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Title:
UREA COMPOUNDS AS GKA ACTIVATORS
Document Type and Number:
WIPO Patent Application WO/2013/086397
Kind Code:
A1
Abstract:
The present invention relates to compounds, to pharmaceutical compositions comprising the compounds, to a process for making the compounds and to the use of the compounds in therapy. More particularly, it relates to certain glucokinase activators of Formulas 1 and 1a, useful in the treatment of diseases and disorders that would benefit from activation of glucokinase.

Inventors:
HOUZE JONATHAN B (US)
DRANSFIELD PAUL (US)
PATTAROPONG VATEE (US)
DU XIAOHUI (US)
FU ZICE (US)
LAI SUJEN (US)
PARK JAEHYEON (US)
JIAO XIANYUN (US)
KOHN TODD J (US)
AICHER THOMAS DANIEL (US)
BOYD STEVEN ARMEN (US)
BENCSIK JOSEF (CA)
CONDROSKI KEVIN RONALD (US)
HINKLIN RONALD JAY (US)
KRASER CHRISTOPHER F (US)
PRATT SCOTT (US)
SINGH AJAY (US)
WENGLOWSKY STEVEN MARK (US)
BOYS MARK LAURENCE (US)
CHICARELLI MARK JOSEPH (US)
MOHR PETER J (US)
CARDOZO MARIO G (US)
Application Number:
US2012/068547
Publication Date:
June 13, 2013
Filing Date:
December 07, 2012
Export Citation:
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Assignee:
ARRAY BIOPHARMA INC. (3200 Walnut Street, Boulder, Colorado, 80301, US)
AMGEN INC. (One Amgen Center Drive, MS 28-2-CThousand Oaks, California, 91320, US)
International Classes:
C07C275/00
Foreign References:
US20090247526A1
US7186725B2
Other References:
KUMARI ET AL.: 'Comparative Docking Assessment of Glucokinase Interactions with its Allosteric Activators' CURRENT CHEMICAL GENOMICS vol. 2, 2008, pages 76 - 89
Attorney, Agent or Firm:
SKERPON, Joseph M. (Banner & Witcoff Ltd, 1100 13th Street, N.W.,Suite 120, Washington District of Columbia, 20005-4051, US)
Download PDF:
Claims:
A compotmd. of Formula la:

R.1 is H, alkyi, aitayi halctiilky , alkfixy, hyiifgxyaikyi, arairioatky!, a!koxyaikyl hydrttxyalKoxy&ikyi, a1¾:oxyca oswla«iis5iiijSk i, eydoaSkyl, cydrialkylalkyl. asyl, atalkyl heierocydyl or heterocydyialkyl, wherein the ryeloaJkyi ary!. or keferoeydyl ring m cydoalkyi cydoalkyialfcyk aryl, aralkyl heferocydyi or teerocydySalky! is ¾ftsub$tU¾ted or sabsiimted wish ofte or two subsiitti nts isdejasenitesity .selected .ftosa hydroxy, alkoxy. alkyi oxo or ha!oi

K h it iiikyi. or halo;

R' is H, halo, alkoxy ixmyl, aima ar oswl eyaoo. yanoalkyS, alky!earhoiiyk

hydroxys! koxyaiky I ydroxyalkoxyhaioalkyl, alkoxyalkoxyhalosi!kyl, alkoxyalkoxyalkyi, afaikoxyalkeayt hydmxyal¾oxy¾te>yls afalkoxyaifcy»y}, hydroxyalkoxydkytsyl,

alkoxycar ooyialky.l, alkylsulfonylalkyi alkylsutfoiry aikeoyi, alky!sulfimylalkynyl heteecyc!yia!kenyl detocy ylalkyfiyL aikoxyaikyrtyiJwdrttxya!kyHy! or XR4 ;;

X Is a bos¾i -0 ·, or S(0)K

rs is 0. ! , or 2;

R4 & alkyi hydroxyalkyl ha!ealkyl alkoxyalkyi alkoxyalkesyl, alkoxycaifeoftylalkyl, carboxya!kyi affiinocarisoftylalkyl, alk laaUHocarijoaylalkyl, aryl, eydoaikyl, yclealkenyi etoocyc!yk aeaikyi araikoi!yk aryk!kyoyi, cydoaikySalky!, cydoaikylateryl,

cydoa!feyiaikyiryl. heiefocydykdkyl or beterot:ycly!caj¾o«yla!kyi: herein die flag to :R* Is ofisiibstltuied or subst wied wish 1 -3 subsdiuoiis imk^ mfcmfy e! cfed .from ft. afkyi fcafo, haioalkyi hydroxyi alkoxy, haloalkoxy, atyl aikylssiifoiryi, hsteroeydyi aoxirioxuffoiiyl, alkyiarnioosaifofiyS, eyafio, alkoxytarhoHyi, carhoxy, amino, RE -alky!, a!koxyaikyi, hydr xyalkyl or RSR!¾€(==QS where * Is alky.) a ad R* is alkyi aikoxyalky!, arniooaikyi or si kyia«¾«oal.kyl or ksre R* and Rb lageiter wilh die t irogen form a heterocydy! flag uiKtihsiiiiri&d or s Miioued with aiky!;

5 Js myl, ara! yi, heterocydyiaikyL eydoalky], or hCterotydyl. wbes m R.s ¼ mryibsihmed or substituted with. i^.sahsaituwas lsdep$>«da».ly selected from alkyi, alkoxy, hydroxy!, halo, Moskyi cysno. aikoxyearboiiyi, carboxy, acyL cydoalkyl, klmxyeiy.l hydroxyaikyi alkoxyalliyl, oxw, -N8R , alfcyi-NRR or K;ii: C(==0) vvte R* is aikyl and R¾ is aikosy¾ik l or soiinoaikyi;

where R and R is H, alkyi, acyl teterocydyi hfiierocyciyiaikyl or cyeloa!kyl, where the taerocyciyla!kyi cydealkyi and heterocydyl .rings are «osufeso*t«ied or substituted' with !-3 substi brents independently selected from aikyl, alkoxy, hydroxy, halo, haloaik i cyano, or carboxy* or R and E can together with the N fmn heieiocyd !:

R6 is atyl. atalkyl, heterocydyL hdewcyeiy!aikyk or eydaa!kyL hefdn eac of Sh aforementioned nags is unsubstiuied or substituted with 1-4 substttuents independentl selected from aikyl. hair). haloaikyL aikoxy, alkosyearbeisyl, earhoxy, aroirkrc&rbonyl,

tererocydyiearbonyh cyano, cv ioaikyl hetefoeyciyl, hydroxyaikyL alkoxyiaikyL NR'R\ CH¾NRR : oxo or acyi;

Gi C o ;

L is G. S H, or CM,0;

isE flf L-Rs ; and

Fislior L-Rs;

provided

ft) when is R ten Pis L-R'\or

m whetr is L-Rsthen.P isH;

Cliij when G is M. then P is i„R(i;

fete provided when Rs Is R Rs is raethyl R* is li L is 0, sod P is H, tk Rs is fiot

isoqttlnoli«-6-y{« q isobn -iS !( 2 ·οχο··ϊ .g-dihydroqaino H-B-yl, 4-jteth l-2 ο ό-1.2- dihydroq«ir}oliii-6-yi, 2-«ieihyl -t>xo-i>2-dlhydt¾-i¾jquinollivS--yI< i »4-di«u l-2 -OXQ- - di dm(«i»oliH-6-yi S^jdoro-!nnetlv^ 5J-t¾fl«t>to-l,4- dimdhyi~2-oxn~.i .H-di)ivdroquisioHo-S~yl i -methyl- 1 H-½daxoi-5-yl, or 3-sie .l-3H- tmida^{4,5-h3pyr in~6-yl;

fetter provided, when R;i i R cyano or iodo. R? is R I, is G, and P is R then it i not

(substiluted ami«ocarboiryb-54id.oiyi:

fetter provided when R3 is R R" is H, L is 0, and P is H< then Rs is not substituted phenyl.8 (snbsfiruted u?ea 4-qninoiyl 7~suh.«it.»ted 1 ,2,3,4 strahydromphthyi or 4 -substituted oapki!tyi;

further provided when R3 is H, R' is H, I is niorpholiisyiethyi, I, is (I and P is H. then R' is oot

2·- (3 -tertbtrtylph¾iylamiso) -methyl- 5beftBio azoi i;

further provided when R3 is Br, Rs is methyl R2 is R L is 0: and P is R then Rs is sot 5,7- difiiiortvl ,3> rfed i^-ox6 Hii¾ di ^liwiift-6~ylt 5,7-dfi«o^l-met¾y-2-axo-4' iHiluQmn3ehi -di¾. droq»i»oiiii-6-y.l 5J-difiao«>- -etliyi -tnerhyl-¾-oxo ,2- di d quimdiR^

further provided hen .R:} is l~ s l» iH¾'raz8!- - .Rl is methyl, RJ is H, I. is O and P is H, ihen R3 isnoi L^ i-iH-pyrszo-S-yi;

farther provided w en R3 is i-methyl- iH-pyimoI -!>.yl R' ts methyl. R2 is H> L is 0, and P is H, then Rs is sot 2--oiethyl ·οχο·1 ,2-{Hisydmtsoq«h»lin»6-ylt 5J-dffn«jro ,4 -df«e i-2» xo- i ..Z-dEhydroqainolin-e-yi. or i -dJ¾aethyl-2-oxo · 1 ,2-^ii)ydroq«inotio--6-yl;

further provided R2 is not haio when R3 is H, R1 is met l, L is 0, P is H and Rs is 5-¾ai«o!ii i: further provided R2 is sot ch! ro when R3 is bromo. R{ is rneihyl L Is 0, P is H aod Rs is 5- q-dnoiinvi:

further provided R:i is not phenyl or reri-buiyl when L is 0, R8 Is 2-e 1~3-pyridyl 2-m¾hy.l-3- pyridyl or 2,6-din«stfiyl-3^y«dyi 3 is It R3 is S-pytidyk o, bromo, meitoxyefiroxy or trifiuoromethyl asd G is CH:

further provided Rs is .not.4"ffiei i.-2-imsx¾.zo] ifne i. wta B* is R Rs is g-pyndyiibio, P is 2- te l-3-pyndyioxy and G is CH;

farther provided R;i is .sot 4 -aieibyipheayl or 2^dim$ i he l or i 12 -d!hydroxy-2-p!!e:riyleiliyi when R! is methyl. R;i is H, G is N. sod P is 2-:ffie%i-3-pyridy]e y;

and a pharmaceutically acceptable salt thereof.

2.. Compound of Claim 1 wherein R! is C! 5 alkyl, C2.6 alkeayi Ct.s haloalkyl, Cs.s aikoxy, Cj ii hydroxyaikyl, C}.« affiino&ikyt C( s ai.koxy-Cj.(; alkyl, C?.$ hydroxyaIkoxy-€j alkyi, C¾. aryk€β,«, aryi-C3 s alkyi, 540 mentee lieterocydy! or §40 ioembered heteraeyclyl-Css aikyi , wherein die aryl or heferocyciyl riog is unsubsUtated or substituted with one or tw sH&siitaeots in epen ently selected from CMS a!kyi hydroxy, oxo or halo; arid a pharmaceutically acceptable salt thereo

3. Compound of Claim I wherein Rf is methyl, ethyl, propyl, aliyi teri-bntyi uifluora- erhyk Riethoxy, methoxyeihyi., rydroxyefliyi, hydroxy-propyl, 2,3-dihydroxypropyi, L2- dihydroxypmpyi. hydroxyethoxyethyl, BOC-ainiaoeihyl arateefttyi 2-hydroxyj)kmyl« iyf.3~ hydrosypk^yloieilyi, 44iydroxy-phenylm hyi, 4 1uoropbenyimeShyi phenethyl {«orp tjMs¾ yletyl, 2-pyrfdyl*Beftiy!, 3-pyiidyimethyi, 4- yridyh»othyl, ivmerhyi--2--.ox84,2-- dibydropyridinylmefhyi, imfdazol-5~ylmethyi, I -me {4a»dazo{~4-yi.«K»thyi I-methyMmidazoH-- yksethyf 4-a)ethyl-{mlda2ol--2-ylroe i, S-raethyl-hnidajso!-Z-y iseiliyl, 1 dimethylpyra¾til--4- yltrsedryi, 2-«j«hyirhia«i>lyl»5-iftdhyl, S»methyl-isexazol-3-ylt«t¾hyl of phenyl; and a

pharmaceutically acceptable salt theeof

4. Cotnpotmd of Claim 1 wherein Rf is 2-pyddylmdhy.l. 3-pyndy1 eif L 4- pyrldylisetlwi, -∞thyli»ijda2.>l:-2-yl««!tli l hnid8»> -5- lim? l. l-metb liH dax l-S-yime-b i !,5-diffie 'ipyra?t}i -ytoethyi, 2--tn«i1iylth az<>l--5-yifne *i> S-metbyllsoxazoKi-yl f)-ffied yl -2-oxo- i ,2-dihydf opyrfd-3-yljneti»yl or morphoba- ~yfeflx t; and & pharmaceuticall acce table salt thereof.

5. Compound of Claim 1 wherelo Rl is methyl; . and 3 ha m ceuticall acceptable salt iiienxtf .

6. Compound of Claim 1 wherein R" is H, methyl chlem, or fluoro; and a

phara& emicauy acceptable salt thereof.

7. Compound of Claim I wherein R" is H; ami a p'hanuaa'uilca'tly acceptable salt K-!Vof.

8. Compound of Claim 1 whereia R"' is .$(0)« R\ and a is 0, .1, or 2; and a pharosac «ically acceptable salt thereof,

9.. Com oaed of Claim 1 wh rein R-t is S ¾ ; and a pharmaceutically acceptable salt

19, Compound of Claim I wherein R.4 is€¾,« aikyl, C:j.e feydsxrxysikyl Gj.,s hatoalkyl C hydroxyalkyftyi C S aikoxy-C3.s alky f , C<.« alkoxy-C;;,* alkenyl C;.« alkoxy-C¾,s alkyoyl, C1 aiko yciir!j rtyiCj (1 aikyl, C(.g fcarhoxyalkyk 3ralmi«arb»Byl:-C 1.¾ aikyl Ci« alkylaminoairib nyl-Cj.i, aikyl g-is aryl, C%.i cycloalkyl, C¾. ? cycSoalkeny!., 5-10 ftiem ejed heiefocyelyl (¾.«} aryl-Ct-s alkyL Ce.{i> aryl-C;>.s aikenyi Que airy.l-C6.« aikynyl, C¾« eycloaikylCt.s aikyl, {¾« c do8lk i-C¾.<i alkeay.1 C3,i; i.:ycloalkyi-Ci.s alkyuyl, 5-10 membered hetocydyl-Cj.¾ alkyi or 5-10 numbere

heteroeyciyfcarbotiyl-Ci .6 aikyl; wherein the ayl, cydoaikyt, cycioa!kenyi or te xtty i l ring in R* is- uostrbstimtai ox substituted with 1-3 sabstiftieats independently select from C, .e aikyl halo, Ci-g haloa'ikyl, hydroxyl, Cj .¾ alkoxy, Ct-e acy Cj.g alkylsuifoiiyi, C¾ .§ aikoxyearbonyi carboxy, 5- 8 membered heterocydyl¾ cyano, C{ alkoxy-C3..¾ alkyK- Cf ,(i ydraxyalkyL C> * ha!oaikoxy, C- $ aikyS , aminosolfoayi, alkylaminosuiibnyi, or RaRh C(™0) where .Ra is . 6 aikyl and R!> is€<.δ aikyl, C{..& atkoxy-Cs.$ aikyl, G¾. amiooaikyl or Q (i alk l--Ct.-saxafnoatkyi, or wher &* and Rf' together with she nitrogen forre a 5 or 8 emhered heterocyclic ring onsuhstituied o substituted with€;..¾ aikyl: aruf -a pharmaceutically acceptable salt i!tereof.

11. Compou d of Cla iro 1 where o R* is .inetliajsycsrbouybselhyH o,

methoxycarbaoyfeifiylttiio, methfixypropyhfeio, 4-nietl50xyi3«t-2-yidrso, iwds'oxypropyiihso, 3,4- dl!iydroxybiUyli io, eatfeoxyeihylthk. (methy!£a»iiS(K:arboayl};8«;ihyltiiio«

({Umeili ia^atx¾rb«R i}jne 1i¾l , C3-hydtx>xy-3-me -j[buiyl}tkio> (2 -hydrf 4cy- g-iKeibylbutyl^Mo. difaoromethykhio, (tnorpfeo.M-i-4- .l)catix«yh»fttfey¾ to..0 -tet.-botoxye»ibe-iyl pipeiid!n-4-; l)roe' y!t }tf, {4-ifperfdinyl}tnsi ylt-d>0< (fetK¾ydra--2H->yfa£¾- -y5}is:¾ei¾ylihi i»(¾{rahydro"2H--pyria«-4--yl}ethyJ{liio). (5-mei yl- 2 oxadJa¾oiyl)5aetbyUte,.2-pyridyime 1tblo, 3.4-dlhydmxyey opefiiykk¾>> 4- h dfQji yi: 'iobiixy!thiO:, cyclopenteoykhio, phenyltfaio, faengsylthio, 2-pyridykbo, 2-chk*e- - pyridyltklo, (l^i efsdis i^^ rldy!imethyiihio, (l-methylplperidbi "yl-2-pyridyI}i^thy!tbjo, (i- hy o)£yetb«aylplpefidi» -yl-2-pyrid>4}im 'kirio, I · (I -hydroxyethyipiperidin-'l -yt)- 1- {2- pyridyl)methykhk. l-(l-iaeihyipiperidia-4-yl) -I -(2-pyiid i.raetljyk¾io, 1 - ($>ipejidin-4-yl)- H2- pyridyl)mertiy|tha (l-piperidbiyOtido,. (l-isftpTopyI)pipaidIs-4-yiihlo, (l-methylcarbowi)pii«.-ni¾tv 4-yif io, l-(^r^bwto ytarb iyi} i mdliv - llid0: (i-melfiyl fofty^pipertdki^-y!tliio, (l- isopropykartJonyI)pJp«idin-4 -yltfcio, S -{tne{hoxyc«ikonyl)piperld.l» -yirhk), ί

fmetk^x dh karfj ft li ip^idSiR-^- kbio, i · {dta^ ½mtoi^t 1)piperkii »y.lifek), 1 {«)«fhoxycarh>iiy%>ij>( din.--4-yiihlo> {l-CS-chloro^'d dia^^y^^rid ^- liihio, {i-(2- p rio5!d!ii !)pipef1di!i-4-yi}S !0:. f^iS^klorop razk-X-yOpiperidla^-yOih , I - (tert

uiM e8f iO:ii¥i}¾;n'o!Wiif-:3- kbs:o, 3--ri3e{hyiisox¾zob3[5.4--b:pyild!a---4-yk¾io or (eirak dre-^B- yxB o - 4 - y lib to ; and a pharmaceutically acceptable salt thereof.

12. Compoiiftd of Clakn I wherein is ittei oxypropyfoylfinyl, H«?thoxyprepylsttlfo«y i-{fed- j«iOi¾tarboisyS) !peridiri- yl^ l.-(ieit- aioxycaf o«yl)pipe0dia- - ylsuii oyt of S -pvTidy!su!fbijyi; and a pharmaceutically acceptable salt ttoroof.

13. €iM« fiisad of Claim I wl Rs is ORJi : ami a pharmaceutically acceptable .salt thereof.

.14. Cernpotmd of Claim 1 wherein 'J is methoxypropoxy, 2-{methoxy)proJCixy, bydimyethoxy, kydroxypropoxy.2 iydroxypH>poxy. ί t2-dikydr xypmpoxy. I iydraxy~2- meibylpropaxy. I-kydfoxy utoxy. pheaoxy, 2-Joethyl-3-pyridyl sy« or 3-oxetanylB?etbQsy; and a pfearmaceuikaliy acceptble salt thereof

15. Compound of Claim I whmtn B* s halo, cyano, Cj,8 hao&ikyi. s ¾ cyaaoalkyl C}.« alkoxytac oftyl, C^alk ic riJOByJ, 4-10 membered ketewyciykartKsiyl, amiftQearhofl t C¾.§ alkyl&minoca&oayl, C,.« alkyi C?.(s alkenyk C¾.¾ alkyayl, .g bydraxyaikyl. <¾« hydroxyalfceftyi, C¾.¾ hydroxyaikyoyl, Cj.6 alkaxy-Cs alkyi, Cs.« alk&xy-Cf.¾ a!koxy-C,«, alkyl C akoxy-C).* -alko y-Gt. s halaaikyl C:i .s alkox aikeftyl Ci .g alkoxy ¾. ¾, alkyayk C t .§ sraikoxy- C -f , 6 aikyl, ¾ydi¾xy:-C , .§ aikoxy-Cs s alkyl, h droxy-Cj-e aikoxy-Cte haJoalkyl, C*.s afaikoxy-C¾.¾ aikysryi hydroxy-Ct-s aikexy-€?,« aikysyl, arytexy-Cf i; alkyl C«.ie arylexy-Ckg aifceayi C&.^ aryioxy--t¾,8 aikysyl Ct# alkyl, C$.s crboxyalkyl C.§ alk$)xyt-art¾3n.yi-Ci.¾ hydroxyalkyi, mnincK¾rbo».y{- Ci.s aiSiyi, C>5 aSk iaminocar oiwl Ci.s alkyl, Cs s aUcyfsaii oyI-Ct.« alkyl, C».« a{kytsaifonyl-C2.s aikeayi, C{.« alkyfeulf nyl-Q^ alkyoyl, Cg.i» C3.6 eydoalkyl e cyckialteayi, 4-11 aiembereiS heteroeydyi, Cg. w aryl-C3.6 alkyl. C*.i9 aryi¾ alkenyl. Q » zr lC^ a!kyayL cydoa!kyi-Cl 6 alkyl, Cs-8 eydoalkyl- C{.« hydroxyalkyl Cs,« eycloaikyl-C36 aik»ftyji, (¾.<? eydo8lkyi€2.si aikyn l, 4·· 10 membeed heieftie cl l-CVs alkyl.410 memlsered heiefo^clyl-Q-s alkeayl, 4- i.0 memfceted hefefoiyci i-Ci.s alkyayl, or 4-10 -asem efed hetefoctlylc»bo«yl-Ct .s alkyl; wherein the aryi ydoalkyl eyeMke»ylof heierocydvi ring hi is tiWsd or subsilmied ltb 1-3 sabstiiuents iodff endera!y selected frooi Cj,$ alkyl halo, oxo..RO-, C}..& lialoslkyi, C{.« alkylsull nyfeojiije- Ci.s •alkoxy,.C¾ haloalkoy, hyds i¾y-Cf,salkoxy, C-i.ealkoxy-Ct.s atkoxy, Ci s .alkylsulfbay'l- aikoxy, C:i..ii acyi Cj.s alkyisuifoayl, C^ kox arbasyl, caitoxy, 5-10 embered heterocydyl 5-10 tnemhered he(erocycl lC.Mi alkyl eydoalkyl. C¾« cyc!oalkytCj.* alkyl, amino, aralnosulfonyi, <¾.« !k !ajniiKBalittiwi alkySsaii nyiammo, cyana, carfeoxyy RR -C^ alkyl l4 alkoxy-Ct-s .alkyl, C.t.ii a¾oxyamao-€i,5 alkyl, Ci4 hydroxyalkyl or R*l NCt-0)- where R" Is H. or C.Mt alkyl ami Rh is H, Gi.« alkyl Cs 6 bydroxyaikyi, C,.« aikoxy-CS6 alkyl C}.8 alkylsaifoayl- C £. alkyl. C,.* alkyisulfonylamioo- C,.e alkyl O* afttiaoalkyl or &* alky)-C}.8 asnhwalkyl or whsrs W and R^ together will! the nitrogen form a 5-8 tnerahered heteocydlc ring «as«bstit«ted or substftaled. Mh C.t. § alkyl: and a pharmaceuticall acceptable sab: thereof. lb. Compotmd si Claim 1 hcreis Rs is cyans, methyl, ethyl: propyl isopropyl, 2- methy!propyl 2,2 dlMShyl r yl 2-metbylbutyl, friBaorOHKtttiyl, 3,3,3- inflaoropropyl

flwotiffietbyi., fktoraprcjpyi, liydroxymedsyl, hydroxy ihyl ί -hydroxy -B-meihyleifeyl., 2-lrydro?ey--2- ethylethyl. hydf03£yp.ropyl, 2-hydfoxypropy.l l-frydroxyprop-2-vl i «2-dihydroxypf»pyl, bydroxybaiyl 2-hydmxyb tyl, 1 ,2-dihydroxyhytyl, 2-hydr0xy-2-«mhySbuiyl 2,2- (dibydroxyrneibyi) butyl l iydmx eih«x -2'¾roaK¾t.by 2-^ydroxyefhoxy}ethyi, 2- {hydroxyfi<hoxy)pri>pyl. {rnedioxy:aiei"byl)ed5yi :imiUho elbo.x -2-b avoi?lb l 2-hydfoxy- 2- medwlpsiiiyl 2-.bydf oxy-2-methy{hiexyi , 1 s2»dih droxype8tyl, 2'-k;nzyloxybu*y1, 2- bydrosyethoxybuyl, 2-by«iroxy-2-fne(hylprt>pQsypropyi

etben l, propeo-2-yl, propeu- i-yi. -pmp-1 - \~2 -yl 3-hydro¾'pmp-l -e» -2-yt, I - bydro y-2 ineiiiyiprop isyl 1 - I hydraxypropeiiyl tejv/y1oxyprope«y_l 2-eihexyeils.e!i l 2-bydroxyB«thylpmpenyl 2-ehoxyvloyl, viayl, meid>ylsulfi)«ylpropeayl, njethylsuIfoBylbutenyl, raedyy!sidfony!aHyi, « h!sulfosylb«i-2-ee-i- yl ί ,1 -djQxMoh¾rahydi¾-2H-l iop ai:^ -yteOie«yle^ sEboxycarb isyl !«e!byfcarboi3yl (4- tfetrabydro-pyraayDcaihOHyl, N-meth !^-fmt^teetby amleo ron l, N-iaetljyt-N-

111 (dimer.byiaft'iliioeiliyS-amiHocafhoayl, ttsi-butoxycar ayteetby, ί - hydroxy l -feri- hutox carkwylmetliyl, etboxyarborryipropyl, edioxytsrbony!dhyi. l-hydwxyeftyl- e&oxycart>onyl.elfey.l «M!fhyia«tinotarbtmyl»K!ihyI, meib>¾raiBOcarkmytet y1,

carboxethyi, carbaxyprapyi.

cyanoethyl. cyaoopropyt 4.5-dibydroxyperiiyl 4t5--diftydroxypem.-3-yl. hydr0xy½tynyl

bydfoxypropyiiyl ethyayi 2-cy tepropyhlftyI, Z- ydroxyeiboxybut-l-yji-i-yl 2 -hydroxy- 2- mediy!propoxypiopynyl beaxylox rop-l- H-J -yl fceuxyloxybat- 1 -y«- i -yl b&ftzytoxy¾thoxypr¾>i - y»-l-yl 1 -(l^:sydmxyeyc!openiyi}eihy{wL 3-jaethyl 3-oxeia«yieilwvi weihex but- !-¥«-· 1-yl tn ihoxypentya-I-y!, cyc!opertiyHdeiKiffiethyl, raifcykulfosylpropyi, meibylsulfoni ty,

ptewlthy!, ben¾yl ptieoylprop l S-ddoraphratylrafctbyl, L2-dihydroxy-2 beisy!i;il5ySf

1- yimeihyl, 4-Bo^ i eraz l~ i ed¾4> l-njedi feuJfon l- t eazri- !-yiiSiediyl, --meihykarbooyl- psp«ra2i« -ylraetbyl, morpho]«i-4-yimef¾yi, 3--me5ii I"ffiorpbBiii-4-- ]»ieihyL d)ioi arphabnometby! , (i4-toidoiidQa )rpholiao)infeih i.3-methyl-3-t3xeianyleiay!, (fetrdhydi-o-f«r-2-y.l)meAyl, ft«irBhydm-iar;-3-y!)inefhyl 2,5- to*oywadiB ~ ½

tetf&hydro ran- 3~y]Rjetbyi, t&raiiydmpyra - letbyl 2-hyi¾xymeiIryl--teira!iydr pyi¾si-3- ylimtfhyi 2-hyd«>xyme i-{eira dropyTaB-4-yhuerttyl.2--ffie )iix «5eS¾Yi-tetraSi dropyran--3- yfcoethy], '--me&oxym&ihyi- raby

1.3-dioxo]as:!-4 -pje y!.14-diox rb2--metbyL 1 J -d^oxidβte^bydrø-2H^ί¾kψyί3« - lH hyi? 1.1 - 51deca»-7-

cycl bittybiiei l, 3--oxn-€yt:!fibafylin i)syl. S-hydroxyl^rffl oramebyUydobutylmd!iyl, 3- hydraxy-3-mt^l-ftydoto3tyi-bydroxyi.ae i( tydoptms imedsyi . I-0iydmxycydopeiJiyl)fna l 1- i --{iftt exy dopeRi l}bffimoffl.i>ib i, cydohexyiraerbyl, 3- hydrox - eydohexylmedw!, 4- hydroxy < iok>xyln h i fydohexyiraefhyi,

ydopropy i-tert-b toxycarlwnyH-cydopropyl. -fitboxyxartonyicydopi-opyl, 2-(2-hydroxy-2- asetby jetfcyD -cydapropyl, ^hydroxvB!^thyi-cydepropyl, cydol iyl 2-ydroxy ydobtityl..2- oxocydobatyi, 3-- ydroxyyydobidy], 3--be8¾y¾xycycl¾)baty!, S-b^iz fexy-I-hytrbx c cfobirt^, 3- (2-fjydfoxy-2-ffi d}ySethyi}-cyc]ol>ttSyl! 3-feydfOxymeAy'l- ydot>atyl« 3-siboxycad»ayl- i-lwd!Oxy- cyciobuiyi, 3-etb>xycarbiiiyi-cydob«ry!, cydopeaiyL 3-hydfOxyriie byi.yclopeftiy!, 3,3··

S-carboxy -eydoptsdyi, 4 iydroxynw Uy<:Iopeniyl, 4- hydroxycydopefttyl S-bydroxycydopentyl, 2-¼di«xycydep*3dyi, S- droxy-J-roeth lc cfoiien^l,

2- cix«-cyc!opeoiyl, S-oxo-cyc! peniy!, 2 N i 4-M-ine iamiaacafte} l}c do «« !, 3-{N- i!ivi- N-i«e ¾mii¾Q€8fbon ]i:yclapeidyi , 3~ -|sopmpyl¾mbpc¾rtH)nyi) cy optfniyt cydebexyl , 4~ Iwdroxycydobe yl S-ta dro^c^lote^^ 4-hydi¾xy-4 ·«« !··

nz cydohexy.1, S-oxo-eycfoksyt cycloheptyl, tydopefttesyl 3- -hydroxy- -cydopertfeoy!, 4- lwdroxy«s^ihyi- -n« i< doisenien !, , -bfe(h «ii>xyw l}c'do eoi-2--en-I-yl 3-<ίχο- fydopettten l^-c rboxy-c ciopest-S-eft l 3-fe<¾)rop imBO arbtin lc dopen^2--fiin i, 3- { ydroxy«5efiiyl}cydop«oi- i -en- i -yi , 4 -- (b droxymedwlkydopaii I I -yl, 4 - (b dm me{ l ydo|^m--2-:^ »yI,-cyclohexen 4.4-di.aki l-cyck) exen l.4-rert- huiyl- eydehexeiiyi.4--hydmxycyclohexisiyl 5 %iroxycydehex- l.--ea- 1-yi.44>ydraxy e *yl-- cydofeexeayi 4-(2-hydoxy-2-methyelhyl}¾idohexenyl> 4-casrboxycycloh«x«ayl, 4'«tkxxycarbonyl- eydotexeoyi 4-(a Sdl$ I-ykittton l}^doh!e e»yi, 4fS-cyaao-a !diR-l - yl:casi)0?iy!}cyc!olieserfyI, -CS-fl^a-az-didin-l-ylarfKiny cdolie ^fi l 4-(3-saeifeyteaIf iyl- azeidln-l- iearbos ll c!ok en i, cydohepi oyt !,4-dioxaspiro4,5|i¾c-7-es-7-y1, .1 ,4- dsoxaspli |4,5|deciW5--7-yi.

3- ydroxy-3-oxt¾a»yI: 2-tohydro-ftir>i 3-teira¾ydm-faryl, 2-a«slli l-3 etiah df{j-furyi{ 2 m tiiyl- 24«rahydro uryi ^-fe dm yHKiih l^-tefcra dro-faiyi 2-4iydroxymet!¾-i eii¾hydro--f«r- -yl 2,2- >5'd¾ dmf«fan-2- .l 2-0Xopyn¾Kdi»- 1 -yi„ teirahydt¾pyran-4-y.l 2,2-dlmgthyli(Hra ytS.rapyfai¾- -yl, 5,5- dljndhyiieftah dfop raB-2'->i 2..2..S55-te{rarad yl~2 )-d dro¾faR^-yl , 4-n«oro-iera¾ydropyiat>~1 · yl -^usm-^-* rox -tetrab d{¾py^as--3"yl 4--itero-3--8setboxy--i(Sraliydropyraii-¾--yi 4- hydroxyt6{ra'ydfopyt¾«-4-yi, 4-¾ydroxyi«ifa}?ydropyran-3-yl S-bydroxytiiirafeydfopyras^i-yi 3,4- dj¾ydHx te{ra ydfoyrafi" -y1( 2- xo-teirs.hydropyraj5-4-y]., Sfrtra! dropyx3jv-3-y leia ydropyfan- 3,4-d!bydiO-2H- pyraft-6-yi 3,4 -d dTO-2E-pyi¾fi -5-yi, SJ-dtoeiiiyi-3,8 -dilydro-2H-pyi¾s>-4-yl 2;2- iiueif¾yi 3,6- dihydro-2H-pyi¾n-4-yt , 3,4-2H-dihydmpyraft-4 -yl l4-diaxi!spir {4ildec-7-- B-S-y], I J-dfoxo- iseihiazofidin-2-yl, 14-diaidd½trahyd«-2H-tbiopy aR-4--yi, 1.4-d!oxaH-2-yL 5-m>dioxy-Htdfeyt- 1 ,4- d.iox&a-2-?l« ^teί ίtfίoxyrøfk«yϊ-lt2 ,6-n«ίahydrø yrid· - l> i-.RSit yl-i.E.S -ietrah diTjp rid^- yl l-ft^byki5ifonyi .3,6-tetrahydropyfid-4--ylt I -(dtaeife lamtoocaf oji lj-i ^e- fefta ydropyrid-4'yl ^-{iJKiiho caf oR l^i.Z.S^^etra^ drapidd-^ ], :S-{fn«1 k3ffoesy!j- 1,2,3,6- feirafcydropyrid- -yi i-n hyl-pipeHdin-3-y.l i-ieit-b«toxycarboRyi-pipefidin"4:'yl, J- (dimei.iiylamlaocarboayl)-pipa1diiij-4-yI,

phenyl, 4-chloropheny -metbyiphenyi, 4-raet.byipfceayi

irlflaoi-oiffliiih iphw 4--†j4¾orofi«ihylphefiy!, 4-mdhoxy-3 ria»Oi¾medjyipiie«yi 3- dlilaororadls l-^-fiiiO!O henyi, 2-ffiedwfes fois S heo i S-mefhylsttlfday-lpbeny, 4- methylsul feij ipheswi . S-etbylsulfooylphenyl, 4-fflediyWfooylaminophenyL 3- ίϊ ί efi j ί sit Ioijy 3 a n ί iit hei } y ί .3-3m?thylanitooS'ufoa>lpkmyi, S-cyariophenyi, 4- yaR«phenyl 3- cafhoxyp enyi 3»caiboxy--4"¾ydoxypliesyi, 3-carfeoxy-6-mdhoxypbeny 4-carbaxyphessy], 4.-<y&eo~ 3~H!ethoxypiK?? i 3-cy¾no- -ineteyphenyl, 3-(d5ised5yIami«0€arbor5yi}pherjyl; 2- (dim i! dai!sisiocarb siyl henyl, 4.-(dteeihylaK}ffi<^ar¾oay.i}phe«y.l S-eih lKOijnocsrtosiyl h n l 3- t.N-i¾h i-M--ffi {fi ¾ra}00€ rbo» i tei i, -edj la atxar ony:l>JieH L 4-{N-€ihy!.-N- med5>½ inoearboayl}pheayi, 3-isopr<¾>y{amitK>C3tl>ony.i}shtmyit 3- ( - aiyt- - meibykmiaoeariwnyOii enyi, 3-{ ~pm -N-j»e 1aialiHicarfK«y!pben I« 3-0,2- 3-{ -roeihoxyeftiy.l-M- metlsykrainocartxisyljpheayi -{N~ ydro^«th l-N-«K« kmioocadj^3 l}pbsa» !« 5-«)«{ oxy-3- dia«etbykmkoc3rbonyiph«¾yi, 3--ift8(k) --5 i lan^mK:art>on lphen J, 2-met osy- - dim^bylaranocarbonylphenyl 8-m hoxy-3' rae-tbylaoilteartxiaytp enyl 3-iftei¾oxy-5- eiiiykittinocai%oaylpk«yl; i-bydi¾xy-2- eihyIpwp-2-yl--affilnoc8rbonyl|rfw.oyl,

difeydraxypropySaitsiB csAftay! -pheayl 3- 0 -aztaidsn carbonyHphesyl, 3-{3-fl« ro-a¾etid'in- i- yk:ar ossyi}pS5 sy,L 3-(3-hydroxy-azetMbi-l -yica.rbfi.nyi) phen l , 3- C'3~meik>x -a»siddh l - y!carbosiyilp!iefiyl 3-(3-i«ed"!ylsid.fofsyS-azeddsii-l-yk:srto 3-C4*

moip oi!ii terboifylp!seBYS, 3Hi -pyrroIidH¾dcaitoo !)p s5yL 4-fs(;{lK>xypite«yL 3-me&oxy b(i&yl S-fluoro-S-iiietiiftx bi'B !, 2-i]tforo--3"mfithoxyp enyi, 2-oi«3bow- -ft» amSnosuifony.lpbenyJ« 2- mfii oxy-l-ediy!aidiosuSfonyipheayl.4--meibosy-3-mfd lamiBosy]f sy!pbeftyi; 3-««4 oxy-5- isneihoxycatboitiy!pbenyi, 3-cartey-2-tne{'hoxyphei.iyi.3-difl»ommedioxypbenyl, 3- dSftttor tnsihylpfeiyK S-dlflaofowet yM-flaiwe heft i, 2~:medH>.xyph¾Ryl, 2, -ddnedioxypSiesy.l 3.4-dimeti!ftxyp es5yl 5-ben¾odkxoly

l~aK5ihyl-3-pyra¾oiyl, 1 -merhyl- -pyr8zoiyi, i.S-daTieibyl-4-pyraxolyt. i t3,5-trimeiby~4-pyrazoI l 3· «ie i" - yra2oSyl 3 riflttOf)-ediyi-4--p ai}!vt i · 2.2.2· tnfkoroethyll- ·ργί&«>!ν!( I- « ox. a¾j*fs t -p ra¾3lyt 1 ^i¾a e35-feeft l«it«by!- -- ra2o} l, S-c lobutyW-p rzol L 5 - eydobuiyl ·4·ρνπ!¾οίνί, I · {4-»i rpMls\yI af^nyte^hy]-4-pyra2oiyi i-(4-moiphoiiRyl}e l- pyrazoiyL l-bydfOxyetiiyl-4-pymoJyl, I-hydfoxyeihyl-S-pyrazoIyi i. 5 d!¾x pi-o3yl-5- raKOiyl I- (3!iydraxy-3^Krtiw!b»iyi}-5-pynizolyL i-raeihoJiyetbyl-4-py otyi, 5-pyraxelyl, I -jnetbyl-5- pytaxeiyl, i,3-diHJethyl-5-py.∞o.lyl, i^itt l-3-ttMaomaie¾ l--5'p ra¾»'l , 3- metbykmb\ecaitetiyi--pyi¾»){-S-yl, S-din^tl^!amlRatarbonyl-pyra^Di- S-y!, 3-ise isuifonylamioo- pyrazoi-S-yl 2- n¾r.hyls ]ibny]a»^»i -py.raxo.l-4-yi< Z-metxoxy atbonyl-pyraxoi^i-yi, , ^»aet&yk Ma \y\ , 2- (2- ydroxy-2-med}yk«.y]} - thiazai- 5-yi l,-me I - .5- -.tmldazolyl, 3,5-d!siedwI-isoxasd - - yl, l-RM¾lby'1. razi« -yls l-bydroxypropy.i-iTla2k-4-yIt 1 -Jiydroxybutyl- rriazio-4-yI, (4 .dfl«Qfoo^hy!pben ¾me l-^i8zia-4--yK 2 yatK-3-«ie*yl-ttev5-yi 2- me iosy arboftyl-di!e»-5--yi 2-car hoxyUh rt -5-yL 2-(N-m^b«xy^hyl-N- 2~(lS|.e d-H~roe 4"affikocafbon l}r jea~5- ?, 2- (2 h drox - -2- {«etbykrhyl)thien-5 -yl 3•me{hyi 4-oxadia¾ol-5 -yl S-cyasio-i -meihyipyiroi-2-yi,

2-py!idyl, 3»pyridyi, 4 pvridyi, 2-«je¾yl-5-pyf}dyl 2'm«ih R >yrid l< 2-8iethyl ~pyridyl, 3- metbyl-S-pyddyt 3 rift«or eibyi^5'- yndyl 2--ir!iIatsromeiIiy!-5-py!i i, 2»difiwo.03metby -5- pyridyl, 2-Mfl«OT0i»«ihyl -pyrldyL 2-trifiuorome l-3-pyndyl, 2-i«€ihQxy-3-pyndy 4-i»¾hoxy-3- pyridyl, H-. eihoxy-4-pyrdyi 2-{3-ax^a¾yf)me&«xy -pyridyl, 2-{3-oxetaHyi}Qxy*4-py.ndyl, 5- fk!«m-2-i«dli0 y -pyrSd .3 ¼0f» -pyrtdyl, 2 ·ί¾ί¾·'5 -pyridyl 3-i1ttor¾-S-py«dyl 3-rnedioxy4- m pyrkiyL 2--etboxy -pyri&yi, 2-»iefhoxy-5-pyrjdyf.- 2-(2,3-dhyd«>xypfOj>i8xy)-5-pTjdyf, 2- bydraxymAoxy-S- yridyi, 2- drox¾{¾o -5-p Tidyi E- .ydmxy;fto y- -p r½yi.5-¾oro-2- byrfroxyf'hoxy -)}yridy!.2--med)oxy«rbox¥-5~pyridyl 2-bydr0xy}«sihyi-S-pyri.di 3-f«ei.hoxy--5- E-iaopropoxy-s-pyrklyl, 2dy{Sroxy-2'-!«(?ihylpropixy-5-}n¾idyi, 2'-(meth lst ¾i pi'0pox }-S'-p Tid l 2--{iH«by1sa.fi}fty lamiMfSliftxy · 5-pyridyl, 2-etl)oxypropo¾'-4"pyrtdyl 2-difl»oiOi«edwxy -5-fiytidy]f

2- f} ora- -py!ldyii 2-dik>ro-4--pyt1dyi 2 h fo-5--pyrid-l,.S-dte» S- yridy{, 2-*yaBO-4--pyrtdyl, 2- cyano-S yddyl 2-5fteti-ioxy-3--eya«o-5-pyridyi X-c no-S-jnehyM-pyrki l 2- fcthoxy-8-m<#hyi-$- pyridyl 3-cyaoo--5-pyrkiyt 3- yaii -4-pyridyl 2-toetiiylstdlbs 4 - yildyl, 3-5neihvMioii l-5- 2- siidazel-l-yipyrk! t 2-oxo-;l.2-dibydropy k!is¾- 5-yi i'm¾ -2-oxo-.t,2"dfhy<lmpyridn-4.-y.l, 1·ε !·2-οχα· U-d' -drapytUto-5-yl, l-Isopropyl-2- oxo-L2'd!hy<Sropyridbi-5- i, t-bydrosye{ yl-2--oxo-l,2--dihydr{>pyidin~S-y!,

j.2-t!ibydiOpyr}di:n-5-yt 1•mgS i-2-oxo ,2"dih dra fMi.!v4- i, 2-hydfoxypyrid- - i 2- ydroxypyrid-5-yl, 2~aimn.o€sr!>o«yl-4- pyrkiy{, 2-methykmhK>cart>onyl-4-pyrfdyi.3- 2-!SopfopySai¾!0 carboayi-4--pyfidyl 3 ct d ia«iiisorarboi?y 5

pyridyl

4-pyHdyi. S-mediylsulftffi iaffiissoefb ta^ 2-metb !s«'ifoB {amlJK>eiha!( ~ pyridyl, 2- droxyetbylaminocarb Byl'4»j>yrldyl, 2-lwdroxyed:iy]afni!socarbooy]-5-pyddy!, 3- Swdroxyoihy!a»Mftocarbos5y1:-4~pyridyl.2-f¾'ti«)xyfetttyl»ttbjo««tonyl-4-pyrtdy]! 2- me&ox ettrki^ Z-{1- ifnlda¾4yi}py!id-4-yl S-' yrinttdinyi l-ammo-S-pyfimdinyl 2-<^ano-5-pyrbaIdiayI{ 2-met oxy-5- pyrSmidtayl, 2-eth«xy-5pyfiisdlrsyl 2-isopropoxy-S-pytisiidinyl 2-tf¾«ord8e«>xy-5-pyrtmidi«yl, 4- ttifluoromeihyl-6-pyri iibiyi -tJifioort^ifeyi-i-pyrUaidmyl, 2-dnuoroeihy!-5-pyrbaidtoyl 2- diamh kml»ocai¾6n4 y¾1mjditi-5- L py.axi«4-yl, pyrida*nv4-yi

3- be∞mhi<3B?l, S-beszofaryl, S-sidaS i.2-ox -dihydto- S-.indalyl, 8-iadoiyl, 2-axo--difcydro--iHftdoiyi, l-meftyi'2"OXO-dib dm-6 »d.o£ l iraidaz |:i ,2-aJpyjidfcv3-yl Imidazop ,5-ajpyridirj-f>-yl, ii«ida¾|1.5"a|pyTidiii-7-yb it«idazoII..2-a)pyrldi» -yl. \ J -dioxo-2-in i--3i -.diisydt¾~ e~

raetbykU ~ ioxido-:i4~d%dr0^ 2M- ¼nzoib] (1 A¾oxafhtopft?-8~>i δ-οχο-4 ~m«h l 2,3,4,5- i&sralwdro- fixof!] fl,4jaxapf»-8 -yl •merhyi-5«oxo-2.3<4.5-{eti¾¾ydrQ»be»2o|'i] f l,4'|oxapja-7»yl, · raeti5d 4'dl xido-3«4-dlh dFO- H^ fido|'¾2'b'| {.J ,4]«d3s«Hi-7-y!, wo asKo -yi benxoxassoi-S- yl U-dfoxo-3,4-d!bydro--2H--[U^

n-5(2H}-7-i 4 -

m rfiyttieszoxaxo!-S -yl 2-«ih l e«zoxazol-5-yl; 2-5S(jpropylbei¾oxaz«! -S-y 2-sxi>-2£3!4) - henzod]oxazoi-5-yl < henzoxazoi-S-yl, be8¾qt.bia¾ol-5-yi, beazo&iazoi-S- f .· 2-aiethl tmothiazoI ·

5- yl, J -tm>t yI ndazolyl>

5-

benzolsoxazoi-S-yi.3»methyl.ben¾E)[dJfcoxaz0l.-S-yi --me !- -o o-½a2o|'d]50Jd^I-5- l^2-fne l--

6- -m&flioxy-3-oxo-ben¾jfdj isoxa¾el--5-yl., 2·¾ιβ Ι«χ8¾)ίο{"§, ··¾]ρτί<Η«··5·>' 2 ·8)« Ιαχ32ο1ο|'5.4· b.|pyrtdia»6-yi, !,i--dioxq-4»B}ethyl-3.4- oxo-23- dihydro- 4M-biiida2o{4> 5-b] pyndin-6-y! , 2~WQ-2 J-dihydrobenzo k!.) xazoi-S-yi , 3-<>xo- tenz ld) 11,3)ο »ί¾«ί-δ->¾ 3>3-diGXQ-½ra2o[dl 1 ,¾ xatb|»l-5-yi 6-«iethoxy-2-it«eihyl-3-ax9-2«3- dibydm-l^^felS^-blp ridin^S-yi, iU4l«azo!o|43-a|pytidi^S-yif iiZ4|triazoiol43-a|pyridia- S-yL 3-bydrtJxymefliyt- .Z.^iriezoioli^alp ridirt^-yL ! ί J^ltriazoi C S-alp rldin-T- l.

f:i ,4|dk)XKm2>3-bipyrkilfi--7~yi.6-¾8inoJi«yl, ?- «i«ftlii¾yl, soquiaoiinyi> 7-¾oqidno1inyl 1 ,5- naph rkli»~3-yl« 3-tne l-4H--pyrazo'Jo[3,4--'b]pyrfdin-5-yi iB~pyra»oloj3 -¾pyndisv4~y i- 3- »¾ 4 H--pyra2oo[3,4"bJpyrtd;la-4-y! ami a pbarmacewfeliy acceptably salt thereof.

17. CootpOMod of Cialm 3 where ta ft* is H, or bro o; aad a pharmaceutically acceptable sab: thereof.

18, Compound of Claim I wherein€ CH: and a phan«ac««tlcaKy -acceptable salt thereof.

IS, Cotnpotmd of Oaka 1 wherein G is C- ; is H; P ¾ L-.R8 ; asd s Is 5 memhere nitrogen m»ta¾«¾g teerotyeiyl.5 nserohered oxygen mntaiBhig taeroeydyi 6 jnembered oiirogeo containing hef.eroeyeiyi, 8.me bered oxygen containing- teterocydyt, hen l enzyl -9 tnembered hkydid nitrogen eoatairtiag heferocydyi, 10 ajetnbered bky ic -oxygea coittak tg .beterocydyl or 10 mejnbered bicyebc nitrogeni containing heterocydyt

w herein .R'' is jaisahistiiuted or snbsfiatteri with one or snore stibxiifnenis independently selected imm C|.« alkyi> cyano, balo, Ct.«-alkoxy,€{.§ aioalky], CHi aikoxycarbonyi, carksxy. C;.¾ a!koxy-C; g alkytenijiocarbORyi, CVe aikyiarningcafboayl, C « 3ikyi:ammo-€!ti

aihy!arnincicaitenyl, or fepiioaaSiy substituted 4-6 sjfcmbfcred #iiroge» cosialniiig

Heiefocycfyl]carbonyl ;

and a pharmaceutically acceptable salt thereof.

718

20. Compotmd. of Claim 1 herein G is C- : is M: F is L-R- : and R* :s f tTa!i drofiirany] , teii^ydropyraayi, 3,4-dihydn>-2H4>yraBO (3,2 · c|py ridn i, eferomatiyi bmhydrofi«of2,3»b|f»fyi, plperidinyl. pyridy pytazolyl leiraKo phenyi, tiinoifsiyi, i,2- dibydf !QoiiJolhi l, pyo'oSkkrsyl, benzyl.1,2,3,4 ietra ydroq lfKiiinyi 5,f.7,8 ieffa droq ia !ia qidnoxsHswl, qidnazolteyt, IH-fndazolyi 2H48dazoiyi feoiftdotoyl, |.i,2,4{trlaajfo|.4,S-a|pyrkltayi

3M"irolda¾of4 »ajpyrkbByl, pyradbizisyt pyrazclayl pyrlmidi»yl, 4,§ j «¾hydro-3ii- gyrazoioi3.4-b'jpyeidi«ylt 3,4-dlh d "2H-p ra«&25¾-c'!pyridiR or c fomaayi,

feereh* Rb Is ujisubstK ted o substit te with o»e of more substftuents bidepentteHtly selected fxma .methyl, ethyi eyaso, h tn, fitsos'o, tnefljoxy, triflaoronseihyl, ethoxycarbonyl, tert- btitosycartosyL carboxy, -{in tfi i}- -(met o¾yeth !)amtHO€arboo l (N, - dl«Kj ¾a8Jbiacai oH l, N-imefhylj-!^^ h !ao^ 1 - ediy!pyra5day-4- y.l)cafbosyK or oxo

■and a pharmaceutically acceptable salt thereof.

21. CompfjiisKl ofCiaiml xvheressGfeC- ; i II. P is L-Re ; a¾l Rs is

benzyl, rahydropycat -yl, S-.flttsro-t€tra¾vJfOpyfa»-4^yl 1.4¾c-piperidirt- --yj.

hexahydrof¾ro{2,3~'b]fw-3-yi. ^S-diaxo-pyroHodte-l-yt,

2-pyridyi.3-pyridyl, 4-pyridyt 2'-roethyS,3-pyndyi 2-metbyi-4-pyddy$, 2-m tlri'-5-pyrfdy1( 2- nifcihyi~6-pyri yi 3 n«?thyl ~pyridyL

pyrfdy!, 2:4-diJ thy!-'3-pyridyL 3,4--dimetbyl-5-pyfjdyl, 2.3-dtotbyl-5-pyridyl, iS-dimethyl- 2-pyftdyi, 2!S-d!i«e I-3-pysidyi, 2-«ttiyl»3pyr5di 3-efbyI-5-pyrIdyL 2-ethyl -m iiiy!3 pyrklyl 3-edwl-8^»ethyi-5-pyndyl 3-lsd|sri¾>y! -S-pyndyi 3-prop4-e«-l-yl-5-pyridyi 3-{t- meihy1eihesr4}-5-pyndyi 3-cyck>pK>pyl-5- yrjdyl, 2¾droxyffiethy]-3-pYtidyL 3- hy(b»xyitm!thyl-5-pyfidyl,

ethyi-5-pyridy 2-bydrc)xypnpyl-5-pyf !« 34L2-di y{lsmyeiby!)-5-pyfidyl, 2- ffiSiiorafnet l-a-p nd l 2-fcdfiaotajuethy.l- -pyddyls 2 dfk!ommefbyi-5-pyddyS., 3 nei.hyl- 24riflaofon»>i.byi-5-pyiidyl.> mfiib l-4 nfly m.ffiCiJ;i l - rid l -tnfl«(¾-oio d) l-5-

mefbosy-5 -pyildyl, 3 - {2-ftydfoypr0pyl)-5-pyfldyi 3-{2-hydro¾¾Ayt>-5--pyj l..3--m efkwy-- 5-pyridyl, 3-eihoxy-S-pyridyi.2-raetboxy~4-ffie 'l"3-p>T i 2~ffietey4--«thyl--5-p> k{y{« 2- cyas -3•pyrfdyl, 3 · cyssiio - py r i d i ¾ 3■ i?y · 5 y r i Ϊ .2»cyano-S-tfifl«o«»«etbyi-3-pyrjdyl,

2- cidqro-3~pyr L 2-cblofo-S-pytidyl 3-ddoFo~5~pyrbjyJ> 4-chloro-3-pyiidyl! 3-cMoi¾-4- eyafio-5-pyridyl., 2- l«C!i¾'4-pyddy!, S-iliioro-S-pyddyl 4-tlroro-3-pyrid l..2-c tofo-5 -methyl-

3- py«dyi. ¾-broaw-3-Bf8*yl-5-pyridyl: 13-ditse%I-2- methyi-8-oxopyiMlR-S-yl, i- morp oi:!!iyiraeil¾yi}--3-pyr i< 2 - (tert-b«1ytemtaoc3rl>on .l}-4-pyf}dyl 2- (met-o.y«?tbykoiia( ai ny¾-8-pyrtdi 3-{3-}He.b05<ypb«oy¾~5- yridyi( 3-·{3-β«αΐΌ··5- metboxypbeny1)-5 -pyrfdyl,

S- yiioiifiiiiy].4-chl«ro»5•me yl-pyrimidiJvB-y., 2:4-dhi5fiiiiyI- yri«iid!ft-6-y L 2- c anopyfiiakHB-5-yl, X-trtflttoroftsefit l-^ftoiltfiB-S-ylj 4"flaoropy!iffikiift~2 -yJ , ;>

'fittompyfiia in-2 -yl 4-triflaTOiaeihyI-pyHftMdift-5- i 2'-azetidiisyicarboswi-pyra¾to-5-yi; 2·· dijm¾hylaini«oar )Byl- i¾2iH-5 -yl pytadbvla-S-yi

i.3.5-i mt^ifiyi-4-jyra¾oSySf I-etb>1-5-pyj¾i¾).lyI, i sopropyi-5-pyT8zbiyi, R;thyM~bromo-5- pyrazoly,

dimt¾hytennocs»-b)»yi--5->yrazolylt 1 -metiiyl-S-cyctopropyl-S-pyraxoiyl 1 -ethyHeteol-2-yli he l, 2J-iliiI«orop!waylf 2-! uorop eswi.2.4-<Hfi»orophenyL 2.4.:6-.trjfl.«oro;p.benyi, 2,5- diilaorophawi, 2,3'difltforaph«ByI, 2,6' ifl«ofo-3'Who feen .l 2.<4-df «om-3- meirhoxyphenyi 3-c lompkmyi, 2,6-t!khioropteiyi, 2!3 {k:hkfo fu i 3- u 2~ flyoropbenyl, 3-cbloro-4-flaoroph8nyl.2 hk>ro~6 ¾wopknyi, 3-cblofo-6-4laofopfeieayK 2- f¾i(ii!¾-5 -fdfluoi-O!nefliyiphgo ! , 3-liydri>xymefh iphesiyi.3- hydroxyiii! !pftefsyl 3·· hydroxy ffi8tby'l-5-«K!iiiy1pbenyl, 3-inedioxypheny.l, 2-HieibosypbeoyI., -snei o ypfe«*iyU 2- methyls«lfo«ylpbeflyi4 -«¾B isuMoR t bfi& i< 2·ί½ο(¾-5· eihyfettHbaylpbeftyl, 5·

iS ½w »3mlfoHyl-2 1«ojrfpi«atyi 2 1¾o.ro-5-a»et!¾'k:arbo«ylpbeflyf, Ά- meboxycarbonylphenyL 3-c8fboxyphe« i 2 -medivi- 5-- ilMx ciir osi !pS»B i.2-c oio-5- eih syxar osiyipheisyt 2-flaora-5-8ieihoxy<arbonyIpkw. !!.3-B58thyl-5- «ietb xy artx)«yiplienyi ^h iroxm' 4-5--TtK;thox caFlMJ8ylphfcn l 3-medioxy-5- medsoxycarb(Kiylphei.yl, 2iluoi¾-5-wfthoxycarbonyh»ethylpbeayl« 2-fksoro-5- caAoxyme&yiphenyi, 2-ei¾ylpB«tri 2-i.a«thyi-5- citrboxypliesyl X-^ loro-S-car o pkmyi, ¾wro-5-carksx phe« i> 2·€¾οκ ¾- a mmo f o l phenyl 2-iIuorO"5-amiaocarbonylph««y.l, 2-cyasopheiiyl. -q?n p¾eayt 2- cyaao-3-iirfiylpl¾s S , 2-cyimo- S-Hie wlplieis i 4-cyaao-3-tnei¾yiptie«yi, 2 -cya«< 3- et.bylpk»yi> 4-chlQro-2-cyafK>phenyi 2-chloro~4-eya»op-iei?yI, 3-cfe'loro-2-cya«opbe8y'i, 3-

i^propyJamliiocaf o«y.pheHyls -r«ei y~3-:topropy}amliwai ny.:p eny

3·· sopopyllsnrfaoai oB llphfiByl, 2-:ftse{«yl-$- |Ν· umth t) -N- {j8€te etfi I}amiaocari)on llpi}e« I, 2-η»*ν1-5-|'( Λ? ¾ικ; ¾8^^3^ 'υρ^«>'1> 2-

7in meibykmi m) car ooy 1) phenyl, 2-.fhsoro~ 3- {edwkmi no) arhonyl) hen l, 2- fuoro - 3· ({liwmeti iasHBfiicai-honyilph !i L

2- f]«oro-5'(cyciobai })affi!no<arSi<sny.l}pheriyi.2-flaoro«5- {cyclopefsiyl}}afflinocarbonyl}phesyi.2-fittoro-5-{teirahydft)pyfaK-4»

yl})aminocarboHyl)phe«yi.2-f ot -5-{{ffie{hox mpyl))amin)Mr¼nyl)phenyl 2-flworo-5- {{2.¾efi](yl}3ailttoc«iiooyi)pheoyi, 2-fJiw> --((2»Biet ox^x)pyl)amto*¾:ari»ny!} hefl l42·· ί!»β»-5-((ί 2-c o»-5-i(i- yriO!s«d!i} !.SC<irbosyi|phes5yi, 2<hk>ro-$-({: 3-dto ^ 2-

yia»iiiK5caFb nyi)p enyl> H-iluoro-S^C^rai'diyi^

5-({i-»tbylpy∞ol-4-y!)aiiito()C.ai¼Kyl)ph«}iyl 2-fluoro-S-{teiTaliydropy«n-4- y¾»ethyi):)amlROC3rboHyl}ph8fiy.l, 2-fi!iom-5-({S.3-iSi!Kei]! ipyr32 ]- - y])aftHRoearbaftyi)phmiy!L '2-fi¾OTO-5-((p dd" 'y¾)iieihyIarainoc3J^i5 {phe« l, 2-f|u0.ra-5- a -i¾Joropfperidm~4 -y!) jaminoi&rbflayl) tayl, -fiti««)-S-( Bftc- - ιίόfopφfeή.dm - 'I¾amifioeaTboft ¾ bs8 ?« 2-Π«0^-5-(:!~Βθ€-|}φ^^ 2-.fljw<>- 5-(Litoo«i? -piperidffi 2 ] om-5-(l.-etbyl-p!pei'id}ii-4-

ylllarrtincscarbony p iyl, 2 dl«0rO--S 4-m0rpM 2--ίϊίκ»ο~5--{{4- ch!oro-5-(i- n-olid i fcari30irtd}pheii l 2-chlofO^-{:l-rmhyipyrazbi-4-yl)ca^nyl)phe»yl

3- {2¾ i» da¾oly fce»yi 3-{2-» byt- l-te*¾2 l)phe«yl 3-(2-?»ethy! · I ,2,4-oxadsas:ol-3- >'.!)pheny.l, 3-{3-jBeihyH.2.4-i>xadted-5-yI)phe«yI;

S^rfnoUn L 6-qui«oUnyi« 7-qu!noitayi 8-quinoHnyi, 5 hteo-6-q«inoUn>i 7-ehforo-4- q jaoiii l, 8 hioro*6-qufomlioy1, 2-mdhy]- -^ mdin i, 5,6,7>8-te¾rahyko td3tioUn--5^y> is2,3,4" f fe dtoq«iaob«-5" i, S;b-diineS¾yi-5,6J^ etra?^di¾q«lsoin^S-¾L 4-qumiimbsyl qomyx¾lin-5-yl. i -om-isolndo.il«-4-y1, l-oxo-isaMo^n-S- i -R»¾thyHi «d¾!K>l-4-y.l, 2- raethyI-2E odazol-4- l I-jB¾tbyi- iH-i»dazol-5-yl. -dfosahyl- OWndazoM- l,

t ,2-di'hydfoqatnoiin-6~yi 5 -c iofo-vt -ΒΚΪ 1·»2~ΟΧΟ ,2~di'h dfoq»jm)lin-6~yi

oxo- !..2-dihydraq«iftol!o--6-yl, 2··«χο· 1.2-<Uhydfoqwiiiolio-6-y1.4oxo-dlhydroqidnoliR-l-yl.4·· ox -q«SBo3in (4H}-yi 2-j«ethyf- 1 ~oxo - 1 t2-d!.l?ydroisequi«oiii5 -6-yi, S -dtflumO-U- di!!«hyl-2-oxo I. J-ddiydmqum&bfl-S -yl, 5.?-diiiu»rc>~l ,3,4-triimthyi-2-ox -l .2 ·

dihydfOqutoali»-S-yl{ S;7 !i:0«oro

S, -diO«oro -e†fi !^E« ^ 8 soq«inoU»yi 7- isWsiHOlinyl SdsoqulnoIiHyS, 5 o iH«oil . s«uiiioUft l 1 -methyHH- yrazoiotS^-

713 b]pyridio-3-yi Ι^^,Ιτ-ΐΗ-ίϊτ^ίοΙοΙΒ,^-'^^ΗιίΙπ^^Ι i-ed>yklH^ olof3.4-b)pyrldai-<f- yl, I -jaeihoxyeihyt- 1 H-pyrazolop, 4 >|.|>yridia-3-yl, > iluoro- .1 -jnethy! - 3 H-pyra2»io [ 3.4- hpyridin -3 yL 1 H- i¾zaIo[3,4^)p r!m:d« -yI. Iraida ofJ ..2-aJpyridin-?-y!., iiaidaxoiil ,2- ajpyrkiki 8 yl, 3-me 1-3HHmkl3z»f4,;>-bjpyrjdtfi- -yf, 3^ 4-3B'--tmid3Z(|''i5"bjjyrkH.tt-- β<·)13•methyli»x32ofo|.5,4"b!pyri > - i? {l^^ltnazolo^.S-al ridin-S- 4 ,6J»| r< ^m-3H^ raKolof3, -- lp ridlo»3-y1, 3,4 -di«yd!»-2M-$>yraBei2,3•clpytld|ft-5-yl> 8--ffiethyl-3,4- ifeyd«-2M"pytaao¾3-¾'jpyrkliB--5--yl or S-ctaaaay!; aad a pharmaceutically acceptable sail thereof,

17, Compound of C m 1 wbcreia L Is 0; and a pharaia cPdcaMy acceptable salt thereof,

IS, Compowm! of Qasrs 1 hereia C is€- ; is L-R*; P Is H; and Is 5 membered heterocydyt 8 em'bered eia'ocydyl phenyl. pheayi-Cf -B alkyl, $ memberec! akrogea amieinisg heteroeydyl, or 10 tneanbeted irogea txmtairdag .heteroeydyl

whereia R:> is awsubstituied or substituted wait one or more s bstitueats irKfeptetsdeatiy selected. rom G; g alkyi cyano, halo, oxo, hydroxy!., d .¾ alkoxy, C< .<> haloalkyi Cj.« alXoxycatboayl. e&fboxy, C».« aIkό yaik l «·alk !3a5iooc¾bό8 Ci .«· a!kyiawiiidcarboayl. Ct* a!kykraino-C;..« alkykraiaocarboayi. or iopdooaHy aibstifated 4-6 measbered aitregesi cosiaMag

heteoeyelylfcarbosyi;

aad a pltamiacei scalty acceptable salt thereof.

18. Compound of Claim ! whmto G is C - ; Is L-R5: P is H; and R5 is pyridyl pys olyi, phenyl, beazyl, tetohydropyrarryi. piperidioyl, Kexahydrofurqt'2t3-»]:t¾ryi 2,5-dIoxo- pym>i!ftdi«yl, pyraziayl, pyradlfiziayl. tetrazolyl uiPaxoi iyf, qtdnal yl .l. -dibydro¾«laolinyl.» 5.6J,8 effah drc{|«iaoijii i qafaoxalinyl, iH-fadaxolyl, 2H-inda¾oiyl. [i,2,4|tria¾oiof4,3- ajpyridiayl, isoquiaolioyl, 1 H~pyrszf}}ol3.4-b]pyT$diay!, b«idazoii,2-a]pyridiay.i, 3B--ia»da¾>i.4,5- a] yrSdiayl , isoxaxoiof 5 f4-h]pyr idinyl, [ ί ,2 Jjitrazolo [i ,3-a.j pyridaryi 4,5 ,6,7- tefraaydro*3M- pyra2oio(3>4-bjpyridlii>l 3,4-di!wdro-2ll-py8«oi2,3- ]pyrid{i¾y! or chroinarryl or pyriraidaiy'l; wherein ' is iassabsikaied or substituted wills one or asore sahstitueots asdepeadently selected from fhioro. choro. cyano, ethoxy, trifluoiXiftiethyL etbqx.ycarboB.yi earhaxy, - (methyl) (meihoxyefayijaffiinocarboay! , ( «! -dime;{hyl)amhocafhoayl., t$~ (roetby!) -N - {a«thyteffitaoethyl}aadooi¾rtKMiyl, l-SMdryIpyraziiiy -4-yi)earboiiyi, oxo, oietityl ethyl, or busaxyearfeonyl;

and a pharmaceutically acceptable sal thereof.

15. Compowad of Claim I »½t*iB G is C- : is L-R4; P is H; and R5 is benxyl tetrabydrepyran-4--y.f. '3 l«m-o-fetfahy opyEa«-4-yj 11 -BwNpipfcridift-4<yl, hi>x»thyda)fufoi2<3-b}f«f--3-i 2>5-dk>xo-p,m>ljttdM-i-yl..

a- yrid ia-pydd l 4-pyndyi, 2- e k syridy 2-m«iiiy!-4-pyfid>'i S-insthyl-S-pysidyl 2~ !iieibyi-8 |)yridyl:.3-raetbyI-4-pyiidy 3-me i^^yrf^,4-a}eih .l-3"p ril {, 2,8-dh«ehyl-3~ pyndyl 2,4»dimehyt-3-pyfidyl.2>4-dmi¾hyi-5-pyf¾lyL 2.3-dimetM-5-pyridyS, 4,5-di«isihyl-2» pyndyl 2--edw!-3-pyridyf.3-ethy-5-pyridyl, 2-e 4 -tRetbyl»3-pyridyl> 3- ¾byi:-g-meihyl"3-pyridyl, 3 -isopi-opylS -pyndyl 3»prøρ·· ·eβ··ί·y··5·φ rϊdyl,.S·{t···metfe etheftyί··3· pyridyl 3-cyeiopf-opyl-5 -pyf !dyl, 2-!sydroxymeihyl3-pyridyi 3-hydrox 8»thy! -5-py f idyl, 3-(2- hydfoxyeihyl} -5- -pyridyl, 2--{l-bydmx --l^ ¼byl)-3-«^ih I -pyrldyL 2-hydroxypropyl«5- pyridyl 3-{!,2-dihydn>xyeihyl-5-¾?-ridi 'Irii$ioromeilsyi--3- yTidyi 2 riflu«rGmediyl-4-pyrklyi 2 ri.fluorom¾ 1 -pyTldyl, 3--t^ l-2-{i¾i nsfie i-5-pyidyt 4-Tae l-3--»1fl«orojm«feyl-6- pyridyt 3-Mfl s«3n«ttyi-5-pyiidyi 3-tri8uommethyl-5 -iluore--6-pyndyl 4-tia«wo∞thyl-2- c loi¾-3 y idyl 2~H«;thoxy~S-pyridyi 3-(2-bydroxyympy.l}-5-pyf?dyl.3~(2~hydroxy«5fhyl}-5-- pyridyl S-n^tfeoxy-S-p ridyl, 3-<s* ox7-S-pyridi ~mefhox -4 -meihyi-5-pyndyl 2-ffii¾bt)xy - erfrylS-pyri l, 2»cyaiKi-3-pyTidy.l 3-cyano-4-pyridyl S-cyano-S-pyiidyi 2-cyano-5- tf10aofosied^:- -|w id L 2-c !oro-3--pyfidyI, 2-chtero-5-pysridyi, 3-c loro-S -pyridyl 4-ckforo-3- pyridyl 3-chloro-4-eya»-5-pyridyi.2 -fl om-S-pyritiyl.3-fluero-5-f yridyl, i-f1«oro-3--pyridy], .2- cbloi-o-5^edwS -3-|y!idyL 2-bmmo-3-Biei 1-5-pyridyl, 1 J !iir!ef yl- 2- xop rkbii--5-yi, 1,3- dlme "2-oxo> rk«:a»5- 1, 1 ,2 -d jme l-6»oxopyrldlB-3--yl l -mei S:-2-ox»pyridin-5-yl 2-si!ethyi- 6~oxopyridin ~yl i-t¾hyi-2-oxepyrfdl«-S-yl, 4 ili i^ -ifieih W-oxo yridiif-S- i, i-ethyl-2-mefhyl- S-Dxopyfidin-S-yl, l. -is propy!-:2--OKGpyridi«-5--yL l-sae jyl E- titfia»njeihyi-6-a¾opyridla--4-y i-» feyl-3 rS{l«oK»ejhyl-2-oxppyiidin-4-yi 2-C4- ri5o !soi«i lmedwb -3-pyridyl 2-(tert-butyte aocafboRyI)-4 -pyridyl 2- 3-{3-fluoio-5- rm tbo-xypfeenyl) - 5 -p ridyl ,

5-pyjimtdiayl 4-ch1orO"3-«^fhy-p yimidin--6-y 2,4-di:iMifey.}-pyfimidia-6-yl 2-cyan pyiimidia-S" yl, 2-ttia«orome l-pyfimid¾v-5-y - i o rop y Γ¾» J d ΪΪΪ · 2 y 1 , 5i¾o.ropyfimidm.-2-yi, 4»

iriflijorometoi-pyrisiidin-a-yi S-^tidi^lcartKjn l-p fsxk S- !, 2-dki¾e laialiJocafbonyl-pyr8z.tfl- 5-yl, pyradin»io~3-vl

l,3,5-:triiHeibyl-4-p>woJyl 1 -& i-5--pyr¾¾»iyl l-jsop»py1--5-pyf¾¾oiy3, } -iiihy!- --bfO!«o-S- pyraxoiyl, ! - fi^i -4-iiK*i yi-5-pyr8xoiyi, l--etb l-3-mefhoxynieib {-5-p m¾oJyl. !-roei yl-S- <fi}aeibylai«iaocar}Jony1-5---pyta2olyl. i-metbyl•S-cyclopropyi-S-pyj-axolyl, i -eiiybetezoi-2-yI. pbesiy 2,6-diflaoropiieriyi 2-fi«Ofopiie#yl 2,4-diflu mphmy 2,4.6-»ifl«ompkmy 2,5- di.a«oropheByl, HJ-dyiwoptaj l 2!6-diiluwo-3-aHidio¾ip½» l, 2,4 -diflaora-3 - ineihoxypiienyl, 3-chtaOphe«yl 256-dicMorop{»tt>l 2,3-dkldoropheByl, 3-chtoro-2- fluoropheny 3'C 1oyo- -fl»c)ro bffi! l H-ckIf):ro-6-i«firop!¾es¾yl S-chloyo-e-fiade teiyi, 2- !l«05^--5-¾ffluor0ineiiripben 3diydmxyimHhyIpheny1, S-bydioxyfeftylpljenyl, 3- hytfco ymeihyl-S-a feylphetiyl.3-mi!rhoxyphe«yl.2-aiethoxypkiftyi, -meiiKixyp.hsiiyi, 2- im¾hy.lsft!fo8ylpheny'l, 3-m8 -¾!foay!pk>oy1, 2-fiaoro-5- eihyfealfoiiylpkinyl, S- e ias«iotmUbnyi-2--i]»o«)pbeoy!( 2^¾iortv-5-methyIcsfbo«y!pbeoyit 3-m8&ox earbori i eayl 3-carbexypheayl 2'-!«(?ih I'5-e(i¾w c3iboii Sp efwI, 2-(;hioi:o-3 *fhos carboB lphei¾;i> S-mei oxyrar onylp esiyi, 3--oi(Sliy^5¾tne'feox cai¾onylphenyl S-hytlroxyraeihyl-S · mei oxycarb sylphertyU 3-meihoxy-5--mef o5iy«;a(¾oi)y]ph«iyi, 2-fi«om-S- iftefhox carboiiyimeh lpheiiy.2-iaoro- 5-car boxymethyipheftyJ , 2,6 ·<ϋ|Ι«0Γ0··3•me{hy!phe»yl, 2-«ihylpiiej¾yl, 2-iMth1-5-C8^X p »i 2-c ioro-5-carboxyphe?iyi: 2-fitto»-5-caAoxypSiesw!,

2- cMoj¾-5-aiaaoca¾OR lph8nyl 2-fiuoro-.5-a«U«acarbiO«ylpteiyl 2«yano heHyl 4 · cyasopkuiyl, 2-c aiiQ'3-tni?tii I liessyl 2-€ ai5>"5-s«eib l tenyL 4- ano-3-ine'ftiylp enyl Z~ cya55 -3-e† ylphes]y!; -l-chiof«-2-s:yafioptse»yl 2-ehto-^ anopben i> -jitoro-2- atK>pb«siyt

3- cWoro-6-iyan»pk>nyJ, 2- ¾no-3;6-dS€ loi¾p aiyi 2-iyai» ,6-diflttQmk¾yi 4-cyano-2t6- iiftaof phesyi g-cyano-g-luorophenyi, 2-cyaao-6-cblonipheayK 3-ch1oro-2-cya»o-6~ fla(aopheny],2"C 3fi>-6-teifl«ORi}»etb i henyi 2-cjfaffi>-5 r¾l«orofsed i eRyl 3- soprepyliammtKttr onyllpbeny!,■5-methyl-3 0sopr pyl)amiHot¾rt nyl]pkmyi! 4-*aethy.i-3~ isopropy!) -arnloocar onyllpbeoyl , 2 ziyl 5* -i«jetkyi}-'M'

5-{(isoj»apy¾ambiocartKmyl)phe}iyI, 2dIooro- - (M so rop S-^

2 -nworo -(ieifs1aa?ino}cafbi>si % 2•i¼ero--((Su «x temto)cabo8 i)phe8 l Z-

{(a¾ethox pm 3ii})a«iifto af Qiiyl} h iyL 2-flaom-5 (2-metfe l)ainin car aayl} henyi 2-fl.aom- 5-{{2^»^¾ox [»ap l)amkocafboa l}phe» i, 2·¾<Η»·§-({:Ι -metho -1- me kth 1)'affiiiiocarboRyi}pheiiyi ^Woro-5" (l" smli in i)carbo« l} kiK l> 2-cbiera-5- { >3-0knt l ya^« - l}carbo» l}pbeM l> 2-fluoro-5-{{:t-.meihylpy∞ol-3- y' amkocarboayllpheuyl, -·¾ r(-5-¾J--^fh lρ>τaz ^4- 0am1a cartoa lpsen l 2~f½oro-5~ 2-

y¾«« l)aminacark>My{}pii«tyL 2- fluero-5 (1 -Boc- 3-tom ipeil m- -yl))amiso ari)onyi}phe8yi, 2-flttoro-5-(l -Soc-piperidiri^- ilutTO-5-(plp»jd}n-4~yi)}aml»ocaflK)nyi)phe»yl.2-flu&t -S-( - inorpiKjia3y!))an«.SKj(cfb i¾yl}p]¾Ji l, dluom- d( -w>^h^^^^^ 2- bier^S-CnKfho^hyllamiBO arbicm Jph^vyi E Wira-5 r^yrrol¾J ¾arbcmyi) kui l 2-

tetrazolyi)phenyl 3-C2-mdh l-i -oxadia^

yl)pheoyi

S-qittnolisyl: g-qamcdioyl, ?-quineli«yi S- aiso!iftyl, 5-cbto-6-qai.fiolioyl, 7-cbioro- - ai.no!ioyl , 2f-{«ethyM-q«iaoilftyi, 5,6 Jddra!syiko tiiiio!in- 5-y K 12,3,4- tetobydioqubioSfrS-yl 6 -dhi^ih l-5,6J.8-^r¾h 4«HiaimIirt-S- ls 4-qutazoUnyl qaiacraBn- 5 Ί .1 -oxo-JsotedoilH-4- i l-f)xo-.WHdoHB-6-i 3-«iedwI~.! H odazol-4-yi .2- eibyi~2H- ¾daxoI-4-yl S -iitethyMH-iiidaxo!-S-yS, ί ,3-dis¾e† yMH-¾da¾oI ^y {i ?2, da2olo| ,3- aJpyndi»-§-yl 1 -metJiyl-a-oxo-l^-dih dsHiainoliii-e- l, 4-m¾ I-2-oxo- S.,2-dibyds¾ uii¾oiis-6- yl 5-chloro-J«iethyi-2~axo-l,2--d< > 0qutnol;iH-6-yl< U-dis^by!-2-oxo- 1 ^dihydroqtdnoBo-

6- yl, 2-osi-] 4-oxo-q(iis>oiia- i. i)-yl 2- iiiedwl-i--oxfi-i,2-dih dm}¾o yinoll« -yi, SJ^Iifiaoro^ i^itniiiiiyl- ^o-i^^m^fWtttolin-

d droqttiBolh>8-yl S- iso ainuHovi, ? soqainoiii¾yi 6 voq«iiKiinyl, S-isoqainoRoy'i, 4- iso iiioolii!y!, f•me i-lH»py}azolo{¾!4 -bIpyridm-3-yS, 1 -ethyl- iH yimo !i3,4"b:]pyridia-3-y1, y-ehy1:-iH-.p razokl3,4 }p nd«^4-yL t~»«if]B>syeth l H^ (a?^l»f3, ^Jpj¾k!iiK3^1,.5~ lHij ra2olo('3t4- ]pyrimidi8- -ylJmid¾zoU.2- ajpyrUMn-T-yi ddazofi^ajpyridin-g-yl, 3'« byl,3H mteo|: 5S-bjpyrdin^->i 3-methyl- 3'H-iT«ida2«[4.5-l>{pyridlR-S-yt 3-iueds I osax kd5, -blpyrid!n-4-yj, [3,2:4)tdiazotof43- a]pyndiii-8yt I- i-4.5,6,7-a¾abydro

pyranol2J~]pyndiO-5-y1(6-med{y]--3 ~diiiydm 5-ckoi«a«-yl; and a phsm)8ce«ftca .accetable salt f.bereof,

26. A compound of Claim 1 having Formate Ik: or lid

wherein:

. J is alkyl tik yl haioaikyl alkoxy, hydwixyalkyl. ammoalkyl. alkoxyalkyl

hydroxyalkoxyalky! lkox^ cydoa!kyi, cydoalkyl lky aryl aralky! eterocydyi or heteresyclyialkyl wherem the eydoaiky! aryl, or heterocyclyl ring is cydoalkyl cydoalkyiaikyl asy! ara!ky! heierotydyl or heies¾eydy!alky! is w&utjsbiiiled w l with one of two sabstiftients indegKaKientiy selected from hydroxy, a!kftxy, alkyl, oxe or halo;

R3 is amijiocarboityi, cyano< eyanoatky!. alkylcarbony! teeroeydylearhony!

alkyls inoearhoityi, alfceny! alkyayl hydroxyalkeRy! alkoxyalkoxyidkyS:, aryloxyaite yi alkoxycarboo laSkyl, alk lsuiftmyfalky! a!kylsulf«i¾ytelkmy1« alkylst fo&ylalkyay!

heterocydylalkyny! heterocydylcarboiiyklkyL aikoxyallyey! !tydrt^yaOtyrryi or XR4 ;

X is a bond, -0-, or 5{OS« :

o 0. l . or 2;

R* is alkyl, hydfoxyalkyl aioalky! alkoxyalkyl. aikoxyal e yi, a!lioxycarbonyidkyL carboxyalkyS, aminocarbonyialky! alkylamiB f tonylslky! aryl cydoalkyl cydoaikeny! boteiocyclyi. aralkyl. aralfcenyl, aryialkyny! cydodkyiaikyl cycloaikyia!keoyi, cydoaikylalkynyl, hderacydy kyi or hetowdykarhoo la!kyl; wherein the ring in R* is substituted itb 1-3 s«bstu«enis independeatly selected (mm H, alkyl halo, baloalkyl h drox ! alkoxy, aloalkoxy, aoyi aikyjsoliooy!, fceterocy y aiifisosylibs i, aikylamtoaJfony! cyaso, aikoxycarboiiyi, cartway, amSfto. RR N-Ci« alkyl alkoxyalkyl. hydmxyalkyl or R¾¾,NC(-0}; where * is a!kyl and R!> is alkyl aikoxyalky! a aoalky! or aikylatdnoalky! or where R* aid R¾ together with * ftitrogeit form a hderoeydi ring wnsuSwti feted or .substi uted with alkyl;

R;> is aryl, ara! yl, heterocydyialkyl, cycJoalky'i, or heterocydy! wherein R'"> is amubsii ed or substituted with 1-3 suhstifuents indepe«d¾«jy selected from alky! alkoxy, hydroxy! halo, haioaikyl, eyaso. alkox carboijy! arhoxy, acy! cydoalkyl !teieracyclyl ydfoxyalky! alkoxyalkyl a f RR N-, N-CM alkyl, or B¾¾C(^0) where Ra is alkyl and R¾ is alkoxyalkyl or ajninoaiky! here R and R is Mepe de ίί, alky! aryl heterocycJyl beterocydylaikyi, or cydoalkyl, where the heforocydylalky! cydoalkyl and heterocydyi rings arc tmsuhstltoted or substituted, with 1- 3 tibsiitsiOiiis independently selected from alky! alkoxy, hydroxy, halo, .baloalkyl. eyaoo, or carhoxy; or R asd R can together with the N form heterocydyi;

Rh is aryl aralkyl, heierocydyl, heterocydyiaikyi, m cydoalkyl wherein each of she aforesiefiiioeed rings Is unsutetoie or substituted with selected f om aikyl, halo, baioalkyl a!koxy, alkoxycafbosyi, carboxy, ammocarbonyl, hetemcyclyk¾toftyt, eyaso, cvcioalkyl ea?roc c! i !iydioxyaikyi, aikoxyialkyf, HWR C¾NRK , am or acyi;

1, is 0, S, Cli, or (¾0;

is L-R* : -.

F is L-R" : aad a pharmaceutically acceptable sail thereof;

provided hsn is 1 -melhyi- ϊ Iri - py s¾ z «1 - y ί > L Is 0 and R! is methyl, t ea R* is t 1-ethyMH- py!¾¾oi"5-y!*

further provided whet* R5 is 1 -meihvI-iH-pymoi-S-yl, L is 0 and R! is methy fees) s is aot 2-

S-y!, or J, Hj}mert yl-2-o o-i,E^¾ ditxj»jm Un-6- l:

etby {-pyri

¾?. A compound of Ciaira 1 having Formula .Ti'ia:

R6' ilia wherein R! is Cs.¾ alkyi C¾.« alkenyi C< hatoaikyl, C¾.¾ alkoxy, Cj.e hydroxyalkyl Q.s ■ani toal'kyl Cs ¾ aikoxy-Ci.« a!kyl Cj.g hydroxya koxy- ^ alkyi, C :-s aIkoxycarbonylaml«o-C« aikyl, Cg-is aryl, C u atyl-Cs-s aikyl, 5- 10 taeinbered heterocyclyi or 5-10 avaabered heieraeyeiyi-C), 8 aikyl whereto the aryl or hi%>rocydyl thug is smabisiUutei or substituted with ose or two

suhstititoHts iadepersdeotly -selected' from ¾ .s aikyl, hydroxy, oxo or haio.;

wherein '} is X-R\ eyarso, C{.s haloalkyl. Cj.s cyanoalkyi, Cj.§ alkoxycarbofty!, Cj.¾ aikylearhouyl 4-10 membered betem yclykafbonyi, aminoearboayi Cu; alkylsmhiocarhonyl, C;,¾ aikyl, alkeftyi, C>:,6 afkyny!, C5.« !iydroxyalkyi C¾.s ydro^yalkeny.!, C¾« hydroxyalkyrayl, C.( s aikoxy -€;.¾ aikyi, C;,;6 alkexy-Ct,§ alliox -C;^ aikyl. alkaxy-C{ aikoxy-C3.¾ hakmikyi, C5..g aikoxy~€¾.« aikeoyi,€;.§ aikoxy-C¾ .g aikyayi, Q.s afalkoxy-C5.« alkyi, hydroxy '-€;.$ aita -Cj.* aikyi. hydroxy~Ci-» alkoxy-C5.« haloalkyi. C<.B aralkoxy-€£.« alkyny hydroxy-Cj.B aikoxy-Cs-s aikynyi, C«.u aryl&xy-Ci .g aikyl, a yla y-Ca-g aiketwl, C¾.ui aiky1suKoftyl-C2.8 aikyayi aryl, C3« c doalkyl, C cydoalkenyi, 4-1 1 menibered tetsrocy yf. C*.« aryl- i .6 alky!, Cg.;8 aryi-C?.e aikerryl C&m styl-C^ ajkynyi. C3.s cydoalkyi-C alkyi C3.s. cydoalkyi, Ci hydroxyalky 34 eydoaikybe^ alk xyl C;i.s c doaik lCi s alkyoyl, 440 alkyi, 440 membered e enxydyl-CM aikenyi. 440 srahered heterec c!yi-Ci ii alkyoy!, or 4 0 membered teej¾cyciylc3rfK>nyl»C|.s aikyl: wherein rise aryl, cycksallyi, cycioalkesyl or aeteroeyelyi flag in R3 is unsybstliyted or substituted with 1 -3 siibsiiaiests independentl selected imm C} .g aikyl tele, oxo, RG~. Gf .g hsioaikyl Cj.¾ alkyis»lfo«y&min«-- C{.« aikoxy. teoaikoxy, hydtoxy -C^ aitey, C^8 alkosy-C).*, aikoxy, Ci & aikylsisl!½yl- Ct 6 aikoxy, C:S,ii acyl i4 alkylsalfonyi C< alkoxy<¾rbo»yl, carboxy, 548 tnembered betecocydyl, 5-10 tnerahered hetocydyl -^alkyl, C cydoaikyl C:;.s eyeloaikyl-Cxs aikyl, amino, aniisosulf wk € l alkyiassisosaifenyi Cs.e atkyisaifotiyiaidao, eyaoo, carboxy, RR -< δ iky Ct* alkoxy-CM aikyl Ci.8 alkox feiim>-CYs aikyl Cw hydroxyalkyi or ^NC^Q)- where Ri! is H, of Cs .« alky! and Rb is R, e,.«- aikyl. C,.« hy(toxyalkyl,€,.s dtkaxy-Ct* aikyl G}.« aikvlsylfonyl- C aiky Ct.« .aikyistdfonyiam o- Cj.§ alkyi, Cs .¾ affitaoaikyt or C?,¾ aikyl-C; .6 arnhmaikyi, or where * and Rft together with the nitrogen ion a 5-6 tnerrihered heterocyclic ring oriSubstairted at substituted witb Ct. « alkyi:

wherein X is S or O:

wherein R4 is Ct.« ikyl€}.« hydroxyaikyt, Cj.* baloaikyi. ¾.¾ hydroxyalkynyl C} a ikox - : ,. aikyl C; i; aitey -C2,; aike-wi. ; ,; »ikoxy-€;; S alkynyl, Cf.s atkoxy€ar»orryi-Gi.s aiky C< , carboxy&lkyl amifc(xarbcnyi»€( .¾ alkyi,€; .<; 3lk fefmi«o «*boH l-Ct.8 aikyl, C¼.ys aryl Ds.? eyeloaikyl C3 ?- cydoaikenyl 5- 10 asembered heterocyciyl Cs.j.s aryi-Cj,s aikyl ^m aryl€2.e a!kenyl, CMS aryl · alkynyl Cs« eycioalky€Μί aikyl, C¾ cy osikyl-C^ alkenyt C cydoalkyi-C2.§ aSkynyk 540 rnemhered hetemeyeJyI-€s.¾ aikyl or §40 rnemhered be ?raeyciyk:ar!>oriy!- Cx (1 aikyl; kiKsin the aryl cydoaikyl, cydoatkeiyK or heferocydyi ring m R4 is ^substitut d or substlMed wiik .1 -3

.sutetftuftresi iKiepei itstfly selected. fir<?m Ct.s aikyl halo, Ct.8 aioaikyl Irydrsxyl a!koxy, C,.s acyl, Cj.g alkylsaifbsyi, ¾.s alkosyearhorryk carbosy, 546 raersiteed he!erocydyl. cyano, aitrrao. Cj,. s amiaoaikyl 0¾,3 aikoxy-Ci.« alky], Cf .s bydrasyaikyi. C.5.« haloa!koxy., Cf .» aikyl- RR , at»tnostdfbi¾yi, Cs.e alkykmiaosulfoayl m RSR¾C )} where R* is C,..t< aikyi ami i is C,if aikyl, i aikoxy-C}.§ aikyl C$ s arss oalkyi or Cs.¾ aikyl- C¾ .6 atnio.oalky'1, or where R* and b .together with the nitrOgeri form, a 5 or 8 raembered heteroeydk ring aastibstiiated or stsb&iitated witi) alkyi; where R and R is independently H. C} .¾- aikyl jfshenyt, 54 raere'bwed heieroeyciyl 540 o erabered eta'oc clyl-Cs.8 alkyi. C3 cycioaikyl Cs.s& as-yj-C5 S aikyl Cs.s. cydoalkyl -C1 fi aikyi: wi5e the > henyl C. cycloalkyl asd 5 ( snenibered heserocyciyi rings are msuWluted or .substituted with 1-3 stjlssiiiiteras indepeftd«itly selected wm C5 s alkyi, oxo, C;: .¾ a!koxy, hydroxy, baiO: C).¾ baioaikyl aRO, or carboxy: or R and R can together with the form 540 roernbered bea;roeyelyi:

7215 where ! is phenyl. ISklOmembered k;ierocyciyl, 51 emhered heferacyd l-CM, alkyl m CiA cyxioaikyi where the heterocyciyl, phenyl - m ydoalkyi nd 5-1:0 membered heterocyclyl nogs are tmstibstinited or stibsfiiafeci with -3 s«bs{¾e»†s iiwiepetidenily selected from C(.g aikyi, C¾ .5 aikoxy, hydroxy, oxo, halo, Cs.¾ haioalkyi eyano, or cmb&xy; and

wherein " Is 5 memhered nitrogen contataing heteraeydyi 3 raembered o en containin hei¾oeyeiyi.6 memhered oiiroges containing heteroeyeiyi 6 membered oxygen containing hetefjcycSyl, phenyl ben¾« 9 membered bicydic nitrogea containing heterocyelyl 10 membered bicyeSic -oxygen containing hetemeye!yi ¾:* 10 membered btcyelie «!tro i¾n os-iiai«is¾ IsderocycSyi, wherdn is utmbsUmted or substituted wth ise or mae sabstituenis independentl selected from Cj ii alkyl cyaso, hao, oxo, RO-, Cf.s aioaS.ky!, Cj.s ydroxya&yl C;.§ aikoxy-€}« alkyl C ;

aikoxycarbonyl Cj.s alkyl, C¾« aikenyl C^aikoxycwben carhoxy, <¾« cycioalkyi R alkyl optionally substituted 4-8 umbere boiemcydyi, (optionally substituted 4-6 embered nitrogen containing heterocycfyllcarhonyl RR SC¾ RR SO? RSC.V or R*R¾NCC-0)« where R¾ Is H, or C}.« alkyl and R!* is H< CM? aikyl C3,$ hydroxyalkyL€f.s alkoxy-Cj alkyl, C{.$ ananoalkvi or C$..g lfcyi-Cj-s aininoaikvl, or here R" and RS1 io^eths with the nitfogen form a 4-6 mesfeed

heterocyclic flag rjosuhstrioted or sabstttuted with C} .& aikyl;

provided R! is oof phenyl orfei -b«tyi when R"5 is 2-pyridyUhie, meibcyyehoxy Of ir!ltforcHHJth i and * is 2 ethyi-3 pyridyj, 2-rrsfiihyi-3-pyri«yi, or 2.8-dline 1--3~»yrkiyi;

further provided R1 is not 4-raet¾yjl-2-imidazoiyh«ethyl when * is S-pyridyltldo aod R" is 2-edryl-3- pyridyi;

aod a harmaceuticall acceptable salt thereof,

28. Compotmd of Claim 27 wherein R! Is methyl ethyl propyl, allv tert-faoty tri ooi'O - ethyi methoxy, et-hoxyeftyl, IvyditwEy ethyl bydroxypropyl 2,3-dS¾ydmsyproj>yI, 1.2·

dihydroxypropyl hydfoxyeifeoxyet yl 2-hydroxypheoyh»Kt y1.3- h drox liei! iffiehyl 4-hydi»x - he« teH;h {, 4--B«orophenyimedrl phersethyl morphoBn-4- yiet.hyi 2-pyddylmethyl, 3-py?kiylmd y.t.4-pyridykiethyl, 6-meffey.i-2-oxo-i,2"

dJhydropyridinylmemyi, imklazoi-5-ybiiethyi, -riii>?lryi-in«dazoS~ -yloK*iiryl. i-stieib i-iniidaxdi-S- ylmethyl 4-inetf.vyl- imidazoS--2-yin)etlsyL 5-mer 1-nttkia2»1-2- in» , t,5~dtmetliylpyr¾'t » yktethyl 2-»«l»y ia¾elyl-5>melhyl S-inetbyi-isoxazoi-S-yiinetbyi or phenyl; and a

pharmaceatrcaiiy acceptable salt thereof.

29. Compoasd of Claim 27 wherein Rs is tncthyi; and a pliamsaceaticaliy aeceptahle salt thereof

30. Compound -of Claim 27 whereir! It* is SR*; and 8 pharnsaceaiicaiiy acceptable salt d's reo.

31. Compound of Claim whereto R! is ;mi¾haxypropoxy, 2- feiettesy)>rapoxy , hydroxysthoxy, aydroxypropoxy, 2~hyriroxypro|«ixy, l<2-4&ydroxy^opoxy. i~hydroxy~2~ medrylpiOpoxy.2-]5ydiXsxyb»iixy, phenoxy, 2-meihyi-3~pyridyloxy< 3-oX«taiiyh¾< roxy, otettoxycarbiuoyliaeibyUliio, methoxytarbonyMb Mo, metboxy ropylthto. -methoxyb«l--2"yi!.b£Q, b di tx pi'0|3ySfliSo, 33- iiwdroxybuiy!tbi o, ear boxy etbylthii (sset!s kustsocarbonyl} methylthJo, {diojed isjidnoear oB ijmfcdi iliio, {S-hydroxy-^-meih ibu^Dtbio, (2 %dmx -- "H3e lbat 0fhk>, dlflaorometliylthlo, (^ri byl lpeiaxln-l-y^-caftoj lmeth ithio, {mo^bolStt-4- yl}cad )«ybn¾liyl:ihlo, (1 -terMjutox earbOii l piperidin-4-yl)me lthia) {l- i erfdiswBKiedwli!do, (tetrabydro-2H-pyian-4-yl)a¾(liytiblO i-Uittabydro-gH- ras^-yDethy l , (5-metbyl-H- «xad?a iyi}methyltbio, 2- yridylmethylihio, S^-dJhydrtixyfcyclopenyltblo, 4- hydr«¾:ycyciih xy!ihio, cy lo enie«yIibio, pbe«yI† o, btwyitbio.2-pyridy.lthio, 2 :Moro-4- pyridylilii , {^pJper^io l^-pytidygmefh lthlQ., { 1- iiieiir Ipiperkiin yi 2 py ridyij ineiliyirlilo, (I- h droxyeihenylp erkl to - -yi -2-pyddy;S}me%M«o, I -(l tydroxyethylplperidto-4 -y.l) - 1 - (2- pytfdyl)mihylthto. Hlnneitylpi^ Mpiperidin-S-yi-l-fc- pyridyJ)meihyijio. {4-pip«»ddt»yi}iiito, (1 -isopf8pyr)pipi»ddm-4-ylihlo, {l.-raefl}ylcartOftyi}pipefidio-- (i-iBetbyl¾aFo»yipipefidift-4-ylftiO. (I- iso fop f afiwoyli ip riiSffl^-yithif), { - {ffi«Jk>xyc85¾onyl}piperfdtn-4-yirhk>.1- (atetboxyeihyicarbonyQplpaidja-^-yfthio, l-(d«iJ6¾yteffihBicarbofiyI)plperidiR -yilblo, !

tM o y ai½i^l}piptstidia- -yHhi<, (^{S^h Toi^iinid^^i-yOpi erfdlt - iKKto, {l-{2- pyrlffiid«iyi)p!p«rsdiii- y!}ibioi (1 5 yoK¾j 2to-:2- ]) iperidja -yi)t io» t -{tert- btrt xycarbo«yl}.pyrroUdtH-3-yUhio, 3-meihyltoxa¾aio}.5,4-b|pyridlii-4 -yli o at i shyd -Zi pyra«-4-yHhlo; and a pkimtaceaUcdiy acceptable salt ilterfettf.

32, Compound of Claim 2? teeiss R;! is <qyam>, methyl, tiiyl propyl, isopropyl, 2- ethylpropyl, 2,2'dlniethy.lpTopyl 2 -osf. Sbuiyl, Irifiuororfiethyi, 3,3,3- irifluoropr pyl,

.fiaoromethy.i, .flaoropropyl, hydroxymeby.1. hydmxyeihyl, i -hydmxy-2-m« iyletfcyl, 2- ydroxy-2- meihylethyl, hydroxypropyl, 2 yyd:roxypropyi, l-ydi¾xyprop-2--yl.1,2-dShytiroxypropyl, irydroxyhatyl, 2~hydr x¾aiyl, 1 ,2-dnyxlroxyhu†yl, 2-hydraxy-2~»!^thylha<yl, 2>2- {dibydraxyroe yl) butyl, l~feydroxyethoxy- 2¾9ΒΚΧ; 12 --{hydroxydhoxy}elfayi 2-

{hydroxy ethoxy)propyi. {me »xyoKitfcylethyl, i-mei o yeibftx -g-feroinosrtbyf, 2-fcydmxy-2~ otetbylpeBi l, 2-hydroxy-2»atetbylbfexyl, 1 ,2-dihydfoxypeioryL ^--benzyioxybatyl,.2- bydroxyethoxybatyl, H wdo¾y- "metb l ro ox propyl,

{etab dro rai '-y!}-' drax Enet!i: l .2--f½oro*2-¾ethytbmyl, flXilhoxymethoxymethyl.

metboxy methyl, sietboxypropyl methoxybut l, 4,5-dist$Shoxypeoiyl niethoxypemy!, ethoxyfeiheoyl, fith&tyL propen-2-yl, prop n-i yi, pmp-l-¾¾»-2-yt 3 iydraxy rop*l -s»-2~yl, l-hydroxy-2- metbylpropeftyl, buiesrvl, 3^3-di ethylbttteB*l -y 12- ea2 k) b«le!ttjinK;fta «jpeB-- 1 -yi, 2-t*¾oxyvioy1« mfty&sdfoaylallyl, mhkdfoay¾«-2-ea- i-

(dime!liyiaininoetliyO -amtsoearbqnyi, ieff -feiifoxycai-bonyteiefhyK ί !wdraxy- 1 fert- buioxycarbmiyiorftyt eth0xyeiy¼oy1prapyt et ox-yeadiooyteihyi. ί-hydfoxyelhyl··

raethe^arbooyletyl, meth ia iRoc¾i¾eiii ¾neihyi. mesliyiaftiino arbajwiesliyt

cyanoethyi yaaoprapi IJ-dlhydroxypeolyt 4 -dihydroxypeftt-3-yl, hydroxybatynyi hydtoxypropynyl, eihynyl, 2- yclepropylv.biyi 2-bydroxyelb xybut-i-yn-I-yi, 2-hy<ln>xy-2- nit'fhyiprop xypTopytwi, besszylosyprop- 1 -yiH-yl. benxylox bat-l-yo- 1 -yt, beii?ytoxydboxyprap-I- ya-i-yi, I -(1hydmxyt clopeniyI)etbyByI: 3-iaethyi 3 >xetaft te iiy!> i«etIu)xybuM-yii-i->i mef oxypeoiyn- i- yl c cla e niy i ί citmR mtiiy K orfwisidiboySpropyl met yLsuHbtiylbiiiyf, phenytetfeyi, benzyl pbeny!propy 3pdWomphenyimeihyi.

pkiayletheayl. i-pk¾»y1viay1, pheay hvayi, p rid-2-yl sthyl, -cSilofopyrid-S-yimetbyl, 2-t¾k>xy- S-pyridytobyl, 2*eihoxy-5-pyridyl«?&yayi 4-piperidy iKithyi, l-jriperidylm hyl, 4-jnetaylpS e?a¾iR* :i.-ylmeiliyi 4-8o -pipei8z:te-i-yJmethyl 4-t¾e %uf&oyl-.-pSperazi»-l.-yb'aetbyI,.4-methyJc&cborty!* piperazin- i yiaieihyi, roar holsiM-ykiedi l,

, {l,l--dioxldoihiOii[jorphoijno)meihyl, 3»methy1--3-QxetoyJ.e l, {tea¾bydro--fer- 2 -yb methyl, (i¾iral:f vih-o - i¾t'- 3 y Ϊ j is ieiirtyi , teir< dm mv -yta<;tfi l,

tetrafcydrqp ran-3-yimethyl, ietra¾tydtopyfaa-4-yletl¾l 2 iydwxymeil\yi"ieto¾ydrtpyi¾tv3-- y!atelhyi 2-h^roxya^th l etrab dK}p iaft-4- Ia«d? 2-i¾tfwxya¾tbyl-tt¾ah drop raa - yteeth l, 2-«^hoxyme J-t-e»ahydfopyfaa-4-yli« byi 3- (22-dimedryl- 1 J-dioxo n^-ybpropyl, i ,3-dioxoka4-pmpy!« ! ,4-dioxan.^-methyI, i ,1 -dioxMotetiahydm--2M-ib.lopyra«-4-yl«ietby!« ΙΛ- dioxido4eiralwdm-2H~fbk> rafi"4- ie i,

azaspIt> ll:ie iai5:-:i- !:msibyL 2-oxa-6-azaspira|33I epto-i-ylmtiii'iy], -dioxaspira[4--5'|dec»«-7- yimetbyt, 3-heazyioxy-cydGbtttyln)eibyi, 3--byd:rosy c ciobusyiinet yi, 3-hydtaxy-3- mefhyi- cydotaytemhyl, 3-oxo-cyciobatylmtiiliyl.3-bydroxy-«l^ifhiofomeiby!-tydobaiyimt« l 3- drox ^-mitSiyl-c cIobiif i-bydrox ssetb l yd'opsstrtylmetbyl,.. i- droxycy<:lopeaty])tne i I.- (i»ettoxyc>'dopeaty!}weAyi j<8)ethoxycydepe8{ I)l»oi«&«i€ li cydobexyimetbyl 3-hydroxy-- cydehexyimetbyl, 4-bydfoxy-cydob«xyl8»!tbyI, or tydobexylmethyl; -and a phannaceuti aUy acceptable salt: thereof,

33. Compoand of Claim 2? ysrbwia RJ fscy<k»prapyl, i-tseil-buto^carboByj-l-c eJo top l 2iidoxycarbopyteydopropyL 2-(2- dj»xy-2-methytethyl)-cyc.k>pFopyl 2 -iiydroxyi»ethyl- eydopmpyi cydobaiyi 2-hydroxyQ'diabuiyl, 2-<&<eeydob»tyl, 3- ify droxycyI« usy 13~ benzy!oxycydebuiyi, 3- enzyfoxy- 1 -hydroxy ydobuiyl 3-{2-bydr vy--2-j«etbyI« iyl) - ydotetyt, 3- cydopenfyl, 3 j|ytiroxyme 1eycIop<.i«i i..3,3-dijbydmxyine0tyicyck>piiiyl, 3-car oxy -cydopenryi, - y<froxy«ief]¾y!c c]ip&«iyi> 4--hydr0weydop£«Syi S-lwdrosyeyciopentyh 2*feydro.xycyd0peHfyl 3- hy di'osy- 3-;nK*yi ]cyciopnE ].2 -os -cy clop ftfyL 3 -csxo -cydope«Eyi.2 - ( -ethyl - - mer.hy!amiRo rbonyi}cydogen(yl.3··( •e{hyl »meihy{amfBO€arl>osylcyclopen{yl 3··( - bopfop kffiiKOc rbow c clo ftiyt cydohexyi, l-hydraxycydohexyi 3- y^roxycydohexyt 3- bydt»xy»3-»)«ihyl-cydohe5£yl, 4-hydto8y"4-a)ethy!-cyctohesyl> 3>oxo-cyclofeexyls cydoheptyl, c ci pesleayl 3-hydmx -cydftpeateftyi 4½'dj¾^mfc i -m¾hyl-(^c]ofii:tei} !, 4,4- bis( dro ni¾ i}c d0 e«i-2- H- i- S, 3-oxo-ey lopeatt¾y!, S-caitesy-cydopenf-E-erfyi, 3- tsopr Gpyia»iiTK>tarbofiyi ydop ¾-2 -eayi 3-.{bydroxymertiyic dope»i- 1 -yi < 4- 0sydroxy»se†hy!)cycS©pei5 -en-. -yl, 4-{!¾ydj:o¾y«5i.hyl}eydopeiif-Z-e«- 1 -yl eyddiexsay.1, 4 ,4- dlfiMhy! -ycloiiexeftyl, 4-tei-butyi -cydehexeayi 4-hydroxycydobexeayl, S-hydrexy ydoiiex-i-ei-

me isttlfo«yl~a2didia~ 1 -ykaAonyDcydohexeisyl cydohepftiftyl i,4~d:io.x&spiro{4.3)d«c -T--n ? yl, or J ,4 -dioxi!Spli"o|4.5]dec£iii-T-yl: and a pharmaceutically acceptable salt i!tereof.

34. Comptmod sf Claim 2? wherein J k 3-&ydroxy--3--oxfclanyi 2-teira ydm-fuiyl, 3- tyiiarydm-furyi 2-methyl-3-tetrahydKi-fttryi, 2-'metbyl-2 t¾fa ydiO-f«ryl,.2-hydtOxy«i«ihyl~2-- tettaydfo-furyl.2- di¾5i 8)eti !-ietmh dro-fur -yL 2*2-diifietbyi-2,5-d dr9fura8-3--yL ¾,5- dthydrofuran-3-yi, 2>3-dtSryds¾!umi-3-yI, 4;$-d&y#efui¾»-2-yl, 2-oxopymrtidia- 1 -yl,

te&ahyd?opyra8-4-yi, 2,2-disiefhy!t {s;a}riir«|yyais- - i, 5,5-di»j«ibyketrahydropyran-2-y{.2,2,5,5· teffa«eOiyl-2,5-dlhydrofumn.-3-yl > 4-fluGn tt¾rahydra» ia«4- i 4-fkoto-3-bydroxy- teiTahydropyras-S-yl, -.flKort 3-int'r o y-{etah dro >¾afi-3- l, 4-hydroxi«traiiydix>pyma-4-yl< 4- byd«)xytetrabydRipyraa-3-yl., 3~hydTO ietrahYdr«:p faiv- ~ !, S^-dlli drox idah dro ran^-yl, 2- oxo-tetmhydEopyraa- -y}, tefFah dro iai -y1, tefral$yd pyraR-2~yi SJ-dihydropyran-^-yi 3,6- dl¾ di> fsa-5- i S,8-di ydro-2H-pyran~3-yl , 3,4-dihydro-2H'-pyra»-6-yl.3«4-dlhydro-2H-pyrati-5- yl, fi^-dijaeth l-S.^-dlh dro-^H- a -yl, 2,2-dimetbyl-3>6-dSliydfo-2M-pyraft-4-yl , 3.4-2H- dihyd«)pyraa~4-y; 1 , -diiSis¾sjxlo{' .5)dec-?"eR-8- .l l(l.-dl©xo-sothf82oiidi«-2-y l- •dioxldote{rahydfo-2H-d)iopyran-4-yl, 1 ,4-dk>xan-2-yi S-me Kixy-rae iyl- l,4-dloxan-2-y.l., I t ri- butoxycarbonyi- 1 ,2.3.6- letrahydropytid-4 -yl, 1 -methyl- 1,2,5,6-tetrafwdropyt'id -4-yL ! - meJj isulfoeyl" 1 ,2,3,6-k¾^ydfopyrSd -yt I f diiisehy ias« irio arb styl) - ΐ ,2 ,3,6 u?tm ydiopyxid y ί , !••{mediexyearbGB.y 1}·· f , 2,3 ,8 -teiiahydropy rid- 4 -yi . i. - (metliykarbaayl) 1 , 2,3 J -tettahydi spy rid- 4-yl !-nseihyi -piperidio-3-yl 1 ert43aiaycarhoiiyl-pip«ridin -yl, or 1 -{dhae¾yIasviaocari)ony!- pfp6ridfo-4<yj; and a phara¾a e«iically acceptable salt th reof.

35. Compotmd of Claim 2? hertds R'! is phenyl 4-dderophtenyI.3-meihytp.henyi, 4- meihy!pknyi 2.4 dinetlT l ^nyL -iri0u{>ome ] hes¾'i.4-tr}fiti roroe&ylpb«ii 4-riiei qsy~3- iriHtioroi«¾'tfiyip]ififiyi, 3-ddlu0raaiet i -8t!oro]? eii i> 2-me ¾a!foftylfhenyL 3- tnethylsuifqoyipheii i, 'raetb hulfonylphen i, -eth S.s«!foBylp½i¾yi, 4- ffletby!sylfonylamlaophenyl.

eyaiiopkmyi, 4-cyaROpbeoyl, 3-car oxypbeoy., 3- rbox -4½^mxyphe« l 3-eiii¼xy-8- meibax pbeoyl, -cai¼xy ¾eay 4»cyaBo-3-}««toxypheayl.3-cyaao4.-a¾eihoxypk«yl, 3·· 2-{diffietl lamii}Oca!: »s ]) ei¾ l, 4- {din}ediylajaaocar½«yl}pheai 3-« te i oi:ai¼«yIpf5eny!, 3-iN-ethyi-N- f«t?fl5yi8i8iaocarbf)iw!pl¾wi, -e†!¾yi3miii€arbo»ylpS¾ei i, 4-( -eihyl-N- in ih laisiaocarbosrvilp esryt 3 so|5ro|)yiaiuiiK>€Kr ooylplKiisyi, 3-(N-buy}- - metliylamino ar oByDpheBy!, 3-{N-pmpyI-N-Bje ylai»i8o arbo«ylp e!«yl> 3-(i,2 - -;«¾eihoxyetby'l~M- mei iaffiiaacar ofi li ea i, 4 ^h dmw$t yi-^ S-mei.bosy-3- dlmeir ylatniati arbonylphiiHyl, 3-mi¾lK)xy-5-e{h {a»ji«ocaflKay1 kai It 2-fneihoxy-4- diineibytemioocarboRylpfiesiyL 6-mei;!mxy--3-db:n?Sftyiaminoc3r ojiyipbtiny]! 3-ffieik -S- »t y!38Ji:tioc»feonylpR€ftyl, I i mxy-2"ffieihyf ro -2^

hydfoxyetbyiaHiinocafboayl-pteyi, 2-b drox -- -mie{h iprqp iaffiSsocafiK>n l-- ti i l.1,2- difeydmxypropyiamisocarbonyl-ph yl, S-CI -az fidbiyicarbof! ilphpii i, 3 -(34:liisira-azed.diiv-l · ykarbo!syS:}pk¾yL 3- 3-hydmxy--aHiHd^»4.-ykaifeottyl)pk>«yl!.3-{3-Biedioxy-a¾<¾idm4-

8wr toM» lcai¼ayi) i}e«yl 4-nMk»xyp. :ayl, S-in&liexyphenyl, 3-0uoro-6-meifiosypi¾ syi. S-flawd-S-HKthoxypbeayi, 2-ra ioxy -«jethyt»iHiiK)sulfo«ylphenyl 2- me¾oxy4-eisylai8inosui&ay!phenyl -i*fta -3-me 1anJ o^lf(m l hfcnyi 3-« bQxy-5- methoxycarlxmyiphenyi, 3-carboxy-2" e&oxypk>ny1.3-difiiKirometoxypbenyi, 3-

3.4-di ethox pheayl, or S-besrfki ol l; and a pharmaceutically acceptable salt thereof.

36, Compotmd of Claim 2? reta R3 Is 15- d!isiedwl 4 pyrazolyl, :i ,5-irimeihyl 4 pyrazolyl, 3 -meihy.i-4~pyrastoi.yL 3-infi.i!oro-etbyi

pyrasralyi, l-[2,2.2-biil«oroetbyl|-4-pyrazoly{« !~carboxymeihyl-4-pyrazo'Jyl, 1 - etboxycaj¼oytoiethy1-4--pyra2«lyL 3-cyclobutyi-4-pysazolyl. l-cydob»tyi-4»pyiszoiyl. ί··(4·· ow hQlb^carki^ ftiet l^-p faz-oly), l-(4-aKVpholfnyl}«byl:4-pyra¾«l.yI, J-hydroxye{by!.-4- pyrazolyl, I -hydroxyethyl · S-pyrazolyl, I -hydmxypfopyl-S-pyraxolyl, i · (3· bydr oxy-3«¾¾byi.b iyl)-5 · pyra¾oiyl l-nKstti«xyetfiy-4'py«ol>i a-pyraiolyl, !-raetfay! -5-pytelyl, i -disae i-5--pyrax lyl l «a¾hy}-3-iri{iaa.«)me-byl-5-pyrazol:yi 3-mt¾h lajnint«a^» l- fa¾ol--5- l 3- dla-seibyfainin carbijayl-pynszol-S-yl S-jaeiliylsaifonylajaino-pyOTOl-S-yl, 2-8»thyiswifoB knj o- pyra¾oi4-yl 2-.methosfycai¾oft 1rpyf82oi4- .l< 2{3-dij»sihyi- S-Aiaxoiyf .2-{2-'hydroxy-2- mei kir ]}-thte>l-5-yl. I-metby!-S-imixfezol l, 3<5-d-metby]4soxa¾oM-yl. l.-metby| da$n4-yl> (4- hifl»c»ro»}et l}>be8yl)}a8t y]-td8za-<4-- i> 2-c aiK --«:*h »ifcteiKi l, 2->«-efliO){ycarti08 ! l»ieft--5- 2 · ( -ei yl- · methyi-3:rtHno¾rboiiy!}fh!en-5--y].2»(2»¾ ib!ix -2-!n^ii½1i i)tbien"5"yl, 3--metbyJ.- L24-oxadiazol-- 5--yl< or 5-cyaBO vf -mefhyllpyrroi-X-yl; and a pharmaceutically acceptable salt thereof.

37. Compound if Claim 27 wfeefete Rs is 2-pyndyI, 3-pyddyi, 4-pyridyl, 2-wsihyl- S-pyridy'l:

2- i» byl4-pyridy3, 2-:methyl-3~pyridyi, S-metfiyi-S-pyridyl, 3-tfift« fftrHe†hy-5-> ridy!, 2- irfflaorometbyl-S-pyrld i,

3- yridyl, 2 -meiboxy-S-pyridy'i: 4-im>dioxy-3-pyridyl, 2 -meihoxy-4-p rtdyJ, 2-C3-oxeiawi)jBe£haxy- 4 yruiyi.2~.(3~ox«&nyl)oxy4-pyr?dyl.5-fl»ioro-2-oieihoxy-1~pyfidyl, 3 - 1¾ co- - pyridyl , 2-llttoro--5- pyddyS, .'j-IisoFO-5-pyddyi, 3^a*etk>xy -pyridy.l, 2-fitboxy- 'pyr yl 2- mettoxy- 5-pyr idyl, 242,3- dibydroxyptupQxy)-5«pyftdyl, 2 jydtoxymei.ho3ft'-5-pyfidyI, 2-feydf<ixy<¾boxy-S-py.ridyI, 2- feydroxyef.boxy-4-pyrtdyI, S-lli!om -S^syiboxydiiOx - ^ - rki 2-tnelhoxyetiioxy-5-pyr|dyK 2- bydroxymetbyl---5-pyrfdyl> 3-awt!«}xy-5-pyn{Sy5, 2-¾thoxy-5-pyrfdyi., 2-;bopropoxy---S-py.ddyl, 2- df xy-2 -ffiedw!|>ro ox -p rkyS( 2·(1 ,1.!-trifluoioetbo vJ-S-pyiridyi, 2~cyrJop pyiffiedK>xy~5- pyddiayJ., 2· {roe{hyisolfonyl:propoxy)-5 -pyridyl, 2· (roeili isulfGny]3n^oo¾ ox }-5--p rki l< 2 · eibexyprop&sy4-pyrkly 2-dlflt«>iOH}&tk)Xy-5-pyrkiyl 21yGro-4»pyddyl..2-cbloiO-4-pyxidyi» 2- chloto- 5· pyridyl S-e-h.fero-5-pyldy!, 2-c ¾)o- " rid i 2-^ano-5-pyfidy1, 2 -raeiboxy-3-cys8e-5- pyridyl 2-cyai5o-6-iiiefhyi-4-pyndyi; 2-iweUto y-6-n5eibyi-5-pyrldyl, 3-cyaao-S-pyfidyi 3-cya:io-4- pyridyl, 2 -r««ihyistti-foijyl-5-pyiid 13-8}ethyisulfo«yi-5--pyti yb 2- (ntethyjsulfooykndno} 4-pyri.dyI, 2-¾nedioxycai¾anyl-4 -pyndyi, 2--{¾«idazol- i -y1)pyridyJ, 2-f«etox imiii0me{!iyl- -pY5:!d I, 2-axo-l,2 · difeydropyrklio-3-yl, 1-imithyi-2-oxo ,2-dlhydrapy.ddi«-S-yi!. I.-meiby1-2-ox. -l,2-<iihytlropyridia-4- yl, l-etl) lr -oxO"J>2-dihydi ddifi-5" }, i-is^r<^ l"2-^ o 2-dlb. drop ridi«"5-yl41- h dro eft l-Z-o o-l^-d&dTOp rklift-S- !, J -hydmxypropyi-2-ox - .2-dibydropyfid}a '-yl, 1- me& l-2-oxo-i,2^!iii dm Tidin--4'- i, 2- ydmxypyrid-4-yls 2-bydroxypyrid-5-yi 2-aminoearboftyl-

4 - pyridyl, 2-roedtyi3t«iftocartKHiyl-4--pyTid i, 3-ffifi iasanocarb0n I:-5-:|5 !iii i, 2 - iS0prop teiateocarboa l"4"pyfld l; 3 - iedw-as aoe& b©$tyl-5 -pyddyl , 2- raetbyls«lfo»ylc -femimKartK>«y'I4.-pyridyl, 2--ffielisylsii?foo iaffil«o<>^

3 -Hieb isoioiiyiaroifiosifji 2--meil.ylsaifbnylamiooetboxy'-5 -pyddyl , 2- hydi«xyeibyla«ilnocas'boayl--4-pyiidyi 2 iydra"cy(¾hylajmHocarbony!'5-pyddyl, 3- bydi¾xyeihylarolo¾carbonyl"4-py.ddy1, 2'hydmxyb{iyassla{M¾rbo«yl-4--pyiidyi 2- med»xyetbyia8d«ocarbosyl4-pyridyl 4 ·ί1«οι¾-2-^ΐβ ΐ8Π5ΐ«οο8ϊθθ«'ΐ8 ηο-5-ρν^-1, 2-{ i- ioi¾dass>iyi) yi1d4-yi, 5-py?si«idioyl, 2-iammo-5-pymmdi»yl! 2- a80-5-pyrtfKjd|nyi 2-m¾h0xf-§- pyrloi!disjyl, 2-«ihoxy-5-pyrb«ldl»yl, 2-rsopropoxy--5-py«raidloyi, 2-wnu¾rofeibQxy-5-pyriaiidtnyi - itlfluer mei¾yl-6-pyrimWa.yls 2-trli¾oro«fhy -pyH»jidKxy 2-trifia&toethyl-S-pyftJ«idiiiy!« 2- dimethylamjai rk>nylpyriinidlR-5-yl> py*azia-2<yi yrida¾ta-4-yi; and a phareiaansdcafiy acceptable slt thereof.

38, Compound of Claim 27 whereto RJ is S- etizotMenyl. S-benzofaryL 5-indoy., 2-οΧο·· dih di i -5 -ladolyl, 6-aidoiyl 2.-oxo-d])y(ko-6-todQlylt Ϊ -met l ^ -oxo- ihyd}X> dtklttlyl< iif)ida¾of 1.2- ajpyridbi- ·>! imidagoT ! ,5-a|pyrk!i«-Syi i ldazo f L5-«]pyrjdin-7~y.l; iiiddaxoif 2- a]pyndiiS-8-vL i -dSo o-¾-w 1--3. -d <<fo-2H-beim>f ] 2-methyI- - diox!do -d¾ *>ffi 4- me I-5- xo-2 .4 -tdr dri» )ei .f |14loxapln-7-t 4^liyl-I>I-dtoxldo-3,4'dIydro-2H-

4- methyi-5-oxo-3,3~d ^^ 4-«tefiyi-5-oxo~2!3;,4(5 «†faI¾ydf0- pyrida [ ,2-ί| j ί , 4foxa¾epin~ ? - yi I mmA -4 -yl, 2-msi'ay¾H;ftzow l-S-y|.2 -etbylbeaxoxazoj -5-y? , H-f5ca)fOpy!befi20xazol-5-yL 2-oxo-2(3M}-be«¾o|d|ox3zoi-5-yl , ben¾oxa¾ol-§'-yI, feeezothiazol- 5-yl ae KOf tart-8- l, 2-mathylb ¾£otbiazol-S-yl, 2 50pTapylbsn¾od|tbia¾o:i-8-yi!. ! -n*e†ltyf~$- ben?iraida¾oyl> S-indazolyl l -mebyi-5-indazo!yi δ-lodazoiyl, bmetbyi-S4da2olyl 2-meabyl-2H- Iodazol-4-yl 7-azaindot-6-y!, 1~ »wM-4-yl. l,S~dImet{» l-2,3-di y<!m. H^ m5ki|2,3-b] ridlB-5--

«iedi i-3"Oxo- «i¾«[d|lsosa¾oi-6--yl i-m^hjl-B- HittKXy^-^a^iiy dllsomol-S-i,.2- $aetbyfoxaz0lo|Sf4-¾Jpyddbi-5-yl 2-metbyioxazOlai&t4-blpyfidi«-8-yl, 2-Bethyl-3-ox0-2,3-- dlSwdroisoxa¾oioi5,4- lpyridb!--5-YL -dIoxo -mrihyi-3.4-d ^

yl, 3-iaed¾yl-i.mida2o{! ,2~a]pyddm -y], 2-oxo~:i H mida¾o[4,Svbipyrfditt-2(3H)-6-yI. ia>a¾zop.,2- ajpyridia-7-yi, ia¾d¾¾ofl.,2-ajpyrtdia-S-yl 2-fixa--23- ] ifo H-l id 2o4 -b! ridsa-6-y], 2-oxo- 2 -dibydrabeazo |d)oxa¾al-5 -yl, 3 -oxo -beam {dj (J .3|«xalI¾i i- S-yl.3,3-dioxa- b m \ύ} { 1 JJoxaddol-

5- ylt 111. i triazoJ o .3 - a)pyri.dto-5-yi, i^^Jtflaxoiol ^ajp fLdto-S- l, 3- dfoxymefliyi 1,2,4)tria«oloi4,3--a.lpyridla-8-y!, f ί ;2,4Iiriai5Oit0f ί ,5-3 jpj'fidto-7-.-yl, 2½dr xya¾ ^

bydrt>syme{y.!-2.3-dihydro->i! A jdioxioo j2,34>lpyrid!sv?-yL 6-qai«oHoyl, 7-tjianoliayl.4- isoq aolio f 7-lso¾ainoItoyI, I ,δ-aapbtbyf idin-3-yl 3-ffietby!.- 1 H-pyrazolof 3.4-hpyf idio-5 -yl , iH- pyra2oloI3,4-b]py{3di8»4-yl or 3 - fei.by!-3 M- mzolei.3 ~b)pyndin-4-yi; aad a haratactndlcafJy acceptable sab thereof.

39, Com ound of Claim 27 wherein If is t^rahydmmranyl, rabydmpyraiyl 3, 4jhydro- 2H-pyra«o|3f2-cpyrldi.jy!, chromaayl bexabyds¾iur [2 -:bSfiiryl pip iidlsiy!, pViM yi zoiyt teteolyiptasyl quiaoltoyi, ! 52--dihydroqt Boiiayi. pyrrolidmyl, beozyl, 1 &4 «trahydraqiibioiiayl 5-,6,7,8-iietta¾yxiro< iaoll«yI, qatooxab¾yl< qutezoliayi iH-bKte>Jyi ZH-UMiamfy'J, isoim!o&ryl |i.,2,4|iriazo!0|;4,3-a]pyrk!!ivyl is<« i«o|iiit i> iH-pyra»o!o|3,4- bjpyridioyi iiida¾o{l,2~ajpys:kiiay{« 3H~:sdd¾»o[^«5~a) idiayl,pyradB-?¾ai {, pyrazinyi pyriittidirsyl 4:5:6J-ietra ydro-3H-pyTa2o]o(34-bpyddi!iyi: 3.4-diI¾ydra-2H- yranol2:3-clpyndiisyi:. or cbroiaaa l;

whereto R* is taisubsttoted or stitettee wit one or stoe stibststnenis depead&ntly selected from methyl ethyl cysno, c i r , i\mm> methoxy, irifl oromeihyl, etboxycsrboai tert- btttoxycarbo!tyL mboKy.. N^aie l}-N--(i«eti}«xyet yI}sj»(ftocartx)«yl) { , -- dtoj$&yl)amtoo«r½nyl

ylkarboiryi, or os ;

and a pfeannaeeutieally acceptable salt thereof,

40. Compound of Claim 27 herein M¾ is benzyl {etrahydropymi-4 -yi 341.«oro~ ieirabydropyraa-4-y.l. i-Boe-piperidia-4-yi 2.S-dioxo-py.rm1lndia-i-

2-pyridyl.3--pyridyl, 4-pyridyi, 2-!aeihy!-3-fyi1dyl.2-i»etby'I.-4-pyridyl.2-nietityl-5-pyridy'l, 2- -- pyridyi 2 -diKii«byi - yridyl 2--erfryi3.-pyrfdyi 3-ethyi-5--pyridyt

3 -e i-§--j»e%! -5-pyridyl, 3--i$opropyi5-pyridyi 3-pr p-l-ep l-y! -S-pyridyi 3··(ί~ rae tetheny-l) -5-pyridyl, 3-cydopropyI-5-pyridy, 2-bydmxy«Hi -3-pyrld>i 3- bydfoxy8jfetbyl-5->yridyL 3-(2-bydroxyeityi-5-pyrldyl> 'Hi -hydroxy- l-t»e terbyI}-3-i»e l- 5-pyridyl 2--h¾Itt? y i^ l-5^

pyridyi 2-i?ifi«oroaie d -pyrldyi. 3-in6tfey{-2-rrifiaoromeihyl-5-- pyridyl -m^liyl-3- ifl5K)mm««lvyl -pyddyl> 3- trifiaororaetbyt-S-pyrfdyl.3 ri{iuoroa5e{fcyi--5" 2-metay-§-fyr yi, 3-(2- hyt!foxyprop -pyridyi 3- (2 ydroxyeihyl}~S->yridyi 3-rm?f!¾oxy«5 -pyridyi 3.-e{ oxy--5- pyridyi, 2-ra«thoxy-4--mi«byJ.--5--pyr<dyi..2-mei.bosy-8-e l-5.-pyridyl 2-cyaruv 3- pyridyi 3- c !io- -|} i yK 3-ey3ito- 5-pyridyl.2~c\¾8O-^^rii:1«0a»et y]--3- f ;l, 2·<Μοι¾··3 -pyridyi, 2- chioro-3-py idyl 3- fek)fQ-5-pyridyi 4-cblo.ro-3-pyrklyi 3-dtiori-4-€yano-5-pyridyi 2- fl oro - pyridyi, 3-flaovo-S-pyridyi 4--Oaoft»-3-pyridyi 2-cWoro-5-a5ehyl-3-pyrjdyi 2-bioi«o-3-:(¾e!ltyi - 5-pyridyi I 4-difiieihyf -2-oxopyridIs-5-y1, ] ,3-diaiediyJ-2-0xopyyidia-5»yi lf2«.bneitiyi-6- axopyi!dift-3-y!, ί -«Kitayl-2--ox¾>yrldto-5-yi 2-aw !-6-oxopyrBito-4--yl i--»hyi-2-ox pyrjdin- 5-yL 4-ethyM-iaeihyi-2-oxopyridbi-5-yL 1 -<;0iyS .-2-m> l6-Qxopyrid -5--yi 14$opr>py!-2-- Gxopyridia-5-i 1 «2-dtoietkyi-8- xi yr m-3-yi l-inethyi2-tn tion«efhyi6-oxopyridin-4-yl i~ iae 43-Mfi«onrK^ 2-{ter- h«iyiajjrfaocarb¾nyi}--4-py.ridyi> S-imehoxyethyJaa^aocarboa li-e- yrfd i,.3- {S-aiefiTOx phenyl}-

S-pyridyl.3-(3-fhiofo-5-K{eih«xyii enyl)-5-pyrtd l(

5~pyrin¾diny.l 4 hk«x>r-5-n¾ethy!--pyrjmidifi-6-yl> ■ 1 - I m iiiy Ϊ -py rimidin 6 - yi> 2 - cy a no yimi ci s - 5- yl, 2 rfi«o.«HHetbyi-p rfo3jd}8-5* I, 1uo*»pyratt la-2-yL 5-fiuompyrbsktto-2-yl, 4~ irift orometbyl•■pyrimidm- 5-yl. S - ze!idirsykarfeoa i- yTaxisi -5-yi 2-dimetbylamisocarbonyl- py,f»?j«"5 -yl yradiiixift --S-yb

1 ,5"»i{nefit>-4-pyj¾2olyl, 1 -ethyl -S-pyraxolyl, 1Isopropy!-S-pyfazoiyt i-etftyl-4«brorao-S- pyra&jSyi l-«thyi-4-methyI-5 *pyr¾¾olyL ! .-ethyl-S-meihoxymethyi-S-pyra^olyi, ! -Λ« 1-3- d iK5ih iaaiit}acakStnyl--5-i)yia¾6ll l-i»elhy'l-3-t^clop«)pyi-5-pyr8zoyi: l-eihy!iea¾zoS-2-y?:.

8«d a p amiaceod ally accepta le salt: thereof.

41 , Compound of Claim 2? wherein R5 is ;k¾yi, 2,6-difiuoi-ofjhemi 2 ¾oropheftyi H^-diiluor p ersyi.2.4.8-ifffl«otx)pbsByI, 2J-dU¾ort>pbe«y'l, 2 dinuorophgoyl, ,6 diOuoro 3 md oxyphenyl, 2f " i%om-3- ed)o&yph£ft l, 3 hloropheByi, 2«6-dc or p¾«nyl, 2,3- dichiofop!ienyl.3-diloro-2-.a»wopkayi( S-ckioix -fluaropheiiyl, 2- hioro~6-fi«orbpkmyl 3-rfdore- 8- ffeoraphersyi.2-fi»oro-S-lTSflwt»R5fn«itJiylph8n i.3-hydfOxymefhy.Jphe«yi« 3-hydrexyethyi.pheoyl, 3- feydiOxyi¾etbyi-5-«iei¾ylpbeftyl 3-n aexypheayi 2»wethaxypheayi, 4-i«eihoxypbe«yi, .2- tne ½dfouypbenyl, S-meihyladfoslpbeByl, 2^!i««ro--5 - eihylsa 'oiiySph nyi, 5- 6{ yiaroloos«lfo8yl-2fliiora hasyl, 2 ^Ixjow-S-meili lcarbon lphm l, 3 -roelhoxycarbonylphenyl, 3 carboxyphsay], ^Kifeyl-S-j boxyairiKsa ! te l, ^--ddore-S^dox carbtsis b.^ifSi l, 2-fl«ofQ-5«

oiedso carbony!phesiyi S-ajeihoxy-S-iaetiioxycaib&iiytpheayi, 2-0tK>ro-5-

chi ro-5-aminocarb»aylphe»y.l.2-naoro-5-aminocarbo.nyipk>nyi, 2-cyai¾apbenyl» 4-cyanophetiyl, 2- cyasG-3-sidhyiphenyl, 2-ty¾tio-5-iBet.bylphe}iyl> -cya»o-3-me{¾ lph!e»yl., 2-cyaiio-3-eibyiph wlf 4- cfeiom-2-tyaftopheKy5, 2-da¾«H$-cyao p.heoyl< 3-dfloro-2-cya»ophei).yl, 3-ch$aro-8~cy¾8op¼nyi., 2- cyaiJo~3,S-dkhior plie«yl, 2-eyatKj-3,8-difluoropheayl 4-cya∞-2>S-difiuoropheny 2-cyano-6- 5- ra8 l"3-|(Sso ro i}a}«i80caf}x)ny1|ph€« i ^-ffiab ]-3-f(iso «> >d}aiainocarbo8y11pfee8 2- methyl -5· i' '-(jnefRyi) -N»<metlmy^¾yi}aoiino ari)oayl'{pheayi, 2··οιβώ>Ί··5·|'(Ν,Ν··

•dii«t¾h l)ai«iaoi:i¾-bo8 !)p¾e8!, 2-«Ks 'l-5-| »{rae i>-N-

{methylamfeoethyl5aminocarbony:ijphenyl. S-methy!-S- { I -:o5e l i82n-- "y!}carbon l}pijen 2,8- d!fl»(^-3-((i!^ op l¼«UjJo a^ l} heit>l 2-fl«oro-5-{(fsopmpyl}amiaocari)OBy!)p.heny!, 2- fl«ora-34;( ^ mp :i-N-mt¾imi8o}ca^n ¾p¾en i 2 l« ro-3-({ef! }anioo.)r:afboHy!5p enyl 2- fltt ro-S-^Itior^h la aoJcariKia l'i benyt, ¾qro-5 cycSo ro !med^

(fni'{'hoxypop l¾aft}io(.K»A«Hi i)-p-ifii 2- 1«or< l--((2--metbyi)am}n( .ark>nyl}p¼eRyl> 2-f i05¾-5- {2- oiei.ls0xy| O 5affi!nocarS)sn};i}p eHy], 2-HaoiO-5-{(l.-me|liOxy-l- meihy!e{hyI}affilnocarbosy1)pbe8y1, 2-e!¾fon-5- f(l -pynO RdtoylcarboByl}phenyl 2--ddoro-5- C(i ,3 - di ed 1pyra¾i«- -yl}tarbooy pheoylf 2-flu»ro»5 · {(1•me{hy^yjwi-3-yl}gminocarl) Ryl}p eny.l 2- flttom-5- {i-meihypyr8^i- " am5«ocarbon l) i»» l 2-fl«o.ro-5-((i--jaethyipyra2el-5»

-

0ts«rQpi end¾ - Sj jammoearbes l)pheayi , 2- «aro-5- ! · Bo -3-fiuwopiperidte-4- yl))a»¾iftKarbony¾heftylt 2"fittorø·S-( Boc-pl|>eriαm - I})a 8o ariofty k¾ ϊ, 2-fl«om-5-{l-

yiDamiftocarbiii !iphenyl, 41«ercx (l -8¾tb lp5 t>Etdii3 - l }am}«oc^rlx>n .J phenyl, 2«6-dfl« fO' 5-{l-m hyIf^peffe1in-4-y]))afninocarbony!)pbx>nyl, 2^flaoa>-5-(p eridi^^- l)}an ««{; .jlK>^l} fieii 1,

»wi hoi«yi«h l}am5n()^rlm )pben i.2-eh!oro-5 - Cmft)03Q%lh l»wiiiocarb08.l.) he8yl 2 rfs!oro- 5-{l-pyTrtHdiHylC8rb08yl}phefi l 2-i:idoro-5-{l--me?Iwipyra^ 3-C2- en¾i«Hdazo1 Sj 1iiii! S:( 3-{2··οιε 1··1 3-{2--a hyi~l ,2,4-oxadia¾oi-3-yl}p eayt> 3- «d a pSmmaceuiieaily acceptable s¾U thetwi

42. Compound of CMm 27 wherein R* is S-qutooUnyl 6-¾a .ioUnyl 7-qttfeoImyi 8- ¾ttblO¾«yl.

qulnQlinyi, S.6,?(§ fcrab.ydroqttlaoiia-5-yl(

tetiahydjroquinolia-«¾~y1, 4-φ«¾¾ζοίίηνΙ, quinoxaiin-5-yl, l-oxo4soi«doli»-4-y1, 1 -oxo4soimioii«-6- yl 3- Tuethyi-i H-i8 a»*M-yJ , 2-jn«hyl-2H-ltda¾cl- -yl , i«methyl- 1 H-ndasiol- S -yi , 153-dimei yi- lH «da¾ol-4-yl, (.! ,2,4krazei 43-^yrfdM-8-yS, !.-rae l-2-axo-l ,2-d}fe dto¾«jaoU8-6"> i- a^^yi- -o o-ii -dih dro tdno!in-e- i, 5-ch.lo.ro- l-Bmhyl-2-οχο·-.! -dihydroquawlia-S-yl, 1,4- dts!etfey 2;·o o4..2^ίb dr£«|«ί-^olio· -y'l, 2-oxo-i..2-djhydroquiaoi'in- -yi, 4-oxo~dlhydroqtfi!Kdh J- yt, -ft a-(Hiiioii --:i {4H).-yt 2:-as«hyl- l~©^o4.,2-dlbydr»isoq«lBotta-6-yl, 5 J-dlflooro- i,4-di!¾ieiiiyi - 2- xo -1 ,2-dhydroquinal¾-6-yl, 5;7-dill oro--l ,3,4-!rSine!i;5yi-2-oxo-l ,2-d{hydro¾nino.b8-6-y{, 5,7» djfl«oio-l.-metby1 ·2··«χο·4-ίΓ iilaoroffifcthyi- 1.2--<Iihydraquinelio -yi, 5J-diflat«x)-4-ethyl-i»ise l.- S-oxo-l^-dihydroqaiftoHB-^-yl, 84soquiiK>Un: lt 7-isotjaJadfinyl Msoquinollwb S-isoqaiaoUnyl, 4~ isoquino!inyl, ϊ••«s« "lH--pyrazoio|'3I4'bjpyrdia-3"yl 1-ethyi IH-pyraxoialS -bpyriilin -3-yi., I - erhyMH -pyTazoi p,4-b|pyr)di!i-4 -y!, 18}eihoxydhyHH-pytaz I&3i4-bjpyrid¾-3-l 5-fiu ro-i- siie†hy^lH- yrazoof34-b|iwiidin-3-yl, i M-pyya¾ok>[¾4 -djpyr:h«id» 4-y1s ί a liilax [1 ,2 -a yi idiii-7~ yS, Imldazoll^^pyridin^- l.S-im^l-SH^TOd^oM^-b p rfdiR-S- l, 3-«hyI-3H dazo£4t5- ajpy.rfdai-8-yl S-n b lisdxazolofS^i-blpyridin-i-y!,- fl,2.4}t!iamlo^3--ajj>yrsdin-8-yi l-aieihyl- >5,8J-tet£¾hydfo-3H-pyraxo1o [3«4-¾ | pyx idlrs-3- i 3,44ihydro-- -2M-pyraao {2,3-ej pyrtdhi-S-yl 6- ®etbyl--3.4-dibydro- H-pyraao{2..3-bjpyTidia-5-yI or 5- hroftia»-yi; ami a phsrmaceodeaiSy acceptable alt iherof,.

43, A compoand of Claim J fcavisg Formula 1 a;

wherein s is C¾ .$ aikyl ¾.e alkeay C$,g hafoafkyi. C¾ .s..alkoxy, Ct* hydwxyalkyl, C<« aauftoalky'l Ct.« aikoxy-C-!,« aikyl, Ct « feydraxyalkoxy-Cwi aikyi,€ s> 3lkax carbonyfe5«}»o-G.i.s aikyl Cg-Hi aryl ar i-Cs^ aikyl 5- S 0 meas ered tem ydy! or 5-10 a»tnbet«d heusrocyc!yl-Ci. 6 alkyl, wherein the aryl or hdemeyclyl ring Is «&sabstit»te4 or su stituted with QM o two so stiitBisfc atdepeedetdly selected from Ct* aikyi. Siydroxy, ma or hala:

wherein li' is X-R\ cyano, Cs g haloalkyl, Q.s cyanoalkyl G; .(; aikaxycarbasyi Cj.g aikyiearhoijyl 4-1.0 membered hees-ocyciyfcarbos !. arainocarbonyl. C)4 alkyk iaocarbeayl Cs,¾ alkyl Cg.« alkseti l, C¾.¾ alkyayl, C¾.« hydioxyaikyi, C¾.& hydfoxyalkeayl Cs .¾ Iiydiaxya!kyijy!. C¾ .¾ alta -Ci-ii alkyl C aikoxy «€Υ$ alkaxy-Cw aikyl Cu aikoxy -C

aryli -Ci si aikyi Gn» afytoxy-C** aikeoyi ar lay-C^ alkynyl Cs .¾ aikoxycar ooyl-C- ; aikyi, Cs ii rarboxy aikyl Cf* aikoxycarbooyl-Ci,e h drox aikyi, i« txarlwn l-C3,8 aikyi Ct« aikyiamioocarboswi-Ci.s alkyl Cj,« aikyis«ll½ylCs.§ aikyl C>« a1kylsaifo.8-ylC¾.s alkenyl alkylsalfon .iC?.s alkyayl Cs--to arl <¾.« cydoaikyi, rydoalkeayl 44.1. ns&mbered heterocycly'l C9.}0: tyl-Ci.s aikyi, Ct;,!:i! a ½.« alkenyl aryi-C;- « alkynyi C¾.§ cydoalkyl-Cf* aikyi, C3 S cydoaikyi - C;,g hydroxyalkyi '(¾.¾ cydoaikyi -C2 aikeoyl ¼.$ cydoaikyi -¾.« alkynyi 4 -10 m«{»befed hster&cydyi-Cs .« aikyi, 410 n¾ ¾&ere be&roeyeiyiC?-i; alkenyl 4- 1:0 fserobered hetemcyciyi -€¾.« alkynyi or 440 memberc heter cyclylcafhoayi-Cj..s aikyi; wherda .the aryl, cyctoalkyl, cydoalketiyi or iietetocydyl riagla RJ is uosuastfMed or $ahstk«ted with 1-3 sub^itueots Independentl ssiected &om C14 -alkyl halo, oxo. KO-:, haioaikyi. Cs alkvisyiibftyiaraiao-€(,4 aiko y, C;.g liaioaikoxy, !rydroiiy-Cf .¾> alkoxy. .$ aikox aikoxy, Cj,§ alkyisoifonyl- Ct.-« aikoxy, Cj.s a yi C:s.fi a'lkyWfonyi Cs.5 alkatyearhonyl arboxy, 540 ueiabered hderocydyl 540 iseoi eoad heterotydyi-Cj-s aikyi Qi s cioaik i, C¾.s -<.;ydaaiky.I-C s alkyl, atttb ), aisiHOSuifo y Cj.¾ alky!aadnosulfonyi CM alk>4suIPon iaaji«o; yano, oarboxy, R -Cj.s aikyl Ct-ealkox -C alkyi Ci.« a!koxyiffiim>-CHi alkyl Cs.e hydroxyalkyl or R¾s C(-0}- where R* is H, or Cn alkyi and is H, C, s alkyl, C;,5 Ir droxy lkyl Cu aikoxy44.¾ alkyl Cj,¾ a!kylsalfoiiyl- Cu alkyi Cj ,s alky!s«'lfooykmi«o-€«■ aikyl,. Ct.« aotinoaikyi or Ci aikyiC;.¾ amirfoalkyl or where. Ra and Rb ktgeiher with the nitrogen form a 3-8 meaj'hered 'heterocyclic rlag (j ubstituied or substituted with C} . s aikyl;

berein X is S or 0:

herein is C5 s alkyl i ,e hydroxyalky Cf .g haioaiky!, C¾.« h diOx aJkyn l. Cj.¾ aikoxy- Cs,« alkyi, C alkoxy-C6,« alkeeyl, Ci (i alfctwty-C** alkyayl, C$.6 aikoxyeafbonykC aikyl Cs.$ carboxya!kyL a8UHo arfaowyi-CT.8 alkyl, C- alkyk*r»li >c¾¾oriyl-C-s .« alkyi ^ myl Cj.-; cydoaikyl (¾. · eycloaikersyl S40 iaembered heteroeydyl Q.ts ¾ryl-€t.« aikyl C&w iCj.e alkeoyl Cis m aryl C3. a alkyoyi Cs,« cydoalky'l-Cs .<$ aikyl, C¾.f. tycioalkyi-Ci.s alkeayl C3.¾ eydoaS.kyl~Cy.s alkyny'l., 5-10 membered heterocyclic aikyl or 549 jaembered hetetO yc!ylea5¼nyl-C3..« aikyl; wherein the aryl cydoaikyl eycloaikeeyl or heteroeydyl ring in R4 is uasutetSmted or substituted with 1-3 s isiitaenis ade ii«d«sKll selected frost Cs ,.s aikyl halo, Cj * halealkyi hydroxy], Ct e a&esi , C( -s acyl Ci-s aikyka'lfonyk :,s aSkoxycarbofr l carboxy, 5-18 tneai ered hetetocyclyl, cyano, amino, Cs. « aoanoalkyl Ci g alkoxy-C}.s alkyi ¾ 'dtoxyalkyi Cs,; hafoalkoxy, C,.« alkyl- RR ,

anynosylibrryl Ci i; alkyterhihosa!toyl JTO>NC<«Q) where R* is Ct■« aikyl a d Rfe is ¾,« alkyi Cj.g a!koxy-Cj .s; aikyl, am aoalkyi or€¾ .ti alkyl-Cj.g aminoaikyi, or where R* and Rh together with the nhrogsa form a 5 or S membered !reteoeyciie ring unsubstStuted or substituted with Cf.$ aikyl: whe e R ami R is independently H, C{.« alkyi, phenyl 540 ttembeml heteroe cfyl, 54.0 membered heterocydylCj « alkyi, CM cyeioaikyi C* to afyl-CS.6 aik l CM cyeioaikyi -CJ alkyi; where the , phenyl Cs,6 cyeioaikyi and 540 membered heterocyc!yl rings are trsabslituted or substituted with Ϊ -3 sabstitueets independently seieded from Ct.s alkyi, Φ£ο, d.e alkoxy, hydroxy* halo, Ci,s haloalkyi cyaao, or cathoxy; or R and can togette with, the form 54.0 membered b tero ydyi;

where Rr Is pheayl, 540.membered heterocyciyi. 540 aiembered heterocydyi-Cf * alkyl or Cs.e cydoaiky], where the hereroeydyl, phenyl, C«.s cyeioaikyi ami 5· 10 riies ered hereroeydyi rings are uasubstit«t«d or stibsiiraied 'with 1-3 so!jstiterits !ide eiid sid selected f m t (i alkyl, CH; aikoxy, hydroxy, oxo, halo, Cs.¾ haioalkyi cyaao, or earboxy; and

wherein R* is 5 inei»bered. oiirogee <¾>ntala}ag heterocytiy.1 S rfierrf ered oxygee cox tafafng hetssroeydyl, 6 meraherad eitrogea containing bcierocyciyi, 6 ioembi-red oxygen containing

heterocyeiyl pheiryl, beaiyl 9 memfeered bie dic nitrogen eootaioiog heierocydyl 10 membered bicydi oxygep co»«iaing lietesacyciyl or 10 ioembered bicydie oiiroges coatatoteg hetferoeyclyi, hi3-¾i H1' is «n ¾bsiliHted or sahstttttterf with one or ffirjre sybsiitaents nds ierirleniiy selected from Cs,fi alkyl cyaao, halo, o®, RO-, C(,s. haioaikyl: Cs.s iivdroxyalkyl Cj aikoxy- C:i..« lkyl Cf .B aikox carbooyl- C},« alkyi, {¾« alkeeyl Ct-s alkoxycarbon i carboxy, Cs,s. cydoalkyl, R^alkyl o donaliy syhsU ted 4-8 rfteridj rei! heierocydyS, [opiioaaliy substituted 4-6 i sestibered ditogeo containing hetemeydylSc»$fcon>i KR NS(¾ -< KR RS(¼- or R*R,1NTC{«0}- where Rs is H, or 4 iilk i aad K¾ is Ή, Cs .« al yi, C;.;> k droxya!fcyi€¾ aikoxy-C aifcyi C$.g aramoaSkyl or Cj.« aik l-Cj.s aralnoalkyl. or where R8 ami Rh together with t¾e nitrogen htm a 4- memere iKfeocyclic ring yrusnbsdruied or substituted wth C{.« aikyl and a ptoraaceniicaliy acceptable sak thereof;

provided han -' Is.1 -rnetkyi- iB-pyrazCii-4-yi. -&«ri R! U. methyl, theft W is not 1 -ethyl-iH-pyrazoi- 5-yt;

further provided when R5 is I -methyl-lH-pymol-S-yl,. and R! is methyl, then R6 Is mi 2-«hyl-i'- ¾xo J-di!! droiso uiniiss-8-yi, 5,7-dlflttOfX)-l^-di«teh l-2-oxo s2^ ,drX|uii}o!i»-6--y!5 or l^-ditnetliyl-E-o O'l ^ih dioqaimjlb e-yi

44. Compound of Claim 43 erds R: is sseihyl, ethyl, propyl, .tsopfopyi, teri-buty!. aliyl, triikoro riryl, jsethosyethyl, hydroxyethyl, hydroxypropyi, l,2~dihydroxypropyi«

a hioethyl, phenyl, 2- hydroxy pheiiylrnethyi. - ydw pkm in byl, 4- hydroxy-pheaykietby 4-fitioio pheiiyhnethyl, ffiorp o1in~4-yi thyi, pyridyinithyL 8-mfetliyl-2-0xo- U-dihydropyTidiiiylmfiiliyi, imida¾olyIme£byi< l- ethyMmid&xolylBtethy'J, 2~:nK>†liyifMazolylnK4hyi, or 5 -ft)etfe i-;«soxaczoIyl»iethyl; and a feri ac iicSily acceptable salt thereo

45. Cootpowod of Claim 43 wherein R! is stethyis and a phamiaeeuiicai!y acceptable salt thereof.

46. Coispeand of C m 43 -wlierlo R* is SR*; and a phar maceuticaliy acceptable salt thereof.

47. Compound of Claim 43 wk>rci« R! is .me†!raxypi'Opo:xy S^ffie&oxyipr pox , hydr xyethoxy, hvdroxypropoxy, 2 iydrmypropoxy, I ^thydroxypropoxy. l-hydroxy*2- :me†hyipropo.xy, S-oxstaoviaiethoxy,

mehoxycarlvanyltntiihykhio, rae iosycarbonyletbyiddo. sMsmoxypropylthSo.4-metboxybut-2-y.hhio« hydroxypropyttMo, 3 ~$hydroxybatykhio, cartwjxyethyithio, fsjethylamisocarfcoay meiliyUblo, klinieiliyismin^carbonySjinethylt io, (3- hydroxy 3 tncihyl¾iifyi}tb:io( C2-hydroxy-2-«t hy4batyl)iikJ« diflaoromethykhio, (4-ffiethylpipera¾ln-J -y'J}-carbonyltnelhyiihio:, (roorphokn-l

yftcarbonyhaetbyHhto, (t -tert -bntoxycaibosyt pipeiidio -yi)meii iihio. {4-plperid]nyi}md:hyl$hio, {erah djx>~2H~pyra8-- "V))»etli ltWo i-{tetfahyd!«-2H"pyEa8--4">)etbyWijo, (5--8¾Rthyl-2«

oxadteotyOmeiiryhhio.2-pyridylraetbyltk , 3,4-diirydroxycyeiopestylthio.4- hydfoxycyciohexykblo, cyclopenienyltirf , phetiykhio, henaylthio, 2-pyridyIthio, 2-chtoro - pyndyltisio. {4~piperidiny.l- 2--pyridytifteilryiil5io, {l-nietby!pjp¾fidift'4-yi~2 -pyridyilmetlryliStio, {i- i · (1 · trydroxyetlryipiperidin- -y|>- 1 - (2- pyridy!)mei yft k>. : - 0 -fflstayipiperkba-l -yl) -(2-pynd>f!)methylthi > i-(piperidi«-4-yl)-: - (2- pyr(ly.iraer.b)¾hio, {4-piperidiayl)tMo< {l-isopropyi) 5peridin~4-yli lo! (l-me c8r' oa l)jHX>H{iin- 4-ykhio, i - {ttirt-btitoxycafboHyi}piperidift-4-yl{ jo.0 -mei y aii 8yl)piperidi»-4-yH o< (I- Lsojrojyk d H 1}pt|>eridf!¾- -yltibtf, l~(imtiiOJW«afbo y1) ip«?tdjs~ i ¾W«>, i- (meik>xye icar|kinyl}pip¾idiB-4-yl{'hio, 3.- {diinef ajmnocarbowl}pfperdifi-;l -yltkio, i - {xaet¾oxyc3fbo«y¾plp«,idia-4»yltl\io« (M5--eita>pyrfmklf«"2 - ϊ} |> ί per id ίϊ - 4 - y I) i ici . { l-(2~ yrimidi yij iperklii 4-yl} hioi (l»{5"Chioropyfa«i.n-2"yipiperkljn»4-y}f o. I -(tert- i)«io>^carfeonyi}pya«I!d!8-3-yUbfe« S-methyllsoxazolofS^I-b'lpyfidift^ylthio or {etra ydfo-2H- pyKav4-yUhk>; and a phannamtiicaliy acceptable salt thereof.

48. Comp und of Claim 43 fcereiB R's is cyann, methy ethyl* propyl , Lsopropyt 2- {sefiryipropyS, 2,2'dlmfeihyiprbpyt 2-n¥s0t lbaiyJ, infiuorosieihyi, 3.3.3· oitlmroprypyl ifeoromeihy fhioropropyl hydtoxymetby'l, fcydroxyeihyi i -hydroxy -2- meihyieihyl 2-byd:roxy-2- mei yied l iiydmxypropy Z-bydr xypropyl, J•Kydt0xypmp-2-yl LX^iih dfosy-pro yi, aydrbx batyl 2-hydroxyiJutyl, -dihydroxyauiyi 2,2- (ddiydroxyr!iethyl)b«iyl 2-(«ydr0xyea¼xy)ethyl 2- (!wdi¾xyeiSo.xy}pi:opyl, (metlio iseth ij iyi. !.-:raetboxyeibox -2- l)roi«oei¾ 1, 2-h. dasxy -2- mei ipeai 2~hydroxy-2-meihyihexyl t^-dibydfoxypeftryi, 2-bea^yloxybutyi, 2- hydi»yethoxy «tyi.2--hydrajiy--2-iBediyi)iopoxybiityl, 2-i droxy-2-mediyIprapoxyp py!, (j«tehydmpyK«i--4-yl}--hyiroxymc,ibyl» 2 ]¾tofo-2--methylbuiyl n»!K) «ieihaxy}«eih s

metboKymetfayl, ssethoxypropyi tseihoxybyiyi 4.5-dim«tho.xyp«ttyt -metkoxypepty ■othayethepyl thenfyt, propen-2-yi, I-bydroxy-2- ethylprfcpeayi byieo l 3i3-dltBt,d}ytb«te»-l-yl> B-benzyiosybytenyl-HiehoxyprepeB-i-yi, bydroxypropeny.1, beBzyloxypropeayl 2-ethoxy(.*teiyl( E-bydroxysfieibyiproperjyL 2-eilsoxyvinyl, vi y fnertsyis«ifb«ylprop i i, meihyisuifoaylbateeyi, ineiiiylsulfoaylally i«etblsuilb«yl¾iit-2 -ea-l - yl. efboxyearboayl o$etbyfcarbo?iyl (4- ietah dro-pyrfis !lcsf ii l -m^h ^-(iJ^thox e i)asS«ocatloa l, . -mefhyi-N- {dim^ l¾ni^ra ¾-amii.iot:arboji i, iat njtoxyeaik>aybaethy], i-liydfoxy-i -tert- hutoxy rhonylraethy edioxycartwny'Jpfopyl., etkwycarbanytehyi, i-bydfoxyefhyl-

-disa¾h iiam5aoi¾rboayietbyl, dlBtethylafajaocafboaylprop-yl, carboxyeihyl arboxypropyi.

cyasot'ihyl. cyaftopropyL 4.5-dihydroxypemyi, s 5 - d dro pi? αΐ■ 3· l . iiydroxyb«iyayi.

h dfQjiypiOp ii L ethynyl 2-cyciopropyIyiayi 2-bydrox>«dioxybut -;yii-i-yl, 2-hydroxy-2- me iyipfopGxyptopynyi. beszyloxyprop- i-yft-l-yl beaxyloxybit- i-yi- l-yl b&ftzyioxyetboxyprop-i- ya-I-yl I•(i-feydrc¾'€yciopentyl}5!tby«yi 3-usethyl 3-oxela«yle{hy»yl i«ed-joxybut-l-y«-i-yi methsxypfentyiv- 1 -yl cyelopeniyUdejiewthyl meby!sa|foftyiprop-yl med¾?lsaJfonyibaty pbes iethyl benz l, ptebySpropyL 3-:Wo«jph&»yl«.ietbyI{ i,2-<lihydfl}xy-2-pbeayIe{by 2~yim«fhyi, 2-c loropytid-5-yImef¾l 2-et.hoxy- 5-pyi¾ykt yl, -etb xy-S-pyridy'tefh Ryl, 4-piperfciyimeth.yi, 1 -pip ridylm ihyl, 4-»jethylpi t¾¾j¾a- l- kmOiyL 4-Boc-p.pefaxin- 1 -ylffiefisyS, 4tnet isulfoRyl- ips!raxia-l- iwfhyl, 4~i«edwkarbo«y.-- piperadod -yitneihyl, .oiorpboHivi-ytoH!liiyl, 3~me?¾ I-«io lio{io~4-y]:OieihyK S i ftto p¾oI »nK>*h i , (1 J -dsoxidoihioffiorpbolioQlffleibyl,.3-me l--3-oxeta8 leihyi (letfa ydro-fur--2-yl)methyi.

{tetrahydi¾-f«f-3-yI) methyl, 2,5 -dioxop o-oiidlB-l -yfeihyl tetrabydiOpyraa-4-ylms l

teirafeydrop r*R"3- teie 'l; etfah dm}3iyisn- -- le l, 2-bydrQ5^methyl-tetmiiy«ifo.pyr3R-3-- yteeihyl , 2 -{jydr^u«¾hyl-te{fa dm i¾e -yii»e l 2-a>e{hoxyt«e l-»afeydK)pyraa-3- yliBiShyt, -m hoxyn¾:i^d- dralwdro^ -(2,¾4ia}e 3-L3-diax>Iaii-4-yl} i« yi5 1 ,3-ilioxfilaii- -propyl I,4-iiioxan-2-s«et] 5f I , ! -dioxldoier«shydro-2H hi0pyrSK-4*y{me i i J - dlo^d»4eii¾hydfo-2H-{ttopyran -yli¾hy!, ίera dίo2H-ϋ»o yr¾J- ' to8?th , 6-oxa-l- a¾aspiro|3,3]he iS!Vl-yb«ei!yS, 2- ¾a-8-azasplrot3.3.|heptaa-6--yte}«s l: i,4-diQxaspkd[4.$jde aft-7- yitneihyl S-feeiffydoxy-cyckibaiyiffie!hy!, 3-hydr0xycyd fei«yteetbyl« 3~hydraxy i~meiby]~ cycSobuty net yi, 3-oxO' yclokis imeli l( 3-hyd.mxy-34dfluommsthyl yclokitylm8iiiyl« 3· ydr0xy-3-methyl- yciob«ryl½'dr0xyta«ihy1, cydopeaiyhntlhyt, , J-0iydraxycyc! pe«iy)mei;hyI« ί· (aieihoxycyc!opiiftiyijmerliyi , 1 - ( me io cy dope:nty1} broaKimetbyi , cyc bexylmeihyi.3- bydroxy- cydob Kytaei yi.4-hydi¾xy -cy ! !i¾?xybBethyi, or cydohexyiftiefbyl; w& a p!iamtaeeirikaily aeceptafoie sail thereof!

49. Compotirtd of Os um 43 wherein R:! is eydopropyl, i-ieft-buoxycarbORyi-l»cydop«jpyi. 2••«bexywboBylcydopr¾yi» 2· {2-^ydra y-2 -me ie%I}--cyd<ipsxspyi dm^aidhyf- cydopropyL cycl btstyL 2-bydroxy<;yc )«t , 2-oxacydobtttyl 3-liydroxycydobatyl 3- S:ie?'(Ky!oK t dobiii ii 3-faeftKyioxy-I-hydroxy ydobufyI, 3--{2--hydroxy ---2-mcifiy!ethy1.) -eydefoyiyt, 3- bydroxyjrietbyl-cydQiiByl, 3-ethoxyo»bo«yi-^hydt»xy--cyx oi>utyl, S-ethoxycarbony!-cydobutyt, cydop niyl 3 iyxiroxymetbylcydopx!ntyi 3.3--d iiroxyfneitiykydop S:tyi, 3-c^boxy-yc peatyl, 4-iiydroxynjiS.bykydopeuiyl 4-hydrOxyydopeiHyi, 3-

bydiTJsy-3-:mi>i ylcycit)p«nty], 2-oxo-cydope«†yl 3-t)xo-cyd p««iyl, -CN-efii i- - medjy!aminoearboay^eydoptmiyl, S-^-e^l- -jJie^iamtei atboiry!J idopeiiiyl, 3-| - i.vopropyia¾laocarbony.l)cydopea{yi, ydo exyi, 4-bydr«sycyclobexy!, 3-feydroxycydoteyl..3- di¾xy"3-methy]"Cyd«hex l.4-bydroxy--4 net! l- yyiobexyi., 3-oxo-cyciohexyt cyctoliepsyl cydopenfeayl, Shydroxy-tydopenteayi. 4iydr ytBei i- *m¾by]- dop«ateB l> 4,4- bis(bydiosyH}¾¾ySjcyc!op«ot-2 -eri- i -yi.3-oxo-cy k>peetmy1.3--cafboxy-cyc!i3pes«--2--es;iy!, 3- !s r iismH»€arboi^l y€lop iH-2-¾ny!, 3 hyd« yffiediy3i)cydopt¾«-l-eR-i--yI» 4- (iiydroxy«ii?ihy!)cyd&pei¾i- 5 -en- l.-y], 4--{bydra y«s&tl5yi}cydopeoi-2--e!:i- 1-yl cydohexesiyt 4.4- diiseiby!-cydoltexeKyS, 4-hydr xycydohexe»yl{ S-iiydroxy'cydote-I-ai-

I-yl, 4 »drax n)ttii i" ydolie es"i l 44l- ydrexy-2-mebyetfiyi}cyclobexetw!: 4- carboxycyctebexetiyl, 4-«(toxyca?bosiyi--cydoliexe«yl 4-(a2Midbid-¾arb»»yl)cydobexettyl, 4-(3- fyaHO-ax^ldia-i-ylcarion jJ dohexenyii 4^3 1uofo-a¾elsdi«-i-ykarbionyi)cydol)exis»y1, 4-0- e wl ulfoi^ cydoteptfsnyt i..4.-di xa$pko(4.5id«¾>7-«[J-7-i or l,4-dioxaspfro[ 5]deca:n--7~yl; and a pharmaceutically acce table salt thereof.

58, Compound of Claim 43 w erein RJ is 3-hydfoxy»3-ox¾ian l, Z-fegahydnMury 3- tetraS dro -foryl, Z-iiydmxymethyl-Z- teirafeydro-itifyl, 24:iydro ymediy! fitra!^d!-o-!!i -4-yL 2;2-diosethyl-2,5-dihydrofaf8»>3-yl, 2,5- dfbyds¾fea«--3-yi, 2,3-di ydrofi«¾«-3"yi 4,S-difeyfef«raft--2-yL 2-oxopytroHdSn-l-yl

2, -d««e :P raliydmpytaa -4-yt 5i-diiit& 1tt¾¾feydr<)pyraft-2-yL 2,2,5,5·· tr¾i«i byl-2fivdihydmfurasi-3-yi , 4 l«ofo-tetra!iydropyi'an-4-yl, ~fiuora-3 i.ytlroxyv

4- hy roxytelrahydropyran-S-yi, 3--lwdt,yxytefsal¾yd:f¾p r i!-4-yL 3,4-dlh draKyiet« dro yt¾i5-4-yl 2- oxo- rahydropyrao-4-yi, tetrahydropyraa^-yi, tea¾hydrepyran-2-yl, 3,6-di'hydfOpyrao-4-yl , 3,6- dlfeyvltopyraa-S-yi S,6^ihydo 2M-pyran-3~y.l , 3,4--dihydro-2H*pyt¾n-ihYl, S,4-dilsydm-2M-pyran-S-- yl S.S-dtmilh .l-S.S-dth dro^H-p Eaji^-yl, Z^-dtnerh K S-dth dro-XH- tat^- l , 3,4.-2M- dtbydropyraa^-yi, i,4-di05?aspiro|4.3)d«c-7-sai-8-yl, Udioso-isoihiaKolidiH-ii-yi, 1, - dJoxldotetrahydre-2H' hiqyfa«- "yL i.4-dloxao-2-yl 5-mshox>'-niieihyl-iJ-dloxaB-2-yl, I-fert-

I - (Sifiihoxycarbosyl) - . ,2,3,6-etrahy'dmpytid-4-yl 1 nMhlea?b « lH > 2,3,6- ieiralyyclropytid 4 -yl , I · -methyi--pip ldin- 3-yL l^rt¼k)xycarixi»yi-plp«rtdlft--4-yI, or I-idji8et ½»l«Cfoafb 8 l) - pip«ridi:3i-4 -yi: and a lwnsaeeudcalJy acceptable salt thereof.

SI, Cofn aii!d of Claim 43 whereto Rs ¾ phenyl, 4-ddonjphenyL 3-methylpheayi, 4- memylpkmyi, 2,4-dtoetliyiphenyl, 3-trifl«i*onietbylp½»yi.4-ifffl«oromt4 ylpi«siyl.4~Hiethoxy-3- frifiiioromei ylpbe!syl, S-dinuoroTset yl^-fluOm ten l, 2-me&ykulf0oylpfce«yL.3- methylstdfooyiphesyi.4-meibylstdfonylp¾^yi 3-ethy «lfooylpl^iyi 4- melhy1s«lfo«ylammophenyi 3-metbyM.foriyiammopheny.i, 3~»ietbykmiao«u'ifbnyipheny.l, 3- cyaaopfiersyl, 4-cyaiiopbenyS, 3-cafboxyphtmyi, 3- rboxy-4-]sydoxyp]}ej!yL 3-earboxy-6- .oietboxypbeoVli 4 carhoxypheayL -cyan«-3 m&fexyphes i, 3- cy ft» - edtoxyphe«yl, 3- {dioiethylaBilJK)caFbonyl}plK;nyli -idiinedi biiniiKicarKsn bt'ft l, 4- {dlflietitylaiHbioearboftyDpliesyl,.3-«tbylandnooarboftylphenyl, 3-{ -ethyl.-N~

m dwIam!socad)0!iy!p!ieii l l-etb !aii socaAon lpbe l, 4-( -«{ yf N- .ojetbylao5inocajtq»yl}pheayl.3-isoprc^ylai«lBocatl>oaylpheinyl, 3-( -)aryl-N- o½dsylai«inocarbo«yi}piesyl, 3"{ -pi¾pyl- -m8 lar»lriocarho«ylpheHyl 3-(l,2- dihydri>x ro iam¾}^^ S-CN-ftiedi xyethyl- - me lami«ocarboa> heayIt 4 -bydfox«ih>d- -«jetbyIamimwbow I}ph«ii S-methoxy-3- dimethykmiaocarbofjylpbe«yl, 3- «t1io>^-S-eihytearfmc¾tony1pfeea ls 2-methoxy-4- S-meiiifsx -S- etbykmmocarbtmylpi«sayl, i- ^rox --2-m«ifeylsmp-¾-yl-«ffi}-io¾fboayl bea l,

Siyd«)xyi4h laH¾it5qci3ibo:nyS ' h«i S, 2- iraxy-2-me »«) yaa}liKH: {tooyI- l«!oyi, 1,2- dihydroxypfopyfeiriliiocarboiw -phenyl, 3-0 -azeldsisyfcarboiwljp si l, 3-{3-fl«oro-azet{din- 1- ylcarboayOptetyl, 3-(3-iiydroxy-iiKetkim--l -yleafbonyijphetiyi, 3--{3--imdmxy--a idin - ykatbony phenyl, 3-{3-ffie isttlfoayI-azettdio--:{ -yl rboayOphenyl 3-(4·- t«c»pholiaylcarb«Bylpfee»yl '3-{I-pyffoli<iliiyk«rt»nyl}p¾eftyl 4-«ik>xyptesyL 3-HS¾hoxyphes5y!; 3-RuOTO-6-8jeh xypheayl, 2-fittoro-S~raeUtoxyphenyl 2-rae¾hoxy-4-aK«feylaiaiiM)«ilfoaylpbeayl, 2- ffierti0 -4-e to«() fo« Ipteyi -s ox -m¾4ky^^^^

3-carbQxy-2<meHi©xyphea L 3-dif1aoroo.u;tboxyp!¾'Byi.3- dlfi«oroffiei!iyiphe«yt 3-4ifluo{Omfe i- -.fluOJt fiea i, 2-nid¾oxy aeB. l 2,4-dUae{¾oxyp eiiyl> 34-difiieilwxypbeny r 3-berizodioxoiyi; and a paara»ceafteally acceptable salt thereof.

52. Compound of Claim 43 wherein Rs is !-jne l-3-pytai¾>lyi l-methyl- -pyramiyi 1,5- diiftemyl- ~pyr azo!y!, i ,3, 5-4T5i«i hyl- -pyra¾oIyi .3-raetby'i.-4-pyraxoiyl« 3 - triikoro-eihyl4 - pyrazolyi, 1- 12,2,2--irl0yoKXiihyIj -i f yraxolyL i -car!>oxy5ii«f¾yi- -pyraxolyl I··

emoxyoarb»nylmeibyi4-pyra¾lyl 3-cycfobutyl-4--py?azalyl J-cycUb«ty:1.4-pyra¾olyi 1 -(4- rnor f½iHwl}carl30iwlrne l- -p !-azolyS:. l- (4- moiphoSinyS}«dwi-4-py!:azoSyI. Pbydi!xyei yi- 4- py.fa¾o.lyl, i--lwdroxyiiil:fyP5-pyt3¾o]yi S.--hydioxyprepyt--5-pyrai:oiyi i-{3-hydfoxy-3-me 'lboty]}-5- pyiazolyL i-}-nethoxy«(feyJ-4-¾?razotyi, 5- yra¾3lyit I ·ι«« 1··5 -pyrasioiyl, LS-dtosetbyl-S-pyraxaiyl, ndlϊ l-3·tίifl[αomrøe ^5· azolyl> 3-oiedwiaHiinocaAoj¾ --pyrazo!-S--yi .3- dl8}ethyk«jSaocarbo« .l-pyrazoI--5-yi> 3-i»ethy' \tifonykmiao-pyfa«ol-&-yi 2-rne¾ylsulfonyla!»ino- pyi¾¾oi.-4yyi 2-meihoxycarbonyi-pyrazoI-4 -yl 24-dM*ei yi-5-miazalyf.2- t2-Iiydroxy-2 - metbykihyD-ihiaxoi-S-y. l-me* l-5¾ toyl 3,5-dteietbyMstxa¾oi -yl. l-meiy rtas5n - ldsopropyl-bi&zm- -yl( 1 -fiydroxypmpyl-iria !R-4-yl, 1.4ydroxybntyl-H:k?j»-4-yl5 (4- fifiuoroaiemyipheaylj ssetbyl - tda¾n -yi, 2-cyaaO"3-a b. -{hien-5 -yl , 2".n¾thoxycarbo.nyl--tj iai- 5- yl l-cajfej yi-tfekmr-S- i, 2-( --raediox eih ^

metbyl-anrfnoarbony^tbjen-S-yl 2-(2-bydw^y-¾-raeth>4ethyl)tMea --y 3-sseihyi- U -oxadiazo-l- 5-yl of 5~cyaao-:i-»iethytpyTfol-:2"yl; and a paanaacea-UcaOy acceptable salt thereof.

53. Compoaad of Claim 43 wbeml R3 is 2 -pyridyi.3-pyndyl.4»pyrid l 2-me i-5-pyridyl.

2- -ni0tlwi- --pyridyl! 2-jaetbyl -3- yridyi.3-metbyl- -pyridyi 3-tnilaoramethy 5- yridyi.2- ifl«iiroioeili:y!-5 -pyridyi, 2--d¾l«oroiaetbyl-5-pyddyl> 2-iril¾&(xmietl3 i-4--pyi'idyi.2»tr l«w>»¾8Shyl--

3- pyrldyl X-methoxy-S- yiidyl 4-ifi thoxy-3-pyr>dyl, 2-»}edioxy-4-pyridy!, 2-{3-oxeiai!yS}i« th xy-

4- pyridyl 2-{3-«x¾iaPyI)oxy4-pyridyi, S-lluoro-i -nffidio -l- ridyl, 3--0iiOR>-4-pyridyl 2*fl«.oro-5-~ pyridyi, 3-flttoro-5-pyridyl, 3-metHoxy- -pyddyl, 2- Etoxy-4-pyridyS, 2-¾ tboxV"5-pys1dyl 2-{2,3- d¾ydroxypropoxy}-5- -pyridyi, 2-bydra>inet¥oxy - S-pyridyl, ¾-hydrosyef'hoxy- S-pvfidyl.2- hydroxy«t¾oxy -pyri(iyl.5-¾ fo- -by<ift«yiShxy -pyrUi l..2-mefJ xyfittey-5-pyri({yl 2- 3~*neiboxy~5-pyridyi, -etbaxy-S-pyrtdyt 2 sopropoxy-5-pyr 1. Z~ ydwx -S-iiie!ih fSip x -S-p ridyl, 2~{I.J. ^4r}{¾iOWthoxy)~5- iid l, 2-yc!op*opylaje&oxy-5~ pyridtoyl.2-(ffieihyls«1!bftyipro|>oxy)-5-pyndy].2»(ffi¾byJ5aI¾n laminoet ox>0-5- r L 2- etboxyprapoxy-4-:pyi>idyi 2-diflttGtoftK!tl«ix'y--5-->yrkSyl 2-l1«o.ro-4-pyrkiyl 2-cbl.oro-4-pyftdyl.2- cbloixs-S-pyiidyl, 3-cbiom-S-pyrWy, 2-eyarto- 4- yridyi, 2--cyaao-5-pyrtdy1., i-mefkoxy-S-eyafio-S- pyridy, 2-me(hoxy-6"{«ethyI-5-pyridyi, 3-cyaM--S--pyfkiyl 3-cyaiv4- pyridyi, 2 - s« et «y 1 · 5 - y rldy : 3-i«.ethylsuifotiyi- 5- pyridyi 2-(nKi* lsdibtt>½nfeo}-4- yddyl i-siiedw carixxwM- iid i, 2-0i«Sdazei -Ad}pyridyL 2-o.ieioxylHi¾ siiei]¾yl-4~pyridyl 2-osP- l 2- dlhydropyrid!«-3-y.l ^methy1- - xo-4>2- ajydro y dn-5* 1, i-iae l-2-oxo-i.'2-dihydropyrSdin- - yi i-e I-2-«xo ;2-dii!ydropyridir 5--yS, l-isij !¾ !- -oxo- i ,2-di yds¾pyridiii-5-yl Ϊ - hyd xyediyl -2 -oxo-i ,2-dihydfopyridfn-S-yi. i~hydroxypropyi--2~oxo ,2- ihydropyTid« S-yi( :!>· m>e l"2"O o < -dlh drop ir H"4- i:> 2-iiydroxypynd -yt 2- yx oxypyrid'5-y.l, '2-amimicarb .8yl-

4- pyridyi, 2-me kmiiuk:arb«»yi -pyrldy1« 3-iaetbyiaadsocatk>nyl-5-pyfkiyl, 2- isopropy!ammot¾rbofty 1-4- pyridyL 3-dier.by?amiHOcarboayl-5-pyTldyl, 2- e iSttl'fo« leib>¾m}80«rbon ] 4"p klyl 2 -ffietiwlst fen ta

5- mdbyfeuiibn ferainoe^lasjnocai^B 'i-S-pyrid l, 2-mdb> u1fonyferaino«thoxy-5-pyi yi'2- hydr(»cyetbyktniRocarbo»y{-4--pyridyl 2- 'di'oxy^hylamiooar oayl-S-pyddy.,.3- iwdrox oih ia» fto«ii' iRyi: -p rid l, Z^^dmxy iaylaftrfaocaAon M- yfdy!,. "Ί~

imidazolyl)pyrid-4-yir S-pyrirasdiiryt 2-amioo-S-p dmidmyl 2-cyafto-5-p> baIdfeyi.2-i« thoxy-5- pynmidbtyl, 2-ethexy-S-pyrtndlayi 2-isopropoxy-S-pytisikUnyl 2-tri-fl«ord8d«>xy-5-pysrtmidi«yl, 4- tri.fluoromethyl-6-pyri dbi>i -tt!fioor^ifeyi-i-pyrUaidmyl, 2-ttinuijroeiby!-5-pyrbJrida>yl 2- di¾^hylamkiocarfx>nyIpyri dM-S--yl( ymiB- -yl, pyridaz.bi4-yi: and a pharniaceutically acce table sail, ihat l

54, Compound, of Claim 43 whmda ! b 3-bea20thteny.l, 5½ismuyi, S-lndoM, 2-oxo- dliwdro-a-indolyb g-mdoiyl B-oxo-dibydro-fj-adolyl, |.-raet.byl-2-oxo~d¾ydfo-6 '»doiyl« imidazof ί.,2- alpyrkiiii- 3-yi, i idazof J.,§--a|pyfidin-f>-yK Iml ssjof ί .5 ajpyridia- 7 -yi, bakiazojl . > ajpyridiii- b-yi, J J -dJoxo~2-meh ]-3t4~dihydro~2H^HZolbj [i^.Sjoxatbiass^ja-S-yi 2-raetbyM J - dioxldo .4-<libydi«-2H-½a2o|¥ji1. ioxatbiazsplft-8-yl, ?-:R5etiK>xy-2-aietbyl.- U -dloxido-3.4- dihydro~2H" ej2o|¥ji"i)4.5'}oxathia¾eplO"8--y

beftzofbHi A5]« idto 4- me^5-oxo-2 «4,5-t«Tab dra¾«?^|.R|l, |s^i^?-- l, 4-iaetbyH.I-dtoxido-3,4-dhydK)-2E- pyridt)i3,2-l] {i jihiazon-T-yl beB¾exa.2ol-5->i b¾nzoxaz i-6-yi ί J-dif)xo-3,4-dihyd!¾-2ii- f i,4|osafIiiepiBoi23-b{pyridiJi-8^L U iox:ido--3A-dl!miro-2H-^

74-1 4 - mefliyl-5-oxo-St4-di ydrobeRi;of| f MJoxaxepis- 52M)-7-yi, 4 -meikyi-5' Oxo-2.3.4,5- tetrahyiiro- pyr(io3.2-.f [l,^)<»(8zepln-7-yl, najxoxaxoM-yi..2-mei.by!beazowiiI-S-yl, 2-i? I enzoxa5toi-§-yl. 2-isopropyifcen2 Sszol-3--yl -ttso-2i3H)--hen2o[d|osaKol-5-yS! , henzox&soMJ-yi. ber¾oflda¾oi--3 -yi, bi'ftzoihiaol-ii-yi, 2~ffiethy!be»80i'hiazol~; yI« 2-fsopropylb8i¾ofd'|{hi8Z l-6-y{, i -ns tliyi-S - eozimidazolyl S-sndazolyl I ·:«¾ί 1··5 -todazolyi, 8 nda?,o{yi i -meth l- &-¾id¾oly 2-inet yl-2H~ indazol-4- l ?-&zaiik!ol"8-yIv T-aiaiocioS -4-yl i(S-dla)e -2,3-libyd«>-iH»p¾Oi(>|¾,3-¾jpyrtda-5'- 3 -i«eibyibei!z [d|feoxazoi-5-yi, 2- mc i l-S-ox -be aofdliso azCii-S- l, 2-^eih i^-8>6th^xy -e^ 2- mediyto azoIolS - lpsddia-S- l, 2-meihyloxa:i0to[5>i-bpyrldl«-6~yL 2-i¾eisyi-3-ox«-2i3- d¾ dQtwxa»f)loi§-4-¾)pyrfdin-5- 'l} i >i--dk)xo- --mt4¾yK 4^ i dro-2H-pyrido|3 { J ,4'j.dwazift-?- yl S-mt'th .^.hnidajaj .Z-aJ ridin-e- i 2-«x9-lH-:ji»ida¾ai4.5-b)pyrSdlj>-'2(3H}-8iyi, imidazole a|pynd -7-yt l idazofl,2-ajpyridi8-8-yl> 2-oxo-2,3-d dfo-iH-teida¾oi4,3-b)pyridiR-8-yI.2-oxo- 2,3-dihydrobenzo|dloxa¾oi-5-yi, toxoid) 11 ,3}oxatiiiol*5»y1, 3,3-dteo-fcK;nzoidll'.l.3|oxafMol« |!:!2,41t.nazo!.oi4!3- ajpyddia-5-yl, [l>2>4].ria5t»>lo{4>3-ajpyridiEii-8-yl!. S-b dtj^tn^h l- -^^ltH^xoidl^S-aJp ridbi-e- i |:i>2> |idazQi.ofL5-sjpyridii ?"yl 2b drQX>¾}eth - L -dih dro~ ^

bydiOxy}«efty]-2.S-dUiydro- 11.41textnoI2i3-¾)py«dftv-7-yl.8 -qo.inoliswi. ?-qttiiiolioyl, 4 - isoqainolinyi.7 -ssoqoiooliisyi I .S--«3phdtyrk¾o~3-y), 3-«K!thy1-lH~pyT3Zolo{3>44}|pyridin-5-yi IH- pyra2o)of3,4-b)pyrid.o» -y! ©t 3--incdiy!-lH--pyt32o](>|'3.y4>bjpyrldte--4--yU aad a pharmaceuticall acceptable salt thaeo

SS. Coj8po«nd of Claim 43 w refet a is rahydK>ft«¾HyI, iefrah dmp auyl, 3.4-diiiydro- piperidinyl, pyrkiyi, pyraaaJy!.. te»a¾o!ylphej.yi quinoBnyi, L¾-dilsydroquisoSinyl. pyrmlidmyt benzyl. l«2,3,4-teiJ'ahydroquiHoliay.i 5,SJ,8-terta ytlfoq inoi¾«yl. qulttoxalkjyl, quJuazoiinyi iM ndazoiyi 2H~indam]yl, isoindoltoyl, |l,2,4jtrM^lo|4,3-a)pyridlnyl, lH-pjra26kf3,4-dJ|¾?'riifijdinyl, iso »im>lioyL JH-pyra¾>lof3,4- blpyridiiwl,. 3:H" teoi4«5-a)p iidte i, pyradteinyl, pyrazlnyt,

pyrlittid yl 4,5,§>7-te«^ydro-3H'-pyfazol.0(3,4^|pyrfdiayl, 3,4-dibydt«-2H-pyraao}2,3-c}pyrtdbiyl, or ebro!isanyi,

w er in . * is t sabstiitited or substituted with- ΟΪΚΪ or mom substituants asdopeadentfy selected from metby'i, ethyl, cyaao, cMoro,. fluo«).< methoxy, tr Ifkiorameihyi, elhoxycsfbpnyi btsloxyeaf hooyl earhoxy. -(mediyi}-N (medioxye l)aisiKOcar> nyl. {N, »

.l.-;Rielliyipyia2jBy-4-- y])&:ii'bfii5y!,. or o<·:>:

and a pfeanftaeeaticaM acceptable sals thereof. 56, Compotmd of Ct&im 43 wherein R:; is benzyl tettahydtopyraa-4-yi 3-βαοκ>- ietrali drop ran^- ], 1 -Bo€-p!peddi?s -yi hexabydi ftiroH,3-b]ft!fAVyl 2,5- dioxo p rmi iilin ~ -

2-pyrkJyl, 3-pyddyL 4-pyddyi, 2-«H«fiy -3f yddyl 2-iiKii'hyl-4 -pyik , 2-me i~3-pyndyl 2- methyl--6--p>Tidyl 3-metfcyl-4--p>tldyl.3--s¾ethy1.-5-pyrjdyl, 4-meiSwI-3-pyddyL 2.g-di.me i-3- pyridy!, 24-d } ky§-3-pyrk¾l 2 , -dia*eihyi-5-pyjrJdylf 2,3-diH«thyi-5-pyndyi.4 i««hyl-2- pytldy!, 2 dimethyl»3-pytktyit 2-«lwi-3-pyrkiyi 3-ed l-S-pyddyt 2-«ihyl--&-roetyl-3--pyridyl< S-diiyl-e-awthyl-S-pyrtd i, 3-is pfo y!-5-pyddyL 3-piop- i-es-I-yi-S-pyridji 3-(l- medft-1eli¾«iyS}--5--pyridyl, S-cycSopmpyi-S-pysidy!, 3- k dfosymeth l-S' f id l 3-(2diydro¾yil¾yl)-5-pyf idyl, 2~{1 -hydroxy- l-methy1ethyi-3-n hyt- S-pyridyl 2-hydroKypropyl-5-pyTidyl 3-fl ^difiydroxyet yl) -S-pyridyS, 2-trifkommei yS-3- pyridyl, 2-tniuorosiethyi -pyf1dy!: 2 rill«oroB¾edw!-5--pyi'Idyi! 3-«»th l-2-irifl«»o.8ietfeyl-5- pyridyl i^riie i- 4Tiil!Somffi (i¾4-S rki ], 3 nfl«oroinedwl-'5'pyrkSyl, 3-trif1»orome&yi-5- f!aoio-6-pyrkiyl, 4»Sr ifltsoroawf yl- 2-chloro-S- pyddyL 2-.fi h«xy-5-pytid l< 3· (2- ydroxypropyij-5-pytidyI, 3~(2-hydroxyi>iliyi)-5-pyridylt 3-a½ikoxy-5-: yridyL 3-ew ixy-5- pyddyi 2--fiteikoxy- -ineihyi-5-pyridyl, 2-t»eihoxy-6-ethyi pyfidy' 2-eyano-3--pyrkiyt 3- ey380--4-pyridy 3-cya«o-5-p idyl 2 -c ano- §-tji8«oro«)e(hyi-3-pyf klyi 2-dii.on>-3-pyridyi, 2- chki!X)-S-pyridyi, 3-chi«ro-5~pyfldyl, 4'Chfcro-3-pyddyL 3-dilor -f~cy8no-5-pyrWyi 2-ftaore-5- pyridyl, 34:kom-5--pyndyl, 4-fi«oio-3-py5:idyl, 2 - eh! or - 5 - t¾e i!v ! ·- 3 - py ridy 1 f 2-bro o--3-- & [-- 5-pyridyl J,4.dit««ihyl-2-Wcoj>'ridiil-5-yl, l,3-di!: eihy!-2 oxopyridirs-5--yS, i,2--dimi>thyi-6-- oxopyfidis- 3 vL l.--meihyi-2-oxopyddijj-5-yl: 2 Methyl -6-oxopyridtn -4-yi, 1 -«lfeyI--2 -oxopyrldift-- S-yi.4 -ethyl- i-im%i.-2-«xQpyi1dl»-5->i ! -e l-a-»)e l-6-oxspyridi»--5- l i-lsopmpyl-2- qsopyiids!i-5-yS, t>2-dim»thy{-S-oXoisyrida-3-ylt ^t^thyl-a-tnfiuom^h i-e-wco yridin^- i, 1- mediy]-3-idf¾s0mied !-2--oxopyndiii-4-yi 2-{4-morphol$nylnm¾y{}-3-pyr&!yI,

b«iykmiisoca!to!wi)-4-pyndyi 2--{meih0xy$i !amiiiocaAonyi) -pyndyl> 3-{3-met¾osyphsiyl} - 5-pyridyl 3»(. i«om«5-medKJ^kw])"5-pyridyl,

5~ rimidia i -chloro"S-s>e ]- yrimidin -y{, 2, -dM l-pyfimidift-S-yi 2 yanopyrimidia-5- yl -irdliiorai!ie i- yni'f»dHi-5-yl, 4-flu&rop}tSm in-2->l S-fluoropyrra$Rlio-2-yi 4- tHf««roae{hyl~pTiH-idi«-5-yi 2-azetid:inylcarfeoByI--pyfazft-5-yl..2-diraet.hylafiiiao arhonyl- py:¾zi:n-5-yl, pyradteii>-3-yl,

1 ,3,5 rimdii i - ra20l l< i-fct yl-S-pwasralyi, i -Isopropyl-S-pyrazolyf, i~e&yl ¾orao~5- pyrazolyl, l-e l-4--meth> -5-pyrazolyl, 1 -^liyi- 3-methoxymethyl- 5--pyfsz< i> l-ftieiiiyi-3- dii«e 'lamS«oc8i¼nyl--S--pyi¾2oIyi l'a*(byl~3--c>'cloprqpyl-5--pyrazolyl 1 H?diylte»¾zol-2-¾ and a phai aceaiically acce table salt thereo

57. Compound of Claim 43 wheseirs Rv is pk syl, 2,8-d!l4uorop¾ Byl, - fltsyropheavi 2,4-diflkoi¾p!?i3syi 2,4,8-ixlfhioropiiertyl, 2,5-di u0rop!ie«yL 2,3-dlflaorophenyi, 2,6-d «ort>-3- metbexypbenyl, 2>4-diftuoro-3-a>ethoxypheny.l, 3-chlQfophenyi, 2,8-dickoropheayi 2,3- 3-dteo- fuoropbesiyt 2-ii«ora-5-t.riSuoro8wifeylpheoy!, S-sydroxymetbylphenyl, 3-b draxye 'ipheayi 3- hydt isysH ^-ffietfeylpheKyi. S-roe^oypbenyL 2-a¾?ih«sxypieny.l, j-methwtyptanyi, 2- mei.hy!s«l.fo«yiphenyi.3- meihylsidfoiiySp ayi.2-!laor -- 5- ethyfs lfoflyiphenyi 5- •ethylainnos l:loayl.-2-fi«omp eayi, 2--fl«om-5-:ox!t ylearboftyip ei¾'l! S-metbexyeafbeaylphaiyl, 3·· caifeoxypheayi, 2--m«hyi-5-«thQxycarlwylpheftyl, 2- >lor> S-e£b^carbm} l h^

mei o car oftylphes i: .3--metyi--5-i¾eihoxycatbo8ylph¾.>yi 3- ydrayraethyI-5- i dioxycarbofiyi beriyL 3-t«ei oxy-S-niethoxysjrtx>ny¾¾ie«yl 2-fl¾»ro-5- ffierttexycarboaylnj hylphetiy!.2 1«ora-5-csrb yn:islb 1pb o 1, 2,(>^iflao 3-mt'h ip.heis j, E- ethylphsayt, 2-iaethyl-S ar oxy phenyl t -dil«ro-5~eaf oxypbeoyl, H-flu nvS-c^rboxypfeenyi, 2- 2-

cyaoo-3-ffi¾by] enyL 2-cyano~5-a¾8{hylphenyt, 4-cyaa0-3-me pfeenyi, 2-cyaoo-3-e tphenyi 4- chiof o- -2-cyanopheaylf 2-cklofo- -4-cyanophesyi, 3-cfelorO"2-cyanopfee»yl, 3-cfe] m-6 ya»opheny!, 2- tyano-S -diditempkmyl, S-cyaao-S^-ilifluoi-o km !, 4 yano-2,8-diflaofop eny.l.2-cyaao-S- fiapfo en l, 2- yatKi-8-chIaropha)yi S-cWora^-caao^-fluompfeen J, 2-cyaw>-S

trifltteromethylpheayL 2-cyan -5-tti'fia©rof»8iliylp !8yi, 3- 1 (ls p«jp I}aial'aocas:k)ny]|pheny.L 5- ffieihyl-3-|(iSo »|> !} inii!0€arbon ilphi'n if 4-«iethyl~3*l{:lsopfopyl)amisKK¾rbo»yi|pki»yi> 2- mei yi- 5-|N ijj^th l)-- '¼dhax eib anrioo€a(½oyl]Afto 1, 2 -meiyl- 5-|j I¾- •dim«rtiyl)aia¾ocatboHyljphea;yl, dlll«oii -3-((Is To i5an¾:«ocai ofiyi)phei5yl 2-fluorc^-S-{ClsopK)pyi)aminocarbOByi}pheKyl> 2- fi ofo-3-({N-is<^ropyl-N-«ie(hyk»jko}carlx)nyl)pteyl, Z-fla io-S- eCb ksjjindJcar Qftyli kwi, 2- {kora-3-({B« {wlb kadno)cark>H l} tei i,

E-0ooro-S-(cydobmyl)}am5necaA0f{yl}pf¾et¾yI, 2.fl«oro-5-({^-elop«.>n{y!)}amkocatk>ay.l}p¾efty.l 2- .fiaoro-S^et{¾ drap aa--4" !)}a5a}fiocarkay hepyl Z-fiwm^S-

({aieSfe xy ffi !jJamioo r o yilp enyi, 2-fl«o.ro«5"(C2"metbyl)ami¾ocarl)oriyi}pheayi, 2^fiaoa-§- (C2-md.b xyp.ropyl}amiaikark>ayi}pheay.

metbykifhy.i}.affiSaocarb6ay.i)paeny '2~£ oro-5"{fi -pyrroSindsiiybc rboayli liej!yi 2-d>ioro-5 0 >3- dim¾ yl fa¾to~ -- !)caj¾oft i) hieft l, 2-H««f¾-5-i(! ^aedwi m^ 2- fl«ofo -{{l^meth rai;oi-^ 0amloor^r{«»i p¾«ayi', 2-ilao.ro-5*((i-meihylpyrazo!~5- yl)a}ainocarboayl}paeayl, 2-i]MOio--5-((i-ffieh ! ra^ 2··Αυοκ·§·- {toa^i do yran - lrnetbyl))aHJ{nt«¾ri»»y!} bea>1« 2--OiiOro-5-((1 -di5iied ipyrazo1" - yl}amlftocarbony¾paeayl ^-fltiOf -^-CCp rid^-yiaetb llsaiiOc^^tt ^ph^B l, 2-¾aoro;-5-{3- fittOm iperfdit}-4-yl))ajtiiaoc-ari)oay!iphenyi{:Π«ο«>-§-·{1··Β{Κ:-3-ί1?ΐ0ιίορΐρ0ΓΜ»-4- -fi«oro-5-(4-mar hol5«y¾}am5»o«feoRyl} l»^y:l, 2~¾ori>»5~((4--

B-ai hoI:hi leth l) rfiiBoCiirbonYl)plK'o 2-ckloro- 5··(1•pyrto^lnylcartony{}phei5.yl 2<«Mor¾-5--(i -ms^pwa-ziB-l-yU r on Sphenyl, 3-(2- teozimidazolyOphftKyl, 3-{2-me i-l-te{razoiyl}.ptei>i

{S-imhyi-iA^oxadlazoi-S- feeeyi; aad-a p arsaaeeotieally acceptable sab: thereof.

58. Com ound of CMm 43 wherein Rs is S-qubiofeiyi 6-quino!inyl 7-qa«! iioyl 8- quinoHftyi S-chlaro-S- amoIiisyb 7-ch!or - a¾f5fii$isy!, 8-chlore-6-q«ii¾fil$sy!, 2~TaeihyI~4- qutoaMnyl 5,6,7,84eirhydroquUK>lin-5-y.l

*.ird ydroquinoli8-5-yI, 4-qui«azoitoyi iitaxaltiv-S-yi, I -o o somdoiB - i i-oxo-isob«!olm-6- I-oi«thyMH4«da3i¾il.4>-yl . -diroeihyl- iH4adaz .l-4" l« [i ^^jiriazoloH.S-ai rfdli^ -yl, 1.roe i-2~oxo- lf2-dihydfoqmno] -6-l 4- iiKit l-Z-ox -l^-dihydro ataftiin-fi- !, 5 lo:ro4--riR 4^ i«4- d!metBy-2-oxo-l,2-djhydfeq«boi.in-C*-yi., -ox^42--d droqHimd.!s-6-yi, 4-oxo-dihydroq«teolin-i- yl 4-οχο-ψϊΜΗή- 1 (4H)-yJ:.2 meiiiyl Ϊ -axo-l,2-d}hy<?foi«oqu5«oli»-4-yi 5,7-dii¾OK>r-t4-di8»{¾.yl- -'Oxo4. -dl ydi'« iii!)C)Sis¾-6- i 5 ^i««oro i. ria?6 1-2-oxo-li-d%daKiiftoliB-6-> 5.7» diflat!!O! -methyl- -a - 44Ailmmi kyl-l ,2-di ydr qainolin-6--yI55V7-difl m- 4 -efbyl - 1 ·¾€ !·· 2 oxo 4 ,2-dibydiCi. uIfiaHsi4-yl 8 st3tj«i8o.l¾ty 7-isoqtilnoimyl, 64sequ¾K>BByJ.> 5 sW|«i«oliay 4- !soqttisolwsyi, i-j thyim- yimjkilS -blp rfdto-S-yl, ί -eifeyl 1H -pyjaalo[3; -ialp ridm- 3 yL I-

yi. brdd^i.^p ii^^^^ 3-me%l-3H4TuIda¾o{4)5- bjpyrid -6- i 3-m«hyiisoxa2'.6k(5>4-b|pyridi«-4-y.l il 4!ma?.&loi4.3-a]pyrldin-8-y.l

>5Jj etr -dw-8H-j¾Ta¾oio|3> -b] ridit-3- l> 34:'di.bydm-2H--pyramf23-dpyrfd:m:-5-yl.6·- medwl-3.4-di.bydm· 2M--pyram|2,3-bjpyrldis- S-y! or S-c mmim- i; and a pharm ceuticall acceptable sail thereof.

59. A compound of Claim i selected {torn the group cons&dftg of

M8: 2 v^ rax - - e^^

me!lryksrea;

i-(5-cyd»prripyl:-4-^

1 - {(3- (1 - 1 fi - pyi¾¾ol- 5 -y i) oxy) - 543- by dm

i4S4^ds-3 ¾yd« t: ^

H5-(i,S-diiiydfo- H- ra^^^ L (5 - (S d j.b df o-t¾I- p ras - 3-y

1 (3 - f(l -ethyl- iH-pyram]--5-y oxy)--5»(^rahydra--2ii-pyr5m-4 -ylmethyl) -2-fyridbiyl} 'S-methylurea; or a pharoiaceuiieaily -aceepiahie salt thereof.

60, Cosipoiiisd of Claim I whe ein W is II of a p m¾eeutfeaIly-acc6ptable salt t e eof,

Si . A. pharmaceutical composuiaft,' which comprises a compou d of Formula la as deleted m any on of claims 1 io SO, or a pharmacemic&Hy acceptable sail thereof, arid a pharmaceutically ;H repsac-h: diluent or arrier,

62. A compound of Formula la according to any one of claims 1 io 80. or a harffiaceijticaliy acceptable salt thereof, far use It therapy.

63. The wse o a com ound of Formula ia accordin to my am of claims I so 68. or a pharmaceutically accepta le sail thereof, irt die ma ifacture of a .ffiedicaoiest far th treatment of diseases or disorders mediated J>y deficient levels of ghicokioase activity or which cm be treated by activating ghscokirsasc.

64. A com ound of Formula ia ax defined in any one of date 1 io 60, or a pharmaceutically acceptable sail thereof for use ia treating diseases or disorders me iated by deficient levels of glocokioase activity or which c¾.a be tfeated by acilvaliag gloeolioase.

65. The asc according to claim 63 or the . compound according to claim 63, whereto the disease or disorder is diabetes.

66. A method of treating a patient diagnosed with diabetes comprising adottofctratioa of a compO!icd of Claim I .

Description:
ίΙΙΪΕΑ COMPOUNDS AS G A ACTIVATORS w OF HE INVENTION

The present invention related to novel compounds, to pharmaceutical compositions cornprismg the compounds, to a process for making die compounds and to the use of the com ounds la therapy. More particularly, it relates to certain gjiteokinase activators useful in- the treatment f diseases d disorders that oxtld benefit from activation of gincokinase,

BACKGROUND Of THE INVENTION

Glucokioase i exok ase IV or D> is a glycolytic enssyiris that plays, an importaat. role irt blood sugar regulation .related to glucose utifeattoti a»d metabolism in the liver and pancreatic beta cells. Serving as a glucose sessor, gtoeokiuase controls lasma glucose, levels. Glucokinaae plays a doal rob in .reducing plasma glucose levels; glucose-mediated activation of the en¾ymc in hepatocytes facilitates hepatic giocose npiafcc aad glycogen synthesis, while that la pancreatic beta ceils ultimately induces ins lin seeretio«. Both of these effects in turn reduce plasma glucose levels.

Clinical evidence has shown that, glueokitiase variants with, decreased, and increased activities are associated with mature easel, diabetes of the y ung { O0Y2) and persistent: hyperinsul nemic hypoglycemia &( infancy (PHHI), respectively. lso, aoo n.sulin dependent diabetes rneilitos (NIDDM) patients have been reported to have inappropriately lo giueokaiase activity; Ftirtherrnare. overexpressioa of glucokiuase it* dietary or gesetie animal models of diabetes either prevents, aoKiiorafes, or reverses the progress of pathological. symptoms in the disease. For these reasons, compounds that activate gfecokiaase have been sought by the pitasaaceatjeai liidustry.

International patent application, Publication No. WO 2 7/OS3345, which was published on May 10, 200?, discloses as giocokinase act ators certain 2-an«.aopyridiiie derivatives bearing at the 3 -position a meihyieneoxy-dkrked aromatic group a d on. the ammo group a heteroaryl ring, such as dna/oly! or i A4-lmadiazoiyl

it has .now been found that pyridyl ureas are useful as glneokirtase activators. Cettain of these •compounds have been, found to have an outstanding combination of properties that especially adapts them, for oral use to control plasma glucose levels.

SU MARY OF THE I E TION

The present invention comprises a new class of compounds useful is the treatment of diseases, such as diabetes. Accordingly, the Invention als coinprises pharmaceutical compositions comprising the amipourtds, methods for the treattniini of diabetes, usin the compounds and compositions of the invention, and intermediates and processes useiul l¾r the preparation of the compounds of the invention.

I ' Tie compounds of the invers on are represented by the tMlowisg general structure:

aa a piuiraiaceuuca ' Hy acceptable salt thereof wherein G, P, ', R- 1 and R 5 are deikied below.

he foregoing merely imi *e& certain aspects of ihe an¾iwi©« a«d is not iisfcnded, nor should it be censiriied, as limiting the iaveithon in any ay - Ail patents, patent applications and other publications recited herein are hereby incorporated by reference in their entirety.

Detailed Description of The Invent ion

One aspect oi the -current iventiOH relates to eois onrids having the general structure of foraruSa 1 :

w erein:

R ! is H, alky], aifcenyl, haloaikyl a!k xy, hydroxyaikyl, amisoalkyh alkoxyalkyl hydroxyaikoxyalkyl, aikoxycarbojiyianduoaikyi eyeloalkyt cycloalky kyk aryl, aralkyi, heteroeycly! or heteroeycly laffcyl whereto the cydoalkyl, aryl or heierocydyi ring in cycloatkyi, cycSostkyialkyl aryl, ara!kyl, heteroeyclyi or heterocyciyialky! is uns nbstituted or substituted with one or two sabsiiiiteuix tadepsndeatiy selected, from hydroxy, alkoxy. alkyl, oxo or halo;

S- - is M. alliYh or hale;

¾- is M, halo, haloaikyl, alkaxyearbonyl, asmioearboii S, aikoxvaikynyl, bydroxyalkynyi or-

X ;

X is a bond, -0-, or ~SCG}» ;

rus 0, L or 2:

R" is aikyl hydroxyalkyl,. alteyaikyL alfco yaltetyl, alkoxyeartery!aikyl carboxyalkyl, amitjocaiboxiyialfeyi, alfcylaHJiftocarbotiy alkyl, atyl c doglkyl, cyc!oalkenyh heteroeyclyi,. aralky!, araikeBvL aryiaikyayi cycloaikylalkyk eyeloaikyMkesyi eydoaifcyl-dkyayl, h terocyciyialkyl or beieroeyciyieatboayialkyf wherein ike ring n R* Is ousubsiittitcd or substituted witis ί -3 sa st¾e«& independently seieeted from H, aikyi.,. balo, hsiiealkyi hydimyl slkoxy, baioalkoxy, acyl,

ikyisid.i nyk heteroeyc ' lyl, aaibu>«ulfoayi, alkyUH»is ss«}ib:oyk cyaso, aikoxycarborryi, carboxy, an*no, RR'N-aliyi aikoxyaik i, kydroxyaikyl or Κ¾ ¾ Ο-0} where R s Is aikyi and l fi is aikyi afkoxys ' lkyl, aBriuoaikyi or aikyiamiaoalkyi, or where R :s and R s> together ttli ike niirogcn form a heicioeyclyi rin tmsubstiio ' tod or substituted witis aikyi;

R ? is atyl ara!kyi heterocyeSy lalkyL eydoa!ky 1 or teerocyclyl, whefeirs 1* is mtsubs iaied or aibstiuted i i-3 substituems itrdepeHdet!i selected item aikyi aikoxy: h droxys bate, baioiiSkyl cyaao, aJkoxycarboffyb carboxy, acyi, cydoaikyh iieterocyclyl hydtoxyaikyi aikoxyalkyi, oxo, -NRR \ aikyl-^RR/ or R a R ! ¾i€( }) where R* is a!kyi and R fc is alkexyaiky! or araiaoaikyi;

where R aad R' is H, aikyi ryl, keterocytiyb .heteto ydy ' lalky or eycloa!kyL where the iieterocydylaikyL cycloaikyl aftd fceterocyeJyl sobstitueats are tmsobstitaisd or substituted %-itb 1-3 SubstiMteats indepeadeiaiy selected .from aikyi, alkox . hydroxy, haio, hafeaikyl cyaao, or earkox : or R * and. J? can together with the N ibna aeieroeye-ly!;

R" is aryi araikyi, heieracyeiyi, heteroeyciyl ikyi, or cycioslkyi, wherein each of the ioe!Bei!!oKSii jjogs is unswbstituted or substituted with 1-4 sabstiteeots i eperidcatly selected from aikyi, halo, haioalkyk a!koxy,, alkoxyearboayi carhoxy, aiBinocarboiry1 s heicrocycl jcarbonyi, eyaao, cycioaikyl, ireiexocyciyi, hydresyaikyl aikoxyiaikyl, RR', C ' ftNRR", asa of acyi:

GisOQorM;

LisO, S,C¾orG¾0;

Qk¾ or-L-R :a»d

F is or L-R* ;

provided

when Q is H; dre P is ~L-S S , or

when Q is -L~R S «se» P is H:

wheaGi IheaP is-L-R*;

iurdier pro vided when ;s is ft R ! is miikyl S : is ft L is O, and P ia ft fttea R s is aof i -methyi-2-oxo- i . .2-dibydroqimiQii8-6-yk isoqaiftoiia-S-yi, i * soqtti«oMo?6-yk q iaoiia-6-yi, 2-oxo- i. i 2-dihydraq;oi!5ollO:-6-yi.4-niei yl~2-ox:o~l ,2~diiiydroqiiiii0iiB- 6~yi, 2-metbyH.-oxo- 1 ,2-dihydro-isoqaiaoHsv6-yi, } ,4-dioset¾yl-2-oso-i ^-dihydroquiaoiln-fi-yi, 5- chloro-t ioeih -2-oxr i > 2-dib d oa iia"6- L 5j-di¾0!:r 1 ,4-d»»efhyl « 2-Ox - ' l .2- d.¾ydfo uHKsli«'6- I t S -methyl- 1 H-i»da¾oiV5-yi, or 3»m4hy-3H- j midi«o 5-b]pyiidj«-6*yi

ftjitJter provided hen R s is Br, R ! is Biel yi, R- is H, L is 0, mi ? is H, tbea ? is not 5,?- difiooro- 1 > 4 riated>yl -o 0'l > 2-d¾ydix) uttKjUa-6- k 5,7-diOuoro- 1 -m8thyl-2-oxo-4- u1lli!Oro«ie*y!-k2-diirydroqir!«olin-6-yl SJ-dOii ro-^eikyi-i -aietby]-2-exo-k2-diirydroqinnoii»-6- y i, or 2-irifiib i- 1 -oxo- ϊ , 2-rliky dro-i soq taol i a-6-y I; farther provided v ert ;! is 1 -methykl H-p szo -yf S ; is med L 1 is H, L is O and P is H. then R is not. l-e&yMH-pynisraM-yl.

farther provided When R 5 is S -raethy I B-p *azol-S-yl, R s is methyl R 2 is H, L is O fcnd P is H fhea ' mi 2- sihyi-l-mo- 1 ,2-diixy4foisoii«iiKsit»-<i-yi, 3,7-diflaoro- S 5 κ&«ε% ; |-2^«Η ,2- di!rydi )Qiiittoiiri.-6-yi, or 1 ,4 ¾met yl-2 « QX:©-:l .2~diS:rydro^:ttnotht-6~yi;

former pro vided R ;; is 00! halo when. R ? is it R s is methyl, L is O., is H aad R s is 5- qwpphiryl:

finrte provided ft" is not chk whea R " is bromo, R s is methyl L is 0„ P is H ami R ? is 5- qyiaoitoyi;

further provided ft 5 is not phenyl or tert-butyi virfeesj L is 0, S* is 2-e1¾yi-3-pyridyL 2~ stbyS-

3- pyridyX or 2,6Kbjneihyl-3-pyridyi R ; is H, R' Is 2~pyridyiihio i fermtro . , meibosye!.hoxy or triiluororaediv! aad G is CM:

further provided 1 ! is not 4-8jetfeyl-2-iiHjda∞iy.teei¾yl wfcea R 2 is , is 2~pyiidyii iio, P is 2-ediyl-3-pyridyloxy aad G is CH:

.further provided R ? is aot 4-nieihy]phenyL 2,4-dia¾oii.ryipbesyl or 1 J-dibydrosy-2- phenyleiayl wfee K ' is nwihyi R ' is H, G is , »od P is 2-raethyi~3-pyrtdyiox ;

so a pternaceuiicaHy acceptable saii thereof

in another erahodisaeat, I s is H, aS&yh C 2 .*. alkeayi.. C ; .. 6 haioaikyi, C f aikoxy, C S feydKwcya&yi, «»»no ik C« afexy-Cw; afkyl C s . s hydroxya!kaxy-C^: affcyl, aryl, C s .» axyf-C;.* atkyl 5- ί 0 membered heicfoeyelyl or 5- 1 msmbered heiero£yeiyi-C alky! svhereia the axy? or heteroeyeiyt ring is unsubsuttued or substituted will;: oae or two subsihtsems iudepeademly selected from C;* aSfcyl. hydroxy, oxo . or halo: arid a pharmaceutically acceptable salt thereof:

in gnother exabodirrienE, R' is H, .methyl, efhyK propyl, isop opy ierf-buiyl, allyi, Eri QoorO- ethyl etboxy, meihoxyethyi, hydroxyelhyl, i droxypropyl, 2,3-dihydroxypF pyi,

bydroxyethoxyeiayl ;ra¾a¾oet:liyl, phetryl, pheivyiethyl, 2-.hydfoxyphe«yime{hyi 3- hyt¾ )x h »yto h l, ^ ydroxy- heaylmethy 4>fJuoropheo>½efhyl, pyndytmethyk 6-a)ct¾ l » 2- oxo- i, >-dib. 4r«j>yr dmyln¾e a l., 4-metb.yi.baida?.olyhaetb.yi , ffiiidamlySmasiiyf i-)Bfiihyi-

tetrabydrofiiiyieiliyl; aad. a pham¾«ceut j C8!ly acceptable- salt thereof:

In another ejabodancot, R ! is 2-pyridyia)ithyl .S-pyridyhsetby!, 4-pyridyS:raeibyJ,. 4- iHefhy!isriidazQi-2-y:(i edryS, isaida ol-S-yltHeihyi :i-aiethyiiri«da.¾ol-5-y!nieihyi,

4- yiri ) ethyi,

haefiry! or riwrp!:ioiii!-4-y!ethyt and a phamxaCsut caUy acceptable salt thereof:.

In snofher eiabodimeat, R s is xnethyl, efSry! or hydroxyefiryl; -and a pbamtaceaUealry acceptable salt thereof " : i another embodiment, R" is B, mstayi, chiofo, or f! oro; aad a pl miacetttteaily acceptable salt thereof,

in another embodiment, R ': is H; atid a pharmaceutic ll acceptable salt thereof

In another mibodbneot R s is - SiO),. W and a is 0, 5., ex 2; and a pharmaceutically acceptable salt thereof:

in another embodiment, R ,: is - SR : arid a plmramcexdieally acceptable salt thereof * in aaotner em odiment, R' is€·« a!kyL€;. < ; hydroxyajkyi, Cs.* alk:oxy-CV<> alkyl C>-« alkoxy- C ¾5 alkenyl, ' C M alkoxyca&oayl-Cj.* aikyl, carboxya!kyi aminocarboii l-Cs.i, aikyl, CW alkyl C«c> aryl C eyeloalky cycloalfceisyi 5-10 isembered heterocyelyl Q.,m ary½. s alkyJ, (¾.;« aryi-Gj,* slkeay ' l C cycSoalkyl-Cs.* alkyl 5-iO tnersbered whereiri the aryl cycloalkyt cycbalkeoyl or hetere-cyely ring in R ! is xiasufestituted or substituted with 1-3 stibstitaeats independently selected from Ci.«. alkyl halo, haloa!kyl hyd ox !. Cs.« alKosy, C*.* acy , C alkylsidioay!, C M ; aikoxye&rhonyL c¾i¾sxv, 5-16 niembered heterocyclyl, amino, CV* sniiiioaikyi, C alkyl, or C f : bydroxyalkyi; and a p amiaeeutiealiy acceptable sail thereof

la another embo iment, ! is tnevhoxycarlxjayhiieihylibto, ineiboxycarbonyledrylthio, rficihexypropy!ibio, -tadtoK>¾«an-2- libto. ydH>x iop fe¼jo. 3,4-ilibydiexybuty¾hi¾

carhoxyethyiiiiio, (a)ediyiaa)ini)carbaay])! e byldiio, (dime iylaffiio^ar o«yl)iBetbyllbio, (3- i:iydroxy- -rj:i©j:Sr i)aiyi)!¾! f (2- ydf xy-2-HK;!iyl irt:yl}diso, {4-meih Ipiperazi - i -yS

crtrbonyhaetnylths ,

Hittrahydro-2H- pyrai -y ctiiykhio, <5~J:aeth.yl-2-oxadkxoiyl)jaetbyl{ io, 2 ^ pyrtdyhnethv!tb.i0 ! .3.4- 2- pyridy it io, {4-p.iperidiayDihiOi ( I -isopropylp5pendlr!-4-yl)tblo, (i -ffistiiylc rriOBylp!peridia-4-yl t kx Htert-butoxycarboiiyOpiperidta^-yliliio,. Cl-me lsuUoi{yipiperid«>-4~yl)t.liiO, (1- iSQp:ropyicarboaylp!peridis:t-4-Y:}ifeio, l-{dim¾byl:amiaocarboay!)pipeddia-4-ylib! s, i- (iB.eil:tosycafbo«yi}p!peridia-4-y thio, (l»{5-cMoropyrimidm-2-yl piperidKi-4-yl)thio, (i-(2-.

Htert- bi(ioxy arbosyi)py!ToKdiiv3-yidiiQ, 3-metbyiisoxa o]o 5,4-b|pytsd5i!-4-y]tbio of ietrabydro-afi- p ras^-yhfeio; a«d a phanaaceuticsily acceptable salt thereof:

in another effibodHoeot, R ' is oiet oxyprapylsulfiay tsethoxypt py foayl. 1 -Ctert- bx«oxycai 0ttyl^jpfirid¾)- -y{.sx}itiay 2-pyndylsidiniyl Mt«rt-b4t& yearb«ny p«periditt- - yisu!topy!, or 2-pyridylsalfoayi; a id a p¾rmaeet«waHy acceptable salt thereof:

in another embodiment, R* is - ORk and a pin»«mce»feHy acceptable salt thsreof.

In another embodiment, R J is tnethoxyetijoxy, or 2-!aetl5yi-3~pyridy!oxy; and is

h rmaceuti ll acceptable salt thereof. aaother embo imen R <!' is Q.* hafcalk k C w - alkoxycsrboayi a itoc&rfooayi,€;.¾ alkyl Cw slkoxy-Cw aft i, C i aifcoxy-C altoyl, C- ( . s alkoxy- C. alkyay , C 5 ..i alkoxycatfcotiyl-Ci.* alkyl. C w carbmyalkyi its!ii¾ carboayS-C< aikyk Q.; $ aryl C;s.s cycl ;.:; atkyk aryi-Cj.s atayl ,s aikenyi cyeloalkyS- C 3 -s alkyayl, !ieierocydyI « C t ,s alky!, «r 4-10 meffibered heterooy^ ar K^ alkyl; wherem site aryl, cydoAyl cycioaltoyl of bctsfcicyciyl ring kt K* is uosubstiUtisd r sifeoitite with \ -3

alkyKha!o, CVslmloaikyl, bydmxyl, a!koxy, C w

aey,€:.<; al ylsuiioriy, ; , s ako&ycarbotryK carboxv, 5-10 mambered heierocyclyi ambio, « atsisoalkyk hydroxy alkyl; and a pharmaceutically acceptable sail dk-r of

la another c;i¾bodii«e«i, R* is

meihyi, isopropyK 2- ieih> pro|>yl : 2,2-dirae lpropyl, 2-ffieth.yibaiyI, trifluoro sifeyl, feydroxyebyi ftydraxybaiyl, 2~»ydr0xy-2-mefby¾asyk 2~hydmxy~2-n:Siiy:p£»syi, 2rhydi: xY-2- meftiyihexyi, i ,2-di.iiydroxypeatyk metboxypropyt. merSmxybutyi aw&oxpeatyl, meftiox psfl- - y k aietliosypeaiya- 1 -yi. ef oxycarboayl, -meliyl^^rngtbo^xthy^aiHiaocarb^n -arethyl- - {dH etiylai3:ii:noetlw!)-ana:f5eca:rbat}yf et iayaarbari ipi-opyt arte p-r pyl 4.5-dihydre ypeKiyi, propea-2-yl, .hy roxybotyayi,.2-cyclop pyieiJieayt, 2-etlioxyviayl. " 3,:5-diraetiiy!butea-i-y, pbeayleiiiyk betm- pheiryipr yl- 3-c¾ior pheayli«eihyl.1.l-dih ikoxy-S-pjeft lel yl, pbeBykiiheriy .•pih tylvitiyt, pheayethynyl, pyrid.-2-yl:nis!lsy! ; 4-piperidyiiXi tixyS.. morp¾obsi-4-

yi)propyl cyciobexyiaieO i, cyclobesy!ei!iyL cyciopropyi, cycksbexy cydopeaiyl cyciohepryl cycSope»l¾Byl cycioSiexesyl 4,4-d.imethy ' i.-cyclo ' ft«x«»yK 4-tert-basyl-cydobex- 1 -eayk cy¾iobep†er¾y I, teb b d:rf3i ra! ' i:- - l 3,6-dihydrop aa-4*y.l, l^-diosa^iro^Jjciec^-en-H- i, \j - dioxidoieirahydro-2H-d«opyran-4-yi a l4m¾aox ca^.n l-.U2 HiSttsh dfop rid-4-yK 1- raed5yist!ll¾nyS-l, J,6-reirabydrt}pyr5d-4-yI.1 -(dimedyiamfsoca^

phea l, 4-cMoropaeayl 5 3-mef:bylplieayi.4-raei:by)ph.eftyi ; 2 5 4-dto»ffeylpbsfty1, 3- irsO:u¾rom«hylp¾efiyk 4-i:rinao melhy1phefiyK 4-:a!fiiS:iox - -iriflHor mfid:v lih£;«yl 2- methylsai foayipheay i, 3-i»e Isttlfo»yipaeayl, 4-taetbylstiifofty¾>aeayi, 4- medvybulfosjyiamiaapheayl, 3Maet y!sulfoByiamiiiepfcm l,

cyariopheyyl 4 ya.aopi¾s«yk 4 yao<3-¾-Kiethoxypli.coyl ; 3-c i«)q-4-a)c{hox ¾e yl, 3- t!i:ipediyi jabspca a lipb.a) i, . -i«e oxyp eii i ! , ' .Vajet oxyp eayl, 3-dir» r0raetioxypbi:i!yl, 3- dillijoroineiityi beii k 2-siet oxypbersyt 2,4-duneiiioxypbeiryl, :S-s:ne5hy:]-3~pyfaxoiy!, L-iaethyi-4-pyraiS>!yL 1.S-dimeifeyM-pyfazoiyl, 5. AS^nmeshyM- pyra¾oSyi 3-u½thyi-4-pyrazo!yi 5 S-ftydroxyethyM-pyrazoiy!, ί -5¾ef.hsxye5¾yi"4-pyTazoS.yi, 1 -methyl- S-pyrazo!yi ! -mc i-5-f.oiidaxoIy 3.5-diBieil;iyS-

2-pyridyt 3-pyridyl 4-pyridyi.2-raeihyl-5-pyrid¾ : L 2-nK; S- - rsd Iy2-H)edi;y!-3^yndyS i

ird1:a0i'OHJC!h i-- -p ;-idyL 2-welK>xyK pyridyI, $-ftuem- ' aj«bOxy-4-pyrii3i 2-es!j0xy-4-pyr i S-aetSiiOxy-S-pyridyL 3 « tas!tay-5 « pyrtdyl 2-fi»om-4-pyridy, 2-chloiO-4-pyridyL 2 aSoT»-5-pyridy 3-chloiO-5-pyjidyL 2-cyano-4- pyridyL 2-cyaao^S~pyridyl, 2-insi¾oxy-3-cyas)o-5~pyridy], B-eysoo-S-pyndyL 3-cya O-4-pyi!dyl, ?- i:fiediyisidii)ayi-5-pyridyl, 2-oxo-L2-di¾ydro|>yndi5i-3-yi, 2-hydroxypyrid-4-yi, 2-isydr¾sypyrid-5-yl, S-pyrkaidinyt 2-ami«o~5-pyritaldiayi 2^ aao-5-pytitaklh.iyl, pyra¾ia-2-y I, pyri a ia-4-yL 3- beaz-oiakoy } , miisteoj ' 1 ,2r-a|pyridy? or 2-»seJkylbeaxoxit?»l-5-y¾

and a p.bi«tn¾£eylic¾.Uy acceptable sail thereof

h another saabodtntea is M, or bm and. a pfran»aceutic y acceptable salt thereof. fi aaote mbodimeat, 6 is CH; aad a p¾arn¾¾¾{«kaily acceptable salt thereof.

la anolher eni isaem. G is C-Q; Q is Hi P is -i,-R s ; and R* 5 mesabcred aittdgea coataaiag hcierocye!yt.5 mstabered oxygeii eoataiaiag hsierocyclyi, 6 romib sd miro im c Hi i»i«g beierocyciyl 6 HKfabered o ygen coxtSaiaiRg e&w clyl, pheny enz l 9 saeathered bicyclk nitrogea coaiaiaiag iseterocy ! S, IP :iag-jab$red bieyelic oxygen eoatsarfag hcierocydyi or Hi etabefed bicyciic ta ogea c siiaiaipg toerocyclyi

whereia R '' uasafestituted or subsiihiled vvtfti oae or raore sufcstitueais tadependeatby selected from C t . <> alkyl, cysao, lu o. C s . < s sikoxy.€';.« !ut! aikyl, C , alxosycsfboHyl, arboK , C,* aikox.y-Cs.«.8ik.yia««aocarboayK C aikylamiaoc-aitaryi aUc laKitovCj,* eikylaminocarboayl, or [optionally substituted 4-6 membered nifto-faa coataiaiag hcicrdcyciyijcarboayl:

aad a p¾an»ac¾nk:a ' Hy acceptable sal, thereof.

i a&other embodiment, G is C-Q; Q is H; is ~L~R £ ; aad R* is tetrahydrofMmnyl..

leiiahydiopyninyl 3.4-d!l:i¥dr -2H-py!¾no[3,2-cjpyridayl, chro aayl, piperidirc pyridyL pyrazoiyl, phenyl xH ' aoai 1 ^-dihydroqitiaolmy, pyrroHdiKyi. beazyl 5A ' ?«8-fetraaydroqa!aob ' ayl, qiimoxaiiayL IM-sida¾aIyS..2H-indszoiyl 1M-

selected froai sneftyj, edi i cyaao, oa!oro, iivtom, saeibox , trifiaoxoiaethy sthox carboay, teri- bifiOxycarbsayj : carboxy, -{H!ehyl N-(iaeihoxyc i t)<tt^

dia'iedi [)aiaiaocsr oayi -(p}ed:) l} l-n}(3by!pyfaaoy-4- :y IjcarboayL or oxo;

aad a ptena«atcsHy acccpabls salt uics¾oi hi aaother embodiment, G is C-Q; Q is H; P is ~-L~ 5 ; md i is

2~ a yl-3~pyridyh 2~c f~3-pyri4yl 2 yano~ - ytt L 3 h!o:m-4 ¥8S:¾o-5-pyridyi, ! 3,5-»ii«ef:hyl-4-pyi¾xosy],. ' i -eihyl-S-pymzoiyl, i-effiy!-4-

I;eirahydrofuraft*3-yi, I 3-Quoyo-tetraiiydro» 2H- yraa^- 5 -metbyHetrahy<iri 2H- y5-aa» -yl 5 3-etby!-lKU8liydro>2H-)yi¾si-4-yl 1 m-

pteiiyi, 2,6-diiluorsphiiHyl 2-iluoroplwsiyl 2/4-difl oropbeavl 2,4 ( 6-idflBoro ¾iiii > 2,5- d uoropheayl 2,3-difi»or0pl:feayS, 26-difl«OO-3-isei:bosypi5e«yl, 2,4~dinuoro-3- e&oxypl:ieayS, 2,6-dkhSaropheRvL 2 i 3-dichior0pbeayl 3 hIoro~2-rluoTOpl>eftyl, 21 are-?-i]«orap¾eayS, 3-cidoro- -i¾ioro ¾esi i -!lu E»-S-iri.0o«i- H)¾di tp ea !, 3-fiiethoxy eu i, 2-¾«ethoxyph«i l 4- me&oxypheftyl, -med> l~S-eibc)s c£!rbo !pliie8 L 2-ehyIplisoyl 2~meiliyi-5 rhoxYpbe«yt, 3- chior0-2-cy<i»opbenyL 2-cyaixs-6-tdSa(»i>mefliy{plsoyl ( 2-«¾.tby-5-} -(me{ yi}-N- (met i) yed3 i) miK0CiiS¾oay!j ¾fi!:iyK 2~a}cd)yi-5-i(N > M-dimeb Saniiipc;»

5- -(md]i ]h ~iri£U^^ 2-tneftiy.l-5-<i-ine{hyipyya¾iny-4~ yi)eartx»nyi)pkcftyi 5 besxyi,

3~qw:n»imyt 5-ijaiaoiinyt S-qaniOin l T-^ainoliayt, 8-qoii)©l.myf.5- btOTS»6-qui«eHftyl 5,6,7,8-tetatwdroqu ai j ^ qumoxaii-i-5-yj, 3- m«hyWH-iada«oi-4 « yl 2 « m« :½H-i«4a¾0i-4 « yJ, f '«Ki¾ {-rH-ia azol- -yl, i -aiciiiyl- ' l H « mtof- S-yl, [ { ^^jtri'dz loHJ-alp ridsa-S-yl, S^T-dib dra-Si-^e ciopeHU^ l rsdi^S- S, dirom a-4--yi 5 3,4- dih dr^2H ) {¾i i el JMia- >yi Hp b i-2"sx« ^^

i ,2-dii iydroqun.ioha-6-yl , 5 Moro«! -R.iethy-2- xo- ! ,2~dibydm umo!H5-S- ! t i ,4-ddmhy ί-2-οχο- 1 ,2- diiiydr qaift lia-ii-yl, 2-oxo- S ,2-diiwSraq»i8oHsi-6-y 2-raetliyM - ο-1 ,2 US:s dro ui8oliB-6-yL 5,7-

dibydroqiiHioiisi-d-yi - if!u ro-I-rae >d- -o o- -ii£1^ 5,7- di8«0fo-4-et.hyl- S -n^thyl-2-osi l,2^{ ^?(^tt8ioiin-6-yi, S-soguinoMn l ? sftqam»;ffi L 6* i soqtimoHftyl , 5-isoqu¾u>.Hayl , I -methyl- !. H-py razois f 3,4-b ' jpy.rid.ift-3-yi imidazo[ . ,2~a]pyridin~?-yt, b:nid!i¾dS ' ] < 2-ajpyrid¾i-S-y?, ^ncifc i-5H-u ^^^

rimi iii i ;

an a phso-f«aceutic£tU acceptable salt «$i¾a£

lo aaothcr eatbodanem, L h O: nd a pharmaceutically acceptabl; salt thereof.

iii aaoiher embodimen G is C-Q: Q is -L-R < ; P is K: d H 5 is 5 aicmbered teieracydyt 6 meaJbwd eiCiX!cyc! L pbeayi hen l-C^ alkyS, 9 iaembered xiitixjgea co S iaig heterocyclyS, Or Ϊ meoibefeddtfOgett COiiiaiaifig beifiracyc!yt

herda R 51 is yusubstituted or substituted with or<e or mo sabsiliiseais independently sel¾S¾! from C . a!ky!, c-yano * a!o, y o, hydroxy! CVs aikexy, C¾„ fi hatoalkyt C;. s aifeoxyearboayS, earboxyy G.« gikoxya!ky|-C[.s adtykniiftPearboiiyL C<- fi aiKylataiaocarbonyl CM? alkyiamino-Ci.* alkylammoeartwRyl w joptionaHy subsutwied 4-6 raembered akrogea couiaimng heierocy cS yica rboayi;

d a pharmaceutically acceptable salt iiicreot

io aaoiher eiiibodii Ct . G is C-Q; Q is -L-R 5 ; P is it; md * is ayxidyb pyiazelyl pynxjHdiny!, pheayl, beazyl quinolinyf, \ ,2-diliydroqiii»0lffiy!., qtHBOxabtsyl IH-mdazolyl 2H- iad-tzoiyl,

ajpyi'idiayl JH-jmiteoRS-it ridtayJ, pynaildioyb sir I,2 , -iey¾¾yd!-oqBaO:iftyL

whefeia R* is inmi ed or substituted wish e-ae or f»ore sabsiityents independently selected from i!uoro, chioro, eyano, rae-thosiy, tTifluoromedt i eiioxycarbopyi, carboxy,. -(saefi)yi)- K-(meiiio ed) l)aminocarbonyL

(msd iamiiioetl !jaminacar oiwi, i-i«cray!pyraziiiy-4-yl carbofiyi, oxo, methyl, ethyl > or biaoxyearboswl;

and a p.ban«ace«ijc3 ' Hy acceptable saft thereof.

in fsaodiej: e hodimeai, G is C-Q; Q is -L-R;'. F is H; and R 5 is 2~msd¾4-½yndyl 2-etbyP 3-pyridyi 2,6-dimethyI-3Hpyridyt 2-cyttnc-3-pyridyL -cbioro-4-cy;»}o-5-pyridyL },3,5-trime1hyM- pyramiyL l-ethyl-5-pyfaa»|y|, phenyl, 2 } 6-d iflwoaheny I s 2-

difi-uoro-S-ffieOsoxypheayl, 2 ; 4-dtfS«oro-3-s«ei.hi!sypbcnyS., 2 J <S-dsdtio:roplie:oyl i 2 -dicMoropfeeayl 3- cMofO-2-Saorophenyl, 2-c¾ore-0~l¾oroph ryl S-ebloro^- uoropIieayl S-flaoro-S- triiluoEomefhylphenyl, 3*m¾iSoxyp¾eriy!., 2-aieth.oxypheayI, 4-taeihoxyphsayl, 2~xfteiftyl-5- e iOxycarboay!ptieayL 2-c l:pl:ieayL 2-!«byb5 arboxypbeti:y!, 3 0fo-2-iyaisopl:ieayl 2-i»®t y - 2-niet y!-5-i(N > M- dtmeth Oatamocafb a ijphea i, 2-mediyl-5-[ ' N-{mefhyl)-N-

Cnieiiwla:dn e0i i) miBocaf oayl jpaenyi 2-1aed l-S-{]-røeL l yra ίa - !) ar oayl} ίΐeβyS, benzyl, S-quiaolinyl, ( S-tp-iholinyi.

5 < i? ,S-lcs¾hyd3-o< : ao!ii:t--5-yl, q¾¾JOxtUn- - L -:ined:¾y! M-!iidaxoP4^

yl l-meth !- 1 R-indaznl-S-yl, [i,2,4]iriszo!o4,3-a]pYridia-8-y!, i-methyl-2-oxo-],2-dihy4t«Qt!lnolin- b~yl , 4~i:nel1:ryi-2-oxO" ,2-dih dro£|nincSin-6-y S-clilom- i -tne(¾yl-2-oxo- i ,2-dikydroquin0ii»-6-yl, l,4-dH«ethyi-2-oxo-l,2-djhvdr q8ineHiv6-yi, 2-oxo- } 5 2-dhydroQ«laoUn-6-yl, 2- eiayt-l-oxo-l ,2- dSiydroq«ii3tilia-6- l S 5 7- ifiiioro>

dii3Ki!:ryl-2-oxo-i,2-ddjydroc|UHioSja-(?-yb 5,?-dlfi¾oro-l-methyl-2r ^4-tri{l«oJ3JWhyi } ,2-

chtoro-5-mei:hyi-6-pyrimidiny! or S.:f 7 T 8-{eq¾h droquinoIii!-5-¥i; and a phitnnacettttc&lly acceptable salt, iher eoL Another aspect oftae current treventiorj relates to commands li in the general smt ture of formula Us a»d lib

whereht:

R* is H, aikyl aS&enyl. haloaikvL alkoxy, hydroxysalkyl, ambioaikyh aJfeoxyaiky , cyciosikyiaikyk aryl, aralkyl, heteKJcyciyi or heserocyciyialkyk wherehs ihe eycloaikyk aryk or hsteroeycJyS. Hag tn cyeioslkyi, cycioaikyialkyL aryk aralkyl, tocrocyclyi or heisrocyciylal&yl is urrsubsiisuted or substituted with am or two sa sisiiseiys iRdepeade!itiy selected fi¾ta hydroxy, aikoxy, aikyl, oxo Or iialo:

R ? is H, ' hal , haioaikyl, aikoxycarboayk armiioearboayk alkosyalkyayi, hydroxyaikyayi or-

X.R ;

X h fooPd, - or -SfO)ts ;

a is SI, 1 , or 2;

R ': is aikyl , hydroxyaikyk aikoxyaikyl, alkoxystlkeByk idkoxyoarfao yiaikyl ciirboxyaikyt iiraiyocarboiiyiaikyl aikyianiinocarboitylaSkyl. aryl cycloa!kyt cyctoalkesryt, beierocy lyk aralkyi, arsikertyS, arylalkynyk cycloalkyialkyk cycioafky keayk cycloafiiyMkyny!, h&teroeyclyiatkyS or hetefocyclylcarbonjla ' lk l; wherein the ring in K* is suhstutsted with. 1-3 suhstkoents iadepeiideatly selected from H. aikyl. halo, baS.oa.lkyi, Isydroxyl, ikoxy, haloalkoxy, acyl, aikyis»iib«yt.

heteroe-yc!yl, aitknosslibnyk alkykmutostiifouyl, cyano,. aik xycarboayi, carboxy, aramo, RR'N-C;^ aikyl, aikoxyalky!, bydrosyalkyi or S ¾ C(~0 , where R* is aikyl arid S 5' is alky!., alkoxyalkyi, .a nmoalky.1 or alkyiarairmslkyl, or where R :i and R !> together whit the nitrogen form a heterocyclic riag yasibstitiiied or substituted wkli aikyl;

R ; ' Is aryl araiky!, iieterocyelykdkyk eyeloalkyi, or heierocydyl, w wiu * is ymabst!hrtei! or substituted with 1-3 substiftteftts iadepeadeatly selected from a&yl, aikoxy, hydroxy!, halo,

StaioaSkyl eyaaa, alkoxycarbottyi, earboxy, acyl, cycloaikyl, teeroeyelyi, hydrosyaiky!, aikoxyalkyi, oxo, R' -i RR ^-Ci^ alfcyi, or R"R li NC{-0) where R ¾ is aikyl and R FC is alkoxyalkyi or aixtinoaiky!; where S. and. R * is independently H, aJkyl. ar l, heterocyeiyL hei.eroeyelyia.lkyi, or cydoatkyi, (with the heieroeyclyiaikyl cycioaikyl and ' heterocyc!y! rings are unsubstkmed or substituted ith I -3 substitnsnts iadepeademly selected from idkyS, aikoxy, hydroxy, halo, naioalfcyi cy ns, or carboxy); ex R' and 8. cast together ltn the K for hclerocyciyl;

¾* is aryt aralkyl hetewyclyl, heisrocyciyiaikyl, or cyetoalkyl wherein each of die aforen¾;inkme rings Is -unsuostituted oi substituted with i -4 subsiituents independently selected ftero aikyi hs!o, Ilafoalkyt, a&oxy, aikoxyeadaoxiyi, 'caiboxy, amin0eai¾ jn.yi, neterOeyeiyicarboriyL eyatto, cycioaikyl, hetetocyclyl, iwdroxyaiky t koxy i kyl Nfc * R\ Cf¼NRR\ oxo or acy

! , is O, S, CH 3 or CH ? 0;

Q is "L-R ;' ; and

P is -rf ;

provided wfiea R :i is H, ¾ ; is methyl, aad L is O, then

yl » :i -ti¾ediy!-2-oxo-l s 2-di]);ydroq irio!iri-6-y!, isoqui»oirn-5-yl, feoqaift«?lii¾-6-yI, t|Ufjioil«-{>-yl 2-oxo- 2-metlyyi- ! -oxo- i,2-dihydro- isoq«i»oli«-6-yi, i,4-dimeilwi-2-ox -] ,2-dihydroquinoiiri~6-yl 5-chlor -i-i«sthyl-2-oxo-l ,2- dii¾ d oq(.i!i:¾0:hii-6- l 5: > 7- ift»to ,4- imethyi-2^ l-methyMB- mda¾jl-¾~yt or ~n:!eihyl-.3M-j¾idazo[4,5-blpyrsdiB-6~ i;:

.fuKlier provided when 5 ss Br, L is 0 and S.' is methyl, {he is not SJ-diftuoro-J ,4- i:rsiiiethyi~2-oxo-

di ydroqriiitotiis-fr-yi, 5, " ?-dif!MOfo-4-ethyl-

,2"dii:iydro-feoqumoIia-d-yS;

farther provided when R ! is l-i¾eihy!- iH-pyri oI-4-yl L is O and R ! is e&yi. Him S 5 is not Ι ·€ϊίίνί-· ίΗ··ρν!¾ ο!·5··ν:Ι;

Sirtner provided: when R ;i is l^methykl Hrpyw.ol-5-yl, L is 0 and ! is methyl to R 5 is not 5,?-di¾uoro-l,4-dimet.byi-2-oxo- 1 ,2-dl.hydroq«l»oUn.-6- yl, or i,4-djraetbyi-2-oxo-l ^-ib' ydroqtnaoiia-S-yS;

fu t er provided R ¾ is .mH phenyl or ien-htiiyS. when L is Q. R? is 2-ed]yJ-3-pyridyS, 2-n¾diiyi-

3- pyridy ar 2,6-dimethyS-3-pyridyI and l i is 2-pyridylthk>, bromo, rnethoxyethoxy or

trifiuprosisth l;;

fefher provided { is net 4-n)e )-2-ii¾id¾iOiyi):neihy! when J h 2-pyridyft &, L is O,. and R* is -ed.ryi-3~pyrsdyl;

aad a pharmaceutically acceptable salt { ere f

Another aspect: of the correal invention .relates to camponuds ia iag file gene al structure of formula ίΠ

I I

-wherein s is C aikyl C M Staay!, Ct-s hsioalky aikoxy, C t .<. hydroxyaikyl C t a iaoalkyl C t , s aikoxy-C;.,; aikyl C iiydroxyalkoxy-Cj.s aikyi, C,.« aikoxycarborfylamiri-C;.* aikyl, Cs-.;ii aryl, C ( ,ia w≠-Ci.* aikyl 540 ra&snfeered he&recyeivl of S-IO membered

ai l, wherein the a«yl of teerocy yi rn is imsafestitwied or sybs!ltafcxl with me or two.

wherem R ? &-4X-8. 4 , Mlo, C« baioidkyi, C s .« aikoxyearboreyl aminOcaAogyl, Ct aikyl, C,.* hyiiroxyaikyl Cj. s hytiroxya!kyiiyl CM alkoxy-Ci.;; aikyl, RI . alkoxy-C¾.« alkeoyl C t ,s ik xyC ? ^ alkyrsyS, Cui alk xycarboayl-C: sikyi, C>* eaxbos sikyi, a mocarlxsi l-Ct-is. aikyl C¾.RI axyi, cycioalkyi, C * eydoaiksnyl 440 embered teTOc cryl, «tt l-C w aikyl€*, m aryl-CW alkenyj, C & m aryi-C^ aikyayl {¾.« cydoaikyl }.*, aikyl C . 5 cyctoalkyi-¾. s dkeoyl <¾,; eyeioaikyi- Ck 4 aikyiiyl hfiterocyclyl-Cj.i aikyl or 440 Ktembettd bei rocyciyl arboji l-C;:..;-; aikyl wherein Ac aryl, cycioalkyi, cycloaikerry! or hderocyclyl ri»g m R 1 is iisobsftiutcd or subsliiuied wii!i I 4 sufcsjtes-tts irtdepet¾de¾ly selected torn C aik l halo,€$.« haioalkyl hydroxy}, Cl.s aikoxy, Cj.* baloaSkosy,€;. f; acyl Q^alkyisitlfoayl C^alkoxycartjoftyi. carhoxy, 5-10 raembered hetei jcyclyl, amino, araiaosuifcayl€> alkyiaawaosull nyl, cya»o, earhoxy, %R * ~C s .i. aikyl, CJ.<; aiko.x -Cj. f i allyl,. C¾.« hydroxyalkyl or R¾ -NC0-O where R '5 is Cu -alfeyl aad * ' is tl < < sikyi, c»« sikoxy-CW aikyl Ci, s sm oalkyl sir Cx* aik hC;,* amiaoalky or where R* and R !> together with the nittogeo form a 5-6 embercd heterocyclic -ring yasufesiiftited or siibsbiaied with alky l

wherein X is S or O;

wherein R i! is Cw akyl hydroxyalkyl, M > hydroxyalkyayl, C«s a]koxy-Ci. s aikyl, C ; .<, aifcoxy-C:„ f i aJkisryi, altey-C 6 ,* alkyiryl C s .« alkoxy¾arbonylCi. t ; aikyl, C** carboxyalkyl aikyl, (¾.;« aryl€¾.& cycloatkyl C. s cycioaikei l 540 erober d itettwcyly aryi-Cw -aikyl <¾. { « -aryi-CV* alkenyl ar £-€ ½ aikyriyl C ; . ft cyci.oalkyi-C 3 . ;: aikyl C,. ¾ cycloaikyi- j.s aikenyl C 5 cyeloalkyi-C.,, aikysyl, 540 i:oci»bci'ed heisrocyci.yi-Cl. fi aikyl or xemmhcx i heferocyciylcarboay!-C; aikyl; wheei the aryl, cycloalkyl cyclo ikenyl or het rocydyl ring R 4 is utisubslitued or su¾stit«t<ed will 1-3 substitucftls ϊΐϊ de rs¾<i e:n f.l y selected from. C s . 6 aikyl halo, C } ha'oaikyl, hydi¾xyi C 5 .. t aikoxy, C< .< > acyl C;.,, aikyisiiiSonyi,€·,,<; alkoxyesrboay carboxy, 546 metnbered .beerocyclyi, eyano, mni , C ; . i. amiuoaikyi, a&oxy-C..* aikyl, C ? . ¾ hydroxyaikyl C¾. s haloaikoxy.€;.¾ aik l- RRl ataiBOSidloiiyi, a!kylaniinesaifbfiyl, of R^MCCjO) where 3 is C > aikyl and R !> is Ct« aikyl. Ci A a!koxy~Cf.i. alkyi, C>· : aaiiuoaifcyl or C ; . <t a!kyl-C.^ aarinoaikyk or whee R* a R' : together with, the nitrogen form, a 5 or <> atembered heterocyclic ring unsnlwitiiaied or substituted with C ; alkyi; where Rand I * is indepesdeftdy H, C^a!xyL. pSeisyi, 5-10 emfeered helcrocyci S, 5-10 taeateed fteterecycty!-Q.* alkyi or€ ? ..·» cycloaikyt (with the helefocyciyi-CV« alkyi, phenyl C¾.. 5 . cycioa%l and 5- io ftietnbered heteroeyelyl rings are ^su stitued or substituted with C 5 . c alkyi, Cws alfcexy, hydroxy, hale, C ; .« haioaSkyl cyancu or car/boxy); or R * and R can together wtft the fym\ S- 10 roeoshered heteisicycSyi; aftd

wherein R° is 5 aembered anrogeft coat&iaiag heterxscyclyL S tneii ered osygesj eoaiaiaiag heterocyciyl 6 membered attrogea coataiaiag eterovydyl 6 ajsmbered oxygea coataiaing heterocyciyl, pbsrryl benzyl 9 meinhered hicycik. mhrogea eeiriasnjag bererocyelyl 10 stabered cyciic oxygen containing eterocyclyJ or 10 awm eed bioyclic aitrogea coaiainiag leterocydyL wfeerem .R ¾ is asubsumted or substituted with oae or awre sahstuue ' ms mdependeuUv selected .tea C :;., f : alky!, cyaao, halo, C«s alkoxy, C t .s haloa!kyl Cs.s a!koxycarboriyl earboxy, CM a!koxy-Ct.$ aSkylamiiiaearfeoiryl w kylamiaoeatBoa l, aikyiami»0~Cs.« alkyminoctrfeonyk ©r

[optionally substituted 4-6 niea&ersd aitrogea coaraiaiag eierocyclyljcarhonyi;

provided R* is not phenyl or ten-bntyi when * is 2~pyt!dykhio, brotoo, -Bsstaosyethoxy or tri¾otes»et:byl and R* is 2-ethyW- yridyl, 2 - in¾cihy|-¾-pyRdy5;

further provided R s is not 4-o«*t¾yi-2-«aida/olylraethyl waea R * is l-pyridylilno ami R ft is 2- etliyM- yridyl;

sad a phmaae ttfcal!y aeeeptabii? salt thereof,

hi aaother srobodisie L R s is mehyl ethyl propyl, ally I ten-baiy!, ttiftuoro-ethyi raethoxy, methoxyethyk hydroxyethyl, hydroxypmpyl, 2 . ,3-di ydroxypropyl, hydroxyedsoxyedryl, BOC~ aaifiioethyl aminoetay, 2-hydit!xypheiiylsne!:hyh S-faydcoxypheayhaethyl.4-!iydrosy-pi:i¾nyh3:isihyl, 4-l]ii roahet]y!i:netbyl pheaeihyl, iae^bolia-4-ylesbyL 2-py.ridyimethyl 5-pyridy!methyl, 4- p ridylaietbyi 6-niel yS-2 ixo-1 -diSiydropyddiayl!«e y!, ?mMas3l~5-yifiKihyb -aretbyS-lraidazol- 4~yli:net¾yS, !-methyI-itatdai:oI-S-ylraei.hyL 4-ri " ietfiyl-i«]idiizo!-2--yii:neiriyL 5-me!.hyI4raida¾i)l~2- ylmethyl. I -diiaeit ip is l^- hiieiby!., 2-:m£i«y.bMa2GiyJ.-5« cttyl, 5-met yl-.isoxi¾:biVyh«et l or phenyl; and. a phanmcsuticaHy acceptable salt tasreof.

In another e tKh em, R 1 is methyl or ethyl and a phansaestMicaHy acceptable sail thereof.

In another erabodimem, R ': is - S.R*; and a pharinaceiii icaily acceptabk salt tb.ere& in aaother erabodiaisot, R ' is methoxyearbotiyhnesbyhliio, inethoxyearbonyktliyltino, inetltoxypropyblao, 4-raettey ' bttta»-2-«ylfhio, > rB£thoxy-2-mctlryl-baian-2-yijltio J 4- yd!¾xy-2- earboxyeiiryishio,.

tlaei yhmaaoearboiiyi ' taiei y- ' U jg, .t ' diiactiiylatmaoear oaylmjcihy ' U io . , (:5-hydf Xy-.V

etaylbutyiithio,. i2 rydroxy-2-HiethyIbat:y!}!bio, (^ai thy^^em^t^i- i ^^ ^^^y^^ taiorplioini-4-yl icarbo yla¾ed¾dU» l-i¾r

piperidiayliaietbySthso, <tetmhydr «2H-p faa^ {)tathymi . . i-(tetrabydro-2H-pyTaa-4-yl)ethy!tiiiP, (S-metSiyl- -es d ^ol S}nrieilw!i o, 2-pyridyiraediykblo > 3,4^ihydr0xycy ope»i>$hk>,.4- hydiXBtycyciohssykSiio, cyciopesitSHyfrtiio. p¾aySdm iscKx Uhio, 2-p>T3dyiih!0.. {4-pipmdmyiH iOi, ( !-jso]>rapyiplpci1dia-4-yi}iIif0 : (1 -BKdi Scarboft ipiperidift^- St ^ Ϊ -it.cn- i«ox¥car tsK li ipmdii) « 4-;y!ddo, (1 -BKiliysuifo:tty})|>tpaidffi- -y iu0 5 . (I-

fiiieitey¾aTboxiy))plperidj»^- l{hi j (i 5- ow yfiffik!¾j-2-y) ip€r w- -y ti»O > ( H2'

nmki yij i erkiM^^ ' {-{t«0-

pyraft-4-yIihio; a»d a phsnaaceatkally acceptable suit h reof,

in anoher embodiment, R* is

bro o, raediyl isopropyl 2^raei.byi ropy.i, .2,2-d i!et ylpropyl, 2-tnd¾y.Uutyi,

irifiuoromeibyl, livdrnxyetbyl, hydroxybtuyl, 2-hydioxy«2-.eit¾hylbutyi 2-bydrosy-2-mehy!pemyl 2- hydtoxy-2"Wd)yl¾exyl s l,2-d:ffeydroxypeni:yi : rosOioxyptopyi, met oxybutyi, raethoxypei«y! 5 awiho ro ft- ! -yl 5-meih0x e8tya-i- i., eihoxycsrbonyi , iSi-nieiiiy!-N- iiiiedK!xyed:iy!)iiK!!Mocarbos L

edsexyca >o«yta:byS s sthoxyearhonyipr^yJ * ethoxyearboftyihuty I s caf px re^yl 4„5- dihydroxypcntyl, propen-2-yl 4¾droKyb«¾?a-J.-yi, 4-medwxykrf n-I- l 2-cyeb¾propyivigyi > 2- cihoxyvsByl, -dsnci yl ¾S:ei i-yi. phsnyleifoyl, bfiaxyi. pbenySpropyl s S-chlofopheaylniednd, .1 ,2- dj¾ydroxy-2-pteytethvl 5 paeByleteay, I-pheoylvmyS, pbes lediyay!, pydd-2-yh»et¾y 4- tetfabydiopyr¾fl-4»ylsthyi t 3-

(2,2 « dtae i ,3-dk>xe!aa^ cyc!otey, cyeSopeatyl cyc beplyl cyciopeirteByl, cyctehexeayl, 4,4-d «ethy1-cyc!o! ' ieji-esyL 4«iert- ' baiy.l- c dohexeayL cyetohepteayl

tetebydropyrai ' i-4-yi 3,6-dihydi'opyra«-4*yi l,4-dioxa»piro{4,5 ]dec*7-en<8-yi i J - d Ad.doteiTabydro-2H-d>iopynii5~4-yi, i - ieri-buioxycarbo¾yl]-5 ,6-d¾ydix>-2H-pyrid-4-yS, .1 ulpxycarboayi- 1,2,3 ^-ietrabydrop rki-*^!, I -meili isdfo«yI-: 2 > 3 > 6 > te(ra¾ydr<ip> .t - - i i I - dimei yl^iKk3^ayl ^^ i-{m dmycartouyi;H > 2, Hctmli di{>p rid- 4-yL I -(HieihyScarbo»yl)-l ,2,3,6-ietrabydi¾pyrid-4-yL .1 -tei-b»toxycatt »y^pipendbi-4-y.l, S - (di:ftiedi iafiiHiG arboKyl p!p iidi:i!-4- l HN^-dsraeiihylammoca^

p!ieisyL 4--el oropfteayt 3-!»ediy}pHe»yl, *««e '? h«iiyl t i - i.fi¾. i be» l, .3- Uifluoro!«cthylphe»yi, 4-trill«.oro«Ktliy!pheftyi , 4- ^h<« -3-tii(«efomcrijylp enyl 5 2- methy ylfoByipheayl, 3-!»ed ) lsxil.foB1pheft l 5 4-ta$thyte«i&»yl:pheayt, 4'

(d»«ediylaiidaoc8fboPyli bePyL 4-«iedsoxypbeiiy 3-rae!hosypbeiyL 3-dii¾ioroinedJoxypbe«yl, 3- diS¾Jo¾x>i:nei¾yipiieay!, 3-d!il oromsd>yS-4-i¾s«ropSie! " iyL 2-tset.h«syp. e:iiyL.2,4-dim«1¾oxypbeayi ' 3,4-diniet.hoxypbenyL 5-be«¾xidiosoSyI, :S-s:ne5hy:]-3~pyfaxoiy!, 1.5"dimeifey!~4~pyf3zoiyl.5.,3,S-»-iineshyM-

pyra¾oSyi -u½t.hyi-4-py.razo!yi 5 S.~¾ydroxye†hyi--4~pyrazoiy!, ί -5¾ef.hsxye5¾yi"4-pyTaz S.yi, l-intliyl- S-pyrazo!yi ! -mc i-5-f.oiidaxoIy 3.5-<imiei¾yl- isssxii¾0:-4- L

2-pyridyt 3-pyri yl 4-pyridyi.2-i»ethyl-5 -pyridyL -nKi yS-^ yrid lyS-Hiedwl-^ yn yS, 3~t:ri¾erafne!iiyh5"pyrid l 2-trifluixrom©tby^5 « pyridyl 5 2HnfluoTOme W-p ridy!,, 2- irHl:a0iw!JC!hyi-- -p ;-idyL 2-welK>xyK pyridyI, 2^!setboxy- *pyiidyl $-ftuem- ' aj«bOxy-4-pyrii3i 3«fluof0-4-pyrid>i 3-i¾e5:hosy-4-pyiidyL 2-dii0xy-4-pyr i 2 »edoxy-5-pyridyi 3-tas!tay-5« pyrtdyl 2-fi»om-4-pyridy, 2-chloiO-4-pyridyL 2~c¾joTO-5-pyfidyL 3-chloiO-5- yjit!yL 2-cyano-4-

i:fie{1iyisidii)ayS-5-pyridyl, 2-oxo-L2-di¾ydro|>yndi5i-3-yi, 2-hydroxypyrid-4-yl, 2-i¾ydfo¾ypyrid-5~yL S-pyrkaidinyt 2-ami«o-5-pyrnaidi«yi 2-c aao-5-pyfimklkiyl, pyraxia-2-y I, pyridazis.i-4~yt 3- beaxoiaieoyi, «tda¾o l 5 2r-a|pyridia-3-yI or 2-nje 5feen«oji«?.ol-5-yl;

and a twmseeuiieaHy acceptable sals thereof.

Is another enibodimeat, wherein R* is ietra ydrofefssryt tsirahydropyranyi, , ~ds dro-2H- chromanyl, pysTo!idmyl p-iperidmyl, pyridyi, pyraasoyi, phsayf b tyK qoino!iayL ! dihy t^uifl0lmt 5.6,7: J-teteawdio HSioiii i quinexsHiiyi 1 H-jndazolyL 2H- if lazoiyi ,2.4]inazoio4.3-ajpyridi&yi. isoqwiaolby, 6 s 7~dihydro-5H-cyc$op itabjpyrid«yl, 1M- pytwk>[3 5 4-b]pyridmyt aoidasoj 4,2-a ' jpyrkiiiiyi, or pyriratdhiyl, wherein * is uHsa xitote or uibsdruied. sviti ' s o or more substituents i«di?pea<k»t!y sele ted tea oiei yl sibyl, cyaa . cMom.0uor x metl sx , iriOuerome iyl, cdsmyeaihoa L ie.it- feutoxyearboayi, cmbxy, i»t*Oiyi)- -(∞fhos eUi I}mimK;arboay f »N*

:!.- e8rylpyra2iHy-4- yI)cafb «yl .or oxo;

ami a lihiffroacetukaily acceptable salt thereof.

In -an ther embodi ent, R 6 s 2~mei¾yl-3-pyTidyl, 2-ed)yf-3- yndyt 2-cy;iSio-3-pyrtdyl 3- chtes«-4-cy SJiCf- S-py ri dy!,

i ,3. ; 5-t.rimethy]-4-pym¾olyL ki^Hti edwi-S-pyraxol f, .1 -ei¾yl-5~pyrazoiyl ].-ediyl-4- chios'o-S-pyrazoSyS,

t£H¾hydro.furai 3.-yj. ]-BO€~py:o¾Sidi:i5-3-yL ?eira3:iydn>-2H--pyi¾ft-4- L 3~i¾0ro eiraliydrs 214~pyi:a«-4~yl 3-K!ei yI-ietra ydro-2H-pyr<i»-4- , -ediyS-teiraii¥di¾-2H-pyi¾5v4-yi i ! -sen- bui Oxy cit rbci !iy ipipe td i !). ' -y ! .

p!teyj, . 2,6-difl«ot¾pbenyJ, 2-fl ' U0f¾p c»yt 2, -ddlwfo Siefi L 2 t 4,6-i:riSla ropi:(e»yS, 2,5- dlflo rop ertyl, 2,3-di&orop ©riyi 2 > S*dfi»o¾- -n:ie{ os efjyl 2.4 !il]tsoro-3.mei oxypl:i©H L 2.6-dic!doropaeayt 2,3-dic Eorop!5eayt ' J^loto-S-fla ro heay^ 2-chloro-<>-ftuo-roptetyi, 3-cWoro- ii-f soroplsenyl 2-fl«oro ^ 5-trjfi«ommeitiylpbeoyl, 3-«ieikJx ptie!i l 2-iiieA¾¾ypheayL.4- i.netiioxyp e«yl 2-m dj l~S-eS:liox cafboi5y!p L 2«ethylp.heay-, 2-iBSiIiy]-5-carboxypl.iea l 3- ch1om- -c a»a ¾6ay « 2-cyaa -6-t!:s:0:iioroa¾eth:yipheayi, 2-jaefhyi-5-fNM;methyl)-N- (meii:iGsye^yl)anitaocarbowi|pfeawi, 2-met:hyi-5^(N,^

5-N^5ethyl)-N-( ' ;B^^^ I -O afc p rax sty-4- yi}carboriyi}pheayS, beozyk

3-cjuiftoliayL S-qitmotioyl.6~quiaolmyi, 7-quinoHoyk &-quinoliayl, 5-chofo-6-q«j»oHay!, - qiiiooxifiift>5-yl 3- mefbyI-IH--iada¾iI-4-yS ! 2-irteth t-2H-:tt ij}3»i- -> ϊ -meth l I H½.da S-4-yb i-H»«i i>}.B-iateoJ- 5-yL ( !2 > 41u , ¾axo > -a|pyrjd!ii-8.yt 6 ά όκ>5:Η-^.Ιο^ηίφ) >¾ώη- >1, cii!Oiaaa-4-yL 3,4- d!bydfo-2H-pyrano[3 -Cjj)yrain~4-yi f-mei l-2~oxo ,2 !ii^

i,4-di.tsei yi-2-Qso-L2- ds ydfoqaiaeiai-fi-yl 2-o o-L2-diqydToq«iaoI : sii-6-yl 2-iJKS%-]:-o O'] A 2-dih lroQumdBn:-6- l > S,7-

di.0:t}O:O-4~ diyi-l-a!eiS i-2-oxi>- 1 ,2-dihy(troQ ist5oHft-6-yU fc-isix n lm l, ? soquiaoiiayl, 6- isoquiaoliayl S-isoquinoltayl,

irakiaxop .2--a]pyridii>-6-yi > -niel¾ ]- H-i5iida^ -b|i> ridi¾-is- i or 4<Wom-S-iae i-6- pyrisHidkiyS; aad a phataaecmWijr acceptable salt thereat

Another aspect of Hie -earrem invea oa relates to compounds kaviag the geaeral structure of forimila

whereia 5 h alkyi, Cj.« a!keayl, 4 la!oalky!, ¾.* tSktmy. C« hytiroxyalky], CM S aoiiaoaJkyl C )4 alk»yy s a!kyk C M q-droxy-C,..;, a&oxy-Ct-* &%t C..« a!coK caibo» la»a¾o-C w atkyl CVi* isryl, C aryi-Cw alky 5-10 meaibered tiete-rocydyl or 5-10 sSBembered heierwyelyK-V s aSkyi, hereiu die aryi ϊ lieterocyclyl riag is laisahsi!aned Or substituted with o«e or two svibstkums i eperidenily selected froas G ( .s sSkyl hydroxy, oxo or halo;

wherein R 3 is --X-Ry H« halo, C s .. fi hiiS aikyl Q,<. aikoxycarbdHvL amfaoearhoHyl C^alky, C;:« hydtexya!kyt C M aikex w C. , alkoxy-C M aitayl C i ikoxycarhoii i a!kyi, C c&rboxyalkyL aminocar o»yl-CV* alkyi s aryi, C s .$ cydoa!kyl, C..* cycloalke-nyt 4-i& memhered. heterocyclyi. aryi-C;.,, alkyt C* 46 iyl-C« a!keayt, C*.«» aryl-C^ alkynyL M cy ioalkyS-C;., alky], hfierocyciyl- ^ alky]. CM hydroxyalkynyl, CM a!kosy-C * alkynyl, C M cycioaikyI-C 2 . T ; alkeny]. C eycioalkyi ¾. & aikyayl 4-1-0 nistnb red..helerocyclylcarbOKy-C ' us alkyl; wherein the aryi, cyctoalky!, cycioaSkeayl or heterocyclyl ring, sn R 5 is uasubstitnted or Siibsbtaied with t -3 subsB ' taents independeatly selected fxosa CM alk t, halo, C haioaikyl Hydroxy!, aSkoxy, C s .¾ acyl, C:,i alkyisulfoayl, G s . f , aikoxyearhouyl, earhoxyy 5- 10 raembered h&erocyciyl, amine.€,·.. armsroaikyL CV S aikoxy-€V< 5 alfcyk C hyir xyafi yi C -haloaltesy, RR'N-C alkyh

ammosulfoay!, C< 4 aikylaiMjaotulfoayL cyano, or. R s ¾Ci~0) where R" is C-^ alkyl and R ¾ is alky}, Ci.. a)koxy~C;.tv aikyi axamoalkyi , or where R a a»<l R fc together with ih« -nitrogen form a 5 or 6 membered heterocyclic ring irasufestJ&rted or sabssitused wish where sad. ' is Independently H 5 €,.;; alky!, phenyl, 5- 10 mmibmd hetetoeyclyi, 5-10 aiemhered het rocycJyl-C^ slky!, or cycioa!kyl (wish she aetemcyciyi-C; .,;. aikyi, phenyl C 3 . 6 cyeioaifcy! and 5- U) aserahered heie-roeyeSyl nags are unsabstituted or substituted with 1 -3 sabsliiucfils independently selected &ora aikyl (. * alkoxy, hydroxy, halo, CM haloaikyl cyan®, or carboxy); or R and R .can togethe with the for 546 abisher d heserocyeiyi;

wherein X is S or O;

wherein R s is Cs.«, a!kyk C*.« hydre.xya.lkyl,. Ct. fi alkexy-Cw alkyi, Ci alkoxy-CV* a!kenyS. €;,<; aikoxyearbosyi-Ci.i. aikyl earboxyalkyi, i asaoesrboayl-C; .;, aikyl C ¾ .s alk iaminoc&Tboiiyi- alkyi, aryl, C <; cycloaikyl cydoaikeayi, 5- H) srieiabered heterocyciyl, £ ,t> ar i-Cw; aikyl atyS-C;.,; aikeayt C*. i-C^ a&yjjyl, ¾·* eyelo lkyi-C; aikyl C** eyeloal&yl-C^ aikenyl C¾* cyelealkyl-C aikyayi, 5-;iS ) menibered heseRicyelyl-C- 4 a!kyl or 5- 1 num e ed heterocycSyiearboayS-C;.. <; , a!kyl; wherein the ary.1, cydoaiky cyctoaikenyl or hetar cyclyi ting m R : is uasabssiiiaed or substituted with 1-3 subst!t«et«sinde- sa«demiy selected fmm C aikyl halo, C ; .s haloalkyi, hydroxy!. M a ' lkoxy. Cj.« haioaSkoxy, CM. aeyi, C..* alkyisdioayl anmosisi ionyl CV¾. al]iyki»i:aosuif¾sy! s €■,<; alkoxyeafboay sarboxy, cyano, 546 inmteed heterocyciy amfae, RR * N-C>* alfcyi-, Q. a a!koxy-C^ aikyl G , ; !rydroxyaJkyl or ^Cc-O) where ' R s is C,.« aiky assd R b is C,.^ a&y!, a ko y-C^ aikyk C actaaoalky! or C £ kyS-C :i , fi an«nc«tkyl , or whore R* md together with the BUr ge¾ &na 25 or (i n nbaod iteteroeycl c rm misnbstiaued or sssbstiteted. with j - : -; alleys: aad.

wherem 5 embered nitrogen contalai g ' heterocyciyl, 6 osemfeered nitrogen c saainlftg beierocyclyl, p eayl. 9 memhered mlm sii eosfc aiag aeterocyciyl, or i>) saearbered aitrogea coiiiainii5g beierocyclyl

wherem R ;1 is vtasahsfitxrted o sabsiiSttied wish 00s or snore sobstitaeais iadepeodeail seSe ted from C,« aikyl cyaao, alo, oxo, feydroxyk C s .g alk.oxy\ C>, i: , li lealkyi, Cj* aikoxycatboay carboxy. aikoxy-Ci . 6 aikylairiiaocarboriyl, -alkylamiaoeaitoftyl. C ; .s alfc lamiao-C 3 ^ alky!&oiinocarbonyl or i;optio:oa ly ¾ibsi« ' «fe4 4-6 ffienibered aiaxsgeft coataisring

SicifffrjcyciyiicarboByi;

provided bsn R 3 is H. R. ; is methyl, then R s is aos .M i-aietbyl- 2-oxi5-k2-dihyd.iO uii o!is:i-6-yi tso ¾tao5m>5- 1 o Utt >lm-6-yl, qBinoIiri-6-yS, 2-oxo-i ,2- d hydroqusao!iis-fe-yt 4-a>cSl5yl-2-oK.Q-I,;2-dibydro riiri0iiH-6--yi 2-meibyi- 1 -oxo-1 ,2*dihydro- isot iilftoMa-6-y.l, i^utje&yl^-oxO-l^dih droqKiooIin-^ l,, 5-ebloro-i -iai;iliyi-2-oxo-!,2- dikydro^aikilm-6-yl S,?-dif]aoro- i ,4-di etii}4-2-ox.o~:i ^-dsbydroqwin iiii-f-yL :l-mefhy.i-lH- j adaxoi-5-yU or ¾-.iK*h l-3H-Hn{femf ,5-b]p idin-6-yi.:

further provided wh n R 5 is w and R ! is met l {tea R* is not 5 s 7-difl«.oro- 13 :i 4-i:i½eihyi:- 2-i>.to-l-2-£¾ ydroq ' tt»xoiiiH')-y1, S? iii t:to-l-at£diy!~2-oxo~4^

6-yi, 5,7-dii¾«m-4~s¾:yl.. i -met yl-2-οχθ* 1.2-di!iydmq iasSm-6-yl or 2-meihykl *oxo» i ,2-dihydro-

kti&m provided hen R s is J -sselSyl-lH-pyxa oM- i s aad * is tre&v!. theif R* is «oi l- farte provided when R 5 is I -issflryi-i K-pyra¾oi-5-yi aad R ! is. nseUvyi tlaai R 5 is tm 2- mefhyi- 1, -exo- i ,2-dihydroiso uiiioiia-{ ' ?-yS, S,7-dMI uoiro- S4-d seth S~2-oxo~ I ^diitydroqomoUn-d-y S, or I ! 4-diii " )t > f:iy!-2-oxo-l ,.2-di¾ydroqiit!ioiir(-6-yl: aad a pkanriamideaHy acceptable salt ihereof, in aaote embodimeat, R s is methyl, eiivyi, propyl, s!!yl tfiihiors-eiiiyi, inetoxyet yL hydroxyeihyi, hydsOxypropyi, hydr xyesrioxyeihyl 2-4iydroxypfeeftyiraethyi .Vfaydraxypfeeayhsetkyi, 4-!5ydroxy-plie«y]ffieliyi.4-i¾ }ro ' pheayhueibyi > raorphtflia-4-yiet!ryI, pyridyiaieihyL 6-n¾et]iyi-2~ oxo-l ( 2-dihydmpyridmy.lmetbyl, iiaidasEol fiss-fh K l--methyi m}d8¾oi imethyI, 2·

«)cth lil:ii;izosy!i:nei!j i, or 5-j»ethyl-jsos.a¾o}>a>c 1; aad a pkamxaeettaeaUy acceptable salt thereof.

In aBoiher ejubo tmeni. heeia R ! ismeihyl or ethyl; nd a p! ajacendea!iy aceepiabie saft thereof.

in another ein¾od:iai<in R ? is - SfC and a pbrnaaceuticaily acceptable s&lt teeof.

in aiioiher em odiment, R r BJirtfeoxycsirboaytaiethyHfHo.. roelhexycarboaytetfoyHhio,. medjoxy re ylthio,

carboxyethyUhio, (rae jy!amu¾ocafbo«yi)nffiipylibio, {3~ h di^x ^-!rietiv ibiJty ilsio, -(2-b ar s ; -2--me l xJt lH ' bio, ( ~xa<!(h qj eraZKi- 1 -yt>- Cia oii Beiliyiihio, {moTpi¾oli.i^4-y!)carbo!iy!.aieihyIfi)io, (i-teil-butoxycarboiiyS. piper i di«-4- yl)met.bykh.to, fietraiiydfo-2H-pyran-4-yi.}meiiriiit!0. i -iteirairydro-SM- >o:an- -yl}etb kh^ 2-pyndyi ethy!tkio, 3,4- dibydroxycy opeittyidiio, 4-aydr©xy yetehexyl.ikt0, cyc psataayHhio, pheay io, besmdthio, 2- pyiidytf o, {4-piperidi«yi)i iG, (i~aieliyicarboayi}ptperid!a-4-y:!tiii0, i kr^b«ioxycarbo«y!)piperidift-4-yh)iio : {1-Bicihylsuit½y])p-iperidi ' n-4-yit.bio 5 (S- isopropyicarbonyi}pipcridia-4-yli!fio, i-dimt vylatBii^W oi J^i eriidia^- iihio, l- tincthosycarhoiiy])f>iperid!it-4-yStbio, (i-{5-cidoropyria!jdin-2-yl)psperida!-4-yI}!.hio s (l~(2- yriaidjBybpifieridio^-yf^hio, (i-{5 « cMoropym¾ii ) -2--y pif^ridio-4-yl)thio ? HtW'

or tekshydso-2H- py!¾a-4-y:iil:iio; and a hamaceuticall acc table sail ihereof.

Inimother embodimetft R J is brotao, methyl, kopfopyf, 2-?itet y!piX)pyl 2,2-dimetbyIpropyl 2-«ietbyip«{yl tTi iaoranieftivL hydrexyecbyl. kydroxybuiyl, 2-hy oxy-2-«ietliyib«lyI, 2-¾ydroxy-2- metfiylperrtyl, 2-¾ydaxy-2-methy¾exy 3.,2-dibydroxyfetttyl, me oxypropyl metboxybutyi metteypeaty uuetboxypropea- l-yi, ftKilhoxypem n-: -yl etkjxyearbosy N-nietliyl- '-

eiboxyearbonvlpropyi, carboxypr pyl 4 J-di ydro: ypci5!:yl, pi'opea-2-yK drex feiays i 2~ cyctopixspylvtiiyt, 2-stf»oxyvtnyl, S^H&tnefh !buteB-l-yl, H-¾<hwycyc5opattyl)e}:byixy!; ? p eaySethyt beiiz L plieaySpropyL 3-diSor¾|> ¾?ylmeiIiyL

pHeay!eiheoyL ! -p enylvliwL p eftyiet yx!yi, pyrki-2-ybKctkyt 4»piperidyl;isei!!yl., i«csphoRn«4- !cU-aS:fyd«J yi¾ - -yie!lsyL H2.2-d!S5e0i S- -dmK !;H!- - y ' Dpfdpyl cyctohex¾¾ethyl 5 eyc!ohexyietisyl cydopmpyt, c c!ohex t cyc!opefityL cyeSobeptyL cye!opeittiSiyL cye!obexeay!, 4,4~dfised}yi-cycfo!iexeayl > 4-tert-bull-cydo¾exeayI, cyclohepieayl, tea¾bydropyfaa-4-yl 3,6-d!liydfopyr¾n-4-yL ! ,4-dioxaxpko4.5 idsc-7-ea-S-yL ί J- dioxidoteirbydrp>2H^hi9 TiKi-.- J, i-tesl-butoxyeaT osyi- I,2,3,6-¾ei!¾lwdiOpynd-4-yL i -

}-isKd:io¾yc3rboKyi)-i s 2, ,6-icir<d:iydfop ^(«5cdiyic3:rboi!yl}-l ! 2 i 3,6-iesraljydropytid-4-yi > !-ieft- !i!Mycarfeiii !- lpa-idi:S!- ~y! i i-(:diaieliyia;si:noca:rbosyi}-pipeildi})-4-yl,

haiyi 4-cfe!orop enyL 3-aKiS¾ylphe:iiy] ¾ 4-methylpfeeayi l 2 t-dimeU*yipheay 3- triflttororae ydpJienyL 2- «wdiyfeiiifeaySpbetiyi

i«c{fey.ls»lfo« l3imiKspbcft 3-indhyisttlto»ylairaiKipbcoyl, 3-incAyiajoioosttf«ayipba)yi, 3- ftygnopfretiyi, 4" yajSopttea L 4-cyaao-3-aK! <xypfeayL 3-cya«o-4«{«etboxyphe«y!, 3·

{dmiifth ia-miflodirboa ^ Sss ^ 4*me!h0xypbeny¼.3--m«?£hosypbet ' }y! y 3-drl«oroH ' 5«tfeox h$H i 5 3-

3,4~da»¾ xypo£»yi 5-benxodioxolyl,

1- a>el¾y!-3-pyt8i»iyl l-methy -pyraxoiyl, i dimedjy!-4i>yrazoiyl ί ,3,S-Pia>ei¾y!-4- pyrazoiyl, 3- !]wl-4-py 0lvL 3-lriilu0ro-es¾yi-4-pyi:airoiyi, 3-cyciQ¾«tyl-4-pyrazoiyi 1- hydroxyeifcyM-pyiazoiyi, ]-metli6xyethyi-4-pyra¾»Jyl 5 i -ni&fhyi-S-pyfszolyK i,3-dtmetbyi-5- pymzoiyL 2,4-dii5iej¾y!-5-ikia¾>iyL S -meihy!-S-iia!da olyi 3 > S-dlmetSwS--isoxaz l:4-yi,

Hifi:aifi¾ )es yl-3- yrid t 2-mc(boxy-3^pyridyl.2-!«edwxy-4-pyridyI s 5-0:aoi¾-2-a5ci!ioxy-4-py!-tdyl .3*.flwt¾*4-p ri<lyL 3*»jelboxy-4-pyri.dyl, 2-etS¾Ky-4-pyii.dyl 2-a5cd:toxy-5-pyi'idyi, 3-}jieita:*5? pyjldyl 2 ]«em-4-pyridyi 2-c ofo-4-pyridyL 2-c o.ro-5-pyridy} 5 ^cbioro-5-pytfdyi, 2-cy<mo-4- pyridy 1, 2-cyaao--5"pyridy

medjylsa!fojBy|*5*pyridy? ?

5-pyilaiid :iy[;2-aaiias-5-pyraai iayl 2-cyaa(»5-pyrimk:i«yt pynszia-S-yl pyridii2i«-½L 3- bgaxoiiileayt ½ida*G t ,2~ajpyridyi or 2-t¾e ib «xoxa¾ol>5>yi; a»d a phamiaceurically acceptable sab. i ereoS. ' . I.» sxotber e bo iment,..R* is pyridy!, pyraxolyJ, phenyl, quinoliny!, quiaoxaiinyl IH-todaxolyL 2H½ ,v.oiyl, p,2,4JbiaxoIoi4 ,3- ajpytidiayl, iso(«moHoyt 3 H~pmoto| >] y?idb>yl, amda?,©! ' l.,2-ajpvridj»yl, 3H-j«»d¾¾0|;4 5 5- jpys'idsiiyS, ox pyrimidiiiyi,

herein . 3 is unsubsttUited or sifeiibiie with one. of twre sobstiuierHS iadependeaily selected from -m &yi, ethy, cyarto, chi ro, fliioxo, ^csnoxy, trifluofomtjiiiyi ethoxycarboayl,.

byio yca! ' oi5yS, carboxy, N-{meh l^H¾i«ltey m»iKK¾rktty, ( ,^ϊ'*·

dimei Da:^ I-oieiliylpyraaay-4- carbosyf, oroxo;

and a ph&rn ceaiica!Jy acceptable; Salt thereof,

in another m odiment, R : is 2- etbyi-3-pyridyt 2,6-airaeihyI-3-pyridyl 2-etby!-3~pyndyL 2-eyasi0-3-pyridyL -cl ' dor - -cyaKO--5-i>yiidyi,

! 3,S4ran<;iiiyi-4i>yrazoiyL I -ef¾y!-5-pym¾oiyl 5

gfeeiiyi, 2,6-difiis0!-op¾eRy.t, 2-fi&oro;phe«yi, 2 f 4-difiii.orOpSieny.!, 2,4,6HriilBo pheayS., 2,5- dMnorophenyi 2,3-dsfmorophenyi 2,6-diiI»o∞-3-in.c : bo;ypiieayi, 2,4-diikuro- -sireilioxypbenyl, 2,6-dic]iioiXipbs:8yl, 2,Vdkhior»piie«yi 3-d:dofo-2":ilaoropbeoyL 2-chloro-6-fi«oro[)iKsayl, 3-ehksro- i-ilijoropbeis:yt 2"fiuom-5-a:i:Su0:ro«icd!yipfeeHy:i, 3~metbexypheiiy|, "aKih&x phES! i, 4- metboxyphmyl, 2-s«et!5yi-5-edio?;ycar&Qaylpbe»Y!, 2-elbyipiraiy, 2-me i-5 arboxypS:¾e«yi 3- cMoo-2-cyanopheayl, 2-ine!!:y!-5- N4aiediyl}-jS; ajediCix etb

[( ,>¾*dimeO¾yS}ami(iocaAe i jii !i l : 2--njeUjy ; i-S-i¾-Cirsei yi : )-H.

(meth ii ^

$A7,ii- S¾1raljydro ai»oiia-5-yl, 6, -d.imedxyi-S,6J,8-ieP¾bydroqia»oli»-S-yi, qainoxaiin-S-yl 3-«ssibyS~iH- iadazoM-yl, 2 « me l-2H-?»daxo -yl I -^i l-iH-widaxoS-S^i, i ,2,4]tria2oi.o[4,3-a]pyridi! ' i.8i,d, i-ai:eihyi-2-o.xo-L : 2-dthydaiqidn.oHn~6-yi, 4-.methy!-2-0X6~.l ,2-dife dro<5 iaoK»-6^ i 5-chtoio-I- 2-exp-l.,2- dibydroqainelm^-yi 2-mei.by!- i -oxo- \ .2-d¾iydioqiifa¾iis-6-yL.5.7-dHlaofo»L4-dia)e i-2-OXO- ,2- dibydroc|»inolia-6-y}, S,?-dii}u0m-l,3, ^Tinie5ir}-2-os0- S,?-difiuom-i- oiediyl.-2-oso-4-tnfi«o:naKjetb.yl- 1 ,2-dj.hydroqifflolio-6-yU 5 : J-diilaoro-4-ed:iyl-i-a!es:hy!-2-oxi>-l,2- .5 s¾ uiaoH yL nidiiyi-Iii-

pyra^io[3,4-bipyridis-3-yl, imsda o! i .2-alpyridi»-7-yl, biisda oSi .2-¾|pyfidift-6-yl, 3-iaef:by!-3H- iridda®f4,5-bipyridi:f!--6-yL or 4-chloro-5^me8iyl-6»pyrimjdiayi; arid, a phamiaeeutfoally acceptable s b thereof Another aspect of he sun-eat invention relates to compounds li in the general structure of

Fotrmsla la:

where n ' :

* is i'L aikyi, alkeityl, haiealkyt. alkoxy, hy roxyalkyl amirioaikyS, aikoxyalkyl, hytoxyaifcoxyalfcyL alkoxyearoofiyiaminoalkyi cycioalkyi, cyctoalkylaikyl, aryl, araikyl, heterocyclyl or heierocyc!ylaikyi, wherein ike cycioalkyi aryl, or Itereroeyclyl nag in eycIoaikyL cycioalky!alkyl aryl aralkyL. heterocyclyl or heterocyclylalkyi is tmsubsH toted or substituted wit.lt one or two suhsutneota independently selected from, hydroxy, alkoxy, alky], oxo or halo;

R ! is H > alkyi, or Mo:

R ' is H, Itaks, aUcoxyc-trbenyi, amioocarlaoftyL cyan©, eyattoalkyk alkylcarbonyi, heteroeyelyicarbooyk aikyiaffi!:noc;¾- oayk alkersyk aikyoyi, hydroxyalkeayi, hydroxy alkyrryk aikoxyalkoxyalkyl, aryloxyaikyk aryloxyalkenyk aryloxyalkyayl, aralkoxy aikyt

hydroxyaikoxyalkyi, hydroxyalkoxy idoaikyl, alkcxyaikoxyhaioalkyL aikoxvaikoxyaikyl, at¾lkoxyalkerr , bydroxyalkoxyalkeriyk amikosyatkynyi, hy&exyalkosyaikya k

alkoxycarbosytalkyl, . aikosycarb ftyihy<irosyalkyi t alkylstilfo^alkyt aikylstilioaylateyl, aikyfe I!bnylalkyRyt heterocyclylalfcenyl. heterocycly kyayl, aikoxyalkyayi, hydroxyaikynyl or -

X is a otiil, -O, or -S{Q)a ;

a rs , I. or 2;

S: ; is aikyt irydroxyalkyL baloaikyL alkoxyalkyi, alkoxyalkeayL alkoxycarbonylalkyU earhoxya kyl, ammocarbooykl ' kyl, aikylatnioocarbooylal ' kyl, aryl, eyctoalkyi, cycloalken l, heterocycSyl, aralkyi, aralketvyi arylalkyttyi cyeloalky! alkyi cyc!ealkyiaikenyk cycloalkyiaikyriyk heierocyclylaikyi or aeteroeyelyiearboiryialkyS; wherein the ri-ag in R "J is umubstituied or substituted witit i-3 SHbsiiiifeais iadepeodea!ly selected fma¾ H, aikyl, halo, haioaikyl, kydimyi, alkox .

haloaikoxy, acyl aikyisolfonyl heterocyclyl, atninosuifottyl, aikylaraiaostsirooyi cyaao.

alkoxycarbooyk ear oxy, ataiso, RR'N-aikyi, alkosyaikyk hydrexyalkyi or ^I CC-O} where is aikyi an R ! ' is alky}, alkoxyalkyS, aniiaeaikyl or alkyiaaj joa!kyt or where R B md R fe together »tU the nitrogen .form a heterocyclyl riag msofesf:ii«!.e or sifbsiiiaied with aikyi:

M ? is aryl, ara!kyl heteroeydyl lkyL cycioalkyi, or heterocyclyl, whereto R s is rum ssiihxied or substituted with 1-3 stibstttueots independently selected frosts alfcvl alkoxy, hydroxy!, telo, haloalkyf, cymo, alk.oxyca$¾anyL, earhoxy, acyk cyeiosikyk .heterocyciyl, hydrexyalkyk aikoxyakyL oxo, -NRR " , alkyi- RR' or B¾ i; NC{ >} here is aikyi aud R fa is alkoxyaikyi or aminoai yl: where ilmd 1' is H, alkyi, «≠, beierowciyl i3.eicr0cyciylal.kyL or cyeloa!kyi where the heferocyrfy&i&yi, cyetoalkyi aad heiosocyciyt rings, axe oashbstitirted or sabstifxrted wiia 1-3 sobstittserss ind eBdemhy selected from aikyi, aJkexy, hydroxy, halo, !taloalky! eyario, or carboxy; or R' iid R cm together w¾h the N form taerocydyi;

* is at} 1 !, aralkyi, heterocydyl, heterocyeiylaiky!, or cycloaikyl, whereat each of she fifoieitKmbose rings is urisubsfifured or subsiiiuted with 1 sMbsutaests iadepeadeiw!y selected tea a!kyl ha io > ha l ss ik y f s alkoxy, aikoxyc-atfe tty carboxy, ainiaecarbonyl teterocydykarboayl, cymio, eyeioalkyk heterocydyk hydroxyaikyl sfayiaifcyl, R¾\ CH> RE V , mo or acyi;

GisC-Qof N;

his (XS.i ' H; ΓΪ·Ι;0.

Q s or-L-l ¥ ;ai5d

PisM f-L-l 6 ;

provided

(i) whea Q is H; tires P is ~L-R* , or

(it) wSseaQ s- - te.Pis¾

iiti) wfeea G is N, then P is - ,-R*;

further p ided vvbea R* s H, R s is rneihyl J is H, L is 0, and P is H, skat R s is not

,2 r ii:ri¾z0i [4,3-a]pyrfd-8--yl v i-methyi--2-oxo-I > 2-d(byciroqoinoii}j»6-yl istxphiioiU l-yf, isoqui»o!io÷(i-yS s qitirujdn-o-yl 2-oso-L2-dibyclroquioolir!'-6-¥i, 4-Uiethyi»2-o?co-!,2- di] ; i do¾« :iolHi-6-yl 2-raeUjyl~S-0xo~t,2-dibydfo-iso{T«itffiIi» ' 6-yi, i,4-ddaet!s¥i-2 ^ oxi)-I,2-

dii«ethyi-2-oxo-L -di]]ydfoqd!.noim-6-yt .! -meflryl- lH ' azol « 5-yi or 3-irietlryl-3H- imidazof4J-b]pyfidm~r>-y1:

fur e provdd when. R* is H, ey&rso or iodo, i is H, L is O, aad P is H, then R ' is not . - tsnbstitiiied.ami:t!Ocarfoor(yi)-5-ij¾doiyi;

.fttrther rodded when R ; is H, R :i is H, L is 0, am$ P is H, t m ' is not substituted phenyl, 8- (sisfesiititied -urea 4-<|tti»olyi T-substiuaed S ,2,3,4-ieir3¾ydrooaph i or -subsiiimed oapiiltyk

further provided when R 5 is B, R 2 is H, I s is jBorpaoUaylsthyi, L is O s . aad P is H, then R ' is not

further pr ided when 3 is Br, R' is methyl i$ H, I. is 0, aad P is H, iim R ! is «ot 5,7- difhxoro-1 ,3,4*tri«K¾hyl-2-oxo ^-dihydrotu:«iolin « 6-yk 5,7-di¾oro- S -fflethy!-2»<jxo-4- triikoror!5ethy!-t ,2-dibydfoqtriii0iin-6-yi 5,7KlMaoro -edi M^

diijydroquMiolia-fc-yL or 2-nisihyI-] oxo-i : .2-d ¾ydro-boquirfoiin-6-yI; .taker provided when R 3 is i-methyi- H-pyraaeJ-4-*L . R l is mefhyi, 1 ; is B, L is O md P is ft iaea R. is not ! -ethyl- i H-pyrazol-5-yl;

taiier provided hsti R* is 1-meiayi- Jii-pyrazol-5-yh R ! is methyl R 3 is Η » I is O, and. P is PI. ihm R 5 is not 2-medryl~i -oxo- i .2-<ii¾ydroisoq«ii!Oii:t5-6-yK 5 J-diiIa<SO- i ,4-<«i»d.hyl-2-o»o- il-d iwdro^smolin-d- t or i ,4-dimethyi-2-a o- } ,2-dihydre iiii¾oIifi-6-yi:

further provided R " is Jiot hate yihea J is if R ! is fflethyL L is O, P is H -an H s is 5- aiHplm l; further provided R 2 is sot cittw© vvfteft R* is brorao, R. ! is methyl, L is O. P is H md R* is 5- q-iiao nyi.

fiirther provided R is »o! p eayl or ieri-buiyi wheu L is (X R s is 2-ethyi~ pyridyf 2-rael:¾y!-: ~ pyridyf or 2,6-diffie5hyj-3-pyTidyl, R 2 is H, R ': is 2-pyndyRhio < brovmy medioxyerhexy or triiliioriiiweih l and G is CH;

further provided R is not 4-me:dwi-2-!:midazoiyl!BeiiiyI wh¾« R :' is H, R* is 2-pyridyiibio, P is 2- ediyI-3-pyridyioxy and G is CH;

further provided R" is noid-methySp eayl or 2,4-diiB&ifeyipheriyi or l t 2-d.i¾ydr0.x.y-2-phe.nykir*yl w½ea R ! is tnetby R 2 is H, G is N, an P is 2-methyk½yridyioxy;

and ;i pharmaceutically acceptable salt thereof,

in another mbo iaierti R * is If.

in another erahadisaeai, R * is Cj« alkyl,€ .« alkeayl, C ; . <; aloaikyf aikoxy,€; .* aydroxya&yi, ainiaoaifcy €;..« alkoxy-C w; alJkyl, C s . s hydroxya!koxy-Cws a l s C<^ & aryl C s . s » aty!*Cs.« aikyl S- ' i membered heierocyelyl of 5- 10 memhered heimseyciyi-Cj ..-; alky! , wherein the axy! or teerocydy! flag-is uusubstittiied or substituted w th otie or two s«bsuiisems iudepaideml sdectcd ironi C aifcyl. hydroxy, oxo or halo.

in anot r £«} fc ditrtenU R 1 is medtyk eflsyi, propyi. yiiyS. rert-biiryL

In another eiMbodiutmu 1 is tri£luoro~e.tkyf. meUtox>\ medtoxvethyL hydrojiyefhyi hydroxypmpy!, 2,3-difeydiT!xypropyL L2-dthydroxypropyi, hydr xyeihoxyeiPyi, BOC-aistaoetityi amiooethyl t 2'bydroxyp¾eaylroeihy 5 » hydroxyphe»y ethyl, .4-hydroxy^henyliT¾.thyl, 4- nuoropaeiiy.haeth.yJ , phenethyi a¾orp¾olm-4-yle^ayl, 2-pyridyimetiryL j-pyridyiitsetiiyL 4- pyrk!y!med h 6-nKil:iyi-2-oxQ-L2-dthydropyridinyitsedryL imidaxol-S-y!meilryf i - eihyl-imk!axoS- 4-y!aiedsyi, i -mei:hy}-it5iid;txei--5-yS.t»ei. yi < . 4-toedsyl-«Bida¾o.i-2-y!aiethyi. i 5-oief¾y)-H>itda? , .0l-2- yhrtethyL 5-medryj.-i¾}xamt-3~yhBerkyj.

or heayi.

«i aaofhex ribodinKai, R 1 is 2-pyridy tne!fiyk 3-pyridytoiethyl, 4-pyridylmethyl, 4- «jet1iy!i!akla¾:ol»2.-yhs<it yL 8ald ¾Ql- *ylja 8).yi :i- icJhyli iidazoi-5- ?8K;thyi, } ,5-diaiethylpyf82«l-

ylmetSvyi or »«5rrihotot- «ytethyl

in a otier emb dhsiSiii, R' is niei!ryl, edry! or rydroxyethyl

ϊ« aa dier embodiiaeoi, R ! is raetiry!, I another embodiment, : is H„ methyl uoro, or fhioro.

in another embodiment, R' is H.

In. another embodiment, R ? is » S(0) a aad n is 0, i, or 2,

In another em odiment, R* is --- SR.*.

[ft another embodiment, R ? is - OR .

M ihm. embcdimesi, R l is CM alky!, Cj-e-h dfoxya k l, atoatkyl, QM;

hydioxyaikyiryi. M alkox -C f ^ alkyl. C t alfcoxy-Q.6 alkeayk ? , f ¾ alkoxy- M alkysyi Q. 6 aikoxycarboayi-C f .;; alkyl. CM carboxyaikyl, alkyl

alkylamiaocar osyl-C-s-g alkyl, C^o sry Q?. ? cycloalkyl,. .. ? cycioaikertyl 5-18 membered. heteroeyeiyl C & -ia aryl-C 3 . 6 .alkyl. C ¾ .. i& ar !-C^:■alkenyl ¾. T » r S-C 2 ^ aikyayl, C M , cycloalkyi-Cj* alky!, CM eydoalkylC alkeayk CM eydoaikyl- aSkyiiyi, 5-10 membered kaerocydyl-CM alkyl or 540 oiembered he eixx;ycJylcafboayl-C- w aiky whereia the isry!, cyeioaikyl cyeioalkesyl or heterocyelyl ring jo. * is ttas« ' bstit»ted or substituted with t-3 subsiituepls independently sel cted from CM alkyl, halo. CM haloaikyl, bydroxyl CM alkoxy. CM acyi, C M alkylsul&syl M alkoxycarbonyl, earboxy, 5-1 membered heieTOeyciyl cyano, ammo, CM a«»a©aikyl, M alko - alkyl, C w liydroxyalkyL€{. ¾ haloaJfeoxy, CM aikyi-M R " , amiaosulfo.uyl, C ¾ .g a!kylaminosulfotry], or rfNCi-O) where R s is C ( .« alkyl and 5 ' is C i alkyl alkoxy-CM alkyl, C M sraiaoaikyi or CM a¾yl-Cj,s ammoalkyl, where I s and i! together with the nitrogen form a 5 or 6 memberetl heterocyclic r g onsubstituted or substituted with CM alkyl

ia axK>¾er embodhaeai, R' is .methoxyp poxy. .S-imedioxyjpropoxy, irydroxyethoxy,

S. -hydroxy-2~xaeiI lpropoxy, 2-

hydroxybufoxy, pheaoxy, ^-meihyS-S-pyridylasy, or S-o efanyimethoxy.

in another emfeodiineia., R: ' is msthoxycarboiwk hyldjio, rnethoxy pro yith to, 4-Hiethoxybut-2~yttb to , hydioxypropy ! ί faio, 3 ,4KS ihydroxyb u iyl tfaio, eatboxyetliyttliio, (rrietiwlammoearbotry imetbylthio, idimethyiarrisnoearboay nretbyhbio, (3-hydroxy-3-taetS:!ylbyty!)tb.io : , (2-hydroxy-2-Biet!iyib«tyi)tluo ! $il»oromethyithio, (4- met !pi ra2m-l- i)- ^bon ½ieth khi! , (morptol:m « 4>yi carbo:nylT«ctb.yithio, {1-tert- (4-pipendmyl)methyithi®, ftetrabyd5:o-2H-pyraa- 4-yi)mcthy hio, I^ ctt¾¾ydi<)-2H-pyran-4-yiK¾hyl.i»j», (S-a^etbyl-l-oxadsazoIy!laietbyUbio, 2-pyridyl»¾ethy}thi , 3,4-dibydroxycycioperttyldiio, 4-bydroxycydofcexyithkK

cyclopentenylt io, phetryh!iio, beozylthio, 2-pyridyifcs , 2-chiQi -4-pyiidyltbio ! (4- piperidinyl*2-pyndyl)methylibio, { 1 -methyiptperiditi~4-yl¾ (1- bydmxyetbmylptperidra^-yl-2-pyridy!}me itb¾, l -( i.~bydraxyetbyipiperid):n-4-y!)-l-{2- pyiidy)!»e k io, 1 -i l-methylpipcridk-4*yl)-l -(2-pyridy!)ntc&yHh}<>, l-{pipcridis-4-yi)- l- ' 2*pyddyi)M!\ethy¾hio, (4-piperidinyl)tko, ( I -isopfopvi}piperidin-4 » 1thi» r {

me ic8it nyi)p-iperidm-4-y : lihi , I -(krt utoxyc.a^nyi}pipcridin- -yltb:io } (i » ms^ yisuiftjn Opiperidin^yl- o, (l-isopr pycas^nyl)pip«ijdm-4-ykbi ? i- (mefeixyii^rboijyli p^ridm^^dtfei ,. i ¾eiboxyeii^!carbosy])piperidia-4-y.Uhio J

(diraerfeylmioocarboRyl)piperidi -yi.rhio, IK^etbox ari^i jjpi eridn^- iibio, ( H$- cWoropyr{mjdin-2~yi)piperidj»!-4-yl)tho, ( 1 -(2-pyTiraid5ay!}piperidso-4-yl)dii«, (1 -(5- ch!ofopyra2;itT-2-yl}p5peridra-4-yl}ii3io, i~(ieri-buioxycarboi3yi)pyfrol.kim-3~yl.diio. ? 3- met ylisoxa20lop x 4 > b)pyiidin-4-yld«o or ieiraljydr&-2H-pyr£ai-4-y itho^

in a«od¾r eaibodi!iKnL R J isineilwx propylsuIfisyL medwsy ro !si^iba S, Hi«f«" butoxyc^boayOpjperklia^- Jsulfe!yl, 2~pyridy!siili¾yl {•{ten-batOXy ar ouyl^peridiB^-

In another eaibodastem, R 5 is in ioxypropoxy, 2«{n¾etboxy)propoxy., yt oxyetbox y, hydrbxypropoxy, 2-faydraxypropoxy, I j-dlhydrosyproposy, 1 -bydroxy-2>medtyipropoxy% 2- hydroxyteoxy, pSimoxy.2-meihyk3-pyridySoxy, or 3-ox¾taylmetb<jxy.

in aaoiber eaibedi«¾2M., R. ? is metbox e^o . or 2-msdiyi-3-pyndYi«xy .

in asmber eia odmssnt, R '5 is !neiboxyciirboiiy!methySibio, aieiboxyearboaylabySihio, medsoxypropybhio, -jHetboxybu{-2-ybbio $ hydroxypr opyU.hio s 3 ,4-dihydroxybw1yi{hto.

earboxvediykbio, (oi^h kojkiocar os i^Tsethybbio^ (dioi^tbylsotiaoca^on i^^thyb o, (3~ bydiOxy-. «)c ibu¾?l>thio 5 (2 tydm?iy-2-!iteihy!bi(iyI)!:hio ! difiaonBetbyiihio, (4-:o5ethylpfperaxHi-l.- . yi)-carboaylm0fhyUldo, {moipboi .i »-4-y:i) ¾bo«y imeib iihio, { I -teri- o xycaiboiiyl pspexidi --4-- yMethybbii (4.piperiiii|}yS}s«etbyItlifo. (t«u:ahydto-2H«pym»-4->1>s)c8iyilh¾, 1 -( ' tettaliydio-2H- pyr;ui-4-y : l}e3sylibio, (5'-niet:iyi-2-oxadi3¾oSy:}iiiethy!tbi t 2-pyddylme&y!tbt(>, 3 : 4- dibYi!fxsxycyciopeaty!ilPo, 4-bydroxycyci hexyltiri.o ¾ cyclopeateayUbio, pbeaylthio, beii^y!tbio, 2- pyridyhbii?, 2-cblo5O-4-pyody!ibio. C4-pperidffiy!-2-pyridyS)n^i¾yiibw, { 1 -n5et y!pip«rdi »*4-yl-;S- p rid i) )e¾ ldb j- dro^^ (4-plpefjdi«yi)t.hio, (i- bjopropySipiperidia-4-y¾ io, (l-metbyteTboayl)pip8ridi»-4-yidnit),

- lo, (i-meiIsylsuliPnyi}p!peridm-4-yk 1- (n5sttoxycaibonyl)pipendin-4-yiri«o . , i-(niei 0xyetb¥carb ayl)piperidi«-4-yid;Ho, i- {diaieibylaaiinocarbo:nyl)piperk!l»-4-yllhio, H«>elboxycarboay.lpipeddin-4-y do, (l-iS- cidoropyr Bi;diB-2-ySjpiperidi:n-4-yl)ihio T ( 1 -( 2-pyxtni s d s n I >pi eri db¾- -y i)j l:t s o : . i -<S-chl«ropyr3¾tH- 2-yl¾)ipmdtiv4-yi}tbt . ' ief-kjt xycar oay^p sol ja- - iibo, 3-ffieibyS.is»ssmiofS,4-b]>yiri.di:!3- 4-yifhso »r

in another smxbodtiHe , R'* is H,

in m Q m mfoodm i, 3 b hate, cyano, C x .-> h g ioalkyl C ( ,, s cyaaoa&yl, C

aikoxycarbonyi C>,; aSk ! asboEi l 4-10 ms ered C ¾ aikyfcaninoeasfcmi i C M t alkyl. Cj. f , aikenyl,€¾.«, alkyayl C t .« byilroxyaSkyl C hydroxyalkeuyk€. s hydroxyalkyayt C alk y-C^ aikyf s Q.« askoxy-€ s * a ' ikoxy-Ci alky], C aJtey-Cw aikosy-C s . haisalkyi C ¾ .« altey-C aikerjyi C s alkoxy-Q;.* aikyayl C« ara]koxy-C 3 . s alky), bydroxy-C;.,; alkasy C¾.* alkyk hydroxy-C^ alkoxy-Cj.4 haksalkyk C t .« af&lkoxy-C'^ aikyoy!, hydrox -C aSiox - :;- s alkynyi,€ it> ar loxy-C;.,? alkyl CM« aryioxy-C 6 .« a!keayL Cs^ mytexy- ^ aikyayl, C w 8}¾¾xycaf oftyi*Ci.« alkyl, C carfaoxya!kyl, CM,

C;.« a!kyi, CV« alky]8a«aoCaffe¾fiyl-Cj.s alkyl C 3- s a!kylsulfO«yi-Ci.« alkyl alkylsrdibxryl-¾..< ii!keayl C H alkyisulietry!-CT. f , afkyayl . , C«. t » sryl C ;R; cycloalkyl C*. & cyctoa!keayl 4-11 oieiftteed aeteroeyelvL Cs. ro aryl-C 3 alkyl, C fr: « aryl-Cj,* alkenyl, C s . ie at l-C^ iaiyir l CVs cyt alkyl-C ; alkyl 3 cyclpslkyi- Ct-s liydroxyalkyL cye]oal&yJ~C:«; alkeayi, C cycloalkyl - .^ alkysyl 4- 10 eaibered iieierocyclyl-Ci-.* alkyL .4-10 mem ered .bsteroeyclyi-Q.^ alkeay!, 4- 10 mciabered beterocyc! alkyay or 4-10 in&m emi hetefocyeiylcarboiiyl-Ci^ alkyl; vvaerem Hie aryl cycloalkyl, cycioalkeny! or bcteroeydyl: jin ia 1C is uasabsui«¾ or sabstltuted with 1-3 sabstitoeots iodepeadcfttly selected ' from Cs.« alkyl, halo, o.xo, O-. C*.« haloalkyl, CI -s alkyls«]fo.ny¼mtao- C^ afkoxy, Q.« haloalkoxy, alkoxy.€,.<$ alkoxy-CV* ¾lkoxy, aikyisutthayi- Q.* afkpxy, Ci_. 6 acyl C¾.« a!kyki!tibrjyi, ikoxycarb»»yl, carboxy, .5-10 ioerabered .heierocyciyi.5-10 num ered heiexec clyi s^ a!kyl, C%.* cycloalkyl C cydtia!kyl-CV* alkyl ¾Ϊ»«Ι& tniKOS«lfeftyl C;.. i:i ai ! -C< <; alkyl, C ; .s aikoxy-C t .& alkyl where 8:' :is H, or C M a!ky! a»d is I CM atkyt w bydrexyalkyi, C { .« alk y-Cs* alk i, C:, : > alkySsiilibiryl C».¾ alkyl, C».« •a&ylsulfoay!aa fio- C w alkyl amtooalk ! or C:^ aiky!-C:^ amiijoaikyl or leie R* i 8 !l togetiier -vwtlt the nitrogea form a 5-6 mesnbered hete?ecyclic ring unsubsiihii d or s«bsdtui$d wiik C ( . alkyl.

fa itnoflei embodimeirt, ¾ ;: is bromp, cyawo, mctJwl, etftyi propyl isopropy 2- methylpropyl 2,2¾ίΒϊο{Ιι?ίρΓορν 2-«neby ' lb iy]- trifi p!Oinethyt 3,3,3- triiltsoropropy!, fluoromeibyl iluoropropyl hydroxymeiliy!, hydroxyefliyl :t 2- !tydroxy-2-methy!etbyl hydroxy propyl, 2-hyd?oxypfopy!, !-hyckoxyprop-2-yl, 1,2- dihydroxypropyl, hydroxyboiy!, 2-ljydroxyburyi, 1 ,2-dibydsOxybaiy 2-hy<3K)xy-2~ me iyibutyi 2,2-(dibydroxyn¾5thyf)buyl 5 l-bydroxyetboxy-2-b.romoethyf, 2- iiydroxyetboxy lei!jy L 2-(iiydiOxyei!ioxy}prQpyl, (jriethoxymetbyi )ei!j , I -meCho¾yd!ioxy-2- boi oetiwL 2-hydit»xy-2-met}iy!pe«tyl > -h i&OXy-S-meh ihe y L2--dihy(3rox:ypentyL 2- berszylcixyboiyi, 2-:hydroxyethoxybutyI s 2-¾yd:r xy-2-i erhylpropoxybotyi, 2-hy<fct)xy-2- metbylpropoxypropyl, (tefmhydropyra«-4--yi}-liydroxyT«otbyL 2-il oro-2-aiethy¾ fyl ! metboxymeiboxymethyl, .raeboxy.raeibyl, medaoxypfopyl, melhoxybutyl, 4,5- dimediox o!ityl ffleihoxypeatyl e mx ethenyi et eayl propea-2-yl, propen-l -yi, prop- 1 -

2d ctt-2-yt 3*hy<b¾xyprop<- l-ca-2-yl, l- ydroxy-2-meS !propcayL »ici¾t 3 A 3-dimet ylbatea- 1 -yl, -benzy!oxybiiesyinietteypropen- yL bydrosypropesyL bei}2yfoxyprope¾t 2- etboxyctbciiyb 2-liydJ>xym«thylpP0p«ayl > 2-eiboxyviiiyi vmyl, meibykol&ny!propenyl, methyisidt sylbtueayL methy!sulfosiyially!, m ihlsui{bnylbu-2-ea-!-yI, 3,1 - dk idoteix& ydio-2f:i i ¾^^ ethoxyearboayl, methylcarboayl.

(4-teii¾bydiO-pyranyl}c3rbonyL ~raefe i-N^«5et x cthyl}amiaocartfon , N-metbyl-M- (dinjet¾ykminoeihy1)~anjm car ay!, tert-butoxycai onylmehyl, i^Tydroxy-l-tert- biaoxycarbony!meihyf, etbosycarboaySpropyb etboxycarkjayktfeyi. !-bydroxyetbyl-

dm>ethy. Miftocarbo»ylethyl, dmiethy miao arboeylpropyl, carboxyed l carboxypfopyl, cyanoelhyij eyaaopropyt, 4 } S~dihydra-xypentyI J .4,5-dihydroxypea£-~3-y! f bydroxybutynyi, hydioxypropyoyl, elbyayl, 2~cyctopR>py ' !vi»yf, 2-hydfoxyeih0xybot-l-ya*!-yl, 2-hydroxy-2- meihyipropoxypropyi!yl, beazyioxyprop- l-yn- 1 -yl, effczyloxybat-l -yn-l-yl,.

bes^yloxyetboxyprop-i -ya- !-yi i ~{ !- ydmxycyclopeniynethynyb 3~ai£ihyi~3- xe¾tnyktfeyayl, taet oxybui- ' i ~y»- 1 «yl, meihoxypeatyn-l -y t eydopeatyUdeaeraeibyL mediyisalferiylprepyl, ttietbyistdfenyl atyi, pbeayiethy ' f, benz l, pbeayipropyb 3- ehiarxjpheayimctiyi, 1 -dihydrox -S-pbenySetbyi pheayletbcayl, 1 -plieay siyl, pbessy!eftyayl; pyfkl-2-y!meibyb 2~diioropyrid-5-ylro£thyi 2- th xy-S-pyridytetbyi, 2- eiboxy-s-pyridylediyoyl 4-pipefidyhachyl, I -prperidytoetfcyl, 4-iaedwi i er&Ki«~ ! - yimet yi, 4-Boc-pipera«in-l-yh»ethyi 5 -n¾e&yts\jlibftyl-p.}perazi«- > -ylraetliyt 4- methylcarijoayl-pipera^ia-l-ylaieihyl, moipboIia-4-y!ffiet!iyi, 3-nieibyl-s¾orpholin-4~ y iieJayi tfeiomftrpbolmomethyl , ( I j --dbxid tbia¾iiorpholffi0)aie iyi, 3-ffit?tbyb3- oxetaaykihyi (ietfaI>ydro-ur-2-yi)me I, (tcttabydro-fei-3~yi)«iethyI, 2,5~dioxopyrrolsdla- I -ykifeyL i£ifahydropyrao-4-yh:»eibyl ; tetrahydropyraa-3--ylme:byb ieo¾hydfopyma-4~ i EbyI,y2 wdrax meihyte 2-bydioxymed5y!-ieiTahyds:opyKis-4- yiaicdiyi 2-a>etli0xymethyi-teti-ahydi-opyf¾i--

4- yhaetbyl, 3-(2,2-diinethyb 1 ~dk>xo!aft-4-yi¾smpyL S -dioxolaa-4-prop I, ! ,4»4soxas-2- aiedi i ! J. ! xidotetrai dro-2H-t iG r£in-4-- iiBeiliyi, 1 J -di0Xido-tefi¾bydro-2H- 6-ox * l-azaapifof 3.3 ]bepiaa- 1 - ylmeibyi 2-oxa-6-azaspiro{ ' 3 ,3 }heptaa-6-ylaiethyL L4-dioxaspk0j4,5 )decai3-7-ybaet ' hyI, 3- beazy!oxy-cyckbuiyiroetbyl 3~bydroxyeyciobuiylffieihy1, 3-hydroxy-3-!¾efbyi- cyelobitfybaetbyi, 3-oxo-eyclobufyl«ied>yl, S- dox ^-irifl oaeih l-c clo aij'lmetb li

5- bydmxy-'S-aiethybcyclobuiybbydroxyaiediyb cyclopeatylmetfeyl, , 1- (hydroxycycIopeaty aictbyl, Hmedioxyeyelopentyi jmet yi, 1 -

2? (fiicdiox c clo eni l)bmraoi¾cihyi eydo cxylracthyi J-hydroxy-eycIohexylnte(h I, 4* h drosy-cycioSiexylmei!w!, cy ohexylmethyl

ΪΗ .asotftef e o iment. * U cydopropyL 1 -tert-b«toi:ycarbo«y : i- 1.-cydop-ropyl, 2 - etiiosycai'boaylcyclopropyl, 2-(2-hydrosy-2-meiby ihyi)-cyc!0propyL.2-hydroxy etbyl- cyclopf pyi, cyciobatyt, 2-hyd.roxycycl uiyl, 2-oxocyclobuyL 3-hydroxycyciobuiy!j 3~ S-benzyioxy-i-bydroxycycSobuiyL 3-(2-feydroxy-2-Siethy t yl . )- cydobutyl, 3 -by dr oxymetry! -cyelobaiyl , 3-efeoxyearb ay!.- 1 -hydraxy-eye b lyl, 3- eihoxycarbonyl-cycl buiy.1, cydoperslyi 3-kydraxymeihyicyeiopesiyI, 3,3- dihydr xyraeihylcyclo cntyl,. J-cm'b xy-cyclopeftfcy!, ^h ^ meih lt clopeniyl,..4- hydroxycyclopesityl, -ivdrosyeyciopesityi Sdwdfoxycyciopeiny!, 3~hydi¾xy-3- siethyfcyc!openiyl 2-oxo-eyclop njiy!, 3-oxo-cycIopeiUyL, 2-(N-eiiiyI- - a½thybmmocafb 3¾yS)cyclopeniyl ¥ 3-(N~ethyi- -meiby!ainiaocaibonyl)cyc]opeiiiyL 3~( * ½opropj¾mmocarf)onyl)cyclopcntyl ! . eydo exy!, 4diydroxycyc!ohexyS : , 3- Iwdrox y cydohexyi 3-h:ydraxy~3~msthyl-cye!obexyL 4-hydroxy-4-iiiediyi-cyc!ohexy! s 3- oxo-eydohexyf, eyc!o eptvL eydopenienyi 3~bydroxy yciopei5ttnyi, 4-hydroxymetbyi-4- meijbyl'cyd«pentcnyi, ^- ' sCb dm nieth ij clopcnt- -eR- i-yi 3-¾xa-cydopei»e«yl, 3- car!>osy-cyciopo«i-2-eiwb 3-isopropyl8miacK>arbonyl.cyc.ldpem-2-cayi, 3- (liydroxymeti i)cyc!ope3ii- -ead-yi 4-(bydmxymeibyl) ydQpeni-i-eH-i~yi 4- (hydix>xy»5ethyi)cycio-peai-2-ett » i-y1, cyctobexeayl 4,4-dij«eiI }~cyclobexenyi, 4-teit-btJiyi » cyotobexenyi 4 iydroxycydo¼xenyl, 5 -bydfoxycydohex- 1 -en- 1 -yl, 4- y ds>xyraethyl~ c dohexea l j 4-(2 ^ hydroxy ^ 2-met.hyeibyi)eyc!ohexenyi...4-carboxysydo.hexeiiy j i, 4~ ethoxycar boiiy f-cyciobexctiy i .4-{a2etidia - ί -yi carbony i}cydphexenyl 4-3 -cyairo-azdidm- l-yka!¾oiwl)cyc1 hexeayl .4-(3-f iOro-axetid:i«-l-ylcarl uy} -ydohi5xeuyl, 4-(3~ mchykulfom a n tA-yl mbom eydobeptepyb l > 4-dlos.aspiro[4 v ]d:ec~

?-e«-?-yb {. i 4-diox.aspiro4,5jdecan-7-yl.

Is another em odiaienL R 5 is3¾draxy-3-oxeJaiiyt 2-ietrahydr *feyl, 34cirabydi¾- iuryt 2-meiby!-3 - ieftahydio-t ry I , 2-mcdiy b2-ietrahydro»-fi«y I, 2¾droxy»tethyl-2- tetrabydro-f ty., 2-hydroxyraet¾yS~ietrabydro-¾ir~4-y!, 2 5 2-dtnie{byS-2,5-dihydfX:&s-an-3~yl ! 2,5-dihydiO&raa-3-y s 2,3~ ibydro&rao-3-yl 4 5 5-dihydra&ra»-2-yI s 2-oxopyrrolidu^ I >y I, teiiaI dropyraii-4-yl 2 -dme letr^^<feq rai 4-- l, 5 < 5-d}met ySieti'ii!iydi'opyra»-2-y!, 2 j ? 5 s 5~i¾teaffiet:byl~2 5 5-dibydroforan-3-y1 4-i¾iar -ieo ! 8bydr >yraii-4-yi s 4-.¾oro-3- hydroxy-tctraliydropyTan-3-yl, 4-fl:Ooro-3-.raetboxy-tetrahydropyrao-3-y1 5 4- hydroxytetrahydropyTar!-4-yi,

y L 2-oxo-iclxahydr p ras-4-yl teira dropyian-3-yi, icfo¾hydropynra-2-yI, 3,6-dikydropyim-4-yl S^-dihydropyran-S-yi 5^-dihydro-2H-pyra»~

3- yl , 3 ! 4-di!5:ydro-2H--py!¾rs-6-yl > 3,4-dihydsO-2H-pyra¾-5-yi

pyran-4-yl, l^-dmicthl-S^dih dro-lH-pyraa-^-yl , 3 i 4-2M-ddwdropyran-4-yl : , 1,4- diaxaspsf [ .5|dec-?-eo-8-yI s .1 J -droxo-ko M mfid a-l-yb .! J.-di xid{>tetrahydro-2H- ihIopyra3-4~yl 14-d >xa.n~2- t 5~me.hoxy~meth.yki ..4-dk>xan-2-yl. l-tett-botoxyctrbonyl- S-aiethyki > 2 5 5,6 e¾¾hydf pyrjd-4->i ϊ -methyisulfonyl- ].,2 i 36-iel;rahyd¾OpyTid-4~yi ! 1 - (a e ioxycarboayl)- ! ,2,3 3 6-teiraiiydrapyrid~4-yl, 1 -(mei ylcarbo yi}- i^^^^-ieirhydro r -

4- yL kmediyl-piperidin-3-yt i-im- i$t0xycarbonyl-piperidin-4-yi i- d j met¾ k?«¾<xarbo )~piper : id:in" « l.

In another em odms u, R 5 is phenyl, 4-cbioropheayI.3~methylphenyi 4>methylphenyi, 2,4-dimeihyIphe yl 3-iiiflnoro.raetby!pbei L 4H*i£hioromethylphmyi, 4-raeiiroxy-3~ trifuopometbylphenyl, .S-diftuoromethyi^fuotophettyl, 2.»net ' hyls«lfo»ylphenyi , 3- raethylsulibnylpheayL 4-methyIsulfonylphenyi 3-eifay!suIiooyIp eayi 4~

mei y!sulfonyiammopbenyl, S-methylsuIfonylnnjmophenyl, 3-raetbyl:ami«osid.fosylpIie»yi 5 . 3- yanoptoy!., 4-cyanop en l, .J- arboxypbcsyl, 3-caiboxy-4-!iydroxypiieriy1 < 3-eathoxy-6~ metexypheayt., 4-carbexypheoyI,.4-cyano~3-methoxyph jyl * 3-eyano-4-ineihoxypbei5yl : .3-

(dimethyla» aocarbo«yi)pheay, 3-exby!an aocarboiiyfpl ) crtyl 3-(N-etbyi~ - meihylammoarbony ' lpbeayl, 4-eshylamiftocar oay ' }pb«iy! ! .4-{ -e{byi- -

meiiySaffl«io aibo«y!)pheiiyI, J-CM-propyi-N-ii ifay!aaiiaocafkinylpbep l, 3~(1 ,2-

meib iamfao r on pheayl, 4-CN~kydro ciSy^ 5- mediox -S-dimeibylamiBoearboii iphenyi, 3-me{ ; hosy~5-efbySaaiisocarbo:nyipb.eayL 2- metliOxy-4-dimethylami»oeait0syipbe»yl, 6-meiiox -3^ime la«iiaocar o» l jiyl : , 3- mediOxy-S-etbylaarin carbon ipbcnyl , I -hydK)Xy-2-inefhyiprop-2-yl-aiuj aocarbortylpfteayl„ iiydroxyeibyiaminocarb ayl-phenyl 2-hydroxy-2-meihylpr0pylani»K ¾J^ny!-p ' henyU 1,3-

1 -yi arboayDpheayl, 3-(3-bydi¾xy-azetidia- l-yfearb ayI)pbe»yI .? 3~(3-i«edioxy-azeiidia- k y!earbony pheny.,.3-(3-metbyls¾dfony !-axcddm- i -y!earbanyi)phe«yL 3-(4- moqj!ioHiiyicarboiiyl jpheayl, 3~f I -pyiToiidiaykarb nyOphenyi, 4- ethoxypheriyi, 3- metboxypheay!, 3-fluor -6-i ? aeiboxypbeayL 2-fl«oro-5-meihoxy beHyb 2 i raetboxy-4- raethylamiaosttUbnylpfeenyi, 2-x¾eiho55.y-4-ethy]amm s«1frjip.hc»y! > 4-methoxy-3- 3-mc¾ox -5-mebox¾af o«y lici S, 3-caiboxy-2- mei!wsyphefsy!, 3-drfl oromethoxyp eayl,.3-diiTuofometh.ylpUen.yl, 3-dif1:t!oromethy!~4- iluorophenyL 2-mcthoxyplicny], 2,4~diffi«i)0xypbe8yL 3, ~dimefhQxyph.eayi 5- beimxikjxofyt

iaaftotber eis odiissint R 5 is !-¾ethyi-3-pytazoSyI, medi M- razoi i, L5- diroeliy ' M-pyrazo ' lyi, 1 i 5-trimetyi-4-pyrszo!yS 3-me¾yi-4-pyra2o!yl > 3-trifl oro-e†hyl-4- p iazo!yl, l-p.,2,2-trif!aofoeihyS|-4-pyraaoIyL l-earboxymethYM-pyra^oiyi i- e&axycarbonylme&yl^-pyxazoiyl, 3-cyctobiiiyl-4-py lyl s I -cyc!obuiyl-4-py olyI, I -{4- morphoijftyl)c¾r oaytoeUjyl- -p>tazolyi, i ' {4*m fph !myl)etbyl-4- yraz Iyl, I- hydroxyeihyM-pywzo!yi i- ydi-o-xyeiby!-S-pyrazo!Yi, l~hydroxypiropy1~5-pyrazG>SyL I-3- hydraxy-S-meiby!bufyO-S-pyrazoiY!. !'i:«etboxyethY!-4-pyrazoiyL 5-pyrazcdyL I-raediyl-S- pyrazoly!, l,3-diiBetby!-5-pyTazolyl l-methyl-3 riMorome. y^S-pyrazoly!, 3- meEby!atiii iiocai'bonyl -p ra^oi-5- 1 , 3-dimcihy { animoesirbao ii-pyi ¾ zo 5 - 5 -yl„ 3 ··

methySsuIipn laraiBO-pyrazoi-S-yl, l-ineth^ulfon iamjao-yrazoM-y.!, 2- ffieilaoxycarbGnyl-pyTazo!-4-y!.2, ~di sthyl-5~feiaadyl. > 2~(2-hydroxy-2-met¾y!ethyi)- i azobS-yL I-n½lhyl--5-imidaxoiyS ! 3,5-diJrieiby!-i$axazol-4-yL l- etyi-biazm-4-yL I- isopmpyl-fi-jazin-4-y!, 1 -bydroxypropyi4ria !ii-4-yl, 1 -hydroxy buiYRriazin-4-yL (4- riiuoro¾elbylpheny1)niethyl-triazm-4-yi, 2-cya8o-3-meihy!~ihiai-5-yl > 2- mei aYcaihon l-ibiea-S- i, 2-cajfcoxyi-thjeB>5-yl, 2-{N-»5etboxye i- - meib Samiaocr oiwIlibiert-S- i, 2^^th !-N-me , i-ammocart al)thka"5- l, 2-(2- hydrox.y-2-methyleihy1)t kn-5~yi, S-eyano-l-meihyipyn-oS- 2-yL

In anote-emb dHiieat, R ;i s 2-pyridyl 3-pyridyi 4-pyddy! ? 2- edwl-5-pyridyL 2- mefhyM-pyridyL 2-i«edw1~3-pyridyl.3~ e†lwb5-pyridyl 3-tr!f1:uorometbyi-5-pYridyt 2- irifJaor meihy I-5-pyri.dyb 2-dit1.uofomel.hyi-5-pyrid.y.l ; 2-irifJuorojneihy I-4-pyridyl, 2- t«fluoix>me 4-3-pyridyl, 2-raethoxy-3-pyridyl, 4-!»edtoxy-3 » pyiidyL 2-medioxy « 4-pyndyi, 2-i3-oxcia«yl)iHeiboxy-4-pyridyL 2-{3-oxetanyI)oxy*4*pyiidyS ! 5-.fluoro-2"»5ethO ' Xy-4- pvndyi, ' 3~fliiDro~4-pyridyl.2-fS.uoro-5-pyrtdy! ( 3~£!isofo~5-pyridyS 5 3-medaoxy-4~pyridyb 2- efepxy-4-pyridyl 2-n.ie†boxy-5-pyfkiyl 2-i2J~dihydroxypropoxy)-5-pyridyl, 2- hyi!roxyraeihoxy-5-pyridyl, 2-bydroxyeiboxy"5-pyridyL 2-hyd:s : oxycdioxy » 4-pyridy!, 5~ f!uor0-2-i5ydr0xyeihoxy-4--pyndyl s 2-metbGxyed.s0xy-5-pyridyl : 2-hydroxymet¾y1-S-pyridyl, S-meffeoxy-S-pyridyi, 2~etboxy-S-pyfidyl s 2-isoprop0xy-5~pyridyi 2~hydroxy-2- meibypropoxy-S-pyridyi, 2-(Ll , ! -tri¾OKiedioxy>5-pyndyl> 2-cyctopropylmeQjoxy-S- pyrsdisiyb 2-(a:5ed}yisttl:¾8ylpropOKy)-5-pyridyL 2-(mcthyls«lfonylanHnoe¾oxy 3-pyridy ' L 2-«tboxypropiixy-4-pyridyl, 2-dillaoroi¾eihoxy-5-pyridyL 2-fiuoro-4-pyfidyl, 2- hloro-4- 2-cyaacj-5-pyrid !, 2- i):isiho y-3~cyano-5-pyridyi N 2-cyaao-¾-mes :l-4-pyridyt 2-m«¾roxy-6-meihy!-5-p¥ridyS., 3- cyam>5>pyridyl, 3-cyaa«-4-pyridyl J 2-methyls ifo£tyl-5~pyridyl. S-m thyisuifoi I-S-pyridyi, 2-{iBethy!s»lfouylanuno)^~pyri.dyi 2~!¾etli sy afbonyi~4-pyndyL 2-(i.ffiida¾oI-i-yi)pyridyL 2-metoxyimiao.raetfeyl~4-pyr}dyi. f 2~oxo-l i ¾ cliO yricli o - 3 - K > -nietbyi.-2~oxo- j ,2- dihydropyridin-S-yl, l~methyi-2-oxo~l 5 2-dihydro yridin-4-yi i i-eftyi-2- sa-l ,2- di yd*opyridisi-5-yL, i-is propyl-2-ο χ ο-ί ,2~dihydropyrki«i-5-yL l-hydroxyeihyl- ox -l ( 2- dibydropyridin-5-yl, I •• hydioxypropyl-2-οχθ" i ,2-dihydro y«din-5-yI, I -.metljyI-2-οχό- 12· dfSiydi'Opyridf!i-4-yl, 2-hydiOxypyi'ici-4-yl 2-hydroxypyrid-5-yl 2-ami«0eadx)«yl-4-pyridyl, 2-raefeyiaminocarbo«yl-4-pyTidyI i 3-rae{;l5yk£ni»ocaFbo«yi-5-pyridyl ? 2- isopropylaminocai>o.n.yl « -pyridyl 5 3-iit ylamm carf5imyI>5-pyddyl 5 2- mcbyls«!fbttylet ' hylan«nocarlK)ttyi"4-pyridyl > 2 methyls«IfoH laraiftocti» ]m«mocai i »n M- pyridyi, 3-mei yisuif nylamfnoelhylaminocafboKyl-5-pyr yl 2- ffiedsyisulibnylaraiftoei oxy-S-pyridyl, 2-hydfoxyethyianiiiiocarbo»yI-4~pytidyl ? 2- ydroxyetliylamiaocafbonyl-S-pyridyi, 3 wdmxyeiS ia;mi!>>carb«5iyi-4--pyridy], 2- l5y<!roxy oiylanifnoca5½oi>yi-4-pyridyt > 2-mc?hoxyetliyl8mmoc«rbon>4-4^yridyi 5 4-fluo:« -2- met yamifiocaibonyiaramo-S-pyridyl 1 2~{1 -3mid8¾oiy1}pyfid-4-y1, S-pyrimidiiiyi 2-atjHno-S- pyrimidisyl 2-eya«o*S~pyrimidi! L 2-medtoxy-5 « pyri idmyL 2-edioxy-S-pynraidmyl, 2· isopropoxy-5 > pyrimidiisyL 2-tjii! otoe&oxy-5> : py«t«idmyl, 4-ti1i!u roa½tliyi-6-py«»ud5«yl > 2-tri1:Oi¾roed:iyS-4-pyi-iraidiny!.2-iri£l:ooroethyi.-5~py rim}di¾iyl, 2- dlfficiliy!amiP iCarbanylpyrimidin-S-y!., pyra¾;di-2-yt T a¾m- - L

In aaote embodkaeai, ! is 34>enzoi eoyl 5-beazoforyL 5½dolyS, 2-0xo-diSiydfo-5- indolyl, 6-indolyi, 2-oxo-dihydro-6-indolyl, ' i-»sethyl-2-oxo-dihydfO-6 «d lyI, usidazoj 12- imidazof 1 ,2- a]pyrid -6-yl ! J-diox ^2~metbyS-3 > 4-dibydro-2H4en [b]

methyl- I J -dioxido-3,4-dibydK)-2H-beiizofb|| 1 ? 4,5|i(xatfeia2;cpift-ii-yi ?-- edioxy-2~iBethyl- ] , ! -dios:!do-3 : 4-dibydro-2H-beai»|b] ! T ,5 joxathiszepis-S-yb ?-S«oro-2-m6ihy!-l s l~ d xido-3 ,4-di b dro-2H -bei¾»] ' b j { l A5 ]ox i iazepi«- - i i 5*i>xD- '-weih 3[-23A5- teirabydiX)-be«20fj i,4joxspia-S-yb 4Hne%i>5-ox -2 » 4,5-teirah dro-«azo[i]p s )oxa jn- f-yl, 4-metfe M -dioxi o^W-dih^ro be»20xaxoi-5-yi benrnxaaol-fc-yl, 1 , ! -dioxo- ,4-dib dro-2H-|: I ! 4]oxatbiepiiio| 2 5 3-b]pyr}din-S~yl f L \ -diexido- 3.,4-d5hydr -2M-| Ί ,4]oxaibiept!ioi:2,3-b ] yndifi-8-yi, 4-meifiyb5-oxo-3,4-- dihydJroben o[ j[i > 4]oxax p i-5(2H}-7-yi, 4-niet yl-5- x -2 > 3 < 4 ! 5-¾itra ' hydro-py«4o|3 > 2''

51 f|[ ί ,4]ox8i5cptfi-7-yl, enzexazoM-yl, 2-raethylbe»OTxazo!-5*yi 2-e&ylbctsei>xazol*5-y}, 2- jsopi»pyibeii¾QXa2o ' l-5-yI, 2-oxo-2(3H}- 02o|;d}oxaiioi » 5 » Y!, , eaxosaaol-C- l

benzodbazoi-S-yi beiizoi iazo!-6-yi, 2-mcthylbenzoihiazol-S-yl- 2-js6 r0 ' i c«2«{ ' d]tbia2:ol- 6-yl, raetby!-S-benziffiidaiiolyL 5 »daz©iyt, I -ffletlwI-S-itidazo!yl b-iadazolyl, l-met!iyl~6- indaz iyb 2-met¾yi-2Hr:mda? -yI, 7- ¾3ad0!- - I, 7~azaiiidoi-4~yi i s 5-d.a¾ethyi-2 - dthydro- 1 H-pym)lD[¾3-b]pyrjdi»-5-yJ y Z^-dib dro-lH- iTdloP^-blpyridm-S- l, benzoisoxazol-S-yi, 3-meifeylbe«zo!;d p.sosi5xoi-S-yI, 2-ffiei¾yl-3-oxo-beH¾o[d sosa2o!-5-yl. 2-me&yl 3 z lo5 5 4>b}pyrtdm~S-y.1, 2- tnet !oxax I lS^- Jp ridin-S-y 2-mediyb3-oxo-23-dibydroisoxa^oi |5,4- lpyridja-5*yl, 1 , 1 -di0 o-4-:me$ i~3,4-di :y ro^ 3-msdwl-omd xoi 12~ a ] pyridiH-6~yL 2-oxo* Ϊ H-i.midazo4,5^ipyridin-2(3H)-6-yl ! imidazoj l,2-a]pyridi«~7-yl, imidazole 1 ,2~a}pyndin-8-yf 5 2-oxo-2,3-dibydro- Ϊ H-i.midazi>[4 i 5- ipyridiii-6-yl, 2-oxo-23-

5-yl, I l,2,4jiriazoio|4,3-alpyTid:ifi-5-yl, i ,2,4 [iriazoiof43-a|pyridi«-6-yl ! 3-bydmxymetlayb 2-hydrxyme I-2,3- dih dw-lL4]di0siaoi2 j-b]pyridin-7-y! > 3- di¾xymcihyl- > 3-dife^Q- ' I > -jdoxte'o2 - b] pyridif[-7-yl 6-qumoHnyl, 7-quHSou ' tryl , -isoqamo!.iny.l, 7 soquinoUpy.l > I 5 5-naph$ yridin-

3- yI, 3-metfeyi-IH-pyrazok>3,4-b|pyridia-5-yL lH-pyfazo |3,4-b]-pyridia-4-yl or -fnethyV I H-pyrazolo j 3 ,4-b Jpysidi ϊΐ-4-y ί .

in nother eiitbediment, R: is. H, or btomo.

G IsCH; sad a pharmaceutically aefteptebfc s&!nhereaf, la anote embodiment, G is C-Q; Q is H; md P is

in another ambodisiefft, R !f is 5 membered aitrogea containing aeferocyoiyb 5 nicaibcred xygea cofifaisbsg beiefocyclyl 6 ift rabered aisrogea couftratag boSsrocyctyl 6 membercd oxygea caataiiiiag heterocycyi, p!ieay i, benxyi, 9 raembered bicyciic nitrogen soai&intag lieiefoc c! L i 0 memhere bicyciic oxygen coatalalag heterocyclyl or 10 merobered bicydic nitrogen cmta-ining aetefoeyeiyi; wherein R ' h nnsabsiiiated or xubsbruted wills one or .more snbstitaer s mdependeati selecte ..from sikyl cyano..halo. C>.« alkoxy, Cs .baloalky C aSkoxyearbonyS, earboxy, s s.5koxy-C 3 .<: aikylammocarbooyL C t .* slkyta )inocarbenyl€ ¾ .* ¾lkytoi«o-C.^ alxyi&tsi&ocarbosyt or [optionally substitute 4-6 membered nitrogea conai i g aetCfocy yljcarbony},

In. another mboduse , R* is tetrabydrof raiiyl, ietrahydmpyrcawl s 4-di¾ydro-2H- ynmof 3,2-cJpyridny L cbromanyl. texaiiydtofero|2 ~b liury.i, psperidirryl, p ridy!, pyrazo!yl., tetramylpheriyl, qumoliiryt, 1,2-dihydroquinolinyi, pyrrolidinyi, berixyl, 1,2,3,4- c&ah diOtjaiiJo!ray! 5,6 ,7 J-iefra ydfoqidttobo l, quinoxalmyl, qirinazoiinyl, 1 B-ipdazo!yi, 2B ndaiialyI, isofedoimyi, IH-pyrazolol3,4-djpyrimidis:yI, isoqui&ol yl, .1 H-pyra¾olo3,4-b]pyri<iny1, imidazo[ i,2-a)pyri ' dmyl > SH-imidaxoj 4,5- ajpyridinyt pyradmzmyl, pyrazmyl, pydraidmyl, ^S^J-t trab dro-SH- vT zalo ^- blpyridiayl B.^ihydn^H- raiJol^^-cl ridky!- or chroma y wherein R* is uasubsrhme or subsiittued with oms or mors subsiiUisms independently selected from methy l ethyl, eyaao, chloro, rftiora, -methoxy, triftaffoiaetayi.. etfioxycar oayl, ten-bufoxycar oayl, carbosy. N-(raet,hyl)- - { ,HHljmeifc ljam3«oeas¾oayK H-{s»edwl-K-

!:n aj¾Qirer emfeodanest R* is benzyl, i.etral¾ydr0py : f;«3-4-y!, 3-l!!jor¾-ieti'a ydropyra«-4~yL I-

4- pyridyi 2-raedyyl~5-pyndyL 2-i»et]iyl-<)-pyddyl 3-meiS:iy!-4-pyridyl. A-mei yi-S-pyridyb 4-«!eihyi- 3i)y?idyt2,6-dis}gd I-3i>yridyL 2,4-di e i~3-pyrklyL 2,4-dime%i-5 3 ndyi 2 dimeibyt-S" pyridyL 4 dimemy1-2~p ridyS i 2 t 5-dii:«s¾b i-3-pyiidyi 2-eihy!-3-pyiidyi.3-ediy?-5-py{idyk 2- thyl- 6- -et¾y{-3-pyridyl > 3 t yl-iHi»%l-S-pyrjdyU3-^ ^ yl-5-pyik1yi, A-ptxsp-i-esi-i-yi-S-pyridy 3- ( I -merhyle*e«yl}-5-p ridy 1 , 3 yc propyl-5-pyndyi, 2½drax ei^t-3- yrid l > S^dmx aietB l-

5- pyridyi -(2-b rox ed^ 2- hydroxypropyl-5 » pyodi H

tiii]«or0i»eihyl-4-pyi1dyi ( 2-ii-ifit!oro!«eibyS-S-pyrf dyi -med}y}-2^rii1uoromethyi-5-pyridyi 4 ifleihyl-l-ttiRu roft«;thy-6--pyridyl, 3"trifluoieraetlv>d*5-pyridyi f 3^riih«ofOH^th l.5-ntt «>- - ndyl 5 4-irifliioronisil}yl-2-ehiofo-3-pyTsdyi.2-meihoxy*5~pyridy : i > 3-i2-bydroxypropyi-5-pyridyi, 3-{2- bydroxyethyO-S-pyridy!, 3-mffSboxy-S-pyridyl 2- me(boxy-^eiayi-5-pyndyb 2 yano~3-pyrkiyi i 3-cyaai 4-pyridyl, 3-cyana-5- yridyl, 2-cyaao-5 « frifiuor meShyl-3-pyridyS, 2~chS ro-3-pyridyi, 2-ch!ero-5-pyndyl 3 hlor«-5-pyridyi 4-chk>ro-.- pyndyl hIoro~4 yano-5~p>Tidyl < .2-:0 at¾-5~pyridy? f ,3~0isasO-S-pyridyl 4-IIi}or -3-pyridyL 2- chloro~5~modjyi-3-pyfid l, 2-bro«w-3-meihyI-S-py«dy{,

dimeth i-2-oxopyridlfi:-5-yi, ] > 2-dii»eihy!-i>-Oii0pyridii>3-y !, 1 -raetiry!-2~oxopyridio~v 1.2-mefh I- f*- SGpyridi:i5-4-y] i \ -cmyl- -axopytidiK-S-y, 4-etby !- S -mefhyM-oxopyxidm-5-yl,,. ί t&yl-2-»5s1 yi-

6- xopyridift-5-yL i -lsop!¾py?~2- x0pyiidia-5-yl > :i-me l-2- (rtluormt|j^<!Xo yridifl* - i-nieihyi-3 « f.nili!omie l-2-oxopyrk1jf¾- -y!, 2- 4- 0ioipkj ayh»ediyi)- ' 3-pyridy}, 2-{ser i« !a :HnocarbOi:tyi}- - y id l, 2- (meiito ed)yianj :¾o <» osiy!)-6- rid !, 3-3-s{etI)Q-x> bc«yi>-5> tid | > 3-{3-i¾ioro-5- i»etboxypbctiyi)-5*pyiidyf.

I ' M another eatbodiaieut, R s is 5 > pyrimkiaiyl s ·4-ε¾1οΓ0^ -ο¾1 {* νϊίίΐι½·β-6-^ 5 2,4- 2*cyaropyrimidifr-5<?i t 2-i ifii{o-rometbyi- yt«aidH-5-yi, 4- fluerop rimidin-2-yI, 5-iliioropyriraldsa-2-yi < 4-trifluoroBie1hyl-p>-rmtdia-5-yl ? 2-i½eiidinyk;ss-boayl-

In. aaother eai odmient, R '"' is S3 ~aimediyi-4-pyni:io)yi S -cihyi-S-pyra oS l i-jsepropykS- Kttolyi, i -e yi-4 ro o-$- yK5zoi l, kedsy!~4-xne 1-5-pyramtyi, l-ef:Siyl-2-iaeiboxyiwei:hyl~5- pyi-a¾}Syl l -metli l-3 » dlro^tylam¾ioct^n -5^ rd¾oiyl, Ί -mefh l-S-cyclo fo yl-S-pyraioI , 1- ediY¾eteoi-2-yL

Pi s otte embodmrcat, R 4 is pfteflyl, 2,6-d!fbioropSjg!iyi.2-ihiarophsayl 2.4 idloorophem'L

fu m-3>mefttdxyphea J, 3-cIioro riyt 2,6-di iompbeay, 2 -dc oropheay,

.Otiiiropbenyi, 3 1d«ra-6~ikto.ropbeiiy!,2--il iiro-5- triiluoroiBed phers i, 3-b droKyi:nsJi i iiea l¾¾droxy¾fij lpb«n ]i 3-h dro > !.by - etfeylpbenyt, 3>medmxyp ' hettyl, 2-r £0 )x hen ' i > 4-ffieiboxypbe«yl, 2-m<ahysulfoay{pbeay|, 3- i:nctiiyisa!foiiyipS)c»yI, 2-iiuoro-5-cthylsaifoftyIphoiy S-ethyLwiaosulfoftyl-l-au foptoyl, 2- ilttoro-S-msb ksrboaylphen l.3- ei.h0xycarboayiphenyi t 3 -c;»:bos : henyl 2«met¾yi-5- eiksxycarboay!phes l 2-c ofo-5-e { iKJxycarbonylp say 2 > fliK5ro^5-met.hoxyc5irbonyIp myl, 3- mcthyi-S-ffietbosycai-boftyipfeeayl, S-bydroxyinctbyi-S-ffieibosyc rbo ySpbeay!, 3-raed)osy-5- nielboxycarfeoayipbeoyl 2-fl«0fO»5-H»«{bo y<^r o s6efi}yl be¾ i 2-flu.oroi'5- Ciir oxyineibyi beit l, 2 ? ii-diflt.io:ro-3-a!etbyipbe«yt 2-etbyIphei¾ s 2-B ¾ l-5-earbQ y heo ¾ 2- eMar©*5 -$rtK*x h©Byl, io-S- andiKK r o yipbeEi , 2-

mciby!p!ieayi, 4-c Mo-3-ineft\ l iea {,.2 yaao-3 ' et¾yi tey„ 4~ddoro « a55opaeiiyl, 2-diloro-4- c anopta 3- ii!os -2 ysi« pbeay!, 3 hloro~6-c¾oop.b nyi « 2 ya.tto-3/>-dichloropb.<3jy{ > 2- cyaao-^^-diSu roptoyl, 4-cyano-2 > d- : diOue(OpticjiyL.2-cyi«io-6-fl«oropi!esy!, 2-cy o-iS- cl.il oro eiwi, 3-cbioro-2-cyaao-6-fbiOTopliaiyi, ^- ai&ft-uiilit romed l teil, 2-cyaHO-S- biSluomaiediyipbeayl, 3-{( Qpfopyl)ai¾i«ocarbo3iyi|pbmyi, S-raetbyI- -

dimethy1.}£a¾iaocaTboHyl ' |p eayi, 2-mediyI-5- -{a>^hyl -

(mdfe lasMft^tk iJasaitiocatbo i^ e l, 2-wt ykH J -me }p J¾ a)- - ))carbon l.) bδfi l, 2,6- 4i¾cw-:M<is© ro y1)aai^ 2*flw^S4¾t> top })aiiHaoc8¾m ijipbeii 2 » fiuom-3-(flY-isopropyS » M-raediylaRs io)c8i¾ofiyl)pbt 2-fl«csO-3-{{e }araiao)cait ft3d}ph«iyi ! 2- flaoro-S^flx^iOeib !aftkiO aito yli e y 2-fluon 5^^clopropyto ihyl)a»ij«c> ii:¾oayl}pheayl > 2-fbi m-5-(cycl0buiyl))mniHocar onyi}pbe«yi S-naoro-i-Ci cto eirtyi^vaK 'b n pk^ ^ 2-

^mertoxy ro l^amiadcarboa pae yS,, 2>aiiOfo-5 2-Kte 1>kaia carK>n 1^ 8B l, 2-!lnoro-5- ((2-meiboxyi>ro{5y 1 )3¾MiKK»rbony1.}pi¾e».yi

iesli !edwlwiniisoar db ijpiieswi, 2-c toro-5~i{ S. - ymjliadiB Jcar oK iipIieii i, 2-diioTO-5~{{ L3-

fluoro-5 04methyip> 2-S¾iOiX)-5~((i-!«s¾.yipyTi¾¾«l-5-

Cteti¾hyd«s yraii- ->½i^^ ^ ^ 2-flaoro-5-(< I -<lio5e5¾ySpytj ol-4- l}ii!i:i!BOcarboit S) ea t -i]«om-5-{C rid« -yti^ iytaramoc r m 2-fl«ifO-5-(i" yI})a!ni»ocarb«ftyi)p eayL 2-ί¾οκ 5~ί i-t»eil)ylp^eridin^-yl )amiaocarbo»yip jyi, 2,t>~di0uoro- S4;S-ra£ihyIpiperidin-4-yIJ^^^

2- 1¾ ioro- -t^-morpha linyjJamisKX ar ony I ipfiesi i, 2-fltjpro~5*( : (4-

54]-p riO!idiiiyk3:boa i} bei5 l 2-cbloro-544-raeihylpyrazia-4-yl)carb«t5yl}phei5yl, 3-{2- .>-(2-raei.by!- .! 2J~ox i xd- -yi h£nyt 3- (3-a½†!:5y! ,2,4-asaJbizoI-5-yl}pi¾;nyi.

Ja simite etnbodiaieab R :' is .5-qt! oHnvL 6-ijuiaotKay, 7-q«jooKfty 8-qai»o.li«y} 5 S-cblom- 6-Quisoi«¾yi, . 5.6?,8- teffabydr qtiiw!ia-S-y lJ3,4-f:eirahyd;roqt!i;nobii-5-yL 6.6^a}id¾ k J 5 8 s^ah lroqMi o.h ' «-5- yj, 4>cjtt(iMK0!ii) L qaiaoxiiiia-S-y!, koxO-is0 ' iadoHf)-4-yi., l-o o s iHdoSiB-6~yl 3-ajei!iyl-? i3- i»d;!zo^4- l 2-tHethy½f »dazol- -y, l-meihyi- } ¾aKia cibS- S, U-dsmefh ^ S H^ndaaoM-yl, n, ,4]ma ol:oi j j] dd:^S- !, i -m fhy 2'0Xo- i ¾¾^Γ0¾«ϊ8ο1¾-6-> -melbyl-2-ixt>* K2- dih droqaisiobH-b-y!, 54&i0« i«mt^:i .i«2-o^^ i,4-dimeihyl-2"0xo~i,2- dibyd!'oq»i!5oibi- -yl 2-oxo- S ,2'dilwdroquinoiis:i-6-yS, 4-0xo-dihydfoqiimo.li»- 1 -yl < 4-oxo-quiao!ls- i(4H} « yL 2 » med.ryi4..oxo4. d.¾^ Sj-difliio^l Adimer.hy]--2H>xo- ! ,2- SJ-difluoca-I- ieii¾yi.-2-oxo-i ; 2- dibydi¾¾tan0lift-6-yi S-lsoqibtw!inyL T-iso aiaoh ' ayl, ii-isoqisnoSiayi S-iseqtiiiioSinyS, 4- isequifiolifiyf, i - yi .B yK¾zoio[24- ! yrld!«-3- t i~e S-IH-pyr¾zoso[3.4^]pyridin-3--yl, .1 - es:hy]-:S -pyfa o!ci 3,4-b|pyi:idii!-4-yb ί-me .o cίHyl·lH-¾¾ ίo[3, -b|p rid^a-3- 5 5- ioro-.- jnetbyH H-p fs o 3 ! -¾jp i!:kbfl~ -yL ijsktof i,2.a)py dia-7-

y 1, t!iblfizo i .2-2lpvfidfft-6-yl 3-ffie!:hyl-3H:-i.raidazo[4J^}pyrid ^S-yl -si!etbyI-3H-i5¾idazo4,5- lpyridift-%13.«] d:iySisoxaz Soi5.4-b] ridia^- L i ; 2 ! 4triazoioi4 -itipyridia-S--yi i-j«eti¾yi.«

met k¾ r 4-d dio-2H* yn«i |;2,3- lp ridjn-.S-y:{ or 5-cteaaa-yl,

in aaotser eaibodaiieai, I. Is 0.

Ja smmlm .embodiment, G is C-Q; Q k -L-.R*; nd P is if.. I iiaot!i r embodiment, R is 5 jae bsrsd nitrogea contahirag hc-terocyciyi, 5 membered oxygen coittaiaibg feterocyctyl 6 mem ered nitrogen c«numiing teerocyciyi, 6 raeaibered oxygen containing heterocyeiyi, pbeayi, benzyl 9 jsembcred. bicyc!ic -nitrogen coaiaiaiag heieraeyeM, J taeajbered fejcyelic oxygen containing iieterocyc ox 1 rcteaibexed bicydxc nitregeg coftiaisxiag hei«roeyciyi; wherein R* is imsub-sdtuied or substituted with one or more subso ' t ems indepeadaaly selected from Q . aSkyl cyaao, h£tl , C Mi alkoxy, C^s hiiioaifcyt Ci.« aikoxycarboayi carboxy * C f ,s koxy-Ci.s ai&ykiii!ii! c r oHyi, Ct« a&ylaraiao rbonyi, idkyS iaiao-Ci.* aikyiamisocarboayL or [optionally substituted 4-g aieiabered nitrogen comaioing het£T«cydy!]carboayl

in another embodiment, R 5 is iettahydrotW yt ieiraiydropyraoyl 3 s 4 « dtkydro-2H- py.rano3,2-e jpyridnyl, chromany ' l, hexahyiroi¾ro[2 J-b jforyl piperidtny ' !., pyridyl, pyraKoiy!, ieiiazolylpheayi qamdKnyJL 1,2-dibydroqi!inoliayl pyrro!idiny!, benzyl

quinoxaiinyl, quiaazofiayt IH-iodaz ly IH-indaiioly}, isoiadoHnyl, [-K2 > 4jiriazolo4,3-a]pyridio:yl, 1 M-p)¾¾z lo[ 3,4-djpyrimidmy ' l, ssoquiiio!myi, i H-pyra¾oto3 s 4-b|pyTidiay3, imidazof L3-a|pyridisiyi s 3H-iMida¾oj4,5~ a]pyri.di»yl, pyradioxtnyl, pyrazmy ' l, pyrimidmyl, 4 5 5,6 ? 7-tetrahydro-3H~pyra2oIo3,4~ bjpyridioyi S^-dih dro^H-p raii l^^-cJ yiditJ l, or chro anyi; wherein R° is unabstimted or substituted with one or more sufesttaents iadepeodeatiy selected from raeffty], ethyl eyaao. chioro. timed, methoxy, ri 0 uoroj a« iiiyL edtsxyearboayt, tm-bytoxycarbooyl, carboxy. N-(«5etljyip - ifteihox ediy aaiinocarboiiyb {N,N-dnn<?di 0aiaj8Qcai¾oa K N-saeth i}-?^- te¾i¾½iiia «hyi)amm «iE oayi oxo.

la another embodiment, R* is enzyl, tetrmhydr pyr3M-4-yl, 3 T«oro-tetrahydropyraa-4~y {- Boc ' ptperidm- -yl 2,5-<!ioxo«pyiroli»d!«>t-yl

ΪΗ smother etntodiroettt, R > is 2-pyrsdyh 3 » pyrtdyi ; 4-pyridyl : 2-(aethyl-3-pyridyi t 2-me&yi-

4- pyrjdyl.2-raetby!~S-pyridyi, 2-raeiayS-6-pyrdyl -meiSiy!-4-pyrisSyI 3-f.aetiiy!-5-pyridyL 4~«ie yi-

3- pyndyl 2 dimethyl-3-pyridyl, 2,4-dimemyl3-pyridyl 2^dio¾ 15~pyridyl 2 -dimetbyi-5- pyridyl 4:5-dime h2 ?yridyl 2 ; 5-dunet!iy!-3i3yi%S, 2-eihyl3-pyndyL 3-ethy!-3-pyridyl 2-ei¾yh 6~nseth.yl~3-pyr.idyi., 3-etbyi-S-nii;tIiyl-5-pyndy!, 3-;sopix>pyi-5-pyridyl 3~prop-i-at-1-yl-5~pyridyt 3- (.1 -in<;d:iykihenyl}-5-pytidyl 3 y opropy ' f-5-pyridyl, 2-hydroxys:ns!¾.yi-3-pyTidyl .Vfeydimy ethyi-

5- pyridyl 3^2½'dmx e .l 5-p>^d ^ 2- aydmxypropyl-5-pyridyl, 3-( i,2-d droxyeibyi)~5-p> idyl 2-triiInorotnei¾yi-3-pyrjdyi, 2- trit1uoro ethyl-4-pyridyl -srffiaoromeibyS-S-pyridyt 3-raethyl2-irif]uo:roi«etbyl-5-pyridyi, 4- a)ci yl-3-iri5aoroaKiS:¾y!-f»-pyridyi, .-tiiflaorometbyi-S-pyddyi. -u:!:Sl:Uftroaiek i-5-nao -6- yrfdyl - p-!l]i!om!«eibyi-2 lo!)-3- rjd L.2-»*etey-5-pyridy$ s 3-(2-!xydm ypJOpyi}-5-pyridyi, 3-(2- Hydroxyethy!}-5-pyridyl -H3eihox *5-pyrid l t 3-etl!asy-5-pyridyi 2 » Hiei oxy4-iBetliyi-5-pyddyl 2- 8i¾lhoxy-6-ediy^5-pyfidyi, 2-cyaiio-3~pyridy 3-eyaii»"4-pyrkiyl 3-cya»o-5-pyddyL 2-cy(t«.o-5> 3-chtofo-5-pytidyi 4-chlom-3- pymlyl, 2-flaare-S-pysidyl, 3-i¾i0ro-5~pytidyL 4-.! »pr0-3-py.ridyi > 2- c!ilom- ~f:neShyl-3-pyrit!yt 2½¾m0-3- edw1~5- ri L ] .4-dimetbyH-o«Qpyridin-5-yL 1 ,3- diiaethy]~2- sopyridia-S-yi. ! ,2-dimeth y)~6~ox0py:iidio-3- ί . ! -meihyl-2-oxopyf idin-5--y L 2-TO 1- 6-0xopys:kii!i-4~y!, 1 -cd-yl-2-OKopyridia-S-yl, 4-ehyi- ! -o:ie1:hy!-2- xopy:ddi«-5-yL ! -eiayl-2-ajeih:yl- 6«oxop ridffi-5-yl s ' l-isopropy!-2-ox pyridin-5 » yi ? ί ,2 « diraS l-6«oxQpyridm-3-yl, i-methyl-2- wiaiB5roi«{¾yl-6-ox pyiidift-4-yl l « B)e i-3-tdStt nssstbyi-2^xo !d.«i > -y$, 2-4- m ipS5 iinyimeii!yi)-3-pyr!.dyl HKr b k«iUi!ocarbOif -4- i'idyt 2- 3-0-flo ri-5-

!«et oxypl:ie«y!)-5-pyKdyl.

in fa Jffeer embodiment, is S-pyri uiinyl, 4-diI«rQ- «etij l-p r!mkbn-6- l, 2,4- diifieia l- rmidin^-yi 2-cya¾iopyriniidsa-5-yS, 2-trit¾iomt¾eibyl-pyTii:nid3si-S-yi, 4- fltt ropyfimjditt-2-y!, 5-i]:aoropyr?!nidis'!-2--yl 4-irii1uoi^nes!iyi->yrii«idi:a-5-yL 2-azeiidisy!carbonyS- py.razia-5-yi 2-dia5Ci!iy:!<» iBOC3rbo:nyl-|>yrszfii-S-yi pyradtftda-3-y.

ia aaoifeet ffitnboduaen S-eibyl-5-pyi¾ioIyI. ! -isop:opyi-5- pyra<¾>iyL i-eiSiyf-4-bsro«.io-5-pyra¾ ly], \ -ei¾yI-4-aieibyi-5-pynix !yi ί - i hyi -3 -ΚΪ e i os inei¾ l -5 - pyramSyi, l-m^hyW- HQeth laiajaoca oa l-S-pyfas^l i, l-metbyl-^- yctei^opyl-S-pyraxoJyi, I-

in aziote embo Bseai. R s s henyl 2 ? 6-di uorophaiyl 2- «or0pl:te«y! 2,4-djSuoropiseayl, 2 i ; 6 « t?'ifliiOTO Sjc!: } > 2,5- iilwfOptoyl 2 { 3-dj:f:U0f0phe»yl, 2 -d}ftuoro-3 " Bieih Jypheay:l ! .2,4- diftuoro-.t-miit oxyphenyi, 3-eb!orephe!iyl, 2 t 6<iicboTOpteiyl 2 ! 3-di}iS«ropte»yl .3-ddoro-2* fluofoplieayl, 3-chlOio -i¼ ?O te3i i 2-chie.i-0-i><-fluo.f0p.tejyI. « 3 ο½-ό-ΑΗ ϊο &«&νΙ, 2-β«οϊο-5- trifl oromeftiylpenyl, 3-¾ydroxyraethylph.aty{ ( 3-bydroxyethy ' fp tiyl, 3-faydroxyt»ttli l-5- raedwlplicayl, 3-raet:hexyph¾syl, 2-meu¼xyp enyl, -jaethoxpto i, 2-.a*et« Mi0n lph«»i 3- medyIsa|.fonyip eayl, 2 ϊ«οκ>-5- eOtyisulfopyipheayl 5-e% : S.aiiii« sirf& I--2^i eri) liea ], 2- flaoro-5-raet!iyfciirbonyipheayl 3-ijfteth.oxy£arhonylp eayl. J-carbaxypseisyi, 2-aie.th.yl-5- eihoxycarbonylpfeeayl.2-eli ro-5~e!¾ xy<;axba»yiplseayi, 2-i1xjoi-5-a)st ox c8rb R i hea l > 3- :methyk5-mci oxycarbosyiphenyU 3-¾ydmxymed5yl-5-:nKil:toxyc3:d5o:fiyipheny!.3-maaoxy-S-

carboxymeihyJphei y yi.2,6- i8yere-3-me '! hsm i, 2*eftySpaeayl 5 2-j«e i-5-car ex> i pheayl > 2- i¾- -<-

»iefh I bcayl t 4-c a}io-3-aic( y:l li«ayi > 2-cyaao-:5-ethyphe«y.4-chtef¾-2-cya«opamyl, 2-chletx>-4- cyiin pbeoyt 3 hior0-2-eyaHophtfnyl, 2-cyaHO* .S-tfichiorophenyi, 2- cya»0-3. -di i!of ' QpheayL 4-«ya«o-2,6-d«flx«>iopli«iyl, 2-cyan0<s-fitt©?O heByt 5 2-cyaao-6- cl orop eayi 3< Ioro-2-cyiino-S l«orophenyl, 2 yano-6-iriflaoTOae iy!pheisyl 2~cyao -5- td0aoroi!»si.bylp¾anyi, 3-iiso ro I)aminoca:rboii> S i¾e^yi i 5-a5ei¾y|-3- S(<s0propyS}ammoc3rboiiy pte«yl 4-meUwi-3- (isoprdpy!}amiBoca^oayij:pbeayl, 2*t»eihy 5«} ' N- ?

■dimethy I jams sjocarbenyi jplxaiyi .2-meiSiyI-5 -[^-{awiSi i)- -

diiluoro- -(<isopropyS)<f!Bitsoca:fbo:nys}|>hc¾yL S ^ iwo i-S-iCsopmpy^^Hioc-ai^s ^pte 2- ftuo!X> » 3^{N*i$a^^ 2<a«oi-o-3-{{eihy¼raino)cai eByl)phcnyl 2-

( : (2-m¾¾oxyprapy¾ )ammocaibon y Dpbeny i .2- f joro-5 -({ I -meihoxy- ϊ - a)cdi ledw])aniSfiocar ony S)pheny 12-chlora-S~(( 1 -pyrroiiadio Dear bo«yi)pk syt 2-diloro-5-{( 1 ,3-

iBda^ ertdia ' 4-yl}}iH HWca:¾oii i)ph£;B i, 2-f|ifOi¾--5-{l-Boc»3--fSuorc^i er!d:bi- - y!))8a)iftficai citj ])p R i s 2-:f1uoro-5~(:!-8oc-pipendia~4^

i]iiOi¾ethyi- iperk!itt- - i)} H» i!caito 2 - 0t ϊΰ ro- 5- i -« sit > 1 -{>i <; ri d

y!))aHrf«ocaiteftyf) eftyl 2 luoro-5H ~aied:»4ppm 2,6-iiifli.io-ro-

raerpboSia ie¾ I8inisi0car on I)pl¾n i t 2-chlot^5 medrox et¾i)ammocaxbonyi} : he»yi 2-chi ro- 5-{l -pyrffilidinylcarboa Opliaiyi, 2-cftksro-5«(i -«)ethylpyra i«-4-yi)carbmyI}p e»yi 3->(2~ benxiaiida oSyl .spiieay] , 3«2-mefty.l- i 4errBxoiyl}p»£«yl. 342-aiethyl- i ,2,4-oxadmxol-3- Sipbetvy 1 , 3- ?-meth.y1- i; ,2,4-ox!idiazol-5-yi}piteayl.

in. aaotber sa odi iefit, S > is .l-cjaiaoliayl fH?uinolm {, 7-qxtinol yi, 8-qmn.oSisy L 5-efek> b-qiiiiioiiayi, ?-c¾oro-4-q«inoUayi ? 8-c¾o 6-quinoWi3V.1, 2-medwi-4-<«!» l5ayi, 5,6,7 J- ielndjydiOqufiioiia-S-yl

y!, 4^«ins¾s>.liayl.. q«i.«oxaliti-5-y - J -os.o-iseiadoito-4-y, i-axcHSoiadoSm-fi-yl, 3-me!:hy}- !H « tHda¾o!-4-yl,2-a>.cih l-2H-{»da¾oI-4-yl s i -Bxei yl-lH-fBdaz^I-S-yx. J .3-dit55ef¾yl-lH-iBdi! el-4-yi, f i. > 2 > 4|tria¾6{0| ' > 3-iVipyridi«-8-yl ! . I « ai£!hyl-2-o o-k2<kh dre^

d:¾ydroq« ic!:» 6"vl.

dibyd(Xsqoi!isHi)>6-yl, 2-oxO- 1 ,2-dibydroquiaci!i:i÷6-yi.4-oxo~dihydroq«i»olj»-l-yi > 4-OJio-qxaHOift- 5,7-diOuoro- 1 ,4-dSmethyl-2 « oxo-l,2- dbyilro u5 o!iB- ( 5-yt 5,7- i i¼0ro- 1 -

»ieSi!yI- ~0xo-4 iftyorm3:ied.5 ?-i,2~di^ 5J-difi:aero-4-edxyi-l-s3:ietbyk2-oxo-! > 2'- d¾'dixsqmn, 1.ia-6-y!, 8-is q«moIinyl ( ?-jsoq«iao ayl < {Hsoquhiolhiyl, S-iso uiiwii yi, 4- isoQiiinoUny!, ! -n¾il:!y!-iH-p razoio[ , - |p r!dni-5- l i.-ei yi-lH-pyniioloS ' 3,4-bipyridiii- -yl I ~ me M H.-pyoiico{o|3 5 4-b]pyridi«-3-y] s f e-p x zofolS^-dpyir&aido^-yl, t«ikfe>p .2-aJpyiidia-7- y I (Kiii!az ! ! ,2-a]pytid!a-6-yi, -n:i¾:h i- H-ift3ida^[4 -b]p rilto-5-y I 5-wihyl-3H-.»idazo[4,5- b Ipyri ia-e-yl -fli:0:f bsi) a¾!oi5, - p ridi« -yl i ,2,4]iria oio4 -iilpyi¼i»-S--yi l-methyl-

me¾4^; %'di 2H>p f»80p b ; |p ridin> - l or $-d« u-yl.

Another aspect of the ' cumstt itrvsatk relates to cQmpm & liming ii geaerai structure of Famm!a lie and lid

wherebi;

I s is alkyi, aikcny!, ha!ostkyi, a!koxy, hydroxyalkyl, amiaoalkyl, alkoxyalkyl, hydrdxyaikoxyslkyi, alko ycarbonylamkoalkyl, cydoalkyi, cyc!oafky kyl, aryi aralkyL heterocyciyl or heierocyclylalk l, wherein the cy oalky!, aryl, or feeteroeydyl rin cycloalkyi, cycioaik lalkyl aryk araiky!, heterocyciyl or heterocydyialkyl is ^substituted or sabshiuted with one or two stsbstiiuests mriepersdeniiy selected from hydroxy, alfcoxy, alky!, oxo or halo;

is iii5i»io«rrbos¾ . cyaao. cyar»«8ikyL a!kytearborryb hstetocydyicaifcoayi

¾{kj'kmif.ocarbo¾yl alkenyi. alkynyK bydroxya!kcayi aSkoxyalkoxyaSkyk arySoxyaikerryf, alfcoxycarbony!aikyi, alkylsttlfony!aikyl alky isuifoayiailieBy!, aikyk«tr»ylai.kyoy 1 >

bciciocyciyi lkynyL befcmc cl SeaibCio JaSkyl, a!koxyaikyoyh bydroxyaikysyi o-^XK* ;

X is a hood, "0-, or ~SiO)a ;

n k 0. I , or 2; l ': is aifcy.1 hydroxyaikyk ha!oaikyl, idkoxyalky!, alkoxyalkenyl, aikoxyearbooyklkyi, ea.rbo.xya Iky k arninoearbicmylaikyi, alkytoin car on lakyl, aryi cycioalkyl cydoatenyl, heierocyciyl araikyi, araikeayl, arylaik ayk cy loalkyWky eyeloalkyialkenyk cyco&lkylalfcyayi, hetmieyciylaScyi or hetero-yciyicarboft lalkyl; wherebxlhe ring in. 's is substituted with 1-3 sobsi!isei!ts inde endeKU selected from I aikyl akx haioaikyl hydroxyl alkoxy, haloalkoxy, acyl, sfiky!sifSfoiiyL heieroeydyh amraosulfoayi lk !aim suiiOfiyl eyarto, alkoxycarboriyS, carboxy, amrfto, RR'N-C;.* alkyL alfcoxyalkyk hydmxya!kyi Oi k¾^C« } }, wliere a is alky! and !> is aikyl iiikoxya!kyl amirsoalky! of slk toiiioaikyl, or where T d R 6 logeto with 8te tuiroget* form a heterocyclic ring unsubsbtuteci or substituted with aky I;

5 s aryi, aralkyl, heterocycSylaifcyk eyeloaikyl or heierocyciyl, wherein R 5 is oasubsbiuied or substituted with i-3 substhuents in ependentl selected from aikyl aikoxy, hydroxy!, halo, haioaikyl, cyano, alkoxyearbooyl earboxy, acy!, cye!ofiikyl heterocyciyl, hydrox alkyi, alkox alkyl oxo, RR' -, .RR ' N-C 3 .<s alkyt or R'R^Ci-O) where I s is alkyi and is a!koxyaikyl o asmoeaikyl; where R sad R * is isdepeademly H, alkyl, srvL aereroeyelyt heterocyclySalkyk or eyeloaikyi, wfcere the lieierocydyiaikyi eycioa!kyi an aeteroeyelyl rings are nxubsmuied or substituted with.1- 3 sabstkoents ndependently selected .rom alky k alkoxy,. hydroxy, halo, haioaikyl cyano, or carboxy; or 11' as i R can togeite with &e.N form heterocyciyk

R !> is aryi, araikyi, heierocyciyl heterocyelylalkyi, or cyc!oaikyi wherein each of the a ioremeisEioaed iags is »«s\ s0i«ed or substituted with 1-4 sttbstituents independently selected from aikyl, halo, haioaikyl atkoxy, aikoxycarborryL, carboxy, smiij carhoflyi, eierocyclyleaAoiiyL Cya»o, sycSoa!kyi, hctsioeyclyl, iiydtoxy aik l a!ko ytaikyL MRU', CifcMRRy oxo or acyl

Lis O, S, CJ¾. orCHsO;

F is ··; -R : - ;

provided when R 5 is RnelhyMH-pyrazoM-yt I is O and R' is methyl, thea * is not 1 -ethyl- i H-

6-yt, or S ,4-dimes:hy!-2~o o~ i .2-diiiydri>q«iaohii-6-yl:

fnrt¾fir provided R ! is net. ph nl or lert-htityi when L is O, R t: is 2-ethy -pyridyk 2-:methyl-3- pyridyk or 2,6-dirnethy!-3-pyridyl and R 3 is 2- yridylhio, raethoxyethoxy ortiifluwomethy!; &r!¾ei iOvided: R ! is no! -K5e l » 2-ia«da?.oiyia)ethyl wbesr R ? is 2-p fidylt!iio, I, is C¾. and R* is 2· ethyl-^-pyridyi. Another aspect, of the current mventioti relates to compoands ha in the general structure of

Formula Hia:

ssia H. ! is C w S& ), CM afte . Cw laleaikyL C w a!koxy, CM> Iqrdtexya , CV« am« ) 0alk.y!. C w aikoxy-CV« ®k≠, C,* lrydrox.yalkoxy-C } .« alkyl, C M alkex m¾o ylaw.iTO-C!.« alkyl ¾.· ¾ , aryi aiyl-C^ alkyl, 5- ί 0 memhered heteracyclyi or 5 » 10 embered l:teterocycfyl-¾. ; , alkyl wherein the aryl or heierocyclyi ri?sg is tmsnbstituted or su siiiisied with one or ma substifttsrits ladepeiK eii l selected from C M , alkyl ydroxy, oxo or halo;

wherein R s is -X- ' R ' i cyaiio, C« haloaikyl Cut cyaaoalkyi, C ¾ a!koxyearboiryl€=,«■ C,.* alkyl ;. ; : altesayl,€ * .« alkynyl, C ; ,. ( i Ir drexyalkyt C w hydroxyalke yi C¾^ hyciroxyalkyoyl Cvs. alkoxy-C;.* alkyl C M aik xy-Cw alkoxy~Ci. s alkyl &Ik xy-C w; alkoxy-C haloaikyl CM alkenyl, C$« aikosy-C 2 . S alkysyl, aralkoxy-Ci.* alkyl, hy<iroxy-C ; ,. ( alkoxy-C { .§ alkyl, hydroxy-Cs,;, aikox -Cs.* liafealkyL C ; .« aralkoxy-C;.;,. alkynyl. hydroxy-C;^ alfcoxy-C?^ alkynyl Q,^ aryloyy-Ct.i. alkyl C S:F< > aryloxy-Cj.?. afkenyl, CM» aryloxy-C;^. alkytiyl€;.„ aikoxycarhonyi-C -; Isydroxyaikyl amioocaiton lC:.,, aikyi C»« a!ky! oikioeaAafsylCi., .alkyl,. C s .« a ky suiforryl-Cw alkyl, C,.« a ky su!fofiyl-C alkeayl, Cj* aSkyl$u!fo«yi-C;. s alkynyl, C s ..t e aryl,€?.* cycioalkyl, cycloalkeayl 4-1 j a¾w»bered heterocyclyl. i*! aiylC ; . s alkyl, Q. w aryi-C^ alkesyi C s* nrylC, :-. aikyrtyl eyc!oalkyS-Q,; alkyl cycioalkyl- C Irydroxyaik l C;. s cycSoalkyi-C;:^ alkerryl C s . ft cyeioa!kyi-C :f , s . alkynyl 4-10 einfcered heicrocyciylCs.* alkyl, 4-10 xaemhered h«er0cyciyS-C M alkeuyl 4- 10 trett&eted beterocycSyl-C: ^ alkynyl, or 4~ i 0 nts bmd kelerocyciy learbotiyl-Cs.-i. alkyl; whereha the ar l, cycioalkyl, cycloalksm or Iteteroeyeiyl ring in R ' is (^substituted: or substituted with 1-3 .substitueats s ependeatiy selected irom. C s .. ;; alkyl halo, oxo, RO-, i * haloaikyl, ^. glkyisnifoa terrana- d.« aSloxy, C; ., ; oalkoxy, h droxy ^ alkoxy, C alkox -C^ aftoxy. CM alkylsalfoayl- alkoxy, Ci.s asryl C< . ; ; alkylsalfonyl, ^. alk s-ycarb oyi. carboxy, 5-10 tacmbered heteroeyelyl, 5-10 mes:nbere heterocyclyi-C 3 ,« alkyl cycioalkyl, cycloalkyl-G;.;, alkyl armao, aminos lfoiryl Ci.i. alkyiamitsostilioityl alkyl sulionylaramo, cyaao, carboxy, RR' -Cs.?, alkyl, Ci-« alkoxy- ^ alkyl C ¾ . ¾ alkoxy tsrijj! -C 5 ..i alkyl, lydiXixyalkyl or R ¾ R Si NC(-0}- tiere R ,! is H. or C alkyl aad. ;- is H, Ci .6 alkyl C w liydr xya!kyl Cj.g alkoxy-Cs,* alkyl C ; .« a!kyladfbiiyl- C 5 .« alkyl, C w slkylsaJfsnytolao- Ct . 6 alkyl, C ( .« aniisioaSkyi or C ; .s al l-C^ amiaoalkyl, or where R* aad to ether with, the nitrogen forai a 5-6 membered heteroeye!ic ring atmtbsihuied er substituted with C S . sai.kyl:

wherein X is SorO;

cai oxya cy att noca wr - ^ a y M ai am Oc¾i oii b i^ a y, i-;,. ary

Qs.? cycioidkesyl 5-Ui inerflbered. heterocyeiyt QMO i8yl-C$.« aikyt QMO arybC>..r; gikertyk sryt- C ¾5 alkynyl C M cycIoalkybCu,; alkyl C M cyc!oa!kyl-C ¾ dfceayf, C M cycloalky!-C;,;, lkyriyl 5~H) membeted het rocydy!-C^ alkyl or -10 merabered heierocy i Sciirboij bC;.,; sikyl; witereki the aryl cyeioalkyl cydQaikenyl or-heterocycly) ring in * is umuhsn ' tuted or substituted iib 1-3 subsiiiBicHfeiadepesi siiti selected from Ci* alkyl, halo, Ci-s.haloalkyl hydroxy!. CM aikoxy, CM acyi C M alkyfsaSiorryl C M S alkoxyearbort l carboxy, 5-16 enibered heterocyc ' iyl, cyaao, amino, C.. i. aojmoalfcyi C . alkoxy-Cj.* alkyl C t .« hydroxyaikyi, C s .« haioaikox ; aSkyl- RR\

atsiaosuii nyl C^ alk U^nosa!fos i, r R'R !> C( 0) where R* is alkyl and is C t * aStyi, C u; aJkosy-C f .¾ afkyl, C s .«. atfriaoaikyi or C ; .« aik.yi.-C ; araiuoaikyK or where R A and ¾ logeiber with the nitrogen form ¾ 5 or 6 numbered heterocyclic ring onsabstitated or .substituted will! j.* alkyl; where R and R' is inde endentl H. C« alkyl. phenyl 5-W raefbbctedlietcrecyclyi, 5-10 tnetwhered he!eroeyeSyS-C<.. alkyl, C?.§ eyeloalkyl QMO ary ' i-C i aik CM eycSoa!ky!-C. M aikyi; where the , pheriyh C M cyeioalkyl arid 5- 10 membered hefCiOcyclyi rings are uttsubsututed or Su situte with sybstitaents in ependentl selected from C alkyl, ox , Ct* sikoxy, hydroxy, halo, Ci,§ haloaSky! syaito, or earboyy; or W and can together wiili the foria 540 snembercd heicrocyciy!;

where R is phenyl.5-10 membered heterocyci l 5- 10 estbered !seierocyeiyi-C 3 . fi alkyl, or C«.«. cyeioalkyl where the keierocyclyl, pherryL C cyeioalkyl and 5-10 aiembered heierecydyl .rings are «j.«»bst a† or substituted with i -3 sabstiiuertts. tadepeaderiSiy aeleeied from C t . ( ; alkyl. C« aSkoxy, bydoaxy, oxo, halo, C s .«. haioa!kyS. cyano, or carboxy aisd

whereiri R ft ts 5 s«et»bered..nitrogetv co.»¾dni:ng heieroeyc.iyl, 5 tnejitbered xygei cbntaming heSerocyciyl, 6 membei^d. nitrogen eoalaiaiag beieroeyeiyk 6 tHembered oxygen, contatiing

beterocyclyi, pheayi, bea¾yl, 9 !Hembered breyebe nittxsgea coafainkg heieroeyely] 10 membered bicychc oxygen co:atairtiitg lieiet'ocyclyi or 10 jRjcmbered bicycSie irtirogeo coniaitmtg lieletOGyclyi, whereta is unstibstoied or substiiated with ose or laore subsiitrseats tadepeodastiy selected frost Ct« alkyl cyaiso. halo, οχό, RO C t . s haSoalkyl C bydioxyatkyl sikoxy- alkyl Ci.« ifiko y !Sitot! b alkyl, C s alkcuy CM alkoxycarbo»yl, carboxy, cyeloa!ky), ^alkyl o tioiialiy sitbsiitoied 4-6 membereii heterocyclyi, lopiioitally s«bsiitatcd 4-6 fHeaibered nitrogen cmiainiag heterocyelylJearboMyi, R' SOj-, RE' SO . ^-, RSO or R¾^C-0}- where R* is VL or tVs a!kyi and R h is H, C T .« alkyh bydrosyaikyl C M aikoxy-C^ ;i aikyi, aodiioaikyi or C M aikyl-C).{. amiaoalkyt, or where R* and ¾> iogaitoer with the iirogen form a -6 jss fesred heterocyclic ring omubstftat d or substituted with G.* slkyi;

provided R 5 is not phenyl -or tert-b tyi wliesi 1 ' is 2-pyridyUfci.s, tfteiaoxyeitey or t ftttoroisetftyl and R s is

farther provided R* is not.4-imhyi-2-imidS2-oly)methyi kft R " h 2-pyridyftkio and R* is 2-ethy$-3- pyridyl,

lii another em odime t, R ! is metftyt, l, propyl, aftyJ, teri-botyS,

tRiii oxyethyl bydroxyetkyi, hydfoxyprop l 2,3-d¾ydro>i:ypropyS, 1,2-dihydfoxyprdpyl hydroxyeth xyeihy, BOC-aminoeskvl miaoeih>i, ¾dtox h8ij lt»8ftiyl, 3-hydroxyptenytothyi, 4-hydroxy-p.hs.a>¾fisikyI s phede!kyl morp oUo-4-yfcthyk 2-pyridyimeskyL S- pyndykridliyi, 4-pyr5dy'i:n«diyL

o>ediyS-natda^o!-4-ylme!:hyi, l-mediyi*s ida¾o : I-5-yioiei]iy!, 4-me iyi-nai a¾:0l-2-y!iBe!liyi, 5- fficd-yWmfd xol^- h Cthyi l,5-dirae!¾yipyt¾¾ol-4~y]i:ncdiyi.2-raethyhhi3¾3iyl-S-is etbyi 5-inethyl- isoxaz i-i-y aethyS. or pkeayi.

hi another embodiment, I. 5 is methyl or eth l.

in another em odiment, I s is nwvhyi

In aBoiker ^ϋκκΗκκαι. is raediexypropoxy, 2 ' f«etbpx ) :fo oxy, kydrexytihoxy.

hydroxyp-ropoxy, 2-hydroxypropQsy, i,2-dihydroxypropox.y, i-hydroxy-2-nsetiiylpmpoxy, 2- by roxybxitoxy, pheaoxy, 2 » Hseibyi-3- rid¥ioxy -o eia¾ io:iedi0sy, mefbOxycadJonylS ia bJiio, Irydxoxypropyiihio, 3,4- diii dr ybirrlto

(diH k laniimcarboii raedr b io, (3-hydimy-3-!Hethy!b»i i)d{io, (2-.hydroxy-2-ti5Sihyibuty ' i}hio > di uerometyiibio, (4-me^ylpipcr^.in-l-yiHarbo»yJmeihyltbio, 0ttofphoiin.-4- y csfbony iieibybhi , C i -ierr-buioxycarboriyl

(ie -alwdro-2H-pyraii-4~yi}metby!diio t i-{reinr¾ydm-2H:~py:rat 4~yI)eibyS.diio, (5- ethyl-2- o 8di¾zo] t}K!iiibyS.!kfO r 2-pyndylm£thykkio, 3,4-di!jydrosycyciopeitiyS.shio.4- IvydrcixycycSokexykh.io. cyeiope eoykSno, phen.ySilno. benzyithio, S-pyridyldiio, 2-cfeloro-4- pyridyl o. (4 « ptpendiayl-2-pyridy!)methylihk> > fi-m^h ! i T!dia- - K2-p>Tid l)a)e hjo, (ϊ- i -i }-bydrosyct¾ylpjpcridta-4-yi)- i -{2- pyndyfknetliySthio, I -{ i -me&>i i eridin-4-yO-I-^ ! .-(piperidii* -yi)- I 42-

isopropyicarbo(xyi)piperidii 4-ykkio, i-iiixeii50xycarboiiy5)pip 5idsa-4-y!tiko, i- fmeihox 0tb !ca^}5: l r eridii)* *yi( io 5 H;dim(^iyiaftinxocaJtoayl)pi)siidiH* -yh , !♦ f jtiethoxycarbojiy i}pspendiP~4-yh:hio, ( ί KS-ddomp duildut-l- ^piperidsi^- Ofiii , ( ' I -(2- pyrirakl!£iy!)pipcridijj--4-yl)s¾¾0:, i}-5-ckioropyi3¾n-2~y1)pii)cridra-4-yl)}¾io s l- ' sri- but x cajiKui .{}p ro}idin-3- iihjo, 3-methYliso¾a^oloi5,4-fejpy!:}di:n-4-YSfhio or tetrahydre-2M- pyr<m-4-y.lihio.

in aaother em odiment, R : is - OR\

In aaofiher efisbodimcfit, R J is me!isoxyprepoxy; 2-(mc:d:ioxy>prep»xY, Jiydxe.wethcjxy, I4w raxy -me£¾yj. r oxy, 2- hydroxyfeutoxy, p eiioxy, -niei !- -pyridylo v, ' 5-oxetanyhi)sth.oxy ,

hi another -embodtowjot, R* is - SR.".

In another etabodh¾ent, l¾ J is metijoxycarb isy!meibyliiMO, metlipxycsr ony ' ieth ltitio, meftios ptop li &^-meiboxy tJt-- no, bydroxypropyidiio, 3,4-dihydroxybuiylihsot, cavhoxysiayifhio, i ' rne^ B- 'd xy-?-$pe ¾¾{ !)t¾o, (2-hytoxy-2-x¾ethy.l^atyl)ifcto, d o romeih liisip, (4-metbylp}pef3¾«?- ϊ -yi} ar 0si inieti5vl!. 0, <mofpbolm-4-y i}carbo» bjuethy : Uhk>, ( i -l rt-buto caijon ! jpen m-4- yf)me¾ylr»50, i4-piperidia S)m«hy1ii¾so s ({etrahydi^2H > ra«-4-yl)metbylth.to , i -(ietrahydre.-2H- py.r¾s-4-yi)eih.yiihio, (5-nieiby!-2-oxadiazoi : yi)-nK!j:iyil5io f 2~py:ridy!me i¾!0, S,4~

dihydffixycycSopesiSylihio, 4-isydroxycycioiiesyliido, cydopeai&tjylthio, pheayiihio, beazyithio, 2- pyridyikfo, 2 aloav4-py*idylth:b > (4-pjperiditjyl-2-pyrid'l.;»)cihylihw !i ( ! -oietbyipjperidtR-4-y}-2-

i-sHeib icar oHyi)piperidiB- *yld¾io, Mfeft-i?ot xycarbd:ftyi)pip$Hditt* 4-y hto, < .1 -me{a salf0»yl) i er idja^y io, (i-iM> ro t«a^0ft l)pi½rMia-4- jio s

(n:ietboxyciii ' bofiy!)p!pendla-4-yiiblo ; l-(msih0 yetb !carbooy!}p^eridi5-4- i io, i- {dime{iyk»smocaxboayl)pipOTd{a-4-y{ihiP. i -(meaioxycai o»yI)p¾)ejid}»-4-yHbio, ( 1

cί.ilorόp rim!dy-2" i} i 1άiί - l)Si.iίo, (i-{2-pyri«)idmyi)piperidi)]-4-yI)ihio i . iH^ oropyrazin* 2-> )ptperidi«-4-yi)ihi<x i-ltm¾iOxy ar onY! : } nol!d«i- - Iibio, S-nieiii bsoxazofolS - jpyridla- 4-ykhio or ieifiiS)ydr«-2H-py!:;a-4-y!ibio.

aaotber embodiment, R # is cyaao, meth l, ethyl " propyl, isopropyl.2-methylpropyi, 2,2 ' dimetayipropyL I-meihy!biityl, trUlyaroaiethyl,.3,3,3- ixiiluoropropyt flnoromeihyi, finoropropyi, hydroxyniafityS, hydroxycsayl, ! -bydK>xy-2-»)c;ifeyietby] s 2-hydr0xy-2-med)ylsShyl, iiydroxyprepyi:. 2-¾ydroxYp:rapyL } -¾ydr»xy prop"2-yl. i ,2-dibydro^yp«>pyi hydrpxybmyl.2-hyd:raxyb«iy:!, 1,2- dihydrexybuiy, 2-hydroxy-2-«ietbyiba(y},2>2-{*hydroxy Kl¾yt^)wlyi. } -hydroxy ethoxy-2- bfOBJpe&yl, 2 hydr0 ;d:iOxy sesiiyl Sj draxyetl50x ) i'o i (medJOxymeiayl)ethyl, i - fiiethoxycd:ioxy « -t)vimoed:i l 2*by ro y»2->3Je lpe8iy! A 2¾dr«xy-2-iSi¾hyihexyi, 1,2- liilwdroxypeffiyl 2-be(izyl?xytniiyf, ' 2 « hydfOxyet¾oxyb " i¾yl, 2^ydR5s.y-2 ' --mc(h :tp( ¾>o i>tttyi x 2- bydroxy-2-tnel!iyipropoxypropyI, (ietmb dropy«a-4-y)-bydroxy5aeih.>4, 2«fi«mv2-mt¾aylbuiyL, HistJioxyaieiboxymed-iyl, laethoxynifeihy!, aKHhoxypropyi, nieth xyboiyl 4,5-dimeihoxypefJtyi metboxypeatyl, etlioxyeibeny!, e&ea J, propet.5-2»yl, propea-l-yi, prop-i-ea-2- l, 3-bydroxypap-

e¾z os tii wjiiei t)xypm efi- !-y i rox pR^oi . ea^loxypropeny., -ei oxye eriy -ffieiwteuifeayibvitcfiyJ, niei ylsalioKylatlyL ¾etbls«.tfoay ' lb«t-2-m-i-y:I, i .-d«x kki«trah 1r(^2H thM¾5ysai^ - left ^Leihoxyei L edioxycarfei>ayl :met&ylearbooyl {^isfraliydm-pyna l!ear iiis i, N-methy|.

boiOxycar OHylmstlxl.,

eihoxycarboBy!etfiyL !-by^roxye^l-!iieibosy ar os klsyi, me iamtaocar oa li»e I, jT byteiaoear oa ietb i, dimeth>¾m5aocarbo¾y ethy ' {, dki5srttyianriaoc:st%o»yip wi carboxyeSayi, carboxypropyl cyaabdayl cy ndpFpp l, 4,5-dibydroxypesiyi 4,5-diaydtoxypem-3- yi, ' hydroxybutyay.1, £¾ydrax ropya l e&yxiyl, 2 ydopopylvayi 2-hy droxyeiaoxybai- *yn ) « l 2-¾ d!Oxy-2-meth !p!¾p0x pF0p »yi beaxyk!xyprop-l-ya- j -yl bt .yibxyb«t- ! -yii-l-yi, b«!¾ So yet oxyprop- ! -yn- 1 -yl ! .-( , 5 -hydiXsxycyc!opcnty etliyny ! t 3-aicrti ί-3-oxetaa lethynyi, metltosybi!i.-) -ya-l-yl, meibosypeaSyn-i -yl eyelopeMyik!eaeajeibyi, a¾efhyis»lfo«ypi»pyl, i»eibyhu!ibnylb¾iyt pheayiethy benzyl, pfeeaylpr pyl, i c&ior&pbenylmeihyh L2-dihydiOxy-2- paeay!efbyl pbgnyletheayl l-paeaylviayl.. phcftycthysyj, pyrid-2-ytethy 2-chioropy id 5- yhae&y!, 2-£d):0xy-5-pyrtdylethyi, 2-£dxix -S-pynd ietti S5yl ½} m to h i- piperidyaneihy!, 4~aieibyl;pipcf'a¾a)-l-y!ineihyl 4-Boc-ptpeta«a- ί -ylmeihyl,.4-a*eiaylsulfisyi--

nKJrpiiob!i-4- ksie!fi i, d:Hon:toii3! sSiaoisiSili S , ( l,l- i doβϊ^ H^O ho.{iϊi ftϊe!by! > -ifietbyk3- oxetitay ieitiyl {teimbydro-ftir-2-yS}mei:byl, 2 > 5-dioxopyi«s!idtu- Ϊ -

Iiydroxyi»etbyl: elxabyd-r«|n ; ra8-3-y metbyL 2-!iydroxyHKtbyl-ielxabydr«pyra8-4-yto¾ctbyL 2- meiIi0xy.nieibyl-iebal.iydropyran-3-yi.mei yL 2^.ne5teymefbyl-feiTakydropyran"4-y!meibyi 3~(2,2- diaieibyi-L3-dtoxoSaft-4-yI)propyi, l.,3-dioxofea-4-propy.l L4-dioxaii-2-«iet¾yi }J- diosido½irshydro-2H-t jopys-aft-4-yii» ih.yl. I ^ioxd -i^Eah do^H^tCf Eaa^- lethy], fc5i3l:iydffi-2M-d)ictpy!¾a-4-ybi!eiby1 ; 6-oxa- { -axas trof . 3;jh.qi¾a-l-ylmeihyl.2-oxa-6- ii¾ssp!!-e 3. ibeps:iffi-6- it«edwL l^-di xaspiro^.S ' idecaa-T- lmeihyl, -be»2y1oxy~

cyclobaiylawlhyi 3-hydiOxycycobHiy¾5KiiiyS > 3-bydmxy-3--Diei:lsyi-cycSob 5y Beibyi.3-oxo-

hydrexyoseffcyi, cyciopeaiyteshyl }. bydrosycycopei«y{}iRcrhyi, }-it5iellioxycyciopeniyi)aiehyi, i-(aied5.oxyc t!o e:a b ; roiH0in i ] :i L cyclobesylmeiiiyl, 3-hydroxy yc!ohcxyfatt lhy, 4-hydroxy » cyc!oissxvimsiby?, or cycloSiexybiist yl,

ii j another e«bodte)cot 5 J is cyclopr pyS,

dioxycarbooyScyciopropyl 2 ¾ , dr xy- -aisthykliyl) yclopr py!, 2 ¾ydrosyi ' aediy!-cyciopTopyL cycksbuiyL 2-by£Sros:ycyclobi!tyl ! 2-oxo yd0b«iyl « 3 iydmxycye!i.)buSyL 3-be8zyk>xyeyefobmyL 3- beaxyioxy- 1 -hydrosye clbbuiy I 3'(2 iydroxy-2-met ykiJ:iyS} yc!ebwlyl, 3-hydroxyrasrtby!- cydobuiyi cyelopeffiyL 3- hydrexymeSS j ylcyciopeiityl X3-dihydfoxy« } ethylc ciopem l, 3-c¾fcoxy-c clppcs { yl, 4- hydrexymdfeyleyciopeniy], 4-bydrmycyclope?ayl, 3-hydroxycyclopeaSyl, 2~ ydroxycydopaityl 3- liyttiwxy-i-ifKtbyicydopeniyK 2-ox.o-eyelepeHiyb 3-oxo-cyc!opeiHyb 2-fN-eihyi-H- raethylaminocr onyi^yctopemyl, K^-e l- -jiK!{1^1amtois rt©»yl)c>¾iopeniyi 3-{N- i^piOpylaiHtoOcarboa ^cy l CKtyl, cydohexyt 44rydroxycyctc> exyl 3~byd y oxycydohexyl 3- ydi¾xy-3 n<sd:iy:l-cyc!obex:yi : 4jydTO y- -ioedi I !ob-e yi 3-oxO-cyc:SoI¾xy!, eydobeptyl yciope eayi, 3-byitrt ) xy-cydo eate»yL 4 ) df xyi¾eib R-«ie 1'C> ;fttea !, 4,4- bis(i:i dro «ie^y!!c c:0 es5i-2-a:!-i- > 3>oxo-cyc}opeittmyl,, 3-caf oxy>cycopeni-2-e»yl, 3- isopropy!amissocarbonyScyclopetw-S-eisyL ^-{byd!sx aielis i cIopeiil-l-es-l-yl, 4- iyd¾'osy¾¾etbyS)cydopei.ii- 1 -en- i -yl 4-(hydToxymei yI)cycIop;ii†:-2-eii:-i-y,L cyctohexetwl 4,4~ dlmeiSiyl-cycloliexesiyi, 4-iett-b«tyi yc hexe«yl, 4-h dmx c dohext¾ I i 5 j <iro >y ies«I-8isi-' i -yl, 4-hyiiiXixyi;ne!¾yl-cytlohi;x«;ftyi.4-(2-¾yd:roxy-2-methy cdiyi}cy¾lobi;xCfiyL 4- Ciidioxy eyelo¾exe:ny 4-ei¾.oxyc;»:boayl-cye3ti¾.ex<;!)y S.4-(a«;tldi»- i-yicarbftfi bcyciolifixeayL 4-{3- yano-azendin-l-ylcarboKyOcycloSKxenyl 4-(3-fliiOTO-szeidb^i-yIcarbanyi)cy

id-di0x¾spiro[4-.5]dec~?-ea~?-yi, or S , -die «s r8[ . |deesia-7-y!.

in another embodiHieni, 1 ? is 3-bydrsxy-3~ox<:iaijyi, 2-tetfahydro-ftuyl c(«{fey ro-£t«yl 5 .2~

dibydn:¾raa --yl > 5-dibyd«5teM-2-yU 2-&xopym>lidi*H-y.l. teirahydropyfiwi-4-yt, 2,2- dii«ed IieU" 'iyitropyf ' aE5- - l S > 5-din:iehy!tetrabyi!f¾pyriHi-2-yl 2,2,5,5-ί««¾»κ '!« ,3- dibydi>fisia«-3-yi„ -Sioro-t.etrab: drQ yKm- - l 4-fl 0fo-3- ydr«xy~t¾if8hydf>>yn{»- ' 5-yt ! .4-fJyom- 3*mediox -ieiia])ydio Ta«-3- 4-bydroxyieu ' abyttr pyfan-4-yt i dro ¾tra dr ij ffsa-3- S < 3- bydroxyietrabydropy¾n-4-yS, 3 > 4^5 droxytetiahydropy.nin-4-yi, 2-oxo*tetr¾bydropyr3a-4-yi seirdwdrepyra»~3-yL ieis:a1:iydfipyn»)-2-yi, ; 6-dihydrepyi:aa-4-yi T .3 ~ddiydropyns:i}~5-yL 5,6- dlb;ydi¾-2H-{jyr aa-3-yi , ,4-dihydii>-2H-pyi¾o~6-yl ,4-di!ryd:ro-2H-p raa-S-yi 6 s 6-d. «etby 1-3.b- dihydr0-2B~pyfa«~4~yl, 2,2-dimei¾.yl-3,6-d:t!wdiO ' -2H-pyf¾«-4-yl , d-2H-dilrydr»pyras-4-yi, i.,4-

i : ,4-diosa«.-2«y|, S-mdtesy-nwiftyi-i , -dio j sH-2-i i -iert-bu(ox: cai8>«y?-J ,2 J,6-teiia!¾ydropynd-4- yl } -methyl- { ^ ^-teix&h ro rid-^yi, l-nKdiys8«]fony!d.,23 > 6-icifdiydfopyrid-4-y!. i»

(di:i¾efliy!aH ] jftoc rb sayi)-L i i»eihosyca^dByl L2. H«¾aiydtopyrid- 4-yL :i-(sief!iyicar o«y!}-K2 ,b-t !raliy xopyrid-4-yi. i-methyi-pipendia-S^yl, l-tet- yiOx Ear oisyi-p!pei!.diH- » i, or l-(dHl»th i«ai^¾tb0ttyl)^i «ldii)- -yi

In another embodiment, R 3 is pheoyt 4-cMoro ho»yl, 3-metirySphersyl 4-meihylphenyl 2,4- diiftefhyipheayi, S-lrifl ' uorOme^ylphen 4-irffla<?r«sjeihyip siiy.l 4~sned " si>xy-3- triUuororaelhyipiieftyi,, 3-di!iviormaeti5y!*4-liooropbe«yI, metbyisal foayipaeayi, 4MaetbyJailfbayipaeay1, S^tbyJsttlfoaylp eayi, 4-

cya«ophcayi s 4 yaaop efiy1, 3-cju-bos.yph.coyl» 3-s8fhoxy-6- {Hefhosyphco l, 4-€ rboxyp!ia}yL 4-cyaiXs-3-«3«hoxypheiiyl, 3-cya»o-4-B¾sifeoxy{!t¾sayl J 3- tditn!hy aRiHwarboa l^j a i, 2<dimeth lanim «t¼siyij^heny i 4-

a^t!i UaoinQcar ofiyljphen l, -{N-h drox e : i¾^ 5-$|iethaxy*3* dlmefe!amiaocar ciii l feiiyL 3-ajethoxy-5-ethy{ajaiaoeai¾o»ylph8a > 2-iu iox. - - diinediylaininacai ' boftylpfe ft i, 6-nied30x - -dm3ed:iyianiit5(Csrbaftyl hes> ! > 3~i:ne¾hoxy-5- elh l!«»mQe¾tt8fl lpjieoyL S !vdmx -2- e i rcsp~2-yl~;am^^

d¾ydr xypi py{¾s»j»ocar oay:l-pi»y1, 3-(l-33ief:tdiaytelK)«yl}|iieBy) 5 3-(3-fl.«o-ro-aa«iidio-. { -

ylc<irbofty|} lieayi, 3-(3-iaethylstilfoayl-am!d{a-l-yicartoayl}p ayl s 344-

«i0rp!i lii:yic8i¾ia i i hc i, 3- -p roHdiii lc¾b05:yi} ^ei:yi, .^aiethQxy he i,.3-o:ieiioxypbef!yS, 3^ [Iiioro-6÷!5ieiS:iox eii ! ; 2-flwo«>-$-m<?taoxypaeayi,.2*meihox ^-a ' iirth iaH¾t»s«lfoHy piei ' 5 }, 2»

drn«oromet!iylp¾enyL 3-dii<iomn:Kd:5 i-4-IIuoTo hcayL 2~msiIioxyph£»yl, 2,4-diiaedjox phenyi, 3,4"dn.«edioxyplii3iyl or S-beazodksxoIyi.

Maamher erabo mieat, R is l-aie K3-pTa¾.oiyi. i-met.hyl-4-pyrx.zoyi, i t 5-di!.net¾yi-4- p ra l, 1 ^ S-irimeSiyl^- razoSyl, 3-HJS†.i3y]-4~pyra o!yS, -†nl¾iOfo--eil¾ -4- Tc5i:oI S > 3- 2 ; 2,2- iri.QuoradaylM«pyra¾o{yJ . I -Ci»:boxyxt3eihyl-4-pyi¾zo].yL I-ediox carbftftyla^ais M-p i oly 3- cycf.obtHyi-4-pyrf!zoiyi S.~cyciobuiyl-4~pyrazoh4 H ; -a^¾o i^1)cai¾M>a U&{hyi-4- ^a¾oi J > Ϊ- M-s«o^hoi.Hiyi>eihyi-4-pyrazoiyl ; |.-aydrosye{hyi-4-pyraxoi¾ i-bydroxy« l-5-pyra2elyl 5 1 - bydf xypropy!-S-pyrszolyl j-4 ): dim -: i3iefli ib i !}-S- ^ ra^oi: i. Ht»edipx i l:~4 ^ pyi-{ii:Cf] l, S-pynszoiyt l-aieih jVS-pyraxolyl , I J-diiiKshy!-S-pyrszoiyl, i-metby!-3-ifii]¾oroft!eiby5-5-pyi¾?ii!y! > 3MS6t laaiHiocaib « l- yr¾¾;oi » S-yl, :Ma»ib te»a j »ocarboayi-p r2iel'-5-yi i 3- «Je {sxi?.fo la»i«o )y{¾¾oi-.- J, 2*8}t¾B?¼ttlf©tt ¼ttH4^

yi 2-mgthoxycarbony kMes-5-yl 2-carbox. l-lbiea-S-yi, 2 N»«ieitey i¼4-N-

4? or 5-cy8»o-l-raetbylpyrrol-2-yL

In aiiothcr embodiment, R ! is 2-pyrkJyS, 3~py:ridyL 4-pyridyL 2-m<iiliyS-5~pyridyl.2-ms¾hyM- pyridyl 2-¾£ihyS-3-py:'idyt 3-tf!ef:hy!~5-pyf ' tdyl.3 -tr i ,0¾i ortsrsiet h 1- -py r id :i , 2-ttiRi }f«KSCi :l

!Ηόί1ίό χ ν-3-ρνικίνί, "H)edmy-3- yrkiyl2-n:iedi0sy- -p iidy 2>{3- xeiaiiy!;)Hiedioxy « 4-pyridyl 2- p-ox«tsayl}Oxy-4-pyridyi 5-M Qro-2*med>oxy- -pytWy!, 3-fhioo-4«pyi!.dy!, 2 » ikiCtro-5-pyiidyl.3 » iluOi-o-S- yridyi -medi0XY-4-pyridyl 2-£ihoxy-4-pyndyL 2-raetey-$-pyidyi, 2-{23- dihydfoxypjropoxyh5'pyridyl, 2 iydmxymeth xy-5i)yridyI, 2- ydfosyeihoxy-5-pyridyi, 2- l¾ydroxyef.boxy-4-py,ridyI, 5-i1i:!(3iO-2-hydToxyet¾oxy-4-pyridyl i 2-i.nstfjoxyeii¾oxy-5 ^ pyr!dyi, 2- hydiosyraediyl-S-pyridyi, S-wtte ^^ i^ l-sthox -S-pwd 2 s»propoxy-S~pyridyL 2- bydrox:y-2-iHed>y1propoxy-5-pyridyl 2«C : i ,1,14rif5«oroetboxy 5-py?idyU 2 yciop«>py!methGxy*S« py ridiiiy S, 2-iincf isulfonylpropoxy )-5-pyridyI , 2-mcdi isHifo«yia«5inee )<ix )- - r!d l 2- e{k)xypropas.y-4-pyj:idy] s 2-di:Sl«oroa¾fi^)^x -5-pYrtd:yS ! 2-itti<3!»~4-pyridyt 2-eh.!im-4-pyridyi : , 2~ cbiotQ-S-pyridyU 3-chIc*i:o-5-pyndyi..2-cya» -4-pyTidyL 2-cyan -S~pyndyL 2-mei oxy-3-cyaiJ0-5- pyridyl . , 2 yano-6-}BeihyM-pyn.dyI, 2-metboxy-6-»wihyl-S-pyridy?, 3~syas»-S-pyridyi 3-eya«e>~4- pyridyi, 2 » incih:ylattSf i!Y!--5-pyiidyi, 3'iimh lsui*¾yi~5~ yTkhjd.2M;H» soll¾6ylia«»tioH"f ' r i<i ^ 2-(ii«ida¾ol- ί -y pyrid 12-i»ei:oxyfsi!!:no¾«ei:hyi-4-py!id:yl, 2-oxo~ i ,2- diS:iyd!¾pyridiii-3-yl l-iaefhy!-2-οχο- 1 ,2-dihydiopyi1diif-S~yl I~Kiet!syi-2-ox - ! .l-dihydnspyrkim-^ yL r»ediy^2-0xo-I,2-di ydropyridiH-5- !, ί ¾oprop i- ^oxo- \ { 2*dihydropyridis*5-yi, 1» aydJ « ^2-o^o-^ ^ ?» rjdiB-5- i i iydfoxypi¾pyi-2-{>xo-i dibydiOp Jidia-5-yl., i- metbyl~2-oxe~ 1 ,2'di.bydixjpyrkb»-4~ I 2 iydmxypyrki- -yl, 2-bydroxyp nd-5-y 1, 2-ammocarbo«yl-

4- pyrsdyI, 24ne¾'l mi80ca o»yI- - nd > 3-tttcthylatni»ocarb »y1-5-py«dy.l, 2- !s ro I.aii]iiio sf[Ki.iY!-4 j rid L 3-di<¾ l8J.mnocartK>n i»5-p r yi, 2- raetby!sidfonyi.ei ySainin0carbQiiyl-4-pYridyi 2-raediy]sulibny!araiaoeiI.iy!aByn0csrbony^4-pvndyi>

3- meixyls«lt ylaminogtbyl¾m}»ocartoay 5-pyri<lyl, 2-metfeylsv foaybmiofitboxy-5-pyridyL 2- .hydroxyediylaiBi:nocsfbo«Y!-4-pyidyl.2 iydmxy¾hyiaraiao<:arf>ORyl-5-|>yr!dyS, 3- dmxyet^lamino rfjiin l-^ tid l 2-iiydmxyhtiiyiiiKi5:nocarbD«y!-4-pyridyL2- n:ied}oxyediyiamiJwcarboa l- --p ridyl i

i!:ii}da/o!y pyr!d-4-yi.

lo iuiot cr embodiment, R ' is 5 « pyrimkls:ityK 2-a«itao-5-pyrimldisyi 5 2-qy3ao-S-pyrtoadinyl

5- nieibiix -S-pyrfjidddsyi, 2~sth xy-5-pvs"i]iiidi:oyl T 2 « isQprop¾xy-S-pynmid(!wi.2-irii5¾oroeth xy-5- pyrii:i ) i:dii¾yl ^riiviOfQiiiefhyi-i rHBidHJ l, ri¾oroet yN4- iimkbftyi, 2-tri0ttOR>StKy1-$- pyriniidkyL 2^mK{h iaimnoc5u¼Byi r«i½dift-5-yl. pyr zia-2-y, pyrida2«*4- l

In anoiher em o ime t, R J is 3-bea¾o{hienyl, S-bsazoar S, 5-iadoly, 2-oxo- thydro-S- indolyi, ft-indcslyi, 2-oxf.i-d iy r -6-½do! ! : . Ί -aiedi l-I-oxo-ddi dxo-S-iiidi!iyi imkteo i,2- s ' jpyridm-Hi imida^op ,5-^yndio~6-yi, imidassjl ! -alpyridii -yS, imda¾o£ ! ,2~6f^yridia-<S-yi

pyrkta{32-¾] !. 5 4|il:da¾eii-7.yL beHioxazoS-S-yi, b<o oxazol-6-y i, }. , i-dio o-S.^bydf -lH- iK4]oxatbieph:!o(2 - |py!-idjii-8--yi U^kwido-a t *d m*2H^^^

4- o li !~5~oxo~3yiH^

rtdo{3,2 ' Sn:4Soxa«e iB-7- 1 > teazoxszob4-yL S-medi l esi o isxol-S- l, 2-edityIbeo20Kazo!~S- l

5- isopropylbeszoxazol-S-yS., 2-oso-2C3H}43eH¾o(d|oxa?:oi-5-yL , beHzoxszel-b-yi beiizoddazoS-5-yl, beHxodiazoS-b- l, 2-i«cdiylbesi.?;os:biazol-5-y!, 24s0piOpyibenzo[d]i iaxoi-6- i, l-med l-S- bePzisisdaiioSyi S-ktdazo!yl i ~meiJi kS½da I I, 6-b:ida2oIyl, ί -iiisihy S~iH»dazoiyL 2-meiIiyi-2H- indazoM-vi 7-azaiidoHi-yl 7-azakidoS-4-yL 1 ,S^ffie l-2.3-dlhydro-m- iTolo}2 -¾l «^»-5- YL 2 J-d!i dro-iM- YiTo]Os2,3^p ridln- -yl b a¾oisosazol-5-yt 3-:ffiei¾yibei).zi d]fS¾x¾zo!-5-yl.2- medi l-3-axe-bss20d]isoxa^ 2- a)ctbyio¾3zolo|S,4-fc|pyndsj]-5-y! s 2-a)cdiyfexszolof5 i 4-bjpyr¾d:iii-6-yS ! 2-iBe¾yi-3-o¾0-2,3-

ajpyrfdiB-i-yli irakteo 2-ajpyndin-8-yi t 2-o o~ < :t!ydxa-]H40¾d¾^

11 ,2,4 ' ]ίπ«¾ο1ο 1.S-ajpyridiB-T- i, 2di d?ox rae b ^2 bby ro^yW^ 3* ydrox mtli i-23 ^^ 6- imioUnyL 7-tjuittoimy.K 4- isoqoin«Iinyl 7-isoqai«o.ll»yl, L5-«apbtbyrid?a-3-yb 3~sietlwS-].H"pyrazol 3,4-b]pyt-idin-5-yS, I H- ργϊ:8 ζ οίί)[ .4~¾]ργΓΪ4ϊ β -4-νί 0f -mei. !-¾-pym^ ] e -^l ^¾"*-^- la an.oibe.r embo imen <! is ietra drof«i¾n.yl, telraiiydfopyrimyL 3,4-d8iydro-2H- pyfimo[33-cJpyridiryL chromaayl, bexshydraibro! ' 23-b]i¾sr L pipaidhiyl, pyridyi pymmlyl.

ielni o!ySp enyl umoHsyl, 1,2-dihydfoquiaolmyl, pyiTolidissyL benzyl.1 . ,2 s .3 5 4-iefrahydro «inob ' iiyi SA ' I^-tsirah ^foqmHQlia l, qia»oxal»iyS, quiijazotkiyb lH £idiixq)yL 2H ; ~ffidazoS:yi. koindmmyL i f 2 i 4|i):ia¾otof4 f 3-<ijpyi1dsiiyb iH-pyrazoio ,4-d]pyrimidinyUsoq«is¾itfty!. ?H-p>Ta*o!o - ¾- m:i &¾>f f S-aJpyndmyi, pyrcuiiazmyi, pyrazi yl,

Or cfciojsasjy I;

wherein R" is uosabstuirted or substituted with out m: more subsbaseals irsdepeHdemly sii!ecled imm ine iyl ethyl, cyano, eidoro, ftw©ro, meiks , trifki omdbyl, eib^xycarboayl teri- butOtxycarboayi, carboxy. ' -{m¾b l- a diox t^iy{)a!:»iBO ai¾oay ( ,N~ l~m«hyi ym;drey-4~ yi)car oayl or oxo.

fa aaote-e»*odioienC, R* is

Boc-pipei-kiis-4-yl, iiex<!Sxydro.fiif ![2,3-b].fi:if-3-yl. or 2,5-dioxo-pyrro!iidfa- .5 -y!.

{.« another embodiment, R ft is 2- yridyl, 3-pyndyi 4 » pyrkiyL 2-HKi y!-¾"pyridyl 2-a)eifey!-4- pyridy t 2-methyS-5-pyriiiyI : 2-fflethy!-6-pyr!dyi t 3-owl¾yl-4-pyxid>l 3- ein>d-5*pyri.dy5, 4-aiet!iyl-3- pyMy 2 s 4-dime8iyI-5-pyddyL 2 daaed:iyS--5- yridyl 4 dhii sy?-2-pyrsdyl 2,5< ime l-3-pyrfdyi, 2~efe!~3i>yridyL 3-£thy1~5~pyridyL 2-et yl- 6-metfeyi~3-pyridyi, 3 -eiS lyl- 6 - s iliyi - 5 -py rkSy 3 , 3-isopropyl-5-pyridyl 3-piOp-i-eii-i-yI-5-pyrid:yl 3- (i-i«<;ihy!eihsftyi 5--py:ri:dy] > 3-cyciop:r0pyl-S-pyridyi > 2-S)ydroxya !¾y|-3-pyrkSy! ; 3-hydroxyj¾eifeyJ- 5-pyridyt 3 2- ydrox e lV -p ndyU 2-(l-¾ydr©xy~; -txie isdiyi)-3--meiayS-5-pyridyl, 2- hydroxypropyl>5-pyri<Syi, 3-( ,2-dibydroxyetiiy!}-S-pyridyl 2-i:n.0uoiO!Bei!iyi-3-pytidyl, 2- mfittororaedsyM-pyddyL l-ii- fliiOiXiSBe hyi-S-p fidyi 3-¾«el:!iy]-2-irffIi(oro!«ethyI-S-pyiidyl - aKdiyl-3-!:dil!i !:oi»filhyl-fi-py:rf.dyl. S-iriilaOfOiaei yl-S-pyridyL -i r iil-aoremetiiy ΐ -5 - il ii.oro-6-pv rt d i ,

aydroxyethy]}-5-pyridyl 3-a)eShoxy~5-pynciyi 3-et!59sy-5-pyridyl s 2-a)cdiOxy-4-rae!:hyl-5-pyddyL 2- nieJtey-ii-e!iyi-S-pyddy!.2-c afte*5*py«dy?, 3~£ysn»»4-pyridyt 3-cyaao-5-pyridyS.2-cyin ) .0 " 5- «1f!uommeit!yI-3-pyddyf., 2 blo:r^3-pyddyi,.2-ciijou S-pyrtdyl 3-chio<xs-5-pyridyi s 4~coiore>-3- pyddyl, 3-chtoii3-4-eyaao~ -pyridyi, 2-rttK»:o « 5-pyridyl.3-fittOr©-5-pyridyl, 4- os¾-3-pyddyl 2- ctiiori -faedi i-3- yridyi, 2 *ro»X l-roetbyl-5-pyrktyl, I,4-dsaiedjyi-2-oxopyridia-5-yi > i,3- dimc S-2-ixopyridin-5-yL I -di 5 ihy!-6-o?v0 ridi8- -yS s !-meib i-2-o ci r iiJ-5-yL S-mef yl* S-0xopyrids»-4-yL l-eSiyl-2:-oxopyfldii5-S~Yl 4-eihyS-I-a5ediy!~2-oxopyidis:!-5-y1 > i-etbyi-2-meihyl-- ( i-oxop ' yridm-5-yI, -isopopy!-2~oxopyndia-5-yi t 1 ,2- im^h l-e-oxopyddia-S-yl,. I -saediyi-2- fd.fluQtBjet.h 1 *6-ox0pyrMin~4-yt 1 -B i ^ ^Mkonjtii;ih i « 2*o op rid».i-4- .U 2-{4*

RiotpholinyimediyI)-3-pyddy], 2-(t n-biiiyiam)tsocsirboayi)-4-pyTldyL 2-

meihosy Sieny ! -5-pyr idy S,

in anotbfer embodiment,. R" is 5-py«midinyl, 4 hlQro-5-m^hy.!-pyri!rnidiii-6-yi, 2,4-di.nietliyS- pyrknidin«6-yi.2-cya!iopynfMid!a--5-yi ; 2-!nf!iioroaK!ityi-pyriinidisvS-yI, : 4-ilporopyii!¾i<li:i5-2-yl 5- ¾or©pyamidt8-2-yi 4-idi]iforoffi ihyS ; -py:rio:iid!a-5--y! i 2-3 ea ' da icaAop ]-ij 3zt -5-y!, 2- diftietby!arajao arxs«yl-pyra2.io-5-y pyt¾df«aa-3-yi

iii eno&er embodiment, ' * is i x 3,S-»mis;8iyl » 4-pyi¾i:oyl > i-sthyi « 5-pyra2»i>1 t i -isopropyl-S- l-ethyl.-3-m©{¾o?yi8ef.hy}-5- pyra¾»iyl ί -:med5yl-3 ' dimc(hy¾ma^K^a¼w ^5^yf¾wl i \ -aicUiyi^-cycio i'O S-S-pyia ol S, 1- «thytewoI-2 « yi.

fa anpf&er smbodimeat, R* ' is phenyl 2,6--dm«t)TO IiS! S, 2-fiyon¾>teyi,

2A6-ttd]yorapbeayl 2 t 5-dil¼omphenyI, 2,3Hb uoTOphenyS ; 2,6-diil«oro-3-a'iei;hoxypasHyl, 2„4- djiuoto-3-meth sypb.enyI,.3-chio:rep-betiyh 2,6~dicMoroph£s !; 2,3-dkM0rophe¾yL 3-ch.loro-2~ ¾Ofopto l 5 3-c ]oro- -fl orophenyl. ( 2 S!ora-{! ]¾oro iieiiyl i 3 l:i]oTO-6-Sl»omp e!wS ! 2-f|« ro-5- iriftuatOincsfeyi iiea S-bydroxymetiiylphfinyt 3-liydroxyef:hylp ere l.. rhyd isymd yM- meihyiphcKyL 3-itte{¾osy|>Sscny! t 3- raethy!stil feaypheny 1, 2-fiuom-S- eibyisiiifoBylplieay!, S-ethylamjnos if nyW-iiuorop-heayl, 2- OttQro-S-ffieSityfcarb Ei l heHyl S-meih¾xyc.ai¼B3(i he» l 5 3-carboxyplit!»y, 2-Hiethy!-5-

d)Ioro-5-c^boxypheuyi, 2 ^^

aoiiaocarboityipheay!, 2-cyaiKjpteyl, 4-cyaftoptoyl, 2- aao»3>methylp.beu K 2-cy¾ae-$-

yaiKi-3,6-dii1uorcfpheayl y8tH-2,6*d!!¾i05¾pkeal > 2 ya»(W$-i]tt#roph<my ' !, 2-cyano-6~ chiorop eayl .I ' Chlof^- ano-fj-fiyom^i.sn J, 2-sy3» -64fi:ftusroa¾cihylEb.fi«y1 > 2-eya«o-5- i:ri¾omm¾!w!phaiyl 3^(iso m yi}a!iH:nocafbo:o !| heB L S-mesk !-i- |:(isopropyijansiaocirbO!iyl ' |plieiiyl, .4^mby]-3-{jso|>:r pyl)ai»iao afbonyi|phenyl, l-iaetbyl-S-fN- {metbylhH m«¾0x etbyl}8mi»cart>o«yl.pb«»yI« 2-«Ki!iyi--5~|( , -

2-il«ora-5 c c.k>bm ^^ 2*

ra diylcdsyllasidJiocar oay pbeayK 2-cb1oro~5-i{ I -| s »SindiayS}carboiiy!}p¾e:£iy 2-e oro-S-iV ' i .3-

fluoro-5-(( ! etfe ip ra^o - )8ffiifiocar o:8 ];^.bc;8 }- 2-fltK>m-5-{(l-}B iayipyfass)|-5-

netf3liydT0 ran~ - [m£d5 ¾ 2-f¾i ra-5-((i ,3 -dimeihyipyra^ l-*- :¾aiUiteca OHyS) te!yL 2-i1mvo yrid > 2-ytmeth l)amHi^a5t i ¾ beft i 5 2-0 or -5-<3- Huoroptp∞dM «yi))amino SJ^ayi)pbe»yI, 2-fiuoro-5-(!-B0c-3-il»or piperjdsi--4- 2-¾or«-5-( i- i)u roe&yi-pip<;r!di«-4-yi}t8a:SiBOcarb ay y]}}&miaoc5irboayl>ptoy.l li¾fo-5-{ i-metb>4pp^ 2,6-diHnoH- S^i-aisihyi i endm^- l)^ 2-¾ora-S pi eridiiv4- ¾ ^ ^^

5-{i*pyroidmykar c«iyl}p enyl 2 loro-5^1-ffiehylpyr¾i - - icrbonyi¾)h«nyi, 3-{2- befizjH5id «>Sy p¾e:?!yi 5 3-(2*i ediy!-l4eirazolyl}phaiyl 3~(2*i:nediyl-l > 2 i 4-oxadi:s¾ei-3-Yr)pbe(iyL 3 » ( -i«eihy!- \ ,2, - xadiazp!.S- teH i.

in auoSser eBi odsseai, ft* is S^uiao!iay 6^uis¾o-to -quiaolbwL ^uiaoUai 5 hlOi > d-qumoli&y!, 7«chfero- -quiBoUayU S^ oro^-qu ioimyl, 2-isediy!-4-<iuiao!ii!yi 3,6,7^- i.efra ydro idaolin-5-yK S,2 > :i4-iefrabydro i aoiiii-5--yL 6,6-dimeiaYi-5 > 6J,S eiK ;i drD{^.iia&I£i-5- L <ju azp¾ f, qidftaxaibi-5-yl, l-o;«-ssoi)idoIjn-4-y_, 1 -oxo-isomdofe-S-y, A-tfietSiyl-iH- iHdszoi-4- l2-meih i-2H Hda2o!- .yl l aed:i i- H-i a.¾(5l-5-yL i -dHa&diyi-!H.sidaz<ji-4-yi, ^4¾ria o!;4 a|pyddm-8-yl Mmhyl-2-oxo- ! d dfoq«}no.H«-6-y!, 4~mciby ί-2-ο χ ο- 4,2- d!¾ydroq(.isao]i:t¾-f-yi, S-chloro-!-meihyl^ !xo-l^-di& dro tjjioHs^'!, L4-dimed:5yt-2~oxo-l,2-

i<4H)-yi > 2-iseilry!-S -0X0- ! ,2~d ¾ droi soq w SK oi:n -f 5~ l, .V-diiltsoro-l ,:4-dimediyl-2rOtJ?o-l.,2- dihydroq«j«olHi-6-y

isoquii-otinyl, l- -Π«ΟΓΟ-Ι· mediy!-iH-pyra¾:o! i3,4-bipyndia-3-yL lH« ymzoloPAd| >TiMidm- « i, btudexafl ,2-ajpyridin-?- yl imittexoi

b]pyndift~6-y l^ieih i-

Anoiaer aspect o.f ¾e current invention re-Sates to compounds having the genera! stnjenire of Formula iV,-.

wherda B; is C S . S afkyl, (¾.* alkeovJ, CM aaioalkyi, C,.$ a&oxy, C { « bydroxyalfcyl. C 5 .. s isminaai.kyL Ci-« altec -C^ sikyl C t . f> hydrex »lkaxy-C w ; alkyid. A aI.koxycarbasylamiao-C:;.. fi <dky] s <¾. i8 aryi C*.»* aryi-Cs-e aiky!, 5- ! 0 racmbered feeteraeycly! or 5-SO num ered fceterocycIyl-Ci. 6 aikyl, wherein the a∑yl aeierecyely.1 ring is tmsnhstltuted or substhutiid with one or two suhsiHusais inde endentl selected from Q.« alky ] , hydroxy, oao or halo;

wherein 5 is ~X-R\ cya«o. CM haloalkyl C¾.« eyanoalkyi C< .& aikaxyearboftyi, C s . ¾ alkykafbonyi 4-10 ajembcfedbeten yelylcar ony!l, iniiiocarbonyl, alkylatninocarbouyi,€;. < < alkyny CW kyaroxyalkyb CM hydroxys! kenyi Cj.« bydroxyaltayl, C5 alkoxy-C^ alkyl a!koxy-C^ a!kosy- Wi aikyl C f , % alfcoxy-Cw a!koxy-C , a!oaB lCi-s akoxy-Cj,:, ateyl, Cs^ alkoxy-Cj-s alkyoyl ¾.* aiaikoxy-C;.<; alkyl, ¾yd»x *C:.s akoxy-Ct.* alkyi I dfo -C^ &lkoxy-C 3 kaloaikyi i ar»lkoxy-C : .>,,; alkynyl ydim - ^; alkosy-C^ alkynyl C (; , M aryloxy-C),;, alkyi t **, myioxy-C ( , atke«yl Gw* stTytoxy«C ¾ * aikysryl€;.« aikoxyearborty½, < ; alkyl, C«s carboxyalkyi, alkoxycafbony . ' x^ bydsmyaikyi ami«oca ai i-C;.,ii alkyi d->i aikylaminocarbctwkCj.i alkyi C,,-; aik lsySlbn kCj.. alkyi, C,. fi aikylsalibtiykCj.* alfceayi C i:<; alky!srdiboybCj.,; aikysyi, C*. T0 aryi C s . 6 ycloalkyk ί , ; cycloafeiiyi, 4 1 inerahered heisrocyeiyi, Q..io aryf-C } .« alkyl, aryl-C 2 . f ; alkenyi CM* aryl-C 2 .<; alkysyJ, CM. cyeSoalkyl-C;.,, alkyi C 5 .g eyeteaiky!- t 5 ,« IvydmxyaikyL cyeioalkybC^ alkeayi cycloalkybCj., alkynyl, 4-10 membered hel¾rocyciyi-C. s .« alkyl, 4- 1 menibered Steter0cyeiyl-C?.<; alkenyi, 4-10 membered heteroeyclyl-Cj.* alkynyl, or 4-10 nxanbered fceteroc cykarhonyl-C M S alkyi; yyhereto the aryl, syeloalkyl cycioalfcenyi 01 belet&cyclyl ring in 1C is aosybsinaled ¾r substituted with 1-3 su stituents independently selected froitt C s .« alkyi halo, oxo, RC C { .* aioalfcyl, C K; aJkyisu!foBy!araiao- aikoxy, C;.<; ialoalkoxy, !iydraxy-Cj,s aikoxy, % 4 alkoxy-C ^ aikoxy, C * alkylsalfony b C f .s aikoxy, Cw acyi alkykullbn i C 5 ,<. -alkoxycaAoiryi carboxy, 5-10 nwmbefed ' h«leioeyclyl, 5*Ϊ0 atembefcd he roc d l-Cs^ alkyi, cycloalkyk C yloalkyl-C^ alkyl, araitic?, aminosulfeuyl, Ci.cj a!kyiaabfiosriiioayl C** alkylsu!lon laraiao, cyaao, -carbox , R * N«C S . & alkyi, alkoxy-C^

alkyls«lfo3iyS.a!«ltio- Ct* aikyl, C f . s ajalnoalkyl or C;. ; , ik i-Ci.* amitJoalkyi or where R s aad R ¾ iogeiber wit!t rise niimg is fbnrt a 5-6 membered beferocyeiic riag sios bslifttled or sabstkoted ith C ( . ή alkyl;

wherein X Is S or O;

wherein It' is C s .. s alkyi C;. ;> kydroxyaikyl, C1 baioalkyl, Cj,s hydrox alkyayl, C(.« aikoxy- C;.s alkyl Cs,« aikoxy-C^ aJkeayi Cj, s aikax - s^ alkynyl, C. i4 lkiixycafbooyl-Ci.,, alkyi, carfeoxyalky!, 8tnifi0carbo:«yI-C ( . $ alkyi. C M i alk laioinocar oftyS- ;^ alkyl, &,. . aryi C^ 7 eyeloalkyl, C.y yeloaikcnyi 5-10 Jiieinbered heierecyciyl, *,& at bCi.s alkyl, Cs.- ;i! aryl-C^ aikenyl, C^ ®yl- alkynyl atowi, CL S c cS0aSkyI-C: M; alkynyl -½ .unentered aeterocyclyl-Ci.« alkyl or 5- 10 menrbered beterocye!yicarbo ylC;.,; aikyil; witsieia ite aryl, cycloalkyi cyc!ealkeay! or heteocyclyl ring sn W is uasubstt ' iuted or s bsbiaied with 1-3 sobsbtiieiils tids ' endeJUiy selec-led from alk i hale, C kilpaikyi hydfbxyi C :I .5 alfcoxy, C acyl C;.s alkylstrSidoyi C % * alkoxycarboayl carboxy, 5-16 inesihered beteroeyclvi cyaao, amlao, C ; . s .ami$iealfcyl, C|.* aikoxy-C;^ aikyi Ci* hydro&ya j kyi, C. wi liiik>al.fe>xy, i alkyl-NRR\

amwosttUbuy!,€< aikykm ostsifoayi, R¾¾CH)) where I s Is C w attd R Si is C* alkyl C;.s alkoxy-Ci.* alkyi C 5 . <; ««tau>alkyl or€:.,; alkyi-C;.* atninoalkyl or where IT and R fe together wit the nitrogen form a 5 or 6 raexbhered heterocyclic r rg unsubstimted or substituted with Cj. 6 alkyi, where S- and R' is independently H, aikyi, phenyl, 5- i 0 memhered he eroeyelyl, 5- ! 0 oieaAered heterocyclylC^ alkyl Cj,« cydoalkyi, C«,<$ aryUC^ alkyi, C,,s eycloa!ky ^ alkyi; \v1¾»e she t phenyl Cs-s eydoaikyi and 5-K ) roembered. heieiocydyi rings are XBlsubStifated Oi substituted wtfit I -3 subsiifttems i»depe»d«at!y selected from aikyi, oxo, C-. , atey, hydrox , halo. CM haloa!kyi cyane, or carboxy; or R * and ft COB together witb the K ibrm 5- 10 raernbered heterocydyi;

where R 1 is phenyl, 5-10 e bered hsiemeydyL 5- lb nieinbersd ieteroeydyi-Cs.i. aikyi, or C cycloaikyl ¾v>here the heterocyciyi phenyl, C :; , < ; cydoalkyi and 5-H> um ered heteroc eiyl t ngs are ttosubsb ' tuted or substituted with 1-3 suhstkuents iadepeaden ly selected from C ( . f , alkyl C s .s alkoxy, hydroxy, oso, halo. Cs .≤ habaikyl eyanes, or earbexy; and

wherein R- is 5 nu be ed anrogea containin heterocyclyl, 5 numbered■ xygen eoaiairatrg heterocydyi, 6 numbe ed aitrogea containing heterocydyi, 6 atetobered oxygen eoatiaaiag lieterocyttiyi, pheayl, benzyl 9 tnembersd bicyclic nitrogen coatamktg cierse eiyl 10 roembered bicyclic oxygeri containing heterocydyi or JO riiembered bicydie aitrogea containiag heterocydyi, ijereits R <! is OKSK stittited of substituted with one or -more substittieftts independently selected from C G aikyi, Cyano, halo, oxo, RO-, C»« haioatkyi, Cs-s h droxyaikyl, aikyi, C» alii xycarbosyl- Ci,§ aifeyl CM aiketryl ,6 alkoxycattooyl cartoxy. CM cycloaikyl, R* -alkyl, optionally substituted 4-6 m hbered beterocyc , [optionally substituted 4-6 raerabered. tntrogen cowaming hfeteroeyciyllc.arboriyl RR " MSi¾ -, R " S0 2 -, RSO ; or R s R ! 'KC(- : 0)- where s is H, or C; . 4 alkyi aad R b is Ή, C alkyl, Q Iiydroxyalkyi C f ^ aSliosy-C; .¾ aikyi, C M ammoalky.1 or C aikyI-€), 6 amuioaikyi or wfere R s aiid R h together with the nitrogen form a 4-6 Htembsred heterocyclk ring nmubsdttrted or subsiiitried with Q.* aikyi;

provided whe R 3 is l-aielhyi- iH-pyraaol.-4-yl, .»nd R ! is methyl, then R. $ is sot i-e!hy.l M-pyj¾¾ol-

5-yi;

furdrar provided %vhea R 5 is ! -ojetbyl- ' i H-pyra¾ l-S-yl, aud R* is methyl t¾ea R s is «oi .2-snethyl-l - or

ί ^-diraetbyl^-oxo- ' l ,2-dihydroqui«olis-6-yl.

iii -anoiber eriibodimeot, R ! is metiwi, ethyl ro yl sliyl terf-butyl triihioro-etiryi, nteihoxjy (sethoxyetirvl hydroxye&y), Uydroxypropyl, l^- ihydroxypropy ' l, 1,2-diirydiOxy ropyi,

Irydroxyethoxyethy , OC-airfiiioethyl amirtoeshyl, 2-hy.droxy'phenyhae l y 3-liydroxyp¾ertyh ethyi ; 4-hydroxy-pSi.ei;yltrrel!syi, 4-fi orophettyteethyl, phenelkyi, jBorpboUn-4-y ' leiir l 2-pyridyhJ5emyi, 3- pyridyiiTiet!ryl -pyridyhnefiy.l, o-methyi-2-oxo- i ,2-dihy ' dropyridiaylmethyl, imida*0 ' i-5-yto.te$*y5, 1 - me yl-«.nj0¾zol-4-yime$}.ty.i, l-methyl-aaidaeb!rS-ylmethyl, -!3 eiityi-i»Mda < iol-2-yit»elkyi, 5- raet!iYl-i:niidii¾ol-2-yiine!liyL I J-dim&diyipym:£ i.-4-yimediyL 2-me iyfilik¾o -5-mfit¾yi S-methyl- isoxaxok ylsneihyi or phenyl.

in. another embodiment, ¾ is methyl or edsyi

in another efiibo im.ciiC R ! is selhyt

f.n another embodiment, R ' is raethoxyprajoxy, 2 « {ffieihoxy)propoxy, hydrosvetheixy, hydroxypropoxy, 2^ydroxypropoxy : 1 ,2<jihydxo ypropoxy. i -ivydiox -S-Bfl-thyipiopoxy,.2- Mdrox butox , pheaoxy, 2~meihy pytidytexy,,

moiiioxycarboay!eibyliliio, methoxypropy : hio, 4-nMk)xybur-2-y iiao, aydroxypropy liao, 3 ,4- dl¾ydroxybuiyi0ao, carboxyeiiiyitlHO, (isieUi lamiHoc r oayliiBei!sySiiiio,

(dimeili iairi nocarboisy meth iiiso, (3-liydr»xy-3-meihySb«iyI !.hio, (2-iiydsmy-2-n:seiliiy!biny!)iivf0, di i3omi.ns1¾yliiiio, ( -raei.b Ipipsr3¾s-i-y!)-^^

3l!ydm-2H-pyraft-4-y!)«J:iySli!io, (S-iHetbyl-2- 3 < 4-dihyd}-oxycycfopei«ylthi.o, - S:¾ydmxycycSoSiexylii»o, cyelopea&nyit o, piietiylthio, benzylfiho, 2~pyrid lsisio, 2-chioro- - pytidyidsiiX (4-piperidifiy1-2-pyfidyI)it>ed:¾y!i!!ie ; (i-sived) ! pefidift-4-yI-2- rfd ftn ;di !d)i:o i h xlrox ethes i ipeiidm^^ 3:-{J-hydi'oxyediyipipei:idii!-4-yI)-i-{2--

py y!jnietby P s, ( -ppe .«iy t o., (If-sopropyOppefi iH^-yts ), ( saei y!carboay)p e a*- 4~ybhio, J - tes^ a x eaxbefiyOpipsridai^-yiddo, (l-methyis«ifoftyl}pip«rid.«)i>4»y!ihjo, ! * is .i¾p i ¾¾oHyl;)pipeif iki- -yM«o« i^ajeiteyar oay} .lp ridto- - iiijo, 1- (n:ictboxyed Icarboiiynpiperidia-4-yi!lHo. Hdimeth laaimoc¾bo»y5) ipe t3m^-yi8MQ, 1- Ciaeiftoxyc&rbe«yi)i>!peridi«-4-ylthio, (M5 !d0fop rimfdi -2-yi) i m

pyrimidinyi.}pipefi.dm-4-yI)thlo, (i -(5- hiorx>pyraxm~2-yi)piperidm-4- !)thio, .1 -f tert- b«ioxycarbonyl)pym>Mdi&-3- iio., 3-med 1ls(xf! J ¾Io|5.4-b|pyddj«-4-yIibio or ietrabydra-2H- pynm-4-yMiio.

in. another embodiment R : is ~ Q.R*.

in another embodunem, R" is raethoxypropoxy, 2- :nei¾oxy}propaxy, .hydmxyethoxy, hydmxypropoxy, 2-hydroypropoxy.3 -dihydroxypropoxy, i-hydrosy^2-Jsei|iyipr<¾>os.y, 2- hydroxybisioxy, pnenoxy, 2-mci i-S-pyridyioxy, 3~»xeiasySmeihoxy .

in nother embodiment R 3 is - SR '5 .

in -another embodixbcftt, R ,! is a iw ear^alsaeth W o. metlioxyearboaylethy!t!ao, aefhoxy TOpyKhto^-imho ybttt-i-yiflnOj ¾yd!¾xypfopylthio, 3,4-di!: ( ydiOxybxrtyitbio, • aboxyei ylt o, {methylsmiao arboa i^ei it io, (ditaethyJsmiaocatboayijiaeiiiyithio, 0- i5ydmxy-3-me{hyib lyi]tl)io ; (2-bydmsy-2-n ' ieiS5ylba{yi)tiiio > dillaominetiwiilao, {4-rae!jw!pipera m- l-yil-s-arb swSffifi&ylthio, (nioi ho1ia-4-y[}ca*OHyimediykbio, ri-ie«¾uo c3i¾OH l pipsrsdia-4- yl)i.aediy! ao, (4-piperidiiiy!}a:i£ibyite i.-(!:eira¾ydro-2H- 3,4- dihydroxycydopemylihio, 4-¾ydmxycyetohex.yfihio s cyciopeMtayatHO, phcayM o,

pyridyblbo, 2-cii!os¾-4-pysidyii:iio,

pyndyl}mGt:hyithio, ½< { roxyeJhai i i^r } iHi-4-y!-2-pyrid>)ffied. lihk{ > 1-(ϊ- h ox eih l i<ni m^ l-(l-i¾ietl\yIpiperidiH-4 « yI)--i-{2~

pyrkiy!lpwhy!iSiio, {^p5perkiaj- - !)-i-2-pridyi}r«iehy¾h}0 > (4*pip;ridmyi¾thi© f ( \ - sopi pylppi;tk1i^4-ySthii. -mctby -tWfi Opiijerkia^ylfhio, '{ "{te -{Hrtoxy€3rbo» i) i erid:tt- 4-νΙιΜό, ( -H liyisulfoayl^ipeRdia-^yli te, ( i ~!a0pmpy!csrboftyl|3iperidia-4~y!diio, 1 - <meikx>¾aiboa l)pipertdm^-yiftiio, H5∞te et !c¾tk5« I)pi^ridiu^y iu , I- (djme%amin csi%oa )p.i e5id¾« - H.Kio, 1 -fme¾0syc< boijy! ip«ridt¾i-4-ySih}o, ( } · 5-

4-yii kt or !dmbydro-2B~pyran-4-yltbi0.

ia fsaot ei: smbodiitteaU l: s is cy¾:fi£>. meihyl, «t¾yr propyl, isopropyl 2~meS yip:ropyS ; 2,2 ' dimethylpropt ; 2-niethyibdtyI, trifiis ronieiiiyl, 3,3,3- trMkoropfopyL ilaoroiBethyl, iHiofopropyl b droxymesbyL hydroxyeilryl l iyxfcoxy-2-me |od:iyi, 2- ydrosy-2-a¾e 1e l s hydimypropyl, 2- ydmsyprogyi, i !:ydraxyprop--2-yl, I ^-dibydfosypr pyl, hydroxybiity!- 2-hy<h¾xykiiyl, J ,2- dihydroxybu.ty.1, 2-hydroxy-2-B*ss 1kky.l, 2,2-(di!rydroxysi!etbyS.¾i)tyi : . l-ii dfoxyeiaoxy-2- btemoetbyf, 2-(hydiOxyef es;y)ethyi.2-S:iydi'03cye!¾oxy}propyL (nipdio s eihyljeib l I- ni¾ilioxyel:hoxy-2»bro«ioefbyb 24jyd:i¾xy-2-njeiby!pe«iyl, 2-!5ydrox -2 ).e! S ¾yi., 1 ,2* dihydioxypemyL 2- hydr0xy-2- ediyipf0poxypropy 2 !aoro-2-mediyfbuiyL iBetaoxyaieth»xymediyl, meikixy eSlivl ethoxyp-ropyi,, fnedtoxybaty ' i, 4,5-dlmsi:hoxypefttyl inetiioxypeatyl, edioxyetheayl, etaeayi, propen-2-yS, propai-l-yL prop- i -ea-2-νί, 3-bydroxyps¾p- i - e»-2-yl, feydroxy-2-metbylpfopeayi, batenyt, 3 s 3-dim¾ i Mm-I-y 2- bea?ylo y ier! L$i^d)Qsyproperi-S- l, hydroxypropenyl, ' bea^y xypropenvi 2-eUwxysttoyt, 2- met Ssiiiibiiyibiiten l. a {ayisHifoayMlyl,K}ethls»lfoay!kH-»2-ea-I-yi i -diox$dot¾tohydro » 2H-thiopyrai 4- y]c ei i.ed)0xy¾byi, dlioxycas:bo«yi i5ie!ii icsi¾ft L (4-ief^lsydro-symny{jcarkwyL N-ssediyl- N^medio dlt l)^ tort- butoxycaf oayhaethyi. !-hydroxy-l^al-bftoxycarboaylraethyl, etboxycarboftyipropyl, et ox ciii ' ci ylesiiv:, i«feydr xyeeiy!-ffieiboxyc.ar¾onyietliyl, iaeih laJniHOCarbonyljaeihyl, ttKitkykttsiaetcar oa l-etfeyl, d :p d:i aa»ficsesfhoit ! di L diaieh jatmaQcastoayl ra ls caitoxyet l carboxypmpyL eyaitoPtbyl, c aswpropyi, 4 -dibydroxype!Kyt 4,5-dibydroxypem-3- yl, Irdroxybutyayl, bydroxypfopynyi, eft*yayl,.2 yclopropyh½y!, 2-bydroxyethoxybut~l -yji-l-yi 2 iy wx -2-jaeiby1 mpo beBxyioxy ui-i-yH-l-yl bet yfoxyet oxyprop* I «ya« 1 - 11 -{ S - ydmxye c!opem I)e†b »yl -aieth b-3 -oxeteo letbyjiy I,

niei yisuifbnylbi iyi. s pheoyiefhyl benzyl, phsfcyjprofsyl, 3-dil.orophenylmethyl, h2-dibydmxy-2~ pbeoyiei yi. jsheaylefiiesyl, l-pbcftylviiiy!, pta iethyayl pydd-2- haef:by} » 2-chiompyrid-5- y :nchyi, 2-e{¾osy-5-pyrkiVkihyi, 2-edmxy-5«pyrkiyled}:ynyt -pipcridy is«cihyK 5 - piperi y!aietbyi.4-ftietliyipiperazffi » 1 -ylmethyi, 4-B *pipera2to-l-yk«ie{hyi, 4-meshylsal osyl- piperawa- ! -yimeiby 4-a)¾hyicaxbonyi-pl era¾s)!- i -ylmethy!, iKOi hoi«B- -y ' Uae:ihy!, 3 « xnei y1- KH>fpaoI¾i-4-yimetfeyi, tl«omor{¾toSi«omeiiiy1. } {i 5 l -dtox}dotlijooiiOipihoki o}meib 3-meihyK3- ox ailytethyi (teir;ui rd4^ - ^ ij-dioxopyrrolsdiii-i- yietayi, 2- hYdroxymed " iyi-iein:d> dro ra«-3~y1mediyi, 2-]ydrox ms i ke£^ 2- H3eiliosYmeihyS~ rah drop r<m-5- im€diyL -^tte pie^d^etr^b dx yTajj^- iKieth l, -(2,2- dime l- 3Kl50X0i;m- -y!}prepyl 1 t 3-diox ias-4.pf pyL i s 4-dlosaP-2-oie L Li - dioxk1oietrabydro-2H4-iiopyxan-4-y}mciiy$, 1 , i-diaf do^etra¾ydfo-2H-thiopyr3a- ~yfcihyl, !eirai^ydro-2M-il!iop rai^ -ylm£th 5-oK.a -a2iisp!ro3 ]1:repiaft4-yS.nieiliy! : , 2~ost-6- azas ira3,3!h^5fi:n-6-yIi:nei!iyi, L4-diftxas|)iro[ : decan-?-yim l:¾yt 3¾Rzy.k>xy- cycte ofylfMethYlj -feydtasycyciobH.tyiatetb.yi, .Vi>ydrosy-iM«et¾yi- yciobtJtyimelhyl, 3-ox.o- eyddnrtytaeibyi, ^a mx -SHiii!luer©^ 34i dr0s -¾-R:!eb !-c ¾So !.d !- bydroxymethyt ycfopatt imethy), i -{ ydroxycycfopei«yS)s«e!:hYl, 3 -(me{ oxy yciopcatyl)oset¾yl 5 l-(mei&osyeycl)p!»lyJ)b})a>calfiihyl. { cyclohexyb:nei yl, 3 i drox -i;ycl:0¾e yiRieh i, 4-hydroxy- cyc!ibexyhns!lsyL or cydobsxyixaedfyS.

Is another aaibodiaiem, R 3 is cydep¾pyl iHett½U ycay H }4 -cyddptopyl, 2 - edioxyearbonyScydopropyL 2 2-bydroxy-2 ^ nie8iyiethy] cyelopropyI > 2-hydroxymei¾yi-cye!opropyi

cydobuiy!, 3^th0xycarbQJiyi-I-hyimxy-cyclobu(yl, 3-eib0xyc;¾rboByl-cyclobi!iyi, cyc!opentyi 3- hydroxy diiiylcydopeniy], 3 -d)h dro.x njea)ylcyelppent l A 3-c!K¾oxy-cycl perayi, 4- .hydroxyii5S jyicycl>p¾ilyl, 4-:tydfixycycS!pesiyS, A-hydroxycyclopeasyb 24iydtt>xyeydopeaiy;, ,V

i»p^y¾t!8iss carboHyi)c d pe t i, cydohexyt 4-bydr»s:ycycte¾exy} > 3-hy4rixycydehssyl, 3- cydoaepiyl, cyc!opejjisny 3 i d y<yd0 emaiyl, 4 ) d(wy3:oeO i i-4-a:teth i>c cSo ef!i:eay!.4,4- i¾; dro>,ymet yl)<ydo ettt":2-e8-i-i S-oxe-cydopeateayi, 3-c8i:box yciop »i-2.cfi f, 3-

(!iydroxyBietbyl)cyclopeat- S -en- 1 -yS, 4-(bydresy«iediy!}cycSox:irt-2-eii-I-yi, cydofeexesyi 4,4- disnd l-cyelpiiexes L 4-t¾it-b¾iyi-cydohexesyJ, 4-hydroxycyctobsxeay 1.5-Si dxox yelaiisx- 1 -SH- Ϊ -yl 4-hydr0xy0leiiiyt-CYc!obexe«yS ; 4- -bydroxy-2-«isdiye8iyi}cyc!obexenyL 4-

5? 4-;3- a-7-y? ! ox ! ,4-di ¾}s iiO| . Jdccai!-?--yi.

f.« another embodiment, .R " is 3-hydroxyy-exeiimyi 24etrahydr0*-fUry!, 3«tetrahydm-f«ryi 5 2-

hydroxyn¾ei JHstra yd{)-fui- -yl, 2Ai-diHJs iy!-2,5-dib dTOfs!ia -3- l 2 S 3- dibydi¾1¾iaii-3-yl 4 d dmfur&a-2~yl, 2-oxopyrfo!idiu-i-yL te iydro rm^-yi, 2 ,2- dii« iyltei:aiiydiep }¾ri-4- l,

di ydf»fltrs¾-3-yl , 4-iluoro-½indiydix>pyraa-4-yI i 4-l1«8iO-3-S;iydroxy-ietraI')yd!Op n : !ii-3-- i ( 4-iluoro- 3-

I.5ydr¾syieiahydiopyra»~4-yi 3/-dibydimyieraIjydiopyfa-»-4-yl« 2-OKO'ieia ydjopyran-4--yS t tettahydropytan-S-yl,. iwa¾ydropyt3S-2-yI.3,f>-dihydropyraiv4-yi..3.6-<ii ydropyra»-S-yl 5,6- d!i:iydro-2H-pyi¾n-3-yi , 3 T .4-d]hydf¾-2M-pyr8i:i-f)-y! T .3 + 4-dl ydro-2H-pynin-5-yL. ^.S-dimfiih i-S^- dihydro-IH-pyran^-yi, 2 J-di!ieilsy]-3 i 6-dihydro--2H--pYran-4-yS..3 < 4-ifi-dhydmpymn.-4-yI, i A- di©xas>iro( ' 4.51dec-7-ea -yl, l,l.-dtoxo-isorhiazoHdi«-2-y] 5 :! :i ]-dioyidoieirabYd:ro-2!l l:dopyfa«-4-yl i ' ,4-doxin 2-y

I- (4«iJ«byiam« «rb«iy * 2 > 3 > 6-tetn d}O ridi » ^ Hmediox caEbos O-^S^^-tembydtiopyiid-

4- yl, 1 xti«ihy1c«f » D-^2,3 >-K<ir5ih drop rid^- i-iH¾Siyi-piparidHi-3-yi v I-teri- butoxycafboayi-piperidia^-yl,, or I Hdto>s¾l H})o i¼i} p^eridi8^- L

In s i er embodiment. R " is phenyl 4-ehloropbe«y!, 3~me&y1pfi£»yt d-ioedwI teHyi, 2,4- 4»tHeiboxy- ' 3- fdfiuoroineihylpbeayl 3~difl.uoro«ieihyl- -flmrophei.iyi 3- raediy!siilfonyipiieayl, 4-metby!sulfo»ylphei.tyl S-edwlsiflfbnyipheayi 4- raed)Yls ifoisyars3i¾opS:¾erty1, 3-rae >>suifoaylam}« phsayl ' 3-5»elby ' kmi ' aosulfoaylp{jeayl, ' 3- •cyanopheayi, 4-cyaftOpb.euyl, 3-eadyaxypkenyS, 3 arf>oxy-4-hydmxypl!fii!yh 3-e¾it>oxy-d- medwsyphenyL 4-carboxyplxaiyt 4-cyas¾-3-!.nsi¾oxypS.ie!iyi 3-cya¾o-4-ii¾thoxypiieiJy1 5 3- tdiffie!liyi :ndsiecarh«ft ^ 4- i4»»eiftyte«i(«8to HN-eth:yi-N- ojefbykramoej b eylpheay, 4-etbylaj»iaocaiix>»y1pbc8yl, 4-(i -e!hy]- - -N- Ή 52

mei&ylaminocarbouyijph^ 5-5iiethojcy-3- dimdli lianinocas oB lpfejsyL 3-meih¾my-5 » e¾kybns!:ai?earbony!phenyl 2-jaeU¾6xy-4- dimediylaiMoocar onySpiieiiyi, 6-raediox - ~ imeihy! mm^ 3-methoxy-3* hydroxyei yiaminocarbojiyS-phc:nyi -h ^roxy-S-wethylpropytemtnocarbon l JUenl, K2-

lcstfcois Ophc !, 3-(3-hydro^y-a»ctkSko-:{->carbonylphei-yl.3-t3-iae!:SKss y-azciid(ft- i - ; IcaA ii I}p sf5 l 3-(3-med:vySsuSfbiiy^a2eudi¾)- i -yirarlOTyilp eayL 3-(4- ftioxpbo! (ayicarb a pheay, 3-{l-pyiroSidiiiy!c£(rb<3ayi)ph.e yi, -t ¾et^ so syphc ay I, 3-ai«b0xypheayl 5

MhfOTe-d-nieiho yphea ^^ ^

meiioxyearbonylpbeayl, 5-carboxy-2 « mefiioxy beiiyl S-difluorome&axypbeay!, 3~

diSluQroinsih i iieH l 3-diiltK>Tomed> i-4-!¾iO!Ophe:!i i, 2-nie†.hi¾¾yph<;¾yI 2,4-4im.dfc0xypiieay.i, 3,4-ditie†¾oxypS¾syl -or 5 xsn¾odioxolyt

in xoixsr embodiment, R* is l-oieibyl3-pyra¾5lyl 1 »em i- -pyta;ioSyt L5-dimetbyM- pyrazolyi, i i 3 ! 5-trs:t5ieil]yl-4~pyrazo!yi : . -medsyi-4-pyKS¾aSy!, 3-rff1i(0ro-e!liyi-4-pyrazoiyS : , l-2,2,2- plilaoroe!ii i -p m pl - cyeSobuiy-4-pynteolyi I i- {4-»^hol:i«yl)ethy -py!fa¾oiyI s ! -hy r<»tyef¾yJ-4-pyrsi¾olyl 5 l-bydrexyelhyk^-pyxa^Iyi, i- l-ajefbo ye ' ihyM-pyraxol l, S-pvimdyL { -B¾jifeylr5 « pyra¾oly.i, 1 ,3-dHsetby {-5-pyra»o}y! , I -Bissih l-S-trinMiiaoHxeiii t-S-p iaz ll, S^aetliyiaOK ociHtiOayi^ ^oi-S^ !, S-diJiieifeyteHiiocartiooyl- xaKof-S-y^ 3- Hied j y!suSi¾riySaxii:dso-p ns2d»5-yl 2-tH<^ !sx<Hb ytaiaix\o>-|)yi8xoi- - i, -ttieJhOxycilfboH i-p riKo

dimethyI-isoxa2oi-4-yI, i-met yS-tris2ia-4-yi l-jso .f p Hna2a5-4- l, l^iydsmyprop Mfiaxia^yL 1 ~hydraxyhuiyi-i:ri32«i-4--yl ^{riflttooinelb i feen Ometh i-tria^is^-yi, 2-*yaBO-3- edjyMhie»-5- yl 2-meilioxycaf¾o«yl-tii!ef]-5-Yl, 2-carboxyi-ddeii-5-yL 2-(; -n:ieihoX ed}yl-^

mediyfeiS3yl)fiite:i¾-5-yL, -aicd:¾ i-i i 2, -ox3 i3xo!~5- L or 5-cyaao- l-metbylpyrroW-yl,

in aaotber embodiment .R :i is 2-pyridyf, 3~py:ridyL 4-pyridvl .2 -met l -5 - py s: idy I 2~a5ciby!- - pyiidy!, 2~ £Uwi-3-pyridyl 3-methyl.«5-pyridyi ? 3-tr>.II«oroaK;t yi-5-pyndy.!, 2 Πί!ΐκκο¾κίην!-5- pyndyi 2-dfiIii fos:iei:byl-5-pyddyi : -btiffeiOromef yM- rjd i, 2-f:rii¾ii!¾:nwihyi-3-pyfidy) 2- metbijiSy-3-pyiidyl 4-infiilioxy-3-pyridyi, 2-iaetbosy-4~pyridyL 2-(3-oxdaftyS)a)silwy-4-pyridyi, 2- (3-oxetaayl}oxy-4-pyfidyl, S-H«ofo-2-raeth xy-4-pytidyi, 3-fl«oro-4-pyridyl 5 . -flioro-5-pyridy}, 3- flaoro-5-pyridyi, 3-mefhosy- -pyridyl # 2-etboxy « 4-pyridyl, 2-iaetboxy-5-pytidyl 2 « {2,3- d re pro ox S- rn

b d5OxysiIi0 -4* Hcl l S-Suoro » 2¾'dro eb y- ^ yrid i r 2-methox eite -5 > p ddyl 2* feydroxymeib l-S-pyridyi, 3-Hictboxy-5-pyridyL 2- iboxy-S-pyridyl, 2-i$optopoxy-5~py idyl, 2- dm -2~Kied ; Ipi:0p4ixy-5-pyridyi, 2 K I j rifiii0roeibesy)-5-py?3dy!, 2 yciopmpyimeihoxy-5- pyndiBvi ^ethyIsuif n iprop»^ et.}KOxypaipoxy-4-;p nd i 2-diO«.0Fcmietb»xy-S~pyisdyl 2-lTuo:re-4-pyri. yl « 2~e o ~4-pyndyl, 2- cWoro-S-pyridy ' l, i-chlaro-S-pyridy 2«cya»o-4-pyiidyl, 2-cya»o-5-pyddyi, 2-iBetioxy-3-cyaiio-5- pyi!dyL2 ya«o--6-nieil:iyS-4--py:tidyI i 2-ffiidhc¾ ^ft¾etwk-|! ddl r 3^¾ftO-5-pyddy» 3~eysno-4- pyrkiyl l-KieiSiyhuSibKyl-S-pyiiiiiyl, 3-!Mei:hyhul.ioi)y!-5-pyridy!, 2^0Kf¾y!suifi>t}ylatn«J0)- -pyiidy} i

2- ffi£ ioxycai&oswl-4-pyriGyl

dibydr pyrid»j- ' 3 « yl ί ^ejhyl-S-Cfxo-l^-d ydm yriditi-S-yL i -«5et¾y{-2^oso-l,2-dihy<iropydda « 4- S, 5 -efSiy!-2-οχθ- 1 dihyd? pyndia-S-y > l-jsop jyl^-O o^l^-diliydfO yii ifi-S'-yl, 1 - hydf«x:y« yi~2~0xo- 1 a-dlh dm ridiii-S- l l iydr0xypiopy!-2- xi- i a-di!sydmpyridis-S-yi !- meflsyl-2-ex:o- 1 ; -d i dop r i:tiin~4-y , 2-¾ydroxypyrid-4-yl 2-i.¾yd.roxypyxid-5- !, 2-assi»ocarbo»y!- 4-pyndyl, 2-«3ed5yki«¾nocarbo¾yl-4-pyndyl ~m2d)ySam5aocari>oii l- --pyrid I 2- isopTopySamiiiocarbony-4-pyridyl, 3-dm ykmmoicaTboii {-5 ^ pyt3d 2- mediylswlfoB iexh b iKscarboayM J ridyt, 2-oxeiii fe»If ayl3miooe to

bydmxyedwIarai»oc;¾rboHyi-4-pyTk!yt 2-!iydroxybiyy?anii?i carboftyS--4-pyridyl, 2-

imklazoiylJpyrid-4-y!.

in aaoiket aafcodiiaeat, S.' is S-pyriintdinyl.2-?u»jso-S-pyffimdtayi, 2-cyaao-5-pyri«»di«yi 5 2-fiieilioxy-5-pyrHi)id(5iy!, 2 -ti: tio s - S - p S" i:t ni tl i ΪΪ y 1 , -isopropoxy-5«pyd}Sid}H i y 2-tdfluoroc{¾>'xy-S- yrfmidtH { y -{riiIooroxt)«i&y { - - yr«ddi>sy{, 2- ifi»oroedxyk4-pyri id:bxyi.2-frii1soK>etb i"5- pyximklisyS, S-diaMiylamitie^wboa !pytkuidiu^S-y pyi¾¾«-2-yl., pyxkiazi8* --yL

I , I -diox.o-2-mci yi-3,4-d.t y dro-2H-baxzob J 1 ,4,5 joxathiazepiix- -8-y i 2-tnstfiyl- i , 1 -d!oxido-3 ,4- dibydro-2H-¾s5K0bi ] ,4,S i xs!ixiasiepiix^-yS, 7- ethoxy-2-sssthyl-] , ] -dioxkle-3,4-dihydn 2H- en oyl 1 ,43iQsiilii3ii2e Hi-B-yL. ?-Oiioro-2-5«ei¾yM J-diaxi o-3,4-di!)ydTO-2M- benzo[bj[i ,4,5|oxa†Mazep!B-¾~yL 5-Qx-4~ffie¾¾yl-2,3,4,S-feira¾ydm~bex5zerfi:|; joxapk-fi-yl 4-~ oie )-5-oso-2 i 3 ( 4,5--i:efraisydro-bejizpf][ ! .4]oxapiix~?~y i, 4-raetlsyl-l , 1 -diesido-3 i 4-diitydro-2H- pyrk!o3,2-¾j! i,4|dxia¾on-?-yi, esxiOxazo!-S-yi, b<¾z xazoH~yl ! , ! -diQxo- 4-di ydro-2i!- i ; 4joxadxtep¾oP¾-b|py«dii!-8-yl :Ll-d!Ox:tdo-3,4-dihydm-2H- i .4]oxalb^iioi2 ( -b| yrid!ix-8-- l

pyrido|3,2-f|f L.4jQxazepki-?-vi be«zoxazoh4-y! ! 2-i«eiby! eiizaxazoi-5-yl, 2-edxy]bei}zoxazo!~S-yi 2 s;Qps¾pyibe zox{!zol--S-yi 2-oxe-2{3H)-be«¾:oi;d ss.82ol-5>yL , bcHzoxazoi-6-yl

beazobiazol-d-yi -iBeft) lbeK2oi iazo{-5- l, 2~isd «¾)ylbeni;Q[d ' Jtb.iai , .oR>- l, S-iaedxyI-5- beazhxiidazoSyi, 5-md^«iy1, i~mei?iyi-S a3azoIyi, &-k)daze:!yt, i-xiied) S~6-iHdamlyb 2~m&iiiyi-2M- bxda oi- -yI, 7-a¾ai oi-6-yl T-azai oM-yl ί diiii xyS~2,2-dibydro- il!-pyrro [2,3-b]pyridiij-5- yl 2 < 3-di½di¾-iH-pyr}-oioi2,3-b|py5-idla-5-yl benzoisoxszoi-S-yl 3-jttethyibett»©d)isox5}Xoi-5- 2-

diby4f¾i¾oxa^ [5, - ] yridfi:i-S-yl L S -dia¾»>-4H»di5yk¾ s 4-i¾ydit>2H-pyiMo[3>2-b¾ M1*>»*'H- 7 ~ yl :i-m¾¾y1-in»itezo[l ,2-a]pyTidi.i)-6-yi, 2 « oxo- 1 H-imlda2»[4,5~i}]pyriili!i-2(3S}--6-y!, mMvml I a]pyridki-7-y ja»da?.o( L2-a jpyrkim-S-yL 2-0X0-2,3-di!iydro- ί H-»s!diizoi ,5-blp ridla-6-- i 2-oxo- 2,3-di¾sydrobeHzoi;d;|osa2©-5- t, 3 » jxo-bei¾i»tdH i

γύάϊΆ~$-γ

hydmsymef;byl-2.3-diIiydm- ! ,4jdios!fio2,3-feJpyr!dj.si-7-yI S-qainolm l 7-q«inoUnyI« - isoqiii»oii«yl 7-iSoqumolKiyl, 1 , 5-aap l:J ¾y ri -y { , 3-im ^}Hp ra¾otop,4-&Jp tido-5--i, 1H* pyr&i;olo| ' 3,4-b|}> ridf-R-4-yI or 3-raetbyM B~py:ra:o!o3,4-b|pynd»]-4~yL

ia fisodi j: embodiment, is tetta¾ydroi¾mayl ?eti¾hyi|sw yi:iia l 3,4~d!b.ydro~2H- pyr¾op ( 2-c|pyrid»yl cbromanyL S:¾exaS:5ydmbii , o[25-b|ftiry{ > piperidiny], pyridyl pyraxolyi, teirai !ylpbco l s iooHayl, ! ' ,2-dihy(fe qtii«olinyl» pynOlidiiiyl benzyl. i,2 ,4-{etra ydrcK:uiooHftyl S.SJ.S-teP'a driiquinoii yt qoisioxidia i.. quH»¾«l.myI ' . ί H-iodazoly 2H-i»da;i&iy isoindoliayl p ,2.4]friazol.ol4 ~a]pyiidinyI, 1 H-pyra ilof3 f 4-d!pyrii¾fdi«yl isoqusKoitnyJ, lH-pyfa2olo[3.4- bjpyriiiiiiy hibdsxoi E ,2-aJpyrid:m.yL 3H: m5d zoi t 5- lp iid:t yi, iaciteiayi, pyra isyl

or clii OiaP

wbereiu R ^ i% uasafestituted or substihssd vviflj ose or siorc substitusnts independently selected from metbyL ethyl, cysno, dofo, 11»ore, srsetboxy, iri iIyoromed:*y : l ethosc carboiiyl, iert- b toxycarboayl, (K; - .t ed)yS)an¾¾ocarbonyi2^^ -me&ylpyj¾¾iiiy-4- y!)carboayi or om

la ao er ei!ifeodifttsal S ? is beazyl ieirab:ydropyr&i^4-yJ, 3-IIiioro ebaayxlrepyrai 4-yL i- Boc-p!peridiii-4-yL S:¾exa]iydroi¾ro[2 -b|iiii-3-y], or 2,5-dioxo- yn-olis:idia-l-yl.

lo aaoiber embodiment, R* is 2-pyrklyL 3-pyridyl, 4-pyrtdyL 2-nKiiiyi-3 « pyridyl 2-m<¾hyi-4- pyridyl 2~ftie xyS:-S-pyridyl 2-raed}y]~6-pyrid L 3-meti{yi-4-pyridyl 3-£K¾S:¾yi-S~p ridy], 4-«)c;d -3- pyridyl 2 s 6-dtjaethyl-3-py}idyi 5 2 5 4-dis¾ethyk3-pyridyl, 2,4-dimel:hy } -5~pyndyi, 23- ins2lt»yl-5~ pyridy 4, S -dt κίίίΐ! 1- 2 - ridy 1 : 2 ! 5-diffie!!iyl-3-py[idyL 2-ed:iyi-3-pysidy! : , 3-s yl-S-pyridy 2-cds>1-

hy droxypropy ' f-5-py ndy L 2-fnfI«o!-om¾¾yS-3-pynd I 2- mi ororae yM-pyridyl, 2^:niittoromsi1wi-S-pymiyl 3-metby!-2-lrU¼o.romcthyl-5-pyrklyl, 4-

6! 4-tnf¾i mi¾el:5yl-2-chioiiO-3--pyTsdyl 2-raethosy-5-py.rid.yi :-(2 sydr0xyjropyi)-5-pyridyi.3-(2- hydrosycdiy!)-5-pyr!dyI : 3-raes:hosy-5-pyridy) 3~ed:ioxy-S-pyridyt 2-med5oxy-4~ma yi-5-pyHdyi 5 2- methax.y-ft- hyi-S-pyridyi 2-cyano-3-pyridyl 3-CYiiRO-4-pyis.dyk 3 y&oo-5 « pyrkiyl, 2-cyai!O-S- irifii!Or ffied i-i-p riciyL 2-cidoro~3-pyi1i!yi.2-cIilero-5-pyridyl 3-c loK>-5-pyrjdyL 4-chtero-3« pyrkiyt ¾-chloro-4 > cyaoo-5-pyrklyi 2-flxK>:f«-5-pyri.dyl, 3-fhioro-5-pytidyi 4 » i1:uofQ-3-pyfidyi 2-

dlffiei:S:iyI-2-oxopyridis-5-yL K2-dim s!iy!-{>-cxopyjidla-3-yl i-meil:!yi-2-oxopyrMiii--5-yL 2-mei yI- -oxopy}:idH.!- -yi I -£d}y!~2~oxx>pyridiis~5-y1, 4-ethyI- 1 -i»siiiyl-2-oxopyridi«-5-yl i~e S-2-o.i£t yi~ 6-osof5yridnj-5-y,!, J -fsopropyi- -oxopyrid js-s-y 1, t ,2-diaie!.lwi-6- xe}yridiK-3-yL S -i»ed5y?-2- f:riiuon«s;thyi-6-oxopyTid¾ii-4-yS, i-meibyS-3-iri o«n¾ct yS-2-oxopyridin-4-yi 2-(~

morpi5oId!:y!meiiiy}-3-pyridyL 2-{Ser!-bvfiy!im:ds:Socar oftyi}-4-pyrtdyi 2- <ffiethoxyciby:iami«ocar^«y})-^pyiidyi -(3-«>ciS:ioxYpl:teayl}-S-pyr!dyl 3-{3-ff«oro-5- ffiedioxypaesiylVS-pyridyi.

la s ote embodiraeat, B: ' is 5-pyrh«id«iyi 4<hior^5-raethyJ-pydraldiiJ-fi-y < 2,4-dimeriiyi- pyriraidiit-6-yt 2-cy3Hopyriffiidi0.-5-yl, 2-tfjiltKrowthyi-pyri!»jdi»-5-y!, 4--i]u0repyn:m:td«: 2-yt 5- fltiftiO yrifiiidin-S-yS, 4-¾rinijoroi!)Ci yS-p ii:aid3i^5-yl 2-¾¾«t:kfeylcarboayl-pyr¾«ifi.-5-yi 2- dkndhylaauoociiriOByl- yra^iH-S-yi, pyfadb¾ :n-3-yI.

in asodier embedimort * * is i ,3,5 « t«K«i » -pyraz0jyi -ediy!-S-pyta/Olyl ϊ-isopropyl-S- pyr&soiyi, I-ethyM¾omo*5-pyia¾0iyf, l«sthyi-4--s3¾?i y1*5-pyrazo!yi l^t 3-3-rae† ex m<;t i-5- pyi&io!yi, Ϊ -isediy!~3-c «io io yi- - ra¾oIyL i - e 3yMetri o!-2- l

In another mbodimsm. R ' is phen 2 ,6 -<i i ius ro h « l . l-Buoidpheayl 2,4-d!.flu«}'yphesyi 2,4,6-triflm>ropherty. 2,3-dil]iiOfopI:ieayl 2 5 ( diftuoro-3-me ¾oxyptoyi 2,4- dii?«om-3-raedioxypher!yi 3-chloropi!eayL 2^-di >feropftenyl, 2 -dkhlQrophsnyi 3-eh.!oro-2~ Huofop enyi ' 3-c ' hioro-4-.rlo roph<jnyi 2-chloro-6-iluofophesyi ' 3-c ioTo~6-lnomphe8 i, 2-i¾oro~S- ir j.fi.iioroaiS!¾ylplies:i i 5 3-feydroxy et ylphen.yl , S- &oxyst ylpheByl.3-hydroxy erhyl-5~ ahylplieayi, 3-methoxyphenyI, 2-meihoxyp eayl, 4-methoxyphenyi, I-ni bylsulfonySpiienyL 3- oie*y]s«lfo»y{pheny 2-{l!jor>-5- ethyisuifonyipheayi, 5-ethyia««acsuifony -a«omplra8i 5 2- OtiOro-S-firfi fc r o ypften l ^w osyciH^ftyipSeri l^S-Ca^ay heB l, 2-8tethyl-5- eibosycarbooylpheayi 2-chloa , !-5-«thoxyc?{fboftylp eayi 2-i}«oi -S- ei «s e;irhc!¾)yi heayl3- meib f-5-«Kdoxycarl50ii Sp ci!yl, 3-hydm yim I-5^si«ih xyawtx)« i he«y! # 3»n½ihexy5-> laeilwxyeafbon i hertyi, 2-fiuoro- ^«ieisox cai»p } s)sihy:$ liiiiiy{, 2·-β«0Γ¾-5- CiijbO ffie!ii iphe l 2 > ia«3i-o-3-xttcihyphe;ft i 2-ehyip e«y > 2-mfiihy1.-5-;af boxyphmy, 2- c iof^-S-ciu ox e^

.an.»«ocarbOH i h«tjy 2-cyaijpp ef.iyI, 4-cy¾ioplimyi, 2-cy;mo-3-H5¾iyiphei!yL 2-cyai*&-5- me&ylph vtyi 4-cyas.o-3-methyIpIieiiyi 2 yaito-3-er}jylphe»yi 4- ¾ ' ioto-2- ya«ophjenyi 2-chior -4- cyaaoplienyi, 3-c!iloro-2-cyas¾Cfpbeayi, 3 i:rfon 6 ana ¾fi:ft L 2-cy mo-i -di lo p snyl, 2- c »o~ i i-diiIu0m h iyL 4 2-cy8M0-6-fluorophmyl 5 2-cy8«o-6- chtorophenyi * 3 hto-:2-c 3a«k6-flo.«ffO tei L 2^ a¾)o-f)-i:ri «DrotKe!:h ) ]iaiyL 2-cyano-5- uiiluoromahy!piieiiy!, 3-[(isopropyl);a}iHioaa'boi:yS.]p!ieKyI.:.5-mefliyI-3- f{lso ro l} fiiif5i3carb iiyllph¾y ^roediyl^-fiiso ropyl^miw ^nyllpheny}, 2-mei y!-5 - fKKO:i S}-NHa " iefboxy£ iy!)am

diSef yr) !Sii!JOc r ci«yij !^

dift w^S^ii^pmpyOftmkw^boa pim i, 2-luo^-5-{<tsopapyi)a5niaocaftooyi>p.heByi, 2- i10ro- i ~isop¾¾p !- - ^^

S »i>-^<fli >roefH laa»nQ)c^¾M)M l)ph<»i ! < 2~i1i!«ra-5-{cyeiop!Opybj:ied ¾^

2-Qu f0-5-(cydobuiyl>aniiaocaroByi}p cH4, 2-0«ori>*5-<c c!ope i^^^ 2- i¾0m-5^iara y<iropyra»~4^ 2-Hijoro-5-

((meho ypropyl)smi5¾oca5:boji l¾>he¾ l, -fluoro-54{ -Biel¾ l}aai½ecsrt50.R l)pbeft I» 2-iiuom-5- ((2-mei}iOxypropyl)sini5K>carbenyS)pbenyl 2-.fiyom-5-(:i-«ethoxy-l- a)c¾ ied5 l)a:m:taocar oi)y!)p¾ej>yi, 2- hlorcH5-((i > roijadta l)cafboftyl¾fteiyl 2-c¾oro-5-{(i,.?-

flwro-S-ft!ssethyi raao ^ 2-fiaoro-5-{< ί -met¾ylpyr¾¾ei-5- S)mm«ocarb£Ui ! i !K l 2-fluoro^S i 4nei¾ >a/«M-y1}aaa:»oc^bo»yi)ptoy 2 « fk!oro-5-

i1 oropipendi^ - )siraniocar oiiyi}p}i¾iyt 2-f1 ora-3-(S-Boc-3-!luoropiperidis:-4- y )aftiiaocarboayl)p¾s«yl 2-i1«oro-S-( i-B c- ipendin^- ^ajBiiJOcajtei l ' iptoyl, 2-0aore-5~i ' \ - flis meii5 ]- ipaidH.i- ^y)} miao *o« i) «e« !, 2-iiuoro--5-(l-el yi-p5pefidm-4--

5-{l-aiethy{pipan iR-4-y]))^

-i¾ira-5~( ~morp oIi« S)}a^

«M^SioSia i & l!ainoocar ony!}p!ii;n L 2 k!af -5-(meth0xyediyS.¼mk¾ocarb«a i}p¾ fi 2-chlom-

5- (l-py:r!:oli<li»y!c rb<ai>yi)p1ieRyi.2 W :a>5-(l^a)^feylpyya¾«v4-yl)<K«bo«yI)pheayi > 3-{2- bcHxi«ada*olyi) k¾y ;3-(2-ni<;ih -lH;ir^i>i i} hfe¾yl ; -(2:»«jeihyi-4.,24- admKoi- - l)p eB i, 3-

hi motksi hodk iit, R 5 is 5-qttiBol:iay fe-qiiixioHisyi 7-qttia©l»iyi, 8-qi(HM>ii»yL 5<hIoiO>

6- qui»oliayi,

tstnihydj-oqaia iia-S-yi 1,,2^,4-isB-ahydj-oqaiaoiia-S-yl,.6 s 6-dmfiihyl\$,6J,S gtmbyd« Bi»<!liii-5- yl, 4- i!Hia¾o¾a i > ukioxaiki-S-yl, S-o -isosido!jn^-yS, i-oxo-isoindokft-fi-yL 3~aiekiy!-iH- indazoM-yl, i rineikyf - i H-radazol-5-y, t dbne¾yi- ! H-kids¾>k4-y L [1 > 2 i 41aia¾0!o|4 > 3--a]pyridiii-8-yi ]-melhyi-2-oxo- i di ydfoqaiaobi»-S-yL 4-meSiyl-2»oso- ί ,2-

dihydroq«inoii¾-6-yl.2-oxo-l ,2-dihydr«q:Dino!ffi~6-yL 4~oxo-di droci«i n ti»- 1 -y -oxii-q«?a0Ho-

dih;ydfX!qiiif ) o!:Bi-6-y!. 5,7-diflaoav ' }- metbyH « oxo-4 » tti£l«ororaeihy^ 1 ,2-dfhydroqt!ffloUo.-6-y!.5 J-<lifi.uofo-4-«d:iy!-S-meibyS-2-o o- 1 ,2- di ydroq«iH(sli!i- -yl, S-isa iiSiicdift l, 7 » isoqui«otinyi WsoquuwHnyl, 5-i$oq«aH3ltttyl 4-

y ' L 5mida¾o l i 2--aipyridii¾-i5-.yl, 3-mcif yI-3H-iinidaKo4,5-bjpyridin- -yi. f : :nsi > iiiyS-3H-ji«iiax«[ ' 4,S- ' b ' |pyndm-ii-yi 3 -siet y! lsoxa?:oio5 ,4-b ipyridin-4-y!„ [ L2,4]t:ria?oio43-aipyridin-¾-yi , S -«t?th - ^SA^tem^c^H-p motoiS^blp ddki-a- l, , -diijydro-2e 3 rauof2 -c] y i dia-5- l mciliyl-3 5 4-i{hydro-2H-pyr3ao|2 > 3-b]pyridio-5-yl or 5-c-hroims-yl me particular e bodimciiis of the inversion are etiuroerated here:

L A compound of Formai a la :

wfeareiii;

R J is H, aikyl aik&syl ioaikyi, aikoxy, hydroxyaikyl aminoaikyl aikoxyalkyl, hydroxyaikoxyakyl, a!koxycafboiiyiamhioaSkyl, eydoaikyl, eycloaikyiaiky?, aryi, aralkyl.

heter cyelyi or hetsrocyeJy kyi, bsrein t¾e cycloaikyl sryl or .beierocyclyi ring in cycloaikyl., cycioaikylaikyl atyl, aralkyl heserocyclyl or heterecycJyMkyi is uissabstirytecl or substituted with oae or two s»bsiii«e«is independently selected f ta -hydroxy, alkoxy, aikyl, oxo or halo;

l : isH,iiIk k r!5alo;

is H, halo, alkoxyearboayi, amisocarbouyl cyaao, cyaaoalkyl, alkylcarbosyl heierocyciyiearboiiyl, alkylaBriaoc rho yl alkeayS. aikynyi hydroxyalkeayk hydroxyalkyoyl, alkoxyalkoxyaikyl, aryloxyalkyl, aryloxyalkenyi, aryloxy¾lkyoyl, araikcxy Skyk

bydroxyaikoxyaikyi, bydroxyalkoxyhaloaikyl, aikoxyaikoxyhaksa.lk.yl > alkoxyalkoxyalkyl, aralkoxyalkenyl, hydroxyalkoxyalk nyi, aralkoxyaikyayl, hydxoxyalkxixyalkyiiyL

aikoxycarbO!sylaikyl, alkoxycarboriylhydroxyalkyS, aikyisiilfoaylalkyt alkylsuifonyia ' lkenyi. s kyist fooyiaikyfi S, bceroeyciyMkeoyi, heierocyciyiaHiytyyi, aikojcyalkyayi, hydroxyaSkysyi or - X : ;

X is a bead, -0- ? or -S( . )a ;

a i& <λ Lor 2;

i: : is aikyl ydroxyafkyl haldaikyi, alkoxyaikyl alkoxyalkenyi,, alkoxycarboriyfalkyt cajboxyaikyk aHiiuocajoiiylaSfcyl, alkylaattoocarbojylakyl, aryk ydoaikyi, cyc!oalkciryk beieioeyciyL ara!kyS, andkea aryiaikyoyi, cycSixiikyS ikyL eyctoaikylalkefryl cycioalky&dfcynyl, heterocydyi ikyi or ererocyclyicarboirySa!k S; wfeerdn tile ring hi R* is ^substituted or substituted with i -3 substit eatx iudeperrteisify selected from H. a!kyi, halo, haioalkyl hydroxyi, alkoxy, haioaikoxy, acyl, aLkySsid yL heie.racyeiy.1 a iaosojfoayi, trtkylaainasuUhtiyi cyano, sikoxycarbooyl, catboxy, aoiiw), RR'N-aikyk aSkoxyalkyk hydroxys ikyi or .R*R b NC( >) here R a is alky! and b is aikyl a!koxyafkyl atrj oalky ' i or alkyiairsirsoaikyS, or where ' St md b iogeiher with the nitrogen form a acicroeyciyl risg. imsubstituted or substituted with aikyl;

R" is Ei l aralky.1, haeroeycSyi lkyL cy oai&yL or feeteroeyelyi, teein. R 5 is »as»hstit».ted or substituted with, i- substituems independently selected -torn aikyl, aikoxy, hydroxyi Mo, baioaSkyi, eyano, aikoxycarbotiyi, catboxy, acyt cycioaikyi teteroeyclyl, .hydxoxyalkyi, alkoxvalkyi, xo, - R \ aikyL RR." or R¾ 5> C(-0) feere R* is ' ikyl a»d R b is afeyaiky! or ataisoaiky!; where. R and R" is H, aikyi, aryl, hcterocyctyi, iieterocycJyialkyi, or cyeloaifcy!, fee the. heferocyciyiaikyl cycioaikyi and hgteroCycJy! rings are utmtbyituted Or substituted with 1-3 siibstiiuerjis mdepeadetttiy selected irosn alkyi aikoxy, hydroxy, haio, aloalkyi cyano, orcarboxy; or R' and R caa. togeter nfc tits N ibrat teerocycly!;

R 1! is aryl araikyk heterocyclyi, hereroeyclyiaikyl or cycioaikyi, wherein each of† aforementioned rings is unsubsututed or substituted with Ϊ-4 substitueuts bfdependeutiy selected froxn aikyi halo, aloalkyl, aikoxy, aikoxy carbomd, carooxy. ami«ocarbo«yt, emeycly!carhoiryi cyano, cycioaikyi, heterocyeiyi, hydroxyaikyk aikoxyialkyl, R'R ' , CiLNRR', oxo or acyi;

G is C-Q or ;

L sO ; S,C¾orCe ;; 0.;

Q is ii or -L-.R 5 ; aad.

F is H or ~L~R S :

provided

(iv) when Q is H ; tbeu P is ~L~R (i , or

(v> whcB. Q is -L-R 5 then F is tt;

<vi> hsii G is M, t!ses P is ---L-g*;

further providd vv½fi 5 is fi. ; is Kicihyi, R :; is H, L is 0, arsd P is H : t u J is not

I i > 2 > ]triazoicf4,3~ajpyr!d;-S-yL i -tae .ryl-2-oxo- i ^ 2-diliydroq««io o-6-yl, isoqaiiioiirs-5-yL isoqiiii5oil»-6-yi, .quinoiiB-6-yi, -oxo- i ^-(isirydro aiaolia-S-yl, 4-ineIiiyi-2-oso-I,2- dikydroqujaoiiH-o-yl 2-inethyi-i-o)io-S .,2-dUiydro-isoquiiioiut-6-yi, 1 ,4-dimsth l-2-οκ - 12~ hydre^dn Ha-d- l S-c loro-:i-m.ihy!-2-oxo- l, -di%dFO¾mJi la-6-yi, 5,7-d luoro- 1,4- dimethy!-2-oxo- Ϊ 5 2-3iliydroq Hioiio-6-yl s .1 -mod:ryi H-feda¾o!~5-yS > or :-ηκί1ϊν!-^Η- ja»da?.o| : 4 5 5-b|p ndio-iS-y I

further provided when R 5 k H, cyaoo at iodo, R 5 k H, L is O s and P k H, then R 5 k ix>t Ϊ -

farther provided when R 5 is H, R* is H, L is 0, am! P is H dies R 5 is ml substituted heny 8-

(siibsiJiiiied -ure«H-<|KiftOil ^-substituted i ,2^4-tei:tahydroftaphthyJ. or 4«sy&siitttied ttaphh l;

further po ided when R 5 is H, R J is H, R s L is O. and P is H, then * is act

further provided wisen R* is Br, R ! is .methyl, is R L is O, a»d P is H, to R $ is not 5,7- d!luei^\lA44rimsthyl-2 x -l,2^ 5 > 7-difittoro-i-o5el: yi-2*oxo~- tridttomniethyl- i J-di ydmqidiiolin-ft-yl, 5,7-dii¾iO!¾-4~ediyl:-!-iKet!5yi-2-oso-1,2- dihydroquiaol -fky], or 2~methyl~ i-oxo~ ! ,2-dihyd:ro-isoQiiij:ioy:ii-6-yl.;

further provided when R ;; is i-metii l-lH-p raKoM- R ! is methyl, R' ; is H, Lis O an P is Pi, theo R ' not :l -cUiyl-iH-py . rasi»l-5-yi:

furdier pro vided when R. s is i -taei¾yi-:i H-pyr; oi-S-yi R* is methyl is B, I. is O. and P is H, •to..R* k aot 2-incd:iyi-l-oxo-l ; 2-di1 dmiso !«m¾iia-6-y! S,?-difl«oro-l 5 4-d;iraethy]-2-oso- 1 ,2-dibydro({X!}ftoh»-i>-yl } or ί > 4-d}»Kih t-2-o . -I,2-djh d}-oqa«}K>li«-6-yl;

tefejr provided R J is «ot haio when R ? k R, R ! is fsne!fiyi, L is O, P is H and R 5 is S-quinolmy ftttilrer provided R J is mi htofo when R s is bromo, R s is methyl . , L is 0, P is H and R ? k 5- qahioliny ' f;

further provided R is :nof phenyl or rerl¾u r wseis L is 0, 8* is 2-ediy:-3-pyridyL 2-imUHyi-3- pyndyl or 2,6-diiftel]w]"3-pyridyL R :; is H, .R 5 is 2-pyridyh1tio>, bromo, methoxyetay or trifluoromelhyi nd G is CH;

.teller provided I s is not 4-:raefhyl-2-imid<mlylraet¾yl wheo .R 2 is e, R 5 is 2-pyridyltfeio, P is 2- ettiyi-3-pyridyS.oxy and G is CH;

.tefcer provided is not 4-: efhyiph.(inyJ or 2,4-diraethyIghenyl or I 5 2-dthydroxy-2-pheny.IethyI

hen .R l is methyl is H, G is , and P is 2-methyk?-pyridyoxy;

and a pharmaceutically acceptable sail: thereof.

2. Com ound of Claim I wherein R* k Cv« ftlkyi. C;.« g!fcenyl C M S haloalkyi, C¾« alko y C:,;, hydro yalkyi C,, ( , amtosslk ?,

iiryii, a!ky!„ 5-f tsiaiibered he!emeyelyi or 5- SO mewbered beierocyciyl-CV* aikyl„ wherein ilie ¾ryl or h«terocyelyl riag is uiisubsdtuted- or snbstuuted w one or two sBbsiiiaent mdepsitdeHfly seleeted ir a C ( , ikyi, hydroxy, oxo or halo; arid a phawnaceiibcaiiy acceptable sak thereoP 3. Com ound, of Ca n ί wherein is methyl, ethyl propyl, ailyl, lert-buiyh mlltsor - ethyl, methoxy, raetbaxysthyl, hydroxyerhy], hydroxypsOpyh 2,3-dihydroxyptopyi- L2~ dihydtmyprepyS, hydroxy ethoxysihyl, BOC-asMnoethyi, aoniaoeihyl, 2-iiydf0xyptexyltne{¾yi, 3~ hydroxypheHyhnetfryl, 4-¾ydfoxy-pli«)yte8tliyi, -fluorophmytoefliyi, pheaetftyl, morpho!ia*4- ytethyl 2 « pyridyfaftChyl, 3-pyrk!yli:aediyl, 4-pyridylrfHithyL §»m {hyl-2-oso-l ,2- dibydro yildinylfflethy imiteoi-S-ylmetbl., i-HWh Hmiteoi-S- ylmeiiryl L5-dimei¾y!pyrazoi-4- ylmeihyi, 2-tnec y ¾ls26lyl-S~iaeihy{ s S-mcthy!-is ?ta¾:o!~3-ySniethyi or phenyl; aad a

p a«»¾ccuti ca!iy acceptable sail thereof.

4. Compound of Claim I where ! is 2-pyTidyt¾ieihyi -pyridyiraediyl 4- pyridySifteibyl 4-w iiroida ol-2-yimsihyl iraidazoi-S-yhiiethy .l-s¾iihyliBilda»}l-5-yl¾5etftyl,

1 ¾d-3 ~y neiiiyi or raorpholtn-4-y.lethy]; sad a ptemr.a¾caaseal!y acceptable salt thereof.

5. CeM eiHid of Ck i ' ¾:b«ia H: is Diethyl sad a plmi¾toitiea-Uy acceptable sat thereof.

6. CosH oufid of Claim \ wherdn R 5 is H, methyl eidcra, or fSoorO; aftd a

p raiaeeutkaily acceptable salt ifeereC

?, Compound of Claim S wherein R* is B; and a pfe_mn»ceutica!ly ac e table ssit ift .iCOf.

8. Compound of Claim ί wherein R 5 is - S(0) !S ¾* and a is 0, 1 , or 2; and a plisnBiiceuikaii acce table salt thereof

9. Co«5po«Hd of Cairo I h reto R ' is ~- S :i ; aad » ph saaceatiealiy acceptable salt ihereaf. i i). Compoxmd of Claim i wherein 4 is C^ alkyh€;.< > liydroxyalkyl C ( .. s . haloaikyl iryclroxyaikynyi, C s , 6 alkoxy-C¾.. fi Ayi ;r Q.« αχγΌ* a&cflyl, Ci , , 5

aikes c rtioH l-O-i, alkyf Ci.. s -csrboxyalkyl, aminsjc ih a i-Ci.* alkyl C ; .« aiky¼d«ofcarijottvl-Cj.«- alkyt C f rxo aryi C 3 .. y cycloalkyL CV? cydoaiketiyt 5- 10 roembeosd iteierocydyt arjfl«C>* alkyt C«a aryl-C M sikeiivi. C e W≠~C M - i alkyfivl Q.« cycioalkyl-C^ aiky!, C¼. s cyclc¾¾yi-C ; . 4 a!keayh CVs cyvIoaiky!-C;.^ alkyayi 5-Ϊ raetabered . ' heierocyclyl-C^ aiky!, or 5-10 nteMbered h.eierocyclykarfaotryi-Ci.! > alk l; whereas the sayh cycioarkyi eyeloaikemd or heteroeyc ring in.8* is onsufestitttied. ox substituted with 1-3 snbstitueRfsttidcpcadcmly selected .ftom C^< > aifc i, ide, haioaiky bydroxyi Cj. <; alkoxy, C>. ft aeyi,€:.,, alkyisulfopyL C- , $ al.ke-xycarbor»yh eatey, 5- ϊ 6 taembered hetcrocydy!, eyarfo,. amiiKJ,€<. i; anxoisiikyk Ci^ aikoxy-C;^ aikyi, C<. $ IrydroxyS'kyi, Cj-s haloaikoxy, aikyI~NER\ atairwsid&rryl aifcylaminosttlfonyi, or R¾ ! 'NCt ; <3> where R* is G 5 , a&yf aad R i! »-Ct* alky!, Ci aikoxy-Cs.« lkyh C w > arotooaiky! or alkyl-Cr.* a iaoalfcyi, or Wl¾se * arsd together with die pitrogstt f&t a 5 or 6 memfeers heterocyclic ring u»sr*sdt«ietl or .substituted vvi& C>* alky.; a a pharmaceuticall acceptable salt dietcof.

11. Compound of Claim 1 whereto I "' is mehoxycatbonyhKediylftiio,

sifieflsoxycarboyySsibylfldo, mefhox pi pyltMo, 4-me†lioxybiH~2-ylthio, hydroxy propyiihio, 3,4- dibydroxybuty ao, earboxyedry!ih.50, (metl.5ylas.n.toocarbo«yl}mei!iyid.»o,

{dimeihylarsmocsrboiiy methyltliio. {3- ydroxy-3-imetkyibmyj)i:hio i (24rydroxy~2-aie!iiyibikyi}thk\ diiluoro efhyitfn'o, (4-meil!y}p!per zin-!-y!)-;arbosySmes:S hb.ii> ; {8:ierpb.oljn-4- y ' Jcarbonyl«iethylthio, i. ert-hutoxycarhoRyi piperidis:i-4-yi)medw¾bio, (4-piperidinyl)mst .yiiMo, {teiraiiydro- H-pyras^- !jinediy iiio, Ht¾f h dt6-2H^ ?j - - i)ethyti>}0 5 (S-s»etbyi-2- 0x ta/x>Syl . toiethyiibi.o, 2-pyridyIi»ethySdski > ,:4-dfl:tydrQxycyctep «ySthio, 4- hydroxycyeiohe yiihki, cycIopcneHy1tiHO s phesyltfuo,. beo-tyiiho, 2-pyridylildo s 2-ehioro-4- pyddyhbfo, {4-piperi.di»yl-2 « yddyl;>m«{hy{l¾i > Cl-methy!pipendio-4 « yb2-pyndy½^ (1-

pyiidyI)msdiy!il:iio ; ί-(ϊ-ίίί«%Ι:ρίρ^ i-(p.a5sr i8-4-yl) -{2- pyridyl)meUiyIibto, (4«piperidiayl>tM0, (i-lso3ropyi}piperyiB-4-ySi!iio > (i-merSiylcarbonylipjpendia- 4-yUble, -(tcrt- tttosyc r oRy ipcridifi^- iibo,- (l-metbylsulfoayOpipmdin-^-yli o, (I - ssopropyicar bony lpiperidto-4>y liido, i med«sycarboiiyS.piperid!.n-4-ySib.i , I - (nicii! xyed>yiearbo«yi} iperida>-4-yidiio, i-(din.¾ediyiaminocarboayi}psperidin-4-yiibio, l- (ia.eil:to.xycarbor¾yl}p!peridii^4-yUtM.O,. (i-{5-ch1.owpyr!midia-2-yi)p!pendiB-4-yl)dd.o > (i-(2-

pyrasi-4-y do; and a ha m ceutic ll acce table salt thereof.

12. Compotiiid of Claim $ wherein R' is me wx propylsu!flrsyl «¾*thoxypropyl-aufonyi

y!saSfopy!, or 2-pyftdy:lsulfoay{; aid a pharmaeetdkaily acceptable salt itm t

13. Compound of Claim I whereto R* is - OR'; aad. a pharmaceuticall acceptable salt thereof. 14, Compound, of Claim I wherein R' is iBetliost propox , 2-(m<Sao¾y>prop0xy, by roxyeihoxy, hydroxypropoxy, 2-liydmxyproposy, i2-di¾.ydr0xypropexy, !-hy.droxy-2-- raethylpropo.xy, 2-kydroxybutoxy, pheaoxy 2-iacthyl-3-pyidyks.y . , oir ^-osesaytsaethoxy; aad a phaxmssteuacal!y aecepfii ic sail thereof.

15, Co:in !«fi£l of Claim 1 wherein R* is halo, eyaao, C f .s haloalkyi, C w cyanoalkyi, C;. 6 alkoxyeafboay!,€(.« aiky!carboayb - to me bered heierocydyicarfeoay!, amlaocaitoiryk C,.* iiikylaiuiijociirbouyl Cs, & aikyi C M - ; alkeflyl, C :i , fi . alkyny ' k Cj. & ii drPx aikyl C ¾& hydroxyaiksayi, -s hydroxyakyay, C W aikoxy-C^ aikyi G .« sikox -Cw, a!koxy-C,,*, aikyi ataxy-Cut aik0xv-C 3 .. f. itaiosikyi C;.. ; ; ato -C;;^ aikeoyi C¾. i; alko -C^ aikyayi€;.<> araitoxy~C M < aiky I¾ydf»xy-Cy¾ aikoxy-C^ aikyi, bydroxy-Cs. aikoxy-G,*; haloalkyi O.. * araikoxy-C;,* aikyayi liy roxy-Ci. i;

idkoxy-C :; ,.fi alky»yk <¾.m &ryk>x.y-C f . s aikyi C i; . iiS atylox -C 3 ^ alkeayl, atytoxv-C ; . s aikyoyi C ; aikoxycarboay !-€;.<; aikyi€).* cartwxyalkyk C?.* alk xycafbo»>i-Cf.*liyd!Ox¾lky1 5 aaiiaocarboayl- Cj.« alfcy.1, -< > aiky¾msae:arboay.l-C w aik Cs-s aikyisuifoayl-C^ ikyi. Cw aikyixolfesy!-Qn:. aikenyi C g alkyls¾Ub&yK¾, § aikyayl C Hi( aryi C « eycloaikyi C*.* cydoalkcayi, 4~,i i raejaber d feeterocycly), C ayyi-C S « aikyi. aryi-C 2 , ;> aik i Q. S(i aryl-C¾. s aikysyi C;.. s eycioaikyi-Gi aikyi CM cyeioa!kyi- CM bydroxyaifcyi i eycioalkyiCVs aikesyi C.wcycloaikyt*Cj.« a&yjjyi.4-

10 laembere heterocy SyiC;.* aikyi.4-iO asembered. efmseyeiy 1-CM alfceayl, 4- i 0 maabered iielsiOcyciy!-Ca.;; ik nyi or 4-1.0 nte beied whereii! the aryi cycio ikyL cyckialketiyl ofheterocy !yl ring m ° is KHsa shtuied or ssibstitoted with.1-3 su sfit ents iade eftdsm! selected &&m CM aikyi halo, om B.0% CM baloalky!, alkyisutfoaytemo- Cw aikoxy,€;.,; Moaikoxy, h droxy-CYs aikoxy, « aikos.y-C ( .. s aikoxy, C aikyfe lfonyi- C f . f* aikoxy, C;.. G acyl Ci,« alkyisitifoiivi C s ,« a!kijx cafbotsyi Carboxy, 3-10 BseBi ered beiero yciyi, 5-10 membered beteTocyciyiCj.* aikyi, CM eycloaikyi, CY« cycloaik i-C;.,; aikyi amiao, aminosui&fiyi C;.f, aikylamittosulfojiyi C^a!fcyisuHbnykmiao,. cya»o 5 arboxy, RR S -Ci.*- aikyi€ 5 .« alkox -C{^ aikyi Ci.i aik xyimiao-C:^ aikyi C * liydsmyaikyi or R¾ Sl C( ¾- where R" is H > or C w aik i aad R ¾ is H, Ci-s aikyi C s .« feydroxyalkyl Cs-s alk05s.y-C 3 .« aikyi. Cj. <; aikylsulioJvyl- C,.« aikyi d 4 alkyisuifd!iyiamHi - C s . f; aikyi, d.«. aminoaikyl or C;. (; aikyi-Cj.i, am¾K>aIkyk or where R s and≠ C gethet ih the aitrogei! fomx a S-6 membered heterocyclic ti uasifbsiii ied or substitated with. C } . 6 aiky); and a piannaceiiiica!iy aceepiabie sait ife'eef .

16, Coajpxnuid ofClSim I wherein ,? is eyaao. a¾?thyk ethyk propyl, isopf pyl, 2- metii l iO i, 2,2 ' divosd:tylp:ropyi 2-isietiyibaiyi, triflwot08.fiS 5 3,3,3» ii-flooiOptO y

fiuorosrjcifiyi, fiu r propyi hydfOxyHieiayl, llydrosyethyi, 1 -llydioxy^-methyieihyk.2-hydroxy -2- meftryleibyl, hydroxypropyi, 2~hydroxypr pyi I -hydroxyprop-2-yf , i ,2-di ydi¾xypropyl hydmxybutyk 2-hydroxy¾»ty!, 1 ,2-dihydroxyb«{ k 2-hydroxy-2-ai8 ibaiyi 2,2- (dihydroxymetiylabtiiyi, l-hydroxyetk>xy«2-bTOtaoeiliyi, 2-{bydroxyediOxyedjyi 2-

60 (.hydmxyetlK>^.y)p«>p ; , (aisdiox nieiiivte L S - e$hexyetboxy-2 »mtx>e!byl, 2-hydroxy-2~ ed lpeaiyL 2-i¾ydroxy-2-met yS.hesyl :l 2-d! ydroxypmyi 2-benzyloxybpiyl.2- hydroxycsfeoxybiiiy), 2-hydmxy-2-methyipropoxybityi ; 2-h droxy-2«a)iidi lpr po yp; i :!, (eiid) d«^yrai(-4- - y4fos «3c iyi 2-fi«oro-2-!»etby5bttiyl, meiimymethoxyBicthyl, raethoxymet y meftoxypropyl metboxybaiyl, 4, aie ioxypentyi sihoxyet esy!, etUeilyl, propea-2-yl prope»-S--yi prpp-l-eit-i-yl, 34:iydroxypi0p-!-e «2-yi, ! -bydraxy-2- raefbylprQpeayL b«.d¾ayS, 3 dte€«j l x«en.* 1 -yl, 2-beazyioxy¾KayLffieiS¾xypropcis.- J -yl

!ivdroxypropeHyl, ea^lox prop^ngl, l-etboxyetiienyl, 2 iydr0x n:tetS5 !p!Opeav[ > S-eiboxyviayt vinyl me&ytea!ftffiySpropeayi, meriiylsalfonyibiiteayi, met yisuifoaySally, ft.iet.lilsuifoaylbut-2-ea-i- yl i J-d)Oxi oiesm ydro-2H iop r^^ etftoxyeatbonyl n b Sc&s >im h (4- teiialwdro- rany car ofi i -med S~:^ni¾^ " -iwebyi- - d«aei!iyiamjaoediyiHiai«ocarbonyl teri-batosycarboayioiet]¾yl Hiydroxy-Rert- bsrtoxycarbo:f!yii:ne!hyl. crh«xycaibo»yp-ro|>yL citoxycaifcoayletbyi, I -hydroxyetbyl-

s anoelby}, cyaaopropyS, 4,5-iii ydroxypei!tyS.4S-dibydraxype«i-3~yl kydiOxybatyayl iydraxypicpy!vyi, edms S, 2-eyc!opropyhi«yt 2-by «3xySlh0xyb\«T.I--y»-L-yl, 2-hyds¾xy-2- i:nc(hylpiopoxypropyt}y?, ba ytoxyprop- { -yn-l-yl, essEykssybtt-i-yii-i-yi, baKysoxYeiboxypfop-i- γίϊ- 1 -yl. ^i-bysimx cyiifopecayli^ih iiyl, 3-m£byi » 3-oxetany.teibyB.yi t awthoxybKi- i -ya « I -yl, «KHboxyperilya÷I~y .c eio niyiideagHKiih l mtHbyisidfoa l ro i : , mei ylsidibayihmyb pheayieihyl, b¾ft¾yi, pbcaylpropyi, 3-c!il ropbe»y!isel:hyL i^dili drox -S-phea byl

pb.e«yiethe»y! > l-pbeayivisyi ptoyfeiaysyl pyrid-2-yl ei¾.yL.2-cfii 5x>pyr!d-5-yImetiiyl, 2-etboxy- 5-pyridyleihyt 2-e ' thoxy-5-pyjidyIeihynyi, 4-piperidyIa?eibyS, I-piperidyleteihyL 4-RKibySpip¾riiz::fs- i*yb.neliiyl, 4*Boc^ipm hi~l- iraedwL ^

pipdraxin- \ -ybaeibyl, moj boJm-4-y{mer.byl,..Vtn.el¾yl-mofpbol.tft-4-yteetiiyi ? tbonroi boliaoBisib l . { i , i *diox5dob.iomotpb«I»e}m$tbyK ¾-m<thy1-3-oseb»iy)ejhyi.. (i:eP:al¾ydro-b.a'-2-yi):ft]i;5l:iyL (te«¾bydro-ftKVyl)metb.yi , 2.5-dioxopy.rrolid i -yieiiiyl

fciTahydi¾pyran-3-YijaeiS:iyl ien¾bydropy*iio-4-yleifayi 2^

dioxido-teii¾hydfO-2H-tiii pyfa«-4 » yte l, etra df -lH-iiij pyrais^ ajediyl, 6-oxa-i- aA s u ' o , ]1:iepiK-i- b«<;ih i, 2-oxa-6-a?¾piro| ' 3,3]hepi«JJ-6-y!meiliyi ! . j,4-d.joxaspsfo4,5]il«caH-7 » y »etby1 3¾»¾yiQxy-cyelobutyta !!l-hydfOXy-S-BKihyl- cyclobutyfmetbyt 3-oxo-cydo¾»ty!med:!yL -b dfox^ 3- l:5ydraKy-3-medyS :yefebuiyI-¾ydroxynietlryl, eycfopeaiyl efbyt , 5 -ihydtoxycyc ' tope J« ! )raeihy ' l , 1 - C!ffleSfioxYCYclopeatyimKtSi L l-(j»^feox tyci pm{ ))b¾¾omeii5yt cydflhexyimeihyi,

cyc iex¾?eth 1,4-h drox : clQteyl.tiKili cyclosexylniefei,

cvdopropy!, I - tori -butos c sbo s¾ ! - J -cycSepropyi, 2 -aboxyc;irboi lcyclojras>yi, 2-(2-bydra?¾f-2- !i!etby! !iiy1)-cyckipiO{)yL 2-bydioxy):iseibyI.-cyi:Sopxopyl ( cydofeuiyi, 2-hyd«¾xycyc!obaty:l, 2- ecycSo iity!, 3-hydr0xycydeb!iyt 3-beHyl xycycS bu!yl -bei« lox : A l:rdQx c cloii f L S- (2- ydroxy-2-;ffidliylehyli cyclo¼Uyl, S- drox ^hyl-cycto iUy!, 3- « eihexyc«boayt-i-hydroxy- eycio ttiy!, 3-ei! >xyc rbci«:yi-€yc!ob«iyi cydopsiiiyt 3 i drqxy!tjffdi leyClopeft L 3,3- diSiydroxyaseibySc clopefciiyi , 3~carboxy¾ydop£»fyl 4 ryd:foxymediy!cy lOpeittyl 4- hy roxycyclopeatyl, 3- yi!faxycyclop«atyI, 2- ydmxy£ydope»fyL 3 ¾yd.mxy-3-raedityfcydopmyL 2-oxo-cycSopenty!, 3-o«¾-eyd«pe»ryi 2-i -ei¾yi-N-med^Samiiioear oayl)eycJope»ryI 3-( " -eibyl- N-med)v1amsiiecarbosy!)cycSopeaiiy', -iso myla5«¾}:50caT oriyl}cycIo ei¾ l, cydo¾exyt 4- ¾ydroxycydo exyl, iydmxyeydo]¾£xyt 3-liydraxy-3-n)¾i!iyi-cyc!o!:i8xyL 4-i5ydroxy-4-iaei!ty : S- cydobcxyi, 3-oxo-cycloiiexyi, cyddiepryb cycJopeuSesyi 3 sydroKv ydc>pa«e«yi 4- liydmxymeibyS.^-nie!iiy!-cydopeaveftyl..4,4-bi:s(S^ydroxyri elliyi}cyci peai-2-en-! -yi.3-oxo- eydopeittea t, 3-cs^x elo e -2-e» l 3 sopmpyIamin<3carbonylcy Sope»t-2--eiiyi, 3- i]iyd!O yraei!y}}cydopeiii- 1 -civ $ -yl 4-lrydr» ymefb l)cyeiopeii!- ! -m- 1 -yl 4- fhydroxyB:iei!iy!}cycj.opes:!i-2-cii- ! -yl 4-† i-biityS~ cyciahexcnyi.4 ryd«>xycyd.ohexe» I S^ydroxycydebcx- i -co- { -y!, 4-.hydroxy?setbyl- cycio cxeriyl 4-{2-hydiOsy-2-R}etbys! :yl; :yctabcsc»yl 4 a oxy ! S!exeBy -ffib.ox ca!'bo» l- c ciohexenyt, 4-iaze!:idhi.- ! - :Scar o«yi} cloiiexeH l 4-(i-cyamva«?iisiin*l- 4»<3-fluo«va¾:etid«v i -yicadj siy cydohexeayl 4-(3-mei y l&uifosy!- a¾etidisvI-ykafboi5yl)cycSoS.iexeHyt eydotepteay!, ! > 4-djoxaspiro|4.5]dec-7-eis-7-y!, L4- di xaspii'of .5 jdeca! 7- L

3-j:rydioxy-3-oxet;¾«yi 2-ietrd.rydro-r!ifyL 3-ietiaydro-iuryi, 2-meii l-3-ie!iahydi«-fdi:yi 2-mei.hyl* 2-teifabydro-biiYi..2-hyd:roxyi«dliyS-2-i¾ms^ 22*

S-oxopyrrolklitr-i-y!, tejra ydi-opyran.-4-yL 2.,2-di.t5JCtfey.Hctahydt^pyraa-4.- : yl 5

dimfithylletrahydr pyf¾»-2-yl, 2: l 25,5-ietoi«c¾¾yl-2J-di&yd¾-oi«:i'an-3-yL 4-fl¾^m-te!:rahyd:r«pyia«-4- yi 5 4-f!iorfi ?-l)ydroxy-fcirahydfopymv3-yi.4-fhioro-3-nie!]mxy-ie!¾hydfo py:r;j:t3-3-yL 4-

py uvS-yl,. -diYdKi-2M-|j raii~5-yL 6,6-^^ 2^-diraelyS-3,S- dihydr *2H-pyran-4-yl . J 5 4-2H><iihydiC$>yran«4-y{ ! , U4- toxa^!fu4J|dcc-?¾ii-B-y, ij-diox - isoi:«a¾o{idiii-2-y! , i J -dipxidoteirahydf¾-2H-{ io yran-4-y L I ,4-dioxan-2-yl, »eih ~ine i« I ,,4- djQxan-2-yi. l-mes.!iyi-I,2,5,6-ietrahydt-opyrid-4- yl ! -mdbylsii!ibay!- i ^ ^-ielabydFopyrid-d-y!, I -(diraeilwiaraiiiocaboayi}-: %6- tsmshydmpyild-4-yL !-(iney¾o¾yc8Ao« S}-L3J,6-etKs!i ds¾ dd-4- l MmstSiylcitffeoayiM,2, ' 3,6- £cm¾ydro yn ^4 s l-t5¾ l-pjp®idi«-3-y{, i-!firl-btiiosyc;5rbo!jyi-pipe idi!>-4-yi.

(diftieJityl¾oaao ¾» * oayl)-pj|¾ridi:n-4'yl,.

phenyl,.4 htaopaeayl, 3-Hiethyl:p e«yi, 4-Kiea * iyipheayl, 2,4-daaetby5p c»yl, 3- tti ftaoromethy (phenyl, 4-mnttoro:methylpbeoyl .4*meihoxy- -irifl«o omei 1phienyi ; 3- diMu roOJet¾yl-4-ihfof pheoyl, 2-H)cd:ty!suifb«yIpbeiiyL 3 « xinei ylsu.ifi>nylpi}«ftyl 4 »

mediylsyJiboyiphesyi -ei¾y !siiHoB i beny 4*met¾y?sf!ia!iyii««iiiophefty ' i 5 .5- 3-cyanopbesyi 4 y;iBopbe yt 3- carbosyphesyi, 3-catboxy-4- ydi¾xypbeByL arkis - { ?-i.nei!jo ypfie}iyi, 4 a&Qxy h r l 4-cyano-

( ' -et yl-^-meii.5yl ai«ocarbo«yip!te»yi, 4-eti5y!£«¾Hi0carboaySpi.¾ettyL 4-{N-eibyi-N- mc{b .i8mi8 C3-tanyi)p.beB l, 3-isoprapy!ainis>oc;ii¾oftyiplie!):yi : 3-4 r "b«fyl- - «¾ei laa-!incs srfeftiiyl)pS)etwl 3-fK-prapyi-N-niediyIs:ffi:»}.ociH-bosyS;pSieayi 3- ,.2- d¾ydfox>^ropykm38ocadx>«yl}-4-hydmxy-pbenyl, N-iaefeoxye iyl- - a)ctbyia¾:nifti3cai'b0ayi)pS) »yl s 4 N-bydroxyethyl-N-m bytoj»ocar oayl)pheay:i, S-saetboxy-.-

dindhylaaai !carbooyipheayl, e-ojeiho y-S-dbjclhyiaroiR^aljoaylphcnyi, 3-a>«0ioxy-5- ediylans!:tiocaxboiiyl b«Hyi, {^ diOx ^mstbylprop-l- l-aiabiOca^OBy^heHyl,.

b:ydiX) yed! !a:niim)c r onyi-|5hei5yi, 24) di¾xy-2»n}e$hyi fo 5.mHiflot<5rboH l^heHyi > Ϊ^* dih dmx »p kiai»o idx>«y1- toiy 3 !-azetid«}:ykai:b syS)plie8yS s -{3-¾iOfcs-a¾eu< si-l - ylc&rbe.nyl)pheayl, 3-(3 ^^ 3-{3-ioeibt)xy-a ist!diH-l- y lcsxb m I)pbe»yl -G -tmt isal ieayl-aswiidiB- 1 y{ carbony!) phenyl , 3~(4~

-i]«oiO-b-!:Kei xyf>hesi i 2-fl¾i m-5-raetisoxyphe:ny], 2Hne(hoxy-^mei.hylammos«lfonyiphmy.l 2- ffied50s - -e!b lasiifto$idi ayi iieayL 4- ½t oxy-3^met¾ lamHios«Joa |p eK l > « m tb sy-^ :metbox:ycaf¾Oft.yl>¾$ftyl.3-carboxy-2-ffiS!¾0£yphe:t jyi.3-di:(iuoR>aieiftOxypteiy.l, 3- dinuoromethy!phenyi, -diSti mnKS:¾yl-4-iltiot ' o befl S, 2-meikoxypfae» l 2,4^imetbosypb.e«.yl, -djroet oxyphenyi,.5-bcft2iodk¾xoiyt

S -sx;dwi--3-py!fa o!yt i-?ttetb i -p m¾i l ; I d»ne 1-4- y?a^ l, IJ^Hii eih : -pyrazo!yl S-meihyM-p y oi t 3-b1iIiiOfO-ediyi-4-pyr¾¾i>Sy! s l-f^^^-tdfluoroesayi j-4-pyi-axo!yi.1 ·· i-etho ycajtoaylmeeiyI-4-pyfa¾ l, 3- y€lo¾»iy5--4-py;¾K0iyb I- tyclobuiy!-4-pyra^olyl K4*.mo^lK>l yl}ca^^^ H4-«iorpholi«y!)etbyl - pyi¾«iiyt ! -hy<fcoxyfithyH-py}¾2oJyl. i-!iydr xyetbyi-5-pyriWcslyl, { sydfOxypiopy1>5-pyt¾2o!yl, (3-i5ydFOxy-3-med:iylbatyI}-5-pyra¾SyL 5-pyfa¾oiyL l»∞sthyl~5- py eSyl, !J-iSimeikyi-S-pyTaxoiyi, ]-i«ei]wI-3-try:kio:rom b i-5-p i-a¾oi L 3- aiesliylaajioocar oo l Jyis^ol-S-y!, B^k^ih laaiiaoc^s^nl- j^oi-S^ i 3-meibyIsuffo8yla¾«ao« pyra¾ei-S-<yi ? -met Istrffon ki»¾i0- ji¾^^ ^

ihkzoSyt 2 2~S:iydro¾y-2-me*ySeti:iyi)4iiiazoi-5-yl f-!¾ef.hy!-5-iRiid;izo!y 3,5-dJi«sthyHsox8-KOi- - y I J.-i»ethyi.-»ia¾aft- -yl, 1 -isopJ¾py!-i!ia i»-4-y l ί -iiydroxypfOpyS-ii:ii¾!i5-4-yi ÷ i-feydroxybtJtyt- ti:ia/,!ts-4-yl, ( -tri!la ro«5e{|iyip!ico>)m«d.yl-«iai:i»-4-> , 2-cyi»» 3-i)3etbyJ-tbim-5-yi, 2- 24N r -.metb0xye i-N »

oieih laoiiROCitbonytHWeK-S- i,, 2-(N^ih 1^ 45)eih l-{tt»me wbony}ihieft-5 » yL 2-(2-bydroxy-2- mefbyteil:iy:S)ihlefi-5'-y 3-n)eiby:S-i,2,4-oxadiazo!--5-yl 5<yaRO4H:oc0:iyipyn¾I-2-yS,

meiiy!-5-pyridyl nflvioro sthyi^i-pyridyf, 2-lii uo.t-omethyI-S--pyri:dyf 2-dii1iiOFOiset yl-5- pyridyi, 2-iii t>rometbyS~4-pyr!dyl, 2 rifittoromediyI-3-pyfjdyL 2-merhoxy-3-pyridy s 4-rae!.boxy-3- pyridyL 2-nieiiioxy-4-pyr!dyi 5 2-{3~oxe¾s :)}iiei i!x -. - rdyS :! 2-(3-oiiet<¾s " syi}«xy-4-pyndy ;> 5- i1iS-oro-2-meili»sy-4-pyridyl 3-fl«oro-4-pyridyL 2-{ksoro-5-pyridyL 3-l!uoro-3-pyTidyL 3-r«eihoxy-4* pyridyL 2-crh«xy-4i>yrjdyl, 2-meibi3xy-5~pyrfdyk 2-f23^isbydroxyprapoxyj-5-p>-tidyi, 2- ¾yd5:oxymeiboxy-5-pyridy!, 2-byd5¾xyeiboxy-5-pyd:dyL 2-1:iydf0XYeiboxy-4-py:ri;dyl.5-.f ioro-2~ S:¾ydmxyesbexy-4-pyridy!, 2-ineftioxy«h0xy-5-jsyridyl < 2 iydroxyn»t¾yl-5-pyridyI, 3-meihoxy-5- pyridyK 2 d:ioxy-S-pyndyi 2-tS0propoxy-5-pyridyi, 2 }ydmxy-2-a)cdiylpropoxy-5-py:ddy! ! 24 \ J .i - friSji05:oet!i&sy)-¾-pyi ' idyl 2-cyck) i¾ i5iietbftsy ' 5-p<ddft i, 2-iinelbyiSttlt¾Byi.p«j : poxy 5«p tidyl 2 ined:iyisttlib:nyii3:mfsio¾Shoxyj-5^yndy!, 2-e ioxypiopoxy-4-pYfidy!., 2-diflijot(»Bieiboxy-5~pyfk1yi, 2-{Jti0ro4 « pyridyi t 2-chloi t-4-pyiidy!, i-ciiioro'S-pyrkiyl - l:dtii'o~5-pyridyi, 2 ya 0-4~pyndyi, 2 »

.pyiidyl, J-cyayo-S-p n L 3~syaao-4-pyridyl, 2-miiiisyfeulJ¾8yi » 5-pyridyl 3-iaeihylsu!fo.ayH- pyndyl, 24wediylsu!¾8y ' fe»t»aoH--pyndyl >

2-TOeio yii; " «s:!05:ne& i- -pyrid I, 2-oxo- ! t 2-d}bydropyridi8-4-yi, i-isediy!-2-oxo 1 2-difcydropyridi»- 5~vL 1 -mel!iyi-2-o.x -I.2'dibydropyf!din-4-yl I -e iyi-2-oxo-I < 2-dihyd!¾pyridl«-5-yi > i -isopfopyl*2- .1 -fiydfoxyei.byI-2-oxo-.l ,2 -di y dm yri cii ri- 5 -y 1.54iydroxyprDpyS-2~oxo- L2-dihydmpyndm-5-yL l-meihy!~2-axo4i ,2 !i5:i ¾^ 2- bydroxypynd-S-yk 2-aMi»oearbo»yi-4-pyiidyl 2-med ^ 3- methylami «0CiSrbo»yi-S-pyridyS , 2 s propyiaminocarbonyi~4-pyrldyi 3-dieth s .i«aiaoc¾rbom f i-5- pyrklyl, 2-raeih fBifea lef¾ l¾niao a} eayM ) ridyl i 2-!i!ei: Is:aii¾RyiaKd:noe!ij lani!»Gc oa S- 4-pyiidyl

pyrklyl 2~hydroxy¾d:5yta«5i^<icaf¾oftyI-4-pyfidyi r 2-!iydr xyetbySaiKitiocarbos:iyi-5-pyrsdyl s 3- h d½xyeth l5imi:ftoa}fbHiyi- -p iidyl, 2 !ydx¾xybxitylawifloc8ibo«yl-4-pyridyt 2- 07ed50 stfeyiaBiiHO ar o5 ' !yi- - yTs.d l, 4 kiOi>-2-«5ediy!ani!«ocarbo«y!aaiino-5 » pyridyl 2~(l- m.da¾ly!)pynd-4~y!, S-pydisidinyL S-amiiio^S-pyiimidBi l^-c aa -S-pyriHttdio l.2-mclhoxy-S- pyrirsidiayl, 2~eiboxy~5-pyr«md!s5y? t 2 sopr0poxy-S-pyrimidi»yl 2-trUl«oroetb0xy-5-j>yrat»dinyI, 4' idiluoro s^ l^-pym ^ 2-5:di1«oroe!lwl-5-pyrirak!!ayL 2- dlmed.5yl3ms:¾ocar onyIpyrs5:«ldifi--5-yl. pyta¾ii:-2-yl pyrid»xift-4-yl 3-bea¾od¾e:RyL 5-beaxefiiiyl, 5-iadoiyl, 2-ox> dihydro-S-mdc4yi. : 6-iadoSyl. > 2-oxo-dihydro-iS-:mdCiiyL. i-a)eli i-2-o¾0-dihydro-6~Midoiyt i idaxoi i jpyiidiH.-3-yi. i idaxoj 1 -ajpyr.idift~6-yl bmdszoj Ϊ ,5-a]pyr¾j»--?-yi, i»»dt«o| ' 1 ,2-ajpy>idia-i>-y! 5 ! J -dioxo-2-infirhyl-3,4-di ydre-2H-

iseilty!- 1 ,! -dioxkio-3, HSi ydro- H- eazoib}i 1 , ^ ]0s£U]:ii sii iiE- -yt 5-όχ -4-Ηϊ«!ιν1-2 : , > A5-

4]oxaildepis¾[2 -- : b] yiidiii--8-yl.4-raeihy?~5-oxo-3Ad5¾ydrob^^

a)cdiyl-5-«xo-2 i 3,4J-feiraI:5ydro~pyrsdo ! 2-fl ^! ^lo xe in-T- l, bej.¾oxazoi-4-yi, 2- mediyIbeB2osa¾o!-5-yl, 2^ihyhen*oxa;¾el~5-} t 2-is pr-epylbe«xoxa«ol « 5-y!. > 2-oxo*20H)~ bea¾o[djoxa¾ol-5-yl s . beaxo&asol-G-yl., hesKQdifaio-S- b tozotbia¾»l-6-yl ; .2-mei:h>4beaio 5&¾>i-

5- yi.2-isap:ropyibenxi)[d]thia 6i-6-yi. ! i -nie!¾ l-5 jeazii«fdaioj l 5-lad&¾>.ly.l, S -5i¾fiibyS-5-iad¾iolyI,

6- iada¾>lyL i~ai¾¾yi-6-i«daa3!y!, 2-i«e¾y.l-2M adaxo!-4-yI, 7-s¾aindol-6-yt 7~a¾¾indfti-4~yL 1 dj«ic l-2,3-d¾yd5t>-:{H-p miol ' 2,3-bj yridto-5- 1 s 2 > 3-diaydro-iH-py«»io2,?-b]pytidi!v5-y{, ¼azo¼0xa¾oJ- -yl 3.- eib ! e «o| s6xazoi-^ 2-jwi:hyi- e-nieilio -^-o o-beezo!dlisoxa o!-S- b 2-i∞t ylox8«ol.o|.5 ! 4-felpyiidin-S-yl, 2-H!eibyS.oxa^oio|5 ( 4- blpyr(dift-8-yl2 » «ieiby! -ox ! , I -dioxo-4-metftyi-3 t 4- dihydrQ-2K«pyriifop < 2-bj( i ]l } m;?m*7-yi, 2* xo- 1 II » sm:kia^[4,5^jpyridbj » 2{3H}-6-yl mddszo[U-a]p dds^ , yt imldiszoi S-ajp ndiS'S- i, 2-oxo-2 dihydro- S H-imkia¾of . 4,5-b.te tdia-6-y ί, a-oxo-S ^ B-dibydro en oldJox iio!-S-yl, 3-oxo-

S^l 4i d¾yraei y! 1A

hyd medi !- .3~dih dm L4 :>4wdrojiya5£t&yi-2, -dibydro- [i ; 4]di si:aoi2 > 3 )pyri.dift-?-yS, 6-qaiao.Uayi 7-quln.olmyL 44$»qib:«ob:ayl, ?4.soq«iaoii«yl, LS- nap hyridia-3-yl, 3-methyl-:lH-pmzolo}\4-bjpyf .tt-5-yl, lB~pyra2oioj:3Abjpyridia-4-y] .or - f»ediy]-!H~pyr3i:elop,4-b|pyridi:a-4-yl; and a pitanstaceaiicaiiy acceptable salt thereat

17, Coffipoiad. of Claim wherein ' is H„ or rda¾>: and a pteinaeeiaiealiy acceptable saii thereof.

18, Co ound of Claim S hereift G is CM; nod a pbannacetitipa!iy itctcp te sals s hereof 19:. Cotnpotmd. of Claim S %vhe?¾ia G is C-Q; Q is B; i> is -L- s .; aad 8 s is 5 numbered nitrogen coi«.¾i«uig aeterocyctyl 5 i¾a¾bered oxygen containing heterocyciyl, 6 numbered nitrogen containing aetcrocye!yl, 6 raembeted oxygea c a aiaing isetetocyc yl, phenyl. benzyl, 9 esH ered bkyclic nitrogen costaiaisg hc&rocycl l, i -meja ' bctcd bicycHc oxygea .eoayaaiag netssoeyciyl or 1-0 raembered bicyciic nitrogen containin hetetocyciyl*

wherein R ' is uasnbstituted or sirbstiftrted wis* one csr more snbstitucftts independently se!ecicd from Ci- alkyi, eyaso. halo, C t .« affcoxy, Cs^ haloaikyl,€$« ai&oxycarbony!, eatboxy, C 5 .<;

alkoxy-C s kyiamitioc-srbaayl, aikylaaiiaocarbdfiyl, Cj.fi alfcyla iiio-Cs.*

alkylsaminocarboiiyl or (optionally substituted - membered nitrogen cotitamsig

]ifiierocyciyl|caibonyi;

and a p&sn sceuucsO acceptable salt thereof

.20. Compound of Claim 1 wherein <3 is C-Q; Q is 14; P is ~L-R S ; nd R" is

te fatwdrofiirsayl, seirahydropyranyi 3,4~dihydro-2H-pynii^]3 2- ]pyridayl, ehmraanyi, l:iexaS.rydroiiii¾>[2 -b]furyL piperidinyL pyridyl pyrazolyi tett&zalylphenyl, qidnannyi Ϊ.2- dihydroquiaoHayJ, pyiro inyf beimd, S 5 6 s ? J 8-ieu¾hydro uiaoS.iayf ■QtaaoxaifnyL ia ^H yL } iWadaz l l, SH-iadiwoiyi, isoiadoim l* ( i ,2,4}trim :l0i43-:3]pyrtdi&yl, iH-pyf'axoloiS^-dl yriiiiidiayl isoqifiiiobnyl, :l H-pyta:mloj . 3 ,4-b jpyridinyb imtdazo[ i ,2-ajpyridiayi 3H-imida*o|4,5-ajpyridiayL pyTadinzinyl, pyraxrnyl,, pyriaridiay!, 4,5 > t ? « tett¾bydm-3H- pyfais l lS lpyridro U 3 t *dihydro-2H^ {¾noi;2 y ¾-cjp ridift ! y of caToraanyl,,

wtoersia E" is uosubstitaied or substftuisd. with o«s or more subsiitueais independently selected ifom methyl eihyi cy&ao, -chioro, rlaoro, elhoxy, tritiuommeffayl edio&ycarbonyl, teri- ¼t©xycarbonyi, car oxy, K-<a)gthyI : N-(.tne{¾oxyetliyl)5aaiaoearboBy t (K.H-

yl)csrhonyS.. or oxo;

and a pbarnsacentkaby acceptable salt thereof.

2i . Compound of Claim 3 svfcerein Q Is C-Q; Q is H; ? is -L-R s ; md ** is

l -Boc-psperidin-4-yi.

2-pyridyl, 3-pyridyl 4-pyridyL 2-nieIi]yl-3-pysidyl 2-ineibyl-4-pyndyI- 2-me*feyl-S-pyridyi, 2- metivyi-ii-pyridyi, 3--!aejl:y! » 4-pyddyL 3<m«thyl-5-pyridyl, 4-mediybi-pyndyl, 2,6-dintethyi-3- pyridyl 2,4-dimetbyf 3-pyridyl 2 -^^ ^ ^ 4, -daBeiby:l- 2-pyridyi 2.5-dauethyl-3-pyridyj > 2-¾hyi « 3-pyri yi, 3-e!byl-5-pyiidyl 2-csbyb6-niethyl-3- pyridyf, 3-etiryl-6-med'iyi-5-pyridyi ' 3 sopropyi-5-pyridyi, 3-prop-i-eri-l-y!-5-pyridyl 3-( snediyled¾eny! 5-pyriiiyi, 3- yt:i propyi-S-pyridyS, 2-hyc¾Osy!nei¾yi-3-pyiidyl 3- bydroxymeihyi.-5-pyridy 3H2-bydroxye¾y!}-S.pyridyS 2«{1 "hydroxy- 1 mietnyted5yi;i-3~ ra£i:hy!~5-pyridyL 2- ydroxypropyS-S-pyridyL 34 S .2~.d&ydroxyethyi)-5~pyridyK 2- fnfluoroti!Cihyi-S-pyTidyi, 2 n:iliiO»i)Kl.hyl-4-pyridyl, 2-uifiuoro!¾ef.hyl-3-pyridyi, 3-mei.hy!- 24:ri8uorome£hy]-5-pyridyK 4-Bic 1-S-ttifittotan¾M¾yi-6-pyr-dy 3-trifluoroKiei y!-5- pyndyi, 3»Bi}lt tf^scihy{-5-flw(>:{Xi-{)- y ' rkiyi 5 4-f:tiilaoiOB:iei¾y!-2-c:i)ioro-3-pyridyl : , 2- njethoxy-5-pyridyl, 3-{2 > iiydroxypropy 5 < pyri l !H^-hydtgxye^i^S-p rid l ^ ^^netlioxy- 5-pyridyt 3-e:ihoxy-5-pyridyl 2*iaeihasy-4-a)ef yl « 5-pyrjd l, 2-¾iethoxy-i>-ed:iy!--5-pyr!dyL 2 » cyano-3-pyriOyl, 3-cy¾i s-4-pyiidy!, S-cy&fio-.S-pyfidyi S-c ario^^ iihiCironietb i-S- i d i 4-e!doro-34iyndyI, 3-ebbro-4- cysi:iio-5-pyr)dyL 24luoro-5«pyri yl, 3~ilooro-5-pyridyl 4-fii sro-3~pyridyL 2-cbbro-5-mediyi-

3- pyridyl, 2-liOirao-3-n:ie?l:iyi-5-pyri.dyK 1 ,4-d¾¾;d:¾y!-2-exopyrid5i¾-5-yI I f 3-d!f:»eiayl-2- yxopyridin-S- i .1 ,2-d«ifithy!-6~0xapyF5df.n-3--yl 1 -meifc !-2-:Oxopyrid!a-5-yl 2-i:neifeyi-6- OKopyn:d¾-4-yl l-e{i.¾yl-2-oxopytidia-5-yL 4-eiIiyi-l-medjyi-2-oxopyridiH-5-y), i-etayl*2~ a)cr y.M)-oxo|>yn ' di»-5-yi, :t sopropy.l-24>xopyrid¾-5-yK 1 ,2~d!mdayl !-ox0p ik1¾i-S~ t 1- «5cdiy!-2-lnOu05:niedwl-6-oxopyddin-4-yi i i-n iiyl-S^ iilaomie iyi^-oxopyrida^- S, 2- 4- mOTpiioS!:tiy]s:neiis : yi)-3-pyridyi 2-(ier^b!«yS≤anii¾0CiirbonyS.)-4-py!idyl > 2- Cs!eti>osy¾d:iyla»dftocarb0ftyi)-6-pyridyl, .^(. n^feo phea -S-pyrid , 3-{3-f!uoi«-5- «.iet¾oxypheaj ! l}-5-pyridyi

5-pyrimidioyi, 4-c Soi -5-a!e:S> S-pydrak!iii-ii-yi, 24 ibBednd-pydmkiaW>~yl 2- eys»opyrP:»idio~5-yl 2-iriilooro«iethyi-pyr iiiilit!-5-yl, 4*flxiof0pyr «di«-2-yK S- i]iiOi¾spyriisddi»»2-yl 4-u:iR«oromsdj S- rimidiH-5» t 2-axgtida ' }yiear%onyt-pyfa2a ' i-S-y!- 2* dimcthyamaK^oxiyH^idi^S-y},. pyradi»¾ia-3-yK

t ,3,5 rimet.hyl- -pwolyl < l-si!iyi-S-pyta^oSy I, j-isopropyS~S-pyra¾dyi i -ei. ' hyl-4-bromo-5- pyra¾oiyi s i-ciftyl-4-m«&yi-5-pyrai!oS:yJ > l-&tby^3-a>8¾KSrxymeifty?-5-py oiyl, i-«ieihyS-3- dii»ed l:aiiBaocarboii I-5-pysisxoi I ; l-met]?yI-3 yx1opK)p -5-p>razo>iy1, .1 -ei¾yl†etei¾oi-2>yl; piieayi, 2,{>-dtiluo;ropIiei5yL 2-iIi!oroplie:t!yL 24~dillu0rophs¾y], 2 A64nitii0i¾pSieayi.2,5- diil oropb^ l ^ a^-^if!itomph^a ., 2 -d:if1ii io- -m¾h«x p fi9 L 2 5 4-dii¾KSO~3- .aiethos.ypheft.yK -chlo¾»pSieii S 5 2 J-diddoropaeftyL 2, -dic ifiroph.en.y 3~ch.!orc»-2- fluorophmy, 3 « c lQro-44IuQrophenyi > 2-ch.!oro-6-il oropiieiiy!. ; 3-cMor«v6-fl»oroph?ayK 2- H.ttoro-5-{f}.fi:uoiOmeiiiy¾)heayK 3 ydroxymslaylphsftyK MjydroxyethylpheayK 3- hydroxymeihyil-S-Kiethylphmy 1, -aietlicxyp coy K l-SKitexy tasyK 4-«hoxyph.e«yK 2- medwlsidios SpSieayl 3-aiehy}stiifofty¾)heay 24laoro-S- ethy ¾ foay IpheayK 5- et : hylatnin0s«lfo»yl. » 2-fltt©«>pheayl, 2-fluoro-5-med!yIcar o yl.p eayi ! 3- me tox eatbpayl hea K^^carboxy hen K S-meUjyl-S-eihox carborsy ijai l 2-c ' hloro*3- edioxyca(¾OHy!pheRy!,2-fl oro > 5-ffie!ft

!neijox csf aa l beB i 5 i drox «ietb !^5-iB«¾ios cart)oa I hea l, 3-i»efk>xy-5- a)efiioxycarboaylphei¾yl.2~. tiOi¾-5-a)ei?iosycarboayimed'!y]pae!iyi > 2-fUioro~5- carboxysnei!iybijeayL 2 ! 6-dUlaero-3 aeO:iyipl!e«yl 2-ethyIpfeiyK 2-i¾el.fey!-5- eadjoxypaeayi

araioocatoyiftoyi 2-.fl»oro-S-am¾oc85¾onyiplifi-iyl, 2-eyatiopheKyl, 4^yaiK>phmy.l, 2- c <¾iio-3-ini > i yl SKis 2~eyaao-3- eihylphcsiyL 4 Mo:av2-cya»0pheayt 2 hi0ro- y¾ o¾ea l, 3-ch!0«-2-cy asKsphcoy 1 > 3- c!i!os i-f ) *cya:t5o ¾eayi f 2-cyaKO « 3 s -dic&eroptoyI, 2-cyatia-J > 6-4i¾oropheHyl 5 -cya»o-2,6- difcoro beH l 2-ey

flaonjphesyi, 2-cyaftO"6-trif!ii rometSjySj en:y! : 2 iin.o-5-iriS¾iOioraef ! S): i5yS, 3- [{so ropyliiHftiaocaAoay!iplieayi

(m2ift sy«d:i !}amiii0 ar o ! j lieayl, 2-Hisi¾

a)eftsy!-5-j: m€thyS)- : N-(a " ifii lsa¾ 2-metlyy]-5-(i> aedty! yt3¾&-4- l)eaA^

i]ii0!¾-5-(Boprop !)a:nifno arb<5syi} !ieftyi : 2-flaoi-o~3-((K-tsopropyI-^- a¾esfeylaa5ift }caf| >ay i)pl:seay 1 , 2- fkiof o-3 ~(i ci y U*mino)c8ibo«yJ )p¾eay 1 , 2- flaof o-3 -

2- i¾ !ro-5-{c cS£> i l)}a ^^

(cyc!epeHiy!)aifiisiiicaf¾eayI)p¾<;ayl, 2 " Piwro- HfeKab di:opyi'ta) : - -.

yl)}aa¾iaoc;irboi5yi)phei5yl s 2-8ii0ro-5-((mei:!m propy!i)a i^^

{(2-m£. yi.>aj«jao ar onyl>phenvl ! 2-%όΓθ « 5 2-οκ!ίίο: χγ ρί£φγ!^^^^ 2- ihioa S- (I-met ipyr;^ 2-tliiom- -({i-mei!iyipyTa¾oI-4-- 2 1uoro* 5^(i*i^]xyS ra¾oM^

y!n:ied i}}aaii!K3cari>onyI)phenyl 2-il»oi¾-5-f(i J-d»:nediyipyTazoi-4- y]}aKiiaocai:boay1}pl:ieayi 2~i¾ore-S-{ p nd-2- kw

(2?-rl«Ofopiperid.i .- l)>aminoca}¼a i)pheji i.2-Ou fi>-S-(!.-Boc-3-.ni0roplpaidia-4- y!))aminoc3rt>ofty.lphmyi 2-iiaoro-5 i-Boi; rsd5a-4~ ^ 2-¾soi¾-

yl})aftji«OCarboByi}ptoiv ' l, -S«om' -i4-mi;ihy! i e:d¾ 2 diOuoro-SHi-meawl s er ^ 2-iluof -5-( ' p5pendio-4-

a>OTpbola]ylei!iy!}amiaocai¾oay!)pbeay!, 2~cblQi ; o~S arfi0 eih l}a yr^^

c {ofo-5 > {t-p «oU ( litt l€ittbonyl> hm l 5 2-chtoiX>-5 < {{ » «¾eih p ra¾H>4- i) »bon i5fiR

3- {2>btw,«mdazoiy1 spheoyl 3-(2^η¾ίί!νΙ-ί -ieSTazoiyOpasiyL 3-(2-ί»εών!- 1 J,4-oxadj¾o!-3~ y i )phcii.y S 3-i 3-oieiayP 1 ? 2,4-osadiazQ : i-5-yi)phe».yi;. $-.qm»oi»iyl ? 6-qylttolmy!, 7-qataoii» i S-qumelinyL 5-cbtoro-6~qyin Hn.yl,. ?-cbfo:ro-4~ taolinyl, S-chiom-fi-qiuiiosinyL 2-mcthyM~qoinoHnyi S ^T. -teirahytiroQuiKoIiiV'S-y., l,2^4- rahydr0quinoH.t¾-5-yi 5 fi^dimeHi !-S^^-tetra^

qwist>3tal«5-5-yl, i Hsxo soM)do.lks-4-yl, I-oscs-isokidoifii-fs-y, 3-methyl- I l.l-itKterf-4-y:t, 2~ methy 1-2.H -jndazoM- 11 -tBethy i~ I H-mdaSi-S- t 1 d:imef¾yl » IH-mfco-4~yf, i-roelh l-2H)xo f -dfe

l,2-dihydro ui»OljiW>- $-cfti R - i ^ { i-2-os. -I,2-dihy4to ijinOlj«-i>- ^ l,4-diiiiet yi-2- oxi 1 -diS:) dra{lul»oHs}-6-yl 2-όχό- J ,2-di y o^|UHioUfi-6-yl, 4^xo-dihydroqui»0lin~ 1 - i 4> 0xo-qui»o!in { H yL^ SJ-diOuoro-i^-

d)bydf¾q«!Hol!ii-6-yI ! -dii1tsaro-l-msdi i- -o:xe-4-irjflHOTOi«e^

S ,?-diftuom-4-eihyl- aeai bl-as -j ^di ydroquinoiiH-0-yi, 8-isdqiiiBo!myL 7- isoquiiioiinyi 6-feoqtafiei yl, S-lsoquiaoltByi 4-iso ui¾oii«yl l-raethy 1- I H-pynueolop s 4- bj:pyridiH-5-yl 1~ νΙ~ iH-p rszot!op^-bjp ridift-S- l 1 -et y.l H-pyrazoio[3 4Vjpyrid.m-4- yl l-ineibo ; x eti ]-.lH:- yr^olc 3,4-bjp Tidis:i-3-y], 5~iuaro-l-mediyi-]M-pynixofo3,4- blpyridia-S-yi iH-pyj¾¾oio[ 4-d]pyrtn:ddi:R-4-yl ( ¾ί>ϊ da ss 1 s 2-a j py r iitin- 7 - I , i.mtdazo[ 1,2-

6-yi.3-o:iel y!isoxazoio[54-b]pyi1dsii-4~yL ! ,2,4 jirisK4»[4,3-a jpyridin-8-yi, i-meial- ,5 ?4etmhydi¾-3H-pysa/o ;3 t - ½idii^3-y > S^^rffo-lH-pyrasi^^^^lg ndiR-S- l, Of 5*cfiroftia«y5.; a»d a phannaceuticady acceptable salt teebl. i 7, Compound of Cfeisi 1 whereia L is O; a»d a pb»ra¾ae«uticafly acceptable sail: thereof.

.18. Compound of Claim 1 lierein G is C-Q; Q is P is H; and ' R 5 is S membered hcterocyclyl, (> emos red heterocy yl, phenyl, pheoyl-C}.* alfcyt 9 merabered mitogen cooiakiog heseraeyclyf or 10 msmbensd nitrogen containing hetesoe l,

wherein R " is imsubsduued or .substituted widi one or more subsriusersis indepeaden.dy selected from C¾.. a¾yi cy&tso, halo, oxo, liydrox L€ alfcoxy, baio&lk l C tik yammyl earboxy, s-* aSk x aik i-Ct.,, alk lamtoocadw L 0.. ί; slkyiimaoearbonyt C|.¾ aifcy!a i o-C.;, aikylaaHoocarbooyl, or [optionally substituted 4-6 merabered nitrogen comaninig

heterocycSyllcafboftyl;

aada pharmaceutically acceptable salt thereof,

19. Compo-uad of Claim i wherein G is C-Q: Q $ -L-R"; P is H: and R* is pyridyl pyra«4yl < phenyl, benzyl, tetfahydiopyran t piperidmyl

pynx4iadioy! x pyraxinyl pyadttmnyi tetra¾olyl, t|uina*oli»yL qainoliayl, .1 ,2-dihydTotwifi nyl, n quiaoxiiliay!, m-ifldaaelyi, 2H-mdazo!yl f ί s 4}triaeolo{;

jpyndimi jsoquoolinyl imidazof i,2-a.jpyridi8yl, 3H-ftnid&¾J ' 4 5 5 « ajpyridim isosaxo S,4-b)pyfidii)yi, [1 ,4}iri;i2o!o|4,3-a]pyridifiyL 4,5.i>.7-f:eira yd:ra-3H- py«w<!!op ? 4-bjpyi'idf»yl. : i 4-diSiy4f<s-2H-pyraKO:2 : :3-b]py)-id!):iyS or ebroxoafryl or gyrimkliny!;

wherein " is imsabstituted or substituted, vdtb one or more substttucftts iadepeadsntly se!ecied from Suoro, chloro. cyaue, Hieiboxy, triikioremetliyL ethpxycarboiiyL carboxy* K-<i:tjeri¾'l)-N-

{metioxye jy msoc

H¾tfeyiamiaos !}amlaocarbo«yi l iieibySpyr;r^!»y-4-yi)carb<st5yl om methyl, ethyl, or buioxycarboijyl;

and 3 p!isrs aceafieally acceptable salt thereof.

25. Compound of Claim i wherem G h C-Q; Q is -L-R*; P is H; am! s is

btnzy], ieirahydropymo~4-yL :5-fi»oro-t<¾r3iiydropyraa-4-y:{ 5 }-Boc-pfperid i- ~yi,

£xahy rob O2 -b]ft >^

2-pyridyl 3~pyridyL 4-pyridyI, 2-meihy.kl-pyridyl, 2-met¾yi-4-pyTkiyI, ; 2-jjiethyi-5-pyrldy.l, 2- iftei!:iyi-i>-pyridy] s 3ro& :l-4-j>yridyi 5 S4BediyS-S-py!ldyl 4-HietS)yi-3-pyrtiiyi.2,6-diraethy1~3-

pyrtdyi, 2,S-<3i:RieiI]ys-:¾-pyri:dyi ( 2-<ahy!-3-pyridy; 1 3~e iyi-5-pyridyl 2-ed)yi-6-raet¾yl-3-p ridyI y 3- cd:(y[-6-meihyl-5--pyndyL i-isopropyl-S-pyridyl .i-prap> i -eft« 1 -y!-S-pyridyt 3-<l«metfcyiefeflyl}-5- pyridyS, i-hydroxynieibyi-S-pyridyi, 3-{2- !iydroxye !>5-py:iidyl 2^l i dro y- ^I»UϊyI 1¾yi)-3 Iletl ^ ridy 2¾droxyptopyl-5- pyridyl, 2-tn ' iftior meihy 1-4-pyndyt 2-friiI«ororae(hyI-5-pyridyi J-sjctli i-a ritl oromefh i-S- rid !, 4-iBetlxyi-3-lriiIuarometbyM- pyridyL 3-txiQ oK5B« i » 5-pyridyl, 3Hriiluor metbyl-5-fii!OT -6-pyiidyi, 4-tTifluorotV}fiihy{<-2- cS:doro~3-pyridyi 2-.met oxy-5-pyridyl, 3-{2-irydrexypropYl)-5-pyridyL 3-(2-.lrydfox.yetb.yl}-5- pyridyl.3-)«fit¾oxy-5-pyddyi, . -ethoxy-S~pyn.dyi, 2-:n¾.tfeo.xy-6- ethyi~5-pyridyi.2 * cyaao-3«py.ridyL 3-cys«ci-4-pyridyi, 3~cyaao-S-pyridyi ; 2-cyaao-5- iril¾}QTOinfid:¾ i-3-pyfid. i 2-ciitoro-3-pyridy.l, l-cMoro-S-pyridyl, 3-chioro-5-pyddyL 4-ch¼ro-3- pyndyL S-cidoro-4-cyaao-5-pyridyI, 2-l¾i iXs-5-pyridyL 3-0uoi¾- ~pyridyL 4-:i¾joro-3-pyi1dy! ; 2- d:daro-5-pii;ti:tyS-^- yrid i, 2.-b5¾p3o-.3-Kietii 1-5- i'idyl i,4-dii5iebyl2-ox )yridia-5-vl, 1,3- dbaethyi-2-oxopyridiK-S-yl, } .,2^iiBetbyl-6- )xopyrid;ia-<3-yl, 1 -raefiiy}-2-oxopyridio-5-yi, 2*oset¾yl- -oxopyi;di.ii-4-yi, ί -edi l-S-oxopyridm-S-yi,

fi-oxopyridm-S-yl, i-|¾ propy?-2-tix pyrsdi«-5- l ! i,2~disfieibyi-6-oxipyridia-3-yi {-m«thy ' !-2- lriilocs oieS¾yi-6-o O rfdi - -yS. NojetJtyl-S-tdiM nwebyi^- xo ridja^- l, 2-(4- ri:i0rpbolirsy!raedryI)-3-pyTidyl, 2-(i:srt-burylaHii»e arboi}yl}-4-pyridyi, 2- (meh xyeiix ia£ftj¾K)cait!onySi-<}-p nd L 3-3-rjs.feoxyp.he«> i l hS-p nd

7 2-cyariopvrlmkb«-5~ yl 2-ίΓίβ«0Γ0«^:¾ν1-ρ τ!«·ίί^ί!>5-·ν1, 4-i¾orQp Ti 5diii-2-yt 5-il«0.ropyriinl4m-2-yl, 4~

V"\ I pvj;i ii)!::ii- -νΐ.

ί ,5-I:dised5 i- -p ! ¾olyl i -ei!iyl-S-pyrazQiyl.. -isopropyS-5-pyiy»olyL ! -ed:iyI- -brome-S- pyraxoSyL I -ediy!-4-mediyi-S-j>yraxoi l I ^ '-3 « ro«to {»e¾yi-5- -yi¾i:oyl s I -methyl -3- I jiiiybKiia oM- t phenyl l/ ittmstephay 2~iJaorc>pkayi 2 t 4~di0u6rftphesyl 24,6-¾if!uofeplieiiyt 2,5-diIluoE¾pS:igHyi -d!¾oroptaiyt ,6- fluoro-3-r»dhox ^ ^ ^ 3-di!oix>pheayL 2,6-dkhifm>phenyi, 2 *$cblor®pheayi, 3 ¾lQro-2- ti»ropi>en S,.3-c] " oTO^-ikiora ¾ea l, 2-ci¾loro-

6- n«orop e»yi, 3-efcl0m-fi~11ucraphei) L 2 1iKmv5 nf1yoron^

3-hydroxyei&yipiie«yI, 3 iydioxyKieibyl-5*iu<;0iyipbeny1, 2-85«thoxyp.heay 4- fficoioxypaeayt, 2-i»etbyl¾jifofty¾)heH l, ; me,byisdfoaylp&eay1, 2-ihioro-S- ebyisaiibfiylpiieiiyi, 5- ei!i la!i¾inos¾dfbii S-2~l]iiii¾|ih£«yl 2-:{¾iom-5-a)ei k¾it>o« !pbeoyt 3-ΐΐΚϊΙ¾ο:χν£:3:Γ¾ο«ν1ρ]¾η 13- catb xyp aiy ' t 2-.nieib1-5»s ?xyc»fbo»y.|p.he»yt < 2~ hSoii 5-efiios car «¾iySpbi;n L 2-.fluoro-5- 3-«)«iayS-S-med}ox carb»ft ]piie!xyi:.3-l)ydmx.ym«¾yl-S- HWthoxycarboaySphciiy!, 3-HW ),ox -- -8K;diexycSfbo«y! be y!, 2«ila¾re-5- incdioxycarbonyaiethySphejiyl 2-fi«oto-S-c3i oxyoiel¾y]pbcnyi I 2,6-Mu»fe-$-B > iaylph<myI.2- eihylpheayi, 2 « m£tbyi-5 yjboxypl:teByl 2*ehl¾ro*5-carb3xyptayi, i.-iluoro-S-carlw ypbcnyL 2- c or^5*5ffi0ftoCar¾ Syi h«H i, 2-fi« ro-3"ao¾ :>ocar i« i beriyl .2-ev¾iophC > ayi 4-eyaaoph ayi, 2* sya«o-3- iiid! Ipbii!]: l 4- cMoro»2-cya&opb.e&yi t 2<ΜθΓθ~ - ¾»ορΙϊο>νΙ 3-cb:or -2-cya«opij£iiy1, 3-d:doro-b-cyaE5opbe3iyL 2- cya»e-3 > d-dfcblerop eRyl, 2~cyaao- ' 3,6-diiluo.ropljeay 4-c a5JO-2, Kb8uoropbeft L 2-eyano-S~ i¾j Fo be» l 2«cyaao~6 liIorapl: yL iom-2^

{rifluommetfeylpteiyl . , 2-cyano-5-infltsQTOS3eiityiplsei5yb 3-{(isopmpyl)amiaK¾rbonyl]pliaiyf..5- meibyl-S-Kisoprop i^fttoocatboayriph^!i ., -why^34 kopwpy{)ami«oa¾sB(«yi;} iv∞y!., 2- :m$&y1.-5-[ md« i)- ^

dimethyJ.}ai»laoc¾iTboayl ' |p}ieayi ? 2-i¾edsy]-5- -(ined:iy!)- -

di¾Oia-3 (is propyi)amffi 2»:0wro-5-{(fS»pmp i}am 2- 2-ftHi!m-3-{{ed¾ylaraH:io) «rbo y!y he¾> !. ; 2- fiaoro-3-< ]uor«d: y]3ffim

2-f¾i io-S-(cyc!obutyl))mniHocar ny]}pbe»yl S-naoro-iHi clqpemyi^vaVK ' ny pk^y^ 2- ¾oro-5-iteP¾ dra|¾¾^

<mertox> ropyl))ammdc-ati>oay aeayi 2 > flwf ^5-(i2-me 1>amia carixjn 1pheB l, 3-!lnoro-5- ( 2-n>ethoxy ropy I )afcMnocark>ny1 }phs».yi 2- iI»or -5 -(.1 -meSfeoxy- 1 - meSli ledwI sainisocarbOb Sj iieswi, 2-ddoro-5~i( S. -pyrrPiladiB iJcarboii iipiiea i, 2*cWoro-5«(Ci < 3-

i1ii0ro-5 (i-aietii lp ^ 2-S¾iOiX)-5~((i-!«s¾.yipyTi¾¾«l-5-

Cteti¾hyd«s yraii- ->½ietf^^ ^ ^ 2-flaoro-5-(< I -<lio5e5¾ySpytj ol-4- yl}ii!i:i!BOcarboityS)p eayL 2:-i]«om-5-{( yrid« - t^^ yiytaramocarbm^^ 2<-ihi0ti -5»(l~ ¾OR^ Upipg n^yl) . )aiai^aife a-lg ]¾jyl > 2-fl«oro-:5Hl-eihYl-pip rdd:i-4- yI})a!ni»ocarb«ftyi)p eayL 2-rluoro-5-i i-t»eil)ylp^eridin^-yl )amiaocarbo»yi)p. eByi, 2,6-diiltioro- S S-ra£ibyIpiperidin-4-yIJ^

2- 1¾ ioro- -i4-morpba linyjtemisKX arboay I }pf>esiyi, 2-fltjpro~5*( : (4- 0i:0T bo!biyleiiiy!}amii5ocad3{)H I)pieayl,

5-{ l-pyrroiidinylcirboay phenyi, 2-cl: oro-5-ii-raeibylpy¾zia-4-yl)carb«fiyl} bei5yl, 3-{2- bea¾midis¾Syi}p¾. !iyi..>-t2-raethyi- i -5et!¾ oiy})pheiiyI .H2-meby]-.l ,4~ox i xd- - i Si£n i 3- f3-a^iby! ,2,4-osadiai!Ol-5-y!.}p]¾;nyS,

S-quiaoJisiyi.6-Quiii»;i:ftyi 5 . i- uiaoiiayl S-qtdftolifiyt S-cbloro-d-qtdfioliftyl 7 bio:ro- -qd«oKf) L 8- &hleto-6-q«K!olmyl 2-metftyMK i«s¾yl 5 f 67,S etrAydtwqoiti©HB-5-.yt i, 23.4-

1- faedsy!- rH-!(idswisi-5- L Ϊ ~disH¾:5i M H-s:»d zo14-yi [133trs«zob| -ap r!dia-¾- i l-ateibyi- .¾K;i& l-2-oxo-I d¾yd5Oqttmoli«-'i-> 5-chloro- ί -πκώνί-2*<3Λθ- i3~dihyd?e¾ai?io!ia-6-Yl t, ^a^ l-2-oxo-3. «dibydroqumoli»-6-y{ ! .2-oxo-i ,2-dihydroq«inoUn-<- 1,

5,7 « dif¾iom-i 3 » 4 « tnmtthyI-2-oxo*1 ,2- dihydroq»ffi ii5i-6-yl 5jKM1ium-l-ra£tli l~ -a 0~ -^^^ ^ 5.7- di¾or©-4-etb f- S 6- iSOCftimoUoy 5-iso «iao »y:,4-isoqiHaoi iyi 5 i-m0ii)yWH-p jfi^ol 5 - pyr}di» {, l-slbyMH- pyras5ete[ . ¾4 > jpyrid*n-3-yi i-etby!- I H~pyra¾i 33-b|pyridiii-4-yL I -aiedioxyeiiiy!- 1 M~ pyra¾oksS,4-b¾iyridjin-3-yl 5 S-flaoro- ! -laef&y I ii-py:ra olo|3 ; 4-bjpYrkiiJt-¾-yi ! lM-pyra oI.o3,4-

h]pyridii}-5-yL 3-SKiiiyS-3li-i:ffiidaxcf[43-b]pyridif)-6-yi i 3-nidi!yHsoxazoSo53-bIpyfidiii-4-yi : , H.3;4|piami0(4 -aj Yridi!:t-8- i : ,

tfih dro- M- >rarK}2 H^ n m ^ ^ or 5* Chroniiiii-yS; ami a p»an«aeeL«icid!y acceptable 5¾1: Sseisof: A eomposmd of Claim S having Fonmik lie or lid

w erem:

I s is a!kyk alkeayi ¼loa1ky.l, alkoxy, .hydroxyaikyl aaitaoglkyi, aikoxyalky!,

byciroxyaSkoxyalkyk lkoxycarfiosyl mmoaikyi cycloaikyk eyeloalkylaikyk aryl, aralkyl, eierocyd l or beiaEocycSyklkyk whsieta iiie cydoaikyL aryl, arheierocydyi risig i¾ cydoalkyl cyeSoaikyialkyk aryl aYaikyl, hcierocyciyi or beserocyei kyl is uosubsiiiuted or substituted wills. OM r two si!bsiit»e»is tndepetrdaii!y selected fmm hydroxy, alfcoxy, aikyi όχθ Or halo:

&' is a:t¾faoC£trbouyL cyatto, ey¾n ?a!ky], aikyicarbosyk bewocyciyicarbonyt

<i!.kylai5iijiocarboayi : aSkeriyt. alkytiyl, bydroxya!keftyk aSkoxyaikoxyaikyk arySoxyaikeoyi.

alkoxycar oHylalkyl alkyisuifoiiyialikyL aliyktd!bsyiaikeoyl aikylsiilibriyialkyoyi,

heterocydykslkynyl h¾sracydy1earbo«yfaifcyi, alkaxyalkyayl, !¾ ; droxya!ky«yi or-KW

X i& b0Hd, O- 5 or -SiO) ;

n is ik l, ox :

R* is alkyl hydraxyaO yl faaloalkyi, alkoxyaiky!, atkoxyaSkeiiyL a!koxycarbosy!aiky!, earboxyaikyS, aminocarboayia!kyl, aikylarainocarborryiaSkyL aryl cycloalkyi, eyelealkeiwi, heterocyciyl, ataikyi sTalken i, arylaskyiiyi, cydoalkylalky!, cycIoalkyialkeHy! : cycloaikyk]kyiryk heierocyciylaikyi or bcierocycS:yS.carbo»ylaikyS.; bereia the ring R* ts stil ibttcd with .1 -.5 suhstimeais kdspendentiy selected, from H, alkyi, halo, haioalkyi hydrox k alkoxyy aaloaikosy, acyi, a!kylsiilfonyk h terocyclyl a iaosuKbw ' i, atkyiarairwsttifea i, cyaoa, aikox earboiryk earboxy, rniino, R 'N ' -C;^ aikyk alkoxyaikyk hydroxyalky! or ^R^NCO-O}, wb«re W is alky! ;¾εί R* is alkyl a!fcoxyalkyi, anrmioalkyl or aSkyisoJao alkyi w \ ¾a¾ R 8 and. R* ' together with tae ajtr gea form a heterocyclic ring ^substitute or sabsrjtuted with alkyl;

R' is aryl aralkyk aeterocyc yialkyl, cvcloaikyl or Merocyc!yL wftereia R' is tia&tibstiiafed or substituted with 1-3 sa ' bstiixicafs ia rcndeatJy selected fh»a alkyl alkoxy, aydroxy haie, m haioaikyi, cymo, aikox earixmyL carhoxy, acyl eyelosikyl heterocyclyl, feydroxyalkyk alkoxyalkyl. oxo, RR'lsk RR"N-C S aikyl, or .R-R ,! C( .)) where R a is alkyi and R ¾ is alkoxyaikyl or aoiinoaikyl; where I. aad is irrdepeadendy H, alky!, aryl, ¾etferoc«)yl > feeicroeyel ialkyL or cyeioalkyL *te die eteroeyeiylalkyS, cycloalkyS andheieiOeyelyS. rings , are *ssssuhsi:t£utcd oi substituted with I- 3 siibsiitiseHis independently selected from iiik l aikoxy, hydroxy, halo, haioaikyi eyaao. or carboxy; or :R' aad caa together wills the K fnt?) heieroeyclyl ;

* is aryl, aralkyl, heierocyelyi, eterocyelylaiky!.. or cycteaikyl, wherein each of she sfomiKsati sed rings is unsubsrifuted or sabsiitoied with 1 substiiuesis i&deperidently selected tea alkyi Irate, foidkyl aikoxy, idkoxycatho«yl car oxy, m aecKr&my!, hiaerocyciylesrboftyt cyano, eysfealfcyk heieroeydyL hydroxyalkyJ, atayia&yl, 'Sl€H> RRl mo -or acyl;

Qis-L-R s ;.aad

P is -L-S" : aad a . p armaceutically acceptable salt thereof;

provided whe» R 5 is ! -methyl! H-pyraxoi-4~yl, 1. is 0 end R' is methyl. then..R* is not 1 -ethyi-lH- pyra¾oi-5-yI;

tmhcf provided when R' is l-medr i-I.H^pyfaxol-5-yi, L is O and R ! is methyl, ihm Br is not 2- methyb } -oxD- 1 j liiiydrOisoqanioiin-o-yt 5 J-diiIa«ro- i -di:R)eO^yS-2- x¾÷i, -dihy ro ui5 |.ij:i-

6~yl or 1 ,4-riimethy:l-2-oxo- }. s 2-dihydmqoiftoita-6-y.l;- further provided R. ! is not phenyl, or tert-hiityi whea L is O, R ¾ is 2-ethy-S-pyrjdy!, 2 « methyi-3- pyrkiy or 2 i 6*diine!fiyi-3« yrldy5 : md * is 2-pyridyith.io, niethoxyedioxy or iriOuororoeihyl; further provided s is not 4¾$elliyi-2-k8ida¾;olytee l whea R 5 is 2-pyridy iio, L is 0, sad R 6 is 2- eStyi-3-pyridyl.

27, A coinpoa of Cknn I having Formula ΪΪ.Ϊ&:

wherein R ! is C s .« alkyi, C M a!kenyl, haioaikyi. C;.* aikoxy, C t .« aydroxyaikyt,. C s ,, ataiaoaikyi Q... 5 aSkoxy-C:.* alkyi, Ci.s hydroxyalk xy-CVs

alkyi C so £»yi, aryi -Cs alkyi.5-iO membered heterocydyi or 5-10 num eed eieroc clyl-Q. . . * alkyi wherein she aryl or lieierocycl l rtrsg is im.s¾bsfii»led ox substituted with Ofte or two

Sabstitue ts t depead al selected fretit Ci.* alkyi hydroxy, oxo or halo;

S3 hereia R* is-X-R*, eyaao, . ¾ . rt baioaikyi C.i. ¾ cyanoalkyh Gj. s ahtoxycarbouyL

aikylcarhoRyi, 440 membcred heterocyclyScarboayl, arakKjearboay.1, alkyiamlnocarbonyl, C ; ., ; alky], C;... alkenyi, (/.··., alkyayi, C ; , s hydroxyalkyt . 6 hydroxyaifceayi Cj.. s hydroxyalfcyayi,. Cs.. 5 aikoxy-C^ alkyl, C^- aikoxy-C^ alkc&y-Ci,* aikyi, C ; .. s aikffxy-C(. 6 ai.koxy-C ; ,, hakmlkyk C ; , <; al.kox.y-C 2 . g alk«syt C S , S a!koxy-Cj.« alkyayl C S ..gralkoxy-C aikyi, hydroxy-O s aikoxy-Cw aikyi bydroxy-C f ,s alfcoxy- ^ ha ' ioslky ' i, 4 ai¾ikoxy » C;j.. alkyayl, h <frox -Ci.j} aIkexy-C¾ aikyayi, aryloxy- i. 6 akky!, s.<« arySoxy ¾.s : aikettyi, <¾.«> afytey-C M alkv L <¾.« alfcoxyCarboriybC:.* alkyl Cj,; csrboxya!kyk Cj, s alkyl aIkyls«ii¾ayI-C« a!k¾iyi, C wi alkylsidionyi-C^ aikysiyi, CM .O aryl cyeioalkyk CM cydosSkeriyi, 4-11 membercd beierocyciyi, C ; ;.. !C aryi-Cj.s alkyl, C«. w ar i-C;^ a!keayl, C*. ¾ > aryK;¾« alkyoyl, ¾.* cyeioalkyi-C; alkyl, C^ cyeloaSkyl- C M hydroxyaikyi C M cycloalkyi-C^ alksrsyi, C M ; cycloaikyl-C M aikytryl - 10 merabcrsd heieroeyciyi-C ; alkyl, 4- i 0 tamibered aeterocye.lyl-C>.<s aikerivi, 4- S 0 membered feeieroc dy!-Cj-s aikyayi, or 4-1.0 membered Iifiter0c clylcaj¾o»yi-C). . aikyk. wherein the aryl cycloal.kyk cycioaikawl or heteracyciyi nag m I s is ansobstibited or substituted with, i-3 sitbstimenfs indepeadentfy selected from C aikyi. halo * ©xo, RO-,€¾.«, iiaioalkyi, C s ,§ alkylsulfoayteiao-€>..<; aikexy. CM haloa!koxy,, ydro^ -Cu* alkoxy, C,.» alkex -Ci.« akexy, C s aikylsulfoayt- C».« aikoxy. CMS acyi, aikylsairoayi C<. <: alkoxycar oayl, esroxy, 5-10 rnemhered beieroeyeiyi.5-10

HKiK ered heteiocyctyi-Ci.. 4 aikyi, C : <,;, cycioaikyl, C ; , s cycSo iky!-C;.s aikyi, asaiao, aninosyJfoByL . C;. sfik kin isosiilfosi l Cs^ alkyis«l¾«y¼nii;o<j, cyan©, carboxy, R ' ^ s aikyi, Ct« alkox -Cj.* aliiyl C 5 . 6 aitoxyimino-Ci.s alkyl, C;, < ; Itydroxyalkyl or R s R¾C O}- where R* is H, or CK aikyi md H ¾ is H, aikyi, C s .s hydrox alkyl C», ; aikoxy-C^ aikyi, C ikyiailibiwl- C w alkyl, Cj* abi:yis lf¾s:iySai»ii! -- Cf.« aikyi C W; affiffioal¾yl or aiky { -C. w > ¾»»ί κι !> of: wSsere 8* »d ¾ !> together itfc the nitrogcai form a 5-6 meaiberd hsterocyclic ting imsubsthuted o¾ subssUttued with Q. ft alkyl;

wherein is S or O:

herela R' is alkyl, C ; . ( , hydroxya!kyi, Ct-s baiaaikyi. bydroxyalkyayi. CM. aikoxy- Ci ,4 aikyi, Q.s alkoxy-Q ,·; alkeayi, alkoxy-G^ alkyayl, . ;i aS.koxy arbonyl--C 1 . s aikyi, £* Λ cafboxya!kyk a anqearfeoa l-Ci.* aikyi, aikyi, atyi, cycioaiky],. C^.? cy !oalke¾yi, 5-10 S rsa redteeiwc clyl, C 5 ,. I0 -^yl-C^ aikyi Cs-m 8tji½ alkeayl, Cs. i8 aryi- cyc!oaikyi-Cj. f , alkeayl, C ? . $ cycioaik f-Cr>.. 5 aSkyoyk 5-i0 iHei ered heterocyeiyl-Ci. f i alkyl, or 5- If ) iwai eed beteroc ciylcarbO ybC;.,; aikyi; wieiein. ike aryi, cycksaikyl, cy loaikesyi or beisx cyciyl rin ¾ R 's is yasabsiiMtied or sribsibaicd witb i- mbUiiu s inie&t&zmi? elected, from C & aikyi, halo, Ct.i. kaioaikyl hydroxy!, CV* alkoxy, CVs ifcyk€;,,; aikykuStbriyi, Cj. f ; alkoxycarboayk carboxy, 5-iC* membered boieroeyclyk cyafio, -ammo, C ; . i„ aramoalkyl. aSk sy-Ci.* alkyl C M . iryi¼xya!kyL C 5 .«. liafoa!kexy, C>.<; aiky!-NRR', ama salfo»yl,€i* alkyla«jisoswii¾fiyl or R'R^N i-O) where R s is. C s .« aikyi a b is G w alkyl,

S4: Ci A a!koxy~€f.i. alkyl, C> · : aaimoaJkyl or€ M < alkyl-C 3 ,« aannoaikyk or whe e R* and R' : together with, the nitrogen .ton. a 5 or <> e bered heterocyclic ring unsabsiihttcd or substituted with 14 alkyl; where R and IT is independently H, C^. alkyl, pkeryl, 5-10 emfeered heserocyciyi, 5- 10 taenteed heterocy yl-Cj.* atkyL eydoalky C$. j6 aryt-C^ alkyl, C eydoalkyi-C¾„ alkyl; where the , pbsnyl C ? .« eyc!eaikyi and ' 5-10 merabered. heterocyciyi rings are unsubstituted or Substituted with 5-3 substifufirtts jadependemly selected from C > alkyl, e>xo : a!koxy, hydroxy, ba!o, 0> atoaiky! cyaiiO > or carhoxy; or R + an R east together with the form 5-10 !«embere heteroey !yl;

where R : is phenyl, 5-i0 «3e-m ered heierocyc!yf, .5-10 laetrsbered heterecyelyi-CM. alkyl, or C:i.. f : cyeloaikyL where she beterocyeiyl, phenyl, C « eydoaikyl and 5-10.tftes¾bered beierocyclyl rings are m^wbs uiied or substUnted with 1-3 swbsmnents isdepeadentSy selected from C alkyl, Cu lkoxy, hydroxy, oxo, halo, C«i haloalkyl cyano, or carboxy: and

wherein R" is 5 rae tjeted ajtrogea coruataiag heteroeydyL 5 mejsfeered oxygea eoafaiaiag heterocyclyl, 6. eaibered alleges containing heterocyclyl < > membere oxygen comaiahig heteroeyelyl phenyl, benzyl 9 membered. hicyclic nitrogen cc-tttaiaiag hetsrocyelyl 10 ntsffibsred ' felcyeUc axygea centeifttng hsterocydyJ or 10 merobered hicyclic a trogea .containing heterocyclyl . wherein R" is taisahstituied or sahsfci&tfsdw h ©ne or mom snbstituetits independently selected front C;.. s alkyl, cyaao, halo, 0x0, RO-, C > haloaiky Cj.« hydroxyalkyl, C- alkoxy- C w stlkyi, C«« aikoxycar ort i- C t -s alfcyi, Cj.( alkeriyl, CM> aikoxyesrboiryk carboxy. C cycioa ' lkyi . R-a!kyh optionally substituted 4-6 membered lieieroeydyl (optionally substituted 4-6 niemhered mtrogen somaisia hetoocydyijcaitonyi RR' SO¾ -, RR' $i¾ % RSOr or R* ^NC( :K 0h where R 8 is H, or C t ,i kyl sad R : is ii, c w alkyl€>,« !rydroxyaikyi, C W aikox - ^ .alkyl C w aramoaikyl or C,. ¾ alkyi-C WI ammoaifcyl or Where R s and R !> together with, the nitrogen form a 4-6 jaemberod heierocyebe ring nasubstUtued Q.r substituted with CM * alkyl;

provided R ! is aot phenyl or tert-btnyi whea I 5 is 2-pyridyit¾io, msthoxyetboxy ortrit uorometb l and ' R s is 2-etbyi-3-pyridy 2-Hjeihyl-3-pyridyk or 2,0-dimethyI-3-pyTidyi;

aallter provided R s is not d-aiethyl-l-iaiidaxolylaietliyi hea. R " is 2-pyridylthto aad. R* is 2-ethyi-3- pyridyl:

and. a pkanaaeetsiiea!! acceptable salt thereof;

28. Cotnpotiad. of Claim 27 hereia R ! is meihyi, ethyl, propyl, allyk ten-btityl, triflaoro- ethy atefhesxy, laethosyetby!, hydroxyeikyS, bydfoxypropyl, 2, -dibydroxyprQpyl, 1,2- dibydi¾xypropyi, irydfttxyetb-oxyeihyl OC-aaaaoethyl, aoiiaoeth l, 2-bydfo yphe!^yhne8iy 3- h dTOs heayiitiedi L 4-hydroxy-phenyhaethy 4-fl fOxcipheftyiHiethy!, pheaeikyi, a:toipboita-4- ylethyi. 2-pyrldylmethyS, 3-pyr dylmetby , 4-pyndyImetbyh ft-methy1-2-ox«-l,2- i-ine¾y:-imidaiol-4-yl]:rt¾ihyi, i-iiteihyi-iaildazoi-5- ylmethyl 4-rue hyi-iiiada¾oi-2-yliued¾yL 5-iaethyl-knidaxol-2-ylmet}jy L5-dimediylpyrazok4- y I etbyL 2Vm<„i¾yh.hia£Oiy1~5-:m<iihyK 5~metkvi-iso¾s^ol-3-yimetl¾ ; i or henyl; and a

phannaceutolly acceptable salt thereof.

29. C0H¾K«!iid. of Claim 27 wherein R : is mesh i; and pha-m¾<e¾«t»c¾% acceptable salt thereof,

30, Compound, of Claim 27 wba'eis R* is - ¾>R ! ; a»d a phatmaceuuea!iy te fbte salt thereof

31 , Compound of Claim 27 hereift ¾ ? is .^stkoxypropoxy, 2-(raefimy)preppxy, hydioxyetboSy, hydEcmy ropoxy 2 h rox prapoxy, .1 ,2-d5l†ydroxypropo5iy, I -hydfoxy-2- emylpropoxy, 2 iydroxyhiito.xy, pbenoxy, 2- eikyl-3-pyridy jxy,.3-bxetaiiyi edioxy,

inctlioxycarbo»yhBethyithio, n¾2th«5yc-arbo»ylethythio. nreihaxypropyJtao, 4-85eijhoxy ut-2-yiihjo >

feydmxypmpyfe o, ^^my smy ut i o, c^t oxyet yt o, nietiy mmo?a} }% iiK^ l† . , (dknetb teinocajti^ij l^sthyhhio, {3^ydroxy-3-Hiethylbiityl>thio, (2-hydmxy-2-metliySb«iyi)iS:HO, diSluoro eihylihics,

y!)carbosiy!:iJ!.ei¾yl!:b!.o, (l-½ii. uoxycar e ptperidia^yi «eil)y!i«o. C4-pipci)<ii:ny!)«ietiiylthio, 0eirahydf -2H^ymiv4-yriimcfey.U¾io.. Htetri¾iydr^2H-pyras-4-yl)et!iylfhio 5 <S-!sethyl-2- oxa atzolyft ethyl&io, 2-pyxidylms :iifaio >

hydroxycydohexykhio, cycIopeBtenybkic, pheriyilkks, beHzykhio, 2-pyridyhkk, 2-eMoro*4- (I- h droxyeiheayipi eddb ^ ϊ -( 1 -hyd ' roxyethy ipiperidisi-4-y {)- 1 -{2- i -( I -iiiethylpiperidin-4- yl >- 1 -f 2-pyridyI ) et»yimio. ! -(pipendi»-4-yi>- 1 -{2-

pytdyl}methykhii\ (4-piperid iyltf.hio, (l-isoprepyi}p5peridiii-4-ySdiio, (i-mefbylcarb0nylp!perid5a- 4-ykb.te, .1 ^teft-butoxyc«rb«Ryl>pipeddin-4- Mdo, (I-nietl¾ylsulIbnyl}piperidin-4-ykhio, {l~ jSQ rop ka^a ^ eHdn^'-yUfeiOi i-{n:sedioxycarboiiyS : )p}peridii } -4-ykbio,

(; eil:ioxyediylcarf o»yi}pipm I-

py ras-4-yiiJ:iio; and a pham¾{cc»tica¾y acceptable salt thereof:

32. Compound ofClaim 27 w ereks R* is cygyc, wie& l, ethyl · propyl, Isopyopyl 2- medsy! ropyi, 2,2 " dime iptt¾>yL 2-:methy!butyi triftuofontethyt 333- tfjftooropfOp t,

Huoawt yl, fluoropropyt. hydroxymethyS, kydroxyethyl, i sydroxy-2-iEetby!etbyS > 2-bydroxy-2~ melkytetbyl kydroxyprapyl.2 $y#0xypropyi, 1 -bydrexyprop-2-yL k2-di¾ydmxypropyL hydroxybutyh 2¾draxybutyi ! J-dibydroxybmy?, 2 sydmxy~2-o:ie†hyibmyi, 2,2* {ddi droxymet^ii ufyS, i~h rtxye†hosy-2-bremoe^^

{l5yd:!-0xyeihoxy)propy.t (meSk^xyiTietii ijeii i, i -me&o et$rox -2 onweti5 i, 2-Iiydroxy-2- raethylpeaiyi 2-¾ydr0sy-2-?i!ethyS: e:xy] ! L2~dd:iydraxypeMyi 2-benzy xyb«iyl.2- S}y¾!xy«hoxybuiyl t 2 ; fydi'oxy-2-iKediy!prop0syini(:yl.2-hyd:roxy-2~raed:iyl pmpoxypi ' opyt iieirab dijp ra»^-yl}-bydTOx a¾edi L -a«oro¾»othyftmi l > raethosyineflioxysieihyi,

eibsiiyL propen-2~yL pmp£¾ « i-yt piftp*I-eo-2-y!.3-S:tydi¾s;yprop-i-C <-2-yS : ! 4*ydioxy* ' 2- aiediy ipropeayi bi eay I, 3 J-dii«ediyS ufea- 1 -yl 24¾axy!oxyb«ieay Unethoxy \ -yl ¾iiox eth2n l, 24iydroxymthylpmpejiyi,.2-¾hoxyv«iyl vfayl raeiylsuISenylprepeayl raeL ylsulfsnylbuiesyU

yl L !-dioxidos.e!ra ydro-2H-dii«pyr<ia-4-y!eibcfiyLed30xy edtoxycarbon l meibylearbonyL {4- tetiid dro- yKia Ocafboityl N-iae^yS4¾-{mei oxyediyl}an:HiK>carbo»yS2

{dbBcdiyi;ui!iB0ei!j i)-amii)Cfcarbc>ft l ts >«i0s ¾!t n i«5elJh l s 14iydiOxy4-tm- biitoxyciifbpiiyime yl, eihpxycarljoaylpi spyl. edipxyearboayleihyL .{ -liydmxyecbyl-

dimfidxy!amiaoesr oo ]^ carbo yethyl. carboxypropy cyanoet y cyanop'opyl 4,S-d¾ydrQxype:ntyl 4,S-dl ydroxypesi- -yl bydi xywyayl hydmicyjHopynyl.. eifeyayl, 2-cyclopj-opySvinyl 24¾'dt¾xycdioxybifi- ί -yn- 1 -yl 2½dixssy-2- Hiediyip apoxyprepyi!y!, be zytoxyprop- i-ys-i-yl, bsazyoxyfei -I-ye- - l* oi y!oxyetboxypiOp-i - yn-!*yl t l-( etfctexybw- f-y«> -yl, ttteiboxype»tys -yl„ cy lopsaiybdsPssiKib i, iBeifeyis !ibayipropyi, me lsid&dyib«iyl, pbenylediyl, bsmxyl pfeetrlpropyl, 3-d5!«rapbe»ytaed¾yi 1 , ^ diS:s d5 , 0 y~ ->beiiyie!b l.

pfeeayleihcayl, i-pisesyiviswS, phenyieibysyl. pyrid-2-yte.diyi, 2-iMor!opyrid-5-yln¾eihyl, 2-¾ttey~ S-pyridylefttyU 2-ed)oxy-5-pyridyfeii:iyByL 4«pi ' peridyteieihyi, s-pipendyl iei yl, 4-i.ne{byS.piperais.u-

piperiixiii- S -ySBieiisyt m0fph«Ha4« imet.hy?., -a5ethyi-niorpholia~4-yli»e¾yb ihiomo^ho!jaotaeihyl , ( i -¾i xidoibi0raos:pbQiino)rseibyL 3-s^ii:jbyi-3-0xci iyi£Shyl. ^½{ta¾ dro-f«r- - l):R)!et¾yK (ieimbydro-inr-3y«} ed}yt 2,5-di xopyrmUdin.- \ -yl i yl {e{raliydmpymt-4-y3me l, teir;djydropyt¾i)-3-ylBicihyl {gim ydropym«-4-y1cfhyl 5 2-bydiXsxyincd:¾y!-ter;s?5:ydropyran-3-

bmh b 2-m<; :ioxyraeth }~fei^^^ 3422-diincd:iyl-i -dt0xiilan-4-y!)propyi l,3-dios0!a - -piO y! : , 1 ,4-d{osa««2-m«ihy > i -4ioxido½in\h dEO-2H M p i¾a»4- Ii«0ih 14 - dioxido~teit^ drc-2M^ 6-oxa-l- itzasp iit ,3 jhepistt- i -y bneibyi,

UB<¾¾yl 3¾ yloxy-cy IcfcutyimetUyi, 34)ydioxycycSob«(y!iaetbyI, 34 dmxy-3-«5ed:syS- yc b tySaicibyb 3-aso-cycSebiHyimei.byI, 3 ^ dmsy-3 rl «omiHei!;i i-c e!ob»iyimei yl 3- hydroxy « 3-metbd clobutyl4iydJoxymet.Uyi, cye peytyimethyl , I -(hy<b¾xycy ' {opsHtyi;»a«ifeyi I - m im-diioSYCYcl peatyiimeiSi L l-(«i^feoxycyciope»ly))b i}aomerisyt cyckihexylmeibyS, 3-hydfoxy- cycSohexyi eoby 4-hydrox K^cIolsesyimei¾yl 5 or eyelotayim<2%1; and a piii¾rm<¾ ecu ι ie a lly acceptable salt tkereoi.

31 Compound of Claim 27 herein R;' is cydopropyt,

2 » «{feoxyc8rb « lcydopropyl, S-iS-hydroxy^-saethyteihyi cydopro }, l-li driix meih l- cycl pfopyi, cydobtity 2-bydamycydobulyl, 2 « oxocyelob»iyi 5 3-bydroxyCydemif:yt 3- beaxyloxyeydobsiiyL 3-beaxy!oxy- 1 -aydmxycydobisiyl 3-{2½dit>x -2-itiet.hylcUlyi)-c>'clob«i>' L 3- b dffis: meOjyl cl0b«j:yi 3-efisoxycarboayl- l-Isyd

cyelopcnfyl, 3-bydroxym liykyeiopeaiyL 33-d¾ydroxyi«etbylcy Iopesi:yl, S-carboxy-cydopeiUy!, 4^ droxyinedi le ciopen^ ?-hydroxyeydqpemyi, 2-¾ydroxycd p«>ty 3- bydr&sy-B-iaei yScyciopeBiy!, 2-oxo-cyelop«Styl, 3-jxo-cyc!op¾: l, 2-{N-i'&yl-N~ 3- l:¾ydio¾y-3-methy~cycIahexyl 4~faydi»xy-4-iie!:hyRydo.hexyl > 3~oxo-cycli? exyi> cydoheptyi eydopmeayi.3-hyitay-cyc!opeaieoyJ, 4-hydroxyi«eibyl-4-sidhyl-cyc { opeK{esy1, ,4- bis(b o «iei!iyi}e elo ei!t2-eii- } -yl, 3-ox©-¾>¾fopei!teayL 3-cafboxy-iiydopgot-l- iyl,..5- isopTOpyiamiaoearbmy ieydopem-2-ert yS, 3-(hy0rosy«>c .l)cyd pea{-l ~ - 1 -yl 4- {hydroxy:»>ei¾yi)cycopeai ' -l » e»- i -yl 4 » hyciisxy» j eti5yF)cyclopeat-2-e»- 1 -yl, c ohexett 4,4* dh:ii«{by:S-cy !ohe!i.e!iyi, 4 ert: H¾yi-eydobexeayi 4-byi¾«Ky:y iobexiSsyl ; S iy roxyey oh x~ ! *(?&- .1 -yl, # i diQs melb: l » « ¾iiiiss;xea l, -( x d \ - -a¾t¾y¾l>:yl)c.yctotoeH i y 4*

iirboxyc cIoiifixsH i, 4-etbaji:ycarbj»y!-cydobexeayl, 4-(3- cyaTJO-azeddijj-I-ylcat sonyl ydobcxenyU H^ iu0ro-a¾di4m--i- ic rb ¾>)c d tet¾yl ( 4-(3- medyIsa}fony{-a∞iidH^l-ylcai onyOcydobe.&ny!, cydoaepfenvl, K4-dioxasp}fo[4.5]dec-7-eB-7-y], or L4-dioxasp!r i ' 4.5|di;cati-7-yI; and a pbatmaceirtiGaSSy acceptable salt teeof.

34, Compound of >d»i 27 iiefda R* is 3-hy x>xy-3-o;i.e†¾nyl 2-i£frdwdi¾-!¼yi >- ietehydro-i ryL 2-mdhyk-teifahy ro-i¾ryl 2-nKt1:iy!-2-iarahydro-fi.iryi > 2-bydr sya)Sibyi-2- i rahydro-i iy!, S-hydtoxy iefJbyJ-tdrabydro-ftt -yi, 2 ? -d j nieii 3 y 1 -2 ; 5~c! s b dro ¾¾ m 3 - .2 ; 5- dlbydi¾fii:raii-3-yL 2.3-difcydrof«ran-3-yi 4 > S-dihyitofiB¾«-2-y 2-ox pytm!ids!-I-YL

tc¾!¾hydi-opys¾a-4-y! > 2.2-di:Riefr(yiteira]!ydmpy?-;ift-4-yi 5 s 5-dfmdh.yUet«{ y fopyrii8-2-y} > 2.2 > 5.5" ie 'i i'e hyl-l -dib dTOPsias-B- f , 4-ili!<!iO-tvi alsydropyr;Hi-4-yl, 4-¾oi-o- -b d;f¾xy- {eti ' ;di d?O i¾s!--3 -y I 4»n.ooro-3««Ka«oxy»ietr»bydnopyra»-¾-yi, 4-byd? ' 0xyie ra bydropyrafi-4- I, 4- h di¾xyie!x bydiij yi¾0* - L 5ydiw eP¾ drop ra«- -yL 3.4-dihydroxyi«rahydj-Qpyra«-4-yl.2- oso-ietrahydropyKm-4-yI,, tetmhyd.ropyr«-3-yl, teirahyda>pyratt-2-yi 3,6~dihydropyn»i-4-yL 3,6- dibydftspynm-S-yl 5 s 6-dibydro-2H-pyT<a{-3-y! , 3 ? 4-diby£Sry-2H-pyr;iT!-S- yl e^-dimei^!-S^Kblsydro^e j rau^- l 2 > 2-d½d}jyk 6-d.ihydm-2H « pyrdt^4-yi„ 3,4-214- d¾'dix5pyra»- -yl ;i t 4-diosasp-.»»4.5]dec-?-en-8-yK b S.-dio¾o-]soihif» iidia-2-yL 1.4- d. xfdo&Ta ydro-2H-s.hiopyrai 4-yL ] ,4-dfOx.;m-2.-yl 5-memoxy~ eihyS-] f 4-dioxan-2-yi 5 i-tcri- bi os ciU ^ lxmyl-J.^^ffti^ydro yrid^-yi,, S -mcthyi-l2 5 5 ?-ts{ra ydroi!ydd-4-yi, 1 -

i-i efc!-pi eT!:di -3- l, i

;plp:ndi«-4-y:S; acce ta le salt thereat

35. Compound of Claim 27 iiereiis W is phenyl, 4- hSotepfieiryl 3-mcdjy!pbeisyb 4- me%'Ubsfl ! < 2 t 4-dunsi¾y.lnhe«yK 3~frii]yoranidhylp enyL 4-tnfHioromethylphenyl, 4-rae!¾exy-3- tnilitorPmethypheiiyL.3-dinuoroHjeiiryS-4-l]u n;)phiS:i5yi, 2-mei .?s Ub8yiphe.ny}, 3- mcttiylsiiUboylpheByl, 4-:ffit:S¾lsii!iboy!phenyS, 3-emylsulfoiry!pbeayL 4- fnc iylsulfo»yaaB»opbcsyl s 3- ed:s Isi foa to:«i0pS)ei5yI,..-mcrhylasnifiosulfoaylpbcnyl, 3- cyaaespks! l, -cy«wp&e» i > S-eatboxypbeayl, 3~earbixy iydroxypbeayL 3-csfboxy-6- tncfhoxypbeayl 4~ca.rbi>xyplres:iyS, 4-cyas:io-3-i»ed50syphenyL, 3-cyano-4-R!eihoxypheny 3- {dHS«hyiamtoocajbosyl)|li.fisyl 5 2-{dijaethyla$» j iiocarbo»yf]phen 5 4- Cdfniediyian'!«»c;»boisyl)p¾efiyi, ' 3-«(hyla»tSn0eaibo8ylpb«oy!.3-( ' N-e?iiyi-N- incih !aniiftiicar Qayl !^n !:, 4-eihy!a:mtsiocarboi>y!phaiyl 4-( -si yi- - meihylaatttJocarbCHiy pteyS, 3-feopfo y:{aaai3^ai¼»y!p} %l t 3-( ' K- xityl:' -'

HjeUiyiaHii«o atb «yl).p¾ei ' ryl y 3"{N~ ro yi-M*m i¾yhgiba.o^

difeydroxypiopyta

dimedwlaaiinecafboaylphaayl.3-a>eltoxy-S-ctrylam!So arbo8yipS:ie«yl 2-iii«th«xy-4* dimedwSaraiaocaAoay!pbesyS, 6H.ne:l¾oxy-3-dimeiby1ammoc;¾t a«ylpi]eay! < 3-mei.hoxy-5~ eihy!amifiocarboayipiiea l, l- dmx - -met lpro ^- l-ajaKiocerfwti l benyi.,.

h drox edi iajsinocas ftnyi-pheiiyl 2-bydroxy-2-iaetbyIpropySMniH: e££rbonyi-ph<?syi., i,2- dib:ydi¾xypropyfei!»n^c¾it>ftftyi-pi)cfiyL 34 }-azeddmyfcart>onyl)phe¾fL 3-i3-il!5oro-azetidia-i- ]c&r 0.B I) hen J t -^ 3 3-medioxy~axettdi&-l- }4carboay ) )pheay } , .-(3-ij>i*h lsufi»5 !-a»3etidiiv } -ylcarbo»y.)phe»yl 5 3-(4-

3-l4«OK>-6-»sethoxyphe»yl..2-fit>m~S-aiellm ph nyK 2- 5cdmy-4-t5id:hysaaa«osidfoa !phesi i 2- ttieibosy^eth laB^midfoay heftyl -melhoxy-:km eiylao«»oSM}fc«iy } )h)iyl 5 3-s»ethoxy-5<« a-seiiioxycaitsoaylpheayl.3-arboxy-2-aie¾!ioxypbeiiyl.3-diI laororsie >xypheiyl, 3~

dlluorGfttefiiylpheayL J-ditoomnieih i-^fixioc heayl, 2-HKthoxyp.Beayl, 2 > 4-dimethoxyphe.tt> < ' 3,4-d«¾etlioxypheay!, or 5¾ odioxolyl; sad a. pharmaceuticall acceptable sail thereof. Mi. Ccsmpmnd-otCMm 27 wherein R* is l-meibyi-3-pyraao!yl.. I - emW- razo! l 5,S- diraeihyl.- -pywol i 1 ,15-iriraeihyt-4-pym¾Eolyl 3-s¾ > i y!-4-pyr3.miyl 3-irif!u&ro-e{hyi-4- py ra oiy 1, 1 -2,2,2-iiifl!Oi setl ! )-4-pyt¾ioiyK 1 -esrboxy maxky S-4-py ramly I J - ei osycai¾i>ny!incil:tyS-4-pyri5zo!yl, 3-cyc!o iiy1- - yf:azo!yl, }.-cyciofe«tyl- -pyR>zolyi !-( - raorpbolftyi)car nvlraert5yl- «p miefi l 1«{4«nJ rp!j H.ayl)etbyM-pyra2o!yL ! - ydroxyeiSwl*4 » pyrazoiyL i -Siydioxyethyi-5-pyrazo!vL ί ί -( - ydi0xy-3*aieil]yl it{yi 5- pynszoiyL htt5cJ¾oxyet¾ }- »-pw.ol S- raiKOS i, i-m¾byi'5-pyr;«o!yl ί ,3-difii by*5~pyr oiyt i-n ii l-3- :iSlud0mei]jy!-S->yrazo! i ^-met ylammocar oa ^p axoJ-S- i, 3- dimef yia«iinocarbo»yS:-pyraz0l-5-yL 3-ineSi ¾sidiba lsmiae- Taiioi-S- l, 2«nietayI fonyla c p Qj»4-yi s 2-methoxycarboi:¾y! yr<¾ol-4-.yL 2,4-diraethyl-S-thr^oIyl, 2-{2-i drcixy-2- i:ncf1iyled i)-ilijaz«S-5-yl, 1 ~i:«ei1iyl-5-Ji¾ida¾oIyl f 3 ^ iimei !-soxazol-^l, I -me%MnazHHk l ,

1- isQpi' pyi-triaiiin-4-yl I iydroxyp«>pyl da*ia-4^yl, ί -bydmxyfoiityl-u:b¾«-4-yl, (4- tri¾omme pheayl)i»clhyl-Jsiis-4-y], l-cyaso-S-Jsetbyi-ibieji-S-yl, 2-i»s0ioxycaiiK>»yl-{ }C8-5- yL -ca!-bcixyi-biea-S-yS, 2-( -med¾xveUiyi^^

ffie i-amiiwcai¾o»yl)tfeien-5-yi ?

5-yl, or 5- ya o-i-stetbyipytr»i-2-yk aid a p armaceuticall acceptable salt. tteeo£

37. Compound of Claim 27 wherein is 2-pyridy ' i, 3-pyridyt 4-pyndyl 5 2-.tHet¾yl-5-pyridyf s

2- iefiiy! » 4-pyiidyL 2-isic0:ty1-3-pyr)dyl 3 « i:!Kthyl-i-pyi'idyL . ):anuoroJn.¾¾tt i- - Tidy! T 2- triiluorom«?t¾yl-5-pyddyl, 2-diQoorom<!$hyl-$*pyrklyi > 2-tdSaos¾«nei!iyi-4*-py:ndyi, 2 rfhioroiBetby!-

3- pyridyi 2-Hneftoxy-3-pyJidyl, 4^iKiboxy-3- ridyS ! 2-iaeilmy*4 » py«dyi, -osstasiy!5iiKi1:i y--

4- pyridyl, 2-(3-ox¾a&yl)oxy-4~pyndyf, 5~tluoro-2~meOioxy-4-py:fidy!.3 luGro-4-pyridyl. Mhsoro-S- pyridyl, 3 1uoro-3-pyndyb 3-itieib?xy-4-pyridyi > 2-etboxy-4-pyndyL 2-me{tay-:5-pyri<iyi ! , 2-{2,3- di¾ydroxypmpo ; xy}-S-pyridyi 2- rox meiS.».x -5-^^^ 2- bydroxyeiiiDsy-4-pvridyI.5-fiuifo-2-bydroxye&oxy-4-pyHdy i 2-raethoxyeilK!xy~S-pyridyi 2- bydrax.ymediyi-5~pyridvt S- e wx -S- yrid i, 2-eil:iixy-5-pyndyK 2-isopi¾poxy-5-pyrldyl 2- ydros -2-:m£diylpro}>os - -p ridyi.2-C 1,1,1 -friiltifirofitb xyhS-pyrfdyl .2-eyc!opmpyl:iK;ihoxy-S- pyndiiivl, 2^raet.byIsa1i¾nyipfOpoxy)-S-pyridyi 2^methy!&«i.i¾nykmi!io<Shoxy)-3-pyridyi ? 2- e5:bosypiOpoxy-4-pysidyl. -djfluosonselfeoxy-S-pydd-yl, 2-£hioi0-4-pyn<iyi 5 2-ch1.0to*4-pyndyL 2-

2-nieil)Oj;yt;arbony-4-pyridyL 2-{»Μϊ<ί&?.ο!÷ i-yDpyad l. ' 2^oetoxy«»m mgthy ' i-4-pyridy{, 2-oxo-i x 2- dibydropyridi:i)-3>yL l-mdfeyl- -OMO-i^^hydfQpyrfditi-S-yl, !-fticdiy!-2-axo-I,2-dii:iydropyddii5.-4-- yl, I -eiiiy 1-2-0X0- ί -di ydropyridla-S-yL I -isspr py!-2-oxo- 1 i- l:iydro;syed I-2-oxo- 1 -dibydropyridin-S-yi I-bydmxypropyI-2-oso-i,2-di!jyd¾x>py;ridjn-5-yL 1- mediy!-2-όχο- ί 2-diliydropyridio-4-yt 3-feydroxypyrid.-4-yl 2-bydiesypynd-5*yl, 2-ami8QCarbonyl«

!SopropyiaHiinocarboayl^-pyridyl.3-diei yiaminocarbi?nyI-5-syndyL 2- rae )y } sxdfoftyiei¾ laimi^^

«i0t¾ox eh ia«j«oC5«&on {- -p iid l

inttdai»!yi}pyrkM-yi, S-pytimid iyi 2-amlii - yrisnid!ayL i-cysao-S-pyrimidniyl 2«me&ftxy~5- pynmk!iayt 2~eihoxy~5-pyn»adiayt 2~isopropoxy-5-pyrimid f, 2-iriiiuo.roetboxy-5-pyriittidi ' ayI,4- « S]uor0raet !--i>-|jyi1$r!5diiryI 2-«1S]uoroe!iry'-4-pynm!df:nys s 2-5ril«oiA>et!!y!-5-p riradla L 2- dliiKi¾ lamjnocari?81 nmkbii- - L . pyra¾in-2->t pyndaz»)-4-yi; and a pharmaceutically acceptable sail itewf.

2%. Compound of Claim 27 wherein 1 ' is 3-bea¾0!l:»enyk S-hftaxofhryi, 5-iado!yL 2-oso- dihydro-S-bidolyi, 6-indolyl, 2-oxo-dihydro-6-.i«dolyI, .i-meihy.l-2«oso-dihydro-6-}.»doiy.t irak!azop ,2-a]pyridi¾v3-yi. iraidaao s S~a]py:tidio-7-yL imidazop ,2- a)py:ridin-6-yi,

dkixf do- ! 4-dibydm-2H-be:i½ob ]p A5]ex hi¾¾pfe-8 « yj , 7→««hoxy-2-raet¾yt-l .1 -dte.tdo<-3.4- djh dr^H^axefhJtl^.Sjoxathi ^epja-S- i, 7-fiwro-2-iis!ihyl.« I , -do sdo-S^-dib dxo^H- beHzoib] I > 4 > 5joxaibi¾zep:s«.^-yL 5-©xo^m$tyl-2A tei^^ 4- meibyl- ^o-2^A^8tfeydj^ eiJ^ff| W]oxapi8-7-yL 4 « slbyi » 1 J -di xk ^^-dis dro^H- p>T5dop,2-bl| ' I A }iteon~?-yi, beazoxazol-S-yl bt oxa¾oK»«yl, I ,I-dioxo-3,4-d¾ydro-2H>

pyridoi3,2-f)|;4,4] xazep5!:¾-7-yL benzoxa20l-4-yi 2-raedwIbe«xoxazo!-5-yL 2-erfeylfesKOxazoi-5-yl 2-isopmpylbesizoxazol-5-yi ; 2-o:x¾-2(3.H b;ftzo]i|| s>iii¾oJ-5-yi., , beftzoxazol.-6-yi, bei¾xCit &/c-5- L beftzodiilazoS-6-yl, 2-meihyfcei:½ai¾3iKoi-5- l, i-isoprpyJbeaxosdjiliiazol-S-yL i-m.eihy benzimid&zoryl, 5-inda yi i-raeftyl-S-indazoiyi 6-kidaz !yi, i-nKiS.iyi-6-indazoSyk 2-m«†.hyt~2fi- Sada»ol-4-y}»

yKS^Hihydf^iH-iS nOlol^-^ip ridjo-S- S, he»zoisoxazol«5-yt -n!ehyibeiizo[djisoxazo!"5-yl 2* raed5yK5 sxo4:¾¾z0d!:^

ttiefh loxazelol ' . -fe ' l yrid. i^- l,. HWh te5i¾lo[S > 4-bj ridi i 2-fneibyl-3~sso-2 - dibytoibsoxa^oi»5,4-blpyridin-5-yl I , I -dioxt* -med} k%4^

aj yridla-7-yi, iraidaxoj l,2-a]pyndi«-8-yL 2-oxo-2J.d!bydro-ie-i:m¾azo[4J-bjpyridia-6-yL 2-oxb- 2.3-dibydr¾bcnzefdioxa¾eS-5-yl 3-oxo-bea2o|:d!P3!oxaffe¾oi-5-yL 3.,3-di^o- en?:i>| ' dj}:i,3 ' ^athibi» | · ί,2·Λ ^ο I.,5-8tem1!a-7-yI, 2~hydre¾ymeiiiyi-2.¾-cHhydro-| ί4ldioxi«o2. -b]pyTklH 7-y 3- h ro£ meds i-2.3-di¾y ro^^ ^ 6-qui«ola>y}, T-quinotfsyl, 4- isoquiodlinyK 7-isoq«a¾>{5»yi 5 1 -saphibyndisrf-yS, S-Hjethyl-iH- yfaz-oki -felpyndiiJf-S- t Ί - pyi-a¾¾to[3, -b]pyridiii:-4-yS or 3-methyl*i.H-pyra?.oioi3,4-b]pyridis-4-;y 1; and a pliarmace«iica% acceptable s lt thereof, -

iefiiizoil eftyK qamo ' liny ϊ .,2-dibydroqaia H ' nyi pyrroMdisiyK benx l J,2 v 3 ? 4-tetrabydroqum Hn i 5,6J -iefTa ydroquin«i¾wL qmnoxalinyl, qubjzslmyi, ί H-iodaxoiyl. IH- sda^oi l feomdoiioyi

Π iH-pyn«eio .4-d]pyrin«di«yl isoqu! o!isyl IH-pyrszoloj 3,4-

bjpyridis l, biiida o ! ,2-s|pyridiftyL 3H-imidaz0:4 ~alpyridinyL pyradmsaayt, pyr&riayl,

3 t 4-dl!iydro-2H-py:raftoi2J-cjpydd!S:iyi s

or chr omanyl;

¾:hsrei« R." is xmsobsiiMcd or subsbiski widi am: or mo .sebstttweais nkpendeniiy selected ftom t h≠, cthyi, eysao, cUim, Baoro. mcasox , triilaordraetbyl ethex carbenyl ten- btitoxycaibosyt carboxy, Ν-·μ;η¾! ί)~Ν^^^ ( ,N- dimet!ryi)a:mimicarbmyt kme. iylpyn»:iay-4» y earboriyi, .or exo;

a ad a ptossaceuuca!iy acesptable salt i a-os:

40, Compound of Claim 27 hereia R '; is b¾ 1,

teitahydropy.ran.-4-yl S -Boc-pipaidii.i-4-yi bexahydroiijfo23-b|&!r-3-yL 2 > 5-diox0-pymli ' adi»-i- l

2-pyndyL 3-pyndyL 4-pyridyl, 2-met.hyI-3-pyridyI, 2-raeiby1-4-pytidyl $ 2-meifiyi-5-pyridyL 2- meihy.l-6-pyridyi, S- efl^-M-pyrfdyl, S-KietbyS-S-pyridyi 4-medryi-3-pyr.tdyt 2,6-dii»gdryl-3- pyridyi 2,4-di eiiry]-3-pyridyL 2 > 4-dim^hyl-5-pyridyI, 2J~d¾nei¾y.!-5iyridyL 4,5-dis«eibyi-2- pytidyi 2 : 5-di:i)ie!iiy]-3--pyridyl 2-eihykkpyn.dyi, 3-etbyl:-5-pysidy!,2-edryi-6-£ncd yi-3-pyrsdyL 3-8aiyW5-iiK. k5 ' pyridyi, ~is ps¾py:!-5-pyridyi, " 3~prop- i-erH-yi-S-pyridy?, 3 | - mcihylethc8y})-5~pyridy}.3-cycopropyl-5-pyndyl 2-hyd:roxymediyi-3-pys1dy!, 3- feydf0,ymetbyl-5-pyrldyi ; 3-i2-hyd;(¾syed5yis*5-pyridyl.2 l¾droxy- -»ieihyteihyI)- ' 3*metbyl«- -p rjd i, 2-hydroxypropyl.-5-pyiidyL Ή 1 ,2-<jajydiosyetbyi)-5-pyridyL 2-tri6ymimet k» pyridyl, 2 » triflx«xromfiihyl.-4-pyridyi, 2-iri.fiooromeiriykS-pyr j dyl, 3-H)8thyl « 2-lriftoorom«{hy '{ -S- pyridyi, 4a^th W-irii½or a>e l-6-pyld I, 3-triiuorometlryi-5-pyri:dyi 3-trii!uo!Omedjy!-S- iluoro-iHiyTi l, rii¾^ 2-methoxy-5- yridyI, 3- - hydmxyprepyl >-5-pyridy1 < 3-i 2-hydroxyetiryi )^5-pyridyl 3 -iaeilsoxy -S-pyndy!, 3-ethoxy«5~ pyridyi, 2-«ieibo3ty-4-jaethyi-5-;pyii<iyi, 2-methos.y-6-eh:yi-S-pyridyl, 2~cyano~3-pyrt ' dyl ! 3- cysno-4-pyri4yi ? 3-cymi«-5-pyri¾yl, 2 y3no~5^ril¾oroRieth i-3-p rid 2-cbloro-3-pyrid.y ' l» 2- eiifom-S-pyricSyS, 3 J:do5¾-5-p ddyL 4-c¾loro-3-py«dy}, -chier»-4-cya«o-S-)yridyi, 2-fluom-5-

5-pyridyi -&methy]- iXo rid:in - L S -difiJesl!yI-2-oxopyridi -5-yL i,2 « dteth i-fr- 0s.o yi;:ds.H- - L E » meihy-2-osopyiklm-5 » yl y 2-ro«hyl-6-oxopyridin-4-yi l-et ' yl-2-oxopyridiK- 5-yi -e!¾ l-l-mcy:iyS-2- :Ki5 !'idiii--5~y:, :^gd!yi-2-n:(efSi S-6-Ox !idii5>5* L ! -jsopfijpyb2- osopyiidia-5-yi, L2-:dii» S-6-0xopyridi«-3- I, ί -meiK ί-2-Jii nuomieii ! -oxop Edin -yL ! - ed:s f-3-:n!iiioni:Kfe 2-{t ri- iHyismji!ecsrboa ll^-j rid i, 2-j«etha ei¾yla no«^t¾&aylK^ *5 y]* 3-(3-i«<;!¾&xypi¾eayI}-

yi 2-ir i ooi3KiJ:iyi- ri):nidis S- i > 4-ftuoropyrimfcfia-2~y], 5-fi.«oropyri«Mdin-2-yl, 4- iriO:»o!-oifte iy!-pyri«».din-5-yi, 2-az-e dj«ytoarboayI-pyrszfs-5-yl < .2-d?8¾eth in).««sc»i>0fiyl.'- pyrazia-5-yi pymdin ia- -yl,

S 5 3,S-iffiet¾ l-4-pyra¾o¾' ! -e 'l-5-pyra¾oyi, 1 s»propyk pys¾olyi $.-edvyi.~4-broino-5~

pyrazo!yl, ! -c{¾ l- -H)ed¾'l-5-pyKKoyL i^^-S-aictfeo ycijelfe i-S-p t&xol i, i-Hseiiiy!-3- d«netlw{aiHj»oc8t oayl-S-pyra2ioly, l-iHe } .-3-cyciopi^yf-5-pyra«o}yl s 3 ihylummi-2~yt aad s pharmaceutically ac e ta le saii (hereof.

41 , Coiapeuad of Claim 27 teeia R* is pl:ts«yi, 2 difl er«;pteiyL 2- ' fl-uc*opfeen l, 2,4-dli1uoropb8ayl, 2,5-difiioro h i l 2 difluoropheayi, 2,6-dii!«om-3-

diciUoroptet l 3-chtaro-2-ft«oropheiiy, 3-cfel.oro-4-.fiooTopIie«yi > 2 Mora-6 luareptaiyi, 3 hk>ro-

6- il««F0jjbeny 2 » l¾ stx>-5-.ri{i«oro.nM5ti { ylphenyf, 3-hydffixy ethylphmyi 3-hydfQxyefliyipijeuy, 3- bydrexya¾tl3yi-5~ji52ilsyiphefiyl i-vsetboxyphenyL -4-metboxypiiejij'{ > 2- .meihylstd foay hheftyl, - i setS5 l.saSi !)yS hen i, 2-il»ofo-§- ethyisiilfaayipheayh 5~

«hytoja suio!i i-2-n oa¾>heftvl, 2-ftuoro-S-metbyIc8Ti) ayipiieayl, 3-jaetboxyc«rboHylpteayl, 3- carboxypheayl, 2-K!et])y!-5-efJ:to ycar oi5y!pIiei)yi. l-cWera-S-ethosycavbeaylphcayl, 2·¾ΪΟΪ« 5- i»e!:hiisycai¼r! Iphes).yL -metli l-5-iRSihox casbo« i0K!!ti l, 3-hydr0xyftje%l-5- raeibosycsrtsooylpheayl. J-melliox -S-sBeibox arbOii i heii i, 2-¾oro-5- 2- etSiy5pb«Pyl HHie *C85¼ y e»yl* 2<dor0-S-c;siboxypl:tes:?yS, -i¾:iOr0-S-caffe0x p!ieiiyL 2 " ChiofO-S-a-tainO ar oJiyi he ij -fiaOro^5-aa)iuoC-a ' ffeo ' 43ylpbct).yi., 2 ya«QpbettyU 4-cyaftophfifty{ > 2- cyaao- -med'i Spissiyi, 2-cyaEOS-taethylphen:yL imo- - e iylpik¾ i > 2-cyam>-3-ertiy{p¾e» l, 4- 2- fluorophenyl, 3-elioro-2-cy8fto~6-n¾oroph.e»yl, 2-cyano-ij- iniloominetSiy! lieii t 2- cyan o- 5 -iril ΐ3ίΐτοχ«ΐ?ί5ι Ι .¾ e«y ί , 3-} oprapy1)»nmo arbon l] lK:j¾i ; 5-

me%i « 5-{N B>d« l)- -<i»eite 2-jactl¾ylr5-(i(H,N-

fi$iei y¼m«iOeayiam5»O ar oay11 teiyi 2*methy 5--{ I -metit i ym^ii^ - !)ca^oiiyi) beiiyL 2 >- iauW » 3-¾isop-m - }amH?¾art¾>ny0pften

2-! »oro-5-(cyctob«iyl})smjnocarbonyI)pheftyK2-fl 2-

•{(2-ro«h.oxypropyl ¾aH!Kscsr ooy I heoy I s 2-a«oro-5-( -a)cfhoxy-S- awi leth !j iB H-Ocarbofty plie yi, 2 hloro-S-((i-pyn m >y{)c f^jiyi^ iyl.2-d).Sc>i¾-5-{(Li- diffi iy!pyTaxi& -yi}eaf oay!)phea 2- l¾¾oTO-5H(i-a!eib ]p nt2ol-4- l} n:iiaoc; o» i)^ }-:mef¾ylpymzol-5- y!)aintaocar¼ftyt)pl¾:ftyl. r 2-ΐ¾:θΐ:ο-5--(ΐ 1 -me{a lpyw)M>y)ammteslK»i i)pb£3i } s 2-f|«e*i¾-5-

S)a H«ocai 0iiyi) !iC yS, 2-fiuoro>5^{ yri -2- !iBidi^^

fl y ofo i eridiH^- l)}?^^^^^^!)!)^^'!,, 2-flyof -5 » {I-Bo^-fiuoropiperiiiia- - y l)}a«ttao ;Mtoay rjpbsa 12 -il «sro

2-i!uosO-5-(Ue¾y1-p5pent!in-4- yl))aiaia»ar ayl).fiiaeayl -i1uoro-S « CI-me wIpsper 2 > 6-3ifluote- 5 l-a¾i1iyIpipa1dm-4-yi))araiaocarb ayI)pI.¾eayi -ikioro-5H i er r^- i^^

2-i]«ora-5~(4~morpao!to

mofph<>S:b)yieil¾yl}as:ninocarboftyi)pb<; yi.2 b.!oi , o-5-(meii:ftsyfiihyi : )sniiaocarb«syl)pfeesyi 2-c¾iOTO- 5-{l-pyrraii:di»ykarboayS.)p!>.esi;yl, ¾Mro-S-{l~mediyl raan~^^ 3-{2~ benzb:nida¾SyS spiifiiiyl 3-f2-aiei¾yi-i-teifazoiyi)pS:¾e»y, 3-(2-aist¾yl-l2,4-oxadi^Pl-3-yi>ph.cny1. > 3- (3-n:iethyl-i 2,4-oxacba o!--5-y!}p:iie:£Sy]; and apitanstaceaiicaiiy acceptable salt teeof.

42. Com ound, of Clais 27 wbcreia :! is S-qtmiolioy}, 6- uiaeiiayl 7-qumoIin L 8- qas olio i, 5 -<ti sl is* -6- aii ϊΰ S siy Ϊ , ? h!aTO-4~i|taooimyi 8-c¾lofO-6-Qufl}Ofa ' ayi.2-iHe5!iyi-4- q iftoHflyl 5,6;7,: e!iaby(3rp ' ai: ob.(^5«yi„ 1,2 j,4-|:eiiabydra iiHiO,H:( 5-yi, 6, - 1! ί:£ίϊ« =I:t y Ϊ - 5 , ,7, - »te» roquia&li«*5-yl 4-q«iaa?.olio>'l qisawxaiiiJ-S-yi, S-Qxo-isoindoBa-δ·· yt 3-metiw H-mda¾^ l-raei.by!-ie-!:ftda¾S-5-yt 1 -djmetfeyl- l ' H-iada¾ol-4-yi, j " L2 ]irisz:9!t 4 t 3 ¾| yf«ii«-S-yl ! -m84ii {-:2^ ^-I d¾ aroQmno ' ii»* -y{, 4- iaeta !-2- χο- i , *diiiydro i!i5.iolia- l 5-cb io- l-siethyJ4 « oxo- i ,2 SihydroquiHoiia-i I { A- yl 4-oxo- «iiioii:n-]( H}-yK 5,?-difluOfO-l,4-dimet.b I- 2-oso-l,2-dd:iydro<i!:nnO:!iii-6-yL 5^-dif]«0i'«-L.3,4-irii¾eiiiyi-2-e?iO- ! ,2~dsl:rydr0qid«ob:fi-6-yL 5/7- 4ifb.HiO-i-roeiS)yS~2-ox 5.,7-^U t !ro-4-cil:«yl-l-met -i- 2«ox. -l;2 « d!h iToqiiiiiolffi-6-yl > S-isoqirinotoiyi, 7-iso tstoo!inyi, 6 so¾umoi yt, S-lsoqaiwHayl, 4 « isoqui oHiiyl i ^ndiiyl-^W-^a/Oot^^Jpyridm-S-yt, l-e&yH H-pyt¾¾. fo[ ' . ¾ ; .4-b]pyiidiB-3-yL i - H-p ra€>i , ipyrk§iii- -yI : , n}eibo yeIί^> -:ίH- yra^)ioI3 5 ^;ί{> ί·^di«-3-yl, 5-ίΚ«»¾-1-

y imitol i ; 2~ajpyridi«~ -yk 3-met yi-3H-jmida¾;o[ 4 b]pyridiif~S-yk 3- eth} -3H m(da¾<>[4,5- l-njelhyl- 4,5,6,? sn¾l¾ f do-3H~ ^^ 3 -ddiydro~ H 3ycanop,3-cj yridf:ii- -yl, C a iyK3,4^ih <ite » 2H-p ranoi " 2 * 3-bte"ridia-5-yi or 5-c{»otmin-yi; mid a pl½ra>ace«tk»Hy acceptable sah teeof. compound of Claim .{ haing Formula IV :

%yhereto s is C alky!, C>.« akeayi, I Mori , C s . s alkoxy, C M hydroacyaiky), C¾, s ammoa!ky Cj* aifcoxy-C,.«. alkyl hydmxyaikoxy-Ci.* aikyk C}. ¾ akoxycarfoo«yiam: o-C;,f. aSkyi C;„-i(? at l C«.» ary!-C^ alfcyt 5-10 merabered .hsierocyc or 5-10 meotbcrcd kierocvclyl-Cs. s alky!, whereto she ar l or lieterocyciyl dag is uasahsittated-Or subsOtated with ©«e oi two su idttieats wdepeod atiy selected from C tik≠, h drox , ox© or Hal c

hereto & J is --X-R 4 , : yan x C ( « haloidkyl, C cyaooattcy), Cw aikoxy arbosyl C u > aSky!c iboiiy!, 4- US memhered hetcrocyctylcaf ottvl, aioloocarbooyl, C alfcyiammocarhonyt,€-,;, alkyl alkeriyk t ¾ alkyayU€;.< > !iydroxvalk l, Cj, s hydroxyaikeiiyl C M hydroxy&kyayi.. Gi ^ aS.koxy-C 3 .< > aikyi C M - alkox -C^ alkox -Cs^ aikyi C ) . aSk x -C^ tikoxpCn NdoaikyiC aikoxy*Q.«. alkoayk C ; akoxy-C;,-; alkynyi C w ara!koxv-C:^ a!kv!, hydroxy-C; lkox ).-, alky!. hydroxy-C), s _dkoxy-C. W ; lialoa!ky!, araikoxy-Cj.* slkynyh .hydroxy-Q.* alkoxy-Cj. 6 aikynyl,€?«.«> arytaxy-C f ..s alkyl, C¾. w aryloxy-Cj.* aikeayl <¾.«> aryiaxy- , aikviiyL CY« siko ycarbQ» l-Ci.* aikyi C s .* Ixydmxyalkyi amkiocarbo» i-C ; .<; aikyl, C s . 6 aikykniisioearbosyl-Cs <: al!kyl C s . s aikyi.suifb»y!-C,.. (; alky!,.

ai.kyls lftiftyl-Cj.i. alkyayl,. C , aryi, C 5 ., ri cydoalkyi, C s .i eyc ailceiiyk 4- ! 1 membered lieiereeyeSyi i.m aryi-C;., aikyi aryi-Q: a!keoyk <¾» ary!-C,., alkysiyl. Cm eycJoa!kyi-C;..*, alkyl C 3 . fi cycioaikyi- Q. s hydroxy&lkyl, C$ < t > cycioalk i-Ci..;, aSkeriyl C¼ cycio&lkyi-Q.. * alkyoyi 4-10 metnbered heterocyelyl- ^. aBsyi » mcrabered hctefocydyK &S enyl, 4-10 em ers^ hcierocyciyl-C^ alkyoyl or A-i 0 tsembered lieieixseyel le&rboivyi-C j.* alkyi; herein t e aryl, cycioaikyi, c eioalkeiiyi or taei ' oc ciyi ring " m R" 1 is -aasttbstituted r substituted vwih i-3 ¾absimienls independently selected from alkyl halo, oxo, RCk h&loeikyl, alkyisu!fon lamino- C M aftcoxy, Cj halealkoxy, lrydroxy*C(.s alkoxy, C;.« slkoxy-C^ alktsxy, C % 4 a&yJsu!feftyt- C ( ,< a&exy, C;.« acyl Cj a!kylsnlfoftyl- al mycarboriyi carboxy, 5- 1 merobered heterocyciyl 5 0 membered eteroc cSyi-Cs^ alkyl C M cyeioalfcyi C M cycloaffcylC;.;, alkyl ammo, aniiftosuiibiiy G:,,fi aikytoiiiosuiftmyL C * alkykm!fortyla mo, cyaao, carboxy, RE N-C ; alfcyi, Cs^ alkoxy-Q.*- alkyl « aSkoxyimmo-C;.* alkyl CM; . ydmxya&yj or R i: R i! N€(-Oi- where R s is Ή, or C.^.a ' lky.1 and R s is H, Ci.s alkyl C , bydroxyaikyl C w aikoxy-C^ a!kyl - s4 aikylstsSt yi- C ; .s alkyl C«. 6 alkylsidi aylamirio- C ; alkyi amisoalkyi or t\.« alkyi-C^ amiftoaikyl or where R 3 and R !> together with the nitrogen fons a 5-6 mcrabcred l*eterocyclie ring tjasubsiituied or substituted with O. alkyl;

Sterein isSo O;

herem * is alkyi, C } .<; . ydrftxyalkyl€}.$ iialoalkyl M isy roxya!kynyi, C -s aifcnxy- Cw alkyl Ci-6 aikos.y-Ci-« aiksayl, C?.« aitexy-Cj.<< a&yayl C>* aikoxycarborryi-Cs.,, alkyi Cs.« carhoxyaikyl amtaoa«fbOHyJ-C ¾ aikyl C>.s alkyfere aocatfeoayl-Cs .§ aikyl <¾.«> aryl, C?.? cycioaikyi C s .:; cycloaikeftyi 5 » K ) wfiW iieterocyelyl t o aryl-Cs * aikyl ar l- w, aikeijyi Q.» aryi- t « a!kytiyi, C?. s cye!oalkyS-C:.,;, alkyi C¾ « cydoalkyi-C^ atks.n i, C s .« cydoatkyl-C s aikynyi S- SO aismbefed w reta the ary cycioaikyi cycloalkenyl or heterocyciyl nog R* uasubstitued or substituted vvtfft i -3 substaaeats iade iiociexi y ¾¾fcct<id from aikyU«tfo, C>* imioa!iyk hydrox !, Cs.- 6

acyi Cj alkyisitlfotryl€,.« aikoxycarbonyl earbosy, 5*i 6 " mem ' bered teemcyciyl cyatto, mino. Ct. β aaanoalkyl, C,,* aikoxy-C ; ,^ alkyl, hydroxyaikyi C w: haioa!koxy, alkyl-KRR " , aminosuUbayl C. 4 aikylarainosuifbsiyi, or ίί¾ !> €(^0) where S s is C S .« alk i a¾d R !> is C alkyl d lkox -Cs.i.: alkyl, Cs ,- anti«oalkyl or alkyl-Cs.* aawnmikyl fir h re I a:ad R i! to ether with. the mixogsn a 5 or 6 siembered heterocyclic ring unStsbstifttted or subsutiaed wiilr Q .« lkyl; where R and R * is iodependcotly H, d.« alkyl p ej l 5- S 0 membered hetsrocyclyl, 5-10 tsembered heteroeyclyt-C w aikyi. M cycioaikyi a i-Ci,, alkyl, eyeioaIkys-C 3 ,, alkyi: where site . phenyl C } .s eycieaikyl and 5-10 merahered hctarocyclyi rings are orisafestiaited: or substituted widi 1-3 substtttieats Mepe«de«t!y selected froHi C w . alkyl oxo, alkoxy, hydroxy, halo, Q- 6 Ijalfiiiik i cys»o, or carbo y; or ' R * aftd & t together with the M fyrm 5-1 aeateed heie¾eyeiyl;

where ^ is pbeayl S-i me tabs red heierocyclyl S-i ificiHbered hetemcyclyl-Cs.s, aikyi, or C:;„i( cycioaikyi where the heferocyciyl phenyl C M cyci aikyi mi 5- i;0 membered heierocyclyl risigs are t»«a>fest.thi† or swbssiiuted with i-3 subsiitueais iadependeady selected froia C,.s aikyi,€,,·, alkoxv, hydroxy; oxo, halo, C¾.¾. hate!ky cvaao, or carboxy; and

wherein R ¾ is 5 toerabered atirogeo containing he!eroeyelyl, 5 taenifcered oxygen containing, heieiocyclyi.6 ajenihened niixogen containing bererocyc! S, 6 jnerabcred oxygen containing

heierocyclyl.. phenyl benz l metnbmxl tricyclic nitrogea containing heterocyclyV SO meaibere bieyelie oxygen contahiiag aeieroeyclyS or 10 xneittbere bicycilc niirogett containing eieroeyelyS, wherein S <! is nisubsbfiiie or substituted wih one r ftiore swbsiHuenls inde endentl selected. from C : ,. <s a!kyl yaiio, halo. hydroxyalkyt C;, ; adkdxy- a!ky!, C s , ; 5fikoxycsrbo«yl- a!kyl, C ; .. fi alkeayi M a ioxycarbosyl carboxy, cyci a!kyl R^alkyL optjonaily substituted 4-6 num ered heierocyeSyl opdoaally su stitute 4-6 toernhered rsiifogers eoniamkg heSsrocycSyiJearhoiiyt RR'KSOj-, RR' RSO r or R¾ s 1NG(^0}- hets R ' is E f or

C( alk l and R rs 5¾ C,. 4 alky Cw ydroxyaikyl C), S ; alkoxy-C< « alkyl CM nmoaikyi or C« ■alkyi.-C f .ft amaKjalkyi or where R" and R ¾< together with t e aitrogen ten a -6 mernbered heterocyclic rirrg ansiibstinaed or sahsiipsied with CV f; . aikyk ¾nd ¾ l mse iiiicali acceptable sail thereof

provided when R. 5 is I -medtyl-l. -pyra¾ol-4«y aad.R* is- methyl thett R 5 isaot l-ethyi-iH-pyra^o!-

5-yi;

farther provided wben.R 5 is l-roeihyi-iH-pyraiof-S-yf, and R. ! is .methyl. Steal; ' is aot l-meshyS-l- or

44, Compousd efC!akn 43 hereia R : is methyl, ethyl propy l, jsopropyi, ierbbmyl ally!, trifluoroethyl, medKsx eib L hydroxyei¾yl bydroxypropyS,

hydroxyeiltoxyethyl aatuioetb l p sm-l, 3-iiydroxyp eiiyltneS!:iyi, 4- hydroxy-phenylaiefayl, 4 inoro ltmyltttet.hyI, 3i jrphoUa-4-yle(hyl pyri.dylmesi.ryi, 6-iitethy!-2-oxo- L2-dsbydropyridiay!raedryl, imidaxoiylmedryi, S-siietbyl-iojidaiolyioieliryl, ^-iBeSliyiihiaiol lHiethyi, or S-iaotliyl-i.soxazoSylffieibyi; and a pharrnaceaneaSly acceptable sait thereof.

45, Coaipoiad of Claim 43 wherein R ; is iseihyi; and a pharm ceutcall acceptable -s& thereat

46. Cosnpotsad of Claim 3 herem R ¾ is - SR '5 ; and a iia nsaeeubcaB acceptable safe thereof

47. Compound of CiaiSii 43 wbej¾t» K ? is met oxypropoxy, 2-( : !aetb<3xy)pFopoxy, hydrssyetboxy, bydoxypropoxy, S-hydrsxypropoxy, 2-dibydroxypropoxy, !-bydrosy-2- metfjylpropoxy, 2-hy msybyhSty, pbeaoxy, S-itKt i-i-pyrid loxy, 3-oxetatiyUti diOxy,

9? medmyctufcottyioMNb k ie, aiedio&yearboiiyicihykbio,. aiethg&ypropyMdo, 4-a>e¾LOxyb«<-2-y!tbio > bydroxypropyithkx

(diraeJit l¾ft JOcaf Qa a^ ii5ks 5 (3-iiydroxy-3-£i)<ii¾ylfeu!:y:!}ih¾o. f2-I¾ydrosy-2-!Betbyib«iyI)tI»o, diflaoro«ietby¾bia, ( -a3C(bylpi{Ki¾zio- - )-c&rto:o lxi)CCh ijhks 5 iBKsrp¾o!io « - yikarboay!metbyiibio, { !-iert-bsifo ycarboiiyl pipmdl -4 ; iim«diy!iido f (4ikp ndaiyl}aieibyUhio > fteta yiS ^H-pyMH^-y TOiykbto, ί-({«π ·&ο-2Η-β^ϊ8ΐΐ^γΙ)δ ώα {5 » «ί«ί¾ {-2·> xadiaii y!}metbyiih.io : 2-pyrk1yimet yS kc> t 3 ! iai dfo yc cio e»!y!!hio, 4- bydffis cyciohesy!tSiid, cyc!dpc!iieay!ih , pbeay!diio, beazyfibio, 2-pyftdylthio, 2~c oP 4- pyrtdyii!ao, (4-plpsridiHy!-2-pyi1dy}}a:!8fbylthso, (S:-med:s S per¾ir:^ ^

pyridy ajethyMbio, {4-piperidmyI)dii0< i i sop∞pyl)piptn:idm- -yltirio, (I -i«eihy!carboHyl)piperidia- 4-yitS:ao, }.^m- utoxycato:o ^tpef di»- - U io! v (i-roehyls«ifoayl}pj|x;ridia-4-yliluo, ( 1 - isopropylcii!tonyi)piperMift-4-yl.fblQ, i-iaiediox cas^a Sj iperdb - lthi , 1- fHiedK>xyefbyIcarbosyI)piper!dia--4-ykbio, i ~{iim&h^i mnoaxbQiry i c a^~y no, I - (ffied)oxycarba yl}pipe:ddla-4^yiifeia, ( H:5-cWojOyr»midHi-2- {)pjpcridift^-yi)t . {.I -<2*

bikoxyea^o:ny!}py!Toisd!ii-3-ykbio s .3-a¾edTy!isoxa:iOto5,4~&|pyridbi-4-yi¾k! or teiraaydro~2H- py:r;H!-4-yhhio: gad a pfcm:aacii«ucikly acceptable saft thereof.

48, CoiB gisPd a Chun 43 teeia R :? k cyaao, ixieikyi etbyt ropyl, feaprapyl 2- medsy!propyl 2 i 2 " dM«aiby!prepyi > 2- ethyibutyl, triflttoromethyk 5.3,3- irifiuoropropy!, fltioroHteibyL flworopropy ' t, feydroxyraethy!, kydrexyeiky l-hydroxy-2- h teibyl.2-¾ydraxV-2- metbvlethyi, ydroxyprapyi, 2-hydroxypropyi Hsydraxyprop-S-yl, i,2-dihydraxyp»p l, bvdroxybutyb 24tyd?myfex yl, I ( 2 Hhydr0xyha†ylL 2-l;ydroxy-2-iirethyS.batyi 2.2- (dibydr xyajediyljbutyj, i-hydroxyetho.xj'- -broiaiJst.hyl, 2~{¾ydroxyedioxy}einyj, 2- 2-liydmxy-2- metbylpeatyk 2-bydroxy-2-«ietSwS e¾yl ;U2-dihydroxypemy;l, 2-bcazyloxybaiyL 2- bydmxycdioxybaiy ] , 2-hydroxy-2-raetbylprepoxybtif:yi > 2-bydroxy-2-a)eiky!propoxypropyl fetiabydfopyra»-4-yi)-bydr¾syBiedjy!, 2*fli^ro-2-.!«e 1bu t > taethoxyawthoxymelayi, methoxymcthyl. merhoxypropy]. raethoxybiayl, 4,5-dmetlioxypssafyi, aicdiox pm l. hexye!iiea y S, etbejiyl pxopeit-2-yJ, propea- i-yt, prop-l-eft-2-yl,, 3dadri>xypiop*i<a^2 » yl. I -!iyd(¾xy-2' inethylpropeHy ufeavl, 3,3-diraethyl.ba nv I -yi 2-beazyloxy »¾ay Kmsitlioxy pmpen- ! -yl, hydPoxypfo eayt, 2-«¾hos.yethe»yL 2-:hydroxymethyipropsaiyi > 2-eth xyvi:Hyl vinyl methylsaifonyipro enyl, rae&ylsuifoaylbutenyi methyisuifoayiaJly i¾»thfeaifoByibut>2-ea-l- ;yi i , i -dioxk¼iekalwdro-2M^ ¾iiioxye¾¼syl. msitbyi arbony!, (4-

Uia¾.bydio-pyra:syl)caTfeo«yi N-:msdiyi~ iTieta^ (dmsethyl¾amoethyi)-sa»toocaj:b »yi, eit-butoxy&ttboaylaietkyl. !-hydroxy-!-ten- bwtox car ayiraethyl, etboxycarbonyfpropyi , ethosy " carfaonytefh I I -bydroxyeihyl- fKethox car aft kiiiyS, mei¾yiamin:ociirboi>ylmei¾yi, im iara ocarbonytei },

diraeih liiBiinocai'boiiyfcth l s dfnie liiiKiiiocar oii Spt spyl. carbcsxyialxyt carfxsxyprepyl, cyanoetijyi eyanopropyL 4,5-!ihydroxy>emyI : , dihydrQx eint-3-yl 5 hydroxytaynyi bysSrosyj3!'opyxsyL tthyiiy!, 2 ydopf«pyJ.vi»yl, 2-hydrLx:<ytthoxyb t-l -yit-1 -yl, 2hydr ¾y-2- .OiCt ipro &x io yn l

yii-l-yL l-( l-!xydrexycyci pe8tyI}eibys]yL 3 »si!iyh3-oxetaiiykihyxiyL met ' hoxybat- l -yxt-i-yl ineilioxyp ntya-i-yL cydopeatyiidate stB l, methy!sulf nyiprepyl. meihylsuifoaylbutyl,

pbsayietbyi benzyl pbeay!prqpyi, , cblorepfeeaytoeibyl I ^i-dsii dixs -S-pbssr lsi& i pMnyMhen K i -phenyl viayl phaiyletbynyi pyrid-S-yiraetbvi, S-chiompyrid-S-yhsetiw 2-ei oxy- S-pyrk!ytei.hyI, 2-ei 0xy-5-pyridyIetbypyi, 4-plperidylBictbyL l^piperi^UiKahyl ^ ^-ixiethyl t erassitt-

1 -yJmethy -Boci>i ei ja-i- !me:{fc -raet¾ fcwifonyi- J era3i!H i-yhs«t y

, (i4-dioxld tlsiomorpS:¾oI¾:i }meiS.¾yi 3-!»eilwi~3-oxet;ffiyledxyI (i¾iK¾¾ dm-Pir-2- l)xriediyl, {tei!:aiiydro-i¾x!--3-yI)ii>ed:iyl 2 5 5-dwxQp n¾iidin -yiethyi s tetraijydropyraa-4- ii)seih.yi :!

y (methyl, 2-)tydmxyx3KiSxy!-5ep-ahydropynift-4-y iiei yi 2-saet os aidhyl^efah ^fo m«-.- y!ioedxyl, 2-ffiei oxyHieUyl-u^^^

! 3HlsoxoSan-4-pft)|>yS, 1 > 4 iox3a~2- :feihyL i 5 {-Kdioxido<¾fab dfo-^H-fl o y««- -yin}eJhy:{ 5 I .- a¾aspiroi3;3 ' jbeptaB-l.-ytetbyl -oxa-fi-a«as m j; iepia»^-yimet l L4-dioxsspimj4,5jd£cai - yhxied L i- ea^ fex -cydo xiiiy!met& i, 3-hydroxy yc! btrtyIinei8yI, ydrsxy-3-aietfey1- cyciobutytoeihyl, S-os -cyclobitfylmeihyi 3-h droxy«3-{rUltK5.roraebj 7dob«tyh¾th l 3- hydrox - -ineiSx l- cio Hi l^wdr xyxBssli i, cyclopeiny.biiet.byI, , i-<bydcoxycyclopatftyitnetiiy i~ !ia;ij:io.xycycS.opeaiyl)methyl lH^iboxyc cSi>peRf i)}roiaomej¾yl cycioaexyimerii.yl.3«¾ydrexy- cydoaexylmeibyl, 4-feydfoxy-cycfc es.yhnetbyl, or cyclobexybsieiityS; and a pharmaceutically acceptable sab. hereof.

49. Copsp xiixd of Oaim 43 wljcreixt R ¾ is cyciaprapyL \ -ien-btitoxycarboayl-:! -eyd&propyl-

2 i»oKycarbeayicycl©propyi , 2-{2-hydroxy-2-aietbykUiy.l)- ydopropy} , 2-hydrox metb h cycJ pfOpyl, cyclobxityl 2-Siydxoxycy lo0«iyI > ~ox.0cyel0bm i s 3½droxycyc!« iii:yl 3- beazy!oxycyctebuiyl 3-beazy!oxy> I - byiliXix;ycydob«iyi 3-{2 tydrosy-2-a.«stbyi8%i}-<yclob«iy 3- byd(¾x;yiofi xy yc!c i!iyl, S-eiisox carboa b t isydrexy-cyclobdtyl .3-¾:Iioxyc8(¾CtHyI-c cto¾«iy 3-cart»sy-cyciopt¾»iyU. 4-hydri.)xy!nc¾yicyel0peslyl,.4-bydyoxycydopeisfyl 3 iydroxyeyeiope y! < 2-hydroxycyciop<?«iyl.3- bydfC5sy-3-x¾etby!cyc!opeBiyt 2- xo-cyciopcs:«yl, 3-jxo-cyciopes:n l 2-( ~e8iVl-. ~ raet!iykni5«oca5¾oayi}cycIop?s«yL 3-(H-ethyl-H-ajet!)yiamiirocaffeoayS)cyciopeaiyL 3-K- isppropyl.8raiiSiocaiix>nyJ)cyc]opeJi{yl, eycSohexyi 4-hyd.rosycycIohexyl ¾ydrosycycloliexyi, ^ h da¾y-3-:a:!n: l-c ^ 3-exo~eyc!i>he:xyi, cyciohepfyl

•cyciope»a«3iyl, :i dro«y ; dope»ieft l4 ) dro^^^ 4,4- is(t} tox iBed5 ik cio «m ' 2-es:^1 yL oxcs-cycJopeftteny! f -caitoxy-cyciopejy-2>¾oyl.3> i^piOpyiamiflocarbonytcycl eKt^-eo l, 34¾ydr?xyiaeihyi)«yc ' !opi!iit- i n- 1 -yt, 4 «

(Iiydro:tysieihyi}cy eyetohexeixyL 4,4- dfm ri-e doltexeayt 4-seit-bySy1-cycSoiexe«yt 4 iydmxyeyciehexe&yL S-hyd-msycyclohsx-I-eii-

yano-a¾eitdin-l-ylcaTboK i)c cio]ifisen L 4 3-fi^JOTo-^ elidπ !- !earβπ ί)cydobexeί.ϊ !, 4-0~ me& ls lfoa m¾idia-i- lcai¾on Ue dt%exeKyl cyclohepieayl.

or 3 ,4-d!OXiispiroi 4.5|dec»w-y:i; aad a pharmacxuidca!iy acceptable salt thereof.

50, Compound of Claim 43 wiicrda 3¾ 5 is 3-hydmsy-3-isetaayi 24eteS:iydio kryL 3- tetr&hydro-i yl 2-aiediyl4Mea¾hydi;o-f¾fy.l, 2-!¾et])y!-2-leini¾ydro-ftiryl i 24sydrexyraeihyi-2-

«rahyd:ro4»-yL 2 ¾ydK^^ S . ^-'diKi -S^-djfeydt^aEaii-H' 2,5*· diisyd)i>ianik->-ji.2,3-dihydi¾i\):ran-3-y! ! .4 s 5--diS:iydmi\fraa-2-y 2-oxop n¾liiif!i- ! -yt

tesiahydiopyny:i-4-y1, 2 > 2-d«iiethyUet!¾hyd! ' OpyiaJi-4-y!, 5,5- itaethyte-t'/ < ¾jy(fcopynin»2-yl, 2,2,5,5- fe&anieilsy i-2 ? 5-dihy dmftir««:*-3-yl , 4-fhi T» etrsdiydro xaf !-4-y I, 4 ¾iO?o÷3-hydr0xy*

fetialryd:ropyntf}-3-yL -fto 4-S:rydi9xytcu¾!iydr0pyrisa-4-y!,4- hydroxyieii ' ahyd!'opytaa-3-yl, 3-liydmxyleirabydropytso-4-yl, 3 > 4-diydmxyieiTaIjydropyra»-4'-yl 2- oxo-ietra ydropyi3ii-4-yL ieira¾ydropyrsB-3-yL («¾atrydfO . pyraji-2-yl.3 i-dibydropyrsR-4-yL 3,6- dihydFopymn-5-yl j .5J-d!S.iydffi-2H-pyran-3-yi„ 3,4-dibydrQ-2frpyra«-6*yl, ?^ & dm~2H< y∞*-S~ yl 6,6-dis«edw!-3, -djlrydro-2B-pyRm-4--yi 2,2-dimetbyl-3 > ^lhydfo-2H-pyraii-4-yi , 3,4~2H~ dihydiXp¥m:i¾-4~yl 1 > 4~dio asp5i¾4.5 jdec-7-ea-8-yl !., l-dlo¾& sijdiiazoljdkt-2- l 1 ,1- dl xidoteH-afeydro-2ii-d«opyi¾n~4-yL i,4-dioxas-2-yi 5~mediax ~ £thyS.4 ,4-dioxa»-2-yS, i-ien- huioxycarhonyl- 1. ,2,3,6-t«trahydropyrid-4-y L .1 - efhyi- 1,2,5 ,64eiRdiydffipynd~4-yi ! ]. - niedw!std:ib S- ,2, ,6-ieiah di! rid-4- ], HdM^^iaiaaioca^a !j-l^S^Hctrah dr p riiM- l, i^iaetlm ca^a r ^Z^ Hetrab dio yrid^- f, Hsfiet Sc rbeHyIM,2;½^

i-mefcl ¾peridin~3- L {m-btttoxycarbo:8y}-pipef}dia-4-yi, or {.-diraefiiykmiao srboayl- piperidi»-4-y:!; &\ά a hadMCe«fe a epta le s»¾ (hereof.

51, Coaj Oiind Of Claim 43 hsfeis J is phenyl 4-eh j afcsp!ffiisyi 3-Hjedjy!pS:ieHy!, 4- mer&ylp eayi, 2 > 4-dune0iylpb«i}yl, 34rilliJ rom« 1p 8a L -tnftao medi ! teiyi, 4-«ie!:hoxy-3- trrflxipromethylphenyl -diiliiorQi¾eth i- -0uiirof eByl 2-iHei¾ylsylfoayi|? eHy!, 3- mo jyl&uifowyjphepyi, 4-msi:hyIsiilf iry!phs!iyS, 3-eibyIsiili iry!phcsyi 4- cvanop enyi 4-cy¾nopheny 3-carbosypha)' 3 arboxy~4 iydr¾xyp enyi : , S-earboxy-b- raeibaxyphcnyK 4-carboxyp¾ei5yi i 4-c aixs-3-mei oxypheayi, :3 ais0 - ciho fte8 ! 5

(iiRjelliy BiHie ia' iH iiphea i, 2-(d¾ad¾yaBMj)war Oi ipbs! L 4- (dimeii!iylamtiH ^rboay 3-(N-et¾yi-N- ifietre!aoxlH carbofiy!phenyL 4-eihy!ii!ii!Soc rbo!:t SpS) i i 4»{K-dfayi-i"i>

metSi ! !aliioc bcsn iip enyi, x [$o o y!amiiiotai n ip33eji S, 3-{N jttty!- »

3-( ί

dlfe dfoxy ro yto«8<» tteiyl) -hydm y-pbeayl, 3-( ' -met oxyediyI~ - aiefiiyiaaiinQcarbenylspS'isnyi, 5-iriedioxy-3- dli«fiia !aa)jni)caiijOi ip¾esiyi, 3-rae¾oxy-5~sd iaminoe3rbo£iylphenyL 2-i«fiiaoxy-4- diffiefelaiM!tocarbon Spheiiyi, 6-meib xy- -diffid¾ Iami8 car on l be!:syl 3-inet:h>xy-5- eiiiylajBinoearboiiylpbefty!, t}ydr»xy-2-!iiet lpr0^^ dihydmsypropyiamiiiocaf oayl-piieayl 3-( i-azetidmylcsrboay plsesyL 3-{3-i]ifftro-a¾ii:di»- i - yk;i5'boi5:yS}phefiyl 3-(3-hydixssy-aze!:id!Si- !-y!car»o:ny}}>S5cfty! s 3~( «medmKy-a¾bds:fi-l~ yIca e:i): !ipliea L 3"i«etb ls:a!:i¾ y 3-C4- i«or hoHs icait»ftyO toyi, :Hi-py?<¾Sii»syc3rbonyl)pliefiyi s 4-me{ oxypheay{. ? 3-i»etb¾s.ypbcRyl- 3-0»oro-6-t}>«thox pto>i 2-i}«o{«-5-metboxy hen i t 2-»ietl»sy- -mebyiaffiKftos»{f0«y { pbettyJ, 2- H ' je$ho « -e-ihytettM»«s«!fony} te¾'i 5 4-sm Sm- -5-Hie r l mb ^ ^^^ S-roei o ^S- mcdjoxycarb oylphsayl 3- fb0x -2*mst- s IieB l 3-diS»or0isssliox pSiS!i 3- difiuomojei ylpbeHyS.3-difi«oro«hyl-4-iluo.rop.benyl, 2«aieSto ptei 2,4-dlmeUjosypbe«yL S^-dmiedios pben l, or S-feenzod xoIy! aad a pharmaceuticall accepta le salt. taeree

52, Compotmd ef Claim 43 wh 'eia R ,! is i-iiietbyi.-3-pyra¾o?yi f i-maby!-4-?yfsz6iyb 5,5- diraetbyf-4-pyraxoIy ' { « i ,3,5-frimefb M-pyniiioIyl 3-n¾i!hyl-4-pyr3zo!yl, 3-iriS¾!OT -eibyI-4- p razoiy L ί 2 ; 2,2-n:!i½¾!¾ei y I]~4-pyni¾oiyi , I -csrboxy metby I -4-p mstly L } - ethoxytattonyhaeihyl^ l-cyci.obtHyi-4-pyraz6iyb i.-{4- n:50^)o!si i}carbosiy¾weihy! -pymKe]yI v :-(4-mofpfeolmy])ethylr4-py!¾xolyt 1 -bydrosyetbyl-4- pyra2«SyL i -bydriisyeibyS-S-pyra olyL ! -liydrosypropy i-S-pyra oly! t I -{S-hydras -i-aied^ibii!yij-S- pyra^o!yi. ! -«ietho e }-4- w,o{ ] 5 S-pyrazo!y!, i-iitetbyi-S-pyraxoiyS, I J-dfJsci yl-S-pyra o!yl

dimethyla{a¾oc?iri>o8.y^ ymz-el-5-y!, Snoicgiyl^ fonylasH j ao-pyiaiJ l-S-yi, 2-ajeibyIs»H¾8yiamino- pyra¾©J « 4-yi 5 2-{2.-hydroxy » 2- eft*ytelbyiMbiazol-5~yi f -aiediyi-5-)msdazo!yl 3 > 5-dimeibyl-isosa¾c«i-4-yL ! -ttK? !-tfksi5-4- L 3 - 0 r0p i-lria2¾i-4-yt 1 iydrexypi0py1-mazai-4-yt i -hydrosybutyi-niaz!«-4-yl, (4- 2-iHel!ioxycafboayS-ihiea-5- iO] mcibyHmmoc8rbo»yiH¾te-5-yl, 2 2-Ssydroxy-2-n:¾erhy?eiiiyi)¾ieii-5-yt 3-mei&yM,2,4-oxad¾¾»*- S-yl or 5-cyaao- ί -axei¾ylpyrml-2-yi; and a paanmceaiicaliy acceptable sal t m .

51 Compound of Claim 4 w siei R :t is 2-pyndyi 3-pytfdyl, 4-pytldyl, 2-iBef¾yl-5-pyndyL

2- n!2th:y|«4»pyridyl 2-^thyi-3-p ridyi: jmh I-5-pyridyl t 3-uf!ifOi ieihyi-5-pyndy!, 2- irifi:aofOHJediyi-5-pytidyL - ifh½roiaeti S~5*pyridyi, 2*oif5:uoiQiBelwi-4- yi'idyl 2-»ifiuoKKixci 1-

3- pyridyl 2"medjoxy-3-pyridy!, 4-HtefS:iosy-3-py«dyt 2-aidl¾axy~4¾ id.y{ ! , 2-C3>oxe(attyl¾astt½xy-

4- pyridyi 2--{3-i)xeiaoyi)0xy-4-pyTidyL 5-Il«0m-2-raed>oxy- jyrid L 3-fS o5»-4-pyndyS, 2-il»oro-5~ pyridyi, 3-ft«oSx 5-pyridyi 3-:nisiii©xy-4-pyndyL 2-eihsxy-4-pyiidyL 2*.n¾itfioxy-5-pyrid l, 2~{2S- d¾ydmxypr»poxy)-5-pyndyl 2-«ydroxyi«ef]30xy-5-pyridyl, 2-hydroxyef.h«xy-5-pyridyI 2~ ay<fr0xyedjax?-4*pyri«$yt, 5-iitioro-2-hydi xyetfcoxy-4-pyridyl 2>meiioxyethoxy>5-pyrfdyl, 2- hydra>iMethyk5-p> idyI > S-met oxy-S-pyridyl, 2-stksxy-5-pyddyl > 2-sopropos.y-5-pyiidyl 2- hydffixy-2-medwlp3-opfisy-S-|yridyI, 2-(l J i :di¾j.05:oelSiixy}-S--py)idyl 2-eyrf.opropy! edicsxy-S- pyridiiiyl, 2 msthyfeuifoaylpr(^poxy>-5-pyridyl ! .2^wt yls»ifoaylaminoeth xy)-5-pyridy], 2~ 2-cW«te-4-pyridyl, 2- citoo-S-pyridyt 3-cMero-5«pyridyI.2 ystto-4-pyridyl 2.<¾?«0»S-pyrid i, 2-ffieiHoxy-3-eyaiK>»5~ pyddyl, 2 ysno-6-methyM-pyndy.l, 2-i.aethox.y"6-a>c 1-5-py l, 3-cyano-S-pyridl, 3-cyaao-4- pyddyl, -HKii:iySsttSf i:yh5'-pyiid i 3 » a*2i y!suifo«yi-5*pyiidyL 2>(o!etiiyl¾)ifbsyiifniit50}-4- ridyl 2*nieifioK cs!¾o!} S-4»pyrid i.2-( dflida^ol- 5 -y}pyridyl 2-sHe|:oxyhBHiOffiei yM-py!'idyJ...2-oxo- i ,2~ l-m ¾4-2-oxo* ί Xlfti do yfidiB-Ht -i»et]]yi- -ox¾>- 1 ,2-di j-dr»pynito-4-

hydroxyeihy!-2-oxo- 1 ,2-diiiydropyidm-5-yl, 14:jydi¾xypropyS-2-oxo-l -ddwdropyrkSa-S-yl 1

4-pyridyl, 2HftsihylaminocarboayM-pyddyi, 3-jtaci ylaimis>eart> ' oiiyi-S-pyddyi 2- iSopmpySi«smocaib ayi-4-pyridyL.3-drediyiamif¾ica:rboftyl-5-pyddyl i 2- :med)y)s«ifoa li aaH^watKjnyJ-4^ dyl 2-ffi 5yS Ibft lso« 0ed:i Ss^^^^

3~aiet is«li ay!aaiinoe^Ylai»kiocarb ayi-5-pyridyL 2-me{¾ylsuUbnyi^mK5tk>t -5-p dd J ? 2- S)ydmxycdjyiaa3i:noc3rfeoiiyl-4-py:tidyL 2-l5ydroxy«shy1«mmocarbOKyl-5-p rldyl > 3- hydi¾sycthyi;a iftofcaibOi!ys-4-pyii 2'

ojed)osyethyiajainoearboayl-4-pyTidyJ, 4-fl^O-2^c{ i3mio car o« lao«BQ-5-p ridl 2-0- S-pyiimidiiiyt 2-ami O-S-py«midiayS, 2-cyaso-S-pyriiBidiayi 2-π½Οϊ ν-5- pyriaudiayl, 2-eiliioxy-5-pyri«»disiyl 2 s0 ro o Y-S- yninidi»yL -mik^^ 4~ Ui0:ooroHjediy!-5-p riJft:idii3yl 2Hri0:i!oiOe!hyi-4-pyriioldii)yL 2 - 5 s: i ilis tXXiet h:y 1-5 -py r i ί ί sitii : ΪΥ ΐ , .2» di¾ed:iy!3aiinocsrbofiy!pyna5idiii-5-yl. pyTs¾iii-2-yi > ndaxm^-yl; arid a p!wsaaceutkaHy acceptable salt thereof. 54, Compound, of O&iro 4.1 w ereiii R "! is S-bcnzoihleayl, S- eazofufyi, S-indolji*, 2-oxo- dibydro-5~mdoiyt ft-indoiyl S-osO'dihydro-b-iiicioiyt !-mediyl-l-oxo-dliiydro-iS-ii loiyl.

mwd&ioj ' S ,2-a jp-yndia-S-yi, imidazoi ' 1 ,S-a lpyridia-7-yS, itoida*©} ' ! ,2-

dihydro-2M- en3»bJ[ ! A5]ox«thia¾pft « 8-yL 7-Πικ)Γ0~2 η5 {-1 -4ώχϊόο*3,4 « όϊ¾^ίΓ0-2Η-

pyrtdol3,2-¾]i S ,4!lbisioo-7-yb esimxa -S-yi bePzoxazoi-ft-yk ! , 1 -dioxo-a^-di dro- H-

pyr!doj i 3,2~f¾ I^lasaxepin-^-yi beazoxazoM-yl 2-ineihy! enzo iKii-5-yL 2-£dwibeP dKazob5-yL 2-tsopropylbei55iOxii¾ob5-yi. > 2-oso-2(3H)- ea» (d.|o3<-aKol-S-yl, , bea¾oxa«ol-6-yl, feeaz diiazot-S-yS, bea¾CilS¾i;½0l-6- I 2-meibyibe!) oibiazol-5-y!, 2-iiopropyibenzod]ib:iazil-6-yi !.-i«£i:hyl~5- 6-i azolyl i-j»fithyi-6-mdazofyl, 2-aseihy{-2H- mdazoi- -yl 7-a¾i¾idoi-6-yi 7-azakidob4-yl

yl, 2 di iydK - } Hxp rroioj 2 J. ] tt :a}÷S-.yl to¾0tea«0i- -yl. ¾-me¾ !bett«ejd]ts0xaiioi-5-yl 2- n)ediyi-3-ox0-bc:n¾o[d]isoxazoS-S-yi 2H«edyi-6-fiia11i«xy-3-ox0-baizo[d)isoxazoi-S-yl 2- aiediyloxazolojiS^-^j rjdiH-S-y!, -«κΟϊνίθχ«ζο1 ί5Α·%1ρνϊ'^1ίί!-6^12-i 2thyi-3-oxo-2,3- diS:i drofsosaiofo(5 i :)ij ridb!-5« l ' { ^djox -^mediyi^^^Hi dro-iH-pyrkioSS^-blj , |β ' ι&;?:ύ*-7« yi 3*a¾ibyHmida*»i . 1 ,2-ateridiJH vl, 2-«^ο-1Ι1 ω¾8¾ο[ ^ ^^« ¾-20ΗΗ-1 ii»idazop a|pytsdj»-7-yL liaid zop ,2-ajpyndli5-S-yl 2-oxo-22>-ddiydre- H- nlda¾oS4,5-bipyrk5m-b.yl, 2-oxo- 2,3-dihydiobo¾«o{;d;]oxa¾ol-5- I > 3-oso 3eax0dj i .3joxa ' daoJ-5-yU 3,3-dioxo-fee«¾o(;di:l

ajpyTldia-5-y], iL2,4jroazo!oi4 < 3-a|pyridi:ti--b-yl . h irox TOe ^

isoqumpIinyJ., T^soq iaolinyl, I J-aaplubyTkba-B-yL 3-aiei i-IH^yra¾o¾ 3,4-b]pyridin-5-yS, IH- pyraxoS^3,4~b]pyndm»4-y! of 3-a5cdjyl-ili-pyra^o!o[3,4--b]pyddfji-4-y1; and a pharmaceutically acceptable sab tfeeteaf:

2H-pyraao|32-c3pyf'i(fayl cluwaa l- exahydi«fuio ' 2,3-bj¾r>d, pipendiiiyl, pyridyJ* pyra/otyl, istrazolyipbeHyl abtoiinyl i,2-di ydr0qttiaoii«yl, pyi o!ldt yS, to?.yl I,23,4-!eu:ai:iydroquiaoHifyi 2H-indaz lyl jsoiadoliayl, H f 2 ]tria«oSoi4,3-£i]pyrid:biyi, jH-p-ym¾o | ' 3 ( 4-d]pyrimkl:xsyL is^ aiPol wl IK-pyi¾2ok ,4- pyradisziHyL pyraziavL or cbrom nyi.

yvtetm R is uasnbsttoted or substituted -with one er mot- substituents isdepeadeftUy seected .from meh l, ethyl, cymio, eMoro, ilwro, melhoxy, uiftuoromeihyi eihox ciii oH i,

btti ' osycarboayl, carboxy, -Coieth ^- -CJiK!h x eib^ammocarbOK , ( , *

diBK!h iHids! caiboxsyi, N-{jmb ihN ' me*yaariftO©tb j¾Miinocar nyl t \ -ftJethy!pyfSi:my-4- yDcafboiiyL or oxd:

a«d -a banMceatiCislly accepta le- sab teeof.

56. Com ound of Claim 43 wherein is beazyi ieU¾¾ydropyr;io-4-yi 3-iiso!'o- tesrahydropyraH-4-yl i-Boe-pipsridi^4~yi besa¾ydfoi¾iX)[23-¾|S\ir-3-yl 2,5-d x0-pYrroSindfii-i- yi

2-pyddyi, 3-pyndyi 4-pyridyt 2-iBC{hyl-3-pyr l 5 2-raethyM-pyfidy:i, 2-iae I-5-pyddyt 5 2- m¾byl~6-pyddyl.3-mei.byl~4-pyridyL 3-m.a&yi-5~pyndyL 4-meshy!-3~pyridyl : , 2 H$ime l-3- pyridyt 2/4~d :nei yi-3-pyTk!yl, 2^ 4,5-dii»£i.byi-2- pyridyl 2,S-dmeihyl-3-pyndy:t, l-ediyK^pyddyL 3-e{hy-5-pyridyi 5 2--ebryl-6-s«ed)yl-3-pyrfdyi. 3'tse tepyl-5-pyrtdyL 3-prop-:i -¾«.·.! -yi-5-pyf idyl 3-(! - i»ediyki aiyi}-S-pyridyl 3-cyciopmpy!-5-pyj-jdyb 2-feydroxymetliykVpyridyi, 3-

S-pyrk!yl 2 iydxoxypropyl-5-pyridyl 3-(i.2-d;ibydroxy¾diy ; l}-5-pyrk!yl 2--{rd¼ero¾ethyiT? - pyrid S,

pyridyl, 4-sjei yl-3-tri0«oroiBeiIiy!~6-pyridyi 3 ri ' Huoft>5SK;tfejd-5-pyridyl 3-trifl«oromediyl-5- iioro-fi-pyTidyL 4-irifluoroified i-2-c&loro-3-pyridyL.2~s:nei¾oxy-S->yrldyl 3-(2~

bydFOxypiopy : S)'5-pyndyi 3-{2-]>ydiosy2ibyS)-5-pyridyi, 3-me†i]bxy-5*pyridyl, 3-sdioxy-S- pyddy!, 2-tnsboxy-4-iiiethyl-5-pyHdyi 2-raei.boxy-i>-es¾yi-S-pyTk!yl 2~cyas:io~3-pyridyL 3- cysno-4-pyiidyl . , ~cysiio-5-pyndyi., 2-eyasio--S-ijifliiorsKietbyS-3-pyridy:l 2-chtom-3-pyi1dyi., 2- cbloto-S-p k S, 3-chl03:o-5-pyddyl r 4-d>.Sos¾-3~pyridyL .3-chiofO-4-ey8¾o-5-pyr.tdyi.2-fitK»:o-5- pyridyi 3-fi»oro-5-pyridyl i 4 tuoro~3-pvndyi > 2-chlom-5-methy.l-3-ijyridyl 2-b«Jj.t ?-3-methyJ.- 5-pyridyi !. ! 4-dimetbyi~2-oxopyndia-S-yI.. S -diraeti!y}-2~oxopyridin-5-yS.1 ,2-li:i5i fJ:iyl-6- oxopyik!ifi-3-y!, Mtteib i^a opyrldift-S- }, ^roed:i 6'0so n «s-- »yi, y-c iyl^ opyrkim--

3xopy !.diii-5-yi ^-diBicdii S-e-o p ridni'-S- i ' t-wcihyUir-ttinaonaetbyl-ft-oxopyddi^-yl, }.*

bttytorbiOcafboayiH-pyridyi, 2- ' me { h x et¾ lamaioc gj ¼ay^^y« ' dyi ; 3. 3-methesyphenyl 5-p ndyl, -( - fSuoro-5 -mail joxypbeay!)- 5-pyridyi

S-p rimidifi S, -chl9:ro- -meib i~p riraK!!i-6- L 2,4-dimethyi-5yds ' «3d¾-<)-yI, 2. wp riiu hi*5- yl, 2-triiI«or«n:fetbyl 5ytimidi0-S-yi > 4-f¾or«pyri3:«idio-2~yl.5-iluompyriittdm-2-yl, - pys¾in-5-yl pyfadkmn-3-yi

-c8.yM-ferojHO-S- pyr&xoiy!, l-e ; i-4-mell)yk5-pyrais>!yi, I^t l-3-metbos.ya)e ; i-5-jyra«ily neAyi-3- diis<;t !amlsoc3d50ft l--5-p mffit l t » mie{hyl-3-cyclepf(¾51-5-pyr32¾)lyl, i-ei: ykett¾¾al-2-yl: and a phiwrna eajically acceptable sat there f

57. Com ound of Claim 43 w efeis R* is phenyl, 2^~dffiuO}xpbe»yL 24¾<^>#he»i ,4-di0yoT<jpIie¾yl 2,4,6-trflii!.oix>pheijyl 2,5-dlOuoiOpbeayl 2,3-dii¾soi pfeesyl 2 > <-dlfluoro-3- 3 b!orap¾sayl, .2,6-di ' e oropheay!., 2,3- dschloropheayl 5 .hioffi~2-ii»«ropheviyL 3 hl0r - ' ¾aor p¾ea l,2 Jofo-6^finorop¾e»yl 3-cIilar«- 6-OiiotspheEyL 2-iIitom-5-5Tli¾-oromsfeyipi5eayl, 3 $ydr0x me ! hea l < .3 iydre&ye&yipksB.y}, 3- S:iydroxys»e!: yl-5-ffle i iiylp ctiyl, -meihoxypaeayl, 2-raetteyphsi>.yl > 4-tHd&oxyphe3Byi 5 2- arahyteu!ibay!pSienvL 3-methy!suSfoByiphei L 2-.ftuoro-5- eibylsaliotiylpbesyL 5- d ' hy nmosuUb«y-2-11uoro henyI < 2-il cir -5-meihykarb :ayipSK > nyi 3-.BicfS.H.xycarboiiySpSienYL 3- carbQs toyi , 2-n¾2tB1-$-ette a« oa ¾iiea>i 5 2-^1oro-5-ctteycarfeonyipto.y{ s 2~ftuoro-5 « 8¾ethoxycarboay:iptoyl,. i-nieih i-S-tHeSjas carbon ipbsj^i.3-.bydie>xy«¾et -5- fficOioxycafboaylpbenyl, 3-a)«h.oxy-5-oiethoxycar!aRy]pb«nyi, 2-fiiioro-S- «W(hoxycarboayh«fitbyl;phe»y:{, 2-i»or0-5-q« ox mei;hy!p:«!i i, 2,6 !i0.«0o- sK!i:( iphc:i!ySy2- 2-ch!oro-5"C.iirbqiiypb«Byi, 2-i0«oro-5 ar oxyp »yi, 2* d:doro-5-ao:a«ocaiboayipb««yl, 2 « naoiO-5-aniiao ¾r onyiphea> 2- ya»ipl:!e»yl 4-cy8»op.feeay1, 2- an^-tu^i lpbea i^^ aaa-S-TOtb ' ^tei S, 4-c aito~3¾neih !pheR l 2~cyaao-3-eibyiphenyl 4- c¾!er&-2-cyas«piieoyL 2-cWoro-4-cyan«¾jbc»yI, 3 b5oro-2-cya»op eiiyi, 3-c?:diro-6~cys«opS:i¾iy!.2- cyatto-3.6-d!cbles)piieayL 2-cyaBO-3 < 6-difl!f0i:ef> e»yi 4-cyaii *2 ; 6-diSl»«!:opSiaiiyL 2-cyano-6- S oropheayl 2-cya«o-6-ch]0rophe¾ l, 3-diS.offi-2-.yaao-6-liii05X>p! ' ienyS, 2-ey_4no-f>- b1.0:i!ama5C5¾ ipli2i¾yl, i-cyaiiO-S-iriO-iioroiiieshyipliea L 3- (!$opfppyl)atsinx>caFbosyi]pb.e3yi., 5- :med?yl-3-|:(i:sops¾pyl}aniiaoc)rboayijpiteayS ; 4-Kie^

raedwl~5-| -Cn¾iiiy!}-H-{n:iediox esi i)amHte 2-HK i « 5-} ' $^- disi:iei:Syl )affi»ioc rb«Ryi}pbeHyl 2- s(?i¾yl-5-[ls-iai.efhy - '-

diSaom-3-i(isopropyS)as«ii50carboi!yi)ph¾5yi, 2~i¾i0i¾-5-{(fsopmpyl)a:ni:iaoc rbony!jphe3yi r 2- fiaoroe^( -i5opopyi- ^Hethy!a!ai»o) 2 < «oro-3-{{e05 la»iiao)eai¼By toy 2-

flu S^ i irop r a^- JsmiHoearboa Opie^l 2-iksor«-S-

( i^ed^osy iO lilaismoca o!i OpliesjyL 2-¾oto-5 f2-ja«ih I)3 >inQ<¾r oftyJ.^ben L .2*fluoro5- (<2-i»etlioxyptopyi)a ao irb a i.}pfee»y:! > 2-i¾ioro-5-({ ! -oietaoxy-l- raet!iy!cihyl)ami:n cafboiiyi)pbeitYl, 2-dd !:o-S-({.S-pynroliftdiaYl)ca:rbo«yl)p esyL 2~sMoft>5-( ( S .3-

n«oro-5« i-ffi i i yrazoM- ^ 2-fltioro-5-((l-m£ii]iylpyK{a»i.-5-

ljiasxbocarbon ^ 2-ilitOf¾-5-( ί -

Ouaroeifsy^ i eodi^^

yf^ai.ninocarbooylsphanyl, 2~iI «ro-5 i-aKih l i em^

SKl-ra£d} 1pipen in-4~yI})a^

2-Q«∞> ^4-rao^boli» ).)atn;mK rbony : l} h!efty} > 2-ί¾ιοτο-ί-((4- i:fi fplioiii!yicdiyt)amiitoc3f o«yi}piieayl 2rC¾l ro-5-iffict¾ox <¾¾y)affimocariKm I)p.he8yI : , 2-ehioro- 5-0 -pyfi¾S.id.f«yk3:rboay!)plieiiyL 2-diioro-5-( 1 -meih l Y.qizii^ -yi}carbpi¾y¾piieiiyi.3-(2- beaximidazoSyljpteiyL 3-£2-raethyi~ I -½tm¾plyl)phenyl, lM2-methyl>I ^^-oxadiazoi-S- !J hea !, 3- { -in€ih;yi-i , -0 adi x3l-5-yS) lieK i- aad a phart«acct«.caUy acceptable sa.lt. ihereof.

58. Compound ofCMtn 3 wherein. R* is S-quisoiinyi 6-qtssn Iinyl, 7-Cjahioiiiiyi 8- uiiJoliHvl, S-ddore'-6< :iofoi i, 7-c k}fO-4-q«ja ' tiayi > S-eldom « 6K moSffi L 2-ajcibyl>4- fi.S-diai t yki.b.T.S- teaajy<!r«¾iuae ii-5- 4-qoisaxoUsyt quinos !iri-S-y Ϊ -Pxo4aoiPd«liB.-4-y!, I -ox » j5»adoHa-6 » y!, 3-ίη ών1-!Η-ίϊ:ώζο!-4-γΙ 2-5afi s¥i- ¾-isida¾S-4-yi, S -inetSiyi-I H-iadazol-S-yL i ^-disHeib l-

yl, 4-oxo-q«5»ote-l(4H yl., 2-meihyl- ^xo-i^-dib^rQlsogmiwji i^-yl,. ^7-d uoro- 1 ,4-dimet.hyl- 2~mo- 1 ,2~dlbydj:oqaiao:bii-6- l ?

iiu0io -meilwS~2-oxo~4^^ 5,?-diil«ero-4-ethyM-a>e{iiyi- 2:-oso-:L > 2-dd:¾yd3Oqai5iolia--6-yi, so umeSisiyi, 7-¾soq!i:is«SinyL ^-isoqamo iiyi, 5-isoq .kQi.iHyl.4- isequittpli y I. i -joeihyi-lH-p fakJJolJ^j yrtd j a^- l, :i^b l-}H^yta¾otop,4^>)p?idjii * . ; } -

,5A7-teiraliyda5H-p wol^,4- | >^dtt}>3-i 3 i 4~dibydro-2H-pyra»o2J-cjpyTidiB-5-y! i - :n^iby-3,4~di1iydro-2H-pyi¾no2.J-b]pynd:i-5¾ f i sr S-cbrbamn-yl and a phanBaceuiicaily acceptable salt thereof. 60. Compound of Claim i wherein R. 5 is H, or .a phaffiiace tka!ly-isccepfa i salt thereof.

A Sktftfiy of specific cossposntSs ef p&rticulat iirferest isfem Foi«i»la I consists of eoffippimds and phanaaectificayy-accepliiblederivaiivei; thereof as fallows:

l ttieIh i-. S- i*xiieihyt-lH-f^

i~mei£ -3-( ~(^da0Hn~5^^

(Eh I -i5-(2-cyciop:¾py1viftyi)^

c o ty- ^

i-{5-cyek ) pc«Syl-4-i26-dsfI»oiop!iSiioxy}pyodi»-2-y

HM3-d:Ooro-2-i¾}0¾¾pheooxy^

I-i4H3-di!oro-2-fl»oro her»o^^ ^

H 3-efiiofo~2-iliiOi« i^

;H H3 hIoro~2-!I»omphenox }^

! 2 > 6-(]iflooropheHOxyi~5- lieH

iH4-(2 ; 6-diiaor0pS:ie«o¾y)-S-i4-f»ed)0xypheny

H442 ,6K] i 0 uoro ta

-i 3 ^ - (2, 6-difiy orso! iox }-<S-(2 -

SO?

H3«(2>ediylpyridm-3-ytaxy}-5 ^

fS)-^{ -{3-¾ydro y-3-methyS: ifiySth¾

methylufea;

f$) -medwI" 5K e!r^

y!exypyF!d!a-2- i)!f¾a;

y!)«s¾a:

N5-(ds-4 iy r0x?cyclota

methyhfrea:

ytoxy)pyrid»i-2-y:!}-5-o:iethyK(re hydrochloride;

H H2-¾SreI :nd :*3^½ )-5 ½

carboxa ide;

raeihyl 4-C5 !-¾ MH: } ra20l~S^

carboxylase:

i 5-f.i-f5-chioropyT3xis-2-yl)pipsridin-4-yirt« me&yHxrea;

l-i5-(es-; -dikydsmyc d^

ii!cd hirc ;

i-{3 (2~eibySpyridii^3-y!)oxy

i-{5-{3-n5edi xy r0 y!ih:ioi-4-{t|»i o!in-5-y }-{ -( ! d"di0uoi¾ e«o }«S-(2 i t-osyethvi} ry i-{4-(2,6-d!fluofXip <;Hos;y}-2 , -(tr!fi:oofXffi i-(5-cycS0propy-4-(2,f~dUiuorophea xy)pyr (S)-i-med l-3H5-{iett¾Aydro-2H ) rss-4- !i,ido yt)»rs¾

A family of sped.lk- compounds of part cular interest itMtt Formula J consists ofeompotiads and pharm cetttseaiSy-aceeptab!e derivatives thereof as follows:-

memyiurea

t-( {5"rneib.0xy 3- yndir^

H-M-Vi-dih dro-SH-^^

K5-(5^i¾ d o~2B p rit}-3--ylj- *C(i ,2-diiaethy!-6-oxo. ue-d lr df -S- ytidia i toxyH-pyriditty!}-

3-Bi.e S ; tyi).(fC<i;

i-(5 2-feydmxye†!.ryl)-4H(3-medwi-3-pyridiriyl) or

! -C3-(( ! -e!i! l-lH- yrs^

Another aspect o fite invention relate ta a phamsaeeutical composition comprising a corn oii!id of fonouia 14 V and la, lie * fid, 1.11a nd Wa aad a lmftMcetjacaiiy-acceplable diluent or earner.

Anotta aspect of the iisveittioa relates to the use of a compound aceoxdiag to aay of ttte above emboditaems as a raediastaeat

Another aspec t of dte soveatioa relates to the use of a compound according to say of die above embodiments in die ntanafacinre of a medicament for die t e t ent of diabetes.

The compounds of this .iiive.tit.ion .may have at general several asymmetric centers and are typicaiiy depicted .in Use form of racenae mixtures. This invention is ended to encompass racemlc mixtures, partially :raeernlc mixtures .and separate etiantkinters and diasieromers.

The pressm: tavendqa iacindes .all pharmacentic lly acceptable isotopicisfiy-Iabehed compounds of the present rovenrion whereat one or more atoms are replaced by atoms having the same atomic numbec, but as atomic mass or mass nutnbet different from the atomic mass or mass number which predominates ta nature.

Examples of isotopes suitable fox inclusion in the compounds of the iisvenlion me hide, but are not limited to, isotopes of hydiogea, such as ¾ aad carbon * such as * U C mi C S chlorine, such as '¾!, fluorine, such as is F, iodine, such .as iZ aad % ««rogen, saeh as ¾ and ¾. oxygen, su as ! Ό, Ϊ: Ό and !s O, phosphorus, such as aad sulphur, such as S S.

Certaia isoiopieally-labeUcd compounds Of t¾e presetst nrve»h " oH, tor example, those incorporaiiag a radioactive isotope, are useful in drug a d/or substrate tissue distribution studies. The radioactive isotopes tritium, s,e. ¾ and carbon- 1 , i.e. i C, are particularly o eM f this propose HI vie of their ease of mcosporatioo and ready means of detection.

Substitution with heavier isotopes siscl¾ as denietiato, i.e. ¾, may afford certain therapeutic advantages resulting from greaser iac!aboiic stability, for example, increased is vivo half-life or reduced dosage tequireaKBts, and hence may be p efe red in some ©ipctnnsiances.

Substitution with pOSi!Ton emitting isotopes, such as H C ¾ F, ,; Ό and ,? N ' t eaa be useful i:» Posisr fi ' emission Topography (PET) studies ' for esam ing substrate receptor occupancy.

isoiopicaH -labe!ed coniponads of the preseat iave-uiion caa generally be prepared by eoavaafional techniques known to those skilled in Sim art or by processes analogous to those described in the accompanying Examples and Preparations rising an appropriate Isotopsealiy-iabeled . ea ent in place of the noa-iabeled teage.ii!. previously employed.

Paartaaceutteany acceptable solvates ia accordance with the invention include those wherein the solvent of erysiaiii^aboa tnay be Isotopicaliy substituted, e g. ΐ , d*-acetone, s-i MSO.

Specific embodiments of the present invention include the comp unds e>;emp.hfied in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polynwrphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof, Unless otherwise specified, the following definitions apply to tcrsns Sound in tire specification and claims:

The terra "11" denotes a single hydrogen atom. This radical, tnay be attached, for example, to aft oxygen atom to form a hydroxy! adical

Where the te :! "alky!" s used, either atone or within other terms such as "it fo lkyi" and "alkylamiae",, it embraces linear or branched radicals having ne to about twelve carbon atoms. More preferred aikyl radicals are "lower a!kyl" radicals having one to about sis carbou atoms, Examples of such radicals include aseth i, ethyl, a-propyk isoprop l, o-bntyj, isobutyl, .i e-b tyL

isoasnyS, hexyi and the like. Even snore preferred are lower aikyl radicals having oae or two carbon atoms, the. term "alkylaay?" embraces bridging d vaieftt aikyi radicals such as tnethyleayl and ethyiestyl;

The term "aikenyi" embraces linear or branched radicals having two to abou twelve carbon, atoms. ore preferred aikenyi. radicals are "lower alkeayi" radicals ' having two to about six carbon atoms. Examples of .such radicals include ethenyi ally! and the like. Even more preferred are lower aikenyi adic ls havin two to tb:ree carbon atoms.

The terra "alkynyi" embraces linear o branched radicals having two to about twelve carbon atoms. More preferred alfcynyl radicals are "lower alkynyi" radicals having two so about six carbon atoms. Examples of such radicals include etaynyl and due like. Even more preferred are lower alkyayl .radicals having two to three carbon .atoms.

The term "!ta!o" fuearts halogens such as fluorine, chlorine, bromine or iodine ataas.

The icon "baloalkyl" embraces radicals wherein any one or moreOftfce aikyl carbon ' atoms is substituted svith !ta as defined above. Specifically embraced are monoltaloulkyi, diha a&yi and polyhaioalkyi radicals including perliatoalkyl A monohaloalkyl radical, for one example, y have either an iodo. hmmo, cklore or ikoro atom within ike r dical Dihaio and. polyhaloaikyi. radicals may have two onaore of Die s me halo atoms or a combiaatlori of differeat Ira radicals, "Lower haloa-lky!" embraces radicals h ving 1 -6 ' carbon atoms. Even more preferred are lower nabaikyl radicals ha ing o to three rbon atoms. Examp es of hatoalkyi radicals include fluotomethyl, diSneraffiemyl,. triituOTOmethyl, drioromethyL dicMoromethyl tricldOKHnethyl, pentafluoroethyL heptafluorcpfcipyi diilu rocldQr mediy!, diCh-loroS orrmtethyl diituaroeibyl. dHtueropfopyl-, dic-klofoethyl akd d!eWoropropyl "Per uoroa!k i" m& alkyl radicals haviag all hydrogen atoms, replaced with ilaore atoms. Examples include triflacjromciiryi and peaiafluoroeihyl.

The term "hydroxyalky ' means an. alkyl group in which one or more hydrogen^ has een replaced with a hydroxy! group.

The tens 'ttydroxyalkynyl" means aikysyi group m which one or more hydrogens to feeen replaced with a hydroxy! group.

The term ' ¾}»ao&lky means an alkyl group in which one or more hydrogens has been replaced with aa tsmko oup.

The term "alkoxy" embrace linear or branched oxy-eootaining radicals each, kaviag aJfcyj. portions of one to atat ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicsls haviag one to six carboa atotHS. Examples of suck radicals include methoxy. etiioxy. pixspoxy, buroxy n reii-hutoxy. E ven more preferred are lower alkoxy radicals haviag one ia three carta atoms.

The term "alkoxyaiky!" embraces alkyl radicals each haviag alkoxy portions of sate to about ten carta atoms. More preferred aikexya&yi radicals are "lower alkoxyalkyP radicals ha ing one so six carbon atoms. Examples of such radicals include stretkoxymethyl, etboxyraethyL a»d

methoxyetkyl.

lite term "alkoxyaikeny!" embraces a&eayi radicals each having alkoxy portions o.f two to about, ten carta atoms. More preferred alkoxya!kenyl radicals are ' 'lower alkoxyaikeayl" radicals having two to six carboa atoms. Examples of suck. radicals include methoxyethenyi.

' The term "alkoxyaSkynyi." embraces alkyayt radicals each having alkoxy portions of two to about tea carboa moms. More- preferred alkoxyalkynyl radicals are "lower alkoxyaikynyl" radicals having two to six carta atoms. Examples of such radicals include methoxy eih ny!.

The term "irydmxy lkoxyaifcyr embraces aikoxyaiklyS. adicals of one to about ten carboa. atoms each having one or more hydroxy readicals. More preferred kydroxyaikoxyaikyl radicals are "lower hydroxyaikoxyalkyl" radicals haviog one to sis. carta atoms. Examples of Such radicals include iiydroxynictboxyraetbyL Isydroxycthosymethyl and hydroxytnettayethyl

Alkoxy radicals may be farther substituted With one or more halo atoms,, such as ftuoro, -ckloro or hromo, to provide ¾doalkoxy" radicals. Even more preferred are lower haloalkoxy radicals haviag one to three carboa atoms. Examples of such, radicals include fluots ethoxy, ch roraethoxy, triiluoforae hoxy, rnflnoroethoxy, ituoroetkoxy and fluoropropoxy.

i l l The term "ar l", alone or in combination, means a carhaevcHe aromatic system containing one or two rings wherein such rings ay be attached together in a laseci manner. The term "aryi " embraces aromatic radicals such- as phe l, nsphtfcyl, hideoyl, tetrahydronaphihyls and indariyL More preferred atyi is phenyl. Said "aryl" gr up Bia have I to 3 substiments such as. lower alkyl, hydroxy!, halo, haioalkyl, tuiro, cyano, alkoxy and lower alkykunino. Phenyl substituted with -0-€i¾-0- fonus the as ' l be o to olyi substktteot.

The term 'lieie ocycH 1 }" embraces saturated, partially sahusted and unsaturated heteroatom- containing ring radicals, where the heieroatoras stay be selected from nitrogen,, sulfur and oxygen, it does not inclnde rin s containing -O0-,~0-S- or -S-S- portions. Said "heterocyctyi" group may have 5 to ? substituents such as hydroxy!, Bee, .halo., fiatoalkyi, cyauo, lower aikyi, lower araiky!, oxo, lower alkoxy, am no and lower alkylammo,

Examples oCsausraied heterocyclic radicals include saturated 3 to 6-membered

heteronxJtiocycHc groups containing i to 4 nitrogen atoms [e.g. pyrrolidinyi. iraidazolidinyl, piperidmyl, pyrroknyi, piperazinyVj; saturated 3 to 6-membered heteromonocyeiic group containing .1 to 2 oxygen atoms and I to 3 nitrogen atoms [e.g. morpholiayl]; saturated 3 to 6-membered heterotrtonocyciic group containing 1 to 2 salfijr atoms and 1 to 3 nitrogen, atoms [eg., diiaxoiidmyi]. Examples of partially saturated heterocydyl radicals me-lude dihydrmhiaryi, dlhydropymayi, dthydrofyryi and di!rydrothiaxoJyl.

xamples of unsaturated tseterocyc-Hc radicals, also termed "keteroatyl" radicals, mclede unsaturated 5 to 6 meaibeied Sete^mouocyciyi group containing 1 to 4 nitrogen atoms, for example, pywol-yl, imidaxoiyl, pyra¾olyl, 2-pyridyl 3-pyridyi 4-pyrtdyS, pyriuudyl, pyraztsyl pyrida«ktyl « triaxo!y! [e.g., 4H- t,2,4 ria*olyI, I H-L2,3-iria oiyl 2H- L2 trlazoiyi]; unsaturated 5- to 6~ raembered heteromonocyelic group containing an oxygen atom, for example, pyr&nyL 2- «ryL 3-fttryI, etc.; unsaturated 5 to 6-menibered beteromonocyclic -group cotttakdng a sulfur atom, for example, 2- flnenyl, 3-ihienyl, etc.; unsaturated 5- to 6-membered heteromouocyciie group conta ig I to 2 oxygen atoms and i to 3 nitrogen atoms, for example, OXSHOIYI, is x yl oxadiazolyl [e.g., 1 ,2,4- oxadifizolyi. L3,4~oxadia;?oi;yL i ,2,5^xadia¾>.ly.l]; unsatu ated 5 to 6-memhered hetcra onoc eHo group containing 1 to 2 sul&r atoms and J to 3.nitrogen atoms * for example, thiazoiyl, toiadiazolyl je.g., i,2,44 adiazo yf 1 ,3,4-dsiadia:iolyL 1 25"ihia ia¾&jylj.

The term also embraces radicals en; keterocyelie radicals are fusedkohdeosed w¾h aryl radicals: unsaturated condensed heterocyclic .group eo a mng 1 to 5 nitrogen atoms, for example, indo!yi isoindoiyi, i ' ndolixitryi enidiiidazoi i. qamoSyL isoqulnolyl indawlyt, henzotriazQiyl. tetrazolopyndaziftyi le,g,, teba¾oio i ' KS-b pyridazmylj; unsaturated condensed heterocyclic group -eoutaming i to 2 oxygen atoms mi i to 3 nitrogen toms [e.g. oenzoxajtolyl, benmtadia2olyl.¾ unsaturated condensed heterocyclic group containing ϊ to 2 suite atoms and 1 to 3 uitrogeu atoms [e.g,, be izo htazol L henzothiadi acet l ]; and saturated, partially nsaturated ' and unsaturated condensed keterocyclic group -contam g i to 2 oxygen or sulfur atoms [e.g. ben¾efuryl < kenxotkienyl 2 -dihydro-fee»¾op ,4 jdioxmyl aud dihydf be xoftiryJl Preferred lieterocyelic radicals include five to sen metn ersd .fused or imfused ..radicals. More preferred, exam les of heieroaryl radicals include qusHolyl, ise uijelyL iiisidazolyl. pyridyl iiiiefiyl, thiaxolyi, oxazoK , i¾ryi and pymzioyl. Other preferred heieroary! radicals are 5- or 6-raem ex ' ed ieteroaiyl,. containing, one or two lieteroaRuas selected from sulfttf, nitrogen and oxygen, selected from ildenyl firry!., pyrrol}! indazolyt, pyraxolyl oxazolyl, trsa oly iiiikia/oiyl, pyxa^o!yi isoxa¾!yi. isothiazoiy! pyiidyL piperidiHyi and pyia kiyf

Particula ex mples -of «o«-nstf«ge». eoirtaxiUfig l:iet:eroafyi iiioHide pyran}! 2-fxiryl, 3-¾sryt, 2- thtefiyt 3 rrie»yl, bei^furyl, beaxotlders i mi the like.

Particular examples of partially saturated arid saturated tesrocy dyi include pynsKdiayl * iraklazoiidmyi, pjpe.ridmyi. pyrroHtryt pyraxo ' Iidmyi piptxmnyi, sorphoHayK tetralrydropyrarryi, thia^oS myl, ddrydroiStletwl, 23-diitydfo-beHxo l ; 4]dioxatryl, sndoimyl, mjadoMryl,

diStydrobesitotbieityi, diitydrob nxoiisryl, isocbroiaaayt, chrotnanyi, l,2-di]rydroqiHi5o!yL 1,2,3,4- te5:rahydro-fsot]t(i:noiyl 5 i,2,3,4-teira ydro~qa.isio!yS..2,:l,4.4 > 9,y -)Kis.ah dro-lH- - i - tiorar i

beaxo 5 ,4 jdioxasyl , 2-3-dihy<fco- \ B- lA'-beazo{ ' d|!S0thikzol-6-yl, dihydropyrartyl. di!rydmluryl and. diiiydrotliia o!y!, and the like.

iHei«¾cyeie" means a Hag com risin at least one carbon atom and at least one other atom, selected .(torn N„ O and S . Examples of eter cycies that may be found. In the claims sncfede,. b are sot limited to, die. followoig;

,S3

coEiiaiiiiH lieierocyelyl nd oxygen containing heietocyeiyi are self expla iiog m ' most cases. Heterocyclic- nags haviug iatrogea and either oxygeH or sutfitr atoms shall still be defined as nitrogen containing heteroeyciyl

The terms "carboxy" ©r "c rboxyF, whether used alone or with: other terms, mh as

"carboxysikyi", denies -C¾H.

The term carbonyl", whether, used alone or with other terms, snch as "animoe-aTfeojiyi", denotes -(€- )}-.

The term "car osyaik l", denotes an. alky! radical substituted wish, a carboxy.

The tens, "aikoxyearboiryl" enotes m ester group, a¾8tai.«mg. sikoxy substituted carfconvi.

The term l 'a}k.oxycarbo»ylamifi«aikyP ' means ninoalkyi group in which one or more hydrogens as bees replaced with, art aik xyearboayl. group. An example would be BOC- ainfiioraet i

The terra •' aik.oxyearbosyial.kv means as alkyl gmugr m ich orse or more hydrogens .has been replaced with an alkoxyeaihoiiy! group. An example would be iaetft sycai¼tiyi(55etftyi.

The Sena "anjiaoegiijaayS" denotes an amide grou of she feunyla -C( ;:: 0) H a ..

The term "ataiaocattORyfcdkyP means m alky! group i:n which one or mare hydrogens has bees replaced with amnsocarbaoyi group. An example -would be autiiiocarboay methyl.

The tenss " -alk laraliiocarboayi' ' and denote aa noeatbon l radicals h kpeadesitly substituted with one or two alkyl radicals, respectively. More preierred are "lower idkylanuaocarbotr P having lower alky! radicals as described above attached to an arranoearborryl radical.

The terras "N-aikySamiaocarbonyjaikyi'' and ''N^-dialkylaBiiaoearbonyiaikyr 5 derseae alkykmiiiocarboayl radicals independently substituted w th ne or two alky* radicals, respectively. More preferred are "lower alkySarmaoearboay lalkyl" haviag alkylarniaocarbonyl radicals as described above attached to an lower alky} radical

The term "sralkyl" eiabraees aryi-stibsiitated alkyl radicals. Preferable stalky i radicals are "lower aialkyl" radicals having afyl. radicals attached to alky! adicals havia ne to six carbon mm. Evc-.fi more preferred are "phenyl" attached to alkyl p rtions ' haviag one to three carbon atoms. Examples of such radicals include ben yl, dipherwimetlryi a&d pheayiethyk The aryi la said araikyl may be additionally subsijt.at.ed ith liaio, aikyl, alkoxy, halkoalkyl an aloalkosy.

The terns "amlkenyi" embraces aryl-siibstimted alkenyi radicals. Preferable araikerfyi radicals are "Soever aralkenyl" radicals having aryi radicals atatdhed to a'kenyl radicals ha ing two to six carbon atoms. Even more preferred are " phenyl" attached to alky! portions Itavirtg one to three carbon atoms. Examples of such radicals me lade phexiylethenyl. The aryi io said aralkenyl msy be addiiiorially substituted with a!a, aikyl. alkoxy, iialkoaiicyl and haioalkoxy.

The terra "amlkynyf embraces ary!-strbstimte aikytryl radicals. Preferable oralkyoyl radicals are "lower araikyrry radicals t kxg sryl radicals attached to aikytryl radicals feavisg two to sis carbon atoms. Evert more preferred are phenyl attached lo alkyrr i portions havi g t to three earbort atoms. Examples pf such radicals .include phenylet ynyl. The aryi in said araikyrtyl may he additionally substituted ith fcaio, alkyt alkoxy, halkoalkyl and haioalkoxy.

The term ¾.terocycly.lalkyl" embraces hcierocyciyl-sufestiMed -aikyl radicals. Preferable heterocydylalkyi radicals are "lower .heterocyclylaiky . radicals having hcierocycly.1 radicals attached, to aikyl radicals ' having one to six carbon, atoms. £*¾n more p-reierred are.5-1-0 membered heteroeyclyl attached to aikyl portions having one to three carbon -atoms. The heteroeyclyl m said heterocydySatkyl may be additionally .substituted wit bald, aikyl. alkoxy. ha!koa!kyl and ha aikosy.

The term "alkyiamino" embraces "N-aikylamiao" and "KN-dialky!amioo" where amino group tire s bsiiUfted with e e aikyl .radical and with two iodependettt aikyl radicals, respectively, More pre Scored alky tamiocs radicals are "lower aikyiamino" radicals having am or two aikyl radicals of one to six carbon atoms, attached to a aitrogeu atom. Eves, more preferred are Sow«r alkylatrilfto radicals having one to. three carbon atoms, Suitable alkyiamino radicals may be mono or dialkyiarrtino such as -rjietkyiajsiiio. N-ethykutinO, RN-diraethykmino, R -diethytaoihto nd the like,

lite term aryiatiiino" denotes amino groups which have beett substituted with one or two aryi radicals, such, as N-jjhaayl amino. The aryiamino radicals .may be further substituted on the aryi ring portion of the radical.

The term "heteroarylamino" denotes mo groups which, have been substituted with one or two heteroaryl radicals, such as Rthienyia ino, The " eteroarylamino" radicals may be- further substitttted on. the heteroaryl riag portion of the radical.

The term "teteroatyloxy" embraces oprioual!y substimted ' hcieroaryl radicals,, as dejfiaed above, attached to an oxygen atom.

The term "cycSoaikyi" includes saturated carbocyehc groups. Preferred eyeloalkyl groups include CyC* rings,. Mo e preferred com ound iuchsde, cycloper!iyk cyclopropyl, and cyelobexyi

The terra "cycloaiky!aiky ' embraces c c a!kyl- ttbstltuted aikyl radical ' s. Preferable cyc!oa!kylalkyl radicals are "lower cycioalkyialkyl ' ' radicals having C;-C; cycSoa!kyi radicals attached to aikyl radicals ha ving one to six carbon atoms. Evsen mors ' preferred are cyclohesyl attached to aikyl portions ha ving, one to three carbon atoms. .Examples of such radicals include cyolohex.yimet.hyL He cycloalkyi in said cyc!oalkyialkyS may be additionally substituted with lower atkyl.

The term "cycloal.ky¼lke»y embraces eycloalkyl-sttbstitoted allsenyl radicals. Preferable cycioalkykdkeayl radicals are "lower cycloalkylalkeoy radicals having CrC* eycloalfcyi radicals attached to alky! radicals having two to six carbon atoms. Even mare preferred are eyelohexyl attached to alkeftyl portions having two to three carbon atoms. Examples of stteh radicals iodide eycioaexy!edreayl T e cydoalkyi in said cycioalkyiaikeayi may ' be additionally substituted with lower alk i.

The term "cycloalkylaSkyayi" embrac * cycloalkyi-sabsiiniled aSkyoyi radicals. Preferable eydoal ytaikyayt radicals are "lower cydoalkyialkyoyS radicals having Cj?Q; cydoalkyl radicals attached to alfcyayl radicals havi as two to six earboa atoms. .Even oiore preferred are e dohexyl attached to alkyny! portions ' having two to three carbon atetns. Examples of such. radicals include eydohex lethynyi. The c ctoalkyl in said cycloaikylalfcynyl may be additionally sitbstimted wish lower alkyi.

The term, " cycioalkenyl" includes partially unsaturated earhocycile groups. Preferred yeloaikeiayl groups include rings. More preferred compounds incinde, cydopentenyj aad cyclohex tiyi.

The terra "sttlfonyl", whether used alone or linked to other terms such as aikyfstsSfooyS. denotes respectively divalent radicals -SOr.

The terins "sttlfsnryl" and " nn saii a denotes a salioayl radical substituted with an amine radical, fomiiag a sulfonamide (-SO ; HH>).

lite term "aikylatninosnUony iscSades "N-alky lanrinosuH uyr where snifamyl radicals are aidepoadeatly substituted with oae or two alky! ntdsc¾ ' t(s). More referred a kylanaoosulfony radicals are "lower alkyiaadiiosultbnyt" radicals having one to six. carbon atoms. Even more preferred are lower alkylammosulfonyi radicals having one to three carbon atoms. Examples of such tower alkykramos dfonyi radicals Include ' N-methytomosnifonyl, and -ethylatwinostdfonyl,

' The term ¾lkyla .tnoalfcyr includes "N-aikyianmwalkyS" whe e alfcy! radical are independently substituted with an. alkylamino radical. Mom preferred alkyi an¾«oatkyl radicals are "lower alkylam noalkyr radicals having one to six carbon atoms.

The term "a!kyistilibay inchides sulfonyS. radicals snbsiitaled with an alkyi radical. More preferred alky!snl&nyl radicals are "lower aikyisulfonyl" radicals having one to six carbon atoms. Even snore preferred are lower alky ' lsalfonyi radicals having one to three carbon atoms. Examples of such, lower alkylsulfoayl. radicals include methyisu.!rbny ' 1 and ethyls«li¾8y:l.

" Beazo group", al ae or in combination, means the divalent

of which is -CH^CH- ' B ' «, that when viciaaliy attached to another ring forms a bea*ene-h¾e rh ' ig-*l¾r example ictralwdronaplimyiene, indole aad the like.

The term v ¾xo" represents the groups -~0 (as in carfconyl).

1.16 Tie mm aikyJ radicals, Preferable heierocyclyScarbonytailiyJ radicals are "Sower i¾ e teroc cl i si kyiai.k ] " radicals having heterocyelylearboayl radicals attached to alky] radicals Staving one to six carbos* atoms. Even raotc preferred are 5- S asembered heterocyclvJ attached to earbony! astd alk l portions having oue to three carbon atons. The heierocyclyi in said hetetocyeiyiearbonylalkyi may be additionally substituted, vvith halo, alkyl alkoxy, liaikoaikyl aad Im!osikoxy.

* fetriHaceoticaily*ac«p»i Se salt" twaus a salt prepared by conventional means, and are well k» wa b those skilled in the art. he ^hamiacologicaliy acceptable salts" iuclude basic salts of inorganic and organic acids, including but not litoiied to hydrochloric acid, liydmbrotsk acid, sulfuric acid, osphoric acid, njethanestufouic acid, etlmnesoltdmc acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, .fitmanc acid, succinic acid, tnaieic acid, salicylic acid, benzoic acid, phettylacetic acid,, mandelic acid and the like. Whm eompouads of the toveation include m. ■acidic fiffieiica suck as a carhoxy grotfp. then mutable pbanuaeeaticaiiy acceptable caiiott pairs for the earhosy gronp are well known so those skilled in t&e ar aad iaciade alkaSiee, alkaline earth, anmuuii tn, cjna ternary a iaoni rn cations and. the like. For additional exaraples oi

"pharmacologically acceptable salts," .tee ί α aad.Berge et ah, .1, Phami. Sci 66: S { i 97?},

''Saturated, partially-saturated or unsaturated" includes sabsiiiMents saturated with hydrogens, substttueats completely unsaturated with hydrogens and substitusnts partially saturated with hydrogens.

f t Leaving group" generally refers io groups readily dispiaeeabie by a uucteopirlie, sack as an amine,, a thiol or art alcohol aitdeopirite. Such leaving groups are welt known to the aft. Exa ples of suck leaving groups inelttde, bat are not limited

ha es, triilates, tosytases aud die like. Preferred leaving groups are indicated herein where appropriate.

" ' Protecting group" generally refers to groups well known in the art which are used to prevent selected reactive groups, suck as earboxy, amino, hydroxy, arercapto aad the like, from undergoing, nndesired reactions, such as nueieopltilie, eleetropMie, oxidation, reduction, aad the like. Preferred protecting groups are indicated herein where appropriate. Examples of amnio protecting groups include, but are not limited to, aralk l, substituted araSkyi, cycloalkenylalkyi aad substituted eycSoalksayS. alkyl ally!, ubstituted ally!, acyl aSkoxycarbonyl, ar lkoKycafbanyt, silyS and die fifce. Examples of aralkyi include, but are not limited to, beaxyl, ortho-meihylbeaxyl, trityl and berizhydryi, w!ach can be optionally substituted with haiogea. alkyl, aikoxy. hydroxy, nitro, acylaatlno, acyl and the like, artd salts, such as phosphonium and aauaoniust salts. ' E am les of aryi groups include phenyl, na hthyl, hxianyl, aniliracenyl, 9-(9-piKayltlaOreriyl} : ptenanihiSflyl, dureuyi aad the like. Examples efcyck>alke«ylalkyl or substituted cycloaikylenytalkyl radicals, preferably have 6-10 carbon atoms, ej ds, but are not limited to, cycSofeexeayi ethyl and the like. Suitable aey ' l, alkoxycarbotryl and aralkoxycatbotty.1 groups include be«¾yloxycarboa i, t-bulaxycarbonyi, iso~ hutoxyearhoayl, bertKoyi, substituted . benzo l, btttyryi, acetyl, triftuoroacety tric oro acetyl, pht aloyl and the like.. A mixture of protecting groups can be used to protect, the same amino group, such as a primary amino roup cm be protected by both an arafei group and an aralkoxycsirhooyl group. Amino ptoteet-hg groups, cm also form a heterocyclic ring with the -nitrogen to which they -arc attached, for ex m le, l,2^is{methylene)bmene> phthaSmidyl, sticemtnady nialehmdyl and the like and where these heterocyclic groups can further Include adjo uing aryl aad eyeloaikyi rings, lit addition, the heterocyclic groups can be mono-, di- or iri-substi ated, such as fotE piUba!iffii yl Amino roups may .also be protected against nsdesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, (olueaesulfoaic acid, tr iluoroacetic acid and the like. ' Many Of the amino protecting groups are also suitable for protecting carboxy, hydroxy nd mcroapto groups. For example, araikyi groups. Aikyi. groups are also suitable groups ibr protecting hydroxy and ereapto groups, such as tert-butyl.

S 1 protecting groups- are silicon, atoms Optionally substituted by one or more alky S, aryl and arslkyi groups.. Suitable silyl protecting groups iadude, but are not !imiied to, nimethylsily!, triethykilyl, riisopropyisifyi, ten-btriyldimethylsilyS., dimethylphenylsilyl, 1,2- bts(di»5ethyisiiyi}bei¾¾cne, ? ,2-bis dio«sthyls¾yl)eth«a)e aad dipl myl ethyisiiyl. SiSyiation of as. amino groups provide on - or di-siSyiamino groups. Siiylation of ami oaicohoi. compounds cars, lead to a N, ,0-!:tisilyl derivative. Rem val of the silyl function frots a siiyS ether function is readily accomplished by treatment with * for example, a tncfal hydroxide of ammouium fluoride reagent eifiser as a discrete reaction, step or ki sifts during a reaction with ' the alcohol gro\«p. Suitable silylatiag agents are, for example,, triteci ylsilyl chloride, tert-b tybdrtricihyisiiyi chloride, pkaryidlsnei! y lyl chloride, dipbeayboemyS silyl chloride or their combination products with itaidaxole or O f .

Methods for sitylaiion Diamines aad removal of silyl protecting groups are well kaowa to those skilled in the .art. Methods of preparation of these amine derivatives .from corresponding amino acids, amino acid amides or in acid esters are also well known to those skilled in. the art of organic chemistry including amino aeid/aruino acid ester or aminoake-ho!. chemistry.

Protecting groups ate removed under corj.diti.ous which will .not affect the remaining portion, of the mo!ecwlc. These methods are well known in the art. and include acid hydrolysis,

hydrogeaolysis and five like. A preferred method involves removal of a protecting group, such as removal of a heiKyloxyearbonyi group by .hydrogepolysis «iUi«B palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and she tike or mixtures thereof. A. t-butoxycarbonyl protecting group can be removed tnifeiitg an inorganic or organic acid, such as HCl or iriiluoroaeetic a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt ars readily be aextttalked to yield the free amine, Carboxy protecting group, Such as methyl, ethyl, benzyl ien-buiyf, 4- tethoxyphe¾y1n5ethyi aad the like, can be removed under hydrolysis aad ' hydrogeholysis conditions well known to those ' skilled in the art.

I I S it should be acted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidise and guaoidioe groups, heteroatoni substituted heteroa example as illustrated in the following examples:

and though, one form is named, described, displayed audVo? claimed herein, ail the tautomeric forms are intended, to be inherently included in such name, description, display and/or e!ahn.

Prodrugs of the expounds of tins invention, are also contemplated by this invention, A prodrug is as. active or inactive con)oound. that, is modified chemically through its vivo physiological actioa, such as hydrolysis, metabolism and tits like, into a compound of this invention .following administration of the prodrug, to a patient. He suitability an techniques involved in making nd using prodrugs are well known by those skilled iu die art. For a general discussion ofprodragS involving este see Svensson nd Tunek Drug Metabolis Reviews 165 (1988) sod Bundgaard Design of Prodrugs, Elsevier f 1 85). Examples of a masked earbexylate anion include a variety of esters, such ' as alky! (for example, methyl, eth l), cycioaikyi (for example, cyclo ' hexyi), aralkyi (lor example, ben¾yi, p- ethyxyben&y!), and. alkyicai^nytoxyaikyl (fox csaia le, pivai^yloxymethyl). Amines have been masked as arylysAouyloxymethyl substitmed derivatives which are cleaved by esterases in vivo releasing tlte free drug and formaldehyde (Buapard J, Med. Chera. 251» ( 1989)}. Also, drugs containing an acidi H group, such as imidazole, iraide, indole and ibe like, have been masked, with ' N-acyloxy ethyi groups (Sundgaard Design of Prodrugs, Elsevier (H¾S)). Hydroxy groups have been masked as esters and ethers. BP 039,051 (Sloan and Little, 4/1 l¾.i ) discloses Mannich-base hydroxamtc acid prodrugs, their preparation and ase.

The speciftcadoa and claims contain listing of species using the language "selected .from . . . and , . and "i , . . or . . ," (sometimes reserred So as Markush groups). When this language is used m this appficatfoa, unless otherwise stated it is ateaat to iac ude the grou as ¾ whole, or any stogie members thereof, or any subgroups thereof The use of this language is merely for shorthand purposes -and is not meant in aoy way to limit the removal of ktdividual demerits or sabgronps as needed.

Utility and Methods of Use

The compounds of the resent invention can. be used as prophylactics, or therapeutic agents for treating diseases of disorders mediated by deficient levels of gliisokinase activity or which can be treated by activating giucokinase including, but not limited to, diabetes melSitns, impaired glucose tolerance, IFG (impaired lasting glucose) and IFG (impaired fasting giyceisia), as well as other diseases and disorders such, as those discussed below. Furthermore, the compounds of the present

1. 1 9 nven tion can be also used to preveM the progressio n of the hordedlae type, impaired glucose tolerance, fFG (impaired lasting glucose) or IFG (impaired fasting glycerols) to diabetes raeilibts.

Accordingly, another aspect of the invention provides methods of treating or preventing diseas.es or conditfcifa-s described herein by. administering to a marnnml, such as a human, a therapeutically effective atmmntof a compound ofForraula I

The phrase ''therapeutically effective amount" meatis an amount of a compotind f the present iaveitfien that (i) treats or prevents the particular disease, cO ' ftditiou. or disorder, fii) attenuates, aoieliorates, or eliminates oae of mote syim¾oms of the particular disease, cohditiPtt, or disorder, or (iii) p vents -or -delays the onset of one or store symptoms of the particular disease, cond oe, or disorder described herein.

The amount, of a compound of Formula J that wilt correspond to- such art amount ' will vary -depending upon iactors such as the particular t nnpeund, disease condition aad its severity, the identity- (e.g., weight) of the mammal ht seed: of treatment, but can ne ertheless be routinely determined by one skilled la the a t

The terms ¾eat" and ''treatment" refer to both therapeutic treatment aad prophylactic measures., wherein the object is to slow down, (lessen) an taideshed .physiological change or disorder. For purposes of this inveutteii, be-ic! i u-i or desired clinical results include, but are am limited to. alleviation of symptoms, dhni shmertt of extent of disease, stabilized i.e, ( not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of itse disease stale, and remission (whether partial or total), whether detectable or undetectable. '' reatment * can also mean prolonging- survival as compared to expected survival if not ieceiving treatment Those to need of treatment include those, already wish the -condition or disorder as well as those prone- to have, the condition or disorder or those in which the condition or disorder is to be slowed down or alleviated.

As used herein the terms "prevent" or " reheating* means the prevention of the onset, recurrence or spread, in whole or in. pari, of the disease or condition as described herein., or a symptom thereof

As used herein., the term "raamsnar refers to a. warm-blooded animal iftat has or is at risk of developing a disease, described hereto and includes, but is aot limited to, guinea pigs, dogs, cats, rats, mice,, hamsters, aad primates, including .bumaas.

in certain embodiments, toe methods, o f this invention are useful for treating diabetes tnei!iitts. Diabetes mellims Is a coadiiioa where the tasting plasma glucose level (glucose concentration in venous plasma) is greater than or equal to 126 mgAit (tested on two occasions* and the 2-ltour plasma glucose level of a 75 g oral glucose tolerance test (OGl ' T) is greater than or equal to 200 nig/di. Additional classic symptoms include polydipsia, -polyphagia and olyu i ,

la certain embodiments, the methods, o f t h is it ention are useful for treating the syndrome of impaired glucose tolerance IGT). IGT is diagnosed by the presentation of a lasting plasma glucose level of less than 126 ing/d.l and a 2-hour post-oral glucose challenge lever greater than 1 0 mg dL. The compounds of the present iaventioa ess be also nsed as prophylactics or therapeutic agents of diabetic complications such- as, bat not limited to, netiropat ' hy, Hcpii.ropa.thy, retinopathy, cataract, microangiopathy, osteopenia, diabetic hyperosmolar coma, infectious diseases {e.g., respiratory- hu¾cti ix > uriaaty tract infection, gastrointestinal tract infection, dermal soft tissue infection. Sow iirnb infection etc), diabetic gaugreae, xerostomia, decreased sense ofhearmg, cerebrovascular disease, peripheral circulatory d sturba ce, esc.

The compounds of the present invention can be also issecl as prophylactics or therapeutic agents in die treaiHteul of diseases arid disorders such, as, but trot limited to, obesity, metabolic syiidrome (syndrome X), hyperinsu!ineraia., hyperissaimeraia^adaccd sensory disorder, dysiipoproteiae ia (abnormal lipoproteins in the blood) including diabetic dyslipidemia, hyperlipk!eaiia, hyperlipoproteiaeaaa {excess of lipoproteins in the blood) including type 1, ϊί-a Caypercholesieroiet a * ϊί-b, II.L IV {hypertriglyceridemia) and V (hypertriglyceridemia). Sow HDL levels, high. LDL levels, atherosclerosis asd its sequelae, vascular restenosis, neurodegenerative disease, depression, CNS disorders, liver steatosis, osteoporosis, hypertension, renal, diseases (e.g,, diabetic nephropathy., glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disorder etc), tsyocardiac infarction, .angina pectoris, and cerebrovascular disease (e.g., cerebral iafarstioR, cerebral apoplexy).

The compounds of lite present invention eaa be used at combination with one or mere additional drags, for exatnpie a eorapoua that works by the same or a different mecluaite of action, such as insulin preparations, agerus for iniprovin iasidin resistanee, alpha-gbfcasidase inhibitors,, biguapides, insulin secretagogues, dip^ dylpeptidttse iV {DPP IV) tahibiiors, beta-3 agoatsts, atayiin agonists, phosphoi rosine phosphatase iahibitors, g!uconsogenesis inhibitors, sodiian-giueose cotransporter iahibitors, known thera eutic agents for diabetic complications, aritihypcrhpidemie agents,, hypotensive, agents, and antiobesiry agents. An example of an agent far irnp.txmag iasnivn resistance is an agonist for peroxisome pro!iferator-aofivaved. receptor-gamma (PPA. gamma).

Administration and Phamisceutiesl Con:$o$itioa«

in. general., the compounds of this invention eaa be ad iniste ed in a therapeutically effective amount by any of the accepted modes of administration, for agents that serve similar nt.tlifs.es. The actual amount of a compound, of this invention, i.e ., the active ingredieat,, depends ttpon numerous factors, such as tltc severity of the disease to be reated, the age.aad relative health of tbe subject, the potency of the eompowad nsed, the route and orm of adniinistration, and other factors.

Therapentkaliy effective amounts of compounds of formula 0) amy range front approximately 0.1-ΙΘ00 sag per day.

in general compounds of ibis . invention cast be administered as pharmaceutical cotnpositioas by any one of the following routes: oral, systemic {e.g., transdermal, intranasal or by suppository), or parenteral tea,, intramuscular, intravenous or sabeutaneoas) administration. The preferred manner of administration is oral -using a convenient daily dosage regimen, which cat! be adjusted according to the degree of affliction. Compositions can take me form of tablets, pills, capsules, semisolids, powders sustained release foramlattotts, solutions, suspensions, elixirs, aerosols, or my other appropriate cosnposttions.

The choice of formulation depends on various, factors, such as the m de of drug, administration {e.g., for oral administration, formulations in the form of tafelets, pills or capsules are preferred) a»d 8te bioavailability of lite drug saijsts ce. Recently, pharmaceutical formulations have been developed especially for drugs thai show poor bioavailability teed, upoa the principle mat ' bioavailability can be iacreased by kieieasiag ie surface are Le,, decreasing panicle size. For example, U.S. Pat. No. 4,107,28:3 describes a pharmaceutical fomndalioa iravbtg panicles fci the ss¾e raage from W to 1,000 raft m which die active material is supported on. a crosshnked {¾atrix of ntsero oleeules. IJ .S. Psi. No. 5,1.45,684 describes the producfton or a pharmaceutical iomniiatioa in which ihe drag sabstaace is pulverke l to naaopamcies (average panicle sixe of 400 MIX) in the presence of a surface modifier and then dispersed la a liquid me ian to give a phartnacetmcat fortmdation that exhibits remarkably high bioavailability.

The compositions are comprised oil in general, compounds of the present invention in combination with at least one .pharmaceu ically acceptable excipient Acceptable e&cipieots are nontoxic, aid administration, and do not adversel affect the therapenhc benefit of the compounds of the present inveot ft. Such exeipieni: may he aay solid, liquid, .semi-solid or, in she case of an aerosol composition, gaseous exci e that is generally availa le to ose of skill in the art.

Solid phamtaceuneal sxcipients include staren, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flow, chalk, silica gel, i«agaesita» sieatate, sodiitiu. stearste, glycerol oiouostearate, sodium chloride, dried skint milk and the like. Liquid and. semisolid excipients may be selected, fro glycerol, propylene glycol water, sihanof and various oils, sadodhig those of petroleum, artbsal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, raerai oil. sesame oil etc. Preferred liquid carriers, particularly lor injectable solutions, include water, saliae, aqueous dextrose, and .glycols.

Compressed gases may he nsed to dts ei^e a compound of this invention in aerosol, form, inert gases suitable tor this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical exctpients and . their - formulations are described in Remington's Pha maceutic^ Sciences, Gennaro, A. :R. { ack :P«bHs ' lttag ' Co»paity, iSt ed., P s),

The level, of the compound, ia a. formulation, can vary within the full range employed by those skilled in the ait. Typically, the formulation contains, on a wei ht percent (wt ) basis, from about 0.01-^9.99 wt % of a compounds of the present invention based on the total formulation, with tlis balance being one or more suitable pharmaceutical exeipients, Preferably, the compound is present at a level of about !-80 wi %.

1.22 COMBINATIONS

While the compounds, of the myemiou can be .a&nmistered as the sole active pha jaceatical agent, ifeey can al o be used is combination with o«e or .more compo nds of the invemioa or other agents. Whea administered as. a combination, die therapeutic ageats cm be fonraslated as separate c6rapos oons are administered at the sam time or sequentially at different tim s, or die therapeutic agents can be given as a single composition.

The phrase "co-therapy" (m "combhiation-ineia«y' , f n e.fiiai¾ uSS f a compound of the present iaveation and another pharmaceutical agent, is intekded to embrace administration, of each agent in a sequential manner ra a regimen that will provide beneficial e fleets ofthe drug combination * and is intended as. well to embrace coa minist ati n of these " agents in a substantially simultaneous manner, such as in a single capsule having a fi xed ratio of these active agents or ia multiple, separate capsules .for each agent.

Specifically, the adnnmstration ofcomponads ofthe present invention may be in conjunction, with additi nal therapies knows to those skilled in the art in the prevention or treatment of neoplasia, such s with radiation therap -or with cytostatic or cytotoxic ageats.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the accepted dosage tanges. Coatpounds of Formula I may also he administered se uentially with known anti-diabetes agents when a combinat on formulation is inappropriate. The invention is aot limited ia she sequence of administration; compounds of the iaveotiaa may be administered, either prior to. simultaneous with, or subsequent to adnanistrsiion of she kao a a fi- diabetes agent.

If the pattest is to receive or is receiving multiple pharmaceutically active compounds, the compounds cm be administered shnxtltaaeo sly, or seqaetttially. For exaruple. is the esse of tablets, the active compounds may be .found o tablet or ia separate tablets, which can. be administered at once or sequentially in any order, la addition, k should be recognized that the compositions may be different forats. For example, one or :more compounds may be delivered via a tablet, while another is administered via Injection or orally as a syrup. Ail combinations, delivery methods and administration, sequences are coaieniplated.

The compounds o the present invention may nsed in the manufacture of a medicament for the treatment of a disease and/or condition mediated by GKA, such as ty e 2 diabetes.

The compounds o the present invention sta be used ia combination wi h other

pharmaceu icall active eoaipounds. It is noted that the term "pharmaceutically active compoauds" can include biologies, such as proteins * antibodies and pepttbodies. Examples of other

pharntaceutieaiiy active eo tpo mds iiKluile, bra are not limited to: (a) dipeptidyl peptidase IV {DPP- IV) Inhibitors sttch as Vildaghptin (Novsms), Skagliptm (Merck&C ), Saxagliptin ( MS)

AHogiiptm (Takeds); (h) insulin seasjl½r¾ ihci diftg ft) PPARy agonists sttch as tits giitazones fe,g,, irogiitaxone, pioglita^one, edaglitazone, rosiglitazoae, and the like) and other PPAR ligsnds, including PPARa/γ dual agonists -such, as i a¾glha¾ar ( MS) and tesagljtassar { AstraZeseea), aad PPAR agosists such asfonoSbric acid derivatives (gemfibrozil cloiibraie, fenofrbrate and exai brate), <u) btguaaides. snch asmetformiu and plie bmun, and (»i) proiem tyrosine pnosprratase-iS (PIP- iS) mhifeito-is (c) insulin f sfisulhi irasietics (d) mcreb and hicretift mmrctics such as (i) Exenatide available from AaiyUn i½nr^eatk ls, (i) amylin and amy!m niimebes such as prantlmfide acetate, available as Sytntifl* (In) GLP-1 , GLP-I mimet c^ and GLP-I receptor agonists. iv> GIF, GIF iraeiks and GIF receptor agoaists; (e) sulfonylureas, sad other insulin secretogogu s, such as tolbutamide, giy oride, gKclazide, glipizide, giirocpMde, oiegiitirndes, and repaglinide: (I) giu osidaseJahibiSpre (such, as acarbose aad miglite.1); (g> ghseagoa receptor antagonist (h) PACAP, PACAP lalnicte, arid PACAP receptor agonists; (i;> cholesterol towering agents such as <i) HM6- CoA reductase tnhi&itoss t ' lovastaiiri, simvssiatni, -piav-astatin, cerivastathi, il«%¾s i«.. atorvastaim. tavastattn, and rosavasiatf-n, and other statins), fii) bile acid scqtiestraats such as diolextyramine, colestipol atui dialkyilamiaoalkyl derivatives of a cross-baked c xtrajt, nieotiayl alcohol nicotinic acid or a..salt thereof, (iv) PPARu agonists such as feaofibiic acid derivatives (geiafihroid!, clofibrafe, feuofibKaie aad bez&Bbiate), i ) PPARo/y dual agonists such as sntiiagiilazai (BMS) and tesagbtaxar (AstraZeneca),. (vi) inhibitors of cholesterol absorption, such as bc saoslerol audexeiinabe, <vH) acyS CoA; cholesterol acyliratisferase inhibitors such as avasiraibe, aad (viii) anti-asidaots such as probticoi; (?) PPARd agonists such as GW-50i 516 from GSK; (k) anti-obesity compounds such as fenfluramine, (ies ooflxumnine, C ecai C. stbxitraaiiae, orlistat, neuropeptide VI. or YS antagonists, MTP inhibito s . , squ&iene synthase inhibitor, lipoxygenase inhibitor, ACAT inhibitor, Ne ropeptide Canaabiaoid€ ' B-1 receptor .auiago sts,€B~i receptor inverse agonists and antagonists, fatty acid oxidation

inhi itors, appetite suppressaats (!) adrenergic receptor agonists, .melaaoeortin receptor agonists, iti. particular melauocortiu*4 receptor agonists, gfa-reitu antagonists, and mekuav eoaeemfaiiaf aoraioae (MCM) receptor antagonists; (m) ileal bi e -acid iraasportet Mvibitors; (ft) agems iotendcd. for use ia isfiananatory conditions sucfc as as ir n, mn ste oi al antWafla aioty drugs,

ghscoeariicoids, a^ul a , aa selective cyelo0xyge»ase-2 inhibitors: (o) aatiltyperienstve agents such as. ACE iab!bttors (eaalapfil, Msiaopril, captopxil, . quinapril, fosiuoprol, ramipril spirapril, tandoiapril), aagieieasin-H (AT- 1) receptor blockers (fosarfaa, caudesartaa, stsesarran, vafsartaa, temusartan, eprosariau), eta blockers and calcium cnanrsel blockers; sad (pj .glocokiaase activators (G As); (q) agents which can be used for the preveat n, delay of progression or trea ttneat of nsorodegeoenaive disorders, cognitive disorders or a drug for inTprovsag iaeasory soch as aoii- iafta raatory drags, atuioxidants, neuroprotective agents, gSataiaate receptor satago sts,.

acetylcholine esterase inlnbitors, hutyry!caoliaesterase inhibitors, MAO inhibitors, doparoin agonists or antagonists, inhtbisers of gararaa aad beta secretases, inhibitors of amyloid aggregation, amyloid beta peptide, antibodies to amyloid beta peptide, inhibitors of acetylcholinesterase, giucoklnase activators,, agents directed t saoduiating G¾BA, Μ0Α, cattaafeiaoid, AMP A, kajnate, pitosphodiesiBmse PDE), P.KA, PKC, CS.EB o aooKopte systems; ( r } ieakocyte growth promoters iatended for the treatment and prevention of reduced bone marrow production, ipfeetio s diseases, hartnoue dependent disorders, mUatraaator diseases, HIV, allergies, lettkocytopenfet, and tfieymatisxft; (¾} SGLT2 bibitjitor; (t) glycogen pifOsphory!ase inhi it r (») aP2 iu bi rs; (y) araiuopeptidase tahtbitot (w) vasopept dase inhibitors like aapril sio inhibitors and/or ACE inhibitors or dual. KBF/AC£ inhibitor; (x) growth hormone secretogogue for enhancing growth harmoae levels and for treating growth .retardation dw rfism or metabolic disorders or where die disorder is an iajary, or a wound in need oi ' healiag, or a mamtKan. patient ecovering from surgery; (y) 5-HT 3 or 5-HT 4 receptor modulators (tegasemd, cisapride, aor-cisapride, rea^apride, xaeopride, nrosap ide, pmca!opride, buspirone, noreisaprlde, ciiansetroa, ramosetron, az&seiron, ondaasetrou, etc.); {¾) aldose reductase inhibitors: (2b) sorbitol dehydrogenase mfeihkors; (Zc) AGE inhibitors; (2d) erythropoietin agonist such as EPO, EPO osmetics, -aad EPO receptor -agonists, The compounds of the presettt invention may also be used it?, corabiaauoa with GP 40 agoaists.

The compounds of the -present ' invention caa also e used i« eomb-iaatiou wit s FGF-2 I compounds, and particularly .for the ireatsaeai of type 2 diabetes. Examples of FGF-21 eoaipouads are disclosed ia U.S. patent .no, ?,67 ί , ! .80; LIS, patent ao. 7,667,008;. U.S. pateat ao. 7,459,540; U.S, patent fto. 7,6% J 72; PCI " application publication so, WO 2010/042747; and PCT appUeatioa publication ao. WO 2 S I49I7 i .

The compound of the present invention can be also be used in combination with anakinra, particularly for the treatment of type 2 diabetes. in one particular aspect:, ibo eerapisands of the psesent inveaiion may be used in combination wsih metformin.

Syat tie Metfeoiis

The caiapoands of the iaveiakm ea» be prepared acconjmg to the following procedures of Scuemes whtma the sif simms are as dsl ed for Formulas HV, ¾ lie, IM, Ilia and iVa, above, exeepi hee state .

Use following abbreviations ma . ' be used herein.:

9-BoHihieycio(3,3, i fyonane

Ar argoii

AC.N, C . <¾C u mti

AciO acetic anhydride

A-plios is[(dl-tert-butylphe!iyIpbosphirre)jipa?Iaiii«i»

diciiiorkie

AfHpbos

aq aqueous

ATP adenosine

Br bromine:

BBr, feoron iribromicfe

u-BoPAdj butyl di* I -adasaasi Iphosphine

Ca!ed or Ca!c¾ calculated

CDC! . cSiloiofonu-deiaerated

Π .Ί· chloroform

Cone . concesffated

C¾C<¾ cesium c¾rbonat£

i ' -ii copper Iodide

.DCE L2-dichioroetIia:ae

DCM, CH;C!;; dicdororiretoHe

DBA dietby wiae

DEAD diei yla odscarboxy!ate

' 0IA0 diisopropylazodicarbosySate

DIPEA dsisopropyiethy ' i amine

DMA ditnelftauo!ai iRe

' DUE 1 ,2-di«ie† oxyei:ha»e

DMF N,N-dinieiiiyifor!«amids MF-d< deui crated Ή $ϊ -dimeihylfotniamide

MSO di!iieihyi sulf xide

DMSQ-dfS deuterated dimethyl sulfoxide

O dcisteriiios oxide

EPTA eiiiylersedsamme ieixaacetie acid

EDC EDC-HC1 N ί « <«ife>½uino)methyI.eiK;> 3 , 3-ϋ Hwd lpiapgHe* 13~ diamine hydrochloride.

ESi kettospray ionization

1:5.0 diethyl ether

i¾ methyiamirte

EtOAc ethyl accuse

X¾OH ethyl atehol

FBS fetal bovine -serum

g gams

h hour hexeiiuoropitesphafe)

H : hydrogen

HCl hydrochloric acid

Hi iry roiodic acid

i¾SC¼ sulfuric acid

HNOj rafcric&cid

ilCOIi (orotic add

¾ H ; byteme.

¾0 \vaier

¾0> bydmgeri peroxde

Hex licxaues

MM PA hexameiiy!phosp oraraide

HOAc aceti acid

HOBt I-itydroxybeazotoazBle

PiPLC high pressure liquid ehmmmograpiv

HOPE hush density polyethylene

HEPES -{2 ! ' droxyeiIj ])- ip2rszraeciisatte salioaic «&

ΪΡΑ or iPrOH isop'opy? alcohol

KOH potasxbrm hydroxide

JCO J potassium carbonate

12? K ¾ PO: po¾issi¾i¾ phospfcfte irihas

KOAc oiiissiisni aceate

L lifer

LCMS. LC-MS or LCMS liquid dmrni togriiph

IDA liihiisffi diisopropylain e

IK I iHhium chloride

UOH liiht m tsydroxide

ni¾ mass divided by charge

MeQB mctttyi alcohol

MeQH~d4 deuterated methanol

Me :i SO,

«tg milligrams

ami

mL miSbmer?

gSO* msgsesiism sulfate

MS mass sgeetm

MTBE mei yS ten butyl ether

N trogeii

NH; amtnoxiist

NEh irieihyiamiiife

N¾CI. atmsoitium ehioride

ΝΗ ί.ϊΗ smittoakim hydroxide

Νίίί Αθ,ΒΗ Sodium iris eto yhoroliydride

NaBH, sodium horohydride

Na i sodium chloride

iiH sodium: hydride

Nit! sodium iodide

NaOH sodium hydroxide

K¾CC sodsoHi car oaate

aHCOs sodium btcarfeoaate

a :i so ium ;! ;d

sodium nuri-c

Ma>SO, sodium sulfite

KBS ' -fcroiiiossc hiim i de

-i»g(b J»«>ipfeoi8i«-N-oxjde NMR BMC ' ter magnetic resonance

OsCH osmium isteoxide

PMe : ; ίπ»κώΊρίκ>5 β»«

Ρ¾. iripl ' seaylpiiosphiije

P(0}Plu iK-pteylp¾osp i»e oxide

PdiFPlisk te^ ίki^β^te l· lto hi8e)paHad^«m( >

Pd(PP!i; >Ci;. ts5s(lriph<;ayl-phosp ne}paiiadiiun (ii)ck!oridii

Pdi dba} ; > fsidi eaKvI ideacacctone)palkdi»m

fdyid h :uis{di&e«^yl¾de«eace!.o£ie)dipaSlsdj«m (0)

Pd(dppf);;Cl ? i(i j-¾isrd! he» lp!iosp!iin0}faroces ' !fi] dichSoiops! iiumfll}

MC½ pafladwan cbiorfafe

Pd/C palladium cm carbon.

Pd. paii::di»m

P potecting group

Pes. ion positive JOH

n or R room tem erature

Sat, ssmriticd

S-P!ios 2 » Dsc e!ol:sex Spta^

ΤΒΊ O-CBesizotri mA « I ~y i)-N ,H > "J '-letrameihylumniura l tmfluoro ome

TFA. tnfuoroscsticacd

THF tetia ydmiuraii

T S~€i ;nn;c; ) hi!yi chlodde

TsCS. ftssyi chloride

weight

TF.E 2,2..2 riiltiOTOSvh;SH0i

tSiiOH test tatanol

Xajiiphos ^S-BisC pis^

Zti dtiC

Zii8r> ^tne bromide Scheme

Fyridyl iwsm 7 can be prepared according to the method set out. io Scheme I , Alcohol 1 is first treated with, strong base, such as NaH, at a temperature ot about RT, then, with a 2-haio-4- nitropyridine 2 to siff rd the pyric!inyi ethers 3. Pyridyt carbamates 4 are -prepared by tfeatroent of the pyrk!y! ethers 3 wish substituted carbamates, s«eh as ters-butyi carbamate, ia the presence of a catalyst, sttch as Pdi iba)? at a temperature, above RT, preferably at a temperature above 50 ' ' C, and m re preferably at a temperature of about .90 °C, Treatment of the pyddtti » 2-ylcarbamate 4 with acid, preferably TFA* at a temperaiarc of about RX ; affords the pyridia-2«a»ii»e 5, The 5-bromo-pyridin-2- .yl atnine 6 is prepared by hrx>mi»au ' .o» of the pyrid« 2-yta.mjne S such, as ftfa treatftiCBt with Bs¾ in AcOH. iTcamisat of the 5-b?»tiio-pyridii5-2-ambte 6 with.4-t5itrophe»y I earboaoc!ilondate at a te«i: erai¾ife of aboist RT. followed by substituted atiiines affords the desired 5-br©sno pyridyl areas 7.

Scheme 2

3

4~Sufestiuaed 2-pyridyi ureas 8. i fee prepared ccording to the taethod set oat in Scheme 2, Pyridfeyl ether 3 is coupled with ' ubsti uted areas wish the us of a catalyst, aea its PdiCdfet * , and 5~ (d^teTt-batyip. ospWao)-1^3 , ,5 1 Hrip.heayi~ H~1 ,4 >bipyfa¾ol , si a temperature above RT, preferably at a temperature above 50 S C, aad mo e preferably at a temperature of about 90 "G, to a ford the desired ureas S. Scheme 3

An alternative method to prepare 4-subsUtuted 2-p-y.ridyi s«¾as 8 is shawii in Scheme 3. i- Substitute wirea θ is comb ned with 2-c oro-4H«tropyridine 2 using Bucbwalii chemistry [e.g. i.l'- Bapk 1-2-y1iiHert- t«yiphosp¾i»e, and. palladium catalyst surfs as Pd dba}¾ I at a em erature above R , referabl at a temperature above 50 *€.;. and snore preferably at a tersperaittre of about 90 , to afford the. ( -ate 3irki?a-2-yl)«rea 11, The alcohol, R s -OH. is. u¾aied wish him, such as MaH at RT, thett cooled to a temperature below RT, preferably at ab ut 0 X.. then is combined with (4- 11 at a temperature above RT; preferabl at a temperature above 50 X, and more preferably at a temperature of about ?0 °C to afford the desired substituted ureas 8.

Scheme 4

7

13

4,5-ftisubsti toted 2-pynd.yS. ureas 13 can. be prepared according to the method set out la Scheme Using Suzuki coupling or similar Pd catalysed cbantsstry, 1 -(5¾om0-pyTidin- ~ l}- - susbriftttsd ureas are combmed with substituted boroai acids arid s catalyst such as ' Pd(P¾j 4 at a te perature-above RT, preferably at a temperature above 50 "C, and mors preferably at a tem ^raturs o.f about 80 to afford the desired corapo rsids 13. S lsesss 5

8

Aa:aheniaS.tv<? masked to pepare 2-pyridi) areas 7 & skomi is Sc eme 5.

Bto iaatiotf of (3-subsiimied -jiyTidin-l-yi u!-ea 8. such as by treatment wish NBS at a ieis entlisre bei eea 0 *€ and RT affords tbe desired s«b¾¾uted i-(5-br0nio-pyrsdift-2-yi :¾-sxf sdased urea 7.

Smminais ' h

45-Disabsmiiied 2-pyridv!} wreas 19 can be prepared according to tfus raetbod set out in Setene .6. reoibiatton of pyridy! carbamate 4 in .MF ¾uc& as with NBS ¾ a T«mpci¾i fe o.fahowt T arl rds the 5-bmmo pyridyi carbamate IS. Other substitution the pyridy ring is accoriipi shed, such -as by fteattneni of the brctiio iritomiediate with base, (e.g. DiEA), P catalyst (e.g. P< b¾ Xatitphos aftdsnethyi 3-!»eicaptopfopaaoatc at a temperature above RT. preferably at a tasiperature above 50 X, a» more preferably at a tem erat re , ofabout $S f, C to provide the

raethy¾uwaptopropa» te pyridyi cat¼ra»te; {X is S) 1.4 Modiikatioa of the .substituetrts is possible, Such as a«versk»x of the i>icihy:lmetei¾>iopropaxt©atc SUbstituettt to dher 17, such as treatment, mlk ase, e,g. potassium 2-i»etSrvipropaa-2-otaie and substituted alky! feaiides (e.g. 1~ bi imo-3-«K Sioxy .fo a«e) at » temperature of about RT, to yield the ether Π, Deproteetion md conversion of the free amine 18 to a isrea is a complished as described in Setose 1. Alternatively,, using the proeeduie described in Scheme 8, tie etfeer 17 is treated with a substituted ehlorofomiaie, taett a substituted amia to yield the desired ureas 19.

Scheme 7

3 > 5~0istsbsfituted 2-pyridyl ureas 21 cm be prepared according to the method set out m Sciieioe 7, isocyajiatoeihane is reacted with 3,5-djisubstiiuted pyridi¾-2-amiae 20 at a temperature above RT, preferably at a temperature above 5(1 :, C aad rnore preferably at a temperature of about 60 X to about 70 *C to afford urea 2. .

Scheme 8

21

22

3 J-DisubstitiJted 2-pyridyi ttreas il am be prepared according to ihe mei&od set out la Scheme 8. The substituted pyridifi-2-as¾aie 20 was .reacted with ciiSoroforsnaies, such as 4« mtopfeeayl carbouocMoridate to ai&td a mixture of mono- and bis- carbamates 22, Carbamates 22 are reacted wills primary atniaes R ' -NHj to afford- file desired ureas 2! . tauc 9

23 24

3,3 » Di:Siibsiitmed 2-pyridyS «rsas 21 caii be prepared 'ac ording to e mefl-tod set o«t in Scheote 9. Substituted S -(5*%romopyTidl«-2-y!)-3-sibsiituted xirea 23 is treated with pyridin-l- lboroixte acid a»d a palladium ca talyst such as .Pd(PPhi>-i at. a temperature above RT„ preferably at a temperature above 50 "C, and raore preferably at a temperature of a ou 80 K C to afford the desired substituted pyndi yl: urea 24, ScheiTse ί.0

25

23

3,5-Di:¾ihx!.ii.i$!.e 2-pyddyl ureas 25 cart be prepared according to the method set out in Scheme 10. l-{5-Br mo yridisi-2-yi}- -metl5yl«rea is treated wkh Xaittpfcos, esters a«d a palladium eatsS s† such as Pd^dba.; at a temperature above RT, preferably at a temperature above 50 sud tnore preferably at & t mperature of about 95 <J C to afford the desired pyndmyi-esters .25.

Se ' itettte I !

21

¾5~0Kubsiimfed 2-pymiyS ureas 21 can be prepared, aceordiag to the method set out in Scheme 1 . Pyridiiry!-esters 25 are treated with, base such pota ' Ss ttu 2-methy )ro ' pati-2-ol&te aad a substituted haskle at a teisipei&tttre abotrt RT to yieki the desired substituted pyridyi ureas 21,

Scheme 12

3,5-Disiibstuuied 2-pyridyS ureas .21 also can fee prepared aceor ing to the xuetsod set out in Scheme 12. Protected hydro pyridSn-2-yl}ifi£itg 26 is deprotected, suds as with, ac d * sQch as HC! * to afford the hydroxy compound 27. The hydroxy compound 27 is reated with PPh ? , DIAD and a substtotfid alcohol {R*-OM} at a temperature of about T to afford die 3 > 5«Ksttfest-tuted eotapouuds 21 .

Sc eme 13

3,5-Distthsti uued 2-pyridyl ureas 2 also can be prepared.accord ug to t e method set out its Sehatno I 3. eaction of 5-broa>o-2-e iiofO-3-fluofopyridHie 29, a substiMcd. alcohol 28 and a base, such .as CsjCOi at a temperature of about RT affords S-bmmo-l-chlorop.vndiae alcohols Mi. The alcohols 30, Xaatphos, a palladium catalyst such as Pd 2 (e%a)j and a stibsiitwted thlolethcr <R*XH where X is sulf r) sit a tem erature above RT; preferably at a t m erature above 50 ° ff KiS 5- ohloro ' pw diiics 31, Tre tment of the 2-chlorop^iaes M, ^substituted mm 5- d: s«- at a temperature of about RT provides die desired ureas 21,

Oampouwds 7, $, It, 13, J 5, 16, Π, U > 19, 20, 21, 22, 25, 24, 25, 26, 27, 30 and 31 illustrated in the .above Schemes, wherein the variables in each formula are as defmed for Formula I, are also believed to be no el atid provide a farther aspect of this invention.

The staffing compounds defined m Schemes 1-13 may also be present with functional groups in protected tons if necessary and/or ia the form of salts, provided a salt-fonahsg group is present aud She reaction ia salt form is possible, if so desired, oae compound of formulas I-iV, ia, He, lid, ilia arid TV& can be converted into another compound, of totimdas H V, la, Oc, lid, Ilia and JVa or a N- oxsde thereof: a compound of formulas 1-.FV, la, lie, lid. Ilia and IVa can be converted :luto a salt; a salt of a eompotmd of foraitslas l-IV, la. He, lid, ilia and. iV cm be converted into the- free compound or another salt: andfor a. mixture of isomeric compounds of formulas I-lV, ia, lie. lid, iiia a«d JVa Cart be separated, into ihe individual isomers.

-Osides can be o tained in. a known s tnaer by -reacting a compound of formulas ί-iV, ia > He, Ed, 1I and IV» with hydrogen peroxide or a peracid, e.g. J h!oroperoxy-bes;« ie acid, in as inert solvent, e,g, dichloroawt aKe, at a temperature between aboni - 10*35*0, s ch as about -0 C C - RT,

If one or more oilier functional groups, for example earboxy, hydroxy, amino, or trtercapto . , are or need to be protected art a compound of formulas Ϊ-!V ami fa, lie, lid, Ilia ami TVa or ia the synthesis of a eon:ax¾s.od of formulas LTV and ia,. lie,. ΪΙά, Ills and IVa, because they .should oof. take . pan in the reacti * these are such groups as are usually used Irs the synthesis of .peptide compounds, and also of cep alosporins arid penicillins, as well as nucleic add de ivati es and sugars,

The protecting groups may already be preseai in precursors and should protect the ftwscto&l groups concerned against unwanted secondary reactions, such as aeySatioss, etlierifkations . , esterliieaiiaos, oxidations, solvolysis, arid similar reactions, it is a characteristic of mtccdag groups that tlte tod themselves readily, .e. without «ndesired se dfldaryfeactioRs, to fesaovat, typically by solvoiysis. reduction, hotolysis or also by eiwy e activity, !br example under conditions analogous to physiological conditions, -and that they are not present ia the end-products. The specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned above and hereinafter.

The protection of such functional groups by such protecting gfoups, the protecting groups themselves, and their removal reactions are described for example in. standard reference rks, such as i, F, W, McGmie, ""Protective Gro ps in Organic Chemistry", P!emtm Press, London ami " New- York 973, in. T. W, Greene, "Protective Gronps in. Organic Synthesis" Wiley, N w York 1981, m "The Peptides"; Vohtrrte 5 (editors: £. Gross and 1 Meienholer), Academic Press, .London and. New York l$8i s in "Mei odea der orgaaisciien Chemle" (Methods of organic chemistry) . Honben eyt, 4th edition, Voltune 15.0 , Georg Thieioe Verlag, Stuttgart 197 , Is H.-D. Jaknbke and.H, Jescheit, "Aininosaoren, Peptide, Proteine" (Amino acids, peptides, proteins), Verlag Cherrue, Weinheim * Deerileid Beach, a«d Basel 1982. atsd hi joehen Lchtoaofi, "C emie dst Ka lenbydraie:

Mofiosticcbaiide and priva e" (Chemistry of carbohydrates: -monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

I n the additional process steps, carried out as desired, .fitnetiosiai groups o f th starting compounds which should not take part in die reaction m y be present in unprotected icon or ma be protected for- example by one- or more o f the protecting groups mentioned abo e under "protecting groups ", " l re protecting groups are then wholly or partly removed according to one of the methods described there.

13? Salts of a compound, oflbr aias 1-J.V and la. He; lid, ilia and J ' Va mth a saMbrming group may be prepared .in a :»Kt¾fisr kaow ' a per se. Add .additioa salts f corirpounds of forsriulas l-fV, la, He, lid. lila and iVa may thus be obtained by treatment with m acid or with a suitable asson exchange reagent. A salt with two acid mo e ules ( for exam le a dihalogetbde of a coajpoxin of formulas !-t ' V, la, lie, ΪΜ, ilia and TV'a) iaay also he converted into a salt wi h one acid molecule- pe com ound ' .for example a iROrio!ialogenide); fills m y be do c by tieainrg to a twit, or forcsaoi le by healing as a solid under a high vacuum ai. elevated temperature, for example -from about 130*0 to about i?0*C, one molecule of the acid being expelled per molecule of a compound of formulas I4V and la, lie, lid, 1.0a and IV ' a.

Sa ts can nsoaiiy fee converted fo tree compounds, eg. by treating with suitable feasts agents, fof example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, typically poias inns carbonate or sodiara hydroxide.

All. process steps described here caa be carried out under known reaction conditions, preferably uader those specifically meatioaed, in the absence of or usually in. the presence of solvents or dilueuts,; preferably saelt as are inert: to the reagents used ami able to dissolve these, in tire absence or presence of catalysts, condensing agents or aeutralmag agents, for example ioa exchangers, typically cation exchangers, for example t) the H+ form, ' depending on lite type of reaction and/or reactariis at reduced, normal, or elevated tetapersture, tor example m the range front about » I 0*C to about m)*€, preferably fx ' om about -8 . to about S 5iPC, for example at about -80 to about 6ό ΰ ά at RT, a about *20 to about 4( C or at the boilin poi«t of the solvent -used, under atmospheric pressure or its a closed, vessel, where appropriate under pressure, and/or in aa inert atmosphere, for example under argon or a ' rogea.

Salts may be present ail starbrrg compounds arid transients, if these contain salt-farmiag groups. Salts may also be present during the reaction of such compounds, provided the reaction, is .not thereby disturbed.

In certain cases, typically in liydmgcaraiiors processes, it is possible to achieve stereoselective reactions, allowing for example easier recovery of individual isomers.

Tire solvents from which those can be selected which are suitable for the reacEtott tsr question include for example water, esters, typically lower alky!-lower alkaaoates, e.g., ethyl acetate, ethers, typically aliphatic ethers, e.g., diethylether, or cye.be ethers, e.g„ IMF, liquid aromatic hydrocarbons, typically benzene or toluene, alcohols, typically eOH, EfOH or i -propa.uoi, a-propanol, oitriies, typically CH?CN, haiogeuated hydrocarbons, typically DCM, acid amides, typically DMF, bases, typically heterocyclic iiitiogeu bases, e.g. pyridine, carboxyiic acids, typicaliy lower alkanecafbokyiie acids, e.g„ AcOM, carboxylic acid anhydrides, typically lower alkaae acid anhydrides, e.g„ acetic anhydride, cyclic, linear, or branched Irydrocarbons. typicall eyelohexaae, hexane, or isoperrisoe, or

1.3S mixtures of these solvents, eg,, aqueous solutions, unless otherwise stated in the description of the process. Such soivexst mixtures may also e used in processing, for xam is in chromatograph ,

The invention relates also to those .forms of the process in which one sfcarts from a compound obtainable at ny stage as a transient aiid eaiii.es out the missin steps, or breaks off die process at any stage, or forms a starting material under the. reaction conditions, or uses said starting material, in the form of a reactive derivative er salt, or prOifeees a compoun obtainable by means of the process according to the invention and processes the said compound /» i in the preferred embodiment, one starts from those starting materials which. lead to the compounds described above as preferred.

The compounds of forasnias V, la, lie, ' lid. Ma and W. including their salts, are also obtainable in die iorm of hydrates, or their crystals can include lor example .the solvent used for crystallization {present as solvates).

New starting materials asd/or intermediates, as well as processes for the preparation thereof,, are likewise the subject of this nvention, x the preferred embodiment, such starting materials are used and .reaction, conditions so selected as to enable- the preferred compounds to be obtained.

its di preparation of Starting materials, existing function l groups which do not participate in { e reaction should, if -necessary, be protected. deferred protecting groups,, their introduction and their removal are described above or m the examples.

Ail emainin g starling materials are knovwt, capable of being prepared according to know processes, or commercially obtaina le; is particular, they be prepared using processes as described in the examples.

Compounds of the present invention can possess, in general one or more asymmetric carbon, atoms and ate inns capable of existing itt the form of optical Isomers and thus occur as race-mates and faeetn mixtures, scaleraie mixtures, single enantiomers, drvtdual diasiereomers and diastereomerk mixtures. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, by formation of diastereo!somerk salts, by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diaeety!t&rtaric. dibcnxoyllariatic, ditoluoyltartarie, and camphorsulfomc -acid and then separation sf the .mixture of diastereoisossers by crystallization followed by liberation of site optically active bases from these salts, A different process- for separation of optica! Isomers involves the use of a ehiral chromatography eofonsa optimally cliosen to jsaxi isse the separation of the enantiomers. Still another available method involves synthesis o covalent dtastereoisotnene molecules by .reacting compounds of the invention with an opticall pure acid in an activated form or a optically pate isocyanate. The symteixed dlastereoisornets Caii be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and. then hydrolyzed to deliver the enantiomericaiiy pure, compound Use optically active compounds of the invention c n likewise be obtained by itsisg optically active starting ' materials. These isomers may be in the form of a free acid, a free base, an ester or a salt All. sxich isomeric forms of these cesnponoils are expressly inciaded is tits present ioveaiiot

The compounds may also occur in cis-or trans- or B- or Z- double bond isomeric form . All Such isomeric forms of such compeamis ate expressly inducted :tft site prese t mvemioa. A ll crystal forms of the compounds, described herein are expressly inciaded in {fee present inveatioa.

Substanents on ring moieties (e.g., prtenyt thienyl, etc.) may be attached to specific atoms, whereby they are ended to be fixed to that ato , or they raay be drawn tmarlached to a specific atom, whereby they are intended to be attached at any available atom that is not already substimied by an atom other than H (hydrogen).

Tie compounds of this .invention may eomain heterocyclic ring systems attached to another riitg system. Such heterocyclic ring systems x y be attached through a carbon atotn or a heteroatonr in the ring system.

Alternatively, a compound of any of the formulas delineated herein may be synthesized according to my of She processes delineated herein in the processes delineated herein, the steps may be performed iti mi alternate order and my be preceded, or followed, by additional

protcetiort/deprotectsOR steps as tsecesssaiy. Tire processes t«ay further comprise use of appropriate reaction coad ons, raehtding inert soivems, additional reageats, such as bases (e,g,„ IDA, MEA, pyridi&e, >€%, and the like), catalysts, and salt forms of the above. The intermediates may be isolated or carried on in≠ t with or. without p ification. Purification methods re known in the art and include, for example, ctyst totfcn, ehix>matograp.hy (liquid and gas phase, simulated moving bed ("SMB")), extraction, distillation, trituration, reverse phase HP ' LC and the like. Reactions conditions such as temperature, duration, pressure, and atmosphere (inert gas, ambient) are known in the art and may be adjusted as appropriate for the reaction.

As can be appreciated by the skilled artisan, the above synthetic schemes are not. iatended to comprise a comprehensive list of all means by which the compounds described a d claimed in. this po!icatioB. may be synthesized. Fnrihet methods vdli be evident to those of ordinary skill ia the art, Additionally, the various synthetic steps described above amy be performed in an alternate sequence •or Older t give die desired compounds. Synthetic chemistry transformations and protecting grou methodologies (protection and. deprotecsion} useful hi synChesuitsg the inhibitor compounds described herein are known hi the art and include,, for example, those such as described m R. Larock,

Cmpre &ixiw Org ic Ihrmfamaiim , VCH Publishers (1989); T.W. Greene .and P.G.M. Wats, Pmt i Group* m Orga ic Synthesis, 3rd, Ed.. John Wiley arid Sorts < 1999K L, Pieser a&d , Pieser, Pifiser and fiber's Hmgentofi r Organic Synthesis, Mm Wiley m\d Sons (1994); A, Kaf.riixky and A, Poxharski, Handbook of Heterocyclic Cbet^ktry, 2 !S) Bd. <20i>i); M. Bodansi&y, A.

Boda»s¾ky: Tkep ctke of Peptide Smihe Springer-Verlag, Berlin Heidelberg im; I Seydea- Persne: JtUbctom iy the Ah im- WUey-VCM, 199?; and L. Paquette, s&, tcyd(%mtw fR g fm for Organic S nth&siv. Mm Wiley and Sam (1995).

The coi«po«»ds tsf " t is htveatioa stay- be modified by nding a pro riate fuact«o»aluies to enhance selective biological properties. Such niodilleations are known tbe art sad incfeide (hose which iiKt ' cas biological r^aetfatioa into a given biological CDmpamaeat (e,g„ blood, lymphatic system., central BOVSUS system), increase era! availability, increase solobility to allow adniinistraiion by injection, alter metabolism arid .alter rate of excretion.

The foi lowing examples contain detailed descriptions of the methods of preparation of compounds of Formulas MV and la. Be, I , Ilia and IVa. These detailed descriptions fall within the scope, arid serve to exemplify, the above described General Synthetic Procedures which form part of the iaveation. These detailed descriptions arc presented for illustrative purposes only sad are not: intended as a estr ct on. the scope of the invention.

EXPERIMENTAL

Unless otherwise noted,, all materials were obiaiaed &am commercial .suppliers and used without further pirdflcatioa. All parts are by weight and iesoperautres are its degrees centigrade u&less otherwise indicated. AS! microwave assisted reactions were conducted with a Smith Synthesiser' " ' 5 from Biotag 13 * 3 . Ail ee∞|X>an4S showed NMR spectra consistent with their assigne stntctares. Melting pohrts were determined on a Btieki apparatus arid are uncorrected. MS data was detertirfoed by eleetrospray .fomzadon " teehnfc e. All examples were purified to ><¾>% purity as determined by high'perforaiaace liquid ohomatogra hy. Unless otherwise stated, reactions were rtns at ' RT.

Unless otherwise indicated, BPLC analyses were ma on. Agilent Model. 1 UN) system, with an Agilent Technologies Z rbax SB«Cs(5 μ) reverse p ase column (4,6 x I §0..mra) run at 30 °C with a So rate of " about ! .50 mt/tata (Agiteftt Teclaiologies, Sant Clara, CA). The mobile phase used solvent A <¾ . Q/0.1% TFA) and solvent B {ACN/0,1% TFA) with a 11 onn gradient fro 5% to H>0% ACN. The gradient was followed by a 2 «HB, return to 5% ACN and about a 2.5 rnin, re-equilibration ( flush).

LC-MS Methods:

Unless otherwise indicated, samples were ma on an Agilent model- 1 100 LC-MSD system with an AgHdit Tcch oiogies X.D.B-C ¾ (3.5μ) reverse phase eo-htma {4,6 x 75 mm) sx 30 S C. The flo w rate was onstan .and ranged from about 0.75 raL/min. to abom 1 .0 mL/min.The mobile phase used a mixture of solvent A {H ? 0¾ ! %HCO ; H or TEA) and solvent B (ACNiO.1 % .HCOjH or TEA) with a 5 to for a gradient ifont 10% to 90% solvent B. The gradient was followed by a 0,5 rain period 9 mm

14] time period to return to 16% rolveatB ami s 2.5 mm K) sol ent B re^ tnlibratjoa (lush) of the eohimii

M i analyses used am Agilent 1200 LCMS with a single quad MSB (06120) with a rauiti - mode source. Mobile -phase A cousisls of¾0 cofttainmg t 1PA and 0.1% foome acid. M bile phase B consists of ACN containing 1% I.PA and (U% formic ac d, Separation occurred with a gradie»t siartiag at 5% mobile phase B and sading at 95% mobile phase 8 over 3 or 5 «itoes -using a Halo (Advanced Materials Teehaetogy) CIS column 50 s 2. Jjttm, 2.7μι6 particle e. Flow was set t I «5½mn and ioaizauoa occurred with both ESI and APCl i& both positive and negative modes.

Where in icated, compounds ofthe present invention were purified via .reverse phase HPLC asiag t e following coaditkms:

Prep HPLC method 1 Preparative reverse-phase HPLC was performed on a 30 250 jam Pheno enex Luaa Pf P(2) periluorophersyi column PN: OOG~4448-UO-A 5 tua particle, A = 0.1% If A to water; B - 0.1% TFA in. ACR Th -column md SO inch, 0.020 id skinless steel segment of tubing were it rierseci hlto a 45 °C glycol balls; Flow = ;: 40 mL mill 1 Gm ient: 0 -* 5 mm tsQcfaOc at (¾10% B; 5→ 60 mi n 'li near gradiem so 55% B 6 ~* 70 nsirr. isocratic at i¾55% B; at 70.01 mm. slop to 100% 8, hold lor 10 mio; at 80,1 raia, Sep to 10 ¾B; 8 i itc cod.

Prep HPLC tftetfaod 2 Preparative reverse-phase HPLC was performed on a Waters terra Prep C i MS Packed by Yvdae/Tke Separation Creep, 50 m x 300 mm (FN ΡΑϋΟΟΟ-050730, 10 urn panicle size, spherical shape, - 0.1% TFA hi water; B - 1 % TFB - 0, 1% TFA - 89.9% ACM: glycol from s external heat transfer unit set to 45 *C was ilowed though the colmxin jacket. The manual injector sample loop, and the precoiama tuhirig were immersed into the heat transfer bath ); gradient: 0 ····>· 4 mai@20 jniL/ in, 25% B;4 → 5 min, 20 -···> S 00 mLAttfoi 25% B; 5 ·-, 25 minf 100 mL/tnin, linear, gradient to 55% 8; 25 ····» 35 min 100 mL mia, isocratic at 5S¾B: 35 min,. step to ί.Ο0%Β ί¾ ί00 ι ,όΏίηι 35 ~- 50 taiaii tK) ssi.Anis. }00%B; 50 m!}), step to 25%B (¾ :l 00

Prep HPLC et od 3 Preparative reverse-phase HPLC was performed on a GiSson GX-2S¾ 1 equipped with a Phsnomenes. Syrsergi CS 8 column (Part Rv. 00F-4435-U0-AX) {! 50 s. 30 m, S pm) or a SiiiaChom XT C 18 column (S/M 1019ί 5 091240s with U V detection at 254 nrrs eHitirsg with 5- 95% C¾CK in H ;i O with 0,1% TFA lor 1 1 min at 45 nuVasm, The gradient is followed by a i minute return to 5% CB;CK

Prep HPLC tne hod 4 Preparative reverse-phase HPLC was perforated on a Shimadjai S ' SL- lOAP auto !itjeclor and Simn&sku FRC-IOA Inaction collector equipped with a Pheno eriex Sysiergi CI S column (Part No. OOF-4430-ϋΟ-ΑΧ) ( 150 x 30 mm, 1.0 pm> with UV detectioa at 25 run eluting wit 5~ίί10% CHjCN in. water with 0.1% IF A. for 15 rain at 35 ralimia. The gradient is followed by a \ mffiuts rcisrti to 5% CH¾CH,

Prep HPLC arethod 5 Preparative reverse-plmse HP ' LC was erfo ated, with a Phenomeaex Gere»m-NX Cm I Mi A column (100 s 21. mm, 5 μπΐ) with tJV detedioo as 254 ntn (Waters 2487 or. Waters P ) elutiug sih 10-60% or 10-90% C¾CN m water with 0, i% ¾OH for 8 mia at 44 mL mi is followed by a 2 mkuie return So 10%€%CM

Unless otherwise indicated, all mass spectral data for starting materials, iutennediates and/or exemplary corapounds are reported as mass/charge (nv ' z), having an (M^-ff ) or (Μ-Η ' ) molecular ion, depending oa the ioraanioa mode (positive or negative). The oleetdsr ion reported was obtained by eiectrospray detection method. Confounds having an isotopic -atom, such as bromine and the like, are reported -aecordmg to {he detected isotopic pattern, as appreciated by those skilled ia the art.

Alternatively, APC!. is used as a aieihod of atass -detection.

tep A: A stirred, suspension, of 2-faromopyrkii&-3-oi (50g 5 287.t&mol} in Ac>0 (i SO mL) under a drying tube as heated to reilux for 3 h and then cooled to RI\ The reaction was concentrated to remove as mn i EGA c as possible. The reaction was pou red ov-er 00 g of ice with stiiTiog. After 5 min, solid NajCC was added portionwise until pH~ ; 7 was reached. 100 j«L of EoO was added to the.inix.uire and. stirred for 5 min. The layers were separata! and rtte aqueous plm%c extracted 4 x j 00 mL with MIBE. T re c oibioed orginrics were washed 3 x 200 ml. with J%0 and. Ϊ .x .2(H) mL with ferine. The orgaoies were dried, over MgSG*. filtered and concentrated to afford erode 2-broroopyridirt-3-yj acetate (63 g, 100% yield). The oiateriat was used in the nest reaction withont my further purification.

Sjea : 2'-B o iSop r di i-i-yi acetate (03 g s 202 romol) was dissolve m.DMF {#»«iL) and Ραα 2 (ΡΡ1ϊ ί }ϊ ( UL2 g, M.6 smnoi) and irj o:iyi(visiyijstarurgiie (Ϊ05 g, 321 mmol) were added and the reaction was {seated at .145 for 3 !s. The reacti n was cooled arid partitioned between water an EiOAc, washed with H :f <X dried over N¾Si¾. filtered and concentrated The residue pwrified ver silica gei (EiQAc to hexaaes) to afford foe 2-vinylpyrid30-3-yi (30.0 g 5 63,0% yield} as yellow oil

Step€': A Parr vessel charged with 2~vinyipyridin-S~yl acetate (30,0 g, 184 jrtsBol), MeOE (200 mL.) and Ϊ0% Pd/C (4.9 g, 4.S mmoi). The reaction was shaken at 30 psi H : . pressure tor 2.5 It. The reaction mixture was the filtered though Ce!ite to afford 2 ¾hylp ridit^-y1 acetate as a clear oil. This material was used in the next reaction wrtliont any further purification.

Step : 2-Ethylpyridiii- -yi acetate (30g, 182 mmol . ) was dissolved in MeOH (200 ml.) an sodium methaaokie (14.7 g, 272.4 mmol) was added atid the reaction heated 60 *C for 2 . The reaction was cooled and concentrated to afford, an ot!. s which was partitioned between 15% MeOH in. CH 2 Ci 2 rtd ' ¾0 ( 100 mLs and extracted with 15% MeOH in CH 2 ¾ (3 X 75 mL). Dried over Ma 2 S0.v. filtered and coaesiWfatsd to affotd 2-eihy Hdia-¾-oi (½¾ 7,1.5% yield) as a white solid. lion 2

Step A: Benzoic add (136. { g s \ 115 mtm\) was dissolved: in DMF (1200 ml) and K.OH {62.54 g, S 1 1.5 raraol) was added ami die teactioa heaied So 50 *C for I. b. .3 Mompeitt >e-2,4-dio:fie { SO g„ 1. { 15 imml) was slowly added ami stirred ai: 50 °C overnight The mixture was cooled and p ured ixW- .5 L ¾0 > extracted with Εί,Ο (5 X I L), washed wiife saturated aqueous Mii ; CL brifle and E ) (2 X i L} t dried over a 2 O«, filtered aird concentrated so afford 2.4-d.i0xopenta«-3-yl feeaxoitte {224.9 g, 1021 πΚΗθΙ, δΙ.δί % yield) as yellow oil.

S p 8; 2,4-Dioxope«ia«-3~yI besixoate (224.9 g, 1 21 mmol) was dissolved in EtGH (2 L) and cooled as as ice balls, Metityihydrazine (108,2 ml 2042 mmol) was added slowly and th reaction was stirred at RT overnight. The reaction was concentrated and taken into the ' next reaction without further purification,

Step C; Grade i AS-trirttethyS-ni-pYraz M- ! benxostie (235.2 « 1021 mmol) was dissolved in EtO.H (I Lk 3 NaOH (510.7 ml 1532 oi) was added and the reaction was stirred at: RT for 2 h. The EtOH was removed in. vacuo. The aqueous layer was extracted with EtOA.e (500 ssL). The aqueous layer was neutralized to pH S with 6 N HO and the resultant solids were tillered, to ai&rd l,3,5-mtseslsyt- 1 H-pyra l-4-ol (62,9 g„ 4&.S % yield) .as a white solid. e turn 3

4-MethOxyb tan~2-oS (800 ra , 7.6 .mmoi) was dissol ved i C¾Ci 2 (SO ml) and Ei 5 ( 285 added and stirred at RT. Methaaestn onyl chloride (599 pi, 7,68 mmol) was added and stirred a RT for, 20 win. The reaction was paMitioned. between !¾0 a» CB 2 {¾, dried over ajSCXi, filtered, and concentrated to afford »iacdioxybvrta«*:2 » yi methanesalfoaate (1 ,3 g > 7.13 mraol, 92.9 % yieki) as a clear colorless oil

SM ) ¾, 34.2 mxml) as dissolved in C¾€l 2 (50 !!iL}. pyridine (Ϊ S .. I rat 137 !¾moi} its added and tfte reaction eo&isd in 8ft ice bad*, 4 » Metlwlbeaisens- ί -suifoayl chloride (8.48 §, 44,5 raraol) was added slowly asid ie anxttwe was stirred at T cs eriHglff : The reaebd was parfbioaed between IN HO. and CHjClj, washed again ith IN HCL sat ' aHCO¾ bri&e, dried over ¾SO», filtered aad concentrated The resiste was purified over silica gel (5: ! to 1: 1 :hexafle:EtOAe) to afford <¾)-Η2 2^Μ«^1 » ^1-όΙοχ9ΐ¾ο-½Ι ' )8ώ ί 4- nietljy ' f euze-aesulfonafe g, 29.6 lamo!, $6,5 % Yield} as a dear oil.

Via fbc route to Pispaiatiois 4, the i awiisg co*»oOB» was prepared;

¾g iiots 6

in .1 rat. of DMf were combiaed qoin.oRsi-d-oi (0.500 g, 3,44 mraol} aad 1 - (0,483 g, 3.62 mraol) gad stirred at R overnight. The reaciioB was heated to 40 °C for 2 days. Tlte reaeba was po-xtred into water f ? 5 mL) and then extracted with BtOAc (.½:UK> ioL>, washed with waief (50 sal), brims (50 mL), dried. over Mg$(¾, filtered, a«d eoa eJ!tt¾ted, The residue was purified over silica gel (100% H2CI2} to afford 5-cbl.oroq»iftel ta-6-οί (0,450 g, 2, lis ·)!·!(·:>!, 6 i . i % yield). e ties. 7

Stgj A: fit 20 rat of DMf were combined ( ¾>¾¾ NaH (1.390 g, 34.75 rn l] and 6- fe di )x i:Kso!n!-2{ ί ¾;KH$« (I..75 g, tra»e¾. ibis was stirred for 30 mm with Hj sparging feeibre Me a Sa » (2.569 ml 27.15 ttttnoi) was ded slowly and ie reaction was stirred at .RT or 2 h. The reaeticnr was c ncentra e and dissolved i CHjGfe wtiif 0.1 % eOH.00 mL) and to this was added i 0 mL ofEtGAc and. filtered. The tlhrate was concentrated and purified over silica gel ( 1 : ί EtOAc:CH:jCS;>) to afford ^-HJetho y-i-ntsri l^!i^^in-lCii^-oa CLS? g, 7.468 miml 68.77 % yield).

Step B I» 7S mL ofCH ;; C¾ was dissolved 6»rae.!!ioK -meii!^ (1,5? g ;

¾.30 tnmoi} and cooled to -78 X: before I BBr= (24.9 m 24.9 mrn l) was added and die reaction was slowly warmed to 0 "C. After J it, t e reaeiiots 60 mL oi " 2: 1 water: 50% NaOH was added, T¾e pH was lowered to 2 via the addition of concentrated HO and stirred i r 15 mm. The solids were filtered, washed wills CM ? €¾ aad dried to afford 6-irydroxy- i -me¾yiqnmoim-2( l-H)-one Π ,33 g, 91, 5% yield).

Following, the procedure in Preparation 7 lie following compound was prepared:

Pre aratioH Structure Name Data

6-bydroxy- 1 ,4- Mass

8 cl3¾etb:yks« }.t l B- spectrum (apci) mfz

2(lH)-oi5e ■■■ i W i i .M r ! h

e sioo 9

5 , 7-d sis uoro- -¾y dr0xy- -itnf .ooro noi in-2 ( i. Sf ' i-onc

Step A: to 50 mL of ' DM were .combined NaH (60¾ dispersal In oil) fJ .14 g, 28.6 mmol} and 2 > 6-dii¾! io~4-aittopiteiioi (5.0 g, 28.6 miml) slowly at RT, TMs was stirred at RT for 30 min ' before iodomeiharte ( 1 ,78 ml 28.6 sr nol) was added slowly. Aiter 16 Is, 0.25 eq of iodoraemane (0,445 mL) were added sfowiv. The following .morning, .1 NaOH (100 mL) was added to foe reaction and it was stirred for 30 min before the reaction was poured into a separatory usnel containing EiOAc (300 mL), The -aqueous layer was extracted with EiOAc (300 mLl The orgamcs were combined * washed with 1 NaOH (TOO roL), ¾0 (2x 100 xssL), and coaceulra ed wader reduced ■pressure to yield i ,3 ' ^iOiioro-2 » tBe{h0x -S-a{trobes)2«ne (5.97 g, 1.6 rnrocl i l l % yield) which was used as is. Step B: is 100 mi-o .EtOH was dissolved ! 5 3-dif1«oro-2-methasy-5-»itt¾be5i¾iie (5.9? g:. 30 ,6 tHin S) sa 5¾ is -was e acuated ar*i back tille with Nj 3s before 10% Ρύ/C (3.36 « , 3,16 rmiii) was added. The reaction was again -evacuated but jjhfs time backfilled with .!¾ 3.x. The reaction was '!i c iitiiitied i!ritkr atmospheric. B> aad the next onuR the reactioii as filtered, eoneeair ted. x dst reduced pressure, a«d patiOad over silica gel e!asing with 10% irexanes »i€¾€¾ to obtalfi 3.5- djflootx)-4-meihox anUiac (3,4 g, 2 ! ,4 -mmol, 67.7 % yield)

Step C: ' to 6.BiL of toluene were coiabnaed 3, -di aoTO-4--a:ieiS:¾C5xyaji «ie (0.500 g, 3,14 ffim i), ethyl 4. , -ir!il!,icsro-3- s: a:taiioais {0,868: g, 4.71 tntno!}, aad water (0,125 ml,, &M nmi t} aad 0¾e. reaction flask was fitted with- a condenser asd heated to reilux under ;>. Afifcr 8 It, the reacOoti was concentrated ortder reduced pressure. The resttHiag residue was dissol ved v¾SQ.< ((> mL) i!«d treated in a sealed container to SO * C. After 5 h Ore reaetioa was cooled to RT and it was poured into 20 ml, of a vvaterice slurry sad to it was added 50% aOH to reach pH™2, The resulting white solids were collected via vacuum Sltnrtioi!, washed with wate, aad dried is a vacuum oven to yieid SJ-diilu ro-O^wdroxy^ ^ (0.716 g 5 2,57 , 81..? % y ield) Mass s ecrou;! (apei-iieg) na¾ ::: 264.0 ( -i ),

The followin compounds were all prepared in a similar inanaer uslrta the appropriate alpha*

e i ' nm 13

I S O ml. of DMF ere combined 4-(4,4.5 : 5-ie!:&mei !-L3 t 2-d}Oxaboroiss-2-y!)-!li- py:ra«>ie (S.(i g s 25.77 imwl), .i-btomo-2-meffeoxyeihsae (4.298 » .30.92 m o!}, and C¾COj (5.0.49 g, 32.21 tsrao!) at ST and the reaction wits sparged with or 20 mm before it was .sealed ¾nd heale to ί ό <C with igorous stirring. The reaction was cootiriued overnight. The reaction was d&ited with 20 ail, of water and then extracted with EtOAe (3x 100 mi). Th combined organic* were tfcea waslted wi h b iK (3x50 iJiL.}, dried over MgSOs, filtered, and removed />? rae?«>. The crude was purified b etaaatography wit 3%-5% acetone to {¾£¾. The desired fractious were combined, removed tmder reduced pressure, a«d dried trader high vacuum (product slightly volatile) to yield I- (2.mcrSioxyetby!)-4H4 t 4 1 5-teu-aincrSiyS-i i K-pyraxote (5.19, 20,61 jninol yield). Mass spednsm (apcts miz - 23 .1 ( -t-M)

The tbliowsag compound was prepred is the same way with appropriate starting juaterial .

Step A: 1» 30 ruL ofN 2 sparged (15 mia} DME were combined I-methy rres ( 1.69 , 22.S !Hiiioi) and flaeiy ground tribasie potassium phosphate {5.65 g, 26.6 msrsol and this was sparged for 5 mm before i¾¾(dba)j (0.« g, 0 760.mmoi) m& \ } I -bi£iap :!)syi-2-yMi m-b«f I hos si; (i;2) g, 3.04 fti!HOl were gilded and this was sparged for another 5 tnin before the :reaetio.trwas healed to 60 fl C for a oae cmspk k period. After that tfcne, the reaction was cooled to RT arid 2-chlo:ro-4- fmOf pyrkft«e. (2.0 g, 15.2 rnmel ' ) was added. This mixture was spar ed for i mm with ; before t¾ reaction was sealed and heated to 95* C overnight lie reaction was diluted mik 150 mL of 1:1 C;H jCi:.:B OAc theft filtered, The cake was washed sedentarily with. C¾C¾ arsd BtOAe ( 10 mL of each) md then discarded. The iltafe was coiieetitfated w c o a»d the resulting residue was purified by chromatography with 20% acetone a€¾<¾.. Product coniam g. fractions, were combined, concentrated in vacuo., and dried on ' high vacutsm to yi ld H ' 4-flaoTOpynd.tOr2>yl)-3- raethylnrea ( 1,3 ! g, 1,59 mmol 49.9 % yield).

Step 8: lit I rut of DMP were combined ] -(4-il oropyr i8--2-yS)-3-meS:hyiurea C J &0 g, 0,59:1 m e>\) mi NBS (if 1 5 g, 0.591 ramol} and this was stirred at RT overnight. To the reaction was then added 6 l, of water and t he suspension was stored, orously for 30 n*ia before the solid was collected via vacuum lilrariou to afford H ' 5-bramo -fluorop>¾dm-2-y.l)-3-met.hylurea (0, I 6 g, 0427 rmuol 72.3 % yield;!. Mass spectrum. ! ape i) re .' == 245,9, 247.9 (½-;-«). e liot? 16

Step A: i» 10 tnL of DMA were combined aH (60% dispersion in oil} (0,4831 g, 1 .09 nrmol) aod phetxyl methanol (1.253 mi 12.0» mmo.i> at RT. The deprotoaatkta was continued- for 40 mm ' before K5-tm>ti^-fl«or p ddh^2*yJ ' 3-snC¾ twa (2.0 g, 8.063 ΪΙΗΒΟΙ) was added. The reaction was heated lo SO « C arid stirred overnight. After that time the reaction was diluted with 1 0 mL of H;:0 aad stirred, vigorously and a white precipitate formed. The solids were collected via vacatur* rllirat oa and were washed, wills 1.0 m ' L of ¾0 aad taea 20 tub of BtO. The solid was dried in a vseaam overt to yield

85.96 % yield),

Step B; its 20 m ' L ofdioxaae were combined i 4-(beRzyioxy)-3-brotwopyrtdtn-2-yl>-3- raetbyiurea (2.5 g, 7,430 ramol}, ί - t¾iei:h ΐ ~ 5 -f 4,4, 5.5 -tetrsfsieiis 1- i ,3,2-dioxaboro!art-2-yi)-lH- pyraxoie (2.32 \ g, 1 1 ,15 mmol), and K¾C0 5 (1 145 ml 22.31 raoiol) aad. this was sparged, for i 0 rain illi Ar. After that time PdChCdppf) {%€¾ (0.9109 g, 1.1 15 nuool) was added, the reaction was sparged with Ar for SO mia, sealed, and. heated to 1(H ) *€ overnight I¾e .reaction was diluted with EtOAc {100 rot) and the organic was collected. The aqueous was then extracted with EtOAc {2x1.00 »L) arid once wiib C ' ¾Clj ( ί 00 mL). The combined orgastics were ihest dried over MgSOi, filtered, and removed m vaam. The resulting crude was purified over silica gel (15-30% acetone in Cf¾C xv? 0,5% NHjO ) t afford l-{4-{te ylax }-5-( l.'met yl-}H-py^z ^5- ])p rk¾^2-yl)-3-«)dh :U»ea (1,359 & 4S maiol, 54.17 % yield).

Step C; 1B 6 i»L of HO were combined !

l)p r!dsii-2' l)- -metl>yk!rea (0.1 0 g, 0,445 mmel} and -amiaoeihaoethiol S droehiortde (0.0758 g, 0.607 mi i) and this was heated to 100 °C. After 6 h Oie paction was complete and cooled m m ice bath- To the sti ag- .reaction was added 50% NaOH. to a pH ~ ] 2 and Ore reaction was stirred at SI for 20 rain. The pH was then adjusted between 3- wiiis 6 M ' B ' O asd a solid formed. This solid was collected via vacuum filtration and dried in a vacuum -ove-a to yield i 4-hydroxy-5> 1 -tneltyl- IB ' - pyra oi-5-yi)pyridi!i-2-yl}-3-iMe!:iiylurea (0.070 g, 0.283 ramot 63.7 % yield). Mass .spectrum (apei) ra/z - 248. }. i +H) e ! ion 17

I-( -¾o.re~2X^

i a vial with 8 xaL of dioxane were combined M5-Dr0o:ro-4~fiuoropyrfdiu~2-yi e- mei Utfea (6S0 m$, 2.62 siuaoi), 2 trifta«x)mei¾y yridjft'4-ylb ro«k acid (750 g, 3.93 rmsoi), nd .aqueous ( 93 ί, 7.86 miml. At was bubbled into ibis arixtme for 5 mm followed by addition ofPd(PPlt?¼ (303 ¾g, 0.262 inm>t). Ar was bubbled into die mixture for another 60 sec before it was sealed and heated to SO " for 50. T½ reaction, was diluted with C¾Cij and purified on silica- column ( 10-25% aceione, f¾C½) to afford H^-tootiI'^trifiyo^Hieihy^^^'^ip dditi-e- y.i)-3-methylurea (230 mg, , 0.7i mmol, 27.1 % yield). Mass spectrum (apci) u¾¾- 315,1 (M÷H) e thm 18

2-me.h.o.x.y-5 4^

1.51 A stirred mixture of 5-feroKio-2-methosyb imniirile f] g. 4,8 mrnol), hisCpim&ola oldiborro (1 ,46 g, 5,75 β)«)οΐ PdC!jid pi);- co le wiiii CH_C¾ (0.39 g, 0, & iranqi), mid KOAc ( 1.43 g, ! 4,6 raraol) is dry dioxatte 15 mh) was purged 3x with Ar asd placed tmdsr stcMttt 3x. The mi ure was heated to 90 r ' . After 21 h, the t eae ion was cooled to RT tfeen filtered tfefougti Ceiite. Tte -organic solvent was removed under reduced pressure, and the res due was pursued oa silica gel (0-25% EtOAc id s s) afford hite ,3,2* ai xak«s!atv2*y te«2on|«iie. Ή N R (400 MI½, DJCHLOROMBTHAKE-dj) « pp - 7.99 (2 H, m), ?. 0 (.1 a d, -8, Hz), 3.96 (3 H, s), 1.3-2 ( 12 hi s). Mass Speetnan (pos.) mfc 260.2

e tieit If

In 10 mi o 2: 1 dioxaae:ws er were corufeiaed <S-bfo»}«h2-ffieihyliso( tiaioUn- ί (2M)-ose ( I ,00 r 4.20 Hitnoi), md soikl OH (1.41 g ; 25.2 mraoi). The mixture was sparged with ÷¾ for 10 xnm before ' Pd:<(d ii}.¾ (0) (QM5 g, 0.420 - moi), and di~ erf- iJiyi(2 , : .4 , > 6 ! -uiisopropy¾iphenyI*2 » yljp ospldtie (0.3$? g, 0.840 flasol} were added atkl (his was sparged with Nj for 30 aan bel ¾'e it was sealed and ' heated to 100 : 'C, After 8 li produce was observed. The reaction, was diluted with I NaOM (50 at) -and was extracted with EtOAc (50 niL) and feCfe (50 L). The remaining aqueous was theft acidified with 6M MO and the resulting solid was collected \in vacuum iBlratiosi arid washed wish EtOAc ( 10 mL) to remove color and. a bright white solid remained. To the aqueous was added a saturating -anxfttat of solid aCi: and. it was again extracted: with EtOAc (2x 100 ml.) aad combined organks were dried over MgSO, ; , filtered, and removed in vacua. The crude was shea takea op hi C%t¾ wh.lt 5% Me-GH whet* a. solid formed and isolated via vacuum ffitrattan. The solids were combined to yield o-hydroxy- -RKthylisoguiiKjfia- 1 <2H)-one (0.465 g, 2,65 mmol, 63.2 % yield). Mass Spectrum (apei) 176.1 (M- H),

in H ml of 0.M.F were combined ^hydrox -l -methylqtsinoIin-K li-!}-one (0,700 g, 4.00 οίϊϊϊοί) Μά N-chl ms«cctojmid« {0,560 g;« 4.20 imnol} at R.T and Stirred m 40 "C, After 2 h die reaction was complete. The reaction was coaled to IT asd to it was added 50 mL of water slowl followed b she addition § s«L of EtOAc. The mixture was stirred for S κ d t e resulting soli s O s formed were then isolated via vacuum filtration and washed with water {5 t«L>, ' k (5 raL). ιναά dried iii a vacuum oven overnight to yield 5 hi^o^-¾ rOi y»i-«t Yl . «ROlffi-2{ H)-ofie (0.674 g, 3.22 tmuoL 80.5 % yield). Mass Spectruis (apCMteg) mft ^ 208.0, 210.0 (M~H). e tion 21.

A tmxvm of HS- on\o» <2,S- irItK>^ (! .00 g < 2.70 mme>l} : 4,4,4 , 5 4' i 5 ; 5,5' , -oetoieJity}-2 ; r- j}{ I j.2-dioxal orolaae) ( l .4i8 ' .g 5 5,58 mmoS), KQAc i .096 g. 1 1.17 ramol) and PdC¾dppt) (0.228 a, 0.279 aunt in l.4-dioxa«e ( 13.96 mi. 2.79 ramol) was degassed by s aad was then .stirred at 100 a C overnight. %e mixture was cooled to RT and 20 mi. I HC! aqueous solution was added., lite resulting mixture as extracted with EtOAc p raL x 4). The combined, extracts were dried with anhydrous Na 2 SO. s and coiicentrated in vacuo, Tfee residue was purified by silica gel cols rn using 0- 100% EtOAc gradieai in.bexane to give 3 i 3 mg of -(4- (2,6-di:n.ireror^enoxy)-S-{4A.5 < S ^^

M (400 MHz , CDC0) 0,20 (br s, .IH), 8.53 (s, IB), 8.48 (s s IE), 7.20 (m, IH), 7.04 (m, 2H), 5.05 (S, iH). 2,83 (d s J * 4.0Hz, . 131 (s. !2Hi

Under an inert atmosphere, in a preeooled vessel at -20 °C were placed aB¾ 1,20 31 .7 ramol), CEC¾ (150 niLl, EiQH (5.5 fill, 95.0 n¾»oi) and. (tetrabydtofuraii-2-yl)metbanoi (4i. l mi. 422 mm®)) md l:hs mixture was stirred, for ί 5 mm. To he mixture was added a solution of (2Ε,2Έ)~ ί E, ' J ¾}.{((] S,2S>- 1 ,2-diphenyle.th¾ae « -I,2 «

di.ylJbs:S(azarryl.yi& cdba! .(!.!.)

(0.503 g, 0,148 mm®\) if) CHC!¾ (75 cast) and e^^niiethy!-T^-dl ydrixiwmolH SieH oiw (3.? g, 21. J fijfiiiif) i.a CHCU {25 ml.) -were successively- added a.ad the a«xt«re w stirred at -20 °€ sad. slowly warmed to R ' f overnight. 11K reaction was quenched t aqueous H 4 CL separated and. concentrated. The residue was partitioaed between E jQ aad -water, washed with water (x3) aud Mae t 2> x . dri d over ¾$(¾, l ltefed and eortcemraied. Use residae was purified over silica :ge! <70 to i ) % EtOAc its taa«e.s) to afford { hSji-d!mst] --3,<', " ,8-5et ahjdro^jinQlis-5-ot (fit* mg. J 8,4 % yield). e tu ' m 23

In It glass beaker et.hyihydramie oxalate (5430 g, 361 .7 unnof) was combined with water (40 mi). To Use resaltrag slurry 50% w/v NaOH solution was added { W sa ) to adjust pH to 9.5 (by pH-meter). Tie mixture wa heated to 40 » C and methyl tranrf-met oxyaerylate (25.93 ml 241 . S m oi) was added dropwiss over I h. pH was adjusted . periodically by addition o 50% w/v NaOH. .soko ' oa to 9.2-9.6 ra ge. After, the completion of feed, the mixture was agitated for. additional 3 at 40 *C and the H was adjusted occasionally to 9.2-9.6 range. Upon reaction completion the mixture was cooled to 2 °C aad filtered. The rlkrate was evaporated to i 50 ini vo hrtse, cooled so 5 *C atid filtered again, The filtrate was the» acidified to pi! 4-5 with 6M I- l { 4¾il) aad extracted with 6x200i«l of 3: 5. CHG.yl.PA mixture. The combiaed extracts ere dried a:nd evaporated to an amber oil which was purified over silica gel (20% eOH/EtOAc) to afford :Ueihyi M-f yimol-5- i (I S.25 g ; 162,8 ii!P i l 67.50 % yield) as yeilow solid. iojs 24

The solveals and all liquid reag is were degassed with..!% sparge 30 mm prior to use, To a solution of 7 ; S-d!l!ydroqumoii»-5{6HV ne (2%, 136 xnx i) m C¾(¾ (2S0 ait) was added HE (16 rot. 136 rael} aad fonat ' c acid (7,0 ml, i SO asnol). The- auxture. was stirred at RT for 5 mm aad IR, 2R.-S.ti catalyst (1.3 g, 2,04 mai) was dded, The mixture was stirred under positive K¼ pressure ov«!¾i lit The mixture was coneeafrated aad the browa color residue obtaiaed was dissolved in CH 3 C¾ (5 mi.) and purified over silica gel 000% BQAe)

«I i S.5 g, §1,2 % yield) as a bro n solid.

Via t ic rewic -to .Pxeparatioia 24, with he appropriate catalyst, the ibliowiij comp imds; were prepared:

Step A: To a 500 raL muad bottom flask added mddrtHn's acid ( ! .0 g, 76.5 axtaol) d trhheth ' i orthoibrmsie (83.0 rai 765 lamoi). The colorless solution ' was heated a reOux (505 <: C) tor two h. 3- etirylisoxazoi-5-amine (7.50 : 70.5 moi) was added as a solution in triaielhyl ortfeofor aie (83.6 au. 765 xrasioi) and a precipitate formed lmost .bajaediatcly. More triraethyl orthofortaate (50 rat) was added to help stirring. The mixture was heated at reflux: f r another 2 h. The hear was reaxsved aad the soi veut was evaporated, " Falueae was used te am&opc say remta ag solvent. The crude solid was triturated with ¾0 aad the solid was removed, washed with Et¾0 and dried to afford 2 diit5emy.l-S-C(3-rae?.byfe

( ί 2;4g, 64.3 % yield) of each colored ase le-iifcg crystals..

Step B: Dowite-ra A 5 ml.) was .heated to 240 ¾ C ia m oil bad:*. 2 .DimethyI~5-{{3- g, 28,9 iamel) was added to small poriioirs as a soisd over i 3 mm. lite dark solutioa was stirred at 240 °C tot 5 tain aiid cooled io RT. The crude material was dissolved, in MeOil absorbed ora silica aad purified over silica gel («> io 4% MeOH in EiOAc) io afford the desired compound as a pale yellow solid. The solid was triturated with 180% EiOAc and the white powder removed by iHtrauon aod dried o afford 3-riieilryiisoxa2oiot5,4- bjpyrjdin~4-i I. (1,08 g, 25,0% yield).

StejxC: 3-Medwilso¾ai;olo S,4'-blpyTid5ia-4--oi (556 m , 3.663 mi i) was diluted with piiosphoryi trichloride (3,354 ml, 36,63 mitioi) aad heated !o 100 "C ibr I It I¾e reaction was cookd io RT aad poyred onto 10% ice and. steed rapidly. The pH was adjr ed to.7 wiih aOH and extracted wa¾€¾€¾, dried over ¾SO. f , filtered and eoneerarated to afford 4~ddoro-3- t¾ed¾yliso¾a^oio|5,4-bjpyTidiiie (5? mg, 93,27% yield) asd a white solid.

Step A: Teii-ahydro-2H-pyran-4-earbiddehyde ( 1.2 g, 1 1 mmol) was dissolved fei TMF (70 ml.,) and cooled io aa ice bail), 3M Methyi ag esiyai bromide (3.5 mi, 1 1 «υίί ΐ.) was added arid the reaction was stirred at: RT ibr 2 ii and quenched wife mp uu N¾CI, extracted with. EtOAc, dried Over ¾ 2 SO.^ filtefed aad coficsHtraied to afford i-{tclTaii dyo~2H ?y: a. :-4- i) eihafiol (0.7 g, 5.4 mmoi, 54 % yield) as a clear colorless oil.

¾ 8; l- Tstnth dr¾-2H-pyi8il-4-y ethaaol {700 m , 5.3 matol) was dissolved is CH-j ¾ (50 mL) and E( ; (824 μί„ 5.91 mmol) was added. etharieailibny] chloride (477 p.], 5.91 imaoi) was added aad the reaeaoa stirred at RT tor 30 nasi. The reaction was partitioned between water and CHjC , dried, ItSiered and coiiceatraied to ailbrd KteteSryd:ro-2H-pyran'4-yS)eiiryl iaoiharicsiilfoaate ( 1 ,05 g, 5.04 rnro L 93,8 % yield) as a clear colorless Oil.

£ l!OO 30

(t am- o .ocycl0h^

7~0xafeicycie[2.2. ijheptane (2.79 ml, 27.5 imm\ * Nal (4,12 g, 27,5 rnmol) attd dry CH 5 CN (20 ni were stirred under ·¾. C feroirimsf!syisdaiie (3.48 ml 273 mtwi) was added slowly si RT with api stirring. The mixture was stirred at RT for ti and heated at retlux for 3 k The mixture was cooled to RT, extracted with teases (5x3 mL} and corteettira ed to afford (iraas-4- i«doc¥c!ohex !«xj ; i ime t> ; !si]3ae (4.8 g, ] < x l 58.5 % yield) as a dear -colorless oil e t n 31:

c^giope.nt-3-cr¾y -mefeylfeengenesuIfonate

C op it-3-snoi (500 tng, 5,9 mxml) was dissolved m CH 2 C¾ (30 ml) and pyridine (0,57 mL, 7. S roaiQi) and TsCl ( i .25 6.5 mmol) were added aad die reaction was stirred ovenrighi. The readier* was coneeairated and the miAive purified o er silica gei. (1.00%€¾€¾) to afford cvcloperrt- 3-erryi 4-s:nei yibe» ertesa'f iiiite ( i 91% yield) a$ a grey crystallise solid. e tim 32

Step A; A flask was ctoged with. 2-j»ei¾ylpy id|H-3-o (3. g. 273 mraoS) and D F ( iOO mL). Natl (0.760 g, 30.2 mmol) was added and. stirred for 5 rasa. S-Br0mo-3-idSropicoii»o»ihite (6.26 y 27.5 mo) .) was added and stirred tor 10 ism. The reactios was poured into a flask contaimog 300 SBL saturated H. ( CI asd 300 mL water with vigorous stirring. The solids were filtered and dried under high cuum to afford »bro»)Q-3-(2«me ri (7.7S g, 97,0% ieki) as light tan solid,

.Step B: A .flask was charged

207 ΒΜΪΟΙ) attd Β ; .$0* (203 g, 200S mmoi). The reaction, was sirred at RT oversight. Water (500 mL) wfis added careful ry m& tjeutr&lfeed using 50% ¾OH to p.H 5,0, The mixture was extracted with Ci¾C ' sad BfOAe, dried sa £0¾eiitiated to

yioxy)pksoKa»»lde (63.0 g, 204 rnmo 98,9 % yield) as a yellow solid,

Ste C; A flask was charged with 2M MaOH (256 ml 51 1 msriol) arid cooled to 0 Br, (7,85 m 153 t«taol) was added sad stirred for I S mm.

yi sy}pie t!)iar!ide 01 ,5 g, ί 02 ίοίοοί) in dioxaae (650 mi.) was added gad stirred at ST overn ght T¾e aqueous layer was extracted wsia EtOAc aad C¾C . The organic layers ware wasted with water, Mae, diied, eorsceiifrated aad purified over silica gel (25-30-75400%· EtOAc hi !texa»es) to ailbrd 5-¾r€>«5a-M2-R) fliylpyr¾ g, 43 txmv l 41.9 % yield) as a y l low so l td.

Via the route m Preparation 32, the foiknvfeg cof¾p<s.iads were prsp&recir

e tioss 37

3-f2-t?thy pyridin-3-yj^^^

Step A: 2-Εών1ρ>¾άίκ-3-όί (27.5 g, 223 xmxol) was dissolved m DMF i¾0 xaL) aadcooteci in as ice bath. NaH g„ 223 mmol) was added porticsmvise mid stirred Iti ice bails for 30 KHB.5- Boi:BO-3"iitto lcoii!)oi:tfii¾ (S0.9 g, 223 tnmol) ¾¾$ added rn one portion wd stiraed in ice baih. After ί h, pyridiae-2i ! H}-i io:i!e (24:S g.225 moi) was added, fallowed by N&H (8.93 & 223 mmol} d mim stirred vi\ ice bsHlt. After i is, die rcactkm was sdired overnight, thei! the mixture was concentrated m vacuo to 300 mL and poured j«to 3 L wafer with vigorous stirriiig. The sriisiyrc was extracted witSt EtOAc (x3 washed water aad brine (x2} ? dried over ¾:SO.^ filtered sad g, 242 m oi,

108% yield) as s d¾rk oil

(pyndm-2- ltirio)p ridt^2^iaewas synthesized.

Via the route in Prepaf isii ' 37 (he following cotr siads were prepared:

IS9

e iioii 44

3--j(¾.¾-d½ietfoyjpyrM

S?cp A * .2,;6-.Di»ielliyjpyridii)- -of (5.25 g.42.6 mmol) was dissolved ia PM.F (8 rat) ami coeieij to 0 S C. K H (Ϊ ,16 g, 4S. m ei) was added in poriiows ai* the mixture siifred fo 30 rftia...V Cfeloro-5-tri0iwtome0$yi}p{CoHROHitdie (8.00 g, $ .7 mHtoi) was added, dte trdxtrire was warmed t T and ίαΰά avemigbt. The mxtafe was tituted ¾ EtOAc (300 ml) 4 ashed with Na!€ : i¾, water O times;, brine, dried over ¾SO.s, decolorized with D», filtered a«d evaporated to give 3« yield) as Ig brows solid.

SiepB-C: FoSio kg e steps ai Prepatarian 32 steps 8 aad C, 3-(2,6-diriieiiiy!pyridiri-3- ylasy)-5~{iri.fi.Homr55emyl)Dyrid»i-2-amii}s was x rfeesized.

Via the route in P:rsp&r&vii>a 44 (fee i ag cijaipoasds ys¾re- prepared:

e s km 46

S-brom¾-3"(2~te

2-M<¾hyip nd»i-3-ol (616 1 g, 5,69 rn oi) was dissolved in THF (] 0 mL) and cooled to 0 i! , NaH { .2 8 g, $.69 Hftx!ol} was- added aad e reaction "was stirred for 38 tain.

awiae ( 1 ,2 g. 4.75 mmol) was dissolved in THF (2. ml.) id added io the reactioa. The readies was heated to reflux fov 2 \i, DMP -(4 mL.) was ai ed aad heated again atttiiltix ovenrfg t Ilse reaction was cooled o R ' f, dikiied wish water (50 rat) and sfeed vigot'oasly. The resrdtaat solids, were ilhered aad was ed ik water to afibfd 5-bfomo^- 2-«tet yipyridin* - k xy }pyjr&?in-2~amms {1.15 g, 4,09 rnmoi, 86.2 % yield) as a brosvn solid. i 41

i? ?romo-3"C5. ¾~te^^

Step A: S^.T^-Teteihydro^idiioMii-S-oi (2.85 g, 19,1. tn oi), 2~£mropyridin~3-o! (2.68 g, 19.1 ra el), PPfc (6.8 ¾ 26.0 rnmoi) were dissolved in THF (60 mL). DIAD (5.15 ml, 26,<) mmo ) was added slowly and the reaction was stin¾d at RT ovennghf. The react ion as partitioned between, water asd EtOAc, The aqueous layer was extracted with CH ¾. The combined orpaies were dried over ¾SO¾ s filtered aad coaecntrated. The resi ue was purified over silica gel. (25-50-10*3% EtOAc in hexa»es) !o afford 6.0 g of crude 5-(2-¾iH¾pyridia~ >- ^ as yedow oil

Ste 8: 5-(2- itropyfidir!*3-yiox )- 5.6.7 ' ,8-ieii';iii ifa idiiol .t te (2,0 g, 7,3? riimel) was -dissolved ia H0.4c (50 taL), The reaction was cooled ϊο 6 "C aad Zrs dust (2.41 g, 36,9 iiinioli was added aad stirred lor i.0 rftia. The reaction was filtered over eclite and washed wtjft EtOAc. The filtrate was Heiittaiteed with NaHCOj, extracted with EtOAc (3 X i SO raL) and CftCij (2 X 100 rot), dried over ?¾ §<>. · !, filtered aad coiieeRtrated. The residue was parilied over silica gel (160% EtOAc

16} to 5% a oni&ied MeOH m C¾C¾) to afford .3-(5 y 6,7 J-†etrahydroqu!Tioila-S- xy>pyr!dm-2- atnine (0.642 g, 2.66 mrnoL ' 36. ί % yield) as light brts solid.

Step C: 3-(S,6,?.8-Te?:ral>ydroqtii:i5Olift-5-yi x ;)pyridm-2-amiae. (0.642 g, 2i>6 mmol) was dissolved ift acetic acid (20 i»L). Br> (0. S 3 ml, 2,66 minor) was added and she reaction siiffed at T for Ϊ0 raia. Water was added a»d the reaction was neutralized with K>€i¾. The mixture was extracted with EtOAc, dried over ¾$(¾, t!ltered aad eo eentrated, The residue was purified Over silica el (0 to 3% ammemated MeOH hi EtOAc) to sflbrd .S-feroMO-S-CS/jJ J-tetr5diydroqoiao!irs-5- y!oxy} yridiis-2-aisirie (0.723 g, 2.15 mriioi, 8(1.6 % yield) as yellow solid.

e t m 50

Step A: A saJii!ioM of 5¾omo-3-(2-mc{ yl{ >T}dis-. ¾s. }p> id!s-2-3B»ae {.LO g, 3.57 :mi»o!) m dioxaiie a»L) and tBuGH (24 mL) as treated wish di-iert--hi.ify! d.icaibonate (2.3 g, 10»? raiHol) and heated to 65 "C overnight More g, 10.-7 maid) was added nd ' healed overnight More d«-ieft¾tty! diearbortate (2.34 g, 10.7 rorool > was added and siiffed for 3 days, Tte mixture was cooled, paradorted between EtOAc. and queous aHCC¾ > washed wish 0. H NaOlt dried over N,¾.S0. F > filtered »Β4 eoacentrated. The residue was purified o er silica gel (i;.i E OAe id bexaiies) to affi»d me Us-BbC product { L53 g, 3. i 9 t iraoT 89.2 % yieid).

Step B: The bis-Bctc product f m the previous reaction. ( ! .5 g, 3. 12 msaoi) was dissolved at dioxaue (30 ird,), Xaniphos (0.090 g, 0.156 Hanoi Ϊ and :KH¾l- -lsO JiOpyipFO ai)-2-a» !ae ί 1.0? ml 6,2 mA) were added aad the reaction bubbled thouglt with N for 5 mitt. Μ ^ (0,0? } 5 g, 0.0?gi m al) were added am! ihe eacitij was pluaged into a 95 *€ oil baiu aad stirred ' Uiider M ; for 1 Is. The reaction was cooled, to R " X\ fUt¾red though Celiie and coventrated. Hie residue was purified over sslica i {2: 1 Ei Ac hi hexanes} to. affor raethyS.

ylilwrjjipropsuoaie (1 .6 g, 3.08 mrnol 98.6 ¾ yield) as a» .amber oil

mJa. IM Potassium 2-meihyljsropaii~2«oiale i» THF (9.24 nil, 9.24 mmoi) was added sad ta reaetiea was stirred for 30 seconds, i -Bromo-3-ineihoxyprcp.¾iJe (0,435 ml, 3.70 maid) was added and the feactioR stirred, at RT for i h, queuched with aqueous Hi-LCT extracted with. EtOAc, dried over Hib 0 4 , Ijstered ad ermeemrated. Use residue was purified over siiica gel (75% EtOAe m hexaues) to afford teri-bmyi 5-(3-meilwxyprepyit¾ (700 tag, 1,73 raiuol 56, S % yield) as aa oil

Step 0; teri- ' Burvi 3- 3e:rie0H5 p op hh o s- "i2»r«ed

ylcaibaamte (700 tug. ί .73 amiolj was dissolved its C!TCij (20 t«L) and a (idle MeOH { I ,uiL) was added, 4 ' N HQ la dioxaoe (8r«L) was added. After 4 the reactloa was coaeeiiftated to remove saost HQ, pamtioaed between saturated aqueous NaHC0 5 aad C¾t¾, dried over : a>SC0„ iiliered aad coaceu rsted. The residue was purified over ssiiea gel (5 to 10% MeOH is. EtOAc) to afford 5-(3- m.efto yp o yIiMo)-3^me^ (370 mg, L2 i ruaio!, 70,2 % yield) as a white soiiri. t!Oti SI

3-Fl«orodihydm.2H-pyma-4(3H)-oae (1.0 g, 8.4? SMUO!} was placed l« THF (J5utL) aad cooled to -78 . . L-selectri4e i» THF (IM, 9.31 ml, 931 ntmo ' l} was added dfopsvise, arid the reaction was stirred for 20 rain. MeOH: (1.03 ml, 25.4 Uisaol) arid NaOH (25.4 ml 25. msaol) were added, and the reaction was stirred at RT for 30 ts . Pla ed .reaction on ice bath owed by addition of H 2 0 (2 ml 42.3 mU dropwise and the reaction was stirred for 30 raia, Briae (24 mL) was added, and the reaction was extracted witli EtOAe (;2X50SBL). The organic fraction was separated, dried over MgSC , i commimted to give fee -crude material, which was pari iied by sili a chroiaatogrspby (5:1 to 3 : 1 CHsCJ^EtOAc to give (3S R)^-a«oioietrahydr -2H- >^a«- ~o.M " .125 rag, 12.3 % yield) s a clear oii,

Step A: Dissolved di)s:ydm-2Hi?yr3S-4( H)-oftc (2,5 g, 24.9? mmo\) sxid H .PA (4.344 ml 24.97 rmnol) in 2¾}L ΤΒί- ' HI via! iti stirbar aside!: ¾. Cooled to 0 "C and added .IDA ( 1X13 ml, 27.47 mmoSj and stirred for 30 rain Added Sodossethaoe (233? ml, 37.46 mmoii) and stirred it* an. ice bath allowing the ice birth to gradua ' Uy warns to RT ©-« its own. After 16 % site mixture was dilated with 25 nil hexanes with stwrittg. This mixture was added to a 10% silica column and ehtfed with EtjO.. This was coacenifated to provide 3 taethyia¾ dro-2H.pyf¾«-4(3H ene ( , g ; 35% pyre). litis material as used at the next reaeiioa without airy further puriiicarioji.

Sieg B; 3- ethyIdi.hydfo-2H-py5:;m-4{3H)-oae (4.0 g, J3.0 rml 35¾> was placed m Tiff (ilmh) and cooled to -7* »C. L-seiee-tride in IHF (1 M, 23.3 ml 23,3 mml) was added drop tse, said tie reaction was stirred for 20 aria. eOH ( 5..5H ml 38.9 mmoi) and NaOH (38.9 ml 38.9 matof) were added, and (he reaction was stirred at IT for 30 am Placed reaction, on ice hath followed by addit n afi¾Oj (4.4.1 ml 64.8 nioi) dropwise and the reaction was stirred for 30 mm. Brine (24taL) was added, aad the reaction was extracted with EtGAC (2XS0 ,). Concentrated in vacao -until the crude mixture weiglad 2 Jig, Purified on silica gel usiag a gradient from pare Cl-lCl to 30% EtOAe/Ce ; C.½ silica gel to afford i3S.4R)-3^BeiIiyS:teaa ydi-o-2H-pyra:n-4-o) ffiOfeog, 5. l /a iiOk 9M%) as a clear oil. e tion 53

Os-3-gthvj|etra|jvd

Sieo A: D}iiY K5- H-pyras- (3H)- ue (2,5 , 25.0 mmol) and Η ΡΛ (4.34 ml. 25,0 aanoJ) were dissolved irt 25 ml, dry THF is via! with a stir bar wider Nj, Cooled to 0 °C mi added IDA (10.2 m 32.5 mmo!) and stirred 30 min. Added .iodoethaae (5,84 , 37,5 mmel) and stirred ice bads all»wmg d:¾e ice bath to gradually warns on lis own overnight Tae mixmre was diluted with 5(h«L hexarses and added to a !OOg silica column and eltrted with efher. Tills mixture was concentrated to provide 3~et y!di!rydro-2HiJyras- (5.H:)- He (5 0i»g. 2.93n.ii»ol) as a clear oil. This material was used m the next reaction w thout any further purification.

Step .8: 3-HS¾y!di¾:ydro-2e-pyrati-~4(3H)-oae (0.5 g, 2,93 mwsl was placed in THF (4 «L> aad cooled to -78 °C, L-seiecvride in THF (.1 M > 4.10 ml, 4.10 mmol.) was added drap ise. ; a ad (fee reaction was stirred foi.20 r in, MeOH {0,256 ml, 8.78 mmol) and NaOH (8.78 ml. 8.78 mmol) were added, and the re et irwas warmed to T with stirring over 20 ηίϊα, Reaction was placed ' back OS see feath, thm ¾{¾. (0.995 tni. ! 4,6 mmol) was carefully added dropwise aad me reaction was stirred for 30 mm. Brine iSrsL) was tlteri added, and the e ction was extracted with EtOAfi (2X1 SniL), Concentrated ia vacuo aad puriiied oa silica gel .el itiag with 250mL 25% EiOAe/aexanes, tfaea 25ftt&L 50% EtOAc/hexaries, Concetittated sad placed en Srigii vacatart for 20 ana to obtain (3S,4R)- 3.e hetrai5:ydro-2H--pyrait-4-oi (300 m$, 7H$ % yield) as a clear oil. e tion 54

.1 -Eiliyi- 5. -pyntzol-5-oS (5.00 g, 44,6 mmol) was dissolved in D F {49.5 ml) and CsCO; (17.4 g, 53.5 mmol) was added and the slurry w s stirred for 20 min. To die slurry was added 5- bm!«o-2-e]iloro-3-ii«ot ' opjrsdiPc (938 g, 44.6 mmol) and die slurry was S Sirred pyemigh Another 92)0 g ofCsCOj ( i .80 eq toted) was added and die reaction was heated to 60 C and stirred for 4,5 h. The reaction was ihm diluted with water (200 mL) arid hh mixture was extracted with EtOAc (2 x 400 ml). The .com ined organic layers were ash with water (1 x.300 mL), IK Li€l soiaiion ( I x 300 ml.) and rine Π x 200 i&L) and dried, o er g$<¾. The vf«dc was purified over si ica gfel (O to 70% EtOAc : hexaaes} so give 5-bromo-2 hloro-!H(l-ethyl- 1 H-p ra20i-5 d)ax py idine (9.00 g, 29.7 mmol 66.7% yield) as a white solid. Ή R t MH¾ SQ-d «5 ppra 8.48 0. H, d, -2.2 H¾, $.01 (I H, ;;: 2.2 ttz), ?.4i {1 H, d, « 2,2 Ttto. 5.S? (1 H, d, * > 22 Hz), 4.05 (2 H, q, -7,2 ' Hz), 1.33 (3 It L -7.2 H2i.it. Mass spectrum (ESI) m/x ····= 301,9, 303.9, 305. S (M÷H).

6 ίίθίϊ ¾>»

5-B¾¾m -2-ciil0ro-3-((i -ei¾yl- !. - yfa¾ol.-5- l) xy) > r 0iae (773 mg, 2.55 mmol), pe3ii- ~ ya-i-o! (0.236 mi, 2.55 jnsaol) and NF¾ (1 ,42 ml 10.2 mmol) were added to DMF (3.5 ml). CM (15.0 rag, 0.077 mmoS.) and A-Piios (20.0 mg, 0.077 mmol) were then added under nitrogen. The reacOoa was !teated to 80 °C aod stirred i:br 90 -ram. The mixture was cooled arid d¾ied.wiih EtOAc (200 mh). The mixmre was extracted witlt 2K HC! solution ( I s 50 mi,), water (1 s 50 tnL), 1M LiCl .solution (1 x 50 ml) and brine 0 x. 50 raL}. The organic layer was dried over MgS(¾. filtered, and coijcetrirated under reduced pressure. The esidue wax then puriiied ove silica gel (15 to 90% EtOAc : lscxaa.es) to give 5-(6 i0?¾-5-((i -ethyl- 1 ^yi¾«ol-5»yl)o.x.y)pyridt»-3-yj)peiit-4-yn- 1 -ol (545 iHg, Ϊ .78.mtao.1, 69J% yield). Ή R. (400 MHa, SO~d 6 ) a ppm i ( I. H, d, 2. Hx) ; 7.65 (i ii d, =-2.0 H¾ 7.40 C I H, d, -2.0 }¾}, 5,83 {I H, d, ===2,0 Hz), 4,51 { $ ) '· , t, =-5,2 Hz} ; 4.04 (2 Pi, tj, -7,2 Hz , 3.49 (2 B, q, « 6.1 H¾. 2.46 - 2.50 (2 H, m), 1.63 - 1.77 (2 H, m% 1.32 (3 H, i, -7, !fc). Mass spectrum. (ESI) m z ~ 306.0 (M+M).

Following me procedure in Preparation 55, die .following co npou a¾ prepared: e turn 57

?-(6-Ciilor - -i{ i -et yl-I -pyns/ol^5-yl xy)pyrk]ift-3«y!)peai-4«ya- 1 -ol (220 mg, 0.720 His:»oi) was dissolved m TH.P (7 snj) and cooled to *C. NaH (60% dispcrsioa) 02,0 tag, 0.79 aimaf was added .and the mlxiuic was stirred at 0 :' C for .15 mill. Methyl iodide (0.049 ml 0 ' .? rmiio! t was added and he ' resufung solution was wanrsed slowly to RT over .5.5 k The reaction wa quenched with water and extracted with EtOAe (2 x 75 -ruL). The combined organic layers were washed with brine (i x 30 nit) and dried over MgSO*. The crude was purified over silica gel (40 ιο 100% EiOAc ; hexanes) to give 2-eS:dom~3-({l-ejfeyi- i -pyr8¾el « 5-yf)Qxy)-5 5-ffie ho^ypet«.-l-y¾-l-yi>p ^dit® (99 mg, 0,31 ironot 43% yield). ¾ M {400 Wfe, C € ' / ) 6 ppm 8.20 (1 H, d, -2.0 Hz), 7.42 {{ IS, d 5 « 2.2 Hz), 7.36 ( I H, d, -2.0 H¾), 5.66 (1 H s d. -2.2 H¾ 4.09 (2 H, ¾ -7.2· Hz), .3.4? (2 R -6.2 3 « 3 ii. ·>>. 2.49 (2 li, s; 7, : i }fe) ( ί .79 - L9? {2 H. m% 1.43 {3 !. t s ^7.2 Hz). Mass spectrum (ES!) toht 320.0

Following the procedure in .Preparation 5?, the following compound was prepared:

Preparatios | Structur I N me j Data

m e

Step A: 95% NaH (3.65 & Ϊ 4 tmml) was dissolved in DM ( 100 tut) and 2-metb ?pyridm- 3-oi (15.0 g.. 137 romel) was slowly added and stirred at RT ier 1 k 2- hloro-4-n.iif0pyrkI¾e (22.9 g, 144 TOKi i) was added aad stirred for 3 Is at RT. The reacticti was poured iato water and- extracted wii!i EtOAe i iL washed with water, dried, over N¾SO< t filtered and concentrated to ailbrd 3-(2- d^or»pyrid;r 4-ylaxy)-2-medwIpyridii>e (30 g, 136 mmol, .98.9 % yield) as yellow solid.

Step B: 3 2-CS.dQropyridin.-4-yioxY}-2-.nKriry5pyridf.ns (30 g, L35 mmoi), tert-butyl carbamate (39.8 g, 33 mm©l) arid K; 5 PO.i (34.6.g, 163 mraol) were dissolved in toiueae (600.tat.} arid degassed with J½, Pdi ba)* (7.8 ί g, i 3,6 mjsol) wss adde and the reaaioa was further de assed wiih j. Degassed water ( 150 wL) was added and the feaciioa heated at -90 *C oversight The reaction was cooled, and fKtttitkxoed between water nd EtOAc, extracte wiiii EtOAc (4 x 0.5 L), dried over M ^SO filtered aad coriceiitrated. The -residue was purified ove silica gel (25 to Ϊ 00% EtOAe is hexa ses} to afford tert- atyl 4-(2-methyip rid-i¾- -yioxy^ (27 g, 66% yield). 89.60 mmoi) was dissolved m C¾0> (250 t»L) and TEA (150 A was added ¾ the reaction, stirred at RT overnight. The readies as coacejifra ed and partitioned between. EtOAc and aqueous NafclCOj. dried over N 2 SO. ( , tittered and concentrated. The residue was punrled over silica gel (SO to 190% -EtOAc in exaries followed by 10% a nioinated MeOH in EtOAc) to afford 4-(2-raetJ:¾yipyri.dii 3- io:xy}pyrtdt¾-2-a«M:»e (13.39 g, 60.1.0 rornol, 73.77 % yield) as off white solid. Step Ώ: 4 2- e?:hylpytidin-3^4osyjpyridjn-2-amiae (3.0 g„ 1.4.9 m o\) was dissolved, its HOAc (50 :»iL}, Bs¾ (0.764 ml, !4,9 tmaot) was added slowly and surfed si RT for SO mm. Water {.1 0 mL) was added, arid neutralized HOAc using saturated soiirtios ofMaHCO ? . The mixture was extracted with EiO Ac, dried over Na 2 SOi, filtered and eorseefitraied. The residue was purified o er silica gel ( 100% EtOAc) to afford 5-im5mo«4-(2-metirl ^ (2.74 , 9.78 iJiatol, 65,6 % yields as white solid.

Ste E: 5- f n.ie^2 « ateth> idia- 4o ) > idia-2-a»«»e (Km nig, 0357 aaao!) was dissolved fa THF (3 mL) and pyridine ( MA μΐ, 1 ,07 « S aad 4-iiidop enyl carb noeh!orsdate (144 rag, 0.714 mmQl) were added arid stirred at RT, After 3 h, i¾G ; as added (3 Λ), mor 4- o.ilmphstryl carfeonochloridate was added asd die rsactkm was stirred ai. IT, After 2 mors h, : 33% raethaaaniiije in EtOM (Wr μΤ 7.14 roroel) was added and stirred ai RT pverai fat lite reaction was par tioaed beHveen water and CH 2 C¾ extracted (x2), dried over a?$Q.-s, Oltered and eoacesfcaSed. The residue was purified over silica gel (0 to 2% MeOH Ed) Ac) to afford l-(5-broH!o-4-(2- oted¾yIpyridi«~3-yioxy}pyridtn-2-yi)~3-n¾ij:ryk-ea ( .i rag, 0.267 mmol, 74,9 % yield) as a while solid. Mass Speetraffi (apci) xafx :: ÷ 337,0, 339.0 ( -s-H).

Foliciwirig: ihe procedure in Example 1. the fofto iag compound was prepared:

i« 3

MS-Br0rao- -{2 ; 6 hilu0o er^^ (58 rag, 0.140 aimol) and

CsjCOj ( 136 ing, 0, 19 mmel} were dissolved is DMF (1 ,5 ) a«d water (0.15 mL) a purged with j. ^gwy!^- t» bicycto(3; i.l»OHSHe (M μΐ, 0,419 smxtt) and PdC½(dppl) CH><¾ ( I L4 rug, «, 140 rorooi) Were added arid she reaction was heated to 80 C C for 45 mm. The reaction was

m cooled to ST, partitioned betweea EtOAc aad ater, washed with brine, dried over N¾SO < t, filtered mid cosiccHixsied a:nd purified over silica gel. (80% BfOAe m hexsttes) So aifofd I - ' S- cwxyM-iS-,.^- difl«wopbjoesy)pyfidm-2- l)-.-mc't¾yU}rea (34.2 tng, 0.0926 rnxrni, 663 % yield) as a white solid. Mass specinsm ( pci) ο¾¾ « 370.1 ( - fl). m e 4

HS"Brora«-4 2,6- ii¾0rof>ta (50 rag, (U40 tamd!) and 6- aieth lpyndin-S- lbwomc acid <3£j .2 rag, 0.279 mmoi) were dissolved in MeCX¾.€i¾OMe (2 o:¾L) and 2M Ni COj (209 u.i 0,419 mmoi) was added and the reaeiioa bubbled with ftitrogea for 5 aria. PdP:Plt : ;).:: G2.3 m , 0.0279 lamol) was added and the re&eiioa heated to 75 °€ overnight-. The reaction was cooled to RT, p.art ioned between ¾¾er and EtOAc, dried over !¾SOs, filtered aad eoaceMfiiied. The residue was purified over silica, gel (2% eOH i» EtGAc) to afibid crude roduct The residue was diss lved, in€ ' !- €¾. i M HCS is EtjO (200 uL) was added, aad. co:neearated The

taea tlleed to afford K4-{2,6-di:flii rop ^ ^^^

hydrochloride- (25.9 rag.0,0637 mtaol, 45.6 % yield) as a while solid. Mass speQutio (apci) m/z ™:

S 5

.i-t¾etbv1-3-{4-{2-:mefevtovTidia-3-yl ytoYridia-2-viKsrea

1.70 Step A; aB (I AY? g s 42 J mmol) was dissolved in DMF (25 L) and 3-hyd:roxy-2- aieihyipyiicSiiie (4.40 g, 40,3 mmol} as dded slowly and stirred fot 1 k 2-CMero-4-!iiiropyridiiie {6,7 i g, 42.3 tnmo!) was added and die reaction was stirred, " The. reaction was parfctiioaed between water mid EtOAc, washed wish water (1,5 L). dried o er ibSO.;, .-filtered aad concentrated ¾o afford 2 iikro -{2-raeU¾yI> r mH'tex )pyrid:me . g f S> ,9% yield) as a yellow solid.

1,13 »a« l, 1 -ttteihyuieif

(0,101 g, 36 tafool), s! ¾POi( .36! g y 1.70 comb ied I» 2 mi of DME and sparged with j for 5 « before Pdj¾dba , ¾ {0.0519 g, 0.05S6 ramol) and 5-{di--{eil-- u¾y!phosplfno)-r,3\5 ! - iri tienyl- I'H-l '-bipyra^oie (0.113 0.227 rasoi} ere added and 1fte reaction was agaiii sparged ith ' ? for 5 in before was se led arid heated to 90 for 3 days. The reseter was cooled and diluted with CH-Cij (75 xxiL) an filtered. The fdhate was conciliate and purified over silica gel n00¾ EtOAc to .1 -KKithyi- {4~(2-metriyipym^ {0.142 g.0.550 mx i.

48.5 % yield). Mass spectrum, (apei) m<¾ ~ : 259.1 (M.-H ).

Following rate procedure rat Example 5 , the following compounds were prepared using ett S^dNet^ti lph^sphiBo^i^S^S'-t ipheR i- Π 1- S ^'-bipyraxote or 1 '~bmaphthyl-2-yidi-teri- htn S.phospliiae as the iigand in Step .8:

( R )- 1 -methyl -3-(4-{ ,6, 7β 4eii ahyd¾ ) *rea |S)-.j -racily

S - ci yliireii (Ί . ( )? g, 14.4 ακηοΐ), K¾PO, !; (3:05 g, 14.4 mn¾>i), }„ P-biHagh hyl-2- ldi-ten- 'butylphesphine (0,38 g., 0,959 rarooi), and Ι ½!ά1?; > (0,439 g, 0.479 mmo!) were com ined i» 18.raL of DME, sparged ' witl ' i At for- 10 nrfn, a¾d complexo! for I h a 45 °C before 5-(2-c toi " opyxid3»-4- lox i-S ^ /.S-ietr Sr iSrOiju iioline (2.5 g, <>,59 mmoi wiss added gir the reac oii was again sfjaigeci with At lor 5 mm attd then, sealed aad coatmaed at 90 ,? C overnight The reactor was diluted with 200 mL «1Ί : ! CH3Ci :! ;EtOA wuh 20 mL of si , sonicated, stiricd for 1 rain, filtered, and c sceiitesed. The residue was purified ever silica gel (¾0% to 100% EtOAc hi Q¾C¾ to 3% MeOH in C¾€1:;> to aftbrd an impure material The residue was dissolved in CMiC i 15 mi.) a¾d diluted wi h 65 mL of EbO Hexaaes (20 mL) were added aad the solution was somcsted for 20 mm and the resuitam solids were itlieredaad dried to afford iace«.ttc. trmteriai The faceituc materia ' ! was separated by ebtrad cJtrosrjatograph to afford both; coaoricnaers (Column: ΟίΨί 20mm X 250m.ta, f Sow Rate:

i.73 65mL/min, 10% EtOH in mp critk i C<¾). Mass spectrum (apex) m¾ - 239.1 ( *H) for the s itiug peak and mv. - 299,0 i -H> for > \ K seeotid eiutittg pak. m &¥)

Step A: i- e l«re (0,584 g, 7.S8 mmol}, K}PC¾ (.2, 1 g, 9.46 mmoi), I.i'-biaapluhyl-S- yld>4s«- ¾{*ip as bM>c (0,25 J g > 0.65 ! mxmix P¾(dba) ? (0289 g.0.3 IS «a«o}) wee combiised aad the vessel was evacuated and backfilled wth Ar before 6 mL of DMB wears added and (lie reaction was Sparged for 1 S mm before $¾e teaeticm was sealed and then stirred at 45 *C for ewre h.2-€h¼ro-4- oiiropyridiae ( } .00 g, 6.31 aasxoiji was added rid tbe reaction.- was sparged for 5 ia. wills Ar before the reaction was sealed and heated TO 90 "C overnight T e reaction was diluted with I : I

B0Ae:CHit¾ (150 inL) and 20 ml ofMcOH and then sonicated for 5 rain and S!ie:red. The filtrate was concentrated it» vacuo aad the residue was purified over silica gel (25% EiOAc in C*¾C¾) fo afford ]-raethyS-3-( -nitopyrid :i-2-yi)«£¾a (0,813 ¾.4,14 niraoL 65.7 ¾ yield) as a yeilow-oraage solid.

Step : in 2 nit of DMF were combined 2-ethylpyridin-3-oi (0.0 2 g, 0,765 ramo.1) md NaM (0.0506 g, 0.765 xnmof). This mixsure was stirred for S mia at RT, lire reactioa was cooled to 0 °C tfaea i -;m«iJ:iy 3-( *«! iji5yts.di: (().150 g, 0,765 mmoi) was added and the reaction was stirred at 70 X .overnight. The reacdoR was slowly ad ed to 40 mL of water with stiring at RT. The ■aqueous layer was sattrrased wash solid a l asd ifee» extracted with EtOA.c (2:xS0 ml.}, dried over MgB<¾, mtere , aiid co.nce»»ated. The residue was purified o ver silica get i : 1 EiQAc:Cf¾C ) to I - ( -(2-eihyipyri n 3-ylax^ ^ ^ 0,279 raraoi 36.5 % yield). Mass specrin, (apci) mh ;:: 2734 (Μ·*-Η)

Following the procedure to Exam le 19, the following; compoun s ere prepared:

fcsaraple Simetore ! Name I Data

I ?5

1

at.4 1: C ove-raignt mid i m at T lor 6 h. ater (150 mL) and. saturated sHCOj (50 r«L) was added ■and tiie solids thai formed were collected via vacuum filtration, washed wit Etj»0 (50 mL>, sad dried in a vacuom oven toatlbsd l-i5~bromo-4 qm:fiolm- -ylONy^ (1.18 g, .3.16 mmo,75.0 % yield). Mass spectrum (apci) oft 52 372.9, 374.9 (M-rH).

Foilowiag the procedure j« Example 56. rise lo iog compounds ee prepared:

I so

M e 69

etfivl -j3-mcjhyM

Step A: la 35 ml. o.fOMF were corabiaed cjtdt«3iir»-S-of. (5.0 g s 34.4 mm©}) and KaH ( ί .45 g. 36.2 xmt) id stirred at. RT for 1.5 k before Che reactioa was cooled io 0 aad ei y! 4,6* dkhiomnieoiiHate (7M g, 34.4 ram&l) was added siesvly. The readiest was stirred at 0 °C for 4.li and warmed to RT overnight T ie ieactiem was diluted with 1 ::1 saturated Nal C0 3 : water (306 roLs and extracted wii!s BrOAe (3x250 t«L}. The combined orgarsles were washed with water (200 ml), brine (200 mL), dried over gSO, : , filtered, and concentrated. The residue was purified over silica gel (Ϊ0 % EtGAs in Cf¾CU} to ' οΐύ a 10; 1 mm&tre ethyl 6-€S)]o?o- -(qt»ii0lm-5-yIox }nico!:iJiii†e (¾09 g, 23,8 ( smoL 69.0 % yield) gnd ethyl hloio- { K asBOia-5- }os.y)ni«ottftai«.

Step !-Mcdtytum {0.282 g, 18» mmo!), ,ΡΟ,; (0.S69 g,

yldke«-b ' utyipfeosphme <Ό.121. g, 0.304 inmoS}, a»ri Pd¾{dba>< (0.13 g, 0.1.52 t?¾«oi) were combined ta 5 i»L of DME aad sparged with Ar for 13 s . and stirred for i h at 55 *C. After feu time, ethyl 6- c oftv4^»molia-5->1osy)Bieoiitt8te (1.0 g > 104 rnmoi) as added a ad (fee s¾actl©« was Sparged with Ar for 5 tttitt before it was sealed and heated to M "C over the eekead, The reac oa was cooled and diluted with !;i Ei0Ac;CH:<CS (100 mL), sonicated, iasd, aadcoucentriSediH vacuo, Ths esidue as purified o er silica gel (75% EtGAc in. CM a C¾) to afford ethyl 6-{3-ms(i ' )yS.«reido)-4- i^¾ii¾0:lfir-5-yioxy)!iieoijnaie (0.286 g, 0.78 i rntml 25.7 % yield). Mass spe tretm tapes mfz ~M>7£

rt¾ e 79

4-m lhyl-3-i2-(3 ¾ethyl«reido)

In. mL of 1:1: MeOH:THF was dissolved ehyi. -i c .l-3 2^-n5eih iufe{fo)pT5d¾- - ytoxy.to∞te (0.200 g, 0.607 mraoi} and io ii was added 2M NaOH {1,52 m.l 3.04 mrool) at KT and this was stis red at T overnight. The reaeiiosi was concentrated, and. ifee resuming solids were then taken «p is water and pB adjusted to 3-4. The resultant solids collected via vacuum, filtration and washed wir.S¾ Et : Q. The sol id wa triturated with E¾0 a:ad solid was collected via vacuum filtratiots o afford 4-njet yl*3-(2H3-ffiC yUire:ido)pyridia acid { 150 xng, 803% yield). Mass sp tntts (apci) /z - 302,0 {M-'-H}, iolte ing the procedure in Example 70, dse folSowiug compound was prepared:

Example Stoiciitre atm- m e 2

Step A: Ethyl 6 3-med> 2i!Tey:o}^-{t n»io!m-5* lox )nicoiina{e (0.250 g, 0.682 anno!) was taken up la THE (3 rati,} d to the tesettOB was added 2M NaOH ( 1.02 ml 2.05 UHBO!) slowly. The reaction was stirred overnight. Hie eaction was concentrated a»d diluted with 2 tnL of water a»d to ihis was added co.ac. MCI imul s pM of 3-4 was readied. The solids were filtered and dried, to afford 6^!3-rae !v«-es<k>)-4^ ' ttTOlia-5-yloxy)oico{¾i.ic acid (0.242 g, 0.735 stmol.. JOS % yield).

Step 6; In I ml, of DMF were combined

•add (0.050 g, 0.15 onao!), HQST-HjO (0.011 > 0.074 rnol), tmd EDO (0.034 g, 0.1.8 mrnol) tod this was stirred ibr rata before -aie.fh xy » ¾«-!¾^hyk(hat«»s«}e (0.016 g, 0.18 xmnoh was added and the reactioa was stirred lor 4 . The reaction, wits concentrated ap pu ified over silica gel (i% MeOH in EtOAc)

yios. }!i!cella;is«ide {0.039 g, 0.095 rome-h 64 yield). Mass spectrum -(apci) a*¾ 410.0 (M-fll).

m e 74 vdrodiioride

fa { JHL of DMF were com ined 4-raehyI-H2 ?-ftJe I«reMo^ ddift- - o ) ea2.oic acid (0.025 g, 0.0 mM, HOBT-¾0 ,09 g, 0,12 mmoi), awl EDO (0 H¾ g, ( f. too x l) at RT ami sorted for ! mat before 2 ^ s«ef¾osy-N-s¾.ihylethan»iMme (0.015 g, 0.17 mmoi) was added arid Stirred for..1 h. Th« reacsioa was dihiied with water ( 10 niL) and solids crashed (mi. The reaction " was stirred for 10 m md solids ere collected via vacuum fi ratiofi and aste with mmh i water. The solids were dissolved is MeOH (1 IHL) aii llseii 4 SlCi in dksxiine was added β drops} arid ibis solution was theft coaceutrated. Tlie solid was dissolved in minimal C.¾C¾ awd to tliis was slowly added EtjO itntil solids were observed more E½Q was added (total volume 10 raL). The solids were collected via vacuum, filtration and washed wt i¾0 to o tani ' ^-(2-« hox^ l}- , Hli»ie -3- (2-(3-nie^wS.ufeido)pyridsi:i-4~yloxy)benziii9!de hydrochloride (0.016 g 5 0.039 raraoi 47 % yield). Mass spectrum (apei) z ~ 373.1 ( -s-H-HCij,

FoSIowlag the procedure i» Example 74, tlie lowiftg eompooffds were prepared:

Mass

spectrum apd ) m/z : -

{4imethvlaa«»o tethv I 464.0, 466.0

>N,4- · H-.'B€S; diroethylbeftzaniide

dliv roehlonde ro · 78

I-(4-C2,6-cji:fl«oropi¾eae^ )-5-( y mldj

I ^ « 8mmo^^2,C 3inuoropbmox ) idav-2 « ! jh3-»*ei¾ tea {0.050 g, ø.14 MHSOI), pynmidisi-S-yiboroasc acid i 0,035 g, 0.2S siraol), and Κ : .;0¾ (0,21 J , 0,42 mraol) were comb-msd 2 mL of DME and sparged win* Nj. for IS nikx beiore Pd(Pi¾is {0.032 g, 0,028 mmel) was added asd the reaction was agaia sparged for 5 mia ' elore k was sealed and heated to 80 °£ overnight The n ctioa was cooled and diluted with I : ϊ Ei0Ac:CH 3 2 (50 mL) and filtered. The filtrate was concealed .aad purilfed over silica gc! (25 to 80% B ' tOAc ia (¾.¾} to afford l-(4-{2,6- g.0.034 mmoi, 24 % yield).

Mass speetmm (apei) a¾¾ - : 358.0 (M*H>.

Fo.How¾tg the procedure is Example 78, the followng eompoiisds were prepared:

Mass

9 fiuarop enoxy)-5- speeirutti

U-roeSyyi-lH- ( pei miz py zol-4- yi)pyridio~2~yl)~3~ (M+H) iHct ylwea

M ' 4-(3-chtero-2- Mass iluorophet. >xy}-5~ spectraiB (i-methyMH- fapci)»y ' z :::: pyr< o\~> 326.1 y!;pvrid!ii-2-vl)-3- (M-S-.H) i ei ylurea

Mass m difI:itoro--3- spectru rneth vph$.noxy>- (apei}m¾™ 5~{l-mefhyl B- 390,1 pyfazoi-5- (M- H) yi)pyridii:t-2-yii-3- methyiurea i-nefe!-3-(S~(f~ Mass i ttiethvi- IR-jmszoi- spectrum

5-νΙ)-4~{2Α6~ (apes) mlz ::: Efiflooj¾jAeaoxy)p 37¾.i yridi«.-2-yl)«rea (M+H)

K4-(<5-chlaro-i- Mass m ae& i"2- * 1 ,2- s ectrum dihydroquiaelift-^- iapei mlz :::: y)oxy)-5-{ 1- 439.0. 41.0 methyl- 1 H-pyraxo!- (

5 « yl)pyrid?n-2-yI

3-metbyiurea

: yUurea m « 106

Step!: Following the procedure :ia Example 56 and starting with 14 r ) A- im&thyi-l-e - (S-femmo-4 i 1 ,4- 0.422 mmoL

62.!% yield) was xymbesized.

Step2: Folow ng she procedure a Example ' ?S aod

00~] dihyd:reqoma^^ (0.050 g,CU 2 mmbl), i.-c;4- i,4- m sndhylursa (QM g s 0.013 t 27 % yield) was syBlaesixed. Mass Spectrum. (¾pei) m¾ ~ 4)92

m 107

(0.125 g, 0.335 mmoS), 1- medw)-5-(4 A5 ema»eihy}- 1 ,%2^1wateo3is-2-yi)-W-«-nid¾?.ok CO. J39 g, 0.670 mrae!.), md jCO? (0.670 mi 1.34 minor) were corah ed in 2 ml, o dioxaae and sparged with Ar for 2 n¾a before Pd(PP! ls (0.038? g : 0.0335 romol) was added The reaction was sparged for 5· mitt, sealed, and healed to 90 t overnight. To (lie reacibsr was added E•n].ed:iyl-5-(4 t 4.5 4 5-|:eu¾B;0:iy 1- , ,2- dioxabora!an~2-yi)- 1 B^md xoie (0.! 39 g, 0.670 ml), P¾i>db¾ (0.0! 53 g, 0.0! 6? mroo¾ and XFHOS (O,Oi6 g„ O.033S nmrnl) and the reaction was sparged for 5 raia fo.ib.re eiag sealed and healed to 95 "C for 2 days. The reaclioii was cooled to RT, diluted wtt¾ C:¾C! : .. aitd purified over silica gel. (5% eOH in C¾C½

l . HK^«RO¾n-5-ylox >pyrid¾ 2- i)«ri5 (0.055 g.0.140 miiio, 4}.?% yield). Mass spectrum (apei) z ~ 375.0 (M÷H).

Following the procedure in Example 107, the following compound was prepared:

m el 9

oieltryi ~(^

in 5 mL of dioxaae were combi

meffcyl rea (0,5® g s S .346 rm olj, methyl 3-mercapi opr»pa808te (0.3629 mi, 3349 tnmoJ}, DIEA (0.9334 rat 5,359 mmo!}, ftfed (0.1227 g, 0.1340 ramoi). and ¾Mj)hos (0.1 50 0.2679 mmol). This mixture was sparged wiils Ar for 15 min. before if was sealed and beared to 100 1> C ovemigfet The reaction was poured iato EiOAc (I SO mL) and water (50 nsL) arid shaken vigorously, dried over MgSO*, j¾tere& and coaceattated. The res«!tia§ residue was dried on high vaeaum arid thea triiaratcd with 2:1 : {€.¾C¾:B*0Ae:E½O so afford methyl

3-y i:tie}pri>paaoiite (0,404 g, 0.9795 mawf, 73. | { % yield) as a white solid. Mass specmtffl (apei m/z - 4 i3,d (M-f¾), following, the praeedure in Exam le 109, the folio iag coiapoiffliis were prepared usin lite appropriate starting irjiSedak:

m e!18

in 1.ml ofTB ' f was suspended

Sib:s pra ¾» i!te (0,075 g, 0.1 H xa ol) befoe Ar as bifbbied {hough l¾r I mm, ' I ' M KOtBu in IHF (0.55 mlAlSS mmtfi) was added, smd re&ciisrj ss stirred, for 30 sec before I-brorao-3- ieihoxyprypaf¾ (0,042 g, 0,27 mitt !) was a ded. Ate' 30 torn !¾e reaction was dilated wish Clf>Cl> and to it was added 0.25 m.L of eOH and all the solids were dissolved. This was purified over

yield}. Mass speciram {apci i :»¾¾ 3.9 M .( ' -i-H .

Following the procedure in Example 11 ·, the following compouads were prepared:

S p.A; Folk swin proed re In EOT .pie i ¾ ami starting with i -l^- ro; i50-4^( u5«o!is

StepB: is . ml- of T.H was suspended τ» tethyl 3~(<H2 -.tJteifeylurek So)-4-f>¾i S.BOii!-6- yloxy)p yrid in-3 -ykhi o)pmpaaoaie (0.150 g, .36- 1 rnmol) and sparged with Ar ibr 2 mi a before l p tassHstu.2-metiiylp topan-2-oiiiw to THF (1.09 ι n 1.09 mi il) was added and the spargiag was g, 0.546 aajioij wa s added in 0. S

ofTHF. ¾ !'e»c» i as complete af es: 1.5 h d as diluted wnh Cii i j <i d it iikd o er silu gel (95% EiOAc in C MjCIj) to afford \ -{5-(3-i«e! n-O-y!o xy)p ridiH-2-

3 » i&el¾yhirea (0. ! ( & .246.mmol, ?.6 % yield ). Mass spectrins (apd) sr :■; ·:: 39

e 127 In 2 ftit of TH

yUlii0)pro»aaoafe (0, 100 g, 0.242 mm l) and sparged with Af for 2 rain before IM porassi«ra 2- metJjy!pfopaa-2-oS.3te is THF (0.727 ml, 0.727 tnmol) was added atid this was eoadraied for 45 sec with sparging before 4-3netiu .x uian-2-vl raettoesuifoi rte .{ .066 g, .3-6 imao!) was added . 0.5 s«L of THF The reacOfto was {.hen scaled uader. Ar aad coi«ia«.ed at IT. A fter 4- > another. 20 m of mesylate was added in 0.25 mh of THF and l*e reaction was eontsaned at U.T overs ig!i!. The reaction was dilated with CM>€¾ (3 mL) and purified e er silica gel (90% EtOAc is. CfFCU to aiford lacemic BJ&texia!., Tlte t¾ce ic ma rial was separated by ehirai chromato a Colornrr.Oi 20ΗΗΠ X 25Qftim, Flow Rats: SSiaL/mio, 1 % cOH in supercritical C<¾). Mass spcctrini! (apci) mi?. === -4 ΐ 3. ί |Μ·Ηϊ) for rite Γ elutiiig peak aad -RV¾ 413.0 (Mt-H) for the seeottil eksti g peak:. s» e 12$

Step A: 5a 1 .0 rni, of THF was suspended rnediyl 3 6^3-mefoyKn-eid6.M-{i|uiftOlia > -6- ylos:y) yr}dm-.VyWao)propaao8ic (0,050 g, o,l2 m ol) and sparged with. AT for. { 5»i¾ be or I M potassium 2-a)s0iyiprop&n-2-oiaie m THF (036 ml 0.36 aitsxsi) was added followed by iS)-2-(2,2- diioe0 I-L3-d!osoiao-4-yi)ei!iyi 4-«ieiliiySben¾eaes«(ibaate tO.055 g, 0.1 ¾ miiso!). After 2 % ilmeadied was dihired w ' ith€¾(¾ and purified over silica gel (80% EiOAe to afford rS)- 1 - (0,042 g, 0.084 ϊίΗϊϊΰΙ 60 % yield}.

weekend. T e reaciioii was concent ated and iala-O fp hi ! mi, of MeOH aad to it was added K¾OH {0,026 ml, 0.370 ta oi) arid tfte reaction was .aga-ia concentrated to dryness. The solids were

yield). Mass specirwn {apci) m& ~ 4 Ϊ5.0 ( ^H),

Following iae procedure ia Example i.28, die following cotapound was prepared:

m e ΪΜ

1 -pac thvi -3-;{ 5-{ 2- xo- 1 ihydropyri di»-;3--yI)-4--| qui aol i rt-5 -yloxylpyf sdi rt-2-y 1 furea

l-( -Methoxy* -( ui^ (0,045 g, O. ' i 12 samci) was dissolved hi ! ml of MeCN aad to this was added TMS-Ci (β.0356 ffll, 0.280 raraol) aad Na (0,108 g, l .12 aas i) aad M& was comiased at 90 "C o ernight. The reaction was cooled sad diluted wiiii c-oaceatraied N-¾QH aad stirred for S. in before it was poured imo- a bipfcasi mixmrs of EiOAc m& saturated NaMCC The- phases were separate md dried over MgSO. ¾ filtered, and eottceritiaied. The residue was dissolved €¾€¾. widi minimal MeOH. To this was added B¼»0 and the solid was collected via vacuum Shratton an washed with E¼0 to afford i-mcta -3-(S-(2-oso- i ?-dihydropyndii^3~y!)^- ii!i¾oi!.H (0,023 g, 0.0594 m al 53,0 % yield).

Mass spectrum tape; s m-> 8S.O (M÷H), m e 131

Step A: Ii 100 JHL of DMF were eejobined 60% NaH ( .985 g, 102,1 mmel) aad qu»w}!io«5- ol {14.12 g, 97,27 miaoi) at Tmd suited for 30 am* before 2 hiori)-4-astmpyTidi«e {15,42 g, 97.27 mmoi) was added slowly a RT, The reaction v¾as stirred at RT overnight. The reaction was poured iato water (300 roL) and extracted with EtOAc {3x300 :oiL.}, The comhioed organics-wer thea washed ife IN NaOH (100.mL), water (2x100 mL% Mm (100 sVL), dried over MaSO. s , filtered, and coacetrtntted. The resulting orange cmde was suspended in. C¾Cf ( 30 niL) and this slurry was sonicated tor 5 mm before 300 nil of hexanes were added and the res ftiag suspension, was sordeated with swirling !¾r 5 mitt. The pale pink, solids were filtered md dried and the filtrate was concentrated and a second crop isolated to afford 5-(2-chlorop ridin-4-y:{oxy) 5«ino ae (2 .8 g, 93,03 mrnoL 95,54 % yield).

Step B: in ! 50 rot of 4: 1 tohx«ne:vvi«er (sparged, for 20 mm with j before addition) were combiaed 5^2 hloropyridior4-ytey . jqu-BXsl»ie (23,8 g. 92, " romol), tstt-btiiyl carbamate (16,3 g, 139 ftanot), jFO. } {54.0 g, 278 i»iaoi) > Pd : dba} 5 (4.25 g, 4.64 mtmll rid XaaiPBOS (2M g > 4.64 Hiio i) and this mixture was stir-red at ET and sparged, wii for 29 ixt-ai before the reaction was -sealed and healed to 100 °C overnight. The reaction was added to a separatory furaiei containing 500 ml. of EtOAe and the aq, was removed. The organic was diluted with 500 ml. ofC¾C½. w/ 10% MeOH and stirred for 20 mm before it was 1¾:ered though a pad of Ceine, Tlse Slira-te was eoticentrated to afford 34,5 g of crude teft-bntyl K¾ui to- >> o.x ) > i a- - {c8J¼t te, which was taken forward without further ptniflcafion. Step C: Ιδ 200 ml of€¾(.¾ was siispsnde . iert-bttfyl 4-{q«¾i0im-5-ytey:>pyridin-2- ylcarbataate (31.3 g s 92.78 ssrnol) arid cooled to 0 *C before TFA- (7 ? .48 mi 027.8 mm&\) was added, slowly. After 2 h, another 25 ml of TFA were added.. After 5.5 h, the reaction was eoRcemrated and toiueoe was added at urterviiis id help remove the TFA. 100 mL of i NaOH was added to the residue and this was stirred while a soluto of 50 w% NaOH was added via pipette until the pH was

9. 0¾C¾ 6 0 siL) -was added arid s ir ed for U mn. The Solids were Steed to afford 2,25g of product. The filtrate was washed with CITCO {x¾ dried over MgSO* filtered arid concentrated. The residue was triturated witkC¾(¾ (300 mL) id filtered to afford 1 i ,2g ofcomj^aad. The remaining filtrate as purified over silica gel (l¾ eQB m ' EtOAe w/ 0.75% N¾OH) to afford a eom iiied yield of 4^iinoiin-5-yioxy)pyridin-2~anime {11.9 g, 05% yield).

Step D: la 220 mL of 3: 1 i-buiatie! (165 mL):dtoxaae (55 mL) were combated 40q»inoIin--S- ytoxyifwridm-2-a i«e (17.88 g v 60.2» samel) an B0C3O (32.89 g, 150.7 mmo\) md this was fitted with a coadeoser aad bested to OS *C. After 3 b, the reaction was cooled and eoneeittrated to half vohsme. lie .resulting slurry was diltued with, saturated NaflCCO (500 mLj and extracted. wMt EtOAe (3x250 mL), dried Over MgSOt, filtered, aftd soReeniiated. The esidue was adsorbe onto i 50 g of siiim arsd purified o e silica gel (30% EiOAc m CFLCO) to afford, tatt-butyi 4-(qajao.iat-5- yiox-y)pyridffi-2-ylcarbainaifi ( .5 g : 67, yield),

S ep E: I 100 mL of DMF was suspended lerObtsiyi -{qt«ttO:Un-5-ytoxy pytidia-2- ylearbansate t.8.8 §, 20 n wsl) aud cooled to 0 l V. before NBS {4.6 g : 26 ffi oi) was -added ia one portion and the reaction was stirred at RT for 2 days. The ' reaction was partitioned between water (300 mL) artd EtOAe (200 j¾L) and stirred for 30 mm before the solids were littered to afford tert-butyi $^

2-yiearbamate (9.05 g, 21.00 mrnol), DiEA (1.1 4 tnl 05.08 mmoi), Pd 2 db% (0,9952 g, 1.085 mmolX and Xaatpho i 1.255 g, 2J.09 mtao!) and this was sparged with for .SO mm. before methyl 3- mercaptopmptaoate (3.520 ml 32.54 - mA) was added and the eaetiea was sparged for another 5.0 mist before if was sealed aad healed to 95 T overnight. The reaction was cooled to RT, filtered though Celue arid ciJtieentrated, The residue was purified over silica gel ( 10 to 25% EtOAe ia CHjCb) so a rd methyl :M6-{iert :uto*yca^

yfthiotproparsoate (7.7 g, 7 % yield).

lihfo)prepanoaie (3,0 g, 6.0 itnno! was dissolved ia THF (40 mL) sad ' H% bubbled though for 5 mia. I potassium 2-fne Ipropan ~oiate ta THF (20 tab 20 rorijof) -was added aad the reac iOft stirred vigorously for 30 sec, I -Ba iio>3-meihoxypropatte (0.03 ml, 7.9 tttmot) wa added and the reaction was stirred at RT ier 5 rain. TOe reaction was. ueached wills aqueous >¾0, extracted with EtOAe, dried -over N¾½$0 filtered wad concentrated. The residue w,¾s p¾?ifi over silica gel (75 i 1 0% EOAc in rsexaises) to afford tert¾«yi

yiearharaate (2.5 g, 5.7 m i> 86 % yield) as a pale yellow solid.

Step li: ierf Bsityi 3*raetho>^ pr pylt icM-^ (2.5 g, 5.66 amtoi) was dissolved t« CftCfe (30 mLj and MeOH (5 raL) and tte 4 HCi MI dimatte (5 roLi -was added and. she reaction, was stirred at RT for 2 is. More acid {{{) t»L} was added and the reaction was stored at RT overnight. TM reaction was concentrated and partitioned between EtOAc aad aqueous NaHCO ? , The maUaat solids were flHered sad dried to afTord 5-{3-methoxypropyiiliio!- 4-(q¾sisoiift-:5-y: xy}py;ridift-2-am!iie (! .15 g r 3.37 xmimi, 59.5 % yield) as a: white solid.

Step T: In I raL of CHjCfc ere combined 5-(3-iaed50syp¾xpyiiiho)-4-( «!sohi¾-5- ylosy}pyridi«-2-aiaise (0.025 g, 0.073 r»mol>, .pyridine (0.018 mi, 0.22 imnol), asd -ntropben J chlerofortn&te (0.0.12 g, 0,16 mrno!} at 0 , wanned so RT and stirred for oversight 2M Etfeaaajsise. (0.73 mi, i .5 maws) in. THF was added a»d timed at RT for 3 h. The reaction was concentrated -aria * KjCO; (0.030 g, 0.22 mmoi) was added with 2 raL of EtOH and this was stirred at RT over the weekend. The reaction was diluted with C¾C¾ and filtered. The filtrate was concentrated and purified over silica gel (75% to 90¾ EtOAc in C¾C½) to afford a erode atatetiaf. hic was purified via reverse phase chromatography (20 to 7 % ACM in water) io afford Ϊ -ettt Ϊ- 3 - (5-ΐ 3 - mei ox txs y!ihi^^ {0.009 g, 0.022 mtttoi, 30 % yield). Mass speetftnri (apes) sn/z∞ 413,1 (M t H). followin she procedure ia Exam le 1 1, the fetlowhsg comporisids were prepared:

Example Structure Name Data

] 2-metrsoxve(hvl)-3- Mass

132 (5-(3-_ ' speetnjrn

.mcii30xypropyHhio)- - (apci) fz ::::

( uinoii»-:5* ' 443,2 yioxv)j5Yridii?-2- :!)iirea (M : lit

-i2-hydro.x.vethvi)-.3- Mass

133 : x; OH 1

' (5-(3~ spcctrina metiioxypropy!&jo - (apes) HVZ ■■■■■■

00 " (q-ui.nolm~.S- 429.1

yicsxy)p Y? m-2 -y!) rea ( +H?

I -( 3-¾v&mvpropy! V3- Mass

134 ' (5-(3- spectrn.n

medi x.ypro ykhio - {apdjtrt/z™

(qmnoii«~5- 443.2 yioxy)pyridin-2-yl)iirea (M+ii)

hydrochloride

Step A: in 2 iuL ofJMF were cosibtaed NaH (60% dispersion, is oil) (0.0716 g„ 1.79 o ) g, 1,79 ΗΜ.ΪΟΙ) asd spaige with r¾

for .30 alio bsfere 2 h!o.T -»» ro yRdme (0.28 g, 1,19 mtftoi) -was adde aad ihe teactidii was co iiiaiiiJcS at RT. After 4 h, EtOAc (Ϊ ml.) and water (S ittl.} were added the reaction and stirred vigorously for 30 niia before it was poured into water (50 niL) and EiOAC (50 m.L) HI a separatoty funnel The- solids that forared were colimed via vaeun iikratioa and were- wasted with EsOAc (5 raL). The solids 009 tag) were found to be desired compot d. The organic layer was collected * The aqueous saver was extracted wsth EtOAc (50 h) and the combined orpitics were dried over MgSO^ filtered, and eoacerriraied. The residue was triturated with 5% MeOH in C¾€¾ and trie solids were collected via vacuum, fihratiert and cornbiaed w&h. the soS s from above to yield 6-(2-.cliksro jyddm- yield). Mass

Spectrum (apei) ra/x™ 323.0 (M-rST).

Step 8: In 1 niL of DMF were coiabiaed NaH (60% dispersion in oil) (0.0389 g.. 0.973 xntnoi) 57 g, 0.487 mrao ) and sparged with Nj for 35 m before dimethyl . sulfate (0,(5598 ml, 0,632 tiimei) was added EH R ' t, After I h (he teaetlOH was -complete a»d was diluted with€ ' ¾€¾ (5 iitL and diet! lostded. directly osrto silica aad. purified over silica gel elating wit 20% ETOAC la C'i¾(¾ to yield 6-{2 Siioropyridia-4~yioxy}- 5?-di«uoro-l ,4^Hne l<j«inol:t^2(lH)-one (0. ί 00 , 0.297 mraol 61 i> % yield). Mass Spccttwm

Step C: 1« J ml, of dimeiSiexyethatie were eorobiaed I -uieihy irea (0.0S30 g, 0.445 rornoi},. finely groimd ashy-drows potassium phosphate (9 J 10 g : 0.520 «Μ¾ΟΓ>,

tris(dibeMzyIideneacei: ne}dl idiaditim(0) .(0.0272 g,

h»t lpbo¾>M«e (0,0237 0,0504 i) and this was sparged for Ϊ 5 aua with ' !% before it was heated to 60 °C tor 45 mis. The reaction was cooled io HI and O~(2~cl)j0Topyridi»-4-yloxy}-5,?- difluoro-J ,4-dii¾ethy¾tdaoli«-2{ I Hi-ooe (0.100 g, 0,207 mrael) was added. The itactUm was sparged fcr 5 mm before it was sealed and heated m 90 "C, Ai r # h the reaeikm as diluted with.10%

MeQH is CE S <¾ 175 ml) nd stirred for 50 mm before if was filtered via v c um fiifraOon, The ffhrate- was cencersirated under reduced pressure purified over silica gel efoted wi¾i 2% MeO ' H m EiOAc to yield I-(4^5.J^1ifl«oro-i $ 4 iHneih ^

raethykirea (0.020 g„ 0.0660 rmno, 22,2 % yield)..Mass Spectrum (apci) m.¾= 375. i ( -KR).

Step .P: In I raL of D F were combined I -{4-{5,?-difluoro-I ^ ne& W- xo-i ,2- m o!) aud BS fQ.026 g, 0,14 itttKol} at RT-and stirred overnight. Water ( 1.0 h) was added id the reaction was vigorously stirred. The resulting solids were collected vis vacuum filtration to yied ]-(5-bromo--(5 -diiluorp- - dteetSryl-2-oxo- i ^l%droqukio^ (0.045 g, 0.099 mmol, 09 % yield). Mass Spectftufl (apci) tatjp* 453.0, 55,0 ( ' ΜΗ-Ϊ),

Step E: I» 1 ait ofdioxatie were combined Η ' ι»αϊθ^5^> ίΙβοοι·ο « >{, > 8η« ½*οχο· l,2^ihydro¾uiao!in~6-yloxy (0.0225 g, 0,0496 mmol), j-metiryl-5-

(4 > 4 > 5 > 5~f:etra:n:ietiryl-L3,2 i!05iahor0iaE-2-yl) (0,0258 g, 0,1,24 mnao!), and aqueous

K C (0.0993 ml, 0, 1.99 mmol) and this was sparged with nitrogen for 2 x x bfe Fd( Ph ? .)* (0.00574 g, 0,00496 κίκτοϊ) was added an toe reaction was sparged for another 1 rain before it was sealed aad heated to 1 0 "C. After 6 h the reaetioa was diluted with CH 5 C¾ aad loaded directly onto silica gel and eiyted with i % eOH in EtOAe w/ i %N¾0H to yi d i-(4-(S?-dff]ti0ira- ~ djmerhyl-2~0xo ,2-difcydroqu.i&0to

meihytea (MM> g, 0.0128 mrnoi, 25. S % yield). Mass Spectrum -fapci) m 455, 1 (M H), m e 137

1 -( -bt)rii:0-4-( 5 , 7- di Otroro- 1 , 3 ^4- > ^Y~ * ^*^ ~I . ¾ dro<f u hiolia-6"

Step A: in 2 mL ©C0MF were eou

2(1 BVone (0.171 g, 0.759 waiol) and NaH (6& dti≠mm\ in oi! }( .03O4 g, 0.75 moi) asd tins was sparged wi th Nj for 45 m t at RT with stiraftg before 2„5- i¾r «ttO-4 » »it! )pyiidiBe {0,21.4 g, 0.759 mmoi) was added in 1 mL oi ' DMF. The reastkm was comfcmed overnight. The xt monuag a suspension of &H (60% disperaoa in oil) {0.86 7 g, 1 ,52 mmoi) in 1 m ' L of DMF was added and this was stored for 45 mil* at RT with oitrogm sparging before dimethyl sulfate $.108 mi, 1.14 amtol) was added. After 3 h the reaction was diluted with water (20 mL) and stirred vigorously. To Site reaction as added EtOAc (50 mL) and water (30· .) nd. the :res«fjiag fjiphasie soiutioa was separated aad die aqueous was extracted with EtOAc (3x50 mL), The ot$ k portions were, eotribiaed, washed with i (50 t), dried over gSO^ filtered, and cortceotrated. The residue was purified over silica get dining with 3% EtOAc

5 s 7-difl«ore-i,3 > 4-?rinief¾yiqmi sl«i-2(lH)-<JHe (0. i 7? g, 0.373 mmoi, -49.2 % yield).

Step B; fa i rnL of dimettoitxysthaiie were c ffibiaed l-metkylurea (0.0 IS g. 0,56 ( 5 tamol), anliydrOus finely ground K ? P0 s ( ' 0.1 9 g, 0,653 mnioi), Pdvfdba); « . Ί71 g, 0.0187 ηκηο!), and Ι, Γ- topiittiy{-2-yidHm- «tyiph.osp .iae ( 0.0298 g, 0.0747 m«K>)) tmd this was sparged itb 2 for 10 mm before it was beared to 50 * C under 3¾ for I h. The reaction was cooled to RT and 6~(2 ; 5- g, 0,37? raraol) was added. The reaction* was sparged with. >. for 5 min before it was sealed and heated to 5 "C. The next morning the heat was increased to 60 4 C. After 48 ii rise reaction was diluted with C¾i¾ (5 m ' L), loaded directly OMO sihea gd and eluied with 15% EtOAc m CH£h 1% ΝΗ,ΟΗ to yield a mixture of

methyiursa and j -iS- o io^-fS -dilliJom- \ A4--riuie.hyl-2-oxo- i .2-djltydroq«itioiin-6- yios.y)|wridi:n-2-y])-¾-met!ry:iijrea.

Step C: in $»L of D were combined s mixture of 1 -( S ^^i^mwO-L^^-irirncib i^- l-{5-broino-4-(5,7-di.fl«ore~l,3,4- trimeth S-2- XO- i ,2 ii:hydia ibHo . "6-yios:y)pyri:d an (0,025? g. 0. i 44 mmoi.) ai RT overnight The next day 4 mg . of BS were added. Ate 3,5 h water (10 nil) and EtOAc {10 i«L were added and solids that resulted were coHeeied via vacuum fditatiou and dried in a vacuum oven to yield lH ¾omi)-4-{5J-dii1¾oro-i,3,4-i^

lox }pyridat-2- l)-3-aielhyl«ica ' 0X023 g, 0.0492 irnao!, 13.? % yield- over Wo steps:.} ass Spectrum (¾pci) 467,0, 469.0 (M H).

The foHevvmg ctunpou s were prepared x the same in&tttier ttsmg the appropriatel ftt ' ftctloaaiixed ii jaoS i κ pteioist

Siep A: uino!hvS-o! (39S rig, 2.74 moid} was dissolved in DM? (15 raL) a» -cooled is ice bath.60 NaH ( 110 HIS, 2.74 radio!) was added afed the resetters stirred for 10 xaia.2,4,6- TncMoropyriiiifte (500 mg, 2.74 mraol) was added a i the reaction stirred ai T ovm gii The reactio was soared into- 200 r&L water, stirred ibr 20 mm and filtered. The Sitraied was extracted with EtOAc and oe n ined wis!t the solids gad purified over silica gel (30% EtOAc in heximes) I» afford 5K2 i-dtchIofopyTidm-4-yloxy)qu<aoiiHe (SW mg, 1.99 mmoi, 72.7 % yield) m a white solid {?: ! !!·!· of pdt to xmdesired isoirien.

Step B: Following the procedure m Example 15. step A, 5-(2.6-dicl:ij0ro|)yridia-4- lqxyi uiiJoli c {560 mg, 1.92 m ol) aHbfded

methvlurea (96 log, 0.292 mh 15,2 % yield) as a whi e solid. Mass spectrum (ape?) tz - 329.0 I !-H).

Following the ptde-ednre in Example ! 40, and sing 2-brmr»- ! 6-dsili:iOi ndiPe the Ibjiowing coiTs orsRd was syatoesiKid:

m e 142

H6-€hiom-4-Cqumoii»-5-yto^ tag. 0.228 i ffisiol) was dissolved ii) DMF (2 mL) aiid Br, fl I M gt 0,228} mmoi) was added and stirred ai RT oversight. More breanae (1.1.69 μϊ, 0.228 ! asnol) was added. After I h, itrns Bt 2 (1 1.69 pi o,22Ki mmo-l) was added aisd die reaction, WHS poured into water and stirred vigorously. N&HCO ? aud iaHSOj were added to queaeh HBr a«d Br 2 . After -stirring for 20 in, she reaction was filtered and dried in vacuum, Following the procedure to Exampe 142, the following cotnpouad was syntek«d:

.: ' s¾ e 144 rocthyl roa

Step A: in dioxaue (2,0 mL) were combined H3¾omo^qt«n Ko-5-ylox )p ridiri*2- $ - 3-meiiiylurea (50 mg, 0.13 -join !}, M ic^botyldimhy^

I i ,2-<li.o ab iolaiw2-yr)-lH-p K¾? le (7Ϊ tri .0,20 aunoli, said 2M K 2 CO;i (2θί μΐ 0.40 oioiol), N 2 was bubbled into ibis mixture for 5 rain followed by addition, of Pd(Fi¾s (15 mg, 0,013 mmo). N-> was bubbled into the mi ture for another i mia before it was seated aad heated to 100 *C ov«raig¾t. Dilated reaction mixture with 10 mL CHjCI? md loaded directly onto a silica colvtsau and etuted with a gradient froia 15-40% aeetoue/CM b to obtain ΚΗΗ *^*^&^

pya:ioi~4-yl)-4-{^ B^ fiig.0.067 mol t 50% pure., 50% yield). Mass spectrurn (apc-i) mfz » 519.2 (M.- H)

StepB: Dissolved

£quiao:tia-5-yloxy^ 0.067 mmol) fi.5iii : L eOi'i added I 2 HG

( !. \ μΐ, 0. ! 3 tamo!) and. stirred at RT overnight. Treated mixture with 3 h saturated aHCOj I iiowed by extraction with.3m.L <¾(¾,. The or&mic layer was l ade to a silica column and efeed first with 75:23:2 C¾¾ :ace.iOne:¾ ihm with 44:44; !0:2 CHjC :8ceime eOH:Ei ? to obi i -45-1 ! -(2-liyds-oxyeihyS}- ! H-pysmo - i.)-4-(qdnoi:itt~5-yiox>\ipy^ ( mg,

0.020 ioHiol, 29 % yield) as a taa solid. Mass spectru-n-tapd) mi?. ::; 40-52 (M-M-i). m c 1.45

: H4-(2. : 6-dif1uom^

mechyterea

Step A: fa i mL ©fdloxaoe ere combined H2 im-but di ethyl

tc{faro«iiyl-l. y ?,2^io atoelaft-2->)-m-p taj;oie (0.148 g, 0.49 mmo!). i -(5-brai«o-4-<2.6- dii »ori{5be»OK p dd(i:t-2-yI}- -B:id¾ .i5-ca «0. H)0 , 0.279 msnol), 2M K 2 C0 5 (0.419 sit flu¾8 .mmo) and Pd(PP¾¾ (0,0323 g, 0.0279 nimol) arid Otis was sparged wiit Nj ftr 10 sun before it was sealed and heated to 500 X overnight After thai time the reaction was dilated widt C¾C1 ; . and ihe¾ loaded directly onto silica and purified b chromatography wOh ί 5% acetone in. CHjGj. Desired fractions were combined, eoacentrai in m o, mi. dried oo high- vacaum to yied I -{5-( 1 ~{2-ί terabit iy dimeiii isil ί oxvei v 1)- Ϊ H-py ra¾oI~4-yJ >-4-C2 , iuoro bedox }p)?rid:i ft- 2 -y:I )- -tneli y litre a (0.073 g, 0.130 rao 46.7 % yield).

pyrazoi-4-yis-4-(2 > S-diiltiorophenoxy)pyn (0.073 g, 0J4 nsoi) and I2 HCI

(OJ024 mi, 0.29 mmo!) and stirred overnight. The reaction was complete after that time and to it was added solid aHCOx ( 100 mg). This was stirred. -overnight bei½¾ 20 niL of CH 2 C¾ were added and the reaction was filtered. The rinse was concentrated in vetato and then purified by >mmatography with 30% aceresse in O¾C0. with 0.5% NHsOM. Product containing fractions were combined, eoncsntrased -warn, and dried on nigh vacoum eld j -i H ,¾~difl«.oropfeer! x 5-'i l -i^- irydmx eth lHH-pyra^ (0.027 g, -QM m ol 47 yield). Mass speetnfiri. ( pci) mk 390.1 (M÷H). m e 146

. roethyl i-ea

$tq> A: in I h ( dioxaarwere combined 1·¾.ικ; 1-5>( Α5,5-½»35η¾% ΐ,3

(3 θΧ3ίχ)Γθ½»-2- Ί}-1Η-ρ Γί!2· 5« (0,067 g t 0.32 imnol), (-(5- r mo- -S¾iCiro dd(ft-2-yl 3- raedwStirea (0.040 g, 0.16 mmoi), and 2M ¾C0. 5 (0,32 mi, 0,65 mmol) asd this was sparged with ; for 3 mm before ?d(P.Ph.i% (0.019 a, 0.0.10 mmol) was added. The reactio was sparged for another 2 min before it was sealed and heated to 50 *C for 2 h, Co«¾>o«iid was observed after that th and ihe reaction was beared to 65 «C aad. faster eonversloa was cleaaly observed after 3 &. The reaction was -continued, oversight. The reaction was diSiiied with€%C and eimmaiogmp ed with 20% acetone in Ci¾Ci 2 , Product comainhig . ractions were combined, cenceatfated in e ), md dried on high vacuum 10 yield. H4-:0«oro-5 l -ί»δ ^ (0,020 g, 0,076 inaol, 47 % yield).

Step .8: to 1 BiL of DM A were combined 5-eMoro-2-fluorophe«ei (0.013.. jal, 0. i 1 rame!), I- (4-fluor0-S-( l-meiiryi- ] iI-pyf¾¾Ol-5-yS)p (0,020 g, 0.080 ΒΗΪΙΟΙΪ, arid

Cs 2 CO ? (03 ) 52 g, O.i 6 mmol} axtii \ h s beated to 80 °C oversight Heating was increased to 9 «C and coatuiued overnight, I ' bs rtOxt ittonring the reacliaa was diluted with 5 isL of water and extracted wii!i EtOAc (3x50 ml,}. The organis s were Ootribi»e& < dried over MgSOu, filtered., and removed in mem. Die crude was c!iomatogi¾p!ied with 10% acctoue In€I¾C¾ with 0.5% MH. 5 OH. esked fractions were combined, concentrated in and dried on high vacuus* to yield l.-(4-(5-chioffi-2- 03M 5 mmol, 16 % m e 147 met!iyl ea

StepAr.fe 2 tnt, of dioxiuie w

0,742) (0.046 nil, 0,27 mnmi) a«d this was sparged with. N¾ for 2. mm before P j{db h { .02 g, 0,0*3 mtftoi) a»d:XaoPHQS ( Q MS ,g, 0.027 msmi) were added aod sparged with ISO for 5 min ' before

g, 0.20 sKio!) was added atid the reaction was sparged with s for i mm before the reac oB was sealed and healed to 50 "C tor 2 h, Minima! reaction was o ' bsetved. The reaction was toed to 05 "C aad faster conversion was cleanly observed. The i«acttaa was continued overnight at 65 *C and die next morning ibe reaeiioa was diluted with Q¾(¾, loaded directly oato silica add elated with 20% acetone in.€ ' ¾<¾.. Desired itactioas were combined, eonee&Oaied in mem. and dried oa high vacuum to yield l44-.Slisora-543 t0:x -^ ^ ^ ( QM9 g,

0.003 mia l 4? % yield).

Step 8: 1B i. ml, of DMA were combined 5-cldojO-2-Siioropheaoi (0.0 J * rah 0.099 mtnoi), i- ( -¾ioro-5 5¾dro> -3-K^ (0.019 g. : 0.000 mmo!), aad

C JCOJ (0.04 g, 0.13 mmol) d this was sealed aad heated to ¾> *C. The next morning .heating was increased sllgiitiy to 90 X and eoriinied overnight The next owning the reaetloa was diluted with 5 mL of water arid extracted with EtO c {3x50 tnL). The ergardes were Cotabreed, dried ovet .gSt¾, filtered, and removed m vac . The resulting crude was padSed by chromatography with 19% aceton m C¾C¾ with 0.5% Nlt,OH. Desired S¾«iioas were combmed, eoacoiftated in vac a, and dried On high accina so yield H^S^KIofO- -fliK^^ ' teOexy^S- -hydiox ^*

tneti lb ito (0.009 g„ 0.020 stawl, 3 % yield). Mass spectrum. (apes)

IB¾ = 414.0,416,0 i e $48 i-(4-((5- : c orp-4-ey pyr

yl)-3-mctbyIiii-ea

2J0

In 0.5 xnLof DMA were combined l-(4- yd-rexy-5 l -meihyi- ί H«pTazoi-5«yl)pyridm-2^yl«

S- etbyiures {0.040 g..0,16 mtnol), 3,5-die¾Soroisosicerii)ooi!riie (0.042 g, 0.24. tni} ' i}, and ¾C<¾ (0.i)58 g.0.1 S mii!oi) sad the reaedari was sparged with for I ms«, seaies! aftd ' heated to 90 X over the weeken . The .reaction was diluted with water i5 mia and dies, extracted with EtOAc (3x75 mL). The organic* were co bine , dried over MgSO.}, filtered, aad removed in weaa. he resultkig erode was purified by chmnmtogrspiry with 10% acesoae in C¾C½ with 0.5% ¾GH. Product eosiai&mg tractions were combined, concentrated in em, d dried on high vacuus* to yield S -(4-(5-c. k>ro-4- cyaf!0pyridin-3-¥ xy}-5-(l-Kieibyi- 1 H«pyfa¾(i-5>y!)pyridit 2>yJ)-3-H5ethyl«iea (0,007 g, 0.017 xrnno f 0 % yield), ass speenim ap s) ¾ ~ 3841, 386.0 ( - H).

Fo!lowsag the procedure w Example 148, the following cosapoaads were prepared;

m e 15

III

To a solution ef fers-byfyi 4-(>-{3-3sa«i6ylui««^o)^{q«iftoKtv-5-yloxy ' )pytid:«ii-3- ylt -to ' jpiperklioe- S -carboxylase { ifJO mg, 0, 196» m l) i : S.3Ceto«e; eOH (4 mL) wit N»H€t¾ (I {».5 B¾ 0.196 !i!H!oi) at RT was added, she fet equivalent o Osoae (121 mg, 0. IM ol). Th i m was stirred for 2 k Filtered off salts aid added !OmL CHjCl;:, Washed with 3 mL of water, T¾e rgitBtcs were dried over a ; S0 4 and concerted to obtain terc-buj ! 4-(6-(3-!nesl5}dtii-eido>-4- rag, 0. i2S mmoi, 64,0 %yieid).

Mass spectrum (ape m/z 526,2 ( ÷H).

Following the procedure id Exatup ' le S 51, Site foifeviag corapoaifds were prepared:

ESS c 153

2 J ?

To. a soiudtii): of tert-fctktyl fH3-m£ibyiisreido}- qiiimiii^

ylih50}j5i eridnie-i~carbai¾iaic (!<¾} mg, 0. i 96 mmoi} in S : i acetoije:M¾OH (4 mL) wish NaHC(¾ ( 5.6.5 jag. (i.196 asa-iel at RT was added Oxoae (242 mg 5 0-392 SHSKQS). The mixture was stirred for 18 Filtered o f sails and added 1.5mL CH ::: C! : ., Washed with 4mL od water, aad dried orgames over 1%$0*. The CHjClj sokmon sai at RT for 3 h aad crystals formed. Collected cr stals which

casboxylats (21 tng, 0.039 mmH 20. ? % ield:). Mass xpecir&m (apci) tts/x * 542.2 {M÷ ' H>.

Fqile ia s e procedure in Example f 53, she foUowiiig componnd as prepared:

Jh 2 mL DMA were co.B?hiftsd q«iao.Un-5-oJ (0.026 5 0.18 ί«ί«ο¾ i-(4-.fl»0FO-2- (rifliKTem«tb l -b^yri¾i^6«>)»3 5K; uf¾a (0.04 , 0, 13 sBtnol). md K ¾ CQ 5 {0.035 g, 0,25 tnmoi). This tnbuurc was sealed .and heated to 90 "C overnight Added 4mL ater md atin:e<i for 10 mm. Filtered off recipitate- which was found So be I-a!eti)yl-3H -(qi«s:¾aSii^5~ylax5 -2- (t.riiluorom.eihy ^ ' - i yTidi.n-ii- ^ureis (35 mg, 0.079 JMBOI, 62 % yield}. Mass xpecfru (apci) mix - 440. Ϊ {M+Hj

Followin the procedure in Esaiapte 155, the fol low tag coispomids were prepared:

2i4 m e .158

H5-(€ydo¾ex-;l-^

To a .stirred solution of i- 5-brotno-3-(2,f) -difht >rophe:i!Ox Y pyri dsn-2~y i K -R& hy iur a (0, ί

0.27 ' ) t noi) and eyctehexei .-i-ylboroac ac (0J )? ·> 0.56.mmo!} in DMF (2.79 mi) was added

Pt!(F Piij),; (0.03 g, 0.028 t »οϊ) followed by C O; (0 116 g 5 0.84 mtno!). " Hie reacts on as neatec to u K) ¾ C md stirred for 161 i. Water was. added t > qifCi tea the reactiori the mixtur ; was extracts; with ElOAc, followed by est nsctksa with C%C¾. oiBiisiised organles were co c©) rsted «5 VilCl o. The u oe prod ct is purified on silica g el ehr iag with ίί-50% EtOAc iu hex; -sues to afford l-( " 5 •i y k>ik'>: · > ¾- ! · y; ; -. ! - ( 2 , 6 -di β ίίθϊ'ορΐιείίθχ y }pyik in-2-y -3»mai:ty:lareii {0.058 g .0.163 liltilOS

58 ¾· > yield). Mass spectrum (ES.I) a¾% 36* > <& t ·Κ>. Following lite proeet aire in ExartipSe 158, tfc ¾ Uo mg cojapoaads were prep tred:

21$

m e 170

To a solution of l-(5-{cyefehep(-i-c«-.l - iM 2.6-ds.0.»oro h ®xy)^^

metiykirea (0.03 , 0.035 mrrtoi) in Εϊθίί (0,35 ml) ¾¾ added MC (0.037 g 0.O ' ? 5 ffiare!). The resulting SHxmre was .stirred uader aa af:os>^hcre-ofl¾ for 24.b. The misiure was filtered chough a silica v.ci plug i d eOHcei)i!¾ie>;! in vitcito so give !-(3-c c!.o!:!egi H2^

yi}- -meii5 !8rea (0.9102 g, 0.02? unaoJ, 78 % yield). Mass spectrum (ESI) m¾ ~ 376.1 (M B). Following the procedure in Example 170, the fbltewiag.cotnpouuds were prepared:

m 174

iiuofopl^aoxy}^ { J g, 0,2-S ΗΏΙΙΟΙ) and pofassinm. meOiyluTOrpohoS e tri-au rbbomie (0.064 g < 0.31 mmof} I» THF/watfer (H>? , 3 ml) as added Cs>C0 5 {0.273 g„ 0.84 moi The reaction mixture was heated to ICQ °C for 3 days. Tie reaction was eooied to RT and water was added to quenc tbc rea tion. The mixture -was extracted wids EtOAc, followed by extraction with C¾CU. The combine orgaaies were concentrated in vacuo. The crude was paritled O silica gel ctotiHg with 0-100% MeOli in C¾CI ; ; to give ie desired .eotupotmd, which was further rectysteiltesd tea ether to af!brd H4-(2,6-diiiu rophetH y

a¾ethylt»«i (0,0042 g, 0.01 i mmsA, 4 % yield). Mass spectrum (BSI) m ?. - .179,0 (M->i ), m e 175

Step A: To a flask was added Lid (159 ni , 3.7 mtaoi) a¾d the flask was dried under high vacttom m 155 *C for 30r ia, Then Z» (269 iag, 4,32 tntnol) was added a id die flask, was dried again urtder high vacuum for 2.0 ttiin at \ $5 . ¾ flask was cooled down to RT and aidiydrous THF was added (5 ml) under N-j .followed by i ,2-dlbrofiioet aBe (0,0 l ( > The flask was healed, to 65 * wish a heat gun briefly and cooled down and then c&iorotriraethylsiiaoe. (4.75 μΐ, 0.037 tu ol) was added. After stirring ' briefly, 5 drops of 1M soUfttoa of iodise in THF was added. A hi the reaction was stirred briefly aad 4-{bromometlryi)tetfidrydra-2 i-pyran (670 nig,.3.74 ro l) in i ifi . THF was added. The reaction was heated to 50 *C overnight to aitbrd {(tetrahydro-2H-pyi¾J- 4-yi)iuethyl izinc(il) bromide (0.624 M, 6 raL). Let die zinc settle a bit ihen the reagent was used directl for next step.

Step B: A flask with H$-¾ osio- d2,&-dii:ko opta {80 rag,

0.223 tmaoi) was added diaeetoxypailadiur (5.02 mg, 0.022 mmo-l), S-Pfcos (18,34 mg, 0.045 mmol) and purged with H 2 . Degassed THF (2 aiL) was added followed by {(tetrak dro-2H-pyra»- - yl)met ylkinc{li ' ) bromide ( .790 ail,, J 17 tnmol). The reactios s heated to reflux i r 7 k Saturated NM^CS. was added and the mixture was extracted with ' EtOAc. The EtOAc layer was dried aud coaceaaatcd aud purified with silica get c r matogra h firs! 0-50% EiO Ae Hesaues then 0-7% MeOH/C.M 2 Ci 2 gradieni separation) to afford l-{4-(2.6 li:O: 0«iphenoxy)-5- (tetr;ihydrO"21-l-pyna:i- - yl)methyi}pyridiR-2-yI)- -me†¾y!i.ii-ea 56 m$ {66¾)« Mass speerram (EST) m/z * MH.2 (svH-H). Ή N R (4(H) M¾ CDCij) S ppm 8.93 (br,. s., Ϊ H> 7.9 J {br,. s., ! H) 7,80 {s, ! H) 7. L - 7.1 fro, 1 H > 6,90 - 7.06 (is, 2 H} 5.84 <¾r. s.. i- ffi 3.89 (dd, ::; I U , 3, 52 Hz, 2 K) 3,29 - 1 1.15 ' Hz, 2 B) 2.75 ( l - .69 H ' ¾ 3 H) 2.58 id, -?.24 ¾ 2 H) ! ,86 (ddd, -! i 35, 7.53, 3,81 H¾ i H) 1 ,53 (d, - .i 1 Hi, 2 H) 1.3! (qd, -12.32, .70 ¾.2 Hi

Following the procedure in-Exa ple ί 75, the following compoutKis were prepared:

m e !78

A flask with ethyl « ( 2J iiilu0ro heMx )-^ (2 i mg, 0.0.53 ramo.1) was added MeQH (0.5 mt), TH.F (0.500 mL), .IN LiDH (0.267 mL, 0.534 mmol).. The reaction was sorted m R ' F overnight Then si was diluted with water aud Hsmtrai&ed with HCl Precipitate was generated. EiOAc was added, however, the precipiates were partially soluble, in. EtOAe. So the solutioiu xture was .filtered, ΎΜ precipitates ' were dried. o« high vactatta. The EtOAc layer was dried, and concentrated io obtain a white solid. The precipitates and ifee solid was combined to afford a total ef 19 mg 4 4-i:2 ; iMi1nor0pkef.myH acid (0.052 mo 97%). Mass specmiKi (ESI) ¾ 366.2 (M-+H), l H. R (400 Mife. D SO-*¾ ppra 12.05 <¾-. s., 1 H) 9.03 (s t I H) 8.00 {$_ 1 Hi 7 ; 65 (fee s. ( 1 Hi 7,30 - 7.53 ivx 3 H; 6,80 {$, 1 H) 2.59 - 2.72 (m, 5 H) 2.27 ( -7,43 H¾ 2 H) ί .83 {quia, « 7.48 ¾ 2 H). m 17*>

A ]¾ degassed jnixi e of H^ Hdifluoro feeao^ VS^AS j S-^trmethyl-KS^- dio:xab0(¾laiv2-yS)pyridin-2-yS 3-t)ie!hy:«i;a (144 tag, 0355 mmoi).2-<fcro«KmK?thy.0pyndi&e hvdroferajmds. {135 mg.0.533 mtaoi), Pd(PPl¾).s (4 I mg 5 0.036 mmol) aad 2. M aqueous ¾ CO.i solution ( 0 tnJU 1.0 mmol) in 1.7 mL of l,2-dm¾thoxyeii:iaHe was stirred at 100 *C for 4 h and Use mixfttrewas coaled to RT S filtered though a sdof Ceiitc and washed the Cellie thoroughly With EiOAc, The ftltralc was eoiieentriued and tire residue was perilled fey reverse phase HPLC fo give 8.7 f«g of } -c -(2{s-difiior0p eaox )-5-tpyiidiri-2-y Mass s ectrum

ESI (pos, -rt - 37Ϊ.0 (M-i-H) ! H NMR ;4Q0 K/ , CDCk) i 8,?3 {d, J - 4.0Hz, !B>. S.00 is, iU\ 7.93 (H, IH), 7.50 (d f j ' ~ H.0¾ IH), 7,46 <d > J - 8.QHZ, IH), 7,45 (it J - 8.0H*, IH), 7,57 (m, IH), 7, 13 ira 3H).4.4Ϊ (s, 2B>, 2.84 (d, J-4.0H?:, 3H).

m c 180

Ti a ?% degassed mixture i -(5¾oi!.o~ -(2^di.0. tax^

(0.050 g, 0.140 tsmel), { ^«)e%.i««:fi»iyf)phe8 ii^m«k add (0.042 g, 0.209 itttsol) imd K s CO ;! (0.ii38 mi, 0.4 S mmo\) in _,4-dioxans (0. !40 ml, 0.0 !4 nsixtol) was added . ίΡΜι*}·, Μ g, «,014 miaol). The resulting mixture in a sealed tube was aiinred ai 1 0 °C overnight Hie mixture was cooled to RT and direciiy subjected to reverse phase IIFLC purification to give 49, 1 tag of i -{4-(2,6- <K^la0s-a he> xyh5 -(H¾eihy1sttSi¾ii i} ^ Mass specimtn ESI

(50S. ) m/z « 434.0 (M+B) S H M (400 HX , CDC1?) δ 8, i I £d. J - 4.0¾ !H), 8,09 (d, JHt.0E& LB), 8.04 (s, m% 7. HZ (43= 0Hsr, .1 H), ".55 fbr s. ! H>, 7. 8 {m.1H), ?. IS (dd, 3=8.0, iLOHsr, 2H), 3.14 ( s, 3H), 2,85 {& H.0¾ 3Hl

Following the procedure ia Example I SO, h ftslSo iag c pounds e e prepared:

Til m e 194

rag, 0.058 mrool) and Rd/C {10 wf:.%(dfy basis). 6. 1 rag, 5.77 μ*ηο1) in MeOH (2 0 mi, 49.4 asjioi) u.«der a s!iooa of ¾ was siirea as RT for i h. The .mixture was filtere ttougfe & pad. of Ceiite. The filtrate was coKccftini&d. i!Jid t¾c msidue was purified by H.RLC to give 9.9. «ta of i-(4-{2,6~ difi¾:iQi'o i:ie!:toxy)-5-i ϊ -pfeeHy-tol^l)p .diH-2-yl 3-mcm ¼(¾.a. Mass spccinfiii ES. (pos .) ni/z. ~ 384.0 (M+.H) ¾ R (400 MBz , OX¾) § 7.65 i , 1H) ? 7.10-7. 19 (m, 3H), 7.28-7.40 iffi s 4,03 (m, JH), 3.07 (m, ί ¾ 2,84 {Or s, JH), 2.82. <d„ J- .0&, L73 (ct 3H).

To a (0, 1 I i g, 0.3 \ 0 i!itfioi} and (ZV Ϊ -c¾0xy>*2.-(lri¼{ylstaa»y3;)ctlienc (0,132 HSL, 0,372 mmoi) ift iokieae (3 mL) was added P^PPh*) (0.072 g, 0,062 isatol). The reaction was heated to S :I0*C &ffd sti riag coattaucd for 16 h. The mixture, was cor e itnded aud purified OB silica gel eluOfi with 0 - S0% EtOAc i» exanes to ai d i H -f^d^-d!ft^ (0.091 g s 0.26 mwA, % yield). Mass specwan (ESi) m.¾ ~ 350.0 <M*H). ¾ M1 (500 MH¾. CDCfe) & 8.87 (s s i H), 7.19 - 7.27 (m, 2R), 7.06 i - 135 Hz, 2M), 6.3(5 (d, ~ 7.09 H¾ IHj, 5.61 (d, - 7.09 Hz, IH), 4.05 (d, - 7.09 Hz, 2H), 2.87 (d, - 4.65 Hz, 3H), 1.41 (t, - 7.09 i$z, 3H>.

Following the procedure in ..Example 195, the tawiiig coavjf&uad was prepared:

I I 7- : yS}-3-m diyiurea Ϊ

Step A:. A mixture oi{Z)-i"(4 « (2,6~drihK>r pfe

mctbykiiea (0,045 g ¾ 0.13 «j»¾>i) aad 4 aqueous solution of HQ (0.129 ml, 0,515 iBjaoi ia TBf (0,6 mL) was heated to reflux for 1.5 . Hie mixture svas cooled to ftT and poured into saturated aqueous aHCOs solution. (20 mL). The orga&iex were extracted imo CHjQ x (2 x 20 mL), collected, dried over MgS<¾ and concentrated under vacuum So yield. i~(4-(2,6-diilisoTop¾iisoxy)-5-{2-- oxoeili S ipyrid!s:i-2~yl)-3 .5iethyiurea (0,033 g, 0. i 0 mmo , SO % yield). Ste B To a soiuto of l-i4-C2,6-di8«oroph£ao¾y}^

toeUwteea (0,033 g,. (5.10 ftiiao ) in MeOH { ! mL) was added sodiu bore ydride (0.0039 g, 0J0 mmol). The rcjjctlojl was stirred at RT for 1.5 It. Additional NaB¾ (0,003 g, 0J0 nxi l) was added, md the reaction was siirted for 2 h. The mixture was concentrated artel the ens.de product was partitioned between EiOAc and Ο.ί^ aOH^;,, 11.se ojgaaic layer as collected dried over MgSC¾ and eoneerittaied in vaarnrsi The erode ' product as purified < silica gel eliaing with 0 - !0% MeOH -in CH;C! :f to give H ~¾6-diiluo^^

(0.0 I 3 g, (5.040 jamoi, 39 % yield). Mass spectrum (ES ) m ¾ - 324 M (M-HT), Ή NMR (500 MHz,. CDCDjt § 7,95 - 8.05 {ro„ 1M), " 22 - 7.26 (m, 1H), 7,01 - 7.15 ( , 5¾.3.95 ts, 2i¾ 3.00 < 5> 2H), 2.88 f d. - 4.65 H /:. 3Hk s¾ e 1.98

( 129 mg, 0,36 os.noli, 3-

pyridylboromc acid .{92 tag, 0,75 »χ«κ>¾ a-seyelohe¾.yIp!iospbiae (23 rag, (5,083 tmmll arid Pd :! (dha}¾ (36 mg, (5,04 tntnol) were added to a via! then degassed and backfilled with Ar. To the vial, 1,4- Dioxane (3 mL) and aqueous 1.5 l¾PQ.< (0.72 sal, 0,94 mxml) were added ' by syringe. The resulting reaetiou was heated to 90 ( . After 19 % the reaction was cooled to RT then concentrated under reduced pressure. The residue was filtered though, a 0.45 pro. GHP Aerodise (heu loaded oato silica gel (0-65% of presafxed 89:9: 1 C¾CL: MeOH: N¾OM in OfcCb) to afford a film that was

MR (40ό MHz. DiCHLOROMETHAHE-d:) S j>pu8J4 (1 H. d, -1.6 Hzi, .75 ( I H, br. s.}. 8.58 - 8.65 (I H. 5D), 8.14 ( I H, s) ( 8.0(5 0 H. dt, :;; *.0 > 1.9 H? >. 7.43 ( i 11 άά. 4.9 B¾ 7,28 ( i H, u. -8.5, 6.0 H¾>, 7.04 - 7,15 (2 H > m% (>.22 ( 1 H, br. s.), 2.81 (3 H, d, «« 4.7 Hz). Mass Spectrum ipos,} ove: 357, 1 (M†B \ Following th« proce ure Example 1 8. the following co-ftigeoiKiS ee prepared

Ή5

in e 2 1

1 -(5-Brot»o-4H2A-di¾tQrophesoxy )pyTk!in--2-yS)-3 iielh¥ Sttfea ( 149 m . 0,42 mmol), 2·- raef:hoxj'-5-(44 i 5 f 5~!:et:raiTsetiivl-l J.2-dioKabofola5;i-;2.-yI)feen;¾i5¾siJ<i (2.20 tag, 0.85 mrnol), trieydohexylp osphlne (20 rag, 0.09! mrn l), and Pd^dba}.-. (40 rag, 0.044 mn oi) were added to a vial thee degassed aad backlllSecS with AT. TO the ia , dioxaae (2 m ' L) and aqueous 1.3 M potassium phosphate tribasic (0,8 rat 1.04 nanof) were added by syringe. The resyftiag reaction was heated to 90 *C, Alter I S 11. the rea ti n was cooled to RT thea concentrated -under reduced pressure. The residue was filtered though a 0,45μπι GHP Aefodlse t ien loaded, onto silica gel (0-50% of EtOAc in CH;Ci}) to afford a solid drat was treated whit MeOH then heated oir the roiovap to SO a C without vac. After 20 vena, the lieierogeitous solution was filtered, hot to alTord a white solkl 1 ~< S-(3-e.y rio- 4~HW¾ ]Kmy!}- -i2 ! iS- ¾ (0.0494 g. j ' 2 -nuwl, 29.0 yield). ¾ NMR (500 M¾ D SO-dg) ppra 9.23 ( ! H, $}, B.24 ( S U, $} > 7.S7 - 7M (2 IT m). ?.¾ - 7.54 (5 H : m), 7M (I H, s), 3, .96 (3 H, s), 2M (3 H « . I.fe). Mass Spectrum (pos.) m¾:

FcsJIo' iiig t e rocedare itt Example 241, the following coiiipoyiid* were prepared:

m 246

l-C4 » (2,6-ds£liioro^

j)-3-»¾ethyi rea

Step A: l.~(5~Bromo 034

resaitiag reaction was oeaied to 1 0 ; C. After i 9 ¾, the reaction, was cooled t RT thea dilated wit , water. After extracting x with CI¾C¾, the orgasrics were pooled (hen dried over anhydrous MgSOs. After filtrado and conmiteitk , silica gel was added to the black residue iiteit loaded onto a silica gel cesiums (0-55% ofpranixe $9:9; I C¾€¾: MeOH: ¾OB ia C¾C¾) So afford black film that was fenhe purified with reverse-phase iiPLC by dissolving i IS ta in 8 tnl. of 0,1 % TP A in. MeCK (25-90% of premlxed 0. S % IF A in MeCN! sa 0.1 % TP A m -water.) Fractions containing desired •compound were combined then concentrated under reduced prep re. The residue was dissolved in C¾C¾ thea washed twice with saturated aqueous aMCO; and once whit brine. After drying over ;mhyd:reus M SO^ fiteratioa, .and eonceatrafioa, the residue as idemited as ! -ΐ4-(2.6- di0uorphenDxy)~5- s 6- ihyd^ Mass Spectrum

(pos.)tne: 57S..1 (M-Hff.

Step 8: To a vial containing s -f2 > 6-djlao0 benoxy)-5-i3 ! 6-di.lr^

y{)pyrjdin-.2-yi}--3-}»ethyhirea 0.2 mm !) was added MeOH (2 ml,} and Water (0,5 m .

The mirnm was cooled. in art ice bath, the** after 15 mm, owns (¾06 j»g, 0.5 im iy was added in portioas. The eaction was warmed to 23 After 1.5 b, die oxofte was filtered off and rinsed with MeOH and CHjCk The filtrate was- oncentrated under reduced pressure then pnrtfted on silica gel <0~wm of a remised solution of 89:9; i€%(¾: MeOH: ¾QH in€¾€¾} to-: afford a brawn film as 1. -(4(2 T 6-4iftuoroplienexy }-$-(!, 1^^^

tne ylutea (0.01.31 g, 0.032 i noU 1X49 % yield). Mass Spec(ram.(pos,) me: 410.0 <M+H> * .

Stg C: To a fJask containing i-(4-(2,6-dii¾sorop¾eaoxy)-5-(i J-dioxido-3,iS-dihydro-2H- thiopyran^-yl}pyridi»-2--yi)-3-iBetbyi i-ea (13 rag, 0.032 aanoi) m EtOH (2 mL) and EOAc (2 mL ) was added Pd/C (10 % , Big, 0.035 aimoi). The ilask. was evacuated and backfilled ith 3 and stirred at 23 °C. After 5 tain, the aitrogen was replaced with After 11 t¾.e reaction mixture was filtered though a Ceiite plug and concentrated in. vacuo to afford a colorless residue that was eriled w$i reverse-phase HPLC by dissolving in.3 mi. of DM? ( H)~«)% of premised 0, i TFA in MeC in 0. I % TFA. la water.) FiactiotiS contaiaing desired product were c mbined then eoacentnaed u»der reduced pressure. The residue was dissolved .in CHjCSj ihea washed: wice wish saturated a ue us NaHC<¾ and once with brine. After dtyiag over anhydrous gSO*. filtration, and concentration, ths while solid was ide»tified as J *C4-(2 6-diiluorop]:ieaoxy)-5-( I , ! -dioxkiotetrahydro- 1139 % yield). ¾ MR {500

M H/. DiCHiX)ROMETi A E*d;t) δ ppm 7.90 (1 H, hi; a.), 7.3 1 - 7.42 U H, 7. 15 (2 H, i. -B.2 Hz), 6.74 (I br. s.}, 3.12 - 3,31 (5 PL m), 2 W, 4 « 4.6 Hz). 2.33 - 2,50 <4 PL m). Mass Spectrum (pos.) mfc: 41 2 J ( -s-H) "1' , m e 247

A mixture of

manA), 2-{trib«iy1s½»ayi)pyridine (0.21. ml 0,56 jnraol). and Pd(PPiu}, ; (42 mg ( 0.037 aunol) .to auhydious mbmm (2 mL) was degassed by Nj, T!ie mixture was. healed to 1 0 "C. After 23 h, the reaction was cooled to .RT dies eo eetnraicd under reduced pressure:. The black, solid was filtered though a. 0.45 fM GHP Acrodise then loaded: onto silica gel (0-55% of presided « :9: 1 CiPCk

lid,

yield . ¾ NMR (400 MHz, DiCHLOROMBTHAME-d- ? ) S ppm 8J5 ( i H > br. s.), .m - 8.79 (I H ; m S.66 Π s) ; 7.96 (I a i "*7.8 Ez) > ?M (I H, td ?A I -9 I i 7.22 - 7.35 (2 R t»}, 7.03 > 7. j (2 H, Ά\) > &Λ Η (ί H, far. s .,!, 2.80 ( 3 PL d, ~ .7 Bx). Mass Spectrum fpos.j m 357. ϊ ί Μ ΗΡ .

Following the- procedure in Example 247, die foUo lrig coniponads were prepared: Structure Name Date

Mass spectrum

248 dtfluorophehoxyjkS- (ES!) ra/st - 358.0

{;pyrazifi~2-y!)pyri din- ( +H).

2-yI)-3*.rae iorea

H4-i >/>- ass spectrum

2 diilyoropfeerioxy) -5- (ESI) - 358,0

(l>yridazi:n--4- y!)pyridin 2~yl)~3~

methyktrea j« e. 2S6

A .flask was charged

(202 mg, 0.56 mmo! palladium (0) acetate (42 mg, 0,063 amio{). and 2-dkycSohexylp¾ospl:iH¾o-

bromide is THF (6 ml.. 3.00 »¾»oi) were added by sylioge arider A:r, ' flic resulting ieaetioft was heated to 70 X After l 7.5 , the faction, was coaled to ST ihea diluted with. EtOAc. After washing the ©rgaaks ouce with saturated, aqueous N¾C! solution and nce- with brme, the organic layer was dried over anhydrous Na¾S<¾. After litotioa and conceatration, the residue w loaded et«o st!ics gel (0-40% of premised 89:9: 1 C¾C¾: MeOH: H¾OH ifi C¾jCfe) to afford yellow oil ihat was farther purified with reverse-phase HPLC by disserving 163 mg iu 10 mi of , 1 % TFA sa MsCN. (25-90% όί prearixed 0.1 % TFA in eC i« 0.3 % TF to wa¾r,> Fractions eoBtatoiag desired produci were combined mi coaeeutraied under re uced pressure. The residue was dissolved in CH-JCIJ then washed twiee mih. saturated aqueous aHCOj and once with brine. Ate drying over ■afthydroiiS MgSO-i, fiitrauon,. and oncwratiofl.. i ' he white solid was identified as S -(S- Ccye!oiiexySmethjd}-4-t2.6 ii¾ {0,0199 g, 0.053 romoi, 9.30

% yield). : i i N R (500 i fc. DMSO-d,,} 5 ppm 8.9 { 1 H. s), ?i>5 ( I H, s) ? 7 ½ (1 Π. br. 7.32 - 7.50 (3 H, m), 6.76 (i PL s), 2.63 (3 H, d. -4.6 M¾ 2.53 (2 H. ;;: 6.6 Ife), 1 ,50 - 1.72 (0 R m)„ 1.09 - f .28 O ft t»), 0.89 - 1.04 (2 PL m). Mass Specntun (pes.) mar. 376, t ( ÷M}\ m e 251

HS korao~442.6-dii ^ ( 154 g, 0.43 mmo!;h i- erhvtryfcyc.topem.au.oi (0.1.5 mL, 1 ,35 mmol). Cat ( ! 7 .tag, 0.09.1 mmo\% and MCU& i¾) 2 (32 tug, 0.045 imwft) were added to a vial then degassed aad backfilled with Ar, To the vial, anhydrous DMF (3 KJL) then Ni¾ (0,5 mL, 3.5 romo!) were added by syringe. The re dies was heated to i OO ''€. Ate 24 h, the reaction was cooled to RT dies diluted with water. After extracting x with Ci¾CS>, the argatu ' es were pooled t en dried over anltydrotts MgS{¼. After filitatiori. arid, eoncestration, the residae was loaded oma silica gel (0-50% of premised M;9:,i C¾et: MeOH; f¾QH ia C¾Ci > to ■afford a yellow film that was triturated with EfOAc to afford a ant solid as i-(4-<2 5 6-

mmol, 53.9 % yield). Ή MS,(50«) MHz. DMSO-do " . ) o ppm 9.26 (1 H, s), 8,21. (i H, s), 7,44 - 7.5.1 ( i ft : t >. 7.36 - 7,44 (2 E, m), 7,28 - 7.36 (1 H. nil 7.00 (1 f s} : 5.35 (i ft s), 2.62 (3 ft d. j- .6 H¾ 1.79 - 1.95 (4 H, : ra), 1.59 - 1.79 (4 Pi m). Mass Spectrum, (pos. %W& 388. ! (M÷H ) ; . i e 232

Step A: irt 2 mL of BMP were cotpbioed aH (60% dispersion o oil) (0.0716 g, I .79 ssmo!} a«d j iifluaro-6¾dm y- -i8etiiy!q»Hio} fi-2 ί HBme (0,378 g ^ ,79 RTOOI) aed this was sparged with. j fo 30 mm bete 2-dliOfO-4-»¾ro-pyfidiBe (0.284 g„ 1 ,7 mmol) w s added and the reaction was coatin ed at :RT. lie .reaction was complet ate 4 h and to the reaction was added 1 mL of EtOAc and 5 mL of water. This was stirred v gorousl for 30 mia before it was poured htfo 50 mL of water mi 50 mL of EtOAc i» a separatory fnrnel This was shaken vigorously xd tile resulting emu!siou was filtered arid the solids were- collected aad washed with. BiOAc. the solids contained product .and were retained. The organic layer «w collected, the aqueous was washed with another 50 mL of ' EtOAe aad the combined orgaaics were dried over MgSO^ filtered, sad. removed fa wcm. The crude was rate up. in C¾Cij to preparation for etanaiogtaphy whet) solids were observed. A small amotmi of eOH (0.5 mL> did act sel hilke the solid and so the suspension, was sonicated .for I rain and the solids were collected via acuum filtration. These solids were com ined wiiii die solids ftont above to yield

0..4S7 iitmoi, 27.2 % ield).

Ste B: to i mL- of 0 F were combine NaH (60% dispersiap in oil) (0,0189 g, 0.97 tumo ) tsitnol) and this was stirred with N :i sparging lor 35 mm bete dimethyl sulfate (0.0598 ml 0.632 mmol) was added and this was stirred at RT, After I h the reaction was complete sad diluted with C¾€¾ (5 m ' L) and then loaded directly onto silica and ehi ed with.20% EtOAc in C¾(¾. Desired fractions were combated, concentrated in , and dried on high vacuum to yield O- S-diiar rM^- i xy S,?- 0.29? ntmoL 61 , % yield).

Step D: la I ml of . eOClLGi¾OMe were combined net!iylnrea (0.0330 g, 0.445 mmol) and fsttely greoitd aahydroos s P .s (0.1 S O g, 0.520 asmorj md this was sparged .for 5 atirt with ' before Pdj(d:ba . )j (0.0136 « , 0.0148 mraol) and. 1 i feiiiaphthyi.~2-yldi-teri.~biHyiphosj hitie (0.0237 g, 0.0594 maiol) were added. This mixture was then sparged ior 10 rnitx with 1si 2 before it was heated to 66 "C for a 45 mitt. 7¾e reaction was coaled to RT ;md 6-(2-eh|os: p>TiiiiR-4-y. xy-5 J-difiuoro- 1,4- ds«)?03y:S oifte!!ii-2(iH}-!He (O. UK! g, CS.29? mol) as added Ths reasipii was sparged for 5 mia widi N before it was sealed and Seated to 90 B €. The reaedos was cotwiaued over the weekend a«d after that tk\vi the reaction was diluted with 7S t!iL ofC¾O a w¾h 1 % MeOH md stirred for 30 tarn before it was littered. The solids were discarded, and the rsise was corrcsmrras i« >¾£t«* and then piriified over sl!tcs gei (0-2% MeOH in OAe). Pioduct couiamiag fracuoas were coffibi ed, concentrated io acuo, a»d dried on aigh vacuum io yield i -C4-(:5 > 7-diSluoro- L4-di!nei!iy!-2-oxo- 1 ,2- dihydrøqι»π Si5i- - lo }p ίdiί 2- -3-meti i«re (0.026 g, 0.0660 mmoi, 22.2 % yield) Mass Spectrum (sp ) s«z ;;; 375.1 ( .÷H).

r» e 253

-i, 5 -(( 1 - Ethyl- i -pyrazQl- - v 1oxy )-6-{3-meth^l : re o)p/ytid;ia-3 -yl toanok a i d

Ethyl - . 5~(( 1 <ed:iy1-i -f)yraKsi>5 » ytks y)"6-C -ioediyiK£fdo)py k!i:n- ¾-y!)btia«oiU£ (10 «¾ 0.027 HH!W! w s dissolved in 0.5 nil. of a I : ! M<eOH:THF mi ture. LiOH (2M S !B. (133 ui, 0,266 mim\) was added mi surred overnight ie completion. The mixture was acidified wiih IM HCi Sqkiio!! to pH 5 arid con evir ted to dryftcss and placed under high va uunf to gve die hydrochloride safi of 4-(5-{( .1 > f v l-lH-pyrazoi-S^^^^ acid {9.2 tng,

0.026 irnml 99 % yield). ¾ NMR (4(H ) ¾ 0 D ) 6 ' ppm 7M (i H, <L -1.8 Jfcs), 7.W 0 Ή, d, =2.0 Hz), 7.04 i I ¾ fcr. s), SM ( I H. d ; -2. Hz), 4.05 (2 H, ¾ -7.2 Η ), 2.94 ø K, s) ; 234 (2 H, t,.. -?.fiH2}„ 2.2i>a¾i =W¾)J.I2,a¾(j«i«, < J. Hz) 4 U9(3H,t, ^3 Hi). Mass spectrum (ESI) rn/z - 348. i (M-t-H). e 254

To a stirred (0.100 g t 0,10 mmoi) a»d c clopropylborootc acid (0.052 g, 0.6 ' { moiol) io dioxane (2 rat) w s added Fd:;d 8)y (0.02$ g, 0.030 mmoi),, followed fey oicycIobexyl hospMne (0.017 g, 0.06Ϊ ismo!) and aqueous 1 ,3 M pofassnftn pbospbaie solutioti (0.5S5 mL y 0,761 mmoi). Tb.e reacOois was bested, to 90 °C and stiff isig sosomsed for 10 b. The ixti uje was cosceottated md purified oo silica gel dmiag with 0 ~50¾ BtOAc in hexanes to afford i -(5 yci propyS~4-(2,6-diil!ioroplie»oxy)pyridisi-2- yl>3-me¾durea (0,045 g, 0.14 mmoi, 46 % yield). Mm sp rmn (ESI) ta¾ ~ 320.0 ( ¾ΐ). S M NMR (4(H ) M¾, CDC!i) < 7,60 is. IB).7.32 - 7,43 un. IBs.7.08 - 7.26 : 3B} : , 2M id, -3.3 Hz, 3H 2.01 - 2.21 (Ά Ui » .02 A.1.9 (ift, 2H).0.68 --0,82 {m, 2M), m « 255

5-(?Yddin-2-y iiii!o)-3-{! , < 4T¾«er¾ I H-p razoS.-5- i }pyr ii 2-affiijie (i 00 mg, 0.305 raol) was dissolved in THf (1 mL) and tsoc>'a»stoetha«e (484 μΐ,, 6 J I nunoi), added and the reaction was heated to 60 «C in a vial for 4 h. Hie reaction was tested: to 70 "C be iod a blast shield overnigh The reaction was cooled to .RT and diluted widi C£LC¾ (5 mL).2g ofPS-fcisamiae resm was added ;«κΙ the reaction was stirred RT for 2 li. h reaction, was filtered,, as d with CHjCi eOH cycles (x¾ concentrate and purified on <¾ reverse phase (20 to 95% ACM in waict ' j to afford

yi)atea <8«3 g, 0.202 mm 66.0 ¾ yield) as a white Mass spectrins (apei) h ~ ¾>9, i < ÷H . Ή NMR (COCK) § 9.20 {!, -4.5 i-¾ E H) s 8.33 (m,. !!¾ 8.1 i <s 5 I }, 7.55-7.40 (m, 2H), 7.06-6.98 ()¾ 3H 3,57 (s, 3i¾ 3.4? (m, 2H), 2.15 (s, H), i,?3 (s, 3Hj, 1.28 it, -7.0 ii/..5Hi.

!-iOS. !-3-(5-b! SBO-3- Mm specmiat

(ptatyii o!ipyrid - (apci) m/z. :::

2~yl)urea 364,0, 366.0

m t? 266

i-ASIyi-3-(3-(2-edryIpynd^ (70 rag, O.J 72 iiH!i b w dissolved in THPrwater 4:1 (2 uiL) ml O (26,2 ni , 0,223 rm l) and 2.5% osmhffi VHI) OKjde (21.5 μ], : O.C)0!72 raffiol) i« tBuOH ' ere added xs die micton was stirred at j¾T oveoHgiit, More C ¾ ( ί 00 «L) was added sod the reaction was suited, at S¾X for 4 h. Saturated a ueous aHS(¼ (0.5 mL) was added aud the reaction was stilted. Ibr 10 i» ; Solid NaHC ( 3¾ as added to neutr lise the reaction filtered dirough Ceiite and coaceatraied. The residue was purified <m silica gel 00% MeOi-i in EiOAc to a ¾id

yiaxy)-SHi?yndia-2-yItS:do)pyrfdiii'2-yl)nrea (42, mg, 0.0972 mtsoi, 56,6 % yield) as a clear glass. Mass specrnan (apei) mfe - 442.. I < +H). 5 H M (CDC¾) S 9.65 it, -5.9 Hz, H), 8.46 (m, 1H), 8,32 (m, 1H), 8. i.2 (s, i H).7.68 (s, i H), 7.50 (ΐί, « .8, i . H¾, ill).7.29 (d, -8.211..··:, ili).7.19 (dd, ^8.0, 4.5 Hz, 11!}, 7.65-6,98 (in, 3H), 3.89 (si, IK), 3.67 (ra, 2H), 3.59 t, ;s 5. Ife.2H), 3.20 (d, -4.5 e¾ ffi), 3.0S 0, -5.3 !·! ., i:H), 2.80 (q,. 7,5 Hz.2H). i .26 it, -7,6 Hz.3H;.

mraoi) was -dissolved to CHjCT (5 ml.) aad pyridine (224 ϊ, 2,7? ratnol) as added.4-iistrop¾esiyS carbopachlaridiiie (373 atg. ).M5 iaiaoi) was dded poftiomvisfc and the teaetioa was siir ed at RT for 1 h to afford a mixture ofmoao- aad bi.s-aiiropae»yi eartsas:n;i!es, which was used as m aliquot ia tie !■ ·.··<¾ reaciioa.

Step B: A. i sat aliquot (0. ! 8 mmo!.} from the previous step was added to a suspsxisioa of (4- (KH mg,.0.550 in io aad Etj (153 μ.!, ί JOrtrmo!) in€¾CV(i mL). I¾e reaction was s¾rre-d at RT overnight. T e reaciioa was partitioned- between water and C¾Ct . > drie over Na :J SG. 5 , filtered aad co«eeirirated. The residue was -purified on silica gel ( io IO¾¾MeOH ia BtOAe) to ox l^^ihyp^d«^3-y.toy -S-^ ridin2» yidiro}pyridifi-2-)d)--3-C(4-meibyi-! H»imjdai5ol*2-yi)aieth i)uea (46.4 m , 0, ί 01 mxml 543 % yield) as a um solid. Mass spectrum, (apei) iWz 462.1 ( -J-H), Έ. : M iCDCK) 9.93 (t. 5.9 Hz, SH), 9M {as, IH 8.46 (d, -k?!fa, IH).8.30 (ai, IH), 8.0 id, -L 1fe, !Μ},?.ί>ί is, II¾ 7.48 (ΙΐΙ -7.8, 1.8 IK), 7.28 -(m, I ¾ .18 « 8.2, .7 Hsr, i ¾ 7.05-6.96 {m, 3H), 6.65 < S> I Hi.4.56 (d, -6.1 Hz.2H 2.79 «]. -7,6 Hx, 21-1), 2.23 3H), 1.26 «, -7.4 \ .3H),

Following the procedare in Example 267, the foiio iag compounds were also syafliesized:

256

m «311

5-Bromo- » f 6 250 nig, β.783 mmoD was dissolved in (¾<¾ (7 mt! and pyridine { ι89 ϊ, 2.34 m toi) was added.4-nitro.phen i carbonocii!oridate (3 i S rag, 1.50 xo oi) was added and the reaction was stirred for i h at RT.33% M iatiamine to EtGE (735 rag, 7.81 ramel) was added and the eaction was stirred at RT overnight. The reaction was partitioned between water and€%<¾ washed with i. NaOH, dried over ajSQ*, ititered and concealrated. The residue was dissolved in .EtOH (10 ml.) and excess ; CO? was added and stirred at .RT for 4 k Use reaction was filtered, concentrated and purified over silica gel ¾ MeOH. in EtOAe) to afford raeenac material that, was separated by ehiral chromatography (Column: Om 2H m X 25 tnm, Flow Bate: 35roUnuX 25% EtO« in Supereriticai CO¾) to afford, both separated isomers. Mass pectrum (apes) iz - 376.9, 378.9 (M-+H) for od enasdomers. J H KMR. (CDC¾) δ ¾099 (m, i HE), S.57 idd, 4.71.8 it/. Ϊ II 7,87 (il .: >'> Hz, i H), 7.56 idd. 7-S, 1,6 Ife, Li-i), 7.34 (& -2.01¼ IH), 7.25 (s, ΪΗ).7.1? idd, " : 5.0 ίϊζ : IM15.42 it -77 Hz. ill), 3.1 ϊ <&„ -E7_8, 4,5 ϊ¾ SB}.3.00-2.90 (in, 11), 2,20-1,89 (¾ 4H).

yi}H!:eid.Q}el:h>¾arb;;u«aie (50 « , 98 rrmiol) was dissolved i» Ci¾C½/ eOH (1:1, I m ' L) add 4N HC1 ia disxane { t mL) was added aod the reactioit was stated at RT over the weekettd. Tlse reaction, was pa«itoed bet een tU NjCOj and extracted (s2) wi.¾ The aqueous layer was salted out and extracted with i 5% eOB in CHj x- rise organic l yers were combined, dried vet a>SO.i : littered aad coueeutnt ' ted. The residue was purified on reverse phase (5 to 8Ci¾ ACN in water). The residue was dissol ved is C¾Cij/MeOH a.ad 4 HCI in M added d the solvents were remo d to afford K2-anrmoe iKM ^ ^ ^^

2-y!)«re diiiydroc oride (15.1 sag, 0,0312 imaol 31.9 % yield) as while solid. Mass spectrum (apci) Hi& - 41 L0 (M÷H-2MCi). ! H R {d^DMSO} S 9.49 is, iff , 9:26 (t -5.7 Hz, 1M), 8.48 (d, -5,3 H¾, IH), 8.37 (m, SB), 128 ( « =2.0 f¾ IH}, <bs, 3H) > 7-84 (d, "8.2 ¾, IH), 7.73 (s, IH), .7.68 ( , 2H), 7,20-7.13 (m 2H), ,69 (m, IH), 3,55-3.44 (ra, 3H>, 3.06 (¾ -7,4 H¾ 2H), 1.30 (i, Hi, 3M).

mmol)

added and the reaction was stirred at R.T overnight The reaction was carefs.il iy added to aqueous NafiCOs with a .little aMSO ? . added, to quench excess oxidant. The reaction was extracted with C:H !; : (x2) f dried over Na 2 $0.<, filtered aad concentrated so afford I <3-<2-eth3f )y»idtH-3- lo y>-5 ' (pyridin-2-yls¾5i¾yl}pyridffi^^ (75 mg, 0, 13 ) rniml, 91 % yield) as a. white solid.

Mass Spectrum (apci) mfe » 39S.1 ( +i-I). ¾ H R {CDCTO 59,07 (q : -4,5 H¾ ί Ms, 8,46 («Ϊ, 211), B.27 (d : ™L8 Hz. lH),7.S«(d > ;;; .8 ¾ .1 H), 7.S3 ftd, -7Λ!..6Η¾ ί B), 7.57 (s, 1ft), 7.29 (is. JH), 7.15 (HI, 2H), 7.00 (ά, - S .9 Hz, LH), 2.95 (d, - .7 Hz, 3H), 160 2H), L 1 ({, -7.6 Hz, 3Η·. m e3l

i 3-2~£thyl yt{ in~3-^ (65 mg,

0.16 awnoi) as dissolved ia HOAc (2 raL) aid S-chloto sax xiimo-tc acid (40,3 sag, 0. i 64 tnmo!) was added and the resctiofi was stirred at El for 4 k The roa.cfio« was carefully added to rjueo s MaB€?¾ with a Jfttte a!!SQ; ? added to q mch excess oxidant Extracted it¾ 0¾C! 2 {x2}, dried over NsjSO,;,. tlhered and conce»i:raieil. The residue was purified on reverse ase (20 to 80% &C in waer) to afford i-i3-(2~ehyi Yridm^

(27.2 ing, 0,0658 iranol, 40,2 % yield) as a whits? solid. Mass speefftstn (apei) iwz ::: 414, 1 (M÷H), ¾ NMR (CD£¾) § 9.09 (q,. « ,5 Ha:, IH), 8.60 ( , I H>, 8.56 (d, ==2,0 Hz.1 H), 8.54 (dd, -4.7, 1.6 Hz, IH), 110 (d, « 8.0 Hz, !H), 7,92 (id, - .6, 1,4 Hz, IH), 7.77 (s, i¾ 7,47 (dd, -7.6, 4.7 Hz, I B), 7.34 id, « .0 Jfe, SB), 7,28 (dd, "8.2, 1 ,6 Hz, I B> < 7.24 (dd, ~ , 4,5 H¾ 1 H), 3.00 (d, -4,7 Hz, 3H), 2.72 (rg, « 7.6H¾,2H), 1.22 (t, -7,6Hz,3H},

l~f 2- tfay!p^

i H ' 2-E( yi yrldk5-3" l x i-SH^ tag, 0,0797 mmo.1) was dissolved Ϊ» 1 : 1 ¾C¾:HOAc ( ί .5 -mL) sa 3-c iirsbei5 opsrisofe acid (43.2 g, 0.175 mdl) ms added and stilted at. RT overnight. The reaction was Rea ied by pouring mm aaueoas aHCO¾ with a ssaaii a iormi ofNaMSO* and exiracied wit CH 2 ¼ φκ3), dried over NajSO,, filtered arsd ceaceatraied. The residue was p-tirified over stMea: gel (0 to W% MeOH to EtOAc) so afford M2-e!iiy!pyridi«-3-ytex -5-(3-mci ' hos>^roj)yistdfoi>yip>-ridiiv2-yiH- methyhirea (173 mg, 0,04.24 ϊΒΗίοΙ 53.5 % yieds as a while solid. Mass Speetrym (apes) si/z ~ 409.0 (M-i¾). ! H N R (COCiO S 9.08 (q, Mz, \ B; 8.5S (dd, - .\ 1.8 Hz, I W S-42 id,

.0 H , !H , 2 : i {s, J.H}, 7.31-7.23 (m, 2H), 7.11 {d, -2.0Hz, iHj.3,4( t -5,7 ¾ fHV3,27 & 3Hl, 3J3 (m, 2H), 3.03 (d, -4,7Hz, 3H), 2~6 ¾, -".4 ΗΛ IH;. L94 (m, 2H), 1.27 (j, -7,4 Hz, 3H). m e 31 (>

(50 tng, ,1 s raraol) was dissolved is daaeifeoxyiliatie (2 iaL) aad pyridin-3-yiboroiiic acid (36,5 sag, 0,297 BBSIS!) atkl 2M N¾COj. (222 uL 0.445 mmol) was added mil She reaction bubbled with M :; for S taia. Ρ¾ΡΡ1¾).< (ί?. I ssg, 0.0148 msBol) was added ami the reaction was plunged iftte m 0 °C oil bath under > for i ]:¾, The reactioa was cooled to RT, partitioned betweea water aod EtOAc, dried over sodium sulfate, filtered- and concentrated. The residue was pariiied over silica i (Ί $% MeOH in EtOAc) to afford

yield) as a while solid. Mass spectrum (apci) aa¾ - 336. ί (M÷H), ¾ (CiX¾) S 9.24 (q, -4.5 Hz, iM), 8.67 (m, IH), 8.60 id, -4.9 IM), 8.45 (d, -4.5 Hz, iM), 8.1 <> (s, I H), 7.68 (m, iff), 7.58 «s, l.H), 7,34 (dd, -S3 4.9 iiz, Ui...7,29 (d, -8.2 Hz, i:BJ, 7.22 (dd, 4.7 Hz, Hit.6.97 (s, IH), 3.03 (d, -4,7 ¾, 3M>, 2.51 (s, 3H).

Foitowiag: the procedure ia E arnp!e 316, the loSSowmg compounds were also syaiaesixed:

Example Marae

m « 337

H5-BtoraoyK2-meihySpyridiB~3-^ (.100 mg., 0,30 aiJiiol) w dissolved in dioxa«e (3 jaL) and.N-et¾ i-N-isoprop Ipf(¾J8H-2-aij¾ftc (10 ul s .0.59 :mrooi) and. Xaiit os (8.6∑ug, 0.P 15 irimoS} were added a«d the reaciioa aod bubbled with K> for { tal». Methyl . merea topropaooaie (39 μ.| 5 0,36 tmml) and Pdjdba, (6,8 mg, 0.0074 mraol) were added and tlj« rsacHoa w s plysg sate a 95 *C oil bai ' h atider K¾ for:? s. The reacuori Was cooled to RT, filtered though Celife, eoacernrated and purified over silica i (5% MeOH i« EiOAcj to afford liKSh l S 2~meiSyip ridift- - lo y n¾, 0,24 ttiMoS, 82, 1 % yield) as a pale yellow solid. Mass spectrum (apci) mfz «■ 377 J { ÷M>. Ή R <ΟΧ¾}δ9.].{ {q, -4.1 Hz, IB), 8.45 (dd, « . , .1.8 ¾ IB), 7.9H (d, -1. ¾ IB), 7.50(8, VH), 7,25 (dd, -8.2. S .8 ¾ 1 H) < 7.22 <dd s -8. , 4.5 H¾ 1H), 6.8? 01 -2.0 ¾ I H)» 3,55 (s, 3B), 3.00 (d, -4 " ¾ 3H, 2,9? (t. -7.0 H¾ 2H), 2,53 (L -7.2 H/.2H), 2.4? (s, 3H),

efei 3i;5-i2-t3¾iiiiySpy^ (90 mg, 0,239 mmoS) was dissolved m THf (2 i»L) and purged with >¾. Potassum -w . ^ropan- ~ olaic (1 is THF; 83? μΐ 0.837 tnmol) was added and stirred at IT for 30 secotids.2- <BrajmraethyI)pyridine hydrabroadds (60.5 sag.0.239 mrnoi) was added aad the reaction, was stirred t RT iu)der : ; for 1..5 is. The reacjjoii was qt nfeed mth aqiKjows N¾CI* -extracied wilfe EiOAe, dried o er Na_SO:{. fihered aa coacetJtfaia . The residue was ptaiied over silica gel. (10% MeOH io BOAC) to afford

yki)eih>M o)pyri<lm-2-yl)«i«a (59.2 m , 0.155 ra o.l 64.9 % yield? as a clear glass. Mass spectrum fapci) n¾¾ - 382. i (M-Hl } H MMR (CDCi $ 9.08 (in, !H), 8.43 (m, 2H), 7.9 (m, ΪΗ), 7.57 (t, •« 7.S *i¾ IMS, 7.45 (s, iH), 7.20-7.10 in\ 4H 6,S9 (s, 1 4.03 (s, 2M), 2.98 (d, -4.5 3M1 .39 s, 3M).

H 0-etby)-i.B~ Mass

ργ¾χοΙ-5~ν!όχν -5~ sp6ctft.ua hydroxycyctofeexykhio }p 392 J yr i»!--2>yS)-3-aieihyiiiiea

m «387

ing, ti s rnsaol) was dissolved is THF (4 mL) ¾fid , was bubbled iliosgis for 5 mm. IM Potassium 2 nedrylpropa»-2-oSa†e hi Tf F (11 5 μΐ 1.20 rnmel) was added nd the reads was stirred at RT for 30 see, -Methoxybut-to-2-yf. metbancsuifoaaie (109 rag, 0.598 moi) was added aad the action was -stirred at RT i r 4 h. The reaction was quenched with aqueous N¾C¾. extracted with EtGAc, dried over %SO. } , filtered aad cone strated. Th residue was purified, over silica gel (0 to 5% MeOH to EiOAc) to .afford racermc material. The recemic material was separated by cbirai. chm«mtogni|5ay to afford t , eaantiomers (Column: ADsH 20mm X 2S0rum. Flow Rate:

6$mhimte 7% MeOH in s^ remica! CO ¾ ). Mass spectrum. (aocj) av¾ 377.0 {M+H> for the Γ ! ek».ti»§ peak aad m& - 377.1 (M-+H) for the second e itfag peak.,Ή NME. (CDCki S 9.14 (q, -4.3 Hi, ill), H.43 (d , -4,1, 23) Ife, III), 7.98 (s, J Bs 7,23 (Hi, 2}|}, 6.87 {d, -1.8 !¾, IB), 3,51 --3,37 (fH.2H), 3.26.(s, Ms.3.09 (q, - .a H?, i I), 3.0(1 (4 -4.7 H.>.3H, 2.47 ( 3S-I), 1.80-1.6 (ra, 2H), 1,20 (4 **6 ' .8 3Hi.

Hi e3S8

: !¾io)i>ro a!)Oi5ie f 130 mg, 0,312 minol) as dissolved in THF (3 mL) md N 2 babbled tbaugh for 5 !iifii. 1M Potassium 2-met¾ylpW3paa-2-o «¾e in TBI- (936 μί, 0.936 ramoi) was added aad the reaction was stated for 30 sec, l-Bioiao-3-meihosyp:fopaae (42,8 μϊ, 0.375 mmi.) was added -and die reaetkm was stirred at R ' T for 1 h. The reaction was partiuooed hetwcea ater arid EtQAe. extracted with EtOAc (x2} : dried over H¾>$0. ¾> . filtered and fiQacenttated. The residae was purified over silica gel (5% MeQE in EtOAc) to afford 80 tag ofraeemic material The raceraic aten i was separated by cliiral ciiroimtqgi»jp¾y to afford feoth esiaHtioatm. {Column: ODE 20atM.X 250mi«, Flow Rate: 35mL/oii¾ 25%. EtOH m Supercritical CO;,). Mass spectrum (apci) ma ~ 403,0 (M+H) for both eaantaaers. ¾ tfMR <GDC%) δ 8.05 -7.4 ¾ ¾ ,5* id, -5.5 ¾ I B), 8.02 (s IE), 7.» a. -6.2 Hz, »¾ 7,65 is, 1 H) ? 7.30 (at, iH), 6.16 (s, IE), 3.52 (L -5.9 Ez. IE), 3.50-3.39 (:t¾, 2H), 3.35 (s s 3M} ; 3.32-3.2 i (iB, J.H), 3, 14 (t, « 7.2 2H> : 2.S2 (s, 3H) 5 2.35-2,2) <tn, 3.H), 2,05 <m, iH), VM (in, 2E). ta e 3S9 dihydrOC loiide

iert-B¾|:yl H(5-(2-mcd:i ii>vri0ffi

yi.dit»}t> ?ihyi}pipetidhie-i-cat¾osyla¾ (65 g, 0.533 mmot) was diss l ed An CIOCO i hh 1 % MeOH) (3 taL) aad 4N MCI ia di&s&tK (2 taL) was added and stirred: at HT fbi 30 aatu The reaction was coiiceatrated aad dried iii a acuum ©veil to afford lHii i $ ^ KH 2 - ,¾8i Py r idj»-¾- s : y)-5- piperidiii-4-y!i:fiethy idiiO)pyridiH-2~yl¼aea dihydrochforfde (56.9 aig, 0.524 tamol, 93.0 % yield) as a wiBie solid Mass spectrum tepct) m/x - 388,1 <M÷H-2HCl). ¾ NMR (d-DMSO) δ 9.19 (s. IHX 8.90 (in, 2¾ (bs, Ϊ Η), «.47 ¾ -SO, U H*. U¾ 8/15 ( , -J .8 ffe, I H , 7.73-7.63 (ni, 3H), 3.70 (at 2H), 3,38 (s. 3-.4S IH), 2.78 (ta, 4Hi, 2.70 is, 3H), ! .67 {m > ΓΕ), 1.35 (»¾.2H).

Following the procedHre in Example 389;, lite foHowiag compounds were also syistliesixsd:

220

I 5-Bro«ie- -(2-n! i!Y yridiB- -yo^ { ί 00 rag.0.296 imnol) and Cs:. i¾ (28 mg, O.S87 Hanoi ! were dissolved ia D F (3 raL) aad water (0,3 BIL) and pur ed with Hj.0,5M 9^ eHzyl-9¾{¾t>ic Cto.3.3,I]H<maae < S .7 raL» 0.88? rarao!) aisd PdCljidppf) C¾ ¾ (24.1 nig, 0.026 nonet) were added and the reaction was heated So 60 *C for I l The reaction was cooled to RT, oisriisiened between EiOAe and water, was ed with ferine, dried over l¼SO. : , filtered a»d co«e¾mr¾led and purified over silica gel (2% MeOH i» EtOAc) to afftm! l-(5-fetwyl-3-$2- :meiSiylpys:sdsii-3-yIoxy}pyfaz»i-2-y!) (75.8 mg.0.2!? SMJXS, 73 % yield) as- a w&iie solid.. Mass spednim {apd} /z∞ 350.1 (M-i-H). Ή NMR i€DC¾i S HM =4J 8.45 m, » 4Λ .1 Λ ¾. m \ 7.64 (s, IE), 7.4? is, 1¾ 7,34 (dd, =8.0, i .2 Hz, i.B), 7.26-?,] 7 ( m> 4H>, 7.K) (S , 2M), 3.E0 {s, 2Ii). 2.97 ( 4.7 Hz, 3H).2.32 ¾ 3H),

Fo!!owsa she procedure ia Exarnpk 394, {he following corapounds were also syathesued;

Structure .Name Data

395 l 5- d:i¾yi- « -' Mass speCSiam meihyfpyrid¾i-3- iapci) m.¾ 349.2 yfey}pyridjn.-2-yi}- 3-i.aelliy!are

m e 3' <>

(E)-l-Mem t-3~( ~C2~a^^^ (50 ta , (1.138 a aioi) was dissolved in EiOM. (4 ml..} aad EtOAc i mL) and 10% Pd/C was added, A ί¾ ¼{1OOB. was added ai\d the reaction was siiired ai T overnight. The reaofioa was filtered though Cetiie aad coneeairated. The residue was purified, over silica gel 1 0% BiOAc) io afford l~«)etliyI-3~(3-{2~ 01,2 oig, 0.0-859 mmoi 62.1 % yield) as a white solid. Mass spectrum (apci) m/x - 364.1 ( H). ¾ MM (CDC ) δ 8,85 (q, « 4.3 Hz, 1H), 8. 0¾ « 4.7. 1.4 ¾ IB), 7.55 (s, !H), 7.4? (s. 1 H\ 735 <dd ( 1.4 H¾ ΪΗ), 7.26-7.14 ø»,

II ΐ 7.02 ί it-. 2H), 2.99 (d, -4.7 Hz, 31% 2.82 (is, iiXv. 2.40 »·>. 3Hy

Fol ' lowiag. the procedure ia Example 396, {¾e following coiapoahds were also syaihesized:

2 ? as t> 9 tt thviarca

(E}-I -Me iyS- -(3'-{2 « Hi£M (50 rog, () .1 8 jaiaoH was disso ed ia 2; S THF:water (2 mL) a«d NMO ί 17,8 mg, - . ' l 52 maxol) and 2.5% Gs<¼ (t 7.4 jd, 0,(10 i 38 mmei) ia tBuOH was added aad the teact s was stirred at. Rt overnight. The reaciios was qiiese!ied with 3 uecm$ K&HSOj. pas siioiied et eea fcriae imi EtOAc, dried over N%S(¾, ffiiered and. oHce Snited. ' the sidue was pari ikd over silica get { ϊύ¾ KfcOH i» EtO. ) so afford ! -i ' 5-

nig, 0.0685 asmoi, 49,5 % y ield) as a wMie sold. Mass spectrum (apci) o¾¾ ~ 396.1 ( -H8), *H ' NM (CDCS-i) δ 8.79 {m, IH), 8,46 it -3.1 Hz, J H), 7.64 is, !H), 7.52 (s. IB), 7,30-7,24 ( , 38), 7.21 (d„ -2. Hz, 2Hs.7. i I (m, 2M) ( 4.64 {¾ 2H), 2.99 id. -4,7 H;\ 3¾ 2. S3 fd, -6,4 ¾ iH). 2.82 (d, -2.9 i!/, IB), 2,36 (s, 3M), !H¼«¾Yio.* )-S-( -ffie o^

Step Ar as dissolved ia dioxstss 150 mi) aad Xaiaphos (0.4H2

2-a lne 5,8Cf ml, 33.3 ramol) were added, and Hj was kibbled through the reaclioi! .for 10 mia. Methyl 3-m cat.ptopmpaaoatfc (2, 16 l 200 iimiol) sail Pdbd a s {0.38 i g, 0. 16 ' ramoi) were added, the reactiosi w s heated at 80 tt C for 3 and. cooled to RT (n-ernigltL The reaction was filtered through Ceiite and concentrated, Tfee resdue was purified o er silica gel (80% .EtOAc in Itaanes te

UH % yield) a art orange oil,

SlcpB: Methyl S4be:¾yloxy>6 3-^^ <6 < 3 g.17

!iimol) was dissolved \h THF { HKI mV) mid ½ was biibbled fitougb ¾»r id mm. ! M Potassium 2- rijs ipropaH-2-olate in THF (50 ml SO »aaoi) was added sotrjewaat slowly aud stirred at RT tor 30 seconds iffider N, I -Bromo-3-meiioxy ropaH8 (2.8 g, t & mmo-i) was added and the reaction was stirred at RT for .2 h. Tie reaction was quenched will aaueous ¾CS. extracted with EtOAc, dried over NajSCu filtered sad cosceatra!ed. The residue was purified over silica gel (I I EtOAc in exaaes) lo-afford H3 be¾zyloxy)-5 3-rae^ g, 14 rmnoL 86 % yield) as a yellow oil Mass spectrum (apci) mtz - 302. i ( wi-i). Ή NMR iCDCIj) _> 9:2 (m, m 7.55 {ra, 3¾ 7.47 (s, 1H), 7.41 -730 (ra.4H), 5.40 i , 2H), 5AQ (t, -5.7 Hz, 2H), 332 <>..3H) t 2.91 (d. « 4,7 \ .3i¾ 2.88 (t, « 7.2 K/.2H) : . i .75 fm, 2H). m e 480

Step A; i 3 BenK la y)^H - :tet!)ox iJop Si¾iO (700 mg ; i.94 ramol) i 2~ami»oeiha8etaiol hydrochloride (330 ing, 2.90 mtno!) were dissolved in (M HCI { 10 siL) and heated to reflux for I Sr. The reaction was cooled to RT and tre che mih slow addhioa of aqueous aHCO*. When the pFi reached 7 the reaction was extracted with EtOAc (x4) t dried over filtered and concentrated. The residue was purified over silica gel <5% MeOH la EtOAc) to afibrd i-(3-¾ydroxy~S-i3-raeth0xypropy!tiho)pyr {250 rag, 0.92 ί mmo 47.6

% yield) as a clear colorless ol,

Step B: 1 -( -Hy osy~5^ ^^ 000 mg, 0,39 tataol) was dissolved in tolueae <3 mL) and P.l¾ (96.7 rag.0.309 airnol) and (S)-tett-bmyl 3- hydroxypyr.ro1idin.e- l-carboxylais (69.0 mg K 0.369 o ' i) was added d stilted at RT under > . WAD (73. Ϊ pL 0,369 mmol) was added dropw½e aad he reactfoa was stirred at RT for Ϊ h. The reaeuoa was coaeemrated. and purified over silica gel (SO t© 100% EiO Ac m exanes) (a atlerd enide material. The residue was dissolved in. EiOH md excess KjC0 5 was added md stirred at 75 *C Overnight. The reaciioa was cooled : filtered, eomsmrated attd putt Red via reverse phase <C«¾, 10 to 9 % ACM in water) to afford. (RHerpbuty; 3 3 -rpethoxypr0 Sto

3-y!osv)pyrro!!di!:(e-i-ciirboxyiate(58 i 3 mg, 0,132 iflrrtoS, 35.9 % ield) as aii amber glass. Mass spectrum (apd) m/z - 441.2 (M-HS). J H E (CDCI;) 69, 16 " (m, I H} ? 7.83 (s, IH), 7.24 (m, IB), 7,06 {IB, H\ 4,92 (m, iH), 3.69 uky -12.7, 4.3 ¾ l), 3,66-3.49 (ra, H), 3.46 ft, -6,1 H . ,2H), 3.3:2 (s, 3H), 2.96 d, ~4J Hz, 3H), 2.90 (i, « 7.2 B , 2H), 2.1 (m, 2H , 1.84 (m, 2H), L49 (s : , 9H

2 " 6

latao.) was: sifs ei).ded la C.¾<¾ (I raL} arid NF% {61.4 }i ' L, 0.4 1. moi) was added .and stirred at RT. Ac 2 G (8,33 ΐ,, 0.0881 rarao.) was added and stirred at S.T for 20 mm. Tae reaction was partittoned bet een aqueous atlCO? a¾d dii¾d over ¾SO¾ filtered aid concentrated.

The residue was purified ove silica gel (5 IQ eQB t¼ BtOAcj itt afford ! -i.S-il-'

ecrylp! eiidlH- -ySdio)-3 2-ffie i as a wMtc solid.

Mass s e trin (apci) m¾ ^416,0 (M÷H), ¾ NMR (CDC ) ύ 9.20 {q t * « 4.3 Hz, {H 8.42 (dd, -4.1, I.S¾ IH 8.01 (d, =!.!¾ 1H), ?,3i-7,23 (m, 3H), 6.S8 id, IH), 4.32 (in, IH),

3.76 (m, m, 3.52 (m, IB), 3,05-2,9? Cm, 4M).2.83 (m, Sl¾ 2.48 is, 3B), 2.0? (s, 3E>, 1.8* (m, IH), Ϊ.44 (ra, 2H).

Following the procedure in Exam le 4 Π , t e following compounds were also synthesized

m *> 4 S ' )

iftfeydroc&iorid (50 njg, 0, ϋ» imnol ) was suspen ed i« {¾t¾ { ! mL) in a vial aad ' ϊ¾ (75,7 pt 0,543 mraoi) was added, ollowed by 2,5-dchtoru sinidiHe {16,2 jng, 0.109 mind) and sealed. The rcacdors was lieaied to 40 *€ fox days. The reaction was cooled to RT, concentrated and p rified over silica gel SO to 100% EtOAc m hexaaes) to afford

tag, 0,0492 raol, 45.3 % yield) as a white solid. Mass spectrum (apd) miz ~ 500,0 (M÷H). ¾ M R (CDi¾) 59.1 (q t ~4. Ez, 111).8.50 -35 ¾ M> ( 8,2 {m, 2i¾.8.0] (d. -2,0 Hsr, I ), 7.51 is,. :!H), 7,22 (d, -3.1 Hz, 2H),d. 7(d f ~L8H¾, Ϊ.Μ 4.5! {¾», 2H}. ; 3.30-2.97 <SH), 2.70 ¾ « 7.6 Hz, 2H>, .90 to, 2H¾ 1.48 (m.2H), 1.2? (t, =-76 ΛΗ m e 2i)

( J51 i¾i II>9a)«iol rwere dissolved m DM? (2 mL)a»d heated to 70 "C Overnight The reaction was ooaceftoated and purified over silica gel (2 to.5% MeOB. m EtOAc) so afford i-{5-< -(5~ e !or p tt¾,d«-2- l)^ i ' 0.020 « 0.0400 iraao Ϊ 4 % yield) as yellow solid. Mass.spectn«a (apei) m/z » 500.0 (M-KH). ¾ ' R (€BC¾) * 9.08 (m, IH), 8.51 (i, -2.9 H¾, IB), 8.04 (d, -1.4 Hz, 2Ή), 7,83 (cl -L4 M¾, ?H), 7.4" ( ¾ IH).7. 1 (ia ( 2H),6. i iro, 1H>, 4.12 {*¾, -:!3.<A J ¾ 2H), 3. !0-3,0I (m, 3H), 3.00 d, -4.7 Hx.3H), 2.89 (m, 2.¾ L95 (m.2H). ] .60-1.50 (m, 2H), .132 ft, -7.6 Hz, 3H), m e 421

|SH-¾sthyj-3-{¾B^

Step A:

yiihfo)propaKoaie (0,200 g, 0,480 Hirtjol) was dissolved at THF (5 mL), N was b bled thougfe for 5 tmn, iet! IM potassiom 2~me%ip'opa:a-2-siaie i« IMF ( } .44 mi, 1,44 xomsl) was added and suored for 30 secoods. Ten-butyl 4½dop¾>endine- Ί >cwfax 1ate (0.1:49 g t 0.480 ϊόϊοοί was added aad die reaction was stirred at RT overnight.. The reaction ax quenched with saturated .¾CI and extracted ith EfOAc and CftCk The combined oganic layers ere dried over N¾SO, : , filtered and oriceatiaied. The residue was purified over silica gel (0 to 5% MeOli is BtOAc followed by 5% MeOH in€:¾€¾) to afford (S>tert-bufyi 4 6 3-»iethyhireido)-S-(3 i 6;~,8^ yte )p iid!a-3-ylt|Ho)pip«idi:iie-l-caiteyl.ate 00. Jpg > 12.2 % yield).

yltM0}piperidiae~ 1 - -bosykte (0.030 g.0,058 mmoi) was dissolved in CHC½ (5 mh) and a few drops of MeOH. N HCl 'ia dioxaiies (0, 55 aa\ 0.58 mi) was added atttl stirred at RT overnight. The reaction was ttmcceirated i xmd cude is nest step.

Siep C; (S)-t-Met yi»3-{5-^ipeiidi^4^S:iaio

2-yl)wea dihydroc torid (0,028 g, .QSSs mt il 2-cMoropyfi k!!ae (0.00¥¾ g, 0.058 mmoi) arid N~ fivyl- s0 TO yl opH-2-aHj«re (0.050 0.29 mmoi} were dissolved ia DMF (i rtiLj arid ' healed to 00 1> C for 8.h. The reaction was cooled aa coaeestrated padded tisiag prep TLC with 5% MeQB. ia EtOAc to atlbrd (S)-l-meOwMK^

ietrahydro uinoSia-S-yioxy)^^^ (0.0 H) g, 0.020 maioi, 35 % yield) as yellow solid.

Mass spectrum (apci) mz - 492.0 (M ¾ R (CDC¾) §«U7 (q s -4.7 Hz, 1H).8.57 (dd, , I .<) Hz, 1H), 8.29 (d, -4,9 Hz, 2H), 7.92 (d, - i .8 Hz, 1H), 7.60 (dd, -7.8, 1 ,2 Hz, iff), 7.32 (s, 2H} S 7,18 (dd, -7.8, .7, 1H), 6.4H ·'.. -4.9 Hz, Ul>.5.45 -m. ill) 4.0S (d i 3. : S V 3,9 ffe, 1H)> 3,20-3,06 (in, 4B), 3,01-2.92 (m, H), 1.19-1.87 (m, 6Ηχ 1.59 <ra, 2R>. ta «422 dihydrocii!pttde

i~M ' ethyK3 3-(2-»teThytpyo

trtilnofoaceiate) (100 mg, 0.166 rao) as suspended in .DCE (2 mh) and N-ethy i- - isopropylpropan-2-an.iiae (57.9 ul 0,332 nm¾ol) aad propjm-2-one (122 jd, L66 aitae!) were added aad stirred for 10 Mill. NaiOAe BH (88.1 aig, 0,4 i 6.mraol) was added and th reaction was stirred at RT over the weekend. The reaetioa was partitioned, between a ueous NaHCO ? aad C¾C¼ .> dried over sjSO.;:. filtere aad concentraied, The residue was purified over silica gel (10% MeOM ia EtOAc with ¾) its afford M5-(i sopropyipiper ir^^

2-yl)-. «tethyiurea dihydrocidoiide (40.2 rise, 0.0S23 !, 49,5 % yieidj as a white solid after HC salt .formation. Mass spectrum (apci) am - 4iO.I (MH-i-2-HCi}. S HN R (4-D SO) § 10.55 (m, Hi), 9.29 (s, IH).8.90 (ni, ii .8,46 (d, -5,3 Rz. !Hk S.21 (4 -2.0 tfe. ϊ II v.7.87 (d, -8.4 Hz, IE}..7,76-7.6$ (m, 3H% 3.69 (ni, JH), 3.48 (m, 1H), 38 fjjj, iM), 3.29 (m.2H), 3.2S~3,05 : (m, 2H>, 2,92 (S , 2ii}, .2,73 d. <i 1.2.02- 1.85 (:fis, 4H>.1,22 (d, -6.6 Mz.6H), m e 23

Meibyi 3H5-G-edr34pyidra^ ( ί 00 mg« 0.256 aimol) was dissolved to THP Π..5 ml * } , IN aOH (256 jit, 0.256 im«oi) was added aad the tsaciiou -was stirred at RT overnight. The reaction WK poured into water aad extecied wth ElOAc. The aqueou Saver was acidified to pH 4 and extracted with 10% eOH iivO¾t¾ to afford an oil Tie ol was. purified ia reverse phase C t », 10 to 90% ACM in wafer) to ail rd 3~(5-i ' 2-

52.0 % yield) as a to solid after dryin . Mass speemsm (apes) m.¾ - 377.0 ( ÷M). ¾ NMR (¾- MSO) 68.90 (q, -4 J Hz, IB), 8.70 (s, IK), 8.34 (dd. -4.5, L2 H?, J.H), ¾.0i (d, .6 Hz, 1H) 7.30 (dd, -8 ¾ I.H) 5 ?.25(dd t s; 8.0, 4,5 Hz, iH), 7. E (d, = ; ( SHzJH) } 2.95 (t -7,0 Hz, 2H},2.K2¾ -?,4 H¾ 2H), 2.78 d, -4,7 Hz, 30), 233 fm, 2H), 1,20 (t, -7. &.3H). m a 424 su dvyksrea

Step A: (S)-Meihyl 3-id-G~i S:¾ hira

yld)!o) ropa! ' ioate (0.200 g, 0.480 nxnxol) was dissolved in IMF (4 mLi. ? was bubbted though for 5 mm. IM Potassiiit 2-}Wthy1>r0 ' aii-2-olate ia " f ' HP { f .44 trd, 1,44 mtnol) as added and the re&etfott was stified at RT lor 30 seconds. (S)- 2,:2-Djme i « i dtoxol ii-4-y])«i l 4~ raethytoaseoesulfoaafe (0 J 88 g.0.624 asA) $ added atid the reaction, s stirred at RT for 2 Is. Jim reaction ¾¾a quenched with aqueous N1¾Q sad ecitsfiejjtsated. T¾s .residue was purified over silica gel (0 to 7% McOHin EiOAc) to affor :t-{5-(2-( ' (S)-2,2-d»Hei.byI- i ^iaxo m-4- y!}et!ry!i o)-3-(C$)«S.^ (0.136 g, 0.297 iiiHioL6S. % yield). issolved i« eOH (4 nit ! and 4 HO in dioxaoe (0.222 inl Q.890 ramo;l) sad B : .0 («.267 g, 14.8 mints!) were added a»d the. reaction was sirred at RT lor .2 h. The reaction was concentrated aad purified over silica gel (100% EtOAc followed fay 5% mtaamtied MeOH in C%C¾) to aiibrd K5-iiS)-3,4.

0.210 l 70.9 % yield). Mass spectrum (apci) mz · 419.2 (M-H¾,. ¾r N R. (OX¾ . ) (q, «4.7 Hz, IK), 8.54 (dd, - .7, 1,6 ¾ 1 H, 7.85 (d, 1.H), 7.59 (del i .4 Hz, IH), 7.3 i

(m, 2H1, 7.1? (dd, « 7 4.9 ¾ IH), .5.45 (m ; JHX 3.87 (a, i H) v 3i54 (dd 4 -i I 3.3 Ife, ill), 3.45 (ckt. 10.0.7.210?. i H) s 3.15-3.01 « ' «·, 21¾ 2,99-2,88 (m, 5H) :( 2.17-2.00 (m, 3.H), 190 {m, !H). i.82-i.60(m„ 2H).

in <· 427

(S}~ S -( {Cy ^eoi-3~ea ii]»0)-3^

lasthyfeirea (OJ.O0 g, 0.252 mmtf}, was dissolved in TB.F (3 tnl). NMO (0.0768 0.328 mraoi} was added: followed by 2.5 t% Os -s ψΜΙύ l, 0.00252 mmol) in. t-BuOH.1¾ reaetfoa was stirred at 8X oversight. The je¾ iios:i was pss1itioi¾d. b t een aqueous sad EtGAc dried over >¾SO. }< filtered aad. concentrated. The residue was pitriijed over silica gd ( SO io 20% MeOH ia EtOAc) to afford crude material tdeh was purified a ain via reverse phase {¾, JO lo §0% ACN in water) io afi rci I --i S-tcis^ dSs dros eycIog^^^

iefra ydroinxbJolia-S-yio^ (8,0 tog, 0.021 rarao!) as a wlsite solid. Mass spectrum (apci) m¾ = 43 *M ; †|¾, Ή HUB. (d s -DMSO} S 8.9 (q, -4.5 I¾, iH 5 8,4 (¾ =4.7, \ ,0 is/. SO 7.82 (del - . , 1 ,6 <{ ..1 Vr,.7.75-7.68 fm, 2H) f "57 (d t -7. U . ί H , 7,25 <dd. -7.8 : 4.7 Hz, I H 5.7S (t 1 H} : 4.51 (m, 2Bs 3.94 ¾ i tt), 3,70 m, 1 3.3 S (§, 2l¾ 3.00-2.78 0«, 3H , 2.75 (d > -4 H¾, 3% 2. J9 (tn, i¾ I ..84 <m, IMX L69 <m, 1H), .1.6 (ox iH),

Following the procedure in Example 427, Use foiloviag comptmad was sitfhesized:

m e 429

lH3-(2 ¾¾yI diB « 3~ io^^

0.55? misol) ant! PP¾ (146 tug, 0.55? miaol) were added imd stirred at RT. DI.AD (i 10 uL 0.55? ttamX) was added dropwise aad the rcacti a was stiffed at RT for 3 . T¾e reacrioti was partitioned between water aad O Ac, dried e ver N¾SC !. filtered and coiieenrraied. Hie residue was purified over silica gel to afford a mi ture of P(0)P1¾ and. traas-4-(5-(2-ethyip ndtH-?-y1ox }-6-(3- methyl«reido)pyridBi-:J-y½»0)eyci0i«exy'l -»«roteiX05rte i 192 x»g > 0,348 mmet Kit ) % yield).

Slep B:

ylt¾to)cyciohexy:[ -ftiifOtei2 5«e ( 192 tag, 0,348 tmnol) was dissolved in THF (3 laL) afid IM aOH (696 μΐ .696 raraot) was added and th action was stirred at RT overnight. Th reaction was partitioned between t¾Ci & ¾OAe, dried over MajSO.*, filtered arid eoiseeairated. The residue was purified via reverse ph e c¾roji«atogTaphy 10 to 90% ACN m water) to afford J- (3-(2-e%i yridm- -y:^

0.0914 wmol 26. % yield) as a clear glass. Mass spectrum (apes ) «¾¾ * 403.0 (MrH). ¾ NMR (COC¾) $ 9.14 (m, IM), 8.49 (m, 1.H), 7.90 (m. iH), 7.53 ( IE% 7.21 2H) : 6.85 (m, IH). 3.60 IH), 3,00 <d. « 4.? M¾ 5Ηχ 2.83-2.70 (is, 3H) ; L95 (n¾ 3H), MM .55 ( , M Ϊ .36-1.20 (n% mx m « 430

Step A: H3-{BaHyio>;y)-S 3-rimiboxypropY^ (700 sag, i .94

Ktiaol) astd 2-8sai5:ii il:i 5MS«ol hydroelitodde (330 sag, 2,90 rnmoi) were dissolved in 6M HQ ( H) xxtL) and heated to relltix for 1 S The reacfc ' oa was cooled to RT and -quenched with stow addition of aqueous SiaHCO%, When pH reached ?„ the reaction was extracted wit!) EfOAc ix4? ) dried over axSO f c filtered aad concentrated: The residue Was purified over silica gel (5% MeOH in EtQM) to afford H3-¾:ydroxy-5-(3-raethoxyprapy½^^ (250 mg, 0.921 amol 47,6

% yield) as a clear colorless oil

BHaoi) T for 10 mm. 2-Fiu0ro-3-(iriiku romethyl) eiizonitrile (58. i pi, 0.405 xmrni) was added aad the mct &x was steed at RT for 7 h. Use reactioa as quea ied with sat H¾Ci <SmL) and extracte with 20mL 0¾C¾ and concentrated in vacsio an placed a high aemsts over jxig i to remove DMF, Pitrifed -using a gradient from pure EiOAc to 10% McOHEfOAc to iseiaie i-(3^2-cy¾ne-6-

mmo\ > 3.4% yield) as a fat! solid. Mass speetmffl (apci) iwz = 441.1 <M+K>. S H NMR fCDC ) δ 8.93 (br S, ill), 8 ( , j ^ 7, jfe, !HK S.0I <d, J ~ S.O !¾ Itt% ?.?3 (m, ill},.7.00 (d, j - 2. ¾ I H), 7,37 ¾ j - 2,3 , 1 H) : 4.34 i hr 5, IH) S 3.44 (m, 2H), 3.30 s.3Bs.2,95 O. j - 7,0 Β.··:, 2Kh 2,91 id, j-4,7H¾2H¾ ί 8ί.<η·.2Hi. ra a 431 v¾h -t¾¾eh : i rea

l-(3HiS-EiiYS.lH-pyfaz i-S-yi}ox )-5- :te»:a1w

S ihylurca (0.02 i g, 0,0572 onaol) was dissolved is TMF and N-chlorosuccima¾de (0.037 g, 0,275 mtttol) was added aad sdrfed-at 50 : C for 2 is. The teactiosi was ottceiitnited and the crude mixtu

2H), 3.95 id! « I , 3.5 Hz, 2H), .37 (til Hi 3, .3 Hz, 2M), 3,07-2.98 (m, 4H), i.SO (in, 2H>, i .59 (jm, 2H), 1.39 it, -7.2 Hz, 3Hs.

t» e 32

i - 3^(3-¾seih^^

.Step A: 5 » BK!rao*2-di]oro-3-Sl«oropyiid»ie (2.0 g, 9.50 aimoi) was dissolved 18 30 oil DMSO. I ,3.5"Trimei¾yi~.i fi-pyrazol- -ol (1.20 g, 9.50 oi) and { .5.0 g, 9.50 rotao!) were added aod the reaction was stirred at RT for 3 days. Water (300 mL) was added which produced a white precipitate which was collected by filiratiaa, washed with water am! dried under .high vacuum to give S~b.roKio-2-eli!©ro-3~i .1 ,3.5-o1me^yi~l H-py ¾l- -yiosy)p>dd«¾e (2.16 g. ?2¾) as a white solid.

Step B: 5*.Broa>o.-2-chloro-:MW (0.500 s 1.58 fiimo;), DiEA (0.550 ml 3.16 iHiaol) and Xanipbos (0.0 14 g ( 0.158 mtmt were dissolved is dtoxaoe and degassed with Ht i¾r 5 mia. P vf ba);; (0.0733 g, 0.0790 fsmoi) was add d. K 3 was bubbled thou h for anote 5 nun and 3-meth©xypK)pa»e- 1 -thiol (Ο.2Ϊ0 ml 1 .58.mmoi) was added and. the ieactfoft was heated to 50 : C for 6 The reaction was partitioned between EtOAc -and wafer and the organic layer was washed with water, then briae and dried over SOi aad thes concentrated to a bro n oil. The crude mixture was purified via silica gel chromatography

(hexasies/acetone) to give 2-chi ro-5 3-i«efl:a^

yloxyipyridirse (0.444 g, 82%) as a clear oil

Step C: i-Met.hyiurea (23, rag, 0,322 mmoi% 5-idi-ieri.^ tyip¾ospS ino) (3 S'-tnphes ' iyS- ΓΗ- 5 ,4 " -hipyra¾:oie ( 16.3 mg, 0.0322 xmxml) and K PO< {51.3 m , 0.242 mvaot) were taken up in DME as a siurry. was bubbled though ibr 5 mia. Mi(dba)> (738 aig, 0.00806 mmoi) was added, j was bubbled though ibr 5 mm and the soluttoa was stirred tor j boor at RT, A solraioa of 2- chloio-5-(3-aieii)oxypropy lthio)-3-{ 1 ,5-trimethyl- 1 H~pyra«d-4~y iQxy)pyridsoe (55,1 rag, 0.161 rraaoi.) in DME was degassed will] N : > for 5 mia, added (he reaetios and was heated to 120 " C for 48 h. The reaction, was partitioned he-tween EtOAc and. water and the organic layer was washed with water, then brine and dried over ¾$(¾ attd to s concentrated to a brown ail. The crude mixture was purified via reverse p ase C ; * e}irooiatog«¾phy (witteoMeC ) to give 1 -{5-{{3- i!5Cihoxypropyl)ri«o)-3-((i,3 ; S-iitBie!iiyi-I.Hi>y <0;006 ' . g, .1 l¾) as a ear oil Miss spsctomi (apd) m/z = 38.2 (M+H). ¾ .R (CDC¾) δ 9Λ4 (q, : - .5 f.k. ΪΜ), .8 (d, ~ϊ .6 Hi, 1MX 7.S5 (s 5 Hi).6.87 id, -1.7 ¾ iii-.3.75 ; . ·>.3i¾ 3 5. (t -5.<; Hz. 2H>, 329 (s, 3|¾ 3.00 u =. - . Hi, 3M), 2.82 (i, 7.2 Hi, 2i¾ 2.08 (s.3H), 2.02 (s, 311), 178 (κ·, 2H). followin i¾© procedure in Exa>:npk 432, the fti lowfeg cosmos, mds we also sysilissi ett

2.88 Followmg t&e procedure- is Example 432, Step C, the following compounds were also s>Othessi¾ed using either aad S-cdi-tesl-boi) Sphosiihioo}- \ vy,5~fcrjpheoyl- V -1 , M»pyr&£6te or I,!'- hiMp:h )- -ld e^fetu ^hosp]mie as ie iigasjd:

m e 44 " ?

Step A: 5-BE¾nio- -ftuorop ryis:i-2-amli5e {0.200 g, ! .05 tnmoi) was dissolved in C¾C1> and pyridine (0.254 ml, 344 «»»ol) ws added followed by 4-aitroplienyl carborsociiioridate (0.44 g, 2.20 mrao!). The te im* was stirred at RT for 5 & Me&yiamine (0.52 l 4. I S rarool) m EtOH was added and stirred for 2 li. Water was added, Uts layers were .separated aftd (he organic was dried over ajSCXfe filtered and CGOceu&ated. The crude mixture s purified via silica gel

chmmtttograpty (hexanes^ace&me) to pve S-{5-l3roino- ] ororjyridi«-2-} )-3-methySorea (0.135 g, 52%) as -a tao solid.

SiepB: i ^5«8ro«K>-3-fl»tx) yndr«»2->d 3-a)ediiy.Utre (0. 1.0 g.0.040 xsajol), S -methyl- lH-i«da¾0l-5-ol (0,0066 g, 0,044 mmoi), ? CO¾ {0.011 g, 0,081 mtml) were takeu. up in NMF and knued to 80 °C for ί b h. The reaeiioii was pariluoncd. between. EtO Ac and water ant! the organc layer s w s ed wish water, thea bone and dried over tto -concentrated to a brawn oil.

The crude misiiire as purified via silica gel e¾re:3!.aiograpiry (he anesac-eioKe} to give ^5^rao)®> 3-f (i-r eifeyi- J.M-m^ (0.010 g, 67%) as a clear oil. Mass spectum (apd) mis∞ 76.0, 378.0 ( +H), m e 448

{.netftylnrea

} -( 5-Brorao-3-< l -n ' ietbyl-lH-ind5^oi-5-yloxy)p :rfdtt>2-yl ^-»Ktfeyl«rca (0.0085 g, 0.023 rraaol) * 4-inercspto-2-meibyi.h«taB-2-oi (0.0030 g.0.025 mnsoiK OI.EA (0.0079 ml, 0.045 tsraol), and Xa:o!phos (0.0013 g : .0.0023 mats!) was dissolved is dioxase and 1¾ was bubbled diougb for 5 nun, Fdd a : ¾ (0,0010 g, ,0G ί i mrnol) w s added, !% was bubbled though for 5 ruin and the eaction was heated to §0 °C tor ob« h. he reaction was partitioned between EtOAe and water and the organic layer as washed with- water, t es brine and dried o er N jSO:* then eo»ceotrai¾d to a browit oil. Use crude mixture was purified via silica gel chromatography (hexaaesacetoae) to give ((i-lw ' roxy^niethySbuM

as e 449

Slep A: To a flask was added Lit! (159 «sg, 3.74 max*) aad die .flask s dried wader high vacuum at 155 *C for 3 min. Theu. zm (269 tag, 4.12 mojol) was added sad the flask was dried again under high vacuum for 20 min at 155 . The flask was cooled to .RT and auhydroas THF was added (5 ml) under M> followed by ! ^ibroraoethane (0.016 ad,, 0.187 nmml). The flask was heated to 6 °C ills a heal: em briefly, cooled aad ii (4.75 pi, 0,037 maso!) was added. Afte siirtiog briefly, 5 drops of ! M solution oft..in THF as added. The teactkai -w s stirred ' briefly and 4-{broiS0o^dryi}ietra ydro-2.H-pyTaa (670 tag, 3.74 mrnol) in I mL THF was added. The yeaeiioti was heated to 50 a C overnight ie afford f;(tei:ra ydro-2H-pyran~4- S}i:rjeriiyliziac(II;i braraide (0.024 M, 6 mL). After the st¾¾c settled, the reagent was used directly for the next step,

Step B To a Bask, with

(85 rag, 0.252 n«:ooi) was added diaecrosypaliadiiits (5.60 trig, 0.025 jamoi), S-PSJOS (20.70 :tag, 0.050 iunioi) and the reaction i ssk was put on high. v¾ t«3:n. uiap for 10 irsinates and. fhen Ailed iiit j. Degassed THF (2 mL) was added followed by ({toirabydro-2H^ ^- i)ii ray. zinc(£I) bromide (I 056 a¾L, 1 .008 ttw)) generated im in previoas ste . The reacOoa was heated to reflux for 7 h. Saturated H.,Ci was added aad Use mixture was extracted with EtOAe. The EtOAc layer was dried aad coocentrated aad purified wisii silica gel chromatography (0-7% MeOH ¾Clj gradient sepanstiO ). The ft ctiosii ; eoaiaiijed the prodaci was further purified by reverse phase ftPLC to afford 1 * eihy! » 3-(3.((2-«:rt

ytlnrsa (47 tag, 0.132 mrnol 52.3%). Mass spectrum (E i) /jt - 357.2 (M÷H . 5 H MM (400 MHz.. CBC¾) d ppas 9.16 ¾ -4.1 1 H/. I H) S .34 (ΐ,. -3,03 Ife, 1 H i 7.01 - 7.76 tm, 1 O) 7.32 (s, 1 H) 7.12 (4. -3.13 ¾ 2 H) 0.55 (d, -1 ,5? i¾ 1 H) 3.S5 (dd, -Π .25, 3,42 Hit, 2 H) 3.10 - 3.31 (m, 2 H).2.92 (d, -4.B9 Hz. 3 H) 2.41 i s, 3 H) 2.33 (it ~7M z, 2 H) l .47 - 1.53 (as, 1 H) 1.41 (d, -13. i I Hz, 2 H) i . 13 - 1.27 (m, 2 H).

Following the procedur in Example 449, the following compounds were prepared:

Folic • tttg ibe proce ure nx Example 449 Fart 1 3, the follovviiig coiapouac >5 were prepared:

m < > 466

To a flask witb ($H-{5 3^2,2~dvme¾yl-i J^^^ ^

yl)ox )pyridift*2-yljh3-i)K8iylH(¾ii ( 18.9 mg, 0.04ii ϋϋηό!) was dded EiQH (1 ,4 mL) aftd 0.14 fill. ΪΉ HCl The rea tion was heated to 70 *C for 2 h. ' Water was added followed by sons saturated aH ' CCH solmlon to neutralize the reaction to $M 7. Then die reaction was extracted with EtQAe. The EtOAc layer was dried sad coaceatrated. The crude product was ritssed With E¾0 and filtered and dried to iUTord (§)«.! -(5 4,5-dihydroxypmtyl

melhyturce ί 15 rag, 0.040 mmol, W%). Mass specraaa (ESI) nz - 37 .2 {M÷H>. Ή MR (400 Hz, eOH) δ ppm 8.30 (dd. - .09, L37 Hz, 1 H) 7.91 {d, -1.37 Ex, I H) 7.41 (dd, -8.22, U ¾ I 11) 734 (dd, -8,31, 4.70 ¾ I Η) 0. 6( -1.70 Hz, I H) 3.52 - 3.65 r«, 5. H ' ) 3.38 - .3.4.6 fH„ 2 i l l 204 is, 3 H) 2,80 (q„ -7.03 H¾, 2 H) 2,47 - 2.6S im, 2 Hi 1.66 - S .78 (t», 1 H) ,4S - S.,04 ( , 21-1} 1 ,36 (ddil - 1 ,35, 9,(?5, 4.211¾ ! }|) 1.29 (i, -7,53 ¾.3 H ni e 46?

H (2-<¾hyl yrid^

A iksfc if ethyl 4-(54(2-eftiylpyTidis:i-3~y]}^

(1.2 ffig, 0.031 motel) was a¾eetroped with toluene. hen anhydrous. E½Q (1 uiL) was added. ¾ ¾sk was carded in ice-bath. Then mei¾yttit ti sohidori, ί />m Ei¾0 (0.007 mL, 0.155 msrnX) was added dmpwtse asd a white cloudy mix formed. The flask was raised to RT. to THF { Ϊ .0 mt) was added. The re cts©!} was stirred for i h and quenched with saturated H 4 CI sotoiioa. lite reaction was extracted with. EtOAc, dried a»4 coftcesifttte. ' The crude was purified oa reverse phase HPLC wii!i i -40% gradiem to affoid 1 <<:H{2-elhy yridm-.-yl)0xy 5-( ' 4-hydro^-4- iieti j y ipeui y i>p ντΐΐί i β -2 - y ί- 5 -tie iity [«t¾a (3.2 nig,.0,0086 mmol, 28%). Mass -spectrum (ESi) intern? Hi NMR (400 \!H,>. CDCE) S ppm. . < 4 ==4. so B;-\ 1 H) 8.3(4 (i, -3,0;? H¾ 1 H 7.69 i¾ -1,76 M¾ .1 ?¾ 7,32 {s, 1 H) ?. Ϊ0 id. 2.05 !i .2 H) 0,60 id, 1.7 H¾ I H 2,92 (4 -4.69 ϊ¾, 3 H) 2.69 - 2.80 », 2 H) 2.40 fj, -7.53 Hz, 2 H) .{ .45 - 1.55 (ra, 2 H) J .32 - 1.39 (set, 2 H) LZl (I, -7.63 .4M) U0(s, 6 l-i).

Foll jag the procedure in Example 67 the following -corapouuds were prepared :

m « 71.

S-f¾3J,di yfe2^

T© a stirred solution of 3 H5-l«orao~3K{ -m ii^

(65 sng, 0. m mmel) h 2.6 mL degassed. F was added MiPPluk (22 tag, 0.0s 9 immi), 3 CO.? (80 jag, 0.578 mojoi).2-0,6-diSwd:ro-2H-pyra^4-yt}^ r .2-doxabomLw (8 i sig.0. 86 mmol). Stirring coatinued at KXPC overnight Water was added to queael.t me reaction and the ixiwt was exfraeted with EtOAc. The organic layer was dried and coa emraKd in vacuo. The cf¾cte produci was. purified on .siMca gel to afford 37,5 i»g l 5-(3 ^d¾ <iro-2H > pyr«)-4>-yl 3* ({2-niethy3pydd:isv3-yl}osy)|?yr {51%% Mass spectrum (ESI) ~ 34 i .2

(M+H), ! n NM (400 MM¾ C.DC ) f 9.25 (d. ^ . 0 M¾. i H) 8.43 (dd, 4. { 1, 2.1S ϋ,;·. S H) 7.96 -1,96 ¾ I H) 7,46 (br, s.„ I H) 7,15 - 7.26 (HI, 2 H) 6,85 (ά, -1.96 Hz, I K) 5,87 - 6.00 (m x i H) 4.26 q. -2.8? ¾ 2 R) 3,89 (0 ~ 48.¾ 2 H) 3.01 (d, -4.69 ¾ 3 H) 2.51 ( f 3 R) 2,3.1 - 2.43 (m, 2 H.}..

Following the procedure io Example 47) the following compounds were prepared:

ns e 474

To a soiu&Hi of i 54 ^-d£ y<k>-2H~ m^

y!)-3-met yJ«iea. (29 mg, QMS mxml) in EtOH. (0.852 tnL, QMS mxwl), EtOAc 0.8S2 tuL, 0,085 lass!) was add d Pd/C 08.13 mg, 0.017 mmoi). The mixture was first purged wish H ;! i m stirred K«de.r ¾ baloo for 24- k The reaction, was filiered. iSiow ii a pad of Ce!iie and coocentrafed to afibr

(75%). Mass specimra (ESI) m/z 343.2 (M-H!). ¾ M1. (400 !¾. CDG-?) S 9.24 (br. s., ! H 835 - 8.5 } {fn, I H) 7.« (d, -1.76 i¾ i H) 7.41 (br. , I H) ?.I4~ 7.24 <rft, 2 Hi 6,69 (d, ::: ! .76 Hz, f B) 3,98 - 4.09 (on, 2 H) 3.46 (td, 1, 5, 3,33 H¾ 2. H i 2,89 - 3. H5 pa, 3 H) 2,56 - 2.72 S H) 2.49 (s, 3 1.57 - \ .74 («L 4 H).

m e 476

A itesk

{ .lSOg, 0,427 mmol), FdC¾{PF¾)i < (80 g, 0.043 nmtoll EkN (0.048 ml, 0,342. terncS), pheaylaeeiyteiis (0.094 ml, 0.854 mrnol), and Cai i I .447 μΐ 0.043 ramol} was purged with .> ia

29? dark. De assed IMF (2. i 36 ml) was added. The reaction was heated to r/eflyx in die dark overnight !tei cooled to T. The reaciioii was diluted with EtOAc. washed th riae, dried over gSO^ fUtored aod coaccttttatod m. vacuo to give the crude fiiaterial. The enide material was pu ied by si!iea gel chrormttograp ehittog with 0 % to } 0 ¾ MeOH CMjCi ¾ to provide l-0{(2- ei ylpyftd R"3-ylio y)-5* lKHy (0.530 g, 0,349 imttoi, 82 % yield) as a white solid, Mass speeiniffi (ESI) XfU ' z ~ 373.0 (M-v.H). '.Η NMS. (400 M¾ CiX¾) S ppm 8,51. ( i l , d¾l "4,5, 2,0 }¾ 8. ]0 ί 1 H, d, -2.0 Hz), ?. S ( " i H, eld, ::: 6.7, 3.0 H¾ 7,20 - 7.36 (6 H, JB) 5 6.89 (i d, -2.0 ¾}, 3.03 (3 H,4 - Hz), 2.83 (2 H, d, -7. H¾ 1.33 (3 H, t, - .4 ILO.

s¾ e 47<>

Step A: To a sototton of l-(3-{(2-ed)ylpyddia-3-yl)os: 5--Cphe!}ykdiyayi)pyj-idii!-2-yl)-3- met y himt (O,0I3 g, 0.033 iraaol) m EtOH O. 70 m!) and EtOAc (0,7 Hit) was added Liadlar catalyst (2, rag) at 25 * C, The reaction was stirred s; 25 ;> C uader ¾ atmosphere overnight id give. a mixture of B and 2 oieila iroi mie. A), Step B : To a solutim of

raethyhirea (0,022.g, 0.059 mmol) ¾» foHieae (0,537 ml} aad ϊ¾0 (0.054 ml) was added (Pd(dppf)C¾ (0.724 ta , .S86 iimal).. (1.637 mg, 2.95 μχηοΐλ trtetaylstlaas (0,01.7 ml, 0.1 sulfate pea!ahytoe (2.212 nig, %M μχηοΙ) at.RT. The reacton was lieaied to reflux Overnight The reaction was coiice trated to give a mixture of E arid Z ofei!a (mixture B, This; t puri/ usieg pre arative HPLC to give {2}-l-(:H2--eth lpyri4« ?- y x ^S-sty^lpydd i^-ryi s-imei kteJt 0.00 Ϊ 3 g.3.47 μχαθΐ) as a whi!e »iid. Mass specgaas (ESI) m/« = 7 0 {M Hji, l U R (400 MHz, ET A O -t¾)5 pm ' 8,29<t 11 d " 4.3. 0 Hz), 7.89 (1 H, s), 7.02 - 7,27 Π B, t«>, 0.68 (.1 Hy d, - . Hz), 6.61 (I E, $}, 6,48 (2 Ή. ! H s d, -9.0 ife), 2,920 H. s>, 2.6? (2 R, ¾ -7,5 ¾}, .1.15 O H, t, -7,5 Ffe),

To a. solution of

(0,020 g s 0.054 mad ia MeOH (0,537 ml) a»d Bi.OAe (0.537 ml) was added Pd ,57 mg,.8.00 μκκ»Ι) at 25 °C. The reaction was stirred at 25 a C utider I atm of¾ alawsphere overaigSsi The Mixture was filtered Ikougit a pad of Celue, ¾md. washed will:? EiOAc. ¾e ft Urate was coti enirated la give l-(3-((2-ethyipyridisi-3-yi)oxy)- -p?).esKiliySp (0.01.7 g, 0.045 mmei,

S4 % yield). Mass spectrum (ESI) ro.¾ - 377,0 ( ÷H). S B ' NMR (400 MHz :> ET A O -<¾) δ pprn 8.29 (I ¾ 4 ==4.3, 2.0 lfe} ; 7,8 (I. H, si 7,02 - 7.50 (7 H, , 6.6S (I H, s), 2.¾2 (3 H„ ¾ 2,85 - 2.95 (6 I! m), 2.07 (2 ¾ ¾ -7.5 Η? I .15 (3 H, i. -7,5 Ife),

Fallowing die procedure in Example 48Θ, the lbSlo¾½g compounds w re also synthesized:

, ... Example ., j Structur N me Data

481 ]-(3-((2-et&ylpvrkiia-3- Mass spectrum

y] o,xy)-S-(4- (ESI) ia¾"-" :

.hy roxyb«tyl}pyridjn>2- 345,0 <M*H)

m 84S3

To a sit d solution of

(0,10 g, 0.285 xtitnpl} and cycte&sxea- 1 -yVo xt id {0,072 g, 0.509 nmiol) in dioxaue (2 t»L} was added Pdrfd a)* (0.026 g„ 0.028 m o!) followed by {ii ' c clO$iex^lphos bA«e (0.016 & 0.05? ramo!),. aqueous \ .3 potassium phosphate (0.548 ml, 0.7 i.2 KISSOI), Us reaction was toted to 90 ~ € and stim cQMwmd for 16 a. The mxtitre was-«0nceaarated- md purified on siiiea gel ehiOng ith 0 -- 2.5% eOH is CH ? (¾ io afford

eiay½rea (0.080 a.0.227 irnml m, % yield). Mass speei m (ESI) mtz « 353.0 (MH-H). ¾ NM (400 Η:·. CDCls i 3 . ί (br. s.„ IE), 8.47 (X - 3.03 H¾, ! H 7.96 { ;i: -3¾ ¾ 1 Hs.7.42 is, SHX7,20{d ; -3. S3 Hz t 2¾ 6,87 (d, ~ !.9 ¾ lH),5.94(S t 11¾ 3.03 4 = « 4.70 f¾ .SB), 2,¾(q, - 7.50 ¾, 21-1), 2,23 - 2.32 {», 2W>, .1.2 - 2.22 f m, 2H), - ! .83(« 2Μ), 1.62- LOO

(m,2H)., 1.320, === 7.63 }¾, H).

To a solution of 1 -(5-(cyc!ohex- S -es- J -y !}-3 i2-et y ipy:ridio-3-y 0oxy}pyndffi-2-yI}-3- methyhire* (0.055 §, 0.156 mtmt) mMcOE (0.35 nil) was added S% Fd( . 0i¾ g, 0.005 mmol). The •resaltisg mixt re was sited wader aa atmosphere of¾ for 24 h. The mixture- was filtered through a s rfage filer mi concentrated in vacuo to give HS :yclqhex;ykM^

yi 5-saettwhirea. ( m g, 0 35 rnmoK 8? % yield). Mass spectrum .(ESS > mix - 355.0 (MH-H). ¾ NMR (400 MM¾ C.DCH) 6 ' 48 idd, - 1.96, 4,30 Hz, IH 7.8 i <d, - i .56 Hz, i H), ?J4- 7.25 ( , 2Ά &72 (d, - 1.57 Hz, iH.3.02 (d, - 4.70 jfe, 3H>.2M (q, - 7.63 Hx, 2H) ( 2.41 <i. - n,74 ¾ 1H), 1,66 - S .92 (m, 5H>, 1.2) - 1.39 (res, 8H.

m e

dihydro-il^'-bipyridmej- L(2¾-€ar xy!aie (0. Ul$ g, 0.239 mraol) its C¾¾ (2 mh) was added TFA (0.184 mL 2.39 mrflol). The ieacticii was stirred ai: RT for 16 h then cenceJKrated uttder vacuum to . yield

yOurea ' ¼2-†rinuofoaeetate (0.081 g, 0.18 mvaoi, 75 % yield).

yDurea 2,2,2-iriiluoroacetate {0,040 g, 0.12 irimol), (4inietb.v3amsao.)car o«yi chloride (0.014 mi, 0.15 mm©!} axsfil DIE A. (0.70 ml 4.0 maia!) were esm ed ifi a mixture of€¾<¾ (! mt) and DMP (0.5 aiL) solution. The readies was stilted at RT for 2 h and concentrated under vacuum. The crude product was purified on silica gel during with - 10% Me-QH in CH ? ' to give NJNhftn fyb <S- 2-meihyipyndi«-3-ylox^^ ) ' aibQxa i<k (0.025 g, 0.06 i mmol 52 % yield). Mass spectrum (ESi) mh 41 LI (M÷H). ¾ N (500 Hz, CDCL d 9.23 (by. s„ ί ί¾ 8.44 (s, .1 ¾ 2.96 (s, tH), 7.45 (br. s., 1H). 7.23 (% 2H), 6.77 - 6,93 (in, I H} ; 5.S? (br. s,, I H}, ;¾.*g id, - 2,03 H ; 2H\. .42 ft, - 5.62 i¾, 2B), 3.03 {d x - 4.65 H . 3!¾ 2J5 0¾ 6HL 2.52 (s ( 311), 2.40 - 2.48 (ΪΗ, 2H),

m e *>3

H|3¾hjiM¾2d^

Step A:: A.50 niL rd«ad ' bcsttoxrt flask was charged -virftlt !^-boc- «inefit fe«e* ipecd ¾e. (i.785 i ' «L, 9.05 lamol) iHsder A.r. A solution of 0,5 M ra TH ' f ( i 8. 5 mL, 9.23 mrao) was added a.0 °C then the reaction was stirred at RT Ssr 2 . The resulting sortition was added to a HKxtere f K5-hto o- (2-msihy^^ (0.61 g, U09

!Biaol}., .PdC¾ ppi) (0.044 g ( 0.054 mmo!), ir¾shenylaj:s5»e (0.045 raL, 0. IS 1 m oi),. C¾CQj (0.725 g.2.225 rrsino!.!, D f (4 mL) md water (0.36 L). Th.e jsktftre was heated at 6 °C and stirred .for i 0 k After cooHag to R.T and. pouring into water, hie pH was adjusted to f 1 with 10% NaOH (s¾i , a« the mixture was extracted with Bt.QAc (2 x 50 at!,). The ombined organic e tract were dried with M SOi- filtered, a»d concentrated is vacuum. The crude was purified as silica gel ehaifig with.0 - 2.5% eOH in C¾C½ to give im-b ≠

eihyl:areid£f>pyridis:i--3~y^ g, 0,}2 mmoi, 67% yfehft, Mass spsctttii <£$]} m/x ~- 456,1 (M÷H).

Step 8: To a sohxtioa of fer-butyf. H(5-((2-meii)yipyridi^^^

g, 0. ! mmoi) ia CHjCb (1 ml) was added TFA < . Ϊ raL, 1 ,298 ΠΪΪ ΟΙ). The reaction was stirred, at T tot 16 h. to coftcerittated tauter vacuum is yield

yt)<xm 2,:2,2-infle Taae«tate (0,034 g, 0,072 pm U 60 % yield). Mass speetram (ESlj 'miz - 356,0 ( +H). ! H M {500 MHz, MeO - < «} § 8,44· (dd, - 1 ,22,.5 8 Π/, 1 l 7.98 id. - ί .7! R\ my 7.69- .79 (¾ i¾.7.61. fdd, - 5.26, 8.44 ¾ W% 7.34 (d, - L~i ¾ l¾ 3.37 id, - 13.20 H¾, 2.IT), 2.R5 - 2.99 (tft, 5H 5 2,68 (s, 3M), 2.59 (d, - 6,60 Ms-,.2S¾ i .78 - 1.91 (rs, 3M), 1 ·· 1.48 ins.31 is.

Hi e 494

i -f3-(i I -Ethyl- 1 -pyK$¾ l » S-y:{) x )-5-<5-«3e{iuxx pe«t-l-y;»- I « yl)pyiidi«-2 » yi)-3 » »)ethylttt¾a

{35 g, 0,09S mm&l) as dssolve in. ErOAc (0,5 ml). To ihc solution was addsd pteanim {IV) oxide (2.80 xug, 0.0 i 2 mraoi). The reaction flask was flushed with tt 2> then stirred under a ¾ bailooH for 24 k The toy was filtered over a pad of Cei ' te ami washed with: EiOAe, The filtrate was cosceattated to give H3 { Ϊ -ethyl- ' !

Hiethyiurea (33 mg, 0.091 ausol 93 % yield). IH MR (400 M¾ C C7 } <5 ppm 9,21 (3 ¾ br. q, -4.3,.4.3, 4.3 Hz), ?.?« (i H, d, = 1.8 Hit), 7,44 f 1 R d. -2.2 Hz), 7.28 (1 R or. s), 7.W , d, -2,0 Hz), 5.67 ( I II. d ; 2.011,0.4.05 (2 H. q. 7. :< Hz), 3,34 {2 H, i -6.5 Hz), 3.31 G II. s),

1. 8 (311 d, -1 Hz), 2,50 {2 H, ==7,6.5¾, f .48 - 1.64 (4 Si. Hi)..1.42 (3 R, t, 7.2 Vv 1,30 -

1..39 (2. H, m). Mass spec hum. {BSij z - 362.0 ( -t-H).

f oilowifig the procedure in Example 494, the following coKipotmd was also sys« e¾ize4: £ mrsplc I tructtirfc ame | Daia ] Mass spectrum.

: yi ' 3Z0l-5-y !)oxy}~5-(4- (ESis :!! >: :::

348.1 ;M -H > θ5

H:oct¾ : [ -M$'-i¾"»ig^ ¾f gy j'jdj i:j '6'-y I ) ¾?g¾

To ¾ stirred solodoa of l-{5 romo- ^{(2-amhySp rid^^^^

(0. i 08 g, 0.320 i»i»oI} a»d 2-(lribWiylsi{»i»y¾pylidi»e (0. ί 3 HJL, 0.406 HWOOJ) in idl seEie (3 mL WESS added Pd Pfe ¾ .N {0.074 g, 0.064 latnol). The reacdop was heated ί€> f K*°C and slirted fo 2 T¾e i«ac£i0ii was cow itiraied md purified on silica ge e!uttag ' wiiis 0 - 5% MeOi-I i» C3¾C¾ to afford 1- (0.068 g, 0,203 mmo!, 63.3 % yield). Mm spectom<ESi) f» z - 336.0 (M- ; -B). ¾ MR (400 MHz, COCK) S 9.33 id, - 4.30 ¾ IB), 8.56 - 8,63 <m, !H), 8,52 (d, - I ,96 M¾ i¾ 8,44 (dd, - 1,37, 4.70 ¾ IH " .73 (dt, - i .76. 7,73 Hz, 1 7.55 - 7.65 < , 3H), 7.18 - 7.25 (m, 2H), 3.04 (d. - 4.70 Hz. 3H). 2.53 (s. >M). « 97

4-(S-(( S -El!iyj- 1 -pyr¾zo|-§-y j)oxy^ acid.

Ethyl 4-(5-C(i-aSwl-i -pyrazal-5-yl)oxyK ^ (10 rag,

0.02? ΚΪΠΪΟΙ} was dissolved in 0.5 rot of a ! : S MeOJTTMF mixture. LtOH (2M sola) ( 133 jti, 0.266 mm&!) was added md stirred ovcrsHgM to co» jjle¾i*. The sskmre was acidified .w th 1 . HO. solutioH to pH 5 aad conccatratcd. so dryness a»d placed under high vactiura to give jhe

acid (9.2 mg, 0.026 mmol 9 % yield). Ή MS. (400 MHz, C Ct ) S ppm 7.78 (! R. d, =l..g Hz:), 7.40 (1 H, d, " 10 Hz), 7,04 { ί H. bi'. S), 5,66 { ί H. d, -2,0 Hz}, 4.05 (2 H, q. -7.2 H¾) > 2.94 (3 R s>, 2.54 (2 H, L -7.6 Hz), 2.26 (2 il =7.2 Hz), 1.82 (2 R . quia, -7,4 H¾ .1 ,39 (3 H, t, -73 Hz}. Mass spectrum ESi> txVz « 3 *. I <M*B}. m e 498

The compound was prepared following the procedure m Example 197. Mass spectrum (ESI) xivx ^ 302.9 (M-¾), - 4<>0

To a SOO-mL rouid-bo tomed flask were added iydi»xy-5-metbyIpyridit«. (7.23 g < 64. ffisritol), cesium fluoride (1 .64 g, 96 mtnol) and I-(3-b o o~ -i¾K}iopyrfe

U5, 4 g, 64.3 mraol) ia A CN (320 mi). The reaetion was heated at reflux at 80 « C for IS h. The reaction was cooied to RT, eoaeemritied and. diluted with water. The white precipitate was filtered, collected and dried uuder reduced pressure to give l 5-bfeino-4-{(5-!iiethyi:pyridiu--3- yi oxy pyndiji-2-yl)-3-methylure;¾ (20.4 g, 60.5 imrnk 94 % yield) as a white solid. Mass spectrum (ESI) i»¾- 336.9, 339.0 (M- H). ¾ NMR {400 M¾ CDC! 5 ) ¾ S (, " i H), 8.30 ¾ SMX 8.24 (s, m S. ? is, Ϊ H) s 6,08 IB), 2.83 <d. - 4,7 ife, 31% 2.4! s.3H> m e 5iW

Step A: A iiask was charged with.5~broiti0-3-{(2-met!¾yipyri& (1200 mg,

4.14 mtml ) was added potassium phosphate. anirdrous <} 756 jitg.8.27 mmol), 2-di-i- ^¾½¾ο Ι« η ο^2Λ^ό -^¾··1-Ι.,}-½)ΙΚ35>'Ι (263 mg s 0,620 ( saoll .ph.eo.oi (506 ssg, 5.38 x noi), palladium (U> aeci&te (93 sa , 0.414 na«ol),. The .flask was flushed with, taimgets ttxdee high vacovns. Degassed toluene was added. The reaction was heated to 520 *C overnight for 22 h. he reaction was fdtered through. ceflte.-at i toiieemiaisd The erode material was absor ed o»?03 plug of silica gel &wl purified by elwamaicgrspfey mxtgh a Bixli-Sep pre-packed silica gel column ehttmg wiift a gfsdie»a of 0 % so 50% EtOAc is. hsxases. to provide 60 tag o.f 3H(2-fiieii yip>ddio-3-yl)oxy}-5- pbeaoxypic lkoaitri ' Se. Mass spectnas (ESI) m¾-- 304, (M ' ÷H).

Step B.: made simila thai described i» Step B of preparation 32.

S : tej C: Pre ay

To a {610 tog, 1,898 moi) was added .eOH (9 mL) and the flask was cooled down io 0 rt C. NBS (439 ig, 2.468 atatoi) followed ' by 0,0 ml. wa er was added nd the readier! was cooled for i. mm. Then a i mL of KOH (1 t¾L, 9.74 ta ol) ift water was added dropwise and die reaction was then raised to R and sbired overnight Reaetiori was not completed. So it was toted to 65 gree overnight. 1.09 mg ROB so 0,4 m fLO was added in the morning and heating was c«i«i«ued overnight. The reaction was dilmed with ί 5 rnL water, I HC1 was added to adjust the re etioo to weakly basic, More water was added and preeipitaies were generated. MS showed the precipitates were product, which was dried on highvac at 70 degree to give 4 i I ) trig Mass spcetftttfl {ESI} rfife === 322,2 (M : ÷H), ), ! H " N (400 MHsc, CDCL) § ppm 8. 6 (M y =- .69, 1 ,37 Hz, } H) 7.75 (s s I H) 7,29 - 7.34 (m, 2 M) 7.21 - 7.25 (m. 1. H) 7.14 - 7.19 (nt, 1 H) 7.04 - 7,10 ø», I H) 6.88 - 6.9S (iii, 2 H) 6,67 (d ( 2.3 - Hz, 1. H) 4.73 ·> .. 2 H) 2.55 (s, 3 H).

A

azeoiroped with toluene and dried on.. high-vac. DCM (2.5 mL) was added to the re&etioa followed by pyridine (0,962 ΪΙΪΙ,, 0,764 mmo)). Then 4-aitrophenyi carboriochioridate (92 mg, 0,458 mrt oi) was added. After 45mm f mote aimjpheayj ehloroihraiate and 15 atkroiiser of pyridine were added.. Stirred, lot another 15 mm. Then mefhananHae (0,509 raL, 1.0 i 9 tsmoi) and NEt* (0.106 h, 0,764 mmol) were added. The flask wa capped with a yellow poiyet yktie cap to prevent raahviataiae to escap!e nd the reaction was stirred overnight. Water was added and the reaction was ext acted with EtOAc.. The EtOAc layer was washed with Nal-lCOj 2s and brine once. The crude was directly purified by reverse-phase preparative HPLC «sing (i .1 % TFA in eC /¾0, gradient 10 % to 50 % to ro ide product comaiMuaied with niirophesroi So it was repurified by c!iroaiatogtaphy tnrongSi a Redi-Sep pre-packed si lica gel column eitiUug with a gradient of 0 % to 50 % EtOAc in hexanes than n gradient oi ' 2-8% MeQII/DCM to provide 9 mg of I-raethy!-3-ί 3-(i 2- ^^

pheooxypyrtdio-2-yi)iirea. Mass spectrum (ESI) ra/x - 351.2 (M+H). J H ' N R (400 ffe, MeOH-d4) S ppm 8.32 (dd, -4,89, L37 ¾ i H) 7.82 (d, -2. 5 ¾ 1 H i 7.49 (dd, 1 , 1,27 ¾ i H) 7.28 - 7.40 (m, 3 H) 7.07 - 7.20 (ox I H) 6.92 - 7.03 (ra, 2 H) 6.78 (d, -2,35 Uz, I H) 2.94 (s, 3 H) 2.50 («, 3 Hi. f oHowing the procedure in m e 449, the fellowiag cornpouuds were prepared; I S-( ( ; h.{< ψ:ψ< Πίϊίϊί -.3 -

Mass sjredrt&a (BSD

5 B clbyi|y ' f:«i)ii-3- f»¾ - 398,1 (M-^-H). ν!)«χν}ργ(χϋκ·2·νΕ}·3·

HieSh Saiis

(S)-] -{5-(4,5- diffiii&tisy ea iy j }-3 -(ft -

Mass, ? c! ;·!::η (ESS) ethyl- § R--py£;sz<ii--S-- m¾ - 392.2- (iVi Hi), y ijox :!gy ridsfi --2 -· y I)- 3

!:siefltyh!i¾s

I -i ' .>ii. {- SiSoi op iiib ' :Si-3- i H H M;:s< !.p ¾ ?dn¾a S! !

S 17 c'shy'jy ritUa-i-

!¾¾ ~ 398,1 ( -÷B), yj)axy) yi¾diR-2-yi>-3->

ί awSfe Sifrea

Fallo ng (Sis tocesclufe to m e 476, #>¾ foifo mg co$¾¾uad. as repared:

Following ike. procedure m at e 481), il Mtemtig compound was pre aid;

m & S25

3J2

To a mg,

0,057 mmol) was added EDC (22,04 m , 0,1 5 lamol}, MOBt hydrate (0.0} mL, 0.115 mmoi). Then DMf 02 rat) was added, followed by methyteas solution (0.05? uiL . \ 15 tamo!}, 0ΪΡΕΑ (6.035 mL, 0.1:§8 mraei}. The reaction was sealed, wh a yellow polyethylene cap ais.d sdrred •ovemig i Water was added io the readies f i lowed by ex&actSon ith EtOAe, TSe organic layer was dried and concentrated. The etude material was absorbed ¾io a plug of silica gel d praitkd by Chromatography t roiigh Rc Ssp pe-p cked silica gel c tana ehjiitrg with, a gradient of 0 % to 8 % MeOH in DCM to provide Ϊ S

-mci ylhBtanasHide, which was Kpiuiik by reverse-phase preparative HPLC usiiig 0.1% TF A in MeC /M;A gradient 10 % to 50 %, to provide 7.8 rag-of^f .Wifluoo hem'c HH^ raeih K«¾ o> ndin>5* i>^*H^t }oam« aifc. Mass s ecSiriHi (EST.) mfz :;i 379,2 (M-i-B , S H MM . ! H m. (400 MHz, MeOH-¾ 6 ppm 7.91 (s, I H) 7.22 - 731 (m, S H) 7.09 is, 2 M) 6,24 - 6.28 (Hi, 1 H) 6,26 (s, 1 Hi 2.71 < S> M) 2.63 - 2.69 (ra.2 H) 2.61 is,.5 H) 2,12 - 2.20 (m, 2 H) 1.85 - 1.94 (m, 2 H). following: fhs. procedure is jaa « §25, th foiiowmg c m ound was repared:

Example Structure am Data

4-(4-i2 : f3-(Sliui ) fts-

Mass spectfiHii {ESi}

526 j«sthy¾H¾5do) siifB-7_ ixftsfcami e

3i3

FoMowi.Bg the procedure m m « 1 the i iSo iitg coiaeoisad was prepared:

[ Example Structure Name Data

.1 -<5-aJ - -{2 Mass s t'triiS).

1 534 di -fi«crop.hc«oxy-)pyridm* (ESi)i ' d/¾- 320.2

2-yihS-!:Hetiiyiufsa (M.-rH , 5. e S35

To a flask wuh H^ai!y4- d^ {25 mg, 0,078 mtmi) was iidcied IHF (2 isL), ¾0 «2.000 mL}, I m OsO* (0.098 t&L, 7.83 u oS) in t-B«OH (2.5¾ eight se!yiion) was added followed by KMO H8. 4 mg, 0.15? mmd). T e reaction was stirred fat ' about 3 days. Hie reaction, was quenched mth sodium oetabi sulfite soJutfoa and extracted with EtOAc. The EtOAc Saver was dried td concentrated. The crude material was absorbed o to a plug of silica gel aad puriiled by ciimraaiograpiry through a Rcdt-Sep pre-packed silica gel column slating with a gradient οίθ % to 10 % MeOH in DCM. is> pravide 18 mg of i-<4-(2,6-difl.uo;r >.be«os )-S-(2,:3- dihYdroxypropyi)pyrid¾i-2~yi }-3~meihyl.ui¾a as a white solid. Mass spectrum {ESI) m ! z ~ 354.2 (M-R). ¾ NMR (400 MHz, MeOH-d4) 8 ppro. OS { S> i H) 7.31 - 7.43 (ra. 1 H) 7.15 - 7.26 <m, 2 H) 6.38 is, i m 3,95 - 4.05 (ia ! !-!} 3.56 - 3.63 (m, I H) 3.48 - 336 iph I H) 3.03 (dd, - .89, 5.09 «¾, 1 H) 2.82 (s, 3 H> 2.72 (dd, i 3,99, 7.92 il/.. Ϊ M),

Following die procedure ra «B S35, die foiiowiftg compound was prepared:

ϊ» e 537

A .flask with {SH- 4<2 ( ikli-¾o^ (f.4 m , 0,037 raraol) was a eoroped Jli tolueiie flushed w h _ .Diraeilioxyjsethahe I .5 ml, was added to dissolve i & starting material. The. reejios w cooled down in m. Ice-bath. Th 2,6- iuOdsne m$, 0.092 mmol 2.5 ©¾«ay) was added followed, fey dropwise addition oftrimtth feilyi trifiuororaethaRCSftlfosatie (10.(527 tsL, 0. ! 51 Hanoi 4. S cq«K').The reaction was raised to RT and stirred for IS h„ then uenched with saturated NaHCO* . The reactiow was diluted wiift EiOAc, she organc- layer was was ed mifo hi sodium hydrogen sul&ie and bnae, dried (MgS0. < ), ami evaporated ift vacuo. The crude was purified y reverse-phase preparative HPLC using- J % T A. in

CM ; CN/HA gractat 10 % to ?0 ¾, to provide 2.7 sag of iS)-I-(5.{3-ii,3-diosola»-4- 1}propyl)-4- (.a^-dtil oro ieMOx Jiwridiii-a- lj^-raet!rkis-ei!, Mass spectrum (ESI) ni¾ « 394.2 ( ÷B). ! H HMR . (400 MHz, MeOH-d4» δ ppra S.04 is, E Hi 7.32 - 7.45 (m. i H) 7.22 is, 2 Hi 6.32 - 6.43 n I B? 4,98 is, 1 H.) 4.84 (s.1 H) 3.93 -4.1! («!, 2 H) 3.40 - 3.48 <m, 1 II) 2.75 - 2.B9 im t 5 H) 1.60 - ! .9 (tx 4 H). so e 538

A flask with iH ; 3-broi O-4-((5-eiliyipyfidin-3-yl)osy)pyn , 0.228 mmoi} was added potassium fluoride (0.02! mi, 0.91 ] mmo!). palladium (ii) acetate (5.1 mg ( 0.023 romoi) and purged wsili N> Degassed DMF (1.5 mL) was added fo.ii.owed by\2-cy ope»t«iv{ -ose {0.076 ml,, 0,91 ί mmoi). The reaction was heated overnight Water -was added follo ed by EtOAc exttscttah The crade was purified by reverse-phase preparative HPLC using 0, 1 % TFA iti

CH3C /H>0 to pievide ii) ra of 1 -i4H<S-ei¾ l y ^ I --en- 1 - l)pyridie}-2^y})-3-ajet yl{{rea. Mass spectrum (ESI) m : == 353.2 ( ·÷!·ί>, ' H MM (500 MHz. MeOH-d4) 8 jjpm 8,61 (s, i H) S.44 (cL «=1.22 ¾, 1 H) 8.33 (4 -2.45 Hx, ϊ H) 7,64 s, 1 H) &R5 is, i BK.59 (s, ! H) 1.26 <dd, ==4,7?, 2.8 ! H¾ 2 Hi 2.85 (s, 3 H) 2.80 (q, ===7.58 ¾, 2 H) 2.5? Ceil 2.29 H:-\ 2 H; L (t, -7.46 >E-:, 3 H)

'

3ί?

ollowing in 198, were prepared: se corapouOii was prepaied by f ikiwirig !¾e piecedure in Exampe 195, Mass specttisiH {ESI} m/¾ 9:9.2 (M-i-H). m «556

To a solution of 0.20 rnmoi) and iaethy e»ecyc ooentaae (0.2 ί 5 ml, 2.045 tnol) in DCM (4.0 raL) was added Itoveyda- grubbs catalyst 2nd geseEWjou (12. SI rag, 0.020 mroo!) at it. The resultiag reaction, .ratxiyre was degassed dirce times aad stirred at. 55 0 C trader Nj overnight. Tfee reaction mixtur was directly purified by reverse-phase prepsradve HPLC using 0, i % TF.A t» CHjC H gradient S O % to 90 % to give the tide compound,

3-me%iore.s. ass spectrum (ESI) mix ~ 353.2 (M+fi), : H NM.R (400 MHz, CDG¾ 8 ppna 9.38 (4 M, br, s.), 8,62 ( I H, dd, -4.3, 2,3 ϋ/ϊ. 8,03 (i H. s>, 7,48 - 7,7ft (2 H, nu, 7,23 ( s: H, 4 -I ,6 Hz), 6.16 - 6.24 (I H, · :* .. 3.24 (2 H, , -7,6 Hz), 2,99 (3 H. : d, -4,3 Hz}, 2.50 (2 H, i, H¾), 238 (2

H, i; -7.0 Hz), 1.8.1 (2 ¾ qnin, -6.9 Hz), 1,59 - 1 ,73 (2 ft m}. S ,43 (3 ft!, -7.6 ¾},

Hie cempoaad was repared by ibiio isg the procedure in Example 556. Mass speeirrau (ESI) mtz-~ 343.2 (Μ·ί«).

S 558

Tlie eentpcmnd was prepared by following the procedure to Example 480. Mass spectrum (ESI) tB/ ~ 355: (M÷H). prepared:

fit e 562

3-C½omoff^

To a soiuttotf of

8¾elbyiure.a (i 5X1 ing, 0,041 SHIBOI) a McOl! (4Xi aibn ' as added N8S f 33 -twg.0.047 πκ η α!) at o 'C. The resuming re ction la itire was stirred at.0 °C uader N¾ .for 2li and thso. sOrred as n for 1 . I¾e reaction &iixf«re ax directly purilfed b rev¾rse~pltase preparative HPLC using 0..{% I A is CH :? € .¾Cy gradi nt 10 % io 90 % to gi ve she title i mipoimd. Mass spectrum (ES I) m/x = 464,4 (M*H). ¾ MR (400 MHz, CDCfe) S ppm 9M (i 11 d, ¾ Hz). ».6S (2 H, <J, « 3.7 H¾) f 8.0? (1 H« it ~LS Hz), 7,44 - 7.60 (2 H, mL 731 (1 R d, -i .6 Ms¾ 4. LI (1 i-L s), 3.29 (3 H ( s), 3.10 - .23 f:2 H, in), 2.94 - 3M (3 H, ), 2,18 (1 H, d, -6.7 fe), 1.93 - 2. SO (4 H, m), J .69 - 1.9 (3 H. m), 1 9

The compound was prepared by following the rocedssTc ia Bxampk 48(1 using l-f5-(bi¾m {i- Starting material. ass sped-mm (ESI) rate - 385.2 (MH-H). m e 5 ( >4

/"τ·· ''' ·· ' ·Μ i t's' ·

methviirea

To s soioisan. of

raeihylyrea (I. S 9,0 Rig, 0.38 mmA) in ( -0 tnL) sad B ¾ 0 {0.2 ml,} was added BS Χ>. I rag, 0.3? } ! i o!) si 0 X. The resulting reaction mteuie was stirred at wider K for ί 8 h. The rea ksft labttuie was sSireedy purified by revers-e- ase prc mi e HPI.C «s g. U%TFA in

CHJCN/HJO, gradient 10 ¾ to 90 % to give the cosipoi«xd, 3-{5-{b«)K»( *- Mass spectrum

fESDxtVi? - 450.2 (M4-H).

j.;-;(3 ({^e y¾yndi¾-3,y¾

medivjuiea

To a soUiiiei! of I ~C5-(br ;:Bo( 5 ^hydroxycyclope8tyI)me(;y!!*3i{2-ed5y tpyridis-3*yt)oxy }pyridi«--2-- yi)-3~a)etfey.hj:rea ( 1.0 mg, 0, i 13 mmol) MeOM ( i 0 mi.) and EtQAc (5,0 mi.) was added Pd (10 i %, 0.918 t¾L, 0.017 πίϊΒοΙ), The reaction mixture was .subjected to thfee cycles of

evaeuaiioa/back-iilling \vit¾ ¾ and stilted at si issder Hj t>t 2.5 k he catalyst was .filtrated out. The solves:!! was sho ed, the miction mixture was urified by reverse-phase prepaiaive HPLC using Q .1% TFA in. CH NMiCX gradient 10 % to 90 % ¾> give the title eompoaad. Mass s^eetram (ESI) m¾ - 37 !.:·! (Mi-H). ; H NMR (40 MHz. CDCSj) ¾ ppm H.Si ( i ii, dd, s ¾2, .3 Hz).7.04 (1 it d, -1.4 Hz), 7.64 Π H, dd, -8.4, 1.4 Hz), 7.55 (1 H, dd, =8.4, 5.3 I¾, 7.41 (I H, d. »L6 Hz), 4.40 (2 H, d, - , Hz), 3.03 (2 H, , -7.6 Hz), 2,75 - 2.91 (3 H, m), 2.04 (i H, d, -8.0 Hz), 1.44 - ϊ .73 (5 a m), ί .30 ~ J .44 (2 H, m), 1,27 - 1.30 (3 H, m).

melhyiurea

To a .ms easica solution of il 00% dispersion m miaerat oil (0,035 ml 2.77 mrnol) in DMF (7.08 ail) was added ¾exa¾ydro-asfoS ' 2,3-b]Osaa-3-oi, (3r,3as,0ar ?-e0 (0.3 g.2.305 x&cml) at 0 °C and resulting saisiife was stirred at rt for 30 mm and 5-¾ >ji >-2 iiiQr -3-:n oropyridifte (0,534 g, 2.54 ro oi) .»¾ DMF ( 1.0 ml) was added. The reaction was stirssd at n for 4 a. The reaction mixture was diluted with EfOAc (60 mi) and washed with water a:nd brim, dried over MgSO.}. The solvent was removed

was used for nest step without .further purification. Mass spectrum (ESi) mtz - 32 J .0 (Μ-ί-Η),

O fiioro-^dsoxy-S-t^ wasssade by followiag the procedure in Bxampie.198, Mass speciHsm (ESi) ffi<¾ :;: 303. i (M3-H). J H (400 MlfeCDO ? ) 8 ppra 8,49(1 H,d, -2.3 }¾, 8.25 (1 H, d, -2.0 Hz), 7,90 (I H, d, -^, Hz), 7.37 (5 a S), 7,00 (5 a, 4 Hz).5.80 (i H, d, -5. I Hz), 4.9? - 5.09 (1 H, m), 4.44 (2 H, q, -7.0 Hz), 4,25(5 Rd , -9.8,6,1 Hz), 4,04 -4,5? (2 H, m), 4.0 i (! H,dd, -9.8,6.3 Hz), 3.22(5 H, dd, 2.2 Bx), 2.35 (I H, cii. -i3.!,2.?H¾ IM - 2.07 (5 H, la), 1.50 {3 H,t, -7.0 Hz).

PPdd ::;; ((ddfefeaa));;ii ((2222..22 ii»»gg,, 00..002244 r mormooti)} a ant dl ddli eerrii--kk«« !!((22\\44\\66 ,, --trriiiiss0o mr pp ll--33 >>--dd!i}}««eeliteho yy----tii ii « bbiippIliteeiiityyii||--22-- S D}pp!!ii»osspphhii»aee (( 2211..3388 mmgg,, 00..004444 % mmsmi l) wweerree sslluurrrriieedd i hni I Ϊ ' HΗFΡ ( (00..,5555 m mll)) aanndd wwaatteerr ((11..00 μμΐΐ •• 00..005555 t imwrnuoil)).. T Thhiiss mmiixxttuurere wwaass hheeaatteedd aatt 11 1100 **€€ foforr fifivvee ms$n, rreessnniUtiinngg iinn aa bbllaacckk rreeaaccttiioonn m miixxttuurree wwiitthh aa fi ftnnee pppptt.. TThhee Ii --mmeetthhyyiiuurreeaa (6S55..33 nniig,, 00,,888822 iratnmoilj),, ^ 6 dhitelotoo- « i6^'-eeidiooxxy^>5-({aS,5aE,6aS}- hheexxaahSryddroromi\ffr00 22 ~~bbjjii¾¾nnffim--3-^ylfe t nnsgg,. 00..222211 . mmnmoit)} aanndd Cs,CO ? , 9999..99%%

( (mmeettaall b baassiiss.)) ( (2266,,55 iidd,, Ρ Ρ33::>11 msmipol!)) wweerree sslluurrrriieedd »»fln TTHHFF ( (00..5555 ssaall)).. TThhee pprree--aacctOivvaaiieedd ccaattaallyysstt ssoolluuttiioon wwaas ddii ss ttraannssffeerrrreedd ttoo S thhee rreeaaccttiioonn ffllaasskk u unnddeerr aanndd.. tthhee r reeaaccttiioonn wwaass hheeaatteedd aatt 7755 a °CC oovveemmiigghhii.. TThhee LLCCMMSS rreessuullttss i aniddiiceaatteedd tthhee r reeaaccttiioonn wwaass ccoommpplleetteedd.. T Thhee bbrroowwnn rree-aaccttiioonn,, sslluurrrryy wwaass ppuurirififieedd bbyy rreevveerrssee--pphhaassee pprreeppaarraattiivvee i HlPPLLCC lisstinngg 0 o..1! %% TTFFAA ni CCHH ? ?CCNN//¾¾00.. ggrraaddiieenntt 1100 %% ttoo 9900 %% iioo ggiivvee thhee ttiittllee ccoommppoouunndd.. MMaassss ssppeeccttrriinnss ((EESSii)) t ran¾¾ ~~ 440011..22 ((MM**HH ¾¾ N NMMRR ((440000 M MHlfex,. C C»DCC¾tj)) 88 pprms S«..4455 ( (T5. 1 M-1,, ··::..¾¾ .. --22,,55 HH »»,, 77,,9933 ((11 HH .. ss)),, 77,,8866 ((11 HH .. dddd,, ' .Υ Ν, 22,,33 HH// »r,. 77,,3366 (( ii 1I:T1,, ss)),, ( 6>M,9ίί- {( Iί H S I.. dd,,

--8S..6 H H¾/)}, : 55..SS77 ((!! 11--11 dd,, -5, 1 HH?? ::<<.. 55..000 (( SS f 1t4, ¾% --88..11 HHxx 44..4444 ((22 H IT,, q,, --77,,00 HHzz)),, 44.. HH ((II H B,. d ddd,.

--99..44,, 77..22 ΗHχit)),, 44..1177 ((1l M 1-1, 1t --99.. ii I Η¾· ), 33..9966 -- 44,, 1111 ( (22 H II, mk 33.,2233 ((I1 R 11 d dtt,, - -55. ! t ., 22..33 H Hz¾}) « , 22..9999 ( G3 HH.. dd, : --33..99 HH??yy II..99SS -- 22..1144 (( II HH,, mmll 117766 -- 11..9977 ((11 BH .. r «.« , 11 ..4499 ((33 HH,, tt,„ --77,,00 HH¾¾))..

T e compound was prepared by following lite procedure is Example SS6, Mass spectrum. (ESI) m¾ · 360.2 (M-Hi m e 56?

I -i "i vcSi>:>cxU jinctb S i-4-( 2,6-diil uorophsaaxy pyrids»-2-y¾ )-3-rRethy itrre^.

The comp ii was prepared: fey feiiowiag. the procedure in m c 48< Mass -spectrum.

I -(4~t2.6. j j 1 uoT0jhe¾0xy)-5-(( 1. -raethoxycyek^

The coxopoiiitd was pre ared by fqiio ing the roce ure in tin es Si>2 ml 5ί*3, Mass spectrum (ESI) Ϊ . - 392.2 (M÷H), m e 569

The eo-rspouad was prepared by ft!ie fa ihe procedure i m e 5S4, Mass spectrum (ESi) ;nv ·· (NTSO.

mefhyliwea

The compound was prepared by following the pr eeditrc in m 56 usrag tfee appropriate aieo o ' i. Mass speetniift CBSi) 447,0 ( ·:¾).

e 586

To a sohifioti of 1 ^ ' S^I-tamvl -(2,5-dioxopyrrGH.dii l -y1)eihyi)^<chraKiaft-5*yloxy pyridin>2-yl ' 3-niethyl«rea (60 g, 0.1 19 mmoi) that, was made by fallowing the procedure- in Example 562 ia eQH { 5.0 rat) was added sine, gramdc, 20 mesh (78 rag, 1.192 mmoi) a»d ' .N¾Cl crystal (3 IS g, 0.596 mmoi) (saturated ater solution ψ.2 ml). The reaction was sttetfcd at 4 ¾ i¾r i It. LCMS indicted that the reaction was completed. The mkmre was purified by reverse-phase preparative HFLC usSiig 0, 1% TP A in CH 1 /¾0, gradient 5.0 % to 90 % to give the tide compound. ass Sjvciruwi (ESI) ;:;·/ - 425.2 (M+H). S R MR {400 M&, CD€¾) 8 ppm 8.15 (I IT s), 7.23 (111 s), ?.¾7(lH,t, -*.lH/ ( -S2<\ H,d. -7. Hx), 6.47 ' (}: ¾ dd, lfe} > 175 OR d, -7.0 S4¾

4J3 - 4.2? (2 H, ·π>.2.ΚΪ 0 R d, -4.7 i¾ 2.67 (4 H. s), 2,49 - 2M i 1 H, m}, 2.36 - 2.49 ( i H, m), (2 H, dd, -6.4 t 4.2 H/.».1,78 (5 H, d, -7.2 H/j. m e 581

j^4-£cJ¾romiu^

TSie compomd wax pre red by foHowBtg tfes procedure I» m c 195. Mass speamm (ESI) ΪΓ!.¾ ~ : 326,2 (M+H). m e SS2

1 ~(4~j 2.6-diff aorop¾e»:0:s )-5-{ i. ,4-di xaa-2-vi)pyridm-2-yi)-3 -rsetfwl u rsa

To a solution of I-{5-( ¾0in>-lH iy rox ¾ii^^

methyturea ( ' f 00.0 mg, 0.224 imrn in dioxanc {3,00 ml,) and H ;i O ( 4? mi..) was added H OW (40.. 8)g, 1,008 ό¾»οΙ) at >S0 *C, The resulting mi ture was stirred at ¾0 *C iftdef S¾ ibt 4 Is, The WH-XUH; was purified by reverse-pirase preparative HP.LC using 0.1 % TFA. m C¾CN/H ? 0 ; gradient.10 % to 9(5 ¾> to give |¾e iitle co pouud. Mass spectrum (BSD mz ~ 306,2 (M-H ). }' H " M {400 MM¾ CDClsi S pra 7,91 (i E s ?.35(! H, S} ; 7,13 (311 i, *8J Hz), 5.19 (i H, t, -=4.2 Hs43.8.1 -4,05 (4 H : . m) s 314 (2 R. d, -4,3 H ) T 2.82 (3 H, d, «4.7 Uz).

SB B

The eotrspouKd was prepared fey foilo mg tiie procedure in m e 582. The pr duct as isolated as a by-product Mass speciftna (ESi) a/z :::: 322.2 {ϊνΒΉ}. f ollow!fig fhc xocedurc in m $ 198, the followin coiiipoaads were prepared:

miuii kifss. j

Following the procedure in m 449., the iovwag eo aposjisds were prepared:

By fo ' Uo ixig csscKtiaiSy the pfoccdiire in s» e 449, Step B, ihe f lkmiftg c< !Xipoi!ftds were pre ared by a ¾R the co««acfcia available : !ia reagent;

m e 5**7

3-(5 (1-Είίΐίν:ΜΜ-ρ> αζθί.ό dihydrochlqniie (3.3 rag, ,08 { mmel) was dissolved in DMF (0.8 ml). To the solution was added Bt¾ (5 0,4] mrnoi), 2. M meihy lamiise soi«(um TM ' F (20(5 μί 0, 1 miii J) and broino-iris^yrrolidimi pbosphoai»»^J8»mfluoropbespha{e (95 ra , 0.20 romo*). The resulting soJmipR was stirred for 1 ,3 h. l¾e reaction, mixture was tlisn diluted ih ¾Q ( 5 mL) and the mi ture was extracted with EtOAc (2. x 35 mi) and DCM (1 x 35 mL). Th& combined Qrgsaic layers were washed wifli IN LiCl (1 x 25 raL) and ne { 1 x.25 mi) and dried over MgSQ.*. The crude product was then ρ-urii by jBedirm pressure chromatography (silica, 0 to i0% MeOB : DCM) to give 3-(5-((l --ethyl- ii syta^ l-S- (22 mg, β.06 ' 2 ramol WA yield).

Mass spectrum. (ESI) m/x «» 347,0 ( ¾, lU NM (400 M¾ C 0 > ppm 9.16 ' (1 ¾ fcr. s.), 7.83 (I H, d, -1 ,8 Hz), 7.44 ( I. H, d, -2.0 H¾ 7.29 (1 H, br> s. ).7,07 ( i H, S) s 5.6? (I H, d, - 1.8 Hz), 5.44 (I ii bar. s.), 4.05 (2 H. q : -7.2 Hx>, 2,97 (3 H, d, -4.7 H¾} : 2 J? (2 H I -7.3 !¾ 2,77 (3 H. d 5 -4.9 Hz), 2.38 (2 I-.!, j, -7.4 H.?> : J .42 (3 ii S, -7.2 Hji).

By essentially following ihe -procedure bi Example 597, the M!owfcug compounds were prepared:

Exam le Sariiciiire Name Data

3-(S (l.-«t|wi-j: {iWra¾«l-i-y¾( y)-- Mass spectrum

.59$ 6 3H:i:i<;ibytei ' ddo) yiMim-3- l - f ESI) »:¾ = Hfimiiti ip.ii ¾ifisipiite 361.0 (M÷«).

so e 59

:me&yl»re¾

Step A: isoikiaxo iste U -dioxide

3-C ioropmpai3esiil.f ¾y:! chloride f j.5.0 sal .120 rnm ) was added, to .125 ai &fBCM and. cooled to 0 °G. Cbscenmtfe NH.;:OH sohttioa ( 29% w/w was added :ds¾pwise sa die eaction was warmed So RT sad stirred, far. 2.5- days. i¾<3 (40 m! was added &$>d the layers were separated. The organic layer was dried over MgS0< and concentrated to give the erade 3-chteopr»paiie-i-su.lfoaainjde. This material was directly sribrm!ted to the subsequent step, The crude ¾-ehk>r prop5me- I fonaraide (6.9 g, 44 ΐύηκΛ ' ) was slurried io EiOH (25 ml) it d s diu , ep xide (21 g, 30.9 nmsat) wa added and die mi t e was heated at istaed for 24 ¾, The reaction mixture was coacenirated and (he residue was partitioned etween DC and ¾0 ( 2 ηιύ. Use layers were separated ais.d tlse aq eous layer was extracted 0 x 0 ml) with DCM. The Or anic layers were combined d dried over Mg:SO. s to produce crude isotlitealidtns i J -dioxide. ! H NMl. ( 400 MHz, C CI ) δ ppm 4. S 9 (1 it ¾yr. s. 5.44 (2 R. >.7 H ), 3, 10 (2 H, 0 « 7.4 H?.} ; 2.40 - 2.55 (2 H, m). Mass Spectrum (ESI) mie ~ 123.1 < M r H ;.

Step B: i J -dioxide

4 S - B ϊ s{d pbes y i bosp i f}0}- 5 9-d ir! et ^y l:s a:¾i iii en e (57 mg, 0.099 rnraoi),. ssothiaxoiidisie U -dioxide (80 mg. 0.66 mmo\), S-br0rao~2 h.tero-3-{(i-ethy aig, 0,06 mmo\\ CsjCO} 00 mg. 0.91 mmV}., Pd^ bah (30 ta , 0.013 mma ) and three <»gs(rom molecular sieves ( 100 mg) were slurried i» dioxase (2.0 itil) aad placed in a Discover model microwave reactor (CEM. Matthews, NO) at. 100 - ' C for two h. The sha y was diluted wit¾ EtOAe aad DCM thea filtered to remove the solids, The filtrate was eosicentratetl nd th residue was purified by medium pressure chromatography (silica, 0 to 100% BO Ac ; hcximes aad then Bushed with 0 to 10% MeOB : DCM) to give 2-(6-eh.!oro-5-(( i.-ethyl- 1 H-pyni i-5^1 oxy)pyridir^3-yl)!soil:»a¾oiidine 1 y l -dioxide (50 mg, 0:, 15 mm L 22% yield). Mass spectrum (ESI) mfz ~ 342,9 (M+H).

By foUowiftg esseaiially tfee procedure in Step B, tfce following eomponads were prepared:

By iowing essciiisaliy the procedure in Example 432„ Step t¾e fo owtog compounds were pre ared;

1 Example 1 Structure ame ala I '{( ! -eibyl-i H-fiWJ2:al-5-yE)i>xy}- Mass s ectrum

(<ίβ S-iKEfafiydro-2H-pyfaa-4- caH5tffiy1}pyadin-2- i)-3-fiidhy!ifrc.a 374.0 { *-H).

ffl e 604

Step Ay 5-Broino-2*elteo » M<( I i yiAH-0t x -$-y\}<)xy} d$aK {4(H) mg. 1 3 ακηο!) was dissolved i» TNF f 13 mi) and cooled io -78 X. »-&otyi)uhiwsa {1 ,6M :$» cxanes) (0.91 ad, i .4 ramol) was added dropwise and the resohipg yellow solution was stirred for sevea ram. Teti¾hydro- 2-H-pyran^-earbaIdehyde- (0,21 ml 2,0 smool } was thea added dropwise and the solution was wanned to (0 X over a period of 1.5 h. The - reaction was quenc ed with saturated N¾Ci (20 inL) ' and tiiis fHi iifre was extracted with EtOAc 0 s SO «iL). The coxabmed orgashc layers were, washed wills brine (t x 30 mh) a&d dried ever MgSO, s . The crude product was then purified by uiediiun pressure chromatography (silica, 75 io 100% EtOAc : bexaries) to give (6 " hioro*$<{]-et.h kl^

])oxy) yrkii^3-^ mg, 0,42 nmtoL 32% yield). Mass

Spectram (.ESI) ttv ' e i:: 33^,0 ( 4· H).

Step B: The d^hlo o-S^Cl -etl .^

yl)n5C5iiasioi (140 mg, 0.41 mraol) wits dissolved i DCM (3.0 ml) and cooled o 0 T, !.,! , } - Triacetoxy-lJ^j ydi -^l^ixi doxal ^iHHiie (35 mg, 0.83 mtm\) was added and Oie reaction was wanned « RT over 1 ,5 h. The reaciiori was diluted with EtOAc (35 inL) and washed wish IM sodiiiifi diiosrs!iate sotot n (2 x 20 \ saturated NaffCC solaiioa (2 x.20 mL) and rme Q. x 20 The combined .organic layers- were dried over MgSQj and the erode proditc-t was purified by medium, pressure cforomatogfahy (silica, 0 ks ) 00% EtOAc : teases) to give $ hfc>ro-M(i -ethyl- pyra¾ol-S-yl)oxy)pyridin-3-y](tetrahydro-2H-^ (74 mg, 0,22.rmsiol, 53% yield).

Mass Speemxra (BSD ui/e∞ 336.0 (M. * H). Step C Example f B- shown afeo-ve in Example 600, Step C .

Stcp ' D: H3 t ^E i H- ym^^

methylurea <12 mg, 0.032 mmo!) and mcthyiiflpheaylphos h∞«im bromide {23 mg, O.064 ntmol) we e dissolved T.HF < 160 μΐ) and cooled to 0 *C. Potassiu icri¾tiox ' id : (1 ,0. M is THE) (160 ΐ, 0. iOO asao!) was added di¾pwise and the resulting orange mixture was stirrred tit 0 C C for 1.5 ft. Tie rcacdoa was quenched with 3 μΐ, of SM HQ to a pH f sad the . concentrated to dryness. The crude material was purified by reverse-phase preparative HP.LC using a Phenoraeaex Gemini column, 10 m cron, C«J 00 , 150 x 30 turn, J % TFA in CHsC /HjO, gradient .2% to 90% over 25 mitt, to provide K3~((i -etlwl- i l}-pym

me-thy!irrea (3.0 mg, 8.0 μπιοΐ, 25% yield) as the TFA. salt, Mass spectrum (ES ) ra/¾ « 372.2 (MH-H). Step E; Following the procedure in. Example 3 70.. the tide compound was prepared: Mass spectrum (ESI) m&™ 314.0 (M+H).

MS-Bromo-4-t2,6-ditI«o^ C ' l SO g, 0,42 mol) was slurried in

E O (4.2 aiL) and eookd to -78 t: C. s-Butylltthmm (Ϊ .6 . in hexanes) (700 uL i .3 mniol) was then added dropwise. The slurry was stirred lor 45 min at -78 *€ attd thsa raised out of the dry ice bath for live rain that resulted in a slight yellow color change. The slurry was then put back in the dry ice bath and the oxetan-3-o.ne (27.0 μΐ, 0.46 mmol) was added. The .slurry was warmed. sknvly to RT and stirred overnight. The reaction was quenched with ' Saturated H<C1 solution (iO ml) and extracted with EfOAc (3 x 25 laL). The confine organic layers were dried o ver Mg$t¾ and concentrated. The -crude product was purified by raediam pressure chrenialography (silica, 3 to 10% MeOH : DCM} to give i 4a;2,6»diiIyorep¾a^ (9,5 mg,

0,027 mm>\, 6.5% yieid). Mass spectrum (ESI) mix - 352.0 (M+.H). f H R (400 Mlfe. C €1 ) 8 pprrt 9.00 (1 i-l bt, $,), 8.60 (1 11 S) > 8.10 (I H, s), 7.22 - 7.33 (2 ¾ « 7.05 - 7, !. t (2 11 as), 6.04 (I H, si 5 23 (2 M, d, - « 7.2 ¾te), 4.94 (2 H, d, -72 H¾ 2.10 (3 R d, -4.7 Hz) m e <S0&

raethoxy«iliyi)annaos.ttlfk trifluotd« {0.014 ml, 0.07? mmol). The resulting pais yellow solution was stirred for 1.5 h. The reaction was sherr qusached with saturated M C\ solution (5 mL) and extracted with DCM (2 s 20 mL). Use cosnbioed organic layers were dried over gSO. t . lite residue was purified by medium pressure chromatography {silica, 0 to 75% MeOB. : DCM) to gi e 70% pure desired product. Hie erode mterial was puriiled by reverse-phase preparative M ' PLC using a Phenomeaex Gemini comma, 10 aucroa. Cm, i 0 , 150 x 30 mm, 0.1% If A in CH ; ΟΦ¾ίΧ gradient }ø% to 90% over 25 rata to provide the. TFA salt of the desired product. lie IF A salt was ihm stated thro gh ¾η SCX column to give ί -? { S-eth l-JH-p r^oi-S-yiJtox S-B-.RtJoro-S- n:set!rylbuiyl)pyr!dit 2-y}}-S-3:sethyii;rea (7,0 tag, 0.020 tm ), 41 % yield). Mass specrrom (ES) mtz

- 350.0 Ή m tm tea?,, c > o p m 9.55 y a br. 8 . β/π - HI IS <I H. m?, 7.84 <_

U. si, 7,55 { ] if. d, -2.2 Hz), 7.27 (ϊ H, s), 5.67 (Ϊ H, d, -2. H 4,2 i (2 H, q, -7,2 Hz),.2.99 (5 H, -4.5 Ife), 2.SS■· 2.80 (2 R n¾ I - 1.98 (2 H, m), 1.40■· ί .50 (61-1 > in, { .38 i3 EL $> (TFA salt).

By csseutiaSy following the procedure in Exasrsple 606» the following compounds were prepared:

Example structure Name Data t -ø ( i -eihyl-1 H-pyraxoI-S-yi )osy-. Ma p ctniKi re-{3-no«iir K<pyip):idfB-2-yj)-3-- {ES¾ !·;.>: ~

322.0 (M ). m « 60S

Tetrabtiiyits «i!¾onitiJH fluoride trilrydrate 030 nig, 0.42 mmol), triniciii S{( -Kieihyi xt. an-3- .i¼tli>¾yj : )f >i\a (75 n¾ 0.42 m&\ Cui (8.0 mg 0.042 imr % Fii(PP ).! ( 8.t»g, (i:042 mrsxii} were skat d hi IMF (3.0 The reaction, was heated to 80 *C under Ar. The reactfcm mixture was dikifed wtii EOAc (40 mL). This mixture was washed with ¾0 (1 xlO xnL}, \:l H ) ; brine solution (1 10 roL) and brine (1 s 10 taL) and then dried over MgSO<, The crude pre dtset was

$obiecled it meditmi ressure chromatography {$i\k 0 ie> 5% MeOH : DOM) to give lesired product

«Ηί&ϊίΏίΙΙίΐΗ xl wth starting material litis material was purified by reverse phase preps rati e HPLC using a Phe t}.OHi¾!tex Getaifti columtt, 10 irricrofi, C ϊθθ y 150 s: 30 imti, 0.1% TFA in

CB ; £ /:i-y gradient 10% to 90% over 25 miri to provide jbe TFA sa.it of the desired xoduct. Ti ) .e

TFA sals w; *s flies ekised thxeugh s SCX coh««B with 0 to 2M N¾ m MeOH to give S ·<4·< · diOtsoiophe nox.y 5 {3-Hieil ta mg 0,059 mmol.

14% yieid), Mass spectrum (ESI) mix 374.0 < M- !l), l H NMR (400 H», C O ) a ppm 9.2? ( 5. H. br, <>.}, S 88 (1 H. r. s,), 8.54 (1 ft s), ?.15 - 7,26 (1 H. ).6.97 - 7.14 (2 ft m).6.15 (I ft s} ( 4.03

02 Rd, ·? .5 H¾ 4.48 (2 H, i 2,09 - 2M (3 , m), 1.72 (3 H, s).

} -(5-Bro«i -4-(2.6-li:Sl«ofopte)0sy)pyridi pyrmlidiiv2-oae < } 20 g, 1 ,50 mmoi, .{31 mg, 0,24 msaol.), C«I (19 mg > 0,097 rnmoi), sod 5 C0 3 {200 g, i.S t mif we slurried in dfexaoe (4.0 ί¾1) aisd. i&rce. aagsttw moieadar sieves. ( i)0 -mg> were ad ed.. T¾s t¾suiiis}g slurry w placed in a .Discever*»&dei nnemwave reactor ' (CE , Matthews, C> and safed so 120 *C wish vigorous, surrssg for three a. The rsstdiiag blue sltaty was filtered and washed with EtOAc and DCM. The filtrate was conce rated arid tJje residue was purified by me ium pressure chroinatogtfaphy (silica., 0 to ?% Hi MeOH: DCM) to give the desired product ceutamhi ted with lactam ' Starting m terial. T e im ure material was porifled by revise- puase preparative HPLC using a PteifOineftex Gemini column, it) micron, C: S> 1 0 , 150 s 30 mm, 0. i% TFA. in CH^C HA gradient 1.0% to 95% over 25 mm o provide the Tf A sail of Use desired product. The salt was theft free b ed by eintiag die material throu h an SCX column with 0 to 2M HH-5 in. MeO:H so gve l.-(4-(2 < 6-dif:kforopi:ieaoxy}-5-(2-oxopyrrolidiu-i-yi)

{IS nig, 0.041 ni!HoL 8.5 % yield). Mass spectrum (ESI) ,n¾¾ - 363.0 (M÷.H). ¾ HMR. (400 ¾ € a ) 3 ppm 9,0s Π B, s), 8,81 - 8.07 (1 H, ur>.8.10 (1 M s), 7.1 - 7.2? (I H. m), 7,00 - ?.12 (2 H, !«;, 6,1$ ( I B. s), 3.87 (2 H. L -7.0 H s.2,76 ' (3 S-i i, -4,7 Bx} : 2.59 (2 H, L -8.0 H/ , 2,23 (2 H t

m e 616 meflryhrea

0,045 mo\) was dissolved in diqxaae (0,25 tnj,). H ;; SO. :! (2,0 mL of 5% (w/w)) solution was added and the resulting soktioa was heated at US °C for 1.5 . The reaction was cooled to T arid basiSed wish saturated NaMCO? soStftio The: mixture was extracted with EtOAc (3 x 25 mL). The eembmed orgame layers were dried over M SO.< and the crude pioda t was purified by medium pressure cbreo faph (silica, to 10% MeOiTDCM) to give H -(2,6-di8uoro heno:x }-5-^^^ x»g, 0,030 mim 67% yield). Mass spcemnxi {ESI) mfr - 3 .1 < ·*· Hi HMR (400 ife,€ Cf ) 0 pm 9.06 Ϊ ! H, br, .§.), 8. ! 4 (1 H, s}« 7.93 (1 ¾ ¾ 7,1?- 7.2S (I R ra), 6.92 - 7.13 (2 H„ ml 5.94 (I B, sj, 3.50- 3.73 (4 E, ) > 2.8! (3 M, d, -4.7 Hz), 2.65 - 2.75 {2 M, m>.2.45 {1 R b &. 1.65 - 1.76 (2 H, m), 1.78 (.1 H, br. s.} s 0.93 (3 H, s).

:as e 617

,1 -{¾-((4-brouTo-i -ethyl- J H ?y.ra%^^^

l-{3-((i-Etbyi- i H;- ra¾eS-5~yi}0:^

trsg, 0.030 romol) was dissolved in dioxsae {140 ui and bromine {7.4 μΐ, 0.5.4 rnmol) was added. The res itiiig orange solution, was stirred ai RT for 45 min. Ik .reaction was then, dilated with l-LO 0 mL). The mi ture was extracted ith EtOAc { S. x 20 uiL) ami DCM (i x 10 raL). The orgaaie Savers were combined and was ed with RO (i x 20 mL) and brise (.1 x 1 mL) a»d dried over MgSO.,. The crude prodsici was then pirifed by mediu pressure ciirmsatograpby {silica, 0 to 7% MeOH:DCM) to give i 3-{ >mmo-l-et!s l H~ ^^

methyiurea {12 trig, 0.027 mmol, 76 % yield). Mass spectrum- (ESI) m¾ = 440,0 <M H) 5 442.0 (M H). Ή NMR {400 MHz, / 8 pp 9.21 (i br, -q ( -4.3, .3, 3 ffo), 7.7 {] R d, " .6 Η¾ 7.50 ( I H, s}« 7.39 ( ' } ¾ br. s>, 6.72 { ! M, d, - i J H*>, M {2 R q, -7.3 Ha* 3,00 (3 H, d, -4.7 H 2.52 (2 lit, -7.4 Hz), 1,32·· 1.73f3Rs)¾ i.34■ L47 {S tl m), ί ..11 - I.2S (6H s m). m v 618

I "i -({ I - ethy 1- - methy I - 1 H -fiytazoi - -y I¼x y )- 5 - { 44iy qx -4 -t h y Ipsat y py t i dm - *y I j -3 - melhyl ea

raethyksrea. ( ί ί atg, 0.025 mrnoi) was diss lved in. THF (120 μϊ) a&d paSiad nnCIIj acelate (0.280 tng, 1.2 uraol a»d S-Phos ' (L0 t«g, 2.5 unsol) were added. To this mixw* was added dimethvMic (1,0 M m h ' episas:} (220 ΐ, 0,23 ΪΪΙ« >Ϊ> solution, Tfee .mixture was theft, heated TO rerlnx and stirred for 4.5 Si. Use reactiofi was i qus ehad wit , saturated N¾C1 His .mixture was extracted with Etf c (2 x 2(ϊ mL). The combiftesd. layers were washed w h. brine and dried o ver MgS¾. The crude aisiersii was purified by rev¾rsephase preparative HPLC using a P enoiseaex Gemini eotoma, 10 micros, Ct» t 100 , 150 s.30 ΧΜΆ, 0.1 % IV A m CH.-jCM HsO, . gradient 10% so 9S¾ <tver 20 mm to provide 1- f3-((!-0t&yt.-4>*nei»yt-lH-py

(0.6 mg, L6 waroL 6.4 ¾ yield). Mass spectrum (EST) isi/z - 376. Ϊ (MH-H). Ή R. (4(8 ) MHz, C Ci ) 8 pp ,24 (111 br. « 3.9.3.9, 3.9 Hz), 7.75 (1 H, 4, ·* ·}..8 Hz), 7.41 <1 H, ¾.7.37 < 1 Η » ¾}.6.66 (I ft d, -1.8 Hz), 3.95 (2 H, , -7.2 i¾ 3,01 (2 H, i -4.7 Hz), 2.49 (2 H, L -7,4 ¾}, 1,78 (3 H, s), 1.39 - 1.46 (3 H, va).1.32 - 1.38 ( R m.}, 1.18 (611 s).

Tle title co ound, was prepare by esseBiiaJly following the procedure in Example 87ί\ exce t asiog ύ® a!coteS l-( -lrdt«xy-5Klettahydo- ti-p ni: -4^ )p rid and 2-chioro-

5-ihi ropyTiniidi«e Us give S"i4-((5-ii»oropyrimi.dii^2^

yiK netiiyliirea, Mass spccmiii {ESI) \WZ - 348,0 (M+tft 'ίί ΜΕ (500 Hz, SH ) 5 -ppm 9.15 (5 ri s), 9.00 (1 H, s), 8.82 (2 H, $).8.10 (S H, s).6.77 (1 H„ s), 3.95 (2 H, d -13, Hz), 3.39 - 3.4 (2 H, ml 2.650 K d, = « .S Hz), 1...74 - 1.87 (4 H, m}. By essential i:y foUwiag t e procedure is Example $.19, except tssiog t & corresponding reactive aryl fluorides aiid S•{4J:iydresy-s-(ie!riifeyd!)-2H-p>t ; ··· ·ν;}ρν;· ίϋ···:? 1)-3~!:ijcihylatc i as starring

By following essentially t e procedure I» Example :l*M&, the fo owsig compo nds ee prepared:

By IbSSowiHg ess¾ttiaS1y the procedure Example 17 , the Mte iii com oun s were p epared:

m e 635

t λ To a solution of :tuirom<shase ( L i mi, 20 njifiol) w DMF (100 mL) as added aH (60% •dispcfsioft) (0.36 g, Ϊ5 HH&OI ami the mixtuse was stirred for 15 niisy I » (5-8r0iao- ' f]¾oi¾^yr!d!!!-2- y S)-3-f«etbyKf}'ea (2.50 g, 18.08 «ΪΗ»}.) was added, atal ?¾e rcsi i.iiig sohrtieo was heated at S .¾> ' *€> Tite reaction as .hotted for 2,5 h then cooled to RT, The .mixture was tfem diluted with ¾0 (125 ffiL) strsd extracted with EiOAc (} x } 50 mi,). The aqaeoas layers were co:«c«i«r t«d t der high vacuum to give a concentrated, residue. The e i e was dissolved in. a mmhsura-amottnt of water aad extracted wills 10% MeOil:0CM x 100 iftL), The combined pigattfc. law e s were dried over M.gS0 4 axtd die filtrate was coaceritrated to give erode 1 iS^rojiK^^Ciutromet ^^ idin^vl)^' ateihyiuiea (2,0 g, 7,0 mmol, 7(J¾ yield). Mass spectrum (ESI) m/κ 288,9, 29 8 (Ma-ii).

S B: 5.3 ram!) was shi red ia

AcOH (2? ml) nd the slany was cooled to 10 °C, Zinc dust < 1.7 g, 2 msml) was added and the slurry was warmed sfew!y to RT over a period of 8.5 . The reaefkm slurry was diluted with more HOAc ( 50 mi) and then, filtered. The solid was washed with. HOAc and the eo feiaed filtrates were concentrated voider reduced pressure to give tire acetate salt of the desired crude product. The crude materia! was absorbed onto a p wg of silica gel aad purified by chromatography, elating with 7.5% to 10% 2M ammosis m MeOH:.DC , to give

(320 mg s .1.2 mmo , 23% yield). Mass spectrum iBSI) raft 260.9 (M+H).

Step C: A glass mieiawstve reae!ios vessel was charged with i-(4-(anh;aesaetliyl)-5-brOioop) idia-2- y t}-3"i»ei:hyh!i-ea (250 mg, 0,97 mrnol) ad succinic aabyddde {120 a , 1.2 mtrsoi) in D P i 1.3 tuL), and placed in a Discover model microwave reactor (CEM, Matthews, NC) as 100 *C .for 30 tain. The reaction mixture was cooled aad acetic aahydride (0,30 ml, 3,9 aajtol) was added. This mixture was reheated so 100 C for 30 ia, the reaction was cooled aad disrued with water (30 niL) and EiOAc (50 «iL). The layers were separated, a»d the aqueous layer was extracted with DCM (I x 50 atLi, The orgastic layers were cota ifted aad the auxtare was extracted with satarsted ' aHCO ? (3 x 25 taL) aad water (3 x 25 ittL) aad dried over MgSi¾, Tlte erode material was adsorbed opto a plu of silica gel artd purified by chromatography, ektting with 2.5% to 6¾ MeOH:DCM, to give I - 5-hmrao~4- ((2 t 5-dioxopyn-o.bdli^i-yi methyl)pynda 2-yi.)-3- (150 tag, 0,440 mraol 46% yield).

Mass speetrntn (ESI) mfe - 342.9 (M*H). l E N R. (400 ¾ C.DCH) 8 9.3? (1 ¾ ¾ $M (I H, br. ¾ - 1.S, 5.8 ί ί,·.ϊ. 8,20 ( 1 H. sa, 6,54 { 1 K. s) 4,7(5 (2 B . s y 2,93 H . ci> ,,4 a ¾), 2M (3 i t. hi. s.).

By essentially foltewmg the procedure in Example 870, the follawhig eo oru!ds were p e s d:.

e 655

l-{4^betigyl xy?-5-bromopyTidm-2-y ' l)-3-fflci ytee¾

} S-Brom - 1«oro rjd

m ' L, 8.5 mmol) were dissolved in BMF 06 mL). NaH (60% dispersion) (540 mg,, 8,5 mim) was added carefully ' to the solution, Tito resulting dark brows so-utfon was risen stirred at 65 «C for 2.5 days. Tito reaction was then cooled to RT and poured into 300 triL of water. The resulting slurry was .filtered and washed with water. The wet precipitate was dissolved in 550 s«L of a 10% eOH:D€M mixture and thea dried over MgSO<. The filtrate wa fcoacetttfatod So give crude H4- te)^4os )-5-hromoiy jd»fl-2- l)-S-i st yU}&¾ (L5S g, 4.61 Bsssoi 82 % yield). Mass spectrara (ESi) t z - 33<>,2 (M-r¾ 338.2 (M+Hl f .H NMR (DMSO-d,) 3: 9.24 <$, IB), 8, 18 (s\ i.H), 2.36 - 7.49 m. SR), 5,2 ! is, 2H), 2.70 {d, i ^ 4,7 l .3H),

y!}-.3-HKi:hyiifs¾a

prepared:

Following the procedure in Example 4¾$, the ibifowing coss ooads were prepared:

Example btr seiure Nam Data

331

Following die procedure in Example 253, tfee foiiowiag coiapousd was prepared.

1 Example 1 Structure Name Data

3 -i 4- (2,6 - <.¾ fi ϋόί o Ssc!fi < ixy) - o: i -v. jetS iyl i¾ i des ¾i riiSifi-- sKST) ;:; ; V ■■ ¾2.i

Following the procedure in Example 449, the following compouad was prepared:

prepared:

Follcwiag the procedure in Example 467, the following compounds ware prepared;

Example Structure Data

Following the proce ure ¾» Exatap ' 499, Site foi lowng coiiipotrads were prepared:

Structure ame Data

metfey rsa (M H).

all ing the pioeedare i« Example 251, the following coispourid w prepared

' r raethylarea

m e 701

A 0;isfc charged with .3-(4 2,0-di:nuoropta^^ acid (0,007 g, 0.020 mnol.) was added TBTU (7M mg, 0.024 Jnrao!), N-e -N-sop?ap )pro aH-.2^i»$»e. (10.44 pL, ,060 mm© ) , DMF (0,41.5 mt), -«liyi-. -isopropy:i»¾^tt*≥-atstoe ( .5.0,44 μί,, 0.060 mrnai) am ei am x (0,050 sal,, O.lOOininoi). Ί¼ flasfe. was seated a»<3 sirred for 2 h then. e icciiOated to dryoess. Tbe product, was partrtiorsed between water and EtQAe. Tbe organic Sayer was collected, dried over gSO:-, fshered and ce¾cerrir£0ed, Tbe -crude material was purified by reverse- ase preparative HPLC using " 0, 1% TEA m C%C ¾0, padlesit 50 % to Sit ¾, to provide S- ^^dffiuoro hw g„ 6.3 μιηοί, 32 ¾ yield) as a white solid. Mass .spectrum (ESi) raa - 365.1 (M÷-H). ¾ M .R (MeOSkU) § 8.05 ( Sf i H), 7.34 -7.48 (m, ΪΆ% 7. B - 730 ¾ 2H).6.40 (a, ΙΆ), 2.98 - 3,1.1 (m, 2H}„ 2.84 (s t 3H.}„ 2.73 (s, 3 Fit 2.50 (t. J - 7.6 H:.2M). m e 702

To a soiutkm of g, 0.140 miaol) m DMF ø, 14 roL) added, copper (i) cyaside (0.010 g, 0, 575 taoiol). The reactio mi ture was stirred at i 50 for 5 » h dies cooled, to RT. Tbe erode material was purified by ieversi-pkas© preparaii e HPLC wsmg SB C¾. column, 0.1% Tf ' A in C¾CN/¾0, gadient 20 % to BS %. The desired fractions were combined, concentrated, .neutralized widi saturated aqueous HaKCOs solurioa arid extracted with EtOAc. Use organic layer was dried (MgSCo), filtered and c ncerned to give i- (0,0006 g, 2 μηκί, 1.4 % yields as a white solid. Mass spectrum (ESi) m/z 30s.5 ( H). ¾ NMR (MsOH-d,) § 8.44 (s, f Hi, 7,3 S it, J - 8.6 P0 > , IE), 7.15 (t, J - 8.3 Hsr,.2H), 6.68 (s, !.!¾ 2.69 (s ; 3H)

A .flask charged with

0. I t xsoi) hi DC ' M (X22 tat) as purged iih. Ar first thm H 2 .4-¥ifty!-!eir£i&ydro-2H-iiiiopyTa« i , I -dioxide (0. ! .1 i g, 0.692 rams!) sad Moveyda-Grtibbs eatelys! ' 2nd gcaeratios { } 0.08 rog, 0,0 i 6 mmoi) were added. The msctioa mixture was degassed three times then heated as 40 - > C for 1% h. The crude materia! was absorbed onto a plug of silica gel and purified by chroiMiograp y through a Redi-Sep re- acked silica gel. Colasrta (4 g), ehuiiig wis a gradient of 0 % to 100 % EiOAc in hexjwes, to

1)esy}pyndii:^ -y - -iHei!w!:»!¾a (0.0 i4 g r 0,033 tntml 20 % yield) as a« off white solid. Mass 4 Ll {M ; ÷H>, ! H NM.R (MeOH-d.i} o 8.3S (dd, 1 ~ .8, i.3J¾ iH), 8.05 (d, Jf

- B¾ 1H} : 7.39 - 7,47 (HI, IH), 7.35 (dl J - 0,4.6Hz, ί H\ 7, IS (4 j - 1,7 |¾ !H).0.44 id, J

- 16 Λ M¾ IHg 6,1.5 (d,j 7,i¾ il¾ 3. S3 - 3,24 (m, 2H> ( 3.01 - 3,11 (¾ 2H), 2.95 (s.314X2.90 (0;. J - 7.0 H , m% 2.45 - 238 (m, LB), 2, i i - 2.20 (m, 2.¾ 1.99 - 2,09 (ra.2H), L28-OI <m, 3H).

FoUmviag the procedure in Example 486, the ibllowijrg coiapousxls were prepared:

Fal.low.ag the procedure ia .Example 449, the following- compoimds were prepared:

7-mmm

Folte ii )g tire procedure in Exam le 467, th

Folios ing t e pr cedure in Exam le 25 «0, trie following coffipQosiife were prepared:

V ySjl iisSRoste

FoMo i g. the procedure ia Example 253, was prepare :

Example j Structure Name | Data 1 ΗΟ" '' -' " Ή·" ',¾ 'Ν HM" "

" ,·'..·, S Mass spe ftUiH .* ·, , .,. ... ί:.!>1) m; . ~- ,·>4>.1 yS jpmpanok acki |

fallowing &e procedure in Example 195, the following cisspoua was pre are :

Fo!!ewstig tfee procedure ia Example 1 8, she ibliotwsrsg ccampoiiad was prepared:

m e 725

To a sotutiomsf H3 2^*y|pyndin-3-y|-)o )-5^4^xocydoh. s-. { -yl}pyddin-2-yi)~3- methykirea (0.020 g, 0.055 mrao!) in MeOH (0.540 rat) was added piatlmirs (iv) oxide (2.5 mg, 10 fi.iiio!) at 25 *C. The taction laix!tsre was stirred isader Ih aOoasphcre at 25 K C for i 8 !i The .reaction atsxtoe was fihsrsd through a pad of CeHte asd washed with. MeOH. The .Ritrsie was eo ceat rated. The erode asateriaS was absorbed omo a pS¾ of silica gel aad urified by chromatography through a Rsdi-Sep pre-packed silica gel eohtaia (4 g), elatiag with a gradieat of 0 % to 1 % MeOH ifi DCM, The product was fusilier pariSed by revme-phasc preparative HPI..C «s|i¾ aft Eclipse column, 0.1% TP A in CH S CN/¾(X gradiem 10 % n*?(> % over 25 mitt, to provide the TEA sali of die desired prodacl. The desired traetioas were combated, eoaceatraied, neutralized ish saturated aqueous aMCO; so!atioa and extracted with EsOAe. The organic layer was dried (MgSCi , sad coneettrrated to give K ~¾2"edryS idia-3- I o^

2-yi -3-H 5 kire3 (0.008 g, 0.0210 i oL 39 % yield). Mass spectrum (ESI) miz - 3? E l (M * m< m c 726

A. glas mL, 6.60 mmol) x l) m JMMP

(2,75 wit) . , aad placed «i a microwave reactor ai IS « C for i h. Toe reacdoa was cooled to RT, diluted/with 1-fcO (10 mL) and extracted with EiOAc (2 x .10 mL). The conibmed argauie layers were washed with water, brioe and dried over MsSCL. The solution was Bliercd and concentrated is vacuo. The crude material was absorbed onto a ping oi siUca gel d purified by chromatography through a fedi»$ep pre-packed silica gel coltPirxs (12 g), ehrtmg it 0 % io 50 % EtOAc hi bexaftes, to provide bromo-- -(2^~d iii½ 5.36 nunoi, S3 % yield) as as off white solid. Mass spectrum (ESI) mfz ^ 433.0. 435.0 ¾ MR

(CBCh) δ 8.00 id. J - 2.2 H.¾, I H). 7.44 <d, J - 2.0 Hz, 1M), 7,28 (s, !H). 7.09 (d, J - 2.0 H¾, IH), £.41 - 6.SS ( 1, 2H), S.m J - 2.0 ¾ IH), 4,63 { J - 5.3 Hz, 2H), 4.05 (d, J - 7.2 Hz, 2H), 3.83 (d, J - 1.8 .¾ 1.42 ¾. J - 7.2 Hss, 3H). e.

To a soluiiea of -(2,4-dinie!3s0Kybeazyi)-3-(( i ^b l-:iH-p r xoi-S-y ' i;)ox 5^{ietn dj¾-2H-p ra8- 4-yi)metii l)pyridl»-2~asiine (0.359 g, 0.793 tm t) in DCM (« mL) was added 2,2,2-rriiIuoroaeedc acid ( [ ,834 «iL, 23.80 nttftof) at 0 *G The imxiutc was wanned io RT and s irs¾d for 4 h. The mixture was concentrated, diluted. ' wfli DCM, washed with saturated aqueous MaHCO ? sol tion U tnL) and dried over Mg$C¾. The sohtiioH was filtered and eoficeattated in vacuo, lite crude materiai was piirifed by chrawtogxaph trough a Redi÷Sep pre-packed silica gel ΟΙΗΙΚΒ, eiuikig witb a gradient of 0 ¾ to 5 % MeOH ½ DCM. The product was itirttref pariiied by reverse-phase preparative M ' PLC using a SB C* eolmm 0,1% Tf A in CH ? .C /H 2 0, gradient 10 % o 66 % over 25 πϊίίϊ, to prov de

athiue (0.140 g„ 0.463 mmol, 58.4 % yield). Mass spectrum. i ' ES!) m.¾™ 303 J ( Hi). ; H MR (MeOM-cL) § 7.63 is, I R , 7,3? - 1M (m > I H), 7.06 - 7. !4 (ot SH), 5.61 - 70 (at, I.H). 4. Ϊ4 (q, ,i ~ 7.3 Hz, 2Rh 3.92 (<Jd, J · « Ϊ 1.5, 3.7 ' Hz, 2¾ 3,35 - 3.44 (« 2R 2.44 (d, - 7.3 ¾ 2M 1.68 (dt, J - 7,5, 3.9 Hz, IK), 1.55 (d, J - 12.7 ¾ 2E) > 1,37 - 1,46 (m, 3H>, 1.28 (qd, J - i .4,4 Bz. 2H),

6-bromo- 1 -meibyiisid.olio~2-o«e

TO a suspension fK H 66% dispersion in mineral oil (0,130 g, 3.00 rnmol) in toluene (12 m ' L) at 100 *C under ? -was added a solution of 6-broro-2-0xindo!e (6,656 g„ 3.6 rorool) i toluene (3 rot) drop ise. The resulting o¾xt«re was stirred for ί 6 at 100 *€. Aikwards dimethyl sulfate (0.29 mL, 3.96.mmo.1) was added at once and the resulting eaction was stirred at 100 °C for i 8 k The crude mixture was diluted with H¾0, extracted with EtOA The combined organic extracts were dried over MgS<¼, filtered and concentrated under reduced pressure-. The crude was absorbed onto a plug of silica gel and purified by -cJaxuifcUography h ugh -A Redi-Sep pre-paeke -silica gel eotena ft 2 g), slutrog with a gradient of 0 % to 25 % ElOAc in hexaues, to provide 6-bro UQ- I -n¾eth H«doiin-:2-o«e (0.27 i E. 1.19 nn l 40.0. % yield) as an oiT-vvhue solid. Mass spectrum <£Si . ) f!vz « 225.9 (Μ· Η).. H MS. (400 ¾€D€:U 8 7.1 is (1 L dd, -?.8 1.6 & . ), 710 (.{ H, d . , -7.il !¾ 6,97 (1 ¾ d, -1,6 H :·-! 3,47 (2 H. s), 3.20 (3 M, s).

Foi!cmng the procedure, in Example 197, the. following catapouttds were prepared:

166 prepared:

Following the procedure in m e SSf^ the follo ing ii!):i ¾ii)ii was prepared:

Followng ibe procedure la m & W , die i owlttg co oun was prepared:

Example Structure Name Dam

1 -{S y<d« j }r<}pyS- -{i J - g ass speettKro

methyl i H-pyi»;wk}p,4--

752 (ESI) f¾/K ~ 339.0 b jpyridm-. ' l}oxv !pyrtditi-

( m.

.-yS).-3"ii)BiSs i«i:a« m 753

H4 3~c]hI^

raethyhtrea £0.O g f 0,209 mmol), S-!¾xii»o- s.iadefc (0.066 g, 0.3 traot) sud PdrPPfel; (0.024 a, 0.02J jujsol) were suspended ja DMF (0.522 m!) is a 1.0 mL septum-capped rube coftiaisiag a su ' r tg mapet. To this was added aBCOj (0.053 g, 0.626 mtmi) aad water (0.522 mL). The mixture was heated in a Discover model BMC-rtnvavs reacwr (CE , alotews. HC) for 10 mm at 1 SO : -ς. After Ote reaetkm was don , the vial was cooled to RT. The crude xnuUurc was partitioned between EtOAe aud waiter. The combined organic layers were -dried over g O^ filtered a«d concentrated. Thjc crude product was purified by revcrsc-phiise pre arati HPLC using 0,i¾ TFA in C¾CH/¾0. gradient 5 % to 95 % over 25 mat, to give l-i4H -cS:i?oro-2-flis0¾¾j:*

3-!ii«¾yUsrea (0.012- g, 0.028 »s«ol, 1 % yield). Miss spectrum (ESI) . - 427.0 ( ÷H). Ή 'N ' MR (5(K) MHz. eOH-d.,) f> 8,20 { i 8, s 74 - 7.55 (4 H, ja), 7.27 « 7 6 (2 £1 ttt), 7.05 ( i H, it H/i. 6.50 (I H. s), 3.58 - 3.63 (2 H,.i ) s 2.84 (3 H, <ø.

Following i c procedrsrc in fe aratkm if, fuc- toltowisg cossi osgii was prepared:

yl)iithano! {ίνίήί}. m e 761

} -(4-( -2 ,6-1! ) ! rl80ioplier!tticy}-5H4 > 4 ? 5,5 -t≤trsimtitb. i-l ! 3.2-iioxa 0fol¾i-2~ i yik{ifV2- l'-3'- rnciliylureii (0.104 g.0,257 jmnoiL 2-bronxs tiyT aicdlio! < 6.070 mL, 6.5*3 mrnoi), Pd(dppi¾C¾ (0.02 } g, 0.626 imiiol) and 2M aqueous ¾€0j solution (I.2S3 rat., .2,5? mmej) were combined la. DMF (3.0 mL) and treated at 9 *C lurder argoa tor 18 a. The reaction ixture was diluted with EtOAc «¾d water, Tfoe orgaaic istycr as collected,, dried ovefMgSQ*, filtered arid coscert!iated nder reduced pressure-. The crude material was absorbed onto a plug of silica gel and purified by chromatography d sigfe a Redi-Sep pre-packed silica gel co anu (4 g), eiudtig with a gradient of (5 % t 1 ( H ) % EtOAeiu hexaues, to provide l-( K2^-diiluor pheaox 5-{J dro ypK^ «ea»2-' yi)pyridi:n-2-yS-¾-mci yiij;rea (0:034 g.0.10 mmoi, 40 % yield) as hts powder. Mass spectraaj (ESS) in/r s; 36.0 (M÷H). Ή NMil (500 Ml¾ MsOH-t ) 683)8 (1 H. xX 7.32 - 7.43 (I H, raX 7. i 9 (2i e¾ 6.42 {! if. sX 5.58 (1 H, q, · } .(· H/ .34 ; ; 11 d. -1.7 B¾ 4.44 (2 s).2.82 ( 3 H. s}.

.m * 7&2

Step A: To & iOQ-mL rouad-boUoraed iask was added ;l»(4-:{luo∞-5-{2-hydrox etbyl)p^i{ia-2-yl 3- meibyiure* (0.50 g, 2.3 maiol imidazole (0.192 g, 2,83 mmolja d -TMS-CI (0.437 g.2.8 msioi) in D f f mL The reaction mixture was stirred fit RT for 18 h. Mere TMS-Ci (0.437 g : 2.81 mmoi) mid. imidazole (0. ! 86 nxl, 2.81 πκ η α}) were added inie the reaction mixture d stirred for additional 18 h. The reaction was dilated will) water and extracted with EtOAc. The organic layers were Collected arid dried O er gSQ* Tbe solution Was. fsllercd imd coaceitfraied i« vacuo «0 give the crude material. The crude materia! was absorbed omo a plug of silca gel and purified by chfoi¾atopaphy through a Redi-Sep pre-packed silica gel column (12 during with a gradient of 0 % to 50% OOAc in .hexatie, to provide

yl}-3"rsstlry!«rea «1.505 g, 1,54 riant , 65.8 % yiel } as 8» ff-white solid. Mass s eetram (ESI) -328.1 (M-«).

StepB: To a via! was added ΗΗ (*««·*ωγ1^

methyhjrea (0,050 g, 0.15 mitsoIX 3-hydroxy~2-i«ei yi pyridine {0.018 g, 0.17 mnsol) md cesium iXioide (0.058 g.0.38 rn ol) HI MeCN (1.5 ml.}. The eaction as .hea¾d at 80 "C for 18 t then, cooled to RT. The crude material was absorbed onto a ping of silica gel and purified by ehmraatograpity through a Redi-Sep pre-packed silica gel. column (4 g eluiisg with a gradient of 0 %

yi)-3-tnedryiiM¾a (0.020 g, 0.066 mnaot 43. % yield) as while solid. Mass spectrum (ES) su - 3Q i (M÷M). ¾ NMR (500 MHz, MeOH-d s ) 88.35 - 8.4S (I H, m% 8.08 ( I H, sX 7.61 (I tf, d, -7. Ϊ H¾ 7.43 (} i-X dd, «! , .9 H¾), 6.23 (Ϊ .H, S), 3.85 (2 ϋ t ™6.6 Hz), 2,95 (2 ¾ t -6,6 ii¾ 2.80 (8 ¾ SX 2.43 (3H, §}, Following ih¾? proce ure in Exa ple 1 5, the following compound as prepared:

Folio wing the procedure is Example 198, the following com ounds- were prepared:

Ex jsiple 817 :IT4- {2 , S-difluon } ptemxyH

Step A: g, 0.34 sstnol), 2-&g- di! dro-2H-t3)iep i¾a - 3}'4 s J.S-teiam tli l 1,3,2 -didxabor iane ίβ. ίϋ g, 0,74 mml}. P *Pf¾s>4 (46 sag, 8, 4 mrnol), and K¾CQ 3 i¾.iS g, LOS mm©.) were added lo a vial them degassed and baekfi&d iih Ar. To the vial anhydrous DMF (2 r»L) was added by syringe. The resulting reaction was heated to 100 X. After 19 . tie reaction was eooied to RT to dikited with water. After •extracting three times with DCM, the organks were pooled titers dried ove anhydrou MgSO<. After filtration and cftaceair tl ft, silica gd was added to- the black residue to leaded onto: a silica gel coktffis. (0-55% of premised 89:9: 1 DCM: MeOH: M*GH Is DCM) to afford black f.Uoi that as further purified with reverse-phase MPLC by dissolving 113 tng in 8 ml. of 0.1 % TFA m MeC . (25-90% of preruixed 0. ! % TFA. in MeCN in 9. t % TFA in water.) Fractions eontalafeg desired product were combined then concentrated irmier reduced pressure.. The residue as dissolved ia DCM then washed twice with saturated aqueous NaHC0 3 and once with brine. After drying over anhydrous- MgS(¾, filtration, and concentration, the residue was used without further purification. Mass spectrum (ESi) m/¾ - 378,1 ( +H .

Step B: To a viaFcoutaining M - {2,^^

l}-3- ethylurea {8S.5 mg, 0.24 rn i) was added MeOH (2 ml) aad water (0.5 rat). The mixture was cooled la an see bath, theft after - 15 tnia, Oxooe (308 mg, 0.S »«»ol) was added in. portions. Tile reaction was warmed to 2 "C. Afier :1.5 h, the Oxooe was fiStered off and rinsed with MeOH and DCM, The filtrate was concentrated under reduced pressure then purified oft silica gel (0-1.00% of a prennxed solution of 89:9:1 DCM: MeOH: ¾OH in DCM) to afford a brown film as i-(4-(2,6-

9.932 xmrnl 13.49 % yield) thai was used without Farther purification. Mass Spectrum (pes.) «v :

Sttp C: Its a flask cotitainsug 1 - (4- {2.6 - dliluurophemsx ) -5 - (1 J -diosldo-3 > 8-dlfeydro-2H-ifeiopyr^4- yl)pyridii>-2-y1i--3-n etl lwea (I S ang, 0,032 ffiruoij ift EtOM (2 mi.) asd BtOAc (2 sit.) was added Pd C. 10 % (38 ru , 0.035 mmo ' J). The flask was evacuated aad backfilled wi th N 2 and stirred, at 23 *€. After - S mte, lite N 2 was replaced with f½. After IT h, the reaction mixture was filtered through a ceiite plug and concentrated i« vacuo to afford a -colorless residue that was -purified with reverse - phase HPLC by dissolving ia 3 «sL of DMF (10-90% of premixed O.i % TFA to MeCN at 0.1 % TFA in water.) fractions containing desired product were .combined then, concentrated under reduced pressure. T¾e residue was dissolved is DCM thes washed iwicfe ith saturated aqueous NaMCGs and once with brnx » . After drying over aahydroas g$0*, filtration, sad corrceatration, the white soli was identified as 1 -{4 -(2 J-dilIiiorophfiOo?£y}--5 -(l J••diasidoie¾3h dro-2H-t.hiopyrao -yl}pyr(di«-2" y!)-3-me%l«rea (2 rag, S μηΐί . ΠΜ % yield}. ¾ NMR {500 Mttz, DICBLORO ETBANE- d ¾ ) 8 ppm 7M (1 H, or. s,), 7. 1 - 7.42 (i H, m). 7,1.5 (2 H, t, jM H¾), 174 0 H. or. s.), 3.1 - 3.31 {5 a m) < 2.78 (3 ¾ d, J J !½), 2.33 - 2.50 (4 R in). Mass speetnrni (ESI) miz - 412.1. (M+H).

Example 818 ~ -(2,8 -difltiorophenoxy) -δ'-{3· e ikyltsf eido) f 3.3' bi py r kii f ¾ji 5 yl)im 4 t ί Ϊ¾ isesul Ιοηκίϊί ϊίί e

Step A: in a dry round bottom flask, 5 (4^5,5 » teinu?_eJ3^

(0.10 g > 0.47 ramo.1) was dissolved ia dry DCM ' (2 mL) and pyridine (0.12 IHL, 1.47 mmol) . To this mixture w s added methane satfonyl bioridfe (6.056 ml... 0.72 mmol) dropwise. The readfcwi was stirred at 23 X. After 20 h< the reaction was mnceK&ated under reduced pressure to afford a yellow oil as 5"(s8iet ^lsttli »88)!do)p r» iB"3"yiboroftic acid hat was used ithout purtflcatlou. Mass- Specrnxrn (pes.) ns/e; 217.1 (Μ·*·Β . .

Step B; {9.10 g, 0,29 w.iooB, (5-

{oi ih lSHifo!¾affiid:0}p idiiv-3- 1}feo!:onic acid (0.14 g, (IM nrmoJ), frlcyclehexyiphosphirie (17 mg i 0.050 trimol), and Pd ¾ (db3)s (28 mg, 8.03 nHnel) were added to a vial then degassed arid backfilled ltii Ar. To t!se vial, Li-IHo?;a«e (2 mL) and-aqweoas- 1,3 M K 3 PO* (0.56 mL, 0.73- t mi) were added by syringe. The r sulting reaction was heated to 90 X. After 18 h, the reaction was cooled 10 RT then concentrated under reduced pressure. The residae was filtered through a 0.4S \im CMP A wdisc ilieri loaded onto silica gel (0- 100% ofEtGAc In DCM then isocraOe 30% MeOII in DCM) to aftbfd. a film ¾ai was ftather purified with reverse-phase HPLC by dissolving io 2,4 «L of DM (10-90% of premised 0, 1 % TFA in MeCM la 0.1 % TFA i« wafer.) Fracoofts Q»taM«g desired, product were combined then concentrated under reduced pressure, ' The residue was dissolved te DCM then wasted twice with saturate aqueous Ma ' HC0 3 a once with brine. After dryittg over anhydrous MgSi¾, filtration, and concentration, the white wM was identified as N-(4 -{2.6- diHuarophe«oxy>6'--(3 -mei yloreMoi -[3,3'- bi|)yiidiaj ~5-yi}¾eihanes«Il¾nam1de (16 g, 0.03? mora!, 12.73 % yiekh. ¾ tAfft (400 MHz, fJMSO -d 6 ) 8 ppm 10.10 (1 R si. 9.28 (i R s), 8.47 - 8.55 U R in), 8.41 (1 ¾ d, j-2.2 B¾, 8.29 {I R s}, 7,81 - 7.88 (1 R in), 7.34 - 7,54 (4 R m), 7.07 (1 R g, 3.07 (3 R s), 2.60 - 2.69 (3 il ta . Mass spectrum (BS¾ oi/z - 450,1 (M-Ri).

Hxampie 819

-{4--(2,8-di¾eropheno^

Step A: A d y vial couiai ng 4-hrom©pyridln-2-a*u ne (0.50 g< 2.9 rnrftoi} in anhydrous pyridine (8 ml) was cooled in an Ice hath to 0 °C. After J 5 rain, methanesulfosyl chloride (0.46 iftl, 5.95 nniiol) was carefully added dtopwise. The reaction was warmed to 23 "C. After 0.5 h, the reaction was diluted, with EtOAc then washed once with aq. saturated N3HC 3 and once with brine. After drying over anhydrous r¾S{¼, filtration, and concentration, the yellowish solid was treated with IP A t en heated OH the roiovap lo 50 X, without vac. After 30 miu, the solid was filtered hot then washed once with IPA t afford a faint yellow solid as N- {4 -bro¾opyrldin-2-yl}methanfisoif naioide (347m g. 1.38 mmol 47.4 % yield) that was used without, further purification. ¾ M (400 Hz,

DICHLORO ETHA E-da) § ppm 8.13 (1 R d, -5.7 Had * 7.51 (i ft d. M Hi), 7. 8 (1 R M. 1-5.7, 1.8 Hz). 3.16 (3 R s).

Ste B: A stirred mixture of {4¾omopyridin -2-yS)mefenesu ¾3inide (347 Big, 1.38 mrooi) , his(pi»acolato)di oroR (429 mg, i M Minos) , Ρ4$ρρί ¾, complex Avith DCM. (I I sng, 0. ί 4 rasto }, and OAc (432 g, 4.4 max)}) m dry lA-iYmxam il ml.) was purged three times with Ar and placed under vacuum three times. The mixture was heated to 90 *C. After 48 h, die reaedon was cooled to T then filtered through CeHse., The organic solved was removed xier reduced pressure, and the residue was identified as (2· (n)ethyls«lfeaa«>ido pyridin- -yl>boroalc acid t a was used wMltout puriikirticiii. Mass Spectrum (pes.) mk: 237,0

Si p.C: 1 -(S--Bo¾m^H ,8--difi^^ (137 mg, 0.38πκο«1), (2- (m-eth isuifonamklf^pyrtdn-l-yljboijek'; add (16 mg, 0.78.mmol), tic fehexylph¾ipftlMe (22 mg, 0.08 tmml), aod Pi¾( ba} 3 (38 rag, 0.04 mraei) wete added to a vial theft de ased sad backfilled with Ar. To tnevJal, -dioxaue {2 ml) and aqueous i.3 Κ;;Ρί¾ (0.74 ml., 0.90 rarao-l} were added ' by syrioge. The restiioog readies as heated to 90 *C, After 18 S the reactios was cooled to RI theft coticesrtSiiled under reduced ressur, lie residue was filtered teoagft a 0. 5μίΌ GHP Acrodlsc t s! loaded ooto- siKca ge (0-100% of EtOAc in DC des isoetatic 30% M OH in DCM) to afford a brown f!lrn thai was ftmher purified with reverse-phase HPLC by dissolviag in 5 ml. of D F (18-90% of r mised ill %TFA hi MeCN in ill % TFA hi water.) Fractions eontaming desired product were c iobited then eonce rsfed under reduced pressors. The residue was dissolved in DCM ttes washed twice with saturated aqueous NaHC(¾ and once with brare. Alter drying over aol drows MgS(¾., fiJtraiiori, and twceatrailoa, the white solid was identified as N-{4-(2,6- diitaorophe«o*y}-S-(3--m (2 oig, 5.12 ool,

1.340 % yield). ¾ MK (S0O MHz, MeOH-d4) § ppm 8.29 (1 H, s), 8.19 (1 II d, j-5.6 Hat), 7.39 (I H, it, 8,6.6.0 Hz), 7.12 - 7.28 (4 ft, m).0.58 (1 ft, sh .3.18 (3 B, $}, 2.83 (3 ft, s). Mass spectrum (ESi) mz - 450,1 (M-rBh

Following the procedure io Examples 87-S19, the foUortag compounds were prepared:

3S4

\ li[) drfine<'-2 : 'i:ai¾o a!fiids

3S5

Step A.: To s solution of S-d)ioro|>yrld8-2-ol (1 g, ??,5 xamel) in DMF (250 raL), £38 g, i 18 matoi) followed by $«d-Otn cniorodifl«.o«>aeeaie { .4. J g« 93 moi} was added, and the reaction was. heated to 1.00 *C for 3 h. The reaction mixture, was cooled to T; water (300 mi.} was added arid tracted will! diethyl ether (560 rhL x 2). The organic part s dried, over ¾8ί¾. filtered and concentrated to obtain the crude., which was further purified by cohmia chromatography using silica gel {100-200 taesh) and 0-5% EtOAc in h e to afford a colorless oil as S-chiotO-2- (diftKiromeihoxylpyridme. ! H MR { MSOdg.400 MMx) S 8.36.1 (d, 2.8I¾ 1M), 8.07 -8.4 (ra, IH}, 7.672 ( m), 7.177(0. j -8.8 Hz, Hi).

St£pii : A stirred mixture of 5-cWoTO-H-(d fJaorom hoK ) ridtoe {0,13 g, 0,75 tar»o >,

hisCpinacoiatohUksoa (0,21 g, 0,83 matol), Pd{dpp¾(¾, cOi splcx with DCM {62 jag, 0,076 aanol), and KOAc (8.23 g, 2-30 mmnl) is dry 1 ,4-dioxarse (4 ml..) was purged three tunes with At and placed under vaaiur.ii three imes. The mixture was heated to 90 "C, After 21 a. the reaction: was cooled to RT then filtered throtrgh Ceiite, The organic solvent was removed under redaced pressure, and the black residue was identified as (6--{difluommeth03cy)pyvid ' i«--3"yl) ' borr«iic acid that was used Without purification.

Step A; To a dry roand bottom flask containing i » {3"bwmo yrjd}R-2--yl)ettoOBe (240 sag, i.2 want!) was added a premixed solution of anhydrous DCM (2 mL) and anhydrous MeOH (2 mL). After stirring at 0 "C for ~i5 rain, HaB¾ (101 mg, 2.66 anaol) was careialiy adtkd.ai 0 a C. llpoa complete addition., the reaction was wanned to 23 C' C. After i ,5 h, the reaction was cooled in an ice hath, then carefully quenched with water and extracted thre times with DCM. After drying over anhydrous MgSi¾ and filtration, the organic solvent w s removed under reduced pressure. The colorless resides was identified as i"{5-hroraopyridItv2-yi)efhanoi (193. mg, 0.96 raraoL 80 % yield) that was used without purification, ¾ ' N R (400 MI½, DlCHLORQMETHAfyB-dyj 6 ppru 8.50 (i H, d, 2.i) B¾), 7.83 (I H, dd. J«8.4, 2.3 Hx), 7.24 (I H, d, 8.2 Hz), 4.83 (1 M, ¾, .hS.S Hz), 3,64 if H, bt, *.}, 1 ,45 {3 H, d, Hz).

Step B: A. stirred mixture of l-{3-b«»mo}>yridiii-2-y!)ethanol (1S3 ng, 0,96 imiioih

Ms(pinacolato)dibort}B (368 rag, L45 mmolL Pd(dgp%Ck complex with DCM (238 mg, 0.29 mtnoi), arid KOAc (289.mg s 2,94 mmol) in dry 1.4-dioxaae {4 mL) was purged three times with Ar and placed under acuus? three times. Th ix u e was heated to 90 "C. Alter 18 h, the reaction was cooled to RT tnen identified as I-(S- 4 < 4,5,5 «iraja«t s.yi- I,3,2-dioxaiiorol¾n--2-yl)|wriilin -2-yl)ethariol that was used without potif!eatitm. Mass Spednua (pox,} «1%: 168, ϊ (Μ ÷Η . (MS of t e borotdc acid

P feparatkm

Su-p A : A stirred mixture of 2-{ . (5-¾>ino-2py.ddinyi)oxy{-etiiafio1 (306 mg, i.40 jimiol).

bia(pi«a( o!alo)di oi ' f,is (536 mg ' , 2J I mxml}, Pd{df>pi)gC¾, com lex with DCM (347 mg, 0.42 m>«ol) . and KOAc (492 mg. $.0i tatsol) in dry i ,4 dioxane {7 oil.) was purged three times With As and placed under vacuum three times. The mixture was iieahxi to- 90 \ After 18 h, the reaction was cooled to RT tfeen identified as 2-((5 -(4 i 4 t ,5 -ietramsityl- l,S,2--d¾>X8boio-kti-2-yl}pyddia--2- yl}oxy)e:thanol thai was assd wid¾}«t pwl kafion. Mass S e trum (pos.) nv ' e: 2SS.2(M-:-H) ' ,

Preparation

S j er; A : A dry vial -Cdata!nlag 4-brajftopyiidiae-2-caf¾oxyliC add (405 ing, 3, 1 mmo! and HATU (.(,53 g, 4,02 rnmol) was evacuated ajsrl backfilled three fees wit Ar. Dry DMF (10 rnL) than Di ' PEA (1,4 nit. 8,05 nirnol) were added separately b syringe under Ar protection. The mixtur was stirred tinder Ar at 23 X, After 30 rain, g- ethox eih Jantine (0,27 mL, 3.11 mino-1) was added dfopwise- by syringe. Upon complete addition, the reaction was stated at 23 X. After 17 h, me reaction was dilated with water tnen extracted three times with DCM, Tie orgairfcs were pooled iben washed three dmeswiih satnrated aq. ijCi solution, three times saturated aq. aMCOs Sotai a and -once with brine. Alter drying over anhydrous MgSO*. filtration, and concentration. She residue was purified on silica gel (0-25% EtOAe in. DCM) to afford yellow oi as 4-broffio~M-(2- .metb8xye 'l)p|.Collnatnide (375.6 mg, 1.450 mm , 72,2 % yield} that was used widiotri farther purifieaSios. ¾ NMR (500 MH¾-, DiClrlLOROMHTHA E-d,} o ppm 8.38 (1 H, d, j-5.1 Hz), 8.33 (1 H, d. ÷2.0 }> 8.Ο5 - 8.26 (I H. m), 7.62 (1 n, ddj~5.i . 2, Hz}. t 3.5s - S.64 (2 H, m), 3.5i - 3.57 (Ε H, ·»}. 3.37 (3 H, s).

S ep B; A stirred mi ture ofi-bm^- -'iZ-^eAox^et ypfcoliaamide (376 mg, 1.45 ramol , bJs(pina oiato)diboro8 {5.54 tog, 2,18 mmoi}., F CdppiJsC , complex with DCM (38 tng, 0,34 roiooi), and KOAc (500 mg, 51)9 n¾aol} in dry i.4 « dioxa«e (7 -niL) was purged tferee tinies whk Ar assd placed under vacuuta three flutes. The mixtur was leafed io 90 S C, After Ϊ8 h, the reaction was cooled to ET t&ea identified as N"{2"ffiethox e{h i} 4 , ,5.5- mmeil)yi- ,2-dloxa^roIsR-2~ ,yl) coUr$aKtidfe that was used without purification. Mass Spectrum ipos.) rsi/e;

Step A: A stirred mixture ef 4-iodo- - et¾ylpi«>linar«jde .{112 mg, 0,43 fnnioi).

hl Cpitiseo!atoldibototi { 87 tng, 0,66 tempi), Pd(d.ppf)?C¾> complex with DCM {1 6 mg, 0,13 aunoJ}, and KOAc {129.mg, 1.31 mmoi} ia dry 1,4-dioxane {4 tnL) wss purged three times with Ar and placed under vacuum three tees. The mixture was heated to 90 * C. After 18 h. the reaction was cooled to RT titers identified as -methyl ·4-{4.4.·δ,δ· etraraethy!-l 2 -th x& tolm-Z- y]}pieo!hiajaide. Mass Spectrum (90s.) nr e: Ϊ8Ι . (M+ii) * . -3 if.n¾

Step A;:- A dry vial containing 2-{ ' {3-faronio--2p ridin i)os.yj^itkmol (320 rag, 1.47 mmoi} in dry cyciopesiyl tueiltyi ether (10 mL> was cooled is art tee water batb> After 20 una, ail, 60%

dispersion in mineral nil (178 nig, 4.41 mmoi) was added m portions to the cold reaction; solution. After I hour, itx met aee (0. I S mL. 3,06 ΗΪΗΪΟ! was added dropwise by syringe at 0 *C, Upon complete addition of kxiotnetltam 1 . Sire mixture was warmed to 23 * C. After 17 ft, th reaction was heated to 85 * C. After 5 days, the reaction was cooled to 23 * C shea carefully quenched with water. After extracting three rinsex with EtOAc, the organics were pooled thee dried over atthydrous Na¾S<¾. After filtration and coticeiittadote the faint yellow resi ue was purified on. silica gel (0 - i % EtOAc in hexanes) to afford a colorless oil S^rom.O'-2-(2-aw!thox et o }p ridi ie (226 mg, 0,97 rsrso!, 06,3 % yield) that was used without further purification, ! M IN MR (500 MHz, DICHLORO ETHANE^ δ ppra 8.1.7 (1 H« d, 2.4 Ik), 7.66 {J H. dd ( A 2.7 M¾h 6.SS (1 II 4, JM8.8 Hz), 4.34 - 443 (2 H, a , 3.65 - 3.72 {2 H, in), 3.38 (3 IL si.

Step 8: A sited mixture of S-bromo- 2-(2 » metboxy«{ o y)p|frtdi}ie (226 mg, 0.97 mraol), is(pis¾8coia¾))ditoros5 (372 mg, 1. 6 nsmoi}, Pdid pfljC!; ? , complex ith DCM (241 mg, 0.38 oiiool), and KOAc (288 nig. 2.94 mmoi) fa dry 1.,4-dioxaue (5 mi) was p«s¾e<i three times with Ar and placed -under vacuum three ihnes. The mixture was heated to 99 * C, Ate 18 h, the reaction was cooled to RT thee identified as

ylj yridine that was «sed without purification. Mass Spectrum (pos.) m!e 280,1 { V¾} * .

Pre aration

Step A: A dry via! con aining Natl 60% dispersion in mineral oil (240 rag, 8.01 raoiei) in dry cycioperiryl methyl ether (10 m.L) was cooled in an ice water hath. After 20 min, 3· niafexy- i- propanal (0.38 slL, 3.97 rsauoli was added dropwise by syringe to the cold reaciiori solata. After i hsiii, 5-hfe«Ki-2"fi«oro5 kH«e (0.2 mL, 1.94 -ramol) was added dropwise at 0 X,. Upon complete additiott of5-bfomo-2-fluoropyridiae, the mixture was warned to 23 X then carefully heated to 85 X. After 17 h : the reaction was. cooled to 23 X fheii carefully quenched with water. After extracting three tbfies with EtOAc, the organies were pooled then dried oyer anhydrous r¾SOi. After filtration and concentration, the faint yellow residue was purified on silica gel (0-15% EtOAc la hexanes) to afford a colorless oil as 5- woroo-2- {3-OsediOJiypmpOxy) pyridine (439 mg, .1.78 rattiol 92 % y ield) thai was used without further purification. ¾ R (500 H¾ DiCHLOROM ETH NE- d ¾ ) 8 ppm 8, 17 (3 H, d, ' ZA Hz), 7.65 (I H, dd, ]~8,8, 2.4 t¾ 6.62 - t iiS (1 B, m 4,32 (2 H, t j-8,5 Hz),

(2 H, fcfe), 3. 1 (3 M. $), 1.99 (2 H, ¾uin. Hz}.

Stefi B: A stiffed mixture of S-bwrito^-^^-wetb xy i^O o yJ fidiBe (257 rng. 1.04 mo!}.

his(pioaeolato)dibom« (484) rag, 1.58 mmol) , Pd(dppi}¾Cl3, complex with DCM (257 mg, 0.31 misol) . aod KOAc (308 ru , 3.14 rsmol) io dry 1 ,4 -Dioxane ( stL) was purged iixree tiroes with Ar and placed under vacuus) three Uraes. The mixture was healed to 99 *C. Ate 21 h, the reaction: was cooled to RT then identified as 2-(3-melhox\9ropoxy}-5- 4A5 > 5-tet^

yl)pyridine that was used without, purification. Mass Spectrum (pos.) tn/e: 284.1 (MtH) * .

Pre p rat ion

Step A: A dry viai conraiBtag NaH, 60% dispersion in mine al oil (212 tog, 5.30 mmolj in dry eyelopentyi methyl ether (10 laL) was cooled in an. ice water bath. After 20 mm, 1 ~ eihoxy~2-- propaaol (0.35 t, 3.S7 rata©!) was added dropwist' by syringe to the cold reaction solution. After 1 a, 5-biOi«o-2- fluoropyr iae (0.2 laL, L.7 aanol) was added dropwise at *C. Upon complete addition of 5-bromo-2-.fl«oropyri(H8€ 5 the mixture was warmed to 23 * C theft carefully heated !ø 85 * C. After 17 h, the reactirsft was cooled to 23 *C "ihsii carefully quenched with waier. After xt acting three times with EtOAc. the organlcs were pooled theft dried After filtration d concentration, the Ikuit yellow residue was purified en silica gel (0 -10% EfOAc

yield) that was used without further purification. Ή MR (500 MHz, MCHLOROMETHAME- ) δ ppm ίϋδ IS M. d. J*2. Hx), 7.65 (1 H, dd. ,Nf.7, 2.8 H¾ , 8,64 (1 .H, 4 j*8;8 Hz), 5.28 - 5.35 (1 H, aft, 3.54 (1 M. dd, j-40.4, 6.0 Hz). 3.47 (1 It dd, 1-10.5, 4.2 MxJ. 3.35 (3 H, s), 1,28 (3 It d, =6,4

Step B: A stirred mixture oi 5- hrorrt -2- {(1 -ffie{:hoxy ' propan-2-y!)oxy pyrldin (265 jog, 1.08 rstnol), Dss(pi«acoi te}dlboro:fs (41 1 mg, i.6.2 rumo!}, Pd(dppf) ? Cl; ;> complex v>?ith ' DCM (285 nig. 0.32 mmol), and KOAc (323 rag, 3.29 ramoi.) in dry 1 ,4-dioxaae (6 mi) was purged, three times with Ar aod placed under vacuum three times. The ixtsre was heated to 90 " C, Alter 21 a, the reactor was cooled to RT the« identified as 2-(fl - m: ilK)xy iO au-2- ljoxy}- S■(4 i 4 s S,5- eU'aruet|iyl- 1.3,2·· dloxaborolan-i-yS) pyridine that was used withooC purtficatiea. Mass Spectrum {pos,} ra e:

294.1{M+fi} * -

Step A: A dry vial containing 4½ nopicolft¾ic aci (Idling, 1.99 irane!) and HATU (1.52 g, 3,98 mmoi} was evacuated and backfilled three times "wtlh Ar, Dry DMF (10 rat} theu DiPEA (1.4 Ml 8.05 nwaof) were added separately by syringe under Ar protection. The mixture was stirred uader Ar at 23 6 C, After 30 raut, 2-(methyfeHlfoayl)ethartamUje hydrochloride (250 tug, 1.57 mmal} was added n poriioas. Upon complete addition, the reacdoa was stirred at 23 "C- After 17 ' fa, the reaction was diluted with water then, extracted three times with EtOAc The organics ere sooled heft washed three times saturated aq, l^a ' HCOs solution, and once with brine. After drying over anhydrous MgSG filtration, and ranemiratidn, the residue was purified on sfb ' ea get (30-90% MOAc ift hexaoes) to ailbid as

(340 mg, i, 14 mms!, 57,2 % yield) that, was osed tvlOmat further putificaOoa. Ή NMR {500 MHz, SD-ds) δ ppm 9,08 (1 H> t, J»5.9 Hz), 8.55 {Ϊ 1:1 d, J-5. 8.18 (1 H, d, j«2.Q ¾}, 7.92 (:! dd, J-5.1, 2,0 Hz). 3.74 (2 It ¾, 6.S Hz), 3.40 (2 E t, Hz), 3.03 (3 II, s).

Step B: A siSired ixtufe of 4-bromo-N-(2-(methy «tfoayl)e i)plcoHftanUd ; (349 nig, L14 moid), idsfpinaeoiatoldiks-os (43? nig, 1,72 imnol). FdU p il k complex with DCM (280 mg. 0,34 mmoQ, and KOAc (337 mg. 3.43 raoi) is dry i.4-i>loxaae (7 .ml) was purged d>ree times with Ar and placed under a uum three dates. The mi ture was heated to 90 X. After 2! h, Ihe reaction was cooled to ST then identified as N- 2"(niet.hyfe«].fooy e 4) ' 4'C4,4,S,5-tett¾metbyI-- ! .3,2- diosak>fo.lan-2-y1 plco!i»amide that was used without purification. Mass Spectrum (pos.) ai/e; 294, 1(Μ*ίί) ÷ . The LC-MS corresponds to the (2' (2' niefiryi uli½

yl)feOfi o!c sekl

Prep¾ratio?¾

Step A: A dry vial eomaifiitig ' Nail. 60% s persioit !o mineral oil (2.1.7 mg, δ.·4.2 ΟΜΛΟΙ) In dry cyciopenlyl methyl ether (10 ml.} was cooled in an ice water ai s. After 20 min, (SH+)-2* raettexypfopanol (0,34 mL > 3.54 mtsoij was added drepwisfi by syringe to the cold reaction solution. After 1 hour, 5-brorao-2-fl«orQpyridioe (0.2 oil.. 1.74· awao!) was added dropwise at 0 X. Upoo complete addition of 5-bs¾i¾o-2-fl« ropyfidiae 5 the mixture was warmed to 23 *C then earefeiSy heated to 85 X. After 17 h, the eaction was cooled to 23 "C iit carefully quenched with water. After extracting three times with EtOAc, the organic* were o led then dried over anhydrous a^O*. Alter filtration and concentrate, the faint yellow residue was purified on silica gel (0-10% EtOAc in hexanesj to afford a colofiess oil as (S)-.5-bromo-2-{2-me0toxypropox.y pyiidine (393 rag, 1.00 tnmol, 92 yield) tha was used without farther purification. Ή NMR (509 MH¾,

DICH LOR OMETIi ANE- ds) § ppm 8..17 (I H,4 J-2.7 Hit). 7M (I H, dd, J-0.S, 2.7 Hz). 6.69 (.! H, d, tin, 1.1? - 4.28 (2 H, m), 3.87 (1 H, mii»d > 6,2, 0.2, 2, 6.2, 4.4 Hz), 3.3? (3 H, s}< 1,20 (3 H, d. j o 1 Hz;.

Step B: A siift d miklare of (S)~5--hfo«io-- : 2 « (2--aiet¾oxy rofioxy pyrldiHe (204 mg. 1 ,07 roreol), bis(pioacolato)diho.rao (409 mg, i .Si jnmol), 1¾{0|>ρ¾€½, complex with DCM (283 mg, 0.32 miftol). and KOAc (328 rag, 3.34 malol) in dry I .,4-dioxane (6 ml) was prrrged three times with Ar aad placed under vacuum three limes. The mistiii* was heated to 9Q X. Alter 21 h, lite reaction was cooled to RT then identified as (S|-2--(2 -?«eiliosyprepi5xy}-5- (4 ,4,5,5- tetnimet ylvl J -dioxafcoto!ii -- 2-yi}py dfae that was used without purification. Mass Spectnun (pos.) mfe; 294.1 (M+H) * .

Step A: A. dry vial containing 4-broBM) >ico1i»ic add (2-04 tag, 1.0 i snsno .and HATU (778 mg, 2.05 rorool) was evacuated and ' backfilled three limes with At, Dry DMF (5 odd then I¾PEA (fl.53 ml, 3.05 mnioi} were added separately by syringe under At protection. The mix u e was stirred under Ar at 0 X. After 30 mln. . M2-ani»K5tl iyl}.tm » i{iaaesuIfonamlde hydrochloride (26? ing, 1 ,53 rmaol) w added in portions. Upon complete addition, ie reaction was stirred at 23 "C. After 1.7 , the reaction was diluted with water then extracted three times m EtOAc. The organies were pooled then washed three times saturated aq. NaHCQj solotiOR and once with brine. After drying over anhydrous MgSO«, filtration, and eettcenfrat!oa, the residue was parifted on silica pi {30 -90% EtOAc in hexanes} to

ramoi}, Pdg(dba)3 (28 mg, 0.03 m al}, and KOAc (90 mg, 0.92 tmnol) its dr DMP(2 tnL) was purged three times with Ar arid placed under vacuum three times. The mixture was heated to 90 X. After 21 h : the reaction was cooled to RT then ideutifted as coala ring (2-i(2-

(mei yi uiion mi je ^ acid that, was used wi fiOiit rmrification.

Mass Spectra to (pos.) m/e: 288.1 (Μ-ίΤίΓ .

Pres acat ort

Step A: A dry vial eimiaMng 4-bioj«opk:ohttlc acid (303 ntg ( 1.5 mmol) and HATU (1.14 g. 3,0 i mmol) was evacuated and backfilled, three times with Ar. .Dry DMf (7 mL) then DiPEA. (0,79 nit, 54 rorool} were added separately by syring under Ar protection, Tlie mixture was stirred under Ar at 0 X. After 30 mire 4-amino-2-butanoI (0,22 mL, 2.2 riiosoi} was added dropwise. Upon complete addition, the reaction, was stirred at 23 X. After 37 h, the reaction was diluted with water then extracted three times th EtOAc. The organics were pooled then washed, three times saturated aq. MsHCOs solution and ones lls brim. After dr ing over anhydrous MgSCXj, filtration, ami concentration, the residue was purified o.fi silica gel (30-80% EtOAc is hexaiies) to. afford a ellow Rim as - oi«o- -(3-i5 drft)^iju5Yi5 >co]ir5ainid that was used without, further purification. Mass Spectrum (pes.) m/e: 272.9 ( i l } ' .

Step B; A stirred oiixtttre of ^m«50- - ¾ , dro ybutyl Icoteaa tfe -(3! 1 mg, 1.14 mnus!}, bis{pinamlato}diboron (434 rag. L?Immo . «- BaPA<i2 (82 mg. 0.23 mmo!). Pd 2 {dbaf 3 (106 mg, 0.12 rmoo!), sod KOAc (341 mg, 3.47 «aaol) in dry N,N^i«}etiwlacetamide (2,5 RtL was pu ged three times with Ar and placed under vacusixt three times. The -mixture was heated to 90 S C. After 21 h, the reaction was cooled in 1ST then identified as .{2-({3 iydmxyb«tyi)carb^oy!)pyrklin-4-y ' l}b8romfc ■add that was used without puriBeat

Step A: A dry viai codaiu rg Nail 60% dispersion In mineral oil (212 mg, 5..30 psnol) in dry cyclopentyi methyl ether (10 inL) w cooled is w ice water baft. After 20 mm, 1 -pr pajrediol (0.26 L, 3.6 mmol.) was added dropwise by syringe to the cold reaction solution. After 1 hour. $- bromo--2-ik}oropyndiiie {8.2 ml, I .74.mmol} was added dropwise at Θ * C. Upon complete addition

times with EiOAe, She orgaracs were pooled the» dried over anhydrous Na¾S(.¾. After .Miration arid concentration, the faint yellow residue was parified on silica gel (0-40% EtOAc in fiexanes) to afford a colorless oil that solidified as 3-({5-bromopy!idln-2-yt)oxy3pro»aH- l-ol (388.2 mg. 1.664 tnmoL 96 % yield) that was used withatu further p«nfkatio ¾ NMR 000 Ml¾, PiCHLQROMETHANE 5 ppsw 8.17 (1. M, d, Hz), 7J? (1 H, dd, g.§, 2.5 H/3. 6.07 (1 H. d. M,M Hz), 4.42 (2 H, i, j«-6.1 Hz), 3.70 (2 E, I i-6.0 Hz), IM - 2.08 (3 H, m).

Step B: A stirred mixture of 3-{{5½o.mt>p>Tidin.-2-yl)o¾y)propim~.l-ol ' (397 mg, 1.71 nrnrof), bis{pt«3coSa o)dlboTOn (S52 mg, 2.57 tnmoi}, n-BuPAd2 (1-23 mg, 0.34 mmol}, H$b * (161 mg, 0.18 mmo.1). and OAc (510 mg. 5,10 imuol) In dry , --Dii ' n !acetat»ide (3.5 rnL) was purged three times with Ar and placed studer vacaam three times. The mixture was heated to 80 * C . After 2 h, the reaction was cooled to RT then- identified as eoniaiiiiisg S-^S-^^ ^-tetr me h i-lAS- dl05»b rolaa^- l}p>Tl<l¾-2-yi)a3 }propan--l--oi that was used without purification. Mass Spectrum i]jos.) aye: 280.1 ( -ί Η) ' .

Preparation

Step A: A dry vial containing in NaH, 80% dispersion in aiiasral oil .(21 i mg, 5.28 mmoi} dry cyclopeafyi meth l ethe (K) L) was cooled in an ice water hath. After 20 mir -propanoi, 3- CinethyteulfOftyl}- (500 eg, 3.S2 mmol) wax added dropwise b syringe to the cold reaction soiaUOH. After f hou , 5'broino-2-fl«ofopyTidide (0.2 snL L74 mmol) was added dropwise at 0 ¾ C. Upon complete addition of S-hromo -2- uoropyridirj« f the mixture was warmed to 23 then careiaiiy heated to 85 "C, After 17 h, the reaction was cooled to 2 :! C then carefully quenched wtth % . After extracting three times with EtOAc, the organic* were pooled then dried over anhydrous sjS Kj. After filtration and coacetrfraikm. H-prepanol was added to the foamy white solid, then the mixture was heated on the roiovap to 50 *C without vac, After 20.rain, the solvent was removed under reduced pressure to a vohitne -2 ml.. The solid was filtered thee rinsed twice with diethyl ether to afford a whits solid as S-bromo~2> Ci> {methyis«ifeayl)pfoposy)p>Tid¾e (500 mg, 1.7 raraolm¾ yield) that was used without purification ¾ NMR (500 MHz, BMSO-de) § ppm 8.28 0 L d, J-2.2 Hz), 731 (i H, dd, j«8.8, 2.4 Hz). 6.8 (! E, d > J«¾8 Hz), 4.34 (2 H. i. j^8.5 Hz), 3.20 · 3.30 (2 H, m), 3.01 {3 a s), 2.09 · 2JS (2 ii m).

Step B: A .steed atu e of 5 » bws» » -2-C3 » {o5e£h lstd ooyl).pfopO p rtd-ijie (320 mg. i.W miaot), bis(p!oacoiato)dibc)fo8 (420 mg. 1.65 rnmoi), n-8«PAd2 (79.8 mg : 0,223 mmel), Po i ba)* (0} (104 nig. O.il maso! , and KOAc (326.mg, 332 m ol) hi dry N. -diiaedwSaceiafflide {4. mt) was purged three times with Ar and placed unde vacuum three times. The mixture was heated to 90 °C . After 2) h, sire reaction was cooled to RT then identified as containing 2-{3-(a>ethyfe»3» Ryi)propoxy ^ {4 ? 4 ? 5,5 ett8 iethyl~13,2~dio5rahorolaa-2-yi)pyridlHe that was used without purification. Mass Spectru pes.) m/e: 342 J i *M}\

Pre aration:

S¾ A: A dry vial coKtalaiug Naf L 60% dispersion it? mineral oil (245 mg, 6.14 mfml) in dry cytiopentyl methyl ether (10 n\L) was cooled in an ice water bath. After 20 mm, S-msn oxy-l- propanoi (0,38 mL > 3.97 mrnoi} was added dropwise by syringe to the cold reaction solution. After t hour. 4-k ii5o-2--fiu.0TopyridiBe (0,2 m ' L, 1.05 tamo!) was added dropwise ar 0 a C. Upon complete addition of 4-iwomo-2vrluoropyridirse, the aiixture was wanned to 23 *G theu carefaiiy heated to 50 *C. After i hour, the temperature was raised to 85 t: C, After 1? k tire reaction was cooled, to 23 "C t en carefully quenched with water. After extracting three tixsm with BiOAc, tfee orgastics were pooled then dried over anhydrous NagSCl;. After filtration and concentration, the faint ellow resife was puriifed on silica gel φ~ 15%. EtOAc in hexanesj to afford a colorless oil as 4-bromo~2-0-

H, d : _ .5 Hz), .30 {2 E t, =S,5 Hz} : 3.44 (2 , i, j-6.2 Hz), 3.21 - 3.24 {3 il m), 1.90 · 1.96 (2 H, n¾}.

Step B:- A stirred mixture of 4-bf«riio-2-{3-metlKjxyprop >xy)pyridine (388 mg, 1.5 mmol),

bls{ if¾acoiato)dlborot5 (571 trsg, 2,25 fraooih tvBtiPAdS (i 09 tog, 0,30 tmrsoi), Pd ? (dt>a) 3 U42 ~ rng, 0.15 mmol). and KOAc (443 mg, 4,5 Ϊ mmni) in dry N.N' Dii»ethylacetamide (5 mi..} was u ged three times with Ar and placed under vacuum three limes. The mixture was heated, to 90 "€ . After 21 h, the reaction was cooled to R? then identified as containing {2-$-meihoxypropoxy}pvTidin-4~ yl)borooic acid thai, was used without purification. Mass Spectrum (pos.) : 12,1 ( -;-H} '1 ,

Pt paration

Step A: A dry vial containing -S-hreraonicothric acid (231 «ig> ! .15 mmo } and H&TU (889 mg, 2.34 ry DMF (5 mL) than MPEA (0.8 ml, 4.6 mmol) were added separately !>y syringe under Ar proteetioii,. The mixture was stirred -under Ar at 0 "C. After 30 mio, ' - 2-affilnoeihyl}isethanesoifonamide hydrochloride (328 mg, .88 nunoi) was added in portions. Upon complete addition, the reaction was stirred at 23 * C Alter 17 h, the reaction was diluted with water then extracted three tiroes with EtGAe. The organlcs were pooled theft washed three times saturate atp NaHC- ( ¾ solution and once with hrioe. After drying over- an ydrous MgSO*, filtration, and concentration, the residue was purified on silica gel (0-10% MeOH in DCM) to afford a light ta» solid as S-hromo- -(2-{me ¾ulfotmmdo)eu¾y!)i t >thrandde- (110 nig., 0.34 mA, 29.9 % yield) that was used without further purification. 'H MR {SOO MI4¾. D SO-d*} 8 ppm S.98 (I H, d s j-1.7 M¾). 8,81 - M (2 H, m) < 8.43 (1 H. i i-2.1 !¾} > 7.18 (1 H, L j-6.1 Hz). 3,39 (2 H, q, J-B, Hz), 3.1 (2 R . , 6.4 Hz). 2.92 (3 ii s).

Step B: A stirred mixture of 54¾x>m«-- -{ · (}∞thykidfona}nldo)«!thyl}ofcoti!)aoitde (110 mg. 0,34 m»«ol}.. bistpinacolatojdlboron (13 tog, 0.52 mmol), o-BiiPAd2 (25 oig, 0.07 mmol}, Pd ¾ {dha) s (32 .mg, 0.035 mmol), and K ' OAc (104 «ig, 1 ,06 mmol) la dry M ' ,N- ' Dimetliyi.acetantide (3 mL) was purged three times with Ar and placed under vacuum three times. The mixture was heated to W *C . After 21 h, the -reaction was cooied to RT then identified as (5· ((2■

398 {meth lsuifonamidok^^ acid drat was used without ptnffieati«n.

Mass Spectntoi (pas.) is/e; 288. i (M+H) * .

Step A: :i-(!!^tffotn^3-{(2-ethyli>yri 06? mg, 0,48 nmwl}, rnc do¾exyiph s (28 nig, 0.10 mmol}, l ? {d a) ; ¾ (44 xng, 0.048 msaoi}. and 1.3 M K ; sP(¾ 0.2 L, 1,56 mm« were added, to a vial containing 2-({5- {4,4,5. S-iet aisedwl- l ,.3,2-dteak>mfe»-2- y. pyridin-2-yl)oxy)efha«oi 040 mg, 1.28 ol) to i.,4-diox3iie (6 int.), T»e flask w s degassed, aad backfilled with Ar, The resolting reaction was heated to SO .. After 19 h, the. reaction was cooled to RT Chen filtered iraugh a 40 taL disposable filter funnel that, was packed with 1 -5g of Celii , After concentration, tfce residue was diluted with DCM theft loaded onto ¾ silica gel cokitna (0 1 % of MeOM in DCM) to afford a bmwn flbn slat was -further . purified with averse-phas HPLC by dissolving in 4.5 mL of D (10-90% of premixed 0. t % TFA in eCN in 0.1 % TFA hi water.) Fractions containing desired product ' were eomhhfSd then concentrated under reduced pressure. ie residue was dissolved in DCM. tfeeu washed twice with saturated aqueous &HCO ¾ and once with rine. After drying over anhydrous MgS<¾ > filtration, and concentration, the white solid was identified as l-{5-({2-e 1syridin-3-yfi^

(75.8 nig, 0,1.85 mmal, 38.8 % yield). ¾ M R (506 MHz, DMSO-d^ 8 p 9,05 (1 !l d, .2 H¾, 8:73 (:t 14. sk 8,4( 0 H, d, ¾}, 8.36 (1 H, d., jk-2.2 Hx), 8.32 (1 H, . j-4.4, 1..S Hz), 7,93 (1 H, dd, j-8.7. 2.6 Hz 7,48 0 14. d, Hz), 7.20 - 7,29 (214. in), 6,86 (1 14. d, j-8,8 Hz), 4.82 (1 H, t. J-5.5 ml 4.28 (2 H. t. ,N5 J Hz), 3,?S ) (2 H, q, J«5 H¾h 2,8? (2 H, f|, Si .¾}, 2.82 (3 H. d, J« .e Ha), .1.24 (3 II t, j-7.6 Hz). Mass spectrum (ESI) in/x - 440.0 ( *fi).

Example 844

H5-((i~e$nyH.14-p ra

39? Step A: 5½Oi«o-2-d lor«-3"i(i-ethyf (287 mg, 0,88 mw>V}, t eydohexyiphosphiae (50 mg, 0.18 mn¾>.l) . Pd*{dba) 3 (§2 m , 0.089 twnol) , and 1,3 M K 3 PO« (2.1 ml,, 2.? rnmo!) ere added So a vial containing 2 ((5 {4. .5.5- teira«tei yi- ί .3 > 2-di0xaborolan-2~ yl}|jyrfdio--2-yI)oxy}et aRol {340 rag, 1.28 moi) in lA -dium (8 mU. The flask was degassed sad backfilled with Ac, The resulting reaction was heated to 9( *C. After 4.5 ' b, the reaction was cooled to RT and steed oversight al 23 *C. After 17. 5 h, ie black mixture was filtered through a 40 t«L disposable filter fttunel that was packed with 1.5g o Celite, After concentration, the residue was diluted with DCM then loaded onto a silica gel column (0-15% of MeOH in DCM) to aS fl t a brown film that was forte purified with reverse-phase HFLC by dissolving in 6.5 mL of DMF (1 -90% of premised 0.1 % T A hi MeC in 0.1 % TFA in water. Fractions courammg desired product were combined then concentrated under reduced pressure. The residue was dissolved is DCM ihess washed twice with saturated aqueonx NaHC(¼ arid ouc with brine. After drying o er anhydrous MgSO t , filtration, and concentration, the white solid was iden ified as 2-({8 , -ebloi'o-5 < -((i-ethyl- 1 H-pyraxol-S- yl}oxy)-[3J ! -bi }yndiB]- fi-yl)oxy}ethaiioi (56,2 mg, 0.150 mmoi, 17 M % yield). ¾ MR (500 M¾ DMSO-4) 6 ppm 8.67 {I. l , d, .Wit MJ?>, 8-56 (1 E dd, ,Wi$, 0.6 Hss). 8,06 - 8.13 (2 H, m), ?.¾8 (I H, d, j»2.0 H¾). 6.94 (i H, dd, j-8.7. 0.6 Ha), 5,80 (3 H, d, ife > 4. 6 (I H, hr. 4,29 - 4.34 (2 to), 4,10 (E E q, j*7,2 ¾), 3.72 (2 H, . 1-5.1 H¾. 1.37 (3 PL i, j-7.2 H¾). Mass Spectrum iposj t«/e; 361.0 (Μ+Η. .

Step B: 1-Meihylurea (23 mg, 0,31 mmoi},. milled potassium phosphate (101 tag, 0.47 omsol), 5-(di- f i- b«f ylplios iiirio) - 1 1 ,3 : .5 - f f i he tyi- ! 1- 1. £ - hipy f szoiy , t-Buf-BlppyPbos (16 mg, 0.032 rtmio!), and Pd ? (dha);j (15 tog, 0,016 raniol) were eoirrbinetl then the flask was evacuated and backfilled with Ar. Anhydrous l,2-<IUnethoxy«thane (1,5 mL) was added b syringe under Ar protection. The readies was sparged for 10 mkt before heaiiRg the .mixture to 50 *€. for 4» mia. After 45 mm, 2-((6 ! - ehioro--5 ! -((I-eehyf l.M-pyra¾ol -S-yi)oxyH3.3'-h^ (5S m , 0. 18 rSmol) is anhydrous 1 ,2-rijmetfeoxyeihaae (1.5 mL) was added by syringe to the mixture uader Ar protection. Upon complete addition,, the reaction: was heate to 75 *C, After 17 h, the reaction was concentrated under reduced pressu e then purl lied b dry loading oat© silica gel column (0-10% MeOH in DCM) to give a brown, film that was further purified with reverse-phase HPLC by dissolving hr 3,2 mL of DMF (10-90% of pref xed .Ϊ % TFA in ¾ie.CN in 0.1 % TFA in water,) Fractions containing desired product were combined flieo concentrated under .reduced pressure. The residue was dissolved in DCM then, washed twice with saturated aqueous NaHCOg and once with brine. Af ter drying over anhydrous gSO ¾ , filtration, arid eonceniration, the oil- !tiie solid was identified as Ϊ 16707 25 001 or i-(5-((l -ethyl- 1 H -p ra:¾oF5- yl) osy) -6 ! - {2-hydroxyethoxy}- [3,3 ' - bip ldirtj - 6-yl)-3-methylurea (1 ,3 nig. 0,028 mmok 18.21 % yield). ¾ NMR (500 MHz, DM$Od, s } δ ppro 8,94 - 9.0? ( H, ro), 8.43 - 8,47 (i H, «0. 8,40 (i H, d, J-2,0 Hz), 7M (1 H. dd ; j-8,7, 2,6 Hx), 7,77 (I H, d, ¾), 7M (1 ΐί fl . 2.M H¾), 8.90 (1 H > d. j«8.8 Bx), 5.73 (1 H, d, J«2,2 tfe), 4,84 (1 ii, br. s.), 4.27 - 4.33 (2 M, m).4.12 (2 E q, j»7J Hz), 3.72 (2 H, br. s.h 2.82 (3 H, d, j-4.6 Hz), ί ,35 (3 M t. j-7,2 Hz), Mass spectrum (ESI) rn/x * 399 CM-i-H),

Example 845

Step A: 4-brQ«io-^-(2-{{tetra ydm-2B-^^ ^

A. dry via! oirtsiaag 4-brt>nwpicol c add (406 mg, 2.01. anno!) and HATU {j .53 g, 4.03 jmnol) was evacuated and backfilled three tiroes with Ar. Dry D F(10 roL) then DIPEA {1,4 mL, 8.05 mmol) were added separately by synsge under At protection. The ajJxtare was stirred under Ar at 2 !! C. After 30 mm, -C{te{Tah dro-2H->yrao - ))ow)et.bmmiiie (440 mg.3.03 twawlj was added drop ise by syringe. Upon complete addition, the reaction was stirred at.23 After i 7 h, the reaction was dilated with, water then extracted three times with EiOAc, The orgastics ere pooled then washed three, times saturated aq. aMC¾ solution and once with brine. After drying over anhydrous MgS(¾, filtratlOB, and concentration, (be. residue was purified OR silica ge.l (0- 50% EtGAe in hexanes) to afTorf yellow oil as 4- ¾'om»-N-42'-{Hetral5 dro--2H-p ^

(423 rag, 1,28 m il 64,0 % yield) that was -used without further purification. ! H NMR (500 MHz., DlCHLO OMETHA E-dg) S ppm 8,33 · 8.43 {3 Μ,*»}, 7.62 (I H, M, J-5J, 2.0 J¾}. ? 4.80 (1 H < dd, .1- ,6, 2,7 Hz), 3.80 - 3,92 {2 B, .»$}, 3.58 - 3.70 (3 it ), 3.43 - 3,54 (1. H, m), l ,?S - IM (I H, ), IM - 1,77 (1 ii in).1,44 - 1.63 (4 H, m).

Step H: -(2-(ftetr¾h¥d

Dpicolioatnide

Ar ami placed tmder vacuum three times. The mixture was heated to 85 *C . After I S , (be reaction was cooled to RT then identified as K2-4(tetr¾i dra-'2H yrari- 2 yi)oxy)eifry

teiranieihyi - i- ! 3 -dlosabOfOl;m--2- l)pk !i at?iide that was used wUhoat panficadon. Mass Spectrum (pas.) rate: 21Li{ -; H , (Note: LC-MS corresponds to {2- C2-hydmsyed)yi)cai¼«K}yl)pyrkttO"4- yl)horooie acid)

S IL : lJ- itl o o i^^^^ ί -(S-Bromo^- {2,6-dia«t«x}pteioxy . pyrfdio » 2^ ' !) » 5 -mdliylurea { ' 483 mg> 1.35 mmolS.

fricydofexylphospiiiiie (32 o¾ Ci.il mow]), Pd 2 idba) 3 (52 n¾ 0.05? itaaol), and L3 M K s PO* (1.3 it, ! .68 eimol) were added to a vis! containing N- (2- f (ieirah?dro-2FFpyr^

{4A5.5-tetr¾»eth M,3^ (207 g, 0.5S ntmel} in M4taxm»(? rat) , The flask was degassed and backfilled with Ar, The resulting reaciiOfi was heated is § ¾ C Afte .! 9 b, the reaction was cooled to RT then filtered through a 40 ml. disposable filter furmci that was packed illi .1 ,5g of Ce!iie. After -concentration, the residue was diluted with DCM then loaded onto a silica gel column (0-29% ofMeOB m DCM) to aflord a brown film thai was identified as 4-

hipyr!dise]-2'-c¾rboxaraide (178 mg. 0.34 ot §1.2 % yield). Mass Speetmm (pas.) e: 528.1. (M÷H}\

A solution of 4 2 t 8~dii¾iGrap eB^ ' ~(2-((teirahydftv2H-pyraa-2- ¾o )ethyl)^3, '-bis 'iid -2'- »bQxamkfe (178 mg, 0.34 iranoi) and yrid uia p- tokteitesaiibaate, (43 n¾g. 0, Ϊ.7 mmol) I» EtOH (10 oiL) was heated to 55 *C. Alter 3.5 h, the reaction was cooled to 23 * C and stirred overnight. After 18.5 h. Ore ieactiea was coiteesurated under reduced pressure, t en the brown residue was purified by dry loading onto silica gel c lumn; (040% MeOH is DCM) to give a brown ftlta that was further purified with reverse-phase HPLC by dissolving in 4.2 mh of DMF (25-90% of premised 0.1 % TFA lit MeCM in 0.1 % TFA la water.) Fr¾cte coiiia!itisg desired product were combined then concentrated under reduced pressors. The residue was dissolved in DCM. !heti washed twice with saturated aqueous NsM(¾ ¾n os. e with br.bie. After drying over anhydrous M SG 4 , filtration, and concentration, the white solid was identified as 4-(2,6-

0.18 mmo ' l, 52.3 % yield). *H MMR (500 MH¾« D SO-d«> 6 ppm 9.38 (ί H, s). 8.70 - 8.79 (2 ii ia), 8.41 (1 H, s}. 8.33 (1 H, d, .0 Hz). 7.87 (1 ft do, j-S.0, 1.81¾F 7.46 - 7.55 tl ft nij, 7.35 ' - 7.46 (3 ft rtt), 7. S 4 (5. H, s), 4.81 (i. ft hi. s.) . 3,54 (2 FI . d. 3Λ Hz) , 3,40 (2 H. ¾, J-6.0 Hz) . 2.88 (2 ft d. J .4 ' Hz). Mass spectrum (ESI) n¾% =* 444.1 (M*H).

Following the procedure in Example 845. the following compounds were prepared;

Example Structure Name Data

Exam le 848

1··{4··(2,6•d!iluorapheooxy) -6' -(2,S- dihydro ypropexy} · J 3. S f - b I py Ϊ ki I n ] - 6■ y J) -3 -mei yliirea

Step A: A riry vial containing- NaH. 60% dbpexsloti in mineral oil (213 ojg, 5.47 .RIRKJI) In dry cyc!opeaiyS meifeyl edict (10 i¾L! was cooled In art Ice water bath. After 20 tain, Solketal (0.44 sit. 3.54 mraof) was added drop ise fay syriii e to the cold reactiea solution. After i tour, 5-bfotno-2~ fkioro yrsdisc (0.2 raL, 1,74 mmo was added diopw!se at 0 *C. Upon complete addition of 5- bmmo-2-f uoiopvipld!«e, the mixture was w m d to 23 *G then carefully heated to 85 *C. After \ 7 h, the reaction was cooled to 23 then carefully quenc ed with wa ter. After extracting three tiroes with BtOAc. the -organic* were pooled then dried over anhydrous IMa?SO, !; , After filtration and concentration, the aiot yellow .residue was purified on silica gel (0-10% EtOAc i:e hexanes) to afford a colorless oil {48S mg, 1.89 mxml.

87 % yield) that was used without farther purification. *H R (400 Hz,

DlCHLO80METHA E-d x ) δ ppm 8.17 (Ϊ H, dd, j~2,5 > 0.0 ¥i? 7.64 - 7.72 (1 14. m < 0.70 (:i 14. dd. j-8.8, 0.6 Hz}, 4.38 - 4.48 {I H, m), 4.24■ 4,38 (2 B, ro), 4.10 (1 H, dd, j-8.4, 6.5 Hz), 3-80 (i H, dd, J= .4, 6.3 Hz), 1.41 (3 H, s), 1,35 (3 H, s).

Step B:. A stirred mixture of 5-bromo-2-({2,2-dSmeihyM ,3•dioxo n-4-yl)teC4hoxy ipyridinit' (556 mg, 1.93 mtnal), his(p!nacoIat( ditoroB (737 rug. 2,90 niifioi), o ¾iPAd2 (140 mg, 0.39 tamo!), Pd ? (dha)s (178 trig, 0.10 mind), ami OAc (SSI mg, 5.71. tnmof) .in dry MvM-dtejethy ' lacetamidc (4.mL) was purged three times with Ar and placed under vacatrat three times. I ' he mixture was heated to ¾ ) " C . Aikr 21. h, the reaction was cooled to RT men Identified as containing 2 ((2,2 -ΐϊ imetfeyJ ^-dioxolan-- -yS:}ii)ei :iOX ) -5- {4. ,S.5 eti¾ffieihyl - i .3,2 -dioxabero]sie-2 : -yi)pys1di e that was sed without purification. Mass Spectrum fpos.) m/e: 338.1 (M iTif .

Step C: i -{S-Bromo-4 · ( .S-difluoro hiwxy^ Jlduv^-yD-S -nifem teia (266 tsg, 9.57 ramo ) a«d qu ous 4,0 M KgC(¾ (0,44 mL. 1.76 BU»O!) were added to a vial eontariasig 2-((2,2-dlioethyTi,3" dkixoka-4-yi}mei (»(y) -S--{4 ,4,5,5- tetratnethyi 13 ! 2-dloxaborolan » 2:-yl}pyrldifi§ (648 rag, f .93 rranol), n-BuPAdg (140 nig, 0,39 iosnolh and Pdg(dba a (i ' ?S nig, 0.19 mi«ol) i» N,N- diinedrylaceta ide (4 rnL). The flask was- degassed and backfilled with At. The resulting reaction ' was heated to 90 e C. After 19 h, the reaction was tooled to RT ihen diluted wliSi brine. After extracting three times with DCM, the organies were pooled then dried over anhydrotrs MgSOi. After filtration and concentrate, the residue was diluted with DCM then loaded io a silica gel column ( -40% of ' EtOAc In DCM) to afford a yellow Mm that was triturated with diethyl ether io aiford a white solid as l- 2 < 6~driIuoro l«;nox }-6H( , -- ta

hj|5yridli)|-&-yS)-3-ine(iryi!ii'ea (115.0 tag, 0.236 tmaol, 412 % yield}. Mass pectrurs (pos.) sf ¾: 487. 1 iSl .

Step D: To a.sUrred (solution of 1 -C -(E,6^1fl» ro hem)sy)-8' » { 2 < 2-diu{et i-- 1 ,S-di xolan-¾~ in 4: 1 TH (1.6 stl,}/Wate (0,4 ml), at 0 '€ was added TFA (0.1 mL, 1.35 mmoi) dropwise. The reseidng solute was warmed to 23 * C. Alter 3.5 days, the reaction was- carefully seutmllzed by die addition of concentrated

NHjOH solute, then THF was rerfloved under iedueed pressure. The residue was dilated with water then extracted three Utdes-wtth DCM, The orgaraes were pooled ihen dried over anhydrous gSQ*, Atler filtrate and eoncentratioB, the residue was triturated with MeCN io afford a while solid as 1 -

mmoi, 44.8 % yield), ¾ NMR (400 MHz, D SO-d«) S pptn 9,2 i (1 It s), 8,36 (i It d, Ifc), 8.23 (1 H < s) f 7.93 (5. H« dd, 2.3 Hz), 7.33 - ?,56 (4 H, ), 7M (1 H, s), 6,93 (I M. d, j ' =8,6 , 4,92 ii 14, br. s.}, 4,64 (1. H. br. *.}. 4.32 (1 H, dd, j- i 1,0, 4,5 Hz), 419 (J. H, dd. j- Q.O, 6,6 Hz), 3.82 (1 H, br, s.), 3,44 (2 H. br. sd, 2,65 (3 H, d, .3 Hz). Mass spectrum (ESI.) m¾ - 447. i

Example 849

i-(S ' --cyauo : -met»0xy-4-((5--,^

Step A: A stirred t» u«i of S½om -2-meihoxyfik:<tinoaUrtle (25 mg, .3.38 xtmml),

-)js(pinaeola{o dlb n>n (452 mg. 1.78 mmo!}. n-B« d2 (87 mg s 0,24 mrnol), Pii¾fdbs)¾ (f 10 tag, 0..Ϊ2 raraofl. and OAc (35! rag, 3.58 mmoi} in dry - Si!«eil5yl cei Hiide (8 fiiL} was ' urged three times with Ar aod placed ueder vacuum three times. T mixture was heated to 90 *C . After 4 k the reaction was cooled to RT then H5 ½omo -{(5-a:sethyi^

(165 tag. 0.49 mraoi) &od aqueous 4 M 2 .CO ¾ (0,37 il., 1.48 iai«o ) were added to the reaetioa mixture. The flask was degassed and backfilled with At, The resulting reaction was heated to 90 °C, After 20 h., ihe reaction was cooled to RT thea dilated with brine. After extracting three times wit DCM, the orgastics were pooled then dried over anhydrous MgSO, t . After fiitraiioa and concentration* the residoe was diluted with DCM then loaded oato a silica gel column 0-8% of eOH in DCM) to afford a yellow m thai was triturated wills M ' eCN to afford a while solid as 1 · {5^cya«o-6'-oie hoxy · -((5~m tfe ln ridiR^~yl}ox M^ (81 rag. 0 , 21 mo 42 , 7 % yield).

Ή MR (500 Mil¾, DMSO-d, 8 ppm 9.23 (1 H f s), 8.72 (1 B\ d, J-2.4 Hz), 8.S6 (i ¾ d. j-2.4 8.32 ~ 8.44 H, JO), 8.27 (1 if, s), 7,61 (2 H, hr. s.}., 6.93 (i H, $}, 4.04 {3 H, s), 2,66 (3 fi d ( . .O Hz), 2,35 (3 H, s). Mass Spec rtmj. (pos.) m/e: 391.1 ( ti) Mass $pectf rm (ES ra/2 - 391.1

Following the prpeedare fa Example 849, list following compounds were prepared:

Step A:: A y vial cottSaiRiitg NaH, 60% dispersi n! In .mineral ©it (278 rag, B.S5 morel) is dry eyclopenryl .methyl ether (iO iftL) was cooled an ice wafer hath. After 20 rata. M--(2- byd{Xi5£yd yi}{«etha»e¾~!iboaoiide (482 tng, 3,4? mmol} was added dropwise by syringe to the cold, reaction solution. After I hour, S-¾ron50-2-fl«orop , y5idine (0.2 :i»L, 1.74 m»JOl) was added dropwise at 0 * C,. Upon complete additoi of 5-bromo-2-ilyoiopyridiite» the mixtare was warmed to 23 * C then care&l!y healed to 85 , After 4 k the reactioH was cooled to 23 ' * C te* carefully quenched with water. After extracting three times with EtOAc, die orgaoics were pooled than dried o e anhydrous so hira sulfate * After .filtfaiiow and eorseefliigtioit faint yellow residue was purified on silica gel {0-40% EtOAc in hexanes) (6 afford a colorless oil ifeat solidified as N -(2-((5 -kortio yridlH-2- yl}oxy¾edwi)5!iethaoess5lfoE5atnide (133 rtsg, 0.45 nanoi, 25.9 % yield) thai was nsed without farther purification. *.H UUR (500 MHz, P SO-d s ) d pprs 8.2» (i il d, j-2.4 Hz} > 7.92 (i ii. dd. 2 Hz), 7.20 (i H, s), 8.85 (1. H, d, JML8 H¾). 4.29 (2 ¾ t, Hzj, 3.2? - 3.3? (2 ft m). 2.93 (3 B, .s .

Example 855

•Step A: A dry via! coittaiBing NaH. 60% dispersion in mineral oil (235 rag, 5.89 mraol) in dry cyelopemyi sreikyl eiher {10 ml) was moled m an ice water !safh. After 20 mm, 2 -(i iralr dro~2!i- 3.9 mmoi) was added dropwise by syringe to the cold reaction solution. After I h. 4 ¾rH»o-2 1ttoropyrtdh¾¾ (0.2 ml., 1.95 mmoi) was a ded dropwise at 0 X. Upon complete addition of -brorRo- 2 -ft!.(OiOpyridii!e, the mlxfctre was warmed to 23 tb&n carefully to 85 X, After 3 h, the action was cooled to KT and stirred overnight. After 17 h..ifce reaction was carefoliy quenched wit water. After extracting three times with EtOAc. the orgastics were pooled then dried over anhydrous sodium striate. After filtration arsd coacemratioa, the fairst yellow residue was purified on silica gel (0-15% EtOAc in h xaoes} to afford a colorless oil as 4- tomo » 2-&{6»^ (541 g, i M mmol 92 % yield) thai was ased wiihoai further ptiritotion. ¾ NMR (590 Μϊ¾ DiCHLORO ETHA E-d¾) S ppm 7.97 (l ¾ d. j-5.4 H4 7.04 {1 H« dd, 1.6 Hz). 6.96 - 7.01 {1 it m}, 4.82 - 4,67 (I H, te). 4.38 - 4.52 {2 H, m}, 3.98 {1 H < ddd, }~l 1.5. 5,9, 3.4 Hz) ,.3.80 - 3,80 (1 H, «¾) ... 3,74 (i H, ddd. j«l 1.4, 6.4, 3.7 Mi?). 3,43 - 3.52 (1 H, m), Ϊ .7 - L85 (i H, ), L66 - 1.73 (1 H, ja), 1.45 - L82 (4 H, m).

purged three toe with Ar atsd placed t ade* vacuum three times. The mixture was heated to SO X. After 3 h. the reaction was cooled to RT ito ^·{δ-brot ^- .··(2 ' u& oί^IH;Boxy yridϊn-2-yi)-3· ethylurea (150.9 nig, 0.421 mtnol} and aqueous 4.0 M K>Ci¾ {0.33 mL > 1.329 nwnoJ) were added to the reaction mixture. The flask was degassed a«d backfilled with Ar. The KsuMlu reaction was tested to 00 X, After- 19 h. the reaction was cooled to RT then diluted with brim. After extracting three iirses with DC > the orgames were pooled then dried over anhydrous MgS(¾> After filtration and cGscenirai.ioo, the residue was dilated with DCM theo loaded o«to a silica gel column (0 -40% of EtOAc in DCM) to afford a yellow film, as l.-( -(2 ^dilko opheso.x> -2 2-{i:tetr h d o-2H- w fi-2- J ^eito^^SJ^i ini-e-y^-S-methyhire (75 mg. 0.1 mrnol, 36 % yield)- Mass Spectrum ipos.) ro/e: 501.1 (M+H) < :.

Stejj C: A Mtottoft of i-(4-(2£^II^^

blpyrid]is|-S--yi}-3-r«eriryittrea {75 mg, 0.15 mmal) and pyri urn p crft«enesidfohaie, PFTS (18 mg, 0.07 mmal) la EtOH (5 ml) was heated to 55 X, After 2,5 h. the reaction was cooled to 23 X and stltted overnight After 18,5 It. di reaction was concentrated under reduced pressure, then the brown residue was purified by dry loading onto silica gel column {0 % menthanol i» DCM} to afford a yellow fibs that was triturated with MeC ¾ ia afibrd a white solid as l-(4-{2 ; 6- ifluorophenoxy)-2'-{2- hydroxyeihoxyl-iS^'-bipyridinl-g-yO-S-Kiethylurea {22 mg : 0,05 nml, 35,6 % yield). ¾ MR (500 MHz, DMSO-ds) δ ppm 0.30 (1 li $}, 8.32 (I H, $), 8.22 (I H. d, J-S.4 m> -35 - 7.53 (4 H. in), 7.24 (1 H. ά, i-S i 1.9 7.04 (i H, s), 7.07 (1 H. s) t 4.83 (i H. t, j-5.8 Hz), 4.31 (2 M, t, j-5.1 H2 , :i72 i 211 q, JWM > 2.64 (3 H, d, . .61 fa). Mas .Spectrum ρό¾ .} mfe: 417.1 (M

c fitosasfaiSe

Example 859

Step A: A mixture of 1-(5¾OOIO ( SK;¾ (I f 7 mg,

0.35 m«Kil)..4-(Wb i>½amiy1}pyjidaztm> (260 mg.0,?0KH«O1). arid Pd(PF } ),, (43 rag, 0.037 mmol} in anhydr us toluene (2 mL) was degassed by N ;; . The mixture was heated ' o 90 i: C. After S? h. the tfssfiifiB was cooled to RT thea cortceatiaied under reduced pressure . Silica gel was added to th tars residue then loaded tmio a silica gel. column (0-15% MeOH DCM) to afford a -film thai was triturated with MeC to afford a white solid as l-r^tliyl-3-(4r(f5-met yi^yfidjrt-3~yl><>xy}-5- |p t¾is2jt^^y Ti(l5a-2--y!)iai>a (24 :mg, 0.0? mm l 20.60 % yield). f H N E (500 MHz, DkiSQ- ds) S ppm 9.32 - Mi (1 il m), §.3 (i M, s), 9.23 - 9.31 (i ¾ m). 8.44 fl H, s), 8.33 - 8.42 (2 H, m> > 7,98 (1 H. dd, J-5.4. 2.2 Hz), 7.64 0 H. s), 7.54 (I H. bf. s.) > 7.0! (I H, s), 2.66 (3 H, d, 1-4.6 Hz). 2,35 (3 H. s). Mass Spectrum (pes.) «t e: 337,1 ( +H)

Following the procedure in Example 19?. the following cotapouuds were prepared:

Example T Structure j Name j Data

40?

Example 885

To 3 state solution of 2- {diey ohexylphosp!:Hm>H X-F!sos {28 rag,

0-.05S msHoi) . palladium {«} acetate, trim** (20 nig, 0.029 rorooi)., i brora<3-4~((5--« ' ietbylpy idiiv3- y.l) x )pyrid ft-2-yi}-3-e 1«rea (J 00 mg, 0.28 sniioiK and potassium (raorpheiire i

0.58 raato!} in anhy rou cyclop et yi methyl ether (2.5 ml,} was added Cs 2 CC¼ (278 nag, 0.85 oanoi). The reactloa mixture was heated to 95 *C. After 19 h, Water (0.5 tel.,) was added to the niixttire, Alter 41 h. the reacta was cooled to RT tlwa water was added to quench the reaction. The niixisire was extracted three times with DC tkm the organic* were pooled and dried ever anh dtotis MgS<¾. After filtration and eoisceiitratlojs under reduced pressure, the residue was diluted with DCM the« loaded onto a silica gel miasm 0-15% of eOM in OCM) to afford a yellow film that was farther purified with reverse- hase HPLC by dissolving i» 4,2 nil, of DMF (5-30% of premised 0. i % TFA eC In 0.1 % I A in water.) f raefioas coniairdKg desired product were combined then concentrated trader reduced pressure. The residue was dissolved its DCM than washed twice with saturated aqueous aMCC½ and «8 w th brine. After drying over anhydrous MgSt¾, filtration, ami mnaunration. the off- hite solid was identified as i-ethyi-3T4T(5- i«eihyi Tidhr-3~ i)o y)^^^^ (1:3.9 rag, 0.03? tmnol, \ 2i % yield). ¾ NMR (500 MHz, DMSG~ds δ gpet 0.05 (1 M, }, 8,33 {I U, s} t 8.24 (I R d, 1=2.2 Hz), 8.1 1 (1 s), 7.86 (1 H, br. s.), 7.43 {! H, «), 0.86 {} M. $), 3.45 - 3,50 (6 H, r ).. 3.0? - 3.15 (2 fi JB), 2,36 - 2.44 (4 H, m). 2.34 (3 H, s), 1.04 (3 H, =7.I Hz). Mass spectrum {ESI} mk « 372.1 (M-s-M). Following the procedure in 865. the ibil whig confoun s were prepared:

Example suctute Name Data

E am le 870

To a sited olution of 1 ' -{ ~fiu«ro~S'~{2-hyrim^

methy!ures (0.25 g, 0,?5 ramoi), 8-bromo-5-ai«ihy.lpyridfii-S-ol (0.1.55 g, 0.823 mmo.!} in D F (2,50 L) was added cesium carbonate {0.365· g, L12 mai<ri}. Tk > resaMing reaciioa was heated to 100 * C for 4 h. tie .reaction was cooled in ST and quemiied with water. The precipitate was filtered an dried .under vacuum to afford 1- (4- {(6-broma-5 » }iM?thyipyrkitn--3-yl ' Oxy)"6 , Z-hydfoxy-2-- me p¾}K)xy}-[3«3 ' -hipyrl0l8|-6- l}-3-ra«ariyl«ea (0. Hi g, 0.227 x L 30.3 % yield) a white solid. Mass specirum (ESI) mfz » 302.1 , 504.1 (M*H). } H MR (DMSi d ¾ ) 89.19 (s, 1 H) < 8.3 id, j - 2,4 Hz, 01), 8.17 - 8.28 {t« s 211), 7.95 idd, j - 8.7, 2.6 Hz, 1H), 7.30 (d, j - 2.4 !¾ IH} ; 7.74 (br. s. Hi), 6.94 is, 0¾.6,91 (ά, J - 8.8 Hz, U0, 4.63 (s t ill}, 4.07 is, 2H), 2,69 (d, j - 4.8 f¾ 314), 2,38 is,3H).1,20 (s, 614). epaed using rise

f ollowin tl ; ro edure in Exsntpie 870, -he to irsg compcst d was prepared:

Fxa-npSe SiT«ef«re ains Dat

! j{ .-,1 ! 5-((Z-an).iiJO-; - j § t ' "NH a t ' § Mass spears (ES» § pfepeifaiifM S i , t C¥cSo f»p¥l VTfdii3:4-¥i)O t. § § * 1 ί ' Ύ 1 " . ::. *" 1 is/2 -·=■- 272.2 ί *Η). t

Follo ing the ptocedare- Is Exam le 870, the foUo feg casipottatte <«» jsre arfcd;

Structure Name Data

Follo ing tfee prsectee hi ' Exam le 8?0, the following compounds were- prepared using the

Following the prcedure i« Exarfipfe 198. th follo ing prepatfcd:

methylurea

Prepatatioa 11

A glas sai fova e rection vessel was charged with l-(S-(2- dfox>¾ J> -({5-i»e¾yip i ri(li!i-3- y1)ftX7)>yridin-2-y1}-S-r«e ]aim {OU50 g, 0.486 motel) id c&dam carbosafe {0.323 g, 0.992 oaoo!) in DMF (2 mL}. The reaction mixture was stirred and heated in a Discover nmM i crovvave reader (CEM, Matthews, NC) at 120 *' C for 6 rain. The rude rnateriai was absorbed onto a plug of Silica gel ami purified by

ehromategrapby throu h a Redi-Sep pre-packed silica gel column (4 g), e ifing iih. a gradient of 0 % to 20 % MeOH i» C¾C¾ to give 2··$ ·¾«Ϊ(Β»·4 · {{3•roethyl|>yr d}»--3 : -yt)o?¾ i }pyrid.ja- 3-yi)ethasol (0.055 g, 0.224 Bimot 43.2 % yield). Mass spectnms (ESI) ro/z - 246.2 (MVH). * MMR (500 MHz, MeOH-■<) d 8.29 (s, 1.H), 8.21 (s, HI). 7,7? (a. ill), 7.47 (s, ! H), 3.83 (s, 1H). 3,75 (t, SJ Hz, 2H). 2,78 (s, 2 1), 2.40 & 3H>>

Example 958

Methyl 4- fhjorq -3- {(5 - (2-hydraxyetiryl)--2 - $-«*eihykfeide pytld-lo-4 -yl)oxy) ;ft?oate (0, ISO g, 0.523 raiaol) was placed a solution of 4: 1 THFr vater {2,5 atf,) nd thai 10% aqueo s solution of NaQH (0.4 f 8 iftt.. 1.046 oanoi} was added. he reaction nrfxiufe was stitred at RT for 2 h. Tae reaction Wis acidified with I N aqueous solution of HQ thus extracted * Sh δ:1 DCM:iPA. The organic extract was collected and dried over gSO*. The soksioa was filtered and concentrated k vacuo. The crude material was absotbed onto a plug of silica gel and purified ychromatography through, a Redi-Sep pre-packed silica gel column (12 g), skiing with a gradient of 0 % to 10 % MeOH k C¾Cl ¾ , to provide 4-iS«o -C{5H2 mii:«xy¾ add (0.1 7 g, 0.384 .Btmol, 88.5 % yield) as while solid. Mass spectrum {ESI} miz∞ 350.8 ( -tH). Ή NMR (300 MHz, MeOH- *) S 8.12 - 8,19 (m, 2H), 8.08 (dd, ?,6, 2. I½, JH), 7.57 (dd, j - 9.8, 8.8 Hz, mi 6.38 (hi'. s, .iH),.3,91. ft, J - S.J Hz, 2H). 3.0 (i, .1 - 8.1 ife, 2HL 2,80. is, 3H).

Example 959

_ -f] oro-:3-(¾5-d^

3 H H To a SO-mL Maod-bottemed flask was added 4"flttom-3-{t5-{2-hydroxyettyl} » 2-{3- r«edi i reido}BYrk1i - -yi)osy}bii!)z k add (0.0.50 g. 0,1-13 .ms¾>l), 3-m'thoxypropyMmfrw* (0.016 ml, 0.15? i mo!), HBTO (0.060 g. 0.157 mrnol) aad DiPEA (0.07.5 mL, 0.423 rmso!) In DMF (5 8\L). The reaction mi ture was stilted at RT for 18 hrs. The crude material was absorbed oftio a plug of silica gel. a«d purified by cbrf.>oiatog(¾p y through a Redi-Sep pre-packed silica gel cohuan (12 g), dsimg with a gradient of 0 % to 10 % MeOH and 0.1% M¾OH i» C¾Cl¾. The product was further purified by reverse-phase preparative HPLC using 0.1% TFA In C¾CN/HgO, gradient 5% to 95% over 25 mis, to rov de 4--f a s:«-3-{(5-(2-byd.rOxyeiby!}-<;- (3 «!e† yiareido)p tidio-4-yS}Oxy)- -:(3- e&Oxyprop>'l}kiaza fdfe (0.020 g, 0,048 SHOW!, 33.2 % yield) as a white solid. ass spectrum (EST) m'z - 421.1 (M-i-11). ' Ή ΜΒ. (500 MH¾, MeOH- δ 8.1.2 s : Hi}, 7.80 - 7.85 (ra, 211). 7.51 ( , 9.¾ 8.7 H¾ 1H}« 83? (s, IH1 3.89 (t, J»6.2 Hz. 21!}, 3.41 - 3.51 («5. 411), 3,34 (s. 3H), 3.00 (t.

Hz, M), 2.80 (s, 3.H), L8? (qttie. .1-6.5 Hz, 211). ass spectrum (ESI) m/¾ - -448.2 ( ÷M).

Foiiowiog the procedure !o Example 959,. the following compounds were prepared:

3-me.thyiurea - ethyl 2- ( -((5--^

Step Ai To a 250-ro.t reaitd-bottomed flask was added i"{3-biO£na-4"fl«ofe jrjdjfi-2- l}-3" methy irea (2,0 g, 8.00.rjtmol}, 2- eiho,xyc;iFbos)j ; S:vifty!bc>r(!«ic acid ploaeol ester {2.53 11.29 mffiol), Pd(PP!i 3 ) ¾ C½ (0,568 g, 0.806 t iool) &ηά sodium carbonate- (4.2? g, 48,3 mtaol) ¾i 4: 1 mhdu of dkixane: aicr (75 mL). The reaction was purged with Ar thee heated under Ar ' for 18 h at 80 :5 C, ' Hie reaction mixture was diluted with water and extracted with lQ%MeOH !B (%(¾, The organic extract was dried over MgS0 4 , The solution was filter d a«d concentrated in vacuo. The crude product was triturated with ether to give off -white %olid. The filtrate was abstsW Goto a pktg of silica gel sod purified by ehrotnaiogfaphy through a Redi-Sep pre-packed silica gel coksmn {80 gi. elating with a gradient of 0 % to 100 % EiOAc in hexaa wh c was combined with the triturated solid to give (E) -ethyl 3-(4-iluoro--6T3-meiiryte iLi> g, 5.61 tnsnot 69.6 % yield). Mass; speemtm (ES mk « 268.0 ' (M-iTI).

Step B: To a solution of 68% NaM is tram!ral oil (0.072 g, 1,800 ramol} ' DMSO (4 ml} was added trbiiedwlstdfoxofrftim iodide (0.382 g, 1.779 vnrool}. The reaction mixt re was stirred at RT for 1 k © •• Ethyl 3"(4-fiuom-6--{3-raeih ¾reido)))yfld{K "yi)acryl8te (0.317 g, I.1.S8 mrnol) in DMSO (3 mL) was added. The reaction mixture as stirred at RT for 24 h. The reaction mixture was diluted with water, extracted with EtOAc. The organic extract was dried over MgSt¾. He solution was filtered and eostcenli 'aied in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through Red* -Sep pre -packed silica gel column (12 g). eltritog with a gradient of 0 % to 1 0 % EtOAc in Isesane, to provide -ethyl 2 - (4»fl«oro -6 - (3- et yloreyd}py idm--^ f}eycJopropa«i«ad)»sykite (0,0833 g, 0,332 ttxmxA, 28.0 % yield} as white solid. Mass speetrt-snt (ES!) miz 282,1 (M-t-H),

Ste$> C: To a screwed, &p vial was added -ethyl 2-{4-flm>m-8-{3-meatyJureido}pyridlit-3- y cyciopropanecarhoxylate (0,285 g, 0.728 ntmo!). 3 iydroxy-5- niethySpyridi»e (0.1 Ϊ3 g. 1.004 mmo } aad cesium fluoride (0,040 ml, 3.883 mmol} in MeCM (4 mL}, The reaction mixture was stirred at 80 * C lor 2 days. The crude product was purified by chromatography through a Redi -Sep pre-packed silica gel colmms (12 g), elating with a gradient o O % to 4 % MeQH is€¾C¾ to afford

•ethyl 2-f4- ((5-ffisihylBy^

yilcyclopftt aaecar oxyfate (0.05 S g, 0.153 mmol 28.87 % yield) a white solid. Mass speciram (ESI) - 371.2 {M+Hj. ! M NMft (50(1 M¾ MeOH- f ) § 8.48 (s ; Hi), 8.4Q id. j«2,4 Hz, lH) t 7.97 fc, I Hj, 773 £s, 111), 6,42 fa. IU} > 4.15 ( ,1-7.1 Hz, 2H), 2.80 (3 M, s , 2.5-1 2-65 (is, MS, 2.47 s, 3H), L94 2.07 (m t IH), L56 1,63 (ra, IH), 1.53 {tid, j-S.6. 6.6 Hz, IH), L23 (t. J-7, 1 Hz, 3! i).

Example 1018

l-{3-B omO- -({5-me hox j>y^ (0.112 g, 0.31? JMUOI) was placed in 10:1†ofue!ie wa†ei ' (3:0,3 ml.) as a s¾sp<¾s_oa and degassed witfe Ar. Potassiuta cydopropyMlluorolKjrate {0, !:88 , 1.26S stsioi) , palladium acetate (10.08 «¾, ,048 msnoi) and potassitmi phosphate (0.282 g. 0.95 ΐ mmol) were added followed by the ddition oi ' E- dicyc!oh(5xylpliosp «a0^2\6-dS:-i-prs posy -l J'-bipheoyl {RuPhos} (0.044 g, 0.095 iSSfd) . The reaction was stirred at 00 *C aeder Ar atmosp ere for 18 b. The reaction was cooled to RT. The crude material was absorbed onto a plug of silica ge and pat'lfled by chromatography through a Redi- Sep pre-packed silica gel column (12 g , dating with a gradient of 0 % to 5 % MeOH DCM to provide 1 (5-cy opropyl -((S-nKiiha¾ypyrldifi-3-yl}oxy)py^bi-2--yl}-3--ffiethyl«f8 a {G.Q4& g, 0.153 ffliiioi. .2 % yield} as a white solid. Mass spectrum (ESi) miz - 315.1 {M-ll}. ¾ NMR (500 MHz, MeOH- *} δ 8.17 id. J » 2.45 Hz, IH}, 7.99 (d. j - 2.20 H¾. IH).7.8S (s. 1H}> 7.24 {t. j - 2.32 Hz. Ill), 6.49 is. IH), 3.89 (s, 31-1) « 2.82 (s, 3H). 1,8? - 2.08 (m, S B), 0.04 (dd« j - 1.83, 8.4 hit, 2H), 0,74 (dd« J = 1.47. 5,38 lk ( 2M}.

Example 1019

To a hB -mL .round-hottoined flask was added ethyl 2-.{4 5-»jeth lp ri.din -y¾0xy}--6-{3- roefhyierejdoli^rid i -S- lJ^dopTOpas^ai' ax kfie (0.025 g, 0.06? tomcd) to HF (1 ml.).

DiisohutyfakiRHini!K hydride, 1.5 n- toluene (0.10 niL. 0.150 SIOKJI} was added at * C and the reariiaii jfiix ire was steed ' at 0 . Alter I h, more diisohuiylaiamiKam hydride, 1.5 fat toluene (0,10 tnL, 0.150 Jiaaol) was added. The reaction was stirred for additional I The .reaction was queacoed wftn aqueous RoeheS.Ss's salt so!yfclon and extracted, with .EtOAc, The organic extract was collected asiti dried over M SO The solution was filtered and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel arid purif ed by darotnatography through a Redi-Sep pre-packed silica gel eOlumo (4 g), e!uling with a gradient o.f 0 % to 0 % MeOH .in C¾C1 ¾ to

(M*H), ! H N (500 Mf½, eOH- , δ 8.30 is, 1H). 8 2 (d, j - 2.45 1¾ I ' H), 7.91 (s, IK). 7,48 is, 1H), 6,44 is, i ' H}, 3.53 {dd, j - 2.93, 8.36 Hz, 2H)« 2,77 ·· 2.86 {u, 3H), 2,41 {*, 3H) < IM - 1.97 ( m, lH). L42 (d, j * 7.83 Hz, S 11} , 1.01 {id, j 5,07, 8,44 M¾ IE), 0,9 (id. j « 5.20, 8.93 Hz. 1H), The. racemic material was separated by supercritical llaid chromatography (250 x 30 tarn AD-H column with 2 /aiirs MeOH+- (20 mM ¾) * 78 gftuiss CO;:).

.Exstopfc 10

!·. { ¾-{ - lBl ^S!I^

m dwisrea

A ro ud'k> ' tio««¾i iiaxli with ^ 1 ' 2-(4-({5-med¾4pyrid^

3')il}cyctop?o anecarboxyi¾ie (6.025 g.0.067 mol} was azeotroped with toluene and itseo purged illi At. The reaction was first dissolved in THF (I mL) and cooled to 0 * C To the. rotation was added methylUthiurh, 1.6M soltsdoo su diethyl ether {9.3.16 ml, 0.508 nxsml) drop ise. After 5 rnln, the reaction was warmed to ST arid stirred for ose 1¾. The Mxture turned, yelkm The reaction was quenched wild saturated H.TJS solution anil extracted with. EtDAc, The organic layers were collected ami dried over MgSO The crude materia was absorbed ot«o a plug of silica gel and purified by el)roraatogr¾)hy thrw tgh a Rede Sep pre-packed siliea ge ! column (4 gh ei ud e,g with a ra ient of 0 toIO% eOH h 5 C¾C¾, to provide raceadc i - (5- { -2-(2"Rydm> >ypropan-2- yik:vd<;ps< spyi) -4· {(5 ^oethyipyri din-3-yI)oxy}pyddss-2yl}-3-meS¾> kireaj0.022 g, 0,062 mmol 91 % yield) as w i'titt? solid. ass spect , ί'ϊνο ΐ . ,,. ·· , ·*' - .· ¾ .* . ί.ί\ ί ί■

\Οίϊ ξκ ) !ίίί:ί ~ Α< ,ύ t -i-! i, ΐΐ

8.2? 8,37 Cat, ΪΗ).8.22 (d. j - . 5 Ha, ίΐί 791 fe, IH), 7.49 <s, IH), Β.4Ϊ (s, !H). 281 (s,31Tj

2. 1 is, m j.2,04 (td. . j - 5.1.7, 8.99 ¾ 111), 1.27 [s, Oil). L2H (til. ! - 5.72, 8.62 iiz. IB), 1.04 (fd,j

- 452, 10,27 Hz. iH).0,9.1 (id. j ~ 5,04, S I ' M). The racemk: material was separated by supercritical fluid chrorftatogrsph y (250 s: 30 mm 0 -H column with 24 g/nilsi MeOH i20snMN¾) a, <¾> >'min ί Ο..Ϊ

Example 105

1-fS- !.:'< ii droxviw o ί so 2-vl)-4-C(5-methvlnvridia-3-vloxY l) ; ?ddin-2-vfi-3-:r iciiivlurea

Step A: To a sti red so tioo of Nai (2.998 g, 20.0 rnmol) in 15 mL of M Cs^ a RT under nitrogen was added 7 ' S-Cl (2.530 mL. 20.0 mA) dropwise by syringe followed by ¾0 (0.180 mL, 10.0 mmol) and p.rop-2-yn- -l-ol (0.532 mL, JO nimoi). .After siinlsg for I h, the reaction, was tpiesched by addition of water (20 mL). The mixture was extracted with Ε½0. The organic layers were cso blne aad washed with 10% sodium bisulfite solution, saturated NaHCO* and brine. The organic layer was dried over Mg$f , filtered and concentrated to give 2-iodoprop-2-en-l -oi (0.920 g, 5,00 rntool, SO % yield} as a ysiJow ml

Step B: To a stirred solution of 2-Μορ»ρ-2-<?ο·-1-οί (0.920 g, 5,00 vmol) In 10 mL DCM: at 0 ¾ under nitrogen was added imidazole (0,40S g, 6.00 mtftol) followed by a solution of TBDMS-Cl (0.829 g. 5.5 smnoJ) Ui DCM (5 IHL). The reaction wis warmed to RT arid stirred 6» 18 It The i«adloii was diluted with DCM and washed with 2 M aqueous HCI. solute, 10% sodium bisulfite and saturated Nar!CC¾. The organic layers were combined, dried over Mg$t¼, filtered am! eoneernrated. The crude material was purified by chromatography through a S AP silica gel column (50 g), eluttog with poftanfe, to provide rert-butyl(2 (xloaU>½xy)dir«> lang (0.654 g, 2.10 mmo!, 43.8 % yield). Step C; To a stirred suspension of L:me L3 M3~meth Jp rfdi^^

under nitrogen was added te^bai Ua-iodoall ^d ' meih isilaB (0.344 g, 1.15 mmol) followed by .sodium carbonate (0.61 1 g, 5.16 mmol).. The mixture was purged with aitr gen for 1.0 nun.

Pd(PPli;¾ (0.133 g, 0. OS mmol) was added, and di reaction was heated to 80 ¾·. After 18 h, the reaction was cooled to RT aad part.itJoo& i etween PCM and water. The organic layers we combined, dried over MgSQ*. filtered and c p ensated. The crude material was purified by chromaiogtap ry flirough a SNAP silica gel cohorts* (50 g), ekting with a gradient of 30 % acetone in hexanes, to provide i -(tert-b«iy ta

yloxy}pyridin -2 -yl}-3-rned3yliir a (0,320 g, 0.74? rnmol, 64.8 % ield) . Mass spectrum (ESI) miz -

tetrabutyiammoniixm fluoride, 1.0M solution in Tf!F (0.46? n>L, 0.467 n iol) ia Mf (1 mL}. The reaction mixture was stirred at ST fat 1.5 h. The reaction mixture was -diluted widi saturated ¾Ci and extracted with EtOAc. The organic extract was washed with water and dried over MgSO^, The

provide H5-{3-hydr© y ra -l-ei^^

(0.14? g, 0.488 Hanoi, !00 % yield) as white solid. Mass spectRaii (ESi) sWz - 315.1 (M+H), >H NMR (500 MHz, MeOH <} 58.33 (s. Iff). 8.24 (d, J-2.4 H¾ IH), 8.13 (s. IH) { 7.52 ($, IH).8,50 (s, Hi), 5-51 (d. Ife, 1*0. 5.23 - 5.38 (m, IHL 4,45 2H), 2,85 ( , 3H). 2. 2 cs, 3H},

Example 10 6 l 3--(i dr d ox t^^

To a vial was added J - (5- (3· hydiosyptop- !.· eH- -y¾ --{{5 fisea)ylpyridift--3^'J)axy)pyrkila--2--yl)-3-- methyhjrea {0,060 g, 0,191 IVITO!) and Pd/C 10 wt % (dry feasts), wet {0,020 g. 0.01.9 tsmoU in 1: 1 EiOH:MeOH (4 ml). The reaction irskfare was purged with H ¾ and stirred at RT for 3 days. The reaction: aiixtare as filtered through a syringe pS«g aad concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica ge! column. (4 g} : ehalng with a gradient of 0 % to 10 % MeOH Irs. CH ? i¾ to provide 1 ~ 5-{l - h rax pr0pao-2-yl)- -^ (0.023 g, 0,073 u oi

38,1 % yield) as while solid. Mass spectrum {ESI) mfe « 317.1 (M*H). ¾ NMR. {500 MHz, MeOH i 88.31 & ill}, 8.23 fd, &ΖΛ Ex.. ill), S. 10 fe, IH). 7.50 (s, IH), 6,42 «s ; 11% 3.81 {dd ; j- l I.6 ; 6,7 Hz, tM} > 3.89 {dd, j-10.6. 6.7 H¾ IH), 3.31 · 3.25 {«;, III), 2.82 is, 3M). 2.41 (s, 3H} > i .35 {d. j~?.t Mx, 3H). The racemic material was separated by supercridcai fluid chromatography {2$0mm s 21 mm Ltfx-2 c hm with 17.5 g/rrin EiOM {20r M ¾) + 32.S g/rnio CO.).

The following compounds were also obtained from the above prep;

Example Structure a¾a Dat

Esarapfe IS) 9 iZj--i " -i(L2--tii»g w!--6--¾^

Step A: To a stirred soluttoa of t-i5-bro$^ --fl«ofOpyridi»-2-yl)-¾m^ylafea 11.18 -g, 4,76 rnffioi , arid {¾ -Sri uiyi(2-¾¾!toxyviiiySstai r iSiasie (2MZ mL, 5.71 mal) iatoterie {25 ml was added Pd(PPl¼|i (0.550 g» 0.476 mmo!). The-reactkm was heated to HQ * G ami stirring continued for 16 k The mixture was concentrated, and the crude product was purified by dm>tmtegr¾)hy through a RedkSep pre-packed silica gel column (40 g), ekting with a gradient of 0 % to 100 % EiGAc in hexs!se to afford (Z)-l-(5-{2- hox^la .l}-4-fl o jidia-2-y.l}-3-mey5yi«rea (0,291 g, L23i> rorsol, 25.0 % yield) as yellow powder. Mass spectrum (ESI) mk∞ 240J ( +M).

Step B: To a vial eoaSatrjing 5-hydroxy-S -dimeth lp rJdiB-gClH-oee (0.120 g, 0.862 maw ' l) in dr DMF (L2:mL) was .added iZi --(5-(2ethoxyviny½ (0.140 g,

0.585 mmol} arid cesium carbonate (0.572 g, 1,756 mmc&) in pardons at 23 X. Upon complete a dition of b se, the reae0.e« was heated to 1 0 *C. After 0 ft, the reaction was cooled io RT. The reaction mixture was diluted with water and extracted widi EtOAc, The organic extract was dried over MgSC)*. The solution, was filtered and c xjeotrated In vacuo. The crude materia! was absorbed onto a plug of silica gel and purified by c¾ror»at«graphy through, a Redi-Sep pre-packed silica gel coiUHwi (12 g), eMfe wO a gradient of 0 % to 10 % eOH hi ί pro-vide {¾ ' -!-i4-((i,2- diioethy!-6--oxo- i,6--d&^ (0,1.57 g„. (5.438 mtrnl 74.9 % yield) as ligfitye!iow solid. Mass spectrum (ESI] m « 3S9.1 {M*H}. J H NM¾ (306 MH¾, eOH- 58.84 0 H, s), 7.37 0 H. d, j*S.8 Hz). 6.54 {i. H< d, 9.5 H¾)« 6,44 (:i H> d.

H¾). S.35 (I H, s). 5.53 (I H, J«7.1 Hz), 4.05 (2 M, d. j-71 Hz), 3.62 (3 H, s), 2.82 (3 H, s),

2.28 (3 H. s), 1.37 (3 li 1-7.1 iM,

Exampl i 01

A dry via! containing l'-(54:u ) ^ -(^ (0,500 g, -Ptes) (0. S 05 g, 0,148 fnrnol), Pd.{dba)g (0.043 g, 0,07 rarao!) was purged with Ar. Dry I MF (8 raL) was added by syringe. After 5 rain, (2-(te«-i««axy)'2-oxod 'l}zto ® chloride (8.90 rol 4,45 n siol) w¾ added dropwise, U ' poa om lete addition ofxinc solution, tfee vial wa capped, and the mixture was ½a†ed to 85 :" C and stirred, for I S It. LC "MS showed there was .still some starting material. More 1, 2,3,4, 5-pentapheny ' l .I dS. -lm{yi h ^hin& fem)c«iJfi ( -Fhos) ( J0S g. 0.1.48 siraoi}, Pii(dlsa);: {0,043 g, 0. 74 rnmol) and {2-0ert-b«k>Jiy)-2-oxoethyl)zHic(i¾ cMori e (3,0 k 5 o)) we e added. The reaction was stirred at 65 C C, After 6 it, more {2»(teif-hutoxy)-2-oxoetfeyi)«loc{Ii} chloride (3.0 ml, f .5 ramol) was added, and the reaction mixture was stirred oversigh The reaction .mixture was concentrated, diluted with water and extracted with DCM. The organic extract was washed w h saturated aC! ami dried over MgSOi. The soiat km. was filtered and coneeetratsd is vacuo to give the eryde materiel which was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gfei coiamn (40 g). eliding wiih a gradient of 0 % to 2,5 % MeOH io CM ¾ Cl f to provide tert- butyl 2-{ -C(§- : iatHiiyl yi¾ (0.476 g. 1 ,278 rsol,

86 % yield) as off- white solid. Mass spectrum (ESQ ' mfe - 373 J ( +H}< Ή N R (500 MHz, MeOH- ) δ 8.34 (s. ill), 8.22 (d, J-2>4 ¾ ill), 8.08 {$, IH), 7.50 (s, IH), 6.44 {s. IH), 3.64 (s, 2H), 2.S3 is. 3H), 2. Ϊ is, 3H), 1.42 (s, OH), oilowia the procedure is Example 103 , !h« ibllowis compound was prepared;

Example 1034

To a t uiid jotsoraed flask charged with tert-btuyl ^(^((S-imethyipyi dSit-S-ylJo yi-e-iS- me 'iiHtiido)pyrldl»-3-yl)3cetaK? (0.033 g, 0.089 mei) in THF (1 t) was added metiryiliiMurn solution (0.52 ml., 0,572 mmol) drep ise at 0 5 C, eliow prsstipltatio.8.fomted. The mixture was stirred at 0 *C for 1 h. The rea tion was quenched with saturated Mi^Ci^) ami extracted with

DCM. The orgastic extract was collected and dried over MgSO*. The solution was filtered and concentrated is vacuo. The crude material as absorbed oato a plug of silica gel and purified b chromatography through a Redi-Sep pre-packed silica gei -column (4 g), elutitsg with a gradient of 0 % to 10 % MeOH in Cf¾Cij, to provide l-(5~(2~hydrOxy-2-raeth 4pR>pyi} -{(5-nxShylpy idio»3- yi}oxy)p ¾idiri:-2-y¾ -3-:riM<iiiyi!irea (0.009 g. 0.027 maiol, 30.7 % yield) as white oil. Mass speetfrns ( i mat = 33i,f (M+H). *R MMR (500 MHz, MeOH- ) δ 132 (s, IH), 8.21 is, iM), 8.09 IH), 7.49 is, m.6.42 (s. IH), 3.35 (s t 2H), 2.82 is, 3H). 2,4! (s, 311), 1 ,28 (s, 611). i us ί;οηφο«ίκ iwax Isolated as a by ρτί¾1ϊί€ΐ of Example 103-1

Exam le i 03&

To a vial char e with H5-bromo --((5-r I^ (0, 100 g >

0.297 mraai) as purge with Ar. TTff (3 ml.) was added and t e solution was cooled So -78 * C. ethyiHthkirn .soktioo (0.539 ml ' .,, 0.593 mmai} was added then- after 5 mio, buryliithiusn solution in. hexarje (0.318 jn ' L, 0.345 mmd) was added. The rsiixtare was warmed to 0 * ' C and stirred for 25 iti. The orange so-lutfOB was cooled hack to -78 6 C. ' Pro ylene oxide {0.042 oil 0,593 motel) was added, aad the reaction raixiure was warm to RT slowly. Be reaction mixture was stirred for 18 it. The crude material was absorbed oato a plug of silica gel aad purified by chromatography through a Redi- $ep pre-packed s !iea gel column (12 g)„. elating with a gradient of 0 % to 10 % MeOH in G¾CJ ¾ t¾e» farther purified by reverse-phase preparative HH Visin 0.1% TFA in CM ; ;C ¾Q. gradient 5 to 95% over 25 tmn, > provide

mer ykfrea 2,2,2-triilaesroacetate (0.008- g ; 0.018 iomoL 6.27 % yield) as a white oil. Mass sp ctrum (ESI) rate «= 317.0 (M+HL ! H N R (500 Mrk, MeOH - ) δ 8.42 i , IH), 8.32 (s, 1H), 8.18 (d, j-6.8 H¾, ffik 8.93 (d, . A ¾ IH , 0.60 (br. $. ¾ iM). 3.02 - - 11 (til W .2.84 2J0 (m, IH), 2,82 (s, M 2.75 - 2.81 (ro ( MI), 2.49 is, 3H), 1.22 (d,.HU Hz, Ml.

Example 103?

To a 25-mL rmnid- bottomed flask was added terCbutyl 2--{4-<C5- : ft»aiylpyridin-3-y1)eiXy}-6-(3- (0- ί 60 g ( 0.430 nrn i) and 60% NaH in mineral oil. (0,069 g, 1 ,718 nwooS) to If!F (4 mL). The reaction iid««i¾ was stirred for 5 s»in thea T S-C1 (CLIIO mL 0.859 mmo!) was added. After 10 0.430.mmol) was added, and the reaction ttdxttire was stirred for .!& b. UtMtftn bis{i.riine(hyl»Uyi}ariJide (0.8S9 mi, 0.859 torno!) was added and the reaction mi ture was stirred at RT for I h. The eaction mixture was diluted with saturated N¾Cf and extracted with DCM. The organic extract was dried o er MgSO The solution was filtered arid concentrated in vacuo to give the crude material The erode material was absorbed oat.o a pin of silica gel and purified by chromatography tferoogh a Redi-Sep pre-packed silica gel column (4 gj, elating with a gradient of 0 % to 10 % MeOfl is C¾Ci?, The product was further purified by reverse -phase preparative MPLC usin 0.1% TP A in€M s C /¾0, a ient 5 % to 95 % over 2§ mio. to p o i e tert-hntyi i--( -C(¾--me ^

yi}ey «propariecarboxyiaie (0.005 g, 0.010 mmol, 2.35 % yield) as a white glass. Mass spectrum

(ESi) mfe » 399.3 iM-t-H) . ¾ N R (500 Ml¾, MeOH - } S 8.43 (s. 8.30 fe. ill) . 8.09 (s, IH} ( 7.61 (s, im, 6.40 k, I ' M), 2J0 (s, 3H), 2.45 &, 3HJ. 1,55 - 1.70 (m, 2!¾ , 1,39 is, 9H), 0 - 134 (nt, i i !

Example 1038

To a vial charged with .!.-{4-{(! ,2-diMthyl-S-oxo-l .O-dfhydropyrldin-S-yDoj-y -S- {

hydn)x eth>d}p {idin-2-yl}-3-nieihy!«rea (0.012 g, 0.036 mrnal) m DCM (1 ml) was added deoxo- flaor (9.97 pi 0.054 mmol) dropwisc. The oraage solutioa vvss stirred at RT for i h. The .reaction mixture was then quenched with saturated NaHC(¼ solution in a plastic gradual cylinder. The resulting siixk e was ans er ed to a separator^ iusnei and extracted with DCM. The combined organic layers were dried over MgSOT The solution was filtered and concentrated Is vacuo to give the crude tnarerfaJ as a white oil. The crade materia! was absorbed eato a phtg of silica gel and purified by chromatography through a Red -Se pre-packed silica gel column (4 g! elating with a gradient, of 0 % to 10 % e.OH

(0.004 g, 0.012 mntel, 33,3 % yield) as while solid. Mass spectrum (ESf) mfz■» 335.0 (Μ+Μ) . ¾ HM& (400 MH¾, DMSO s) a 8.97 {$, IH), 8.0¾ (s, IH), 7.36 (d, j=d>,8 Hz, ill), 6.70 (s, 1H). 6,40 (d, J - 0.8 Hz, Hi), 4.73 it, 1-6,4 Hz, HI), 4.61 ft, J-6 4 Hz, .ili), 3.48 (s, 3H), 3,06 {t, J-6,3 Hz, IH). 3,00 ft, 6.3 Hz, iM), 2,67 (d, J-4,7 Hz, 3H), 2.20 (5, M i}.

E ample 1039

Step A;-. A ro«ad-¾©ttt»»ed flask wiils ί •• {5 >mt«o- - ((5 fewlh lpyridia-S- lJa^p r iR^-yl}^-- methylurea (0,200 g, 0,533 jnrao!) was diss lved in THF (δ tat) and flushed with Ar. ethylHt um solotios (1,078 sot, L186 oimo ) was added at -78 "C, and the resa ftg mixture was stirred for 5 JO!B, ButylHthlum solution ( 1 ,271 ml., 1,780 ve mi) was added and stirred for 20 oara. DMF (0.115 t sL 1.483 mnioi) was added, and the reaction mixture was wan« to RT ami stirred for i h, The reaalort trsiycitsre was diluted whfs saturated ¾€i a« extracted EtOAc. The organic extract was dried aver MgSO.}, The solution was .filtered and concentrated its vacuo to give the crude .material. The erode oster was absorbed onto a plug of silica gel asd purified by chromatography through a Redi-Sep pre-packed silica gel colunm (4 gh doting with a gradient of 0 % to 100 % BiDAc in teas s, to provide i~C5 b m M (5-roet ipvTidiR-3^^ ^ ^ {().128 g< 0.447 ramol.

75 % y ield) .

Step l To & solution of ! -(5 -ibrioyl -4- ((5-:fiKHhyipYrid8i--3 -y!)oxy}|>yridi«-:2 -y|) --3--me£hyl.«rea (0.060 g. 0.2:iO :fliraoi) is MeOH (2 t«L) was added sodium borohydfide (0,016 g, 0.410 mmol). The react!oa mixture was stared at RT for 2 h.then concentrated in vacuo. The c ' rude product was purified by chromatography through a Redi-Sep pre-packed silica gel a>lum8 (12 g) , eluiing with a gradient of

380,0 ( v!-1). ¾ N R (500 MHz, MeOH- ) δ 8.33 (s. HI), 8.26 id, =2,4 Ife, IT!}, 8.19 (s, IH). 7.53 (s, ill), 6.4 (s, IH), 4.70 is. 2M), 2.82 (S, 3H), 2,42 (s, 311).

' Example 1040

Step k: To a !OQ-ml, mnsd-bottomsd flask was added dlisopropytasitae (LI ml, 731 mrool) :ta THF (12 ml) and cooled to -78 e C B«ty!IMhiufS (3,25 ml, 8,40 mmoi) (1.8 M to hexanes) was added dropwise at -78 e C and stilted for 10 inm. The mixture then was raised out of the dry ice bath for 1.0 mift iheri back to the dr ice bath. 2,2•Diftsetfeyl- rahydm-p rBn-i -tme (0.930 l 8.89 o¾n l) was dissolved in THF (12 mi) t¾eu added slowly to fee LDA solution si ·?8 and stirred for 45 mm, N- Phenyl bs-^fl«oro««k» s«1foriirso¾e (2.71 g, 7.58 MRIOI) dissolved in THF (12 ml) was added slowly, and the reaction was stirred at 0 "C for 2 h. The reaction mixture was queached with water d extracted with hexanes and ether. !¾e combined organic layers were dried over MgSG*. The solution was filtered and concentrated is vacuo to give the crude material as a orange oil of a nrixtare of e.e-dimel yl-^e-dihydfo-aii-pyraa^- l trifl oftwaet anesulfomtte s d 2 f 2-«Jlai«ttft4-3.6-dihydro- 2H-pyrau-4yi trlf1 ffiro«jethaoeisulfoaai« (1.65 g.6,34 nimoi, 92% ield).

Step.8: A mixture of 2,2-dte¾ .l-3Xi-dih dro-2H^ ra8~4- I trfluoromefe»testtlfosa.te : and 8,6- dimeihy] ,8-ililiyd«)-2H-pyraji -yl trifittoforiiefeasesuliooate (1.65 g, 6.34 mmolk

bis(pioaco!ato)dlboro« (2,0 g.7,88 romo#, FdCdppfJssCl* (0,518 g, 0.634 mroo!) and Ac (1,86? g, 19.3 iSiitoO were combined in roto >otteised flask with dk!xan (30 ml). This mixture was heated at 80 °C for 2 days. Tire reaction mixture was cooled, .filtered, over a pad of celste and washed ts'! ElOAc, The filtrate was concentrated and filtered over a pad of silica gel with 20% EtOA : hexanes to give a mixture i2-4 2Klin*eth S-3^^^

dioxaborolsne a« 6 t 6-dte< h-3^-- ^

dioxaljorolane oaaiitifaiively.

StepC: To a vial was added a mixkm of 2-i2,2-tJirtie l-3 > 6--d¾ydt > o--2H-pyraft -yl) - , ,5,5- i,3,2-diox3borofeue (0,283 g, 1.18S amiol). i-(5½ojno-4({Sraefeylpyr¾

3-ifteliwiurea (0.200 g.0.593 m««d), tricydoh xyl hospidoe (0,033 g, 0.110 tamol). Pd2(dba) s (0,054 g.0.059 fKffioi) and s P0 5 (1.369 rat, 1.780 mma!) In dioxase (4 ml}. The heterogeneous mixture was stirred at 86 °C for 18 k The reaction mixture was cooled io RT and dried over MgSCh. The solution as absorbed onto a plug of silica gel and purified b chromatography through a Redl-Sep pre- packed silica gel column (12 g), clttthig with a gradie t ofO % to 5 % MeOH C¾Ck to provide a mixture of 1- (5 -•(2 r 2-dimei l 6- bydra"2H--}yran- 4-yl}-4- (5 n¾etby!pyridisv3- yl)05c }pyridfa-2--yJ) - 3--siethy!tirea a»d l-fS-iS.S-dfineftyl-S.e-d^'dm-ZH-p f e-^yi) · -((5^ 8te ip^iditi^ l)c^ {0.200 g.0.543 mmaL 92 % yield) as yellow oil

The isomers were separated by chromatography (LUX -2 (2x15 cm) LUX-205 x 0.46 as) with 30% Me0H( ¾OH)CO ¾ ) to ive ^{5--(S,6--d!ffiethy]-3.8-ditw^

!)0 y)pyrsdl8-2'- i}-3-Rsel:hylirii , Mass spectrum (ESI) vu/z - 369.1 (M+H), Ή ®MR {500 M!fe. MeOH ) § 8.28 ( S> III), 8.16 (for. s., 3H) < 8.06 (x« !H), 7,4 ΐ (s. IB), 6.50 fe, SB), 5.84 (s, IH}.3.8S if, j-5.4 Hz, 2H), 2.83 is.3H), 2.39 - 2.42 (m t 2HI 2.39 (s.3B), 1.25 OH).

To a high pressure reactio vessel was added .1 -(5-(8.8-diraethyi-3,8-d^

m>eibexyp iidta-S- |}tt 3pyddi»-2-yi)"3-mi ½rea (0.073 g, O. iS mnKti}, Pd/C 10 wt. % (0.202 g, 0.1:90 rn.mil) ia 2,5;1 Ef.OH;DCM (7 ml), The reactioa misflcare was purged with !¾ once (fees stirred tmder 800 psi ¾ for 3 days. The reactio s lu n was filtered through a syringe filter, and the filtrate was cooceatraied under reduced -pressure. The crude material was purified by reverse-phase preparative HPLC uxhig 0.1% TFA is CMjC /HjO, radient 5 % to 95 % over 20 mm. to provide the TFA salt of the product The TFA salt was filtered through a Strata high perf raiss e polymeric solid phase extraction (SPE) to give l-(5 -(2 > 2 ^limi«hylteii¾ihydro-2H-pyraft- -yl)"4- ({5 · meu%oxy yddiB -yi)0xy yridlt^2- !)-3-itieihylarea (0.030 g. 0.077 reto l, 41 % yield) as a white solki. Mass spectrum (ESI) « 387.3 (M+H>. ¾ N R (500 MH¾ MeOH- ) δ 8.1.9 (d, 1-2.4 H¾ IH), 8.08 {s ; Η·!), 8.00 & J-2.2 H¾ JH), 7.2? it, J-2.3 rfe > Η·!|, S.47 is. ilij, 3.88. - 3,92 (m« 311}, 3,?¾ - 3.8? (m, 211s, 3,36 (d, 1-8,3 fix, 111), 2,82 (s, 3H>, i.82 (dd, 9.8, 4 A Hz. 3H>, 1.88 (s, .I H), 1.31 (s, 3ffL 1 ,20 (s, 311). The raeeaiie material was eparated by supercritical flaid chromatography (250 mm 21. mm AD-H eohssr>a with 19 g/mift MeOH [+20nr Arranoaia) ·»· 35 g/min CO?}.

Fofcvlag die procedure above, the following compound as prepared;

44? Exa ple : Structure Natae Data

1-(3 2A

dlmeih !ie5:r¾fe (iro- 2H- ass spe trum

! i \ o' i; -r- - : ·-·· pyr } £ - ¾ - yl) - - ({5 - (ESi) ut/ 3T1.2

1 ! i H H !iief lpyiidia-B-

1 yl)0xyp¥rsdi! ; t--2-yl) S- ,Λ,-¾ methyitfra.

Exam le 4?

An oven-dried vial co taining a sfir bar was charged with Pd¾(dua)s (0.056. g : .0,06 i jtanoi). (9,9· dia:iediy]-9fl-xardiie«e- AdsySfe (Xantphos) (0.078 g, 0.135 umioi), -potassium phos hate (0.328 g, L535 mmoi} asd l~(S-bro»K H(S-nietBYlp ridiR-^^

methylurea (0.207 g, 0.814 ««¾ø!}. The via! was parged with Ar. TMF (g mt) aad cydoou!anriae (O.OBO rat, 0.921.runt©.} were added sequentially. The viai was seaied With screw c p, aad tire mixture ' was stirred an hesied at 80 *€ for 2 days. The reaction Oitxi re was cooled to :RT. The crude materia! was absorbed onto a plug of silca gel and purified by chromatography through a Redi- Sep pm-pacted silica gel column (12 h ©luting, with a gradient of 0 % to 10 % MeOH/BCM and feriher pacified by reverse-phase preparative HPLC wsiag 0.1% TFA in C%C /1¾,0. gradient 5% to

MHz, MeOH- } d 8.34 SHj, 8,22 fti ; j-2.2 Hz, 1H), M (s, 1H), 7,50 (s, ill), 6.44 fs, m M - 4.72 (iB, III), 3.23 - 3.28 {m, IH), 2.98 - 3J8 (m, JH) f ZMi (%, 3H), 2.46 - 58 (m, IB), 2.42 (s.3il) : . 2.27 - 2.38 |«s, !HJ.

Example f 04S To a

{0.029 g, 0,085 siisml) ii MaB¾ C&.?2 g, O.J 78 rnmol) MeOH (1. ml). The reaction mixture was stirred at ' RT for 2 Is. The crude waissiiai. was absorbed onto a plug <; ' sibca gel and purified by chromatography through a Redl-S > pre-packed silica gel column (4 g) < eiutiag with a gradient oi ' O % to 10 % MeOH iu C¾Ci 8i to provide 3 HH0i^^24ryd o>^^

yl)oxy)p , y?idSn-2-y!)-3 «eihyi«r¾a (0.0 IS g.0.049 imml, 54,8 % yield). Mass spectrum. (ESI) 329.0 C -s H). ¾ N R {400 MHx, MeOH- } δ 8.47 - 8.J5 (m, !H>. 8.43 (d t JM..3 H¾ !H), 8,09 (s, IB), 7,75 (t, .7 irk, IB), 6.39 (s, Hi), 4.26 (tp j-7.8 J½, IM}, 3.57 (q, j~ ¾, IB}, 2.88 ($ > 3H} } 2. - 2.52 (s«, 3141 2.26 - 2.3S fm, 111), 2,1» - 2.24 (sa IM), 1.95 (dt j-19.4, §.0 ¾ SB), 1.62 - 1.7? ( , B),

Following the procedure i« Ex 1949. the following compounds were prepared;

E ii k 106:

o a vial was added 1A AAdi!rydTO-Stl- y^ tneib lum* {0.050 g, 0.147 mvmi} am! Seleeifluor {0,000 g, 0.162 mmoi) in MeOH {3 mt).. The reaction was stee at 40 *C Hot 18 h. The solution was concentrated ia vac«o to give the crude material, a«d the crude material was absorbed onto- a piag of silica gel and purified by

d¾mmatography throu h a Redi-Sep pre-packed silica gel column (4 g), eimlng with a -gradient of 0 % to § % MeO!i In CI¾C¾, to provide l-(5-(4 ¼of s-3-Riethoxytt^} dm-2H-^ aa--3-yi}-4-((5-- meirh ipy r jdls-3--yl}o¾')py!idiri- 2-yi} -S-metity!erea (0.0 1 g. 0, 105 mmoi 71.5 % yield) . The isotaefc were se arated by sspercndeal fkki chroffiate-giaplry to gi e l-(5-((3S,4R}-4-fluofO-3-- njeihoxytetrafeydf»-2H-pyra«-3-yl) -4-{(5 · m t hylpyn din- 3 -y !jsxy Jpyrid in-2-yl) -3- nieih hires. Mass spectrum {ESI} - 391,0 (M->-H).

T he following com ounds were also obtafcied from ¾ above prep:

Example 1068 yfj-3--{aetfekrea

To a vial was added i-(S-{5,6-dih ro-2H- mi-3^

medwlurea (0.054 g, 0.159 tamo!) and Sefccif!unr (0.072 g, 0.1S3 flamoi) in a 10 : .1 mixture of MeC {1,5 mi) and water {0,15 rrd). The reaction mixture was stirred at RT for 1.8 h. The reaction mixture was concentrated in vaoio, then s he crude mato- was absorbed onto plug of silica gel and purified fey chromatography tteaugh a Red! -Sep pre -packed silica gel column (12 g). elntiag wiih a gradient of

0 % to !fl %MsOM ' in CH?(.¾, to provide M5 1 -lluora-S-hydro let^

melh lpyldlnr3 » l)o¾ ridB-2- i}-3--miltyl«t¾ (0.050 g, 0,1.33 mmoi.84 % yield). The isomer were separated by supercritical fkrid chronmio rap&y {250 mm x 30 mm AD-H column with 20 g/rais EOH (*-20mM Araraonla) + 30 g/rain COg) t en .further purified by supercritical fluid

c rosnatogsaplw (2506ia¾ x 30 mht IC coimi with 40 g/mift eOli (20ioM A moftla.) + 40 gfmm CO ? ) to gi e Ϊ -(S'({3S S}-4-f¾ioro"3--hydroxyse^^

¥iox ) :iidin-2" !)-3-sis > f k!'ea. Mass s ectrum (EST) · 377.1 (M4I, ¾ MR {406 MHz, CDC § 1.06 - 2.11 im, I H) 2.30 (br.s..1 H) 2.41 fe.3 H) 2.84 {d.. j-4.70 fe, 3 H) 3.44 - 3.64 (ra.

1 Hi 3.83 {«¾ 4i .74, 8.02 Hz, I H) 3.96 - 4,15 (m, 2 H) 5.32 - 5,62 m, 1 H) 8.11 (a, I H) 7.26 (br. s„ i H) 8.J9 -8.48 im..2 H) 8.54 (s, :l H).

Exam le 107S

i iS;jS-¾ydro ycycl¾ ex::i:eft-|-

413 Step .4: HT({5--MethoxypyridM

methyteea (142 mg. 0.344 .ramol) was dissolved ift M«C {:! .0 ml) mid a few drops of water was added followed fey addition of lithium tetraflirorohora e {45 ,2 sa , 0.482 romol). he reaction was stiffed for 2 h and -only a trace ofdesi¾*d prodact was observed. Another aliquot of lithium teftaflooroiaoiate (45.2 ®g, 0.482 ««.«©0 was added aioag with a few more drops of water aad stirred for IS h. Another 5.0 r»L of eC was added nd the reaction was stirred for 2,5 days sod showed so progress so product. The action mixt re was it n concentrated to a volume of -0,3 mL.aftd ■another aliquot, of lithium fetralluoroborate (45.2 mg, 0,482 rnsnoij was add d and stirred for 18 k Finally, the reaction mixture was healed to 80 "C and stirred for 6,5 It. Starting materia! was now completely comwmed. The reaction mixture was cooled to KT atsd diluted with DCM ami eCN, Water was added sad Ae iayers were separated, lie organic layer was dried over MgSi¾. The filtrate was concentrated, to give crude f.-{ -((S-H^ ho^ ri^n^3- l)0x }-5-(5^ evcfoli x- l«ea- 1- ':i)p>-ridin-2-yl}-3-melhyJ.«rt¾. Mass spectrum (ESI) rn a - 388.1 ( ÷! ),

S ep B: 1- (4· {(5 --Methoxypyi o -S- Slox ) •• 5 » (5--o i¾:yelohex-4 » en « yl Tidia-½i^^sm {urea (127 mg,.0,345 marai) was dissolved ia MeOH (2,0 mh) and coolsd to 0 5 C. NaBH 4 (52,2 mg, 1.378 ffiBtol) was then added arid the reaction was stirred at 0 ,: C for 30 rain. The reaction was then quenched with saturated Nai C ( ¾ solution and then tweent ated In vacuo. The material was then, diluted wish water ten extracted with EtOAc (3 x 20 ml.}. The combined efgaai la ers were washed, whir brine (1 x 25 h) and dried aver gSO ;! . The crude nwteriai was purified by reverse- phase preparative HPLC using a Phantnenex Lm& column, 5 micron, C s (2), 100 , 150 x 21.2 mm. 0J TFA in CH :i CN/¾0, gradient 5% to 35% over 25 rnifi to provide th Tf A salt of the desired product. The product was absorbed onto a plug of silica gel arid re-purlfied by chmmatography. elating with i to 10% 2M NH* in MeOH In DCM, to give l-{S-(5-hyiroxycydoh«x-i-en-l -yl)-T(( ^ (9 mg, 0.024 imnoi, 7.05 % yield). Mass spectrum (ESI) ma = 371.2 ( +H), "H NM.R (400 H¾ CDC¾ δ 8.83 (1 IT br. s,j, 8.26 - 8,44 (1 IT m). 8.20 (i -1, d. j^2.5 Hz), 8.03 (i H. d, J»2.2 Hz). 7.95 (I IT s). 6.00 (I H, t, jh2.3 Hz). 6.21 (1 IT s). 5.89 ·■ S.S8 (I H, ), 4.35 {}. H, m. 3.3 Hz), 3,87 {3 H. s),. 2.87 (3 H.„ d, j»4.7 14¾), 2.26■ 2,48 (2 ii ), l.m■ 2,01 (1 li m , 1,79 - 1.80 (2 H. m), 1.83 - IM (4 & ml.

Following the procedure h\ Example 1 1 3, the following: ttfmpeunt!s were prepared: pFe aratiOii

A 10 ml microwave via! was charged wUh E-chloiO- $-fi«orop}Timid e (840 tttg, 6.3 mrnoi}, Pd;>(dba}:; (230 mg, 0.25 niiuol), l., -¾s{diph aiy!pk s bim)ferroeem! (280 m , 0,51 niraoi}, jtiac. cyanide (480 mg, 4Λ tatwt}, ami zinc dust {100 mg« 1.6 mmoi) and d nethylaceianxide (4.0.mL). The mixture was thea sparged with Ar. Tkvvfal was mounted Mo a Discover tnodel microwave reactor CE , Matthews, ' MC) and heated ai 100 "G for 10 is. The reaction mixture was dilated with EiGAc (50 ml.,} and then washed, with brims (3 50 ml.). The orgaaic layer was dried over MgSO* gad evaporated to ryness. The erode mas nal was adsorbed tnito a plug cd silica gel and ptnified by c roftSif grapii , ektting with 0 io 50% EtOAc in hexanes. So give 5--fluofO|>yrtrakhoe-2--car o«lti > tle (190 mg, .5 Hwao!. 24 % yield , ¾ N R (CDCy ,δ 8.74 s, 2M).

Preparation

Step A: M Morap azine.~2-f¾r oxy :ie acid (800 m , 3,8 mxml) was slurred in thionyl chloride (15 mL, 210 mms\} and two drops of DMF were added. The reaetioa mixture was stirred for 18· It tfceit concentrated under vacuum to give crude 5-chkiropy∞lBe-2-carbonyl chloride thai was yse directly in rise a ide ibuiavion. The crude acid chloride (370 m , 2.1 mrool) was dissolved in DCM {20 mL). liimethylamlse {9.5 mi J.S.0 msrolj and E¾ (0.53 ml, 3.8 mmoi) were added and the resulting mixture was stirred for 18 it. The reaction was than qaenched with 0. I dirk acid solution {25 mL). The layers were separated and the organic layer was washed ith water (1 s 25 ml) and (hen tfa ed over MgSO«. The -filtrate -was e ncetifrated, and the erade material as adsorbed onto a plug of silica gel and purified by chromatography, eSurisg with 0 to 100% EtOAc in BCM to give 5-chlorQ-M 5 - dii«etl} Ip !a2!tse-2- arboxamide (ISO mg, 0.970: mmoi 46% yield). Mass spectrum (ESI) iz «

185,9 ( ·ί Hi. *H NMR (CDCW 5 8,78 (d, - 1.4 Hz, iC ), 8.55 (d, - .1.4 Hz, IB), 3, 17 (s, 314),

3.14 is, 3M).

Followin the procedure above, tlse following compound was prepared:

Example ίΟ

Methyl (35

mg, 0,087 nx&l) was dissolved in THF (1.8 mL) 8»d coded to 0 X, Lithium triethyl orohydrstic ii .0 M In THF) ©.36 mL, 0.38 mm i) was thee added dropwsse, T he dear solution turned yeiio and was stirred at 0 X for 45 min. The reaction was tiers quenched a* (5 "C by addin a potassium pemxymonosalfate (276 g, 0.43 mn»!) solution idfcssotved In 8,0 inL ftf water) dropwise. The mixture was extracted with EtOAc and DC.M and then washed with brine. The aqueous layer was co«cati¾ted and then stirred ioouly wit DMSO (5 mL) to extract proriact from the salts. T¾e DMSO layer was th.e» filtered. T¾e crude material was purified hy reverse-phase preparative iiPLC using a PhenomeBex um hmm.5 micron. Cs.{2), 100 ; .150 x 21.2 mm, 0.1% TFA !»

CHaC /HiO, gradient 5% to §5% over 25 m to provide the TFA sail of the product The produoi was adsorbed onto a plug of silica i asxi re-purified ' by chromatography, eluthig. with 0 to 10% 2M aisoi tig hi MeOH i DCM, to give l-CS^i^'dU^lre tmlaH-S-yO^CS-Ji 'thoxy yrida^S* yl)ft,xy)pyridj«-:2-yI-$"}«ethylwrea 0,5 nig, 0.015 jsmoi 17% yield). Mass spectrum (ESI) m'z ~ 377.2 ( '5-H). ¾ NMR (400 MHz, MeOH- ) δ SJ9 (I H, d : . 2,3 Hz), 8.07 (I. H, s), 8.00 (I M d, 2,2 H « 7.26 (I H. t, J-2.3 rfe>, 8.47 U H, si 3,90 (3 H, s), 3,44 - 3.62 (4 II m), 3,20 - 3,28 (1 H, tn), 2.82 (3 IT s), i .9 · 2,08 (4 K, m),

Example 1087

(»/-)- Tt5d.i3R, S" J" ^

The i-{5--(3,8-dtaydr>o--2H-r^ (50 mg, 0.1 0 romol) was dissolved is a 6.0 mh f a 3: 1 mixture of deaterated methanol : EiDAc, The 10% Pd/C (15 tag, 1.4 rnol) was then added aa the reaction flask was flushed wifh deaterten ga and then kept under balloon pressure for 2.5 days. The mi ture was then flushed with nitrogen and diluted with EfOAc then fUftsred over a pad of diatamaeeoas earth. The crade pradact was ik purified ' by medians pressure {silica, 3.5 to 10% MeOH : DCM) to give Impure product. The crude materia! was purified by reverse-phase preparative HPLC uslsg 8 Phenorneaex Ltma column, 5 micron, Cs(2), 100 , ISO x 21.2 mm, 0.1% TFA in CHaC HgD, gradient 5% to 95% over 25 «»« to p ovide the TFA salt of desired product. The TFA salt was then f tee based by eiuiing through ao-SCX co!aarft using 6 to 2M aiwnonia B MeOH as elaeftt to give (15 m , Θ.042 m i>\, 30% yield) assigned as a mixture of els enaa ousers. Mass spectrum (ESi) m/z ~ 382,2 (M+Hh IB NM (400 MHx, 5 3 ppm 8.93 - 0.16 (i il in), 8.84 (i ϋ br. s. ' 5, 8.23 {I R d, j-2,3 f½)« 8.05 ·0 M, d, J-2.3 Hz|, 7,98 (1 H, s), 6.87 - 0,99 SI 14, m) ( 0.18 Π E s), 4.09 (2 14, ύ J * I ί .4, 4,2 Hz), 3.86 0 H > br. s.) , 3 ,49 - 3,62 (2 Fl,. ) . 2,81 (3 H, d, JM.7 Hz) , 1.78 - I l (3 H, m) ,

Following the procedure in Example 1.08?, the following compound was prepared:

me rvhaea

Exam: .:!<·. 1090

-A) - 1 -siethv!- 3-44- ( 5- -methvlpvtidin -3 - v i«xv)- S"i3'-0K0C d«ls x l)i vddn 2-vlHire&

t~Mcil !- -C4-{(5-m^ (47 tng, 0,12 βο!) as dissolved ϊή EtOH (1.2 mL) ami 1.0 MCI (0.35 mL, 0,35 mtool) was added. The. pesultlag sohttlon was stirred for 3.5 days> The reaction was co.RceBtratsd, baslfied with saturate N ' gHCOs ton extracted with EtQAc {3 x 25 B¾L). The cotobhKsd organic layers were washed with brine (I x 30 mL) and dried over MgSO*. The crude material was adsorbed onto a plug el silica gel and purified y d«omat(¾.raphy, eluiiog with 6 to 30% eOB m DCM, to give i-Bjef¾yl-3-(4-C(;5- roeikyipyndiie3-yi}oxy}^ (41 mg, 0. I 16 mmol, 98 % yield).

Mass spectrum {ESI} mk = 355.1 (tv H) . 3 H MR (400 MHz, CDCfc) & 9 :0? (1 H. m, Hz) s 3.39 (1 H, s), 3.34 (1 E, d, J-0.8 Hz), 8.25 (1 IT d, 2.5 Hit), ?M (1 E s), ?J6 - 7.26 (1 fl, ml 6,0? (1 R s), 3.25 - 3,43 (1 H, si). 2M (3 H, d, 4.9 Hz), 2.5? - 2.70 (2 H, in), 2,45 - 2.54 (S H, in), 2.39 - 2.44 (1 H, m). 2.38 (3 & s). 2,07 - 2.22 (2 H, ). 1.32 - 2.06 (1 H, m). 1.73 - 1.89 0 H. n).

The lo iis eompotjods were also obtained from the above prep with, the addition of the rseemie material was separated by supercritical ilusd c romato ra y (3 x 25 era heik-D 1 ( , ) column with 73 mUrnio 25% IP A (02% DEA)/€f¾):

Example 1093

T ed5yL3TT{(Tmeih lpyf¾ (110 nig, 0.31 mmol) was .dissolved I» THE {2.5 mL) and cooled to -78 X. Lithium in- -bafy!Ciwdrido) borate (:! .8 M la IMF) (.I..55 ml., 1.55 nmal} was tea added dropwise and arme to -20 * C over a period, of 2,5 Si, The reaction was quenched wish 'saturated N¾C.l solution ¾o .extracted Willi !tOAc (3 x 30 re].,}. The camhioed organic layers were washed ith brine (1 x 20 ml,}, dried over MgSi¾ and concentrated . The erode .matedai was adsorbed outa ¾ plug of silica gel sod .purified by djromakgraphy * e g with 5 to 10% MeOH in DCM, to give l -(5-( -S^iy rox cyekl^ {(5-!-ti&hytpyrbiia*3-; (75 i«g, 0.2 S. tnmel, 60%) ,. The ram&k material was separated fay supercritical fluid chrojaatograplw (2 x 25 cm OD -I! column with 80 mLmm 20% MoOH ( 0.1% NH.,OH)/CO to give H5-((l.$,3S}-3-hydroxycydahe> .yi)-4-(i5^ n«¾dwi|yndlii-3-yi}o yi vi!ohs 2 y 3 ί i!vtSsyh} ;a. Mass spectrum (ESi) mz ~ 35 7.1 (MTH). ¾ '

N R (480 Mlfe,CD€ y SS.OO fl H, br. sX 8.48 (1 H. s), 8.32 (1 H. br. s.l 8.24 (. H, br.. 7.94 (I

H,s} ( ?.2! (iPihf.. t. 1=3.0, 1.OHzS. O.Q s (i H, S, 4.27 (i H, te.f, J-1,0, L B*),! 1.36 (I It lt :

J 2.3.3.1 Hz}.2.8 ( H, d,JM.7Hz), 2.37 ( , -i s), 2.01 (1 Rd,.M3.5H , u> 0 - 1.97 (2 m}.

1.73 - i .89 (4Rs) ( 1 .46■· 1.72 (2 H, is)

Thf foilovv g compot md: was ί siso ojiainied from the above prep;

A. dry vial eottfaiaing t-5-bromo~ -( . {5-r lethoxyt iy.ridin.-3-y1}oxy)pyridl»-2-y!)-¾-m etSwliirea (135.9 mg, 0.385 oxo ' sol ) , J 3 A3 -pekapheny ' l- I'- lM-i )«tySphospbi«o)ferro«;i«!, -f¾os (28,0 i«g, 0.039

·!ΐ·!ί — .,,.„»..„! «„.J ! .....i s;)!,..! ..,.Ά

· Η :).:!·; ruHiiJ.s!:-. i. J.O Pig, MAI 'i !l!ii) ol) was i t <s«,««!ieu ««w wits*

was added by syringe, After -5 mm, eye job:Hv!¾ »¾: ' bromide, 0.5 M in THF (1.93 n d...0.985 ·!(·)ί !ϊ was added dropwise. After : h. the mlxt ire was 1 seated to 60 S C. After 3,5 days tk reaetiofi was cooled So RT tkiti the organic solvent was removed under reduced pressure. The residue was di!tiSsd •with DCM theft purified on silica, gel (0- 7 % MeOH k DCM) to afford a pink fihs that was further purified with reverse- pbase HPLC by dissolving in.3.7 mL of DMF (10-90%. of premixed 0.1 % T A In MeCN in 0.1 % TEA in water). Fractions containing desired product were c mbine then coricenf ed imdssr re uce pressure. The residue was dissolve in DCM ttei was ed twice with, sstaraied aqueous ' NaHC<¾ d orice with M . Afte dryiag over anhydrous M$S<¾« filtration, aad cencentra ioa. the while solid was Identified as t -{5-cyclQkityl-4-{{5-methoxyp ridlft"3 » yl}( x )pyridin"2-yl}-3-i«t¾hyl«re¾ (54.3 mg, 0.185 traaof, 43>0 % yield). Mass spcetmsj (ESI) nv¾ - 329.2 ( +.H). ¾ NMB (300 MH¾, DMSO-dt) 5 9.02 (I M, s), 8.23 (I. M, d, JWU Ηκ). «.06 (ί H, s). 8.00 (1 R d, 2.2 Hz), 7.8? (J ¾ br. s.), 7.28 {! M. t. j-2.3 lit), 6.75 (1 E s), 3.85 (3 H, s) ( 3,64 (1 M, qtnn, .9 !¾), 2.64 - 2,88 (3 H. m , 2,15 - 2,3) (4 H, m) f 1.03 - 2.04 (1 H. m), 1,73 - 1.37 (I R ii!i.

Following the procedure in Example 1085, the following compounds

oilowhig the procedure m Preparaii n 15 am Ex 870, (he following coaspoanils were re- &;}jii; ki j Structure. ajsc | Data j

To a round bottom flask coma ing 2 u ydi¾x eihylBi¾a (3.26 g, 1 anaof} in a«l¾'dro«s ' DCM (109 mi..} was added imidazole (4,33 g, 63 m ol) than tert-biityldJjnetbyisi yichtedde (8.36 g. 42 romo!). to portions. The cloudy mixture was stirred at 23 "C. After 19 h. the reaction was diluted With water thea extracted three times with DC . The orga s were pooled iheo washed once with .saturated aqueous H .CI then dried over anhydrous MgSi¾. .After filtration and t >aceMratfc>r the colorless residue solidified into a white solid dsat was identified .l-{2-C t«^-butyldirne i- lyl}0Xy)eihyl urea (6. 1 g, 88 % yield) that was used without purification. ¾ NMR (5Q0 MH¾. DMSO-d ¾ ). S ppin 5.8? (1 H. t. Hz), 5.49 (2 H. br. 3.52 (2 R, i, j-S.CS Hz}., 3.04 (2 H, 3=6. i Hz), 0.87 (g It s), 0.0-1 (6

A stirred soluti n of 1 - (3 -feroioo--4 -((5 -meih0xy (134,3 sag,

0,386 »¾»ol), Potassium 1 -tfif]«or .ilKHTdorn«thjlShB n'iOiphcil:bie (368.7 rfig, C .747 jntnol), »·ΒαΡΑ¾ (26,3 rag, 0.073 ji!Riol) , Pd2{d¾a) 3 (33.0 rag, 0.037 mmsrt), and potassium carbonate (|5f ,S a:¾g, Ϊ .13 nuooi) hi .N-dinieilEylacetssfidB (2.5 loU ami water (0.5 mt) was degassed ant! backfilled with At The reaction rfiixtore was ' heated to 100 *C. After 2.5 days the reaction was coole to EX then water was added to qaeaeh tl*e reaction. Tfet? mixture was extracted l!tree dotes with DCM then the orgaaies were pooled and dried over anhydrous gSOU. After f iiratioo and concentration under rednced p ess re, the residue was dilated with DCM then purified OH silica gel (0-10 % MeOM is DCM) to afford a yellow (lira that was further purified with reverse-phase MPLC by dissolving in 4 mt of DMF (5-30 % of preoiixed 0,1 % TFA in MeCN is 0.1 % TFA lit water.) Fractious containing desired product were cossbtaed then eoacenirsted ttnder reduced pressure. The residue was dissolved ia DC tfeeu washed twice with saturated aqueous NaHCi¾ and once with brine. fte drying over anhydrous M SO^ fitaiiott, and c nc ntrati n die white solid was identified as 1 - t ; i hyi- 3 - (4 - (( ~

8.23 (I H, d, j-2.4 Hz). 8,10 (1 H,.s), 8,01 (1 H, d, 1-2.0 Hz , 7.85 (I H. br. si 7.26 (Ϊ. H, t, 1-2.3 H¾|, 6.87 (1 li s), 3.85 (3 H, s), 3.53 (2 R s), 3.08 - 3.18 (2 11, m), 2.64 2.70 (4 ii ny\ 2.54 - 2.60 (4 !t oy, 1.04 (3 1-1 U -7.2 Hz).

Following t e procedure iu Example 1102, the following compounds were prepared;

St p A: 5~Bromo-2-.iodopyndii¾<i (1.1:1 g, 3,90 ntnioi), .¾-bttiy»~2-ol (0,42 roL, 5.36 mntoi},

Pd(P.Ph¾)sC½ (274 jag, 0.39 oim i) , a d C«f CI 49 ai . 0.78 at awl) were added So a vial ih degassed and backfilled with Ar. To She vial anhydrous DMF (II m ,} theo NEfc» (2.7 nil,, 19.4 iftol) were added by syringe. The resulting reaction was heated f» 50 :1 C. After 2.5 h < the reaction was cooled to RT theft dilated with water. After extracting three times with EtOA the organics ere pooled then drie over atthydrotts MgSi¾. After filtration and ee«ee«tfaifc»t, the residue was loaded onto a silica gel col ma (0-65% EtOAc Its heptane) to at&rd a dark yellow oil as 4"(5"hmi»op>'ri:din-2-yl).b«t--3- n -2-ol (701 rag, 79 % yield) that was used without further purification: ! H MM-R (400 ΜΗκ, D SO- d & ) S j>p«3 8,68 (I H, dd, j-2,4. 0.7 Hz), 8.06 (1 H. dd, j«8,4, 2.5 Hz), 7.45 (I M. dd. 4^8.4, 0.8 Hz), 5.58 (1 II d, 5.5 Hz), 4.55 - 4.65 (1 H, at), 1.39 0 H « d, 8,7 l!z).

Step : To a flask coatainmg -C5 iromop> idio-2-y|} ' b«t-3--yu~2~ol (496 mg, 2.10 tnmol} in EtOH (1 .mi..) aad M¾ (0,3 ml., 2,2 nimol} was added pJa amm 0 } oxide (27 nig, 0,12 mmo!). The flask was evacuated ami backfilled with ato¾eo nd stirred at 23 '! C, After - 5 mis. the nitrogen was replaced with ¾. Airer 2 h, the Hiixttsr was f iltered through a Celsie plug tha was risse with EtOAc then EtOH. The organics were pooled then concentrated in vaeso to afford an orange film that was diluted with DCM then, loaded on silica gel 0-00 % EtOAC in h ptan to afford a S ight yello film as 4 · (5-broii!o|jyridin -2 -yli otan- 2-ol (304 rng. 1.32 mmol. 80.2 % yield) that: was used without further purification. ¾ NMR (500 MHz,. D!CHLOROMETHANE-d?} 3 ppm 8.54 (I H, d, j-2.2 Hz), 7.74 (1 ii dd, J*&3, 2,4 HxjK 7,10 (1 IT d, J««.3 Hz), 3.77 (1 H, d¾t, j-8,3, 6.1 , S.t. 6.1, 4.2., 4.2 !½}, 2.87 (2 Ji t, 7.3 i¾, 2,76 (I H, d. J-4.2 Hz) : 1 ,71 » 1,90 (2 H t ra). 1,18 (3 ft d, J =6,1 Ife).

Freparafiors

To a solution of 4-bromop idin«'2-cafboxaj.t!e!wd (532 mg, 2.86 mmal m DCM (20 mh) was added E¾ (0.6 ml,, 4.3 rnmol) then .t«ettoykmlne hydrochloride (252 mg, 3,0 imno!). The .mixture was stirred at ' 23 T, After 3.5 h, Ihe mixture was diluted with DCM thess washed water. Th aqueous layer was re-extracted t ice with DCM. The organic layers wer pooled then dried over anhydrous MgSO. } , Afte llitration and concentration, the light yellow film was r sumably identified as a tnixte of els as trans isomers or 4-hromopicolinaidehyde Q-rfieiityf oxime (106,9 mg, 0,49? mmpl, 17,39 % yield) thai, was used without purification. Mass spectrum {ESI) m z ~ 215,3 M+H).

Example i 11.5 rrtetbyhtrfea

Λ stirred solotioti of 5••{5-l){ei«o-4-((1.2-dimeihy! #-oxf i -dihydropyiidiR-3-yi)oxy)pyridio-2-y methylurea (121,0 sag, 0,330 mmo0. 2-Cd!ey ok¾yiplro^

X ' -Phos (32.0 mg ; 0.067 rmaoljt, arid PtbC ls;)};; {15.7 rug, 0.01? mmo3 in anhydrous TH (2 la ' L) was degassed and backfilled with Ar, Trihwtyl{4,5-48iydrofur n-2-yi)siaimane (0.32 mh, 1 ,005 mmol) was added So the reaction by syringe under Ar protection, then the mixture was heated in the microwave to 1.20 ;: €. After I h, the reaction was copied to RT thes concentrated (aide reduced pressure. The residue was diluted with MeOM then filtered. ' The ' solid, was raised three tim s with MeOH. to afford art off white solid as i~(§-(C5-dihydrof n-2-y¾-4- (CI ^dimeth W- o-l^- d^drop ddm^i-yO x i yr diiv - ^S-sie^liirea ( 04.0 mg. 0.292.mmol 89 % yield). ¾ NM (500 M¾ DMSi i) 6 9.10 - 9.1? « M, m), 8,26 - 8.32 (1. H, m), ?.?4 (1 H, k. s.). 7,34 - 7.4.2 (I. H, ), 6.83 (!. R s), 6.39 (I R d,J-&8 Hz). S.S5 {1 H, j-2.8 Hz), 4.38 (2 H. t, 1*9. Hz), 3.48 {3 H. s), 2.80 (2 a t*U » , 2,8 i¾ 2.82 · 2,69 (3 H, ml 2,18 (3 ¾ s).

Example 1116

T(S ' -^

To a vial containing anhydrous THF (3 mLi was added lithium is Tlim¾¾yi8 'i}a»)ktfi, (326.7 tag,

Mg$(¾. Alter filtration arid, cotKentration, the residue was diluted with DCM then loaded, on silica gel 20-70 % of premixed 3:1 EtGAc: EtOM solution in heptane afford a dear film thai was triturated wills MeCM to afford a white solid as l-^'-lS^doyfeuto^yJ^-iiS-JiKit yipyridia^- yljoxy) · 3 * ' bipyi ln)-6 - )-3-i aeth ltJEP&a (75.2 mg 0178 raraol, 41.7 % yield}. Mass spectntsri CESi) mh - 424,1 (M+H). ¾ MR (400 MHz, DMSOd ¾ ) 6 ' 9.17 (1 H s).8,28 - 8.38 (3 ft ), 8.21 (1 H. yj, 7,89 ·· 7.97 (i H. ffi) .7.71 (1 H. ,1-3.7 Hz), 7.55 (1 M> t. MA Hz §>79 - 8.95 (2 H, ml 4.54 (i H, d, JM.9 z) f 4.34 (2 H, JJ-.¾}, 3-73 - 3.86 (1 H, m 2.67 (3 R, i te Hz), 2.33 (3 H, s} > 1.68 · Ϊ ,88 (2 H. ai) s Li I (3 R. d. j~6»3 Hz). The faceffiie material was separated by supetxr iti&al Held chromatography (2 x 15 cw AS- . cotamn with SO laL/tttin 30 % IP A

( H ;i Gi4}/C(¾.

Example ill 9

iELi&il.:iiB¾^

46?

Step A: To a dry flask co»tajnl»g anhydrous cydopeaiyi meth l et er (IS mL) was added lithium bis(tfiiiKifhylsily }amio¾: (3.3969 g, 20,39 mtml} m portions. The via! was cooled in an ice water hath. Ate 18 min, i, -propanediol (1.2 ait, 16.34 mal) was added dropwise at 0 ; The reaction was wanned to 23 K G by mnoving from the ice water hail). Ate 30 min, 3-hromo-2-flaofopyr : idi«e (03 ittL, 2.91 mawd) as added drop vise, aod the reaa!oii solution becanje doudy. Tie reaction, was carefully heated, to 80 X. Afte 2,5 the reaction was cooled to RT then quenched with saturated aqueous NM4CI solution. After extracting three times with DCM. the er anies were pooled, dried over anhydrous M SO:¾ ilhefed and cottceutraied. The residue was dilated with DCM theu loaded on silica gel fJ - 46 % of EtOAc ia heptane to afford a mi ture of 1 -{($^mmo yT}dm-2~ 1)ox }prop83J~ - ol and 2-((3-brt)inopyridis-2-yI)o«y}piopai}-J -9I (2:19,5 mg, 0.946 mmol, 32.4 % yield).

Step B; To a . mixture of l » {(5-l>tx)TBopyrkhn-2-yl .oxy) mpaa-2-ol and £-{(5-bromopyiidfe 2- yl)oxy)propan- i-ol (21.8.5 mg, 0.946 mmol} is .^ DimettrySaeeia ide {5 ml.) as added

bi$(pMiaco ato)djbaroft (382,7 mg, 1.428 mmol}, n-BoPAd2 (68.0 mg, 0.192 Han i), Pd^t ba);; (87.1 mg, 0.095 tomo!) and ' QAc {233.5 mg. 2,379 ssoioi}. The resulting solution was psaged three times with Ar and placed node* v cuum three times,. The mixture was heated to 100 X. After 4.5 h, the reaction was cooled to RT.

(I.60..Q .mg, 0.47S mmol} an aqueous 4,0 M potassium carbonate (0.38 mL, 1.440 mmol} were added to the reaction mixture. The flask was degassed and backfilled with Ar. The resulting reaction was heated to 100 X. After 22 h, the reaction was cooled to RT then dilated with brine. After extracting three times will? DCM, the orgastics were pooled, dried over anhydrou MgS(¾, filtered and

concentrated. The residue was dilated with DCM then loaded on silica gel 20 - 100 % of prei ' nixed 3: 1 EtOAe ErOH solution In heptane to afford yellow Mm that was farther purified with reverse- phase HPLG by dissolving ia : mL DMSO (Hi- 90% of premixed 0.1. % ΤΡΆ fcj MeC ' to 0.1 % TP A in water.) Fractions containin desired product were combined then concentrated under reduced pressure. The residue was dissolved in BCM then washed twice with saturated aqueous MCO-; and once with ferine. After drying over anhydrous SQ.*, flitratiaa, and concentration, the isomers were separated by supercritical fluid chromatography (250 s 30 mm AO-M cohnrm with 40 L/roio MeOH -i- (20 j« Hs) -!- 60 g/mio C(½) h n further purified fey supercritical fluid chromatography (250 x 30 mm O -H X O -H -coluiVms with 20 stL/mio EtOH + (20 ru N¾ *· 80 g/min C<¾) so give t'B) · - (6^(i--hydroxypropao -2-yl}oxy}-^ (11,3 rag, 0.028 mml). Mass spea m iESl) mfe = 410,1 flvR!fj. f M NMR {500 IR D SO-de) 5 9.17 (1 fi s), 8.28 ■■ 8.3? (3 R .!«}, 8.21 (1 R s), 7.93 (1 R dd, fcS , 2.4 H¾). 7,72 (i II, i. $.}, 7,56 (i R s} : . 8.90 (5. R s), 8.83 (1 R d, j-8.8 Hz), 5, 1.2■ 5.2! {1. R oi), 4.81 {!. H, t, J-5.7 ¾}, 3.58 (1 R dt J-i .i.3, 5,7 RR 3,45 - 3.52 (i R. ot), 2.67 (3 R d, j-4,6 H 2,33 (3 H, 1 ,24 (3 li <t

Hz).

The foHovving compoands were also obtained from t e above prep:

edwiurea

i-(5 3ros«o-4-f;2 -d!lluo.roplH : ;«oxy)py 0.43 !««ioi) ; (5-c atJO-l- medwEl!i^ if«i'-2-yl}feoffinic arid (131 nig, 0,8? mmui). PdCPP ;^ (101 mg } 0,09.tnin i), aad ptitasssuni carbonate (193 nig. ί .38 mmol) were added to a vial men degassed sad backfilled with Ar, To me viai, tetralrydfofunm (3 ml.) and water (1 .ml,} ' were added by syringe. The resulting reseiiots was healed to 60 * C After 17 h, rise reactiosi was coaled to RT then conceatrsted under reduced pressure. The residue was diluted wiih DCM then filtered throagh several.0,45μ.ι« GMP Acrodiscs. The material was loaded era silica gel 0-50 % of premised 3: 1 .EiOAe: MM solution in eptane to afford a light purple film that was purified with reverse-phase HPLC (10-90% of preroixed 0, 1 % TFA bt.MtC is 0.1 % TEA in water.) Ftactfons contalidn desired product were combirsed ii n eoisc is r !sd tnider reduced pressure. The t sidue was irsiaied wit i saturated aqueous MaHGOj, Afies extracting tee tim s with DCM. the organfcs were pooled then dried over anh drous MgSO*. After fihriiiio and concentration, the white solid was identified as :raost!y desired product. The white solid was treated wish MeC then sonicated for 10 mm. The solid as filtered and rinsed twice with MeCN to afford white solid as l-(5 -(5 -cyano- l-meth l-lH-pyrrol-^-y - -CZ - diil« «) e»a^pyridia-2-yI -3-met:hyl«r^i (15.9 nig, 0.039 mol 9,91 % yield). ! H MMR (500 MHz, DMSO-d^ S pm SS (1 H. s), 8.13 - 8, 1? (1 H, sd. 7.34 - 7.51 ( M. m), 7.04 - 7.09 (2 li m). 6.37 (1 It , j-4.2 Mz), 3.66 (3 it s), 2.64 (3 1:1 d, j-4.8 !fe). Mass spectrum (ESI) is6 - 384.2 C ÷H}

Example i 1 3

H4-(3-tyanojteroxy)

Step A; 1 - {5\Bromtv -41^ro|>y idin-2- vl} --a« ¾ «rea (2.0 Ϊ g. 8, 12 HMEJOI) was suspeaded in 1.4· Dfoxaae (55 roL} and wafer (5 ad,} then potassium ey opropyltriflnoroboraie (4,48 g, 30. S smoot}, potassium carbonate (5,0? g. 36.7 srmsoi), and Pdtd pOaClj, complex with DCM (2.01 g, 2,457 mmnl) were added. Ar was babbled through, the .mixture for 10 mio, then the mixtttre was heated !a 90 *G> Alter 20 h , the reaction was cooled to RT then -partitioned between brine and EiOAc. Alter drying over anhydrous sodium sulfate, filtration and eoneeurrailon. the residue was perilled on silica gel 0-30 % tsf 3: i EtOAcEtOH solution in heptane to afford a yellow solid that was treated with BtOAe, The slurry was heate on the rotovap to 50 * €. After 30 tuto, the mixture- was cooled. The solid was filtered then washed once with EtOAc and once with diethyl ether to afford a white solid as I-(S- cyelopfopy!-4-fluorop rid --2- 0-3-m > iiryl«rea (ID4 g, 4.99 inmol, 61.4 % yield). Ή N R (500 MHz, DMSO-dfi) δ pptn S.25 (1 II }■, 7.91 (1 H. dj- J 0.8 Hz), 7.48 (1 H, hr. s,}, 7.24 (1 1:1, d, 1- 2.7 f¾ 2.64 · 2,73 (3 H, m). 1 MS (1 H, it. 5.2 Hz), 0,34 ·· 0.94 (2 H. m} > 0.65 · 0,78 (2 H, m). Mass Spectrum (pos.) M 2.1(1.1 (M idi} " .

Step B: To a stirred solution of 1 · {5- yx{o 8pyl --fltK)rop¥ridta-2-yl) -^metltylarea f lOi mg, 0,43 mmol) and S-cyaaopwenol (75 tng, 0,63 t noi) in DMF (2 uiU was added cesium carbonate (259 trig, 0,8.ismol) in portions. The .resulting solution was heated to t O * C. After 18 h, tire reaction was cooled to 23 *C then carefully quenched with water. After -extracting three -times -with EtOAc, the organics were pooled then dried aver anhydrous sotltna sulfate. After ' filtration and concentration, dte aiaterfal was purified wit reverse-phase flPiC (10-95% of remised 0.1 % TFA in MeCN in 0.1 % TP A in water,) Fractions containing desired product were combined the concentrate ander reduced presstire. Τ!κ· residue was treated wife saturated aqa atis r¾HCi¾, After extracting three times with DCM, the orgastics were pooled ihen dried over anhydrous gS(¾. After filtration arid eonee radori, the while solid was identified as ί• {4--{3-Qyajiopk¾oxy}"$-cy'r:i(>propytpyiidift--2-y l)"3- methylurea (1,5 jag, 0.040 mrnol, !0.i % yield). ¾ NMR {500 MHz, DMSO-dg) 6 ppss 9.83 (1. H, s), 7.87 (1 H, %}.. 7.70 · 7,81 (3 H, 7.67 (I H, t, 7,0 Hfc). 7,50 (I H 5 ddd, j-83 2,4, 1.0 H¾, 6,70 (3 it s), 2.S5 (3 ¾ d..M.6 !¾, ϊ .88 (I H, it .1-8.5, S3 Ox), 0,82 - 0,88 (2 II, tn). 0,68 - 0.75 {2 H, mj. Mass specrrara (ESI) o¾¾ 309,4 { -s-M)

E vampte 1 ί 3

H ' 5 -U -i d! os¾spirol ,51deeafv-8-¾imediy!}- 3-(i2--ethy1pyrfdm-3- vl}o^

S E ; TO a solution of S-sseiisyiese ί A -dio xaspi!O{ .5]deearie (0.087 mL, 0.56 moiol} In degassed

rWI? ft mt \ x tt.t¾« ? is Kjijf in "Fti i,

reflux lor ! 1. theti cooled to BT. The mixlw • was added to a flask containing 5-braj«o-3-(|t- ethyipyridirs- 3-yl}oxy)pk¾ltaft de (0. 100 g. 0.3X0 wml), Pd(dpp¾C¾ {0.042 g, 0.05? nunoft.

¾C(¾ {0.213 g, 1.34 sftraoi], degassed DMF {2 tnl.) arid degassed %0 {0.14 7.8 smnol). The resulting mixture was iseafed at 80 degree for 5 b. The mixture as diluted wirii saturated NaHCO;t s iuiioH, basified ith aqueous 15% NaDSd solution to pH 11 , extracted with EtOAc and washed with brine. The organic layers was dried and concentrated in vacuo. The crude material was purified by reverse- hase preparative HFtC to provide S- 0.4■ dto asp ire f 4 , 5| deca ri- 8 - i n«¾y ί } ·3··{{2·

yJ}0:Xy}pieo ii!ior»de {0.080 g, 0,15 inrnol, 29 % yield), Mass spectrum (ESI) n¾¾ -

Ste B: To a solution

yl) xyipicoiinaniide (60 nig, 0,1.5.1 tnei) in a srsixiure of MeCH (i.5 mQ an water (1.5 HJL) W¾S added .Riefhaiiamiee {0,066 mL, 0.755 samol) and his(ttlfltwroacetaxy) ; tod8 benzene {68,2 jng, 0.159 mo ' l). The .reaction mixt re w¾s stirred at ¾T for .! , 8 h. The reaction mixture was diluted with saturated aHCOj and extracted with EiOAc. Th organic layers ere collected,

( eOlT ) S 8.35 (dd ? - 4.7, 1.4 Hz. 11!}. T.84 (<f, « 1.8 Hz, J H) f 7.39 (dd, « 8.2, 1.6 Hz, 1.H), 7.32 (dd, - 8.2, .7 Ms, IH1. 6.88 (d, - 1.8 I½, lil), 3.89 (%, 4H)« 193 (s, 3H), 2.86 (q, => 7.6 ¾ HE), 2.44 {d, * 7.0 Hz. 2HS, 1.69 (d, » 12.3 Hz. 2HS, 1.53 - Ϊ M (m, 2.H), 3 (id, =* 33,2, 4,0 ih-r. 3H). 1.16 - 1.31 (nt, 511).

Follbwis the procedure in Example 1 1 5, the following compound was prepared; i (5 H A

di.Qxasp!rof .5]decan-8-

V ,i ' " NH Mass spectrum

J 28 ylstethy H- 3- (( -ethy 3 - CESn Jft¾ ^ 0.3 i ii p;. ra o! :i

( ÷H}.

yl)oxy}{>yrldiB-2-yD-3"

i«ethyl«re»

Step A: A flask with l -{§-iiA-4inxa iw\4.$ tec -$~ i^

2-yl)-3-rae ½re& (50 rag, 0,117 mmol} was added EiQR (3.5 raL) and IN HCi (0.352 ml, 0.352 ί««:ίοΙ}. The reaction mixture was heated to 65 ¾ for 2 h. The reaction mixture was neutralised with I NaOi aqueous sohm'oa and eenceairated. The aiixture was diluted with brine and ret acted with EiOAc, The organic layers were collected, dried and concentrated in vacuo * The erode material was absorbed onto a plug of site gel ami purified fay chromatography through a Redi-Sep pre-packed silica gel column, elating with a gradient of 0 % to 10 % MeOIi in CM 2 t¾. to provide i -(3-({2- eilryipy?idi«--3-y3}oxy}-5- {(4^ quantitatively. Step B: .To a flask charged with i- 3-({2-ethylp n m-3-Yl}a^

2-yi) -3- nieihySurea {43 rag, 0.1 .raraoi} was added NaB¾ (17.0 rag, 0. S0 mmol) and MeOfi (2.5 ml.,) . The .reaction mixture w&s stirred for Sh (hen concentrated its vacuo. The reaction mixture was diluted with ¾€l and extracted, with EtOAe. The organic layers we«e collected, dried ami concentrated 1ft vacuo. he erode material, was purified on reverse phase HPLG to provide 1 ·(3··((2· etiiyipyndin- 3 : yt}oxyT (28 mg, 0.073 mmai, 65 % yield}. ass soeetrum (ESI) miz - 385.3 {M ;-H}. The Isomers was separated fey supercritical fluid chromatography {2 & .15 era AD--H wirn wills 60 mtimte i 5% ' 1PA {Q.1 nUiOmi oz).

2-vi} -3-'fneiisvIai¾a

Example 11.30

O

Step A: To a flaks charged wit 3-.-{be»z 1oxy)cyciob«.teao«e. (0,34! mL 2.188 rnmoi) was added IMP (5 mL) and coaled down to 8 :: C, Tebbe reagent, 0.5M solution in toluene ' (4,34 ml-, 2.1(58 mtaol} was added slowly. The reaction was wa med to RT and stirred for 30 rahi, Ether was added to dilute the faction-a i qucuched wills 0.1. M NaGf-l aqueous solution until gas stopped gejieraiiisg. The mixture was filtered, through eelife, dried with gSt¾ ih concentrated under reduced pressure-. 'Ike crude materia! was absorbed onto a plug ofsitka gel and pttrsiled. by chromatography through, a Re i- Sep pre-packed silica gel column elating with, a gradie of 0 % to 2 % EtOAc in hexaaes to provide ((S-medwfes ' sccyciobuto Jim'rlryijbeoz fte (220 mg, 1.26 romoS, 58.2 % yield). ¼ R (CDCS-0 S 7.18 - 7.30 (m, 5H}, 4.72 - 4,84 (m, M ' 4.38 (s, 2B), 4M (t, * δ ' .δ ¾ I >, 2.74 - 2,90 («1, 21-9, 2.59 - 2,74 fc H).

Step B : To a solution ef {{3 6t¾ leae«yel btttox m ti) l be}i2erie (110 mg, 0,631 mol ) in THF {!. mL) was added S- BN ' , 0.SM In THF (1.26 ml 0.63.1 mol). the mixture was heated to refinx for 1 h then cooled t RT. The mixture was added to a flask containing 5-bro«io-3 -((2-eilryipyridin-3- yi}oxy}pieatbramhfc (113 Rig, 0,350 sstnol), Pd(dpp!} ? £¾ (48,9 tng, 0,057 mmol), K ; ;CO s (238 ing, 1.72 rnmoi), degassed DMi ' (2. ml), degassed !¾Q (0.16 nil), Tne resulting jnMure was heated at SO '"'€ for 5 ht. The mixture was diluted with satur ted MaMCO? stdtrtion, basifkd with aqueous 15% NaOH solution to PM 11 , extracted with EtOAe and washed with brine. The organic layers were dried and eoace feated in vacuo, Ί crude .material was absorbed onto a plu of silica gel and purified by chs¾watograpby tfeeugh a edi -Sep pre-packed silica gel ' colnua eiu ag with ' a radien of 0 % to 100 % EtOAc iR ' hexaaes to provide 5-{(3^btn¾yirMc )<^ to *i!5'i)m «i }-3--(C2- &ij ! yridij^-3 : ylSo¾ i€oHBainidti (151 mg, 0.362 mxml, 83.0 % yield). Mass spectmm (ESI) miz ~

Step C To asohuiori of 5--((3--(hee^S:oxy)cyd^

yboxyl ieoiisiauiide (151 rag.0,362 i»mol)i a msxiar of MeC (3 nth) and water (3,00 *aL) was added n banaadne (0.158 aiL, 1.808-ftHUol) and ' bis{Mfl« i«aeeioxy5lodo bea¾eae (IBS mg, 0.380 ϊί?ίη«ί The reactioa iixnaxi was stirred 1½ i.8h then dil ted with saturated MaHCC¾ salidioa aad. ex acte with EiOA . The crade material was purified on reverse phase HFLC to provide I-(5-({3-

Following ihe procedure la Exam le 11,30, the following eompouads were

A flask widri · (5- --{{3-- {herayioxylcyeiohiSt i) methyl) --3 ■■ ((2-¾tby]p r in-3"y¾ xy}pyridift"2--y])"3-- raetiwlurea (80 a¾, 0,202 mn>l) was added Fd/C (32,2 mg > 0,030 mnic4) aftd MeOH, The reacdoo was purged wub hydrogen and sfsrfed urider 1¾ aftnosphere. After 18 h. Addidoaal Pd/C was added aiid ie -reac on was resubmitted o ¾ydrogeftatton. The r¾aetisa ndxtyr was filtered through a pad of Cdiift aad (xsneearated. 1¾ crude materia] was purified by reverse phase HPLC to afford .1 {{2"e ipyridtn-3"Vl>oxy}"S-{{3 - droxj^ clo iii Dftieih p ridJii-S ---y Ϊ) -3-- met hyiurea (26 tog, 0,073 tnsKri, 36 % yield). ess speetruifc (ESI) miz - 357.2 {M+H}. The somers were separated fey i^ rcriikal fluid chromatography (2x15 csa A ' -H column with 85 laUm 20% eOH (0, 1%

NI-! t OH)/C0 3 ).

The fb!lowifig compounds ere also obtained fmm the above prep:

Exam le ! 143

3-ffletl lta¾¾

Step A: To a flask char ed with .M5-.(L4~ 8o*asp|rq^^

S- 4).oxy}pyf5dltt-E-ylj-3-»}eihyl«rea (137 r«g, 0.330 iwaol) was added EtOH (S-mL) atid I f-iCI (0,988 mL, 0,989 ftuaal). The reaction was toted to 6§ a C for 2 h. The reaction y rixture was neutralized vvith IH NaOH -sftkitai and concentrated. The Hrixtare was diluted with ferine aid extracted wi8t BtOAc. ' The organic layers were collected, drie and concentrated in vacuo to give - (3 (l -et¾ i-i B~pyr;^ C! 20 mg,

0.323 miml 98 % yield),

StefiB: A. flask ii!iM3-((i -e yl !i- y

methy!ures (86 sag, 0.232 m.ruol) was azeotroped w th tokens and ih purged with, nitrogen. Tfee reaetkm was dissolved m THF (2.5 mL) ami cooled to 0 °C. To the so.luti.oa was added meihyljiiiiltfsii sok&oa. IMM in diethyl ether (1,085 mL, 1,737 mmoi} dropwlse. After 5 ink, the reaction was warm so RT and stirred for tme h. The reaction turned cioudy- teddish, lite .reaction was uesched ith satorated ¾C1 soi»i!ort and extracted wiife EtOAc. T e o ganic layer was w shed w¾h brine, dried over gSO^ and concentrated in vacuo. The isomers were separated by supercritical fluid chromatography {2 x 25 cm AD-H -coiums with 85 stL/tnin 30% MeOH (0, 1% Ni¾OH /CO¾} to give Η3-((ϊ -eth^

3-wethylurea (9 mg. 0,02 rroooi, 20% yield). Ή NMR (MeOH^ ) 8 7M (s, I H), 7.44 is, IH). 7,20 (s, IB), 5.73 (s. 111), 4,03 - 4.23 <m, 2tt)« 2.91 { , 3H), 2,47 (d, - 4,3 Hz, 214), ! .S (d, - 10,6 Hz, 3H), 1,22 - 1.40 (m, 12M),

Folks irig the procedure ia Example 449. the fbllowiiig com ound was prepared:

47? Following the procedure in Example 467, the following compound was prepared:

Example ilSS

--(3-|fi;ej:h)T-lH-py

To a flask char ed with t-(3"({i--etbyl--l H:-py$82ol-5--yl)oy) -5-<{3- hyd! ixy(ydobitiylj!:n&i!)yi}p idln-2-^I}-3- -meiitylurea ί 120 g, 0,347 nunol was >:«kied De -t»actk perlodinane (192 mg, 0.452 mmd) and€¾(¾ {¾ mi). The reaction was stirred at RT for Ih and 20 fflln then quenched with saturated NaHCQs solution aarl e traced with EtOAc. The os¾anic layer was washed with brine, dried aver gSO* and conceittrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified, by chromatography through a Redi-Sep pre-packed silica, gel column ekting with, a gradient of 0 % to 10 % eOH in CBj£¾ to give l~{3-f(i-ethyWH- pyrazoi-5y*l)ox:y}-S»({3-oxo€Yd^^ (107 mg, 0,31.2 mmal, SO

% yseld). Mass spectrum (ESI) m/z - 34 J (M+H).

Following the procedure xn the preparation of i -(3*{(1-« ΜΗ -pyrazoI-S yl)oxy)-5-((3- oxocydobuts 1) methyl) pyridia- 2 -yl) -3-n¾t! iv cea, the folio* « cojftpot i!td was prepare j:

Example Structure Nan i _c _™ 1 Dai a Ϊ i-(3-(il-eihy ipyndin-3- 1 Mass spi :i itiiii: ]

1156 yljoxy}- s 1 i ' ESB fz -355.2 ! oxocy itbutylfri fi!hyl!pyrid

1,1 , 2·γί}·3·οκ » lltyhirea ¾■ j

Ex imple 1157

i--(3-(£2-eilivi pwidin- 3 · ylkory) · 5- (iS-hydrow■B-firifluoro.melhy evdohm Imeihvilgyridin -2-YIF3- A. flask was

ethylorea (47 rag, 0.133 mmoi) am! cooled to 0 * C. {Tr ]ttorom8t.hyi)tri«»>itiyMlatM; (0.098 mL,

0,663 ffijiio!) was added .followed by teSfab!«yii«n:taoaiai« fluoride, L0 M in THF (0.033 ml,, 0.033 mmoi), and the reaction was stirred for 20 a»o at 0 X. The reaction was warm to R ' F and stirred for 18 h. The reaction was eooW to 0 again, and additional (irtflaorBmethyl)trtwetbyfellaii¾ (0.098 ml,, OJ m»»ol and tebabutylasanosiam fluoride, 1 -0 M i« THF {0,033 ml., 0.033 tnmol) were added. Use reaction mixture was warmed to RT and stirred for 18 h. (Tniliioromeih¥l)ft1rned!yisiiase {0.098 oil., 0.6S3 mmoi), te»3.buiy!ara»io»k»« fluoride, 1,0 In THF (0.033 mL, 0.033 mmoi) and water (20.microliter) W¾fe added, and th reacdors mixture was stirred for 1 day. The crude material was purified by reverse-phase pfeparaiive H.PLC using 0.1% TFA in GH^C /N^O, gradient. 10 % to 14% yield). Mass spectrum (ES0 mfe - 425.2 (Mi-H). Ή MR (400 MM¾ M«OH»d4) 8 ρ ι .3δ (dd, j -170, 1.37 Hz, 1 H) 7.88 (d, i .76 1¾ i. H) 7.37 - 7,45 (nr. 1 Hj 7.25 - 7.38 fei, 1 H) 6.89 (d, jM .78 1¼ 1 H> 2.92 is, 3 H) 2,85 (d, 7.63 ife. 2 HI 2,68 (d, j-7.63 Hz, 2 H) 2.45 - 2,53 (m, 2 H) 2.20 (dt t S.14, 8.1? Hz, 1 ¾ 1.7? - 1.87 (m > H) J .23 - 1.29 (nr. S HS

Example 1 1 8

I -i'Ml I -e ( ί .TS? 3- hydro y-3

Sieo Λ: A flask was cbarged with i--(5-br «io-3-i{i-i»ibyi - H-pyra¾t>l-5--y.l).oxy)pyiidm---2-yi)-3.- methylurea (11.2 g, 32.9 mmoi) and. was azeotroped with toinene. THF (400snl..) was added. Cooled dtJW!i iti dry ice acetone bath. Then roeihylbthimrt {4.12 mL, 65,8 letnel) was added and fbe ..reaction was stirred for 8 min. Reaction changed to yellow. Then ba yi f um (15.80 ml., 39.5 msiol) was added dropwise while with vigorous stirring. After 30 win. ofaddltiOR>(k,3r)-3--(:Ciei1"

htiiyS. imeilwteiiy!}OKy} ^ g, 35.2 mmoi) la 5 l. of THF was added rapidly. The reaction was stirred at same bat temp for 2 nr 40min. and tite hath was removed. &&at Wmm. of stirrin at. ST, reaction, changed into a de r solution. The reaction was quenched th saturated N¾Ci and extracted with EtOAc, The EtOAc layer was dried and concentrated and the crude was purified by silica gel chmoi&iography o.u comMtlash with gradient EtOAc In Hexanes of 9»

(I ^S -C tert- utj

.f¾^l S" 1}o?¾')pyridi8- -yi}-3--o h laf > 8a as the «ta or <$mpenent.

5tq> B: A flask with (5-·({S}-{(i 3S)-3-((t ·but ldirøetby!sil i)oxy^ · ^

me&yieyefQbutyi)(nydro y)ffi

(14.0 g„ 28.5 ' mmdl) was added MeOH (200 inL),sneiha«esulionic acid 00 mL 154 mmoi). The reaction was purged ith % and stirred under a double-layer H ¾ balloon overnight. The reaeiioH was filtered through cetite. Then a , NaOH was added to ad ust the reaction pH to about 7. The reaction was concentrated to remove MeOH mi :te* EtOAe water was added. Extracted with EtOAc. The EtOAc layer was dried arid concentrated asd. the crude as purified by silica gel chromatography on. comb!rlash with gradient EtOAc in. Hexanes of G-70-%. then gradient MeOH in..DCM 2-8%, Mass spectrum HSi) mfz * 378.:! (M+Hi. ¾ NMR (400 MHz, MeOFM4) S pprn 7.83 - §.06 fm. 1 H) 7.46 {d, j-2. lS H¾. Ϊ H 7.33 (d, . ,76 !½. !. H) 5.78 id, j»L9S }¼ I H) 4,46 - 4. S2 (m. 1 H) 4.12 (¾, j-7,24 H¾ 2 H) 2.93 (br, s, 3 H) 2,5 ) - 2,50 (m, 1 H) 1,98 - 2.12 (pi, 2 H) 1.76 - 2 H) 1.39 {}:, j-7.24 ¾, 3 H) 1.28 (s, 3 H).

Example 1159

a¾eoir ped with toluene and purged wit nitrogen. THF (2,5 mL) was added, and the reaction was cooled to -7 'C. i M njethyUdMurn (0.297 ml, 0.475 tnrool) was added, and t e reaction sdxtore was stirred for Sruhmte. 1.8 M butyllubiuro (Q.I 78 ml,, 0.285 mmol) was added, and the mixture, was stirred .for 20 ntin followed by addition of cyciopropas ' ificarboxaidehyde (0.0 mL. 0.583 nuno!). The bath was naturally raised to RT and stirred over night. The reaction turned cloutl -reddish. The reaction was quenched with saturated ¾Ci soluti n and extracted with EtOAc. The organic layer was washed with brine, dried over MgS(¾ and concentrated in vacuo. The crude material was absorbed onto a plug of sOiea gel and purified by chromatograph through a Redi- Sep pre -packed silica gel. catena ekitir¾ with a gradient off) % to SO % BiOAc in cxanes then 2 % to 8 % MeOH in €!¾€?; to give l~(.¾-{cy opropyHhyd

med iuiea (30 J g, 0,091 sissoL 38.5 % yield). Mass spectrum (ESI) i ^ 329.2 ( *H). S H MMR (Me OH) & S.2S - 8.39 (m« 2H), 8.23 fd, - 2.5 ft?.. IM), 7.44 - 7,55 im, 1M).6,44 (s, I.H}, 4.40 (d, = 7,8 ¾ Hi), 2J5 - 2,90 31), 2.42 · (s, 3D), 1.27 · 1.46 ( , IB), .0.59 · 0,70 (sit IH), 0,45 - 0,50 2M).0,31 - 0.4S (Hi, if !).

Follo ing the procedure in Examle 1159. the following oompouads were prepared:

Exam le 1184

5 lr^

(100 g.0.230 :inm l}, 10 % Pd/C {73.5.«¾, 0,069 miaol), e&aiiesuHb«ic acid (0.6 mU 9 mmol), EfOH (3 nil.) a»d MeQH (3 mi) were cowksa&i to a pressure tabe. The ppessare ?y e was hydrogexwted under 45 ps< 18 h. ore rueOjanesuifbsSc acid (0.1 raL.1,5 mmol) and 10 % Fd/C (73,5 mg, 0.069 mn } we added, and the macHoe stb-ture as bydfogenated for another 2 K Later, reaction can be tan under a doable-layered hydroen baiJeo» in. a similar procedure as above ranging from Ki days, with the hydrogen balloon replaced with fresh ones daily. o need to apply high pressure. Hie reaction mixture was ' filtered through a pad of Celfte, neutralized with aqueous NaQB soludos to slightly basic mil oftcestrated. The product was partition between ErOAe and water. The organic layer was collected,, dried over gSO. } and concentrated to vacuo. T e crude material was absorbed onto a plug of silica gel arid purified by chromatography through a Redi-Sep- pre-packed silica get coluoin elating with. a gradient of 0 % to 18 % MeQB in Q¾{¾ to give i-{S- ({ 3 f„3r) -3¾dfoxyeyelo¾isSyi} -({5-methylpyridin--3-yl)oxy;} pyridi n- 2-yij ~3-inethy!«rfcis (59 m , 0.180 eta 78 % yield). Mass spedram (ESI) m¾ - 32S.2 (M+M). J H N ' MR (MeOH- } 8 8.27 - S (mt ( I.H), 8.19 (d, - 2.5 Hz, 111). 8.07 (s, 1H), 7.40 - 7,50 (m. 1H), 6.41 ( s> :ii-l), 4.15 - 4,33 (m, ΪΗ), 3.07 - 3.21 (m. ft!}, 2.83 (%, 3H), 2.66 - 2.79 (m, 2H), 2.41 <s, 3H), 138 - 2.1.7 {at, 2H)..

Followiag tfee procedure In Example 1164, the following compounds were prepared:

~y1)-3~m«!syi»fe ollo ing he procedure in Example 487. i¾e folfewitig compound was prepared;

Example Structure Name Daia

i,.i5.-CCI:s,3s}-S-(2- ydro.xyprapai 2- yi)£yr3obat I)-4-{(5"

meihylpyrit s-

Yl)oxy)pyTidit5-2-yl)-3-

rnedryiarea

Following the procedure ia Exam le 1019, the following com oun was prepared;

Example 117

$!¾ A: A flask as charged with 3- b u¾4o ykyc!obai !iOi5e (! ,00 g, 5.67 rnrooi) an MeOM (24 ml.}. Uix i (0,859 g, 22.70 mmol) was added, and t fi reaction was stirred for 1.5 h. I¾e reaction was queuched w!iii NS¾CI and cosceatmied. Use product was partitioned bet een water ajl EtOAc. The organic layer was collected, dried over MgS Xs and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel arid poriiied by chromatography through a ' Redi-Sep pce-packed silica gel column t give (9,882 , 4.95 Oimol, 87 % yield). ¾ NMR {MeOM-d4} S: 7.20■■ 7.39 {m, SHh 84 is. M} > 3.82 (t, 7,2 Hz, 01), 3.55 - 3, i {m, i.H), 2.64 (did, ~ 8.2, 6.5, £9 H¾ 2Hk 1.7? - 1,95 (m, HH). Sttp B: To a flask charged (72 sag, 4.06 mmo¾ was added C¾C¾ {25 mL), carbon tetrahromlo*. (3383 mg, 1 .14 laiaot) aad NEl¾ (1.30 raL, 9,3 nwaol). Then i¾% (2554 mg, 8.7$ mmoi} was added slowly. The rcac on mixture was stirred ¾ i h, The mixture was diluted with, o-pentane and then poured, into ice-ea!d NaHCO¾ solution, The organic phase was washed with rine, dried over g$<¾ and concentrated te vacua The crude material was absorbed onto a plug of sil ica gel arid purified by chromatography through a Redi-Sep pie-packed silica gel ml m elating with a gradient of 0 % to 25 % EtOAe Irs exanes to give ((3- hroo o?ydob«tox R}eAyl)be82*n¾ (906 mg, 3.76 5 H NMR. (CDC 8 7. -·

7,43 t, SH}, 4.46 - (m, 211), 4,43 (s, 2.58 - 2,84 (m, 4H}.

Step C: To a flask was added lithium cMor!de (139 rag, 3.28 n sdl), and the flask was dried under high vacuum at 155 *C for 30mi Theft zi c (236 mg, 3.60 mmoi) was added, and the flask was dried again tinder high vacams for 20 min ai 155 :i C. The l!ask was cooled do n to RT and anhydrous THF was added (6 ml) asder nitrogen followed by 1,2- dfeosaoeihane (0.0 4 ml, 0.164 tmnoi). 1 ' he fiask was heated to 65 with a beat: gun briefly and cooled do a and then ehforotrlarathylsilane (4.16 pi 0,033 mraol) was added. After s irriiig briefly, 5 drops of 1 solution, of iodine in THF was added. The reaction was slims! briefly arid ((3··

btx)mtK:ycioh«toxy}s»e 0b«tt2eRe (790 mg, 3,28 mmoi) is? THF (i ml) was added. T¾e teactioft mixture was heated to 50 degree and heated for 18 It to afford (3-(beii^lox ;iCTc!obutyi}zinc(il} bromide.

S e To a flask charged whir 1 -( roaio4-{^^

Pbos (58,0 mg, 0.082 mmcrt) and PdCdba}* (4.I..4 mg, O.072 tnmo!), The mtxtwe was purged wifis nitrogen under high vacnam. Degassed THF (4 rot) was added followed by (3- (benxyloxy)cyi:lobatyl}¾irse i} bromide (5,43 ml, 2.97 mxml) generated in the previous step. The reaction was heated to reflux for 19 h. Saturated N¾Ci was added and the reaction mixture was extracted with EtOAc. Tire EiOAc iayei was dried and concentrated mi purified with silica gel chromatography ( 0 - 7% MeOH/DCM gradient separation). The fractions contained the product was farther purified by reverse phase HPLC to afford 1 -(5 -((l.r.3r) -3- (bet¾¾do ty)eyeiobi«yi} -4 -((5- ffieriryipyndio-3-^ (40 g, 0.096 mmoi, 13 % yield}. Mass spectrum

(ESI) miz * 419,1 (M-i- i), Ή NMR (MeOH- } 58.3.1 (s. 11!}, 8.18 (s, IH), 8.13 (s, !M), 7,46 (s. IH). 7,20 - 7.40 (m, 55% 6.40 is. iH), 4,47 (s, 2M>, 4.29 (t. « 5.9 fix, IB), 3.81 (quia. - 13 ix, IH), 2.82 (s, 3ti}, 2.45 - 2.60 {m, 4H), 2,40 (s. 311}.

Example 1 i 73

l (5 f(lr,3 ^^ To A flask cteg«d with

3-me lurt>a {37 aig s 0.088 mai) was added MeOH (3 mL) and Pd/C (18.82 mg. 0.0! 8.mmoi). Th« flask was ur ed with, hydrogen and then stirred amies After 7 h, ¾SC> 4 (0.15 ail-) as added, a«d lbs reaction mixture was stirred for .18 h, ,. Th« reaction mixture was filtered through a pad of eelie, «eairalfe€d witii s m NaOH solution to slightly basic and concentrated lie crude malfc al w s purified by reverse -phase preparative MPLC using 0.1% If A in CI¾CN/HvO, gradient 1.0 % so 30 %, to provide l-CS-C lsJsi-S-hydroxyc ciohtiiyi) . •■ 4-{(5-meth lp>Tidit¾--3--yi)o rv pyridm-2-yl}-3-' oredsylnrea (9,3 t»g, 0.028 mm¾i 32 % yield). Mass spectrum (ESI) rate - 329.1 (M+H), ¾ i? (MsOH- ) δ 8.27 - 8.36 ( f Ui), 8. 19 (d. 2.5 Hz, 3H} 5 8.14 is, IH). 7.46 (s. 110, S. 0 (s, 3H), 4.38 - 4.50 (»i, IH), 3.71 - 3.89 {«ι,. ill), 2.82 (s. 3H), 2,49 - 2.60 (m t 211), 2.32 - 2.46 (m, 5H).

Example 1174

iJ¾hyi;3; ^

A ilask was charged with

y])-3-rnethyiiH¾a (100 mg, 0.305 m l) and Dess-Msstin (168 nig, 0.396 mmol). hen (¾¾ (? mi..} was added. l e reaction e aa ed inic* a clear sa!uiion. Sdrrisg was coisdnosd ior iife b at Rl , Theft saturated aHCC¾ solution was added aud the reaction was extracted with EtOAc. The EiOAc Saver was dried and concentrated id the crude was parff d by 14PLC revere phase, trs!srg 9.1% TP A. !n CH 3 GIM ¾0, gradient 10 % to 40 %, to provide 72 n¾ i ethyl H{5^ y^ ^tu^l}oxy S-{3"Oxocycloi>«^4)pyfMia-2-yl}«rea as a white solid, after basiciffcai!on ao<I extraction of the MPfX fractions. Mass spectrum (ESi) m>¾ = 327,0 (M ill). ¾ MR (400 MHz, MeOH) 8 ppm 8,34 (d t 1*098 Hz, t H) 8,25 (d, 1-2.54 f ix, 1 H) 8.19 (br, s,, 1 H) 7, S3 (U-4-66 Hz, i H) 6.43 - 8.50 (at, Ϊ H) 3,74 - 3.88 (in, i 14} 3,45 - 3.56 (ss, 2 H) 3.35 - 3.45 (is, 2 H 2.82 (s, 3 H) 2.4 (d : J-0.39 Kz, 3 MS.

Example 1175 i--(5-((lt A 3 )-3^

To a ilask charged

yl)«rea (53 mg, 0,102 u$ l) was added sodium baradetueiide (27.2 mg, 0.650 aimoi) srsd thai MeQH (2 ?«!.}. The reaciioft was stirred at I¾T lot 3 hr. Wafer was added followed Ijy extractioa vviih EtOAc The organic layer was concentrated -and par«3ed by reverse- hase preparative HPEC y sisg 0.1% TFA in C¾G\7H 2 0, gradient 10 % to 35 %, provide 30 m of 1 · (5 · {i!.r.3r}-3-4euterifti-3- hydroxytyciobuty]) -4--{{5- : n^ as a w ite solid * Mass spectrins (ESI) i« - 330.2 (M+H), ¾ NMR (400 MHz. MeOH-d.4) S ppm 8,31 (d, 1*0.98 Hz, I H) 8.19 (d, j=2.54 Mz, I H) 8. 8 (s, 3 H) 7.46 fs. ί H) 6.40 (s, 1 H) 3.13 {it, 3 ,¾ 7.65 1½, ί H) 2,83 fe, 3 l is 2.6? - 2.77 fin, 2 H) 2,4 ! k 3 I I; 1,99 - 2,12 fro, 2 H),

To a ' solution of ai 00% dispersion in mineral, oil fi .511 g, 37.8 mrnof) hi THF (11.0 mL) at 0 * C was added eth lene glycol ntonobenzy] ether {4.67 rnL, 32,9 mmo!} dropwis ever IS tain. The reaction inixuire was warmed to RT. After 2 h, propargy! bromide, 80% solution in toluene (3,54 L, 32,9 onnol.) was added dropwise and stirred lot IS h. The mixture was filtered and the sol ent was concentrated in vacuo. The ernde material was absorbed onto a plug of silica gel and. purified by chromatography through Redi-Sep pre-packed silica gel column to give ({2-¾>rop-2-yn-l- ytey)eihoxy)inethyi}benzetie (6.00 g, 31 ,5 ntmo 56 % yield). Hi NMR (400 MHz, CDC1 3 g 7,13 - 7.38 (5 H, is), 4.49 (2 Pi , s), 4.03 - ,19 (2 H, mi, 3,81. -3,7 ! {2 H, m), 3,51. - 3.61 (2 H, m) ,2.3S (I H, l. .Ι - 2.3 Η ·

Preparation

3 < 4-dihydfo-2H" 3yr¾aoi2 3-<:lpyridia--3" l Step A: A ' mixture of 3,5~di n¾no- -p ti.dinecark i-a1deliyd8 (S.O g < i 9 mmol} arid (c¾¼t Qxya½lhyl^e) hen lj l>os iK>.f»oe (6.90 g, 39.8 mmol) in chlorolbrm (45.0 ml.) was stirred at RT for lb then heated at 60 °G for IB h. The reaction mixture was wseetdraied in vacuo. The reaction mixture was concentrated in vacuo, The crude material was absorbed onto a plug of silica gel and purified fey drntniatpgrttphy through a Redi-Sep re-packed siliea gel cohnan, eiuiing with 10 % to 90 % EtOAc to hexaaes, io -afford (E^eihyi 3"{S.S--dtei«opyridin-4-yl}.acrytete (6.3 g> 18 fflinol. 100 % yield). ¾ NMR (400 MHz,€D€¾ & 8,88 {2 11 s) < 7,58 (I II d, j-16.2 Hz), δ.56 (I ft d, j-16.4 HxS .4.32 (2 H, ¾ J=?,0 Ha), .3? 0 H > t Hzj.

Step B: To a soluiion .of (B}-eihyl 3- ,5^Ι^οκ{ρρ Ύ¾¾ο- -νΙ).»θΓ 'ΐ3¾? ί8.¾, 18.81 rnrnoi) IK .BOB 00.0 mi.) was added aB¾ (1.92:! g, 50.8 mmei} at -18 °C. The mixture was stirred at RT for D$ then at 50 !, C for 7 Is. After cooling to RT, glacial HO Ac was added, then the mixture was concentrated iu. vacuo. The residue was dissolved in EtGAc and washed with 1,0 M aqueous HQ. solution, NaHC ¾ and. brine. The organic layer was dried over MgSO,^ filtered and concentrated in vacuo. The crude ojat.er.iai was absorbed onto a plug of silica gel and purified by c romatograph tiaXAigh a Eedi- Sep pre-packed silica get column to afford 3· {3,S-dihro:;nopyfi.diji) -4-yl}propa«- 1 ϊ (5.(1 g, 17 mraoi, 90 % yield), ¾ NMR ( 00 MHz, CDC¾ 8 8.58 (2 M. s) , 3.78 {2 hi. i. 8.3 i½) ( 3.01. 3,1? (2 !i ml 1.79 -1.94 (2 H, ml

Step C: To a solution of 3-(3,5~dllM¾m0p idis^ - |}pjtipair-l -oi (2.5 g, 8,48 tmml) la DME (20 odd was added copper (1) chloride (0.084 g, 0.848 awsoiL 2-anii«opyridi«e (0.080 g, 0,848 m\), and sodium ono ide, 25 wt % solution is MeOH (2.75 g. 12,7 imaoi). The reaction mixture was heated ai 70 " C for 18 is. The reaction was quenched with saturated aqueous HaHC0 3 . (30 ttvL), extracted with ElOAe C:i 20 mL and 60 mL)., The othined organic layers were dried over gSQ.*, f lltered and concentrated la vacao. The crude material was absorbed onto a pl«g of silica gel. and purified by chromatogra hy through a. Redi-Sep pre-packed silica gel column, eliding with a gradient o 10 % to 90 % BtOAc .in hexaues, to provide 5¾o?«0:-3.4Hlihydro--2H- ; pyraHo{ ' 2 > 3--c.lpyddi«e (1,2 g, 5 , 6-1 mmol m % yield). ¾ HMR (400 lfc, CDC¾} δ 8,24 (1 L s), 8.00 (1 ¾ s . 4.15 - 4,29 (2 if...m), 2.76 (2 il i. j -δ.β B¾ ; ! .9h - 2.15 (2 H, m;

Step D: A glass micro wave reaction vessel was charged with 5-biOnio-3,4-dihydr&-2H-pyrat. 2,3- clpyffdiae (0,2 g, 0.93 iranol), N.N ! -<li«ie 'te lem¾lis«rfw « (0,050 mL, 0,467 HUBS! , C«l (0,018 g, 0.093 itJitiol) and anhydrous poiassium phospisai (0.1S8 g. 0,934 n;u¾oi) in water (2.0 mL). The reacdosi: mixture was stirred and heated at 180 * C for 30 min. The mixture was sseufrailxed with 1.0 M aqueous HCI solution to pH 5 - 7, diluted wit water, exdacied with BtOAc (2s30 t«L) a«d dried ever 2S >4. The sohnion was filtered and coiseentrated In vacuo to give 3.,4-dihydro-2H.- pyi ' ano[2.3~e]pyridin:"5-oi (80.0 ing, 0.529 minol, 56.6 % yield). Mass specti ' tsra (ESi) ia ¾ = 152.1 Pre ation

To a mixtare of 2··ρ*χ¾¾ίκ··1··βί (4.4 g, 75 mmol) and ethyl, diazeacetate (3,44 mL 52,8 mmol} was added Indium (in) chloride (1.745 g, 7,89 rnmoi) at 0 X, The rcsuitiag mixture was stirred at RT for 40 mta. The reaction was trenched with water (40 mL) and extracted with EtOAc (80 mL ami 20 «$L}. The combined organic layer was washed with brine (30 mil dried over MgSi>4, filtered and concentrated ia vacuo, lite crude -material was absorbed ortto a plug of silica gel and purified b chromatography through a RetU-S p pre-packed silica gel eo!utnts, elating with gradient 10 % to SO % EtOAc in hexaws, to give eihyl (3.S9 g, 27.4 rnvml, 52,0 % yield),

¾ NMR (400 MHz, CDCg S 4,30 (2 HA, j»2,3 Hz), 4.22 (2 H, q, j-7.0 Hz), 4, 18 (2 14, s), 2,47 fl i t. t, js , H,:L 1.28 (3 li†, J 7. i iix).

following; the proeedure above, the foliowiag compounds

Following the procedure in. Example 1317, the following compounds were prepared:

PreparatSors

To a soklioii of ethyl 2-(prop-2-y¾- Lyloxyjacetate (1.78 g, 12,52 rfisiol) in IMF (20 ml,) was added meftiyiroagfiesKJffi bromide. 1.4 M soiutto la toiuerte/THF (75:25) ( M mL. 27,5 mw>% at 0 * C The reaction rrdxtare as stirred at: RT for l.h. then qu n hed with MeOH (2,0 mL), The srixtare was diluted with wafe (SO ml,} and extracted whh EtOAc (2 s 50 mL). The Combined organic layer was dried over gSC¾, -filtered and eorteet)tt¾ted id vacuo to give 2-m^hy|-l~{p.rop-2- ^l.ytoxy) fopan- 2~ρϊ (! .58 g, 1 .2 m al 97 % yield). ¾ M1 (400 Hz, CDCXd & 4.21 (2 hi, tl J=2.3 Hz), 3.37 (2 R s}, 2. Ι (1 R s), 2.22 (I R $), I .23 (6 H. s

.Preparation

To a sohaloR of a ' HL 60% dispersion n mineral oil (1.427 g< 35.7 rmoe!) and te -N- buiy!3iO iOHii»« iodide (0. 32 g, 0.357.tniaol io THF (50.0 ml), was slowly a<k$ed 3-bu yfl"2-ol (2.30.oil., 35.7 ssiiiol) io THF (5.0 aiL) at: 0 = C, Tfee lesuiiiog mixture was stirred at ET for 30 roio, then b i bromide, 88% (4.36 rot * 35,7 iaa ot) in THf (5.0 «tQ was added. Tie resulting react on mJxtefe was stirred at RT for 18 h. The reaction mixture was filtered, The filtrate was washed wills brine (2 x 20 mL), dried over MgS<¾, and concentrated U\ vacuo to give (0)α(-3· ¾-2··

yloxy aettiyllheftjteae (5.65 g, 35.5 tunisl. 99 % yield), ¾ NMR (400 MHz, CDCy 3 7. to - 7.33 (6 H, m}, 4.7Ϊ (I. H, d, JkU .7 Hz), 4.42 (I. M, d, J- 0 ,5 Hz), 4.12 (1 :H, dd, 1=0.7, 2.0 Hz), 2.37 (i H, d j-2,2 !½) « 1.3S (4 H. d, J-S.7 Hx).

Following she procedure above, me following compounds were prepared:

Srradure f ame

-O.

' 3- ei.hox.vbtst -l~y

Example 1 176

To a solution of i -{H3-{l»a^½xy}^

tnethytea (0,20 g, 0,48 mrnot) in hi MeOHSokeae (30 mh) was added rhodium. 5 wt. % on carbon (0.049 g. 0.0-18 ml). The readies raSxttste » evacuated a d bac MM ttfe hydrogen three times. After stirring ¾i ,RT «nder yd ops, atmosphere far 1:8 h. the mixture was filtered and the fltoe was concentrated m vacuo. The residue was purified by reverse-phase preparative HPLC using 0,1% TFA CH 3 CM/¾0 to provide {∑>-! - (ST3- (be ylo yikit- l-e«-l-y])- -({5- mei ylp S«-3^}aK ')pyiidiR-2-y¾ "mei krei¾ (0.125 g, 0.299 mmol 62.2 % yield). Mass spectrins (ESi) iz - 419.1 (M+H) . H i MMR (400 MI¾, CDCU ό 8,52 (1 H. s) 1 8.41 (1 B, d, j-2.3 Hz), 7.80 ( i IT br, s.), 7.51 (IH. s), 7.20 - 7.42 (8 H, rn), 6.47 (1 H, d ( J~l L? Hz), 6.02 (1 11, dd, J«I ί J. 8.4 i¾, 4.47 (2 s). 4.27 (1 H, ddd, J=8-.3, 8.3, 0.9 Hz). 2.84 (3 H, d, Hz), 2.54 {3 H. s), 1.43 O H, d. j 3 ¾}.

To a solatioB of 1 - (5- (3 - {ben¾ lox Iprop - J -yn- i ~yl) - - ({5 - met y tpyridi o~ 3-yQ oxy)pyrkUn-2 - I) -3- meffeyteea (114.0 tag, 0.283 mmiil) In M.&OR (25 mi) was added LiBdkr catalyst, pail¾d.l«tR OH cakim» carbonate lead poi oried, (80,3 mg t 0.028 mmtij. e reaction, fiiixiare was evaeaated arid backfilled wftir hydfogea three tbses. After sikrkg at ' RT midst hydrogen airnosphere for 18 k, the mixte was filtered and the filtrate was concentrated n vacuo. The residue was purified by reverse- phase preparative HPLC using 0.1% TFA m C1¾CN/M;.0 to provide (Z) -i -(5- (3· (tesyioxylprop- i · en -yl)- -((5 -r«e J:pyr^ (70.0 mg, 0.173 imsiol, 61.1 % yield). Mass spectostn (ESI) toft - 405.2 (M+H). ¾ MR. (40 MHz, CDCld 88,50 (1 11. s), 8.3! 8.42 (1 H, ra), 7.87 (I R s), 7.47 (1 H < s), 7.30 - 7.44 (6 H, m), 6.62 il H, d, J- i 1,5 Has), 6.24 (3 11. d, J*l 1.5 .4.5? (2 H, 8), 4.14 (2 H, dd 6,8, hi Hz), 2.84 (3 H, d. J -4.7 Hz), 2.49 (3 H, s).

Following the procedure in Example i?0, the f lfowiisg compounds were prepared:

Exasiipie Structure arue Data

m

methykjFea

By essesiiailly k> i«g the proesdyre hi Example 170 and Example 250, the foliawisi com aiiiHi

Following She procedure in..Example 251 , ih Mfomag scmpoiittik were prepared;

ea

\ ¾. . j met yhir (Mi-ill. j

Exam le. I 6

cydopentea-l-oae (1.491 «VI., 17.80 aano!), NaHC(¼ (0.602 ml, 17.80 tmxid) and Pd{PPJ5 ; ;)¾:i¾ (6,208 g « 0.297 mmo ) were corabissd i« I-.me†isy^2-pymilkiin»iK> (20 rnL) under a stream of JSU'o gH, The resuhiag mixture was seated and stitml at 130 °C for 18 h. The reaction mixture- was cooled So ΈΤ aad filtered through a pad of et > St¾ and .rinsed will! EtQAc. The filtrate was coneeatrated. The mirie. material was abs rbed oafo a lug of silica gel a d purified fey

chromatography through a RedkSep pre-packed silica gel column (300 g), elutirsg with a gradient of 0 % io 10 % MftOH ia (¾£¾, to provide l··R» l·S··{ ··({5··meίh l yrtdifl!·3·ylK^x )··5··(3· oxeeyelopeat- i -yi}pyrid i-2- : yI}iirea (2,007 g, 1.788 mme!, 30.1 % yield) , Mass spgetram (ESI) ra/z - 339,0 ( ,s-e). ¾ NMR (CDi¾ δ 9,48 is, 1H), 9,08 (hr. s.. IH), 8.38 - 8,49 ¼ 2H), 8.29 (d t - 2.5 H¾ H ): 7.29 & !H), 6.88 it, - 1.5 Hz, tH), 6.17 (s, ill), 3.13 (dd, = 5.1. 3.Ϊ I¼ 2-H), 2.78 (d, « 4,7 H¾, 3i!k 2.51 ■■ 2,61 im, 211).- 2.41 ik 3H). :

S03

Example 1 68

Step A; To a solotiaa of 3 » oxO"l.-cyd.opentaoe :afboxyl c acid (5,9 g, 46.0 a¾noi) in aahydrous eOH 46.0 SJL5 was added thlonyl chloride ti 6-79 m ' L, 230 marol) a opwi¼ at 0 *€. The resulting mixture was stirre at 0 * € for 8 then at T for 18 h. The mixture was concentrated,. The crude .material was absorbed orsto a plug of silica gel aad purified by chromatography tflroagh a Kedi-Sep pre-packed silica gei cahuaa (300 g), ehiting with a. giadieat of0 to 100 % EtOAe ' hemn s, to provide methyl S-oxoeyeio erdanecarboxytote (4.02 g, 28.3 mmca\ 61.4 % yield),

Step B: To a solution of djisopropyiaiafae (5.49 tat, 39.1 mm&l) la 80 ml, of TH ' was added b«tyllflhi«8s solution, 2,0M fa pentam? (19,57 ηύ } 39,1 aimol) at -78 °C dnypwise over a period of 20 mm, The resulting nrixtare was stirred for 3ft rain while gradually wanted to RT. The mixture was

cooled to -78 °C agaia and a sal ifoa of Hieihyl 3-oxocyck>pefitaaeearbt>xyiate (3.71 g, 26.1 «¾»ol) its

THF {20 mL) was added. The resulting mixture was stirred at -78 °€ for 30 min before N -phenyl bls- tilfiaofomethaoe solfcafcnlde (13.89 sr. 39.1 mmol) was added. The resultis:r¾ mixture was stirred for 18 a while gradually wanned to RT. The iiii tate was dilated with 600 mt of EtOAe, washed with water, saturated aqueous aliCOs soktioa, brine respectively. The orgaak layer was collected, dried (atshydrous NasSCld sod concentrated. The residue was purified by chromatogra hy through a Redi- Sep re-packed silica gel column (330 g), eliding with a gradient of 0 % t 100 % ErOAc in hesaees. to provide a mistum of methyl 3- {{(ifilluorom i^ ^

methyl 3-(({trifi«oromedw1)s«l&^^^ (4.11 g, IS.O iarool, 57,4 % yfetd).

Step C: To a mixture of

methyl 3~{({tnflaoromethy^^ (:1S4 rag, 0.599 tmml) in L4- diaxaiie (3 mL) was added i -( "(2.6"<Uft«omp¾«rxs-y}--f)- (4 A<¾-teimnet ! ,3,2~djoxaborotejv2- yl}pyrjdin-2-y )-3--methyI«fe8 (I21m , 0.289 rnmol). !¾(PPh 3 ),s (35 rag, 0.030 atarol) and potassium carbonate f 124 atg, 0,898 mmol) . The reaction tixte was stirred at 0"C for 18 h, cooled to RT. filtered through a pad of eel e and dosed with BtO&c. The filtrate was cortcemrated in vacuo. The residue was purified by reverse-phase preparativ HPLC using 0.1% TFA in CI¾CN/¾0, gradieot 5% to 95% aver 25 mln HPLC io give a mixture of ethyl S- a- i .e-diauos'ophenosyl ^-fS- me lafeido)phenyl}cyciopei¾†-3-e«ecarboxyisle arid methyl 3-{2-(2,S-diflaofopheni¾?y)-4-(3- i«ed5y}uie }phenyi)cydopeirt-ii--eiiecar oxylaie (22.3 rag, 0.0554 mmol}. Mass spe trum ESI (pes.) /z ·.·. 404,0 (\! > H;.

eoecarboxy.iate aod methyl T (2--(2,6--dii¾«)ropnenoxyM

eoeeartoxyiate (0.0223 g, 0.0554 mmol} m THF (2.0 mL) was added diist) «ty taniri«t.a hydride

({!, Ι.βΓϊ rat. 0.166 ramoi) dropwise at 0 °C. The raixfare was stirred at "C for 3 is. Additional diisobutyMtmnoum hydride (0.186 mL. 0,1.86 m«>oi) was added, aud the reaction mixture was stirred for I. h. iijCi an S 5 rat of saturated ®$wms Roeiieli ' s salt solution were added. The resuhtttg mixture was extracted with EtOAc (20 mL x 4). The coiabined extracts were dried with aehydrous soditim stdfate and caoceatratedlo give a m xture -of 0 •• (3-(2 < 6-di0ttorophe«oxy)-4-{3- {hydrfixyn¾ethyi).tyclopent- i -en- l.-y] pheay])-3-raeihyl«rea ami i-(3 » (2«6 » difi«oa>i>h««©xy) -i4- (hydmxymethyikytloper t- 1 -en- i"yi)phenyl)-3-f«ethyIut¾t} ^uanU& ivei . Mass spectrum (ESI) mfe - 37(10 (M+H|.

Sicp E: To a mh of (L(3-(2,0- ilko^

yDpheftyl) -S-methylurea and M3-(2,6-dffluoroi>k > ^

yi)pbeoyl)-3-methylu:rea (0.024 g. 0.064 mmol)) to THF (<L5.mL) was added palladima hydroxide 20% n afDoK (4.41 .rag, 0.28 parol). The reaction mi tu e was stirred under % at RT fo I 8 b. HOAc (0,060 i»L : 1,048 mmol) was added, aod the mixture was stirred at RT artder ¾for 3 days. The mixture was filtered through a pad of CeMte and concentrated. The residue was purified by reverse-phase preparative -HPLC using 0.1% TFA m (¾C /H 2 0, gradient 5% to 95% over 25.mm to give i- (3- (2,6-d!fioaropheoosy 1- A - (3^y^roxytnethyl) ycIopeHty.i phenyl} -3 -med lurea. (15.8 ra , 0.042 miaoL 68 % yield}. Mass spectrin (ESI) k - 378.Ϊ (M iH). Following the procedure in Example 170, the following compounds were prepared::

Example ί 98

Step A: To a mixture of ceixras chloride bfpiah ara e φΜ4 g. 2,211 itnsol) and

MeOH (11 i«L) was slowly added MaB¾ {0.019 mi, 0.553 mmti} at RT and stirred for 1.5 b. The reaeifofi was quenched w tii Ice and cowxmtraied. The residue was chrcsnaiography ifcough a Redf Sep pre-packed silica gel olnrao (1.2 g), eiudsg with a gradient of 0 % to 10 % MeOH to C¾C¾« to provide

ffiethylurea (71 mg > 0.21 mol 38 % yield). ass spectrum (ESI) w'z ~ 3 1.0 (M H).

Step B: To a sokiii o of I · (5-'(3 -hydraxyeycfopeat- i-«o-l-yl}-4-{{S-:flje tpyridlo--3-y0oxy)pyfkHn- 2~yi}-3-iBethyUirea (0.071 g, 0.21 xw l) in T.HF (2 roL) was added paiiadiaei hydroxide oa carbon (0,028 g, 0,042 pfisol . The resulting sreaetlon mixture was stirred under an atmosphere of hydrogen for 3 days. The reaciiors mixture was filtered ihrough a pad of c ite, rinsed wlt!t MeOH a»d concentrated its vacuo. The residue was purilled by reverse-phase preparative HPLC sing Q, 1 % TFA in Ci¾C!¾¾0, gradient 5% to 95% over 25 mm to i e 1 -f S- C3-hydroxy¾yclapeiHyl)-4 - «5· tm lpy^din-3- 1)o^}pyrfdin-2-yl)-3-m¾Ayi«reii (0.0065 g, 0.019 moi, 0.1 % yield). Mass spectmrs (ESt) ok =* 343,0 (M-t-H). lite isomers were first separated by s spercrtol fluid chroniatography (250 mm x 30 mm Lux-2 column with 28 g/mm MeOH (20 t«M i ·> 52 g min CO?}, t½n the ra e ic material was separated by supercritical fluid ckomatography (250 mm x 21 mm AD-H column with. 17 g i EtOH (20 raM N¾ * 51 g/mm COv).

The following compounds were also obtained from the above prep (example 1299 was obtained as

a by-product from sa d procedure):

Example Structure ame Data

Mass l"(5-cydopentyl-4-((5- spectrum

1299 rnefh)d!pyddlii-3- iESn m/¾ - yl)oxy pyr d?«-2-yl) -3- metiiylprea mm

PoHowmg {lie j»ocd« in Example 1135. the following cooipm ds were prepared: Example ISO?

To a seiufsoi of l- e^^

(0.084 g, CM §8 ssiiioi) !ft aniiydrmis THF (10.0 mi, 2 m sii) was added

bromide 3.0M In diethyl et er (Q.188 mL.0-58 n ol) dmpwlse at 0 °C, The ies ifing mixture was stirred at 0 °C far 1 h. Additional .n h foragnesat btomkfe 3.0M: ia diethyl ether (0,188 m ' L.0.56 tnmdl) was added, sad tlie reaction mi ture was stirred a! 0 ! -'€ for I h, More methylasgaesaim bromide 3 J)M in diethyl ether {0.188 mi, 0,564 mmol} was added, and the resulting mMfore was sikred. for additional 1 h. The reaction mixture was qaeached With eO aad conceatratsd. The residiti? was tmnuAo faphy tliroagb a Redi$e.p ie-p cked silica get cotemB (24 gj, efatiag wilts a radien of t % to 1.0 % e(3H m GH 2 Ci, then re-purified by :rev¾fs€- : p ase prepaiatrve HPLC using 0. J. T A in€I¾CN/¾0. gradient 5% to 95% to give .-(5--(cis ½drow-3^et kydopent'J)t-4~ {(5-»^ethy{ yrfdiπ-3- ¾ox }p rfdlι 2- Γ 3· : tt>e 4røea (0.0061 g, 0.0.1? nuwil, 9,10 % yield}. Mass specimm (ESI) jti/z∞ 357.2 (MJ-H). The rae mk: maeial was separated by supercritical Raid chrosttaiograp!sy (250 mm x 21 am 0 -H ceh n with 6 e EtOH (20 $»M H») + 34 g/«tln CO¾)<

The following ompounds were also obtained from the above prep:

Preparation

Step A:: A roxtute of tri.p &«ylpk>sphlne (0,976 g, 3.72 :f»mol} > diisopropyf aodicarboxylate {0.752 g, 3.72 m ' ol) .and 4%tao-2-¼ fa -M^g-hydmx t'tii lj-M^n ili ibt'n^aiirid {{5,880 g, 2.481 ffliuol) to THF { 138 nit.) was stirred at RT for 1.8 h. The njlxtare was eoncea&ated a«d SO oiL of 2.M aqueous HQ solution was added to the residue. The resulting mixture was extracted wltis EtO c {80 mi x 3). The pooled extracts were washed with water, aqueous saturated aHC0¾ solution and oriae respectively, dried (Na 2 S(¾} and couceulrate f The residue was chromatography through a Redi-Sep pre-packed silica gel column {48 g), eiisting with a gra i nt of 1 % to 100 % EtOAc in hexahes, to provide 8- rom " -mgihyi-3,4"dih.ydrobenKoff] [i ,4l xa2eptn-5f2H)-one (0.276 g, LOTS mntrol, 43.4 % yield) . Mass spectrum {ESI} nv'z - 258,1 {M-rMV.

Ste B: A mixture of 8-¾»Omo- -tnethyl-3,4-dihydix}l>en«o[i] | . iJ]ox3zepis-§{2H)--one (0.276 g, 1,078 mt«ol t Pd(d¾>f)¾Ci ? (0.088 g, 0.108 mmd} < bis.(piaacolato}dlboma (0.54? g : 2,155 tamoD and KOAe (0,31? g, 3,23 mm<$ in 1,4-di xaae (10 j«L) was -sparged with nitrogen for 5 mm before the reaction was sealed and heated to §0 f for S h. The ioixtisrfe was cooled to RT. filtered and rinsed with EtOAc The filtrate was coventrated. The residue was efaoiuaiogra by fejugfi a Redi- Sep prepacked siiiea gel column {40 gjL ©luting with a gradient of ! % to 00 % EtOAc in hexanes, to give 4- methyl -8-{L , 5, 5 - tetr oMliy :f -L ,2 - -dioxaboroiat- i-2- l)-^ -di ydK>beiz [. |i ox ?,e ii^S{2M}-oiie (0. g, 0.650 mrnol, 60.3 % yield). Ή MR (CDCy & ?.78 {d, - 7,6 Hz, I H) , 7.5? {dd, - 7,6, 1.0 fk, HI), 7.3? - 7.51 (in, .! f j, 4.3? (t, » 5.2 ¾ 2M), 3.48 (t, - 5.2 ¾ 2H), 3.21 (s. 3H), 1 ,3-4 (s, Ϊ2Η .

Preparation

■Step A; To a solution of 2 ,5 ir me ¾e{!¾hydrof«r<8i-3-Q t> (2.160 i»L, :1 .07 mtnof) hi THF (70.3 ssL, 14,0? rnmot} was added IDA, 2.0M solute n heptase THF/ethyibesizeBe (10,55 siL< 21 ,10 mmoi) at -78 °C, The mixture was stirred for 1 h before n- p eriyi hsM.rifl«oro.o¾thane sulfoulmide (7.54 g, 21,10 mrnol) was added. h restsifo g mixture was stirred lor 18 h while gradually warmed to R ' T, The mixture was diluted with 200 ra ' L of EtOAc and washed with water, saturated aqueous Naf!Ct¾ and brine, dried {f¾SO-ij and eoacsnfcrated. The residue was chromatography through a Redi--$ep pie-packed sifica gel coluoto { 120 g), eludeg with a gradient of 0 % to .30 % EtOAc in hexaoes.. to give E^^ -teteu hyPS J-diiwdroiaraa-S-yl

tfiftuomtwethat u!foaate (0,628 g, 2.29 mrnol 16,2 % yield).

Step B; A mixture of Pd(dppl)?Cls (0, 187 g. 0,229 SUKOIT s{plaaco!ato)diboron {0.756 g, 2,98 ηηοβί), KOAe (0.787 g. 8,01. nnnoi) and 2,2,5,5- mmethyi-2,5--dibydrofur88--3--yl

tri-fluorotnethanesulftmate (0.628 g, 2.29 nnno!) in i.4-dloxaoe {! l t«L) was sparged with nifoogen far

5 tnin before the reaction was sealed asd heate to 90 e C fo 18 L The ' fnixtnre was cooled to S¾T, filtered aod raised with EtOAc, The filtrate was .concentrated. The residue was chromatography through a Redi -Sep pre-packed slltea gel co mn (80 g), eiuting with a radient of 0 % to 80 % Eli c n ke s, to give 4,4,5,5-terraffieShyl -2- ^

dioxaborolane {0,386 g. US mmol, 63,4 % yield}. ¾ NMR (CDC¾ 86.2S (s, I H), 1 ,3? is, SH). i .3: (s. SH), L28 Cs, :s¾i).

Example 1317

( vd foxymtJtbvOcvclote- Hd{n-S-vl}ox?}oYriditt

l¾ ihyS¾i¾a

To a solution of edwl 4-{i- (5- siet yl^

hydride. L0 TI-IF (2.050 ml. 2.050 mm<M »t 0 °C The resulting j»ixt«re ax stirred at 0 ft C for 30 mitt then queaehed with saturated aqueous NsHCC¾ solution. The mixture ' as iltered through a pad of celite, aod rinsed with BtOAc. The flltxate was concentrated. The residae was chromatography through a Redi-Sep pre-packed silica gei column (40 g), eluthig with a gradient of I % to 16 % MeOH Ϊ» C¾(¾, to provide

yi}oxy)pyfidln-2-y!) -3-inetl;!yiari i a (0.302 g, 0.820 -maol 60.0 % yield}. Mass spectr nft (ESi) m'z ~ 378.1 (M÷FI). ¾ NMR (CDCi-0 S 9.08 (½'. s., iH), 829 is, IH}. 8.22 (d, - 2.5 ¾ S B), 7.95 {s, ΪΗ}, ? J 2 - 7.22 (fct : ill}, 6. ί 2 (s, i.H), 5.74 - 5,9(3 (ra. 114), 5,30 (s, 1 H), 3.44 - 3.66 ¼ 214}, 2J4 (4 - 4,7 3Si), 2.39 (or. s, 2f ), 2.36 (s, 3Hj, 2,30 (ύ, - 17,0 Hz, IH), 1.88 (m. 211), 1.29 - 1.48 (in, IH}, The raceralc ruatensl was separated by supercritical fluid dtromatogfaplty {250 mm x 21 mm Lax- 2 column with 2! g/0H« MeOH (20 mM Η^··*· 40 ίύη C0 2 },

Following e procedure i« Example 13!?, the following compounds were prepared

(Examples 1.323 and 1324 were obtained as by-products from said pTocedu.re) :

Λ metylure a

Example 1,3 5

rae k«ea I-{5"(4-( ydfQs msii S)c dopeni- l-e« ~y.i}-4"({5-me?hoxy^

2-yi)-3-msifey]ta¾a (1:1)

Step A; An argon- degassed mixture of l--( ¾Oino-3-%om hesiyl}--3-:OX!tii laj¾a ' {2.5.0 g, 10.12 UHOOI), b¾(pinaci)la¾s)dlboroft (3:85 g, 15.18 ninioi), J OAc (2.98 , 30.4 nmid} and Pd{dp»¾¾ (0.413 g. LS06 mmoi} in SO mL of dioxane was stirred at 9(fC for 18 b. Tlte raxifure was then cooled to ri and diluted with 200 mL of EtOAc, The resulting mixture was washed wttb SO ssL of saturated aqueous ¾Q solution, water and brine, dried ( a :i SO.i) and concentrated. The residue was purified fey ComMF!ash on & 125g silica gel col mn to gi e 1.18 g of 1 -(3 -fitioro-4- {^dS-tetmmet l-JJ^- dioxa rola«^-yl)piiejsyl)--3-»eth l«rea. l H MR (CDC 80,63 (s, 1H), 9.24 (s, lH) f 8.49 (d. =* 8.0 Hz, IM), 8.82 <d. - 12.0 Hz. IM}, 2.S8 {d. *4.0Hz, 3H) sod .1.37 {s, 12H).

StepB: A. nitrogen degassed mixture of J - (3¾ΙΜΚ·4- {4,4,5,5-tetra>neihyl-5 ^...i-diosa orQiau-Z" yi}phe!wi)-3- ioe11syi8i« (1

3 -eiieearhoxylate methyl

fflg, 1.02 nauoi), otassia!o carbofiate (141 -mg, 1.02 οίθϊοΐ), Pd(PPh s ) . i (39 rsg, 9.934 nunol), water (200mL) and dioxane (1.7 ml.) was siisrred at 8δ"0 for 18 h. Th mixture was then cooled to tt and dir diy sub ected to HPLC purification to gi ve 40 rug of a mixture of utethyl 3-(2-fl«oro-4-{3- mefS:¾ylureido}phefiyl}t:y lope«f~2--eoef:ai:toxyi e aaeChyl 3-(2-i1tioro-4 ~(3- inethyhireido) pheoy l)ey opent~3KH&>car boxylate ( : 1) . Mass spectrum (ESI) mfz ·« 294.0 (M * 11} . Ste C: A .mixture ' of a ixtore of methyl 3-(2-fiu m-4-.(3-n^ lufedo)olm{ l} ?cte ent-2- ¾necar¾ox>'late methyl 3--( --i1aor -4-0-^ :!::!} .{4.1 tog.0.14 mmoi), S-meihox -p ri ii S-ol {25 rog, 0.21 mraol) and oesiam carbonate (69 mg.0,210} in 1.5 ml- of l-meth?!-2-pyrrolidindH£ was stirred at 85*C for 24 h. The tnixture was then cooled to ri &ηά. directly sub- ected to.RP-B.PLC purification to give 1 Llmgof a mixture of methyl 3-|2-.((a- e oxypyridin-3-yi)oxVH oieb l 3-(2--{(5- methoxypyndia--3-yS)t^ fl:l). Mass spectrin* (ESi) miz 390.1 (kf+ίί).

Step D; To a solution of a mixture .of methyl 3--f4--((S--ffiet 8sy;pyridisv-3-yS}oxy}-6--(3- o h ka¾ldo} ddin-3-y0^ mi (methyl 3 » (4 » ((5-inef.l»5Q¾s ridio--3- (1; 1} (il.00.mg > Ο.ϋϊ. mm»i)| is te»¾hydrof«f8« { anhydrous {2.0 mL, 24.66 mrstol} was dmpwise added diisob«iylai i«m«m hydride

1,0m solution Is) hexane (Q.083 mi, 0.083 rami) at 6°C. The resulting mixture was stirred at C for Ϊ k and ihe« was quenched wth MfcOH. The fixure was directly su ected to WLC purification to lv« 8.2 jttg-ofa mixture of I~(5^3 liydmx -ffiethy13tydopei«--i-8-«- l-y) -4-({$-

Example 136

Step A: Argon was bubblieg ikxiagh a mbeture of1.4S »ftim>- --(-{5 ' imHh l^ndl«-3->d}aypyddin-

2- i)-3-.05eA>½rea (0.200 g : 0.593 mrael), 2--»!ly.iethyl. akoltol (0.306 ml, 2.9? mmol) : Pd(PFh :5 C ' ¾ (0.042 g, 0.059 mmoi) and MaMCGs (0.069 mi, I..7S0 mmoi) In :i-m«ti¾yl -2-pyiToIidteoi¾ (2.0? mi,

0.503 mmol) for 3 min before it was sealed and stirred at i30°C overnight T¾e mixture was cooled to it and directly purified by Co biPIash (fSCO) on a 24g silica .gel cofenmt using 0-10% of MeOM gradient in DCM to give a mixture which was purified sgaia by P-HFLC to give 142 sag of a mixta* of {EJ--.I -(5-(5-hydroKy|K > »M-e.a-l

meihyteea. i)-f--(5--(5--hyd:raxypi¾ -2-ea-:i-y ^4-((5-m

metylitrea and i-(5-i55ydiox :iM ^

methyiarea.. Mass speetnao (ESI) m/z ~ 343.1 (M+H).

StepBt To a solution gf I - (5- (S- hydra^esi- ! -en-2 -yi) - ((5--methyi|>yridm

3- aieffiyiure (0.044 g.0.120 ramal} In THF (5.0 «xL 0.:i 20 mmol) was added dliodme i¾.00i g, 0.359 xm\) at rt, lie resulting mixture was stirred at rt,. The mixture was cosce-Rirated and dded under vacuum to give the crude product which amft&sed a mixtwre of i-(5- {2- (iodoioeil l}tetra]wdix>i¼rao-2 -ylj-4- ((5•metayipyridin--3"yl)oxy}pyriua-2-yi)--3--ox! larea, i - (5- (3- io oteirah dro-2H-p ran-2-yi}^^^ aad l-(5-

spectrum (ESI) mi* * 469,0 (MVH).

Step C:

3-yl)oxy)pyrjdia-¾-yl) -S-raethylurea,. I · (5- (3½d.oieiraliydro-2H-pyrafi-2-yi} -4-{{5-n¾! Ipyj1dta-3 · yi}oxy)pyridin--2-yl)--3-met y;l«rea aod 1 · {5-tiodo{teirabydf»fora«-2 » y{}iaetbyl) » 4 · {{3 -meslhylpyrida- 3-y o }p rM0i-2--y¾-3-:ffleiIiySiirea (0.015 g, 0.032 mmoi? mllW (5.0 mL.0.032 mtmrf) was added raaey 2800 nickel slurry, is water (0.050 mL, 3.79 nuttoi} at ft The resulting mixture was stirred at n overnight The in ure was filtered over a pad of ceiitfe and wasned wish DCM, di filtrated w s concentrated and the residue was purified by RP-.HPLC to give 5.0 rng ef l-methy}-3-(4-({5- t^l yri iB-3-yl)Qx} -(2- fe^^ .. Mass s ectins {ESI} ί

' Example 1331

Step. A: A si¾t»gen d gassed ixture of -etliyl-N-isopropylprof 5ati-2-atRii " se (0.100 g, 0.267 mmol), H.3-dihyd.roflsfa.a (0,202 mi,, 2S7 mmoL), N-edwi-l -isopropylp! opan-H-aridue (0. 188.ml... 1.07 moi), dlaestoxypailadmm (5.99 mg, 0,027 mrnol) sod silver carbonate (52 mg, 0.187 mmoi) fa 1.35 ml of DMF was placed a sealed tu e and. sited at at 100 °C far 1? Is. The mixture was cooied to rt mil directly sab ected to .RF-HPl ' C pitdflc&fion to give 75 mg of ! - (4- (3- ·ο¾ϊο.Γθ"2-ί1ΐ!θΓορ:Ιΐ6:8θχ }-5·-

(2 , 5 -&ihydft>furs»-2 -yl) pyrkUn-2-yl) -3 - inedwinrea. Mi s ectrin a (ESI) 364.0 (M-tli .

Sies B: A mixtu of 1 « (4··{3·€Μοι«··2·ίΙ« ίΌρΙ)«ιοχν ··5··(2,5··<ί¾ y lrofti.!¾!5 -2 -y l)pyiidiOr- 2 -y 1) -3 · methylurea (0.075 g, 0.206 lajaol). rhodium, 5 % cartas ( ,710 pt, 10.3 ί π ;!ϊ and eOH

(3.0 t«L, 0.206 imnof) tinder a bal!ooR of hydrogea was stirred at. rt. Upon completion, the mixture was filtered ihrough a pad ofCelite. eOH was used to rinse the Celite several times. The filtrate as eottce-ittrated aad the residue w¾ purified by RP-HPLC to give 22,6 :mg of R) - 1 · (4· (3-

cbloK)-2-fittOfopheftosy) - 5- (ietra y drof ratv- E -y ij pytidin- E -y 1.) - 3 - methyl r ea (S) - 1- (4 - (3 -c !om - 2 - flttOro heBOxy) - 5 · (tefta f rydrofaran -2-y 1} py iidl«-2-yS} · 3-me!hykr ιίδ (1 5-6351-33-1), Mass spectrum (ESI) mfe == 366.0 ( +H).

Following ike procedure in Exarapfe 1331, the foll ing * compounds were prepared

raethvlurea {!:! lowing i e procedure in I-Veparaiioe .21, the folfo mg mp aand

ioitawMg the procedure to Example 16 {he foliowle-g eompotmd was prepared:

sam le Siructee Dfiia

4- {4 » ((5- «thylpyridia- |

3-ylj(j y)-l "(3" ] Mass spectrum

1.316 , A.-A . Λ. .n\ethvla«ido)pyr i«-3 - I (ESI) mfa ■■ · 383,2

1. M H e dota* j (M-s-H. t eaecafbexyllc acid |

Folimvin " i e procedure in Preparation 158, in which die bromide is commercially' available or pre ared as described. The baroaic ester is -aoalog tis to exaraple L the fallowing c m ound

Preparation

S-½o siti - 2 - merh !jae iKei l j «x«¾al - ¾ (2H) - o¾

Step A: A To a vigorously stared mixture of sodiam carbonate, anhydrous (18.43 ml, 18.43 rnieel) and odr droxyruethanainirie hydmchiodde (1,155 g, 13,82 jianol) in tetraiiydrofuraa (23.04 ml, 4,6 ί ο»οο0 was added a solution of 3~bro o-≥ tydroxy enzoyi ebbtide (1.083 g, 4.61 tnmoi) hs DCM

(23.04 mi 4,81 mruo!) at 0°C, The resulting mixiure was stuted at .rt tor 18 k. Tie mixture was cooled to 0°C aisd 25 mL of 2N aqueous HO solution was sSo ly added. The resulting mixture was extracted with EtOAc (40 s»L x 4), The pooled extracts were dried with anhydrous sodium sulfate and concentrated , The residue was purified by Com Plash o» a -40s» silica e l coluran S!HSS

0-100% EtOAc gradient in foexane to give 157 nig of 116504-5-3 , Mass ssectrurrt (ESI) rote - 258.1 ( ÷H),

Stgp : To a mixhjre of of S-bmm(^ .2^ih <to^'- -methy.lbeiizamide (0, 157 g, 0.638 maiol), tripMe-ityi pbospbine (0,222 mi 0,957 mmol) and THE (6,38.ml. 0,638 miaofi was added di!sopropyl aKodicarboxylate {O. ' l 88 mi, 0.957 unnoi) si.0°C. The resuifcmg mixture was stirred si rt for 24: k The mixt«r« was then c entra ed and the ressdae was purified by C rnbsFiasfe mi a 1 g silica gel column using 0-80% EtOAc gradient .in he-x e to give 11

raetbyibenxauiide Ή MR (CDC¾} δ 7.96 (d. - 4,0 Hz, IH), 7.60 (dd, - 3.0, 4.0 Hz. if!}. 7.1 (d, - 8.0 H¾ If!}, 3,88 s, 3H).

Fallowing the procedure above, the following contpouads were prepared:

Preparation

7 - broaw- -mttth 3. <; ih dra ?H vri dg[3.2-l> j jl , j tiH¾¾m¾ I . I -dioxid

Step .4: a.) To & n xfttre of 2-bydroxyetfea»e(hSsl (0333 toL, 4.75 mx&ol} aad 5-b!¾iRo-2-dtlot¾-3- i]«oropyrid ias- (LO g, 4,75 mroal) la 7 m.L of DMF wa slowl added NaH {60% dispemoe in taisierai oil 0. 18 g, 10 * 45 nstmol) ! jporiions umiet a» ice bath. Tie -resulting mixture was stimnf at rf for 4 h. To ills soiutoioo was slowly added axone, awnopersalfate &mpouad (7,96 ml > ϊ 4,25 nuaof) under an ice-waier bath. The resulting aiixuire was sited at n for 18 n. The ntixftire was tta filtered through a short, coiuirts of ceh e. The fdiraie eOB efttetud , Tie residue was purified by Coi»blC¾sh oft a 40g silica gel c«iu®m using 0-100% EtOAe grad eni i lexatse io give 0.35 of 5- >mo-2 hlom-3-{viay 1fo«yi)-pyr dine. Mass spectrum (ESI) »¾¾ « 283.8 (M-t-K , Ή M R (CDCy 6 8.68 (d, - 4.0. IB), 8.57 (d, === 4.0H¾. 1H) > 6.88 (dd. « l6 t 8,0 iiz. 1H), 6.6S (ikl

= IS.tV4.8Mz, J.H), 0.35 {<½ - 8.0, 4.0 ife. H).

Step B: A mixtare of aHC(¾ (47.3 tng. 0.563 mntol^ tneihyiamine (2.0m soiuiios in MeOM, 225 pi, 0.450 ntmol} and 5"bramo-2 hbfo-3 · (v jnyisttlfonyOpyridiae (106 mg, 0,375 ) lo MeOH (3752 μ! 0,375 nusol) was fee 1 h. he iai iiire was coftcenirated ¾nd the residae was purified by Cswbl lasb on a 40g silica gel eotenn using 0-100% EtOAe gradi&at in lexane to give iOO wig of 7½o«i«"4- ffidiyl ,4- l!r^ 1,1 -dioxide. Mass spectrum

(ESI) mh 27g.S (M+H). *H MR (CDCy S 8.32 (d. - 4,0 Hz, S Hj, 8,04 (d, - 4.0 Hz, IH), 3.S3 sa, 210, 3.32 ba. 24¾, 3.23 (S, 3HJ. Preparation

7 : komo : 2--«^

Stsp A: To a mixture of 3-k mO"2-fl«orol)eisEoie add (2.0 g, 9, 13 «¾««>(} and oxalyl chloride (2.398 ml 27.4 jjKiioi) in 20 ml of DCM was a ded two drops of DMF. The Kssaltlag mixture was stirred at ft for 30 win and then heated at reflux for ! h. The mixtur

dried ndef vacuum to give .he erode acyi chloride, The crude aeyt chloride was dissovlsd in 20 ml of DCM an dw solution was added to a vigorously stirred mixture of ^.hydroxymediaoamiiie.

hydrochloride (2.288 g, 27.4 mraol) and potassium carbonate, powder (24.35 ml, 30.5 mfnol) l.n THF(18.26 ml, S.i 3 oiffioi} wader an ice -water bath. The resulting mixture was stirred at rt for 18 h. The mixture as concentrated aad the residue, was disso ved la 200 ml. of EtOAc The so ution wss washed with water twice, saturated a ueous .NsHC<¼ solut os and hriue, dried with anhydrous sodium sulfate and conceof ated. The residue was dried under vacumsa to give 2.25 g of the crude pr duu, Mass pectrum (ESI) mfz - 249.9

Step 13: A solution of 3*roiti -2-flao o- .1iydrosy^.«i thyi eirao'dde {0,50 g. 2, id mraol) is dmf (4.03 ml, 2.016 r!!ioo!) was moled to 0«C ami Nail (60% di¾p»srsloe in mineral oil, 0.089 g. 2.217 ffiioofj was added i« portions. The resulting mixture was stirred at IO0°C for 18 h. The mixture wa cooled to rt aad 20 ml, of saturated aqueous B4CI solution was added,. The resulting mixture was extracted with EtOAc (30 ml x 4), The pooled extracts were washed with water (30 rut x4) arid brine, dried with anhydrous sodium sulfate and concentrated. The residue was purified by

Co«iiiiFiask on . a 0g silica gel column using 0- 100% EtOAc gradient in liexane to grve 172 nig of ?- hfomo-2-mefhyfberj.2ofd|isoxs2¾f-3(2¾ -ooe. Mass spectrum (ESI) ?¾ = 229.8 {M*H}. ¾ MR (C C & 7.74 (dd, m 8.0, 4.0%, IH), 7.71 (dd, » 8J, 4.0Hz, IH), 7,14 (dd, » 8.0, 8.0Hz, 1 3.70 (s, 3ΙΊ}..

Preparation.

.Step A : To a mixture of 3--iuercapi 1 -pro-pano! (0.431 ml, 4.99 mmoi) and cesium mioMie (0,418 ml. 5,23 mmal) in DM (4,75 -ml, 4,75 mmol) was slowly added 5-faromfi-2 ¾ {iro-3-0i.ioro yTidin« (LO g, 4,75 !Siool) m portions at rL The resulting .mixture was stirred at ft for 3 , MeOH {5.0 ml,

1 4 mmoi) and wafer (5,(5 ml 278 mmoi) were added, and then cooled fo 0 a C before Oxorse, motiopersulfate compound (7,0 g, 11,4 mmol) was added in portions.. The resulting mixtafe was stirred at rt for !6 h. The mixture was filtered and me precipitate ¾¾s washed with EtOAc. The filtrate was washed with wafer twice and brine respectively, dried with, anhydtws sodium .sulfate arid, concentrated , The residue a dried under vacuum to give 1.35 g of the crude product, 3- ~ 318.0 (MVH), ( 1.35 g, 4.29 mmol} in daHetbylformamide orofuso (42.9 ml 4.29 romol) as added Nail (68% dispersion in mineral oil.

0.180 g, 4. 1 mmoi} la ortions under an ice-water bath. The molting mixture was stirred at :i (ii Q- for 2 h. The mixture was then cooled, to ri. 50 ml, of saturated aqueous NILQ solution was added, asd the resulting mixture was extracted wit EtOAc (50 ml. x 4), The pooled extracts were washed with water and brine, dried with anhydrous sodium saliate and concentrated. The residue was pmifted by ComhlFa!sh on 4Gg sdicagel column -using 0-10% MeOH gradient to hexane- to give 335

8.53 id, -4,0e¾ IK), 8,42 (d, =4Λ, IMS, 4,45 (dd, - 8.0. 8.0Hz. EM). 3.43 (dd. -8.0, 8.0Hz, ZH), 2.50 (iii, 211),

Preparation

½ΜΚί: ^Μ¾

Step A:- To a .mixture of n-metfcylethanfttamiae (0.588 ml 7.31 mmoi) asd Et s (1.019 ml 7.31 rnmol) .iri ' DCM (27.4 mi, 5.4 rornol}. was added a solution of S¾onKi~2-rl«0rabe-fi2ene~:i -suiibn l chloride {.l.Qg, 3.66 mm ) in 10 uti of DCM at rt. The resulting mixture was stirred at it for .24 h. The mixture was-concentrttted and the residue was dissolved in I SO ml,- of EtOAc. The solution was washed with IN aqueous HCi sobtfien. water, saturated aqueous aHCOj solution and brine, -dried with auhydrous sodium sulfate and ranceeftsted. The residue was dried under vaaiaas to give 1 Λ 4 g of the crude product. 5¾om^2-iliio ^ -(2¼^ Mass spectr m (ESI) mix - 311.8 (M+HS. NMR (CDC¾) 5 7,39 {m, 1H), 7.86 (pi, 1H), 7J 1 (dd, - 8,0, 8.0Hz. tto (dd, · 8.0, 4.011K, m), 3.32 (dd, = 8.0·, 4.0J¾ 210, 2.S5 (s, 3H),

Step B To a solution of 5%offiG*2-i1uor¾" -(2- raKy (i,14 g : 3,65 m>l) DM? (36,5 ltd, 3.65 rrimof) was added Nail (80% In rs eral oil 0.161 g, 02 fflsioi) In portions at 0°C arid the. resulting mixture was stirred at 110°C for 24 h. The mixture was (hen cooled t si and SO ml, of saturated aqueous M¾C! solution was added , The mixture was extracted Willi EtOAc (38 uL x 4). The pooled extracts were washed with water, saturated aqueous NaHCOg solution, and brine, dried with an dro s sod um sulfat atid concentrated. The residue was purified by CombiFlash on a 4% silica gei column using 0-400% EtOAc gradient

(CDCls) 3 7,92 (rl -4,0l¼ 110, 7,57 (dd, - 8,0, 4.iiBZ, Hi), 7.06 (d, - 8.0Hz, IH), 4.17 (m t 2H}, 3,73 {m.. m 2.79 (s, 3H).

Fallowing the procedsire above, ie ioilowtrtg compounds were prepared:

Preparation

f b oiftO"2^

Step A:: A iuMtsre of &-femHU>-2-ehloro»3 -fl orapyrldaie (0.515 2A5 uimol) soikeial (0.358, 2.69 mmol) aad cesium carbonate (0.877 g. 2.65 ) ausol) io 5.0 mL of DM? was stirred at 80°C for 20 h. The mixture was cooled to it attd 50 roL of .saturated aqueous ¾Ci. sotatkm was added. The resuitbtg rasxtare was extracted with EtOAc (50 mh x 4). The om ine extracts were washed wills water &od brine, dried (NagS ' O*) aod corseeutrated, Tito .residue was dried to give 0.804 g of the crude product, S ½» o-2-dil«ro- 3-({2 t 2- d^ Mass spectrum

(ESi) mix » 323.fS (M+-H).

Step B: To a soiufior» of 5¾orao-2 hioro-3 -({2,2--dlmeihy!~ i ^ioxoia^ - .l}o-«ho3{y} fi.dine (9.804 g, 2-492 ffiiTtoi) in tetrabydrofuran (12,46. ml 2.492 trtinol) was added 8 ruL of aqueous.2N f-lCI solution at rt. The resultiag mixture was surred at rt. for \ 8 ¾, The mixture was macefttfatsd. arid dried fo give 0,704 g of ih erode product.3~({5-bremo-2 ¾toropydiHn~3- I)o¾} o 8aft-i,2 » <Uol. Mass spectrum (ESi) miz ·» 283.S fM+M).

Step€: A mixture of 3 ((5.-teOm-2"Ch}om idl yl}oxy).}iropa}se- «2"dlol fO. iSSg, 0.70.1 rnrnol) nd cesium carbonate (0,228 g, 0.701 nuns!) m.7,0.r»L of ' DMF was stirred at: 95°C for 24 h. The niixft!i was corded to i'f aad directly purified by ComblFtexh on a 24g silica gel. cfji nin using 0 · 180% Et.OAc¾xaoe m gradifc&f. to giv 33.2 rog .of ?-¾m:i«o -2,3-dtiiydro- :i,4:dioxifio2.3- b|pyridii 3-yl)rnev!iasoi Mass spectrum (ES!) mix « 247.0 (M+H), MR (CDC¾) 87.87 fd, ∞ 4.0 H« : Hi), 7.36 (d, -4,0k, 01), 3.87-4.51 (in, 5H), 2.550r s, !H),

Si J

Following t&e procedure \n Example 198, the fellowteg campoaads were prepared using the appropriate reagents:

. ethyktrea

met ylurea

Following the procedure »¾ Exam le 158, Ae .following as&pousds were repared using tfse

y)-3-n¾e vyl(.ifea

Followiisg ifte ro are in Example 174, the following co pounds ere prepared tisi.sig tfte

Example 1500

Methyl 4 - S -fjifSaos¾pli¾ioxy): 6-S-meihyiaand ) -i¾,4':¾i pyridine I - g ' -carboxyat 11

To a stirred solution of l-(5--bffirfX} - (2,8- ίίΙ«οτο^ OJ g> 0.2-78 mine!) in M $.022 »sL 0.279 mmoi) was added metfey! ^-^^J.S-tetatnefe i- .S -dioxafaawki}- 2-yl)pio ' ltete (0.147 g : 0,558 romol), fallowed by P (dpp¾Cl¾ complex with DCM (0.023 g, 0.028 mmol} a potassitmi carbonate (0.116- , 0.8? 8 mmol). Tire reaction was stirred at !OQX and motitare by LCMS. Alter ( e reacton was < ompiefe. Wafer was added So qtseneh the reaction and ϊίϊΐί ! . ΐ Y sS ν .Ni: <i>. i ;U.l : .'..A- .. i iilH-V ·

in map. The trade product w s padfled on s ilka gel elating with (0-100% EtO Ac in DCM) to- afford methyl 4-(2,6-dif¼ofopheaoxy>-6-!(3--«i 8* yi«rddd)--[3 , - lp ^diej--2 ' "Carbo- lae (0.014 g.

0.034 mmol 12.10 %}, S H NMR (500 MHz, s a ppm 9.30 (1 H. ), 8.81 (1 H, d, j~ J Hz).

8.420 H, $}■, 8.33 {1 M, d, j==TS Ha), ?,92 (1 H, dd, j::4.§, 1 ,7 Hz), ?,30 - 7,54 (4 H, «t}» 7.15 (1- 11 s), 3,86 - 3.98 (3 H, !«} > 2.66 (3 H, d, j-4,6 Hi } Mass spectrum (ESI) rn/z ~ 4-15.0 (M-J-H).

Following the poscedafe in Exarrtple 1500 die f llowin compounds w&fe prepared usin i«e ■apprapfiate reagents:

Exampte i 503 Step A: A stirred mixture

(0.21 ! g, Q.SS ttmiol , bis{piiiae ialo)diliOi¾n (0.224 g, 0,88 n¾>l). Pd{dppf) ? Ck toropiex with DCM (0Λ 47 g, 0. i.80 HHftoi) , and KOAc (0.176 g, i .79 tranoJ) ia dry 1,4- dioxane (5 h) was pur ed three times with Ar and placed under vacuum tkee times. T e mixture was heated at !OCPC for I fi , Afterw ich, the reaction was coaled to ST then concentrated andet redaeed pressure. The black residtm was used without farther purification; as i~(4~{2«6~dtto«raphesoxy} -(4 < 4.5.5-fetr¾meth i~ i .3.2 dioxaberala« 2--yl)p rid » 2 ·ν1)··3 -njet iurfia (0,238 g, 0.587 mm l 100 % yield)

Step Bt

! '{ --(2,6- ilf1«or0 he«^

methyliirea (0,108 , 0.265 rmao!). 5 -brosio-Z-ethylbfeHzoldloxaiii-ole {0.04 g, 0.177 «»80l).

tficydofeexylpitosphhie. (9,92 mg, 0.035 mmoi), artd Pd¾(ti a) :i (0,016 g, 0,018 m al) were added ia a vial then degassed and backfilled with N ¾ . To the vial was added 1,4-dioxaae (1.769 ml) and aqueous ! .3 M potassium phosphate iribasfc. (0. i 13 g, 0,531 mmoij by syringe. The resulting reaction was heated to 100 "C and i ' «omtored by LCMS, Gate the reactioft was complete,, ihe reaction was cooled to T then coBcenirated under reduced pressure. The residue was filtered, then loaded oato silica gel $-00% of prefixed 90:10 DCM: .MeOM hx DCM) to afford a solid ί .-(4--(2 < 6--difluorophenojiy}-5 ' -{2 - 23 % yield) . Ή NMR

(500 MHz, ϋ) ppm 9.14 (1 H, s), 8.18 (i H, i 7.80 (I H, d, j-1.5 Hz), 7,70 (1 li d« £=8.3

Hz), 7,45 ·· 7.53 (2 H, ex), 7.30 - 7,44 (3 H. m). 6.9S (i H. s), 2.93 (2 H. q, j-7,6 Hz), 2.59 (3 H, d» 4.6 Hz), 1 ,29 (3 H, t, j~7,6 Hz), Mass $pecm«¾ (ESI) mk - 425,0 ( ' -s-H), oliowift the procedure in Example 1503, die following compounds were prepared usin &e appropriate reagents:

Examples 1505 - 1517 were prepared foHowlag the procedure in Preparation lM : m which fee bromide Is coiSffierdally available or prepared as described, The boronle e&rer is prepared

medryltirea

55?

To a stirred solution of knidazoU ,2-a.{pyrldin-8-ol (0.1 g, mmo ' l) in DC (3.73 tni, 0.746 min lj was added MElj (0,114 ml, 6,820 rnritol}, aftd l-dinjetfeylaoiHSOByrldiise (9.11 mg, 0.075 fiimoi) followed by a-phewy fe-irifluoromet ane s«U¾nh¾ide (G.293 g, 0,820 loitiols. Stirring continued for 16 ' h, afterwhlch the reaction was oBeentrafed under reduced pressure to yield imidasso[l ,2-a|pyridift-8-yi irifluoroaie hanes ffonaie (0,198 g, 0,744 mtmh 100 % yield) thai was used without parifk:¾iios. Mass spe ni (HSi) mrz ~ 266.9 (M+H),

Fallowing the pfocfi<hii¾* above-, the following c m aiHiiis were prepared using ffee appropriate reagents:

Example 1 8

H4-(2,(^dii¾¾^

raethy!urea (0,1 g, 0.24.7 rruHol). i idazo(i ,2-a]pytidi«-8- i iififlaoroi«eih¾nes«lfiioaie {0.044 g, 0165 raol). iri ydahexylphosphme (9-23 mg.0,833 mal), and Pd¾($>a)$ (0.015 g, 0.036 msfoi) were added to a vial then degassed and baekililed with nitrogen. To the vial, was added I s 4--dk}xane (1.645 ml) and aqueous 1.3 M K 5 PO.4 (0.105 , 0.494 mmdf} by syringe. The resulting read es was healed to .1 0 "C and the reaction was monitored by LCMS, After eo.sr¾)leiiori of !be reaction, the mixture was coaled to EI thes concentrated usder redu ed pressure. The re idue was filtered, thes loaded m silks gel {0-60% of prefixed 90:10 DC ' M.: eOM in DCM) to afford a solid i - (4- {2,6- ■dirlaorophenoxy) -5- {iira ' daxof 1 > 2-a|pyrfdi»·8·yl)p>'ridi>^·2·yl}■·Γ me ·I^)tre¾ (0.0149 g, 0.038 rorooL 22.81 % yield). Ή NMR (50 MMz, $ 8 ?pt» 9.2? (1 H, s), 8.64 (1 II sj, 8.59 (1 H, ύά, jh6.7, IJ Hz), 8.05 (I ii d. j== 1,8 Hz), 7,53 - 7.03 (3 H, 7.3 - 7.52 (3 li HI), 6.94 - 7.10 {2 H, m), 2,6? (4 M. ti. , 1.16 {I H, i, 7.1 H¾). Mass spectrum (ESi) 395.0 ( -i-M), PoIowSag the procedure m E am le 1518, the following ee f)o»«ds were prepared asiag the

Example IS

To a stirred salution of H5dis>aK -(2J- iiluoro (8,1 g, 0.28 aunol), potassium lH-pyrazo1fe-S-Tift»oroborafe (8,053 g, 8>3! m uJ}, PdCGAc (6.27 jag, 0.828 misol) ami tt PSsos precatalyst (0.041 g, 0,056 wximl} in EtOH (2,78 s«l) was addsx! scdatn

56Q carbonate (0.059 g, 0.56 mmoi). The reaction was heated to 85 S C and stirred. Alter the reaction was complete, the reaction was amcentrated in vacuo. The crude product was purified by eate chromatography on silica gel (0 to 50% PCM/10% MeOH in DCM} to gi ve the- desired product H** {2,6^-ifteopfcen^ (0.0028 -g, 8.1 i jnnol, 2M % yield). Ή MMR {500 MMz, DiCHt.OROMETHA.NB ,) S ppm 8.56 {Ϊ. M. s), 7.72 (3 H, d, .1-2.2 > 7.37 - 7.44 (I ft m), 7.19 (3 H. j-8.3 Hz), 6.90 (I li br, s.J, 2,82 - 2.86 (3 II m). Mass s ectrum (EST) /z 346.0 (M- H).

Example 1.5 4

T(2,S"djfJ^^ ^

earbosaOTtde

Step A:

g, 0.28 mmel} in DMF (2.79 ml) was added terttatyl 4»(4,4.5,5 ie raR½ l-i ,2"diexab{>roiaft-2--- yD-S.S-il hydro . pyridtae-l (2H) -carboxv!ate (0.173 g, 0.56 mt«oi), fMlom>d h Pd{PP¾k (0.032 g, 0.028 mnidJ} and potassium carbonate (0.116 g : 0.84 mmoi). Stirring emitted at i0O°C «««1 complete. Water was added to quench die reaction asd the mixture was extracted with EtOAc, followed by DCM. The combined orga es were co.t ¾ntrated in vacuo. The erode produci was purified uu silica gel (during with 0- 100% EtQAc in .hexsnes to give the desired compound; tert-butyl T2,6- liteo hem^

g. 0.165 mmoi. 59.1 % yield). Mass spectrum (ESI) mh = 461 ,9 (M-tM).

Siep B: To a stirred solution of teri-buiy! T(2JEdifl oraphen^^^

(0,076 g. 6.37 mmo!) in DCM (1.65 ml) was added TP A (0,1.27 ml LS 50 mmoi}. Stirring continued: at . 23 * 0 for 1 Tbe reaction was concentrated iit vacuo * The crude product was used without further purificato. l--(4-(2,( d®uoropk«ray)-r,2^3 ' «8 ! etraliydro" 13. '-bip TldiB|-e-yl)-3'«ieihylurea (0.058 g, 0.164 FUJUOI 99 % yield).

Step€ A soiutioii of i, (4-(2 i 6-difl«oropbenftiiy) -r^'J'.O'-tet ah dio- ^'- pytidin) ·8-γ1}-·3- elhyktrea (0,056 g, 0.16 t ml}, DIPEA (0.1 ml 0.57 smnoQi mi (dlaw hyfetninolcaAonyl chloride (0,015 nil 0.155 rrnsol) in DCM (1.55 rn¾ was stirred at RT overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chrarnaiograplsy on a silica gel AW % yield). ! H R (SCK) MHz, fi ) a ppm 9.12 {I M, s)« 8.05 0 & s)« 7.34 ~ 7.57 ( H, ta), 6.89

(1 11. s), 5.98 (J H, di, .1-3.1 , 1,7 Hz), 3.85 (2 H, d. , 2.9 Hz), 3.24 - 3.45 (2 R to), 2.68 - 2.85 (6 H, mh 2,59 - 2.68 (3 11 in), 2.52 - 2,59 (2 H, m). Mass spectrum (ESI) ai¾ - 432.0 (Μ+Η).

Example 15 5

Step A; To a stirred solution, of

yi)pyriiii«-2 -y!^3- methyIui¾a {0.036 g, 0.086 r ml) 1» EiOH (3.97 *ng) was added MCI f 7.86 pi 0,259 ffi!Hoi) . SO rriiig continue at 23*C. Once the reaction was com lete, the orgaaJcs were concentrated irs vacao asd as aqu ous sol oa of aHCO$ was added a«d toe resulitttg mixture was extracted with EtOAc and concentrated in vacuo. The crude prodwet 1 - {4~(2,6-d!fi«oropftettoxyV5~{4~ •oxGeycIohex-1 ··««· 1 -yi).pyridui-2-yi} -S-saetltyiarea {0.032 ' .g. 0.088 mmol, 99 % yield). Mass ' spectrum (ESI) »i& « 374.0 (M+Hk was deemed pure enough sad was takes onto the next step.

Step B;. To a stirred solution f l -(4-(2J-diiIuoropta^

3- s«e kirea (0.032 g. 0,086 ramoi) in MeOH 0.86 mi) was added NsSH* (3,2 sag, 0.086 tnmoi). Stirrin eontiaued at: 23 * C, until deemed complete. The organies we e concentrated is vacuo. IN M€S was added, to quench the reaction. Aftmvhich, an aque us solution of aHC : ¾ as added and the reaction was extracted with. EtOAc, and concentrated in vacuo. ' The crude product was purifie o.n silica gel eiuring with 0- i 00% EtOAc is hex.an.es to give the desired compound. 1 · (4.- (2,6>

difl«st )pl)eftosy5--5 » (4--hydfftxycyclol»!X- l-esT-yilp ddin-E- l^S-ffiet luTO (0.01 g, 0.027 tmnoL 31 % yield), ¾ NMR (500 I¾, s. i B ppm 9.0? (1 H, s), 7,98 (I H, s . 7.54 (! 11, Or. s,),

7.31 - 7.50 (3 II m), G.80 6,83 (i H, ai). 5,69 - 5.84 (1 II, m), 4.68 (I & d, ife). 3,80 (i H, d, 3,9 .}¾), 2.80 - 2,67 (3 H, te). 2,35 - 2.49 (3 H, it) , 2.00 - 2,00 (I H, fuS. 1,79 - 1.89 (I M. ηι) : 1.52 - 1.63 (1 li in). Mass spectrum (ESI) sn ¾ - 376.0 (M-B).

Example IS 6

Id b i^

502

Step A To a solution of 1 (4- {2.{klifluoropheBOxy}"5-- (1 > 4-dioxaspiiX){ ' 4:5)<:Iec-T"eH-S-yl}pyi , iSia-2- yI)-3-tnethy!itrea (0.35 g, 0.84 mmol) in EtQH (8,39 is!) was added Pd/C {9.89 g, 0.84 BMIIOI), The resulting reaction ' mixtur was stirred under a« atmo pher of ' hydrogen for 4 weeks. The reaction mixture as filtered through a silica gel plu and concentrated in vacuo to give ί · (4· {2.8·· difiuoraphenoxy}-5--U,4*Hoxaspiro^^ (0.352 g, 0.838 mmol,

100 % yield). Mass specimai (ESI) m/¾ - 18,9 (M-J-B)

Step B; To

2-yi}-3-rirfiyi«5¾a (0.352 g. 0.84 mmA) in BrOH 18.39 lj was added HC1 (2.52 ml). The reaction trdxtore was stirred continued at Z Q ill deemed complete. Arterwhiefi, the organies were concentrated to vacuo. An a ueo s solution of NaHCC¾ was added ami the resulting mixture was extracted with EtOAc and concentrated in vacuo. The crude product, was deemed e enough and was takes oato the next step. 1 -£4--{2,8-diiiuoropke¾axy)^ ^

toefhytorea (0.315 g t 0.84 mmol 100 yield). M ss spectrtiro (ESI) k ^ 370. (M- M)

Step Ct To a ' stirred sohid H of T 4 · (2.6•diflttoi¾plwnoxy}--5"(4"OXocyclohexyi)pyridto---2"yl }- : 3" niethyiorea (0.840 g, 0.10? mmol} in eOB (1.066 ml) was added sodkos boroh dtide (4.03 j«g, 0.107 iiHiiof). The reaction mixture was stirred continued at.23'C until deemed complete.

Aftefwhicls, the organies were conctwated k\ vacuo. IN HQ was added to quench the reaction. Aft aqueous solution of K%HCO : ¾ was added ami (tie reaction was extracted with EtOAc, and

cooeetirstraied Us vacuo. The crude product was purified mi silica gel elating with 0-50%

EiOAc/EtOH (3/i) in heptanes to give she desired compeared, 1 -(4 -if2 ! 6-dilluoropl>eaoxy)-5-(4- h <-iw c x½he^!) f tHft-2- 1}-3-mei torea (0.015 g, 0.040 mmol. 37.3 % yield) as a 10: 1 .mix u e of diastereomers, ¾ NMR (500 MB¾ DiCHLOROMETHA E 6 ppsa 9.04 (1 H, hr. s.) ; 8.19 (1 H. hr. sJ. 7.% (I si. s). 7.26 (ί .H, !l J«8.5« 5.0 Hz). 7.02 - 7 14 (2 H, m>. 5.8! (1 14, ss. 3.66 (I H, t. J- 10.5 i¼. 2.93 (I H, it. 4-12.2, 3,4. Hz), 2.75 (3 H. d. J* .6 Ik). 1.98 - 2.13 (4 & m), 1.64 (2 H. qd. j- 12.8. 2.7 M¾), L47 ·■ J .S8 (2 H, t«) f 1.35 - 1,47 (2 14. m). Mass spectrum (BSD iw/¾ - 377.0 ( * H).

Example 15 7

;|- (4- ((5--€to (β.85 g,

0.12 mmol}., 4.4.5,5-t^«ti-«ethyl-2-(prop--i"eB--2--y!}--i,3,2--dloxa oj¾fee« {9.040 g, 0.24 mmol) > fricydotesylphos liiite (6,$2.mg« 8,024 «HBO!) , am! Pd 2 {¾l*a):t . (18.80.mg, 0.012 ra«ioI) were added to a via! thea degassed ami backfilled with N ¾ . o tk> vial * i«4-dtoxime (LIS ml) ami aqaeoas 3.3 Κ;ίΡΟ-ΐ (0.075 : 0,35 «u3id) were added by syringe. The resulting reactitjti was heated to 100 "C. Alter the reaction was complete, tk¾ reaction was cooled to RT, water was added and the mixture was extracted EtGAc. Th .-organks were concentrated tmder reduced pressure. The residue was filtered, then loaded onto silica gel (8-58% EiOAc/EtOH (3/1) in heptanes} to afford a solid l-iaethyl-3-{4-((5- {prop-l-&o-2•y1)pyrfdii) -vl)oxy)--2 , - fiil«ojx>a«!thylV- [3,4 » i>ipyridift.!--6-yl} fea (0.0324 g, 0,075 mmoi, 64,0 % yield). Ή NMR (500 MHz, e ppm 9,36 (I H, s), S.83 (S H d, 5.1 Hz),

8.73 (l H, d, j-2.0 Hz). 8,51 (1 H. d. j-2,7 Hz), 8.44 (I H. $}, 8.20 (1. It $}, 8.06 (I M. d, j-SA 1.1 H¾|, 7.94 (1 H, t t j-2.2 Hz). 7,59 (i H, hr. %,), 7.0» (i H. $), 5.8? it H. s), 5.29 (1 II $), 2.67 |3 H, d. j-4.6 Hz), 2.16 (3 H, s). Mass spectrum fESi) m/z - 438.8

Follows tig the procedure abo ve, the following -compounds were prepared ustag the a ppropriate reagents :

Example .1530

l-r»¾jthy¾-3-

To a stirred solution oi^:¾ -ffiedwi-3- { "{^

fS f -4 -b.Ryrjd}«|-6-yl}ufea (0,023 g, 0.053 awnol) iss MeQH (0.529 ml) and EtOAc 0.529 rid) was added Pd/€ 10% {0.563 rng, 5.29 praol) . The resultin reaetfoa was placed tiader aa atmosphere of hydrogen (0.107 mg, 0.053 rarest!) ¾od stirred at 23*C until the reaction was deemed complete. Afterwhlch, the reactiort was filtered asd the organies were sosceiifisied uftdet reduced pressure. The residae was filtered, then loaded onto stitca gel £0 -56% E OAc/Bl H (3 .S } ia heptanes) to afferd a white solid i- : nKsUiyl-3-( -({5-pr pylpy^^

(0.0114 . g, 0,9:26 rarnoi 50.0 % yield). ¾ N R (500 &, 8 ppm.9,38 (1 R s . h 8.82 (J ϋ d. J.- .8 Hz), S.4 (2 E s), 8.43 (I E s) : 8,16 (S H. $), 8.82 (I B, d, j-4,6 lk , 7,53 - 7.66 (2 H, «0, 7.W (1 a 2.56 - 2.72 (5 it m), 1.5? - 1.87 R m} > 0.98 (3 E†, J=7.2 Hz). Mass spectrum (EST) iu/z - (M+H) .

585 Example 1531 ■ (4■r{5^aie ¾OOTdd a■3 ; yI)αχy :3. {

Step A:.- To a solotkm of (4 g,

12 Hanoi) in EiOH (ISO in!) was added Pd{OAt¾ (80O.?ttg ( 2.4 irtmot), Dppf (L4 g. 2.4 mmol) and TEA (5 g> 48 saraol). The resulting wbiture was stirred at W% under CO atmosphere (50p$i) for 18 is.

tnmoi, 61.5% yield).

Step B: To a coaled (i C solution of ethyl 4-({.5-i^teyp dla-3-vI) xy}-8-(3- nwihylinBidofoicotmaie (1.8 g « 520 tnmpi) fat IMF C: 20raL} was added LiA * (60S na , 15.8.mrnoi) in small proiiortv over approximately 30 ntins. After addition, tile reaction mixture was stirred at RT for 12 . The reaeiioxt was cooled ro 0*C thea water was added to qaeaeh the reacdoa. The resaitiRg sofctjoB was extracted with EtQ&c and combined organic layers were dried and concentrated so obtained (! . !. g.

3.61 mmol* 69.4%yifeld).

Step C: To a solution of i (5-0 droxym ^^^

rnethviurea (1 g, 3.28 nanol) h dry DCM (30 ml) and dry D F(0.3 ml) was added $OCl ¾ (0,83 dfopwtse at OT.The resulting solution was warm d to 23T. After Ih. the reaction was co«ceatfal«d to obtained 1- (STd oro w syj -((5-methoxypyridin -3-yl)oxy)pynd - ~3-taetnyfcrea (800 mg, 2.48 mmol, 75.5% yield)..

Step D: To a solution of MS-Cchlora e^

medwiurea (200mg. 0,621 mmol) and 3-nwtl a |>hoIine (3 eqv) la DMF (15 ait) was added N¾HC% (203 rag, 13 mmol) at RT. The reaction mixtu e was stirred at RT overnight. The resoiri g solution was dilated with water and extracted with BtOAc The organic layer was dried, concentrated . J H NMR (400 MH¾,

MeOM-d4) δ 8.46-8.30 (at, 311), ?.67-?.88 (sa, 1.H), 6.(57 (s, l.H), 4,92-4.82 (m. 111}, 4.41-4.38 (m, m)> 4.06 far. 2H), 3.98 (m, 311), 3.86 (m, 1H), 3.06-3,56 s 3B), 3,37-3.3g(ss , Ml 2.82 (%, 314). 1.58- i .54 (sft, l ESl- S (M÷l) ; 388.2 caic. for Ο ί; ¾ι%0 ϊ 387.2. Following, the. procedure above, die foilowtog com ounds were prepared using the appropriate reageais:

3-r«ed)ylurea

Following- Jw proce ure in Preparation ίί excepi us ing DMSOimteadof DM \ i e foil ow ing compotifufe were prepared;

Stmcttse !ame j Data J

By exie ia!l !owiRg ifse procedure is Example J 680, the following compounds wete prepared:

Example Structure Data

(+A>- ! {: " , H'SRAS} I

Q by drox tei ralsydro - 2H -

Mass spectrum pyras!~3-ylH~((5"

CESJ) m/z ··· 375.1

H roeihoxypyiidis-S- {M-!-H). ; S- i ki in · - 3 - y 1 ) - 3 - msihyiurea

By essentially l wJag tl¾e procedure ' Example 66 , the following compounds were prepared except the resakisg racemate was separated by dura! chroaiatagraphy (AD eolitiim,

By essenially following the procedure In Example 606 e cept the comp aad was ultimately purifed fey super critical fluid cfeifal. chromatography ( Φ-Η, 30% MeOHfi ) .l% M¾OH)/CO ¾ 100 ar) site

F

Following the route in pw tkm 32. the feiiowte compounds wefs also sy«thesi.z«d::

arauao bfrocure ame

Prfe arafiOK I

2.4-D!l1iiOiXs-3-hytiroxybefizo;c aciil (4.0 g t 23 mittol) was placed in MeOH (4 ' GmL) a«d cooled to 0 51 {Di ¾ meOi i)lm»e isiiaite (29 ml 5? tn ol) was added dropwise and then stirred ai ΰ V C for 30 hx. The reaction was the« coace»t e diluted wi<¾ DCM, and washed witlr I M aOH, dried (MgSQi), filtered, sad concentrated to give tfee crude product winch was purified by column ehroraatograpw (9:1 DCM:MeGE) to give i s product Ktethyl 2,4-difl«ofo-3-hyii! xybea¾oate (2.S g, 65 % yield).

Preparation U

To a RT soiiitiof) of dimeihyteine ( 13 So mmol) (2M in ' FRF) was added AiM¾ .{J 3 ml, 26 mmol) dtop ise and. stirred for 15 mm at R ; Methyl 5-feydf«Jcy-l-methylrlH-p> i ra¾ole-.- caiboxyiate (2.0 g, 13 mmol) was i m added aad stirred as RT for 30 rata. The reaction as cooled to 0 ' aad slowly queoe ed wsh water, and then acidified to pH 3, and ex traied with 3:1 OCM PA, Ptirsllcailon of the crude- product over si ea gel (500:30-500:45 DCM:MeOM) afTofd ' s -iwdt¾xy- ^,NJ-trsmetiiyl H.pyfs;ioie-3 arboxamide (1.1 g. Si % yield*.

Preparation III

Ethyttrdtaz se oxalate {1 ,34 g, 8,90 mmol) was placed in MeOH (KsxtL) at RT. N¾ (Ϊ ,24 ml, 8.90 mmol) as added, and stirred lor K) inin, then methyl 4-n iioxy-3~oxob«ia«oate (1. IH ml, 8,90 mmol) was added,- aad. heated to reflux overnight and then ptnsred into water, acidified to pH 4, and extracted with 5:1 DCMiiPA. The combined organic tractions were dried (MgSO<}, filtered. coacOTtrated and purified ' over silica gel (500:.15 DC :MeOH) So afford 5 -eii:¾yi-3-(3«ethoxymciavl}- iHi»'fa¾>i-5-ol ( " 1.0 g, 72.0 % yield).

Preparation 1

Stq> A: ^4-¾Oi<>^-imte ^)eoyJ)a etii5. acid (L0 g, 5,43 rnmgi) was diss lved ia DCM (30 mV) aed IM BBrj ( Id,3 ml, 16.3 mmel) w s added and ihe reaction stirred -at RT tor J .hr. The reaction was posited into .aqueous " aHCOj and stirred for 19 mia and extracted witii ether. The aqueous layer was acidified it i HCl, exffacied with DCM ίχΊ drie over sodii is sulfate,, filtered d soneetiifated to afford 2^4*il«oro-3-h droxyp ea l}ae«iic acid SOO g, 4.70 ramoi, 86,6 % yield), Step B: 2-{4-l!uoro-3~liydrosyp«e»yi)ace5ie add (Mil ¾g : , 4.70 mmol) was dissolved in MeOH (20 rtsL) and (dia¾oi»eiliyi)irrmei!iy(siiaiic (235 1 pi 4,70 mrnbi) was added slowly astd stirred at RT tor 10 mtn Tiie reaction, was concentrated to afford methyl.2-(4~iIu0i«-3 .iydroxyp ei:ryi)acetaie (866 ma 4.70 ffiisol, 100 % yield) .

Preparation.

6- 3yd: esyi?r¾m

Step A: 2i*dibrott5o-3-ojethylpyridi«e (4.0 g, 155 ttr&tol) was di solved ia tote*e (150 ml) ami cooled to -78 2.5M B«tyUithiai» (0,82 mi 17, 1 rumo!) was added dropwise arid stirred at -78 *C for 3 hr, Acetofle (S ,41 mi, 19, 1 rnmo!) was added and stirred at 8 X for 2 hr. The reaction was poured into aqueous N¾C1 S extracted with EtQAc, dried over so !om sn.Uate, .altered and coHcensrated, Purified over silica gel (20% EtOAc ia hcxanes) to afford 2 5-bronio-3-i»eiSrylpyridln- 2-yl)propan-2-ol (2.6 g, I S .3 mmol, 70.9 % yield) as a dear, colorless oil,

Steo. B: - 5-hmftiO- -ifted: y1pyridi:iv2-yI)pr«parj:- -fil (100 mg. 0.435 nsjuoi) was dissolved in dioxaae: water (1 : 1 , 4 m.L) aud nitrogen bubbled through ibr 5 mia. Potassium hydroxide (48.8 mg, .869 mmol) Pdjdha 3 ( . 19.9 mg, 0.0217 ΚΜΪΟ!) and d ^te ri - uty ¾ 2 l , 4' , 6 -tr ϊ ί so ro > y !bipii e:a y I -2- yDphosp ftc (36.9 mg, 0,0869 mxmft wre added aad the reaction plunged .into a 90 X o l bath for 2 hr. The reaction was cooled to RT, diluted witii ether, partitioned, aq layer netdrabzed with sat, NHiCL salted out with solid Cf extracted with EiOAe x2 i, dried over sodixisv s«l.fate, filtered atxd co8ceatt¾ted. Purified over silica gel

i eihylpyrldhi-3-ol i 15 rag, 0.089? mmol, . 20.6 % yield). Preparation I

2- i¾!Bo-:S-3«or0-3-i«ed5 ]pyt dtiK {1 ,0 g, 5.26 BKHOI) as dissolved id dry DMF (25 ml.) a seaied tube aad bubbled through with aitroge¾ for 10 m . Copperii) iodide { LOO §, 5.26 mxm\) was added follo ed by methyl 2,2-diil ior -2^fl oKj»»si0« i)iic¾i8i.e (2.34 ml. 18,4 mmol). H reaction was sealed and heated to 100 , After i hr the reaction was cooled to T. Upou carefully opening l¾e seal large pressure release occurs [Keep in hood a«d i¾ee efeittd sasif ]■ The orange mixture: was diluted EtOAc, filtered through celite, partitioned between 50% brine aadEtOAc, washed with 50% brine and brine, dried over sodium sulfate, filtered and coftcenirated. The oil was purified over silica gel (20-50% EtGAc in hexaues to atidrd 600 nig of exude 5-t!uoro-3-Hiethyi-2- {Mfiu roti-KtlJ i)pyndi«e..

Pni arattott II

Step A: A solu ion of 5-te.f5½--2 d s - -i¾eitiylp ridiae (4.47 , 22. mmai) in 6K HQ (28.6 m\ 175. jmaol) was heated at 106 *C tor 24 it. ft was cooled t 5 °C with, ihe iee bath. The pH of the solution was adjusted to --6,5 with solid sodium carbonate. The solid was collected by filtration and wastsed with waler (5 mi), and dried to give 5 jromo-4-methyipyridin-2( IMVoue (3.7 g, 8¾.9% ) as solid.

Step B; A solution of 5-¾ix)Kio-4-metbylpyrtdi»«2{ lH)- T.te (1.00 , 532 tamoi) aad K¾Ci¾ I M g, 133 omtol) in DMF ( H) rrsL) was -added Mel (0.40 sal 638 mrnol} at 0 ¾ C. Th mixture was stirred at 0 a C for 12 h. Thea n was wanned, to RT and stirred at RT for her Ϊ 2 h. Water (10 ml,} was added. The -aqueous layer was extracted wish EtOAe (3x20 xaL). The combined organic layer was washed wiiii brine (20 ML), dried (sodium sulfate), fdtered and concentrated under reduced pressure. The residue obtained was purified by Hash cliroaiaiography over silica gel ( 100: 1 EtOAc:MeOM) to afford S-bron»- 1 ,4-diraeilryipyrtdirj.-2(iH}-0!:iC (0.9 g,8?.S%) as solid.

Step C: To a solution of 5-bromo- l. < 4-d.i!i5eihyS jyridia-2(IH -oue (0.34 g f .1.66 mruoi} and. triffiethyi borate (0. 1 ), 3.65 ninio!) in tefrahydroferau ( l O aL) was added 1 .70 M -BuLi (2, 15 ml, 3.65 Hiiii i) m hexatK* drop wise over 10 nnnufes. The resulting mixture was stirred for 2 h at -78 <: C, arid eth&aep roxoic acid (0.7? ml, 3,6$ tmnol) svas added. After 10 mmutes at -78 ¾ C. the reaction was wanned to 0 C C and. stated 1st i .h, The reaction, was treated with sodium sulfite i).H4 g, 6M rotnol) u¾ water (5 mL}.. Sol vent was reme-ved taider reduced - pressure, lite resvdtkg solid was suspended in 4; i CHChiiPA (30 mL) aad stilted at RT for i h. The solid was removed fey filtratio . The filtrate was eofteeiitrated under .reduced pressure to give S tydrox -l,4-dijimhyip fidin-2(iH}-Oite (0,13 g, 51.2 %} as oil.

Following (fee procedure m Preparaiiois 17, the ibl!sm½g compoxmds wets also s atfeesized:

Preparation 01

Step A: " S-b.romoi>yridm-2-ol (I g, 5.75 mx i) was dissolved in BMP ( 15 mL) aad 60% NaR (0,230 g, 5,75 ίϊϋϊΐόΐ) as added and the i'ea ttoi! stirred at RT for 30 tute, iodoeihime (0.51 1 ml, 6.32 rrtmoi) was added aftd the resetters stirred at RT. After" S hi, the section was pari!iioried between ' wafer sad EtOAc, extracted with EtOAc, washed with htin dried over sodium sulra.se, filtered ¾sxi coineeiiteted. The residue was puriised over silica ge! (70% BtOAc itt hex) to afford 5*brorao-i- ethyJpyridiii-2(iH)-one. (61 mg, 3.06 imftol 53,3 % yield) as a white solid

Step B: 5¾o.ao*l » es !pyridiri-2{ {H)-o'fte 300 frig, { .48 rairio!) was dissotvt ! in diox;&ie i ' 7 tat s, 4, ^^4 S < 5.5\5 ! -QCtameife i- ,2 ' -bi( i J,2-d xab<ir lane (566 rag, 2.23 xw l) and potassium acetate {43? rag, 4.45 tnsK i) were added and ni&ogeri bubbled through for 5 mm. PdClj(dppi *DCM (12 i rag, 0.148 tHtnol) was added and the reaction .heated to 90 ¾ C overnight. The reaction, was cooled to E ' L Stored through ceHte, rinsed wifit EtOAc, eotseetrtrated aad pariSed over silica gel {50% EtOAc \n hmaes) to afford. i-ethyl-5-{4,4,5,5-t«iram«thyi- ,3v2-dioxabofoian-2-yl ipyndi:n-2f Ί EVoae (J50 oj , 1.40 xiv l, 94.6 % yield) as art m er oil.

Following the procedure in Preparadosi ΧΙΠ, the tQilewisg cott-paitnds were also synthesized:

5?6 Pre araiiori I

Ste A: Fmpsa-2-o! (1.19 oil i 5.5 mmoS) was dissolved in DM (40 mh), cooled i» ¾ce bath and 60% NaH (0.620 g, ! S.S ran¾oi) as added. he reaodos was warmed ' io 8.1 : S-h o-l- •chiorop rimidiae (2.0 g.1 .3 nasao!) as .added and the reaction heated to 80 " Coveniight. Ik reaction was diiuigd vs¾h 50% brine, extracted ih EiQAc, washed &¾ briae, Med over sodk«» sulfate, filtered arid. coficemr ed. The reaidsje was purified over siiiea gel (5% Et A. in bexaries) s afford 5-biOaio-2-isop<ipoxypynmidifi.c (043 g, 1. 8 aisaoi, 19.2 % yield) as a clear, colorless oil Sit-g B: 5-broo!o-2-!50>TOpoxypyrui : iidijse t ' 40 (Kg.. ' { . immi) was disolved in dioxarie ( 1 isL). 4 4 ^5 s 5,55-«caα)eh4»2 > 2'- ' ί(}.,.¾,2-d j oxabo«(tee} 7 2 ta , 2.76 ΏΧΟΪΟΙ) and oia&s ua acetate (543 tag, 5,53 auaol j w¾re -added aad nitrogen bubbled through for 5 ma. PdCy f^DCM ( 50 tag, 0.184 mmoi) was added ami the reaction este to 90 ' > € overnight. The reacuoa was cooled to T. diluted wifh ' EtOAc, filtered throu h eelite, rinsed with EiO Ac, eott¾««t ' rated and ' purified over siiica gel (15% EtOAc hexaties) to afford 2 so mp^xy-5 , ! 5 > 5 emmK;ih l'I,3 < 2-d ahoK)!at> 2-yi)pyromdine (422.mg, 1.60 tia l 86.7 ¾ yield.) as a white solid.

Following the procedure is PrepwMtos XIV, the foU wtitg cot¾poiaid was sy&i!iesizcd:

Following the procedure is Prepirafet 13, the following com ounds were also sy thesized:

1 Sirueture ame

4-(4.4 i 5 5 5-tetta.mei y!- 13s2-dioxaborqkn 2- y!H-< 2.2- rifl oroethy!)- 1 B~

pyrazofe

S.~eycloboiyl-4-(4.4,5. i 5- tetrai«etl¾ - 1 ,3,2- .-„-. dioxa ofoian-2-yl)- 1 H- yrsKole

Preparation

Step A: Methyl S^rydroxymeotisMSe (5,1 g, 33.3 wwl). anifcole {2 8 g, 35.0 rnmol), and TBDMS-CS {5.2? g, 35.0 mmoi) ene combined in 60 rah oftetrabyd sfam as RT and this was stirred ttfife a trogen. A precipitate qurckiy i raied. The feactiea was Stirred overnight. After that time, the reaction was coaceirf rated nod t reduced pressure. The residue was pa titiosicd betweeii EtOAc aad saturated aHO¼. The organic was ik wasted twice with I :l waierbr ie, once th bum, dried over MgSC¾ > filtered, and removed, under reduced press re us ailbrd methyl 5~Cteri- b«tyidimet¾yisily1oxy ai«)t.tnate ( 32.8 rnmot 99% yield.},

Sit&fs B: In 10 mi, ofT F was diluted methyl 5~Cieri¾ay3d!U¾ed.iyisiiyi0xy)nicoiinafe (2,0 g, 7 AH ramoi) md cooled to 0 '€ before Me gBr (5M mi U>,5 m>i) was added s !y. The reaction was wamsed to RT and after mxc h the reacdea was di!ased wills, satirratec! N¾Ci and extracted with EiOAc, The org¾fi.cs were then washed wish 1 :.i waienbrtse, Skered, and ren:«>ve ua.der reduced pressure. The- crude was ebramaiographed over silica gei {20% aeetoae in. DCM) to (1 ,82 g„ 6.8} mmo 91 % yield).

Pre arat ion I

(' 5- (:( terr-birt

Stec A: Methyl 5-(ter{-butySd Hieihyis!iy!osy «icodnai (1.82 g, 6. 1 mtm 91.0 % yield) was obtained from methyl 5 rydroxyiHcotii»a*e. ( 1 g. 335 sand) as in fteparasi ri XV Siep A,

sn Step B: fa 5 j»L of THF were eombiaed idumisumO ' H.) UMnm hydride (0.12 g, i mraol) and rncihyi S XQn' K\t≠dirm ^h\fyhxy)ttx t\ ^ ( 1 ,5 g, 5,6 ousel) at 0 °C and allowed to proceed for I hr. After that i ' irae the reacdoii was qusiieited wi th, solid sodfcuM sulfate decahydrate stid stirred vigorously for 10 mm. The. c ude was filtered, concentrated tinder reduced pressure, sad

•chroatatograpaed over silica gel {25% acetone at DCM) to yield . (5-( ' tCri- % yield).

Preparat on Π.

Step A: 3B 5 mL of THF were com ined a-Jott«!¾iai(ill) lithium hydride ( ,J:2 g, X 1 mimi) id methyl 5-(tm-bHtyWjt5iethylsHy sy}«kol «ale (1.5 & SXi t rnl) at 0 "C atid ai tewed io proceed for 1 far. Alter that time Use reaction was quenched with solid sodium satfm dseaiiydraSe and stirred vigorously ibr 10 am Hie crude was then filtered,, concentrated lo under reduced pressure, a»d purified over silica gel (25% acetone in DCM) yield {5-{ic«-b«lykim5cUiy5silylOx.y)pyridi«-¾- yl.ij.ncifeu50l. (0.62 g. 2.6 aimoL 46 % yield).

Step B: fa 2 mL of .DCM were comhiaed (5-(tert-hutyldimetlry^ (0.200 g, 0.835 mmaX) sad Dess- ariiu periodeaate (0390 g, 0.919 mmoi) at 0 <! C. The reaction was allowed to proceed .for & hr and was tbea diluted w h DCM and washed with i : i saturated

HaMC0$: I ' M Na ? 50.¾. The aqifeoos was back extracted with DCM three times. The organics were combined, dried over MgS(¾. filtered, removed under reduced pressure, and dried on. high vacuum o 3 ar. The crude was purified over silica gel (5% acetone in DCM) so a.fford 5-iteri- baryidirnethyisilyloxyteucotittaldehydc g « 0.558 axmoL 42.9 % yield).

S¾J C; 1B 1 mL of THF was cliHised 5^†e t-buty^^ ΦΜ0 g, 0.34 mmoi) and this was cooled m an ice bath ibr 5 nm befarc 3 e gBr{0. I 7 ml-, 0. 1 mtnoi) was added slowly. After Hi min the reaction tvas quenched with 1 : 1 saturated N¾C1; atet aud extracted three tiuses with BtOAc, The orgaaics were dried over MgSO*, filtered and concentrated to yield ί- 5- intnoh 93% yield)

Prepamt!oiii Π !

Step A: !¾ 50 M.< of DMA cooled to ø "C was suspeaied NaM ( 5.70 g, 42.6 mmsil ' ) befor -effeyi 2- hydroxy acetate ( .IB ird, 42.6 amos) was slowly added via s rin e sod 8» vessel was sparged with nitrogen during Ore addition.. The reaction was warmed to RT aad stir for i he. After trial, toe, 5- rom -2-noco yddi!).e (5,00 f 28.4 mmd) was added arid ie reaction was allowed fo proceed at T &r 4 r. The reaction was then diluted with water and extracted twice with EtOAc. The organic was t ' lieft washed se¾ueotia«y with, ί : ί saturated MaHC¾w;«er, i: ί brfete: atcr « brise, dried over MgSCXj, filtered, and coaceatmted to yield ethyl 2-(5-bromei>yridi»-2.ytoxy)aceiaie OM g, 28,8 uunol. yield).

Step : In 30 r L of lEF was diluted ethyl 2-{5-bmftopyridiit-2-y.loxy)acetaie<5. g, 19 mtiiolt and this was cooled to 0 *C before 3 MeMgSr (1.4 ml, 42 m ol) was added slowly. The reaction was warmed to RT after that addition. After one k aturted aq, ' NH»C1 was added slowly to the reaction, and then water was added. This was stirred at RT for S O min before 300 ml of EtOAc was added. Th layers were separated and the organic was washed nytce with i : ! waterrbrme, brine, dried over MgSO,;, filtered, and eoaceatrsted. The erode ptrriiled over silica gel. (2.5% acetone in DCM) to ■afford l S-b^siu^yridia-2-yioxy>-2-meti}yipO H-2-oi (4.2 g.17 mmol 89% yield).

S.tsp.C; irt 30 tnl. efdiox&iie were combined H:3%airK>pyfidiR>2- te >2-methyi m {}a--:2->l (4.2 1, 17 !Bsnol), 44,4\ \5,5 ; 5^5'-octa?5:fethyi- ,2 , ^ii ! dto<xabcKicte) |6.5 g, 26 mm t d OAc (5,0 g, 51 mrnol} and this was sparged iift Ar for 5 tnin before PdCMdppi)*DCM (1.4 g, 1 ,7 tmmt) was added -aad the sparging was comioeed forai &itei ' 5 rnin before the ieactfon was sealed and heated to 100 «C. The nest day the reacttott was dflmed with \ : I DCM: EtOAc and this was filleted. TJie cake was washed with DCM arsd then EtOAc. The organic was removed under reduced, pressure aftd dried h. The residue was purified over silica gel (10% acetone in DCM) to afford 2-meihy.M S^ > ¼ et^

g, \9 mmel 12% yield). following the procedure in Preparation XVii ' l, the foj ' lowiag compounds were also syatfcesked:

PfeparatioB

Sla A: 2-{5-bramopyndi5i-2- .toxy)et ¾}o{ (4.0 g, 18 mmisi) was converted io 2-(5-(4 ! 4 > 5 i .5- 18 ttmeU % yield) fo!towing

Step C of Pre aration XVltt.

Preparation X

Siea A: In 20 :»iL of DMA wete com ined M (1 ,209 g, 30,24 mmo! .mid p eayimethfftol «. ! 32 ml, 3 2 rorooi) as RT god allowed proceed wish stirring for 4 lis . After thai time, ! -(5-bi¾Kso-4- fl orop r!dm-2-yI 3-m0il{ liiea (5.0 g, 20, 16 ftyno!} was added and die reaetioa was allowed to proceed nx 70 *C, After the weekend, the reacaoa was cooled to RT aad ihm diluted mi 120 nil of Wat«f aad stitted vigorously. The solids were celfeeted via vacuum iillrmm ted dried in a -va u m oven to afford l-{ -(be:ft2 fox ^ (659 , 19.60.mrao.197.2 % yield). Step B: in 6 M MCI (25 ml 150- ramol) was dissolved i-(4-:(bes j-'io¾y » 5-bmmop¾ ; ndia~2-yl 3- ateihylufea (3,0 g« mmol} aad 2-a maoe ¾a!}«ifeSoI .hydftJCaforide ( 1.52 g, Π.4 ISHS I. sad lis ied to 1(H ) *C ovcf¾ighrw:ah stirring. The trext raaraillg file solids collecied around the top of the vessel were iatrodaced into the aqueous via staking aad rni stirred, at 10O "C foe another 16 ar. After that time the reaction was cooled in an see bath and His pH was adjusted to 14 wiih 50% NaOH. The pH was then adjusted with COHC. HCI to -5. The .resulting solid was eoSie-eied via vacuum iltotioa atid waslseti wtdi: water. This .material was dried is a ggauth ovea to yield Ϊ -( S - o 55¾ - sy ^ ΕΙ ?i:y i idit 5- 2-y] ί-3-metfc ii!rea (2.6g, 8,49 m tnol, 5% yield j

Example 1548

A jnis.¾.re of i 5-bm«io^-ikioropyTk!a:^2-y!)-3-iJied¾'S.»rea (500 tng, 2.02 RHaol), 5-»!Ci yipyricii»-

(330 trig, 3.02 ntmol} aad potassium carbonate ( ¾36rag ? 6.05.mmol) la dry dtnietlvyl acetamidc (DMAs (5 mLs was stirred under nitrogen with ' heariag to 90 *C ίοτ 3 k The mixture was allowed to coal, diinted with water {30 raL) aad iae solids were collected by filtration. The solids were washed with water (50 L) md then dried un er vacuum So give i-(5-3>romo~ (5-methyi y.ridia-:?- yl)oxy)p>^diae-2-yi}-3-tnet yiurea (540 mg, 79 % yield) as a van colored solid. MS (apci) xa z 337.0, 339.0 < ] -H '

Ex&mpie .1553

Step A:. (1000 mg ( 2.966 awno!), ethyftyit meth is&ffie (1182 uL, 8.304 ma¾l). Etj (!240 pJL 8.S98 BKROI), PdtPPh;);;CSs <104 isig, 0.1 8 tntrsol), irip eoyiphosphins; (39 sa , 0,148 rnmoi) and Cal (14 i»g, 0,074 msrioS) ¾i dr DMF (DMF) (2 «iL) was purged with 'ftitrogea a»d sealed i a fsiifgHeiicalSy stirred vial, ' flic -mixture »s heated at 90 "C for 8 h. After this time, fttnks- aikpots ofei yaykriiaethykilaHe, Eb, Pd{PPSi : jC!; ; tripheiryiphospfeine a«d Cul were added (si«»iar qaasr ties to those, initially added). The .heating was continued ibr a inrthsr 5 Is at which time the imxtore was diluted with water (2.0 !siL) and extracted into ElOAc 0 x 20 mL).%? cetnbitted. extracts were dried (sodium sulfate), filtered and eoftcereirated tittder vaciftrftt The matesiai was purified ve siJiea gel (hex re;EtOA.c (4: t

Step S; To a solution, of mixture of t -roed-ry i-M -(5-meth^

{ iriiticyi; ¾3tyi)e 5yoyl>pyd^ ( 38 g, 2,36 i aols in MeOH (10 ml.) was added potassium carbonate {0 rftg, 4.73 ramol) aad the .mixture ' was stirred at RT .for 5 h. The MeOH was removed under a M w of nitrogen. The .residue was .mixed with .DCM {50 ml) containing. MeOH (5%). The suspension as washed ith water (30 mL dried (MgS : and sodium sttUate), filtered and concentrated under reduced pressure to gi ve t-CS^thyriyM S-methylp^di ^- loxyjpyridia- - yiKVmethylurea. {490 tag, 73 % yield) as a cream colored solid. MS (apci) xnfz 282.9 (M*H).

' Example. 1554

6-(irff]t.iOiO!):ietS)yl)pyis.di:f)-3-oi (360 mg, 2. 1 uitaol) was dissolved m DMA (5 «tL) stxt aH 883 mg, 2.21 rarao!) was added and the reaction stirred at RT fm Ϊ mm. l»{5-bm«K)-4-il iofo . pyridj«-2- yi)-3«raethy1urea (548 rag, 2.21 mraol) was added and the reaction heated to KH ) °€ overnight. The reaction was cooled to RT, dihited with water {25 oiL), stirred for i 0 ratio, filtered and dried. The solids were triturated with <?,%<¾, littered arid dried to afford S -(5-broH30-4-i;6- 1.48 tntnol 67.2 % yield) as a white solid. ! H N R (400 Hz, D SO) S ppm 9.33 <s, I H). «.75 id, j-2,5 H¾, tH), «.41 (s, iH), 8.06 td, ¾ S.H). 7.94 (dd, j=8.6, 2,7 ill), 7.32 (¾, }H), 7.22 s, 1M), 2.64 (d, j-4.7 M¾, y. Mass spectrum (apci) ni¾ - 390.7, 392.7 (Μ+Ή), Example 1555

methyl H(6-etho^

Step A: Usifig site same mefood as Example 1554. meOiyl 3- S-bmnio-2-f3-:nK!h laix:ido)pyridifi-4- yl0s:y)-4-fi«eTe eBiC08ie (0,713 g, Ί .79 aaaoL 44,4 % yield) was obt&ined. Sabstiftiiing sSiCfiiy! 4- flyoro-S-hydroxytazoate for

Step 8; la 5 i«L of ioxane were combine 6*sthoxypyridiR-3-yiberosie acid (0,1 6 g, &?5:5 mxaois, methyl ~C5~bromo-2 3"i»efe g, 0.502 r« oi), and yP0 (0,753 ml 1.51 raoi) and tltis was. sparged with Ax for 10 mm before PdCijfdppf)*DC (0,06 i 5 g, 0,0753 mmoty was added a&d the sparging was continued for 5 niimiies before the reaction was sealed, and heated to .100 "C overnight. After tfcat time, the .reaction was diluted with. DCM. loaded directly onto silica gel ( f 0¾-15% acetone is DCM) to yield methyl 3-(i> ! -efhoxy-6-{3- ra th lureido)-3 , ^ip rid!a-4- i0s )- -ihiOfobeJ¾oai.e (0.143 g, 0,308 ra ol, 61.4 % yeld. ¾ N R (4 ( X ) MHz. C0<¾> ppm 9.05 (s. I H), ¾,33 (d, Hz. iH), 8.19 s, .IH), 8.10 is, iH), 1.95 <ra, IH), 7:85 (dd, , ?,6, 1.91¾, IH), 7,81 (dl J-8,6, 23 ¾> IH).7.27 <¾ ! H), 6.80 id, j-8.6 Hz, IH), 6.04 <>. SH;, 4,40 {q, : 7.0 H¾ 2H), 3,91 (s, 3Ή), (1 4.7 H¾ 3H), i .42, ft j-7.0 Hz, 3H). Mass spsetmio (apci) i.a¾ - 441.2 (M÷H).

Foiiow!.B| the roce ur its Esat»ple 1555, ski; foiewiag compounds cm also be synthesized:

Followin the procedure in Example 7¾ the ibflo Htg compounds were synthesized;

Pollowmg i e procedure i Exam le 155, tite ibllowiag eom OKOcls ere aS:so syatiiesixed:

Exam le 1.588

mmol) was s»spe«ded to diOxaae (1 mL) and 2M K?CO s ί 542 μΐ 0,28 mraol) sad S-eitioxypynMdirr- 5>yibore»ic acid (36 jag, 0.2 i oMie!) were added and the reaction bubbled through with siiroges for 5 m . Pd€½(dppi)*DCM ( 12.mg, 0.014 mtsoi) was add d sad toe reaction bea ed to 90 °C for i ¾.t, Use reaction was cooled to RI\ partitioned betvv«e» water and DCM, extracted with DCM, 10% MeOH to DCM, dried over sodium suU e, filtered aad corseenifated. The residue was- purified over silica get (15% MeOH hx EtOAe) to afford ms ire msterisl The solids were purified C J 8 reverse phase co mm (5 to 95% AC in. water) to sffbid i -iS-iS-dhftsypyriisidift-S-j'!)^^ }.-saethyJ-6- xo- rag, 0.058 majo 41 % yield) as a white

solid. ¾ (400 M¾ CDCf.) o pp 8.99 fs, iHO, 8.67 OA 2H), 8.29 (s t i ¾ 8,09 (s, ill), 726- 7.20 (m, 2H) 6,05 (d, ¾fe, iH), 6.2 (s, IK), 4.4S (q, j-6,7 ¾ ¾ 3.55 (s, 3H), 2.89 (d. J-4..7 ¾ 3M), J - 7 ft, JM.7 ¾ 3H), Mass spectmro (APCi) ra//. - 396.8 ϊΜ-ΗΗ). Following the procedure in Example 5: 586, the M wiiSH titip usids vs¾re also sy hesiiscd:

■ rscihviurea

Example 1604

J-i5 3roiK0-4-(3 hloro- k^^ (100 g, 0.26? mtm\) as dissoived ii) dioxaas (I. i»L) ia a sealed tube aftit 2M potassium carbonate (4 ( 50 ul, 0.80! ami©]) aiKi ethyl 2-(4-(4 > 4,5,5-tei!¾iS:ief:hyl- ί ,3 : 2-dsox;ii>o®Sas-2-y!]- H-pyra^S- l-y!}ace¾te < i 12 tog, 0.400 rmsxiS) were added and. mito en bu led through for 5 rain. PdCI ;; (d pf)*DC i M (21.8 rag, 0.0267 mmo\) was added ¾»d ajtrogea bubbled through for 2 mm and reaction sealed md plunged into a J00 "C Pit bath overnight The reaction was cooled I» RT, water ( H) laL) was added and the resultin solids were filtered. The solids were purified on a C JS reverse phase CGIUSJBI (5 So 95% ACM in water) to atford 2-{4-{4-{3 Moi 2-tI»ompl:seB0^ I H-pyragoi- 1 -yDacetic acid 053 mg : 0.(064 Uitiio!, 13.7 % yield* as a white soik!, ¾ MS (400 MHz, ds-DMSO) δ pptn 9. 12 (s, S H¾ S. 8 (s, 1H), 9.09 (a. ! B) ; ?.&5 is, Ιϊ¾ 7.68 ( m f IH), 7M (t, j~?.Q Ηχ, .2Η), 7.42 {i, J-7.2 i . \ H>, 736 (t j .S. Η,·· . ! Ηχ 630 fs f li¾ 4.60 (s ; 2H} ( 2.65 (d j~4,5 \ w.. 3H>. Mass spectrum APCi) :¾¾∞ 420.1 {M.÷.H}.

Foilo fij the procedure in Bxarupk ! 5S ; the ollowin compounds were prepared substituting T8AF for Κ¾% and usisg the proper starting materials.:

Example 1608

Step A: The nsceriii Ktiistsifeti &ora Example i 60? was »p»sisd by chifttl e&smatogap y (Cojktt JC a ami X 20»a«, Plow Rate: QmL/tx»n > M A- 60% {supercritical C{¾.), MFB÷= 40% (90; 10:0. S MeOiI:iPA: DEA). This material m$ from she first eiutiitg eak and the siercocheoiistry was arbitrarily assigned. 5 Ni R (400 MH/, CDCi ? ) 8 ppm 9.02 (s, IH), 8.4? {§, ! H), S.37 id, j ' ~ I 3 H¾ IH), 8 0 (d. j-23 H¾ S H} < 8.27 (d, 3-23.¾ JH), 6.79 <d, j « 8.c> H¾. ΪΗ), 6.22 {$, I H) t 4.98- 4. 1 i , IH), 4,39 j=7.0 Hz, 2H) > 3.3 {&, I B), 2,83 ( j-4.7 ¾ 3B), 1.49 (il 6.4 ¾ 3H), 1.41 (t, jk7j) H , 3H). Mass s ecmmi istpct . ) κϊώ∞ 4 i .1 (M : ÷ H).

Following the procedure a ove, the i lo ing compound was oisted as ilss second cg ting peak am! stereochemistry was abitraril assigned:

Following the procedure in .Example i55, the following compoumis were prepared subS Miag MaH

ExarBf k ! βϊ 5

Step A: in 20 mt plveoylinsibaaal (3.132 ml 30.24 stumol) at RT and stirred for 4 h. 5>Bro»w4.¾Oit yrk )«-2-y5)-S^»jet yi«r^ (5 0 g, 20. I 6 mm©!} was added- and {he reaction was stared at 70 *C for 72 hr. The reaction was cookd ta RT aad diluted with 120 mL of water and stirrsd vigorously. The solids were collected via vacnum filtratioaand dried i» a vaeiuria oye s io

{6.59 & 19.60 mtuo 97.25 % yield).

Sfep B: hi 3 () ra ' L of dioxane were combined M;4<b ¾2yiox >~5-br0imp

(4,0 g, 12 mmel i « mediyi « -{4A5*5 etra5nethyl- !.A2-dioxaborokn«2 « yiH H*py o e (3.7 g, 18 mmo.1). and potassium carbonate (W ml 36 mmol) and this was sparged for 3 nvirt with Ar.

PdCI:(dppf)*DCM (1,5 g, L8 romei} wits added and the reaction was sparged for SO aria b fore R was sealed and heat d to 100 X. ' for 5 hr. The reaction was cooled to RT, poured into water and. extracted with EtOAc 0x) 00 rat). DCM (1x1.00 h\ dried oyer sodium sulfate; filtered and. concentrated. The solids were purified over silica ge < Ϊ 5 io 30% acetone in DCM wf 0.5% H, ( OH) to afford I - » (be:n^yiosy;)-5-(l oem MM-p>Ta;ml- - ^^ (2.0 g, 5.9 mraoL SO % yield).

Sie C; tnmol}

and 2-amifKMithancmiel hydrochloride ( I .0 g„ S.9 nanal) were, dissolved in 6N i (28 nil, 1.66 mmo ' l) and fceated to 00 -> C for 12 r, Io a separate flask was added 350mL sat rated K ; CO> solution. To fids was added die reac tion solution dropwise -until learning began io occur. Adde another 2t¾sL sat K¾Ci¾ followed by addition of reaction solution umil foaming occurred. Repeated this process until all the .reaction solution was consumed arid the pH o f the new solution was 7. DCM (500 ml.) was added and stirred vigorously;. Tie solve s! .mixture was fdtered and solids dried to afford- W4*

g, 4,6 tmaoL 78 % yield).

Step D: in 2 ml- of DMA were eombaied.2 hioro-6-.mtoro¾es¾onitrile (38 mg ( 0.24 .mraoi). 3 -(4- h dmxy-5-( ~meihyl-lH^^^ (40.nig, 0.16 mmoi), and potassium

-carbonate (45 mg, 0.32 mmol) and this was heaved to 80 for 3½r, The reaction, was cooled to IT and 4ml, water added and stirred for 1 minutes. The precipitate was .filtered and. dried. The solids were triturated in E¾0 for 2hrs with vigorous stirring, filtered a d dried to afford i-{4-{3-chh ro-2- cyanop¾es:iisy)-S-( i -methyl- i H-py^zo -yl)p ridin-2-yI)-3-i«eifey.hflrea (26 mg, 40% yield). Ή NMR (4(!0 MH¾ CPClj} ¾ ppm 9,20 (s, H)., 8.54 (s, j H} ( 'ί.ί 1 (s s SH) ? 7,gg (s, IH), ·.:«) (t ,NU H>, }«), 7.S6 ( ¾ !H), 7.46 <m, IH), 7.32 ¾ j-8.4 i¾ 18), 7.08 IH), 3.85 ( S> 3H), 2.66 i¾ j-4.3 ft?, 31-1}. M ss. spectrum {apci? iwz - 383.1 {M-s-H,

Folio iag the procedure in Example 161 S, the r awi g coaipoutsds were also s ataesiised:

Example Structure ame Dais

K4-(2-c aro~6- Mass cyan0phetMxy}-5~(l * spectrum mehyl - 1 H~pyn3zol-4~ (apci) mfz

1616 y]):pyT5.dis3-2-yl)-3- -383.1

meflwlurea (M+H)

K4~i3,6<ikMo.r< 2- Mass cyaQO|>.heaoxy)~5-( .1 - spectrum

.methyl- 1 H.-py tazol -4~ (apci) ffiz

yl)pyridi«-2-yl)-:- -417.0

161? O, J , ...... CK ri m«ihyl«rea f ¾)

V

H... 1 -{4-(2-cyano-3 6- Mass

diiliioropheao.syV5- spectrum

(!-metiiyl-IH- (apci) mz

161 ¾ pyrazol ~4-yl)py im ' - -385.1

2-y!)~3-}¾ethylure CM+B) l-(4-(2-eyano-3 s 6- Mass diflaoroph.£soxy)-5- spe vru-.n f I-2-hydr xyet¾y1)- i ' apci) mz

f H~pyra?.ol~4- •115 i yI)pyriiJiti-2-yl)-3» CM+H)

meihjarea

l-(4-(3 i 6-dichlor -2- Mass cyimophe«osy)-5-(l - spec-tram

(2½droxyetkyl)-lH ' - (apci) rp/z

1620 pyTazoM--yl)py.ri m~ - 447 Λ

2-yi)-3-meihy!«rea (Μ-ί-1-i)

Mass

41. „ , roet ylphe»oxy 5- spectrum

(apci) m/z

1621 pymzoi-4-yl)pyridia- - 363,1

2~yi)-3-r!iei}iykifea <M÷H)

S<>9 Example 16

J -{5-{3, -ΟίΙ^ίο-2Η^3ντ3η-4-νϊ}- -( I ,2-diH¾5thy !-O SXO- ί ,6-diljyd!»pyndin-'3-yisxy jp ridit^- f }-3- meftt h«¾a ί 58 sag, U4¾ roiftol) was snspeaded f« S. ; l MeOTEtO Ac ,a»d 50% PdC ( 18 mg) was a ded and placed ovendgfot The hydrogen allo was replaced and the reaction ' heated to 45 a for 2 days with occasional refii!ksg of hydrogen balloon. The reaction was cooled to T, filtered throngs eelSte. concentrated and purified over silica gel (\W» MeOH in EtOAc) to afford l-C4-(L2-diiBetiivi-6-oxo- 6-dibydropy

yi)pyridin-2-yS)-3-ri)eiiiy!u:rea f 13 rag, 0,035 Htmo? 72 % yield) as a tan solid. ; H NM.R (400 MHz, CDC ) S P « «.14 (s, IH} < 8.13 is,.1 H), 7.96 {s » H> y 7.10 (d, ,1-9.8 H), 6.54 (d, J^.6 Hz, I B), 5,94 (§, IH), 4.H) (fid, j-ί Ϊ .2, 1:9 ¾ 2H), 3,61-3,54 (m, 5H), I 2 (m. Hi), 2 J (d j ' ~4,5 ¾ 2,23 {¾, i ), i ! .7? toy 4B3, Mass spectroiS. (apci) m/¾ - : 372.9 ( -f-H).

.Example 16 3

Hfi'-etl»&¥~4^ ' i--o;at.hv½

3-i»eiiivki£¾;s

Slap A; To a solution of ethyl 3-amino«4 44rit1 orocrosoHae ΠΟ,Ο g, 54,61 ramoi) in DCM (50 mL) sa pyridine (5, 8 g, 5.3 s.»L, 65,53 aunol) in a water bath,, was added dropwise ethyl mai.os.iyi ■chloride (10.28 g, 8.74 mL, (S826 a¾«*oi:> over 50 mirs. The raktiire was stirred, for 48 iiatRT.. The Solution was diluted ith BtOAc aad wash d with water, IN HCi, saturated aqueous NaRiCQn solution, dried ( gSG and concentrated to 12.9i>g ot ' crude .ethyl 3~(3-eiS:io.xy-3-oxopffipaniaisldo)~ 4 5 4 5 4-trii wo.f¾kJt » 2-eaoais as a yello orange oifwhlch was taken fer afd without ftmher pi!iifkatioii.

Step B.: To a solution of the cmde ei&yl H3 a^osy-3^xopropaiS3B«<ioH^^-i«fl∞o^-2-ea ½te

(1 .¾t g, 43,6 mmol) m EtOH (90 mL ) cooled on a water hath as added otassium t¾stoxide {9,05 g, 80.6? mmol) portloHwise over 25 mi a. Upon complete addition, die ixture was heated at 70 *C for 2 a, tbeo allowed to cooi asid stirred at RT overnight. The solvent was the removed under reduced pressure and the ellow-oraage solid residue was stirred in a saturated solu ion of eitirc acid (100 mL) for 30 mia. The resulting suspension was filtered and ashed several time whit eitirc acid solution to afford crude ethyl 4-hydroxy-2-o:so-( nii1uoroineihy as a light ptalc solid < 13 g).

Siep : To a stirred 6M MCI solution (100 mL) was added portiouwise ethyl 44rydroxy~2-oxo~o- (trifKtoromethylH .2-dilrydropyr!d!ne-3 rhoxyiate (13.9 , 51.8 »l) nd the resulting suspeasioa heated at reflux. -overnight. The-solniioa was cooled i» mi ice bath and neutralized with ¾OH. The precipitate which formed was collected by filtration, and washed wltlt eold water -and hexanes and. dried so afford 4 r>'dt¾5i: -r-{ttiauoroJ»eiHy } yrjdta-2{ 1 H)-o«e (6.62 g, 31. ii mmol 71% Yield) as a •c-res-H colored solid,

Step D; A s km oi dds drox^^ ^ , 9,77 mitioi t and. jCOs (358 g. 24.4 mmo!s in DMF 00 mL) was added iodometltaae (0.730 mL, 1 1.7 mmol) at 0 ,S C. The uiisttiie was stirred at 0 "C aftd warmed s o ly so RT aad stirred at: RT overnight. The reaction mixture was charged with more K : .CO :i {3,38 g, 24.4 mmol) aad Mel {2.7?g, 1 ,22 Ϊ 5 mmol) and the mixture stirred at RT lor iSfo. Water (100 nil) was added resulting lu the separation of a precipitat which was collected by it!tratios washed with water attd dried to afford 2,4-dimethoxy-S- (triiluoroiaetiiv!lpyridlae (570.tag, 2.75 mrnoL 2B¾Yield) as a cream, colored solid. Tire aqueous layer was extracted with 10% IPA-DCM (3 x 40 ml) and the eoajhined extracts washed with brine and dried (MgSC¾) aad concentrated. The residue obtained was purified over silica gel (40% EtOAe in hexanes) to afford -meiao.xy-l-met yHH r tl« mmeth. l) yridiO!>2( l.H}«oae (50( atg, 2.4.1 mmol 24,7 % yield) as a white solid.

Step: E; A. solution- of 4~methoxy- I -methyl-6>(trffluoro.tt5ei»yi)pyO ' dht-2{ Ϊ Hj-oae (500 sug, 2.41 mmol) at 1 ,0 NaOH (20 «.iL)and THF (7 mL) was heated, at 100 °C S¾r 72 h. The mixture was eoo!e-d oa an ice-bath aad acidified with. I N HCL. adjusting the pH. to 3 and then extracted with 5%lPA-EtOAc. The combined organic extracts were washed with brine (hen dried (MgSO and concentrated to afford 4*hydroxy--l -tmt yi-<^ ' tri ' tluoromc^hyl)pyridm- ' 2t ' i H OBS (345 mg t 1.79 mmol, 74% Ykld) as a light yellow solid.

Step . Ft 4-Hydrosy -msthyt-6^ ( 100 mg, 0.518 mmol) was dissolved m DMA. (2,5 mL) aad 60% NaH {20.7 sag, 0.-5.IS nxa ol) was added aad stirred at R for 10 tnia. I -(5-bmm.o-4-iluompyridin-2-yl}-3-ineii:¾yhirei¾ (JO? tng, 0,432 ramo!) was added wd the reacOoti heated to 100 a C overnight ibm ί 20 χ. ev«o»ght agaiit. The reaciort was cooled to RT, and diluted it water (8 «1L aad siirted vigorously for 20 ffii , filtered a»d dried to afford l-(5-ferOi»o- *

( I -ined:iyi!-2-0xo-O-(ii:i:fluC!tO):n«diyl}- j ,2- ihydrapy«di:n-4~ loxy^^^^ (04 mg,

0.223 maicl.51.7 % yield) as a iaa s»iid.

S.t¾> O: I -(S-Bromt K I -inetityi-2^ox»-6*{iT!JJuoro»K!lhyi)-{ ? 2-dih dE¾p rd5a- - iox :)pyTids5-3- l)- 3→net]ryl»rea (40 mg, 0.095 mtml) was dissolved In dioxsrte ( I t) mid 2M KjCO; (93 μ|, 0,10 mmol) aad 6-eti:ioxYpyridit^3-yibomaic acid (24.mg, 0,14 mmoi) were added aad the mixture bubbled through with nuragen lor 5 min. Ma 5 (dppf)*r>CM (7.8 mg, 0,0095 mmol) was added and She reaction stirred af 100 ovendg . Tire readies was cesied to RT, partitioned " between.50% briae and EtOAe, dried over sodium sulfate, filtered and eortceatrared, Porstled over silica gel (00>¾ BtOAc in tames to afford i -(6'-ethoxy-4-(.i -rri¾S.5yl-2~oxo-6-(tri:tIuomtneds.yl)- } -dih dr pjTidm- - ios. -3 5 3 yridi«-r>- -3-i∞¾½ti-¾ (1? r¾¾ 0.037 m ol 39 % yield) as a white solid, ¾ NMR (400 M¾ CDC ) 8 ppm . (s, 11¾ «,24 (¾ 2H), g.19 (m, !H 7.