CA2239781A1 - N-linked ureas and carbamates of heterocyclic thioesters - Google Patents

Abstract

This invention relates to neurotrophic low molecular weight, small molecule N-linked ureas and carbamates of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

Description

N-LI~KED ~REAS AN~ C~R~R~ATES OF
HETE M CYCL}C T~IOFSTERS

This application ls 5 Contlnu2tion-Ln-pa-~5 application of U.S. ~ct~n, A-~l cati_n S~rial No.
08i77~,585 filed Dece.~ber 3 , 5~o.
BACKGROUND OF T~.~ INVENTION

1. FLeld of Invent1on 10~ is inventi3n rel-t-- a neurotr~-ic l~w molec_l5r weig~ht, smaiL mo~ N-Lt-..c~d u~_as~r~
- carbamctes of heterocyclic thLoesters having an affinit~f for FKBP-type ;m~lno-:~ilins, and their use as inhibitors of the enz~ne a_.irIit~ associcted with immunophilin proteins, par.__lL-~rLy peptid~l-prolyl isomerase, or rotamase, enz,.~ activity.

2. D~-ccription of Rel~t~ A~t The term immunophilin - fers to a number vf proteins that serve as rec~~~ors for the princlpcL
;m~tlnsSuppressant drugs, cyc:~sporln A (CsA1, FK506 and rapamycin. Known classes of ~ mophilins ~are cyclophilins and FK506 binai~g proteins, or FKBPs.
--Cyclosporin A binds to cyclGp;nilin A while FK506 ar.d rapamycin bind to FKBP12. These immunophiLin-drug complexes interface with var ous intracellular signal transduction systems, especiaLLy the immune ~and nervous systems.
I~munophilins are known ~o :~ave peptidy'-pro1-yl ' CA 02239781 1998-06-05 ''' ~

isome~~se (PPIase), or rotam_se, enzyme acti~ y .Ic has reen determined that ~~ta-~ase enzyme actlv plays a role in the cata1yzation of th~
inter~rversion or the cis and ~r~ns ~somers c_ pept de and protei~ substrs_2s f3r the ~ ophil ?.
pro~e_-s.
~ munophilins were or g-n ily disccvered an~
studi~~ in the immune tissue. It W2S i?it' all, postui-ted by those skiLled i. ~he art .hat inhibi'_s-.
of the Lmmunophilins' rota..;as~ activity leads ~~
inhibltion of T-cell prolif~-a.ion, thereby causing the immunosuppressive actLvi.y exhioited ~y immllnGsuppressant drugs, suc:r ~s cyclosporirL A, FK50~
and rapamycin. Further stuc; has shown that the inhibition of rotamase activit~, in and o_ itself, does not result in i =unosuppressive activity.
Schreiber et al., Science, 1 99~, vol. 250, pp. 556-559. rnstead, immunosuppress-or. appears to stem Çrsm the formulation of a comple~ of immnnosuppresslant drugs and immunophilins. It has been shown that ~the immllnophilin-drug complexes interact with ternary ~ protein targets as their mode of action. Schreiber~et al., Cell, 1991, -~ol. 66, pp. 807-815. In the case~o, FKBP-F~506 and cycIophilin-CsA, the im~llnsphilin-drug compLexes bind to the enzyme calcineurin and inhibi~
the T-cell receptor signalling which leads r~ T-ceLl proLi_eration. Simil~rl~, the imm~l~ophilin-dr complex or F~3~-r~pamyci~ i~te~acts wit~ t-2 RAFTl/~R~P protein and ln~._~-~s the IL-2 recep~~-signalLing.
I~munophiLins hav_ bee- ounc ~o be present _-high concentrations in '~he centr31 nelvous syste=.
Immuncphilins ~~e enrich2~ ~-JO ~imes mor~ in .:-_ centr-L nervous syst2m tha~ in the immune syste-Within neural tissues, ~ nophilins appear __ influence nitric oxide syn.:esis, neurotransmitt__ release and neuronal process ~x~_nsior It has been Lound that ~ -smGlar concentratio-s of an tmm~lnoSUppresSant suc;~ ~s F~506 and rapamyc--stimulâte neurite outgrowth ~? 3C12 ceLls and s~enso--, neurons, namely dorsal rco. cangLion cells (DRGs'.
Lyons et al., Proc. of Natl. ~cad. Sci., 1994, vc .
91, pp. 31gl-31g5. In whole ~n~m~l experiments, FK5C~
has been shown to stimula_e nerve regeneratic-folLowing facial nerve injur~.
Surprisingl~, it has been found that c~rta_n .~
compaunds with a high afrinit~ for FKBPs are poter.~
rotamase inhibitors and exhibit excellent neurotroph-_ effec~s. Furthermor2, these rotamase inhibitors a_e devoid of ;mml1nosuppressive activity. These findinca suggest the use of rotamase ~nhibitors in treatir~
various peripheral neuropathies ~nd enhâncing neurona:

f regrow~h in the central nervc~ s~stem (CNS)- Studie~s have aemonstrated that r~eU-adeçe~erative disorders sucn as ~lzheimer's dise~se, ~a-kinson's disease, a~d am~tot~3phic l~teral sclarosis ~ S) ma-~; oc_t_- due to the I ss, or decreaaed av2il~_Llty, of â neu-otrophic suhstance spec fic ror a ~a ticulzr po~ulation o~
neurcr.s affected in the disc-d_-.
veral neuro~rophic f-~~ors af_ectinc specLfic neuron2L populations in the centraL nervous system have ~een identified. Fo- example, it has been hypothesized that Alzheimer's disease results from a -- decre2se or loss of nerve grcw~ actor (NGF). It ~as thus been proposed to treat ~enile Dementia of the Alzheimer's Type ~SDAT) pati~n_s with exogenous nerve 1~ growtn factor or other neurotr-phic proteins, such as brain derived growth facto-, gLial derived growth factor, ciliary neurotrophic _actor and neurotropin-3, to increase the survivaL o~ degenerating neuronal - populations.
CL-nical application of _~2se proteins in various ~' neurological disease stat-s is hampered by --; difficulties in the deliver~ and bioavailability~ of large proteins to nervous system targets. By contrast, immunosuppressant s~ugs with neurotrophic activity are relativeLy small and display excellent bioavalLability and specificity. However, when f admin:~_ered chronic~ osuppressant dru~s exhi~i~ a number of potenti~ serious side efLec,5 ncluc-ng nephrotoxlcitv, such as impairment o-g7 ome__lar filtrat on ar.d -~eve-sible inters'itia S fibrc-- s (Kopp et ~1., J. -.. Scc. ~rep~ro ~
1:162~; neurclogical ~efici-a~ such as involunt~-;
tremc-s, or non-speciric cere~--l anainc, such as non-local zed headaches (De Gr_-- e} al., N. ~nç7. J.
M~d., 1987, 317:8Z1); and va_cular hype~rtenslon wi~
complications resulting the~~ rom (Kzhan et al., ~r.
Engl. J. Med., Ig8g, 321:1725).
In order to prevent the side efrects asscciated with use of the immunosu~~_~ssant compounds, the present invention provides non-immunosuppressive compounds cont~ining small molecule FKBP rotamase inhibitors for enhancing reurite outgrowth, ana promoting neuronal growth anc regeneration Ln v2rious neuropathologicaL situations wne-e neuronal repair car.
be facilitated, including: peripheral nerve damage caused by physical injury o~ disease state such as diabetes; physical damage to the centraL ner~ous system (spinal cord and crain); brain dam~gc associated with stroke; and r.eurological disorders relating to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's aisease), and am~otrophic latercl sclerosis.

S

~; ~,.

SUM~ARY OF THE lNvENTION ~.
~ -e present invention ~-lates to neurotroph-c, low ~c ecular weight, smalL ~.cl~cule compounds hav r.g an af~-..ity ror ~KBP-type i~ml~no~hilins. Once bound S to t:--se protelns, the neL-~ -o~hic compcunds a-~poten nhibitors or the er-,~..e acti-~ ti ~ss~ciat-d with --~unophilin proteins, ~--ticularly ep-idyl-prol~f isomerase, or rotamase, er.zyme acti-~it~-. A ke, featu~e of the compounds of _'-.2 present invention is that they do not ex rt any significart immuno-uppressive activit~ in addition to their neurot-ophic actlvity. Anoth-r significant feature is the ro-eL addition of a th-Jester linkage and a~
unexpec_ed increase in bioava-l_bility and potency as compared to compounds lackir.s ~ thioester linka~e.
SpecificalLy, the presen_ invention relates t~ a co~pound of formuLa I: -N ~ \ D

U~ X

or a Fh~rmaceutically acce-t_Die salt, ester, 5_ solvate thereof, wherein:
A -nd B are taken together with the nitrogen an~
carbor atoms to which the~ are respe~tivel~ attached ~ CA 02239781 1998-06-05 ~ .:

to .~-~ a 5-7 me~bered sa urat~d o- ursaturat~
hete-oc~yclic ring cont~ining a~.:J combination c. CH~, o, S, 50, 50 , ~ or NR~;
~ is eithe~ O or S;

' is a direct bond to Z, a C1-Cj st~_ight c-branc:-~d chain a '~yl, or a C -~ straigh or ~~-rch--chain ~Lkenyl, wr.~rein ani or ~ ~ carbo? 5,_OmC ~- S - -alkyl or alkenyL are optionaLli substituted in one o-more positions with ami-.o, halo, haloalkyl, thiocarbonyl, ester, th;oes~e~, alk3xy, alkenox~, cyano, nitro, imino, al.~ylamino, ami~oalkyl, sulfhvdryl, thioalkyl, sulfo-.iL, oxvgen to form a carbonyl, or wherein any of t:~.e carbon atoms of said alkyl or alkenyL are optional j replaced wi~h O, N~, NR~, S, SO, or SO~, wherein P. s selected r~m th_ group consisting of hydrogen, (Cl-C5)-str~ight or branched chain alkyl, (C~-C,)-straight or branchec chain alkenyl or alkynyl, and (C -C;) bridg~ng alk~l wherein said bridging alkyl for~s a heterocvcl c rin .~ , _ starting with the nitrogen OL 1~RL and ending with or.e of the carbon atoms of said al!c~L or alken~l chain, and wherein said heterocyclic r_n.ç is optionalLy fusec to an Pr group;
Z is a direct bond, ~~ a C -C~ str- gh- o branched chain alk~l, or a C -rj straight or branched ~ f~ ~

f ~ v chaln aL'cenyl, wh2rein any o_ ~~ c_~bon a-oms of SG
alkyl cr alken~l are optiona__i su~stitu~~ed in one o-~ore positions with am--~, halo, haloalkyl/
thioc--bonyl, ester, thioe_ ~r, alkcxi, 21k~nOX;, S cyar~, nltro, imino, a:kylam no, ~mir.oaSki:, SU1fh ;drY1~ thioalkyl, suL~~-~il, oxysen to for~ ~
carbc yi, or wherein any Ot ~:-e ca~bon a~toms OL~ Sa i C
alky ~1 alkenyl are option_::i replac_d with O, ~
NR~, S, SO, or SO~, whereir is selec~~d _._GrD. ~~e group consistinq of hydroc--., (C -C-)-str~sght or branched chain alkyl, (C~ str~igh' or br~ncned chai-. alkenyl or alkt~nyl, a-~ (C -Cs) bridging aLkyl where-n said bridging alkyl ___~s a heterocvcLic rl.g start ng with the nitrogen c ~- and ending wi~h cne of tr.e c~rbon atoms of said aLkyl or alkenyl chain, and wherein said heterocyclic -ing is optionallv fuse~
to an .r group;
C and D are lndependent y:
hydrogen, A~, C}-Cs str~ight or branched cha n alkyl, or C~~C5 straight or ~ranched chain alkenyl, ~, ~
wherein any of the carbon A .oms of said alkyL or alkenyl are optionalLy substituted in one or m¢re position(s) with C1-C8 CYC10a11.~1, C5-C/ cycloalkenyl, hydroxyl, carbonyl oxygen, or ~-, wherein said alkyl, alkenyl, cycloalkyl or cycioalkenvl groups 2_e opticr.allv substituted with ~ -C~ alkyl, C -C~ alkeni~, ~ 'CA 02239781 1998-06-05 ~~'. ~

hydro~i, a~ino, halo, haloal~ i, thiocarbon~ , est~, thioester, alkoxy, alkenox-,-, ct~2no, n_trc, imino, alkyLcmino, amlno21kyl, s_t_;~dryL, thioalkvl~
sulfc-yl, where-n any of t:e c_-bor. atoms OL Sa~~
5a1kyl cr alk~nyl a-e o~tiona'_~ substituted in one or more -ositions wlth oxycen _o Lorm a ~2r_,C-.~1, O-where-;~ any OL ~he carbon -toms of said a' ~'~1 O~
alke~yL are optionally replac-d with 0, ~, ~" S, co, or ~, wherein R~ is s :ected from t~e qro~.-10consis ing of hvdrogen, (C -~ )-straig;~L_ or branched chain alk~l, (C.-C~)-straig:rLt _- b ~nched chai- aLkQn~L
or alkinyl, and ~C -C~ bridc- ng aLk~l wherein said bridging alkyl forms a heterocycLic ring sta-ting with the ni rogen OL- NR. and endirc ~ith one of ~he czrbon 15atoms of said aLkyL or alkenyl c;.~in, and wherein said hete-ocyclic ring is optionâlLj fused to an P~ group;
wherein Pr is an aryl or heteroaryL ~oie.~ which is su~stituted or unsubstitu~sa;
~ is oxy~en or sulfur;
20U is either Q or N, whe~e-n when U is 0, then Rt is a lone pair of electrons ar.d R. is setected from the - group consisting of:
P~ as defined above, C3-C9 cycLoalk~l, C -Cj straight or branched ch~in aLkyl or alkenyl, or C;-C6 25straiaht or branched chcin alkyl or alkenyl substituted in one or more positlons l~ith .~, aminG, ~ ~ CA 02239781 1998-06-05 . ~, hal¢, haloaLkyl, hydrox~, trifluoromethyL~ Cl-C~
stra sh. or branched chain al'c~,l, C~-C, s_raig branckea chain alkenyl, carbc j , thisc~rbcn.yl, ~ster, thice-~er, aLkoxy, alkenox;, c~,anc, ni ro, imino, S alkyl~..ino, amlnoalkyl, s lrhvdryl, ~hioalkyl, suL~ l, substltuted alkyl cr alkenyl wherelr. any o_ the c3-bcn atoms of the -l.'cyl or ~lre~yl ar~
aptic -'ly replaced wi,h S, '~, S0~, O, or NR~ whereir R. is selected from the grou~ consisting of hy~rogen, (Cl-C~)-straight or branchec chain alkyl, (Cl-C5)-stralght or branched chain alk~n.~l or alkynyl, and (C -C~) br c'ging alk~yl wherein âa'~ ~_ldging alkyl forms heterocrclic ring starting w~ :~ the nitrogen of NRi and endirg with one of the carbcn a~oms of sai~ alky} or alkenyl chain, and wherein s~td neterocyclic ring is optiorclly fused to an Ar group or C.-C, cycLoalkyl;
and when U is N, R and R~ are selected indeper.dently from the group consisting of:
hydrogen, Ar as defined ~oove, Cl-Cg cycloalkyl, CL-Cj srraIght or branched c:~a-n alkyl or alkenyl, Gr Cl-C5 straight or branched cn2ln alkyl or alkenyl ; substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, tr-fLuoromethyL, CI_C~
straight or branched chain alkyl, G-C~ straight or branched chain alkenyl, carbor.yl, thiocarbonyl, ester, thioester, alkoxy, alkenoxr, cyano, nitro, imino, 7 f~ ~
,.
alky ~~_no, aminoaLkyl, sll~hydr~fl, tnioalctfl, SU1-O..Y1, substituted alk'!l c~ alkenyl whe-ein ar.y OL
the c~-bon atoms of the --lcil or alc_n;fl 2~ e optic _lly replaced wi,_h 5, ~ , Q, or ~-~ whe-2 -S R~ ls s_'ected ~rom the grou_ corsist rg c :idros~n,(C -Cj)-straight or branchec c:-~ n alkyl, (C3-cj)-st-a g:._ or branched chain al'c---,-_ Gr alk~m~; , and (C-C~) b-idaing aLkyl wherein sai- ~~-dging alk; fcrms 5 heter~cyclic ring starting wi_:- he nitrogeh ~_ NR a-.d ending with one of the carbon -_oms of said alktfl or alker,yl chain, and wherein sa ~ heterocyclic ring is optio..ally fused to an Ar grou- or C.-C~ cyc~oalkfl;
cr R. and R~ may be t-ke-. together .5 _O~ a heterocfclic ring.
Tn preferred embodiments, ~- is a cyclic or fused cyclic ring and includes a mcr~-, bi- or ~ricyclic, carbo- or heterocyclic rin~, wnerein th_ ring is either unsubstituted or substituted in one to flve position(s) with halo, haLoalkyL, hydroxyl, nitro, trifLuoromethyl, C~-C6 strais:~t or branched chzin alkyl, C~-C5 straight or brancr;ac chain ~lkenY-l, C -C~
alkoxy, C~-C6 alkenyloxy, phenoxy, benzylox-J, amino~
thiocarbonyl, ester, thioester, cyano, imino, aLkylamino, aminoalkyl, sulfh~idryl, thioalkyl, znd sulfon~1; wherein ~he indivicual ring siz s are s-a members; wherein the heteroc~clic ring cGntains 1-4 :

hetercc~~m(s) seLected from t--- group consls-Lng of ~, N, or S; wherein aromatic or ~_~tia~y alkyl amines ~-_ o~tlc-a'ly oxidized to a cor-~sponding N-oxide.
-_ticularly preterred 3_ groups include phenyl, S benzy , naphthyl, pyrrolyl, ~-i__olidinii, py~ dinjL, pyrim-~inyl, purinyl, au -~-ir.~ so~u .oLin;i, furyl, _hicphenyl, imidazol:i:, oxazoLfl, thi_zolyL, pvrczo yL, and thienyl.
?:-ferred heterocyclic roups ma~ be select~-from ~:~e group consisting of _trrolyl, pyrrolid.nyl, pyrid-nyl, pyrimidinyl, purinyl, ~uinolinyl, isoqu ..olinyl, furyl, t:~ o~henyl, imidazoLyL, oxazol~;L, thiazolyL, pyrazol;:, ~hienyl, piperidinyL, and p perazinyl.
lS 3 preferred embodiment 5_ ~his inventi~n is compound of formula Ir:

~G~ /C

'N ~ \ D

-- ~W

II

or a pharmaceutically accep.cble saLt, ester, c solva.e thereof, wherein:
E, ~, G and H are inde~-ndently CH., O, S, SO, SO, ~' or NR3 wherein at least two of E, F, G, and :-.

' ~ ~.

are C.- ; -is either 0 or S;
~: is a direct bond t~ Z, a C~-C6 s'_aigh~ c-branc~_d chain alkyl, or a C -~~ s-raight or br-nche~
chaln -'kenyl, wherein any o -h3 carbon atoms OL sa alktyl o~ alken~l are optlon~ ~i sl~bstituted n or.e c-more _ositions with -m_~~, halo, :~a:3~'k; , thioc~-bonyl, ester, thioe ~-~, alkoxy, a''~er.~x;, cyanc, nitro, imino, 2 k;1~m; no, aminoaLkyl, sulfhidryl, thioalkyl, sull-e-~ oxygen to form a carbcryl, or wherein any of ~:~e carbon atoms OL S2i n alkyL or alkenyl are optiona ly replaced wi~h 0, N~, NR., â, SO, or S02, wherein ~- is selected 'rcm the group consisting of hydroc_n, (Cl-C6~-straight or lS branched chain alkyl, (C}-C-;-straight or branche~
chain aLkenyL or alkynyl, a-~ iC.-C~) bridg-ng aLk~l wher~in said bridging alkyl r_~5 a heterocyclic ring starting with the nitrogen o L~R. and ~n~i ng with one of the carbon atoms of said ~lkyl or alkenyl chain, _ and wherein said heterocyclic -ing is optionally f~sed to an Ar group;
Z is a direct bond, ~r a Cl-C~ straight o-brancr,~d chain alkyl, or a C--Cj straight or branchea chain alkenyl, wherein any of _:r.e carbon atoms of said alkyl sr alkenyl are optionaL_; substituted in one or more positions with ~m o, halo, haloalk~

r ~

thioc_~onyl, es-er, thioes~-~, alkox~f, alkenO~, cyanc, nitro, imina, a :cylamino, aminoalkyL, sulf~y~r~fL, thioalkyl, sull_rLyL, oxysen to L-Or~ a ca,bcnil, or wherein an~i OL _~~ c~rbon a~oms G ~ Sa1 ~
S alkyl o_ alkenyl are optiona__i r~p~acea wi-h 0, ~r., NR~, ~, 50, cr SO~, wherein ~ t S selected rrom the group ~onsisting of h~jdro~~~, (C.-C~)-strcisht o-~rarc:~- chain a kyl, (C~ -s~_aigh~ ~r _r-.nc,e-chzir. a~keryl or aLkynyl, a~.~ C~) b-id~ ng alkyl ~ 10 where n said bridging aLkvl ~~~s a heterocyclic ring startins with the nitrogen c_ ~ and endlng with or.e of the carbor atoms of sais -- k~iL or clkenyl chain, and wherein szid heterocyclic r ng is optlonallf fusec to an ~- r group;
C and D are independent ,:
hydrogen, Ar, C.-C~ st--~h. or branched chain alkyL, or G-Cs straight or ~r-r.~hed chzin alkenyl, where~n any of the carbon ~toms of said alkyl or alkenyl are optionally substltuted in one or more position(s) with C,-C3 cycloa~kJ', Cc-C? cycloalkenyl, , ~
~ hydroxy~, carbanyl oxygen, or ~-, wherein said alkyl, ;; alkenyL, cycloalkyl or cycloalkenyl groups are optionally substituted with C~-C~ alkyl, C-C5 alkenyl, hydroxy, amino, halo, haloalky', thiocar~onyl, ester, Z5 thio~ster, alkox~f, alkenoxy, ct~no, nitro, iminc, alkyl~ino, amlnoalkyl, sll h~fdryl, ~hioalkyl, ~, .~......................... e~3 ,~
SU1L-'n~Y1~ wherei!l anv of t-_ cT_bon a~_oms or sa.-a alkyl or alkenrl are optiona r s~bsti_uted in one c-more ~ositions with oxygen _o _orm a carbon~l, o-whe-_ n any of the csrb~n 2~0m_ O L s2id alkyl c-S alkeryl are optlonally repLac_~ w_-h 0, ~ , N~., S, cQ, or ~J~, whe~ein R- is s~ ~-d f-om the sr3u, cons-_ting of hT~drager, ~C ~ s_raig-t or branchec cha-. al'~yl, lC~-c~)-straight ~~ _~snchec chair alk~r~:
or Glkynyl, and (~I-C;) brlc~in~ alky wherein 52'~
- 10 brids Lg aLkyl LOr;tLS a he~eroc;_i_c rin- starting w :~
the r. trogen OL NR, and endi ~ w ~h one of the carbcrL
atoms of said alkyl or alken~l ch2-n, ard wherein said heter~cyclic ring is optional~/ ised to an Ar group;
wherein Ar is an cryL o- he ~_oaryl moiet~ which is substituted or unsubstitu~ed;
N is o~ygen or suLfur;
U is either 0 or N, wherei rL ,hen tJ is 0, then ~
is a lone pair of electrons a..~ .~ is selected }rom the grou~ consisting of:
~r as defined above, C.-Cq cycloalkyl, Cl-Cs _ -- , ~.
-~ str~ight or branched chain aLkyi or aL~enyl, or C -C
; straignt or branched châin alkyl or alkenyl substituted in one or more posi.ions with Ar, amino, halo, haloalkyl, hydroxy, tr~r1uoromethyl, C;-C5 straiaht or branched chain _l~rl, C~-C~ straight or branc~ed chain ~Lkenyl, carbcrr~l, _hiocarbonyl, ester, CA 022397Xl l998-06-05 ~, _ thic ~-~er, alkox-l~ al~enox " c~ano, nitro, t ~ ~ ~
zlk~,-Ll~ino, aminoaLk~ l nydryl, t:r ~all.c,l sulf~ yl, su~stituted alkrl _~ zl.'~~nyl wher~ ; r-the _arborl atoms o the -lkyl or 2L~ y'l c~_ S aptle-~lly replac~~ wi_h S, ., S0~, O, cr N~ ~r-~-~, is selected f om the grou_ -or.sistln~ of -;~-~5~ , (c~ stralgh or br5nch_~ c~aln 21ky', (~_~-C i-str--~~.t or branched chain a:k~ l or alk myl, 5nc (C -C,~ c_ ~ging alk~l wherein sa _ brldging alky ~rm3 _ i 10 hete__cyclic ring starting w: ~ the nitrsgen cf N~. z--~ endin~ with one o the carbc- -_sms of sald alkyl ~~
aLkenil chain, ar.d wherein s~ ~ heteroctclic ring -_ ootiar.~lly fused to an Pr 5r__? or C3-c9 cyclc2lkyl;
a~d when U is N, ~. -nd ~ are selecte-indepe-.dently from the grou~ -orsisting OL-:
hydroqen, Ar as defin2d -save, C3-C9 cycloal.k~l, C;-Cs s-raiqht or branched c:-- n alkyl or alke~yl, o-C,.-C5 straight ar branched ~hain alkyl or alkerL;:
~ substituted in ane ar more rc-itions with Ar, ami-e, hala, haloalkyl, hydroxy, .rlfluoromethyl, C ~
:. straight or branched chain 2L~l, C2-Cs straignt o-~ branched chain alkenyl, carbcryl, thiacarbonyl, sster, thioes'er, al1soxy, alkenax~i, cyano, nitro, imir~, al7syla~ino, aminaalkyl, suLfhydryl, thioalkyl, sulfcnyl, substituted aLkyl c- alkenyl wherein any o the carbon atoms af the alk~l ar al~er.yl 2rs 1~

r_, CA 02239781 1998-06-05 y _~
op. _.ally repLace~ ~l;h S, ~, SO~, O, or ~-~ w~e- ~, R. i 3 seiected f_om the gro~~ consistlng OL- ~Yd_~5e~
(C -~;)-stralgh~ o~ br2nch__ chc~n zlk~l, (C -~)_ st~5- ~-r or '~r~-c:r,-d c:-zin z::c--; cr z k,r;~
S C~ dging alkil whe~ein sz ~ b idg~ zlY;~ 5 _ het~_ocycLic ri?.g st--ting w~ t:~.e nit-3gen ~ N~
end -c with one c t:~e carb~- ~ oms o sa ~ c-a7k_. ;1 cha n~ _n~ w:-e-eir, _- ~ heter_c ycl ~ _ _ _a opt --alLy rused to z~ Ar g~~ or C3~cq Cyc ~ Ci_;
or R; and R~ may be tskerL tagether ~o or~ z hete~3cyclic rlng.
In prererr_d embodimen~s, ~ ls a cicli- ~r Lised cycllc rlnq and includes z -.SnC-, bi- or -- ~~c_ic, carbo- or heterocycLic rir~, wherein the ring is eithe- unsu~st,tuted or su~s~ituted in on~ tc ive posi_ion(s) with halo, hal 021.krl, hydrox~ , nitro, trifluorometh~l, Cl-Cj strs 5h~ or branc-ed c.zin alkyl, C~-Cs straight or bra-ched chain alken rl, C -C~
- alkoxy, C~-C6 alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thi~ester, cyano, im no, - alkyl~mino, aminoalk~l, sui hydr~l, thio,_kyl, nd sulfonyl; wherein the indiv dual ring sizes are 5-8 - members; wherein the heteroc~clic ring con.ains 1-4 heteroatom(s) selected from the group consLs~ing G 0 N, or S; wherein aromatic or _ertiary alkyl zmines are ~ptionallv oxidized to a cor-es~onding N-ox-~e -a~~icularlY pre erred ~- c~oups include P~n~;~
be~7i~, naphthyl, py-rolyl, ~ ~~~olidinyl, ov id7n~
pv-~ nyl~ purinyl, ~Ul-G7~ inyl, iSCCU~ n~
ru,~, thiophervl, ~ dz.o ~i_, oxc~o~ t -,7Z~,l ;,, S ~yrz:~ il, ~~.d .hienyl.
e-r~d he_e~oc /cl lc _.,u~s mz~- re sele~
r~Q~ --.2 qro~? consls-ins o ~ ;_rol ;1, pv7~-ol i~inyl, pyrl~ l, pyrimid~ l, ?'~ nvl, c~ noli-. i7, lSocul-ol inyl, fur ~1, , . - oDnenyl, TI d- ZGl~7t -7 10 oxaz~ ~tl~ thia~olyl, pyrazolv~, thlenyl, p7~e~ ldin~
and ~_p2ra7 inyl .
~--other préferred embcc_~ent is 2 c~m~our.d o ro r;nu ' ~ I I I:

É ~S--y--~/

l~W
. Rl :

or ~ pharmaceutically acce~able salt, Pster~ or . , sol~a~e thereo~, whereln:
E, F, and G are independen_ly CH, O, S, SO, S0-, ~H or NE~3 whereLn at least 2 c_ F, F, ~nd G are CE~;
X is either O or S;
~f is a direct bond tc Z, a C.-C s~ raight o~
branc:~.ed chain all~vl, or 2 C -cj straight o- bra~ched ~ ~ CA 02239781 1998-06-05 . f! ~.

chaL~ aLkenyl, whe_ein any o~ _he carbon atcms o_ s~ -alkyl cr alker.tfl 2~e optiona i subs.i, uter i- cne c-marc pasi-ions wlth ~m_ o, 'nzlo, h2 oalC;I, thiac_~ onyl, ester, th7a~ , zlcsxy, alk-r,cx-S CY2LnOr r.lt o, imina, -:k-il 2mino ~ -ml--sul~ -yl, t:-i~a21c~1, su~ , c x ;gr- - ~ ~ ~ - - ~
ca-bc~~/L, o r where ' : 2nV 0 ~ ~ c2r~cr: a~r-.--- ~ S~ ' ~
zlcyl or alkentil a-- co-ior-::i replac~ w _- ~
NR~, 5, SO, o~ SO" wherein ? is select~ rom the group consistin5 OL hYdr~C--~ IC1-C~)-S r-_~;ht C~
brznc-~~ cha~n alkS~l, (C~-C ~-s-raigh- cr 3ranchec chain alkenyL or alklnyl~ a-~ (Cl-C4) bridgirg al~y' wherein said bridaing alkll ~r-ms a heterocvclic ring starting with the ritrogen c- ~ and ending with one af th_ carbon atoms of sai~ ~ikyl or allccni~ chair, and wherein said r~eterocyclio - ng is opt~onally fusec to an ~r group;
Z is a direct band, o- a C -C~ str~ight or branched chain aLkyl, or a C -~s straight or branchec chain alkenyl, wherein any o_ the carbon atoms of sai~
alkyl or alkeny} are optionzLLy substituted Ln ore or - more positions with amino, halo, ha!oaLkyl, thiocarbonyl, ester, thioes er, alkoxy, alkenoxy, tyano, nitro, imino, cl'cylamino, amlnscl'cyl, - 25 sulfhydryl, thioalkyl, sul~or;l, oxygen to form a - carbon~l, or wherein an~ of the carbon a-oms o~ sal~
,~ .

~. ; .~
..
al.c;; o~ 21kel~,1 are opt~ora::; r-~lacec wi- 3 ; NR , _, S0, or S0~, whereir. - is selecte~ ~3m .~e r~ui consis-Lng o' hydrcc--, (c~-c~)-st-a--:-t o-br2rc~~d chci~ 2lkyl, (C~-C- -s~-2lsht G- ~ c-2 S cha - _''.cenyl or alky?S~l~ 2-d (C -C.,) brldg - ~l~c;
wher_ ~ sa~d bridging all.cyl ~--ms 2 heterocS;c__~ ,i?5 star~ ~- with the nitrsgen o ~I~. znd _~cir ..---h c-._ OL ~ _bcn 2_0rrls 5 S2_~ ~_C~' or -l.-.~..i _~.-i., and ~he~ein said heterocyclio ~-- is cp ion~ Lus~-- 10 to ar 3r group;
~ cnd D are independent y:
t ~ycrogen, Ar, C -Cs st-- gh_ o~ branche- cha~n alkvl, or C~-C5 straight or ~--ncned chain -:-c-nyl, Where1 n any of the carbon 2'sms of said a::cyl or lS alke-.;l are optionallv subs~-~ 'ed ln one ~_ more posl'-or.~s) with C3-c~ cycloa:.i , rc~C- c~yclc-:~.eni,-l, hydrGxi-l, carbonyl oxygen, o- --, whereln sa-_ -lkyl, alkenyl, cycloaLkyl or cyclo2lkenyl grou-s are optior.ally substituted with C -C; alkyl, C.-C, a:.cenyl, hydroxy, aminot halo, haloal~y1, thiocarboni', ester, thioester, alkoxy, alkenoxy, cvano, nitro, imino, -; alkylzmino, aminoalkyl, sulfhydry7, th__alkyl, sulronyl, wherein any of the carbon atoms _~ said alkyl or alkenyl are optionallt substituted i. one or more ?ositions with oxyqen ~ rorm a carcc-,l, or whe ei _L any or the carbon -~oms of said a~ rl o-,-, CA 02239781 1998-06-05 aLk~ a-e option211y repLac_~ ~ tn 0~ ~1~ Nn S ~e or CC , whe~ein R. is s-:-ct-d frcm th_ S~~-consisting of hydrog2n, (C.~ str2ig~.t o~ ~ ch-~
chai- ~lls-y-l, (C3-C5) -str~ight -r o ar.ched ch_itn _l'c~
or alc~ JL, 2-~ (C~-c~) bri~~--g alkcyl wr.e-- n se -bridg ng zLkvl fo~s a he e-cc,-clic rina at2~t g wi_-the -. --ogen o_ ~- 2nd end -~ ~-th one of th_ ca-bc-atcms ~- sa-d alk~l 3r alk~n;: -~a n, ard wher~-- sa_-het--oc;clic rlng is option2::-,- rused .~~ ar. ~ lt_;
wnere~n AE~is an a~~l or ~_'eroaryi moie-i whi~:-is s wstituted or unsubs.itu _~;
is ox~ygen or sulfur;
U is 2i ther O or N, wh--~_.. when u ia 0, ;hen is a lcne palr of electrons z-~ ~ is selected ~_om ~-~
lS group consisting of:
A_ as defined above, C-~Cg cycloalkyl, C -C
straight or branched chain a k-jl or aLkenyl, Cr C~~
-- straight or branched ch-_n alkyl or ciken,:
substituted in one or more ~csltions with Ar, aminc, halo, haloalkyl, hydroxy, trirluoromethvl, C -C~
straight or branched chain alkyl, C~-C5 straight o-br~nc~e~ chain alkenyl, carbontl, thiocarbonyl, este', thioester, alkoxy, alkenoxy, cyâno, nitro, iminc~
aLkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfcnyl, substituted alkyl or alkenyl whereir any c - the car~on atoms of the -lkyl or alken;i ~~
..
:~

opticrally replaced with S, S~, S~ , O, or ~,- where5?
R~ is select2d fr3m the Srou- cans sti~g o_t -;
(CL_~j' -s.raight c br-nch_~ C _~ _7 '<yL, (C -C~
stra ch~_ or branched cnzin 21.~ or 2 ~c~.y~ d (C -S C1) b~ g~~g zlk~;~ wherein 52'- Ç~' dgir.g 21k-: _or;ac hete~3cycliC ring s-2r-ing t~ e nit-_cen ~ h~ --c end -- with one o~ the car_~- -~ems o sai~ -lkyl c-~
alk_nil chzin, ~n.d wherein s--~ hetersc~cl_- rir.g s opticnally fused to 2i1 Ar g~~ ; C~-C cic:_al.
ard when U is N, ~: 2-d R- are selecte~
inde~~-den~ly Lram the grou~ r.~ stlng OL:
h~-tdrogen, Ar as define~ -~o~;e, C ~Cg c-_l O21~Y1, C.-C- straight or branched chc-n zlkyl or 2-~enyl, or C -C~ straight o- br2nched c:-c -. alkyl c~ alkenyl substi uted in one or more ~rsitions W~ tn .-~, zmlno, halo, haloalkyl, hydroxy, t-lfluorometh;1, C.-Cj straight or branched chain ~i~ll, G-C~ s--~ight or branched chain alkenyl, carbo-il, thiocarbony , ester, thioester, alkoxy, alkenoxy, cy5no, nitr_, iminc, alkylcmino, aminoaLkyl, s~l~hydrll, --~021kyl, sulfonyl, substituted alkyl o- alcenyi wher_in any or the carbon atoms of the alkll or al:c-~l are optionally replaced with S, S3, S~ , O, or ~l~s wherein R~ is selected from the grou~ carsistin~ or hidrogen, ~c;-c~)-straight or branched chain alkyL, (C3-C5)-straight or branched chain al~~nyl or alkvnyl, aAd (C.--??

' ~., CA 02239781 1998-06-05 ~

c) ~ ging al~rl wher_in szi;- _r_dgins 2 .~yl ~or~Ls-_ hete-_c~cLic ring starting ~ ~ ~ ni-r3ge- o.~ NR -end~ wltn one of the ca ~c- ~ s _ sa - 2l.
alke-.yl ch-in, a-d whe-ei- ~ e~e-_~
S op.i~ y _used to 2n ~ r ~~__~ ~~ c--r~, C ,~_C21 ~Kyl;
~- Rl and R, m2y be t_c-- toc~~~e- ~v _or;D. _ hete-~_ycl1c rinc.
~- preîerre~ ~mbodi~e. ~ s - ~yc:-~ o- -lC-~
cycl _ ring ana includes z -r~ b-- 3r ~ricycl-_, ccrbc- or heterocyclic rin~, -where_n the rlng s eitr.e- unsubstituted or su~-s~-~ te~ in e-.- to Ll~e poslt'~'!n~s) with halo, halc~ d-oxyl, nitr~, trifllcromethyl, C -Cs stra ~:-.- sr 2r2-.~:-e~ cha~i-.
alkyl, C -Cs straight or bra-.~..ê~ cna -. al'.~-nyl, C -Cs alkox-;, C--C~ alkenyloxy, p'r.en~xr, ~enzyl~xy, amino, thioc--oonyl, ester, thi~-.~-, oycr._, imin~, alkyl~ino, aminoalkyl, sul r;dryl, thic~ r.c sulfonyl; wherein the indivlaL2l rirg sizes are S-~membe-s; wherein the heterocyc'lc rlng conta1ns 1-4 heter~atom(s) selected rrom t'~s ~~cup c~nsls-ing or 0, N, or S; wherein aromatic or e- ~ary clkyl amines a-~
7' " optionally axidized to a corres?ondins N-cxide.
~ articularly preferred pr /~~OUpS include phenyi, benzyl, naphthyl, pyrrolyl, p~f-r~Lidlnyl, pyridinylr pyri~. ~inyl, purinyl, qui-.o'inyl, isoquirLclin~7, furyl, thiophenvl, imidazolrl, oxazs7yl, thiazolyl, -' r~

;i pyra_olyl, 2nd ;hienyl.
~-eferred heterocyclic 5~'~pS m2y '52 sele~3,-from _he group consisting o_ _ i~~c' yl, ~yr-oLid~ t pyrid-nyL, ~yrimid-inyl, ~;~---i~ 7 C~l i no t i-ly'' S isoc:~ ~oLinyl, ru-~ '2~cl-i'r, ~ ox-~3_yl, thiazo'~yl, pyr~ , h__n; , ~ ~2~
2~ '?eraLln~
.~ urthe_ particu7 2-' y --~ e- ~~ e .wccimer o-this i~ 2~tion is a ccmFour.d ~~ m~ a --i:

(CH~)n /C

R ~~ ~ D

1, W

TV
or a pharmacêuticalLy acce~e selt, ester, or solvat2 thereof, wherein:
n is 1, 2 or 3 rorming 2 '-7m~mber ~eterocyclic ring;
.- X is either 0 or S;
_ Y is a direct bond to Z, ~ C -C straight or branched chain alkyl, or a C~-C~- st-~igh- or branched chain alkenyl, wherein any or t:e ca-bon a_~ms or s~id alkyl or alkenyl are optionally substitu_ed in one or more positions with aminc, halo, haloalkvl, thiocarbonylt ester, thioest~ ikox,-, alkenoxy, cyano, nitro, imino, ~lk;l-~ino, 2mlnoal~yl, ,~~, ~, ., , sul~:-y~-yL, thioaLkyl, sul ~-.il, oxygen to ~07~
ca ~c~yl, or ~,Jherein ar~v OL _~e carbon atoms ~ s~ -z1kyl c~ zlken~l are optior.~:l/ replacêd w~t;r, ~
NR~, _, SO, or SO" wherein ?~- ~s seLectec .~om t--grou? consistlng of hydroc_-, (C-~-C~)-strzigh_ c branc:~e 7 cha n zlk~l, (C3-_; -st_2ig;~,t G_ --2-C'~--cn2 .. -:kênt~l or 2L~yrjl, - ~ (C -C~ b -cl-,~ z~
where - sa a brid5ing 21 CVl _J-~S 2 heteroc~cl c -i-_ sta,t -c with the nitrogen G_ ~ ~- and ending with c-_ of thê carbon atoms of said _17.~ 1 or àLkenvl chal-, and wr~rein said heteroc~cLic - ng is optioncLly ru32~
to 2n 3' group;
z is a direct bond, __ a Cl-C6 str-ight c-brancLed chzin alkvl, or a C -C~ strai~ht or branch2-chain alkenyl, wherein an~ o- ;~e carb~sn atoms or s~ -aLkyl or alkenyl are optiona~ substitu~ed in one ~-more positions with am -.c, halo, haloalky', thiocarbonyl, ester, thioes_e , aLkoxy, aLkenoxy, cyano, nitro, imino, a"~ylamino, aminoalky_, sulrhydryl, thioalky1, sul ontyl, oxygen to ror~
carbonyl, or wherein any of tne carbon at~ms of sa--.0,~
alkyl or alkenyl are optionaLLy replaced with O, NE,NR~, S, SO, or SO" whereir. R is selected from t:-_ group consisting of hydroc~n, (C!-C~)-straighr o-branch2d chain aIkyl, (Cl-C~j-s-raight or branc:~2d chain alkenyl or alkynyl, a-.d (C.~C4) bridgirng aLky_ ~ CA 02239781 1998-06-05 ~' ~?

whe~-_n s2id br~sing al'cyl ~_~~s a heteroc~;clic r~
sta-. -a with the nitro5erl G_ ~ and endln5~ w?th Or'~3 or .:~_ c-~rbon atcms or said 2~ L or alker.tl cka-n~
anc whe-ein sa-d heterocrcl~ n~ is option.
S .o a ~- group;
C ~nd D a-e indepen.den_ y:
:~yd-.ge1, ~, C--C, s ~~ ~~~ or D' anc-.ed C~:2'-21kyl, c- C -Cj s.raish_ o- __-nched chain ~'~e~
where-- 2.-y o the car~o. -~ems o,~ 5~1A -i.c;l _-alk~nyl are cptionally suhs~-tuted in one or mor~
posi- on(s) with C.-Cg cyclo2~kil, Cs-c- cycloalken~l, hydroxy7, carbonyl oxyger, or ~-, wherein said alky7, alker;l, cycloalkrl or cy_7~alken~rl gr~ups a-e option lly s~bstituted with C -C~ alkyl, C2-C5 alkenyl, hydrox~r, amino, halo, haloalkll, thiocarbon~rl, ester, thioest_r, alkcx~l, alkenoxy, cyano, nitro, imino, alkyL-~ino, aminoalkyl, s~71rhydryl, thioalkrl, sulforyl, wherein any of ~he carbon atoms of ââid alkyl or alkenyl are optionall~i substituted in one cr more positions wlth oxygen to form a carbonyl, or ; wherein any of the carbon ~.oms Oe said alkyl or - aLkenyl are optionally replacad with O, NH, L~Rz, S, S~, or SO~, wherein R7 is selected from the group consistlng of hydro~en, (C.-Cj)-straight or branche~
- 25 chain -lkyl, ~C;-Cs)-straight G- branched chain 2iken~1 or alk m!~l, and (C.-C ) bri~ n~ alkyl whe.~_~ s-1~
..

~ CA 02239781 1998-06-05 bricc-~5 21k~ for:as a netur-~ ring st2-tirlg w-~
the .-l.-~gen o~ NR aLd end - ~l~h cne o~ th~ c-~
atoms ef sald alktil ar alkent~ ain, and wh~r- - s- -het--~_vclic ring is C~tiora y ~used to an 3~ g~~
,~--rein ~r 'S an ar;l G_ ~_eroaryl mc-_.y is s ~s itut_d cr unsubstitu--d;
,~ s oxigen o- sulfur;
s el.her 0 or N, wh_r~_~ when U is 0, t.-- ~
is a l_re pair of electrons ~~ is s21sct ~ .rch --_ grou~ cor.sisting of .. ~
.'~ 2S deflned abo-~e, -C, cycloaL~Jl, C -_j straisht or branched ch2in a-kfl or alkenyl, or C -_;
stral~-. cr branched ch---. alkyl or al~
substituted in ona or more ~os~ lons with ~_, am~
lS halo, haloaLk~l, hydroxy, .-lLluoromethyl, C -C;
stra srt or branched chaln a 'cyl, G-C~ straight .-branc e~ chain alksnyl, carbo-r-fl, thiocarbonyL, es._-, thioes.er, alkoxy, alkenox-i, crano, nitro, i~i-_, .,.
~- alkyl~mino, cminoalk~l, s_'fhydryl, thioalsi:, sulLonyl, substituted alkyl c- ~lkenyl wherein any _~
_,, .
~5 the carbon atoms of the alk~l or alkenyl -~~e s opti~nally replaced with S, SC, S0~, 0, or NR wher~~-n R~ is selected fram the group consisting of hydros~
(Cl-C~)-straight or branched chain aLkyl, (C -C;-stralg~t or branched chain al~P~yl or alkynyl, and ~ -C~) brl~qing alkyl whersln sa - ~ridgins al'<yl forms ~
;

' 27 :

~ CA 02239781 1998-06-05 '''-~''' ~

he;-~~cyclic ring stzrting w_ - the nitrogen o' NR. ~rc en~1-.g with one o_ the carbc- a'-~s or sa ~ ;tl lC~rl C-- zlke--il chai~., a~d whereir _--i ~ 3rocycl ~ r ~c ~5 op.i_-ally fused ~_o ~ ~3- ~r--_- C- C3-c9 Cvcl32 -nd when U is N, ~ a~c R~ a~e selec_ incerendentlv from ths g_~u_ ~-ns_s.ir.g af:
:r.-;~rJsen, ~- ~s de n__ -~o~~, C~-Cg c;clualky , C -C s-raight or branche c~_-~ al.cyl or alkeniL, O-C.-C; straight or branched _ha - alkyl or alken~;l subs ituted in one or more ~~s t ~ns with ~, aminc, halo, h210alkyl, hydrox~r, _-~ ~iuorome ~h;l, ~ -C-straight or brznched chair -:kyL, C~-C, stralght o~
branched chain zlkenyl, carbc -;~, thiocarbonyl, ester, thioester, alkoxti, alkenox;, c~ano, nitro, imino, alkrlamino, aminoalkyl, s_l~hidryl, thioalkyl, sulfonyl, substituted alkyl ~_ -lcenyl wherein any o-the carbon atoms of the al kttl or aLkenyl are optionalLy replaced with S, S~, SG , O, or NR. whe_ein R2 is selected from the grou- -orsisting of hydr~qen, (C -C)-straight or branche- ~ha n alkyL, (C -C)-.
straight or branched chain alk~nyl or alkynyl, and (C -, -; C~) bridging alkyl wherein sald brldging alkyl forms a heteracyclic ring starting wi-:- the nitrogen of NR ar.d ending with one of the c2rbs- !5toms of said alkyl c-alker.yl chain, and wherein s-- d heterocyclic ring is opticnally fused to an Ar grsl_3 or C3-C,~ cycloalkyl;

., -- R. and R- m2y be ~- C3n together t~
hete-_cyclic rir7g.
In preferred embcdi~ents, a_ ls 2 cycl_~ 3_,_ cyc'-_ ri~g and ircludes _ =--c-, bi- o_ C2~ r hete_ocyc7ic ri-. , ,v:.~r~
eitk_- unsubsti~u.ed Gr Su_S~_tu ed in c-_ -~ -v-~
pos~ n(s) wlt;- hzlo, hc~ .cyl, hyc-cx;', -_~
,ri :_orcmethvl, C--C~ st----'-_ or sr~
alk;', C -C, strai~ht or br--~:~_d chain a~ ', ~ -C;
alkoxy, C~-C, al'~enylox~, p~ xy, benzylo~ O, thicc~ ~oryL, ester, thio_s .3r~ ~yano, -i~o, alky'-mino, aminoalkyl, su' h;dryl, thLca'.~ nc sul__n/l; wherein the in~ -l rinc siz-_ _-- ~-~
me~--s; wherein the heter_~;c ic ring con~_--_ 1-~.
lS het~ro2tom(s) seLected from - sroup consls.-~ _f O, N, o- S; wherein aromatic Gr ~ iary alkyl ~~.in__ ar-optio-ally oxidlzed to a co--esDondins N-Gxii-.
.. ~articularty preferred 'r groups include ?:--nyl, .' benzyL, naphthyl, pyrrolyl, p~rolidinyl, py_~ nyl, pyrimidinyl, purinyl, ou cllnyl, isoou no-: -yl, .
furyl, thiophenyl, imidazol-Jl, oxazolyl, t.
'- ~ pyrazolyl, and thienyl.
~referred heterocyclic g-oups may be se'-cted from the group consisting o -trrrolyl, pyrro'i-~nyl, pyrid nyl, pyri~aidin~,rl, purinyl, C'li-.5 _-.~
isc~_-nolinyl, furyl, t~ phenyl, i~ a~~lyl, ....
2g '- '--; ~.

ox_~_ ;7, th~a~olyl, p~-2~0_; , thienyl, P7pe-idiLy and ~ ~era~inyl.
-articula~ly preLerrec -~mpounds o~ th- pres~l-in-v-e-~- on are 5el ec-ed ~rom ~ ~ 5' oup cons 'Sting C-5~-2hervlpropyl (2S) ~ hex-ilcz-b~oy~ )-2-p yr_ _ 7 dir ecc -Dot hi2 tê ( 17 );
' - ene thtil ( 2S ) -N- ~ i~ c h ex~;lc_-b~ vl ) -~ -py--~: i dinecz,-bo thizt~ ( 1 a );
;- (2, 3, 5-Trimêtht/l~ yl ) prc~vl 1- il-a 10ada~- tylczrbamoyl) -2-pyrrol_~inecarbothioat~ ( 19);

3- (2, 3, 5-Trimeth~ ~he~yl jpropyl ~ -(cycl_fhex~lcarb2moYli-2-plr~ necarbothioate (20);
3 - ( 3 - E- 1 u o r o p h e n y ) ? ~ o p y 1 ( 2 S ) - 1 -(Cyc ~nexylcarbamoyl ) -2-~vrr- ~inecarbothi oa.e ( 21 );
153 - ( 2 -Fluoropnen~l ) ~ ~Oryl t 25 ~
adam_n.ylcarbamo~l ) -2 -pyrro - dinecarbothioate ( 22 );
3 - ( 2 - ~ 1 u o r o p h e n y 1 ) p r o p v 1 ( 2 S ) - 1 -(cycLonexylcarbamoyl)-2-pyrrc i dinec2rbothicare (23);
.
.~a ~-~ 3 - I 4-Methylphenyl ) propyl 12S ) -1-20 ~ (cyclshexylcarbamoyl)-2-pyrr5Lldinecarbothioate (2~4);
3 - ( 4 -Me thylphenyl ) ? rop rl ( 2S ) -1~
.., -; adamantylcarbamoyl)-2-ptlrrol ia_necarbothioate (25);
3- ( 4-Methy1pheny13 F~-?Y1 ( 2S ) -1- ( ter t -but tlcarbamoyl) -2-pyrrolidir.~ ~~rbothioate ( 26i;
253- (2-Chlorophenyl) ropyl (2S) -1-cyc 1 chexylcarbamoyl ) -2 -pyr r~ _ i di~ecarbothioate ( 2 7 ~ i . 30 ,_ CA 02239781 1998-06-05 ,, f '.. ~

- 3-(3 5-Dhne-hox~phenyl3~~_~i(2S)~ c -1-~
- n2ph~;- yl ) ethyl1 -carb~~oyl}-2-~olidineca-~ c~n~02 -(2~);
3--D i p ;1 e ~ Y- L p G D yl ( 2 S ) --~ -- { ~ 1 : 3 S t~-yloutyl 3 c2rba~0yll -2-p ~r-olidinec~ c-hi~
(29);
- _ ~ c 1 o ~ x / 1 ~ ( 2 S ' : - 2 ~ -d isc_-~ocyl phen ~7 ) c_rD~moyi -~~ -?rrolid ~ecar-c-~-i~
(31);
3-Cyclohexylpropyl (2_) -1- (hexylcarb~-cyl) -2-pyE-~,l id necarbo.hioate (3~);
3 3-Diphen y lpro~ i 1 (2S) -1- (2 ¢-di~Le -ox ~phenvl) carb~~o~ -rolidinecarrc-hioa -(33);
3-(_ 5-Dimethoxyphenyl; _r~~yl (2S) -1-{ [ (lS ~R) -2-p h e - y 1 - c y c 1 o p r o p; j c a r b 2 rtl O y ! - ~ -pyr clidinecarbothioate (3a);
3 - P h e n y 1 p r o p y 1 ( 2 S ) - 1 - ~ ' 2 4 --Dimethoxyphenyl ) carbamoyl ] -2--yrrolidinecarbo ~hioat-20 (35);
- 3-Phenylpropyl (2S) -1- (l-adamantylcarbamcyl) -2-- pyrroiidinecarbothioate (36);
3-Phenylpropyl (2S) -1- (l--yc ohexylcarb2mo iL) -2-- pyr.olidinecarbothioate ( 37 );
2 5 3 -2henylprop~1 ( 2S ) -1- [ - _d~~cncylamino ) ~ t~ i cx~
roethJi~-2-pyrrolidinecarbo~hicate (38);

.

~ CA 02239781 1998-06-05 r ~

.. ..
3-(3~s-Trlme;hox:iv---yl)propyL ~2s)-.~_ .j :
(hex;~ bamoyl)-2-py-rolld----ca-~othio2t~ ~3C~;
3-(3~4~s-Trlme~hoxyy:---yl~prop~yl (2a)-~_ (ber.~-;:~a~bcmoyL)-2-~Yr~ol ~_ -c-_~othlo2 ~
S <-~henylproptil (25,-:-(di.~ethylc2rscmciL)-2-pyrr-:_~ neczrbot-l oat- (41~;
~-?-.enylpropyl ( 2S ) ~ - ~ -_ i_ ~o1i din/l.c-_c-.cy'~-2-p~;--_'idineca-'~cthioa,~ ( 3-~~.-nylprop~jl (2S)-'- -L~ pniLlr-Gcar~-m pyrroLidlnecarbothloate (a3);
~3-~r.enylpro~l (2S)-l- _ isopropylcarbcmoyl)-2 pyrro' dLnecarbothioate (44~;
3-?henylprcpyl (2S) -1- ,-~-hyl (phen~l)car~a~ovl]-2-py_r~lidinecarbothioate (~_i; and 3-Phenylpro~yl (2S)-~-(diphenylcarbamoyL~-2-pyrroli~inec2rbothio2te.

The present inventio-. also relat_s to a pharmaceutical composi- on comprising a neurotrophically effective ; ount of the compound of - ~, formula r, rl, III or rv, ar.d a pharmaceuticalLv acceptable carrier.
The present invention ru-ther relates to a method of ef ectinq a neuronal 2c_ivity in an ~ m~l, - 25 compris.ng:
2~J~ministering to the c~. m21 a neu~otrcphi~211i .

-3~

~ ~ ~ CA 02239781 1998-06-05 ~. ~ ~.

. ~
effe~ e amount o the c~--mpc-_~- 5~ formul- -, ~, I-_ or ~
~ :-- pres2rt in-~entic. -_-~:e relates ~~ h- us-of 5 .; 3= the compounds o ~ i c_ S ir. ~-_ 3 I below lr. the .,r ~5~-_ion OL ~ ~. ~_CC ~ ~
or -:-_ tre~tme.r o_ - d-_ _s such as ~~-_?:e_-5 neu-c-~ caused 'c~i _hysl -~ or dise_-- St'.3, phys __l dama~e to ~he 5~__~., -.-ysic~l dzm~ G t'~
spin2 cord, stroke 2SS_C'__-~ ,vith br_ - ~Gm2~
Alzhe-mer's Disecse, ~_:k -s_n ~ s D~ Se-a , -~~
~myot--phic la.erzl scle-os-_.
~ :~e present inventio. 2:s_ -ontemplz.ea- _~ocess~s tor m-Luractur ng the nGve _-m~ounds, p2~ u12_ the p-~cesses delineated hei-W i-. Schemes i ~ 2.
~5 DE TAILED DE SCRI PTION O~ THE INVENTION
Definit~ ~ns "Alkyl" means a branched ~~ unbr~nched as~_ur t-d hydroc2rbon chain comprisirL~ - designate~ ~he- o-carbcn ztoms. For example, C -_- straight o~ ~ranch_d alkyl hydrocarbon chain cont2 -s 1 to 6 carrcn atoms, and ircludes but is not limltes to substi.u--.ts Such as methyl, ethyl, propyL, lsc-propyl, bu~-yl, i5G-butyl, tert-but~l, n-pentyl, -.-h xyl, and -h~ lik~, unLess otherwise indicated.
- "~Ll~en~l" mecns a ~ ed or ~ ranc:~.e~

_ i ' ~ CA 02239781 1998-06-05 f; r~

a unsa~~ ted hvd-ocarbon c~a - comprisir.g a desi~2~
numk~- 5L c~-bor. a~oms. Fo~ zmpl~, C -Cs s~-~tch, O_ bra ~ alken~l hvc~oc2r'nc crLain ccntairS 2 t~
car-_e- at~ms ha~ir.c at 1~_s_ one dcusle ~src, ~-~
i!LCl'__-s 'DUt iS not ii~ited t_ SUbS~i~U2nta s ch ~s e.:~e~;i, ~r~cen~;i, is~-r~oce -,1, buter.~ s~-~u-e~
ter~-__~en:iL, n-r2-~enil, r-:-e:~~nyl, ~nc ~~.- l-~.c_~
unl_ss other~ se inc c2 ed.
"~.lkoxy" me_ns the ~rou- -OR whe~ein R iS alkil as h~-ein derined- P-efer2~'y, R is a br-nched cr unbr_-.~h_d saturated hydroc2~~c~ chain ~ontalr:ins 1 t~
6 car_c~ 2to~s.
", r" means an aryl or h-_~roaryl moiety which is subst ~uted or unsubstitute5, especiaLly a clclic o_ fuse~ cvclic ring and ircludes a mono-, bi- G-tricyc!ic, carbo- or heterocyclic ring; wherein the ring is either unsubstituted c- substituted n one t~
five position(s) with halo, haloal~yl, hydrcxyl, nitro, trifluoromethyl, C--C straight or branched _ chain alkyl, G-C~ straight o- branched chain alkenyl, J C.-C5 alkoxy, C~-Cs alkenyloxy, phenoxy, benzyloxy, -; amino, thiocarbonyl, ester, .hioester, cyano, imina, alkyl~mino, aminoalkyl, sul~hydryl, thioalkyl, 2nd sulfonll; wherein the individu21 ring sizes are 5-~
- 25 members; wherein the heteroc/clic ring con.air.s 1-~
heter~atom(s~ selected from the group consis~ing or a, ' ~ CA 02239781 1998-06-05 ~ . .

~, c~ ~; wherein aromatic or ~ ~~iary alk-y: ami~es 2--optior~llv oxid ~ed to a c~r espondi-~ N-oxi~e.
cllarly ~referr~d a~i __ h~t~roa~ moiet--~
r.rl~__ê but a_~ ~o~ ~ ~ ~~~ ~~ ?;r-~-- , c~
S na~h ~ tr-~'yl, ~ .inil, ~yr~
?~ri3J----ir-~ ?u~inyl, G~'_---------i--~ is~__inol~ h''i, ur; , .rLiopneny~, imi~2zo ,-:, cxa7ol~ a,-~
?yr~-~lyl, and th7en~fl.
"--21O" means a- leas- c~~ ~l~oro, cn:_~o, bromc, q 10 or i~do moiety, unless othe~-~ -e l~dicat_~.
"~henyi" lncludes alL ~~-SaS ble iso~e_lc phen~;
r2dic_ s, optionally monosu~ ted or m~: 1-su~s~ -tutec'. wlth substituents s~:-- -d from the gr~~
consisting o-~ amlno, h~_, hcloallc~ , hydrcx~J, tri_luoromethyl, C -Cs strc_g-~_ or bran-hed chaln aLkyl, C--C~ straight or ~--nched cha - alkenyl, carbo-.~l, thiocarbonyl, es~--, thioes._~, alkoxv, alkeroxy, cyano, nitro, iminc, alkylamino, ~inoalkyl, sulf~ydryl, thioalkyl, sul f _n-~r~, NR2 wh~-e1n R2 i s selected from the group cons s'ing of hy~-ogen, (C -Cs)-straight or branched cha-- 2L!CJ1~ (C'-C~j-straigL~~-or branched chain alkenyl or -lkynyl, and (C -C;) bridging alkyl wherein sai~ bridging al~ l forms~ a heterocyclic ring starting wi-:- the nitrog -. Oc ~1 ar.d ending with one of the carbc- a~cms of sa_d alktrl Gr alkenyl chain, and wherein s-id heterocyc_ic ring is * 3, onti_ 211y Lused to an Ar 5--~-?--L~Le ter~ "~har~2ceut -_lly acc~pt2ble s21t, este-, or sol vate~t rerer- ~3 salts, es ers, c-scl-~ s of the slbj2ct cam--ur-Gs w~i ch pC55355 t~-S des -~d ~ha~acol~cical 2ct--;-_; -nd w'ri ch 2-_ r,~
bi 1 --211!~ no~ othe-~ise ~ si--~ s2l , este-, or solv-~93 c2n be,o_--r With inor52-L'_ 2C.rS
SUCh 25 acet2te, adip2~ lgir.c e, aa~crtate~
ben-~--t_, oen7enesulfora.e, ~isul~_te, 'u yrate, ! 10 citrzt2, camphorate, cam~norsul_onate, cyclc en~anepropion2te, dicl_~onate, dodecylsulfate, etha~_suLronate, ~umar2te, ~ oheptaro2te, gluconate, - gLyce~~~hosphate, hemisulfz e, he~t2n~ate, hexanoate, hydr~chloride hvdro'~romid~, hydroiodid2, 2-lS hydrsxtyeth2nesulLon2te, Lactate, maleat L~
methcnesulfonate, naphthylate, 2-naphthalenesul_on2t2, nicotinate, oxalate, sulra e, thiocyanate, tosylate and undecanoate. Base sal., ester, or solv~tes include ammonium salts, alkali metal salts such as sodil~m and potassium salts, aL.c21ine earth metzl salts such as calcium and m~gnesium salts, salt with organic bases such as dicyclohexyia~ine salts, N-merhyl-D-glucamine, and salts with 2mi~0 acLds such as argir.-ne, lvsine, and so f~-th. .lso, the basic nitrogen-containing groups C-? be quarternLzed wLtn such aqents as lower alkyl hcLides, such as meth~l, ~ CA 02239781 1998-06-05 Q

ethy , propyl, and but~ oride, ~ om des 2~C
iod_d~s; dlalk;l sulfates ilc- d ~e~:~yl, die,~
dibu-/l and ~izm-~il sul_2~es, _5~g C.a - hal_de5 s.;--cs ~ 1, 13u-yt, m~--ist~i ~-d st~_--,l c:llorid~s~
b-_m~~s and iod des, a~~ --lides ~ e oeLztl e-c ,~he-e ~ 1 brsm des -nd cth2--. Watl- - o-:-solu~l-or d â-êrsi~le ~-~~uc~s cr2 ~~.__e~v ~- - -.e~.

~ -~ ccm~ou?-~s o - ;n S ;_~ ~i C~i ~.~ ~ p5-S~SS _~
least one as~Nmet~ic cen;e- - ~ thus _~- be ~roducec as mixtures of stereoiscme_s or ~s i~dlvidual enar, iomers or diastereom-_}. ~-e i-divl~u-~ste~eolsomers ma:f be obtained bS/ usir- an opticallv active starting material~ bi ~esolvir~ ~ r-c~mic or non--ccemic mlxture of a ntermed_-te at some lS appr ~riate stace o_ the S~r ~ -SiS, O~ ~~ rCSO1U~iDr~
or tre compound or formula l- . _~ is _~~-rs ~sd tka the individual stereoisome~s as we : ~s mixtures (racemic and non-racemic) OL s_ereoisomers are encom-passed by the scope of the p-~s~nt inv--tion. The a-ster~oisomer at ~tom 1 of fc -.ula I is most prefer~ed due to its greater activity.

i, "lsomers" are different ccmpounds that have the same molecular rormula and -,cludes _yclic iscme~s such as (iso)in~ole and other iccmeric ~~ms o c~clic - 25 moieties.
"Ste_eoiscmers" are iscmers that ~irfer onlv in T_ _ 31 ~ ' CA 02239781 1998-06-05 the ~t2Y the atoms a-e ar.ar5_- i-, space.
l'_nantlomerS" are a pa-~ OL- stereoisomers th~L
are .-c~-superimpcs2ble mir~~ zges OL each cther.
"~izstereaiscmers" a-- s--r~oisomers which 2-_ _~ no. ~-~_o~ images o 2ZCL-~ c-_'~~r.
"~.acemic mix.ure" me_ _ a mix ure cont~in~-s equa'- pa-ts o~ individual e --_ic~ers. 'INcn-.-cLc~
mix_u:~" ls 2 Lm~ xture c-n ~-- -g un~cuzl ~z--, ~-indii _ual en~n~i~me s or s~~_-o some_s.
J 10 The ter~ "preventing n~_-odegenerztion" as used here n includes the ~_ility to prev~n.
neursdegener2tion in pa~tien~s newly diasrLosed as hav--~ a neur3degener2tiv~ ~is_ase, or at risk o devel~oing a new degener-tiv2 disease and ro~
preven.ing further neurodege ~-a_ion ln patients whc are ~lrezdy surfering from 5_ have svmproms or _ neurocegenerative disease.
The term "treatment" as used herein covers an~
treztment of a disease and/o~ condition in an animal, particularly a human, and includes:
(i) preventing a dise2s2 and/or condition f~om - occurrin~ in a subject which ~zv be predisposed to the disease andlor condition bu~ has not yet been diag-nosed as having it;
(ii) inhibiting the dis~ase and/or condi~ion, i.e., ~rresting Lts developm-n.; or ~' : 3 ~iii) relievin5 the c.- 53_S~ /C- Cordit~
i.e., c~using reS-~ssl~n of -~3 C' S__S3 c c/or corc--tion.
~:e sys-e~ used i~ n~~- ~ -e ~ ca?ds of ._--S pres2~ inventicr is sho~n ~_:o~ -~ ~ c_~ounc --fo m_ _ IV as a~ ex~mple.
co~pound o the pres_- ~-;--. or., especic -,-For-.-u - IV, where n n is 1, :' _s ~, ~' s !C.-.-)-, Z s CH, C i s 3-p tridfl~ 3 is E~ T, ?~1 i a 3 I0 and ~2 is 2-meth~lbutyl, is a.ed 3-(3-?y--dyl~- -propy~mercaptyl (2s)-l-[(2--e~ b~ ) carbamoyl pyrr~ idine-2-car~oxylGte.

Comoounds ~f the In~ention - 15 The neurotroPhic low mclecu'_- weiqht, small molecule FK~P inhi'oitor com?slnds _ thls inventlc-have cn afrinitr for FK~D-t r~ ~-u-.~~:~.il-ns, such ~s EKBP12. When the neurotr_-:ric c--..p5u-.~s 5f tkL's ._ in~ention are bound to an FKB3-tt?e ;~ nophilin, th_~
ha~e been found to inhibit t'-e ~rc yl-peotidyl cis-~ .
!~ trans isomerase activity, or rotamase, act -~ity of the ;, ~
binding protein and unexpectedlt s~_imuLate neurLte growth.
Specific exemplifications of _:-es2 embodimerts 25 are presented in TABLE I.

:. ;

. 39 ' ' CA 02239781 1998-06-05 ,_ f TA~LE I: C_W~ S

r(CH-,)n /C
~ ~T~S Y Z/

R--U~ X
W

S
~o n W ~ Z C 3 Rl R2 ~ 1 1 O (CH~)~ CH 3-Dyrldfl H H 2-M_th~lhutyL
- 2 1 O (CH~ CH 3-~-y~idyl H
dimethyLpropfl 3 1 O (CH.)CY. 4-Methox~ 'r H 1,1-phenyl dimethylprop~rl 4 1 O CH CX ~henyl u H 1 1-dimethylpropyl S 1 S (CP;~)- C~ 4-Me~_hoxy r. H Cyclohexyl phenyl 6 1 O (CX). C.1 3-~yr-dyl H H Cyclohexyl :
7 1 S (CH) CH 3-Pyridyl H H Cyclohexyl 8 1 S (CH2)~ CH 3-Pyridyl ;~ Y. 1-A~m~ntyl 9 1 S (C~ CH 3-Pyridfl H H 1 1-~ dimethylpropy 10 1 O (CH~). CH Phenyl ~he yl H 1~
dlmethvlpropyl 11 2 O (CH.)~ CH Phenyl H H 1 1-dimethylpropyl : ~- ~ 12 2 O (CH~) 2 CH Phenyl H H Phenyl ~' 20 13 2 O DirectCH 2-Phenyl 2-PhlnylH Phenyl ; Bond ethyl ethyl - 14 2 O ~irectCH 2-Phenyl 2-PhenfLH Cyclohexyl Bond ethyl ethtl 15 2 S DirectCH 2-~henyl 2-PhenylH Cyclohex~1 Bond ethyl etht 16 2 O (Cn.) CH 4-Methoxy H H Cyclohe~yl phenyl - 17 1 0 (CH~) CH DhênyL H ~ Cyclohexyl Y

r~

No n W " Z C 3 Rl ~2 la 1 O C- CH Fh~nyl .- H Cyclohe~yl 19 1 O (Cr-), C~ 2,3,5 Tri :- H ~m~r,_y, methylphenyl 20 1 ~ tC.~) C~ 2,3,5 Tr~ .-x-;l methvlp,.eryl 21 1 C ~C.i.)~ CH 3-Fluoro :- ~ Ct~clvh_x,-i pkLen il 5 22 1 O (CH ) C~: 2-~ lUOrG ~ n ,'~m;r,._ phe~ Il 23 1 O !C:i,) CH 2- Fl UOrG . '-' C ~clonA.x jl p :n ~ r, J 1 2~ 1 O (C.i~) CH 4-Metn~ ;; C~;clo.t~xil ~h nyl 25 1 O (C.~ CH 4-Methyl .~ H .~-d2m2n_t~1 phenyl 26 1 O (C~ ~. CH 4-Methyl ~- H Tt~rt-'~u.yl phenyl 10 27 1 O (CH.)~ CH 2-Chloro :-. H Cyclohe:x/l phenyl 2a 1 O (CX~)~ CH 3,5-Dlmeth .- H l-Nttpthyle.hyl oxt/phenyl 29 1 O (C.~.). CH Phenyl P:~er;~ H 1,1,3,3-Tetramethylbu--yl 31 1 O (CH.). CH Cyclohexyl H 2,6-Diisopropy phenyi 32 1 O (CH~). CH Cyclohexyl i: ~ HexyL
33 1 O (CH-)- CH Phenyl Ph--.i: X 2,4-Dimsithox~
; phenyl 34 1 O (CH,). CH 3,5-Dimeth P: H 2-Phenylcyclo =' oxyphenyl propyl 35 1 O (CH~)~ CH Phenyl P: H 2,4-Dimethoxy phenyl .
36 1 O (CH,)2 CH Phenyl H H ~m~n;yl 37 1 0 (CH2)~ CH Phenyl H H Cyclohexyl 38 1 0 (CH2)2 CH Phenyl E; H A~m~ntyl 39 1 O (CH~), CH (3,4,5- ~ H Hexyl Trimethoxy) phenyl 40 1 O (CH~~ CH (3,4,S- H H Benzyl - Trimethoxy) - phenyl " 1 .~ , .

N~ n r~ v- Z C D Rl R2 4t I C (C.~)~L CH FL~lênyl H CH. Cr;.

42 1 0 (Ch.) C.~ ?he~yl ~ R ,~ C- -C;,~
C~,- ( cyc: _3 a3 1 0 ~Ch,) . CH ?he~yl ~: R" R = -C~ ,-~-C.-~-CE~;~L- ( c~, c: _~ ) 4g 1 C !-:-. )~ C. 3hê~ R~ =3' ~ c~:;
5 45 1 0 ~C'. j~ CL e~l~iL E CH~ Dher;
4 ~; 1 C ~ ) . CH D.. ên ~jl LL R~ =Dhê

. .

. . .

: I A ~ ;

.

CA 02239781 1998-06-05 ~

. . . r rhe compaunds OL- thQ P~ n~ invention exiSt =a ste-ecisomeric Lor~s, ei'~~- ~~c~-iomers or dia,.e-~oisomers- _nclu~er ,i_~:-in the scope o~ t~-inve t 3 z~e t:~e e~ant cm~~ rzce~lc _o--~" 2--dias~_~eo some_ic mixtu~es _--n_lomers and dias~er3OLsome~S can be 5ep-__-e~ by ~_thods !cnowr ~o t:-_s~ s'cllled in the _--.
Me hods of Using the Com~Gunds of the Inv~ntion The compounds of the D--se-t invention have an a.~in-_~i for the FK506 bind~~-- F 5tein~ particularl;
F~3F12, ~hich ls present in --~ ~~uronal tlssue.
When .h~ inventiv2 compourds -_nd to F~P in neuron~l tissue, they exhib: excellent neurotrophic 5 activi tv . This activlty is __~-ul in the stimul-tion of damage~ neur~ s, ~he promotion OL
neuronal regeneratlon, the ~~e~;ention of neurodegeneration, and the t-e-_ment of several neurological disorders known -, be associated with neuronal degeneration and pe~ eral neuropatnies.
~ ~ --, For the foregoing reaso~~, ;he present ; inven~ion further relates ~c a m~thod of effecting a neuronal a~tivity in an animc , comprising:
cdmlnistering to the an mcl a neurotrophlcally effective amount of a compo~ or formula I, II, TII
or IV.

-. .

~ CA 0223978l l998-06-05 ~

_n 2 pre ~r~ed embodi:nc ~, _he neuroncl ac__v .~ is selected from t~- g~oup consisting O_ s' mu'z~lcn o~ damaged neu~- 5, Framotion a ne -_-a~ re,en-_at70n, pr--,----5. G~-S ne_~~d~sen_ra ion and t-e~ a- r~U~_loC'~~~

C_ S ~ ~ _----~~~ c~mFcu~cs c the ~--s_~~ r-~entior a~e p2-_-_ul a~l~i Ua_ Ul 0. ~-_I~-t' C reu-vdec--es 5''~-in ~a~ ents su~_e.ing from - eu~aaesererat ve dlse-se or who have s~mptomC o_ 2 neUrodeger:eratiVe dlse-sê The co~pounds are ~ S,G use_ul rar pre-~en~ng neurodegeneratlo- ~ati_ntâ new dlccnosed as having 2 neuroc~~~ne~ative disease or~
~ ris~ rar develooing a reur:s~generatlv_ d sease These c~mpaunds are also use~i~l _ar, but no- limi-ed to, ~r~venting neurodegenera_ on in pa. ents suSfe-ing from Parkinson's c secse ar h v~ng symp.oms af ~arklnsan's dis~-se These treatmen.
- methads are exemplified in ths ~TP Madel and data _ descrl~ed herein The neuralogical disord_~s that may be .re2ted include but are not limited a trigeminal . ~ ~
neur21gia; glossopharynge21 rsur21gi2; Bell's Palsy;
myas.henia gravis; muscular dystraphy; ~m~o.rophic later21 sclerasis; progressive muscular at-~phy;
pragressive bulbar inherited muscular atraph!, :..
41.

.~ , --; ~.

..
her.._a~ed; rup~ured or pro'~_ase~ invertebr2-e d s~.
syr.c:~~es; cer~-iczl s2Gnd'ii~-- s; ~lexus aLso_~ers;
tho-__ic outlet destructio ~-,..c-omes; peri ~hr:Zl neu-~pc.hic suc:~ as t;~ose c__a~d r y lezd, dCpsone, ic;~s, pcr?rtJ~ or Gu-ll~ z--- s~mdrom-;
s d_sezse; znd -~:--s r c se_se.
~:~e c-mpcu~~s o the p--a-r r.ver.. on - -part--ili2-iv us_ ul fGr ~r~---~ neu-oloa cal dia~o-~er seiected fro~ the c__u~ consisting of:
periph_raL neu~opathy cGused _; ~h~sicaL 1nju:y o-dise_s- state, pnyslcaL dama-- _c the brain, phvs-_al d2mage to the spinc cord, stroke assoc ated with brain da~ace, --d neurological diso-~er reLating to neurode-~~.eration. ExamDies lS neurc ogical disorders rela _~ _c neurodegener_~
are ~'zhei~er's Disease, F-_.~--s_n's Disease, ar.d amyo.ro~hic lateraL scleros s.
Pharmaceuti~al Compositions of the Invention ~- The present 1nvention alsc relat~s to a Fhzrmc-ceutical composition comprisi.g:
(i) a neurotrophically ef ective amount or the - c~mpound of formula r, II, III or IV, an~
(ii) a pharmaceutically -c~ept2ble carrier.
The above discussion re -_i c to the utillty and ~inistration of the cc~ounds of the present in~en.ion also apDlies to th- -:-armaceutical ~ .

~ 7 , "~

.
comFcs tlons of the present _-~Jer.tior..
~ 'f.e term ''pha~aceutic_ 'y ccce~tz~lê czrri 2S US_r her21n re ers to zn; ~zr-~ ê~ d_luen~
exc _'_nt, sus~endin~ a5er~, ' ~ -~~c'ins 2Cêh_~
S adiu-~,_-.., vehicle, deliveri -ys_em, emuLsilier, disi~ _g~ant, zbsorbant, prc--A--~,cti~e, su~ -ct_nt, co~ _, -la-~;3-_rt, O swes~s-.e~.
_- t:ese pur_oses ths __m_~_r.ds 3 th5 prêSe ,~
i~v~r.--~n mz~i be administe_~ _ly, Far~r~t~r~
' 10 by in:~zlation sprzy, topica7'i, r~ctall~, nasally, bucca'~l~, vagin211y or viz a~. l~pL2nted reser~oir ln dosage ~ormulations contain~ - conventional non-toxic -harmaceutically-acce ~-~Le carriers, zdju~ s and vehicles. The -~.m parenter~L as us~d hereir includes subcutaneous, intravenous, intramlTscular, intraperltone-_7r, intrathecallY, intrav~n.tricularly, intraste~..-l -nd intrzcranial injec.ion or infusion technl~ ~s.
For oral administration, the compounds of the presen' invention may be pro-; ~ed i~ any suitzble dosage form kno~n in the art. ~or example, the ~- compositions may be incorpor _-d into tabLets, powders, granules, beads, chewable lozenges, capsul~s, liquids, aqueous susner.sions or solutions, or sim Lar dosage rorms, u5i - con-ventlonal equipment and techniques knc~. in the art. Tablet . . .
- 4c ~ CA 02239781 1998-06-05 ~ ,-~, ~s dO5~g-L .orms 2_e ~re errer- ~}rle_s ma~ cant~i- -carr 3-S such 2S l-ctos~ r-: 5~ ch, 2nd~c-lubr c~ting àgents such Cs ~- esium ste~r~e.
C~ps_ 3â mati c~ntaln cilt__- - ~cludi?Lg lac ose ~c~
S d- ed c~-n sta~ctn a~ue~u -_ ~er.sior.s mati c3r.~
emuls ~~,-lng and sus~endiLr~ - -s-_s combined wi h ~e ac~_iv~ ingredient.
~ . preparins dosa~~ __r. ~~cor~crcting th-comFcs_-ions c. the in~-er-_-~ -e ~ompcunds ~i also c~ blended with conve---~-al exciplents sucA -s bince~s, including gelatln, ~__selGzinized st~rch, and tL- ~ like; lu~ricants, aU_ as h~drogenated vege__~le oil, ste2ric ac~d, --.d the li~e; diluents, such -s lactose, mannose, 2-~ aUCrOSe;
disi;t-grântâ, such as car~cx-,~ethylcellulose and sodiu~ 5tarch glycolate; sus~~~d~ ng agents, such as poviaor~, polyvinyl alcohol, _-d tne !ike;
absorb2nts, such as siliccr -_.xide; preservativ_s, - such as methylparaben, prop~J __raben, and sodium benzoate; surfactants, such -Sa sodiu~ lauryl .
sulfate, palysorbate 80, anc ~he like; colorants ; such cs ~.D.& C. dyes and la.c2s; flavorants; and sweeten~rs.
Co~positions and methods o~ the invention also m~y utilize controlled rele~s- .echnolog/. Thus, ror ex-mple, the inventive C-L-.-~UndS ma~ be '5 4 : CA 02239781 1998-06-05 ~!

~ , _ inc~~~crated inta a hydroph~--~ palt~mer mat- x ~or con~r~, led r~lease over 2 ~e-_-c o c~ays Su~
can'~~lled rel~-se fllms c~~ ~ cwn to .:e c_.
~zr~ _ulcrlv pr_ er~ed a.e ~~- s~_-mal dellv-e-y S sys.e~s Othe- exzmples c~ ~o t,~ers commorly empleied for th s Fur?ose t~-- m-i be use~ in the pres- _ inve . 5n ~nclude ~ dable e-hi e-_-vir; acetate c3~01v~Le; ard ~~~__dable lactic 2C-C-glycol-c acld copoLymers wh -- ~a~ be used extern2Lly or internallv C-_t- n hydrogels such ~~
poLy(rydroxyeth~lrnethacrylc~ c_ poly(vinyl~lcohG_ alsc mcv be useful, but~ for s:~ _er release cvcles then thr- other polymer rele_=~s s-~stems, such as those mentioned above lS To be efrective theraFe___cclly as central nervous system targets, the compounds or the preser.L
inven.ion should readily pen~Lrcte the blood-brain barrier when peripherally a~ nistered CompGunds which cannot penetrate the bl~cd-brain barrier car, be effectively administeren bi a~ intraventricular _ .~ ~
-~ rout~ or other appropriate de'iJery system suitable - for a~ministration to the brai~

The compounds of the pr-se~t invention mat be ~mi~istered in the form of sterile injectable preparations, for example, as s-erile injectable aqueous or oleasinous suspenc ons These J

i CA 02239781 1998-06-05 ~ > ~ t .. ' ~

suspensions may be for~ulat_~ ccording to ..
teck. ~ues kr.own Ln the zrt -~i~LS suitzble dis~e-sing or we-tlng zgen.s~ c susoe~dlns cç~r 5 The s-~-ile in ec ~bl~ orQp_-_-i~;s mzy z's~ ~e S ste-- - inJect-~le sc utior.s ~~ ~uspen,ions - rc--~oxi_ ?zrente.~lly-acc-pta_:~ ~ luen s o- sol-~ent ro ex-rnple, 2S s~lut_ons i- ,3-~ut2nedio~ c th~e __~eptabie V~rLiC1QS znc ~ -e-tS ~ m~; 'Ce empLei~~ are w2te~, RlrLger's solu~lon znd iso orLic j 10 sodi~3m chloride solution. I z~dition, ste~iLe, fixeà oils z~e conventionall:; em~lo~ed as solver~s or sus-endlng mediums. For ~~.-_ ~ur~ose, an/ bLa-._ fixe~ oil may be emploled ~~:_~ ng s~fr.the.ic mcnc-or di-glvcerides. Fztty aci~a such as oleic zcid and i s glyceride derivative~, inciuding oli-~Je oiL
and __stor oil, especiall~ i- h~lr polYoxyethyLa,cc ~rersisns, are usêLul in the ~ e arztior. OL
injec.ables. These oil solutions or suspensicns may - alsa contain long-chain alco'rol diluents or - 20 dispersants.
The co~pounds of this i-.-i~ntion m~y also be ~ministered rectally in the f~rm of suppositories.
These compositions can be pr~pzr2d by mixing the drug with a suitable non-irrit5~ing excipient whicr is soiid at room temperature, sut liculd at r~c.c tempera~ure and, there~ore, ~ 11 me1t in ~he rect~

~, ;~, ~,,.

to re:~se the à~ug. Such ma~e-i~ls inclu~~ ccc~_ butt_-, be~swzx ~'nd pol~eth~ 51ycols.
- e compouras OL this i /eentlon ~cy clso ce lcm -_stered tarically, es~ y wh2n t;-e S cor.c -_ors -cdressed ~sr tr_- mer.- ir-~olve ~~ê_S -~
ors2.- r~-dili cc_essible D'; -~~ C'1 C-?11 incl_d ~g r.eu-~'ogic_1 diso~_ers o_ he et-, :e-skir, o~ th- iowe~ intestins: _ract. Suit-hle tcpic-' formula.ions are read ly pre~2-ed ~- e--: -or these are~s.
-or topical application _3 ~he eye, or ophthzlmic use, the compounds can be formula~êd -5 micrc-.ized suspensions in ls~ orLic, pH a~usted sterll- saline, or, prerersh ;, as solutio~s in isoto-. c, pH adjusted steril- saline, eithe- wi_- --witr.out a preser~ative such -s ~enzylalkon um chloride. Alternatively ror ~he ophthalmic uses ne = compounds may be formulated ~- an ointment such c5 r petrolatum.
~sr toplcal application ~o the skin, the compounds can be formulated i. 2 suit~ble ointmen ~- cont~ining the compound suspe~Lded or dissolved i-, for ex2mple, ~ mixture with cr._ or more of tne following: minerzl oil, lioui n petrolatumj white petroLGtum, propylene glycol, polt~ox~letht~lene pol~cx ~ropt~lene compound, emulsiLying wax and ., . CA 02239781 1998-06-05 ~ ,.

wa~P~. ~ltern~.iv~l~f, the c_~.~cunds c2r, be - for~ul-ted in 2 suitaDl_ lo -~- c~ c~eam COr'-lrLir the a~~ive comrou~ suspende~ ssGlved ~ r,~ LO-ex~ ~, a m x ~re o~ cne o- ~cr~ o_ the fOLlowinç
mi-~-' oiL, s~ t-~ morcs~-_r--~, polt~scrra _ cetT1rl este-s W2X~ Ce~_P~r;' - __ O~
oc ;;-odecatnQl, ben~il 2L_---: _-~ wz~er.
~pical 2__' i~_ ion L-5- ~ _ 10We- in.es n~'.
trac. ~n be e'S~cted in a r~ ' cuppcsitori J, ' 10 formulation (see above) or ~ ~ cuitabLe enem2 formul2tion.
~0s2ge le-~ieLs on the o~ ~ about 0.1 ~g to about 10,000 m5 of the acti~_ .c-edient compound are userul in the treatment - ~:~e above condirlons, with preferred leveis OL abc ~ 3 1 ms to about 1,~0 mg. The amount o_ acti-~e i 5--- ent that m2~ be combined with the carrler ma e-i_ls to produce a - single dosage form will vary de_ending upon the hcs.
treated and the particular ~o e of adminis~ratlor It is understood, howe-v~e~, that a speciric dose ~ le~eL for any particular patient will depend upon a - ~ariety of factors including ~he actiS~ity of the speci-lc compound employe~, t:~~ age, bodv weiht, generaL health, sex, diet, t me c_ administr~tlon, rate of excretion, drug comb -2_ion, and the severit~ or the particular d s-2se being tre~ted ~~d S

, CA 0223978l l998-06-05 .. ~ ,.
for- _ ac'~inis~:~.ion.
T:~e compc~cs can be ac~_nistered ~ith Othe_ ~ neu~ rhic ag_nts such as _u~c~-op~ c g-_w.
fac~_~ (NC-r~, 5 i51 derive~ W~r r-c-o , b-_-~
S de- ;Qd grcwth f_ctor, cili--; e~rotr_pn_c -~~tc-, an~ --_-ot~opin.-3. The dosa-~ l-vel o othe-neu----~p'r~lc d-'_ss Wi'~ 1 depQ-~ c~. i_'~;Q f~c ~-s prev -.sl-y sta Qd ~nd .he n~ h~c e~_ec -~,e-_-of ~ rug com~ natiGn.
-~ 10 The present invention r__2tes to the use of a-., of th~ compounds saen in Ta~:- in the prepa_at~
of a m_dicament -or the tre_~-.e-_ of a disease suc:~
as pe- pheral neuropathy cau-_~ bv phttsical injur~
or disease stat-, ph~sical c-=2ce to the brain, ph~ys oal damage to the spina: -~rd, stroke associ~ted witn brain damag-, .-~ ~Leimer's Disaase, Park nson's Disease, and amt~ ophic iateral .. , , ~
~ sclerosis.
T~.e present invention 2''SO contemplates ., , processes for manufacturing _:~e novel compounds, .; particularly the processes del~neated in schemes 1 - and 2.

. j , ....

¦~ CA 02239781 1998-06-05 ~e~h~ds of M~kin~ the C~mc~llnds of the ~n~
~ i~e noveL c~mpcunds o _~~s ~~Ver-- ~n m-~; be read ~ prepar2~ b'i s.2nda_~ ~r.icues OL Org2n1 chem s~ry, Util -L~g th2 ge-_--' synth~_Lc oa-~wa~;
dep~__ea helow '-~ d_scrihe- -i Scheme :, cy~
ami~o aciàs 1 ~rot3c.ea b~ _ e blccc nç g_cu_-P or .he amlno acid nitrog_- ~ e -e-c-ed wit"
thic~s RSH to g3.e~at~ thioe-t--5 2 3 '3~ r3~aovai or th3 prot-ct r~5 group, th~ ~e_ ~mi~e 3 ~ai ae reacted with a v rietv OL iS_C ;-n-teS O_ isothiocyanates t~ prc~ide t:-- inal ur_as or thioureas, respectiv~ly (CH )n t~ )n OH R-S~ ~ ~ S R Deplotect Coupling ~ I
¦ O Me~od ¦ I

.

H ~ ~ S - R

- S

SCHE~E I
.~ :

, ~ CA 02239781 1998-06-05 . -_socy2nates (R'NCO) or ~_o.:._ocy~n2te- (R~NCS~.
4 m2-i ~e canveniently prepa-_d ~-3m the cor--s?ondir.g re~lLy a~2il~ ines by ~
wii_:~ -;-osge~e or thio~hcsge -, 55 deFictec -- Sc.,-~,e 2.

W

R' ~ C ~ Cl ~ R'-~CW

S CE~

Thiols R-SH may be ~ ~niently F ~pared from tne corresponding readiii _~aiLable alc~hols 5 halices via a two step replac-~e~t of halid- by - SU1LUr~ as described in Sche~_ 3. Halides may be reacted with thiourea, and t~ rresponding alkyl thiouronium salts hydrolyzed ~ ~ro~ide thi-1s RSH
'- ~ Ir alc~hols are used as the s -~~_ing mater~l 51Sr the' ~.
- ; 15 may be first converted tc the ccrresponding halides ., by st~Q~rd methods.

c, , ~ CA 02239781 1998-06-05 ~
,, :~ S
., I :
PB
R--OH or ~ R--Br ~ R~S~

SCHE~E, Exam~l~s The r ~1 low'ng ex2;r~pLes --e iilust--ti~J~ Ol- t~,~
prese... inventior and are r.c -te-.ded o ~- limit--tions .hereon. Unless othe~ S2 speci L' ed, 211 percentages ar~ based on 100~ b; w_ight of the fir:21 compcund.

~X~MPr.~ 1 Sy~ti~lesis of 3-~3-~yrl~vll-t-~ro~tfl~er~tvl 2S-l-~
r (~-~etllvvlhlltvl)c~rbA~vL~ -ne-2-cA-boxvl~L~

(1) ;; '' ' -3-(3-P~ridtt7)-l-~ro~ylchlorld~
To a solution of 3-(3-~-ldvl)-1-pro~ancl (10 g; 72.4 mmol~ in chloroform (109 m~) was added drop~ise a solutlon or thior-~l chlsride (12.5 g;

j ~

~ CA 02239781 1998-06-05 108.~ ~mol) in chlorofor~ (5~; ~L). The -esul~ ~g mixtu-e was refLuxed for 1 hcurl then pcured l~to ice-colà 50~ aqueaus pot~ss~w~ hydroxide (150 3~) ~he 1--~ers were separated, -~ the orgc.-_ ph_se WCS
S dried, concert~ated, and pu- _i_d on 2 '-__' -2 ~cl col~n, eluting with 40~ et~ acetc-e i- -.exa-e, to obtaln 10 g (6_~) of the ch ~~ e as ~ c_-_- c 1, 1~:
NMR (300 MEZ, CDC13): ~ 2.02-2.11 (m, 2F. ; 2.7 ~m, 2H); 3.51 ~m, 2:i); 7.20 ~m, -); 7.49 (m, 1~ .4 (m, 2~.).

3-(3-Pvri~vl~ rog~rl~e~~~t~n A mixture of 3-(3-pyrl~il)-1-prop; chLo-ide (3 g; 19.4 ~mol) a~d thiourea ( .1.8 g; 19.~ ~moli in ethanol (10 mL) was refluxed _or 24 hours. A~ueous sodium hydroxide, 15 mL of a 0.75 N solu~ion, was added, and the mixture was r~-luxed for -n additional 2 hrs. After cool-ng to room temper-ture, the solvent was remo~ed in v~cuo. Chromatographic purificat1on of the crude thlol on a siLica gel column eluting with 50~ eth~l ~ce-ate ir hexane -; delivered 1.2 g of 3-(3-Pyridyl)-1-propilmercapt2n as a clear liquid IH NMR ~300 ~XZ, CDCl.): ~ 1.34 (m, lH); 1.90 (m, 2H); 2.52 (m, 2.:); 2.71 (m, 2~); 7.81 (m, lH); 7.47 (m, lH); 8.42 (m, 2H).

~ CA 02239781 1998-06-05 ~

~-(3-Pvri~v~ ro~yl-o-c~tvl N- ( ter--butyl;oxvc~rh~nv1\~t~r~0 1 i d;?--2-carboxyl~t~
.~ mixture OL N-(~er~ lyoxycarbonyl)-(S)_ prol-ne (3.0 g; 13.9 mmol); -(3-~yridyl)-1-prop~l~ercaptan (3.20 g; 20.~ ~mcl),dicyclchexylc2rbodiimide (4 _9 g; 22.24 mmc-)~
camphcrsulLonic ~cid (1.08 ~; A . 63 mmcl)~ ~-.~ a-dime hil~minopyrldine (0.60 ; 4.63 mmoi) i- dr y meth~ler.e chloride (100 mL) ~zs stirred ov~rnight.
The reaction mixture was dil-_~d with methylene chloride (S0 mL) and water ~ 00 mL~, and the Layers were separated. The organic ~:ase was washed with wate~ (3 x 100 mL), dried O-J~' magnesium sulrate, and concentrated, and the c-~e residue was purified on a silica gel column elut--.~ with ethyl acetate to obtcin .60 g (95~) of the --ioester CS G t~.lck ci!, H NMR (300 MHZ, CDCl3): ~ 1.45 (s, 9H); 1.70-2.05 ~m, SH); 2.32 (m, 1~); 2.71 ~ L~ 2H~; 2.85 (m, 2H);
3.50 (m, 2H); 4.18 (m, lH); 7.24 ~m, lH); 7.51 (m, lH); 8.48 (m, 2H).

3-l3-Pyridv~ ro~vl~crc~tyl ~rroli~lne-2-~rbox~ te A solution of 3-(3-Pyridvl)-l-merc~pt~l N-(tert-butylyoxycarbonYl)pvr_~ ine-2-CarboxvlatQ
(4.60 g; 13.1 mmol~ in meth~lQrL2 chloride (60 mL) Q CA 02239781 1998-06-05 ~

and _ ,luoroacetic acid (6 m ) was s.lrred at roo~
- tem~e~-ture for three hourc. Saturated potassium car~c~.ate was added until the O'r was basic, and the reac on mixture was extrac-_~ with me~h~ e S chlcr_~e (3x). The combined c-canic ex- ac-s wer~
dried _nd concentrated to ~ie d 2.36 5 (75~, OL- the free -~lne as 2 thick oil, - ~ R (300 l~HZ, CDCl~
1.87-2.Z0 (m, 6H); ~.79 (m, ~ ; 3.03-3.1_ m, ~
total); 3.~4 (m, lH~; 7.32 (~ ); 7.60 (=, lH);
8.57 (m, 2H).

3-(3-~vridvl~ pro~vl~e-~2~t~J1 25-1-~
m~thilbtlt~ carb~m~yll~vrrolid~n--2-c2rbox; ~te (1) A solution of 2-methylbutyLcmine (113 mg; 1.3 mmol) and tri thylamine (132 mg; 1.3 ~mol) in met:~~ylene chloride (5 mL) was added to a solution Ot triphosgene (128 mg; 0.43 ~Lm5'~ in methyle.~
chLoride (S mL). The resulti-g mixture was -efluxed for 1 hour and then cooled to room temperat~re. 3-(3-Pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate (300 mg; 1.3 mmol3 ln 5 mL or me.hylene .- chloride W2S added and the resulting mixtur- was ! stirred for 1 hour and then partitioned bet~een water and a 1:1 mixture of eth~l acetate ard hexane.
The organic phase w~s dried, c-..centr-ted a--d purified by column chromatog-c~hy (S0~ ethJ_ ' 58 ~ CA 02239781 1998-06-05 , ~. :
aceta~~/hexane) to obtain 25~ ~~g (55~) o, the ~-compc~~.d OL Example 1 (1, Ta~ as an oil, H
NMR (_00 MHZ, CDC13): d lH N~r~ (CDCl3, 300 M~;Z):
0.89-,.93 (m, 6H); 1.10-1-20 !~, lH); 1.27 (s, I~
1.36- .60 (m, 2~); 1.72 (s, 2:--,; 1.97-2.28 (m, ~
2.70-2.75 (m, 2H); 2-92-3-54 (~, ~r); 4.45~4.g7 (m, lH); r .2t-7.29 (m, lH); 7,53-7 5r (dd, lH); ~.~6-8.48 ~-, 2H).

Exa~Dl~ 2 Svnthes s or 3- (3-Pvridv~ ro~vl 2S-l- r Dim~th.Jl~ropvl)carb~m~Yll~vrr~lidlne-2-carboxylate (2) Reacti~n of 3-(3-pyridyl)-1-p-opylmercaptyl pyrrolidine-2-carboXylate with ~he isocyanate genera~ed from tert-amylamine and triphosgene, as described for Example 1, prov~ded the compound of Example 2 (2, Table 1) in 62~ yield, lH NMR (CDC13, 300 MHZ): ~ 0.83 (t, 3H); 1.27 (s, 6H); 1.64-1.71 - ~m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (~, 2H); 2.85 (m, 2H); 3.29-3.42 (m, 2H); 4 .1 1 (br, lH); 4.37-4.41 (m, lH;j.
~.

~ CA 02239781 1998-06-05 . . .
~ >
Fx~ 3 Synthesis of 3-~3-2vrid~ ro~ttlme-~-3,vl 25-1-~(cvclohex~ ,kioc~rb~ ;r~ -2-S r~ rboxyl~te (7) A mix_ure of cyclohexylisc,~.-_cy~-.ate :2~ mg; 0.3 mmol), 3-(3-pyrldyL3-1-pro~;:me~capt~il _v-rclidiL-Le-2-carboxylate (200 mg; 0-9 ~ol) 2nd t~:e.hil~mine (90 mg; 0.9 mmol) in 20 mL o~ ~et~L~ler.-L chloride wcs the resulting mixture was s 1-~ed ro- : ~.our znd then ~artitioned between wa~~~ and a i:: mixture OL-.
ethyl acetate and hexane. Th~ organic p..~s2 was dried, concentrated and pur-~~ed by co ~mn chromatography (50~ eth~l zce_ate/hexan~. to obt2 -160 mg ~47~) of the compo~nc ~r Exampl~ ~ (7, T~bl~
I), :H NMR (CDC13, 300 MH2): ~ 1.16-1.43 (m, 6H);
1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.03 (m, 2H3; 3.40-3.6C (m, 2H); '.g5-4.98 (d, lH); 5.26-5.29 (d, lH); 7.17-7.25 (~, ::-?~
_ _ .
FX~MP~ 4 Synthesis of 3-Phenvl~roovl (2s~-l-r cyclohexvlcArb~m~vl)-~-~vrrolidinec~rbothio~te(1, ~ CA 02239781 1998-06-05 The compound was pre~are~ in accordance with -the ~rocedures used in the a~cve examples and yie'ded an optically pure co~pound as 2 S;iClC Whi;e soli-, with a chemical formu_c or C.r:.~N~O~S, a molecular weight of 375.56, ~ (C5C13, 300 ~HZ!:
1.10-1.19 (m,4X); 1.30-1.38 (m,3H); 1.61-1.71 (m,2H)i 1.84-2.03 (m,6H); 2.6_ (t,2H,J=7.75;; 2.87 (t, 2?--~ J=7.57); 3.33-3.39 (m, :-i; 3.46-3.50 (m,l~
3.63-3.67 (~,1~); 4.18 (d, 2?~, ~=7.85)I 4.55 (dd,lH,J=2.14,6.05); 7.11-7.29 (m,SH). Thin Layer Chromatography yielded a result of Rr = 0.43 (50%
E~OAc/Hexane~.

EX~M~r 5 Svn~hesis of Phenethyl (2S~-N-/c~clohexvl~rbamQyl)-2-~trrroli~inec~rbothioate (la) The compound was prepared in accordance with the procedures used for the above examples and yielded an optically pure compound as a clear oil with a molecular formula of C.~3N~O.S, molecular _ weigh~ of 360.63, iH MMR (CDC1., 300 MH~ 1.06--- 1.38 (m,7H); 1.61-1.72 (m,2H); 1.93-2.13 (m,4H);
2.84 (t,2H,J=7.57); 3.10 (t,2Y:,J=7.0); 3.33-3.35 (m,lH); 3.44-3.4S ~m,lH); 3.64-3.67 Im,lH); 4.17 (bd,lH,J=7.94); 4.55 (bd,lH,J=8.37); 7.20-7.31 - (m,SH). Thin La~er Chrmoatography yielded a result~

~1 ''' ~. ~

of R, = 0.18 (50~ Hexane:ETC~c).

.

~a~PT ~.
S~mthesis of 3-(~,3,5-Tri~ henvl~ro~
a~m,~~~~_vlc2rb~0vl)-2-~ttrroi~d~n.ecArhothi2'- (19) The compcund was prepa~~~ iLL accordance with the a~ove exa~ples and yiels_~ ar optically pu~e comFou~d as a colorless oil t~'_;~' a molecular formul2 of C~H4aN~O2S, molecular weisht OL 468.65, E'; NMR
- 10 (CDCl', 300 MXZ): ~ 1.50 (s,3H); i.67 (bs,SH); 1. a2-1.90 (m, 2H); 2.01 (s,6H)i 2 t s-2 . 20 (m,4HJ; 2 . lO
(s,3P:); 2.15 (s,3H); 2.19 (s,3';); 2.63 (t,2H,J=6.66); 3.30 (m,lH); 3.42 (m,lH); 4.15 (s,lH); 4.52 (~,1~3; 7.01 (a,2-,J=10.48). Thi~
Layer Chromatogr2phy yieldec a result of R = 0. a2 (80% EtOAc/hexane).

EXAMpT~ 7 Synthesis of 3- ( 2, 3,5-Trimethv!oheny~)orQp~
~ cyclohaxvlc~ rh~mnvl ) -2-gvrroli~ine~rbothioate (20) The compound was prepared in accord~nce with the procedures used in the above examples and yielded an optlcally pure compound as a colorless oil with a molecular formula G_ C-~H35N~~O?S-O~7S H~O, a molecular weight of 430.13, ~ MR (CDCl., 300 MHZ):
~ 1.06-1.19 (m,3H); 1.22-1.43 (;a,2H~; 1.53-1.55 ~3 CA l):Z2397B1 1998-1)6-05 ~

~m,lH); 1.71-1.74 (m,2H); 1- _-1.80 (m,2H); 1.81- .
1.85 (m,3H); 1.96-2.03 (m,2:-i; 2.10 (s,3H); 2.15 (s,3r:) 2.20 (s,3H3; 2.63 (t,2-,J=7.98); 2.90 (t,2~;
3.38 (q,lH)i 3.40-3.43 (m,l:- ; 3.~1-3.69 (m,lH);
4.19 (d,lH,J=8.22); 4.56 (d,:--); 6.95 (d,2H:,J=12.05)- Thin Lave- ~ matography yi~lded 2 resul_ of R = 0.47 (80# E r _!nexzne).

F~PMP, .~
Synthesis of 3-(3-Fl~loro~hen~ o~yl (2S)-1-(Cvclohex~vlcarbamotrl)-2-~yr~~l dinecArbothiocLe (21) The compound was prepa--~ in accordance with the procedures used in the -~cve examples an yielded an optically pure compound 5S a whlte solid with a molecular formula of C~.H~ C ~-, a mole~ular weight of 392.56, -H NMR (CDCl., 30i ~Z~: ~ 1.07-1.43 (m,6H); 1.63-1.73 (m,2H); 1.~7-2.09 (cm,7H); 2.67 (t,2H,J=7.46); 2.85 (t,2H,J=7.46); 3.35-3.37 (m,lH);
3.46-3.48 (m,lH); 3.65-3.67 l~,lH); 4.19 (d,lH,J=7.84); 4.55 (d,lH,J=7.90); 6.84-6.95 (m,3H);
7.21-7.24 (mjlH). Thin Laye- Chromatography yielded a result of R = 0.19 (20~ EtOAc/hexane).

~XPMPr~
S~mthesis or 3-(~-Fluorooheri ~ro~ 2S~-1-(1-A~m~ntvLcArbAm~vl~-2-~yrroliAlnecarbothioate (22) - ~~e compound was prepa~~d 1-. -ccordance With the p_ocedures used in the a ove examples and yieLded an opticall~ pure com~o~nd as a colorle55 oil ~-,h a molecular Lormul~ G_ C~ H3lN~Q SF, a S molecular wei~ht of 44g.~4, :- ~ (CDC13, 3ao ~HZ):
l.c6 (bs,5H); 1.99 (s,2~); 2.04 (bs,6H); 2~o6-2~l3 (bs,o-~; 2.25 (m,lH); 2-59 (.,2-~; 2.~o (t,2H); 3.-2 (m,1 :- ; 3. 57 (m,lH)i 4.2~ (m,2- ); 4.67 tm,1:~); 7.03 (m, 2'-~ ; 7.18 (m,2H). Thin T 2 ;--- Chromc-3srapnv yielded a result or Rc = 0.70 (_.OPc).

F.XAMP ~
Sv~thesis or 3- (2-Fluoro~henil3~ro~vl (2S)-l-(cvclohexvlc~rhamovl)-2-~vrrolidi~Pc~rhothlo~te (23~) The compound was prepared ln accordance with the procedures used in the abcv~ examples and yielded an optically pure com~curd as a white solid with a molecular formula o_ C~ 'iO.SF, a molecuLar weight of 392.56, lH NMR (CDCl~, 300 MhZ): ~ 1.23-1.32 (m,3H); 1. 41-1.49 (m,3H); 1.74-l.a2 (m,2H);
_~ .
1.93-2.09 (cm,6H); 2.15-2.23 (~,1H~; 2.73 lt,2H);
- 2.94 ( t, 2H); 3.42-3.51 (m,lH); 3.54-3.61 (m,lH);
3.61-3.74 (m, lH); 4.24 (d,lH); 4.55 (d, lH); 6.91-7.03 (m, 2H); 7.15-7.24 (m,2H) . Thin Layer Chromatography yielded 2 result or Rc = 0.55 1, ; ~

FXAMPL~
Synthesis of 3-(4-MeLhvl~ohertJl~oroovl (2S)-l-(cyclohexylcarb~m~vl \ -2-~vrr~l~ nec~rhothio~t~ (2d) The Compound was prepa-~d in accordance with the procedures used in the a_ove examples and yieLded an optically pure compound as a whit~ solic with a molecul~r rormula of C,~Hl2N~O2S-0.25 EtOAc, 2 molecular welgh- or 410.60, ~ R (CDCl3, 300 MP:Z):
~ 1.01-1.21 (m,3H); 1.30-1.~4 (m,2H); 1.61-1.69 (m,2H); 1.75-2.13 (cm,8H); 2.30 (s,3H); 2.53 (t,2H);
2.84 (t,2H~; 3.61 (a,lH); 3.o5-3.69 (m,lH~; 3.72-3.76 (m, lH); 4.21 (d,lH); 4.59 (d, lH); 7.05-7.25 (m,4H). Thin Layer Chromatography yielded a result of R, = 0.84 (80# EtOAc/;hexane) .

F.X~MPT.~ 12 Svnthesis of 3-(a-MethvLphens/l~roE?vl (2S)-1-(1-m~r~tvlc~rh~ yl)-2-~vrrol~ nec~rbo~hioate (25) The compound was prepared in accordance with _~ the procedures used in the above examples and yielded an optically pure compound as a coLorless oil with a molecular formula of C2sH3,N~S-0.10 - EtOAc, a molecular weight of 450.46, IH N~ (CDCl', 300 MHZ): ~ 1.54 (s,SH); 1.66 (bs,6H); 1.85 (q,lH);~
2.03 (s,8H); 2.09 (s,4H); 2.63 (t,2H); 2.86 (t,2H);
3.33 (q,lH); 3.35 (m,lH); 4.08 (s,lH); 4.52 (d,lH);

' CA 02239781 1998-06-05 ~, ~ ~

., ~
7 03-,.14 (m,4H3. Thin La~e~ Ch~omatograph~ yield~d a resu t of R~ = 0.68 (80~ E'OP.c/hexane).

E~r- '~3 SVr~ Q_15 of 3-~4-Methvl~heny7~~o~vl (2c)-i-~tert ~tv -~-h~m~vl)-2-pvrrolidll_c~r~othlo~tQ (26) ~-e compound was prepared n acc~rdanc~ wi,;~
the pr~cedur2s used in the 2"0Ve exanples a-.d yielde~ an optically pure compound as a colorless oil with a molecular formula OL GOH3ON~O2S-O . 3 H20, a molecular weight of 367.94, H. N~R (CDCL,, 300 MHZ):
1.4~ (s,9H); 1.82-1.91 (m,~'-.); 1.95-2.18 ~m,4H);
2.31 ~s,3H); 2.76 (t,2H); 2.~9 ( ,2H); 3.41-3.43 (m,1~;); 3.46-3.49 (m,lH); 4.2a (~s,lH); 4.61 (d,lH3;
7.09-7.12 (m,4H). Thin Layer Chromatcgraphy yielded a result of R. = 0.50 (50% Et~c/hexane).-~XAMPTF 14 Svnthesis of 3-(~-Chloro~hen~ ro~yl (2S)-l-cvclonexylc~rb~m~yl)-2-~vrrQl~dinecarbothio~te (27 The Compound was prepar~d in acccrdance wi;h - the procedures used in the above examples and - yielded an optically pure compound as a light foam with a molecular formula of C,iH.~N~O~SCl, a molecular weigh~ of 408.99, !H NMR (CDCl-., 400 MHZ): ~ 1.05-- 1 42 (m,7H); 1.61-1.78 (m,3H); 1.83-2.17 (m, Sn);

'' ~'' ~

2.87 (t,2E~); 3.0i (q,2H); 3.~2 (a,lH); 3.57 (~,lH);
3.61-3.67 (m,lH); 4.21 (d,lr); 4. 64 (d,lH); 7. 20-7. 31 (~n,3H); 7.56-7.59 (m,1':.~ . Thin Layer Chromatography y elded ~ res_ o- R. = 0.7~
(EtO.~-c!.

EX~MPT- 5 Svnthesi S Ot 3-f3~s-Dimethox~ er~tl) orc~v r r ( lS ) -1- ( 1-n ~hthvl~e~hvll---~~-m~vl~-2-oyrrolidinecArhothio~te (28~
The compound was prepared in accordance with the procedures used in the a~s-~, e examples and yielàed an opticalLy pure ccmr~c~-,d as a colorless oil with a molecular rormula 'J- C~H3~N.03S-0.75 H,O-0.60 EtOAc, a molecular weight of 573.04, 'H NMR
(CDCl3, 400 MHZ): ~ 1.65 (d,3X, J=~ . 76); L.83-1.96 (m,2H) i 1.99-2.07 (m, 3H); 2. 6C !t, 2H, J=7.51); 2.85 (t,2H,J=7.27~; 3.29-3.68 (m,2X); 3.73 (s,6Ej; 4.56 (d, lH,J=6.10); 4.76 (d, lH,J=7.51); 5.78-5.79 (m,lH);

6.29-6.32 (m,3H); 7.40-7.76 (m,4H) i 7.81 td, lH, J=6.90); 7.83 (d, lH, J=7.3 - ); 8.17 -; (d, lH, J=7.72) . Thin Layer Chromatography ~ielded a result of Rf = 0.09 (50% EtOAc/hexane).

EX~MPT ~ 16 Svnthesis gf 3,3-Dlohenvlpr~ovl (2S) -1- r (1,1,3,3-eetr~ethylhiltyl 1 c~rb;~mc~y~
oyrroli~inec~rbothio~te (29) The compound was prepar~~ in accordance with the procedures used in the C~OvQ examples and yielded an opticclly pur~ cc-~cund as a colorless oil w .h a molecula- Lormul2 ~- C~H~oN~O.S-0.25 EtO~c, moleculcr we~h. o- _;2-7d~ -H NMR (CDCl-, 40C
MHZ): ~ 0.88 (t,2X,J=6.57); _.02 (s,9P:); 1.41 (s,3H); 1.42 (s,3H); 1.81 (d,l:~:,J=14.90); i.65 ~d,lH,J=14.90~; 2.04-2.07 (m, -.); 2.29 (q,2H,J=7.83); 2.77 ~t,2H,J=6.g7); 3.29-3.3G ~m,lH);
3.40-3.42 (m,lH); 4.00 (t,lH,J=7.83); 4.32 (s,lh;);
4.53 (dd,lH,J=1.96,7.92); 7.'0-7.27 (m,10H). Thin Layer Chromatography yielded 5 result of Rc = 0.~3 (50~ EtOAc/hexane).

FX~Pr~ ~7 Svnthesis of 3-CvclohexyL~ro~yt ~2S)-'-r(2,6-~iisopro~yL~h~nyl)c~rb~m~vll-2-~yrroli~inec~rhothio~te (31) The compound was prepcr~d in accordance with the procedures used in the above examples and yielded an optically pure compound as a white solid with a molecular formula OL- C~-Hj~N5O,S, a mole~ul-~
weight of 458.58, IH ~MR (CDCL., 400 MHZ): ~ 0.75-- 0.~1 ~m,2H)i 1.15-1.43 (m,lar:)i 1.59-1.61 (m,2H);

~a .. r~ Ç~

1.63-1.82 (m,SH); 2.09-2.36 (a,4H;; 2.83 (t,2H);
3.24 (t,2H~; 3.51-3.79 (m,2~); 4-67-4.71 (m,lH~

7.15-7.20 (m,2HJ; 7-26-7-31 l~,lr)~ Th~n Later Chrcma~ography yielded a r~s_l_ c_ Rf = 0.72 (50 EtO~c~hexane).

~x~M~r~ ~
Svnr:-e~s of 3-C~fclohexv~-c_ : '2S)-1-(hexy'c~rhamovl~-2-~vrrolid~ ~hothi~te ~32) The compound was prepare~ in accordance with the ~rocedures used in the a_~ve examples and yielded an optically pure cor._cund as a colorless oil with a molecular formula o C~,H3eN~O S-O.OS H~O, 2 molecular weight of 483.51, 7 NMR ( CDCl3, 400 MHZ):
~ 0.76-0.91 (m,2H); 1.15-1.4_ (m, laH) i 1 ~ S9-l ~ 61 (m,2H); 1.63-l.a2 (m,SH); 2.5C-2.36 (m,4P;); 2.83 (t,2H); 3.24 (t,2H); 3.51-3.,~- (m,2H); 4.67-4.71 (m,lH); 7.15-7.20 (m,2H); 7.26-7.31 (m,lH). Thin Layer Chromatography yielded ~ result of R~ = O . 35 (50~ EtOAc/hexane).

.: ~k~U~PT.~ lg S~mthesi~ of 3 3-Di~henylgro~ (2S)-1-r(2,4-~ thoxv~henyl)carhamovll-2~ roLidinecarbothio~te (33) - The compound was prepared in accordance with ~ ' CA 02239781 1998-06-05 . ?

the ~-~cedures used in the a~c-~Je exma~:~S ~--yielded an optically pure cc~pound as a whi~,e solid with - moLecuLar formula of C ~E~32N20~S, molec l~r weish,_ or 504.33, IH NM~ (CDCl., ~00 P~:Z): ~ 2.0~-2.19 ~m,4H); 2.30 tq,2H, J=8.,~); 2.78 (td,2:-,3=~.8g,7.10); 3.58 (c,l:i,J=7 57,; 3.6~-3.7O
(m,lr'; 3.77 (2,3H); 3.80 ~s,3::); 3,99 -(t,lH,J=7.76); 4.65 ~dd,lH,J=2.08,8.1~;; 6.'~-o,4~
(m,2'-); 7.14-7.28 (m,10H~; a.o; (d~lH~ .5~--. Th r Layer Chromatography yieldes - resuit G- ~ = 0.63 (EtO~c).

FX~M~T~ 20 Svnthesis of 3-~3,5-Dimethox-,~henvl)~rs~vl (~S)-l-r tlS,2R)-2-~henyl-cycloQro~ rllc~rb~m~ -2-~yrroli~iine~rbothio~te (34) The compound was prepar~ in accordance ,vith the proceAures used in the abo~7e examples and y-elded ~n optically active compound as ar~ oil with a molecul~r formula of C~6H32N,Q~S-O.4 H20, a 3Dolecul~r wel~ht of 475.82, IH NMR (CDCl3, 300 MHZ): ~ 0.86-0.88 (m,lH);
1.12-1.21 (m,2H); 1.82-1.92 (m,2H); 1.94-2.02 (m,2H); 2.05-2.12 (m,2H); 2.60 (t,2EI,J=7.86); 2.84 (dt,2H,J=7.04); 3.33-3.35 (m,l~:~; 3.46-3.48 (;n,lHj;
- 3.75 (s,6H); 4.58 (d,lH,J=6.35); 4.97 !bs,1 r,; 6.28-' CA 02239781 1998-06-05 ~ i ~
'"

6.32 (m,2H); 7.12-7.2S tm,6~:i- Thin Layer Chromatoqraphy yielded a re ;lt of Rf = 0.65 (9 EtOAc/hexane).

S rX.MPT.r ~'~
Svntkesis of 3-~nvlpro~vl ~2S)-l-r(2,4-Dime~Qxv~henv:llccrb~vil-2~ o l idinec2rboth~a~s (35) The compound was prepar d in accordance with the p~ocedures used in the a~c-~Je exampl~s and yielded an optically açtive c~rpound as an oii with a molecular formula of C23H~g~ O~S~ a molecuLar weight of 428.57, lH NMR (CDCl3, 30G ~Z): ~ 1.85-1.90 (m,2H); 2.05-2.19 (m,4H); 2.o7 (t,2H,J=7.52); 2.87 (t,2H,J=6.61); 3.53-3.68 (m,l-), 3.72-3.75 (m,lH);
3.77 (s,3H); 3.83 (s,3H); 4 6~ (dd,lH,J=2.16,8.11);
6.43-6.46 (m,2H); 6.80 (s,lH~; 7.14-7.19 (m,3H);
7.24-7.28 (m,lH); 8.06 (d,lH,J=7.al). Thin Layer Chromatography yielded a res-lt of Rc = 0.45 (50 EtOAc/hexane).
.~.~ _ F.XAMPT.F. 27 - S-ynthesis of 3-Phenvl~ro~vl (2S~-1-(1-~m~ntvlcarb~m~ -2-ovrroli~;nec~rhothio~te (36) The compound was prepared in accordance with the procedures used in ~he above examples and ; 71 ~ CA 02239781 1998-06-05 yielded an optically pure ccr~pour.d as a colorleSs .
oil wi.h a molecular for~ul2 of G,cH34N~o?S, a mole~ r weight of 426.64, :- NMR (CDCl;, 300 M~,z 1.~3-1. 66 (m,6E~); 1.83-2.~. (m,l4H); 2.68 S (t,2:--,J=7.57); 2.86 (t,2H,J= ~23); 3.33-3.45 (m,lri);
4.12 (d,2H,J=7.12); 4.53 (dd,l~,J=2.16,8.16); 7.12-7.29 'm,SH). Thin Layer Ch~_m2.0graphy yielded 2 resu . of R = 0.60 (50~ E-C:_/hexane).

EX~MPT.~ 23 Svnt:r!_sls of 3-Ph~nvl~ro~vl !2S)-l-~l-cycl~:rexvlcarb~m~ 2-ovrrcl di~e~arbathio~te (37) The compound was prepare~ in accordance with lS the ~rocedures used in the a~ove examples and yielded an optically pure compound as a s.ticky white solid with a molecular formul~ OL- C~lH~oN20zS~ a molecul~r weight of 375.56, ~ NMR (CDCl3, 300 MHZ):
~ 1.10-1.19 ~m,4N); 1.30-1.38 (m,3H); 1.61-1.71 (m,2H); 1.84-2.03 (m,6H); 2.65 (t,2H,J=7.75); 2.87 (t,2H,3=7.57); 3.33-3.39 (m,1''3; 3.46-3.50 (m,lH);
3.63-3.67 (m,lH); 4.18 (d,2H,J=7.85); 4.55 ~dd,l~,J=2.14,6.05); 7.11-7.29 (m,5H3. Thin Layer Chromatography yielded a result of R~ = 0.43 (SO~
25- EtOAc/hexane).

~ ~ CA 02239781 1998-06-0~ ~

Ki Test Pro~ re Inhibition of the pepti~yl-prolyl iSomerase (rot~mase) activlty of the inventive compounds c~
be evzluat2d by ~ own methocs described in ~'n~
lite~~ture (~arding, et al., ~Jatur~, 1989, 31 758-760; --clt et al. J. A~. Ch2.~. Scc., 115:9923-g93a) These v21ues are ootained as appar~nt Ki's ard are presen_ed in Table II. The cis-.rans isomer Z2tior of an aLanine-proline bond in a model substr_,e, ~-succiryl-Ala-Ala-Pro-Phe-p-n troanilide, is monitored spectrophotometrically in a chvmotrypsin-coupled assay, which releases Fara-nitroaniLide from the t ans form of the substra.e. The inhibitlon of this rezction ccused by the addition of di'r~_ent lS concentrations of inhibitor is determined, and the data is analyzed as a change in rirst-order rate constant as a function of inhibitor concentration to yield the apparent Ki values.
In a plastic cuvette are added 950 mL of ce cold assay buffer (25 mM HEPES, pH 7.8, 100 mM
~, NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH
7.5, 100 mM NaCl, 1 mM dithiothreitol3, 25 mL of chymotrypsin (50 mg~ml in 1 mM HCl) and 10 mL of test compound at various concéntrations in dimethyl~
sulfoxide. The reaction is initiated by the additlon of S mL of substrate (succinyl-Ala-~he-PrG-~ CA 02239781 1998-06-05 ~

Phe-F2ra-nitraanilide, 5 mg/~~ in 2.35 ~M LiCl in tri f luc roe thano 1 ) .
The absorbance at 390 r~ versus time is monit3red for 90 seçonds usi-, 2 Spectrophotometer S and the rate constants are c___rmi ned fro~ the abso-~z~ce versus tlme data -les.
The data ror these ex2e _..ents for representative compounds are -_es~nted in T~ble II
under the column "Ki".
- 10 The neurotrophic effec;s 5f ~he compounds or the present invention can be ~emo~strated in cellular biological experimen_s in vitro, as descrired below.

Chick Dorsal Root Ganglion Cul tures and Neuri te Outgrowth Dorsal root ganglia were dissected from chick em~ryos of ten day gestation. Whole ganglion explants were cultured on th n layer Matrigel-coates 12 well plates with Liebovitz LlS plus high glucose media supplemented with 2 mM glutamine and 10~ fetal - calf serum, and also containing 10 ~M cytosine B-D
arabinofuranoside (Ara C) at 37~C in an enviror~ent conta ning 5~ CO~. Twenty-four hours later, the DRGs were treated with various immunophilin ligands.
~ort~-eight hours after drug rreatment, the gangliz 7d . ~ CA 02239781 1998-06-05 ~
.~ ~
were visualized under phase c_rt-ast or Horfman Modulation contrast with a Ze_ss P~iovert inverteC
microscope. Photomicrographs c r the explants w made, and neurite cutgrowth n_S cuantitate~.
S Neurites longer than the DRC- di2me'er were Counted ~s positive, with total num~e- o_ neurites quantitated per e ch experim~~_~' condltion. Three to foLr DRC-s are cultu-ed pe- w_l_, ard each treatmert was perrormed in du- _ate.
- 10 The data for these exper ments for representative compounds are -~esented in Table II
under the column "EDso"

. ~ .. , T~Rr ~
In V7 tro Tes~ ~-S~l l r -~x. No. E~
S - 1 +++
2 ++
3 +f 4 ++
S ++
6 +
7 ++

8 +++

9 +++
+++ ~, 11 +~
12 +++
13 ++_ 14 +*+
+++
16 ++
18 *
19 *
*

22 +
23 *
24 *
+
26 *
27 *
28 *
29 *
31 *

TART ~ I I (b ) In Yi tra Test Reslll ts F-X. No . ~D50, n~

-~ 1 2 +++
3 +++
4 ++
S +++
6 ++
7 +++
8 ++++
9 ++++
I0 +++
1 1 +++
12 +++

CA 02239781 1998-06-05 Jr~ ~

13 +*++
14 +++
++++
16 ++

~_~le II(c~: Nu~er~cal ~n Y ro TesL R:'sl!ltS
~x. ~c. Ki,~
1 ~3 5 2 R
0 19 10, ~'JO
6~-21 79c 22 3 A ~

24 60~

28 805~ ;
29 5la~
31 lO,;~C
32 33~_ 33 10,050 10,000 44 10,000 t. Relative potencies of compGunds are ranked according to the followin~ scale: ++++ denot_s Ki or EDS0 ~ 1 nM; +~+ denotes K or EDS0 o~ 1-50 nM;
++ dénotes Ki or ED 50 of 51-200 nM; + denotes Ki or ED of 201-SOO nM; ~ denotes X~ or ED50 of > SOOnM.

~PTP Model of Parkins~n's Dis~se The rem2r'{able neurotro~.L7c and neuror~generative eîfects o ~he present inv_-,ive compounds can be further dem~-str2t2d ir an a- a S model cf neurodegenera.ive _ se se. ~,r? l~c_~
of dopaminergic neurons in ~-~e ls used 2S ar. -n mc:
model OL- Parkinson's Disease- Four wee~ old male CDl writ~ mice are dosed i.~. ~ith 30 ma/kg c~ ~:~T-for S davs. Test compou~ds ~ mg/kg), or veh-~le, are administered s.c. along w--n the ~TP for days, as well as for an addi onal 5 .days fol ~wing cessation of MPTP treatment. .~t 18 da~s foLl~wing MPTP treatment, the animals _re sacri iced ~r.~ the striata are dissected and pe-_1sion-fixed.
Immunostaining is performed c. saggital and corona brain sections using anti-tt~~osine hydroxylase 1 g to quantitate survival and rec~very of dopami-.er~ic neurons. In animals treated w th MPTP and vehicle, a substantial loss of functional dopaminergic terminals is observed as co~ared to non-Lesioned ~ animals. Lesioned animals r~c~iving tes. com-cunds ~- show a significant recovery o~ TH-stained - dopaminergic neurons. Data rrom this model present-quantitation for the recoverJ o TH-positive dopaminergic neurons in the s--iatum or animc~s r~ceiving the compounds or t~e present invent-on.

~ CA 02239781 1998-06-05 ~

~
Data rom representative cor.~_ 1 and lesioned anim ls not receiving the tes- drugs also presents çuant -ation of effects in t:ê aDs~nce of tha co~pc~.nds of the present in-~ .ior S ~he phrase "preventir.g .e -odegêneratlor n rela ~s to the remarkablê a~ of the com~ounds o_ th- present invention to s~~- fic2ntly prevent nerv-ê damage when the compo~ s 2' e given concu_rently with a lesioni-r.~ agent, such as ~PT~.
~ 10 This ~lso provides 2 reasona- e correlation between the Scopê of the claims and _h~ ability to preve~t neurodegeneration in patien-s newLy diagnosed as having a neurodegênerativê c-se5se, or at risk of developing a neurodegenerat v- isease. The - 15 compounds also provide methcds for preventing further neurodegeneration in ~-tients who are alre~dy suffering from or ha-re s~nptoms of a neurodegenerative disease.
The invention being thus described, it wiLl be _ obvious that the same may be v5ried in many ways.
Such variations are not to be regarded as a ~- departure from the spirit ana scope of the invention - and all such modifications a-- inrendêd to be included within the Scopê of the followinq claims.

Claims (41)

WHAT IS CLAIMED IS:

1. A compound of formula I:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B are taken together with the nitrogen and carbon atoms to which they are respectively attached to form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2, O, S, SO, SO2, NH or NR3;
X is either O or S;
Y is a direct bond to Z, a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, /

NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
C and D are independently:
hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions(s) with C3-C9 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C4-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted;
W is oxygen or sulfur;
U is either O or N, wherein when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of:
Ar as defined above, C3-C9 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C9 cycloalkyl;
and when U is N, R1 and R2 are selected independently form the group consisting of:
hydrogen, Ar as defined above, C3-C9 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C2-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C9 cycloalkyl;
or R1 and R2 may be taken together to form a heterocyclic ring.

2. The compound of claim 1, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

3. The compound of claim 1, wherein the compound has an affinity for FKBP-type immunophilins.

4. The compound of claim 3, wherein the FKBP-type immunophilins are FKBP12.

5. The compound of claim 1, wherein the compound inhibits rotamase enzyme activity.

6. The compound of claim 1, wherein the compound is selected from the group consisting of:
3-Phenylpropyl (2S)-1-(1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (17);
Phenethyl (2S) -N-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothiate (18);
3-(2,3,5-Trimethylphenyl)propyl 1-(1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (19);

3-(2,3,5-Trimethylphenyl)propyl 1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (20);
3-(3-Fluorophenyl)propyl (2S)-1-(21);
3-(2-Fluorophenyl)propyl (2S) -1- 1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (22);
3-(2-Fluorophenyl-propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (23);
3-(4-Methylphenyl)propyl (2S)-1-(cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (24);
3-(4-Methylphenyl)propyl (2S)-1- 1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (25);
3-(4-Methylphenyl)propyl (2S)-1- tert-butylcarbamoyl)-2-pyrrolidinecarbothioate (26);
3-(2-Chlorophenyl)propyl (2S) -1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate 27);
3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S)-1-(1-naphthyl)ethyl]-carbamoyl}-2-pyrrolidinecarbothioate (28);
3,3-Diphenylpropyl (2S)-1-[(1,1,3,3-tetramethylbutyl)carbamoyl]-2-pyrrolidinecarbothioate (29);

3-Cyclohexylpropyl (2S)-1-[2,6-diisopropylphenyl)carbamoyl]-2-pyrrolidinecarbothioate (31);
3-Cyclohexylpropyl (2S)-1-(hexylcarbamoyl)-2-pyrrolidinecarbothioate (32);
3,3-Diphenylpropyl (2S)-1-[(2,4-dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (33);
3-(3,5-Dimethoxyphenyl)propyl (2S)-1-{[(1S,2R)-2-phenyl-cyclopropyl]carbamoyl]-2-pyrrolidinecarbothioate (34);
3-Phenylpropyl (2S)-1-[(2,4-Dimethoxyphenyl)carbamoyl]-2-pyrrolidinecarbothioate (35);
3-Phenylpropyl (2S)-1-adamantylcarbamoyl)-2-pyrrolidinecarbothioate (36);
3-Phenylpropyl (2S)-1-(1-cyclohexylcarbamoyl)-2-pyrrolidinecarbothioate (37);
3-Phenylpropyl (2S)-1-[1-adamantylamino) (thioxo)-methyl]-2-pyrrolidinecarbothioate (38);
3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(hexylcarbomoyl)-2-pyrrolidinecarbothioate (39);
3-(3,4,5-Trimethoxyphenyl)propyl (2S)-1-(benzylcarbamoyl)-2-pyrrolidinecarbothioate (40);
3-Phenylpropyl (2S)-1-(dimethylcarbamoyl)-2-pyrrolidinecarbothioate (41);

3-Phenylpropyl (2S)-1-(1-pyrrolidinylcarbonyl)-2-pyrrolidinecarbothioate (42);
3-Phenylpropyl (2S)-1-(morphilinocarbonyl)-2-pyrrolidinecarbothioate (43);
3-Phenylpropyl (2S)-1-(diisopropylcarbamoyl)-2-pyrrolidinecarbothioate (44);
3-Phenylpropyl (2S)-1-[methyl(phenyl)carbamoyl]-2-pyrrolidinecarbothioate (45); and 3-Phenylpropyl (2S)-1-(diphenylcarbamoyl)-2-pyrrolidinecarbothioate (46).

7. A pharmaceutical composition comprising a neurotrophically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

8. A method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of the compound of claim 1.

9. The method of claim 8, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

10. The method or claim 9, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

11. The method of claim 10, wherein the neurological disorder relating neurodegeneration is selected from the group consisting or Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

12. A compound of formula II:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, G and H are independently CH2, O, S, SO, SO2, NH or NR3 wherein at least two of E, F , G, and H
are CH2;
X is either O or S;
Y: is a direct bond to Z,a C1-C5 straight or branched chain alkyl, or a C1-C5, straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alklamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 selected from the group consisting of hydrogen, (C1-C5)-straight or branched chain alkyl, (C3-C5)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C1-C5 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituded in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O,NH, NR2, S, SO, or SO2 wherein R2 is selected from the group cansisting of hydrogen, (C1-C5)-straight or branched chain alkyl, (C3-C5)-straight or branched chain alkenyl or alkynyl, and, (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
C and D are independently:
hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C5 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C9 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C5 alkyl, C2-C5 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl,wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR , S, SO, or SO2 , wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted;
W is oxygen or sulfur;
U is either O or N, when U is O, then R1 is a lone pair of electrons and R1 is selected from the group consisting of:
Ar as defined above, C3-C4 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-~
straight or branched chain alkyl or alkenyl substsituted in one or more positions with Ar, amino halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, akenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any or the carbon atoms or the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C5)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C~-C9 cycloalkyl;
and when U is N, R1 and R2 are selected independently from the group consisting of:
hydrogen, Ar as defined above, C~-C9 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2,O, or NR2 wherein R2 is selected from the group consisting or hydrogen,(C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C9 cycloalkyl;
or R1 and R2 may be taken together to form a heterocyclic ring.

13. The compound of claim 12, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

14. The compound of claim 12, wherein the compound has an affinity for FKBP-type immunophilins.

15. The compound of claim 14, wherein the FKBP-type immunophilins are FKBP12.

16. The compound of claim 12, wherein the compound inhibits rotamase enzyme activity.

17. A pharmaceutical composition comprising a neurotrophically effective amount of the compound of claim 12 and a pharmaceutically acceptable carrier.

18. A method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of the compound of claim 12.

19. The method of claim 18, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

20. The method of claim 19, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

21. The method of claim 20, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

22. A compound of formula III:
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH or NR3 wherein at least 2 of E, F, and G are CH2;
X is either O ar S;
Y is a direct bond to Z, a C1-C6 straight or branched chain alkyl, or 2 C1-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one or the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocylic ring is optionally fused to an Ar group;
Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonly , oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen (C1-C6)-straight or branched chain alkyl, (C3-C6) straight or branched chain alkenyl or alkynyli ana (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen or NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
C and D are independentiy:
hydrogen, Ar, C1-C6 straight or branched chain , alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C9 cycloalkyl C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms or said alkyl or alkenyl are optionally substituted in more or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted;
W is oxygen or sulfur;
U is either O or N, wherein when U is O,then R1 is a lone pair of electrons and R2 is selected from the group consisting of:
Ar as defined above, C3-C9 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C9 cycloalkyl;

and when U is N, R1 and R2 are selected independently from the group consisting of:
hydrogen, Ar as defined above, C3-C9 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl,or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar,amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C5 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2,O
or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C8 cycloalkyl;
or R1 and R2 may be taken together to form a heterocyclic ring.

23. The compound of claim 22, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

24. The compound of claim 22, wherein the compound has an affinity for FKBP-type immunophilins.

25. The compound of claim 24, wherein the FKBP-type immunophilins are FKBP12.

26. The compound of claim 22, wherein the compound inhibits rotamase enzyme activity.

27. The pharmaceutical composition comprising a neurotrophically effective amount of the compound of claim 22 and a pharmaceutically acceptable carrier.

28. A method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of the compound of claim 22.

29. The method of claim 28, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of .

neuronal regeneration, prevention of neursdegeneration and treatment of neurological disorder.

30. The method of claim 29, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

31. The method of claim 30, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

32. A compound of formula IV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

n is 1, 2 or 3 forming a 5-7 member heterocyclic ring;
is either O or S;
Y is a direct bond to Z, a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chair alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C5)-straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
Z is a direct bond, or a C1-C5 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or where any of the carbon atoms of said alkyl or alkenyl are optionally placed with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C5)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR2 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
C and D are independently:
hydrogen, Ar, C1-C5 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, amincalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen (C1-C6) straight or branched chain alkyl, (C3-C5)-straight or branched chain alkenyl or and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group;
wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted;
W is oxygen or sulfur;
U is either O or N, wherein when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of:
Ar as defined above, C2-C3 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy,trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any or the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C3 cycloalkyl;
and when U is N, R1 and R2 are selected independently from the group consisting of:
hydrogen, Ar as defined above, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, or C1-C6 straight or branched chain alkyl or alkenyl substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, , ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2,O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C3-C6)-straight or branched chain alkyl, (C3-C6)-straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms or said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C8 cycloalkyl;
or R1 and R2 may be taken together to form a heterocyclic ring.

33. The compound of claim 32, wherein Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl.

34. The compound of claim 32, wherein the compound has an affinity for FKBP-type immunophilins.

35. The compound of claim 34, wherein the FKBP-type immunophilins are FKBP12.

36. The compound of claim 32, wherein the compound inhibits rotamase enzyme activity.

37. A pharmaceutical composition comprising a neurotrophically effective amount of the compound of claim 32 and a pharmaceutically acceptable carrier.

38. A method of effecting a neuronal activity in an animal, comprising:
administering to the animal a neurotrophically effective amount of the compound of claim 32.

39. The method of claim 38, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.

40. The method of claim 39, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder relating to neurodegeneration.

41. The method of claim 40, wherein the neurological disorder relating to neurodegeneration is selected from the group consisting or Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis.