WO2012158515A1 - Process for the preparation of protease inhibitors - Google Patents

Abstract

A process for preparing enantioselectively a compound of formula (la) or (Ib) over a compound of formulas I-2—1h.

Description

PROCESS FOR THE PREPARATION OF PROTEASE INHIBITORS

Cross-Kefereiice to Related Applications

[0Θ81| This application claims the: benefit of priority of U.S. Provisional Application Ho. 61 /4864.50, filed: May 13, 201 1 , which is incorporated heroin as reference.

Field of the ItiveBiio-tt

002j Thfe invention relates to processes and intermediates -for the preparation of protease inhibitors, i particular,, serine protease inhibitors.

Background of th Invention

JO0O3) Infection by hepatitis C virus ("HCV") is a compelling human medical problem. HCV is recognized as the causative agent for most cases ofnon-A. and non-B hepaii is with a estimated human sero-prevaience of 3% globally (A, Albert! et ai,, "Natural History of Hepatitis C,'V, Hepato g _y 31 (Suppi IX pp. 1 7-24 (1999)}, Nearly four million individuals may be infected in the United States alone. (M,J, Alter et ah, "The Epidemiology of Viral Hepatitis in the United States." Gastroenterol Clin, tforfk Am... 23, pp. 437-455 (1994); M. i Alter "Hepatitis C Virus^■ infection in the United States," J Hep toiogy, 3 l (Suppi. pp. 88-91 ( 1999)).

| ί>04] Upon first exposure to HCV, only about 20% of infected individuals develop acute cluneal hepatitis, while others appear to resolve the infection spontaneously. In. almost 70% of instances, however, the virus establishes a chronic infection that may persist for decades. (S. iwarsop, 'The Natural Course of Chronic Hepatitis," F MS Microbiology Reviews, 14, pp. 201 -204 (1994); P. Lavanehy. "Global Surveillance and Control of Hepatitis C3' J Vital Hepmitis_* 6. pp. 35-47 (1 99)}, Prolonged chronic infection can result i recurrent and progressively worsening liver inflammation, which Often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma. (MC. Kew_» "Hepatitis C and Hepatocellular Carcinoma " FEMS Microbiology R views, 14, pp. 21 1-220. (1 94); i . Saito et. al., "Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carciliop a " Froc. Nail Ae d Set USA, 87, pp. 6547-6549 (1990)), Unfortunately, there are no broadly effective treatments for the debilitating, progression of chronic HCV,

(01)115} Protease inhibitors, and in particular serine protease inhibitors, are useful^' in the treatment of HCV infections, as disclosed in WO 02/18369, WO 02/18369 also discloses processes and intermediates; to the preparat on; of these compounds. These processes lead to raeemizatioii of certain steric carbon centers. See, e.g., pages 223-22, As -result,, a need remains for enanuose!ective processes for the preparation of these compounds.

Sunisnasy of the Inventkm

[00061 ^'This and other needs are met by the present invention, which is directed towards processes- and intermediates for the preparation of ^'protease inhibitors, particularly serine protease inhibitors. In. one aspect, the invention provides processes and intermediates^'. for producing bicyelic deri atives of formula is or lb;

wherein:

rin A is a eyeloatiphatic ring;

ring B is a heterocycio-aliphatic ring containing an additional 0 to 2 hetero atoms, each independentl selected from O, N. and S, thai can be optional iy substituted with 1 to 4 groups, each independently selected from alkyf halo, aikox , aryl. and hydroxy!;

t is H or a protecting group: and

S¾ is ί ϊ, a protecting group, or Ci.r>- aliphatic.

O07j One aspect relates to a process for preparing enantioseleettveS compounds -of formula, la or lb over compounds of formul s lc - Ih;

fla li

where n R_?¾ is. a. protecting group, in the presence of a compound of formula 111;

wherein R.$ and R,_¾ are each independently a

group selected from the group consisting of eyeioaliphatie, heteroeycloalipliatic. atyi and heteroaryl.

P008J Another aspect is di a compound of formula 30:

10

xvhereur ? is defined above, and 7,2 is H or a protecting group;

comprising the steps of:

a. fomiing. a 2 -anion of a. c mpo nd of formula Ha:

ila

wherein Ri* and ring A are defined above, in the presence of a compound of formula ΙΠ:

wherein lis and ftj are defined above;

treating the 2-anion of step a with carbon dioxide to produce enantioseleciively a compound of fpmuvla la; and

reacting the compound of fbrmuk la witli a compound of formula

26

wherein Z<) is a protecting group,

Detailed Beseriptioa of the ¼vej¾f ίάη

Defmiiio

10009} For the purposes of this invention, the chemical elements are identi fied in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics,

15 ^t Ed< Additionally, genera! principles of organic chemistry are described by Thoma

SorreSi in Organic Chemistry, University Science Books, Sansalito ( 1999% and by M.B.

Smith and J. March in Advanced Organic Chemistry, 5^lh Ed., John Wiley & Sons, Mew York

(2001), both of which are hereby incorporated by reference.

[000101 As described herein, compounds of the■■invention ma be optionally substituted with one or more suhstiiuents, such as are illustrated general ly above, or as exemplified by particula classes, subclasses., and species of the inventi n.

[00011]^' It must be noted thai as used herein and in the claims, the singular forms "a, ¹¹

"an " and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a binder" includes two -or more binders, and reference to "a

pharmaceutical agent" includes two or more pharmaceutical agents, and so forth.

[00012] As: used herein, the term '"com ound" refers t the eonipoimdf s) that are defined b structural formulas- respectivel drawn herein. Furthermore, unless otherwise stated, the term "compound^"' can include a salt of the eompound(s).

[00013] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyL an cyeloaiiphatic, each of which is optionally substituted as set ibrth. below.

[00014] As used herein, an "alky!" group refers to a saturated aliphatic hydrocarbon group containing 1 -8 (e.g., 1-6 o 1-4) carbon atoms. An alkyi group ca be straight, cyclic, or branched. Examples of alky ! groups include, but are not limited to. .methyl, ethyi, propyl, i.sopropyL butyl, i so but l. ,yee-bnty], e/T-butyl «-pcntyl, tt-heptyl, or 2-ethylhexyi.. An alkyi group can be substituted (he., optionally substituted) with one or more substitiients selected from the group which consists of halt), cyeloaiiphatic (e.g., eyeloalky! or eyc!oaikenyl).

beteraeycloaliphatie (e.g., heterocyc!oalkyi or heterocyclpal.ke.nyl), aryl heterDar l, aikoxy, aroyh heteroaroyi, acyl (e.g,, (aiiphahe}earbouyl, (cycloaliphaiic)carbonyL or (heteroeyc!oa!iphatj^carhonyl), nitro, cyano, amido (e.g., (cycioalky!alkyi)carboByiarnirto, aryleatbonylamino, aratkyfearbonylauhno, (heterocydoalky car onylamino,,

(heierocycloalkykh.^

¾eter¾aralkylcarbonyiaramo alkylam ocarbonyh eyck>alkylarainocarbonyi.

heterocyc!oalkylarninoearbony arylaminocarhonyl or heteroaiylammoGarbcmyl), amino (e.g., aiiphati amino, cycloaiiphaticammo, or heterocycloaliphaticammo). sulfotayl (e.g.., aliphatic- SO2-), su!fmyl sirliarryl sulfexy, urea, thiourea, suiianioyL sitltkniide, 0x0·, earhoxy, carbamoyl, cye!oahphaticoxy. heterocyeloah iharleoxy, ar loxy. heteroaryloxy, aralkvloxv. heteroaiylalkoxy, alkoxycarbonyl, alkylcarbon.ylox.yv and hydroxy. Without limitation, some examples of substituted alkyls include earboxyalkyl (such as HQOC-alkyi, alkoxycarbonylalkyL and alkylearbonyloxyalkyl), eyanoalkyt, hydroxyaiky alkoxyalkyi acylalkyi, araikyl, (alkoxyaryl)aikyl, (su!i½ i rai o)atk i (such as {aik i-SOi-atnino}aikyl)_? aniinoaikyi, amidoalky I. (cycloalipiiaitcjalky!, and haioalkvi.

fOi iSj A used herein, an "alkenyi" group refers to an aliphatic carbon grou (hat. contains 2-8 (e.g., 2-6. or 2-4} carbon atoms and at least one double bond- Like an aikyi group, an alkenyi group can be straight or branched. Examples of an afken.yi group include, but are not l mited, to. allyl, isoprenyl 2-butonyl, and 2 iexenyl. An alkenyi group: can be- optionally substituted with one or more subslituenrs such as halo, cyctoaliphatle (e.g., eycloalkyl or cyc-loalkenyl)_., heterocycloaliphatic (e,g,, teterocycroaik l or

heteroeycloalkenyl), aryl, heteroaryL alkoxy, aroyk hcteroaroyL acyl (e.g.,

;(a_.iiphaiie)earbon.yl, (eyc.ioalipl . ic)carbonyi, or (hetcrocyeloaltphatie)carbonylh nitro, cyano, amido (e.g., fcyeloaikyialkyjjearbonykmmo, ary!earbonyianimo, ara!kyicarbonylamino, (he erocycio.alkyl)c:arbonylaniino, (heteroeyel.oa.ikyialky!}carbo

heteroarylcarbonylaiTiino, hete.roaralkylcarbonyiavnino a!kyianunocarbonyl.

cycloalkylani-inocarbonyJ, heter cycioalkylami.noe.arbonyl. arylai«inoearb0nyl._¾ or

heteroarylammocarbonyl), amino (e.g., aliphatieamino, eycloaiiphatieamino,

heterocycioaliphaticamino,_.or aliphaiicsulfon la.mirio), sulfonyl (e.g., alkyl-S(¾-,

cyeloaliphatie-SO?-, or.aryl~S0j-}_> sulfinyi, sulfanyl. sulfbxy, urea, thiourea, sul-famoyl, sulfamide, oxo, earhoxy, carbamoyl, cycloaliphaheoxy, heteroeyeioaliphaticoxy, aryloxy, heteroaryloxV_j aralkvloxv. heteroaraikoxy, alkoxycarbonyl, alkyicarbonyloxy, and hydroxy. Without limitation, some examples of substituted alkenyls include eyaaoalkenyl,

aJioxyalkenyi, acylalfcenyl, hydroxyalkenyl, aralkenyJ, (alkoxyaryl)alkeny i,

(suli nylanwno}alkenyl (such as (alkyI-SO- -ammo)alkenyl)- aminoalkenyl, amkioalkeny (c:yeloaiiphatie)aikenyl_s and haloaikenvL $00161 As used herein- an "aikynyP group refers to an aliphatic carbon group that contains 2-8 (e»g„ 2-6 or 2-4] carbon atoms nd has at least one triple bond. An ajkynyi group can be .straight or branched. .Examples of an alkyn l group include, but are not limited to, pro ajrgyl and butyriyi._: An alkynyl group, can be optionally substituted with one or more substituents such- as aroyl, heteroaroyl, a^'lk xy, c eloalkvioxy_? heterocycloalky!oiiy, ary-bxy-, heteroaryloxy, aralkyiox , nit.ro, carboxy, eyano. halo, hydroxy, sul:i¾ inercapto, sulfanyl {e.g., aiiphaticsulfanyl or cycloahphaticsiuifenyl), sulfmyl (e.g., aliphatiesulfmylor cyeloaiiphaiicsulfmyl),. sulfonyl (e. aUphatic-SCV,- afjphaiicamjno-SO?-, or cycloaSipliatic- $⁽¾-}, amido (e.g,, aminocarbonyl,_.alkyiaiiiinocarbonyL a!kylearbonyiamino,

cycloaikylaniinoearhonyl, heterocycloalkylaminocaxbonyl, eyeloalkykarbonylamino, arylaminocarbonyf arylcarbonylamino, a alkylcarbonyiamino,

(heteroeyck^'5alkyl}carbonylamtno:, (eycloalkyialkyljcarbonylammo,

heteroaralkylearbonylamino. heteroarylcarbonyl mino or heteroarylaminoearbonyl), urea_f thiourea, suliamoyL sul&mide, aikoxycarhonyi, alkylcarbonyloxy, cyclojaBphatic, heieroeydoaiiphatie, -ary-L heteroaryl, acyi (e.g., eydoaiiphatic)earbonyl or

(h.eterocyc{oaliphatie)carbonyl)_> amino (e.g., aHphaticanii.no)- su!fox , oxo, carhoxy, carbamoyl, (eydoaliphatiejoxy, (heieroeycloa!ipha.tic:}oxy and (lieteroaryl)alkoxy,

{00017} As used herein, an "amido^" encompasses both "ammocarbony and

"carbony 1 amino; ^' These terms, when used al ne or m connection with another group, refer to an amido group such as - ( ^X)-C(()}- or ~C(0)~N(R^x h, when used terminally, and they refer to an amide group such as -G(0 - (R; )- or -N(R^x}-C 0}- when used internally, wherein R^x and R^Y are . defined below. Examples of amido groups include aiky!atnido {such as alk lcarbonyl amino or alkyiaminocarbonyl), (heterocyeloaliphaticjamido,

(heteroaralkyl)amido, (heteroaryl)amtdo, iheierocyeioaikyl)aIkyIamidp, arylarmdo, araikylamido, (cye|oaikyl)alky!amido. and eyc!oalkylamido,

[00018) As used herein, an "amino" group refers to -NR:" , wherein each ot R^' and is independently selected .from hydrogen, aliphatic, eyclo aliphatic,

(cycloaliphatic)aliphatic, aryl, araliphatie, heteroeycloalipbatie,

(heterocycioa3iphatic)allphatic, heteroaryi, carboxy, sulfenyk sulfinyl, sulfonyl,

(aliphatic)earbonyl, (cyeloaliphatic)carbonyl f{cyeloatiphatic)aliphaiic)carbonyL

arylcarboTvyk (aral iphatic)carbonyl, (beieroeycloaliphai ic}ca.rbony] ,

{(heterocyc!oaliphatie)aiiphaiie)carbonyl, (teteroaryi)earbonyl, and

(heteroara!ipha.tic)carbonyl, each of which, being defined herein and is. optionally substituted. Examples of amin gr ups Include alkyianiino, diai&yiamino, and aryiamino. When the term "amino" s not the terminal group {e,g., aikylearbcTfiyiam.m©)_f: it is represented by -NR^A-. R^A has the same meaning as defined above.

OO *⁾] As used herein, an ry¥^y group, used alone or as part of a larger moiety as in "aralfcyP, "araikoxy^", or ^aryi xyalkyl" refers to monocyclic (e.g., phenyl):, bieyelie^e.g., IndenyL naphthalenyk teirahydronaphthyi, tetrahydroinden i), and tricyclic (e.g., finorenyl tetraliydro&norenyi or tetrahydroanthracenyl, anthracenyi) ring systems m which the monocyclic rin system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic. The bicyclic and tricyclic groups include benzofused 2- to 3-membered carbocyclic rings. For example, a ben ofused group includes phenyl fused with two or mor Q-s carboeycHe moieties. An aryi is optionally substituted with one or more substituents, such as aliphatic (e.g.. alkyl, alkenyl, or aikynyl), cycioaiiphatic, (eyeioaliphaticialipbaiic.. heierocyc!oaHphatie, (heteiOcycioaliphaticjaiiphatie, aryi heteroaryk aikoxy,

(cycioaliphaticjoxy, (heterocycloalipbatie)oxy aryioxy. heteroaryioxy. (araJipbatie)oxy, (heteroaraliphatic)oxy, aroyi, heteroaroyi, anu^*no,.oxo (on a non-aromatic carbocyclic ring of a benzofused bicyefic or tricyclic aryl). nitro, carboxy, amidp; aeyl (e.g., aliphatieearbonyl, (cycloaiiphatic)carbonyl, ((cycioaiiphatic)aiiphaiic)earbonyl, (araliphaticicarbonyl,

(heterocycloaiiphaiicjcarbonybfihetero or

(heieroaraliphatic)carbonyl:), suHbnyi (e.g.. aiiphaiie-SOj- or annno-SOs-i siilflnyl (eg.. aiiphatic~S(<))~ or cycloaliphatic-S(O)-), su!fanyt (e.g., allphatic-S-k cyano, halo, hydroxy, mercapto,, sulfbxy, urea, thiourea, sulfamoyl.. snilarnide, .and carbamoyl Alternatively, an aryi can. be unsubstituted..

0020] Non-limiting examples of substituted ary!s include haloaryl (e.g., mono-, di- (such as /¾/is!-dihaloa:ryl}, or (trihalo}aryi). (carhQxy)aryl (e.g., (a!koxycarbonyl}aryl,

((aralkyl)carbonyloxy)aryl, or (alkoxyearbonyl)aryl), (amido)aryl (eg., (aminocarbonyl)aryk (((a{kyiamino.)alkyUarBmocarbon.yl)aryl_> (ajkylcarhonyl)aminoaryt, (aryiaminocarbonyl)aryl, or (((heteroaryi)amino)carbonyl)aryl), amtnoaryl (e.g.. ((alkyIsitll nyl)amino)aryi or

((dialkyl)amino)aryl}, (eyanoafkyl}aryi. (alkoxy aryl, (sulfamoyl)aryl (e.g.,

(aminosuIi ny]}ary ), (alkylsulfonyjjary (cyano}aryl ihydroxyalkyl)aryL

■((alkosy)al:k lj r l (hydroxy)aryL ((carboxy}alkyi)aryk (((dialkyt)amino}alkyl)aryl, (nitroalkyl)aryf (((alkyls dfo^

((alkyisiiltbnyl)alkyl)aryl, (cyanoalkyi)aryl, (hydiOxyalkyl)aryh (aikylcarbony!)aryL

.alkylaryl, ( ril¾loalkyl}aiyk ^

aminoaryL and (;?i-(beterocycioaliphatk )-o-(aiky !))ary [,. [0002t] As used herein, an "araliphaUe" group, such as "aralkyl " refers to an aliphatic group. (e.g., a M alkyl group) that is substituted with an ary! group. Aliphatic,. aikyL and aryl are defined herein. An example of araiiphatie such as an aralkyl group is benzyl.

[00022] As used herein, a ^"'aralkyT group refers to an alkyl group ( e.g., a Cj.4 alkyl group) that is substituted, with an aryl group. Both alkyl and ary! have been ^'defined above. An example of an aralkyl group is benzyl. An aralkyl is optionally substituted with one or more .subsiituents such as- .aliphatic (e.g., substituted or mrsubsiituted alk l. alkcnyl, or alkyriyl, including carboxya!ky!, hydroxyalkyl, or haloalkyl, such as tri^'flitoromethyl}, cye!oaliphatic (e.g., substituted or unsubsiituted eycloalkyl or eyeloaikeny!),

(cy oalkyl)alkyL heterocycioalkyl (heter cyel0a!kyl)ai:kyl_s aryl, heteroaryl aikoxy, cycloalky!oxy, h^lerocyclcaikyJoxy, aryloxy, heieroary! xy, araikyloxy, heteroaralkyloxy, aroyk heteroaroyl, nttro, carhoxy, alkoxyearbonyl, aiky!earhonyloxy, ami do, (e.g.,

aminoearbonyl, a kylcarbooyiamino. cyckm!kylearbonylamino,

(cycloalky!alkyljearbonyianiino. aryiearbonylainino, araikylearhonylaniino,

(heieroeye!oaikyi}ea!'bonylamir!o. (heterocyeloalkyialkyi)earbonyiamino,

heteroarylcarbonyiamino, or heieroaralkylcarbpnylamino), cyano. halo, hydroxy, acyi, mercapto, aikylsulfanyL suifoxy. urea, thiourea, suliamoy!, sulfkmide, οκο,. and carbamo l

[00023] As used herein, a "bicycHc ring system" includes S- to 12- (e.g.. 9, 10, or 1 1) membered structures that, form two rings, wherein the two rings have at least one atom in common (e.g., 2 -atoms in common). Sieve lie ring systems include bieyeloa!iphatics (e.g., hicycloa!kyl or bicycioa! keny l}, bicycloheieroaliphaties, bieyelie ary is, and bie ehc heteroaryls.

[00024] As used herein, a ^"cycloaliphauc" .group encompasses a "cyctoslkyl" group and a "cyctoalkenyl^" group, each of which being optionally substituted as set forth below, [00025] As used herein, a ^eycloalkyl" group refers to a saturated carboeyclic motto- or bieyclic (fused or bridged) ring of 3-1:0 (e.g., 5-10) carbon atoms. Examples of eycloalkyl group include eyelopropyl, cyclobutyk cyc!openty!., eyciohexyl, eyeloheptyk adamantyk norboniy cubyl, oeta.hydro-indenyl, decahydro-naphthvi bicyefoj3.2.1 ]ociyl,

bieyelo 2.2.2]octyl, bicyclop.3. i jrranyL bieyel:o[3.3.2..]decyi. b cycloP^ JJ et :!., adamantyk azacycloalkyl, and ((amin:Ocarbonyl)eycU>aSkyl}cyc.k:)alkyl< A "cyeloa!kenyP group, as used herein, refers to a non -aroma tic earboeyclic ring: of 3-10 (e.g., 4.-8) -carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include eyelopentenyl, 1.4- cyc!ohexa-di-enyf, eyclohep enyl. eyclooctenyl, hexahydro-indenyL oetalxydro-naphthyk eyelohexenyi eyelopentenyl, bicyclo 2.2.2}octenyl, and bieyclo 3«3.1 jnonenyl, A eycloalkyl or cycloalkenyi group can be o tionally substituted with one -or more substituents such as aliphatic (e.g., aikyi, alkenyl, or lkynyl), eycloaiiphatie, (eycloaiiphatie) .aliphatic, heteiOcyeloaliphatie, (heterocycioa!iphatk) aliphatic, aryi, heteroaryl, alkoxy,

(cycioaliphatic)oxy, (heterocycloaliphatk)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (beteroai'al!phatic)oxy, aroy.l. hetcroaroyl, ..amino, amido (e.g., { aliphatic )carbo.uyl mino.(cyeioaliphatie)earboivylaTnin. v ((cycloaiiphatie )aliph.a†ic)earboTiy arnino

(aryikarbonylamrno, (araiiphatic)carbonyiamino, helerocycioaliphaiic)carbonylamino, ((het rpcycloaliphatk a!iphatk)carbonylamino, (heteix aryi)carixn.iylamiiio, or

(fheterDaraliphatkJearboii lamirjoJ, nitro, earboxy £e,g., HOOC- alkoxyearhonyl. or alkylearhonyloxy), ac l (e.g., (eyc!oaliphatic)carbonyl, (cycloaiipbatic) aiiphatic)oarboiiyi (aral iphati e)c arbonyi , eterocyc loal iphatic k arbony 1,

((heteroeycioalip alic}aiiphaiic)carboriyl, or (heteroaMlipbaticicarbonyl}, eyano, halo, hydroxy, mercapto, sulfcm l (e.g., alkyl-SO?-, or aryl-SOx-), sulilnyl (e.g„ aikyi-S{0}-), solfanyl (e.g., alkyi-S-), sulfoxy, urea, thiourea,, suifamoyi,. sutiaraide, oxo. and carbamoyl.

[00026] As used herein, "'cyclic moiety^"' includes cycloaiipbatic, heteroeycloalipha ic, aryi,. or heteroaryl, each of which has been defi ned previously,

[00027] As used herein, the term 'lieterocyeioaliphatk" encompasses a

heterocyeloalkyl group and a heteroeycloaikeny 1 group, each of which being optionally substituted as set forth: below,

100028] As used herein, a

refers to a 3-3 G nrembered BT BO- or bky!k (fused or bridged.) (e.g., 5- to 1.0-membered mono- or bkycik) saturated ring structure, in which one or more of the ring atoms is: heteroatom (e.g., N, 0, S, or combinations thereof). Examples of a heterocycloalkyl group include piperidyi, piperazyl. teirahydropyranyi, tetr hyd.ro lory I, 1 ,4-di.oxoianyL ,4-diihi.anyf L3~dioxolanyl, oxazolidyl, isoxazoiidy!, mor holra &iom ^holyl OCtahydrobenzoimyl, oeiahydroehromenyl, oeiahydrothiochromeny!, octahydroindolyi, octahydropyrindinyl, decahydroc ui oliny'

bicyc!o[3.2.I]octyi, and 2,6-dioxa~trky op.3.1 .0^J,']nonyl. A monocyclic heterocyeloaiky! group can- be fused with a phenyl moiety such as tetrahydroisoquinoiine. A

"heteroeycioalkenyf' group, as used herein, refers to a mono- or bkylic (e.g., 5- to 10- membered mono- or bk el ) non-aromatic ring structure having one or more double bonds, and wherein, one or more of the ring atoms is a heteroatom (e,g,₅ N, (), or S), Monocyclic and bicydobete oaliphaiics are numbered according to standard chemica! nomenclature. [00029] A eterocycl.oalk ! or heteroeyekaikeayl. group can. be optionally substituted with one or m re sabstituenis such as. aliphatic (e.g., alkyk alkenyl, or alkyiiyl),

eyeloalipkUic. :(cycIoaliphaUc)aHphatie. heierocycloaiiphatic, (heterocycioalipl icjalipbatic, aryL heteroar l, a!koxy, (cycioalsphatic)osy, (beierocycloa]ipbatic)os.y, aryloxy,

heteroafy!oxy,

(e.g., (aliphaiie)earbQny!amino, (cyc aliphaticiearbojiylanunQ,. (eycloaliphatic)

aiiphatic)carbonylamino. (aryl)earbon:y!amino,_: (aral!p.hatic)carbpriylarain(5_;

(het rocycloaiiphatic)carbonylai ino, ((heterocycloaiiphatic) aii;phaiie)eatlx>nylaniino, (heteroaryljcarbonylanibio. or (heleroara!iphatie)carboriy]a iino), nitro. carbo y (e.g..

i:!OOC~. alko ycarboHvL or aiiylcarbonyioxy}, acyl (e.g., (cycloaliphatie)carbonyi.,

((cyciosliphatie) ali.phatic)c&rbouyL (araHphatiejcarboriy!, -.(hctemcyck>aliphatk;)carbonyl- ((heteiXJc clo liphali-CjaiJi haiio^aAon l, or (heteroaraliphatic)earboiTvi}_:. nitro. cya.no, halo, hydroxy, mercapto, sulfenyJ (e.g.₅ alkylsultonyi or arylsuli inyl)_;. stili ny 1 (e.g., a!ky!sulfinyi). sulfanyl (e.g., alkylsuiianyi), sulfoxy, urea, thiourea, sulfanioyh sutfamide, oxo, and carbamoyl

|O0O30] As used herein,, a "heteroary group refers to a monocyclic, bicycl c. or tricyclic ring system ha ving 4 to 15 ring atoms, wherein: one or more of the ring atoms is a heteroatom (e.g., N, ().. S, or combinations thereof) and in which the monocyclic ring system is .aromatic or at least one of the rings in. the bicyclic or tricyclic ring systems is aromatic, A heteroaryl group includes a benzol used ring system, having 2 to 3 rings. For example, a benzofused group includes benzo fused wi h one or two 4 to 8 merabered.

heteroeycloaiiphatic moieties (e.g.. indolizy!, indolyl LsoindoiyL 3H-indoIyl, indoiinyl.

ben¾ [6]^:i¾ryl, benzof/fjthhTOhenyi qninolinyl or isoquinoHnyl). Some examples of heteroaryl are azetidinyl. pyridyl, 1 H-indazolyl, furyl pyrroiyi, thienyl, ihiazoiyi, oxazolyt imidazo!yl, tetrazolyi, benzofuryl, isoquinoiinyb benzthiazoiyl, xantheue, thioxanthene. phenoihiazine, dihydroindole, benzo 3]dioxole, berizo[b furyl, benzo b]thiophenyi, indazoiyl benzimidazolyl. benzthiazo!y!, puryl, einnolyi quinoiyl quinazolyl, phthalazyl, qninazolyk qulnoxalyi isoquinoly!. 411- ui.n.oiizyi benzo-l ,2,5-tMadiazolyk and 1 ,8- napblhyridyl.

{00031] Without linn lation. monocyclic heteroaryls include .fur l, thiophenyl, 2,11- pyrroiyi, pyrroiyi, oxasiolyl. thazolyi, imidazoiyi, pyrazolyi isoxazolyl, isothiazolyl, 1 ,3,4- thiadiazo!yi, 2H~pyranyl, 4-B-pranyl, pyridyl, pyridazyl. pyrimidyL pyrazoiyl, pyrazyl, and 1.3,.5-triazyl. Monocyclic heteroaryls are . numbered according to standard chemical nomenclature., [00032] Without limitation, bicyclie heteroaryls include tadelizyl, mdoiy isoindolyi, 3ii~md lyL mdolkyk benzcsfi i:u^:r l beozo /j thiopheayl_} qumofinyl, isoquinoiinyl, indoiizyk isomdelvl, indo!yi, ben¾ojd]i¾ryL bexo[/?]thiophenyk indazolyl, benzb dazyk benzthiaaaiyh purinyk 4H-quinol.feyl_J quinolyl, isoquinolyk einnolyk phtbalazyk qivhwq!yl, qu oxalyi, 1.8-naphtbyridyk and pieridvl. Bicyclie heteroaryls are numbered, according_, to standard chemical nomenclature.

[00033] A beteroarv I Is optionally substituted with one or more substituents such as aliphatic (e.g., alky I, alkenyl or a!kynyl), cyeloaliphatk, icycioaliphatic)aIipb.atie_T beterocycloaiipbatic, (heterocycloaUphatie}aHphatic. aryk heteroaryl alkoxy,

(cye}oaliphatie}oxy, iheferocycloaUpha ie)oxy. aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaialiphatie)oxy. aroyl heteroaroyl amino, oxo (on a now~amn atie earbocyelic or heterocyclic ring of a bicyclie or tricyclic heteroaryl), earbox , amido. acyl (e.g.,

alipbadeearbonyi, .ieycloaliphatiejcarbonyi, {{cyc ai_:ipbaiic)aliphatic)carbo:Hy!,

farahpbaiie)carboiiyl, (he eroeye!.oaliphatic)carbonyL

((heferoe ^^ or (heteroaraliphaticicarbQTjyl), sulfdriyl (e,g,, aliphat ί es i f ny I or a inosulftmyl), .sulfmyl. (e.g., alipbatiesulilny!), sulfanyi (e.g., allphatiesuli nyt), nitro, eyano, halo, hydroxy, mercapto, suSfoxy, urea, thiourea, siilfarttoyi, sulfaraide, and carbamoyl Alternatively, a heteroaryl can be unsubstituted.

10003 1 Non-limiting examples of substi toted heteroaryk include (halo)heieroaryi (e.g., mono- and di-(halo)heteroaryt), (carboKy)hcieroary! (e.g., (alkoxycarbonyi)hcieroary!), eyanoheteroaryi, mimo^'heteroaiyl. (e.g.. ((alkyisuli¾iwI}amin:o)beteroaryl

and((djalkyi)amino)beteroaryI), (amidotheteroaryl (e.g., aminocarbonylbeteroaryi

((alkykaTbonyl)amiBo)3ieteroaryl, ((((alkyi ¾mIno}aikyI}aminocarbonyl}beieroary!,

(((heteroaryl)amino)earbonyl)lieteroaryL ((heterocycloailphatic)carbonyl)heteroaryL or ((aikylcarboriyI)arrii:!i0)beteiOaryl), (cyan alky{)heteroaryk (alkoxy)heteroaryl

(suliamoY!)beteroaryl (e.g., (an)inosn!fonyl)beteroary]), (sulibnyl)heteroaryi ((e.g..

(atkylsuifonyl heteroaryl), (hydrpxyaikyl)¼eteroa_:ryk (alkoxyalkyl)heteroaryk

(hydroxy_;}heteroaryk ((carboxy)a!ky] )keteroaryL {((dialkyl)arnin0}aiky1)li.eteroaryl,

(beierocycloalipbaiic)heteroaryl_? (eycloaiiphaiic)keteroaryk (nitroalky!)heieroaryl,

(((a!ky!suifonyI)amino)alkyl)heteiOaryk ((alkY!st^lbiryl)alkyl)heteroaryL

(cyanoaiky])heieroaryk (aeyi)he£eroary! (e.g., falkylcarbo«yl)heteroaryl}, (alkyl)heteroaryi and (haioalkyl)heteroaryl (e.g., , tribaioaik !heieroaryl), (00035} As used herein. ^';¾eteroaraHphatic* (such as a heteroaraik l group) refers to an aliphatic group (e.g., a C alkyl group) ihat^'is substituted with, a heteroaryl group. Aliphatic, alkyl, and heteroaryl. have been defined above.

(00036} As used herein, a. "heteroaralkyr group refers to an alkyl group (e.g., a CM alky] .group), that is substituted with, a ..he ternary! group. Both "alkyl^" and ^¾¾eteroaryP have been defined above. A heteroaralkyl is optionally substituted with one or more substituenis, such as .alkyl (including carboxyaikyh hydroxyalkyi and hatoalkyl such as triiluoromethvl). alkenyi a kynyi, eyctoalkyk (eyeloaSkyi)alkyl, heteroeycloalkyl, (he eroeycloalkyl)alkyl, aryl, heieroaryl, alkoxy, cycloalkyioxy, heterocycloaikyloxy, aryloxy, heteroaryloxy, aralkyjoxy, heteroaralk loxy. aroyl, heteroaroyl. tiitro, carhoxy, alkoxyearhcmyi,

alk learbonyloxy, aniinocarhonyk alkylcarbonyiarsiino, cycloalkylcarbonylamino,

(eyel.oalky1alkyi}earbonylam!.nO arylcarbonylamrno, aralky!carbonyla ino,

heierQcyc!oalkyl)carbony!amino, (heterocyeloalkyiaikyOearbonylamino,

heieroarylearbonyianiino, heteroaralkyicarbonyl ffio, cyano, halo, hydroxy, acyl mereapio, alkylsid&uyi sulfbxy, urea, thiourea, sulfamoyk sulfaraide, oxo , and carbamoyl,

100037] As used: herein, an ⁴ⁱaey!"^' grou refers to a forniyi grou or R^A-C(Q (such as alkyl-C(O_.K also referred to as ^*'alkylcarbonyr>- wherein. R: and alkyl have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[00038] As used herein, an "aroyP or 'lieteroaro Γ refers to an ary kC(O)- o a heteroaryl-C(O)-, The aryl and heteroaryl portion of the aroyl or heteroaroyl axe opiionaily substituted, as previously defined..

{00039] As used herein, an ''alkox ' group refers to an alkyl-O- group, wherein, alkyl has bee defined previ usly,

{^'00040] As used herein, a "carbamoyl^'5 grou refers to a group having the structure -O-

CQ-NR.^SR^Y or ~NR^x-CO-0~R^¾, wherein R^x and R^Y have been defined above, and R* can he aliphatic, aryl, araliphatic, heterocyeloaJi hatic, heteroaryl. or heteroaraiiphatie.

[00041] As used herein, ^;'carboxy^ group refers to -CQOH, -COOR , -OC(C)}B, or -

OC(0)R^x when used teruunaily and ~GC(0)~ or -€(0)0- when used internally.

[00042] As used herein, a "haloalinhatie^" group refers to an aliphatic group substituted with 1 -3 halogens. For example, the term haloaikyl includes the gr u ~C ._¾,

100043] As used herein, a "mercapto" group refers to -Sl i .

100044] As used herein, a "suiter' gr up refers to -S(¾H or -S(¾R^X when used terminally and ~S^;({¾- when used internally. |0ΟΘ4δ] As used herein, a "sulikmi-de-' group refers to the structure ~NR^A~S(0)2- N ^{V Z} when used terminally and - ^X-$|0)2- R ~ when used internally, wherein R , R* , and R"' have been defined above.

[00046] As used herein, a "sulfonamide" group refers to the structure -Si O}2-NR^AK' or -NR^x-S(0)₂~R when used terminally and -SiO 2- R^x- or -NR^X -S(C))r when used

Internally, wherein il^x, R and R'" hav been defined above.

|0β047] As used herein, a '^ulfanyp group refers to -S-R^x when used terminally and - S- when used internally, · wherein R^A has been defined above. Examples of sulfanyl include al^'ipiiatie-S-, cycfoaliphatic-S-, and aryl-S-, or the like.

0O 48| As used herein a suifinyl" grou refers to -S(0)~R^A when used terminally and - S(0)- when used internally, wherein R^x has heen defined above. Exeniple of sulfmyl groups include aliphatic-SCO)-, aryi-S(O -, (cyeloaliphalic(aliphatic)} -S(OK cycloalky 1- :S(Q)-, heteroeycioaliphaiie-SiC))--. and heteroaryi-S(0)~, or the like.

|0Q049^'j As used herein, a "sulfony Γ group refers to~S(Q}2-R^' when used terminall and - S(0) - when used internally, wherein R^A has been deilned above. Exemplary sulfonyl groups include aliphatic-SCO};-, aryl-S(<¾r_f- {{eycloaiiphatie(aliphatic):)~S O¾-, eyeloaliphatie- (0)2-, heteroeycloal.ipba ie-S(0)r. heterpai l-S(0¾>-_f and

(eycloallphatic(ainido(a^].iphatie))}-S;{0)2-, or the like.

1_.00050] used herein, a "sulf xy^"5 group refers to -Q-SO-R or ~SO-0~R^X when used terminally and -O-S(O)- or -S^'(0}-0- when used internally, wherein R:^x has been defined above.

[00051} As used herein, a "halogen^" or "h l '^" group refers to fluorine, chlorine, bromine, or iodine:.

[0.0052} As used herein, an "alko ycarbonyF^' group, which is encompassed b "carboxy," used alone or in -combination wi th another group, refers to a group such as alkyi-Q~C(QH

}0O0$3| As used herein, an "afkoxyalkyf^* group refers to an alkyl group such m. alkyl-O- alkyk wherein alkyl has been defined above.

[00054] As used herein, a "carbonyr^* group refer to -C(0}-.

[00055] As used herein, an ¾χ ^!· group refers to; ^::::0.

(00056] As used herein, an "aminoalkyl" group refers to the structure {R^x 2 -alk k

[00057] As used herein, a "eyanoalkyl group, refers to the structure {NC)-alkyl-.

[00058} As used herein, "are grou refers to the structure -N ^X-C()-MR¾ and a "thiourea^" group refers t the structure -NR^X-€S~NR¾^Z when used terminall and -KR^S- CO-NR ^'~ or -NR^X-CS-MR^Y- when used internally, wherein R^x, R^Y, and R^z have been defined above.

[0( 059] As used herein, a "guanidine" group refers to the structure N^C(N(R^XR^Y) N(R^XR^Y) or - iR¾=NR^x)NR¾^v, wherein R.^s and R^¾ have been defined above,

(00060] As \ised herein, an "amid no" grou refers to the structure -C^:::fHR^x)N{R^xR ).

wherein ^x and R have been defined above.

( 061 As used herein, the term "vicinal" refers to the placement of substituents on a grou _: that includes two or more carbon atoms, where n, the substituents are attached to adjacent carbon atoms.

f00062| As used herein, the term "geroinaP^* refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom,

(00063] As used herein, the terms "terminally^" and 'Internally" refer t the location of a group within a substitueni. A group is terminal when the group is present at the end of the substitueni and not further bonded to the rest of the chemical structure. Caybox.yalk.yL i.e.. R^xO(0)C~al.kyl, is an example of a earboxy group used terminally, A group is internal when it is not terminal Alkylcarboxy (e.g., a!kyl-C(O)-C)- or alkyl-O-C(O)-) and aikyiearboxyary!

internally.

00064J As used herein, "cyclic" group includes mono-, hi-, and tri-cyciic ring systems, such as cycloaliphaiic. heteroeyeloaHphatic, aryl. and. heteroaryl. each of which has been defined: above.

100065] As used herein, a "bridged hieyclie ring system"^' refers to a bicyclie

hetcroeyelica!ipahtic ring system or bicyclie cycloaliphaiic ring system in. which, the rings are bridged. Examples of bridged bicyclie ring systems include, but. re not limited to, adamantanyL norbornanyl, bicyclo 3.2.1 fociyi bicycla[ .2_:;2}dctyl- bicyclo[3.3.1 jnonyl btcyeIo 3,2.3]nonyL 2 >xabieycio 2.2.2^'joctyL l-azabieyc!o[2.2.2JoctyK 3- azabkycjop.2:J]oetyl, and 2,6-dioxa-iriCyclo[3,3.1.O^jnonyi A bridged bicyclie ring system can be optionally substituted with one or more substituent such as alkyl (including carboxyaikyL bydroxyalky!, and haloa!kyi such as trii^'luoromethyl),_: alkenyi, alkynyl.

cyc.loalkyL (cyck alkyl)aiky!, h.eierocycioalkyl, ^~het.eroeycIoalkyl)aIfcyl, aryl, heteroaryl alkoxy, eyeloalkyloxy, heterocycloaikyioxy. aryloxy, heteroaryloxy, araikyloxy,

heteroaralkyloxy, aroyf heteroaroyl, nit.ro, earboxy, aikoxycarbonyl, alkylearbony!oxy, ammoearbonyl aikylcarbonylaraino, eycloaikylearboBylamino, (cyc|oalkylai_.k l)carbottyiaimno, arylcarbonyia ino, aralkylcarbonylanjine.

(heierocyc!oalky carbonyiammo:, ^ter0cyel alKyl¾&yl)carbonyIarai»G,

heterDarylcarbonylamino, fecteroaraikyteartoylamm , cyano, halo, hydroxy, aeyl, mercaptp, alkyJsuifanyl sulfbxy, urea, thiourea, sulfamoyh sulfa ide. oxo, and carbamoyl.

[90066] As used herein, an "aliphatic chain^" refers to branched or straight aliphatic group (e,g., alkyl groups, alkenyl. groups, or alkynyl groups). A. straight aliphatic chain has the structure -(€¾)*-, where v is 1 -6, A branched aliphatic chain is_: a straight aliphatic chain that is substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -(CMQ y-, where y is 1.-6 and Q is hydrogen or an aliphatic group; however, Q shali be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl. alkenyl and alkynyl are defined above,

[00067] As used herein, the phrase "optionally substituted" is used interchangeabl wit the phrase "substituted or unsubstituted." As described herein, compounds of the in vention can optionally be substituted with one or more substituents; such as; are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables ¾, ¾, _?. and .¾., as well as other variables, encompass specific groups, such as alkyl and ary!. Unless otherwise noted, each of the specific groups for the variables R₅,_. ¾, ¾, and ¾,_: and other variables contained therein can he optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally substituted with. one- to three of halo, cyano, oxo, alkoxy. hydroxy, amino, nitro, aryl cye!oaliphatic, heierocyeloaliphatic, heieroaryl, haloalkyl. and alkyl. For instance, an alkyl group can be substituted with aikylsulianyl, and the alkylsultany] can be optionally substituted with one to three of halo, cyano, oxo. alkoxy. hydroxy, amino, nit_.ro,_. aryLhaloalk-yi, and -alkyl. As an additional example, the cyeloalkyl portion of a

(eycloaikyl)ca bonyiamino can be optionally substituted with one to three of halo, cyano, alkoxy. hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the tw alkxoy groups can form a ring together with the atorn(s) to which they are bound.

(#08.68.) A used herein, the term "substituted/" whether preceded by the term optionally or not, refers to the replacement of hydrogen radicals in a gi en structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof Unless otherwise indicated, an optionally substituted group can have a substituent at each substifiuable position of the group, and when more than one position in any gi ven structure can. be substituted with more than one su ituent selected from a specified group, the subsiitueni can be either the same or different at every position. A ring snbstiluent, such as a heterocycloa!kyl, can be bound to another ring, suc as a cycloalkyl, to form a s iro-bioyclie rin system, le., both, rings share one common atom. Combinations of subsiituenis envisioned by this invention are those combinations thai result in the formation- of stable o chemicall feasible compounds.

{00069J As used herein, the phrase^•'stabl or chemically feasible" refers to compounds that are not substantially altered when subjected, to conditions to allow for their production, detection, and preterahly their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one .that is not substantiall altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week,

[00070] As used herein, the phrase "preparing enaMi vSe!eeiive.iy'^'> refers to asymmetric synthetic preparation of enantiomerica!ly-enriched compounds. This is further defined as the use of one or more techniques to prepare the desired compound in high enantiomeric excess (i.e., 60% or more). The techniques encompassed may include the use o chirai starting materials (e.g., -chirai pool synthesis), the -use of.chiral auxiliaries and chirai catalysts, and the. application of asymmetric induction,

{000711 As used herein, ^enantiomeric excess'^" or ^e.e,,^** refers to the optical purity of a compound.

[000721 As used herein, "encfa.'exo" refers to the ratio of e¾fo~iso.mers to exo-iso ers.

[00073] As used herein, '"enantiomeric ratio." or "e ," is. the. ratio of the percentage of one enantiomer in a mixture to that of the other,

jO0 74| As used herein, a "protecting group" is defined as a group that is introduced into a molecule to modify a functional group present in a molecule to prevent It from reacting in a subsequent chemical reaction and thus obtain chemoseleciivity. it is removed from the molecule at a later step, in the synthesis. For example, a carbobenzyloxy (Cbz) group can. replace the hydrogen on a amine to prevent it front reactin with an eieetrophile, then the. Cbz group can: be removed by hydrolysis in a later step.

[00075] Acid and amine protecting groups as used herein are: known: in the art (see, e.g., T.W. Greene & P.G.M Wutz, - 'Protective Groups in Organic Synthesis." .3** Edition, John Wiley & Sons, inc. (1999)), Examples of suitable protecting groups for acids include ttn- butoxy, benzyloxy, all ioxy, and inethoxyrnethoxy. Examples of suitable protecting groups for amines include 9-fi.tioreny.lmeth l carbamate, /er/ x«yf carbamate,, benzyl carbamate, irifiaoroaeeianiide, and p-teluenesuifonarnide; 007 ] As used herein, a "effective amount^'' is defined a the amount required to. confer a tberapeiitic effect: on the treated patient and is typically determined based on age, surface area, weight and condition of the patient. The interrel ationship of dosages for animals and ■humans (based on mi Hi grants per meter squared o f body surface) is described by Preireieh et ah. Cancer Ciw &ther. Rep., 50: 219 ( i%6). Body surface area may be approximatel determined from height and weight of the patient. See, e.g.. Scientific ^'Tables, eigy

Pharmaceuticals, Ardsiey, Hew York, 537 (1970}:. As used herein, "patient" refers to a mammal, including a human..

|O0O77| Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diasiereomeric, and geometric (or conformational)) tottns of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (Ej conformational isomers.. Therefore, single

stereochemical isomers as well as enantiomeric, diasiereomeric, and geometric (or eonformational) mixtures of the present compounds are wi thin the scope of the invention. Unless otherwise stated, , ll tautomeric forms of the compounds of the in vention are within the scope of the inveniion.

1000-78] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds thai differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the. replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 'C- or ¹⁴C-enriehed carbon, are within the scope of this invention. Such compounds are useful, for example_* as analytical tools or probes in biological assays,

(00O79J As used herein, "E^'DC" is l H3<hmethyiaminopropyl}~3-ethylearbodiimlde. "HOBf is 1 -hydroxybenzotriaEole,

"Cbsf is beuzyloxyearbonyi ^isDCM" is dichloromethane, and "Boc^"' is k?ri"-butoxycarhonyl,

[00080] As used herein, "Hi N " stands for proton nuclear magnetic resonance, and ^*TLC^* stands for thin layer chromatography.

Embodiments

100081] In one aspect, the invention provides processes and. intermediates for producing bicyclic derivatives of formula la or lb:

I S

la lb wnerem:

ring A is a C₃.₁₂ cycfoal phatie ring;

ring B is a G_. s_?. beteroeycioaHphatic ring containing an additional 0 to 2 heiero atoms^, each independently selected from O, M, d that can be optionally substituted with 1 to 4 groups, each independentl selected from alkyl, halo, alkoxy, aryL and hydroxy!;

Ri is H or a protecting group: and

R? is H or C ι-ϊ2 aliphatic,

[00082] in one embodiment, ring A is a C3-6 cycloaliplmtic ring.

[00085] In another era bod iraent, ring A is eycIopfopyL

[00086] More particularly., ring A is -dimeth leyclopropyL

(00087] More particularly, ring. A is

[00088] in one embodiment, ring B is aryL

[00089] More particularly, ring B is phenyl. 100 901 More_: particularly, ring B is:

00091- 1 In one embodiment, .ring B is a S-raembered: heterocyclic ring.

[00092] In one embodiment, nne B

{000931 In another embodiment, ring B is substituted with a aryi ring optionally substituted with I to 4 groups, each independently selected .firom lkyl, halo, alkoxy, and hydroxy L

1000941 More parti

f 095] In one embodiment, j is H.

f 00096 | in another embodiment, ₅ is a protecting group.

100097] Mo-re^' particularly, _t is fer/-batyl: carbamate (Boc)

{00098f in one embodiment, R₂ is ii.

[00099 j In another embodiment, R₂ &.€_¾.12.aliphatic,

[OOMOOJ More particularly, ₂ i C^ alkyS.

[06010! j In one embodiment, .¾ is methyl ethyl, ff-propy!, im- ISO- b tyl, -w-peuty or i.w-penty;L

{0001021 More particularly, R₂ is fto-butyl

{0001031 in another embodiment, R₂ is /ert- uiyl. 1000104] In a further embodiment, ¾ is a c eloabphatic ring.

[08010$] Another aspect relates to a process for preparing enaniioselectlvely compounds of formula. la or lb over com ounds of formi as ~ lb:

If Ig lb

[000106] The process und of fomniia Ha or lib:

11a lib

wherein R_;!l is proteciing group, und of formula III:

01 wherein R; and R4 are each independently a protecting group, C .n aliphatic, or a cyclic group selected from the group consisting of cyeloallphatic, hetcrocveioaiiphatie. aryh and heteroaryi

J000l07|ln. one embodiment, R_is is i r/~butyl carbamate (Boc .

[GDOlO&JIn one embodiment, the step of carboxyiating a . compound of formula II is in the presence of a compound of .formula Ilia:

Ola

fOO lOS] In another embodiment, the step of carboxyiating a compound of formula 0 is in the presence of a compound of .fo

■Mb

fOOOliOJ In another- embodiment, the step of carboxyiating a compound of tbmru!a Ills in the presence of a compound of

Me

[0001 Π f in another embodiment, the step of carboxyiating a compound of formula I ! is in the presence of a compound of formula. Hid;

[ΟΘ^'ΘΊ 1 ] In another embod ment, the step of carboxylating a compound of formula II is n the presence of .a compound of formula Hie:

ίΠ-e

fOOOJ 13Ι ΪΪ1 one embodiment ¾ is C n aliphatic,

[000114] More particularly, 1¾ is C . unbranched aSkyl.

[000115] In one embodiment, l t is CM branched alky!

[000116} In another embodiment, ,| is Cw branched a!kyL substituted with a cyclic group.

[000117] More particularly. R₄ls C_M. branched alkyl, substituted with a phenyl group.

[000118] in one embodiment iii s a cyclic group.

[000119] More particularly. !¾ is a bkyclie group.

[000120] In one embodiment, the arboxylaiion step comprises treating compound of formula Ha or Ob with carbon dioxide and a lithi um base in the presence of an aproite solvent.

{000121] In on embodimen the aprotic solvent is selected from the group consisting of toluene, ethyl aeetate_? benzene, and methyl te'i-butyl ether (MTBE).

[0001.22] More particularly, the aprotic solvent is MTBE.

[000123] In one embodiment, the lithium base is .¾¾' >iityl lithium.

[000.124] in one embodiment the process of the present invention gives rise to a mixture of products including H a (exo% 1-3 (ex& 1-2: (endo), and 14 (emfo),

[006:125] In one embodiment, after carboxylation. the combined . ^"weight percent in a mixture comprising eonvpotmds of formula la and .(the e:¾:o-isomers) and compounds of ormula Ic and le (the endo4somtti)^:is 100 weight percent, [000126] In one embodiment, the ratio of the eombined weight pereent of ia and id (exo- isomers): to: thai of le and le ( do-iso ets) is at least 60 to 40.

[0001271 More particularly, the ex&fendo ratio is at feast 80 to 20.

[000128f More particularly,, the exafemh ratio is at least 90 to 10.

[006129] More particularly, the exol^'endo ratio is at least 95 to 5.

[000130] More particularly, the exolendo mxo ts at leas 97 to ,

[ΟΟ01.31| 1η one embodiment, the process further comprises the. step of removing a portion o the compounds of formula Ic and/or le f om Che produet mixture.

[000:132] More particularly, the compounds .of formula le and/or k are removed by crystallizing the compound of formula la or lb.

[000133] In another embodiment, the compounds of formula Le and/or le are removed by recrysiailrang the -compound of formula ia or lb.

000134] In one embodiment the ratio of the weight percent of la to Id is at leas 60 to 40. $00135] More particularly, the ratio of the weight percent of la to Id is at least 80 to 20, [0001 M] More particularly, the ratio of the weight percent o la to Id is at least 90 to 10, [000137) More particularly, the ratio of the weight percent of la to Id is at_. least 95 to 5.. 000138] More particularly, he ratio of the weight percent of la to Id is at least 99 to 1 f 000139] More particularly, the ratio of the weight percent of la. to Id is at least 99.6 to 0,4. 1000140] More particularly 1, the ratio of the weight percent of la to id is at least 1 0 to 0, [000141 ] Another aspect is d a compound of formula 1 :

10

wherein ¾ is 1:1, C^_iZ aliphatic, or a protecting group, and Z? is H or a protecting . group, comprising the steps of

a. forming. a 2-arsiori of a compound of formula ila:

I la

^•wherein Rj_a nd ring A are defined above, in the presence of a compound of formula 11;

III

wherein R._¾ and ¾ are defined above;

treating the 2-anion of step a with carbon dioxide to produce

enaniioseleedwly a compound of formula la; and

reacting the compound of formula la with a compound of formula 26:

Z_yHH COOH _^

26

wherein ¾ ¾ a protecting group.

{000142} in one embodiment, the compound. of formula II ί is a compound of formula Ola.ίΗΗίί 43) Irs another embodiment, the com ound of formula HI is a compound of forraula Illb. { O0144| In one embodiment,: the compound of formula 26 is the compound of formula 26-a:

(0001 5J In. another embodiment the compound of onftuk^'26. is the compound: of formula 26-b:

¾-NH^{' "}COOH

26-b

: 46] One aspect is directed to a compound of formula la-t made by the processes disclosed, herein:

£11001 7f Another aspect relates to a compound of formul ia-2 made by the processes disclosed herein:

ia-2

I Another aspect is directed to a .compound, of formula la-3 made by the processe disclosed herein:

fa-3

100 149] Another ispeci relates to a: compound of formula la-4 made by the processes

Ia~4

[000_.150] One aspect is directed to a compound of formula 10-a made by the processes ^■disclosed: herein:

10-a

1000151 ] In one embodiment the compound of formula 10 is a compound of i rmul I0-a_f wherein∑ s H_f and ¾is /erz-hutyl.

1000152] Another aspect relates to a compound of formula 10-b made y the processes disclosed herein:

0-b

[000.153] Another aspect is directed, io a compound of formula 10-e made by the processes disclosed herein:

10-c

[0001541 In one embodiment, the compound of formula 10 is a compound of formula 10-b, wherein Z? is H, and >is im-butYl. 000155] Another aspect relates to a compound of formula 10-d made by the processes

Processes and Intermediate ?;

[000156] i one aspect, the invention provides: a process and intermediates for preparing a compound of formula. la as outlined in Scheme i, wherein Rj, R¾ Ri, R4, and rin A are previously defined.

Scheme 1

|000l57j Carboxylation of the compound of formula Ilk is_: achieved by first forming a 2- anion of ibrmula Ha in the presence of a compound of formula IIL For formation of similar anions, see, ,g„ Daniel. J. Pippel, et, al, J. Org: O em., 199 , 63. 2; Donald J. Gallagher et at, J. Org. ahem., 1995, 60(22), 7092-7093: Shawn T. Kerrick. et al, <l Am. Chem, Sac. 199-1 , Π3.(25), 9708-9710; Donald .1. Gallagher et al., J Org. Chem. , 1995, 60(25), 8 MS- SI 54; and Peter Beak et al, J. Am. Cham- Soc 1 94, 1 Ϊ6(8), 3231-3239. The 2-anion of formula Ha (not. shown in Scheme 1} is prepared by treatment of compound of formula. I la with a strong lithium base (e.g., ,vec-butyiliihiura or isopmpylliihium in a. suitable aprotic solvent (e.g., MTBE, diethyletlier, or toluene) in the presence of a compound of formula III. f 000158] An optically acti ve compound of formul HI can induce enantioselective earboxylation to give a product having an enantiomeric excess (e.e.) of from abo t 10% t about 95% (see, e.g.. Beak c d., J. Org. Chem., 1 95, 60. 8148-S154 . In. the presence of formula IIL a compound of ibrmula Ila can be treated with carbon dioxide to give a mixture of exo ndo compounds, wherein the ex.o enda ratio is 60 to 40, 80 to 20, 90 to 1 (L 95 to 5, or greater than 98 to 2. [000159] Referring to Scheme I. a compound of formula 11a, wherein R.†_a is, e.g.. ieri- butoxyearbanyl (Bae). is prepared. using known methods. See, e.g.. T..W. Greene and P. G. M uts, Protective Groups in Organic Synthesis, 3^rd edition, John Wiley and Sons, Inc. (1999).

[000160) Compounds of formula HI can be prepared as shown in Scheme II A.

[000161] When R₅ and R,_f. are the same, compounds of formul 01 ca be prepared by condensation of a substituted piperdone derivative with formaldehyde or a formaldehyde equivalent,

jOOOI 62] Alternatively, compounds- of formula III can be prepared as sho wn in Scheme IIB.

[000 31 When Rj and R₄ are not the same, the commercially available diproteeted amine can be used to prepare compounds of formula III via a sequence of selective deproteciion reactions and other transforations known to the skilled artisan.

O! 641 Scheme H I depicts the reaction of a compound of form ula -26- with a compound of formula la to form a compound of fo-rmuia ^'28, wherein R? is defined^' above. Scheme !

[0001651 In Scheme HI, a b cyclic aminoester of formula^' la, wherein ¾ is^' tert-hvtyl, is reacted with a protected amino acid, of formula 26 (wherein. Zj is an amine protecting grou and ca be removed under acidic, basic, or hydrogenating conditions dif ferent from those used for removing an 2 protecting group) in the presence of a coupling reagent, to gi e an amide-ester of formula 10. The protecting group ¾ is removed from the¾mide ester of formula 10 to give the amme-ester compound, o f formul 2S,

[000.166J In another embodiment eoinpoun.ds: of formula 28 are intermediates in the synthesis of protease inhibitors according to Scheme IV .

^'1008168] In Scheme IV, the bicyclic aminoester of formula la, which cam be. prepared as described herein, wherein ¾ is rm-butyl, is reacted with a protected amino acid of formula 26 (wherei.il Zi is an amine protecting group and can be removed under acidic, basic, or hydrogenaimg conditions different from those used for removing the ¾ protecting group) in the presence of a coupling reagent, to give an amide-ester of formula 10. The protecting group Z> is removed from the amide-ester of formula 10 to give the amine-ester compound of formula 28. Reaction of the ammo-containing_. compound of formula 28 with, the protected amino acid 29 in the presence of a coupling reagent gives a tripeptide of formula 30.

Removing the protecting group Z in the tripeptide. of formula 30 provides a tree amino- tripeptide of formula 31. Reaction of the aniino-tripeptide of formula 31 with the pyra ine-^'2- carbosyHc acid of formula. 32 in the presence f a coupling reagent yields the amide- tripeptide ester of formula 33. Hydrolysis of the ester of the amide- iri peptide ester of formula 33 provides the amido-tripeptkie acid of formula 34. Reacting the amido-tripeptide acid of formula 34 with the amino-hydroxy amide of formula 18 to the presence of a coupling reagent gives the hydroxy-peptide of formula 35. In the final step, oxi dation of the hydroxy grou of the compound of formula 35 pro vides the compound of formula 4.

f(MIM6*>j In another embodiment, the process of Scheme HI can be scaled for large-scale production, e.g. in a manufacturing plant. Large scale production can. for example, be sealed to greater than .1000 kilos.

|888170) Although in parts of Schemes I to IV. only a single isomer is illustrated for some of the compounds:, the present invention is intended to include all stereoisomers of the compound.

)8881 :i]The following non-limiting examples are set. forth so that the present invention is more .folly understood. These examples are for the purpose of illustration only and are not t be construed, as limiting the scope of the invention in any way.

Examples

Example I : ~fe?-hu oxyea^ (6),

Method !

($00172 } Unde^'r .nitrogen, 3-a^bieycio[3.3v(}}Ronane hydroe 0ride. (1 OO g, 0.677 mol), potassium carbonate ( 187 g, 1.35 mol), MTBE (220 mL). and w er (160 mL) were charged, with stirring, to a .2 L 3-necked round- bmt m flask fitted with a mechanical stirrer, a 500 ml, addition funnel, and a thermometer. The mixture was cooled to 14 to 16. °C. BocjO (ώ-ieri· butyl dicarbonate) (145 g. 0.644 mo!) and ^'fBE (1 0 mL) was charged to a 500^· mL

Erlenmeyer flask. The mixture a : stirred until dissolution was■complete. The solution was poured into the addition funnel and added to the reaction mixture, keeping the reaction temperature below 25 ^C, Water (290 mL) was added to dissolve solids, and the mixture was stirred for 10 to 15 minutes. After removin the aqueous phase, the organic phase was washed with 5% aqueous NaHSQ (twice, 1.45 mL each), then, water (1 5 mi...). The organic phase was concentrated,, and MTBE was added ( 1 .3 L) to give a solution of the title compound in MTBE. See, e.g., SLGrio Η . Chim. Acia. 2-: 67 ( 1959).

Method 2

|000Ϊ73] A solution of potassium carbonate ( 187 g, 1.35 mol) in. water ( 160 mL) was added t , .mixture, of 3-azabtcyek>[3..3,0:]oetane hydrochloride ( 100 g. 0.677 mol.) and MTBE (220 mL), and the resulting mixture was cooled to 14 to 16 ^,3C. A solution of Boc?0 (145 g, 0.644 mol) in MTBE (190 mi) was added while maintaining a temperature below 35 ^*¾< After the addition, the mixture was stirred for 1 hour, then filtered. The solids were washed, with MTBE (50 mL). The phases were then separated, and the organic phase was washed with 5%. aqueous NaHSCX; (twice, 145 mL each) and water (1.45 mL). It was then concentrated to 300 mL unde vacuum. MTBE (300 mL) was added, a d the mixture was concentrated to reduce the water concentration to less tha 550 ppm. The concentrate was diluted with -MTBE (400 mL) to provide a solution of the title compound in MTBE.

Example 2.: (i$,3aR, aS)~ e^baiyl 2n((S}-2-{b *i^

dimeih lbttiandyl)0c^

26 i 27

Method 1

10 0! 74] A 3 L 3 -neck round bottom flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged: ith nitrogen for several minutes. In separate flask, sulfuric acid (46.2 mL, 0.86? mol) was diluted with 442 mL of water. The solution was allowed t cool slightly. Cbz-L-/m Leucine dieyelohexyiannne salt (330.0 g, 0.739 mol) was charged to the reaction flask. ΜΎ Ε (1620 mL) was add d to the reactor, and the mixture was stirred to suspend the salt, The sulfuric- acid solution prepared above was added to the reactor over about 10 minutes, keeping the temperature at 20 5 °C, The mixture was stirred at room temperature for approximately 1 hour, then diluted slowly with water (455 mL). Agitation was stopped, and the layers were allowed to settle. The aqueous phase was withdrawn to provide 1100 mL colorless solution of pH 1. To the organic phase remaining in. the flask was charged additional water (200 mL). The mixture was stirred at room temperature for approximately 1 hour. Agitation was stopped., and the layers were allowed to settle. The aqueous phase was withdrawn to provide 500mL colorless solution of pH 2. The organic phase was heated to about 35 °C, diluted with DMF (300 mL), and concentrated at reduced pressure to the po nt at which distillation slowed significantly, leaving about 500 mL of concentrate. The concentrate.was iransfcrred without rinsing to a 1 L Schot batik. The concentrate, a clear colorless solution, weighed 1 1.6 g, Eksed on solution, assay analysis and the solution weight, the solution contained 187,2 g (0.706^' mol) of

[000175] To a 5 L 4-n.eck round, bottom, flask equipped with an overhead stirrer,

thermocouple, addition funnel and nitrogen inlet were charged H0BT^«i¾( (103.73 g. 0.678 mol 1 .20 molar eq.), EDC'HCI (129.48 g, 0.675 mol, 1 .20 molar eq.% and DMF (480 mL). The slurry was cooled to 0 to 5 °C. A 36.6 weight percent solution of the acid of Cbz-L-fer/- Leueine in DMF (4 1.3 , 0.745 mol., 1.32 molar eq.) was added over 47 minutes to the reaction mixture, while keeping the temperature at 0 to 5 °C. The reaction mixture was stirred for 1 hour and .27 minutes. A. solution of 3-a¾ah5eycl.o(3,3.0)oetane-2-carboxylic acid- i m i ester in isopropyi acetate (28.8 weight percent, 4 Γ4.3 g, 0,564 mol) was added over 53 minutes, while keeping the reaction, temperature at to 5.1 The reaction mixture was warmed to 20±5 °C over about 1 hour. 4-Methylmorpholine (34.29 g. 0.339 mol, 0.60 mola eq.) was. added over 5 minutes. The reaction mixture was agitated for 16 hours, and then isopropyi acetate (980 mL) was added to the .reaction, solution. A solution of histamine^ft2HCl (41.58 g, 0.226 mol, 0.40 molar eq.) in water (53.02 g) was added to the reaction mixture within 4 minutes, followed by 4-met yimorphoime (45.69 g, 0,45- mol, 0J0 molar eq.}. The; reaction mixture was sampled after 3,5 hours. Water (758: mL) was added, and the ndxture was stirred for about 20 minutes, then allowed to settle for 1 1 minutes. The phases were separated. The aqueous phase was; extracted with isopropyi acetate (716 m.L), and the organic phases were combined, 1 aqueous hydrochloric acid was prepared by adding 37 weight percent hydroehlorie acid_;C12¾.3 ml) to water ( 1435 mi). The organic phase was washed for about 20 minifies with the 1 N hydrochloric acid. A 10 weight percent aqueous potassium, carbonate solution- was prepared by dissolvin potassium: carbonate (171 g, 1 .23 rool, 2.1 molar eq.) in water ( 154D nil,). The organic phase was washed with, the 10 weight percent aqueous-potassium carbonate solution for about 20 minutes. The .final clear, pale yellow organic solution (1862.1 gL was sampled and submitted for solution assay. Based on. the solution, assay and the weight of the solution, the solution, contained 2.38.3 g (0.520 tnoi) of product of the title compound,

[000176} ^li! (D SC i_* SOa MHz): δ 7.37 ppm (5 H, s), 7.25-7.33 ppm (1 H, m), 5.03 ppm (2 11 s). 4Λ 7 ppm (1 11 d), 3.98 ppm ( 1 It d 3.67-3.75 ppm (2 H, m), 2.62-2.74 ppm (1 H. ra), 2.48-2.56 ppm (1 11 m), 1.72-1.89 ppm (2 H, m-},. f .60-1.69 ppm (1 1-1, m), 1 .45- 1 ,58 ppm (2 H, ml 1.38 ppm (9 11 s , 136-1.42 ppm (1 11 m>, 0.97 ppm (9 11 s),

Method 2

[000177] A solution of potassium carbonate .(73 g) in water (220 mL) was added to a suspension of (1 S, 2S,5R) 3-azabieyeio[3.3.0]oetane~2~catboxyik^

(80.0 g.) in isopropyl. acetate. (400 mL) .while-maintaining a temperature of about 20 "C. The mixture was stirred lor 0.5 hours, the phases. were separated, and the organic phase was washed with 25 weight percent aqueous potassium carbonate (80 mL) to give a solution of the free base. In a separate flask, aqueous sulfuric acid (400 ml.,, 0.863 M) was added t suspension of Cbz-fM-leoeme dieyelohexvl-aniine salt (1 1 8.4g) in. ^r _'-butyime-tliyl ether (640 ml.) while maintaining- a temperature of about 20 °C. The mixt ure was stirred for 0.5: hours, the phases were separated, and the organic phase was washed with water (200 mL). The phase, were separated, and ~methyim rpholine (80 mL). was added to the organic phase,, whieh was concentrated at reduced pressure at 40 ¾ to 80 ml., to give the free acid as a solution in N-inethymorpholine. This solution, was added to a mixture of EDO HQ (50.8 g) and HOBt hydrate (40.6 g) in N-methylmorpholirie (280 mL) at 0 to 10 °C. The mixture was stirred for 1 hour at about 5 "C. The solution of 3-azabicyclo 3.3.0]oetane~2-earboxylic. teri- butylesttr from, above was added at 0 to 20 ^! C, followed by N-methy morpholine (32 mL). The mixture was stirred fo 6 hours, then diluted with isopropyl acetate (600 mL) followed by I N hydrochloric acid (400 mL), After stirring 0,5 hours, the phases were separated and the organic. hase was washed with 25 weight percent aqueous potassium carbonate (400 mL) and water .(80 mL). The mixture was stirred for about ! hour, and the phases were separated to give a solution of the title compound in isopropyl acetate. Method 3

000Π81 8/2$,5Ε) 3-^^

was suspended in Lsopropyj. acetate (6 vol ). arid a . -solution of potassium carbonate (3.0 eq.) in water (3.5 vol.) was added at 20 to 25°C. The mixture was stirred for 3 hours, then the phases wer separated. The organic phase was washed with water (2 vol).

£080179 j Cbz~to- -.leucme dlcyeloh xyiainin salt (1 .05 eq.) was suspended in isopropy! acetate (6 vol), and sulfuric acid (1 .3 eq.) in water (5 vol.) was added at 2 to 25°C. The mixture was stirred for 30 minutes* the phases were separated, and. the organic phase wa washed with water (2 times, 2.5 vol.).

J 000181 ] The two solutions from above were combined and then cooled to 0 to 5"C. MQBt hydrate (1.1 eq.) and BDC ( IJ eq,) were suspended in the mixture, and the mixture was stirred for 6 hours. The mixture was washed with water (5 vol.), nd the resulting organic phase was treated with L-iysifte ( 1 eq.) and N-methylnrorp.holine (2 eq.) a 20 to 25^BC to destroy excess activated ester. The mixture was then washed with 5 percent potassium carbonate (5 vol.), 1 hydrochloric acid (5 vol.), 5 percent potassium, carbonate (5 vol), and water (twice, 5 vol.) to give a solution of the title compound in isopropyl acetate.

Example 3: (lS aH,6aS)-ii? ?~b«tv! 2-((S)-2-ainino~3,3-d5raethylbutanoyl)- oetah dr oeyciopeata [c] py rrole-i -carhoxy!ate (28 .

(000.1 SI) A 1 L Buchi hydrogenator was purged with nitrogen, three times, A 307.8 g portion of a 12.8 weight percent solution, of (1.S,3-a.R,6aS)- ^-butyl 2-((:S -2- {b£nzyloxyearbony!a mo)-3^

earboxyJate (as prepared by the method of Example 6, Method, t) in isopropy! acetate (3.9.39 g, 0.086 mol) was charged to the reactor, Isopropy! acetate (100 mL) was added to the reactor, A slurry of 50% water and wet 20% Pd( 01¾/earbon (3.97 g) in isopropyl acetate (168 m.L) was prepared and charged to the reactor, and agitation was started. ^'The reactor was pressurized to 30 psig with nitrogen gas and vented, down to atmospheric pressure. This was repeated twice. ^'Then, the reactor was pressurized to 30 psi with hydrogen and vented down to atmospheric pressure. This, was repeated twice. The reactor was pressurized to 30 psig with hydrogen and stirred, at mbient temperature for 1 hour. The mixture was filtered using a Buehner funnel with a Whatman #! filter paper to remove the catalyst. The filter cake was. washed with isopropyi acetate (SO mL), The ocedur was repeated twic more using 617 g and 290.6 g of the 12.8 weight percent solution of the starting compound. The material from the thre hydrogenations were combined and distiiied at reduced pressure (28 torr). The resultant solution (468.68 g) was assayed for the titl compound,

[000182) ^lR NMR (DMSC-d^ 500 MHz): δ 3.96 ppm ( I H, d), 3.67 ppm (1 H, dd)_s 3.53 ppm (1 IT dd)_; 3.19 ppm ( I H, s), 2.66-2.75 ppm fl II m)_} 2.49-2.53 ppm (1 IT ), 1 ,75- 1.92 ppm (2 IT m), 1 ,66-1 ,74 ppm. ( I B _r m , 1.48. .60 ppm (4 H, m), 1 ,38 ppm (9 H, s)_s 1.36 .42 ppm (1 l ro)y 0.91 ppm (9 IT s)

Method 2

[000183) The solution of the Cbz deri ative 27 ten Example 6, Method , was added to 20% Pd(Of-I)2/water (50%, 12.2 g) in a hyclrogenation apparatus. The apparatus was pressurized to 30 psi with hydrogen, then stirred for 2 hours at about 20 -^eC. The mix ure was filtered to remove the catalyst and the filter cake washed with isopropyl acetate (160 mL). The combined filtrates were evaporated with about 4 volumes of heptane at 40 ^CC 2_. to 3 times to remove the isopropyl acetate. The resultant slurry was cooled to 0 "C ami filtered, and the- product was; dried at reduced pressure to give the title compound.

Method 3

[00M841 A solution of (1 S,3aR_;6aS)-/e?-/-butyl 2-((S)-2^am.ino-3 -dim:ethyibutanoyi octahydrocYciopenta[c]pyrrole-i -carboxyiate in isopropyl acetate from Example 6, Method 3. was added t 20% .I (Q!¾ (2 weight percent loading, 50 percent wet) and the mixture was hydrogenated at 2 bar and 20 to 25 °C for 2 hours. The catalyst was removed by filtration, and washed with isopropyl acetate (2 vol.). The filtrate was concentrated to 10 vol. at reduced pressure at 40 ^' *C to give a solution of the title compound in isopropyl acetate.

(000185] White we have presented a number of embodiments of this invention, it is apparent, that our ba c constitution can be altered to provide other embodiments which utilize the compounds and. method of this invention. Therefbre. it will be appreciated that the scope of this invention is to be defined by- the appended, claims rather than by the specific

embodiments which have been represented by way of example.

Claims

What is claimed is:

i . A process for preparing c'nantioseleciively a compound of formula la or lb:

la

over a compound of formulas k - Ih:

Id le

f f l lh comprising the step of arboxylattng a compound of formulas Ila or lib:

in the presence of a compound of formula III:

IH

wherein:

.ring A is a C3.12 eyeloa!i haiie ring

ring B is a C3.₁₂ heterocyctoaHphatic ring containing additional 0 to 2 heteroaronts, each mdependenily seiected from 0, _f and .S, wherein ring B is optionally: substituted with 0 to 4 groups, each independently selected -from afk l halo, aikoxy. aryl, and hydroxy;

Rs is H or a protecting group;

R_i;i is a protecting group;

R; is ! h a protecting group, or C 5 .1 aliphatic; and

^•R'3 and R are each independently a protecting group, C_\.n aliphatic, or a cyclic group selected from the group consisting of cycloaliphatic,

heieroeydoaliphatic, aryl, .and heteraaryl.

The process of claim 1 , wherein ring A is a eycloaliphaiic ring. The process of claim 2. wherein ring A is eyelopeniyl. The process o f claim 3 , where n ring A

The process of claim.2, wherein ring A is cyclopropy l.

the process of claim 5, wherein ring A is J -dime iyleyciopropy!

l re process of claim 6, wherein ring A. Is

The process of claim^' Γ, wherein ring B is aryl.

The process of claim 8, .wherein ring B is phenyl

The process of claim: 9. wherein rin ;

The process of claim 1 , wherein ring B is 5-mem^'bered heterocyclic ring.

The process of claim 1 1 , wherein ring B is

.1 The process of claim I ^', wherein ring B is substituted with an aryl ring optionally substituted with 0 to 4 groups, each independently selected from t e group oansisting of aikyi, halo, aikoxy, -and hydroxy!,

14. The: process of claim

15. The process of claim 1 , wherein i is 1 1.

16. The process of claim 1 , wherein R_} is a protecting group,

17. The process of claim 16, wherein _} is ferr-butyl carbamate (Boc), 1 The process of claim 1 , wherein K;_a i a protecting gronp,

1.9. The process of claim 1. H. wherein ]» is /crz-bntyi carbamate^' (Boc).

20. T!ie process of claim 1, wherein ¾ is I I.

21 . The process of claim 1 , wherein ^'R₃ is€s .52 aliphatic.

22. The process, of claim 1 , wherein R₃ is C a!kyl

23. ^'The process of claim 22. wherein R2 is selected from the group consisting of methyl, ethyl w- ropyL Mo-propyi. Lw-h xyL ieriA iyh ;?~butyL «~pentv and ^o- t l

24. ^'fhe process of claim 23, wherein R? is ft?^ butyl.

25. The rocess-ofc m 21 , wherein ¾ is. a cyeioaliphaiic ring,

26. The process of claim 1 , wherein the step of-earboxylating a compound of formula I!a or O : is . in presence f the compound of formula Ola:

27. The process of -claim. 1, wherein, the step of earboxylating a compound of formula 11a or lib is in presence of th

Illb

28. The process, of claim 1 , wherein the step of earboxylating a compound of formula ITa or li b is. in presence of

Ilk 9, The process of claim. 1 , wherein the step of carboxylating a compound of formula 11a or lib s hi. presence of, the compound of formula Hid:

ilM

30, The process of claim L wherein the step of carboxylating a compound of formula Ha or lib is in presence

31., The process of claim: L wherein ¾ is CY₁₂ aliphatic.

32, The process of claim. 31.. wherein R? is C1 unbranched aikyl

33, The process of claim 1. wherein R,_? is C1 branched aikyl

34. The process of claim I . wherein R.¾ is CM branched aikyl .substituted with a cyclic group.

35, The process of claim 34, wherein ¾ is CM branched aikyi, substituted with a phenyl group.

36. The process of claim I, wherein R,i is a cyclic group.

37. The process of claim 36, wherein R is a: tricyclic group.. The process of claim 1. wherein the earboxylaiion step comprises treating

compound of formula 1.1 with carbon dioxide and a lithium .base in an aprotie solvent.

The process of claim 38; wherein the aprotie solven is selected from toluene ethyl acetate, benzene, and. methyl ten-hafyl ether ΜΎΒΕ,

The process of Claim.39» wherein the aprotie solvent is TtSE,

The process of cl aim 38, wherein the lithium base is s c-but l lith ium .

The process of claim 1 , wherein the combined weight percent in the mixture comprising compounds of formiila la and Id (the evo-isomers) and compounds of formula ic and le (the ioAmxmxs) is ICQ weight percent.

The process of claim 42, wherein the exoi ndo ratio is at least 60 to 40,

The process of claim 1 , further comprising removing a portion of the compounds of formula lc and le from the mixture.

The process of claim. 44. wherein the compounds of formula Ic and le are removed by crystallizing the compound f formula ia.

The process of claim 44. wherein the compounds of formula l.c and le are removed by reerystaU .ing the compound of formula la.

The process of claim 1 , wherein the ratio of the weight percent of la to id at least 60 to 40.

A. process tor preparing a compound of formula 1:0:

10

comprising the ste s of:

a. forming a 2-an.ioii of a compound of formula

Ik

i the presence of a compound. of formula 1 f :

Hi

treating the anion of step a with carbon dioxide to produce enantioselectively a compound of formula !a and

reacting the compound of formula la with a compound of formula 26,

26

in the presence of a coupling reagent;

wherein:

ring A. is a C3.12 cycloaHphatic ring:

.i is H or a protecting group: R> is I I, a protecting group, or CM 2 aliphatic;

R3 and ¾ arc each independently a protecting,

aliphatic, or a cyclic group selected from the group consisting, of cvcloaliphatic,

heterocycioaiiphaiic, aryL and heieroaryl;

Z₂ is H or a protecting group; and

2A is a protecting group.

The process of claim 48 wherein the compound of fortmi!a III i formula if la:

Ufa

The process of claim 4S wherein the compound of foranila ΠΪ is formula H^'l^'br

nib

The process of claim 48 wherein the compound of formula III is formula Die;

The process of clai II is formuia Hid;

Hid

The- rocess of claim a ill is formula Hie:

file

4. The process of claim 4S, wher of formuia 26 is .formula.26-a:

26-a

5. The process of claim 48_* wherein d of^■ formula 26 is formula 26-b:

¾rN

6. The process of claim 48„ la 10 is formula 1^'0-a:

1 -a

^"he process of claim 56, wherein Zj: is H. and is /ert-butyl

58. The process of claim 48. wherein the compound of formula 10 is formula 10~h;

10-b

59. The process: of claim 48. wherein ihe compound of formula 1 is formula 10-e:

60. The process of claim 59, wherein Zs is H, and ¾ is te/t-buty L

1. The process of claim 48, la 10 is formula 1.0-d:

10-d A process for preparing compounds of formula 4:

comprising the steps of:

a. .reacting a compound of formula H-a with a base and€¾ in the presence of a compound of formula ΪΠ to prepare a compound of formula 1 - 1 a:

b. reacting the a compound of formula la with a compound of formula 26 in. fits presence of a coupling reagent to form a compound, of formula 10:

c. removing ¾ from the compound of formula 10. o give a compound of formula

28

d. reacting the compound of formula 28 with a compound, of formula 2:9:

Z-!-S L OOH

2

In the presence of a ound of formula 30:

wherein Z is an amine proteeting-group;

removing the protecting group Z in the compound of formula 30 to give a compound of formula 1 :

react ng the -compound of formul 31 w th, a compound, of formula 3.

32

in the presence ula

hydrolyzbig the ester of the compound of formula 33. to give a compound oi formula 34;

reacting the compound of formula 34 wit a compound of formula 18:

m the presence of a coupling reagent to give a compound, of formula 35;

i oxidizing the compound of formula 35 to give the compound of formula 4.

I^'he process of claim 62, wherein, the process is seated lor large scale production.

A compound of formula ia-1 prepared by the process of claim

i a- i

A compound of formula la -2, prepared by the process of claim 1 :

A compound of formula a-3 process-: of claim-

a-.»

A eompoun . of the f rmul !a~ by the process of claim 1 :

H A compound of formula -a made by ih processes of claim 48:

10-, A compQMsnd of formula 10-b made by the processes of claim 48:

, A compound of form -c made by the processes of claim 48:

10-c

. A, compound o fformuJa 10-d made by the processes of claim 48;

1 0-d