Patent Application: US-201514628373-A

Abstract:
the invention pertains to the use of fused bicyclo heterocyclic adducts of thiohydroxy pyridines or pyrimidines as diacylglycerol o - acyltransferase 1 inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith . other conditions also can be ameliorated or avoided , such as high postprandial triglycerides or diet - related hypertriglyceridemia , cardiovascular risk associated with excessive triglycerides , and insulin resistance / glucose intolerance in overweight patients , those with diabetes or other glucose metabolic disorders such as syndrome x and / or polycystic ovary disease .

Description:
for a variable that occurs more than one time in any substituent , its definition on each occurrence is independent of its definition at every other occurrence . combinations of substituents are permissible only if such combinations result in stable compounds . stable compounds are compounds , which can be isolated in a useful degree of purity from a reaction mixture . additionally , as used in the specification and the appended claims , unless specified to the contrary , the following terms have the meaning indicated below . the term “ alkyl ” refers to a straight or branched or cyclic chain hydrocarbon radical with only single carbon - carbon bonds . representative examples include methyl , ethyl , propyl , isopropyl , cyclopropyl , butyl , isobutyl , tert - butyl , cyclobutyl , pentyl , cyclopentyl , hexyl , and cyclohexyl , all of which may be optionally substituted . alkyl groups are c 1 - c 12 and include alkyl groups that are c 1 - c 8 in some embodiments . the term “ aryl ” refers to aromatic groups which have 5 - 14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl , heterocyclic aryl and biaryl groups , all of which may be optionally substituted . carbocyclic aryl groups are groups which have , in various embodiments , 6 - 10 or 6 - 14 ring atoms wherein the ring atoms on the aromatic ring are carbon atoms . carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups . heterocyclic aryl or heteroaryl groups are groups which have , in various embodiments , 5 - 10 or 5 - 14 ring atoms wherein 1 to 4 heteroatoms are ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms . suitable heteroatoms include oxygen , sulfur , nitrogen , and selenium . suitable heteroaryl groups include furanyl , thienyl , pyridyl , pyrrolyl , n - lower alkyl pyrrolyl , pyridyl - n - oxide , pyrimidyl , pyrazinyl , imidazolyl , and the like , all optionally substituted . the term “ biaryl ” represents aryl groups which have 5 - 14 atoms containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups . such groups may be optionally substituted . suitable biaryl groups include naphthyl and biphenyl . the term “ optionally substituted ” or “ substituted ” includes groups substituted by one to six substituents , independently selected from lower alkyl , lower aryl , lower aralkyl , lower cyclic alkyl , lower heterocycloalkyl , hydroxy , lower alkoxy , lower aryloxy , perhaloalkoxy , aralkoxy , lower heteroaryl , lower heteroaryloxy , lower heteroarylalkyl , lower heteroaralkoxy , azido , amino , halo , lower alkylthio , oxo , lower acylalkyl , lower carboxy esters , carboxyl , - carboxamido , nitro , lower acyloxy , lower aminoalkyl , lower alkylaminoaryl , lower alkylaryl , lower alkylaminoalkyl , lower alkoxyaryl , lower arylamino , lower aralkylamino , sulfonyl , lower - carboxamidoaryl , lower hydroxyalkyl , lower haloalkyl , lower alkylaminoalkylcarboxy -, lower aminocarboxamidoalkyl -, cyano , lower alkoxyalkyl , lower perhaloalkyl , and lower arylalkyloxyalkyl . “ substituted aryl ” and “ substituted heteroaryl ” refers to aryl and heteroaryl groups substituted with 1 - 3 substituents . these substituents are selected from the group consisting of lower alkyl , lower alkoxy , lower perhaloalkyl , halo , hydroxy , and amino . the term “- aralkyl ” refers to an alkylene group substituted with an aryl group . suitable aralkyl groups include benzyl , picolyl , and the like , and may be optionally substituted . “ heteroarylalkyl ” refers to an alkylene group substituted with a heteroaryl group . the term “ alkylaryl -” refers to an aryl group substituted with an alkyl group . “ lower alkylaryl -” refers to such groups where alkyl is lower alkyl . the term “ lower ” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10 , in one aspect up to and including 6 , and in another aspect one to four carbon atoms . such groups may be straight chain , branched , or cyclic . the term “ cyclic alkyl ” or “ cycloalkyl ” refers to alkyl groups that are cyclic of 3 to 10 carbon atoms , and in one aspect are 3 to 6 or 3 to 8 carbon atoms . suitable cyclic groups include norbornyl and cyclopropyl . such groups may be substituted . the term “ heterocyclic ”, “ heterocyclic alkyl ” or “ heterocycloalkyl ” refers to cyclic groups of 3 to 10 atoms , and in one aspect are 3 to 6 atoms , containing at least one heteroatom , in a further aspect are 1 to 3 heteroatoms . suitable heteroatoms include oxygen , sulfur , and nitrogen . heterocyclic groups may be attached through a nitrogen or through a carbon atom in the ring . the heterocyclic alkyl groups include unsaturated cyclic , fused cyclic and spirocyclic groups . suitable heterocyclic groups include pyrrolidinyl , morpholino , morpholinoethyl , and pyridyl . the terms “ arylamino ” ( a ), and “ aralkylamino ” ( b ), respectively , refer to the group — nrr ′ wherein respectively , ( a ) r is aryl and r ′ is hydrogen , alkyl , aralkyl , heterocycloalkyl , or aryl , and ( b ) r is aralkyl and r ′ is hydrogen , aralkyl , aryl , alkyl or heterocycloalkyl . the term “ acyl ” refers to — c ( o ) r where r is alkyl , heterocycloalkyl , or aryl . the term “ carboxy esters ” refers to — c ( o ) or where r is alkyl , aryl , aralkyl , cyclic alkyl , or heterocycloalkyl , all optionally substituted . the term “ oxo ” refers to ═ o in an alkyl or heterocycloalkyl group . the term “ amino ” refers to — nrr ′ where r and r ′ are independently selected from hydrogen , alkyl , aryl , aralkyl and heterocycloalkyl , all except h are optionally substituted ; and r and r ′ can form a cyclic ring system . the term “- carboxylamido ” refers to — conr 2 where each r is independently hydrogen or alkyl . the term “- sulphonylamido ” or “- sulfonylamido ” refers to — s (═ o ) 2 nr 2 where each r is independently hydrogen or alkyl . the term “ halogen ” or “ halo ” refers to — f , — cl , — br and — i . the term “ alkylaminoalkylcarboxy ” refers to the group alkyl - nr - alk - c ( o )— o — where “ alk ” is an alkylene group , and r is a h or lower alkyl . the term “ sulphonyl ” or “ sulfonyl ” refers to — so 2 r , where r is h , alkyl , aryl , aralkyl , or heterocycloalkyl . the term “ sulphonate ” or “ sulfonate ” refers to — so 2 or , where r is — h , alkyl , aryl , aralkyl , or heterocycloalkyl . the term “ alkenyl ” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon - carbon double bond and includes straight - chain , branched - chain and cyclic groups . alkenyl groups may be optionally substituted . suitable alkenyl groups include allyl . “ 1 - alkenyl ” refers to alkenyl groups where the double bond is between the first and second carbon atom . if the 1 - alkenyl group is attached to another group , e . g ., it is a w substituent attached to the cyclic phosphonate , it is attached at the first carbon . the term “ alkynyl ” refers to unsaturated groups which have 2 to 12 atoms and contain at least one carbon - carbon triple bond and includes straight - chain , branched - chain and cyclic groups . alkynyl groups may be optionally substituted . suitable alkynyl groups include ethynyl . “ 1 - alkynyl ” refers to alkynyl groups where the triple bond is between the first and second carbon atom . if the 1 - alkynyl group is attached to another group , e . g ., it is a w substituent attached to the cyclic phosphonate , it is attached at the first carbon . the term “ alkylene ” refers to a divalent straight chain , branched chain or cyclic saturated aliphatic group . in one aspect the alkylene group contains up to and including 10 atoms . in another aspect the alkylene chain contains up to and including 6 atoms . in a further aspect the alkylene groups contains up to and including 4 atoms . the alkylene group can be either straight , branched or cyclic . the term “ acyloxy ” refers to the ester group — o — c ( o ) r , where r is h , alkyl , alkenyl , alkynyl , aryl , aralkyl , or heterocycloalkyl . the term “ aminoalkyl -” refers to the group nr 2 - alk - wherein “ alk ” is an alkylene group and r is selected from — h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term “ alkylaminoalkyl -” refers to the group alkyl - nr - alk - wherein each “ alk ” is an independently selected alkylene , and r is h or lower alkyl . “ lower alkylaminoalkyl -” refers to groups where the alkyl and the alkylene group is lower alkyl and alkylene , respectively . the term “ arylaminoalkyl -” refers to the group aryl - nr - alk - wherein “ alk ” is an alkylene group and r is — h , alkyl , aryl , aralkyl , or heterocycloalkyl . in “ lower arylaminoalkyl -”, the alkylene group is lower alkylene . the term “ alkylaminoaryl -” refers to the group alkyl - nr - aryl - wherein “ aryl ” is a divalent group and r is — h , alkyl , aralkyl , or heterocycloalkyl . in “ lower alkylaminoaryl -”, the alkyl group is lower alkyl . the term “ alkoxyaryl -” refers to an aryl group substituted with an alkyloxy group . in “ lower alkyloxyaryl -”, the alkyl group is lower alkyl . the term “ aryloxyalkyl -” refers to an alkyl group substituted with an aryloxy group . the term “ aralkyloxyalkyl -” refers to the group aryl - alk - o - alk - wherein “ alk ” is an alkylene group . “ lower aralkyloxyalkyl -” refers to such groups where the alkylene groups are lower alkylene . the term “ alkoxyalkyl -” or “ alkyloxyalkyl -” refer to the group alkyl - o - alk - wherein “ alk ” is an alkylene group . in “ lower alkoxyalkyl -”, each alkyl and alkylene is lower alkyl and alkylene , respectively . the term “ alkylthioalkyl -” refers to the group alkyl - s - alk - wherein “ alk ” is an alkylene group . in “ lower alkylthioalkyl -” each alkyl and alkylene is lower alkyl and alkylene , respectively . the term “ amido ” refers to the nr 2 group next to an acyl or sulfonyl group as in nr 2 — c ( o )—, rc ( o )— nr 1 —, nr 2 — s (═ o ) 2 — and rs (═ o ) 2 — nr 1 —, where r and r 1 include — h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term “ carboxamido ” refers to nr 2 — c ( o )— and rc ( o )— nr 1 —, where r and r 1 include — h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term does not include urea , — nr — c ( o )— nr —. the terms “ sulphonamido ” or “ sulfonamido ” refer to nr 2 — s (═ o ) 2 — and rs (═ o ) 2 — nr 1 —, where r and r 1 include — h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term does not include sulfonylurea , — nr — s (═ o ) 2 — nr —. the term “ carboxamidoalkylaryl ” and “ carboxamidoaryl ” refer to an aryl - alk - nr 1 — c ( o ), and ar - nr 1 — c ( o )- alk -, respectively where “ ar ” is aryl , “ alk ” is alkylene , r 1 and r include h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term “ sulfonamidoalkylaryl ” and “ sulfonamidoaryl ” refer to an aryl - alk - nr 1 — s (═ o ) 2 —, and ar - nr 1 — s (═ o ) 2 —, respectively where “ ar ” is aryl , “ alk ” is alkylene , r 1 and r include — h , alkyl , aryl , aralkyl , and heterocycloalkyl . the term “ hydroxyalkyl ” refers to an alkyl group substituted with one — oh . the term “ haloalkyl ” refers to an alkyl group substituted with one halo . the term “ acylalkyl ” refers to an alkyl - c ( o )- alk -, where “ alk ” is alkylene . the term “ aminocarboxamidoalkyl -” refers to the group nr 2 — c ( o )— n ( r )- alk - wherein r is an alkyl group or h and “ alk ” is an alkylene group . “ lower aminocarboxamidoalkyl -” refers to such groups wherein “ alk ” is lower alkylene . the term “ heteroarylalkyl ” refers to an alkylene group substituted with a heteroaryl group . the term “ perhalo ” refers to groups wherein every c — h bond has been replaced with a c - halo bond on an aliphatic or aryl group . suitable perhaloalkyl groups include — cf 3 and — cfcl 2 . the term “ carboxylic acid moiety ” refers to a compound having a carboxylic acid group (— cooh ), and salts thereof , a carboxylic acid ester , or a carboxylic acid surrogate . suitable carboxylic acid surrogates include a tetrazole group , a hydroxamic acid group , a thiazolidinedione group , an acylsulfonamide group , and a 6 - azauracil . ( see , e . g ., the practice of medicinal chemistry ; wemuth , c . g ., ed . ; academic press : new york , 1996 ; p . 203 ). the phrase “ therapeutically effective amount ” means an amount of a compound or a combination of compounds that ameliorates , attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents , modifies , or delays the onset of one or more of the symptoms of a particular disease or condition . the term “ pharmaceutically acceptable salt ” includes salts of compounds of formula i and its prodrugs derived from the combination of a compound of this invention and an organic or inorganic acid or base . suitable acids include acetic acid , adipic acid , benzenesulfonic acid , (+)- 7 , 7 - dimethyl - 2 - oxobicyclo [ 2 . 2 . 1 ] heptane - 1 - methanesulfonic acid , citric acid , 1 , 2 - ethanedisulfonic acid , dodecyl sulfonic acid , fumaric acid , glucoheptonic acid , gluconic acid , glucuronic acid , hippuric acid , hydrochloride hemiethanolic acid , hbr , hcl , hi , 2 - hydroxyethanesulfonic acid , lactic acid , lactobionic acid , maleic acid , methanesulfonic acid , methylbromide acid , methyl sulfuric acid , 2 - naphthalenesulfonic acid , nitric acid , oleic acid , 4 , 4 ′- methylenebis [ 3 - hydroxy - 2 - naphthalenecarboxylic acid ], phosphoric acid , polygalacturonic acid , stearic acid , succinic acid , sulfuric acid , sulfosalicylic acid , tannic acid , tartaric acid , terphthalic acid , and p - toluenesulfonic acid . the term “ animal ” includes birds and mammals , in one embodiment a mammal , including a dog , cat , cow , horse , goat , sheep , pig or human . in one embodiment the animal is a human . in another embodiment the animal is a male . in another embodiment the animal is a female . the term “ hypercholesterolemia ” refers to presence of an abnormally large amount of cholesterol in the cells and plasma of the circulating blood . the term “ hyperlipidemia ” or “ lipemia ” refers to the presence of an abnormally large amount of lipids in the circulating blood . the term “ atherosclerosis ” refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium - sized arteries wherein such deposits provoke fibrosis and calcification . atherosclerosis raises the risk of angina , stroke , heart attack , or other cardiac or cardiovascular conditions . the term “ obesity ” refers to the condition of being obese . being obese is defined as a bmi of 30 . 0 or greater ; and extreme obesity is defined at a bmi of 40 or greater . “ overweight ” is defined as a body mass index of 25 . 0 to 29 . 9 ( this is generally about 10 percent over an ideal body weight ) the term “ impaired glucose tolerance ( igt )” refers to a condition known to precede the development of overt type 2 diabetes . it is characterized by abnormal blood glucose excursions following a meal . the current criteria for the diagnosis of igt are based on 2 - h plasma glucose levels post a 75 g oral glucose test ( 144 - 199 mg / dl ). although variable from population to population studied , igt progresses to full blown niddm at a rate of 1 . 5 to 7 . 3 % per year , with a mean of 3 - 4 % per year . individuals with igt are believed to have a 6 to 10 - fold increased risk in developing niddm . igt is an independent risk factor for the development of cardiovascular disease . the term “ insulin resistance ” is defined clinically as the impaired ability of a known quantity of exogenous or endogenous insulin to increase whole body glucose uptake and utilization . as insulin regulates a wide variety of metabolic processes in addition to glucose homeostasis ( e . g ., lipid and protein metabolism ), the manifestations of insulin resistance are diverse and include one or more of the following : glucose intolerance , hyperinsulinemia , a characteristic dyslipidemia ( high triglycerides ; low high - density lipoprotein cholesterol , and small , dense low - density lipoprotein cholesterol ), obesity , upper - body fat distribution , fat accumulation in the liver ( non - alcoholic fatty liver disease ), nash ( non - alcoholic steatohepatitis ), increased hepatic glucose output , reduced hepatic glucose uptake and storage into glycogen , hypertension , and increased prothrombotic and antifibrinolytic factors . this cluster of cardiovascular - metabolic abnormalities is commonly referred to as “ the insulin resistance syndrome ” or “ the metabolic syndrome ” and may lead to the development of type 2 diabetes , accelerated atherosclerosis , hypertension or polycystic ovarian syndrome . the metabolic syndrome ”“ the metabolic syndrome ” or “ metabolic syndrome x ” is characterized by a group of metabolic risk factors in one person . they include : central obesity ( excessive fat tissue in and around the abdomen ) atherogenic dyslipidemia ( blood fat disorders — mainly high triglycerides and low hdl cholesterol — that foster plaque buildups in artery walls ) raised blood pressure ( 130 / 85 mmhg or higher ) insulin resistance or glucose intolerance ( the body can &# 39 ; t properly use insulin or blood sugar ) prothrombotic state ( e . g ., high fibrinogen or plasminogen activator inhibitor [− 1 ] in the blood ) proinflammatory state ( e . g ., elevated high - sensitivity c - reactive protein in the blood ) according to the present invention , “ metabolic syndrome ” or “ metabolic syndrome x ” is identified by the presence of three or more of these components : fasting blood triglycerides greater than or equal to 150 mg / dl blood hdl cholesterol : men : less than 40 mg / dl women : less than 50 mg / dl blood pressure greater than or equal to 130 / 85 mmhg fasting glucose greater than or equal to 110 mg / dl the term “ metabolic disease ” includes diseases and conditions such as obesity , diabetes and lipid disorders such as hypercholesterolemia , hyperlipidemia , hypertriglyceridemia as well as disorders that are associated with abnormal levels of lipoproteins , lipids , carbohydrates and insulin such as metabolic syndrome x , diabetes , impaired glucose tolerance , atherosclerosis , coronary heart disease , cardiovascular disease . as used herein , the term “ significant ” or “ statistically significant ” means a result ( i . e . experimental assay result ) where the p - value is ≦ 0 . 05 ( i . e . the chance of a type i error is less than 5 %) as determined by an art - accepted measure of statistical significance appropriate to the experimental design . the present invention provides compounds that are useful for treating or preventing conditions and disorders associated with dgat in mammals , particularly humans . one aspect of the invention is directed towards the compounds represented by formula ( i ), pharmaceutically acceptable salts or stereoisomers thereof , q is q 1 , q 2 , q 3 , q 4 , q 5 , q 6 , q 7 , q 8 , or q 9 , as defined herein and for each of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 , q 7 , q 8 , or q 9 , common substituents found in the structures are defined as follows : r 1 is selected from the group consisting of h , ( c 1 - c 8 ) alkyl , halo ( c 1 - c 4 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , c ( o ) r a , or a and nr a r b ; optionally , when x is c ( r 4 ), r a or r b may be combined with r 4 or r 4 may be combined with r 1 to form a 5 -, 6 - or 7 - membered fused ring ; r a and r b are independently selected from the group consisting of h , ( c 1 - c 8 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , fluoro ( c 1 - c 8 ) alkyl , ( c 3 - c 8 ) cycloalkyl , aryl , heteroaryl and aryl ( c 1 - c 4 ) alkyl ; r 2 and r 3 are independently selected from the group consisting of h , ( c 1 - c 8 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , c ( o ) r a , co 2 r a , c ( o ) nr a r b , ( c 1 - c 4 ) alkylene - or a and ( c 1 - c 4 ) perfluoroalkyl ; or r 2 and r 3 may be combined to form a 3 -, 4 -, 5 - or 6 - membered spiro ring ; optionally , having from 0 to 3 heteroatoms selected from the group consisting of n , o and s ; each r 4 is independently selected from the group consisting of h , ( c 1 - c 8 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , fluoro ( c 1 - c 8 ) alkyl , aryl , aryl ( c 1 - c 4 ) alkyl , c ( o ) r a , co 2 r a and c ( o ) nr a r b ; r 6 is an optionally substituted aryl or optionally substituted heteroaryl group , wherein the optional substituents are one or more groups selected from h , ( c 1 - c 4 ) alkyl , halo , halo ( c 1 - c 4 ) alkyl , cyano , ( c 1 - c 4 ) alkoxy , ( c 1 - c 4 ) haloalkoxy , — c ( o ) x r a , — or a , — s ( o ) x r a , — nr a r b , — c ( o ) nr a r b , — nr a c ( o ) r b , — nraco nr a r b , — s ( o ) 2 nr a r b or — nr a s ( o ) 2 nr a r b where x is an integer of 1 or 2 ; r 8 is independently selected from halo , ( c 1 - c 6 ) alkyl , ( c 2 - c 6 ) alkenyl , aryl , heteroaryl , ( c 3 - c 8 ) cycloalkyl , cyano , ( c 1 - c 6 ) haloalkyl , ( c 1 - c 6 ) haloalkoxy , — or a , — o — c ( o )( r a ), — s ( r a ), — s ( o )( r b ), — s ( o ) 2 ( r b ), — c ( o )( r a ), — c ( o )( or a ), — n ( r a ) 2 , — n ( r a )— c ( o )( r a ), — c ( o ) n ( r a ) 2 , — s ( o ) 2 n ( r a ) 2 , —( cr a r b ) t or a , —( cr a r b ) t — o — c ( o )( r a ), —( cr a r b ) t s ( r a ), —( cr a r b ) t s ( o )( r b ), —( cr a r b ) t s ( o ) 2 ( r b ), —( cr a r a ) t c ( o )( r a ), —( cr a r b ) t c ( o )( or a ), —( cr a r b ) r n ( r a r b ) —( cr a r b ) t n ( r a )— c ( o )( r a ), —( cr a r b ) t c ( o ) n ( r a ) 2 , —( cr a r a ) t s ( o ) 2 n ( r a ) 2 or —( cr a r b ) t r a and wherein t is an integer of 1 , 2 , 3 , or 4 ; wherein j is selected from — nr a r b or — or a ; x is selected from the group consisting of c ( r 4 ) and n ; optionally , when x is c ( r 4 ), r a or r b may be combined with r 4 or r 4 may be combined with r 1 to form a 5 -, 6 - or 7 - membered fused ring ; e is selected from the group consisting of o and s ; r 5 is h or ( c 1 - c 4 ) alkyl ; x is n or c ( r 4 ) and when x is c ( r 4 ), r 4 may be combined with r 1 to form a 5 -, 6 - or 7 - membered fused ring ; r 2 and r 3 are as defined above or may be combined with r 5 to form a 3 -, 4 -, 5 - or 6 - membered spiro ring ; optionally , having from 0 to 3 heteroatoms selected from the group consisting of n , o and s ; r 7 is ( c 1 - c 8 ) alkyl , aryl , heteroaryl or ( c 3 - c 8 ) cycloalkyl ; wherein each of the aryl , heteroaryl and cycloalkyl is independently substituted with 1 , 2 , 3 , 4 , or 5 substituents independently selected from the group consisting of ( c 1 - c 8 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , — cn , halogen , ethylenedioxy , methylenedioxy , haloalkyl , — or a , — o — c ( o )( r a ), — s ( r a ), — s ( o )( r b ), — s ( o ) 2 ( r b ), — c ( o )( r a ), — c ( o )( or a ), — n ( r a ) 2 , — n ( r a )— c ( o )( r a ), — c ( o ) n ( r a ) 2 , — s ( o ) 2 n ( r a ) 2 , —( cr a r b ) t or a , —( cr a r b ) t — o — c ( o )( r a ), —( cr a r b ) t s ( r a ), —( cr a r b ) t s ( o )( r b ), —( cr a r b ) t s ( o ) 2 ( r b ), —( cr a r a ) t c ( o )( r a ), —( cr a r b ) t c ( o )( or a ), —( cr a r b ) t n ( r a r b ) —( cr a r b ) t n ( r a )— c ( o )( r a ), —( cr a r b ) t c ( o ) n ( r a ) 2 , —( cr a r a ) t s ( o ) 2 n ( r a ) 2 and —( cr a r b ) t r a , v is — nh —, — o —, —( cr a r b ) t —; where t is an integer of 1 , 2 , 3 , or 4 ; a is a fused ring selected from an aromatic 6 - membered ring containing 0 or 2 n atoms ; the number of r 8 substituents on a ring may be 0 , 1 or 2 and when two of said r 8 substituents are : a ) found on a ring ; b ) ( c 1 - c 6 ) alkyl and c ) attached to adjacent carbon atoms of the ring a , they may be joined together to form a 5 to 7 - membered carbocyclic ring ; and r c is h or ( c 1 - c 6 ) alkyl , hydroxyl ( c 2 - c 6 ) alkyl ; the number of r 8 substituents on a ring may be 0 , 1 , 2 or 3 and when two of said r 8 substituents are : a ) found on a ring ; b ) ( c 1 - c 6 ) alkyl and c ) attached to adjacent carbon atoms of the ring a , they may be joined together to form a 5 to 7 - membered carbocyclic ring they may be joined together to form a 5 to 7 - membered ring containing 0 , 1 , 2 or 3 heteroatoms selected from o , n , s ; or q 9 is a [ 5 , 5 ], [ 5 , 6 ], [ 6 , 5 ] and [ 6 , 6 ] bicylic heterocycle containing 1 to 4 n atoms where g 1 is connected through one of the ring n atoms ; g 1 and g 3 are independently selected from the group consisting of cyclo ( c 3 - c 8 ) alkylene , heterocyclo ( c 3 - c 8 ) alkylene , arylene and heteroarylene , optionally substituted with one or two groups independently selected from halo , ( c 1 - c 6 ) alkyl , ( c 2 - c 6 ) alkenyk ( c 1 - c 6 ) alkoxy , cyano , ( c 1 - c 6 ) haloalkyl , ( c 1 - c 6 ) haloalkoxy , ( c 1 - c 4 ) perfluoroalkyl ; — n ( r a r b ), — n ( r a )— c ( o )( r a ), — c ( o ) n ( r a ) 2 , — s ( o ) 2 n ( r a ) 2 , — s ( o ) 2 ( r b ) and — c ( o )( r a ). g 2 is selected from the group consisting of a bond , ( c 1 - c 4 ) alkylene , ( c 2 - c 4 ) alkenylene , o , n ( r a ) c ( o ), s and s ( o ) 2 ; wherein x is selected from null , o , nh , co , choh , s or s ( o ) 2 ; and y is selected from ( c 1 - c 4 ) alkylene , ( c 3 - c 8 )- cycloalkylene or ( c 3 - c 8 )- heterocycloalkylene , — ch ( r 9 ) c ( r 10 r 11 )— or — n ( r 9 ) c ( r 10 r 11 )— r 10 and r 11 are both hydrogen , and r 9 is hydrogen , ( c 1 - c 6 ) alkyl , ( c 1 - c 6 ) alkoxy , ( c 2 - c 6 ) alkenyl , phenoxy -( c 2 - c 6 ) alkyl , 1 - methyl - 1h - indol - 3 - yl , bis [( c 1 - c 6 ) alkyl ] amino -( c 2 - c 6 ) alkyl , 1 - piperidinyl -( c 2 - c 6 ) alkyl , 1 - pyrrolidinyl -( c 2 - c 6 ) alkyl , or 1 - morpholinyl -( c 2 - c 6 ) alkyl ; r 10 and r 11 are both hydrogen and r 9 is r 12 ( ch 2 ) m , where m is 0 to 3 , and r 12 is phenyl optionally substituted with one or more halogen , hydroxy , ( c 1 - c 6 ) alkyl , ( c 1 - c 6 ) alkoxy , trifluoromethyl or cyano ; r 10 and r 11 are both hydrogen and r 9 is r 12 ( ch 2 ) m , where m is 0 to 3 , and r 12 is 2 - pyridinyl , 3 - pyridinyl , or 4 - pyridinyl , each of which is optionally substituted with halogen , ( c 1 - c 6 ) alkyl , ( c 1 - c 6 ) alkoxy , trifluoromethyl or cyano ; or r 9 is hydrogen , and r 10 and r 11 together with the carbon atom to which they are attached , form a three to five - membered ring , with 0 to 2 heteroatoms independently selected from o , s or n ; or r 10 is hydrogen , and r 9 and r 11 together with the two carbon atoms to which they are attached , form a three - to six - membered ring with 0 to 2 heteroatoms independently selected from o , s or n ; x 1 and x 2 are independently selected from null , ( c ( r a r b )) n , o , nr a , s or co and n is 0 or 1 ; w is selected from h , ( c 1 - c 6 ) alkyl , aryl , heteroaryl or ( c 3 - c 8 ) cycloalkyl ; wherein each of the alkyl , aryl , heteroaryl and cycloalkyl is independently substituted with 1 , 2 , 3 , 4 , or 5 substituents independently selected from the group consisting of ( c 1 - c 6 ) alkyl , ( c 2 - c 8 ) alkenyl , ( c 2 - c 8 ) alkynyl , — cn , halogen , ethylenedioxy , methylenedioxy , haloalkyl , — or a , — o — c ( o )( r a ), — s ( r a ), — s ( o )( r b ), — s ( o ) 2 ( r b ), — c ( o )( r a ), — c ( o )( or a ), — n ( r a ) 2 , — n ( r a )— c ( o )( r a ), — c ( o ) n ( r a ) 2 , — s ( o ) 2 n ( r a ) 2 , —( cr a r b ) t or a , —( cr a r b ) t — o — c ( o )( r a ), —( cr a r b ) t s ( r a ), —( cr a r b ) t s ( o )( r b ), —( cr a r b ) t s ( o ) 2 ( r b ), —( cr a r a ) t c ( o )( r a ), —( cr a r b ) t c ( o )( or a ), —( cr a r b ) t n ( r a r b )—( cr a r b ) t n ( r a )— c ( o )( r a ), —( cr a r b ) t c ( o ) n ( r a ) 2 , —( cr a r a ) t s ( o ) 2 n ( r a ) 2 and —( cr a r b ) t r a , —( cr a r b ) t p ( o )( oh ) 2 , and —( cr a r b ) t p ( o )( oh )( r a ), wherein t is an integer of 1 , 2 , 3 , or 4 ; x 1 and x 2 may be combined to form a 5 -, 6 - or 7 - membered ring having from 0 to 3 heteroatoms selected from the group consisting of nr a , o and s ; or x 1 or x 2 may be combined with w to form a 5 -, 6 - or 7 - membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of nr a , o and s ; z 2 is z 1 , h , — oh , co 2 r a or — c ( o ) n ( r a ) 2 ; with a proviso that when x 2 is o and q is q 1 , q 2 , q 3 , q 4 , q 5 , q 6 , q 7 or q 9 , then x 1 is not ( c ( r a r b )) n and when q is q 8 then z is z 2 and z 2 is z 1 , h , — oh , co 2 r a or — c ( o ) n ( r a ) 2 . another aspect of the invention provides for pharmaceutically acceptable salts of the compounds of formula ( i ), in addition to those discussed in the definitions section of this application . such salts include the conventional non - toxic salts and the quaternary ammonium salts which are formed , for example , from inorganic or organic acids or bases by means well known in the art . for example , such acid addition salts include acetate , adipate , alginate , ascorbate , aspartate , benzoate , benzenesulfonate , bisulfate , butyrate , citrate , camphorate , camphorsulfonate , cinnamate , cyclopentanepropionate , digluconate , dodecylsulfate , ethanesulfonate , fumarate , glucoheptanoate , glycerophosphate , hemisulfate , heptanoate , hexanoate , hydrochloride , hydrobromide , hydroiodide , 2 - hydroxyethanesulfonate , itaconate , lactate , maleate , mandelate , methanesulfonate , 2 - naphthalenesulfonate , nicotinate , nitrate , oxalate , pamoate , pectinate persulfate , 3 - phenylpropionate , picrate , pivalate , propionate , succinate , sulfonate , tartrate , thiocyanate , tosylate , and undecanoate . base salts include alkali metal salts such as potassium and sodium salts , alkaline earth metal salts such as calcium and magnesium salts , and ammonium salts with organic bases such as dicyclohexylamine salts and n - methyl - d - glucamine . additionally , basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl , ethyl , propyl , and butyl chlorides , bromides and iodides ; dialkyl sulfates like dimethyl , diethyl , and dibutyl sulfate and diamyl sulfates ; long chain halides such as decyl , lauryl , myristyl and strearyl chlorides , bromides , and iodides ; aralkyl halides like benzyl and phenethyl bromides and others . another aspect of the invention provides pharmaceutical compositions formed by combining the compounds of this invention with pharmaceutically acceptable carriers , vehicles or diluents . these pharmaceutically acceptable compositions can , then , be administered in a variety of dosage forms such as tablets , powders , lozenges , syrups , injectable solutions and the like . these pharmaceutical compositions can , if desired , contain additional ingredients such as flavorings , binders and / or excipients . thus , one aspect of the invention provides pharmaceutical composition for oral administration . for example , tablets containing various excipients such as sodium citrate , calcium carbonate and / or calcium phosphate , may be employed along with various disintegrants such as starch , alginic acid and / or certain complex silicates , together with binding agents such as polyvinylpyrrolidone , sucrose , gelatin and / or acacia . additionally , lubricating agents such as magnesium stearate , sodium lauryl sulfate and talc are often useful for tabletting purposes . solid compositions comprising the aforementioned excipients , disintegrants and / or lubricating agents may also be employed as fillers in soft and hard filled gelatin capsules . additionally , materials such as lactose or milk sugar and high molecular weight polyethylene glycols can also be utilized in the preparation of soft or hard capsules disclosed herein . when aqueous suspensions or elixirs are desired for oral administration , the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents , coloring matter or dyes and , if desired , emulsifying or suspending agents , together with diluents such as water , ethanol , propylene glycol , glycerin and / or combinations thereof . tablets and capsules disclosed herein can also be formulated with enteric coatings known to those skilled in the art . for parenteral administration , solutions comprising compounds disclosed herein can be formulated in oils ( such as sesame or peanut oil ), aqueous propylene glycol , or in sterile aqueous solutions . aqueous solutions should be suitably buffered , if necessary , and the liquid diluent first rendered isotonic with sufficient saline or glucose . compounds formulated as discussed herein are suitable for intravenous , intramuscular , subcutaneous and intraperitoneal administration . in this connection , the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art . for intranasal administration or administration by inhalation , the compounds or compositions of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer , with the use of a suitable propellant , e . g ., dichlorodifluoromethane , trichlorofluoromethane , dichlorotetrafluoroethane , carbon dioxide or other suitable gas . in the case of a pressurized aerosol , the dosage unit may be determined by providing a valve to deliver a metered amount . the pressurized container or nebulizer may contain a solution or suspension of a compound of this invention . capsules and cartridges ( made , for example , from gelatin ) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch . methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known , or will be apparent in light of this disclosure , to those skilled in this art . methods of preparing pharmaceutical compositions are known to those skilled in the art ( see remington &# 39 ; s pharmaceutical sciences , mack publishing company , easton , pa ., 19th edition ( 1995 )). in another aspect of the invention , methods of inhibiting or reducing the activity of dgat - 1 in enterocytes are provided that comprise contacting an enterocyte with a composition comprising a compound of formula ( i ), or a pharmaceutically acceptable salt of a compound of formula ( i ). in this aspect of the invention , the enterocyte is contacted with an amount of the composition sufficient to inhibit dgat - 1 activity within the cell . this method can be conducted in vitro or in vivo . the terms “ treating ”, “ treated ”, or “ treatment ” as employed herein includes palliating , slowing progression and / or reducing symptoms associated with a disease , such as obesity , insulin resistance syndrome , type 2 diabetes , or adiposity . the phrase “ therapeutically effective amount ” means an amount of a compound of the present invention that ( i ) treats the particular disease , condition , or disorder , ( ii ) attenuates , ameliorates , or eliminates one or more symptoms of the particular disease , condition , or disorder , or ( iii ) delays the onset of one or more symptoms of the particular disease , condition , or disorder described herein . in another aspect of the invention , methods of treating a disease or condition amenable to treatment via dgat - 1 inhibition are provided . these methods comprise administering to a mammal a therapeutically effective amount of a compound of formula ( i ), or a pharmaceutically acceptable salt of the compound , either alone or in combination with an anti - diabetic agent as described above . conditions that can be treated in this aspect of the invention include type 2 diabetes , insulin resistance syndrome , obesity , impaired glucose tolerance , hyperglycemia , high postprandial triglycerides ( very common in diabetes ) or diet - or obesity - related hypertriglyceridemia , cardiovascular risk associated with excessive triglycerides , and insulin resistance and glucose intolerance ( e . g ., improved insulin sensitivity due to reduced deposition of liver and skeletal muscle fat ) seen in overweight patients , those with diabetes or other glucose metabolic disorders such as syndrome x , polycystic ovary disease or other disorders such as diabetic complications that arise from obesity . the present invention also relates to therapeutic methods for treating the above described conditions in a mammal , including a human , wherein a compound of formula ( i ) is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy . the appropriate dosage regimen , the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula ( i ) of this invention being used , the type of pharmaceutical compositions being used , the characteristics of the subject being treated and the severity of the conditions . in general , an effective dosage for the compounds of the present invention is in the range of 0 . 01 mg / kg / day to 1000 mg / kg / day , preferably 0 . 01 mg / kg / day to 600 mg / kg / day of active compound ( i . e ., a compound of formula ( i )) in single or divided doses ( for example , three doses of 200 mg / kg over the course of a day ). some variation in dosage will necessarily occur , however , depending on the condition of the subject being treated . the individual responsible for dosing will , in any event , determine the appropriate dose for the individual subject . practitioners will appreciate that “ kg ” refers to the weight of the subject measured in kilograms . the compounds or compositions of this invention may be administered in single ( e . g ., once daily ) or multiple doses or via constant infusion . the compounds of this invention may also be administered alone or in combination with pharmaceutically acceptable carriers , vehicles or diluents , in either single or multiple doses . the compounds or compositions of the present invention may be administered to a subject in need of treatment by a variety of conventional routes of administration , including orally and parenterally , ( e . g ., intravenously or subcutaneously ). further , the pharmaceutical compositions of this invention may be administered intranasally , as a suppository , or using a “ flash ” formulation , i . e ., allowing the medication to dissolve in the mouth without the need to use water . the compounds are preferably delivered via a route that accesses the alimentary tract , e . g ., orally or nasally . combination therapies utilizing compounds of formula ( i ) are provided by yet another aspect of the invention . thus , compounds of formula ( i ) can be administered in combination ( concomitantly or sequentially and as a single combined composition or as separate compositions that are separately administered ), with anti - diabetic and / or anti - obesity agents known to those skilled in the art . non - limiting examples of anti - obesity agents include : 1 ) central nervous system agents that affect neurotransmitters or neural ion channels , including antidepressants ( bupropion ), selective serotonin 2c receptor agonists , antiseizure agents ( topiramate , zonisamide ), some dopamine antagonists , and cannabinoid - 1 receptor antagonists ( rimonabant ); 2 ) leptin / insulin / central nervous system pathway agents , including leptin analogues , leptin transport and / or leptin receptor promoters , ciliary neurotrophic factor ( axokine ), neuropeptide y and agouti - related peptide antagonists , proopiomelanocortin and cocaine and amphetamine regulated transcript promoters , alpha - melanocyte - stimulating hormone analogues , melanocortin - 4 receptor agonists , and agents that affect insulin metabolism / activity , which include protein - tyrosine phosphatase - 1b inhibitors , peroxisome proliferator activated receptor - gamma receptor antagonists , short - acting bromocriptine ( ergoset ), somatostatin agonists ( octreotide ), and adiponectin ; 3 ) gastrointestinal - neural pathway agents , including those that increase cholecystokinin activity , increase glucagon - like peptide - 1 activity ( extendin 4 , liraglutide , dipeptidyl peptidase iv inhibitors ), and increase protein yy3 - 36 activity and those that decrease ghrelin activity , as well as amylin analogues ( pramlintide ); 4 ) agents that may increase resting metabolic rate (“ selective ” beta - 3 stimulators / agonist , uncoupling protein homologues , and thyroid receptor agonists ); and 5 ) other more diverse agents , including melanin concentrating hormone antagonists , phytostanol analogues , functional oils , p57 , amylase inhibitors , growth hormone fragments , synthetic analogues of dehydroepiandrosterone sulfate , antagonists of adipocyte 11b - hydroxysteroid dehydrogenase type 1 activity , corticotropin - releasing hormone agonists , inhibitors of fatty acid synthesis , carboxypeptidase inhibitors , indanones / indanols , aminosterols , and other gastrointestinal lipase inhibitors ( atl962 ). anti - diabetic agents that can be used in the aforementioned combination therapies include , and are not limited to : insulin ; sulfonylurea compounds , such as glyburide , tolbutamide , acetohexamide , tolazamide , chlorpropamide , glipizide , glimepiride or gliclazide ; meglitinides , such as repaglinide or nateglinide ; biguanides , such as metformin , phenformin or buformin ; thiazolidinediones , such as rosigliazone , pioglitozone or troglitazone , alpha - glucosidase inhibitors , such as miglitol or asarabose ; peptides or peptide analogs , such as glucagon - like peptide 1 , gastric inhibitory peptide , exenatide , exendin - 4 , liraglutide or taspoglatide ; dpp - iv inhibitors , such as vildagliptin or sitaliptin ; amylin analogs , such as pramlintide ; ppara / y ligands , such as aleglitazar , muraglitazar or tesaglitazar ; sglt ( sodium - dependent glucose transporter 1 ) or fbpase ( fructose 1 , 6 - bisphosphatase ) inhibitors , such as those disclosed in u . s . pat . nos . 6 , 967 , 193 ; 6 , 965 , 033 ; 6 , 919 , 322 ; 6 , 489 , 476 ; 6 , 399 , 782 ; or 6 , 110 , 903 each of which is hereby incorporated by reference in its entirety . numerous compounds of the invention have been synthesized and shown to target enterocytes and exhibit inhibition of dgat - 1 . various data are shown by way of example below . the physical characteristics of some molecules of the invention are included in table 1 below . the synthesis of compounds of formula ( i ), wherein the groups q , q 1 , q 2 , q 3 , q 4 , q 5 , q 6 , q 7 , q 8 , q 9 , g 1 , g 2 , g 3 , g 4 , z , z 1 , z 2 , x , x 1 , x 2 , t , e , j , a , d , t , r a , r b , r 1 , r 2 , r 3 , r 4 , r 5 , r 6 , r 7 , r 8 , r 9 , r 10 , r 11 , r 12 and integers t , m , or n have the meanings as set forth in the detailed description section unless otherwise noted , is exemplified in schemes 1 - 8 . compounds of the present invention can be prepared beginning with commercially available starting materials and using general synthetic techniques known to those of skill in the art . outlined below are reaction schemes suitable for preparing such compounds . as illustrated in scheme 1 , compounds of formula 5 can be synthesized starting from commercially available compounds such as of formula 1 . these carbonyl compounds upon wittig type condensation with methylenediphosphonate ester in presence of a base result in the homologoted unsaturated phosphonate adducts ( xu et al , j . org . chem ., 1996 , 61 , 7697 - 7701 ). the resulting olefins undergo facile hydrogenation to give trans - 1 , 4 - or 1 , 3 - substituted ( depending on n variable of the starting materials of formula 1 ) compounds of formula 2 . the conditions of such hydrogenations may be similar to the earlier reported protocols as in wo04047755 . preparation of compounds of formula 3 from 2 may be attained by selective preparation of monophosphonochloridate followed by reaction with aryl or heteroaryl or alkyl or cycloalkyl magnesium halides as previously reported ( morise et al , j . chem . soc . perkin trans . i , 1996 , 2179 - 2185 ). alternatively , h - phosphinates formed from compounds of formula 2 may be coupled to aryl or heteroaryl halide or triflate under palladium catalyzed reaction conditions to introduce - x2 - w group as in formula 3 ( bennett et al , j . chem . soc . perkin trans . i , 1995 , 1145 - 1151 ). synthesis of compounds of formula 4 from 3 can be attained as described earlier in wo04047755 . deprotection of phosphorus ester of 4 can be achieved by a variety of methods depending on the choice of r ′ group . alkyl esters undergo deprotection under bromotrimethyl silane ( tmsbr ) hydrolysis conditions . hexamethyl disilazane is used as an additive with tmsbr where the substrate is acid - sensitive . acid mediated deprotection conditions are used for t - butyl esters . in case of phenyl substituted esters , deprotection may be achieved by base hydrolysis . whereas , benzyl or allyl esters undergo deprotection in neutral conditions such as hydrogenation in the presence of a catalyst and reaction by palladium catalysis , respectively . these deprotection conditions exemplified for conversion of 4 to 5 may be utilized across all the synthetic sequences that are described herein ( schemes 1 - 8 ). alternatively , z group substitution may be introduced at a later stage of the synthesis as shown in scheme 3 . such a synthetic strategy may be applied to prepare compounds of formula 11 from 10 where q is substituted with q1 , q2 , q3 , q4 , q5 , q8 or q9 . compounds of formula 10 can be attained following earlier described procedures in wo04047755 , wo08067257 , wo08134690 , wo08134693 , wo06064189 , wo06134317 , wo07071966 , wo07138304 , wo07138311 , wo07141502 , wo07141517 , wo07141538 , wo07141545 , wo07144571 , and wo08129319 . introduction of z group substitution is accomplished by coupling of compounds of formula 7 with 10 . such coupling reactions where x 1 of 10 is o or s and leaving group ( lg ) of 7 is cl or a substituted or non - substituted phenyl group can be achieved by magnesium alkoxides mediated reactions ( wo07022073 ). compounds of formula 7 may be synthesized by a nucleophilic displacement reaction of 8 . in addition , compounds of formula 7 can be prepared by applying other methods known in the art . for example , pd - catalyzed reactions of aryl , heteroaryl or enol triflate ( kalek et al , org . lett ., 2008 , 10 , 4637 - 4640 , bonnaventure et al , j . org . chem . 2008 , 73 , 6330 - 6340 ) or base mediated reactions of benzylic type of halides with phosphinate 9 ( hubbard et al , bioorg . med . chem . lett ., 2008 , 18 , 679 - 681 . boyd et al , tetrahedron lett ., 1996 , 37 , 5425 - 5426 ; ando et al , j org . chem ., 1999 , 64 , 8406 - 8408 ), or by a well - known arbuzov type of reactions with 6 ( perumal et al , j org chem ., 2006 , 71 , 4778 - 4785 ). compounds that have heterocyclic substitution as in 15 may be obtained from 13 via coupling of precursors of formula 12 . such sequence to 15 may be a linear synthesis as in scheme 1 or convergent sequence as in scheme 3 . synthesis of compounds of formula 12 can be achieved from commercially available halomethylene phosphonate diesters via the transformations that were described earlier in scheme 1 , in the conversion of compounds of formula 2 to 3 . base mediated coupling of 12 and 13 to 14 and conversion to 15 may be achieved as described in wo04047755 . compounds of formula 17 ( scheme 4 ) can be synthesized from 16 where x ′″ is — oh or — nh 2 as described in wo09016462 . compounds of 16 where x ′″ is — oh may be attained starting from a commercially available hydroxyl substituted 1 following the chemistry described in scheme 1 . compounds where x ′″ in 16 is — nh 2 are obtained by direct nitration and reduction sequence ( wo07141502 ) from 2 , or via 16 where x ′″ is substituted with — oh , by pd mediated amination of corresponding triflate ( wo07141517 ). the methods described for amine precursor 16 may also be applied in the preparation of compounds of formula 19 with diverse g3 substitution . such amines of 16 or 19 can be utilized in the synthesis of compounds of formulae of 20 to 22 . synthetic procedures described in wo05044250 , wo06064189 , wo06134317 , wo07071966 , wo07138304 , wo07138311 , wo07141502 , wo07141517 , wo07141538 , wo07141545 , wo07144571 , wo08129319 may be utilized for the preparation of compounds of formulae of 20 to 22 . compounds of formula 25 can be attained from 16 where x ′″ is — nh 2 , via displacement reaction of a commercially available substituted pyrimidine , pyridine or a phenyl substituted precursor ( 23 ). reduction of the resulting displacement product followed by cyclization with a desired r 8 substituted carboxylic acid or aldehyde result in the compounds of formula 25 . alternatively , compounds of 25 can be prepared via a copper mediated n - arylation reaction of 26 and an appropriately functionalized heterocycle as 27 ( jacobsen et al , j . org . chem . 2006 , 71 , 9183 - 9190 ). compounds of formulae 31 and 32 can be made from 29 where x ″ is a group selected from br , i or triflate , utilizing the earlier described procedures ( wo07137103 , wo07137107 , wo06113919 ). preparation of 29 from 28 or 30 from corresponding unsaturated esters may be obtained by michael - type additions ( green , tetrahedron lett ., 1989 , 30 , 4807 - 4810 ). intermediates of formula 30 may be transformed to 29 by friedel - crafts acylation reaction ( zhao et al , j . med . chem ., 2008 , 51 , 380 - 383 ). preparation of compounds of 34 from intermediate 33 may be attained by utilizing the procedures described before ( wo07137103 , wo07137107 , wo06044775 , wo07016538 , wo08099221 , and wo09011285 ). substituted amino phosphonic acid esters can be made with the procedures that are well - known in the literature ( chandrasekhar et al , synlett , 2003 , 4 , 505 - 506 ). monoester 33 can be prepared from corresponding diesters via the reactions described earlier , from 2 to 3 . such compounds can also be made in enatiomerically pure form when r 10 and r 11 are not equivalent ( ordonez et al , tetrahedron , 2009 , 65 , 17 - 49 ). methods of preparation of compounds of the present invention described in schemes 2 to 8 delineate the synthesis of phosphorus esters , protected with r ′ group . such r ′ group may be selected from alkyl , allyl , aryl or benzyl substituents . these esters may be deprotected to compounds of formula i in conditions described for compounds of formula 5 from 4 in scheme 1 . the inhibition of dgat - 1 activity can be assessed in intestinal microsome preparations by monitoring the incorporation of radiolabeled fatty acyl - coa into dag . methods : commercial microsomal preparations containing 60 ug of protein are incubated in assay buffer [ 20 um 1 , 2 - didecanloyl glycerol , 5 um 14 c decanoyl - coa , 5 mm mgcl 2 , 0 . 4 % bsa , 0 . 1 % dimethyl sulfoxide ( dmso ), 50 mm hepes - ph 7 . 5 ] in the presence of varying concentrations of inhibitors that are dispensed from 100 % dmso stock solutions . final assay volumes are 200 ul . reactions are carried out for 45 minutes in 96 - well polystyrene microtiter plates at ambient temperature . following the ambient temperature incubation , assay mixtures are applied to a 96 - well filter plate ( catalog # mshvn4510 , millipore inc . ; billerica , mass .) under vacuum . the filter plate is pre - equilibrated with 100 ul of 70 % ethanol followed by 200 ul of assay buffer . filters are dried , removed and placed in scintillation vials with 4 ml of scintillation cocktail ( catalog # 6013329 ; perkinelmer inc . ; waltham , mass .). de novo 14 c - tag formed in the assay and trapped on the filters is quantified with use of a liquid scintillation counter ( model # ls6500 beckman coulter , inc . ; fullerton , calif .). the ic 50 is defined as the concentration of compound that results in a 50 % reduction in tag synthesis . the following screen can be used to evaluate the effects of dgat - 1 inhibitors on the export of dietary tags from the intestine to the circulation in rodents ( male sprague dawley rats or c57bl / 6 mice ). methods : animals ( housed 2 / cage ) are fasted overnight , and dosed ( po ) the next day with vehicle ( 1 % tween - 80 ) or test compound at doses ranging from 0 . 01 to 30 mg / kg , followed by an oral gavage of olive oil . blood samples are taken at baseline and at appropriate intervals over the course of 4 hours . serum tag levels are determined using the infinity triglyceride reagent per the manufacturer &# 39 ; s instructions . results : compounds 1 , 2 , and 5 reduced the auc 0 - 4h of serum tags following oral administration to sprague dawley rats at doses in the range of 0 . 1 to 30 mg / kg . these results confirm inhibition of enterocyte dgat - 1 by the compounds tested . pharmacokinetic studies in rats are useful for the identification of dgat - 1 inhibitors that have low oral bioavailability and show low systemic exposure ( i . e . low circulating levels in plasma ). methods : groups of male sprague dawley rats ( 200 - 250 g ) ( n = 3 / group ) were administered either an iv bolus ( 1 % tween - 80 , ph adjusted to 7 , vehicle ) or an oral gavage ( 50 % peg - 200 in 1 % tween - 80 vehicle ) of 5 mg / kg of each dgat - 1 inhibitor . blood ( edta ) was collected by tail nick at 0 . 5 , 1 , 2 , 4 , 8 , 10 - 12 and 24 hr post dose . following centrifugation of the blood to obtain plasma , the samples were analyzed by lc - ms / ms method for active metabolite . the pharmacokinetic parameters were calculated by noncompartmental analysis of the plasma concentration - time profile of the active metabolite . the oral bioavailability was determined by dividing the dose - normalized plasma auc value of the active metabolite following oral administration of the dgat - 1 inhibitor by the plasma auc value of the active metabolite after iv bolus administration . results : a summary of the key plasma pharmacokinetic parameters of the dgat - 1 inhibitors evaluated is shown in the table below . compounds of the invention that were tested have low oral bioavailability , & lt ; 10 %, and low systemic exposure as indicated by a cmax & lt ; 0 . 01 ug / ml . in contrast , known dgat inhibitors x , y , and z were found to have high oral bioavailability and high plasma exposure . methods : animals ( rats housed 1 / cage , or mice housed 2 / cage ) are fasted overnight . the next morning , animals are dosed ( po ) with vehicle ( 1 % tween - 80 ) or test compound ( doses ranging from 0 . 1 to 30 mg / kg ). food is then presented immediately following vehicle or compound administration . food is weighed manually at 1 - 3 hour intervals to determine any inhibitory effects on food intake . results : compounds of the invention reduced food intake significantly following oral administration at doses ranging from 0 . 1 to 30 mg / kg . the following procedure may be used to evaluate the effect of test compounds on gut hormone ( e . g ., pyy , glp1 , cck , etc ) secretion in rodents . methods : animals ( male sprague dawley rats or c57bl / 6 mice ) in a fed or fasted state are orally gavaged with a nutrient load ( oil , carbohydrate , and / or protein ) immediately following administration of vehicle or test compound ( doses ranging from 0 . 01 - 30 mg / kg ). baseline and temporal bleeds are taken to determine serum concentrations of gut hormones of interest using commercially available elisa / ria kits as per the manufacturer &# 39 ; s instructions . results : administration of compounds of the invention to rodents at doses ranging from 0 . 1 to 30 mg / kg results in an increase in one or more gut hormones in plasma . the effects of dgat - 1 inhibitors on body weight and adiposity can be assessed in standard animal models of obesity such as the high - fat fed mouse or rat . methods : mice ( diet - induced obese male , c57bl / 6 ) that have been fed a high fat diet for & gt ; 12 weeks are sham - dosed bid with water until acclimated to dosing ( as determined by stable or steadily increasing body weights ). thereafter , vehicle ( 1 % tween - 80 ) or test compound ( doses ranging from 0 . 3 - 30 mg / kg ) are dosed ( po , bid ) daily for up to 28 days . food intake and body weights are monitored daily to determine anorectic and weight loss efficacy . at the end of the study , lean and fat mass can be assessed by nmr . results : compounds of the invention significantly reduce body weight and adiposity after daily administration at doses ranging from 0 . 1 to 30 mg / kg for several days to several weeks . the insulin tolerance test was developed to evaluate insulin sensitivity in humans and in animal models ( monzillo et al , nutrition reviews , 2003 , 61 ( 12 ): 397 - 412 ; bonora et al , j clin endocrinol metab . 1989 , 68 : 374 - 378 ; bergman , endocrine reviews , 1985 , 6 : 45 - 86 ). diet - induced obese ( dio ) mouse or rat models can become insulin resistant with prolonged high fat feeding and have been used to test for improved insulin sensitivity with insulin sensitizing drugs such as glitazones ( guerre - millo m et al , jbc 2000 275 : 16638 - 42 ; schupp m et al ; diabetes , 2005 54 : 3442 - 52 ; arulmozhi dk , 2008 , 60 ( 9 ): 1167 - 73 ) and in genetically manipulated mice ( fujii n . et al , diabetes , 2008 , 57 : 2958 - 66 ; funato h et al , cell metabolism , 2009 , 9 ( 1 ): 64 - 76 ). methods : dio mice or rats that were subchronically or acutely treated with vehicle or test compound ( doses ranging from 0 . 1 - 30 mg / kg ) are fasted for up to 14 hours and are injected ( i . p ., 1u / kg ) with humalog ( a fast - acting insulin analog ). the temporal profile of blood glucose levels is monitored using one - touch glucometers for up to 3 hours post - injection . results : compounds of the invention improve insulin sensitivity after one or multiple weeks of dosing when administered at doses ranging from 0 . 1 to 30 mg / kg / day to dio mice or rats . this is evident from the lower glucose levels following insulin administration in the treated versus the control animals . chen , h . c ., stone , s . j ., zhou , p ., buhman , k . k ., farese , r . v . jr . 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