AU2015201970A1 - Niacin mimetics, and methods of use thereof - Google Patents

Abstract

Disclosed are heterocyclylalkyl- substituted and heteroaralkyl-substituted pyridines, and pharmaceutically acceptable salts and prodrugs thereof, that are active against a range of mammalian therapeutic indications.

Description

NIACIN MIME TICS, AND METHODS OF USE THEREOF RELATED APPLICATION This application claims the benefit of priority to United States Provisional Patent 5 Application serial number 61/358,245, filed June 24, 2010, the contents of which are hereby incorporated by reference. The present application is a divisional application of Australian Application No. 2011270719, which is incorporated in its entirety herein by reference. BACKGROUND 10 Hyperlipidemia and hypercholesterolemia are conditions that have a well established correlation with increased risk of other conditions, such as heart attacks, atherosclerosis, and other deleterious ailments. There are numerous agents available for lowering cholesterol and lipid levels, including gemfibrizol, probucol, and, more recently, the "statins" (e.g., lovastatin). 15 Niacin (nicotinic acid), a water soluble B-complex vitamin, is used orally for the treatment of hyperlipidemia. Niacin has been shown to be effective in reducing total plasma cholesterol (C), low-density lipoproteins LDL-C and very low density lipoprotein triglycerides (VLDL-triglycerides), all of which are associated with health risks. Simultaneously, niacin raises serum levels of high density lipoproteins (HDL-C), which are 20 considered a "healthy" lipoprotein, in patients with types II, III, IV, and V hyperlipoproteinemia. Although the mechanism by which niacin alters lipid profiles has not been well defined, its mechanisms of action have been shown to include inhibition of free fatty acid release from adipose tissue (see Carlson, L. A., Froberg, S. 0. and Nye, E. R., Nicotinic 25 acid in the rat. 11. Acute effects of nicotinic acid on plasma, liver, heart, and muscle lipids, Acta Med Scand 180: 571-579, 1966), and increased lipoprotein lipase activity (see Priego, J. G., Pina, M., Armijo, M., Sunkel, C. and Maroto, M. L., Action of etofibrate, clofibrate and nicotinic acid on the metabolism of lipids in normolipemic rats. Short term effects and method of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than 30 million Americans 30 have elevated blood LDL-C levels. HMG-CoA reductase inhibitors (statins) are the most widely used class of drugs for treating patients with elevated levels of LDL-C. Niacin, however, is the only drug recommended by the American Heart Association for HDL improvement in primary prevention of cardiovascular diseases in addition to lowering - 1 - LDL-C. Nia therapy is not only cosVeffcectae as a monothepy, but it bnla as a comnmation therapy because. i complements the e of other classes or ipd loweriros dr ug. Hionever, niacinis a accond or third choie toi isolated .prcholeseroiemia cause of a high melderne of ide eIfs asociateit ih oral niacim theapy. 'Nevertheless, it has a theraMpuhc notherapy when iethicon of both L D)LC and ti enrides are desired, such as for patients with severe combined h v13erh1pidem'i.t \iacin may~ also be used in combination with other eholestersl-lowerhiig age nts, auch as the' 'staiu", to mnaxiize .ipid-lowering activity. One study show-\ed thiar a niacm/lovasain combination is highly effective im lowering C riglyerides and lipoprotein (a)(LptaW) while retaining niacin's potency in raising i) C (Kashap, , L' Evans iR Simmons, P.D, ohler, R. M. and Mctioven, M. E, New combmation iacin/statin formnulation shows pronounced effects on major lipoproteins and well oleriaed, J Anm Col Card Suppl A 35: 326. 2000) ueAc us been w idely used for reducmn seram choleteol levels because a is considered a cost-effeet e thcrnpy Dails orA do>e of 3 is Wacs in humans reduce levs of total-4 and I. D-C by an average o 2M to 3%% ducetveisc leS e % to 55% mner e HL D1 ' 20% to 15%. And reducLp ms .pin ako educes tota mortalty as *w ll as marerta it fronm coronary anra disa. 2see The (ro~narv Dru' Pro cet A ~Reseach Group AM t\ 2 I Nh 30 1 1 1 and ( anne iP 1 Brge, K. I. Wnng N K St am rT. Friedman, 1. Prnuas, Rt A and Ereden aid. K. Fifteen vear morat, in . oronar- Dmg Pujecat aits:0 longserm beneli with niacim, I Ar to Il C adiol 1243 1255, 104,1 and a hels to sMow or reerse the progression of ath0roseerosis (see Bhmernhorn, D, N , 'Tlm 5 A., Johnson, R L., Sanar co, l F , Aen, S P. and 25 ashin4enmphii L., Beneficiml effect of combined colesipohmnai therapy on coronary thercscierosis and coronary venous bypass uratis AMA 273233,240, 1 e&7 and Cashm-emnphdi C, Mack, \\V J,.Peoa, J MI. SaMnale,t A F.. \en. S' P, and 1 antenhorn, l 1 , Beneficia. eects of clestipol nia cin o coronary atheroscleros 4<5ear fbllonp. JAM/A 264:1013017, 190) Unfortunately, oral nain theIap has side effects that omit its utility Albough nmacin a vitamin, i nmst he used in therapete doses to lower chcsteroi ,\A these doses, both imnediate-ieleae and sunamnedredeuse niacin can have several side effects e iost common side effect of nicin is lushin a wkar feel in the skin usull sociad with redness and sometimes itching, Elushing is not dangerous, hut mosv patients rind it very ucorntortable, which seriously limts patient comphance with niacin therapy Niacin-induecd flushing can be substantialy attenuated by pretreatment with \cycooxygenaw i nhi bitors 4 suggeusting that the vasodiato is caused by a prostagandin~ Srimdied mechanim (s 0Clsn, L A., Nicotinic aid ) finhibition of fit mobiizn lipolyi\ Present status, of etteets on lipid metaboli Adv Exp Med Bita 109: 225-23 4s Liver f tion tests are always monitored in patie n taking niacin since elevation of Serum transaminase leKOS ha5s been associated wit niacin treatment, and sustained-release niacin formlations have been associated with monre serious hver probems (see McKenney M. N Proctor, D Harris S. and Chinchili, V, M., A comparson of the efficacy and toxic effects of sustained- vs immiedite-release niacm in hypercholesteroenmie patients, JA MA 27 h 272-777, 1994: and Stafford, P< S, Blurnewm D. and Pasternak, R. C., Variations in cholesterol management practices of .. sphyNicin \nA m. Col Caritol 29: I 1 6 1997 ) Other known side effhets of oral niacin herpy ichad activton of peptic u lcers, gout, and wvorselnng of dianbetest control. A ccord ingly, the safetv and efficacy of oral niacin therapy is underinnedby the need for careful elinical monitoring and the compounds sde-effect profile 20 One aspect of the present inenton relates to nataem analo" as defied herein, and xnmethods of use thereof agast on or mrue mamnialIan or humn hi rapeute mid Iatums ne aspet of the prese t . uentlon rcu ateN zo ee doC.YLJlky stituted Jcd heteroraltvhsubsttuted pyridhnna, and pharmaceuticals acceptable sals thereof, that are atA e against a range of mammalan madies hn certain eubodinos sAd pyridines or salts thereof comprise at the position or -position a substituent compine a funetional group that is substamital anionic at physiological pH In certain embodiments said pvridmes or sals thereof compose at the 2-posion or position a substtuet eonmpsm a tunch;nal group that is eetron donating to the pyndme' n in canon enbodiments said pvdines or salts thereof comprne at the 5-posmon a stbantuen compngu a funetinal S roup that is suhtnmtally anionic at phiological pH and at the position a subsequent Lomrngn a funtonal group that i :lectron donatmg to the rtdine rmic An aspet of the intvention is a metod of reducing a serm or plasma Leve of at lean o10 ipid selected from the group consiting of totaf z o lesterot low-densit lipoprotci L e glycarides and ipoprotein (a n comprising oraly adninitering to a human in need thereof an eleive amount of a niaci anlog1 or a Sp ha~nacctdil i Ce eptie( salit thereoft Wherein said oral Rdmivumratlri is eChlracrerized by reduced thshng and reduced hepaociluiar d ag, compared i oral adminitraion 1 ni @inwir udn of niediaeease aino. in one embodiment. peak cncentrtion (( o ( te niain anlis 40 prrcei o les of for c uinar (rA dose or nedai e ch Ciroo, peak w to er the e srva at 2. hi VC od nt e ta afint n atd in in ebodmet.the Nowti analog has an FAY(1 rIN rss~:eite 15 PFA 0% OPfnctin nwh is at least (I times Ireate tha the UK' 51 of niain fbr IVArrestSm ii edie ()[R Y9A t in * d h a a h aOn std a i to a h man ar o nnrae a seu ord pls a n c thie t ee popne din (}eDL choleterol tt n one embhodimnent. theta oa auitedtiom is chroerze honissubstantallytn ncrae ai nserum levelaa of asnartaa (ALT) o both in One embhodmnent the mehod fiber compares adinmatermg to the human at east one additional therapeutic agem selected from the group consisting of IN US D-1 inhitors SMT transporter mnhibiors. 5f T agoms, 54 .0 or I \LP ihihoitors g ucosCdase mhbitars ABCA enhancers AC inhibitors AcylkoA ehoisterol 0 avltran'erase mbmtors. acecrope and ee agents anti -dysi spidemi agent ,mti-hy penteaie agens nt-oidas, Apo Al mies Apo Al modulators Apo P mtuies apoh~protEmna ccrcno~nirmieto omad tiigl e d insfer protemn (apu-BVMfP} ihib~urrs, ait Suprtessants mwpn, p l agronists, btc acid ruabsorion mhhibumrs bilk acid sapnestrants bormbeam aLgemsis. BRS3 aL omst t CR igwi ae agomists amK~ agsi cholestrol absorption mbabutor, cholster1i tnsport mhitorms choitervl ester transfer protlemi YCTP) mhibmst CjtT CNITF agests modutuurs combination of acumibe and sinastaun and t atonaistutim 'S C. T dehydroeptandrosierone, delipidated i-iDL) D#AT ant ieense ol igos D A Tl mhibitors D){ATi2 mhni or diarboxylate transporte inhibitors dopummeni agomisis DP receptor antaoni~s czetmobe, FS inhibitors tity acid bindig piutcin (FAMRP inhibtos. fitt acid transpontr i nqutors oatt acid transporter protein (k P) mhdibitor lish mhiors X XR receptor modidators gaianm receptor an tQom ts, eabcncev. rhn antdaonists tn lbo antibedu '1 Pd-1iagmisrs ghi~cagon-ike pepoide-l reetor agomstk glucoCorticoid agonts/iantagonists, glucose tranSpforter ihibitors, MDL. timectics, fl.MvG CoA reductase inhibitor ckompoutnds HA MG-C oA synthectase inhibi tors, hormone sensitiveg I lipase5C antagonists human agoi-reled protins (XR P) H a g sv g t Iata nssivts t~l~N linorgaic cho lesterol sequestrant. L-4f 1)apaquiitt Iept agonists/miodulators, Leptinl5 hase .inibitors, Iipoprteiyn synthesis inhto lorapoprant, low denl.sity li)oVprotein. recerptr indcr oratvtrEpa.eues LxR recetor agonists, iyn kinase inhibitor, Mc3r agoanists, Mc4r agonists. MCH- ? R antaonists, MCH2R I agonists/antagonists, rmeianin 20 concentrating hormone antagonists, m~luR5 a~ ntagonisits microzsomal inglyceride. tranaport. inhibitors, monoaminc re-uptake inhibitors, natural water solibl fIberLs NE transporter' inhiitoers, newuromedi U recepitor' agonists neuropeptide-Y antagotnss nmacin or niacin receptor agonists, niiconiec acid, noradrenergic anorcetic agents. \PY I antagon ists, NPY2 agonists, NIPY4 agonists, NPYS antagonists, non-steroidani-in n lairaatry drug (1NISAL i agents onecga-3 fatty acids, oiiid anonisls, ore>:in receptor antagonists PE inhibitors, phentermimne, pihosphate transporter1 inibitors phy'topharmn compound 57, plant stanols and/or Fatty acid esters of plani stn ios, pltelet aggaregattion inhibitors PPAR-a agonists, PPAR-8 6TAR&6 pa agonists, PPPAJR- agonsts, probucol renin angotensin inhibitors reversed4F, SCb- inhibitors serotonin reuptake inhibitor, SGL T2 mnh itors Squalen epoxidase inh ibiors, squalene synthesis inhibitors, serol bioirynhes inhibitors, symapathomirnetic agonist, thyroid hormone 0i agonists, thyrimeti agJ ents. topiramaie, triglyceride synthesis inhibitors, UiCP-1 activators, UCP-2 activators, (CP activators andeuroortin 1)inding protein antagonists An aspect of the invention is a pharmaceutical compositOtt comprising a niain analog or a pharmaceuticals acceptable salt thereof, and at least one pharmiaceutiecally acceptable recipient; wherein said composition is formulated for oral administration: the niacin analog when administered orall to a human reduces a serum or plasma level of at 5 last one lipid selected from the group consisting of total cholesterol. low-densit l ipoprotein (L1L) cholesterol, iglycerides, and ipoprotein (a); and oral administration ot the composition is characterized by redued flushing and reduced hepatocelular damage, as compared to administration of an equolar orat dose ot niacin. In certain embodiments, the invention relates to any one of the aforementioned O compositons, wherein peak serum or plasma concentration n Q r 1 iain o is 40 percent or less of Cma fOr the equinmoar oral dose of niacin. In one embodiment peak serum or planma concentration (CW) for the niacin analog is 35 pr or less ot mor the equimolar oral dose of niacin, In one embodiment a scr or plasma cncentration (Q ) for the niacin analog is 30 percent or less of C, for the equinmoar oral dose of niacin. In one embodiment, peak serum or pasma concentration (C I) or the niacin analog is 25 percent or less of C. for the eqnuinolar oral dose of cin\n. In one embodiment, peak serum or plasma concentration dCi) for the niacin analog is 20 percent or less of C. for the equnimolar oral dose of niacin. In one embodiWnt, peak serum or plasma comcatra tion (.) for the niacin an naog is 15 percent or less of C? for the >1 equi molar oral dose of niacin. In one embhodinment. pca~k serum or plasnma concentration (C ,for the niacin analog is 10 percent or less of f. for the equioiar oral close of niacin. in one embodiment, peak srum or plasma concentration (C) for the macin analog is 5 percent or eS of Cm for the equirnolar oral dose of niacin, hn one embodiment, peak scrum or plasma concentration (CM for te niacin analog is i percent or less o C. for the equimolar oral dose of niacin, For each of the foregoing emhodiments, it is to be udcertood that comparison is made with an immediate release formulaion of iacin. Method useful frtmeasuring he concenttion aredisce d in in caram mhodinerts the mention relates to any one of the aforementioned sa composnions whe em ti he ratio of peak serum or plasma conemration IC(X to area under the cue at 24 hours A.t . (Le, the runo C7. \ 2 ( for the acin analoi 0 Ih or les In one embodimem, the rtio of pzr concenratin to area under the curve at 2 hon (NA,1 ) (r the a in analog is 0130 h ' or less. in one embodmnm, the rto ts6 of peak conentrdton to area under the Wurve at 24 hous (m A ) fqI t h maeni analog is 9.25 1 or tess In one h mibod l t, the rh f p oncentraton to the curve at 24 hor U ( ) lor the niacin nalo is U0 920hI, oY led In onc emibodimnent the ratio of peak e~oncentraueon to area under the cusrv a 24 hionr or the oe n analog a (1h or 0 as. In one emitadnt, the rdtjo of ea concentration to area under the curve at 24 hours (C'WJAUf s 4 for the niacin anakg fl 10) hi or les n one embodment, the ratio ot pea concentra10o to area under the te UrlV'11d. si .ottr (C A §.r 2) fi tiin .W ISU.V) iQ o, 1le in one embodunent the rati of peak conentration to area under the cure a 24 hOus 1for the niacinaaog is 01 h o ss. i n embodiments he invention relates ) any one of the aforementioned composititons uberein the tune to peak serum or pla sna conentration (ts) thr the niacin analog is in the range of 30 minutes to j hour. in one eobodimem, the tie to peaT oncentration (t,) for the man analog is in the rang ofV I S hours in one embodiment the tine to eak cenaion (tN f the deln andisg s m the rge of 1 to 4 hours hi one embodlinent, the time to peak concentraton (t for the niaem anao in the range of 1 to 3 house. In One embodiment, the time to pea concntration (1. tor the nacin analog is in the rane of to 2 hours in an cmnbodlit, the Inin analog has an Elv fo -arenon ONated OPRI1 09A 211 lnction wih is at iat1 t mes grcate than the Ef nacin for arstnnaed GiPR I 9A funtion. in an ende nt.he niacn anan, when administered orally to 0a man, also increase setuno pasirta ses ofhigh sensiy ipoproteHt) choessterol In an embodiment the mac analog, uhen adnitered oraly to a human, nduces :~5 shatani o iic es in serun levels of W3patat niotas rae(.T} hnn amnnotanserae (~l' orboth. in an embodiment. the niacin analog, when adnitisere oraliv to a human induces uhadnaaily no increae in serm lev els of uricacid, glucose, or both Alltilir th*net of the ink entoUr tzktes to a phadrrnadetl4 eonipos1rt101i composin 30 a cotnound f the present ienton ot pharnaceutcally acceptable al thereof: and a n~haaeneuu. - aceptable exe pfunt \Yet another apect othe invention relates to a o arnd'icc a' lvo'riosition, c'onpflnnyg a voninountd of tlhe: pr esent il\ nvent or a hannacen actablea dtereof niacinan a phrmacecuticaib aceele Another aspect of the l inverion relates to a pharmacouncal composition, corUpnm compound of the present inv enuin or a oharmaceutialh acceptable salt there: a station elected roim the group conosting of aomatomti. ern asiano, louvaslatin, lovasiann. mevast atmi ptavastatm, pray astatuN reouvastain and simovastatuv and a pitannaceutcalh aeptabe excipien The preset Nn vennOn alo 1 e1a to a pharmaceutical composuix comprising a compound ot the present invention or a pharrmaceutically auceptale salt th ereot; miaet, a satin selected trom the group conasing~ ot atorvastato, cerviatin, o luastatil. lo\astati iu. meastain. pta\ ahivastv atal ros, \axtad a and nl asatl; and a pharmaceutical acceptable exciiet Additional therapeume kent4 whch can he cadmnitered wih c oundsofthe indefio are disussed beon Niack. or Neotmic acid. has established eficacy fh the tieaunent of dslpidemnia, but the cliia use of iaem has been lirmed b cutaneous hne a uell-recogmied Jasseolated adverse effect, whahich is esti mated at a pre\valence as lli. as 23 o hs been cited as the mair reason for the discontinuaon of iactn therapy A number of sudi s ha\ve established that moderate does of Orstauiandinnibllntors redue the eutaneous washing response from niacn admiunstrao Other sin 1gies hsA redinig flushmg include regular consistent dosimg, the use of extended-release formulaions, patient tducaton. dsm n nib i meals or at bedewi and thew a.vdt. of alcohol hot beverages. spicy foods, and hot baths or show ers close to or -alter dosmg,. h1 certain embodiments, compounds of the present iention can hav e reduced occurrence or sev erhy of Hlushing when admtustered to an anima particularly a human p-hom For imansa, compounds of abe present invention do nt cause tishing in the male C571A murne model of fhlui n ac insured by laser Doppler lowrmetry, when administered at doses of up to 100 my kg. and even more prefrablY wh en administered. at doses up to 200, 300, or even 500 mgk in certain eodimm ompounds of the present intvenin can be characered by causing less fushng wvhen administered orally WN hen compared to the amont equialent m fol at' amount of M AScPA ' (nci e tende&eas nets, Abbott l abor atori l certam embodiments compounds of the presem invention when administered ortAl to an ascerage pariscnt population, shows a reduction in the number of patients reporting fluhing o f greater than or equa to 5 on thc visual anaon scale oall' when compared to te enlm mrno tOr amont t N NiA3PA \ She nraeet inxeiption alw relates to a method of tretu a disease digo der or condition selected from the group consisting of hvyperbpidemia hy perchoesterokmi hpodysphy dyslipiedem i eroscletosis *Wn cmamrs ar tery disease, £omp~nSImg the tep of adnumisterim to a mammal i need theeof a th arpeutialy effect amount of a enpound or pharmaceuna d comptin of the: presm ientonf Another anee ot he resetivenion relatles to a i m 'f ainadsae disorder, or condition selected from the group consistmg~ of m etabolic uyn drome. obesiy an0 ytv !iv er di ,l diabetes, comprising the step of )dmterin 0 a mammal in need thereof a therapeutically effctiv e amount of a comfpound or pharmaceeutical eomrpoamtion of te present ition. Anteaspect othe es t ient ion rtes to amthd ofmaisnsern hi densNIyPpli rai (Db le composng the step of; adminternto a kmamal ia S icd heeo afterapedziailyettecie arhn.ofacmpond por nameutieal conmposnon of the present ivetion, Another aspect of the preset inenton relates to a method of loIemn sem low densaity lipoprotellri {LDL levels or loweing serunm lpoprotein (a) le\vels, comprising the step or adm imstering to a mamneal in need tnereo~f a therapeutically effecanve amp am of a compound or pharmaceutical compostion of the present inventon, Another of the prsen n ventio r es to a method of iicrean th seru totauncentinnsof adipomd c mpriag t epoadministerng to a mammal in need therefa herapeeticadlveffectie amnt of a compound orptarrinuted composition o1 the present inventn. 2:1 Another aispect of the present invemlion relates to a method of treating a disease,. disorder, or condition selected from the group consisting of congestive heart filure. cardiovascular disease, hypertension, coronary heart disease, angina,. pellagra, Hlarup's syndrome, X arcinoid synnre, arterialt occ usive disease. hy pothyvroi dismn, vasoconstrict ion, osteoarthritis rheumatoid arthritis, A izheier's disease, disorders of the 3o peripheral and central nervous system, hemutological diseases, cancer. inflammation, respiratory d disease, and gastroenterological diseases, comprising the step of adinstering to a mrammal in need thereof a therapeutically e~ftctive amount ot a conmpotund or amraeut cos dtn ofde pesentnntio Fghr in to me p rMpackagAd a o .im Ion, un A an iner ably or other io n istreti on dtho paentnoda the niaci analo arearAatt hein 2 or 3 hoAos 01 wn aoptalcla with Nod th oAddtial spets. endi oniethe in L iv\ntau th invpientio are d fis eus ew graioandar o BIEF DFESCRWIGFN 01F er11i1"FGCURES net grph, limd raon.()omtmrare1 ()4',(A12 Flgur& 1. T1 etoardpYvOnass pe odcopy (l.XItMS) tac tr a RI 1031 houeives/ frnt Soli rhah hi (Shanghaig (hF 18 dioti line§ Fedodtigre pri Te m' o e pa at. n n reeen e.9h fh al leak area of Te trac. Figure 2 elive sarametr of ARVOW a u udn tdoe o Ahn0 s deeed in mt mot gJa ARepsntindg the pak dmostr was a ldo-d. thendnt oredtou tId totalu e ohe L( S trae Itis i h u f presd as p of to ca peas tUpper graph. poder lurnuglan {p standard Cotdiiond 50 wd nos peopotemidi I. ove napnliuidtorrilatot; K>)rom trnera~uelot (No 4 NT, (A A 01' If igtwe,3 bx br d pmtrae of pooe d sa rom hly onamsegs on ee a normal chOw diet (od 10tt, or a h:igha high sugar (i T IIS! diet (doted. line). Figure. 4. !Pl -C: traces of pooled plasma from asr eevigvhce(oi 20 lne). 1200 mg/k Q vnk) maetn (dottd line)or 2201t/gAl-00l (dseln) Fi uRe5. Lipid ce: ramete exchpng as a o ofale00mi and ommilku/d). ARLO01 (H and comyeetng 1We eosrte oc4pnd~te~to hid vaues in 1W/IN Mates Niain0K>0shwe siunifcane wit respect to chage in totl chlseo {T . hi O lWniylppooen(D..a n o~es lipoprotein (1AM. o FigurS 6 an .Creaio ewe idmprmtesadpam ocetain positn The linear correlatinO line s drawn (solid lne) as w 11 as tWhe 9S contidence o zone of the cornehion lioe (dashed caves) Peason r correlauor nffients are ien ihr 10 eacdatastit Y cnfidenc ntan parenthese Vvaies are the results of? Figure &. ( Left graph) (Iora.tion betw een hN-er and plasnu conecutnianons ot' ARIMi0 - HIPS hausters dosed or i dlub. The s'alues for each tsue h a been tranbrmed by ioganith, and therefore the tes are Unideas Rightgaph Corre'vaiQo.n between adipos and plasma concentrauons m the 4ame ammais, Adipose concentrations nase been transtormed by the functon ''Iogarihn ; K winct oaes any aWes hetwaen and 0 into pos i values. This is done fNO au and does not other isc distort the 10 Figures 014L Correlations bhene en liver conceetratilons of ARV-Ql im HF'/US gamers and i values of differed lpid parameters; also. correauons betw een adipose tissue rtwcnemrat ions of AR-01 I nIF hIS hammers and vdues ot different hid parmet ers All \rtties ar e the logarithm of the hpid value versus the logatm of the tissu eoneitations oeiatts are between iUe conentration and hpid Maus i the same n' amumals. dosee eoneetrutions have ben transtormned by the fnetion ''hocviithrn 1' w hich mases any babies between -1 and P io potiye values, This Us done for clarity and does not othernwise distort the distribution of the data set. Figures i A and It In er function test parameters hrom high fe-ated hianiers dosed oraL , ith edc, niacin, or ARI 1 i for .18 day Perenm .hanges are gnven 20 MrSm to cehicle P-vaues are reported from Otaied unpairc tesi comparng to euc Li oKun \2A aspurtate anunntransicraseriASl lA Nure (la dlanmne anmotranserae ALT) F A ,ucose values measured in plasmaMao an I d - ndy of [IF/HS hamsters dosed daiy with vehicle, niacin, or ARI 001 Percen canes are reported in craanson to the vehicle onup valueA P-vabie iR detenmned fom a 2-tailed t-test. Figure 14. lasnma conceNuraton of ARt-00 I i miee dosed wth a smnte admnstrathan of A RT-D I either orally (PD) or iotrapecitoneally IiP Figures i$ A-15D.~ Plasma concentrations of ARI-OP1 from mice dosed with rnuupie duils- om adminstratons of AR/I for 30 consceutrae days, 'out dilPcrent doses were used. Each mouse receined the same mined dose of ARIO0 I every day fA 30 d flgurs 16A amd 16B. Suntnary x' t Cl aN AUC parmetr for ARO(fo dado mtron Y ind p Wnes are Plotted an the mean withm~q stndr er.....e. no \'Th'tlant change in eihrprvetra.aueofo Figure P oo A i n S te gs nentraons oA d in ftd monkeYs e i adomnstatit of AR] 401 eit 4 190 agl nrvnul IV r(y gkg (mpn) Oral) (P8 r Y-aai is logadr Ncal fo clari (Inset; Uam at with the deaxis on a 0 har se. n e n w Fiue1 9, lsa oci~itlso A.RI0 wI aftrsngl adminisraton of 20', mtg kg orallny to (Q) fed monkeys or to (01 tasted eonkeyvs, Valus are man with standard'. Figure 20, Z1511N conontatm of ARtyA) ar repated daily of mn a o it tod nkey. Vale are mean wpit standard or 10 Sampks dAown on dp, 1h (0) Sanlan dram on dg 7, 2 a AR]Ae s to ret e s to ,mane oe exrS z h. lnin~r receor (APR 109A. Linand, reters tonaiwrAU)Osidctd RE ud1\1a vle wi n, as atth i\d in mbea!I iglest i niiott for j roteincuped. to human paes Tu peent ne s te ea prc angergede tiours 'PONt dose, 2 dutistatonfm ndcatd amounts 01ARIM a,1t hmnpins DETAILED D)ESCRIP'TION One aspect ot the anvento relate to niaci a 6azog ki sn" rasngs IMn1-1 leesin mammak os n cerai emo nettecmon tih ivntr av qulo aaer i-li0[-risinhlit thN an; nin while having les onojPTtsytoitc 0~ ~ t tls ag an undesirabte side eec of niac ina itsef keen usead in dose suficent to ratse, 12 serum HDL ievels, Some non-flushing Piacin analOgs are described in .S. Patent Aplicaonh Publication No, 2009/0 1 31h355. ih s hereby iw corporate ie reference in its entirety, in ctant embodiments key trucumral features of the compounds disclosed h in appear to include te placement of a hetocyclarkyV or heoI Akyl group para to the 5 carboxyl group Iin niaciIn. DEFHFNITJONS Fon niencecertan ten epoyed in the specifictni vdtampon. and appended clannms am collead hee A deinns, as defined andusedheein supersede dictinary dcefuntions detnitionsi KtdOCtrn)ltniatmrdate~d by eferdee aind/o odinary 10 rnanu~~sof the deitned tems Zhe arcles -'" and an " ara used heren to ret One t mr th on i... to oneo he Vramina cal ob et of the article. My wayp o exapte nleinn eas oneelement ormore tan one element. The phMse "andor as used hereMin in the speritieati and in the claims, should be understood to mean "either r both' of thseeements so confined, i e. elements that are counctw elv present in some cases anud disjunctively present in other cases. \uluiple elements listed with "andor' should e construed in the sae fashion, ie ,'one Of mor" of the elements so onined. Other elements may optionlally bO present other than the elements specifiaaly identified b; the oan or' elanse, tdK1 umrlated to thoe 0 elements spefically ideMified. Thu s a non-hitmg eumple, a reference to A and" o b7" wben used in conjune ofn wth open-ended language such as "comping" can eer, in one mlodimetL to A only (opt lslinmludlne clenems otMer than S in another emboinnt, io ? onl (optionally mein g clenems other than A), io yet another emboinenm to both A and 13 optionall iuding other element etc. An used herein I th specification and in the claims "or" should be undersood to han the arne raam an W'AdYo as dlimd Wbose. For example. w en separting iem, tn a or or "and of 'o tle inerpreed as h.egg inclusive. e. the inlusion of at least one but alO mnciudmi more than oM , of a number or ist of elemes and ophonally additional unlisted iems. Only terms early indicated to the contrary, such as "only one SO of" or .enetly one of? or, when used in the clamsencnsistin of? will refer to the mnlusion of exaly one element of a number or lit of elemems in geneaut the term 'or" as Used herein shall on be interprted as indic'dog eclusi\ve adlernati\ves {,, ne or the l3 oher but not bot when preceded by iens ofe lusivy, suTh a ithe0 one o "aI ~2 oy or txadev en 'osstnag rssentuil ol t IXI red 01 t eni a have its ordinarymeann used n the fe d of patnt aw As ed herein in iecifcation and i the claimshe phrase wa t ane. in 10ree t at o one or nore elaens, shoud e understod toinan lawt one elene cted rom angon or more of the eentns ihe stof eementsut nt necessanl unctii o at least one of emh and every element specifical listed w ithi he 1i in' C4lowens and niot excludn anly Conttntohns of elemens in Tth 4 f onts.

I dI niion ako allows that elements may opiolnaly be present er Ot r han the ereriets sp ee wlal\ Iv den ed wtin the list of elemet to 1 h.it] h rase 'at leat one> refers. hcther rlted or unrelated to thos elements spectcallv identied, l hu\ n a non tiing exatpi,' or ras one of \ and i oru egi alentl' at least one or \" ar B ort equitvaientk "at at one of A and/or B Can refer., in one embodiment, to at least one., optonall inhdng more thar one, wi th no U present (and optionally incudoiig elements oth"t than B: in another emabodi ment, to at least one, optionall Including moire than one, w x ith no A present (iand optionally incladng elemens otker thn A; in yet another embodiment, to at least one, ona udong moie than one. A. and at least e. optional including move than on, B o and opuonia including other elementa etc It should also he understood that, neas clerly mdicateo 0 the contrary. tm any methods claimted hereil that include or than one tep or aCL te order of the steps or ets of the method is not neessariv lirUted to the order in wiCh the steps or acts of the method in the e N wms, as well s t the speciIcation abo all transiional phrases sich as Compflmsi I eldin carr'inn havinga.' "containin mI ol'in "oldin' i -compose1d of and the like are to be understood to be openrended, t. to mean inludon but not limited to. N un uional praises consistingg o" and consisting essentially of' shall be closed or semi-closed transitional phrases respeci\ et , a'n et foth in the Snted State S Patent Office Maad of Paten Examining -Proc-dures, Section 2111 The terms 'co-administration" and "co-administermg" refer to both concurrent admoin istration (administration of two or more therapeutic agents at die same time) and time varied administration (administration of one or more therapeutic aents at a time different frm that of the administration of an additional therapeutic agenot or ageenis }. as long as the therapeutic agents are presem m the patient tosome extent at the same tin; The trn sol at' refers to a pharmaceuticAlly ,teceptibe Aorm of' a speciled .om pound, uith ne or mocre so' vent noecuies that retains the NisoLopeat effecees of such compound. amples of solvates mctide compounds ot the invention in combination 3 ih whl ents such, fit example, w ater (to ltrm the b drate , isopropan'oL ethanolt methanol dimethyl sulfoxide, ctv acetate, acmue acid, :. anolamne actone. Alo meided are fornulitins ot sae irdNtures Rib'h as a nompoutd of the invention in comb mnoin with two or mae saketnt Thedef on of ch axpressi 0,alkyK n and he ke, when itA ocs ?w noe toan onc in any Atnetlurm. is lnedc o he indepen dkn of its definion &,.lshr in thesame structure. it will be understood that "substitution" or "ubsti with includes the omlicit FisO that such substitio is tiaccordance with penrned valence of the substitute atom and the subsituet, and that the substtution result in stable cmponwend e.g. a 1 comitpounid which does not spontaneously undergo transtformaition such as hy rearrangemneut, cyciation clim 00ination, or other reaction, The: term t substwuted" is also contemplated to include all permissible subattuents of organi compounds In a broad aspect, the permissiWe substuens include ache and ec ihe branchbed arid nubrauehed, earhocyee and heteroc ehie amomaic and nonarmauc ushstuens ot'organie compoMds. Ilhusmrtive subsituents include, for temple, those described herein below The permisthe substuents ma be one or more and the ut or di fferent for appropriate oaic compounds For purposes of this in etion, the beteroatmsmsch asnitrogn may haV b drogen substituents and or any prmsibAe substduents of organic compoUnds described herein which satisfy the valences of the Ihe term "lower" When appended to any of the groups listed below indicates that the group contains less than seven carbons (.e six carbons or iessn For temple "lower alkyl" ret.rs to an alkyl group containing 1-4 carbons. and "lower alkeny" refers to an alkyvenyl group contain 16 carbons, 0 reer ta .u-ed as used herein pertans tcompoundisnd goupsh he at leas one arbonarTon doubt bond or cbonarbon tripl bond 15 ia tera m"aiphan. as used bcei, ptamns to compound and/or groups w ich arc r r anched, hut nor cycic (aso knon a eche or ' opeM,:hin" group:n 'he termn "Cece:b used herein, peItain to compounds and or groups which have one rhV or two or more rngs (e,, spiro fused, bridgedt "\onoeycie' ret'ers to oino~til a(1 r r~tps n oe cogannl '"e" ch" t'et'ers cc (npounds! andi or groups with two OnumsaN The term "aromatic" refers to a planar or polycyclic structure characterized by a cyclicl .onwugated moleular moiety containing, 4n+ eletrons, where ni is the absolu rte value of an integer. Aromati molecules containin fused, or joined. rings also are referred .0 to as bicyclic aromatic rings F-or example, bicyclic aromatic rings conmaining heteroatoms in a hydrocarbon rng structure arc referred to as bicyclic heteroaryl rings, The trm hraron t as used h in refis to An oraiccompound consisting entirely ofbhydrog~en and carbon, for purposes of this invention, the chemical elements arc idnatifed in accordance with ie Periodic Table of the Elements, CAS version, Handbook of Chmistry and Physics, A7t Ed. 198647, inside cover. The term "hjeeratomn" as used hvre is ari-recognized and reers to an aton of any element other than carton or hydrogert Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfar and seenim, 220The term "alky. " mans an alai or cyche hyvdroearbon radtcai containing tronm I to 20, 1 toi 5 or I to i0 carbon atoms, Representative examples of alkyl include but ane iot limited to, nwhyl thy L n-propyt iso-pot4)V nbunyM, sec-utyi, iso-ny, trt-butyl n ptyisonenmyl, neopentyl, n-hexyIL 2-methyleyclopentyL b-(i -ethyieyciopropyihethyi and I -'yclhexyiethyt Te ternm cycloaikyl" 'is a subset of alkyl which rcfers to cycl hydrocarbon radical containig fronm 3 to 15, 3 to 1, or 3 to 7 carbon atoms. examples ot evcloalkyA include, but arce not limited to, cyciopropy! and cycioburyl. The term "aikenyl" as used herein means a straight or branched chain hydrocarbon radial containing ron 2 to 10 carbons and comaining at least one carbon-arbon double 0 bond formed by the removal of two hvdrogcns. Represenative examples of aikenyl include, but arc not limited to, ethenyL 2-propeny 2methy2propenyt 3-butenylt 4- The term "aiynyl" a used herein means eight or branched chain hydroeabon radal contam hom to 0 carhon atom and contAny at teast one carbon-earhm triple bond. RepresnaMn wexample\ of alknI ituclude. but are not houed, o acetylenvL 3 propy nvl - Spropv nv vL MVynv fLCpetYfnli and Iht nbwi.v bhe tm "akyeis ax ' .

4 rtrecognuized. and as used herein pertains to a diradical obtained by r-noving two hydrogen atoms of an alkyi group, as defined above. The term"carbocvclyk" as used herein means a monocyclic or mun icyclihe~g bicyclic, tricycle, etc hydrocarbon radical containing trom 3 to 12 Carbon atoms that is completely saturated or has one or more unsatrated bonds, and for the avoidance of doubt the degree of unsaturation does not resut In an aromatic ring system (Cqg pheny.?. xamprcs of cathocycky grous incude i-cyclopropy\ 1- IyclobuKtyI. 2-scpntyL cycopentnt 3-evyclohe xyl cyclohexey-q and -cyclopentenylmethyt Ih term "hetmecly ", as used en refers to a rdical of a non aromatic, ring system, incuding. but no limited to, tumonclic. bicyceic aid tricclic rings. which can be cornmpetey saturated or which can comain one or more units of unsaturation. for the avoidance of doubt. the degree of unsaturation does not result in an aromatic ing system, and havc 3 to 12 atoms including at least one heteroantom such as nitmen oxygen, or sulfur. For purposes of exemphfication, which should not be construed as limiting the scope of this invention, the following are examples of heterocclic rings: aziridiny, azirinyt oxiranytV thiiranyli, thiPirenvyL dio>:iranyt, diazirinytI azetyL I oxetanyt. oxetyl. thietany. thietyt diazetidinvi. dioiaetnyt dioxetenyt dithietanyL dithicty furyL dioxalanyt pyrrolyi oxtazoY thiazo ly idazoly. oxadiazolyt. thadiazov, triaztyl, triazinyl, isothiazolyv isoxazoyl, thiophonyl pyrazoly erzyL pydyl, pyridaziy, pyrimidinyl cmii'l l00vrazoM. terolyl , vivhpn py nrazinyt triazinyt tetrazmynt quinolinyt isoquinol inylt quinoxahrmy~t unao in yt prirdopyrazinyt benzaoxazolyl. benzothiophenti I benzimidsazolyi, benzonhi azo lyt benzoxaditazotl, benztihiadiazolyti in do IyLi benztriazolyit naphthyridinyA, azepin es azcnd~and NAM.ml TK*rr~m~ azetidin orpholinyt oxopperidmy. oxopyrrolidinytl piperaziny L piperidinyL. pyrrolidit q.tuinictudint i hiomorpholhnv' sctrahydropyranyl and~ tetrahydrofuranyt. The heterocycly groups of the invention are substnuted with (, 1, 2 , 4 or 5 substituents ndepcndendy selected fo therouoniing oAkyL aenvi kyL halo. i loaky. fluooaikvi, hivdrzoxv lkty alrevIxx icmvx .crovivov eeocc o haloalkoxy fuoroal kyioxy, sul fbydryt a lkyth io. haloal kyvho flokbklho alkyenlthio, a-kynylthio, sultonic acid. alkisulfony haloaiklky bony L fluoroalkysulfonyl. akcnyLsulfonyi alkyny'isulfonyt, alkoxysufonyt, hloaikoxysulfonyl fl uorTalkoxysu1 fonyt, aikenyloxyufl fonyti alkynylhxysulfo')ny, aminosfuony suitinic acid aikyLsHyL haoalkysufinyl, fluorOalkylsuiyt, alkenysdlfnyL alkynyiuhfinyl, alOWysudlfny haloalkioxysulfit UfluokoxyV suihnyt Aalkenyoxyslfinyt a)lkynyl1xysulfiny, aminovulitv formylt~ alylarbhonyt h'IaLlkyicaronyt. fluoroalkyicarbonyi aikenycarboyl. alkynykarbonyl carboxyl, akoxycarbonyl. haloalkoxyvcarbonytl fluornalkoxycarbonyt a ikenyioxycarbonyt alkyny loxyvcarbonyt1 alky~larnyloxy, ha loaikyicarbonvxy, fluoroalkyvcarbonyloxy. alkn y lcarbonyoxy, alkynylcaroylaxy, atky ylulfonykixy, haloalk 1iu 1fonyloxy, fluorOealky Istlbyloxy, alkenylsulfonyloxy, alkyL \iTul1 onyloxy. baloakxsulfonylo\xy fluoroalkoxysuldfonyloxy. alkenyMloxysufonyloxa a kynloxyvsufonyvxy, alkyisultinyloxy hajoalkyisuti nyboxy, fluomatkyisulfinxy, a e\ y14 iloaxy 1 Ranysu Ifinyioxy a lkoxyulfinfyloxvy ha lkoxy sufinyoxy l N W uoro lkox yal finvyoxyv' kenyovxysu I flny oxy alkynyxy sultiny Ioxy, amirnosunyxyhu , amino, amido, aminosulf onvyL aminouinyt cyano, ntro ( aido posphinyt phosphory x s itdlyoxy aany fl sad subtients bound to the heterocyyl group through an akyene NoWety (eM tyln Thitr "aryl, as usxd herein.eans ai phenyl, naphthyt I phenianthrenyl, or 20 anthracenyl group. T he aryl groups of thoe pesent inenio c a otonally substiwtd eth 1. , 3. 4 or 3 wbtibtu ndopendent- xelectedl from the group congsiug of alky L alkenvi l kan L. halo, huloalky LfioroalkyL biwdrox. alkoxy, altyoy eu~oxy aitynvbxvmy ear boeyciyioxy, hcteroeyo~oxvl.o baloa kxy, fluorAlky loot sAhydryL alky lthi, huioalkvithuo, duoroalty 1 no, aikae 4e h. ak n klno, su!me acid, aky sulf ny h5alaaltkIuloyt luotoalkia IutimnyE L lkenyiiuIfonyL al k yuvkulfkox L a) koxyanu lony L baloal~koxx'u& iony L. fluoroailkoysu Ion L Alkena vux) svdfonyi tikinwloxsuiffruy ainn~osufony Lsultinieuaid alkvlsultinv haloalksuslfinyi t luotoakts uul inpuL alkenyvlsultil La nylsulliov aikoxyvsuI fimyt halnaikoxyavilhnxyt tluruaikoxsysulftini, alknv loxvulfiny L alk nylox vulfmny amminsul tinyl. t'formiyLcb ati rboni, vt fturalv1r1Ai ]kov a bnaloal k )r larbon. aaony L. alkynykarbonvL. c5arboxiL alkoavearhons L' balkIoxvoemboit tLi(oajkox yearbonyLI aite lm hikearhoun y alkvy Io lxycarbonv L, alkylearbomle vio ulhoalkylearboni loxv tIluoroalky cearbonyl1xy. alkenivlcarbon loxv alkyno learbon vox alk 1sulItonv boy, haboalkys Ign fonyloax ylummt Lndonyloxv, alkeni' lisufamosy, alkY ny 1 donyxloX , haoalkoS utfonx lo, ou otoa dknx fonT II y. a hryo axvsudfoy Qv ,,, al olfsndn1try, a.Wy lsuItins toXY bal'oalk fi n I hmx tiuoralkvnbultiovl >ty, alenyl uting Ioxv, alk nvlti3wsy a 1ko'ulxny ow h i daumoxvulhti yx finoroalkoxvstinyloxy . alkentlm afylox ~dx Ioy S alkan ayloxsaltix xay aonusultin vlo ammno, aink ammfOsu t'onrt a mmn udinyt eyano, nitro, azido, jphospi. phosphoryI s aK s/lows uid arny of 5'aid tubtiuQntS bound to the heterocy xdi u roup thcmugh an aIlkyicne moiety (e g. methbyklneo) The tern "aIY ib artecOgnied, and as tued hre jertais to a duradical obtained by removing to hyvdrown atoms of an aryl, rg, as defined abow 1 The term 'ry layW or "rakv l' as used beein means an ar u p as de=f110I herem. appended to the natent molecular moiety through an alkx i group s detained herei, Represenotaiwe oxamres o'aralky ineha, bit are not hmhed to, Ven yt Qhe~ithI L ihNn ipropy L and tnaphth e alous) The ierarx as> ued heresn means an arvbsubstituted aryal an arvy-ubstituted and heo e s dfine her nresenat xanpesN lide phen phe yl and 44 -mthoxphen dh vrydinyl Thb l term "heteroarya as used herein include radials of aromatic ring systems, melui, hut no lited to, monocy b y ind cyclic r . wIc have 3 to 12 0 atoms ~Cinuing at least one heteroatom, such as nitrogen. oxygen, or suOfur. For purposes ofexemplification which should not be construd as limiting the scope of this invention: am inobenzuiidazole, benzimidazo Ie, azaindioly 1L benzo(b)thieny L. benzimidazo IyLi benzotranyl. henzoxaolya benzothiazojyI benWothiadiazoiyL ibenzoiaz.oWy beKxdizti furany imdz57 iiaoprdn noy indolinyt ndzoy isoindolinyt isoxazoly L isoth iaolyl. isoqymolIny. oxadazooly, oxazolyl, purin y pyranyt pyrazinyt pyrazolyL pyridinyl pyrimidiyt pyrroly pyrrolo{2-dpyrimidiny L pyrzolo[34-d~pyrimidinyi qunonyL quinazlinyt triazoyt thiazol o thiophenyl. tetrahydroidol K tetrazolyl, thiadiaz'o1yL thienyht thiornorpholi.r triazotyI or tropany L. The heteroarv grups of the invention are substituted with 0. 1, 2 3, or 5 substituent indepentdentlyM selected from the roupconsising of alkyl alkeny L alkynyt hako, haioalky fluorna ly, had roxy, alkoxy, alkv'enyl oxy, aikynylox y, carbocyclyl[oxy heterocycdyboxy, haloalkoxy, fluoroalkyloxy s ul'fhy drab, alikylthio, haloalkyalito, fluoroalkylthio. dkI. h~hho hdo- :lkkrm y hdd,.alkynivtthio, suitomc acid. alkvylsulbny Lb hialoaikv iaulfdnviL luooalKia 1uM Y. aYkenylvsn kyLh alkiyvn vimtpyiL alkosui foun U halo atoxstniL tluoroalkomuilfong L alkenl oysuIftni. Lalky vn loxvsultbny, ammosulfonv I sultmic acid a~vlstu~t'ingv~ ht boal Isng LM iiuorahkyni L2r'. atkenyukl fin L alkynykul finytL alkowsultimn hailodnle tosTu 1an, inuOEak MCI hfyint aaknkkyl \%ultiusVt. alktYnylaxyNusutnt mouiyt funnmvL alkv aribsil, hakltkylearbonvL, .tiuotuoalty la n' 1, Aken' 'ciuhonviL alkv nv learbonviL ear'bo 1W aksy ecmbOnly I, haloatoxearbonvl ~ iorO lkoxycearbonyl altenv lmxvearbe~ny ~ tky'nvloxvecatbony L aHV IcarbonYloxy haoalkvYlarofu Iox inluoreakly ylcarbon aen lknvitarlomymx al k ni e lei to Co aikalSul f seloyhi haroalv a isuV s fluor'l1k sufyI i loxy ak enyu ttsny ls alkyn sltinh oy, haloatkoxsuidfonyiox il otma lko ws iufMelory. Nolen torsuWf voloxs aliknylox sultony os al kvtsultilx taloalkysuTinv lo vi fluoroa)k kdftinw Ioxy al ken) vo Rtinv Ioxv atkynvibultiny1m \y alkoxyulfinyty hatoatox unfiy tlurdo cantox CyulI fin> roxI alknit ofvUpruIh oclty alk~nyoxpullu) lxy, amosulin3 lsgfanifl n ao 4aminozsulfn)LS: mslfn eano mm u aido, prhosphm , phosphora sdy1 si h. and nF of said sihstuent.s bound to the heteroay group through an alkkene moiety (it. gmrthv lene) Iihe torm hera tV ne V is a1r-recog nizcd, and as med herin peruin to a diradi cal obtated by rem inu two hdogen atim si to ahetervr it 4 tinyhained abo W The er an tteis AilVa.' or >heteroar alaj i a uNed hereinUeans a heteroary , a defined herein, appended to the rarnt molecubar moety through an alk1 gruup. asene beremt Representaine e a mples of heteroarsladkv I me lude, but are not imated to, pvridin m.'rethy l and 2tthPene l ieth i. The term "fused bick elvFr as used herein means te radical of a bicyebc rig asktm ub weremn the two tntp are oriho-tised, and each un t contaons a toud of tour. five, sin or sev en atoms (P te., carbons and hcteroatoms} neludmne the two fusion atoms, and echb rme can be vomnpietely saturated, can contain ne ortO mlore tinis ol uutuaik tion, or can be completely unsaturatted (eat in0 somle c ase. aroathc )Ior the avoidanCe of doi~ht, the deprce ot unisaruabattn in the fused bleycdyl does not result in an arvl or heteroarsi moty. The erntaloaky means a alki groupgas defied iehere ei a Nestk hydrogen i replaced wih .ahaloeo defined heren. Represenaive example ot afokik incude, but are not limoedt ebromehv nomety.triuormeh dttOTtthV [ and 2h Ao3 Aruoropen The e oa v mearsan rup di n o Ae Al of Weydgens are placed wAn MNO, Te n 'a kyen, s er e inn perins a a obtaiUM by rnmoxto two hydoen atoms of a ain oupa deind$a Uh terra dnox asused heren means anO group Th term "akox" as used herem means an alkyl group. a4 dfined herein, appnded to the parent molecular moiety through an oxygen atom. Representati examples of alkoxy include, but are not imitcd to. metoxy , ppoxy 2-propoxy, butoxy1 0ert-utoxy, pentyfosty, and hexIoy The trns "lkyeynyloxy", "alkynyloxy". crboccyio" and 'iet'ercclyloxy" are likewise defied, The term "aloalkonc" as used herein meanm alko group, a defined herein, w herein at least one hyrge replaced with a ha logen, as defined herein Rerenatn e Examples of hahadkox meude but or not hMited to chlrormethox' yfuoroethoy tflnoonmeihxs and petfluNotbo The term "fluoroalko kx- is AkewSe defined Ihe orm "ary lox) as uSed hern means an try group, a defnie ern m, appended to the parem~ mnokleciar m wortogh an OX~ICyge n'b term "hetcmargloxy' t as used hereinmeans a heteroaryl gnoup, s Idtned herein, uppended' t.' the pao'ent molecular 20 moiety throu ,m oi gcn Thtr "beteroarvlox' is hike:se deined ' he r'ar CO Nikox<" or latl loxvy" as used h -n means an urxAbkvi group as defined herein, appende~d to the parent molecular mio ets ibruh gen T he term "bel\d alkoxx" 1 likewise defined Rq-pr-wegiatc era of ar loY and bieteroary alkone ede, but are not iited to 2-hlorophenymethoxy. n tluoromethy I nheovle~atxy and 2-dimethvlpynidim methoy ies term tfh ItV or 'thto used hein means a -S roup. aprpemed to the parent molecule mnoety tbrough a sulfur, Representar e examples of dlkvlthio inc ude, but are not limited, methwitio, ethylio, iert-bulthio, and hexvlthio. o T he terms 'tdal kyithio^. "'iuoroalkyvthio>' "alkvenyikhmo'> "alkyldho "curbocyelaho'. dad "beterocyclyxdhio'' are hikew ise defined, 'The em "arhi" as sed henn mean ana rup, as dMened herein appnded defined. S ' "tir a lNEW as used hereA means an arylakyl group, eed hern, appended to the i Whrotgh a sulfor T Ze ten Theearvlilk ylhi islknee dened The tem >0u100 as used rrefer o d(Ogrou "Oe erm, 'u nic acr a used herem reWrso 4e0r The term aly' ulfon as used herein means an aly gourt as dezhned heren. appended to the parent moleculh notty through a uny gmup as defned herei. Represenntain e mpewks of alkSU Ion ib include. ut are not limited to mthrdskonl aud ethls t~lfAI ioLms t aslOalkybulfOf\ I. 'ilororaiKm lsidioPJ ' eKa\nltiii u E lkin vulfouyir', "tccire u elylwh V, Theter oc e I ubour . a'Ic ubn\ I aralvkuufur ' 'trnarysulibnv' and "'hemeroaralk suhlfani"' arc Tihe term "aikoAvulfom :as used herAn means an aoy grotp, as defined here appended to the parent molecular mel u as dfmed hetin. .Representaiv e exampIes of allkulony v imdude but are not limited to methoxyul t honL etVsi l and ropmsultouy The terms 'haleko lonv 11 S uo ko yaufonv "alkenloxsu fonynv ' "alk xnylos pulfony L , rho cl jyl ix su fonv ' etero cely i oxt3 m a r oxvs l tony Y r a ks oosufbuyf1 h 1 e troaryvoxsftn' and 'te' aikvloxsafyiopy are ikeise The terms t itly ttoN\ L mesy L and nonalti are anrecoredfj( 'and refer to milrruoromiethanesulonvl P p'toluenesulfony L methaneanulfony L, and nomailuiorobutames lion) ' grot p. respective ely The terms in flatol ate, mesalate, and nonafiate are urrecogurred and ref'er to tritluior'ometh anesuilfinite ester, toluenesilfonate ester, merhanesul fonate eater, a nd nonalluorohutianesul fonate eser fimctioal grroups and motecules that contain said tupsr T ' ios a 'asci noerebi means an aminmo group, as defined Iarein, appended to the parent molecular moiety through a sulfonyl group.

ten uha sed einne0y upor ias Rw win tmu A p is). gace % nu ea r scusd herein r mea nW s roup, any defips aeren a arpended to Ite ulptin mlcuro u ips ey though a arbons u ed heren nmmt R mte X+ampe rf t akanYl mludp , but a n, Inid to, acet L K oxoproythe trYI dcmthv -sprsel o y Las ad I-ox gruyl. A erms ha klyerof nyt! nloralkylasbond Adtmnlkarbony!"ltnlaroy theboc ere y tea ocbrnohteroeaseuserearbonyti arylearbona AQ^, grloteqboyt hTer terarbn as wheeroaralkyearbony a. rheise dined An Viter of"acv as used herein refrrta group a of which im isoi hrto a cmarbog group of eoxises of a eabox group incde eroyt acid byroxmicaci, ayleaarid andSA xaidooy The atm "koxycarbonyP as used herein means an alkx group, as defined herenappen ded to the parem mcular m o y ahro a carbonyi grou ap,. as dhefin h.erei. Rpresentativexamples of aoya include, u but ar not imAed to, methpoxyc arbt ethxycaroy and iorobuoycarbon The terms $t"haloakycarbnyrt ''fluorlkocaronyl", alkenloxycaon o arlocyciarbonI "aralkyloylecarbony", "htraryvoxcarbonylF andvisbnv ' lheteroarva rylocand hererly uus "aekewise defined Tbec termn "aikycarbonyoxy" as used herein means an alkycarbonyl group, as defined herein, appended to the parent rnolecular moiety through an oxygen atom, Representative examples of aikylcartonytoay include, but are not limited to o aetylaxy. ofltcarbonyoQxy, and tert-btyVtcarbonylox The terms "baloalkytcarbonyoxy" flu~earlafornylo><. v '-An eronyloXy', ' 4 a tkynyieiirbony Iodoy ca rboceycyearbonytoxy" "heteroey ycaronyxv, arvylaronytoxy', "aakylcarbonyto>xy" 'heteroarylc arbony l oxy", and 'heteroaralky carbonyloxyv" are I ho term "alkyn ' lOr y^'d, as used hi ere ei tmen A an Iatonui gmop as d ned heroes, appinded to t Se parent moleular ni ets through h an o grn atm The termn. 'haloabYxu fony lod, nuuualk lsunionloxy , 'alkenylvson y oxy', "alkvnyulth o "tJ, earho ch ". o y 'heteroei c dt uon ksy^ >arvuAConx tos' , araks buteosz ", 'hebroaylornc oxy ", "heterciaratdkx (sul onyln\'^, "hatoa'ko\ xps ltonv wox.', 11loornalkooyvat tnny bayu i 'alkenvio t afot lo,' a kywoxvsulfon'los', "earbocyelyloyx uufbnyloay' heterocvd. lvoaar tulfouyloxy', 'ary knysatan kony'>'araikxd loxsutfonyvoox', "heteroaryfousu~tnmtoxd' and "eteroaralk)10sutfouyto lx \ ie kew ise defined, 'Ihe term "numno"' or "anun&' a used here refers to Nt4 aw d substituted deri1vatives thereof' wherein one or b'oth of the hv)draells are indeneldettl replaced with 7 ubStituents .seketed front the group constmgu of alk-1, haksatkvt fluoroatkvtL aikcniyt alkyv uy earbocycch 1 heteroepl~it, arn L andkhv Lbete roany h eteroaralkvlyt lkyleartbonytL hialoat) barbonnytL tiuoroalk yteairkb, t alenybearboug 1 a lkynviearbons xl C atboevctbiearbonyt Lheteboeyelylearbon\ L. ar lrbondL anviearbom L heteroarytlearbonyi. hetwroaralkt earbonvi and die aufon yt and sultiny lgroups den med 25 a oe: or when both hydrogens together are reptlaced with an alhy lene group (to form a neg whigh contains the niogen). Representaiv e examples inchude, but are not limited to naehy larnun.aeetvai r and nineths amino. The tem nird&oa uead herein means an amntirn rupas defined heren apende dto theparent moleuar miety tnrotigh a crboal The tern ano as ed here means a N mup Nfj term 'ttoi' as used hereinmeas a mgp. he term zidas uedherimeas a -N gu The term >osphiny" or phosphineo" as used herein includes -PH and substituted deriv atives thereof wherein one> two Or three of the hydrogens are independently replaced with subtituens selected Wmm the group consisting of alkIN haloAky fluoralkyd alk enyt. alknyVUv carboeycly.t heterocyclyk ary'l aralkytd heteroaryv beteroaralkytvl alkoxyv haloaikoxy, flumralkyloxy, alkenytoxy, a kn yoloxy ctvart c loxy, heterocycdioxy aryloxy. aralkyvaxy, heteroarylovy, heteorralkylioxy ado amino, wro4fli)H and~M n V he term >phosphe:ry ' as Ie hrem i - and substine derivare theofnt herim one or both of the bvdr de l zr odInd n rphi ed with aubsftuents selec ted trom the group consting of alktvi, haloa 1ky the nreaiky l afk, nyt. alk ny L carboevelyl teterocciyhtaryl aralky L, hetemaryl heteraralky, akoxy, tudoalkoxy nuoroal ky oxy atkenv foys yknyfxa.. earboev ety loxy, hetewecvdvloxy a 1y lox araiky iory heteroaryv usbetemoarankylkahd and a dmod 'i he teo'ilyv as used herm mnneludes Hs and subsituMed d eual s theneof wherein one. rwo or Shree ofthe hvnroens are dep ndutlv repAced in subsituturnts . selcted from aller .L hauloalkyt fiuotoalk i altenyt alkynyt ear boeveivl hcter oevelysrb aralk ylt heteroaryL amnd betem osralk) I Represennitvc exampleti include trimthybei i ('TelS). terf'-rnutykblpheny ibyl (TBiPS), et-houldvmiethyv silsd TBES/T15)I!~AIS uropropvi'd'x It I PS), and [2Atriunethylsilvb)ethox ]methyl (iM \t '( he term'ilvy y as used herein means a shyl group, as defined herein, is 20appended to the parent molecule through an oxygen atomic The abbrenalttos \F . Ph, It N, AIs. and \ pr esen~t meth L, ethyt phen>'l, tritluo~rmethanesuhfon Li nonafinombutanesulffonyl LP'toitienestldfony and miethanesubtoust respect vety, A more compreben siwe list of' the soreuiatins idiced by orgmanic chermists of ordmnary skil in the art appears in the first isue of each v olune Of the 25 ,fra vi Orat 'oma r' ti list is typically presented mP a table entitc end un /. ,?stf / ibre Amer. The term "treatin< a used herem. encompass the administration anid or apphiation of one or more compounds described herein, to a subject, for the purpose of rovidina preveemion of or management of, and/or remedy ior a conditon, -vfremtmen' f'or SOthe puipose> of this disclosure, roay, but does not have to, provide a cure; rather, 'treaimknt' nmy he mn the fbrm of management of the conditon, W\hen the compounds described herein are used to Oeat unwanted prohiferating cells includmgi cancers tcnnnt idepaia oritoldestctmion of the undesirable grohttravn lih rnal s e efSeto imala on Ina desired ieehan of reatment unwated rapidiy pli fan els, including cancer cels at the ellular levet s apoprosis The term a used.hrn thas enaes not oni to (nc. but also to SOW the progreFo ofand duce ease. disrer, or condiAtAn , i oe an'treattcan encomganaeent" The term "preventing a used herein inludeseither prevented or lowIng the onset ot a ehmeiafl ev ident disease progr essin altogether or prevnnng or siovmn the onset of as of a isease m mn'idua' risk. U inmludes p iap ettt eatrmemt of how at risk of dvelopiNm a disease The term "Isubiect'^ tot pturpoes of'treatmet mncheks any human or animal subjet who has been diagnosed th, ha symptoms ot, or is at rik of develormgt disorder For methods ot prevention the sthjtexl is any human or aninial stibjeet. Uhe term "opuona deuterated' as usd herein refers to ann adicnt as descrbed above, wherein one ore drogeus ha been replace with a deuterim Examples o F deteatdalkx} miehd ( DI and &D, rhe term aool aw usedeein riders to saona 'maecde and POlntrs Wh have more than one hydroxy L As used herein, a "carbohydrate" (or, equivalently, a "sugar") is a saccharide 20(inciudingt minosaccharides, aligosaccharides and polysaccharides) and/ir a molecule (including oligomers or polymers derived from one or more monosacchaides, e g, by reduction of carbonyl groups, by oxidation ot one or more terminal gups to carboxylie acids, by replacement of one or mow hydroxy groups) by a hydrogen atom, an atmio group, a ihiol group or similar heteroatomic groups, etc. Te term "carbohydrate also includes derivatives of these compounds, in some cases. the carbohydrate may be a pemnose (Le. having 5 carbons)or a hexose (i.e having 6 carbost and in certain instances, the carbohydrate ma' be an oligosaccharde comprising pentose and/or hexose units, e inclding thosedsceddabove $4fbejdral and "stga" as used heen s includes sgarominiett nd sugr iemoietiesl Siiai-mmneues are well known to one of ordinary sill in the an and iclade ho eesiedida nE sentals eobioogyEited byari n aA an C d 'K~ A 12 tmmoeth groupS (Jon templakted Lw the present invmntii i sude ey ioS uch as a ecvcloa4;ane containing one bvr Juxyl mgro on each of three or more rnns atonms as defined by .1 IPMA cuwaion In otter rmboonients such cv yeld mortes mi sude i nonlols aneh S a 0-1hos1oitol SuitrIhc sluvdrlke mDoiceAe incllde deveLle aus 91osip Ke sin. roup imelude linear alkytol Atnd crythritols to naime but a tem It wTi be dopiecidted that sugar rWouit can ct5 in either er he or ae)ChC tonn% Aecrdningly, act be ioann of a~ sigar grot) are colltempidtedo thK present in\vent0io as asuti'e NUs>~ hk11' morn le T he term' pogth ioi" as used herein retbes to small molcetenmd polx mers which I ~ ~ 'N haebr ha n h Niacin asoknown ns ic ai has the r'r -SZ iR R aralkyVt beteraraikyit halogen, nitm. cyano, sulfonic acid, aklulfoxy L arycu foxt hetecroarvyIsulfoxy, kaalky Isulfxyl heteroaraiky isuifoxyi, alkenylisulfoxyi alkynylsulfoxyl, alky lsulfonyi. aryksuifonyt heteroaryisuifonyt1. aralkyisuI fonyiL heteroaraikyvkulfonyti al kenulfny alyysufnthyrx. al koxyv a ryboxy I heteriaryi'ox 'w rakykoxy, heteroar'alkyoxy, aikeyl xy, alkynyoxy, thio, alkythio, ary thi, al ihio, hetroarkythiA, akenyhi atkyny tthio frmyt cyL formvyloxy, ayoxqmy, formyWthio, acylthio, amne, aIkylamin, aryamne, heteroarylamine, ara 1kylay aUkenyiamine, .aikynylamincc. formyliamnine, acylamne,> zarboxyl alkyoxycarbonyi. aryloxycarbonyI hcteroaryioxycarbony L. arakylxvcarbonyi beeiroaralkyoxycarbonyi i) amido, alkykaminecarbony'i arylamnineecrbocnyt heternaryiamiinecarbonyi, aralkyam inonarbo id, beteraaralkylaminearbonyt NXisOC",SN.MR; x s A" o Rl i hydrtogen, alkyl, baioaikyt alckenyit alkynyi carbtAy y heraycyI he'terocyclyaky aryl, aralkyti heterOary heteralkyl fused bicycly t carboxyikyt arylIkenylaryt amido-vubstitutedacetylammoalkitcar Ixy ubst tdacetyimmonaikyt hydroxyaikyl thioalkyiltoaikytaclkoxycrbonyioxyaikylIkyLcarb oxyalkvi.or . an idoal ky; R is hdrognm kower lkyi, lowr uAlenl Loi i a n hoge hvdrmxyk atmmehcarbox) ic eiocakiL ntI ar m aryl aralky! Leteroaralky 'i anc, or nitro; F a byvdrogecn, low er alkyiL low er a"lkenvR koxe as y L hatea, by drouyl. mmine, carbon L e oailky . ariy I eteroryFL aralkl heteroaalkxf cI ko , or mir R is seheed independently for each or u rnce from the Vroup ConSiStym Of tvdrogcn, alky aikcuw L alkyniL arv L heterar arciky L becrmaralkv , logen, minro. a, suifomie acid akv kutmyL arylsaultoo L hteroarvlsfoxy stalvisalinoI beteroaralka vlrufony i alken visutbviv, L avinysuib tytakl >bn arybuitonyIt heteroaryl sulfonyt aralkyvisuifonytK heteroaral kyvsufonyL alkenylsUlfonyL alkysiiVulfony hydroxyt L alkoxy , ary toxy, heteroaryboxyi. arakyl~OXY, heteraasralkyloxyv, alkenyloxy, alkynylox y, tholb s alkyth io, arylihio, .aralkyithio, beteroaralkvylthio. alkenywlthio, aky nyltb is o. forny i. acy , foyx, ayxy formyvti, cylthio a mine, alklamie, I aryamine, heteroarylamine,.SiL arlklneLx heecaakyaine,~. alkeLBnyla m ine, alky LAmi ne formylamnine aTylamine carboxyl, a n oxyca rbony! arVloxycarbony! hetermarylxyca~tronyLaralkyPLyarbonyv , heteroaralkyxlxyarbionyt amido, aLkylaninecarbony aryainv u i ecarbonyl hetroalIaminecarbony LMhralkylamnecarbony L and heteroarakylamt necroiny 10 K UK vdiogen orkmOUZCaikv and na n eWtdents he invent Matesan ne e af mentioned d eodos hr in Areents heternv Ia.ei neeioe 15 comipotnds. whereid :esnts a hhtestyn bdndshrein A is a radid of anovoclan hvin S. hor 7 in atons in cern embodiment. the inveton aes to one of teairem ond k.O~otnd. herinA is aicl 0 bienbeli ng haxiny 9. AK X ii or 12 dna atows 2Q Its comttn 0kodmets the noenioal relates to OC one of theoreetoe composd~s wher~n Nis 0 in certin TOoimns the HO inenio reaes1 an toneofteaorneine cin4iiS ahrein Mx isom to S.n~ compondswheeinN k. N(Wt. in eer-Tak embodimenis, the invewnn relates to any one of the aRomentwioned COO)pounds. wherein is N1910.

In cerw n embodiments, the invention reaes to any ne of the aorementioned compotunds, wherein A is pyrroidinyv im nidazol idinytI thiazol InyO sothazolidinytL oxazolidinyt. oxidiazoidinyt pipeaidinyl. piperaziny thimorphoiyl or Imorpholiyt in certam embodimens the invention relates to any one of the aforemenioned compounds wherein A is imidazolyt pyrazolytsoxoazolyt ox azoyl, isothiavolyL thiazolyt oxiny furazani. oxadiazoy thiadiavolyt triazoly dithiazolyl diazinyL owziny. thiazinM t triaWYt etrazny L iazpiny or hiaz y in CeOtam embodiments the imenton relates to an ne ot the imementioned componrtds. wherein \ is substitute "th i -3 tbsuenta idependently seleted ttm the group consisting of hower aMkyiL halogen Wtro, cyano, sultome aed hydroxYi. aikonyf th-ols.ak tinui, orm L acv L r my acvlnsy formQU thin av io, ain ne alk 'ammne, nor amne gae ean cat-ox yi in Cetai embodiments the imcnuun relates to any ne of the afvementioned compounds wherein \ Is substitute " th I subituent idependeny s leed Bom the iS iITP soliiswting o lner aWkv halogen, uitmo, c\ano, sul NA aeid hydroxvi, Akp', thioL alk.lthio, rmyL aely. hfmnd y-, ac losy., lbormvthn acylthio, amme alkv aidne tmnvlmine ae himine and ear-boxy!. jn cotain embudiments, TeO edon Mates to a oneoe aforementioned I ip a i A is rnot 0hsAttedd 20 in certain embodiments the invention r elates to any one of the alorementioned mnpoimds. wberel Rn is hydrogen or louer alky h co n bdn t invasion rlats to An one of he airemOiA.ned compounds, herein i. hy drn en in contain enTodnnm the enon relate to an one of'heaforenioned COmp8sii-sd whtet~ reit ho alI in certain embodimenms the imenion relates to any ono of tatorementi d iompomds, where-in R is hydrogen in certain embodiments the inwntion relates to any one of tie atrementioned Compounds. w0rcin R is hlydrogen2 and RC is loWer awkv! n certain embodimett the inention re-tis to any one of the aforememioned ompounds wherein R2 is lower alkyL anitd . ii bvdrogen.

nc eNnoditts. the invention relates to an one of Ihe aforenedoned .txpotma tnuiiR~~ ivtoe nd ~ishyran in Ctain mhdinvnm the inventi to an of te afo'r d comipounds wtenf in certain embodimns the invention relates to any one of the afoementioned compounds wherein R i consitin of by droen ower AkA halogen. Pnr yano, sUKfni acid, hy droxyd. alkoxvf t inL a ckyti, ftormy acy , L thryxy tiaey oxy refe omhon ofythe amirenenatkiane formlamneAyamin andl carboxyayov eomopounds. wheremn 7n s 3 aho ete in certain rbodimn the invnon rcd ale0 to mV one of the atone01lnoned in Certan Wnon nt.te invention relas to atm one of the irreto~ compounds, wrhercin Z is net y epold i t euchooicrrcnd uote nt i ulphn anad phisphme O d theineionphmelacts hdnomn of the rri n iood ~ot Npiou-ndsw cJistibxi 2i) in c r;rz emdnav thy invenion relate, to ayone. oftheaoremntine In Iin caodents, the t uelate o aiy onee adorenewioned Compound" WtIMr X is o in arain ebodtimt the inenion te in ctain embodmafl\ the hdnon relate an one of the.Atntioid comrunds.wvril&~ in eacin embdinw fts the veunion reatet a onefte fprinnnted na" is 0 s intcumn O a r Ofta c aumewadim cvulpoundb wherAin \ W d N 1v certinee bodn i i o es to n one o themafonentioned comads wein ww. w NO lw imwo alkyi.o t Incuan embted neats. the invenrian rltes toin on of the afobremnen tined konouds.whrei . hvdogen. OH O N. NHK or~ NH OH a ccew ewtobdinatsthe inven,, ico ate to any one othe aorementioned comindst>dwheein R rprs an n li 11 Wh i AWd Nto ebo nd plyi logi cal eondions Another aspect t ofeovenon e to a compound represented bytusc .o a uIpxpytitclilecnale salt lhereof. n Rh Ai eiN hondeennly or eacwh froo -, riawir'n MCA in apAui po~yw Luo or Apotyttno I R X, Ris R R Nandis either appended to the polyol through an oxygen atom of he poyo ori.ppne o the polythiol through a sulfur atom of the potrhiol A is a heterocyclyl or hetermaryLi optionally deuterated, containing from S to 12 ring 15atoms, including X and N. which is opiionally substituted with I-3 substituenis. independently selected from the groupn consisting of alkyl. alkenwl alkynyt, aryl. beteroaryl, arlky LI heteroaralkyt halogen, nitro, cyano, sulfonic acid, alkylsulfxyl. aryisuI ,foxy heteroaryisulfoxsyl aralkylsul foxy]. heternaralkylsuitfoxyt a] kenylsulfoxyt ~ alkyylulftoxy L alkylsulfonyl arylsulfouyl, hetm emrarsulfonys Iaralkylsulfonyt heteoaralkysulfonytl 20 alken'ylsufonyt, alkynyisulfonyl hydroxt alkoxywil aryioxyt hteoary loxyI aralkyloxys heteroaralkyloxy, alkenyvloxy, alkyvnyx y, thioLalkyltio, arylthio, aralkyh hi, heteroalkylth io, aikenyilthio, alkynylthi o formy acyL. .foryloxy, 'acyloxy,~O fomyhio, acylthio, amine alkylamine arylamine, heteroarylanine, aralkylamine. heteroarakylamine, alkenyla mine, alkynylamine, firmy lamiine, acylamine, carboxy, akyoxycarbonyL 2 nayloxycvarbonyti heteroaryloxycarbonyl, aratkyioxycarbonyl, heteroaralkyl oxycarbonyvt araido *a incarbn arlAninecarbn vi. heteroary Ian;incaronly, x s0.S or t S R is hydrogen al ky lower alkeyl alkynyl oyc ha xoydroy iecclaky L arvy alktL heteroariyl h a arailk, Y e ylyv ca oxya t , ro R' is hvdrogen, lower aMkyL, lower aikenyt lower alkynyi, halogen, hydroxyIl amine, carboxyL cydialkyt aryl heteroaryl. aralky heteroaraikyt eyano, or nitro: a k ' 10th) yro, mvu ar,-Ib r .4 xloe tyyl aoe. vrx R/ 1'. \k is.le in dependentlyIWAs fr each ocrrence firm tbe group conl5siting of. hydrogen, alkyi, alkeny I alkyny, aryd heteoaryl, aiaikyiL heteroatalkyiL halogen, nitro eyano, sLfonic acid. alkylsulfotA ary s.uIfx LOS hettrOaryiuloy L aralky lsulfoxyvl heteraralkylsulfoxyl kL i a ly lxy alynyLsutfoxy, aikylsuifont ytsuLfony l beteroarylsulfonyi to arakybu'fo1NyI I heterparalkylstufo~nyl, akenywsiifony-, Ablkyny lsl *hydroxyt alk oxyl aryyloxyl beteroaryloxylI aralkylo oxy, heterotraikyIoxy, abskenyloxy, aikyn yloxy,. thicoLI alikylthio, arylIthia, araikyithio, hhteoaa lyhia, akenyitti alkynyithie, faomy. aecytformyloxy, aevioxy. formvhtio acyhhi, am ine[ alkyLmine, 0 arylato ine, hetemarlamme, aralkylamine, e teroaraky amine, or kenlamine alkyvInymine formoylamine, aCamine, carboyL alkyloxycarbony 0ay oy c ony L heteraryloxycarbonyt araikyiaxycarbonyt heteraaralkyoxcarbonyt amio alkytvlaminrboyarvlaminec.arbonya, heteroaryilaiecarbonyl, aralkylaminecartbonyt. and heteraraikylamin necar'bonyt; R is hydirogen or tower alkyl and in ettain en bdments. the rnnielates to ao one . .afoen entioted comnpouttd wherein W ixapolya I an cenai embodi rts tha inveion Maes o any o of e aore enoned in catin embodiments he ien' i a kdt anyone of' the afeantioned compounds, herein p ol s n l soi l x.0to or i in certain embodimens the invention creates to aym one of the aforementioned in cen sbodn-10 inuvet ion retm toimemo the irnventioneae compoundswhrei. spo2-yol iinlnvitoti in Cesatnoayoonenof the avron ma to one o e aom ntwhoerd iG omounds.Wrik P is 2. 3. 4, .5, or 6. in c ertai mbodimenms. the inventio relates to any o of te Ahonon cforemenndnedhereinimdisw>herem p ttisvi3 In certam embhOdanemis, the innOn reatest toman un of the afPremeionned cmunds n herein p a d2 inTcirv min e di e t mn iton it te W iU) rnelate th any me~n he.ioen toned compoimundens.l wereinm any ow ofn toives i ain embodiment tho nyon oflte to ramny'oned th aemuntderen no s habeen pis . eI ctan esrbodira ot, the comp.on relte to canyon he at'fernto edaci, onmps cowmn puis 3. thi Coi ebod bnt, the invntyionlates t o any oo of he afoemrbo ed compounds, wrenis id4. in cor w ou t the egree 2 nvenio relate to any oneof Fie alxmennoned compounds. hein is- S. i cerai eowtrienMe the inveti Am ates to art Ce, ofa At has ieen is o vered t hat at least certain of the compounds of the inv ion ha WeSWnh phvsiol ogcal Wadduta of nici. ireudunsialpyiiniclid Manffct of niacin or eample.~ corn pounds of the in-,entzion ohave the Iabiiy to miodulate at leas (o lipid in a deabl Aashion, witout restrictiv s'idefcts or- without tedeuree Addrion. Ai has bWen dicovered that at leas cerank of the comnpouno of th invention do not appear to engage the high-afinity niacin receptor GPR 109A in a manner 0 similar to niacin. GPR09A, also referred to as PUJMA-G and H M74A, is a ember of the nicotinic acid receptor family of protein-coupled redeptors (IPCRsy Wise A et at (200311 o ahn 2'W:9 K Sog a K2 et(al2 003) 1hohm? h w en (w m: 303:364, 9 l GPR 109A knockout nio the effects uNiaM n both lipids and furshing arc eliminated, he flushug effect, but not the pind modifvue effects of macin asbeen asibed to GPR 10\ acination of ERK \ %I A P kruse, ndiated by arrest beta 1 'het arrestnl 41 arrestm beta I knotkout ice, macms effet on tluhmg ht been repred to be teah reduced while the bridM modttmaz edss are maintain, Walers RW et al. 20)1 COM Iner 1109131-21 Sigmiieam t leat certain o tho compounds of Ah in venton have yea ly reduced adtiy to mduce reutmem of Varnein to thmembrae of eels CfeSSn (PR 1 \,A ha1 eat VS reded .fhsuianu en'ect compared to maemn 'et m0aminitain chnmealls 'sniicant desrable lipid 4nodifymng effects. Many of the comounds AM pof' the- iverntion may b v a s h pharmaceutical compatile coutnerions (i.. pharmaceutically acpal sahs) A "pharmaceuically acceptable sa" means any non-toxic salt that, upon administration to a recipient, is capable of providAng. either cdirecty or indwectly, a compomd or a prodrug of a Ii comnpountd of this invention. A "p~~haaetRicas acceptable cotunterion is an ionic Portion of a sat that is not toxic when relased frm the sal upon admtrnation to a recipient, Pharmaceutically compatible salts any be formed with man acids, including hut not liAted to hydrochloric, suifunic, acetic, lactic. tartaric, malic succinic. etc, SAIts tend to be more solub1e in aqueous or other protonc 'Ile an than are t corresponding free base forms Acids commonly employed to form pharmaceuticaly acceptable salts include Iinrganic acids such as hydrogen bisulfide. hydrochloric, .hydmobroidic, sulfurie and' phosphsonic acid as wl as oNran acids such as para-toluenesulfonic, salicylie, atari, bitartaric, ascorbic, mnaileie, besy lie, fumaric, gluconic, g ueuronic, fric, 2igluanec methancsulhonic, ethasnesulfonic, benzenesulfonic, lactic, oxahie, para bromophenylisu tonie. carbon ic, succinic, citric, benzoic arnd acetic acid, and related inorgan ic and organic acids. Stuch pharmaceutically acceptable salts thus incle sulfate, pyrosuifate, bsisulfate, sultite, b isul lite, phosphate, monobydrogenphosphatte, dihydrogenphosphate, metaphosphate, pyrophosphaee, chloride, bromide, iodide, acetate, propionate, decnte capryat, acrylate, formate,. iobutyrate, caprate, heptanate, propioiate, oxalte, naionate, succinate, subcraie, schacate, fumarate, maleate, butyneo L4 dioate, hex yne-1,6-~dioate, benzoate. clorobenizoate,. mnethylbenzoate, dunitrobenzoate, hydroxybenate, methoxy'benzoate, phthalate, terephathalaic, su Ifonrare, xyienesulifamate, in h, phenlactat. phaylroponat, penybutyrate, citrate, lactate, [-hydroxyvbutyrae gjlycolaie, malce tartrait, methnesulfonate, propanesulfronatet, n aph haeno-l-sxtunatc, naphthaliee-2-ulfonate, nmndelate and the like salts, Exemiphny pharmaccutialy acceplabe acid adwhon sas include those formed with mineraodacids such as hydrochloric 5 acd and hydrobrnmc acid, and espeially those formed with argani acids such as malic ac Sun able bases tbrftemdng p arma~enticady< aeprtahic sah s wth acidic timetoud groups includ but arc not wited to, hvdroxidcks ot alkai metas such as odium, p~o}asm, and bAthim hy daides of alahine earh meal such a aleit and magne , b hdroides ol'Other metals. such as aluminum and eme, ananoma, and 'aame ans. such as unosubstituted or hydr o b nonos di , or ridalyldamins. dicyesvke\a amine, inhaty I amine; pyridmne, A-methvhUx-thdatmine; diethylaiome. tricthylamine mono-. bis or tris-{khydroxwlowcer alkyil ammensV such as mono>, bis- oxr tuisohydroxyethylhammie. -hy dmxyten-bor vlanne, or tr(b~vdroxyteilthmxeth ylornine., NN-di-kmer AikyNN (hy drox lower alky amines, such as N-dimethy ( droxyethI amine or tri hy droxethy )amine, N nethyolD ua mm: and amno aids such as argom:, [ne, and the like. eraen cohnds fte invenoi and dheir sales may exis in more than one cstal fen ind therest iention includes each crystal fAn and mixture thereof 20 CertY c oaingnip nds oi thb invation ad their salts P1-w also xiSt in the ni A oleso. xamplehdaes and the posent inentionicds eah soat an n xures therco L Certain comounads of the invention may -ntain one or mre S centr and exist in diheret optiell ate forns When compounds of the inveion contain one Ar em th c podxist n tin o enan umne tors and the present invNt o includes both entonmers nd mitures ot'eiuntiomers sueh as racenc mixtures. ihe enaniimers ma be resoled by methods know n to those skilled n the arm fr example b formatuon of diasercoisomneri sahtaw hich may he prted oi example, by rptalhan tformaunm of diastereosomen deriates or comiplexes which man be So eparated, t'or example', by ecrystallization, Lhas- liquid or liquid( charomaogr aphv; selee live reaction of one enantioner with an cnantioiwpecilic reagent, for example enzynatic esteriicati on; or gayhcltd or liqpid cNromatogaphy in a chiral cnviromnen, lor example on a chirai support fo example Sl x ith bound chiral ligand ' in th: presence of a chiral SOt ft It will be approa oid thA w here di desired %ant is comweried imo another emncal until by one of the eparaion procedures described above. a further step may he used to hberate the desired enanltomeric fornn Altematively, spile eNnjirmers wab e synhewed by asymnietr synthesis using opciel actne reagems substratus cuttavsts or soents or by conertia g one enantiomer into the other by asynietro When a compound of the invention contains more than one chiral cnter, it may Oxist in diastereoisomneric forms, The diastereoisomteric compotmds miay be separated by methods known to those skilled in the ar. fo example chromatography or rystalzation and the individual enantiomers may be separated as described above. Th present invention includes each diaistereoisomer of compounds of thu invention and mnixtus thereof Certain compounds of the invention may exist in different ottomerie fmsor as different geometric isomers, and the present invention includes each rautomer and/or 1 geometric isomler of compounds of thu invention and mixtures thereof Certain compounds of the invention may ex ist in different stable conformational fotrms which may be setirbe. Torsional asynuetry due to restricted rotation about an asyrmmetric single bond, or exampic because of ste hindrance or ring strain, may permit sepaation of different conformers. The present invention includes eac eontormarional is omer of compound~s of the invention and mixtures thereof. Certain compounds of the invention may exist in zwitterioni form and the present invention incudus each :zwitterionic frm of compounds of the invention and mixtures 'The preen iention alo includes ptrodrgs A used herein the term 'rodrug" refers to an agent uhibh is converted io the paren drug mi io by some physiologic vlhemical process (e g.. a pidr on to the physiogical pi i converted to the desired drin form) Pro-druns an often useful because, in some stuatons they muy be easter to cubominster than thre parent druge They maye lo instane. be bsoavdulae by oral admmismition whereas the parent drug is not. I he prodrmg may also hae emved Mslubi in pharmacological compositions ovr rthe parent drug. An example, wiihout Ont uon, of a tpg inuld be a compound of the present ivenutin wheremn P 1 admidr eered as an ester (the "prodrugT to iitatu tatsmural acros a cell membrane where water sotubility is not beneficial but then in is metabolically hydroly zed to the carboxic. acid once inside the cll where water solubiity is beneficial. Po-drgs have many useful properties, For example. a prodrug may be more water soluble than the ultimate drug, there by tacitatn imyrvenous administration of the drop A prodrug may also have a higher level oforal bioavaiability than the ultimate dou. After administration, the prodm is enzymatically or chemicals cleaved to deliver the ultimate drug in the blood Exenmplary prodrug> upon ckleaae rlsehecrepondig free acid, and such .hydroyzabie ester-forming residues of the cornpounds of this innvntion include but are not limited to carboxydie acid substuents (e. (O4H or amot that contains a carboxyic acid) wherein the fee hydrogen is reploaed hy (CeCa)Alky (Cr lkanoyloxymethyt (CrC ~(alanyoyethy mey -aanyxy)-ethy having frn 5 to 10 carbon atoms, alkxycarbonyloxymtethvy having from 3 to 6 carbon atoms 1 (akoxycarboryloxyethyl having from 4 to 7 carbon atoms onethyl- (aikoxycarbonlox)cthyi having from 5 to 8 0 carbon atoms, NX (aikoxycarbonyllamninomnethyl havirng front 3 to B carbon aroms, NN-t (alkox ycarbonyllami no cthylI having from 4 to 10 carbon atorms, 3-pthalhidy L 4 orotono lactonyL ganmma~butyro laceon--yi, di6NN-(CyCflaikylamino(CmC )aikyl (such as W-dimnezhyiainoethyvb carbamoyl-(CKCga lkyvl N ,N-di(C +gallcarbamnoyl-(Cv SC)alky and pipcridino. pyrro ndino or morphol inoG( yalkyl Other exemplary podrugs roase alcohol or aine of a compound of' the invention whenin the free hydroge of a hydroxyl oramne utituent is replaced by (C tfakaoyloxymcthvyt I-((C Ci kanoyioxyithy$. lehyl-l~((Cp C)alkanoyloxye thi ( C Alkoxcarbony-oxymIetyl, N -(CInalkoxycarboltantino 23 methyl, succioyx (C {{ &}alkariyl raramino(CpCalkanoyt arylactyt and a-aminoacyi, or ctaaminoacyl-a-aminoacyl wherein said (t~aminoacyl moieties are independentlyi anty of the naturally occu rring L-aminto aci ds found in proteins -(O)(OH~t -P(O )(O( CpCcdalkyI ) or lycosyl (the radical reswuing from detachment of the hydroxyl of the hemiacetal of a carbohydrate) The phrase pre group as ed hereiA mean temporary subsntuen inhich protect apoiay reactive f a un gounp mo undeired Ahemicaafounain XampT lof such protenng groups include eateofarby ic acidssil etherof alcohols an acetab and Letals oF aldehy des and ketones respectiey The field of protecing group cheny has been reviewed d (Greene. T : Wuis. PGM PArott *Gtvps 'r Ormmik vMttt 3? ed-z Wiley' Nra York, i99 I. Proteted forms of'the inemnMe cwmponids are included withm t h s op. oh tis in ention. The term 'theical'x protected tonno as used. pertains to a compoundW whuch one or more reactaie funcnonal groups are prot:eted from undesirable chemical reactions that is, arc? . the tfrn of a protected or protecting group (also known as a maskcd or masking group}. It may he con enient or desirable to pr:parc. purfy and/or handC the act e Compound in a chemical protected term Sy protctng a a.r aen ye Inn etional group, reactions in\olv ther uprt eted rcacte eunctonal groups can be performed wohout e ected group; the protceto group may beremoved, usually m a subsequent step, without bstaia affetm tOe remainder of the molecule. See, for examp. Protectue Grmups in Organic SS meTi Green and P Winus. Wily, lo1 99L and Protecth'e Groups in 0ramiie sfness T. Green and P. W\\ut Ard WdIon, Jon W\ile and Sons 199). For esample a hydroxy group nun be protected as an ether (,h) or an estr vC YK)R\for oxaple, as a t-utyl ether a henL berAbydryl (diphenr lonei hyl or ityl triphienlmethyi) eiher; a oarethyl-iv O tutidimethyN i i ether; or an owl ester tOf f)C W (O \cY 20 For example, an aidehyde or ketone group may he protected as an acetal or ketal. respctively. in which the carbony! group (0-=O)" is converted to a diether (C(IOR)}) by reaction wvith, fr example, a primary alcohol The aldehyde or ketone group is readily regeneated by hydrolysis using a large excess of water in the presence Of acid, For example, an amine group may be protected, for example, as an anide NRCU(=0)R) or a urethane (-NRC(=GR), for example, as: a methyl amide ( NHC(='O)CIa); a benzyloxy amide (-NHC"(OOCHtCclJ(Hbz); as a t-butoxy amide ( NHC=(=0)OCCHl)NU~oc);~ S 2biphenylaprmpoxy amnide V NHCf= )OCIC H k bCJLNlHoc) a s a 9-fluorenylmriethoxy amsIe (-NHFmoc) as a 6 nitovertryloxy aide (-NHN oc) as a -rimethyiiyvtethytoxy amide -NHT oc), as a 30 t2,2-rrichloroethyoxy amnido (-NHTroc, as an allloxv amide NH A liloc, a (phenylsulfony)ethyloxy anide (-N -Psee); orI in suitable cases ica cycle anines s, an ninode radical For example a earboxylic acid group may be protected as an ester or an amidc. for examprr. as: a benzml estr a =y ester; a methyl Omtai; or a methy I amide. For exaume. a thio roup may beprotected as a thioethr VSR )fr ex ampie. as; a benzyd thioether; or an acetamidomecthyl ether (-SCHWNHC(=O)CHL) Pu AiRACETICAL7)0MPOS TONS tohe inention ruTides pharmax cubcal Omfpostitorn prsin one or more oftta avrcaferenccd compounds in one apct h present ienon provide lharnalcutically acceptable o rpsitio l hih ompnse a therapeuied efidetixe amlounlt o-f i o n Aore of the conpounds dksertd above, inmdatid mgether nit one oU mnl nore phaymaceutically acceptable Carrier- iddta V ansdi or di iuents. t orn addition Ith nvy to~ pdarranaoeical x bawstins charteae b having at es one desied raputic efec of niac and reduction or absence astoendcra side eft oinin in one aspect, the urvctuoH pro\i ide- a pharmiacee~ dal corn positin, comprising a icixn ainailgor a p iecinically acceptable NA thareoi and at last one pharmacerui rally acceptable excipienrt n herch, sd , omrouinon is rmornated for mal admnimstraum the macin atnarg whn ad'imrntend Ora to a human reduces a seturn or oiasnra level of at least one lipid selcted hrnD fk wroup contng~m of total cholester'oL. lOw-denst\ lipoproteins UR) cholesterol i. ride and hpoprotein (a) and oral admmiitation of the composion is characterd by reduced flushg and reduced hepatocelu lar darnage, as compared to administration ofan eqltufim'h oral lose of miacin .A "acin analog' as used herein is a irumr nal analo of macir, otor than niaem (:meotmi acid that, hen adminsereod oral to a sublet has at least one ipid miodulating elfect that is elbaractenstic of orally adminitered niacin A niacin analog has a Structure sindar to that of ninaon. ut diffenrg frn nacin i respect of at least one atom. tluctonal group, sutoittlent, or substucture, w hich :are replaced w ith other :atonE. groups subsntuenh. 01 substruc-tures. Niacin aalos of the invention spee lfieallv c eluhde trnaedbs sustained and exenide-reliee tornuiat inns of niacin, including macin rmulated together with a pohymer. such as -pols-ethsvlene glycol or hy droy ptopvl methyletuiose : hypronellose, Ione enebodnetth niacin analog isa ydinescn ng compound. 41- In one embodimenm, the nicin an dog is notr a embed aa be adindo ei d[ ren I~y l ridinic and aidioIUS Msiosi iaaent Aphkcnn N NtN N< N I N H3CH5< N c N , and of 0r S n Nmbdi ment. die a eianalo speedficed vexcludes acompound represented La ov\wre eA uaramaeeuteahyace eprab nthereof aR Fre -n AA wherein R represents independent fr each occurrence H, alky alkonyL alkynyt aryi, heterotiry L arailkyt, heteraady L, fluoride, chloride, bromnide, iodide, initro, eyano, sulfonic J3 acid. alkylsu lfoxylI ary sL foxy t, heteroaryvslfotxy I aralkyvisuitoxy L, heteroaikysulfoxy vL alkenylsuoiixyt, alkyvnyisuifoxyL alkyisulfonyyl arylsulfonvyt heteroarytsufemy K aral kylsulfonyt heteroara lkylsulfonyv al kenylsulfonytI alkynylsulfonmy, hydroxyl al koxyl, -4y ary0xyiL heteroavrloxv I a ilkyloxy, hetxy, ken oxy, alk oxy, thicoL. alkylthio, ary)thuo, aralky 1nthio,' heearlktha aleyti.aknkifry c fornmyloxy, acylox y, formyl th io, acy io, arnino, alkylamino, aryiamirno, beteroarylanino, aralkylamino, beteriakylanoN alkenylamino, alIkynyhaino, formylami arc.yL amio car boxyate, al1kvyycrbony' F aryoxyc-arbony hetcraarvoxycatbonvi aralky toxycarbony L, heteruaralky loxycarbonytL carboxamido, alky'laminocarbonyiL arylamtinocarbony i. hetrcarylainocarbon i aralkylaminocarbony L or hetercaralkylaminocarbonyl R' represents indpendently tor each occurrence Hi, al L alkenyvl, alkynytA aryl hseteroarl.ara Iky 1 heteroarailky 1L alkylsulfoIny, aryltfony L hetercary isulfonyli. aralky 2?suufonyt, heteroaralkyIsulfotia v atkenylisuilftmyk1 alkyrlnyltlony hi ydroxyi, aiikoxyt. arytox A. beteroaryloxy I aralkyloxy, heteroaraikyloxy alkeny'oxy, alkynyloxy. fbrmy L acyl amino, alkyi anmio, aryailno, heteroarylamino, arlylino, heteroaralkylamino, alkeny lamninro aikynyl Iamino, form mi anro, acyarmnuo. alkyl'oxycatrbonl aryloxycar~bony L. h5etcroaryloxycarbonytI araikyloxycarbonyt1 heteroara Ikyloxycarbonyt. alkylamninocarbonyl aryarninocarbony vm oeteroar yamioton L araky lami nocarbonyt or better aralklaminocarbnyb or the nGo instanceS of R' taken together represent -(CH ,

(CH

2 ) 4CH 4 , -(CH)n or i R" represents independently for each occurrec Htt111 alkyl alkeny L alkynyt aryLI s ieteroary aralky or heeroaral kyi and nr ssL or 4. T'lhe iae im snaic, w ben admimnat ed orally to a human, reduces a scrum o plasma lev ei of at leat one h'pid selected from the group col1tmg of toud chokseroL iowdensa hipopr otemn (L DL) reo~teroL, triglycerides and hpoprotein t at The nmacim analoc is said 25 to reduce a sentoi or p laamu lev el mfat least one lipid nhen aueb sermi or plasma lev el is reduced by anseasirabie amount asecompared to a. pre-tresument baseline, or control levelt in one embodimient the maemn analog is said to reduce a sonrum or plasma lev el of at leasr one lipid when such serumt or pkasma level i5 reduced by at least 5 picenrt of the pre treatnetbaseine, or control levet; that is the serum or plasma lev el is reduced tO no more 50 han 9$ pcrceeit of'die pmrUearent, haseline, or control lee I one embiodimenit rhe niacin analogr is said to reduce a serum or plasma lev el of at least one lipid when such sermi or plasma lev el is reduced b, at leusi 10 percent of the pre-treatmenct, baseline or control leveld In one embodiment the macin analoc is said to reduce a serum or pausmas level of at least one hpid "hen such srum or plasma leve i reduced bV at least peren of the pietreatment. hechne or control lev el, o nl e emnbodmm. the niacm aalog is said to reduce a serum or 'hasma level or'a least one lipid hen auch serum or plasma level is reduced by at least 20 percent of the pretreamen baseline or conrol level As used heremuingi ' erehi to objc ctitam(ouvodihauon, frquently aceomparued by redness and o a subjecme experience of a warm feel inn The mo , mhe arer ith or Wthout ichMg Rishm can be measured objectively using obieve. measurements such as D oppi capillary blood flow me:asurements, ,\lt.nmam e or to adimtlon, tlshing can be maared UAp a soualled vsual analog scale (V AS} which can hbe either obser-brtased or shjeesbased The \.\S iwpiealv involves scormn a sgn or avimitorn on a scate tanning tromt aero (0) to ten i l t w here :ereo corresponds to complete absence of the An or rmpton heang sored, and ten corresponds t am unhearable or mnaxunn( amount or degree of the n er 1smptom being scored. As used herein, "hepatocellular damage" refers to toxic iury to liver parenchymal cells, Hepatocellar damage can be assessed using any suitable rmehod, in one embodiment, hepatocellular damage is assessed by measuring one or more serum liver enzymes, in one enmbodiment, one such ive~r enzyme is aspartate amninorranstrasec(AST, also referred to as SGOT A in one embodiment, one such liver enzyme is alanine aninotransferase (ALT. also referred to as S04 Serum levels of AST and ALT are commonlv measured in clinical practice, and it is not necessary to describe methods for their tmeasuremnent here. Normal serum levels both of ASTI and A LT are generally (0-35 U/L in contrast to ALT. which is found primarily in He liven, AST is also found in other tissues, including heart, skeletal muscle, kidney, and brain. and is thus somewhat less specic as an indicator of iver dysfunction. Although elevated serum levels of AST or A LT may be observed in a variety of nonhepatie conditions, including myocard ia tifrction, these conditions are usually readily distinguished clinicaly fromi liver disease, In lver disease, elevations of serum AST and ALT reflect hepati necrosis. a severe form of hoepatocellular da mage. Oral administration of the composition is characterized by reduced Bushing and M reduced hepatocellular damane, as compared to administration of an equimolam oral dose of niacin. In this context Bushing is said to he reduced when it is reduced by a measurable amount or degree as compared to a corresponding degree ot pushing associated with admnin isrmain of an equimolar oral dose of niacin. In one embodiment, 8kushing is said to he reduced when then rnum degre o amountef sings reduced bya measure denree or unital anred ao the naxnur dere or namomt of Asn issodaed withidnistranon of an equinhi r oald dose otnin. Tn one embodiment, flushig i said to be reduced when Doppler capillry blood flow in relevant tissue is reduced by at least 2 percent as compared ln Dopper cadlary b loud flow in corr ondm relevant tisue associated wth radiation of an eqWinolar oral dose of mam e. the flow is reduced to no more than 9Xpercent of the Doppler tiw n se associated wih adintato" otma capolar blood flow in corrspondin relevantU e a d th astrauen of a eguhuoa oral dose of niacin I one embodien, Iluhng i sad to e redu ed when Doppfler capillary bood flow in relevnt tssue is teduced by at least 5 percent as compared to Doppler capillary blood iow in corresponding relevant tiue asciated w ith admiration ot'an equimolar oral dose f maen h One mboitinent, Meuhinmg i said to be reduced w hen Dotppler capillary blood flow in relevant tissue is reduced byv at least 10) percent as coumpared to Doppler capi rhn blood flow nm consp~onidinig relev ant issue s asociated nith admimistration of an equtiolar oisl dose of niacin in one embodiment, flushing is said to be reduced w hen WAS score for relevant tsue is reduced by at least one (1 ) ton a scal frm 0 to 10) as compared to V'AS score fo corresponding rele an tissue associated with administration of an equolar and dose of macin; ie. the V AS score reduced to no more than one les than the WAS score Wor 1Wcorresponding r el evant tissue associated with administrain, of an equimolar oral dose of nium. For eaumpie. in one such an embodied, flushM is said to be reduced when the ninur VA sore i $ whereas the maximum V,\S score tor responding relevami tisse associated nwitb admuinisraton of an equitmaar oral dose of niacin is @10a Of course, nly of tie foreyoig comparisons can, ad\ant isaeusl, mae on a population basis. For einppe, mean or median values of AST ALT. or WAS snore can be compred. likewIse, mean or edan alues of- maximum ASE maximum A L U, or maximum \WAS score can he roared. comparisonn is nade to an equimolar oral dose of niacin.. An equinmolar oral dose of iacin refers to an equimolar oral dose of niacin i any torn including, fAr example mediate timed sustained. and extendedrelease formuhuains of niacin. In one embodiment an equimolar oral dose is fotmulted in an analogous fashion, e.g, in tablet forn wherein each individual tablet is comprised of the same or essenially the same mar -'15 .

amount of active a e Wus fOr example eomnpanison anbe md im one embodimet, betw een oral doses given as smgdie tablets each tablet conaimig UK nmol of active agent ic g ,Ig ofaenm As an uatenative example, companion can be mid, i another erodiment, between Oral do5es given as two Siagle table each tab t containmu 4,1 rnmoi of acine agent (e. p, 05 of man Excp as may be indied oterwis herein, cl pharmacokineie comansto tiaei M are corl parish to scaid ini atel ease tootrna t in certain embodiment, the\ invention relates to any one o d1e aOF% eleitined eompos~ion. wheretin peak serum rw plasma conccntratRon (> for the nacin analog is .o4)percent or0es o(% 0 for the Altuanlar oral dose of niac 111 11onle enmbodimnt, pe ak sc-ruwt' plasmna cotenano I fou the niaci analot is 35 POeCent <r Of ce for the equimolar oraI douc of iacin In one embodient, peak serum or plasma conceturanoi (C fr the mamcin analog is .3 percent or les of c tor Ohe eqimolar oral dose of macrn. In one embodiment, peak serum or plasma conentrat0n Cma Or the niacin onatIog is 2.O per eor less of C,. for the epuolar ord dose 0f iacm In one embodiment, peak btum or plasma corncenmaoit ' for the niamci analog is ' percent or less of( fAn the eglimolar oral dos of niacn. I one enbodment peak scrm or plasma concentration ({ 1 t\ for0 the niadcin mnlog ix 15. perent OfN ofL tu0 the equnmolart Orat dose of'niacin, Inl one enmhodiment, peath seYtin or a~sni concentriatiof for te niai a.aloc is 10 percent les s e. t oral dose of niacin, in one eMbodiment, peak serum or pasma concentration (C,' for the o ain analo? is 5 percent or less of ( or lt the cquimrdar oral dose of nacin In one embodiment, peak srum or plasma concentration (C.) for the Nac analog is i percent or less of {'X or the egido arl dose of mael. For each of the foregoing ibodimens it s to be understood that companion is made with an immediate release rmon fniacinMeds useI lor easungthe oncenrtionaredisclosed in detil hereinelw In certain embodiments, the invenion relates to any one of the aforementioned com positions nwherein0 peak serumnor plasma conleentr altin ( ) 0 l he comUpoun1d is I t0 30 40 pemnt ofQ fOr the eq 1olar otra dose of niaen. in one embodiment, peak ser dor plasma concentration (C ) fbi the compound is 1 tos peren of C A r the equimolar Orad dose of niiad. In one MMbodiMent, pea 1 serm or pldsma concentration ((im\)lfor tIme comnpoud is .1 to 30 pereen of C! for the eqimolar oral dose niain. In one embodiment peak sru percent of Om for the eimo~lar oral dose of iacin, in one~. emtbodiment, peak serum or plasma concentration (CQml for the compound i is to 20 pertkcen of Com for the equimolar oral dlose of iacm., In one emnbodimnen t, peak serum or pt dsma concentration (la for the compound is 1 to 1 percent of Cmr the equimolar oral dose of niacin,. In one emibodimernt, peak scrum or plasma concenmration (Ca for the compound is I to 10P percent of C for the equimolar oral dose of niacin, For each of the foregoing embodimetnit is to be umderstood that comparison is made with an immediate release formuiation oftnacin. Methods useful for mecasuri ng the concentration are dlisciosed mn lbdetati hereinbelow. hn certain embodiments he ivention relates to any one of the aforememtioned compositions w heremii the radio of peak ser um or plasma concenuratiou k0 to areaide the curve a t 24 hours XACo )(ite. the matio (~ XL C0 a I for the niacin analog is 03 ih or ten In> one em~bodimentu the ratio of peak contcentranenm to ar ea under the curve at 24 1$ hours ILCA;ALN.

4 4 l or th main analog: is 0.30 h or aeN5 in one embodiment, the ratio of peak concnCttration to area under the curve at 24 huurs (C{ &A(r&.

2 4 for the niacim analog is (t25h or less, i one embodment, the rato of peak concentration to alca under the curve at 24 hours ('0 A+ d the maein antliS 0 71 a or les. 1i one emboiment, the ratio of peak concentraton to area under the cur1e a 24 arirs re (0 qA L( e for i hie iaci an k 0 1 h a or less, in one embodiment, the latio o peak coniceptrat'un to area undler the curve at :2( hours (C 2 am A~Uq 'a u te the niunit analog is 0 1t) h " Vess in one emborunem the ratio of peak councemrvatln to area under the curve at 24 hours ( C *WJeX> lor thei niacin analog is 0.0$ h 0 oC \es in on' embodibicm the riat of peak concentranonr to area under the eun 'i 'a.t I hemus dS {Ca AUtC ) for the niain analog is 0.01 hW or les. in certain embodiments, the invention relates to any one of'the aforementioned compositions wherein the ratio of peak aeu rpam ocnrain(. oae ne the curve at 24 hours (AUCn~ti (ie., dt rnuio CtJA UC.:u for the compound is 0.110 h' to 0.3$ i n one embodiment, the ratio of peak concentration to area under the curve at 24 $0 hours ((WAXL('s) for the compound is 0. 10 C' to 0.30 i in one embodiment, the ratio of peak concentration to area under the curve at 24 hours (C.M\AUC,:)x for the comnpound is 0.10 h< to 0.25' h In one embodiment, the ratio of peak concentation to area under the c.urv e at 24 hours (C(>/AUCr.a for the compound Is (1.10 It to 0.20 h '4z >1.

hn eeatu emboditments the mvention relaes to any one of the aforramentioned otpostias whberemn the time to neak stra a Plam Conlcentrah0 tiona'l for the mac'm analog is in the range o) miutesto nours, in one embodiment, the tim to peak concentraion (t) for the nback analo is m the nogn Qt I to 5 hours. in one embohmem the tie to peak coneentranon A ts the nam analog is i the ranu of I to 4 hours in one embodiment the time to peat coneentration it f t n anao in the nge of I to 3 hours. i one embodiment, the tme to peak concentraton (ma tAr h niacn analog is in the ng om W hoars in certain embodiments the invention relates to any one of the afobremientioned it compositions, wherein the niacin aaog has an EC, for p-arrestin mediated GPR109A fiction which is at least 10 times grcater than the EC 50 of niacin for p-arrestnmdite GPR I09A functionrt Er referN to Zhe concentration at which a particular effect achieves 50 percent of its maximum i-arrestin-mediated GPR 109A function is described elsewhere herein in one embodimntw, the nacn analog has an EQ){br p-arrestin -mediate 1 GPRU09A function which is at least 20 times greater than the EC of niacin to parresin mediated GPR P109A function, In ona embodiment, the iacin analog has an EtH for p arrestn-mediated GPIR109A fmetion which is at least 30 times greater than the E&O Of niacin for -aArrestin-mediated OPR 109A function. In one embodiment, the niacin analog has an EC for p-arrestin-rnediathd (PRt 109A tnction which is at least 40 times greater T than the E17V of niacin for -resn-medrated GP 0l9A function, In one embodiment, the macin analog has an E ne p-arresin -'eodiated GPR I09A function which is at least 50 times greater than the EC o ofniacin for I-r re\3in-mediated GPR 10A function. In one onibodiment, the niacin anado has an EC fr -arrestin-mediated OPRI 09A function which is at least l00 timesgrameter than th EV o(t niacin for 0-arrestin-mdiated G GPR P09A function. in certain embodiments the invention relates to any one ef'the aforementioned compositons wherein the i~acnalg hn5 amit~doal to a human, also in creases a ernmi or plamu level of high-densit-.hpoprotein i1DL1 hoeserl.h serm or plasma level of' I! cholesterol increases by at least a measrahe amount 0 compared to a. ere-re.tment, haseine, or control level For example, in one embodiment, senno or phama level of HDb choletet mereass st 8 percent compared to a pre reanmn, baseline, or control leivel i one embodiment, serum or plasma level of HDt lit ro t increases by at least 10 percent compared to a prearment. baseline. or control I\el In one embodiment, serum or plasma level o1 HDL cholesterol mneases b at least 1 5 percent compared to a predreatmenit, baseline, or cotrol les el in one embodimen t, serum or plasma kve I o llL cholesterol increases by at least 20 percent compared to a prereatemt, laselhne, or control level in one embodiwmet, scram or plaah ei el of H IDL cholesterol mnreaSes by ax least 25 percent compared to a prouramen baseline, or cntaro eel in certain embodiments, the invention relates to any one o'the aforementoned compositions w here. the nacm annlog, nhen admiisteied orally to a human, induces substantial. inmerese i serum lexets of aspartae aminotransferase A , atnie 10 ninoransterAse {LT), or bot, in one embodiment, "bstanttalN no increase' in this contet means less than a 20 percent increase Over a pre-reatment, baseline, or control leve in one embodiment, "substantially no increase' means less than a 1 0 percent increase over a oretretatment, baseline, or control leVel In ertain embodimens, the imention relates to ay one of he atorementioned .5 comnpositionS. wherinm the mraem andaloe, uwben. adbamstered orally I to a hmman, induces substantial ly no imerease in serum lev els of uric acid, glucose, oroboth, \ormal serum e of urie acid are 5-K0 in lL, In one embodunm \tubstautradly no iwrease in serUm le\el of uric acid means km haun a K) percent cr"ease over a pretreatment baseline, or control level Nonal ft-in plasma lesc of glucose are ca 75- 11$ med L normall random (2 h postraqnIan plansma levels of gWucw are a - 140 mgcda. cInh one embodiment. "substantially no increase in serum lev el of glucose'^ means less than a 2 percent increase over a pretrieime, baseline, or control ire\ et In one embodimnm, 'substunmialiv no mncrease mn serum kev ei of glucose' means less than a 15 percent mecrete over anrpreactment baseiime, or cornnel leveL In one embodiment "stbstanallv no m5icease in serum lev el of giucose' means less than a 1 1Percent mecrease o\ver a pre treatment, baseline, or control level. in ertain enboimets, te inefntin plates to ny one of te aemetioned compostions whrin theniacin aaogi rersned bs stutcatw I ittX;-~ AN VR4 / m A is a heterocyClyd or betcroaryi optiOnally deuteraied, containing from $ to 2 ring satoms, including X and N, which ~ is ptonally substitute wit 1-3 subtiue indcpendently selcted from the group consisting of akL vly aikynyit aryk. hetecroaryL aradLyt hetemvanalkyt halogen, ntro, cyano, 'ulfonic acid, alkulfoxyl, arysulfodixyi, heteroarylsauifoxyt aralkLsuvlfox y I heteroaradkyisuifoxyl, aikenyhi ulfoxyh aikynyvlsulfoxyl alky~ItUfny, aryLsulfonytl hetraarylsulfonytv aralkylslfony L htet-roraLylsuI iytLrr a kenylulfonyti alkynylsulf ony Lhydroxyi. aikoxyi. arvioxvy. betcrytroxy, zraikylIoxy, hetezroaralkyioxyc alknylo oxy, alkynyvloxy, thiol, aikylho rythio ,e aralkyhhi o, heteroaralkylthio. alIkenylthi c, ailyyi, f. rmyi acyl. formyvioxy, acyloxy, formyithio, acythxia, amnine .alkyiamne~, aryliaminc. hetecroarylamne, aralkyhamine, heteroaralkylamine, I Saikenylamrine, alkynyilmn, formlylamine, cylamine. carboxy L. alky loxycarbony L aryiloxycarbonyt hete~rcary.Lxycarbony L aral kyoxycarbonyti heteroaaLkyoxycarbo~nyL amijdo, a kylamiinecarbonyL ary lamincarbon yL heteroarylanecarbonyi, aralkLaminecarbonyi cuad htercarakvlamnocacbonyt; Xs O S.N or NtR x2 is d n kyL oaik aike .A croccy terocyc eatboxyatkh1 or arybaukenyiarv R$ is hydrogen, lower alkyL kowr alkenyt lowe alkynyt halog~en, hydroxyl, am ca rboxyA, ycloalky t ary hetervarvy.i traWxx hetrozaratky?, ein, or ntro R, is hydrogen, lower akyL liwer alksnvyL lowe a \knti halooen hydroxyl, aminelC carboxy k cyckoalkvtry heteroaryi n fhark htearakyl cyano. or ntro.

R

5 is selected independt\y for de)ch occurrece tfrom th group consising ot hydrogen, aikyl. aikenyt al kynyt. aryl, heteroaryit aralkt heteoaralkyt. halogen, nitro, cyano, sufonic aid, alkyNsuloxy L arylatfOXyI hrOaysulfoxy L aralkyisuifoxyl heteroaral ky I ulfoxyI, aikenylsalfoxy aildkyny'suitiny t aiky sLonyL1 ary isuifony t heteroaryisufoyl. aradyiulfny heteroaralkylsuo y LaxI aikenylsuo y LrvI alkvynysulfnmy, hydroxyi. aikoxyt. aryloxy.t heteroarytoxy L, arakioxy, heteroaraikyloxy aLkeny alkyny o , Saiksthi, ary thio, arakyto heteroaratkyithio. aikenyithio, alkynytthi, formyvL ayle formyloxy, acyioxy, formyitho cylthio, amine, a.Lkyamnine, arya mine, iieteroarvramiine, araikylamiine. heteroarailkylamine, atke'nyamne. alkynytamiue, frmnyaico ne, aicyamine. carboxylINI ak Nycarbonyt arytoxycarbonyi, heteroary'toxycarbonyv I araikyloxxycarb tony bteteroarakyoxycarbonyi, amido, .50 alkylamiinecarbsonyt aryliam~inarbony bea.teroarylaminecarbaionyl. aralkylamtinec arbonyvL and heteroaralkylarninecarbonyl; R- isi hdrogen or lower a6k; and n certain em dimens the invon relte to any onne ofdi mentired comp~ositions wherein A represents heterocry I ncertain embodments thenventio rea to any one of te afore mentioned pOflt~ien~l5 wherein A isa rd eat ta noeyee rig ng g 6 or 7rng atoms, so ina cetain ewbodinvnts the inveton rten to any on f the aforemnentioned COpositiO ereinAis a r fa icych Q iI or 12 ing aom In cottan erodmmnts th nvninrlto any on ofde aforeieilne n:.otx po' io Cbs w enN is 0. in cer ta embOd nunts, the iVCnti rUelateS to any one of the afrrmintioned COmpOsitiO5. \herCin X IS dX in cert ain embodfimn . the inot o relatteh i t an oyn f thIe ar nioin conmsrtons.wheeinX is N in chain trit tezi i epinyrelats o any e of the .rret in certain embodinents, the mentio relaes to any one of the aobrementionJ compositions,. here i is ubtu in crotin mbodimnts, the inveno rlte to antne akof b Stb \\eAtod comnpositorK wherei A is pnarrodi b 4 i a Cf. i llnoidp NO ulidgy?, !Noth~zi~dm;? 'id hha ifinom en oye pmhihdie.nt rinomr mme n man inetohametan 1he ienon ltr bAn on O to compooitons whol nA is n dzK peazo!) 1, isoxoazo13 04.UKM isorhiASoY0h1 ox n lor ainv. uziny teO. in .iamon Im or m. mo the composwns. wherein A is substiued wth I hstue ideedent IC ected from he . digroup costing of lower al l. h iagen. un eano sfonic d hvmovtL alo vi. tho akyl ithio. formyL Aey . 1 enrio aey o frimy hio acythio amine, ak)amine, formiviamine, aelanue and earbo svi ceranmp emodim tsh mention ats Inertaietnorntst n ela oeo taforeme d ~onipositions wherein R is ydrogeno loer avl Ineert em dnts te nKenton Meats o any oe othe afbremeioned ompQst whe n R i hyd in Certain embodintthe invenion reaites to any one of the aWhrenenoned iomposttions whe m. R' is (n lo.n in certain embodimo .n the invention relates to any one of the demennined Cornroilrn. w herein I s I avo 3 ib. in e n eMUod H t vtion r La te anyone anetioned c 0ocanon werinw! Rn isoen; and R Mis , loe aikyl in cerain embodimentshe 0n anie to ne of the atoementioned in certain emhoments, the invenian relates to any one of the rforementioned compositions, wherein R is sleten ndpedetl for hdneacn curec.rm h ru consi rin hdoen, owert aky tL hawoenn reistro cn uonifte adhyrneoedkx i~onpn ORA whereinn mno oo hol, alkylthin, t elt, tormhio acy oie amine kylamuine. n ertai emboentas, the inentord ales to arme of he norneenored 6nmYoartion whrein >od is sh in Ceflin emabodimets Te invenionreas to any one ofth aMW erenioe in cement ernbodirnen the inventon teljte to any Oo ofb th aetntioned it cenmn emodIents. the mnvenion relays o any one o the aforemnened enmxpoatumns W herem I 2. i a carboxy I Isossere in rtnain m'dintents die inetvion relays to amy oe of the wliri01entoned copdtosa eem/atetmzLv.o sodidinond sul foni c dd suitinme sad ae phonnmde, phospbomc acid, phoPhi nh acid, duioin, pyrohdone. >isoxapo o botomec acid. in CerMA emodiments tWe invention reae to ayoeo h beetoe coon A . n co ion-.' in eain embodiment. the invenon relAes to any one of the afinenuined I0comipoitons uberemn R is hmaly i eanembodiments the ne nton ritte any oneof thea.foreniened .olpohcS whre-in XN is S'i in crtan ckd~ient, t eno OQI kTIroae to arty one ofbai aformenioned compositions. wherein R b U in cerai emznnns he nvni i ae oayoeo teaoeetoe e in POnti"VS 'Ari Vt NH N Thcmm Moivvn N 'c inL<K 'ill r e to in n>fd in cano wvw.o IvNmn I an3n ft RCC ndho pcym og udno 2-500 inh w R' R 'and o Cbe appaded o the polof hrogh n oxyen atom ftepolyo Or is appended to the polkiol thrugh a siia aomi of ' e p th ,biol. Q 0t {1 - 1~~.{ < A isa heAterocycly, or het , piona deutcrtd contain frm 5t 12 ring WYoms including X. and ht which is optionally substitutd with lasbtiun .ndependenly sLected firom be group conising of alkl aknT alkytk ary fhtroaryL araikyd ot eeraaly halogen, nitr, cyan, sufIC acid, alky lsulftoy L aryJ uifox, S heteroaryvlsulfbmy 1. araikyilsu lfoxyL1 heteroraky vifoy alikenyvsulfoxyt alyylufoy alkyiaulfonyi aryilsuony heteroarylsulfonyt araikylsulfonyt heteroaraihkisulfoy ailkeny sutfony kn akynyisulfoiv L ydroxyvl, alkoxyl, aryox i heleroaryloxyt aralkyloxy, beteraraikyloxy, aknviyoxy, alkynyloxy, thio, alkyltiro, ary hio, ralkylthio, heteroaralky thio, aikenyhi, ai kynylthio, forny K acyL formioxy, acyloxy, forrylthio, lb aeyvtho, amine, akyl amine, arylamine, eteroarylamine. araikyine, hteraaralkylamina akenyaine, aLyrnamine, formyamine, acyiaine. carboxyl alky aoxycarbon L ary koxycar bonvi, heteroary loxycar bony L aralkyvkoxycarbonyvl heteroaralkyloxycvarb~ony v amido alkyiaineca~rbonyt aryKlaminecarbonytiheteroaryiaminecarbonmyL aralkylaiminecarboti. and heteroa ralkylaminecaroly L, /s~ ~ X \ MO..SN (R \S or mn abogyel. ai k aloakylaakcy alkyra l, caoot. hkaercyd hontcroilyl, ary 1. araikyl. hcttroarv 1. B e/roiy. r used tig carossaIkvE or 20 1$~ is hydrogen. ower alkyL, lower alkeny t lower alikynyt halogen, hvdroxyl amine, carboxyL. cycloalkyti ary L heteroaryl. aralkyl, heteroaraikvy ~l yaok or mtro2 RI is selected inidependenii y for each occurrence from the group consisting of :i hydrogen, alky I. 'lkenytK alkynyvt aryi, ietroaryi, aralkvt hetieroaralkvy, halogen, nitro. eyano, sulfon ic acid, alkyi sudfoxyl, aryis tlfoxyli beteroarylsuIlfoxyL~ arkyl vly hieteroaralkiy sullioxyvi aikeny isuioxy alyyifoy airavittlKl tky 1sulfonay L. arylflouL beicroarvi suifonyL. aa Lyi sutfonyt, heeroaraik kiulonylI, alkenvisul fonyl, alkynylsuIan vi hydroxyl alkoxy L aryloxyl heteroaryloxy a r al\kyloxy, heteroaraikyioxy, aikenyloxy, Walkynlx, tioU ailylho, arylhie. aradLylhio, heteroaralkyhhio, a lkenythio, aikvyylthio, formnyt acyLs xormlaixyacyloixy. tormylthio, acylnho, armne, alkylamnine, aryiurnine, heterozaryilamnine, ariyamine, het'roaraikyl'amine, alkernyilamine, i~ovyl' 5.Kgla nara onvI arvaneearonv hteroarv n ecadhony. aralkylamineearbonv p ons werei W n A i hydraen or wone; a)e and 0in e am sr or :o in con embodhontsh t ten anyone f te a.reent C inpSi1 wteain Ay a inon in certain Mbodimnrt.-s dIe iw ntio re dtes to an. on 0 othe Aorement 1ned cmos iti"on uherein p c is alO indur.i in cemi Modin thibe iwnion relates to ar one of in cmoenue ubere copoiton.wheren said Poivn1 6 aenohdi J~e.W I c n canon werMinots. the invention reas to any one ofteatbenn ie th onmimio d copwioswhereimsi oxnltraio p is ton xerti moiomeit h mm eo'nposii~.owilEfiaipin Ssrio in catta itetos ilnis, the invetio relates toan oeoftei re nto d en oanonofhearmmindcompositionswherein sai p 4, incertam inefl, ereention relates to ao oned composiner 20 Cl~hst~tlt, w eren p is .2. 3. 4. 5. o~r 6. in coVnnebdmns the- invnion reAtes to ary one ofI thUtMMMnienne cp~osiios. Mwei p is 2-100 inclusive. In certata enkodinin. the invention rvjares toan oe f heaonteind copsti.Wherei p is 2.53 inclsive. in certain 2 IM o s21ncluskeso in ceran etnhdimemms Te twntion reAte to any-, ioofteareeind k~niostin. heei J s 2O KIn cet"v.iujdlns teiletoltes to any one oA rotates to win one otfti dorennind(TfO~it ht p is 4. Incean 'N> -.

O in cetatn en modimenes. he invention lates to any one of the foreentioned eompttpotsn whrcinp1si in anotheraspect, the agents of the im entin can b f aidmmunoterl'd as sueh. or adMnistered m miturea with pharmaceutially acceptAle carriers and can aso be adinistered in u nhaion with other a.gentb o once\e thtierapy thu inles sequenual~ Lmucous and separate, or co-admim ni tmon of one or more compound of the utvption, wherein the therapeutic Kllcts of the tIoi anlm ered has no entre disappeared when the subsequent compound is admnttred. In other words. the terms "e-ddmistratnn anid 'oudninsttrngw a used herein, reter 1o both concurrent adm~intist'duin (administrati o-z of !wo or mr e epeNie agents at the same time and te varidadinitration Qadmilintradon of one or More therapeic agents at a te dieret lam that of the adrunston of an addhonal therapeutic agent or agentso as the herapeutic agents are present in the patient t' somle extent at the a time As desnbed in detail below the pharnceutical composttions of the parent \nvuntio1 may be special als brulatcd .Or admiistfalion m sob d or lijcpd foru, inchtin those adapted for the following (1) or Vat ,to euampie, drenches (aqueous or nlon-aqueoas solutions or suspenions tablets e z., those tar geted tb huceal suhogual, and ys)ternie dabsrrnon epasilre boluseas ponder. granules, pastes te application to the tongue; C) paretem adiartion ex~ eanspie, b) intraVentou, iramuscular' 2 ti er1. . -o, ea cpidural nraeumon o iui as. dt ole, a asih1 solution or suspension, or sustamned-release formulation: (3) topical application, for example, as a cern, oiment, or a contrlieodrelease panch or spray applied to Ie s, inmaginuall or mktrareetallv. for example e. as a pessar cream or foau; ( sublingually, (7 ( r tnsdermal I 4 naal v, () puhnonar\ ,t i l Y n atheca lIc The oprase "therapeutically effective amount' as used herin means that amount of a compound, material or composiun cnmprismg a compound ot the present inve non wch is t effective tor produung some desned other apeutc effOc m at last a 'n~populauon of cells in an somal at a reasonable benetWrisk ratio appheable to any medical treatment The phrase "phatmaeutieally aceptailn" is employed herein t refer to those % compounds materials, composition d d ;C dosage f6rms wh bCh are a n the cnope a sound medical iudnant, suitable for use i contact tih the tsues of human beins and dannialswitnout eesie toxicity, 2rrt1atio, allergic response, or other prohlem or cotupi cadon, rimnensurate with a rasonidd benelntisk ratio. The phrase hmaceptable crrier as used herein means a phannaceuticallvaccerable naterna, cmposi on or ehiee, uCh .as a hquid or ohd. tiller, diluenm. excipiet. manufacturig aid lea, hlbricant, tale magnesium, calcnan or zinc tearate. or siew ac I or so vent ieapsung matenat in vo re in carrying or transporting toe subject compound fr one orgun, or portion of the body, to another organ. or potion of te body. leach carrier most be >cceptiabl" in the sense of< hm compathNl nwitb the other minuedients of the formuiation and not iniurious to the patient, Sonu,: eramtp e of materials which can serv e as pharmacenealy-acceptale capers mYKlud 1) Sugar such as lactose. glucose and sucrose:{Q starches. such as corn starch and potato stach; (3) cellulose, and its d as Sodium carboxamethyl celulose. ethyl cellulose and Celhulse acetate, (4) poudared it agaamth, (5) malt (6) gelatn, 7) tale; 0 excipAnts such as cocoa iuter and suppoitors ase: 0) oils such as pean oil, ottenseed ol. santowetr oil sesame oil, ix eoia corn oil and soybean oil; (101 uh cois such as propylene lycot I 2 polyols, such as s WeertM, sorb itol, mannil and polvethIylnne glcol;( 2) \sterS . ucas ethyl oleate antethvi lanrate; J3)aga*r tl4) buffer in agents such as mgnesmum bvydroxde and alurnum hdioxde: (1) agmic acid 16i'prmen-ree wvatr ' isotonic sdine: ( iS) Rnter's solut 19 thyl alcohol 20) p WI btflered solutions, i polyester s, po aronates ando polyahsdnde ano ( . 20other non-tosise compatnble subttrutcas enploye mi ph armaeuncal foirmulations. As Set out above, certain embodiments of the present compounds may contain a basic umetional group. such as amino or alky lami and are thus capable of formng harmaceuicailvtewptahble saTs wh pharma'cuuallycceptable acids. The term "pamcun2 aceptable salt" mb ttlus respect meters to the relatively non-toue organic and orient acid addition salts of compounds of the present ivention. T hese salts can he prepared im im ii theadrminiitration vebicle or the dosage form manutacemrmg process, or bv separately reacting a punted compound ofthe menio in its ree base forn wth a suitable" organie or inorganie acid. and iKolating the sat thus formed during ubpm puntieanon, Representative sahs Mlude the hydrohronide hydrAchlonde, uilfttc, bisulihte, osphair, nitrate, acetate, valerate, oleate, palmitate, stcute, burate, benoat, lactate, phosphate, toslate, etrate, maleat. finarate, atcniate. tartraic, napthvda. rmesjatc, ghucohertonate, lactob ionte, and aurvysuiphonate salts and the hk Sec, for example, Berge a A 190) "Pharmaceutical Salts", . PMami < 149 acceptable sals of the sublet co coo etioial tin toxic salts or quaternary am mnm salts ur the compOLUndS e t , i'rnm non-toc organmc or morgame acids. For example such comvento nOntoxe salt1 include those dern edornm morgamc acids such as hydrochoide, hydrobromc i mWow. uha phrsphone. ntric, and the lhke, and the sats piepared rom orgamc acids such a acetic. propionic, succinic, glycoie, steanre, lactic, mAR4e tmnari. cAt. ascorbic. PaNmitie rmaleic, hydioxymalec, phenvyaceta giutamic neoe, sabeie subabe2 acetosybenzcoie, fumarie, trlenesuhfonie, miethanesuifonic, cdhani disulfonic, oxahe, istonk, and the iikc. i other cases, the compoui of the present in enuon na contain one or more acldte functional groups and, t .us, are capable or forming pbarmaceuteaily-acccptable salt niib pha mace utiuly-acceptAble bases Ihc ter m "pharmaceutwaltacceptablesa" mi these uamtrcee hrelatiy nonoxic, organic and organic base addition salts of compounds of the present inVention The+e salts can likeose be prepared r s n the. 15 adnmmistration vehicle or the dosage forrm manuathetmig p ocess or1w scparatelv reacting VAC?5uc at the hxOA 6 the purified coropoud in its free acid tArnmn Wh a suiable a as he dride, ca bonate or bicarbonate of a phia eeutueallylcceptable metal nation, wh anmmoni r with a pharmaceutically-acceptabhe organic prmarn secondary or tertary amme, Repreentirve alkah of alkaiinue anh sals include the lithum, sodun potassim. kcalium, magnsium, and ahumn sAts and the like, Represetative orga am lines useful for the formation of base addiction salts mehlude ethyi emrgne,. diethylanime, ethy ltnediarninat ettano andtine, diethanolanine, pipcrsin10c andi the like. (Se. for eanmpl1 herge16 et ., Wettings ag is ulsiersand lubras, such as sdun lry a and 25 uanesitr sterate, s ell aclornggents elease sgents a ting aents sweeteng avoringand perfuigageits, pservativsandnioidas canso he present h compostions Examples of pharmace:uticadiyaceptable antio adants include: (I water soluble amtiox id"ants, auch a ascorbie acid eteme bdrochloid sodiom biultetsodrnn ietabsulfite. sdhurn sulntne and the lke: {i oi-soluble antidants such as aseorb\ l pminate, butn lazed b vdroxyanisohe i BilA \ buis lated hmoroxtoluene fiffTt lecithin. propv galate, alphu-tocophero and the ike, and (. metal chelatin agems such as citr aid. euhvienediaumine tetraneetic aci~d {-DTA) sorbtok tartaric acid, phosphoric ac id. and Whe hkcx Formulations o4t the present iention include those skiable for oral nasaL topical (nchuding biccai and sbingual), rectal. vagmial and/or pareteral admnstraton. The rnmaladuaos noa conv emetly be presented n nit dosage torm and may be prepared by any nmthods well known in the an of pharmacy 1t anmmn of active ngredient whicn can be combed with a cam material to produce ol dosage form wil vury depending upon the Ios bemv traete particular modb' of ahnnitran. 'he amsoum ofuative Inoredient w hih can be combined wth a carer niatil 1) ioduce a smgn0 dosage forn will generally be thu amount of the compound w hu. b produies a therapeutic 10 effect Generdly out of one hundred per ce, his amount YIH wanve from about 0. ie cent to about ninety -ne percent of active ingredient. preferaby &rom about S per cent to about TQ per cent, nmoatpriterablv from about 1 U percent to about 3p percent. a eartin eimbodiments a fiunuation of the preset mention comprise an excipicnt seec froen th group consisting of ev elodertrims celuloses psreme fMonmm agens, e Y. hie acids and polymeric camera. e polyesters and po'yankhdndesr and a compound of the present invenmion In cerinm embodimnts, an aforemenioned f ii lation renders orally bioa ad able a coupotnd o the present inveniuon. Methods of preparing these Ormularions or copostions melude hestep of brinn ino o the. present ivntion w ith the carrier and, 20 optinalil, one or more accessory ingredients -in general, the form ulanions~ are prepared by umformly and intimately mgmng io associton a compound of the present invannon w ith quid carries, or finely di aided soid carriers, or both. and then, if necessary, shapig the print. Fonnuatens of tbe invenion stable for oral administration my be in the fo of o psus achets. pill. tablets, loengea (using a labored basis, uully sucrose and acacia or tragaeubt pow ders granules or as a solution or a suspension i an aqueous or non aqueous liquid, or as an oil- neater or watermoiN quid emulmon, or as an eixir or syrup, or as pastnes using an inert iuc \uch as uctatn and gjacerin, or sucrose and acaci) and'or as mouth washes and the ite, remaining a predetermmed amount of a asa ngedin \ compound of the present imemion max also be admimstraed as bolus. eldeuary or paste, soli dosage forms ot to ation for ol aminitratio es table of pilldes ce on der grnos, trouches and m t ke the acta~v ef inZdieftu is mnxed w ith one or more pharmaetc liyaceptable carriers. such as sodmt 650Ci or dialnum h sphae and or any o tho m or estendr sich as tarche hatose, ~emse, lUCOtXs TnotIi, aod or Ahei acid; (2) indr, s'uch as carbooymethylceilulose S a.matcweluhn. polyvinyl pvrrlne, sutose and/or aacsa, (3) humnts. such as elyerol; h I dchsrsegratInu agents. auch deaagardigar, cdalium carbonate, pott or tapioca starh, algnic aid ean silicatcs. and sodiur carbonate: 1 solunin retarding agents, such as parafin (to absorption leni , such .is quateinav ammomum compounds and surfactunts, Suc h apoxamer and sodium lauryl sNHte, (7 wettig aems, stich as, ceti U) alcoboL. glycemol m'onostcarate., and nomiomie su"aat (8) ubsot betut, such as aoin and bentoite clay; Q bicants such as talc, calcm stearite, ' siu scarate, hod polyethyictne gkeok sodium laurvi sulfate, inc stearate. sodium stmaratc, stearic acid, and mn tures t hreot: i~ i0) coloring agents; and (11 mi otos such "' crospouidone or etdvl c ellulose. hl the case of capsules. tablets and pils the p harnmceuuca lcompnositions may also comprise buffering agos Solid compositions ot a similar type may so he cmpioyed as Mets m soft and hardAbelled latin capsules usig such exipients as lactose or milk sugars as well as high molecular weight polyethylene gss a ad the like. A Iablet may be made hv empress n or molding, optionally wth one or more t :SCCeSOtV ocdients ('onpressed tablets may be prepared usmg bmder Ifr exampL,. gelatin or hvdrvipropvlrnethnvl cellulose iubnam, mert dih:<tent, p esena tiRcm dsinotegr ant (or examp,0. sodIum starebn gicolate or ers hnked sodum earhmymcthyi cellulosei. surface-metie or disprsmng agem Molded tablets may be made hr molding i suialN maChne a ntrutre ot the nowdried compound mostened nwith an ier hquid The tablets and other solid dosage lbrnns of the pharmraceutical compositions ofthe preset nention, such as dr ages capsuls pils and granules may optonally be scored or prepared with scanngs and shel such as tetin coanus and other coains nel know n in the pharnutuAtal tormularn' t IeY may also be fAnrdated so as to pro owde slou o, $0 cotrohed release ef the acive mngrzdient therein using tot example, by dr ovpropvlmethyl cellulost im atoIP proportions to puide te desired release prol her polymnnr matres lirposomes ando r1mcrlospheres 't hey may be formulated for ispid I eleasNCe ' iFree-dried. They may he sere de by for vampke, filtration though a bactcrretano 'il'zwv~~~~~~~~6 an cNANI i *nwK~~,i filter, or by incorporatin sterilizingt agents in the fom of sterile solid composidi whiN cani beo dissolved in sterile water, or some other sterile inictable mediumi immediately before use. These compositions may also optionally eonmin opacifyig agents and nay be of a composition that ty release the active ingredients) only, or preterentially, in a certain orion of the gastrointestiaI tract. optionally in a delayed manner, Examples ot embeddinrg compositions which cart be used include polymeric substances and waxes. The actv inrdalso be in microencapsulatd form, if appropriate. with one or more of the above-escribed excipienms tiqu d dosage fr44m for oral whmmstratao of the compounds <f'the A M in in iuIid e phbfraeeut aI' acce[table emullsions, inicroentlsiotns, sol i i tis, Stasplnoinl, syrups and ehors in adIMn to the activ imgrdi ent the liquid dosage frms naY conain iert dimuents comimonlv us'd mn the art, such as foy example. water or other solvents. ublinim gents and emulsifiers, such as 00b0 alcohol isoprop alcondl ethyl carbonate, ethyl acetate n alcobol. benzyl enroate- prpene glycol c ,3-butylene I glycol. oils in particular, cotoseed, uoundnut, com, germ, oMn e, easor and sesatie ols) glyerol. tetrahydrofuryl akohol plyethylcee glycols and atty Ani eters of sorhan, and ulxvre thereot. Bes inert diluents then r comoinsn aso icde ad ans sc as wtting aim neulifying and suspending agens, weenuw lavoring colig. criandpreseraive ag us Suspense in addtonthe acdie compunds mayontansuspending as Uent a ampe. etoxyatediostear lohol, pyoxyhyene rbito and sobin S eters miciocrytailgne ellddne, a nnurnmietira d betone. ar agaran tagacartaid mixtures hereot 2) hornuations of the harmaceutial copoiton of"- the itvniror rectal o-r vainal administration nmay be presented as a suppository which may be prepared by ixSing one or more compounds of the invention with one or more suitable non-irritating recipients or carriers comprising, fr example, cocoa butter, polyethylenie glycol a suppository wax or a salicyate, and which is solid at room temperature. but liquid at body tempeTature and, therWe re, Will melt in the rectum or vaginal cavity and release the active compond Form ulations of the present inventbon which are suitable for v aginal admimisrati~on alns snudc paarap ra gas as faas or spra& iOmnulations audyigs e s tnampon ces theR ainpe pd Dowa,":rvt Wc b r Ahe tolpical lor trasd ermal WAdninstan of a. cmpound o4 this invt mion iclde powders sprays o mtmentts pastes creams Iotion, gels solutions catches and ibalats The: at;ive compound may be nmed under sterile conditions um a pharrnaceutal lyac epuabi carrier, and with any preset aunes. buffer ei proilants wibc nuavbereguired te mn astes reamsarde may eoat in addin to an acdve ompound of t invnion, e n ch as animal and e e a o e 10 naatur, t rcKtmaceinth, cc UIO deriV5ik polthyl e c yt shonies c tesilicic acid. tac and zinc oxide, or mixtures throfl POOders and sptys can contain, in addion to a compound of this ivent Cp11 itsusitch a lacte tale, lict dcRd aluMinum hdtride calcim sdicates and rolyamide powder, or miturs of these substances spraw cn addtonally contan S us a\ propellAnts such as chlortiiurobvdroarbons ad votatie nmsuuwted hndrocarbos such as butane and propane Transdermal patches have the added da g providing control led delivery of a compound of the present invention to the body, Such dosage forms can be made by disnivone or CoiperrinnIS d S~lvng r d<pedn the ccwnpound in the proper medium . Absorption Cnhancers Can 20 also be used to increase the flux of the> compound across the skin, *The rate of such flux can be controd by either providing a re controing mnmbrane or dispersing the compound tn a polye matri orn Ophthalmi fbm nev e oitntens powdes so utns and thelkearc aso teted as hming2 wnhn te sroc-otnis inventin Pharmnaeutiehcompositons of tis inventonsuiparentera dministraton c ri Or of the inventn i combt onwth one or me pensions or emuion, or sterile powder w hich may be reconstted io te ctablsoantionsr da versions prir to s i cotan ars a o adto datsbu rs et ts. solutes ch rende the rmu onotonic ee olood of te intnded recipient orssapending or tiekeniu n ents.

K.amples of slutable aqueous and nonaqucoUs carriers tat may be emploed i the pharthieuticl cpti .olrlon rt ithe invention oiude n:ater, ethanoL polyols (soeh as "lvectoi prour lene plvol polkethviene glYOA, and the likely) and suiable mixtures thereof vegetable ois, such a' n > an,:md mjectabie organic esers suh as thy oWeate. Proper fldhtd ca be namtamed. tor example, by the ue t'coang matenas, siuch as lCeidhinh, iy te maintenance of the required particle size in the ease of dispersions and by the use of sttataiiL ' heseecompostion may also contain aduvans. such as presrvateivs wettig agents ermusi fying ageut arid dispersu agents Prevenion or the action of I meinorganms;t upon thoe subject campoundh may he enslitd b\ the inchtlOn or various antibacteria and amifungal agents for example parben. chlorobutano phenol soie acid, and the ike. f ma als be deirable to include isotonc agety suh.h as suyar soditun lortde and the like into the cormpoilton. In addtton. prolonged absorption of the nneetale pharmacenceat harm mar be brought abou Qv the inclusion of agents which delay absorpton. uch as aluronum onostearak and datn. in sone cams\\ in order to prolor the effect of a dru, it i desirable to slow the absorptouj ot he dun from subuhaneous or mramuscular m;con This resul may he accompnshtd by the use of a tid 'u J ppou of er st alhn or amor phous mateIal hai ng poor w after \olubltx The rate of 'aborpiion of dhe drug hmen depends upon is rate of dissouon bx whih, turni may depend non crystal st and crysalmc form. \lhernatively, delayed absorption of a panreiyadmstered drug formx is accomplished by d isoln or suspehng the drug in o iehile injectable depot fbRa are made br formmg niroencapsule mtrices ot the subject c.ompoumds mn bodegradable polymers suet s poh laende-pot lg ol iode Dependiog on the atio of drug to polomer and the t nme of the partiular polme employed, the rate of drug release can be controlled Exampe of other biodegradable polymers mclude po oithoester) and poly! ay dndAn; Depot injectable formulabns are ao prepared h entrappng the i hiosome n or nmlsions xvhiel are compatible Ibo dy tissue.0 Wheni the compounds of the present imemion are admimsered as pharmaceuticals to humans and amnals they can he gunn Ter se or as a pharmaceutical ompositio omainmng. for example 0, I to 9% (more preferably., 10 to 0%) of acve ingredient in ombmationl with a phat eeutcalli acceptale career T he preparations of the present mweunon may beY Iven ubly parente-rally, toplcally e tar :l . They are it course (I vin mn frms soiale fo vach admmnistraon route For example thev ar, admnstered in tablts or capsule torn I uticeton, ilnoin, ey e iotrin, atirment, sppository adissuan tion bY iml cl or insion or halaton, topical by lotion or ointment, and raul by suppositO The phrases "parenteral admmuanin and "adnistered parenterall< as used heren mean modes ot adm onidstration other tan enteal and topai admAiation. usually b1 injecuin, and include, without lmitatton, imra enous. titramuscular onaarteril, imraheKa I tlmiasplar, itaorbital intacardiac, .itradernnat itrapern oneat io transtraebeal subcutaneous subeuuluar. rararnecular, anubcapsular, suahuhord, inn ra pinal and inastewMa a jniection an inf usion Ta Kphrase "sytemic admistrationv tdnmitred saemicallyv: peripherall admnistationr and "drnmnstered pipheraly" as used herein man the adnustration of compound, drug or other material other than directly mio the central nerwustm s auch 1' that it enters the patients stemi and, thus. i subiect to nmetabobam and 00threibke poeses~ tor euample subcutaneous admmistraion, Compounds nv be administered to humIns and other animals for therapy by any stuitbl route of administration, inc luding oral ly, nasally, as by, for ex ample, a spray, ectally, iravaginally, parenterally, httracisternally and topically, as by powders. ontumems or drops, including buecally and sublingual ly. Reg ardless of the route of demonstration selected the compounds ot the present invention, which may he used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceuttialy-acceprabie dosage forms by conventional methods known to those of skfl in the art. 25 Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invenmlon may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particul ar patient, composition, and mode of admfinistration. without being toxic to the patient The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amde theeof. the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound beng' emplood, the rate and extent of absorption, th duration of the treatment othrdugs conmpounds and/o material used in eomibmtin withea Ar'a compound einioed tesey e 4.A enbit, ondio n. general healh and prior medal hslor of the patient being created andlke factors wed flowflni th SO tricitcl uns. A phnvsician or 4 et ra basing ordmry skill m the an can readily detenmne and presnh the effectie amount of the Ihrmaeuteal composition required For example. the phician or veterinarian could siirt doses of tibe compOtmdS ol'hde nventon employed in the pharmaceutical composiuou n. lx els lower than that reputed i order to achieve the died therapeutic eect nd (wadPal n mem the doage until the desired in keener, a suitable daily doe of a compound of the imenuo 1Wl be that amount of'dhecompound which i the lowest dose effecive io prduce a therapeut ener Such an effective dose il dseneraly depend upon the factors described above General ral, itra ennus intracerebrovenrieulr and subeutancou, doses of the compotmds. of the\ 1 nvetion t a patientL nhen used ior the indiaed cftets will range otmn about P 001to about 100 ra per kilogram of body w eight per day. Oral administration in hrumans is specifically contemplated by thre invention, Oral dosing in adult humans is typical on the order of 01, 5 grams (50 mg) to 10 grams per day, given as a single dose or in divided doses. in one embodiment, oral dosing to adult humans i s 05 grams (500 mg) to 10 grams per day. given as a sgine dose or in divided doses. In one embodiment, o'al dosing to adult humans is 0.5 to 8 grams per day given as a single dose or in divided doses. In one embodiment, oral dosiA to adult humans is 0,5 to 6 grams per day, given as a single dose or in divided doses. In one emabodimen, ral dosing to adult humans is 0.5 to 4 grams per day, given as a single dose or in divided doses, In one emb nordsing to adult humans is 0,5 to 2 grams per day. given as a single dose or in divided doses. in one embodiment, oral dosing to adult humans is 0,5 to I gram per day, given as a single dose or in divided doses. fdesred, e ectv da dse he acti compound may be admiistered as to dhree, fur fiei or moresutadoss adinsterd seprae at approprdiainevs througuthe day, option unt dnsage os Eempary doing i one administration per day W5hie I i is possile for a compound of the present invenuion to be administered 6!alonei pfce t o hdm sst the conpound a .harmaeeudai oirnidaton Ihe tlpOiSakering t e int 8 t mayn hrormated ra isnaan any conyenien wy brus huna or veterdnary medicine. jyenalog~ wih other b arniaccuti eal in another aspect the present iTvention provides pharmace it lacceptahle compoitns whbic comprise a therapeuticaly effective e amount of one or more of the subject compounds as descnhed abtl{, 1 mlatedi. tugether Oith one Or pharmaceuiticaily aceeptabe carrners tadd\ eK) mnd/or diluents A descrbed mi detail belo> the pharreutical c omosnions of th p esem mention mav he specially formulated for adminim ion in sold or nuud fArm, in luding those adapted for the following (1o oral admimsaton, fOr example, drenches (aqu uo= or nonatjlcoos solunons or suspenwoust tablets boluses porders granules paWheo mo apphiatim to the tongue; (2) {\arentenrd adnnnistrattont for examnple. b Geuran o Ik intallseutlar or 15 nt3\venous injection as, (0 example, a sterile soluion or suspns1o 3) t11opal application, for cample, as a cream, ontmen or spray appied to the skin uns or lnucOuiS membrancc or (4) " traI aginally or imfaretab. fOr cxanplc a. a pet Sy rean or roam, (5) sublingually or huccall; (A) ocularl, (7) rransdernmba or it) unsaklv 'he patient reeiving this treatment is any ammal m need including prinates in particular humans. and other mammals, stah as equin crttle, swne and shee: and. pouirvn) and pets in The compound of the invention can be adminstered as such or m admtures with phraemcll ceptabI e carrers andl can also he administered in eon junction with at leas one other active compound. (olunm y therapy thus includes seguemil ntaneous and separate animationn of the active compound i a ui v that the therapeutical effects of he fhat administered out is not entrel disappeared when the subsequenm i adminsered. :Miccu5NMic'roemutlsification technology imroe bioavaiiabilit~y of some lipophilie (water insh1ble) pharmaceutcal agets. Examples include Trimetrine o S(Dorduno, K, et a., Drug Development and Industrial Pharmacy, 17(12n 1685-1713, 1991 and REV 5901 (Sheen, P. C. et at I Pharn Sci 80 ), 712-714, 1991 Among other ing, microenmulsification provides enhanced bioavailabilit by preferemially directing absorptjondo the lvmghti a systemnt of , etreun atorM sytem I ch rby pssethe li ard Par destrion of the Copounds i the patoiy cirelatn 'hlde al suitabe amphiphike earnersan contemplated, m arrier are OWN rho wn-'d -dnpir pwar 1 (A-",d g tenera lv those that hasek Gtneralel Reogmniecdas.Sfe tGR A$ status and that can both solubite the compound of the presemt iention and micronmulsif\ i at a later stage when the solution comIeSm a combat wiOh a eomlx water phase (such as one found n human ast-ntestmai tract)kisl, amphiphihe ingredients that thse requiremems hav e UL ( hy drophilic to irophd.ie bal'anc& valbues .,t .20, and. their strneture contan straight chain alhphat radicak in O rac of('4 to ('20 Fxamples COre polyethytcin& glycolized fatty glvcerides and polyethylenie glycols. CJommerciallyv avaihle amphiphile carriers are particularly contemplated, ineiuding (Gelucire-series Labraflit Labrasoit or Lauroglycol (all manufactured and distributed by Gattefose Corporation, Satnt Priest FranceON PEG-nono-eate, PEG-di oleate, PEGmono-laurate and di-laurate, Lecithin, Polysorbae 0, etc (produced and. distributed by a number of companies in USA and worldwide). Powens HYdrohilihc polymers suMitl for u'se in pbe present Invetinamis w hich are readily wamer-soluble, com be com alettl a4ttttbed to a vesieetrming lipid, and which are tolerated in viNo without toxic affecs ( a. ard biocompatble. Suitable polymer ielude polyethylene alycl <PF) polylaci so termed polyTaAtWde. polylvcohie acid alo termed polyglyeohde a polylaetie-pol leolie acid copolymr and poltny aIobol Exemplary polymers are thoe hang a molecular ei ect of trom about 100 or 120 Daiots up to about 01 or I 10O00 Dahtns and more pwferabl fom about 300 Damons to about 500) Daltons I one embodmnw , the polymer is 25 pohbyileneglycol having a molecular w 'I~ht of fromn about 100 to about SA00) Daltons and more preferably hang a molecular w eight of frorn abouv 3) to about 5000 Dahons In )ne embudhmem, the polGmer i polye7hylnYcol of' 70 Datons (I>PF 70)). Polymers ma'y aho be defiedbv the number of noumers terem: an embodiment of the present iention uiies polmero at least about three mnomes, such PEG polymer 30 . stely 1.50Dats. consist k g of three mnomrs (aprohn 5 D Other hydrophiliepolyners which ay be siable or use n the present invention incud poglinyipgrolde oivntah rline. poiyeth loxazle.polyhydroxypropyl tethaer lm idhe.plvabacryhlunide. poiVdimenth vacryamide ad dedvatized celiloses suh asbydroxynehlexdkor hydregthylcedlooe in cer tasn lmbodimn a irmnilaon of the present mention comp ises a hiocormpa ibe pol mer selected on the goTU consisting of pofyanddes, pohrearbonates polyalkylene. pol Imers of 'ar rye and methac.rylie est ers ptvnv1. n o mners, polaglyohdes pol'\iloxanes t)lyurtha nes and co-poynmera thereoft cellul.osws p r k oplyene, pC odCvan, polome, polymers of lactic acid and lycolie aid, vetylere. ptvsyru .ec nolyvanby drdes poly (ortholezste poly.(butie aqid}. polykvalerie acidI. polvlaetide 'Co,' Saprehitor aon poivsa charides protems polybva alrome acesh, poly, yanoacery ate, ad .0 blends mixtures or ecopolYmaers thereof. C(xniJla'utm (iycludexrins are cyclic olnosaechanides.consos of e\ 7 or 8 elnsc umit designated by the Greek meters alpla. beta arl gamm respectieil The gltcose mltsiar 0 hked by alpha-i,4-glueodie bonds A a consequence ot the chair conformann oithe sugar units, all secondary hydrovI groupwt C 2C 3O are located on .15 one side of the o yn w while all the primary hydroxyl groups at 0 - ar siomed n the otmer side, A' a result, the exteinl faes are hyd'roph ie, making the eye eldesrin waeraul e in contrast, the cauittes of the eye lodeutrns arc hydrophobic, since they are lhned by the bnvdrogcn of atoms (A and ( and by ether-hke oxygens. These nauees all complexation with a v ariety o relate y hy drophobic compounds, imeludm, fr instance, J strong compounds such as 17h-ta.-estradiol see, c an Uden et at Ham: Cell is ( i. Cult, 3:1-3 1 (1994)4R The completion takes place by \,n de \\aals interensad by hydrogen bond unnauon for a general reviw of the chemistry dcyedermns see Wnt A Vnew. ('hem. int Ld Lngt. 33(30 O2 I 1994). The phpsico-chemicali properties of the eyceodextmn derivatives depend strongtil on 5 the kind and the degree of substimon, For simple, their soluhtv in water ran ge tium In additon, they arc sluM in many organirsol ens The propetes of the evclode inins enable the control over eitlyubil of Various formulation components by icreasog or so Nuterou ekidoets anad methods for the preparation hav benescrid. For example. Pare nd 5 a. o 43 incoporaed byreferenee) and Giadnera, U al4aN 3 . ncrporated b efeArn) desrbeeetroneutra 71 eye lodextrins, Other deivati ves inc lude cyclodextrins with c*ation ic properties (Parmeter (l), US Pat. No. 3,4527: incorporate b reference, inble crondl cy chodextr 01iS s, UIS. Pat No, 3420 ;niporthd by reference . and cyclodextrns with anionic properties (Parmneter (lil 1 .. P >at. No. 3,2,1;icorporated 5by reference . Amongn the eyeclodextrin derivatives with anionic properties, czarboxy lie h~~ ~hoit acids.'hV .dhdoWO acids hosp acds, pophinous acids, phosphoric acids, phosphoric acids, zhiophosphonic acids, thiosulphinic acids. and sulfonic acids have been amended to the parent cckxextrin (see, Parmeoter ()U), sprat Furthermore, sulfoatkyl ether cyclodextrin derivatives tave been described by Stella ew at. (U.S. Pat. No,5434127: incorporated b es) reinef tisposea Liposomes consist of at east one lipid hi layer miembrane enclosing a aqueous miema I compare tent m osomes may be chr acterid by memIane ty pc and hb sie. Small umiamellar vesieies (St s ek a \mgle membrane and t pically range between 0 02 and 0 05 pm m diameer; lar: oig a uarno or v eics I WUST are typically arge ) than (,05 pm. Oljolamellar g rc vesieks and muitelaer viemsles havo multiple usually conemne, mernbrane ly er and wr txpcallx arer than 0.1 pmi Iipo 'omnes iOth sen al njuconentrie membranes te several smallemseles contained withm a larger vesyeie, are termed multivesicular vesicles. One aspect of the present ivention relates to formulation composing hposomes 2vcontammg a componud of the pr esenm in en tion. nwhere the hiposone membrane is toroulated to provude a iposome wi h increased carrying capacity Alternamely or n add or. theo compound o fte preset inmion naY he COMitai nithin or adsorbed omo The liposome bilayr of the lposome 7be compound of the presem imenuou may be avgrIgated uth a lpid Luataut and arried wihi te iposomns intal space;n t 'hese cases the hposome membrane is firm ated to resist the disruitive effects of the actie aentsurtacit aggregate, A according to one Cmuodifomt of the present inVCjion, the lipid biLAyeT of a hposome contains lipids derivatized with polyeihylcie glycol (PEG 4 such that the PEG chin extend front the inner Nsurfae of the lipid bilayer into the interior space encapsulated 0 by o 'h some, and extend from the exterior of the lipid bilayer into the surrounding em ironmenti. \ yeagns onane whrihpsme o heprsnr~nctin r i slib7ie orm Aggregates oisurfactant and ative auent (such as emuions or icelles coainINg the aeti ve agent of interest) may be entrapped w th the intor SpaCe 01'liposmies dcordin' to [he present mention A stufacltnt acts to disperse and ouhbze the atiue agen, and may be selected tromn any suitable aliphati, cyelaliphauc or aromatic urfaetant iciludng but rot hmnted to hoeompaube isophocphaidvklmi\ PC'} of Oarving Chain length (for example, fron about C H to about (S0), Poner e-deriAinzed ids such as .P~liipids may also be utilized for mieelle tonuao masv they uv i; tct to inhibit rnellemembrane fusuin and as the addition of a poln mer to ttant mecules decreases the critical ielle conenratiotn (CMC of the s ctreant and aids m ieeile lormdtion. Examples are surtciltants with CMCs in the mieromolar range' hIgher vN'M surfactants may be utizeA to prepare micelles eMrapped whin iposomes of the present enton. however. micele sutrfactant monomers could affect lposome hiayer stabik, ad wouh be a factor in dengug a bposone of a dired sabiy L iponmes seful in the present iention may be prepared by any of a vaety of Stehniques that are known in the art See, eg.,. 1U. Pan No. 423517; Pubished PCI appcaratnms \\ 0 1 405~ New R R C 1 iposomes: A prctial appmroch RI Pres. Oxford IAT00. paes 10; Lasic D20 Liposomes ftom physies to appeatuons. ElsMer Science Pubbhs BV,,\mnterdam, luu# For exam, liposomes useful in the present invention my be prepared by diffusing a lipid derivatized with a hvdroph ili polymer into prefrmed liposomes, such as by exposing preformed iposomes to miceiles composed of lipid-grafted polymers, at lipid concentrations corresponding to the final mole percent of derivatized lipid which is desired in the hiposome. Liposomes containing a hydrophilic polymer can also beW orrned by hom ogxenization, ipid-fid hydration, or e>:trusion techmqpues, as are known int the art 25 In one aspect of the present inventiOn, the Ii posot have substantial ly nomtogeneous sizes in a selected size range, One effbctive sizing method involves extr ing t\a aqeou suspension of the tiooe through a series oft polyctarbtonate membmranes having a seete uniform pore size; the pore size of the membrane wilt correspond rough:y with' the Ilargest sizes of tiposomnes produced by exxtusiont through tha' moitembrane. See e~ Ui S Pat No. 4,737,323. ekai An.1whd r hrese characteristics of a farmuiot ofte parent ietion depend on the encapsata ii aterial the cniraon ot encapsated dru gand ~in th-' prsec ' kY lan plase ndtfers. For example. release o- an he umiued Io o p dependent utmg a pH sensiti~~cseetmgc that releases only at alwp oi h liaie a. higher p1-I as 'r the imtestine, An emtetc coatmng can be used to preem release frnm occurrmny unt il antr passage through the stomach \Mlml tykeng or mitumres of c anmide encapsulated in different materials can be usal to Obtam an Mmal release in the stomach, folowed by later release in the intestine, Release can asho bem plaed michusion of is pore fommne agents W hiCh can ierease w after uptae or ve aSC O' dlml bj diffusolt Aay the capsudc, Exepinetits which modify the sohA0lity of the drug can also be used to cotrol the release rate gents w which enhance degradanon of the nutrx or reicase rom the matin can also be meorporated. TheY can he added to the dru. added as a separate phase (i , as panticulates> or can be co-dissoc in the polymter phase depending on thle compound, in all cases th amount should ho between . 1 and thirY p:teent w, riolymnex} ITypes of degsAS itn tenhiillXcts mec.nde Pnrsame salts, suchb as aonmu urate and rimdloniuti chloride orgjantc acids. such an ez t r acid. Iaenzoo acid and ascorbic acid, inorgamic bases u diom at bnt, potasiumn earboate. elcum caronate zinc Carbonate, nd zine hydroxide, ad ogane bases such as proamme sufate. sperm ine, cholhne, ethanolamine, diethanolatnine, and triethanolarmn and surfactarus, such as Tw eene and PluroA Pore fhrmyi, agents which add merstructure to the matrces y1e. w eater slbeClpld ie as 00sm th n tg1%aeadded as paricll~ates sot chic cromdsA. ucil inrgni salts anid sugars) are" a: S 1he range iotld between one and thrtv percent (w noymerv Uptake can also be manipulated by altering presence time of the particles in the gu This can be achieved, or example, by coating the partile with, or selecting as the encapsulating material a mucosal adhesive polymer. Examples include most tpolymoers with fee carboxyI groups, such as chosn ell Uoses. and especially polyacrylates (as 25 ased herein, polyaerylates refers to polymiers including acrylate groups and muoditied atrylte aipssuch as cyanoaces andmethacrylte One aspect of thenenion relehs to apharmaeuticornpotne comprsing a compourd of the present hivention or aiphaimacnsla pibie sal thereoft and a p harmaceuticalv acceptable excipient in certain emyodoennts N present invention reaes to My one of the afore en cd phurnac~tica con potions wherein h pharmceutic reparati has an for reduingserum holestol. 1 DLandortri glycerde h, in thc rage humanada entpopultonns id no tore than 2 percnf the halt na cncentration of hzmOaceutWa paratonn h ich wod cause ctaneour meniato lshina t in certain mbodiments the present invention relates to any one of the atoemen toned pharmaceutical compositions. wherei the [C for reducing serum 5 cholesterol 4 LDL anid/or triglycerides is no morie than percent of the half mtaximal coneentration of pharmacutcal preparation which would cause cutaneous vasodilation (fdushing} in the average p tien pin in ertain embodiments the preset imenon relates to any one of the atorernenlloned pharnaceltieal composditns werein the pharmacelfl preparti on has 10 an .F:C torredtu'rng secrurn cholesterok i Ob and/or triglyerese xvbeh, in the average ouman patient population, is no more than 20 percent of the concentratun o pharmlaceutcal prepnaaton w hich wonld cause increases mn serum levels of apartite aminrrtan~sferase .AST) and alanme aminotransferdse ALIL reurin: discomtion t admmnistra ato the pharmaceutical preparation. .13 In eita in ernbodtrnents. the present .innctho relates to any one 01'ile aforemcntioned pthuimacerrcial comtpostions wherein sad compostuont i effbeetve. in rrtuk vi a serumn luad without causing ztrrllinaiitri i ttfepatoto\xeil\ and ( ill eletkions m uri, aed leels or ducose level or both. foMiMs admwusuation to aid paulnt that uould reqwre such treatment to be cdcontnued when said compoaition IS ba nestd b! said ptent On per day, ain um hodins tha mpre tMinv on relates to nip oe of ate aorene e drneti c po s talad a aton in certan embodiments, Ike Presen invenrion relates to any one Of the aforernenraned pharmaceutical otnpositdens, wheei the statin is elected from te group 25 c nnao ON~rvatain. cer vastati. P uvatatin lOvastto ineVastan. mt9avasttin in certain embddments the present invention relates to any one of the c."onant'i' idp imccte or oiin formula atd in combination SWit at Weanton additional therapevrc agent selected titon the ro consitin if lI 19 60I inthibtor, 5111 tansporter nhitars. 51fle agoniis. 5-1 o 0 FLP inhihior. oglucoidase inhibitors, ABC\1 enhances ACC hildtrs.. Ac ICoA holerol Otacy l ranferase inhibitors acyb-estrogens, antidtheile a rem~s~ anti-dplipider~.nne ngtents ant-hypertensuve Whibbom a am :aents, alntoidants. Apo A mnietcs Apo A 1 modubior Ap B immetw apobpuproteirne secrctum miektosumaI trigtIceri& tranfcr protein (apo-R/MTP} ihitors. appncY suppreants. apm, 3 agomists, P3 ucid reabor pton whibirp Mk acid sequestrantb, bombesm agomsts, BRS3 PemS t i Ci, amagmlts m§twer aposts >: QfK-\ agmja is chol esterol asorpuen mhibitor, Ch)olestemO i taNporl wnhibtors. Chokstoyl ester transfet protem T(CFTP} inbittors. CN -It CNFIT agoists modulators, a combination of creumribe and simmataun and or turuastatm, CSli 1 dchydroepiardrosterone, deipidated HDL D. AD T antisense olios, DIAT inhibiturs, DCAT inhibitors. dicarboxyate transporer inhibitors, dopanine agonists, DP receptor 10antagonists, ezet; ibe FAS inbitors, fatty acid bindmgn protein (F 7 ARP4 inhhbitrs, fat acid transporter inhibitors, fatty acid transporter pr otein (F ATP) inhibitors, flush inhibitor\ FXR receptor modul ators, gasanin receptor anta gonise gemcabene, ghrehin antagonists, ghrelin amtibodirts, GiLP- agonists, glucagonike peptide-1 receptor agonists, glucocoricoid agonisHtItagonists. glucose transporter in hibt or, H DL mnimtics, H.MG CS(oA reductase. inhibitor compounds, HMG-CtA synlthleutaihbitorsz hormone sensitivye hpase antagonists, human agouti-relatcd proteins (AG RP}. 143 antagonists/iverse agtonists, inorganic cholesterol sequestianos, L-.4f; lapaquistais leptin agonists/rnodukators, keptns lipase inhibitors lipop~otein synthesis inh ibitors, lorapoprant, low density lipopmotein receptor induces or activators, Lp(a reduces. LXR receptor agoniSts, iyn kinabe inhibior. 20 M3r agonists, McAr agonists, MCI R antagonists, 'HR. agonists/antagoniss melanin concentrating hormone antagonism, mluR k ntagonst' m icrosomal triglyceride transport inhibitors, monoamine reuptake mnhitors, natural water soble fibers, NiE ransponter ~nhibitors, neuromedina U reeeptor agon ists, neuropepiC- anaonss n iai Or$3 ci receptor agon ists, ic-otin ic acid, noradreneric anoreetic agents, NPY I antagonists, N PY 21 agonists, NPY4 agonists, NPY5 antagonists. nanoteroidaI anti-nflammatory drug (NSAID) agents. oAea~ fatty acids, opioid anagionists or, inhibitors, phenternine, phosphate trmsporter inhibitors, phvtopharmt compound 57, plant stanok ad/or fatty acid esters of plant sIanoIs, platelet aggregatti inhibitors, PPA Ra agonitsN PPAIR 4d agon ists, PPA:R 4% partial agonists, P.PARP.y agtonists, probusol. reain angiiensin inhibitors, reversed, SCD-O inhibitors, seroon in reuptake inhibitors, SG LT2 tabhib or squalene epoxi dase inhibitorsgualene synthesis inhibitors, sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid hormone k agonists, thynmimetic agemts topiramate, trglyceride synthesisinhibliors, LiP- activators, iCP acivaors UC.3 activators and urocoin binding protein atagomrs in certain emtbodimeuts the present invention relates to a pharmaceuli cal comxpostiton, comnprsn a compound of the present umenfl n or a pharraeutreal lv acceptable sal thereof, usam and a pharmceutcaly acceptable xipient in certain embodimenis the present mnventlon te to a pharmaceuneal cotmpostion.t cotpr1sie a COtfptd 01 the present ra\0ntio Or a pharmnaceutail\ acceptble salt thereof naein; a stati selected iom the group consistig of alor\astatin, co ilastatn, ius astat. lovastali, me vastatin. piarvastatn, pravastatm, msuvastatin andl "Asan alid! ba p m uilacceptble cxqpiec in certa mbodimens the presn invnio rela to A pharmaceuti litk.~cuf kS~4 ,~c . t''of' dv''' t 1'.*il(i-.& comnposition, COmtprising a COmpound of the present in vention or a pharmaceutem~icably acceptable sat thereof; a glitazone selected from the group consisting of trogitazone, nosiglidaZonc, ad pioghita2one; and a pharnmcetcaly aCceptable eXCipl en I. in certain embodiments, the present invention relates to a pharmaceta composition comprisiAg a compound of the present inventon or a pharmaceuticals accepiable salt threof; niacin; a glitazone selected from the group consisting of trogtlita~one, rsigitazone, and piogtazone: and a pharmaceuticaly acceptable excipmnt in certain embodiments. the present inveOtion relates to a pharmaceuneal comosition, conmprisin aopouvnd of the present invention or a pharmlaceutitcalyv acceptable salt thereof; a fibrate selected frlo the group consisting of fenofibrate and bezanhate; and a pharmaceutical acceptable excipient in ceran embodiments the present imenhl rlais to a pharmacy COmpOsttwOn, compriog a compound o thc preset nin\entoin or a pharDnaetuttcal\ acceptable: salt *hteLmah a vibrate selected from the rou~p nsistio 'femoribrate and basfibrate, nd a pharmuceuteail cetable ucl pient ME>GD An aspeCt ot the invention relates to a method of treatng a disease, disorder, or condition selected frot Th "ratp consisting of hyperlipideia. hypercholesterolemia lipodystrophy, dyslipideni a atherosclerosis and coronary artery disease, comprising the 30 step or admIinistering to a mammal in need thereof a therapeuitically effective amount of a oupod of the reseninenton a pataeica aceptbe sit there n one abnhn fnt th nrani renna 1W.Ut An aspect of the m en relates to a method otsaauv a dae diorder, or condiin selected fzlom the group condaating of hyperlipidemia h pereho leserlenmia 3 hpodyspbk dyslipideii atheroaelets and coronary artery OIeSel en mpn iamg the step of admnurerm o to a nmmal in need thereof a ther apeuucally etfeemv" amount of a pharnmaceueal cwoimpuoon of the present im mention In one embonem, tho naml i nurnan. An aspect of the ivention relates to a. rethod of treanny a disease, disorder, or it cndinhon selected from the group constating of metabolie syndrome, obesity. fatty li er disease and diabetes comprising the step of administering to a manmial in need thereof a therapeutical lv cfe ts e anmonm of a ompoumd of the presen in emtion or a pharmaeeueaIly deceptae salt thereof In one eMnbodiment. the mammal is a human. An asneci nf the invention relates to a nethodS of tailt a disease disorder, oY .h eondhton seated fromn the group consisting of metabolic at idrme obesity fatty liver disease, and diabetes, comprising the step oF admnini'stering to a nmnmmal n need thereof a therapeutially effet e amoum of a nharmaetical composion of the prese ientio, I Qnc embodimenm, the mammal is a human. An aspect of the ientinl relates to a method ofrausitu sumo hdihensh W Iloprotein { I0DL levL, comprising the sep of adiinster" to a mamall kin read thereof a therapeutically effectieV amount of a compound oW dj pn esemnown or a p harnmceuticalv acceptable sal thereof In one embodiment tn nanmal iN a huMnon, An aspect of the ienton relates to a method or'.irsng scmn hi'gh -densi)% b hoprotenl M s tep of: a10 s doisterng to a. mamal i need thereof a therapeutically effet~i\e amount of a pharmaceUial composion of the present i\ventionl In one embodiment, the RhImmmal is a human An aspect of the ienton relate to a method oflosuris seron Ioxdenstv lipoprotein ([.) 1lev els or lemg sum tipoproen iti lels compriaing the step of admmniteriust to a manxaI im need thereof a thsrneuticalv efftecive amount ot a 2 ompound of the present invention or a p~harmaeceutiecally nceptahle salt thereof. In one emlbodimnent, the manal is a human.

An aspect of the inventin .rltves to a method of lowcdrwg serum lom denlSity hipoprotein e Dl i lesl or lo ngsmm rpoprotein (a uzxels comprising the stp of adminusterng ro <t manmmal in need thereof a therapetically atefem:,amioum of a. pharma ceauca co )mposition of the present invention. i one emboim'n the 'mmmal is a An usu ofchinve tIon rslatses to a wehoi Of \DwAspcAftelie~nrit' OUNt~ Ouitoig a disease. disorder, or condition selected from the grour conitog of congesie heart fdlun, cardkwascular diisase by pertenson, coronary heart disease, angina, gel lagra, Hartnup's sy ndromie. ritind svndromne, arterial onchutswe disease, hypothnvodiN1, asecnstmetoL 10 osteOatitrtis,.rhtutnnatod arthriti. ;-heimer's d1sase, dTsorders of the peripheral and central nervous system, hematological dsases cancer, inflammaun. respiratory diseases, and astrmenterologieal diseases comiprismng the step of adomm~sernmg to a mannna] mn need thereof a compound of the present invention or a pharmaiccualy acceptaUbl t thereof h one embdunetm the mamal is a human. - An aspect of the inVention relates to a method of treating a disease, disorder. or condition selected from the gro up consisting otf congesive heart tilure cardiovascular disease, hy pertension, coronary heart disease, anijna, pel lagra, Hartnup's syndromre, carcinoid syndrome, arterial occhusNe disease, hypotridi viil:as.cnstrti on g osteoarthritis rheumatoid arthritis, Aizheimner'a disease, disorders of the~ peripheral and 20 central nervous system, hematological i seases, cancer, sni nnamton, respirarltory diseases, and gastroenterological diseases, comprising the step of administering to a mammal in need thereof a pharmaceutical composition of the preSent invention, la one etmbodimnen't, the mammal is a humart in certain eintodnents. they peseninv enn reedo any one of he a toremnentioned ehd, ter comprsnog oadminisieing a therapeda elibctiee amnouin of' stn. Inone such embodiment, the co.dnminitetia iscadministering In certain embodiments, the presentinvention relates to any one of the hoivds. fwrt ~ n OA "0,0 USCA F~ aforemnentioned methd futhr comprising co-adnminister'ing a therapeutically effective 50 amtounit of a statin; wherein the statin is selected from the group) consisting of atorv'astafin, kerivastain, ,lovattin. koastwinme rostuvaistal tin and sivastatin. In one such embodimen, the co-admmistering is co-administering orally, n certain embodiments. the peent invention rehates t on one of the afoprementioned methods, further cornprisnge co-akdmni sring a therapeutically effbetive amount of at least one additonal therapeuti agen selected ron the group consisting of i i p HSD-I inhibitors WT trn porter inhbitors SHT2e agonit a-L orlF LAP inhibitors, 5-g0ucosiase inhibitors, A BCAl enha ertSACC inhibitors. Acyi(.oA:cholesterAl (-acy ltranlstferse inhibitors, aeyvestrogens amidiabe tic agcents, anti dyslipidemic agnts, antihypertensive agents, anti-oxidiants, Apo Ali mimetics, Apo A mod ulators. Apo Em mmets, apolipoproteiniB secretion/microsonma triglyceride transter prteQin (apo-B/MT.P) Uihiors, appetite sutppreskats asphiin f Q goits, bile 'acid re tabsorptin inlhibitOrs, bile acid sequeCstrants, bombctsi agnits, RS3 agoit' CB 1 antagoits/inverse agoitists, CCK-A agionists,~ cholesterol absorptonr inhibitor, cholesterol transport inhibitors, choiesteryl ester transfer protei (CETP) inhibtors, (NTF, CNTF agonstsmodulators, a combiation of ezeimibe and simvastatin and/or atorxstatn, C1L. 1 i 1, dehydroepiandrosteronc, delpidated HDL DGAT antisease oligos, DCOAT hirdibitorm DGAT2 inhibitors, drcarboy late transporter inhitots. dopamine agonists, DP receptor antagoists, ezenimibe, FitAS inibors, atiY acid binding protein (FABP) nohibtors, tat acid npor transporter protein (F TP utsh inhibitors, IAXIR receptor moulators gani recepitor antagonmzts gemneabene, Threh n tagomsts ghtin aiohdie, G Ph agomtni, geagonAike popid- receptor agni ut ieocorocoid agomtatm atagOtA glucose Iaspotir mhnbibiro HDLJ~ nimntic H MC (>nA reduhtase ihiltir compounds hM Gdo A Vyhta mhibitr\hormonie w5t ibe 'jase amagemsts hunim aguttielated proams (ARP Pl h, )m5'ns mS agOnN. I oi iI bS$terol ceqesmti Lt f, lp noaqluniuAt, lpun agonists Umdulatot! eptmns lhpasme hibiors. lrpontem suh esibis ibotsOtapo low de t lipoprutm te eptr - due.N o Ch b\ .

t a 'lort' L.14) redtit.is rt X SvVSctepker A omA5Lts 5)5 n tS&inL inibt Nlc3r agonmists \Mer agonists \CI- 1'1R auntagomst \CliZR agemsts/amagnma/s melai Concnmratlin hormone antagonmst, mluR antagonis microsomal tnglyceridte trmsport hdinors. monoanne reuptuAk idubitors. narrd nater wobble Tiers NF ansporter tuhibitors neuromedmn L receptor agomiss neurop rptde41 antgtom nisiuacim or nmacin reetragonmsts nicotinie acid, ndrenergpe anreieum N\3 m t"agomis NPY agoists NP\Y4 agonsts NP\ antagoiAts nonotemidal unt-mtlananatorv drug i NS AIfD a gents onmegaA lbtt acids, opiod amtagonistea receptor antagonists PI)' tnhibitors phenmerni e, phosphate transonter mi rbbtorS, phy 'tophim compound $7 p tarn 79 stanols andor Ritty acid esters of plant stanol phateet aggregation mnhibtos. PPAR agonmsts PPAR- agomnis PPARA partial agonists PP ARhy agonists probucol. rern angiotensin mhibitors reversed-4E SCD- nhibuors, serotonn reuptake inhibitors. SC L T inhibitors. Sp4eiilnib eposidasc inhibitors. spuiaenesnmhesis ihitors~ Sterol biosythesis bitors, synmpathommnittc agonists thytoid hormone 3 agonists thymnete agents tomramate. tigcide SYthsis inhibitors. ICP, 1 acmvators UCP4 activatois L{P aetiSAato. and orocortin binding protem anwagonist in one such mbodimem, the co~ administein cO adrinieng oa in certain enmbodimients the present iention relates to any one of rthe Saormentioned methods further comp ising cood Mn i stenag a therapeuticaKi eftdae amount of at last one addmonal therapeune agent selected from te group consnnw Of H NI COA teducrase mhibitos, aspirin, cholsteryl ester transfer protein inibiors NAIDs, flares a propotmn convertase subtilinmkeidn type (P('Stisl.unorganmc cho lestencl sequestramns h, vl'OA'echdoesiero I 0-ae frasfemuse inhibitors (FT'P inhibitors. PPAR u auOms PPAR agonsts. ie acd reabsotpuon inhihiors, iAglycernde sythei~s s tors h.npoprotem recD(tor actibators D \T l mhiithors s(- mnhihuors lipase inhibitors DP receptor antagonists apo Al mnodulators cholesterol transport mtbtors mtetormm, nian rceptor modaulvors, and DPPA\ inhibitor. hi one such embodiment the co-adminsternY is co-adrmisterin orall certain embodinments the presnt mention rates to an one of he aoremtntioned methods, further comprs ing co-admimsering a therapeuticaliy eftbctive amount of at least one additional therapeunict get selected irom the group consisting of HiMG Co A reductase inhibiors eolestery ester transfer prot i inhitors aspiin, NSA vibrates P receptor antagonists eratrbe or a combination ot ezemihe and 2 simuvastin. in one such emibodiment, the co-adnunmstering is co-anmnisterng orally. In certain embodiments, the present invention relates to any oney othe aforementioned mtdsfuher comprising co--administering a therapeutieally effective amount of at least one HAMG CoA reductase inhibitor selected imm lovastatin. simvastatin ravastan, atorvastan, fl uvastatin, cerivastatin, rivastatin, rosuvastatni calcium and 0 pitavastatin, In one such enmbodnent, the cO-adninisterin is co-adnnnisterng orally, In etiano etodimentsthe resent inennon relates to any one of te kffrtemvnt.IOOnd hO Ar n ;snoe d e ng vanun, In oae s cmbodment the toadninistering is eoadmnsering oray n certain embodiments, the present in vntion relates to any one of the aforemnentionied methods, further comprsing o-adm ntn a chesery ester transfer ptein~f inlhibitor, in one such embodiment, the co-administerng is* co-adinistecring orally. in certain embodiments, the present invention relates to any one of the aforementioned methods, further comprising co-admimstermg ezetinihe, aispirin, ibuproften, acetaminophen, or a combination of ezretinmibe and simavastatin. In one auch embodiment, the coadmni string is co normally. An aspect of the invention relates to a method of treating hyperipidemia, compriting the step of co-administering to a nmrnal in need thereof a Iherapeutically effective amoun of a compound of the present invention; and a therapeutically efeive amount of niacin, In one embodiment. the co-administerngc is co-administeringx orally, in onem embodimn the mammal is a human. An aspect of the invention relates to a mahod of treating hype idemia, comprising the step of co-admi nistering to a mamnmal in need thereof a thra ecally effective amount ofa pharmaceutical composition of the present invention; and a therapeutically effective amount ofniacin. In one embodiment the co-administering is co 20 administering orally In one embodiment. the mamln is a human. An aspat of the invention relates to a method raising serum hghde h~ioprotei (-DL) levs in a manual compris the step of co-adrimaeri mg to a mammal m need thereof a therapeutically effcuve amount of a compound of the present inenn and u thereutiealb effetie amount of' miacin In one embodbment, the co i adrinsering i co-admmtisterng orally. In one enmbodinment. the mammal is a human. n aspect of the invention relates to a method of raising serutm hugh-densnry liooin (I+01D leels in a rnanuutl comprisig the step of co-animtennmg to a mammal in need thereof a therapeutical ly effecuive a moum eof a pharmaceutical composition of tbe pr esem mnentun, and a therapeuniall effete amount of macm i om m en t d ela tiole is u ne emboimmu An aTAc of the inention relates to a method of lowerng serum low-denlsit lipoprotein (OI I) v\els in a maraa l comprismg the step of coadnmist rtng to a namal in ned thereof a therapeuneal ieffecvie amnt 0f a compound of the present inventnn: an ao thrapeunCally eieme amount of niain In one embedmert the co adl niistei on is co-admini stennely orall vn one 1todowent, the mammal is a burean An aspect ot the vntiion relates to a method of lo"erng serum low-densit tipoprotein (L Ol levels in a nianmmal comprsng the step of co-admmterng to a mammal in need thereof a thcnrpeutiealy ceffetive amount of a phanmaceueal coroiton ohresem venton; and a therapenticaly etteene amount of ntacin in .W 01 emibodinmt.t the en-adtljlie istrg c5 o-adthlnistefnig orally. in olne enthodien,. the mammal is a human. An aspect the ventior relates to a method of scrm lipoprotein t i Lal leveA in a mammal, losing the p f co-admimAt:in to a mammal in nud thereof a therapeutteally effetie amounm of a. compound of the present mnvention; .md a thetapeueailv feetne amout ofnacin. in one embodiment, the eo-abmster mg is Co adtinisterim o NlO In one embodiment, the mammAn i a human, An ajpect uf rthe ieiion relates to a method of Ihn erimgermn l ipoprotem a (a { pIah eAS m a manmal comprsing the qtp of o-?ltnistermg to a mammal m need therenfa thAerCphuly :fwheieamioum of a phmmaeunel composton of the present m in tiot and a therapetea al eflecln e amount ofnaimn In one entodimam, the to admisteng is co-admmisterg oraly. In one embodiment. the mammal is a human, An aspect of the ienon relates to a method of trading hyperbipidemia, btwperboleserhii, atherosclerosis. coronary artery disease. conetie henr tailhne, cardios ascular dinee, hypertnion, coronary heart disease, angina, pellagrax Uartup'sm isynodrome, cav emon syndrome, arterial occluiv e disease, obesity, by potbyronhism, vasoconstrinon, osteoarthrnts rheniatoid arthritis diabetes, AWIhemer 's disease, ipodysrophv mt dvspidenma, comprimne the step of co-admintering to a mammal in need thereof ha tuet icay 'ffeeb' amount of a compound of the present n enon: a therapemicalv e'tective. amont of'niacm and a therapeanealy etetme amoum of a stan. i selec ted fro~m the group n.n ngo tn samcma ian fu\ astaain, louastatn., mevastatin, pa\ station pra, astmin, rsua vat mn and AmnY asat, it In one emood imem, the -adminiternn rs oonistens orally In one embodinem, ite maimnal is a human, .42-- An aspect ot the invention relates to a method oreaing hyperlipidemia, hyvpercholeterormia, athr rsi. coronary anery disease ongesive heart failure, cardiovascultar disease, hypertsion, coronary heart disease, angina, pellagra, .Hartmup's syndrome carcinoid syndrome, arterial occlusive disease, obesity, byvpothyroidisrn. 5' vasoconstrietion, osteoartrtis, rheumatoid arthritis, diabctew, Aklheimrer's disease, lipodystrophy. or dyslpidemia. comprising the step of co-administering to a mammal in need thereoola therapeuically effective amount of a pharmaceutical composition of the presentinvention; a therapeutically effective amount of niacin; and a therapeuticaliy effective amount of a statn selected from the group consisung ot atorvastatin,. eivastating fluvasumn, Movaasa mevastattn, pitavastanin ptvasttin rosuvastatin and siIvastatin, n oneC embodilmnt, the co-admni'stering is co-administering orally. In one emnbodinmt, the mamnmal is aI huan. An aspet of the anventon "''C to a method of treating hypedipidemid, cormprising the ep of co-adininstering to a roammixal in need thereof a tnerapeutically effective aunt of a compound of the present invention a terapeutically efie aount of nAcin and a therapeutically effective amount ofa stain selected fron the group consistin g of atorvastatin, ccriv station, fluvastatn, lovastatin, mvastatin, pitavastatin, pravastatin, msuvastatin and simvastain, In one embodiment, the co-admnirstering is co adotinisteringa oradly In one emlbodimette tammnind s hiumran An aspect ot the invention relates to a method oftreatmg hyperhpidema, corning the step of co-admnustims to a manmnal in need 4 thereot a thrpetcally -. 6 if" nnrui a .-im ion;ll i a row etrecue a m a phaWoutica composition of the present inventi therapeutically effects amount of' acin, and a theiopeutically effective amount of a tatin selected from the group ' onsttingt of atorvastatm, cermvasita im 11asta tu, lov astahn 4 , rnevastat, phavas atam. prIa vstaton, rosuvatatin and simyastatm, In one embod ibm the cot-adlmmitermng is co-adnmiisermge oralty in one embodiment, the maumnai is a human An aspect of the in\ention relates to a niwthodl fratsmg Serum hiehsty hpoprotein ( ID! levs in a. mammal, composing the step of co-admimsterng to a mfetieet e amount of a compound of the preem toinentiot: a therautically effective amount of ma' an. therautileally Nfetive amount of a statin selected from the group consisuing of atorvastarin, cernvasiarin, flurastalin, lov atatint rnevs taltx piasastatlin plavasrtUn, rosvatatin and sim\asatil in one embodiment, the cooidom sering is eo. admimstemng oralby In one embodiment, the tam al iK 0 human An asrect of the invention rehates to a method of omiing± serum high-denshv i a mamal, cmposng the step of c d tn o a rnammal in need thereof a therapeutically effective amount ofa pharmaceutical ornosihon of Pie preset invenion a therapeutical eff"ctMie amoun of m n;:nd a therapeutcally effective amount of a statin selected fom the group consst o of atoTrvastm,~n eern astatin, fl\astind, lo\vastatin, uev a stti n, pit avastat in, pria\ a9aatm0 tosuasata and :Sitln~ atarm Iin One emfbodiCut, the ew, admittermns i co-admmnisteone evol era b rnou tatk nanrnat ishan. Au aspect of the tn\ ntein ;vlotes to a method of lolerimy sro low-densuv ipoprote-m ( R L I eS im a mamm. t pompniemg the ster of co-adinsterng to a nmmmal m0 need thernt ' Ihera~peutteadvy effetive amoont of an coumd of the pr eent in\ventin; a tnerapeaut.l -effactu\e amout of niin; and a theraneutleadlV effect e amount 01 a starin selCted 4nn the group consisung ofator\aNtatm, eemtastatm, .15 iidtitstaatO et3131, 13\930 pr31valtluf rosu \t t and Mhnvastii in one etuhmem ith Lcodmistering is co-adninisterme oral iv in one embodnment, the Imann-al i a iman An aspect of the mnvention relates to a method of lowering serum low-density hpoprotehul 0 1) le\ els in a nmammaaL comprising the step of Co~admmisternug to a 20 mammnial in need thereof a .herape i ettet e& ~ amount of a pharmaccttteal compositon of the present invention; a ther:ipeuncaily effective amount of niacn; and a therstpeutically effeCive amount of a stain hlcted from the group Consiadln of alu rastit crt atil, fnuvastaum, tovatin mevastatut pitaastain, praxatat m rosu\vastatim and sims astaten in one embodiment, the co-admmiistering is co-admistermng oral y, i One ermhodiment, the muminaa iS a human An aspect of the mneution relates to a method of low ring serum hpoprotemn a) ( Upo)) levAls i a imanml cornpnsing the step of coxdministermg to a mammnal m need thero fa tlheiputiealiy effetie amount of a compound oa the present mention; a therapeutically eftetive aont ofmacm, and a therapeuiiealy ietme amount of a stan aele from the gro up consstn of aorasratmn, cem astat, flu\vastatin, lo\vtstau, mestatitm, plavastatin, prav asttui, rosu\vasat in and sm\ vastati, In one embodiment, the oadmnuienn is eo-adnimsteins oray In one ermbodun, the mnemnal is a human, (IPa) ovl Q '",ni'I-d .o.Pxn te440 fU nama nn An aspect ot the invention relates to a method of lowering serum lipoprotemn (a (L0(aD lev els i a mammal .ornpring the ;Iqp of codMinisten to a mammal in ned thereof a thrpuial tefeh e amount of a pbirmaceutieal composition of the present tnvemiotn: a therapeuticaii eftbetiv e amount of niacin; and a therapeuca ally etil'etive S amount of a statmn selected iorn the group consisting o1 atorv ustatin ernasain. fluvitin, lo\astauin nevastain paVastain. pravastatin, rosu1astatin and Simvaistaiin 1n one cmboiment the co-administerng is co-adminsterng orally In one cinhodimnt. the mammnal i a uman heti cia n bodiments th present inventor to an otihe 0 aforemnentioned methand thre attennt .lanuttn. here.saiad s a isvastatin Or atorvagtainC An aspet o the nventoul relates to N iletod of reaini diabetes i a rn odil comvprising the step of eo-administeringa to a mammal in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaeutically acceptable salt thereof, and a glitazone selected from the groupt consisting' of trogitazne rosiglitazone, and pigitaz~one, in one embodiment, the co-administering. is co administering orally. in one embt~odi~memt, the namm a! i a uman. composimp the step ol no- Adn instering to a mammal 1n need thereof a thelrapeuticdlly S eta~ ''amount of a pharmacy il compostin of ' bprsenz inventon; ano a giazone selected from the a roup consisting of tronjhtazone r orightazome, and ploogbrazone. In one embodiment, the eo admmnsetmng is costdnmistering orally In one emibodi memt, the mannad iGa umn An aspet of the invention relate to a nrthod of treatmga diabetes in a. mammal. 2 comnrsmg the step of'oiom em to a mammal in need thereof a therapeuticall efetUiv amount of a ecmpund of the present invention or a plarmlaelleali\aeeptaole salt thereof: nmacin, and a ghliwone selfected from the group consisting of troglitazone, rosdhaoine and prog hazone. In one enmbod iment, the coadomistermga tS co adrnmisterimg ormaI in one embodiment, the mnnmad is a human. JO An aspen. t the inention rates tto a mthod of traatin diabetes in anamal open i o-oadministering to a mam i edhroatherapeuticaly ef.*'jy.emun 'hantama d I empoiin fsthe esent $ irrent; dici:anda Wn VC gpm .5'.

1one enodiente co-p istiag is coadm ern oa l hi iney.odeetm the maniade . uomn An aspect of the inention relates to a letie of trettmg diabetes in a nunmmAl om~rnriing the step of co-admimste~rn to a mammal tm need thereof a therapeuicaly effeive amo ofad e a n aentn ora pharmaCeodial acceptable e salt thiereotL and a librate selected trom the group consina o iinofhrate and e/bhrate in one embodimema the Co-admmstering in co-adirmiterinR orally, in one embodimetu 10 An aspect t the invention relates to a method of treatinig diabetes m a mamnal coompimg the step of co-admimatenmg to a mlmmal in necd Iderofa therapeutial et ective amount ota phamneuidal composiion of the present mention, and a fibrate vadctd from th group consisting of fkRWlOibrte and bzdfibrate. In one entbodtment. the coadministering co -tdmisternne oraly In one mhodiment. the mammal is a human An asped t the iventuon reltes to a method of treating diabetes m a mmmal compisng the Wp of coadmm ato a mammal m need thereof a therapeuily etltective amount t a compound of the present invemnion or a pharmaceutalb acceptable salt thereook main :otd a 'ibrate selected from the grollp cons1sug of enoilbrate and b ezahbrate In one embodrmcnt, the coadinisterm is co-administenny or . In one Sembhodihmient, the mammal a ihma An aspect of Th invention reltes to a method of treating diabetes in a manmal comprising the step of co-administernng to a mammal in need thereof a therapeuticallh etkeeti e amount ofu hammnee'tical composition of ttie prem invention; niaci and a fibrate selected from the group consisting of fenoilbrae and bea *e. In one un5erbodimemt, the co-administering is co-atdmiristcring orally In one ermbodimnet, the mammal is a human. In ceain nboad imei. the resentinDvention reae to ensoef uthe atemeoned m oN and the attendn taAtions herei aid mamal' a. pia incrain embodmnts, the present' ' inton relte to an one offthe ao toned methods and th attendant l a s w n Said narm Is a human n certaum emtoditnents the present eni:tion relates to any one ot we Aktoementioned methods and the attendant humraion w herem aiJ compound ecD[oUrpond or ph13D rmCeuttcid cornposttoR dre adnnd~lae ed orlly in certain embodimens the present im enten relies to anm one of the torementamed methos and the attendant inmatjOs, uherem saw oromA coin pornds or phauvaceuted compositon ar admAyntered ntraenousl. Incain ebdinents, tepesente inon reae oan one o h Op o a ntion d met and the tendai mato wen aid con poun pn or pharaceual congstion are ) dn ard nran in C n emodiaens. resent l neon relates to 1nI one 0ithe afbrernentioned netods and the attendalmatons, h n said compound s.om nn or phannachal con positin aredinisered b hl~in aroe enioedmehods and theattndan r, ainweensi onomn in Colin ES 00 eaupwMma ndte o pndonge a h omoundsO,i-,,. Or pharmaceuical c poionare adlministered ocualk in cern eo dm ts the presen iventony Fttuhti to myW OEK otIhe atoen nticed .nitosadthe attndant.w naos hrj adcrpud in certan enmodumes, the prsent invnion relate to any one of the in cortan ebOdinienits the present Inventy yi rlae to any ones of the atoremmoed tods and the tedatl at, hein sai coIpoutnd. ln Certan ernbcchnow'ta the presen invetio reie otryOt the atrencnoe~ mtod ad heatenat imtaios.whrinsad omoud atoencaroedmetowds andl Whe mttndant linVaions. wherein suid compod> c oun ds or hrmcutca or n position ar aintcrded Sa tneoU lY n cetain enmboe ts the premn irenion relto a n one othe aoIreme ned mehnds and the andan ne t hd coMpoun ceain odint hpresenten n relaes ne he C~~~~I 9 dnW may! tK u pounds a eutcal omposon are mite nas 1"FEMLIHCATIO:N N The Wndmi now gen dra c bed be . udr ud by .~eerece o thei iblioiop-a. whic isincuded meter totpposes ofil0 mto f eti ZT4and embodbnn of chi- presen '.-t lnve'atmon. and i dntnedt lmt h inen m h a on u an xapk I ythetk Sckan Reactiona~ conitins mu AC Mopoie SOL ntrOHl". lO yt i.INaGH hen'r H' lan U- NN NO (iA8 13 mrmob n-PrOH- ( 13 mit and formaldehy de solteuon (irn w atr, 3% (1 i ' I mmnuh were. added to a 50 mo ltak equipped w ith a condenser, The reaction mixturewa reflung with a pre-heated 10) V oil bath for 25 hr under urgon. Then the nmmue allowed to stand at room temperture overnight and a yellow needle crystal was 25 pre ied out I. tee ad no plrectiaiion ioned at roml temperature codrn.l (4 r) O even -1 F9 ridge would he recotmended. IsLtd the crystal hr fltbra0o and w ashed wth a litte ethlwl ether to aftrd the crude product of step I as a HC] sal 0 .5 g, ... S I his cnde product was htirthr puntied by one iow recrystallieed from i-PrU and MciH to give the jprer produce of Ytp k as an offWMhhe or pae yelon powu der 1 .2 ' YAeh purty was P'9. ith A e obe Mannich addwnOn bYrrdet Aas 0.9%) The product of \lep 1 (1uo j d5 ; c\ e nWn >IeOH (20 n9 kWaer i0 miL1, I N1-10M i mL ) w as aed under ee varte oom 1whrc, Itsnimure waI stirted al rooml temperature o erfg, and hen u ph to 2 w ith N LU lIl Altr condensed under k acuum the residue was then further punfied whit prE pah v HPUC eiutog wah scdvent atnmitk and umoter 5 mM i W added) to all'trd K2 g of the tagea omud .AR~ a da Jhte powder (RI S, oal \d vas about A0N Aor two vcpa whben used the crude product of step I) ARR1D tmKd J[07 IM 'A R B.Compound ARIABS A' 7%,'' / A' C ' .72 / 7 44! "/~'~~ «'' ARII)Q5 P. Cumpo and ARI4fl6 (Ncx~ AtWOt*1 ho.tI~ 'V ARL006 'nntI'~Prw e 1fl$Ni~It1 PD("I f)]\*tAP '4' A' 'N N N U N N"' 'F. (tn~pouad ARI1fl}~ ARARII)40 co~~~~~~~~.9 liirs .DSwit1 -? \AP E, pk In n r Studks AR I 0as synthesized a described above, PutiN ua determined dependent beforwuse mn experiment by exminaon ua hm hm taphYman spvieOSCOpy LC&MS I A sample of material uwas disscdved in u ater acetomitrile and imlected onto a MDiscotery l8 everse phase Column he moble phase began as N9 aectontrilewater, whec was hdd for treS minute, aftr which a hMoel gradient was started dhat ran oer 6 inAuites, creasig the percent o 'aectoinl untid a tinai ratiof :2% aeetomtrilemater w as readed, This finalratio w as held for 3 mimt ( deteenon was collected at 215 n, as show n in gme I The major pea iwas dented as N~ARiTO 1 'the.m nm wa dtoitped P te sratio fted are ofe '9soTheao 3 miue) notI n lifted. Stabity was detnned yin oS ARIM,01 under 50 C ith no specified unnidit rerementAt vnous in-e pomins over the course n months da v) a small sample W5 ion of AR] -001 was colleed for aalsis using iM under the same Condiious as ued for prilv determirmationti { e F Eigure 2 shows Ahe ue course OF tabity of ARI-00 under u h cnditons dr stndadn uon(5 ", ngrcgated hunmiditsy 1 rnem ained 98 locpur for aperod 65 d Onl by 90 50 A did ARI 001 ben to show any derradation Ater 90 haya th compound was fond to he 9 . pure xampn 3i: T SVimiuds To nesAgate the e of AR--oi on lipid nodlaion n hmstr mode was doea ndild in T na of Chrme a isratior ofe pond Jis meL As deelopm e and the iets of MA-lI are described hern. tEbt ofiet Vkodiction on the LipidfPrtiylei ofl aners. Like oiher' Vodents the lipid profie in Golden Syrian hamsters predominanty consists of HDL with little LDL or VL DL cholesterol However, on a high-fat diet, hamsters experience an increase in the cholesterol pool including triglyceides and free fhuvae s Adding a sugar to tie driniing 30 water source such as 10I % fructose expands the triglyceeide pool significantly. including the VLDL. On this diet, the hamster becomes a usefid model for investgating the role of \o0 i a dulatoroi rAyretidcs and VD and D cholero Indeediterture soue uae utied is dto g tgate tg rde and e faty Nid modnlag compoundsuch as totibrat We examined the effects of diet modulation on the lipid profile of male Syran Golden hamsters Hamsters were ordered from. Charles R we I 4b (\\ iingnto, \ A. and reQuested to be 11 - 120 v in w Qgu (corespondmgiy n-u C d oldWA ilamntera were kept in cases o 4. per Caw, ond mauwamecd olht Sindln CA e of i t hours on/ 2 hours otY All diets were obtained from Dvets huc. BSethlehem, I' Normal Diet>' w as a standard rodent chow. cata log "RAL pr oduced into pellets. \ter and tis standard clho 1V diet nere ai atble to 0,i-" yroup of hamsters a /F0oon od was added to eVes as needed, but no less frequoml than tWie per week, 'High Fat Diet was the same standad rodent chow supp lemented w th the biwn I 1. % corn oil, i L5% coconut o, 0.% choesterot and 0.% deoxveholate. This is also available directly fronm Dets Inc.. as uatalog 1611201 otd ts were ordered in 10 kg batches nd stored at T .lor durations n of the experiments 144 wecksn and at -20 T oi longer storage fup to SIX monthst Water and this inh tat diet were a abe to this group of hatasters ad duan The "Igh Fat tHoWe group was fed the same fat-supplmtnttd chow as the i bgh fat die>' group 61 120 i but w at uas supplemened wr huctose to a final eon centrtton o 10%. uctose was supphed fAm Now Foods (csalay> no9 and ditibuted by i nly Vit'amin 2 utallo AW1484 Fructose w after w as prepared by adding 400 g of fructose to 4 L of aer and stiryng at room temperature until duoies Frtose wer was stored a '4 C unil use. When prove aided to hamsters. fructose water was iept in a water bottle te hamster cages at room tenmperam x asr w after was r water and hh [it chow w ere provided to this group oif hinsters ad /Wb/trn All animals emuado& on fthen 2 epectiv detfor 1 days To begim ths experiment, ha asters were randomly asgned to groups defined by the hedt modifie'tions above. \fter a ixed ttme, blood w as collected irom hamsters NN 4 to determine the lipid contents of the plasma. Because of limitations in the abhis to adequately collect blood fom hamsters all blood samples were obtined ia a euniuai 0 cardiac picture preceded by asphyiaon with carbon diouide, Blood tap nmatel 2 ml volume) w as collected w a 22G needle into a 5 i syringe nod trariurred to a KATYI'A tube. Tihe samples Uee kept on ice until ecnrifugation ( "4,000 rm fR 10 mimtes at 4 A t senate plasma Pasm was then quoted to tibes for sewage at AO Lpd preters et detet'tamed Ung comMal iv av ailable k4s roi \W\o W i d ) 4cc0rdme to mauldter i direction LApid %vaes boon control aimals (ze day o anmftetre it ecie abOVt nere essential indisinWishaEe see 'abk 0 - day 2 1. both diet ioducaiRons had sitti earn effects on the brid profiles of these hamsters when compared to -minas on normal cbow diet All par ameters w ere. sigmileumt l weeae fom control i psO. in al fr1p\s) nit h e tCh exception of DK As predicted, the ddition Ofirferoe to the high t in, diet fr01her incemed the trinlyceride and fie fatt acid coemtrations to a gater euent than the hih fat diet alone MDL was unchanged 6om the nonnd diet group, reardles of the diet modiflcation Table . ipid values from hamSters on one of three different dies for 21I day. tanis ~were scnced and their plasma was analyzed as described, alues represent the average of mesuremems of each parameter (N=3), wib standard deviation TC: tot cholesteroa: HDL: high-density lipoprotein cholesterol; DL: low-density lipoprtein cholesterol TG ierdes FA a fCtt acids Normal PD 15 ', 325 726±0.2 1igh Fat DPat 6 QN!82*1 Mt K 314± 20** * 12 * 3 65 4 *p< 001 compared to Normal Die within the same parameter *pe001 compared to Normal Diet wuhin the sint parameter Fasprotei liquid chromatophy (fPC} wasusedo separate the different vhdoesterl snbpofapuhots froarEasaples of? hamnster sm Briefly, plasma trierE eaca ampmal nt itnh a o n cohorn nas polled ogeter and applied to an ARIA liquid handing ew h a buperose 6 K0K300 t "0l oM tprodnet #i45 72-0-, GE i ie Sciences> 250 L ot sample wnas applied to the inection NMem. diluted w th 5i of bufer (100 M \a WPA 100 nM NaCTt pH 7 loaded onto h' nlun, and elted with 23.5 iL of buffer at a dow rate of I m. mLm, into tracions of size 024 nof. ach fraon was indtidualh measured for Choleto concentration usig the tota cholemcrol kit fron ako as described above with the followin modiication saimple voume W as increased to 30 gpb and the reagent vohme was deceased to 60 tI FP C traces produce cottiuous curves nith h vi peaks represemmg each of the cholesterol suhpopultion \ DL, LDL, and ID. Buse the coluMna sed m this e pernment is a sieexclusion t olumn, the larget parties appear list while the smallest appear last. Hene V DL is the firt peak on ther aes, folowed by LDL, wit HID appcetruw last. If'each of these peaks is assumed to take a Gaussian distribution, one can deconv oluc the boPL.. trace ito each of these thrve components to detrine the : cointrbutuon that each component mates to the w hole curv e Figure 3 dinstrates the FIC traces of plasma pooled from hamsters on two different diets or three w weeks. The \DL curve is vastly expanded on the high 11 fructose diet The LDL peak is also much huher. lnterestiogly, there is very litle diLterenee o the 14Db peak, indiahng that the dte modihcation has a riuch mon pow erfu Keffct on the nonMH cholesterol populabou This model thn lends uiself to bed, a use i means bv which to measure the effeBts of AR I[001 on \lDL and i D cholesterol 040l tus .> m u v. (%lerta. syl rwn~cides. eovl lo's Mar c i T W i fIS ilatSkm M\ale Golden Syr an hamsters were purchased from Charles River Labs 111120 . 561 day) and aeolInated to a high fat , fructo s (herein, referred to as .i HIEIS'A diet as desbnhed above fr two weeks. Haisters were assigned into cohots by body nweiht after two aek' acehmion to the diot Twve hamsters wer assigned to the vehicle group, i were assigned to re"c' caci n at a dose of 1200 mgkg o 10 were assigned to recent ARi600 1 at a dose of 1120 ngkg. and 10 were assigned to receKe ARk 001 at a dose of 2240 mgkg. At the end of this diet acehmation period, hamsters were g0 orally uxvaed with I m of a sohiNon of vehicle (water) nicin, or AR0GO at one of the two noses. -lainers were dosd once per dal to a total of 1$ days. All amals remained on the above--described H IS diet throughout the dosing period Dosng solutions for cohort werc prepared fWr ' day at a time, ahhouuh enough wn tearaed to Lst tAr a days hich gsl utionwva stored at room ternpera rote betw een adnnm5tratjofls Cohorts were defined accordmn to Table 2 kMvo Leause of the iolzeular weight difference between ni n and ARM 001, doses are gn n both mge an<d mmol Note. tht r200 n erk;of niain ib equivalent to 2240 mg'i of ARIT-0 on a molar bass. TMie 2. Assignments to cohorts for 18 day dMsing study in HF/S hamsters, Compound An\maM s Days (-g/k m---/kg - ----- * Niacin .200 9.75 8s A R I- -- - 8--- ---- - ARL-01 2240 9.758 A shew in ' able 3 AR -001 given ia oral ca age for 18 days at 2240 mg Lg 1 l owx C 'd th LDt~eholetrol and total choksetol lev elW m a HI hamstemmI modeL ARK 001 alko lowered trigyerdws and fre fattY acid levels wih Wo ittl variation between amnmal as illustrated by the small standard dilation Al the molar eIinalent dose of 1200 mgkg, mncnM was unable to confer these effects n this anmal modet suggesung that AR, 001 is at least 1dmnes more etlicauous than macm u th respect to the 1I 1-colentrrl parameter, and at least 1 .54,mes more efficacious than miain wzth respect to the total Tholesterol parameter. Of note are the' wtrlveenide and free fatty acid \values which demonstrated responder s among al anmmAls the 2240 m/k AR[0(1 group. T'at there is a ery smal Sandard deaton among these data points reflect the imprewn e response rate among these ammal The 111 TI atio was cadulated by dividing each individual to hamster' HIL cholesterol levs e Wx his totd cholesterol level The fraction that resumed is the llDIT rano, Thi parameter was ugher than thvehicle cohortk Itwh impre satistical significame (p0,001 ) This does not ikely represent a poeful increase in 9si H DL a the atlte UDIL raue measured ws wereased by only 3 m the 2'40 nm/K A R W00 'goup ompted to whide, R ather the wry powerhc e i h IA1flTC tatio IKet represents a stemwwde reduction in eholestempi populatun mth the es epon of 1D, nhicb wa not ony spared from .h red unt but a pOiblY TIbhe 3. Upid paranckiners n HEmS uaers dosed or h ice nicWnC or A RP. 0 rH :da tt choleser Vaus raean standard iion. due e d n Naed npad N e v he treated. d dn thie 14L 11. "to F F1 (onr mgmub fingdL} (ugkfli hu~q/L Wah/IC Cohor 4 D 44 3 1, N ac 9 075 210 .1 mW/kg si 113 ti 26*x t2. 50. 1(MN .9 01 4253 957 L39 24 mg/kW i i04** i 74* i"3** *i 80** ±0 * * "p<:O0§ compared to VehiCle Wihin the same parameter * p<(00 compared to Vehic within the same parameter ***p 001 S compared to Vehicle within the same parameter K ~The mnesured H DL values were borderline significant (p=0.06) between the 2240 mngjkg A.R.L00 I group and vehicle. There was a considerable increase in significimce when considenngm the celculated H1-DUTC values. The FPLC traces also demonstrated a significant difference in lipid profile between these two groups, PLC was perforrmed as desetbed a= tuens were decorwoluted as desrbed choe Not oby were tVDL and h lDipA k . onsrdeabeead compared to ehice, Whe FUD cure ws * dyn ih ARN14i uice. See niure4 \Male Gsoldeni Sriam hamsters from the preuiouslh described expenmetm deitoristraed a dose dependence on \ R100 ih repet to h40pid aleramn '40 ng kg an efleetwe dose i 18 I dals of dayeatmem fo neai r al par:nters total cbolesterl.t D.L cholesterol, tni ceridets arnd free fatty acidN Hokwver, Itt tn0 tuW shows mdh mlodeCSt effects ont these natameters uwih 00uh the fr::e fgtttvc ad paratuster demn-strating a stHieail sgilcaWnt C Het enmpared to icle Nonetheless the trend in eslear between the doses .tor 'ill lipid parametersnmiesughated. as shown in Fgure 5. \Moreover, at the muolar equivalent dose. ARt-did e fects a more ponwerful response than niacin i all hpi~d paramens. iesue A Ri-001 Lowers LDL. Cholestro4 Tive and Fe Far A cids n a Tme Dependent Atnner. Thirty-wo male Golden Syran hamsters were acclimated over two 15' weeks to a HF/HS diet as described above. A tier a two week induction priod, animals were assumed to cohort fr 1 day- s of t on either vChile or A R001 ( 1 120 Mg/kt or to cohorts for 28 das of xsudy on eihr vehicle or ARTO 1 (i 120 mg/kg). Each of the. tour groups hal 8 hanisters Soluins were prepared and stored a des crd abov. Animal were dosed a volume of I n pet y f rw either 18 or 2S consecutive days, as reviously described. At the end of U itudy hansters were scicedk LI their blood collected ino KEDTA tubes, plasma separated by centrifugation and frozen until analysis All lipds were analyzed ing commercial available kits (Wako USA) as described aboev. In Tale 4 below both 8-day and 2 a hicle animals are combined into a sinl lhice group (N= lo Table 4. IpWid parametems frorri 11S hanster dosed orally u th v vehicle or AR -001 for 1B da cr28 das. Va w s given arc mean 5 standard demaotn P-values a. reported 1mn 2-aled unpoired i-tests compiarmng to vehicle treated wihin die Manie parameter. TC THDL IDL TIG FFA Cnbrt. Ld ( I (mg/l I mg/L) ( dq/ + SU S :Jztn i ±DSD +SS ' hi63 12 W -9-~~ 4-5 A I 66h. 1.460602 1120 mg/kg, I Days +82 + 8 * 2 A40 H 420 W 1, a ASS i ' kpc0.O Icorpamzd Vehcl N Within the sano pwnmter * 0)0 compared to Vehicle idun the s pa ate \RPOD i showed awrahe efets on Npids when a dose of 1120 mg ky was camied out to 2 day. When hamsters we dosed for 2 day instead of 18 days, all linid parameters measured a 1 1ucvd a statisueailly siepoficant dhtference emnpared to s-chicke except fOr HM w hich show d no difference comped 4o vchicL. ihe edutuons seen at I 120 nmg t r 28 do s newr geeatr than aiAer 1$ day of doing. However, these xeucuen> were not nearh as snpresive a those seen wuth .1 daysa at the bher dose of Correlatio emmen Psma L.pi BiU .oarkers and A1 RMO.? Plasma Coenltraions Plasma from the 19 hamsters dosed with ANb0 1 in the above described IP-day study was analyzed for concentraAions of AR 001 Concentrations were determined for these samples, which were collected 2 hours afer the final dose was admmaned. Briefly, plasma drug concemrations fo the nom-LPi pharmaceokinetc experiments were determined by LC-S using an Applied Biosystems 4000Qtrap spectrometer with electrospray ionization. Samples were prepared for analysis by prciitation of pas"ma proteins with coid mthano. I PLC of the samples was done with an Agicr Eclipse Cly column and a methanolwaer rient conaing 0. 1% fomic acid and 5 mM ammoniimi actate. AR400l1 was detected using mudiple reaction monitoring (MR M) in the positive ion mode. For quantiation. a standard curve was measured by addition of known amounts of AR0I0 to plasma from untreated animals and preparing in a manner identical to the samples frm treated animals, All plasma samples vere spiced with 0 ng/m of isotopc-enriched AR nI which served as an internal standard for the LC~MS measurements, All compound concentrations are reported in pM. For correlation analysis. plasma concentrations of ARLI in a given animal were paired with that same animal's lipid parameter. All animals front both dosing gups (t 1 20 mg/kg and 2240 mg/kg) were included in the analysis. These correlations are graphed in Figure 6 and - 9 Figuren 7 Parson v values ere deter ed usingN daa poin as was he twoniled P ale f The daM et vipid parameter changes corneated ell wth plasma levels ot drug meusued 24 hours ater the rinal dose Indeed, teta cholesteL M DL cholesterol, LDL cholesterol inglycindes and Giet acd Ies eols. al at d statistically significant levels of ecrtelauton ( p' O I 1 CoNlatiu i v vti trigveerides vee c eecally notable for having a very high degree oftautistical snifiwatlee, p<Ql} 001 Thee signmticamt corrlations gnive support to the idea that ARI-0) 0 w ni d y responsible fi modulation in lipid values \Moreoer theS e data corroborate die dose-response el'ects seenl i Figr 10 .4kla00! Cnnurwn~ m Hm '. (Ikwe nait P/a :ptap m rf T isse samples w ere harvested from master s mthe abov e-described 8-day experiment to determne the con entr atas or A RIfi)AR in both liver and adipose isue BrelY lver and adipose samples uwere harv ested at the termination of the experiment; tihe samples w ere Tash frozn in liqud nitrogen and then stored at -8 W untO used for analTis To prepare for anaNsas. a sample of iver was excised oern boen mass weighed and homogemed w ith a tissue grinder followed by sntuuon in huter The solid nmateriKh were then removed by cen fuaton. Wn prepar ti ( >JMS analssv ta homogenate wa then treated to the same prepare action techq ue dest enhdl fo. pasma prepar-aton rede /Mw) A sample of adipo was uexised V;om' the ren ns 'mld anstenre to a mortar and pestle cooled wih Iqtdd nitrogen, During grindiWn leioid tliArel was added to ensure the sample of adinose remained solid, The groundsample was transterred to a tared tube to weigh total sample TIs ground sample wan cated 11 i methanol, ana this compound-eontamlng methano wa sparated from ipid by gooling t-20 M1Afer dryngi, he methanol. was issoled inatethe s e thepepared li L( MS anavs in the ame w at liverddlamawee i\ver con"entrations aere reported as rog of AUT0l per nil of honeanized tissu sample xtracted ino buffer Coitentrtions i adupose were reported as rug of AR001 per mg of tissUe revered front the grinding prices. Because of the distribution of tisue concentrations aid hiid parameters te logarnm traustormation was used on all H\ er av samp les w hen determgi ine correlmon, Additionally adipose concentration w ere transtornmed as logarthm + I, sin the logani transtermation produced negative viues for these tissue samples, These transtormatioris allowed the data to he more graphed more lop comeentea Finally, these transfonrnauons are v ahd because the nature of thc PearSOn r corretion coeffient is Mwariant to both logarithm iratsfntiamon 'Od to transposinon Figure 8 graphs the corriion hetueen conctrtions of \.R~00 l in plasma versus liver (left. and in plasma versus adtpose (right VIBoth of these correlatons were highl statistically signiicant With p , 0 I ho each pair fn paaeier Figures 941 graph the onttons bemeen the concetrano of AR 101 in each issue samp. versus the lipid parameters TC', HWI, L OL. T, and F A : concennanon mesurements and al .pid parameters nere trnsfored via loganthm. Pearson r was deteneed usui all data points dliustraied Pvadu~e w as deteriried tbr a 44 lled t-test using 41 data tsits A RIWll hwatxu e4 ,10 11. rapL 51 K-!, ("I'I qoJ * Mo l' mRMN i Hf HNS Amw snr tnestigat.ion f a possible m chamim that could lead to he imrease in HIM. cholesterol focused on changes in the mRNA levels of several genes related to the. regulanon of H ED Uam.ter livers and adipose uere prepared in manners simar to that J! dened for \ RI-00 conentidaion determoatin. Boef, to repare for analysis, a sample of liver was excised rnm the frozen mass. eighed, ,nd homogemzed with a tisue grinder (oilowed by someation in buffer. The soid nvernk were then removd by centrrtungatiott Ihe resulting l\ utt w as used in oQt'R anQl)'is to quantifY 1he specific mR \ measured {id ) tuinmg primers designed fOr the specific sequences o interest iWAl nRN\ quantites wer e normalti ed to veiieie-reated animal, and miRNA lev els w ere expressed as a foldinmcrease or decrease relative to vechicle-weated, The adipose w as treated in a su r a anner to the h t i empte of adipose wa e imed fron tml the vn mass and transferred to a mortar and nestle ured with liquid nown During gndAing. hquid trogen a added to ensure the sample of adipose remamed solid Tle sample 5w as transferred to a tared tube to weigjb total sample. Th is ground samnle w as treated vs ith buffer and prepared br PCR to quantify speciic mRA \quaniUies Table 5. Relative concentrations of AB A1, A poA L SRBL CETP mRNA per mg of liver tissue, and likewise adipose CETP and asponectin mRNA per mg of adipose tissue. from high fi-ed hamsters in vehicle y nacinm or ARI~OiI -reated cohorts, Values are given as a told-change Cormared to the mean of the vehicle values *ld- Message V Niaciw 10 mg/kg ARI01: 2240 mg/kg Iv1 A+ 1 Q± M 1 4 MY Lhvr ApaAI 1.0 N 0 0 L~ P. A7 XI) 0Y 24 Q4~ lAyer SR1I L,0 0 4792 018 L0 033 LverCETP O W0 0 45 L.0 ±t55 205s Li.8 Adipose CTETI P0 +G u 46 1.12 ± (3L2t&0 e to ehicle ctrol ann ms deed, a attsti Al sigcn cora iodn was see bewen dO adApoA mnRN ieel Ths sugeste a.possibe ecdasmi xy' e -R- --- ma---rease DL i- t hamste -de td e 6+ (ralons between AB3CA Al &R-B ad CETP mRNA per ra f ie issneev dLiI ad lzksncs ner en L and doees aRNA per nag adipose ss e vs[ es from tiEd ed hamswers in v ee.nan- r AI-u 10 rated ch orts Corrdlation Vehice iacia: 12010 mngkg ARk~OI: 2240 mg/kg jIHDLj vs Liver ABCA1 0 .07,. 60)> 140 (-04. ) A09 -0 3~ L AQ9 IIDL I vs Liver ApoAl e 32 o0.34. 77)t 0. I9 cl.54 -6 480(0.2kL. A90 (HD~l vs iverSR~BI 1.1,~ 46>19 .083 s A61$(-.029...0 6) .J.1 (-0,75 .65) (HD) vs Liver CLTP 0J (3A 0 -0.4733 ( -X73-.58) Nf30 (0.32 083b IfIU I 'S AA~)SN?0.03 (-,62. 0. ) vs .54 (-0 19- \'9) CA5 (0.28 0 98) -HL- vs Ad-pose ---. \-------- I.43 ( 0 2 0.2 0.31 602" 4 -. 020 - .6 Adiponecti 443 a 4XTO 'I his sl -. o., .5 AIAW am Vaca MAin hn hmo 102d, Exampe 4t Safeity Phtarmacology Studies (Non-GLUP Preliminar twStudies) Because niacin is known to b associNted with liver toxicy and glucose intolerance in a chronic dosing setting, we examined whether AR-00 1, a niacin mme tic, could be assoc iated wvithi similar issues. in order to investigate this, we~ examined the comonhQ liver function al enzymes A ST and A LT in the plasma. of hamsters from experimemt described above in Example 3.These anirnal\ wer dosed 8 eutive day, while being on a HF/US diet for a total of nearly 5 weeks. We also examined thelucose level in the pOlasma of these animals. For pharinu we sntic atudic we uilized wild type mice for both ainle and r~ea ted administratjOn study, Finaily. pharimacokinetic stUdies were .1o corrmborated by data trom sige and repeated administration to monkeys. A. fects on Liver Function A R1-O0H bmproves LYer Function Tests pom Chrmnicallv LDosed H igh Flat-ed Ha nemtr Certain fomulation of niacin are known to cause hepatotoxicityn humans. This led to an investigation of liver fCetion t (A ST. ALT) from plasma of hamsters dosed fr .1 days with ARJ-001. AST and A LT ecre measured sing commercialty available kits (Bio-Quant Diagnostme Kits, San Dieg~o, CA). As expected, AS? and AL T values from untreated hamsters vehiclee goup) were ery igh, as the high fit diet leads to hepatomnegaly and fatty liver. This disease Sate is reflected in the elevated AS and A LT levels, In contrast. AST and ALT levels from AR401 treated animals were significant 20 lower than vehicle, hndeed. AS? was drastically reduced at the 2240 mg/kg doseaden significantly reduced t 6h i120 mg k dose. ALT values were similarly reduced. again in a dose-dependent manner, Se Figure 1S2A and EFgure 12$. S. Etet ol n H Glucose omerauce iet myHp1 1Hmr ie API-OP. Mr, AD fl> hu c O e lanels iam~ng MOhh UW I PLUCnvy N lacr i knoun to ad"erselx affcT glucose levels among diabetic patients The hamster model used ni this apiomeint did produce a population witb eleataed glucose levels as demonstrated by the vehicle inup in Fgure 3 Consistent with effects seen m humans, the g ucoe of niacin-treated ant was mnreased relative to vehide How ever, neither dose of AR 1-00 1 produced any smficant Change in 0lueose leels in companson to the 103< xmpk 5t Phanaekietk Stude A Mouse hit'veStudies Sing& Dose I&armtaoinetic Study of AkRWo! in Wild 1Zpe Mce, WId type C57U6 mice were dosed with a single administration of AR001 in solution either via oral savage (PO) or via itrapertoneal injection (IP) Blood .sample were t colcted at various time points over a 24-hour period; plasma was then analyzed for concentrations of AT R00 i as described earlier, AR1-001 was administered at either a dose of 2240 mg/kgas a single bolus via oral gavage or a dose of 44 mg/kg as aSI bolus via. sitraperioneal WAI01W too oap andou va nrpeic~a ejection Seec. Figure 147 A bl Siotteso dmnisraio iof' R LOPI i.oa n.adinrprtna neto unne poi the remani ag coneeratlon ofAR 0O0 was udndetere Thh 7. Phaehiektic parades ttrn sng dnnnitran gof ARVOP] inwldtp -b --- -- --- -{-- -- - 0 2 dlatnpc I Admtotwn Phcrms okiue tuMPeb a' I Ri-di ein Wd flax A-lin-v Wild type C1 6 mice were dosed with \AR&bO in sohmon via oral gag dahi hf 30 consecube day. (her die course of five 24Tho peods bood was collected, and the resumupl asmrna was analyed for conntrations of ARN&I. Four doses ere uvsed: 9 mgR kP, 1493 mg/kg, 2240 ma lg. and 3 30 rng kg. As expected, ( e lev es and rotal 24. hour exposure (A were doedependent. Phowevar, these ulues were tme nependenL as there as no tcrnd observed between these parmeters and days of administration, ee Figures 15 150 and Figures A-16B, were dosed wIt single adniWstraion o a kN or conound 230Cdisclosed 1its Paker yphcaion b. No. D0MB 23 5 A inctpo e heri reence in sko a sen n bolks ol avage iP).( a-ond 23Q has h . .t B oodemndsavneAN oered a e onmepoints 220 an W ae wwd pas 10 amlo ed zrteohaicR d23C sdud' a Rosk ax shmK1 bit8 'Tale S.ornanson O u unmakinsk paramoere OW inR 60 and 2240 him NiaeinA RCl~01 2230C A U C (11M h) 1969 0766 hie (t) (h) 175 A3W 3 A7 C i; (% - in ) IOU75 . CAa(h J]0.35 1 028 W J4 dRM ws tsuuanAer WASanSWnnKuMgv a3 smglc cand dose 0f5 0 imoli got' A R I-01MZa mlseer o td acr punour frme wee an clles at aripous timeapis era.4rpo plasma n enan f\R 0o hran mRhvfl or AR7 o (esN hoi)59s 309 S ionke in Viv tdies Simgl Dose Rarma ohtnerk Sn4V 0' I 10O l: Imp? i.ndes Fasted nkellys were gaw en a single adnmistration of ARL0 in solution either a ora! gavaue 11P) or vi intravenous inaction J0\ Blood samples wr collected at various time potnis over a 2 hou~r period, phisma 0 r\ hn 'alyaed thr concntrauonm of A R10 AR - OI uos admmistered at either a dose of 288 ngk as a smtuatl bolus v ia oral aae, or a dose ol% mg i kg as a :single his YUa [\ irnection Results arc show. n E igtre 18 SQr gh>Dosl e hCi Studll ./RT-Cll l N<,i / or ls'dAltCWn i ed monkeys w ere fed aid alkmoed some- time to digst before being .ndmniatered.A R1)01 as a 10 hoa on u:a ordo gauag as prev iously described. Results ar e sho vn in Figur'e 19. P arma oli w It.-/u/trph -- an rations of A R1-41 1 a U k asc Kol rev 001 was .admistered to moikeyn ia oral gavage oune per day lbr a total of'seven damys Blood samples were collected atter the first and after the last admimsataons to nanne plasma conemnrratonsof ARt001, There w as very litte difference between the plama concnaions on day i ersus day 7 The ipeatest poim of discrepancy w nas m the C v alue. which wa haher on day ' than on day 1. The concentrations 2 hours after either the first or the las doses were a ential Idenical. See Fljure 20, sampk e6: ARpoolFa to Rerut "I.rrestinthe eN Membrank f Cells so Fprssiing RWgh A~hdtv Nia Reenptor GPRNt1A It has been demnstrated that niacininduced cutaneous flushing is muediated by activation of the niacin receptor, GPR 09A in a 0-arrestin-.de pendentnmanner, Water R W et al. (2009} J Clin Inwest 119:13 122 A-ssay.-ready PathHunter eXpress -Artrestin celia expressing CWPR 1O9A were plated at I W000 cell/well in a 96well plate and stimulated with either v iacin or AR-IA00 , each over a range of concentrations for 90 minutes , protein-coupied receptor (GPCR) activity was detected by measuring the interaction of p arrestin w ith the activated GIPCR using frgalactosid ase enzyrnefamn comlmmto Folowing stimulation with either niacin or ARJIP 0 signal was detected singa the chemiluminescen Pathtunter Detection Reagents. Representative result are shown in to igure 21 iLike niacn. ktimulao4 o (iGPlIf 9AW it 140Ia cnetrtost o m aitled to recruit thanesno to the menmne of cell expressmg GPR 0V\ SMe miacin-mductd 0lushmtw is knowna to he mediated by acinvation of OPRI 0PA in a [Varrestin depeindent m'amier, this tindmng is consistent with the observaton thai. \RI-00I has greatlw Examipe 7: Summary of pharmacologsic studies of A RI-0 0 in anim4 models A lumber of phannracoknetc, afy and vfflaey suie for ARL~0 I hane been competed mn a vanety of animals. ineldn mice, re Golden Sri-m hamsters dogs and ?0 monkeys Ov erall result from these smtude ha e~ established the folione, ARK-O01 deer aed plasma levels of to0al cholestemii DQ ' TO and FFA while mecrcasmna the absolute lev el of HDL-4 and H Dit-TV' ratio, 'the lipid altenng ceet of a one-dai l ds o' A R-00 I were more proounced than the lpt etlcts ob seret with near fold highe o dose mam gir n onec a dy. -NRH 401 gown no daily fy ft 21 das psoducd a greater change in plasma lipid nSpaed t thea me dose o'R 5 en one da d A v an ose dnl pouedhighy sin ant chnes in pama lipids. eratr ha o Lv 4 to the lipi MYei ugefbet dbseMe With the' satotal dose . of AR 001 inn tw d'v Addtonal oe daily AR 0 1vas nnre potent than mcin in 20 Alo Ues (S mel Avpid canne. ('anges in pasma ees of T D% 1 C T LE' and FA ceatedwith Plas and Nver enctmmatous of ARIGO 1 arc rrounti ektd Lvr conentrton o ARI00 I coreated decreases i pia -C 25 TOGn and and ncrase inplsa'DLC AR-00 A s ed no evidence ofapilary vasd ao or hypenma (a proxy of sh) in experiment ning Doppcr capillary blood f neaurementn mic Atiall, clinica symptoms f lsng" wee no observed oer2 days in atso dogs a~mpie Th Wman dina*4trU a ith AR4dI A randomized. double-blind. placebocontrolled study is performed with sequential escalating doses by cohort with observations tor 30 hours post dosing ard return visit on 8t dayI. Study subjects are healthy male and female adult volmneers, age 18-6 years, with LDL-C .> 130 nA/dL and weigh 85 kg, Subjects are rndomly assigned to receive study drug or placeblo, Five periods ofsingle dose es~c'a with 8i subjects per cohort (6 drug: 2 placebo involve a total 40 subjects, Appropriately bIined mtching placebos are provided. Cohort I receives 500 mg of AR-G0t frmulatwd as d single oral tablet, plus eleven pacebo 1 ablet Cohort 2. 1000 rg taken as two $00 g ab le is of A R-01 . pus ten placebo tablets; Cohort 3. 2000 og taken as four 500 mg tablets of ARLOI L plus eigt p cebo tablets: Cohort 4,4000 mg tken as eight 500 mng tablNS ofARt-00l. plus four pLacebo tlets; Corbort 5, 6000 mg taken as twelve 500 mg tablets of A - 00 L Placebo-only subjects take twelve placebo tablets Each tablet ia compressed, film-coaed tablet 15 suitable for oral administration. Prtnary ob o ox e of the study are io evamme th adety and toleroadity of ingle doses of AROO in hWdh adit tnteers a doses ranging ro $00 ng to 6000 mg, Secondary objtectves of the study are to establish the pknetic profile of AR-(0 i in blood after 'ingle dose m heath volunteers; observe changes ini triglyceridese, fi-ee fatty acid an~d other lipid biomarkers: correlate the dose level and plasma drug exposures over time with any chances in fasting triglycerides, Ree any acid and other ipid biomarkers; and establish the effect of A R-00 1 on symptoms of flushing by visual naoy mcr (VAS Pharma\okineti soamps ar coleced at 0- iipeds and a:t 0-'. I $2 6. X, l2. 24. 30 nd 168 hours AMle dosing. The naunjal tof each plams colecton is rcorded. At each collection, 3 mL. of blood is collected into a V t aeutairner tube containing EDTA purple top) and refrigerated immediately. Within 30 minutes of colleeion. the plasma fraction is separated hy centrifugation at 2,000 rpm for 1$ minutes at 4 "C, 36 Analysis of all samples is performed at a cenral laboratory, On Day 1. predose. the losing procedursar perNormed lnial laboratorytestsnlding river ietn (ALT A)' sem biiin CK hatolo 1,1 PI PT, inaly''.sis adliipid c isn panel (LDLC. IDLQCe * Vital sii" * Uin coletio frkbashin PKQ eWeen midnigh and 0 hous(dosig) * mesu laboratory utss meludtog liver a etion ( , AST, serum hbMt m i henmtolo.v and APT P 1at n V and 24 hours podosew Lipi' y R WIHDIVC, te tv aci ON rtridvmidcs. QQan . SL ipid irhvst pai 'i ijDIL (aD) re it ghen and A poA E at n 12 and hours pos dose * at 46 W5 l .hr to * ins at 2 ,2arn posnta rs Add At y arid 5, hours ,t2oe. ad co Phcer ca exanaon at 24 h ours de a hiea ini i ag ina 30 *CIA NYm blod sample &b Phi at A. 5. 2 ICC,6 8, 12, 2,4 and 3.0huspssds de rangin uine M00 Pg in 0h0 imn at 0 t , 6 th 12. 12 to 1 do 24 'A 24 to 3u 0 bours0ngm afe do g m efr10 yo'o ruhyeumb Prclintinarv'n. reut ~n' hishmav clinical trial NOde the reyakaltWbevto that no patem nt ehibied any sionS of OWshNu at any dose oif ARUO WA up t and! ineidoneq Addition preiniiarvrsvdt ar shown in Figmr&c22,' whillustresdos [uber _ prllary res ultsC n inlt sho n i n at C 1 wc illustrates seuma 311? onratin of Af [411 ms ncasurcd over 24 hour in humvans follongy sngl ora .jng Wiorn 500) 6to000 ng, of All-Q 16 1. G, fOr tWe 2000) not dose: of A R W 001 was, about 7ON nglii &LS i;,5 tl Q 15 im00 ing o'f nai ruhyeuoa dose as so 10000 na / a 0 mg'mU), INCORPODRA N XBY REFE RENCE Al pbhcivn and paints mentioned here arc herhy tncorporaed by eterenc n the C ityzty asf endi indivinua pubh icalio. or patent weas seifica land Pindiidua da to A incorporate by eence in cae of c1nl. he preNm applIcain illt speelic enbodiinet of the sunject iknention hae been discused, the Thove .perneator is Illustratne and iot reStnve Many 1ariationof thc inventon u"A become apparent to those skilled n th art upon res ew of ths spetleaton The appetded clams e not intended to e Lan a Wuc emboodirnAet nd vaiitoun, and the lHU 'aopw Af the intnon shold be determined by reference to the ciums aong ith ther ful scope of equivlets and the opliabOn, along wth sh varianons

Claims (13)

1. The method of claim , wherein peak concentration (C ) r the niacin analog is 40 percent or less of C. for the equinoLar oral dose of immediate-release iacrn. . The rmethod of clai . or 2. heren the raio of peak concentration to area under the curve at 24 hours (CK/AUCog for the niacin analog is 03 or less.

4. The method of any one of claims 1-3, wherein theme to peak concentration (1X for the niacin analog is in the range of 1 to 5 hours 5, The method of any one of claims 1-4, wherein the niacin analog has an EC for rb arrestin-mediated GPRI09A function which is a least 10 times greater than the of niacin fi @arrestin-ediated GPR1 09A function..

6.The method of any one of clans 1-5. wherein the niacin analog when adnistered orally to a human also increases a serum or plasma level of high-density lipoprotein (FIDL) cholesterol T. The method of any one of claims 1 -6 wherein said oral administration is characterized by substantialy -no increase in serum levels of asparate aminotransferase (AS aanine arninotransferase (ALT) or both. 8, The method of any one of claims 1-7, further comprising administering to the human a stain.

9. The method of chum 8, wherein die statin is selected fromn the group consising of a torvastatin, cerivastatin, fhwvastatin, lovastatin, mevastatin, pita vastatin. pravastatin rosuvastatmn and simrvastatin 10 The method of any one of claims 1-7, further comprishig adinisterng to the hma least one additional therapeutic agent selected from the group consisting -111 - of 1 I HSDI 1 inhibitors, SHlT transporter inhibitors. 5HT2c agonists, 5-L) or [LAP inhibitors, -Wigucosidase inhibitors, ABCAI enhancers ACC inhibitors, AcyCoAeholesterol O-acyltransferase inhibitors acyestrogens, antidiabetic agents, antadyslipidere agents, anti-hyperdensive n antioxidanisApo Al minieties, Apo Al modulators, Apo E mimics; apolioprotezn B secretionyrn irosomal triglyceride transfer protein (apoIBVMTP) inhibitors appetite suppressants. aspirin. $5 agOnists, bile acid reabsorption ihibitors bite acid sequestran ts., bombesin agoasts BR83 agonists, C1B antagonists/inverse agonists, CCK-A agonists, cholesterol absorption inhibitor) cholesterol transport inhibitors, dolesterysteter trdsfer protein (CETP) inhibitors, V CF.'NTF agonists/modulators, a combination of ezetimibe and sinwvasttin andor atorvastating CSI1 dehydroepiadrosterone delipidated 11DL DGAT antisense ligos, DGATl inhibitors, DGAT2 inhibitors, dicarboxylate transporter inhibitors, dopanine agonists, DP receptor antagonts, eretinibe FAS inhibitors fatty acid binding protein (FABP) inibitorsatty acid transporter inhibitors, fatty acid transporter protein (FATP) inhibitors, flush inhilitors, FXR receptor modulators, galanin receptor antagonists. gemeabene ghrein antagonists ghreiin antibodies GLIP-I agonists, glucagonlike peptide] receptor agonists, gheiocorticoid agonists/a tagonists, glucose tranisporter inhibitors, HD ni netics, HM CoA reductase inhibitor compounds. HMGCoA synthetase inhibitors, hormone sensitive lipase antagonists, human agouti-retwed proteins (AGRP., H- antagonisis/nerse .agonists. inorganic cholesterol sequestrants ,4f, apaquista epti agonists/ioduaors, leptins, Iipase inhibitors, lipoprotein synthesis inhibitors, lorapoprant. low density lipoprotein receptor inducers or activators, Lt(a) reducers. LXR receptor agonists, lyn kinase inhibitor. Mc3r agonists, Mc4r agonists, MCHlR antagornistaMCH2R agon istantaon istsmeanin concentrating hormone antagonistsm(u5 antagonists, microsomal triglyceride transport inhibitors monoarn ine reuptake inhibitors, natural water solube ibe .NE transporter inhibitors, neuromedin U receptor agonists neupeptide anta lists niacin or niacin rnceptor agonists, nicotnic acid. noadrenergic anorectic agentsNPYI antagonists NPY2 agonists, NP4agoists, N 5PY antagonists, nonsteroidal anti inflamnatory drug (NSAID) agents omega fatty acis opioid antagonism orexiti receptor antagonists, PD inhibitors phentennine. phosphate transporter inhibitors, - 112- phtopharn compound 7, plant stanols and/or fatty acid esters of plant stanols, plateet aggregation inhibitors, PPARa agonists, PPAR-6 i PPAR-6 partial .agonists PPA -v ants, pr7obucol renin angiotensin inhibitors, reversed-4F7, SCD1I inhibitors, serotonin reuptake inhibitors SGI 2 inhibitors. squalene epoxidase inhibitors, squalene synthesis ih itors. skrol biosynthests inhibitors sypathoitnietic agonists, thyroid hortone p agonists thyromimetic agents, topiranate, iglyccride synthesis inhibitors, UCP atixators U3CP-2 activators UCP-3 activators, and urocodin binding protein antagonists iA pharmaceutical composition, comprising a niacin analog or a pharmaceutically acceptable salt thereof and at least one pharnaceuicaly acceptable excipient; wherein said composition is formulated for oral administration; the niacin analog when administered oraly to a human reduces a senim or plasma level of at least one lipid selected fiom the gmup consisting of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and lipoprotein (a); and oral administration of the composition is characterized by reduced flushing and reduced hepatocei ular damage., as compared to administration of an equmolar oral dose of niacin, The pharmaceutical composition of claim 11 wherein peak concentration (C )for the niacin analog is 40 percent or less of C, fo the equimolar oral dose of niacin. 13, The pharmaceutical composiion of claim .I. or 1.2, wherein dhe ratio of peak concentration to area under the curve at 24 hours (C /AUO 4 ) for the niacin analog is 0.35 h" or less, 14 The phannaeutcal conposition of any one of claims 1I 13 where, the time to peak concentration ( for the niacin analog is in the range of 30 minutes to S hours, 1 The phanaceutica composition of any one of claims I-14 wherein the niacin anulog hais an EQsfor 3-arrestin-mediated GPR 109A function. which is at least I times greater than the E(.% of niacin for -arrestin-mediated (PRi09A function.

16. The pharmaceutical composition of any one of claims I1 l5, wherein the niacin analog when adminstered orally to a human also increases a serum or plasma level of high-density lipoprotein (HDU cholesterol

113- 17, 71The phanaccutical composition of any one of caim 1. -16. wherein the niacin analog when a dminiStered orally to a human induces substantially no increase in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (AlII or both 18, The phannaceuical composition of any one of cleains II 17, wherein the niacin analog when administered orally to a human induces substantially no increase in serum levels of uric acid., glucose, or both. 19. The pharmaceutical composion of any one of claims I 1-18, wherein the niacin analog is represented by structure 1: R 2 N~ p wherein A is a heterocyclyl or heteroaryl optionally deuterated. containing from 5 to 12 ring atons, including X ad N which is optionally substituted with -3 substituents. independently selected from the group consisting of alkyl. aikenyi, alkynyl aryl heteroaryl, aralkl, heteraaralky, halogen nitro, cyano sulfonic acid, alkylsulfoxyl, arylsulfoxyli, heteroarylsuifoxyl, amalky sulftxyl, heteroaralkylsulfoxyl, alkenylsulfoxy, alkynylsulfoxyl, alkylsulfonyl arylsulfonvy heteroarylsulfonyt anadkyisulfoxyl heteroarakysulfonyl. aIkenilsuffony alkynyisulfonyl, hydroxyl, aikoxylmyloxyl heteroaryloxyl, aralkyloxy. betcroaralkytoxy, alenyloxy, alkynyloxy. thiol, alikylthi o aryl thio, arad kylthio heteroarallkytthio, aikenylthio. alkynythio formyl acyl. formyloxy, acyloxy formyti acyithio, amine, alkyla une, amylIamine, heteroarylamine, aralky Iain e, heteroaralkyuanine, akenylanine, alkynylamie. formylamine, aeyanmine, earboxyl, alkyioxyearbonyl, aryloxcarbony heteroaryloxycarhonyl armlkyloxycarbonyi,

114- heteroaralky loxycarbonylU amido.,aky aminearbonyl, arylamineearbonvI heteroary larminecarbonyv aralkyarmin earonyl ind teroaraikyaminecarbont X is O S, N or N(RA R X Z.is or an isostere of a carboxyl group; X is 0 or 5; 2 is C or 5; fR is hydrogen, alkyl haloalkyL aikenyl/alkynyi earboyyl heterocycivi. heterocyccilaikg, arvi araikyU heteroaryl heteroaralkyfl fused bicycly. carboxyalkyl, or aryialkeny aryl; R is hydrogen, lower alkyl lower alkenyL lower alkynyl. halogen, hydroxyl, amine, carboxyl. cycloaikyl arylv hetero aralki, heteroaralk, cylano, or nitro; R' is hydrogenb lower alkyl, lower alkenyy oweknyla halo gen, hydroxyl, minc carboxyl cyloalkgl arl, heteroaryl aralkyl vheteroaralkyeyano, or fnr R is selected independently for each occurrence from thegoup consisting of hydgen aiyl, alkeryl, a"kyny, ary! he.trry araikyl heteroaralky .halogen. nitro cyano, sulIftnic acid, alkylsulfoxy aryl Su foxy U heteroarvlsulfoxyI aralklsuifoxyl, heteroaralkyIuifoxylakenyIsuifoxyl aiynylsuf.oxyt alkylsulifony I ary;lsudlfonyl' heteroarylsulfonyl, aralkvyIsulfonyl, heteroaraikvisalfonyI alkenysulfony alkyn1YIsulfony. hydroxyl, alkoxyl aryIoxyi heteroaryioxyl aralkyloxkyoxy aikenyoxy alkynyloxy thiot aikyhhio, ary hio, aralkytho heteroaralkylthio alkenylthio, alkynythio, ormyl acyliformyloxx acyloxy. formylthioy. lahio, amine, alkylarine arylamine, heteroarya n d aalkyl amic heteroaralkyIaminmine, alkenylmine aikynyI'laminc, formy e ayia rn ic'am'ie cairbox vi, aikylxycarbonyiaryloxy'Ci viby heteroaryloxycatrboyi aradkyloxycarbonyi, heteroaraikyloxycarbonyl, .amido, alkylarri iecarb ny , u siamrib.iecarbonyvi, beteroaryvlamin ecarbonyl I aakylaminecar'bonyL, arnd heveroaralkylamninecarbonyli; R is hydrogen or lower akyI; and mis ,2,3 or 4. 20. The phannaceutcal composition of claim 19, wherein A represents heterocvciv 2L The pharmaceutical conposiuion of claim 9 wherein A represents heteroary L 22 The pharmaceutical composition of any one of claims 19-21, wherein A is a radical of a monooyclic ring having 5, 6 or 7 ring atoms., 23, The phannaceutical composition of any one of clans 19-21, wherein A is a radical of a bicycle ring having 9. 10J I or 12 ring atoms 24, The pharmaceutical composition of any one of claims 19-2,3, wherein X is 0, 25. The pharmaceutical composition of any one of claims 19 where Xis . 26. The pharmaceutical composition of any one of claims 19-23 wherein X is N. 27, The phannaceuticadomposition of any one of ciaimw 19-23, wherein X is N(R 28 The pharmaceutical composition of claim 19)herein A is pyrrolidinyl inidazolidinyl, thiazolidinl, isothiazolidi iny oxazolidinyl, oxadiazolidinyl, Sp ridinyt piperainyl thimorpnoln Ior morpholiny L 29 The phannaceuti.cal composition of claim 19, wh in A is imidazoly, pyrazolyl isoxoazolyl, oxazolyI. isothiazolyl, thiazolyL oxinyl. furazanyl oxadiazolyt thiadiazolyl, triazolyl, dithiazolyli. diazinyl, oxazinyi thiazinyl triazinyi tetrazinyi, diazepinyi or thiazepinyl 30. The pharmiaceutical composition of any one of claims 19-29, wherein A is substituted with 1-3 substituents independently selected from the group consisting of lower alkyl. halogen, nao, cyano sulfonic acid, hydroxyl akoxyl thiol, alky h io, fOrmy, acyl ionnytoxy acylox tornyIthio ayhhio, amine, alylamnine formylamine, acylamine and carboxyl 31. The pharmaceutical composition of any one ofclaims 19-29, wherein A is substituted with .substituent i.ependenty seected from the, goup consisting of lower alkyl, halogennir, cyano, sulfonic acid. hydroxyl, alkoxyl. thiol, alkylthio, forn-yl, acyl, fonnyoyloxy, loxy iorntio, acyhio. amine.alkylamine. forrnyhani~ne, aeylamine and carboxy I - 16- 32, he pharmaceutical composition of any one ofcainm 19-29, wherein A is not substituited. 33. The phanmceutical composition of any one of claims 19-32, wherein R is hydrogen or lower alkyl. 34, The pharmaceutical composition of any one of claims 19-32, wherein R is hydrogen, 31 lhe pharnaceutical composition of any one of claims 1932, wherein R' is hydrogen or lower alkyl 36. The pharmaceuticals composidon of any one of claims 19-32 wherein R. is hydrogen, 31 The pharmaceutical composition of any one of claims 19-36, wherein R' is lower alkyl and PY is hydrogen. 38 The phannaceuticai composition of any one of clamins 19-36, wherein R is hydrogen; and R' is lower alkyl. 39 The pharmaceutial composition of any one of claims 19-36, wherein Ri is hydrogen. and R is hydrogen. 40, The pharmaceutical composition of any one of claims 19-39, wherein m is 1, 4i ' he pharmaceutical composition of any one of claims 19-39, wherein m is 2. 42. The pharmaceuticaI composition of any one of claims 19-39, wherein m is 3, 43 The phannaceutie caiompo4in of any one of claims 19-39, wherein m is 4. 44 The pharmaceutical composition of any one of claims 1943, wherein R' is selected independently for each occurrence from the group eonssitng of hydrogen, lower lkyt halogen. itro.yano. sulfbnic acid, hydroxy KalkoxyI, hiol. alalgi thio, formyL acy , formyloxya. cylox, formylthio. acyhio, amine, alkylamine, fory lamine acylannine and carboxy IL 41 The pharmaceutical composition of any one of 9ann 9-43, wherein Pis hydrogen. 46. The pharamceutical composition of any one of claims 19-45 wherein Z is carboxyl - 117- 47. The phannaceutical composition of any one ofclaims 19-45, wherein Z is a carboxyl isostere 4A The phannaceutica composition of any one of claims 19-45; wherein Z is tetrazoly, oxazolidinonyl sulfotic acid, sulfinic acid, acylsuphonamide, phosphonic acid, phosphinic acid, hydantoi, pyrmolidione, 3-isoxazoly oir boronic acid. 49 The piannaceutical composition of any one of claims 1945, wherein Z is X2 R 50, The pharmaceuticals composition of claim 49 wherein is 0. 51 The pharnaceuttical composition of clain49, wherenXisS 52 The pharnacetiical composition of any one of claims 49,51, wherein X is 0, 53 The pharmaceuticals composition of any one of canh.s 49-51 wherein Xi is S. 4 The phannaceutical composition of claim 49, wherein Xis 0, and X is () 5T The phannaceutical composition of any one of clans 4954, wherein R is Ihydrog~en. 56, The pharmaceutical composition of any one of daims 49-54, wherein R is owner akyt 57 The pharmaceuticalcomposition of any one of claims 494 whereinRis OH H \N H 01 00 0 C -~ t ~NW> or 0 P 58 The pharnaceutica opposi t ion of ny one of claims 49-54, wherein, R represents an aliphatic group which is iydrolyzd to carboxvi uncr physiological condains 59. The pharmaceutical compOcsition of any one of claims 118, wherein the niacin analog is reflresented by fmmiula IL whereinindependently for each occurrence W is a poLyol or polphiol; p is 2-500 inclusive; R5 x NNR m Riis R 2 i and is either appended to the polyol through an oxygen atom of thc polyol or is appended to the polythi through a sulfur atom of the poivthiol A is a heterocyclyl or heteroaryl optionally detterated containing froni 5 to 12 ring atoms, including X and N, which is otionaly substituted with 3 substituents, independently selected from the group consisting of alkyl, alkenyb akynyt. aryl, heteroaryl aralkyl, heteroaralkyl, halognc nitro, cyano, sulfonic acid, alkylsulfoxyk 119 - aryi sulfoxyl, heteroarylsulfoxyK aralkylsulfoxyl, heterOdalky sidfoxy , alkenylsutfoxyl, alkynylilfoxfti alkyisulfon l t arylulfonyi Iheteroaryi suo y aratkyisulfonyl. hetcroaralkysulfonyIs alken ysulfonya lkyny isulfon yE hydroxyl. aikoxy, aryloxyk viheteroarylvoxy aralkyloxyheteroaraikyioxy] akenyoxy, aikynyoxy, thiogaikxithio, arvi thio, aralkyhbio. hemmaralkylthio aikenyithio aIkynyithio, formyv acy, foyoxy, acyloxy, formycthio, acyhio amine, ailky I amine, arylIamnine, heteroarvinnih'c, arifliniehteroarai kyl amin aikenylamine, alkyny amnine frmyamine, acvlamin.carboxy alkyloxycarbonyl, aryloxycarbonyI heteoaryloxycarbonyl, arakyoxeabony. heteroaraiky ioxycarthonyv amido, aikyani nec arbony , ar htlamnec arbony I heteroarylaminecarbony, aralkylaminecarbonyyi and heteroana kylamniecarbonyv; X is S, N or NRaI; Sis O or S; R is hyd.gen, aIlkyl haoalkyU alkeny alkynyl carbocyclyl, heteracycixl, heterocclyaikyl, aryl, araiky heteroary, hetenoaraikxi fused biyci, carboxyalky, or arylalkenylarylU R2 is hydrogen, lower aiky lowe akenyi lower alkynyl halogen, hydroxyl, amine. eafboxyl cycloalkyl, aryl, he a ary enteroaralkyi cyano, ornaro R3 is hydrogen, lower alkyl Iower alkenyl, hower a/kyyL halogen, hydroxy), amine cartoxy). cycloalkyi aryl, beteroaryl aral heteraraky yato, or ratro: R is selected independenty for ach occurrence trom the group confstng of hydrogen, alkyl alkenyt alkynyl aihe ry aralktI yl, heteroandky halogen, nitro, cyano, sulfonic acid, alkysuifoxyl, arysufoxyI. heteroaryhsidoxyl' aralkyisulfoxyl, heteroaralkyisuifoxyUalnsulfoxy) alkynyisuhbxyi, aikyisulifny arylsuifonyt, hetemoarvisul fonytI. aralkylsulfonytI heteroaralkyiLu) fonyi, a)lkenyv Lu) fonyalkynylsuafbnyl. hydroxyl, alkoxl arvioxyl heteroaryloio, arakyloxyhetroaralkyloxy, alkenylox , alkyloxy, thioh, alkylthilo, aryithio, araikvizhio heteroaraiky hhio, aleyiio alknyhi formyt acyl formyloxy aeyloxy formyhhioacyttino, amine. alkylamine, arylamine, heteroarytamine, araikyiami, heteroaraikylamine, alkenylamine alkynylamine, fonrmylarmne, acyl aine, earboxy' alkglIoxvearbony), arylioxvearbony), heteroaryioxycarbony Uaralkyloxycarbonyl, heteraralkvloxycarbony amido, -120 - alkylatninecarbon I, arylaminecarbony 1, heteroarylaminecarbonyi a amindnaruonyl1 and heteroaralkvlam'iecarbonyl; R is hyldrogi of lower alkyi; and mns I ,2'3, or 4 60, The pharmaceutica composition of claim 59 heroin W is a polythiol 61, The pharmaceutical composition of caim 59 wherein W is a v olyoL 62, The phannaceuticalcomposition of claim 61 wherein said. polyol is a carbohydrate. 63t The phanaeeuti.cal composition. of claim 61 wherein said polyol is maititol, sorbitol, xylitol or isomalt. 64, The phamiaceutical composition of daim 61, wherein said polyol is sorbitol 65 The pharmaceutical compositions of clain 61 wherein said polyol is inositol. 66. The pharmaceutical compositin of any one of claims 59-61 wherein p is 2, 3 4, 5 or 6 67, A compound represented by structure 1, or a pharmaceutically acceptable salt th ereof R51 Rz Ft A]j SN R R 2 W wherein A is a heterocyclyl or heterviy optuonally deuterated containing from S to 12 ring atoms, iniuding X and N. which is optionally substituted with 1- substituents, independently selectedfrom the group consisting of alkyL alkeny. aikynyl ary, heteroaryl aralkyi, heteroralkyl, halogen, nitro, cyano, sultfnic acid, alkylsuifoxyl, arvuitbx heicroarylsfubxyl, aralkyisulfoyv he teroaralkyIsulftxy, alkenysulfxyl, alkynyisulfoxyl, alkylsuafonyL, arylsulfoyl heteroaysulfonyl, - 21 - aralkylsulfonyheteroaralkyisulfony1 alkenyisulfonyi. alkynylsu fonv hydroxyi, alkoxy arvoxyl heteroaryloxylara kyoxy, hezeroaralkyloxy alkenyvoxg, alkyny loxy iol, alky thio. aryrthio. aralky Ithuo, heteroaral kylto, aienytthio. alkynyithio, fornmyl, acyi. formyloxy acyloxy, formyvthio at.y lthio, amine, aikyiamniine, aryliamnili eteroarvlamn, aralkylrinn, heteraarakyiamine, alkenylamine, alkynylamne formyarnine, acylatminecaxyi, alkyloxycarbonyi. aryloxycarbonyl, heturoaryloxycarbonyiaralkyloxyearboni\ heteroaralkyloxycarbonyl, amido, alkylaminecarbonyt rylminecarbonyi. Iheteroaryiaminecatbonyd, aralIkyarinecarbonyl .ad heteroaralkylamineearbonyl X is I, S, N or N(R); xi R Z is or an isostere (of a carboxyl group; X s Oor S; X is Oor S; R is hyirogen akyl, haloalkyl, alkenyl, alkyny1, carbocycly , heterocyclyl, heterocyclyhdky aryl, aralkyl, heteroary' heteroaralkyl.fused bicyclyl. carboxyalkyI, or arylalkenviaryh R2 is hydrogen, lowest alkyl, lowe aeny lower akyniyl halogen hydroxyl, amine. carboxyl, cycloalkyl aryl, hetemoaryIaralky heteoagrak4 cyano. or nitro; R is hydrogen, lower alky, lower alkenyi, lower alkyny, halogen hydroxy anmine, carboxyl, eyeloakvL ary. heteroaryi aralkyi, heteroaraikyt, eyan0 or nitro; R selected independently for each occurrence ron dhe group consisin of hydrogen, aLkyL alkenyi alkdnyI, aryl heteroaryl, araikylh b eteroaadaky. halogen, nitro, cyano sulfonie acid alkyisuifoxyl arylsulfbxyi. heteroarylsutfbxyl aralkyisultbxyl heteroaralkylsulfoxy kisulfoxyl, alkynyisulfbxyi, aikyisulifonvi, arvisufomny hetemaryisul fonytI. aralkvyiufonyt,. heteroaralkyisifonyl, alkenysifnyl. a lkyaisaliny hydrox vi, a]koxyl, aryloxyl, heteroaryioxy, araky loxy. heteroaralkvloxy.alkenox, alkynyloxy thioi, alkyI thio, aryihio, araikvhio, heteroaralklthio, aikenylhio, alkynyhhio. form, acyl formyloxy.acyloxy; formIythio. acylthio, amine, akyamine, arylarnine heteroarxlanrne, aralkylhnrine, heteroaralkylamine. A kenyianuine alkyny ane. formylmine, acylaminc. carboxyl, alkyloxycearbonyl arylox ycarbonyl, h eteroarylxycarbotnyl, aralkyIoxycarbonl, heteroakyoxycarbonyi amido aiky laminecarbonyl4, armnecarbs. .&onyl, he caaramnecarbonyi. araikylaminccarbonyl, and heteroaralkylaminecarbonvl R' i hydrogen or lower alkyl and mi is 1, 2 or 4. 68 The compound of elaim 67, wherein A represents h 69. The compound of elaim 67, wherein A represents heteroaryl, 70O The compound of any one of claims 6769, wherein A is radical of a monocyclic ring having 6 or 7 ring atoms. 7 y1he compound of any one of claims 679, wherein A is a radical of a bicycLe ring having 9. 10, 1i or 12 ring atoms. 72 The mpond. of any one of claims 67-71 Y.inrcin X is 0 731 Th compounof any one of claims 67-71 Yhrein X is S 74. The compound of any one ofl aims 67- 1, wherein X is N. 75. The compound of any one of claims 67717 wherein X is N(R>. 76 The compound of claim 67, wherein A is pyrroidinyL imidazolidinyl, thiazolidiny isothiazodin o"xazolidinyt oxadiazolidiny, . iperidinyl, piperazinyti thiomorpholinyl or morphohnyt 7. The compound of claim 67, wherein A is inidazolyl. pyrazolyl, isoxoazolyi onzlyastzololyi thiazolyi, oxiyi, furazangil, oxudiazolyl, tlhiadiazolyl triazolyl dithiazoly, diazinyl, oxazinyl, thiazinyt, triazinyte n d y or th iazepinyiL 78 The compound of any one of claims 6747. wherein A is substituted with 1 A substituents independently seicted from the group consisting of lower alkyi, hal oger C nitro cyanO SUfMniC acid, hydroxyl, alk oxyl, !04. alkydhio, fonyi aeyI, formyloxy acyloxy. formltvhio, aevhhio, aine alkylamnine. foylaniu, aeyaImne and arhoxyl 123 - 79 Tecopud fay n f clamt,7 hrinAi usiue with 1 substi tent independendy selected from the group consislng of lower alkyl halogen, nitro, cyano sulfoni acid, hydroxVL aloxylthiolalkyvio, formyl, acyl, fonry ox, acylouy, fornyhhio, acylhio, amine alkylamine femiyunine, acylanune and carboxyl 80 le compound of any one of claims 67-77 wherein A is not substituted. 8. The compound of any one of claims 67--80, wherein R is hydrogen or lower aikyL 82. The compound of any one of claims 67-80, Yhrein R is hydrogen. 83 The compound of any one of claims 6780. wherein R3 is hydrogen or lower alkyL 84 The compound of any one of claims 67-0. wherein R is hydrgen 85 The compound of any one of cims 67-84 wherein R is lwer alkyl and R is hydrogen, 86 The compound of any one of claims 6784, wherein R is hydrogen and R is lower alkyl, 87 The compound of any one of chrims 6784 wherein R is hydrogen; and R' is hydrogen. 88 The compound of any one ofla ains 67-84 wherein m Is i1 89. The compound of any one of cla ains 67-84 wherein m is 2. 90 The compound of any one of claims 67-84 wherein m is 3, 91. The compound of any one of claims 6784 wherein m is 4 92 Ie cornpound of any one of clais 67$91 . where i is seected independently for each occurrence front the group consisting of hydrogen, lower alky Ihalogen rnitro, cyano, sdfonic acid, hydroxyl alkoxy, thio alkylthio, formal, acyt formyloxy, acyloxy, formy o hio, amine alLy lamine, formy famine acylamine and carboxyl, 93. The compound of any one of claims 67-91, wherein R> is hydrogen, 94 The compound of any one of claims 6>93,whereinl 7is carboxyl.. 95 lthe compound of any one of claims 6793, wherein Z, is a carboxyl isostere. 124 - 96 The compound of any one of cairms 6>93, whereinZ is etrazolyl oxazolidinonyi. sulfonic acid, sulKni acid, acybulphonamide/phosphoMe ac-d phosphinic acid, hydanton, pyrroIidione. 3-isoxazolyl, or boronic acid. 1 R 97, The compound of any one of claims 6793, wherein Z is 98 The compound of claimt 97, wherein X' is 0, 99. The compound of claims 97, wherein X' is S. 100. The compound of any one of claims 97-99, wherein Xk is O 101 The compound of any one of claims 9799, wherein X 4 is S. 102. The compound of clain 97, wherein X is 0; and X, is 0. 1013 T[he compound of any one of caimhs 97%10.2 where Rk is hydrogen. 104 The compound of any one of plains 97- 102. wherein Rt is lower alkyl. 105 The compound of any one of claims 97 102. wherein i is OH "' NOO - ~~~ ~ Z I.~ IH I li t .. A N '\Q. Nx HN O. HN #O \ (' O0 25 Y 0 .> D 0 uk. 05I -125$- S H 106. The compound of any one of claims 9' 102. wherein R represents an aliphtic group wich is hydrolyzed to cartoxyl under physiologicaiconditions 107, A compound of formula 11 or a pharmaceutieay acceptable adt thereof W R' It wherein, idependenfly for each occurrence, W is a polyoI or polythiol; p is 2-00 inclusive: R'- X1 Rb A N N N R' Ri is R2 RI and is eiher appended to the polyol through an oxygen atom of the polyol or is appended tone no ythi through a Sulfur atom of the olythiol A is a heterocyclyl or heteroaryl, optionally deuterated.containing frorn to 12 ring atoms, icuding X and N:hich is optionally substituted with ,A substituents, indenencty selected frorn the group consisting of alkyl, alkenyt alkynyt arylq heteroaryl. aralkyl, heteroaralkyl haogem nitro, cyano, sulfanic aid, alkyktdxy, aryIsuffoxyi, hetenoaryhIsdfo xy ara ky sulfoxylheteroa ralkIdsulfxyt alkenyisalfoxVy alkynylsitxyi. alkylsulfuyr, aryislfony L heteroaryisulfonyi, aralkvisu lfonyi, heteroaraikyisu fo&y alkenylsulfonyl. alkyn ylsul fonyl, hydro>xyL aloxy tyloxIy, heteroavryloxyl, aLkylovy heterara lkyloxy, aLkenyloxy. S26- alkynyvloxy, thiol, alkylthio oaralky thio, heteroaraikvithioalkenylthio, alkyythio, fonyI, acyl. tobmyloxy, acyloy, fornyithio, acyhlhio, armne aily Iamine. sy Ianne. heteroaryl amine, arakylamine, heteroaralkylamine, aiLkenylarninc alkynylaniine, formylamline acyaunine. carboxyl, alkyloxyearbonyL ary lox carbtonylI hetemoaryioxycarbony Iaralkyloxycaibonyi, heteroara ikyioxycaibonyl, amido, alkyiaminecarbony I arylamnuec arbonyl. heteroaryvinsrecarbony I araikyiamnnecarbonyv and hleteroaralikyiamnineearhonyi; X is O, S N or N R); X is O or S; R is hydrogen, atkyl, haloalkyl, alkenyl, carboycly, heterocyl letrocyclylalkyl, aryl, aralkyl thmaryl, h eteroarabkyi fused bicycly, carboxyalkyi, or arylalknwlaryP Ri isV hydroge lower aky lower adkenyL lower alkyniyL halogen, hydroxyl. amine; carboxy4 cyoaky, ari heteIb yroarl, aralkyl heteroarakyl cyano, or nitro; R' is hydrogen, loweralk> 1 In.' alkenyv lower alkynyl halogen, hydroxyl. anine, carboxyl, eycloalkys aryl, heteroaryl, aralkyi, heterorakyi, cyano, or intro; R' is selected independ ni y for eacd occurrence from.. hegroup consisting of hydrogen alkyl, aike ynyly aryl, heteroaryl, aralksl heteroaralkyI, halogen, nitro, cyano; sutfonic acid, alkysulfoxyl, arylsudfoxyl, beteroaywlsidfoxyli aralkysuftxyleteroarasisulfoxyI alkenyisulfoxyl, alkyny.suifbxyl, alkylsulfbnyl, arylsulfonyl, heteroarylsulfonyl arakyisulfonyI. heteroaralky Isulfng. alkenykulfbngL aikns uI fony hydrxl, ilkoxyl, arvIoxyl, heteroaryloxyL aralkyloy hloxy a.enyloxy, alkynyloxy, thiol, aylthio, iavyhthio. aralkylhio, heteroaralkyItlhio, alkeny lthin, alkynyihio, fornyl, acyl formyloxy. acyioxy formhio acydthio amine, alkylaminsi arylamine, heteroarylamine, aral kylIan-ine. heteroaralkylanine aikenyilamine alkynyiamine. foroy lamine, acylamine. carboxy I lY okycarbony i, ary boxycarbony i, heteroaryboxycarbony, a ralkyloxyearbontv hleterrakyloxycarbonyt amido, alkylarikecarbonyK arylarinecarbonytetrOarylaminecarbor araikyaminecarbonil, and heeroaralkvlaninecarbonyI RY is hydrogen or lower alkyt and - 127- m is 1,2 3 Or 4 108. The compound of claim 107, wherein W is a polythioL 109. The compound of clai nn0 wherein W is a polyol, 1I. The compound of clan 10)9, wherein said polyol is a carbohydrate. 11. Ihe compound of claina 1)9. Wherein said novol is maltitol sorbitol xyio or isonalt, II2. The compound of claim109, wherein said polyol is sorbitol DII The compound of clain 10, wherein said polyol s mositoL I14 The compound of any one ofclainis 10-109, wherein p is 2, 3, 4 5, or 6, I5. The phamaceutical composition of any one of claims 11 -66, wherein the niacin analog has an EC% for reducing sermn cholesterol Dt andor triglycerides which, in the average human patient population is no more than 20 percent of the half maxinal concentration of the nacin analog Which would cause cutaneous vasodiation (lusi ) in te average hman. patient population, 6. The phannaceuticai composition of claim i15, wherein th EciI of the niacin analog Or reducing sermn cholesterol, , DL and/or triglycerides is no more than I percent of the half maximal concentration of the nacin analog which wmud cause cutaneous vasodilation (flushing) in the average human patient population 117, The pharnaceuticai composition of any one of claims 1 1-66 115, and 116, wherein the niacin analog has an EC(, for reducing serum. cholesterol LD and/or triglycerides which, in the average human patient population, is no more than 20 percent of the concentration of the niacin analog which would cause increases in serum levels of aspartate amiunotumnsf erase (Asf) and alanine aminotransferasc (AIX)euring discontinuation of administraion of the pharmaceutical composition, I18. The phannaceutical composition of any one of claims 1 66 and I1 117 werein said niacin analog when admin itered once per day is effective in reducni a serum lipid without causing treatmea.1-imitin(gi hepatotoxiciy and (ii elevations in uric acid levels or glucose levels or both, that would require sch treatment to be discontinued, - 28 I19 The Ohannaceutical composition of any one of caims 11 66 and I15- 118, further compnrisg a stanint 120 The phanaceutical position of claim .19 whrin the station is sealed from the group consistng of atorvastatin, cerivastatn fluvastatin, lovastatin, evastatin, pitavastatin, pravastatRn.orosuvastatin and sis n tin 121, The phamnaceutieal composition of any one of claim 11 -66 and 1 I$-1 1, further comprising at least one additional therapeuti'agent selected from the group consisting of 1. j IISDA inhibitors, SfT transporter inhibitors ET2cagonists ~ LO or FL AP inhibiors, ualucosidase inhibitors.A I enhancers, ACC inhibitors, AeylCoAcho lesterol (tacyltransferase inhibitors, acyl-estrogens, antidiabetic agents. antidyslipidemic agents, anthhypertensive agents, anti oxidants, Apo A.] mnaetics Apo A I. modidators Ao E oprotein-B sccretionrnierosomal triglyceride transfer protein apoiB/MTP) inhibitors. appetite suppressantsaspirin, 3 agonists bile acid reabsorption inhibitors ble acid sequestrants, bombnesn agonsts, BRS3 gonists C antagonistsnBerse agonists, CCKA agoists eholestero absorption inhibitor, cholesterol transport inhibitors. cholesterol etr transfer protein (CETP) inhibitors, CNTF, CNTF agonistsmod ulators a combintion ofezetimibe and simxastatin and/or atorvatatin CSL- .idehydroepiandoserone deli pidated HDL, DOOAT antsense oligos, DOAT I inhibitors. DGAT2 inhibtors, dicarboxylate transporter inhibitors, dopamine aqonists, DP receptor antagoists. ezetinibe. FAS inhibitors, fatty acid binding protein (ABP) inhibitors; tatty acid transporter inhibitors fatty acid. transporter protein (FAT?) inhibitors, flush inhibtors FXR receptor modulators galanin receptor antagonists gemcaben ghreiin antagonists ghreiin antibodies, GLP- I agonits gi ucagoni ike peptide-I receptor agotusts, g ucocorticoid agonists/anatonists glucose transporter inhibitors, HDL mmetics, NM CoA reductase inhibitor compounds, HMI N1C-CoA synthetase inhibitohormonesensitive lipasc antagonists, human agoutui-related prote in (ARP\i)l- antagonists/inverse agonists, inorganic cholesterol sequestrants fL-41, paquistat. leptin gonistsnod ulators. leptins, lipase inhibitors, lipoprotein synthesis inhibitors lorapoprant, low density Upoprotein receptor inducers or activators, Lp(a) reducers LXR receptor agonists lyn kinase inhibitor. Mic3r agonists, M 4r agonists. I C1U 1R antagonists, MCH2R argonists/antagonistsmein concerarating hormone -129 - antagonists mGiuR5 antagonists nmicrosom al triglyeride transport ihibiors, mionoanine reuptake inhibitors natural water soluble NE transporter inhibitors. neuromedin U receptor agonis ts, .europcptideY antagonists, ndacin or niacin receptor agonists, nicatincic acid. noradrenerge anorectic agents, NPY I an tagonists NPY2 agonists, NPY4 ago nists, NPY5 antagonists, nonsteroidal anti inflamnmatory drug (NSAID) agents, omega43 fatty acids, opioid antagonists, orexin rceptor antagonists, PDE inhiblikrs plhentermnie, phosphate ansporter mihibitrs phytopharmn compound 57 plant stanols and/or fatty acid esters of plant stanols platelet aggre i ihbitors, PPAR-cr agonists, PPA1R agonists PPAR6 parta agonists, sPPARy agoniss probucol., renin angiotensin inhibitors., reversed-4F, SC1)Iinibitors serotonin reuptake inhibitors. S(GLT2 inhibitors, squalene epoxidase inhibitors squalene synthesis inhibitorssterol biosynthesis inhibitors, sympathonimetic agonists, thgj'oid hormone 0i agonists. thyiOnumelltic agets topiramate, triglyveede synthesis inhibitors UCP-I activators, UCP-2 activators, UCP-3 actiators and urocortin binding protein antagonists, 122 A method of treating hyperlipidemia hypercholesterolemia lipody trophy, dys ipidemia' atherosclerosis or coronary artery' disease comprising the step of administering~ orally to a patient need thereof a therapeutically effective amount of a compound of any one of claims 67-114, or a pharmaceutical composition of any one of claims 11-66 and 11 5-12 123, A method of treating metaboic syndrome, obesity. fatty liver disease, or diabetes. comprising the step of administering orally to a patient in need thereof a therapentically effective amount of a compound of any one of claims 67114, or a pharmaeeutical composition of an'y one of claims i1-66 and 115121 124, Ar mthod of raising serum high-density ipoprotein (H-DI.) levels, comprshig the step of administering orally to a patient in need thereof a. therapeutically effective amount of a compound of any one of claims 67-114, or a pharmaceucal composiion of any one of claims 1-66 and 11 5-121. 125, A method of lowering scrum low-density lipoprotein (LDL) levels or lowering serum lipoprotei n (a) levels, comprising the step of administering orally to a patient in need thereof a therapeutically effective amount of a compound of any one of - 130 - claims 67-114, or a pharmaceutical composition of any one of claims 11-66 and

115-1211 126 A method of treating congestive heart Ilfaure, cardiovasca disease hbypcnension, coronary heart disease angina, pellagra, Hartnup's syndrome, carcinoid syndrome, arterial occlusive disease, hypothyroidism, vasoconsticionosteoarthrltis, rheumatoid arthritis, Alheimers disease, a disorder of the peripheral and central nervous system a henatological dis ese, cancer, inmiann. a respiratory disease or gastroenterologcal d comprising the step of adniinisterin.goraly to a patin in need therof a therapeuncaly effective amount of a compound of any one of claims 67- 114 or a pharmaceuticals composition of any one of clairts 11-66 and I154 21

127. The method of any one otclaims 122-126, further compriing co-adrninister oraly a therapeutically effective amount of a tatin

128. The method of claim 127. wherein tch station is selected frm the group consisting of atorvastatin, cerivastatin, uvastatin, lovastati., movastatin, pitavasta tin. pravastatin, rosavastatin and si mvastatin,

129. The method of any one of claims 122-126, frher omprising co-adnmnistering orally a therapeutically effective amount of at least one additional therapeutic agent selected from the grup consisting of I11ISE?- inhibitorsE 5T transponer inhibitors, 51fle% aglonists, 5- (O or FLAP inhibitors.uicoside inhibitors, ABCA I enhancers, ACC inhib itors, AcylCoA cho lestemo O-acy Iransferase inhibitors acyl estrogens, antidiabetic agents, anti-dyslipidemic agents anti hypertensivea gents anti-oxidants, Apo Al immetics, Apo A I modulatos Apo E nimetics, apoIi poprotein-B3 secton/microsoma I triglyceride transfer protein {pm BMTP) inhibitors, appetite suppressants, aspirin, 3 agonists, bile aci reabsorption inhibitors, bile acid sequestrarts, borbesin on agoists, lC, antagonists/inverse agois CCK- agonists cholesterol absorption inhibitor, cholesterol transport inhibitors, cholesterylester transfer protein (CETU1Piinhibitors, CNT.CNTP agonistsnodulators. a combination of ezetimibe and sinnthstatin and/ or atorvastatin, CS-I dehydroepiandrosteronedelipidated HDII DGAT antisense oligos, DGAMl inhibitors. DGAT2 inhibitors, dicarboxylate transporter dopami ne agonists, DP receptor antagonists czeuimibe FAS inhibitors, 131 - Iatty aeid binding protein (FABP) inhibitors, fatty acid transporter inhibitors, fatty acid transporter protein (FATP) inhibitors flush inhibitors FR receptor modidators, galanin receptor antagonists, gencabene, ghrein antagonists, ghrein antibodiesGi P1 agoniists, glucagonalike peptide I receptor agonists, gucocorticid agonists/anagonists gucose transporter inhbitors, I-IDL muimetics, HMG CoA reductase inhibitor compounds/ HM GCoA synthetase inhibitors. hormone sensitive lipase anagonists human agoutilated poteins(AGRP, antagoristsdinerse agonists, inorganic cholesterol sequestrants 4f, lapaquistat, leptin agonists.odulators. leptins, lipase inibitors, ipoproti syinth.sis inhibitors, lorapoprant, low density lipoprotein receptor ind acers or activators, Lp(a) reducers. ,CR receptor agonists yn kinase inhibitor Mc3r agonists Mcdr agonists NCH R antagagos. MC2 nists/antagosts, me ianin coneentratig homon antagoists i CiRk antagonists, microsomnal trigyceri de transport inhibitors, monoamine reuptake inhibitors, natural water soubeibe NE transporter inhibitor, neuromedin U receptor agonists, neuropeptide-Y antagonists, macin or niacin receptor agonists reoinic acid, noradrenergic anorcfic agents. NPYI antagonists, NPY2 agonists, NPY4 agonists. NPY5 antagonlss non-steroida anti inflammatory drug (NSAID) agents, omega- fatty acids, opioid antagonists, orexin receptor antagoists PDE inhibiors phentermine, phosphate transporter inhibitors phytopharm compound 57, plant stanols and/or fatty acid esters of plantstanols, platelet aggregation inhibitors, PPA R-. agonists, PPAR-8 agonists .PPAR-8 partial Agaorst sprobucol. ream angiotensin tnibitors reversed4F, SCD-1 inhibitors, serotonun enptake inhibitorSGLT2 inhibitors, squalene epoxidase inhibitors, squalene synthesis inhibitors, sterol biosynthesis inhibitors, sympathomnmeti agonists, thyroid hormone agonisents, synthesis inibitors, UCP~ activators. CP-2 activators UCP-3 activators, and urocortin binding protein antagonists 130 The method of daim 129. wherein the at least one additional therapeutic agent is selected from the group consisting of an Hl-MC4I'oA reductase inhibitor, a cholesteryester transfer protein (CETP) inhibitor, an NSAID, a fibratea proprotein convertase subtilisin/kein type (PCSK9 an inorgan ic cholesterol sequestrant an AcylCoA:choesterol (acyltransferase inhibitor a PPAR agoist, a PAR R agonista bile acid reabsorption inhibior, a triglyceride synthesis inhibitora. -132 - hipoprotein receptor activator a DGAI T inhibitor, a SCO-1 inhibitor, a lpase inhibitor a DPreceptor antagonist an apo A modulatoreholesterol transport inhibitor meformin, niacin receptor agon ist, and DI)PP-V inbibitar, 131, The method of claim 129, wherein the at least one additional therapeutic agent is seected from the grou p consisting of an M - reductase inhitor, cholesteryi ester transfer protein inhibitor. aspirin an NSAID. a fibrate a DP receptor antagonist, ezeinibe, and a combination of ezetimibe and simvastain and/or atorvastatin, 132, The method of claim 130, wherein the at least one additional therapeutic agent is an H- MGCoA red uctase inbbizor selected fron the group consisting of atorastatin, cerivastatin; t uvastatin, lvastatin. pitavastatin, pravastatin/rv astatin, rosavastatin, and sinvastalatin,

133. The method oeaIrn 132n wherein the -IMG CoA reductase inhibitor is sirvastatin or atorvastatin. 134, The method of clairn 132, wherein the at least one additional therapeutic agent is a cholesterd ester transfer protein inhibitor.

135. The method of cai 132, wherein the at least one additional terapeutie agent is ezetimeib aspirin, ofen acetaminophe. or a combination of ezetimibe and sinivastatin andsor atorvastati, -133 -