Oxadiazole derivatives as dgat inhibitors

Abstract

Compounds of formula (I), and salts and pro-drugs thereof: wherein for example R 1 is optionally substituted aryl or heteroaryl; Y is a linking group selected from, for example, a direct bond, and a (substituted) alkyl chain; R 2 is an optionally substituted aryl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group; are described. Processes to make such compounds and their use as DGAT inhibitors, for example in the treatment of obesity, are also described.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt or prodrug thereof, wherein:
 R 1  is an optionally substituted aryl or optionally substituted heteroaryl group, wherein the optional substituents are one or more groups selected from —Z a , —X 2 —(CR 52 R 53 ) w —Z a , —X 2 —(CR 52 R 53 ) a X 3 —Z a , —(CR 52 R 53 ) a X 3 —Z a  and a functional group other than —X 2 —(CR 52 R 53 ) w —Z a  or —X 2 —(CR 52 R 53 ) a —X 3 —Z a ; 
 Y is a direct bond, (CR 40 R 41 ) s  or —X 6 (CR 40 R 41 ) t ; 
 each R 40  and R 41  is independently selected from hydrogen, (1-4C)alkyl, hydroxy, halo, halo(1-4C)alkyl, amino, cyano, (1-4C)alkoxy, (1-4C)haloalkoxy and ((1-3C)alkyl)CONH—; 
 s is 1 to 6; 
 t is 1 to 6, provided that the X 6  atom of —X 6 (CR 40 R 41 ) t — is attached to R 2  and that a single sp3 hybridised carbon atom does not carry two or more bonds to a heteroatom unless the heteratom is a halo; 
 R 2  is an optionally substituted aryl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group, wherein the optional substitutents are one or more groups selected from —Z, —X—(CR 42 R 43 ) u —Z, a group —X—(CR 42 R 43 ) v —X 1 —Z —(CR 42 R 43 ) v —X 1 —Z and a functional group other than —X—(CR 42 R 43 ) u —Z or —X—(CR 42 R 43 ) v —X 1 —Z; 
 Z and Z a  are independently selected from a hydrocarbyl group, a heterocyclic group and a combination thereof, wherein Z and Z a  are optionally substituted on any available atom by one or more functional groups, or by —X 7 —(CR 62 R 63 ) b R 64 ; 
 
       X, X 1 , X 2 , X 3 , X 6  and X 7  are linking groups independently selected from —C(O) x —, —O—, —S(O) y —, —NR 44 —, —C(O)NR 44 —, —OC(O)NR 44 —, —CH═NO—, —NR 44 C(O) x —, —NR 44 CONR 45 , —S(O) 2 NR 44 — and —NR 44 S(O) 2 —;
 x is 1 or 2; 
 y is 0, 1 or 2; 
 R 44  and R 45  are independently selected from hydrogen and C 1-6 alkyl; 
 u and w are independently selected from 0 to 6; 
 v, a and b are independently selected from an integer of from 1 to 6; 
 each R 42 , R 43 , R 52 , R 53 , R 62  and R 63  is independently selected from hydrogen, (1-4C)alkyl, hydroxy, halo, halo(1-4C)alkyl, amino, cyano, (1-4C)alkoxy, (1-4C)haloalkoxy, ((1-3C) alkyl)CONH—, carboxy or a carboxylic acid derivative; and 
 R 64  is a functional group. 
 
     
     
         2 . The compound according to  claim 1  or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 1  is an optionally substituted aryl group. 
     
     
         3 . The compound according to  claim 1  or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 1  is an optionally substituted monocyclic heteroaryl group. 
     
     
         4 . The compound according to  claim 1 , or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 1  is unsubstituted or is substituted by 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl, ethyl, ethynyl, benzyloxy, 3-chlorobenzyloxy, phenoxy, 4-chlorophenoxy, phenyl, benzoyl and anilino. 
     
     
         5 . The compound according to  claim 1  or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 1  is selected from phenyl, naphthyl, indanyl, pyrimidinyl, pyridyl, pyrazolyl, pyrazinyl, thiazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, pyrrolopyridyl, 1,3-benzodioxan-5-yl, benzthiazolyl, benzimidazolyl and quinolyl; optionally substituted with 1, 2 or 3 substituents independently selected from halo, (1-4C)alkyl, ethynyl, (1-4C)alkoxy, hydroxy, (1-4C)alkoxy(1-4C)alkoxy, methoxymethyl, cyanomethyl, hydroxy(1-4C)alkyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, cyano, methylthio, methylsulfonyloxy, methylsulfonyl, ethylsulfonyl, aminocarbonylamino, methoxycarbonylamino, methylcarbonylamino, (1-4C)alkoxycarbonyl, methoxycarbonylmethoxy, benzyloxy, pyridylmethoxy, phenoxy (optionally substituted by methoxy or halo), phenyl (optionally substituted by methoxycarbonyl or carboxy), benzyl, anilino, anilinocarbonyl, aminocarbonyl, benzoyl, benzoylamino, phenylsulfonyl, aminosulfonyl, cyclohexyl, methylpyrimidinyl, triazolyl and morpholino. 
     
     
         6 . The compound according to  claim 1  wherein Y is a direct bond. 
     
     
         7 . The compound according to  claim 1  wherein R 2  is a 5- or 6-membered aromatic ring of sub-structure (a) 
       
         
           
           
               
               
           
         
       
       wherein
 Z 1 , Z 2 , Z 3  and Z 4  are independently —CH—, —CR 6 — or a heteroatom selected from O, S, N(R 50 ) r , and Z 4  may additionally be a direct bond; 
 r is 0 or 1; 
 R 50  is hydrogen or C 1-6 alkyl; 
 R 4  is —Z, —X—(CR 42 R 43 ) u —Z, —X—(CR 42 R 43 ) v —X 1 —Z or —(CR 42 R 43 ) v —X 1 —Z; 
 each R 6  is independently selected from halo, cyano, nitro, amino, hydroxy, haloC 1-6 alkyl, —Z, —X—(CR 42 R 43 ) u —Z, —X—(CR 42 R 43 ) v —X 1 —Z and —(CR 42 R 43 ) v X 1 —Z; 
 and Z, X, X 1  R 42 , R 43 , u and v are as defined in  claim 1 . 
 
     
     
         8 . The compound according to  claim 1  wherein R 2  is substituted by a group Z. 
     
     
         9 . The compound according to  claim 6  or  claim 7  wherein Z is a group of sub formula (x), (y) or (z): 
       
         
           
           
               
               
           
         
       
       wherein
 each ring A or A′ is independently selected from an optionally substituted heterocyclic ring, an optionally substituted cycloalkyl ring and an optionally substituted aryl ring; 
 each R 60  is an optionally substituted (1-6C)alkyl, an optionally substituted (2-6C)alkenyl or an optionally substituted (2-6C)alkynyl; and 
 R 61  is an optionally substituted (1-6C)alkylene, an optionally substituted (2-6C)alkenylene or an optionally substituted (2-6C)alkynylene. 
 
     
     
         10 . The compound according to  claim 1  or  claim 5 , or a pharmaceutically-acceptable salt or prodrug thereof, wherein R 2 —Y is selected from:
 4-(piperazino)phenyl, substituted on the available piperazine nitrogen by a substituent selected from (1-4C)alkyl, acyl, benzyl, ethoxycarbonyl, tert-butoxycarbonyl, pyridyl, cyclopropylmethyl and methoxyethyl;   4-(piperazino)-3-methyl-phenyl, substituted on the available piperazine nitrogen by a substituent selected from acyl and tert-butoxycarbonyl;   4-(piperazino)pyridyl (substituted on the available piperazine nitrogen by a substituent selected from (1-4C)alkyl, acyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoyl, fluorobenzoyl, cyanobenzoyl, methylbenzoyl, pyridylcarbonyl, methylsulfonyl, methoxymethylcarbonyl, phenethylcarbonyl, anilinocarbonyl, benzylaminocarbonyl, phenoxycarbonyl, benzyloxycarbonyl and aminocarbonyl;   4-piperidinophenyl;   benzyloxyphenyl;   (1-4C)alkylphenyl;   pyridylmethoxyphenyl;   N-methylanilinophenyl;   biphenyl;   (chloro)biphenyl;   (methoxycarbonyl)biphenyl;   (ethoxycarbonylmethyl)biphenyl;   (carboxy)biphenyl;   morpholinophenyl;   dimethylmorpholinophenyl;   (morpholino)(chloro)phenyl;   (morpholino)(dichloro)phenyl;   (morpholino)(bromo)phenyl;   (morpholino)(methyl)phenyl;   (morpholino)(fluoro)phenyl;   (morpholino)(cyano)phenyl;   (morpholino)(allyloxycarbonyl)phenyl;   (morpholinoethoxy)phenyl;   morpholinopyridyl;   (morpholino)(chloro)pyridyl;   (morpholino)(fluoro)pyridyl;   phenxoypyridyl;   methoxypyridyl;   butoxypyridyl;   pyridyloxypyridyl;   hydroxybutylpyridyl;   thiomorpholinopyridyl;   phenoxypropyl;   (fluoro)(trifluoromethyl)phenyl;   (N-acyl)homopiperazinophenyl;   (N-acyl)piperazinopyrimidinyl;   methylbenzthiazolyl;   butylthiophenyl;   (methoxythiadiazolyl)aminosulfonylphenyl;   (difluorophenoxy)phenyl;   (dimethyl-oxo-pyridazinyl)phenyl;   (methyl-oxo-thiadiazinyl)phenyl;   methoxycarbonylpropylphenyl;   (methoxycarbonyl)methylthiophenyl;   (rnethoxycarbonyl)adamantyl;   carboxyadamantyl;   (methoxycarbonylmethyl)bi-cyclohexyl;   (carboxy)bi-cyclohexyl;   (ethoxycarbonylethyl)indanyl;   (carboxyethyl)indanyl;   (methoxycarbonyl)phenoxypropyl;   (carboxy)phenoxypropyl;   (carboxypropyl)phenyl;   dicarboxybutylphenyl;   carboxybutylphenyl;   propylsulfonylphenyl;   (carboxy)isopropylsulfonylphenyl;   phenoxyphenyl;   (methoxyphenoxy)phenyl;   methylphenoxyphenyl;   hydroxypropoxyphenyl;   ethoxyethoxyphenyl;   (dimethylaminocarbonyl)isopropoxyphenyl;   (carboxytnethyl)piperidinophenyl;   (methoxycarbonylmethyl)piperidinopyridyl;   (carboxymethyl)piperidinopyridyl;   (carboxy)piperidinopyridyl;   (methoxycarbonyl)piperidinopyridyl;   (carboxy)(methyl)piperidinopyridyl;   (methoxycarbonyl)(methyl)piperidinopyridyl;   (carboxymethyl)(methyl)piperidinopyridyl;   (methoxycarbonyl)piperidyl[(methyl)pyridyl];   (carboxy)piperidyl[(methyl)pyridyl];   (methoxycarbonylmethyl)piperidyl[(methyl)pyridyl];   (carboxymethyl)piperidyl[(methyl)pyridyl];   (carboxyethyl)piperidyl[(methyl)pyridyl];   (ethoxycarbonylethyl)piperidyl[(methyl)pyridyl];   [(methoxycarbonyl)piperidinocarbonylmethyl]cyclohexylphenyl;   [(carboxy)piperidinocarbonylmethyl]cyclohexylphenyl;   [(methoxycarbonyl)isopropylaminocarbonylmethyl]cyclohexylphenyl;   [(carboxy)isopropylaminocarbonylmethyl]cyclohexylphenyl;   [(methoxycarbonyl)pyrrolidinylcarbonylmethyl]cyclohexylphenyl;   [(carboxy)pyrrolidinylcarbonylmethyl]cyclohexylphenyl;   [(methoxycarbonyl)(hydroxy)pyrrolidinylcarbonylmethyl]cyclohexylphenyl;   [(carboxy)(hydroxy)pyrrolidinylcarbonylmethyl]cyclohexylphenyl,   (hydroxyisobutylaminocarbonylmethyl)cyclohexylphenyl;   [(tetrahydrodioxolopyrrolyl)carbonyl]methylcyclohexylphenyl;   (methoxycarbonylpyridyl)piperidino;   (carboxypyridyl)piperidino;   (aminocarbonylpyridyl)piperidino;   (carboxymethylpyridyl)piperidino;   (ethoxycarbonylmethyl)cyclohexylphenyl;   (methoxycarbonylmethyl)cyclohexylphenyl;   cyclohexylphenyl;   (carboxymethyl)cyclohexylphenyl;   (hydroxyethyl)cyclohexylphenyl;   (aminocarbonylmethyl)cyclohexylphenyl;   (cyanomethyl)cyclohexylphenyl;   carboxycyclohexylphenyl;   (dimethylaminocarbonylmethyl)cyclohexylphenyl;   [(N-hydroxyethyl-N-methylaminocarbonylmethyl]cyclohexylphenyl;   [N-(dihydroxypropyl)aminocarbonylmethyl]cyclohexylphenyl;   (aminomethyl)cyclohexylphenyl;   (tertbutoxycarbonylaminomethyl)cyclohexylphenyl;   (methoxycarbonyl)cyclohexyloxyphenyl;   (ethoxycarbonyl)cyclohexyloxyphenyl;   carboxycyclohexyloxyphenyl;   (methoxycarbonyl)cyclopentylphenyl;   (ethoxycarbonylmethyl)cyclopentylphenyl;   (carboxy)cyclopentylphenyl;   (carboxymethyl)cyclopentylphenyl;   (methoxycarbonyl)cyclobutylphenyl;   (ethoxycarbonyl)cyclobutylmethylphenyl;   (carboxy)cyclobutylphenyl;   (carboxy)cyclobutylmethylphenyl;   (carboxyethyl)cyclobutylphenyl;   (ethoxycarbonylethyl)cyclobutylphenyl;   (carboxymethyl)phenylcyclohexyl;   1-(ethoxycarbonyl)ethylcyclohexylphenyl;   1-carboxyethylcyclohexylphenyl;   (2-methoxycarbonyl)isopropy-2-ylcyclohexyl;   (2-carboxy)isoprop-2-ylcyclohexyl;   pyrrolidinylphenyl;   (methoxycarbonylmethyl)cyclohexylpyridyl; and   (carboxymethyl)cyclohexylpyridyl.   
     
     
         11 . The compound of formula (I) as claimed in  claim 1 , which is a compound of formula (IZA), or a pharmaceutically-acceptable salt or pro-drug thereof, 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from phenyl (optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl, ethyl, ethynyl, benzyloxy, 3-chlorobenzyloxy, phenoxy, 4-chlorophenoxy, phenyl, benzoyl and anilino), 2-pyridyl (optionally substituted by chlorophenoxy, chlorobenzyloxy or methoxyphenoxy, and/or substituted with a substituent selected from halo, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy and cyano), 3-pyridyl (optionally substituted as for 2-pyridyl), halopyrimidinyl and trifluoromethylthiazolyl;
 Z 2  is N or CH; 
 R ZA1  and R ZA2  are each independently hydrogen or methyl; 
 R ZA3  is hydrogen or methyl; 
 R 6ZA  is hydrogen, fluoro, chloro or methyl; 
 A is N or CH; 
 X ZA  is a direct bond, —CH 2 — or —O— (except when A is N); 
 m is 0, 1 or 2; 
 n is 0 or 1, provided that m+n=0, 1 or 2; and 
 p is 0 or 1. 
 
     
     
         12 . The compound of formula (I) as claimed in  claim 1 , which is a compound of formula (IZB), or a pharmaceutically-acceptable salt or pro-drug thereof, 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from phenyl (optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl, ethyl, ethynyl, benzyloxy, 3-chlorobenzyloxy, phenoxy, 4-chlorophenoxy, phenyl, benzoyl and anilino), 2-pyridyl (optionally substituted by chlorophenoxy, chlorobenzyloxy or methoxyphenoxy, and/or substituted with a substituent selected from halo, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy and cyano), 3-pyridyl (optionally substitued as for 2-pyridyl), halopyrimidinyl and trifluoromethylthiazolyl;
 Z 2  is N or CH; 
 R 6ZB  is hydrogen, fluoro, chloro or methyl; and 
 X ZB  is O or S. 
 
     
     
         13 . The compound of formula (I) as claimed in  claim 1 , which is a compound of formula (IZC), or a pharmaceutically-acceptable salt or pro-drug thereof, 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from phenyl (optionally substituted with 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methyl, ethyl, ethynyl, benzyloxy, 3-chlorobenzyloxy, phenoxy, 4-chlorophenoxy, phenyl, benzoyl and anilino), 2-pyridyl (optionally substituted by chlorophenoxy, chlorobenzyloxy or methoxyphenoxy, and/or substituted with a substituent selected from halo, trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy and cyano), 3-pyridyl (optionally substitued as for 2-pyridyl), halopyrimidinyl and trifluoromethylthiazolyl;
 Z 2  is N or CH; 
 R 6ZC  is hydrogen, fluoro, chloro or methyl; 
 R ZC  is selected from (1-4C)alkyl, acyl, benzyl, ethoxycarbonyl, tert-butoxycarbonyl, pyridyl, cyclopropylmethyl, methoxyethyl, benzoyl, fluorobenzoyl, cyanobenzoyl, methylbenzoyl, pyridylcarbonyl, methylsulfonyl, methoxymethylcarbonyl, phenethylcarbonyl, anilinocarbonyl, benzylaminocarbonyl, phenoxycarbonyl, benzyloxycarbonyl and aminocarbonyl. 
 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A method for inhibiting DGAT1 activity in a warm-blooded animal in need of such treatment comprising administering to said animal an effective amount of a compound of formula (I) as claimed in  claim 1  or a pharmaceutically-acceptable salt thereof. 
     
     
         17 . A method of treating diabetes mellitus and/or obesity in a warm-blooded animal in need of such treatment comprising administering to said animal an effective amount of a compound of formula (I) as claimed in  claim 1  or a pharmaceutically-acceptable salt thereof. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . A pharmaceutical composition comprising a compound of formula (I) as claimed in  claim 1  or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable excipient or carrier. 
     
     
         21 . A process for preparing a compound according to  claim 1  comprising one of the following steps, wherein all variables are as hereinbefore defined for a compound of formula (I) unless otherwise stated:
 a) reacting a compound of formula (I) to form another compound of formula (I);   b) reacting an amine of formula (2) with a carboxylate salt of formula (3);   
       
         
           
           
               
               
           
         
         c) cyclizing a compound of formula (4) wherein X is S or O; 
       
       
         
           
           
               
               
           
         
         d) when R 2  of formula (I) is substituted by piperazinyl, reacting the piperazine nitrogen with R 5 -LG wherein LG is a leaving group and R 5  is hydrocarbyl or a functional group; 
       
       
         
           
           
               
               
           
         
         e) when R 2  is aryl and is substituted by aryl, by transition metal catalysed aromatic substitution; 
       
       
         
           
           
               
               
           
         
         f) when R 2  is substituted by piperazinyl, by reductive alkylation of the piperazine nitrogen with R 5 —CHO wherein R 5  is hydrocarbyl; 
       
       
         
           
           
               
               
           
         
         g) reacting halogenated R 2  with an amide of formula (7) followed by subsequent removal of protecting group P 1 , 
       
       
         
           
           
               
               
           
         
         wherein Hal is halogen; 
         and thereafter optionally removing any protecting groups, and/or forming a pharmaceutically-acceptable salt or prodrug thereof.