methylpyrazin-2-yl]phenyl}cyclo-hexanecarboxylic acid; or a pharmaceutically-acceptable salt of any of these. 
 
     
     
         8 . A compound as claimed in any one of  claims 1  to  6  wherein a pro-drug thereof is an ester of a carboxy group selected from a (1-6C)alkyl ester, a (1-6C)alkoxymethyl ester, a (1-6C)alkanoyloxymethyl ester, a phthalidyl ester, a (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl ester, a 1,3-dioxolan-2-ylmethyl ester, a (1-6C)alkoxycarbonyloxyethyl ester, an aminocarbonylmethyl ester and a mono- or di-N-((1-6C)alkyl) version of an aminocarbonylmethyl ester. 
     
     
         9 . A compound as claimed in any one of  claims 1  to  6  wherein a mimic or bioisostere of a carboxy group is selected from —SO 3 H, —S(O) 2 NHR 13 , S(O) 2 NHC(O)R 13 , —CH 2 S(O) 2 R 13 , —C(O)NHS(O) 2 R 13 , —C(O)NHOH, —C(O)NHCN, —CH(CF 3 )OH, C(CF 3 ) 2 OH, —P(O)(OH) 2  and groups of sub-formula (ω-(i′) below 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein where p in sub-formula (k) is 1 or 2, R 27  and R 28  are independently selected from hydrogen, hydroxy, (1-6C)alkoxy, thiol, (1-6C)alkylthio, —C(O)R 29 , —S(O)R 30 , —SO 2 R 31 , —NR 32 R 33 , —NHCN, halogen and trihalomethyl, where R 29 , R 30  and R 31  are —OR 34 , (1-6C)alkyl, —NR 32 R 33  or trihalomethyl, R 32  and R 33  are independently selected from hydrogen, (1-6C)alkyl, —SO 2 R 34  and —COR 35 , where R 35  is (1-6C)alkyl or trihalomethyl, and R 34  is hydrogen, (1-6C)alkyl or trihalomethyl and R 13  is selected from hydrogen, (1-6C)alkyl, hydroxy, halo, amino, cyano, ((1-3 C)alkyl)CONH—, carboxy, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, carbamoyl, N-((1-6C)alkyl)carbamoyl, halo((1-6C)alkyl) (such as trifluoromethyl), (1-6C)alkylsulphonyl or (1-6C)alkylsulphinyl. 
       
     
     
         10 . A compound according to any one of  claims 1  to  9  or a pharmaceutically-acceptable salt, or pro-drug thereof for use as a medicament. 
     
     
         11 . A compound, or a pharmaceutically-acceptable salt, or pro-drug thereof, for use as a medicament as claimed in  claim 10  for treating diabetes mellitus and/or obesity in a warm-blooded animal such as a human being. 
     
     
         12 . The use of a compound according to any one of  claims 1  to  9 , or a pharmaceutically-acceptable salt, or pro-drug thereof, in the manufacture of a medicament for use in the production of an inhibition of DGAT-1 activity in a warm-blooded animal such as a human being. 
     
     
         13 . The use of a compound of formula (I), or a pharmaceutically-acceptable salt, or pro-drug thereof, as claimed in  claim 12 , in the manufacture of a medicament for use in the treatment of diabetes mellitus and/or obesity in a warm-blooded animal such as a human being. 
     
     
         14 . A method of treating diabetes mellitus and/or obesity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound according to any one of  claims 1  to  9 , or a pharmaceutically-acceptable salt, or pro-drug thereof. 
     
     
         15 . A pharmaceutical composition which comprises a compound of formula (I) as claimed in any one of  claims 1  to  9 , or a pharmaceutically-acceptable salt, or pro-drug thereof, in association with a pharmaceutically-acceptable excipient or carrier.