RS57603B1

RS57603B1 - Sastav i metod za dijagnozu i tretiranje bolesti povezanih sa degeneracijom neurita

Info

Publication number: RS57603B1
Application number: RS20180785A
Authority: RS
Inventors: Bernhard Mueller; Lili Huang; Philip D Bardwell; Yuliya Kutskova; John Memmott
Original assignee: Abbvie Deutschland; Abbvie Inc
Priority date: 2012-01-27
Filing date: 2013-01-25
Publication date: 2018-11-30
Also published as: US9102722B2; IL284769A; WO2013112922A1; UA118083C2; MY176695A; CY1120390T1; IL232782A0; HK1198831A1; AU2013211939C1; KR102129234B1; US20190276526A1; CA2857967A1; IL232782B; CR20140360A; MX352772B; IL297229A; JP2015508061A; HUE039611T2; LT2807192T; IL316441A

Description

INHIBITORI FOSFODIESTERAZE 4

Ova patentna prijava se nastavlja na prethodne privremene patentne prijave: U.S. serijski broj 60/262,651, podnete 22.1.2001.; U.S. serijski broj 60/267,196, podnete 08.2.2001. i U.S. serijski broj 60/306,140, podnete 14.7.2001.

OBLAST PRONALASKA

Ovaj pronalazak se uopšteno odnosi na oblast inhibicije enzima fosfodiesteraze 4 (PDE4). Određenije, ovaj pronalazak se odnosi na selektivnu inhibiciju PDE4 novim jedinjenj ima, npr. N-supstituisanim anilinom i analozima difenilamina, postupke za dobijanje ovakvih jedinjenja, kompozicija koje sadrže ovakva jedinjenja, i postupke za njihovu upotrebu.

OSNOVA PRONALASKA

Ciklično nukletoditne određene fosfodiesteraze (PDEs) predstavljaju familiju enzima koji katalizuju hidrolizu različitih cikličnih nukleotidnih monofosfata (uključujući cAMP i cGMP). Ovi ciklični nukleotidi deluju kao drugi prenosnici unutar ćelija, i kao prenosnici, nose impulse sa površinskih ćelijskih receptora koji imaju vezane različite hormone i neurotransmitere. PDEs deluje tako da reguliše nivo cikličnih nukleotida unutar ćelije i održava ciklične nukleotidne homeostaze degradirajući ovakve ciklične mononukleotide što rezultuje u okončavanju njihove uloge prenosnika.

PDE enzimi mogu da se grupišu u 11 familija prema njihovoj određenosti prema hidrolizi cAMP ili cGMP, njihovoj osetljivosti na regulaciju kalcijumom, kalmodulinom ili cGMP, i njihovoj selektivnoj inhibiciji različitim jedinjenj ima. Na primer, PDE 1 je stimulisana pomoću Ca2+/kalmodulin. PDE 2 je cGMP zavisna, i nađena je u srcu i nadbubrežnoj žlezdi. PDE 3 je cGMP zavisna, i inhibicija ovog enzima izaziva opuštanje disajnih puteva , anti upalnu i anti depresivnu aktivnost. PDE 5 izgleda daje važna u regulisanju sadržaja cGMP u glatkim vaskularnim mišićima čime inhibitori PDE 5 mogu imati kardio vaskularnu aktivnost. Kako PDE ima posebne biohemijske osobine, verovatno su podvrgnute raznovrsnim različitim oblicima regulacije.

PDE 4 se izdvaja raznim kinetičkim osobinama uključujući nisku Michaelis-ovu konstantu za cAMP i osetljivost na određene lekove. Familija enzima PDE 4 se sastoji od četiri gena, koji daju četiri izoforme PDE 4 enzima označene kao PDE4A, PDE4B, PDE4C i PDE4D [vidi: Wang et al., Expression, Purification, i Characterization of human cAMP-Specific Phosphodiesteraze (PDE4) Subtypes A, B,C, and D,Biochem. Biophys. Res. Comm.234, 320-324 (1997)]. Dodatno, različite spojene varijante svake PDE4 izoforme su identifikovane.

PDE4 izoenzimi su lokalizovani u citosolnim ćelijama i nisu asocirane ni sa kakvim poznatim membranskim strukturama. PDE4 izoenzimi određeno deaktiviraju cAMP katalizirajući njenu hidrolizu u adenozin 5'-monofosfat (AMP). Regulisanje aktivnosti cAMP je važna u mnogim biološkim procesima, uljučujući upale i pamćenje. Inhibitori PDE4 izoenzima kao što su rolipram, piklamilast, CDP-840 i ariflo su snažni anti upalni agensi i stoga mogu biti upotrebljivi u lečenju obolenja u kojima je upala problematična kao što su astma ili artritis. Dalje, rolipram poboljšava moć saznavanja pacova i miševa u primerima za učenje.

Kao dodatak jedinjenj ima kao što je rolipram, derivati ksantina kao što su pentoksifilin, denbufilin i teofilin inhibiraju PDE4 i u poslednje vreme su pod velikom pažnjom zbog njihovih efekata poboljšanja shvatanja. CAMP i cGMP su drugi prenosnici koji posreduju u ćelijskim odgovorima prema mnogim različitim hormonima i neuro transmiterima. Tako, terapeutski značajni efekti mogu biti rezultat inhibicije PDE i posledičnog povećanja intraćelijske cAMP ili cGMP u ključnim ćelijama, kao što su one locirane u nervnom sistemu i drugde u telu.

Rolipram, ranije razvijan kao antidepresant, selektivno inhibira PDE4 enzim i postao je standardni instrument u klasifikaciji PDE enzimskih pod tipova. Rani radovi na polju PDE4 su bili fokusirani na depresije i upale, i značajno su prošireni radi obuhvatanja indikacija kao što je demencija. [ vidi" The PDE IV Familv of Calcium-Phosphodiesterases Enzvmes," John A. Lowe, III, et al. Drugs of the Future 1992, 17(9): 799-807 radi opšteg pregleda]. Dalji klinički razvoj roliprama i drugih PDE4 inhibitora prve generacije je okončan usled profila sporednih efekata ovih jedinjenja. Primarni sporedni efekat kod primata je povraćanje, dok je kod glodara primarni sporedni efekat testikularna degranulacija, slabljenje glatkih vaskularnih mišića, psihotropni efekti, povećanje lučenja želudačne kiseline i stomačna erozija.

IZVOD IZ PRONALASKA

Ovaj pronalazak se odnosi na nova jedinjenja, npr novi N-supstituisani anilin i difenilamin jedinjenja, koja inhibiraju PDE4 enzime, i posebno imaju poboljšane profile sporednih efekata, npr. jedinjenja relativno manje izazivaju povraćanje (kada se porede sa prethodno pomenutim dosada postojećim jedinjenj ima). Poželjno, jedinjenja selektivno inhibiraju PDE4 enzime. Jedinjenja prema ovom pronalasku u isto vreme olakšavalu ulaz u ćelije, posebno ćelije nervnog sistema.

Još dalje, ovaj pronalazak obezbeđuje postupke za sintetizovanje jedinjenja sa

takvom aktivnošću i selektivnošću kao i postupak (i njihove odgovarajuće farmaceutske kompozicije) za lečenje pacijenata, npr. sisara uključujući i ljude, koji zahteva inhibiciju PDE, posebno inhibiciju PDE 4, za stanja bolesti koja obuhvataju povišene intraćelijske nivoe PDE 4 ili snižene cAMP nivoe, npr. obuhvatajući neurološke sindrome, posebno ona stanja koja su povezana sa slabljenjem pamćenja, još posebnije dugotrajna slabljenja pamćenja, pri Čemu do slabljenja pamćenja dolazi usled katabolizma intraćelijskih nivoa cAMP od strane PDE 4 enzima, ili tamo gde slabljenje pamćenja može biti poboljšano efikasnim inhibitovanjem aktivnosti PDE 4 enzima.

U poželjnom aspektu, jedinjenja iz ovog pronalska poboljšavaju stanja kod ovakvih obolenja inhibirajući PDE 4 enzime u dozama koje ne indukuju povraćanje.

Ovaj pronalazak obuhvata jedinjenja sa formulom I:

u kojoj

R<1>je alkil grupa sa 1 do 4 atoma ugljenika, koja se račva ili ne račva i koja nije supstituisana ili je supstituisana jedan ili više puta halogenom (npr. CH3, CH2F, CF3, itd);

R<2>je alkil grupa sa 1 do 12, poželjno 1 do 8 ugljenikovih atoma, koja se račva ili ne račva i koja je nesupstituisana ili supstituisana jedan ili više puta halogenom, hidroksi, cijano, Ci-4-alkoksi, okso grupom ili njihovom kombinacijom, i u kome je, opciono, jedna ili više -CH2CH2- grupa zamenjena u svakom slučaju sa-CH=CH- ili -C=C- (npr., CH3, CH2F, CF3, metoksietil, itd.),

je cikloalkil grupa sa 3 do 10, poželjno 3 do 8 ugljenikovih atoma, koja nije supstituisana ili je supstituisana jedan ili više puta halogenom, hidroksi, okso, cijano grupom, alkil grupom koja ima 1 do 4 ugljenikova atoma, alkoksi grupom koja ima 1 do 4 ugljenikova atoma ili njihovom kombinacijom (npr. ciklopentil),

je cikloalkilalkil grupa koja ima 4 do 16, poželjno 4 do 12 ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilanom delu jedan ili više puta halogenom, okso, cijano, hidroksi, Ci.

4-alkil, Ci_4-alkoksi grupom ili njihovom kombinacijom (npr., ciklopentilmetil, ciklopropilmetil, itd.),

je aril grupa koja ima 6 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom (npr., metilfenil, metoksifenil, hlorofenil, itd.),

je arilalkil grupa u kojoj arilni deo ima 6 do 14 ugljenikovih atoma i u kojoj alkilni deo koji se račva ili ne račva ima 1 do 5 ugljenikovih atoma, gde je arilalkil radikal ne supstituisan ili supstituisan u arilnom delu jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom, i gde je u alkilnom delu jedna ili više -H2CH2- grupa svaka opciono zamenjena sa -CH=CH- ili - C=C- i jedna ili više -CH2-grupa je svaka opciono zamenjena sa -O- ili -NH- i/ili je alkilni deo opciono zamenjen sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom (npr., feniletil, fenilpropil, fenilbutil, metoksifeniletil, metoksifenilpropil, hlorofeniletil, hlorofenilpropil, feniletenil, fenoksietil, fenoksibutil, hlorofenoksietil, hlorofenilaminoetil, itd.),

je delimični nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, hidroksi, nitro, cijano, okso grupom ili njihovom kombinacijom (npr., cikloheksenil, cikloheksadienil, tetrahidroksinaftenil, itd.),

je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, aril, alkil, alkoksi, nitro, cijano, trifluorometil, okso grupom ili njihovom kombinacijom (npr., 3-tienil, 3-tetrahidrofuranil, 3-pirolil, itd.),

ili

je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimični zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili

supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, OCF3, hidroksi, aril, alkil,cijano, trifluorometil, nitro, okso grupom ili njihovom kombinacijom, gde su u alkilnom delu jedna ili više -CH2CH2-grupa svaka opciono zamenjena sa -CH=CH- ili -C=C-, i jedna ili više -CH2- grupa je svaka opciono zamenjena sa -O- ili -NH- i/ili alkilni deo je opciono zamenjena sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom (npr., piridiletil, piridilpropil,

metilpiperaziniletil, itd.);

R<3>je H,

alkil grupa koja ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, cijano, CM-alkoksi grupom, ili njihovom kombinacijom (npr., metil, etil, propil, itd.),

je delimično nezasićena karbociklična grupa u kojoj karbociklična grupa ima 5 do 14 ugljenikovih atoma, i alkilni deo koji je račvast ili nije račvast ima 1 do 5 ugljenikovih atoma, i koja je ne supstituisana ili supstituisana u karbocikličnom delu jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, i gde je alkilni deo opciono supstituisan halogenom, Ci-4-alkoksi, cijano grupom, ili njihovom kombinacijom (npr.,ciklohekseniImetil, itd.),

je arilalkil grupa koja ima 7 do 19 ugljenikovih atoma, gde arilni deo ima 6 do 14 ugljenikovih atoma i alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, trifluorometil, CF3O, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom (npr. benzil, fenetil, fenpropil, metilbenzil, metoksibenzil, trifluorometil, benzil, metilendioksibenzil, itd.), ili

je heteroarilalkil grupa, u kojoj heteroarilni deo može biti delimično ili potpuno zasićen i ima prsten sa 5 do 10 atoma pri čemu je najmanje jedan atom prstena N, O ili S atom, alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, heteroalkilna grupa nije supstituisana ili je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF30, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom (npr. piridilmetil, piridilpropil, metilpiridilmetil, hloropiridilmetil, dihloropiridilmetil, tienilmetil, tiazolmetil, hinolinmetil, izohinolinmetil, piperidinilmetil, furanilmetil, imidazolilmetil, metilimidazolilmetil, pirolilmetil, itd.);

R<4>je H,

aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkenil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, OCF3, amino, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (npr., hidroksimetil) grupe, hidroksamska kiselina, tetrazol-5-il, 2(-heterocikI)tetrazol-5-il (npr., 2-(2-tetrahidropiranil)tetrazol-5-il), hidroksialkoksi, karboksi, alkoksikarbonil (npr., tercijarna butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, fenoksi, trialkilsililoksi (npr., tercijarna butildimetilsilioksi), R<5->L-, grupa ili njihova kombinacija (npr., supstituisani ili ne supstituisani fenil, naftil,

■ i difenil kao što su fenil, metilfenil, hlorofenil, fluorofenil, vinilfenil, cijanofenil, metilendioksifenil, etilfenil, dihlorofenil, karboksifenil, etoksikarbonilfenil, dimetilfenil, hidroksimetilfenil, nitrofenil,

aminofenil, itd.) ili

je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom prstena heteroatom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (npr., hidroksimetil) grupe, hidroksamska kiselina, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (npr., tercijarna butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, fenoksi, trialkilsililoksi (npr., tercijarna

butildimetilsililoksi), R<5->L-, grupa ili njihova kombinacija (npr., piridil, tienil, pirazinil, hinolinil, izohinolinil, pirimidinil, imidazolil, tiazolil, itd.);

R<5>je H,

je alkil grupa koji ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Cm-alkil, CM-alkoksi, okso grupa ili njihova kombinacija (npr., metil, etil, propil, itd.),

je alkilamino ili dialkilamino grupa gde svaki alkilni deo ima nezavisno 1 do 8, poželjno 1 do 4 ugljenikova atoma (npr., dimetilamino, itd.),

je delimično nezasićena karbociklično-alkilna grupa u kojoj karbociklični deo ima 5 do 14 ugljenikovih atoma i alkilni deo ima 1 do 5 ugljenikovih atoma, koja je ne supstituisana ili supstituisana, poželjno

u karbocikličnom delu, jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom (npr.,

cikloheksenilmetil, itd.),

je cikloalkil grupa koja ima 3 do 10, poželjno 3 do 8 ugljenikovih atoma, koja je nesupstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, okso, cijano, alkoksi grupom, alkil grupom sa 1 do 4 ugljenikova atoma ili njihovom kombinacijom (npr., ciklopentil),

je cikloalkil grupa koja ima 4 do 16, poželjno 4 do 12 ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta sa halogenom, okso, cijano, hidroksi, alkil, alkoksi grupom ili njihovom kombinacijom (npr., ciklopentilmetil, ciklopropilmetil, itd.),

je aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil (npr., hidroksimetil) grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (npr., tercijerna butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, (npr., supstituisan ili ne supstituisan fenil i naftil, metilfenil, hlorofenil, fluorofenil, vinilfenil, cijanofenil, metilendioksifenil, etilenfenil, dihlorofenil, karboksifenil, etoksikarbonilfenil, dimetilfenil, hidroksimetilfenil, nitrofenil, aminofenil, itd.),

je arilalkil grupa koja sadrži 7 do 19 ugljenikovih atoma, gde u arilnom delu ima 6 do 14 ugljenikovih atoma i alkilni deo koji se račva ili ne račva, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, trifluorometil, CF3O, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom (npr. benzil, fenetil, fenpropil, metilbenzil, metoksibenzil, trifluorometil, benzil, metilendioksibenzil, itd.),

je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil, (npr., hidroksimetil) grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil (npr., tercijerna

butiloksikarbonil, etoksikarbonil), cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom ili njihovom kombinacijom (npr., piridil, tienil, pirazinil, hinolinil, izohinolinil, pirimidinil, imidazolil, tiazolil, itd.) ili

je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimično zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo koji je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF30, nitro, okso, amino,

alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili susptituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom (npr., piridilmetil, piridilpropil, metilpiridilmetil, itd.);

L je jednostruka veza ili dvovalentni alifatični radikal koji ima 1 do 8

ugljenikovih atoma gde je jedna ili više -CH2-grupa svaka opciono zamenjena sa -O-, -S-, -NR<6->, -S02NH-, -NHS02-, -CO-, -NR<6>CO-, -

CONR<6->, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH-, ili - NHCSNH- (npr., -O-, -CH2, -CO-, -CO-O-, -O-CO-, -CO-NH-, NH-CO-, -CH2CH2CH2-NH-CO-, -CH2-CH2-0-, -S02-NH-CH2CH2-0-, -O-CH2CH2-0-, -CH2-NH-CO-, -CO-NH-CH2-, -S02-NH-, -CH2-NH-S02-,

-CH2CH2CH2-S02-NH-, itd.); i

R<6>jeH

alkil grupa koja ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više

puta sa halogenom, Cj-4-alkil, Ci^-alkoksi, okso grupom ili njihovom kombinacijom (npr., metil, etil, propil, itd.);

pri čemu je najmanje jedan od R<3>i R<4>različiti od H; i njihove farmaceutski prihvatljive soli.

Prema daljem aspektu ovog pronalaska obezbeđuje se vrsta novih jedinjenja prema formulama II i III:

u kojima su R<1>, R<2>, R<3>i R<4>kao stoje prethodno ovde definisano. Jedinjenja ove podvrste I ne samo da imaju PDE4 inhibitornu aktivnost, već su takođe korisni kao intermedijari za dobijanje jedinjenja sa formulom I u kojima su i R<3>i R<4>različiti od H.

Dodatno, poželjna jedinjenja sa formulom I su ona sa pod formulom IV

u k<o>joj su R<1>, R<2>, i R<4>definisani u formuli I ijedan od A, B i D je N a ostali su C. Poželjno, Bje N. Takođe je R<4>poželjno piridil ili fenil koji su u svakom od slučaja supstituisani ili ne supstituisani.

Ovaj pronalazak takođe obuhvata jedinjenja formule I ':

u kojoj

R<1>' je metoksi, F, Cl, CHF2ili CF3;

R<2>' je

alkil grupa koja ima 1 do 12 ugljenikovih atoma,

alkil grupa koja ima 1 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom,

alkenil grupa koja ima 2 do 12 ugljenikovih atoma,

alkenil grupa koja ima 2 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom,

alkinil grupa koja ima 2 do 12 ugljenikovih atoma,

alkinil grupa koja ima 2 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom,

cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma,

cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, alkil grupom ili njihovom kombinacijom,

cikloalkilalkil grupa koja ima 4 do 12 ugljenikovih atoma,

cikloalkilalkil grupa koja ima 4 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, alkil grupom ili njihovom kombinacijom,

delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma,

delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkiloksi, nitro, cijano, okso grupom ili njihovom kombinacijom,

arilalkil grupa koja ima 7 do 26 ugljenikovih atoma,

arilalkil grupa koja ima 7 do 26 ugljenikovih atoma, koja je supstituisana jedan ili više puta sa halogenom, alkil, alkiloksi, nitro, cijano, okso, trifluorometil grupom ili njihovom kombinacijom,

heteroalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu pri čemu je najmanje jedan atom prstena heteroatom, ili

supstituisana heteroalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu pri čemu je najmanje jedan atom prstena heteroatom i koja je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, aril, alkil, alkoksi, nitro, trifluorometil, cijano, amino, alkilamino,

dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, okso, cijano grupom ili njihovom kombinacijom;

X jeOiliS

R<3>je aril grupa koja ima 6 do 14 ugljenikovih atoma

je aril grupa koja ima 6 do 14 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, hidroksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom, heteroaril grupom koji je ne supstituisana ili supstituisana sa halogenom, alkil ili alkoksi grupom ili njihovom kombinacijom,

je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom, ili

je supstituisana heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom koja je supstituisana jedan ili više puta sa halogenom, aril, alkil, alkoksi, cijano,

trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom;

L je -NH-, -NR<4->, -NHCH2-, -NR<4>CH2- ili -CH2NR<4->i R<4>je alkil grupa koja ima 1 do 12 ugljenikovih atoma

je alkil grupa koja ima 1 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom,

je aril grupa koja ima 6 do 14 ugljenikovih atoma koja nije supstituisana ili je supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom, heteroaril grupom ili njihovom kombinacijom,

je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom,

je supstituisana heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom i koja je supstituisana jedan ili više puta sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom,

je arilalkil grupa koja sadrži 7 do 16 ugljenikovih atoma,

je arilalkil grupa koja sadrži 7 do 16 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso, trifluorometil grupom ili njihovom kombinacijom

je heteroarilalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom,

je supstituisana heteroarilalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom i koja je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, okso, cijano grupom ili njihovom kombinacijom;

i njihove farmaceutski prihvatljive soli.

Jedinjenja iz ovog pronalaska su efikasna u inhibiciji, ili promeni aktivnosti PDE4 kod životinja, npr. sisara, posebno ljudi. Ova jedinjenja pokazuju neurološku aktivnost, posebno tamo gde takva aktivnost deluje na razumevanje, uključujući i dugoročno pamćenje. Ova jedinjenja će takođe biti efikasna u lečenju obolenja kod kojih se pojavljuju sniženi nivoi cAMP. Ovo obuhvata ali se ne ograničava na upalna obolenja. Ova jedinjenja takođe mogu funkcionisati kao antidepresanti, ili da se upotrebe za lečenje saznajne i negativne simptome šizofrenije.

Ogledi za određivanje aktivnosti inhibiranja PDE kao i selektivnu aktivnost inhibiranja PDE 4 i selektivnost inhibiranja PDE 4 izoenzima su poznata u struci. Vidi npr., US 6,136,821, čiji obuhvat je ovde uključen kao referenca.

Prema daljem aspektu ovog pronalaska data su jedinjenja upotrebljiva kao intermedijari za dobijanje inhibitora PDE 4 ovde opisani (npr., PDE 4 inhibitori formule I) i/ili upotrebljiva za sintezu radio markiranih analoga inhibitora PDE 4 u obuhvatu ovog pronalaska.

Stoga, data su intermedijarna jedinjenja koja odgovaraju jedinjenj ima formule I, gde suR<2>,R3 i R<4>kao stoje prethodno definisano za formulu I, ali R<1>je H,terc-butildimetilsilil, ili pogodna zaštitna grupa za fenol. Pogodne zaštitne grupe za fenol su opisane, na primer, u Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3<rd>Edition, John Wiley & Sons, 1999, pp. 246 - 293. Ovi intermedijari su takođe upotrebljivi za sinteze radio markiranih jedinjenja, kao što su ona gde R<1>je 3H.3C-,<14>CH3- ili "CH3-, na primer za uklanjanje zaštitnih grupa i reagovanje sa rezultujućim jedinjenjem u kome R<1>je H sa pogodnim radio markiranim reagensima. Ovakva radio markirana jedinjenja su upotrebljiva za određivanje distribucije jedinjenja u tkivu kod životinja, u studijama PET slika, i za studije vezivanja in vivo, ex vivo, i in vitro.

Takođe su data intermedijarna jedinjenja koja odgovaraju jedinjenjima sa formulom I, gde su R<1>, R<3>i R<4>kao što je prethodno definisano za formulu I, ali R2 jeterc-butildimetilsilil, ili pogodna zaštitna grupa za fenol. Pogodne zaštitne grupe za fenol su opisane, na primer, u Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3<rd>Edition, John Wiley & Sons, 1999, pp. 246 - 293. Jedinjenja u kojima R je H su upotrebljiva kao intermedijari, na primer, kao osnova za paralelne ili kombinatorne hemijske primene. Dalje, ova jedinjenja su upotrebljiva za uvođenje radio markera kao što su 3H,<14>C, "C.

Kao što je prethodno opisano, jedinjenja prema formuli II, gde su R<1>, R<2>i R<4>kao stoje prethodno opisano, su upotrebljivi intermedijari za dobijanje jedinjenja prema formuli I gde R<3>nije H.

Takođe, kao stoje prethodno opisano, jedinjenja prema formuli III, gde su R<1>, R<2>i R<3>kao što je prethodno opisano, su upotrebljivi intermedijari za dobijanje jedinjenja prema formuli 1 gde R<4>nije H.

Izraz halogen se ovde odnosi na F, Cl, Br i J. Poželjni halogeni su F i Cl.

Alkil, kao grupa ili supstituent za sebe ili kao deo grupe supstituenata (npr., alkilamino, trialkilsiloksi, aminoalkil, hidroksialkil), označava alifatični ugljovodonični radikal koji ima 1 do 12 ugljenikovih atoma, poželjno 1 do 8 ugljenikovih atoma, posebno 1 do 4 ugljenikova atoma pravog ili račvastog niza. Pogodne alkil grupe uključuju metil, etil, propil, izopropil, butil, sekundarni butil, tercijerni butil, pentil, heksil, heptil, oktil, nonil, decil, undecil i dodecil. Drugi primeri pogodnih alkil grupa uključuju 1-, 2- ili 3-metilbutil, 1,1-, 1,2- ili 2,2-dimetilpropil, 1-etilpropil, 1-, 2-, 3-ili 4- metilpentil, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- ili 3,3-dimetilbutil, 1- ili 2-etilbutil, etilmetilpropil, trimetilpropil, metilheksil, dimetilpentil, etilpentil, etilmetilbutil, dimetilbutil i slično.

Supstituisane alkil grupe su alkil grupe kao stoje prethodno opisano koje su supstituisane na jednoj ili više pozicija sa halogenom, okso, hidroksil, Ci^-alkoksi i/ili cijano grupom. Halogeni su poželjni supstituenti, posebno F i Cl.

Alkoksi označava alkil-O- grupe a alkoksialkoksi označava alkil-O-alkil-O-grupe u kojima su alkilni udeli u saglasnosi sa prethodnim opisima. Pogodne alkoksi i alkoksialkoksi grupe obuhvataju metoksi, etoksi, propoksi, butiksi, pentoksi, heksoksi, heptoksi, oktoksi, metoksimetoksi, etoksimetoksi, propoksimetoksi i metoksietoksi. Poželjne alkoksi grupe su metoksi i etoksi. Slično, alkoksikarbonil označava alkil-O-CO- u kojoj je alkilni udeo u saglasnosti sa prethodnim opisom. Primeri obuhvataju metoksikarbonil, etoksikarbonil, propoksikarbonil i tercijerni butoksikarbonil.

Cikloalkil označava monociklični, biciklični ili triciklični nearomatični zasićeni ugljovodonični radikal koji ima 3 do 10 ugljenikovih atoma, poželjno 3 do 8 ugljenikovih atoma, posebno 3 do 6 ugljenikovih atoma. Pogodne cikloalkil grupe obuhvataju ciklopropil, ciklobutil, ciklopentil, cikioheksil, cikloheptil, ciklooktil, norbornil, l-dekalin, adamant-l-il i adamant-2-il. Ostale pogodne cikloalkil grupe obuhvataju spiropentil, biciklo[2.1 .Ojpentil, biciklo[3.1.0]heksil, spiro[2.4]heptil, spiro[2.5]oktil, biciklo[5.1.0]oktil, spiro[2.6]nonil, biciklo[2.2.0]heksil, spiro[3.3]heptil, biciklo[4.2.0]oktil i spiro[3.5]nonil. Poželjne cikloalkil grupe su ciklopropil, ciklopentil i cikioheksil. Cikloalkil grupa može biti supstituisana, na primer, halogenima i/ili alkil grupama.

Cikloalkilalkil označava cikloalkil-alkil radikale gde su cikloalkilni i alkilni udeli u saglasnosti sa prethodnim opisom. Pogodni primeri obuhvataju ciklopropilmetil i ciklopentilmetil.

Aril, kao grupa ili supstituent za sebe ili kao deo grupe supstituenata, označava aromatični karbociklični radikal koji ima 6 do 14 ugljenikovih atoma, poželjno 6 do 12 ugljenikovih atoma, posebno 6 do 10 ugljenikovih atoma. Pogodne aril grupe obuhvataju fenil, naftil i bifenil, Supstituisane aril grupe obuhvataju gore opisane aril grupe koje su supstituisane jedan ili više puta sa, na primer, halogenom, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil i fenoksi grupom.

Arilalkil označava aril-alkil-radikal u kome su arilni i alkilni udeli u saglasnosti sa prethodnim opisima. Pogodni primeri obuhvataju benzil, 1-fenetil, 2-fenetil, fenpropil, fenbutil, fenpentil i naftilmetil.

Heteroaril označava aromatičnu heterocikličnu grupu koja ima jedan ili dva prstena i ukupni broj od 5 do 10 atoma u prstenu gde je najmanje jedan atom prstena heteroatom. Poželjno, heteroaril grupa sadrži 1 do 3, posebno 1 ili 2, hetero atoma prstena koji su odabrani iz grupe koju čine N, O i S. Pogodne heteroaril grupe obuhvataju furil, tienil, pirolil, pirazolil, imidazolil, triazolil, tetrazolil, ditialil, oksatialil, izoksazolil, oksazolil, tiazolil, izotiazolil, oksadiazolil, oksatriazolil, dioksazolil, oksatiazolil, tiadiazolil, piridil, piridazinil, pirimidinil, pirazinil, triazinil, oksazinil, izoksazinil, oksatiazinil, oksadiazinil, benzofuranil, izobenzofuranil, tionaftenil, izotionaftenil, indolil, izoindolil, indazolil, benzizoksazolil, benzokaszolil, benztiazolil, benzizotiazolil, purinil, benzopiranil, hinolinil, izohinolinil, cinolinil, hinazolinil, naftiridinil i benzoksazinil, npr., 2-tienil, 3-tienil, 2-, 3- ili 4- piridil, 2-, 3-, 4-, 5-, 6-, 7-, ili 8-hinolinil, i 1-, 3-, 4-, 5-, 6-, 7-, ili 8-izohinolinil.

Supstituisani heteroaril označava heteroarilne grupe prethodno opisane koje su supstituisane najednom ili više mesta sa, na primer, halogenom, aril, alkil, alkoksi, karboksi, metilen, cijano, trifluorometil, nitro, okso, amino, alkilamino i dialkilamino grupom.

Heterocikli obuhvataju heteroaril grupe kao što su gore opisane kao i nearomatična ciklična jedinjenja koja sadrže najmanje jedan hetero atom u prstenu, poželjno odabran od N, S ili O, na primer, tetrahidrofuranil, piperidinil, pirolidinil.

Heterocikl-alkil označava heterocikl-alkil-grupu u kojoj su heterociklični i alkilni udeli u saglasnosti sa prethodnim opisima. Pogodni primeri su piridilmetil, tienilmetil, pirimidinilmetil, pirazinilmetil i izohinolinilmetil grupa.

Delimično nezasićene karbociklične strukture su nearomatične monociklične ili biciklične koje imaju 5 do 14 ugljenikova atoma, poželjno 6 do 10 ugljenikovih atoma, u kojima struktura(e) prstena sadrži najmanje jednu C=C vezu. Pogodni primeri su ciklopentil, cikloheksenil, cikloheksadienil, tetrahidronaftenil i indan-2-il

Alkenil označava alifatične radikale pravog ili račvastog niza koji sadrže 2 do 12 ugljenikovih atoma, u kojima jedna ili više -CH2-CH2- struktura je svaka zamenjena sa

CH=CH-. Pogodne alkenil grupe su etenil, 1-propenil, 2-metiletenil, 1-buten, 2-buten, 1-pentenil i 2-pentenil.

Alkinil označava alifatične radikale pravog ili račvastog niza koji sadrže 2 do 12 ugljenikovih atoma, u kojima jedna ili više -CH2-CH2- struktura je svaka zamenjena sa CH^CH-. Pogodne grupe su etinil, propinil,, 1-butinil i 2-butinil.

Acil označava alkanoilne radikale koji imaju 1 do 13 ugljenikovih atoma u kojima alkilni deo može biti supstituisan halogenom, alkil, aril i/ili alkoksi ili aroil radikalima koji imaju 7 do 15 ugljenikovih atoma u kojima arilni deo može biti supstituisan sa, na primer, halogenom, alkil i/ili alkoksi grupom. Pogodne acil grupe obuhvataju formil, acetil, propionil, butanoil i benzoil.

Supstituisani radikali poželjno imaju 1 do 3 supstituenta, posebno 1 do 2 supstituenta.

Ujedinjenjima sa formulom I, R<1>je alkil grupa koja ima poželjno 1 do 4 ugljenikova atoma koja su opciono supstituisana halogenom, poželjno fluorom ili hlorom. Određeno, R<1>je poželjno metil ili difluorometil grupa.

R2 je poželjno cikloalkil, određenije ciklopentil grupa.

R2 je takođe poželjno aril ili arilalkil, određenije supstituisani ili ne supstituisani fenil ili fenilalkil, kao što su fenil, metilfenil, metoksifenil, hlorofenil, fenetil, fenpropil, fenbutil, feniletenil, fenoksietil, fenoksipropil, fenoksibutil, hlorofeniletil, metoksifeniletil, hlorofeniletenil, hlorofenoksietil, hlorofenpropil, metoksifenpropil, metoksifenbutil, hlorofenbutil, nitrofenbutil, hlorofenilaminoetil grupa, i slične,

R<2>su takođe poželjno delimično nezasićene karbociklične grupe, koje su ne supstituisane ili supstituisane, određenije cikloheksenil, cikloheksadienil, indan-2-il grupa.

R<2>je takođe poželjno alkil grupa koja ima 1 do 8 ugljenikovih atoma, posebno 1 do 4 ugljenikova atoma, koja je supstituisana ili ne supstituisana, npr., metil, difluorometil, trifluorometil i metoksietil grupa.

R2 je takođe poželjno heterociklična ili heterocikl-alkil grupa, određenije, radikali u kojima heterociklična grupa ima 5 do 6 atoma u prstenu i 1 do 2 hetero atoma u prstenu odabranih od N, O i S, npr., tetrahidrofuranil, pirolidinil, pirolil, piridilmetil, piridiletil, piridilpropil, piperazinilmetil, piperaziniletil, metilpiperaziniletil grupa i slične.

Poželjni R<2>obuhvata ciklopentil, tetrahidrofuranil, CHF2, metoksietil, ciklopropilmetil, fenetil, fenpropil, feniletenil, fenoksietil, fenoksibutil, fenilaminoetil, indan-2-il, piridiletil i piridilpropil grupu.

R3 je poželjno vodonik, alkil grupa koja ima 1 do 4 ugljenikova atoma (npr., metil, etil, n-propil ili n-butil), arilalkil grupa (npr., sustituisana ili ne supstituisana benzil, fenetil i fenpropil grupa), ili heteroarilalkil grupa (npr., susptituisana ili ne supstituisana piridilmetil, furanilmetil, tienilmetil, pirolilmetil, pirimidinilmetil, tiazolilmetil, izohinolinilmetil i hinolinilmetil grupa). Poželjni supstituenti za aril i heteroaril delove R<3>su F, Cl, CH3, C2H5, OCH3i CN.

R4 je poželjno aril, ili heteroaril, posebno fenil, naftil, bifenil, furanil, pirazinil, piridiminil, piridil, hinolinil, izohinolinil grupa, koja je u svakom slučaju supstituisana ili ne supstituisana jedan ili više puta. Poželjni supstituitenti su OH, F, Cl, CF3, alkil (kao što su metil ili etil), alkoksi (kao što su metoksi i etoksi), CN, vinil, CH2OH, CONHOH, CONH2, metilendioksi, COOH grupa ili njihova kombinacija.

Dodatno, kada je R<4>aril, posebno fenil grupa, poželjni supstituitenti obuhvataju R<5->L-, npr., R<5->, R<5->0-, R<5->CO-, R<5->NH-CO-, R<5->S02-NH-, R<5->S02-NH-alkilen-0-, NH2-alkil-NH-CO-, R<5->alkilen-NH-CO-, R<5->alkilen-NH-CO-, alkil-CO-NH-alkil grupe kao i metil, etil, Cl, F, CN, OCH3, CF3, amino, nitro, HOCH2i COOH grupe.

Kada je R<4>aril grupa supstituisana sa R<5->S02-NH- tada je R<4>poželjno susptituisana fenil grupa a R5 je poželjno metil, etil, propil ili fenil grupa.

Kada je R<4>aril grupa supstituisana sa R<5->S02-NH-alkilen-0- tada je R<4>poželjno susptituisana fenil grupa. U ovakvim slučajevima, R5 je poželjno metil, etil, propil ili fenil grupa i alkilen je poželjno -CH2-, -CH2CH2-, -CH2CH2CH2-.

Kada je R<4>aril grupa supstituisana sa R<5->L- tada je R<4>poželjno susptituisana fenil grupa. Na ovaj način, poželjne R<5>grupe obuhvataju tetrazolil, oksazinil, piperazinil, metilpiperazinil, piridil, metilpiridil, pirolinil, metilpirolinil, piperadinil ili metilpiperadinil, a L je poželjno jednostruka veza, -O-, -CO-, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2-0-, -CH2CFt2-0-, -CH2CH2CH2-0-, -CH2-NH-CH2CH2-0-, -CO-NH- ili -NH-CO-.

Dodatno, poželjni inhibitori PDE 4 u skladu sa ovim pronalaskom su jedinjenja opisana pod formulama Ia - Ih koja odgovaraju formuli I ali pokazuju sledeće poželjne grupe: Ia R<1>je metil ili CHF2grupa;

R je alkil, alkenil, alkinil, cikloalkil, arilalkil, heterocikl-alkil, cikloalkilalkil, aril, ili heterociklična grupa, u svakom slučaju supstituisana ili ne supstituisana;

R3 je H, alkil, arilalkil ili heteroarilalkil grupa, u svakom slučaju supstituisana ili ne supstituisana;

R4 je aril ili heteroaril grupa, u svakom slučaju supstituisana ili ne

supstituisana;

lb R3 je heteroarilalkil grupa, koja je supstituisana ili ne supstituisana;

Ic R<1>je metil ili CHF2grupa; i

R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil).

Id R<1>je metil ili CHF2grupa;

R je ciklopentil grupa;

R<3>heteroarilalkil grupa, koja je u svakom slučaju supstituisana ili ne supstituisana; i

R4 je supstituisana ili ne supstituisana aril ili heteroaril grupa,;

Ie R1 je metil;

R<2>je ciklopentil grupa;

R heteroarilalkil grupa, koja je supstituisana ili ne supstituisana.

If R<1>je metil;

R 2 je ci,klopentil grupa;

R<3>heteroarilalkil grupa, koja je supstituisana ili ne supstituisana;

i

R<4>je fenil grupa koja je supstituisana ili ne supstituisana.

Ig R<1>je metil;

R2 je ciklopentil grupa;

R<3>je piridilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil ili pirazinilmetil grupa koja je u svakom slučaju supstituisana ili ne supstituisana, ili metil, etil ili propil grupa; i R4 je fenil grupa ili fenil grupa supstituisana sa 1 do 3 supstituitenta

Ih R1 je metil;

R2 je ciklopentil grupa;

R<3>je piridilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil ili pirazinilmetil grupa koja je u svakom slučaju supstituisana ili ne supstituisana, ili metil, etil ili propil grupa; i R4 je fenil, naftil, bifenil, piridil, pirimidinil, tiazolil, pirazinil, hinolinil ili izohinolinil grupa, u svakom slučaju supstituisana ili ne supstituisana.

Dodatno, poželjni inhibitori PDE 4 u skladu sa ovim pronalaskom su jedinjenja opisana pod formulama Ha - Ud koja odgovaraju formuli II ali pokazuju sledeće poželjne grupe: Ha R<1>je metil ili CHF2grupa;

R je ciklopentil, CHF2 , ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil) R4 je fenil, naftil, piridil, hinolinil ili izohinolinil grupa, u svakom slučaju supstituisana ili ne supstituisana.

Ilb R<1>je metil ili CHF2grupa;

R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil); i R<4>je fenil grupa koja je supstituisana ili ne supstituisana sa metil, etil, metoksi, Cl, F, CF3, vinil cijano, amino, karboksi, hidroksimetil ili etilsulfonoamido grupom, ili je 3-piridil grupa koja je supstituisana ili ne supstituisana sa karboksi ili alkoksikarbonil grupom.

IIc R<1>je metil

R je ciklopentil; i

R4 je fenil, naftil, piridil, hinolinil ili izohinolinil grupa, u svakom slučaju supstituisana ili ne supstituisana.

Ud R1 je metil

R je ciklopentil; i

R<4>je fenil grupa koja je supstituisana ili ne supstituisana sa metil, etil, metoksi, Cl, F, CF3, vinil, cijano, amino, karboksi, hidroksimetil ili etilsulfonoamido grupom, ili je 3-piridil grupa koja je supstituisana ili ne supstituisana sa karboksi ili alkoksikarbonil grupom.

Dodatno, poželjni inhibitori PDE 4 u skladu sa ovim pronalaskom su jedinjenja opisana pod formulama lila - Illd koja odgovaraju formuli III ali pokazuju sledeće poželjne grupe: lila R<1>je metil ili CHF2grupa;

R je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil); i R<3>je benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, piridilmetil, hinolinilmetil, izohinolinilmetil, tiazolilmetil ili pirolilmetil grupa koja je supstituisana ili ne supstituisana.

Illb R<1>je metil ili CHF2grupa;

R je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil); i R<3>je pirazinilmetil, pirimidinilmetil ili piridilmetil grupa, koja je u svakom slučaju supstituisana ili ne supstituisana.

III c R<1>je metil;

R2 je ciklopentil; i

R<3>je benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, pirazinilmetil, pirimidinilmetil, piridilmetil, hinolinilmetil, izohinolinilmetil, izoimidazolil, tiazolilmetil ili pirolilmetil grupa koja je u svakom slučaju supstituisana ili ne supstituisana.

Illd R1 je metil;

R2 je ciklopentil; i

R je pirazinilmetil, ili piridilmetil grupa, koja je u svakom slučaju supstituisana ili ne supstituisana.

Dodatno, poželjni inhibitori PDE 4 u skladu sa ovim pronalaskom su jedinjenja opisana pod formulama IVa - IVp koja odgovaraju formuli IV, ali pokazuju sledeće poželjne grupe: IVa R<1>je metil ili CHF2grupa;

IVb R<1>je metil ili CHF2grupa; i

BjeN

IVc R<1>je metil ili CHF2grupa; i

IVd R<1>je metil ili CHF2grupa; i

BjeN, i

R<2>je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil).

IVe R<1>je metil ili CHF2grupa; i

R4 je 3-piridil ili fenil grupa, koja u svakom slučaju supstituisana ili ne supstituisana.

IVf R1 je metil ili CHF2 grupa;

BjeN, i

IVg R<1>je metil ili CHF2grupa;

R je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil). R<4>je 3-piridil ili fenil grupa, koja u svakom slučaju supstituisana ili ne supstituisana.

IVh R<1>je metil ili CHF2grupa;

BjeN,

R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil), R4 je 3-piridil ili fenil grupa, koja u svakom slučaju supstituisana ili ne supstituisana.

IVi R<1>je metil ili CHF2grupa, i

R4 je fenil grupa koja je supstituisana u položaju 3- ili 4-.

IVj R<1>je metil ili CHF2grupa,

BjeN,

R<4>je fenil grupa koja je supstituisana u položaju 3- ili 4-.

IVk R<1>je metil ili CHF2grupa,

R 2je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil), i R4 je fenil grupa koja je supstituisana u položaju 3- ili 4-.

IVI R<1>je metil ili CHF2grupa,

BjeN,

R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil), i R4 je fenil grupa koja je supstituisana u položaju 3- ili 4-.

IVm R<1>je metil ili CHF2grupa,

R2 je 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fcnil, 3-etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil ili 4-hidroksimetil-fenil grupa.

IVn R<1>je metil ili CHF2grupa,

BjeN, i

R4 je 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil ili 4-hidroksimetil-fenil grupa.

IVo R<1>je metil ili CHF2grupa,

R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil), i

IVp R<1>je metil ili CHF2grupa,

Bje N, i

R je ciklopentil, CHF2 , ciklopropilmetil, piridiletil (posebno 2-piridiletil), ili tetrahidrofuranil grupa (posebno (3R) tetrahidrofuranil),

i

R4 je 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etilsulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 3-nitro-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etilsulfonamido-fenil, 4-tetrazol-5-il-fenil ili 4-hidroksimetil-fenil grupa.

Poželjni aspekti obuhvataju farmaceutske sastave pod kojima se podrazumeva jedinjenje prema ovom pronalasku i farmaceutski prihvatljivi nosač, i opciono, još jedan agens kao što je u daljem teksu objašnjeno; postupak inhibiranja PDE 4 enzima, posebno izoenzima, npr., kao što je opisano u tipičnom ogledu ili u jednom koji je ovde opisan, biloin vitroiliin vivo( na životinji, npr., životinjskom modelu ili na sisarima ili na ljudima); postupak za tretiranje neuroloških sindroma, npr., gubitak pamćenja, posebno dugoročnog pamćenja, pogoršanje ili umanjenje rszumevanja, pogoršanje pamćenja, itd. postupak za tretiranje bolesnih stanja na koje utiče aktivnost PDE 4, kod sisara, npr., ljudi, npr. onih ovde pomenutih.

Jedinjenja iz ovog pronalaska mogu da se dobiju na uobičajeni način. Neki od postupaka koji mogu da se iskoriste su opisani u daljem tekst. Svi početni materijali su poznati ili mogu da se dobiju na uobičajeni način od poznatih početnih materijala.

Početni nitrofenoli tipa 1 su ili komercijalno dostupni (npr., Rl = CH3) ili napravljeni po objavljenim postupcima )R1 = CH2F ili su oba Rl i R2 = CH2F, vidi Mueller, Klaus-Helmut. Eur.Pat.Appl. (1994), str. 8. CODEN: EPXXDW EP 626361 Al; Touma, Toshihiko; Asai, Tomozuki. Jpn. Kokai Tokkzo Koho (1999), str. 6 CODEN: JKXXAF JP 11071319 A2; Platonov, Andrevv; Seavakov, Andrevv; Maizorova, Helen; Chistokletov, Victor.Int. Symp. Wood. Pulping Chem.1995, 8th, 5, 295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski Joseph M. PCT Int. Appl. (1996), str. 12. CODEN: PIXXD2 WO 9623754 Al 19960808). Intermedijari 3 anilina se dobijaju u dva koraka; prvo, aditivna reakcija daje intermedijar 2, posle čega sledi redukcija nitro grupe. Intermedijarsko nitro jedinjenje 2 može da se dobije brojnim objavljenim postupcima, kao stoje Mitsunobu-ove reakcije ili standardne reakcije alkilacije. Jedinjenja u kojima R2 je aril ili heteroaril mogu da se dobiju reakcijama koje su katalizovane bakrom sa aril ili heteroaril jodidima pod Ullman-ovim uslovima ili vezivanjem aril-, vinil- ili heteroaril- boronična kiseline sa fenolom 2 u prisustvu bakarnog katalizatora (npr. Cu(OAc)2) i baze kao što je TEA. Mitsunobu-ova reakcija između podesno supstituisanog nitrofenola i primarnog ili sekundarnog alkohola upotrebom azodikarboksilata (npr., DEAD, DIAD), i pogodnog fosfina (npr., Pli3P, BU3P) kao rezultat daje alkilisane nitrofenole 2. Mitsunobu-ove reakcije se uopšteno izvode u aprotonskim rastvaračima kao su dihlormetan ili THF. Alternativno, alkilacija može da se postigne reakcijom između podesno supstituisanog nitrofenola i alkil halida u prisustvu baze (npr., K2CO3ili NaH) u polarnom aprotičnom rastvaraču (npr, DMF ili CH3CN).

Nitrokateholi 2 se zatim redukuju do odgovarajućih anilina postupcima standardnim u struci kao stoje hidrogenacija upotrebom pogodnog katalizatora (npr., Pd na ugljeniku) u polarnom protičnom rastvaraču (npr., MeOH ili EtOH) u atmosferi vodonika. Alternativno, nitrokateholi 3 mogu da se redukuju upotrebom hidridnog izvora (npr., NaBH.4) i tranzicionog metalnog katalizatora (npr., NiCb, Pd na ugljeniku ili upotrebom metala (npr., Zn, Sn, Fe) u rastvoru mineralne kiseline (npr., HC1) radi dobijanja odgovarajućih anilina. Uopšteno se u ovim reakcijama upotrebljavaju polarni protični rastvarači kao što su metanol ili etanol.

vV-Arilalkilanilini 4 se sintetizuju standardnim metodama poznatim u struci kao što su redukciona reakcija aminacije, reakcija alkilacije ili redukcijom odgovarajućih amida. Na primer, redukciona reakcija aminacije aril ili arilalkil aldehida sa podesno supstituisanim anilinima u prisustvu borhidridnog redukcionog agensa kao što su NaBFLtili NaBH3CN sa kiselim katalizatorom kao što su sirćetna kiselina ili pTsOH daje željene TV-Arilalkilaniline. Ove reakcije se generalno odvijaju u polarnim protičnim rastvaračima kao što su metanol, etanol, izopropanol, n-propanol i slično.

N-Arilalkilanilini 4 lako podležu N-arilaciji postupcima standardnim u struci uključujući Ullman-ovu reakciju kuplovanja, metalom katalizovano kuplovanje ili aromatsko nukleofiličnu reakciju supstitucije. Na primer, metalom katalizovana reakcija između N-benzilanilina i arilhalida upotrebom paladijumovog katalizatora(npr., Pd2dba3), masivan fosfin ligand bogat elektronima (npr., tributilfosfin) i pogodna baza

(npr, NaOtBu) daju A^-arilalkildifenilamine. Niki i bakar katalizatori su takođe uključeni u reakciju. Rastvarači upotrebljivi u ovoj reakciji uključuju nepolarne

aprotične rastarače kao što su toluen, benzen, ksileni, tetrahidrofuran i druge. Kada se sintetizuju jedinjenja tipa 5 u kojima R4 je alkoksikarbonilfenil, bolje je daje amin 4 spojen sa 1.1 ekvivalentima- terc-butil 3-jodobenzena i da se upotrebljavaju 22 mol % (tBu)3P, 5,5 mol % Pd2(dba)3i 1,3 ekvivalenta tBuONa.

Intermedijari 6 estra karbonske kiseline mogu da se hidrolizuju pod kiselim ili baznim uslovima radi dobijanja odgovarajućih karbonskih kiselina 7. Na primer, etilestar (R5=Et) može biti hidrolizovan upotrebom mešavine vodene baze (npr, NaOH, KOH) i rastvarača koji se mesa sa vodom (npr, EtOH, THF). Dok se t-butil estri mogu hidrolizovati upotrebom vodene kiseline (npr, HCl, mravlja kiselina, TFA) u organskim rastvaračima koji se mešaju sa vodom, ako je potrebno.

Spajanjem zaštićenog tetrazol brom ili jod benzena (npr, 5-(3-jodofenil)-2-(2-tetrahidropiran)tetrazol) sa jV-supstituisanim derivatima 4 anilina dobijaju se THP-zaštićeni tetrazoli 8. Hidroliza THP-zaštićenih tetrazola 8 može da se ostvari upotrebom vodenih kiselina, kao što je HC1 u vodi i rastvarača koji se meša sa vodom kao što je THF ili EtOH radi dobijanja tetrazola 9. Dalje, THP tetrazoli 8 se takođe mogu oksidativno cepati upotrebom reagenasa kao što su CAN i DDQ u halogenisanim ugljovodoničnim rastvaračima kao što su dihlorometan, hloroform, dihloroetan i sličnima da bi se dobili tetrazoli 9.

Alternativno, analozi tetrazola 9 mogu da se naprave od odgovarajućih nitrila tretiranjem sa azidnim jonom (npr, KN3, NaN3, itd.) i protonskog izvora (npr, NH4CI) u polarnom aprotičnom rastvaraču kao što je DMF. Takođe mogu da se naprave tretiranjem sa azidnim jonom i kiselinom po Lewis-u (npr, ZnBr2) u vodi, upotrebom, ako je neophodno, sa vodom mešljivim ko-rastvaračima kao što je izoprpanol. Drugi postupak za dobijanje je tretiranjem nitrila sa kalaj ili silicijum azidima (npr, Me3SiN3, Bu3SnN3) u aprotičnom organskom rastvaraču kao što su benzen, toulen, dihlorometan, dihloroetan, etar, THF i sličnima.

Difenilamini 10 mogu da se dobiju kuplovanjem podesno supstituisanih anilina 3, kao stoje 3-ciklopentiIoksi-4-metoksianilin sa arilbornom kiselinom u prisustvu baze kao stoje trietilamin i bakar katalizatora kao stoje bakar acetat (kao stoje opisano od strane Chan et al,Tetrahedron Lett.,39, 2933-2936 (1998)). Uopšteno, halogenisani rastvarači kao što su dihlorometan, hloroform, dihloroetan i slični kao i aprotični rastvarači kao što su benzen, toluen ili ksilen su korišćeni. Ovakvi difenilamini (npr, 10) mogu poželjnije da se sintetizuju aminacionim reakcijama koje su katalizovane metalom. Na primer, reakcija podesno supstituisanog anilina 3 sa arilhalidom u prisustvu baze (npr, K3PO4, CSCO3ili NaOtBu) i paladijum ili nikl katalizatora, na primer Pd(dppf)Cl2, ligand (npr, dppf) i baza (npr, NaOtBu)(^GS*. 1996, 118, 7217) ili sa Pd2dba3, masivan fosfin ligand bogat elektronima (npr, P(tBu)3, i baza (npr,NaOtBu)( J. Org. Chem.1999, 64, 5575) daju željene difenilamine 10. Rastvarači najuobičajenije upotrebljavani u ovom tipu reakcije uključuju nepolarne aprotične rastvarače kao što su benzen, toulen, dihlormetan, dihloretan, etar, i slične.

Difenilamini 10 se tada mogu alkilovati sa različitim alkil halidima ili arilalkil halidima kao što su, ali se ne ograničava samo na, jodometan, etilbromid, benzilhlorid, 3-(hlorometil)piridin, 4-(hlorometil)-2,6-dihloropiridin i 4-(bromometil)-benzoeva kiselina, ili njihove soli, u prisustvu ne-nukleofilnih baza kao što su natrijum hidrid, kalijum heksametildisilazid ili kalijum diizopropilamid radi dobijanja vV-supstituisanih difenilamina 5. Rastvarači upotrebljivi u ovoj reakciji uljučuju aprotične rastvarače kao benzen, toulen, tetrahidrofuran, etar, DMF i slične.

Karbonske kiseline 7 se mogu dalje obrađivati radi dobijanja karboksamida 11 pomoću postupaka standardnih u struci. Na primer, karbonska kiselina može da se tretira sa pogodnim primarnim ili sekundarnim aminom, u prisustvu pogodnog reagensa za kuplovanje kao što su BOP, pyBOP, ili DCC i baze kao što su Et3N ili DIEA radi dobijanja karboksamida. Ove reakcije se generalno odvijaju u nepolarnim aprotičnim rastvaračima kao što su dihlorometan, hloroform ili dihloroetan.

Estri karbonske kiseline 6 ili karbonske kiseline 7 mogu se redukovati primenom postupaka standardnih u struci radi dobijanja odgovarajućih karboksaldehida ili hidroksimetil analoga. Na primer, aril etil estar (npr, struktura 6, R5 = etil) može biti tretirana sa podesnim redukcionim agensom (npr, LAH, DIBAL itd.) u aprotičnom solventu kao što su etar ili THF, radi dobijanja odgovarajućih karboksaldehida ili hidroksimetil analoga, Ovakvi aldehidi i alkoholi se dalje mogu derivatisati pomoću postupaka standardnih u struci.

Slično, karboksamidi (npr, struktura 11) i nitrili mogu da se redukuju primenom postupaka standardnih u struci radi dobijanja odgovarajućih supstituisanih amina ili aminometil analoga. Na primer, aril karboksamid 11 može da se redukuje sa podesnim redukcionim agensom (npr, LAH) u aprotičnom rastvaraču (npr, benzen, toluen, etar, THF itd) radi dobijanja odgovarajućih supstituisanih aminometil analoga. Pri čemu redukcija aril nitrila daje odgovarajući primami aminometil analog.

Jedinjenja nitrobenzena 12 se mou redukovati do odgovarajućih anilina 13 primenom postupaka standardnih u struci radi kao što je hidrogenacija upotrebom pogodnog katalizatora (npr, Pd na ugljeniku) u polarnom protičnom rastvaraču (npr. EtOH, MeOH itd.) Nitrobenzeni 12 se takođe mogu redukovati upotrebom izvora hidrida (npr, NaBH.4) i tranzicionog metalnog katalizatora (npr, NiCl2, Pd na ugljeniku) u polarnom protičnom rastvaraču kao stoje EtOH, radi dobijanja odgovarajućih anilina 13. Ovi anilini mogu dalje biti supstituisani primenom postupaka standardnih u struci. Na primer, anilini tipa 13 mogu da se alkiluju, aciluju ili sulfoniraju radi dobijanja odgovarajućih N-alkil amina, karboksamida (npr, struktura 15) ili sulfonamida (struktura 14) respektivno. Na primer, sulfonamid se može napraviti iz anilina i odgovarajućeg sulfonil halida ili anhidrid sulfonske kiseline (npr, MeS02Cl, EtS02Cl, BnS02Cl, Ph S02CI itd) u prisustvu baze (npr, Et3N, piridin, DIEA itd.). Pogodni rastvarači za ovu reakciju uključuju nepolarne aprotične rastvarače kao što su dihlorometan, hloroform, etar i slične.

Trialkilsililetri tipa 16 se dobijaju kao što je opisano u šemi 1. Intermedijarima 16 tercijernog butildimetilsilil zaštićenog katehola se lako skida zaštita brojnim postupcima iz literature (vidi Greene, T.W. and Wuts, P.G.M, Protective Groups in Organic Svnthesis, 3<rd>Edition, John Wiley & Sons, 1999, str. 273-276.) kao što je upotreba izvora fluoridnog jona (npr, BU4NF) u aprotičnom rastvaraču kao što su etar ili THF; ili pod kiselim uslovima (npr, KF, 48% HBr, DMF). Rezutujući fenol 17 koji je veoma upotrebljiv sintetizovani intermedijar se može zatim alkilovati postupcima standardnim u struci i na sličan način kao što je opisano za alkilaciju nitrofenola 2 u šemi 1. Na primer, Mitsunobu-ovom reakcijom, reakcijom sa alkil halidom u prisustvu baze, UUman-ovim tipom reakcije spajanja arila ili reakcijom sa vinil-, aril- ili heteroaril borne kiseline u prisustvu bakarnog katalizatora.

Haloalkoksi intermedijari 18, pripremljeni alkilacijom odgovarajućih fenola, mogu biti alkilisani reakcijom sa supstituisanim aminima, alkoholima ili tiolimau prisustvu baze radi dobijanje analoga kao što su 19. Na primer, alkil halid može da se aminuje podesnim primarnim ili sekundarnim aminom i bazom kao što je K2CO3, u polarnom aprotičnm rastvaraču kao što su THF, DMF ili CH3CN.

Mnoge od ovih sinteznih procedura su detaljnije opisane u primerima koji slede.

Svaki prosečan stručnjak iz ove oblasti će prepoznati da neka od jedinjenja formule (I) i (I') mogu da postoje u različitim geometrijaskim izomernim oblicima. Dodatno, neka od jedinjenja iz ovog pronalaska sadrže jedan ili više asimetričnih ugljenikovih atoma pa stoga mogu da postoje u obliku optičkih izomera, kao i u obliku racemske ili ne racemske smeše, i u obliku diastereoizomera i diastereomerne smešeinter alia.Sva ova jedinjenja, uključujući i cis izomere, trans izomere, diastereomične smeše, raceme, neracemske smeše enantiomera i suštinski čiste i čiste enantiomere, su u obuhvatu ovog pronalaska. Suštinski čisti enantiomeri sadrže ne više od 5% masenih odgovarajućeg suprotnog enenatomera, poželjno ne više od 2 %, najpoželjnije ne više od 1%.

Optički izomeri mogu da se dobiju razdvajanjem racemskih smeša na uobičajene načine, na primer, formiranjem diastereoezomernih soli upotrebom optički aktivne

kiseline ili baze ili formiranjem kovalentnih diastereomera. Primeri podesnih kiselina su vinska, diacetil vinska, dibenzoil vinska ditoluoil vinska i kamforsulfo kiselina. Smeše diastereoizomera mogu da se razdvoje na njihove individualne diastereomere na osnovu njihovih fizičkih i/ili hemijskih razlika postupcima poznatim stručnjacima u ovoj oblasti na primer, hromatografijom il frakcionom kristalizacijom. Optički aktivne baze ili kiseline se onda oslobađaju iz izdvojenih diastereomerskih soli. Različiti postupak za separaciju optičkih izomera obuhvata upotrebu hiralne hromatografije (npr, hiralnih HPLC kolona), sa ili bez konvencionalnih derivacija, optimalno izabranih radi maksimiziranja razdvajanja enentiomera. Pogodne hiralne HPLC kolone proizvodi Diacel, npr, Chiracel OD i Chiracel OJ među mnogim drugim, koje se mogu rutinski odabrati. Enzimatske separacije, sa ili bez derivacije, su takođe upotrebljive. Optički aktivna jedinjenja formula I i I' se mogu, slično, dobiti hiralnom sintezom korišćenjem optički aktivnog početnog materijala.

Ovaj pronalazak se takođe odnosi na upotrebljive oblike jedinjenja kao što je ovde obuhvaćeno, kao što su farmaceutski prihvatljive soli i pro lekove svih jedinjenja iz ovog pronalaska. Farmaceutski prihvatljive soli obuhvataju one dobijene reakcijom glavnog jedinjenja, koje se ponaša kao baza, sa neorganskom ili organskom kiselinom radi dobijanja soli, na primer soli hlorovodonične kiseline, sumporne kiseline, fosforne kiseline, metan sulfo kiseline, kamfor sulfo kiseline, oksalne kiseline, maleinske kiseline, ćilibarne kiseline i limunske kiseline. Farmaceutski prihvatljive soli takođe obuhvataju one u kojima glavno jedinjenje ima osobine kiseline i reaguje sa podesnim bazama radi dobijanja, npr, natrijum kalijum, kalcijum, magnezijum, amonijum i holin soli. Stručnjaci iz ove oblasti će dalje prepoznati da se soli nastale dodavanjem kiseline jedinjenja iz patentnih zahteva, mogu napraviti reakcijom jedinjenja sa podesnim neorganskim ili organskim solima pomoću bilo kog poznatog postupka. Alternativno, soli alkalnih i zemnoalkalnih metala se dobijaju reagovanjem jedinjenja iz ovog pronalaska sa podesnom bazom pomoću bilo kog poznatog postupka.

Sledeće su dalji primeri kiselih soli koje se mogu dobiti reakcijom sa neorganskim ili organskim kiselinama: acetati, adipati, alginati, citrati, aspartati, benzoati, benzensulfonati, disulfati, butirati, kamforati, diglukonati, ciklopentanpropionati, dodecilsulfati, etansulfonati, glikoheptanoati, glicerofosfati, hemisulfati, heptanoati, fumarati, hidrobromidi, hidrojodidi, 2-hidroksi-etansulfonati, laktati, maleati, metansulfonati, nikotinati, 2-naftalensulfonati, oksalati, palmoati, pektinati, persulfati, 3-fenilpropionati, pikrati, pivalati, propionati, sukcinati, tartarati, tiocijanati, tozilati, mesilati i undekanoati.

Poželjno, formirane soli su farmaceutski prihvatljive za davanje sisarima, Ipak, farmaceutski neprihvatljive soli ovih jedinjenja su pogodne kao intermedijari, na primer, za izolovanje jedinjenja u obliku soli koja se zatim prevodi u oblik slobodne baze jedinjenja tretiranjem sa alkalnim reagensom. Slobodna baza se tada može, ako postoji želja, prevesti u farmaceutski prihvatljivu so nastalu dodavanjem kiseline.

Jedinjenja iz ovog pronalaska se mogu davati sama ili kao aktivni sastojak formulacije. Stoga, ovaj pronalazak takođe obuhvata farmaceutske formulacije jedinjenja sa formulama I i I' koja sadrže, na primer jedan ili više farmaceutski prihvatljivih nosača.

Brojne standardne refence su dostupne u kojima su opisani postupci za dobijanje različitih formulacija pogodnih za davanje jedinjenja prema ovom pronalasku. Primeri mogućih formulacija i preparata se sadrže, na primer, u Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (najnovije izdanje); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, urednici) najnovije izdanje, izdat od Marcel Dekker, Ine, kao i Remington's Pharmaceutical Sciences (Arthur Osol, urednik), 1553-1593 (najnovije izdanje).

Posmatrano kroz visoku efikasnost inhibicije PDE 4, jedinjenja iz ovog pronalaska mogu da se daju bilo kom pacijentu kome je potrebno ostvariti inhibiciju PDE 4, i/ili poboljšanje spoznavanja. Davanje se može ostvariti prema pacijentovim potrebama, na primer, oralno, nazalno, parenteralno, (supkutano, intravenozno, intramuskularno, intrasternalno ili infuzijom), inhalacijom, rektalno, vaginalno, topikalno, lokalno, transdermalno ili okularno.

Različite čvrste oralne oblike doza se mogu koristiti za davanje jedinjenja iz ovog pronalaska uključujući takve čvrste oblike kao što su tablete, gel kapsule, kapsule, kaplete, granule, lozenge i čiste praškove. Jedinjenja iz ovog pronalaska se mogu davati sama ili kombinovana sa različitim farmaceutski prihvatljivim nosačima, razblaživačima (kao što su saharoza, manitol, laktoza, škrob) i vezivna sredstva poznata u struci, uključujući ali se ne ograničavajući na, suspenzione agense, rastvarače, puferske agense, veziva, dezintegratore, konzervanse, materije za bojenje, materije za ukus, maziva i slično. Kapsule sa kontrolisanim otpuštanjem materijala, tablete i gelovi su takođe u prednosti kod davanja jedinjenja iz ovog pronalaska.

Različite tečne oralne forme doza se takođe mogu uporebiti za davanje jedinjenja iz ovog pronalaska, uključujući vodene i ne vodene rastvore, emulzije, suspenzije, sirupe i eliksire. Ovakve forme doza takođe mogu da sadrže pogodne inertne razblaživače poznate u struci kao što je voda i pogodni ekscipijenti poznati u struci kao što su prezervativi, ovlaživači, zaslađivači, aromati kao i emulgatori i/ili agense za suspezovanje jedinjenja iz ovog pronalaska. Jedinjenja iz ovog pronalaska mogu da se ubrizgaju, na primer, intravenozno, u obliku izotonskog sterilnog rastvora. Drugi preparati su takođe mogući.

Supozitoriji za rektalno davanje jedinjenja iz ovog pronalaska se mogu napraviti mešanjem jedinjenja sa pogodnim inertnim puniocem kao što je kakao puter, salicilati ili polietilen glikoli. Formulacije za vaginalno davanje mogu biti u obliku pesarija, tampona, krema, gela, paste, pene ili spreja sadžavajući, kao dodatak aktivnom sastojku, takve pogodne nosače kakvi su poznati u struci.

Za topično davanje farmaceutska kompozicija može biti u obliku krema, masti, žitke masti, losiona, emulzija, suspenzija, gela, rastvora, pasta, prahova, sprejeva i kapi pogodnih za davanje preko kože, oka, uha ili nosa. Topično davanje može obuhvatiti transdermalno davanje posredstvom transdermalnih flastera.

Takođe se mogu napraviti aerosolne formulacije pogodne za davanje

inhalacijom. Na primer, za tretiranje poremećaja respiratornih organa, jedinenja prema ovom pronalasku se mogu davati inhalacijom u obliku praha (npr., mikronizovana) ili u obliku atomiziranih rastvora ili suspenzija. Aerosolna formulacija može biti smeštena u propelant pod pritiskom.

Jedinjenja se mogu davati kao jedinstveni aktivni agens ili u kombinaciji sa drugim farmaceutskim agensima kao što su drugi agensi koji se upotrebljavaju za tretiranje pogoršanja razumevanja i/ili tretiranje psihoza, npr, drugih inhibitora PDE4, blokatora kalcijumovih kanala, kloinergični lekovi, modulatori adenozin receptora, modulatori amfakina NMDA-R, modulatori mGluR i inhibitori holinesteraze (npr, donepezil, rivastigmin i glantanamin). U ovakvim kombinacijama, svaki aktivni sastojak može da se daje u skladu sa njihovim uobičajenim opsezima doza ili u dozama manjim od uobičajenih opsega doza.

Ovaj pronalazak dalje obuhvata postupke za tretiranje koji uključuju inhibiciju PDE 4 enzima. Tako, ovaj pronalazak uključuje metode selektivne inhibicije PDE 4 enzima kod životinja, npr, sisara, posebno ljudi gde takva inhibicija ima terapeutski efekat, takav da ovakva inhibicija može olakšati stanja koja obuhvataju neurološke sindrome, kao što je gubitak pamćenja, pogotovo dugoročnog pamćenja. Ovakvi postupci podrazumevaju davanje životinjama kojima treba, posebno sisarima, još posebnije ljudima, količinu jedinjenja koja inhibira, samog ili kao deo formulacije, kao što je ovde obuhvaćeno.

Stanje pogoršanja pamćenja sc manifestuje pogoršanjem mogućnosti da se nauči nova informacija i/ili nemogućnosti prisećanja prethodno naučene informacije. Pogoršanje pamćenja je primarni simptom demencije i takođe može biti simptom povezan sa takvim bolestima kao što su Alchajmerova bolest, šizofrenija, Parkinsonova bolest, Hantingtonova bolest, Pikova bolest, Krojcfeld-Jakobsova bolest, HIV, kardiovaskularne bolesti i povrede glave kao i gubitak moći razmevanja usled starosti.

Demencije su bolesti koje uključuju gubitak memorije i dodatno pogoršanje intelekta odvojeno od memorije. Ovaj pronalazak uključuje postupak za tretiranje pacijenata koji pate od pogoršanja pamćenja u svim oblicima demencije. Demencije su klasifikovane prema uzroku i obuhvataju: neurodegenerativne demencije (npr, Alchajmerova bolest, Parkinsonova bolest, Hantongtonova bolest, Pikova bolest), vaskularne (npr, infarkte, hemoragije, srčani poremećaje), mešane vaskularne i Alchajmerova, bakterijski menengitis, Krojcfeld-Jakobsova bolest, multipla skleroza, povrede (npr, subduralni hematom ili traumatična povreda mozga), infekcije (npr, HIV), genetske (daunov sindrom) toksične (npr, teškim metalima, alkoholom, nekim medikamentima), metabolički (npr, nedostatak vitamina B 12 ili folata), CNS hipoksija, Kušingova bolest, psihijatrijska (npr, depresije i šizofrenija), i hidrocefalus.

Ovaj pronalazak obuhvata postupke za rešavanje problema gubitka pamćenja odvojeno od demencije, uključujući blagu pogoršanje razumevanja (MCI) i gubitak moći razmevanja usled starosti. Ovaj pronalazak obuhvata postupke za tretiranje gubitka pamćenja koje je rezultat bolesti. U drugoj primeni, ovaj pronalazak obuhvata postupke za bavljenje gubitkom pamćenja koji je rezultat upotrebe opšte anestezije, hemoterapije, terapije zračenjem, post hirurških trauma i terapeutskih intervencija.

Jedinjenja mogu da se koriste za tretiranje psihijatrijskih stanja uključujući šizofrniju, bipolarnu ili manijačnu depresiju, veliku depresiju i zavisnost od lekova i zavisnost od morfina. Ova jedinjenja mogu poboljšati budnost. Inhibitori PDE 4 mogu da se upotrebe za podizanje nivoa cAMP i čuvanje neurona od apoptoze koja je u toku. Inhibitori PDE 4 su takođe poznati da deluju protiv upala. Kombinacija anti apoptičnih i anti upalnih osobina čine ova jedinjenja upotrebljivim za tretiranje neurodegeneracije koja je posledica bilo kakve bolesti ili povrede, uključujući moždani udar, povrede kičmene moždine, neurogenezu, Alchajmerovu bolest, multiplu sklerozu, amilolaterarnu sklerozu (ALS) i višestruku sistemsku atrofiju (MSA).

Tako, u skladu sa poželjnim ostvarenjem, ovaj pronalazak obuhvata postupke za tretiranje pacijenata koji pate od pogoršanja pamćenja usled, na primer, Alchajmerove bolesti, šizofrenije, Parkinsonove bolesti, Hantongtonove bolesti, Pikove bolesti, Krojcfeld-Jakobsove bolesti, depresije, starenja, povreda glave, moždanog udara, CNS hipoksije, cerebralne senilnosti, multiinfarktne demencije i drugih neuroloških stanja uključujući akutne neuronalne bolesti, kao i HIV i kardiovaskularne bolesti, podrazumevajući davanje efikasne količine jedinjenja prema formuli (I) ili (I') ili njihove farmaceutski prihvatljive soli.

Jedinjenja iz ovog pronalaska se takođe mogu koristiti u postupcima za tretiranje pacijenata koji pate od stanja bolesti okarakterisanih smanjenjem NMDA funkcije, kao što je šizofrenija. Jedinjenja se takođe mogu koristiti za tretiranje psihoza okarakterisanih povišenim nivoima PDE 4, na primer, različiti oblici depresije, kao što su manična depresija, velika depresija i depresija povezana sa psihijatrijskim i neurološkim poremećajima.

Kao stoje pomenuto, jedinjenja iz ovog pronalaska takođe pokazuju anti upalnu aktivnost. Kao rezultat pronađena jedinjenja su upotrebljiva u tretiranju različitih alergijskih i upalnih obolenja, posebno stanja bolesti okarakterisana smanjenim nivoima ciklične AMP i/ili povišenim nivoima fosfodiesteraze 4. Tako, u skladu sa daljim ostvarenjima ovog pronalaska, dat je postupak za tretiranje alergijskih i upalnih stanja bolesti, podrazumevajući davanje efiksne količine jedinjenja prema formuli (I) il i(I') ili njihove farmaceutski prihvatljive soli. Ova bolesna stanja uključuju: astmu, hronični bronhitis, hroničnu opstruktivnu bolest pluća (COPD), atopični dermatitis, urtikariju, alergijski rinitis, alergijski konjuktivitis, proletni konjuktivitis, ezoniofilnu granulomu, psorijazu, upalni artritis, reumatski artritis, septički šuk, ulcerozni kolitis, Kronovu bolest, reperfiizionu povredu miokarda i mozga, hronični glomerulonefritis, endotoksični šok, sindrom poremećaja disanja kod odraslih, cističnu fibrozu, arterijsku restenozu, arterosklerozu, keratozu, reumatidni spondilitis, osteoartritis, pirezu, diabetes melitus, pneumokonioza, hronična bolest opstrukcije disajnih puteva, hronična opstruktivna plućna bolest, toksični i alergijski kontaktni akcem, seborejični ekcem, prost lišaj, opekotine od sunca, svrab genitalne oblasti, alopecija aerata, hipertrofirani ožiljci, diskoidni lupus eritematozis, sistemski lupus eritematozis,, folikularna i raširena pioderma, endogene i eksogene akne, akne rozacea, Begetova bolest, anafilaktoidni purpura nefritis, upalna bolest creva, leukemija, multipla skleroza, gastrointestinalne bolesti, autoimune bolesti i slične.

Inhibitori PDE 4 za tretiranje astme, hroničnog bronhitisa, psorijaze, alergijskog rinitisa i drugih upalnih bolesti i za inhibiranje faktora nekoze tumora su poznati u struci. Vidi, npr, WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 i US 5,935,9778. Ove reference takođe opisuju oglede za određivanje aktivnosti inhibicije PDE 4, i postupak za sintetizovanje ovakvih jedinjenja. Celokupna otkrića ovih dokumenata su ovde navedena kao reference.

Inhibitori PDE 4 mogu da se upotrebe za prevenciju amelioratne osteoporeze, kao antibiotici, za tretiranje kardiovaskularne bolesti mobilišući holesterol iz aterosklerotičnih lezija, za tretiranje reumatičnog artritisa (RA), za dugoročnu inhibiciju proliferacije mesenšimalnih ćelija posle transplantacije, za tretiranje urinarne opstrukcije kao posledice benigne hiperplazije prostate, za gušenje hemotakse i redukciju prodiranja ćelija raka debelog creva, za tretrianje hronične limfocitne leukemije B ćelija (B-CLL), za inhibiciju kontrakcija materice, za umanjenje pulmonano vaskularne ishemično-reperfusione povrede (IRI), za hidraciju rožnjače, za inhibiciju IL-2R izražavanja i time ukidanje HIV-1 DNK nukleotidnog unosa u memoriju T ćelija, za povećanje glukozom indukovanog lučenja insulina, i za sprečavanje i za tretiranje kolitisa i za inhibiranje degranulacije masnih ćelija.

Jedinjenja iz ovog pronalaska mogu da se daju kao sami aktivni agensi ili u kombinaciji sa srugim farmaceutskim agensima kao što su drugi agensi upotrebljeni za tretiranje pogoršenja razumevanja i/ili tretiranje psihoze, npr, drugi inhibitori PDE 4, blokatori kalcijuskih kanala, hloinerski lekovi, modulatori adenozin receptora, modulatori amfakina NMDA-R, modulatori mGluR i inhibitori holinesteraze (npr, donezepil, rivastigmin i glantanamin). U ovakvim kombinacijama, svaki aktivni sastojak može da se daje u skladu sa njihovim uobičajenim opsezima doza ili u dozama manjim od uobičajenih opsega doza.

Doze jedinjenja iz ovog pronalska zavise od rezličitih faktora uključujući određene simptome koji treba da se tretiraju, jačinu simptoma, način davanja, interval učestanosti doza, koje je određeno jedinjenje upotrebljeno, toksikološki profil, farmakokinetički profil jedinjenja i prisustvo bilo kakvih štetnih sporednih efekata, između drugih razmatranja.

Jedinjenja iz ovog pronalaska se tipični daju sisarima u nivoima doza uobičajenim za inhibitore PDE 4 kao što su one do sada poznatih jedinjenja prethodno pomenutih. Na primer, jedinjenja se mogu davati kao jednostruke ili višestruke doze, oralno pri nivou doze od, na primer, 0,1-100 mg/kg/dan, poželjno 0,1-70 mg/kg/dan, specijalno 0,5-10 mg/kg/dan. Jedinični oblik doze može da sadrži, na primer, 0,1 do 50 mg aktivnog jedinjenja. Za intravensko davanje, jedinjenja mogu da se daju kao jednostruke ili višestruke doze, oralno pri nivou doze od, na primer, 0,001 - 50 mg/kg/dan, poželjno 0,001 - 10 mg/kg/dan, specijalno 0,01-1 mg/kg/dan. Jedinični oblik doze može da sadrži, na primer, 0,1 do 10 mg aktivnog jedinjenja.

U sprovođenju procedura iz ovog pronalaska podrazumeva se da se pozivanje na određene pufere, sredine, reagense, ćelije, uslove kulture i slično ne znači i ograničavanje, već da treba da se shvati da su obuhvaćeni svi relevantni materijali koje stručnjak iz ove oblasti prepozna kao interesantne ili vredne u određenom kontekstu u kome je diskusija prezentovana. Na primer, često je moguće zameniti jedan puferski sistem drugim i ostvariti slične ako ne identične rezultate. Stručnjaci iz ove oblasti imaju dovoljno znanje o ovakvim sistemima i metodologijama tako da su u mogućnosti da bez neprikladnog eksperimentisanja naprave takve zamene koje će optimalno služiti njihovim potrebama primenom postupaka i procedura ovde obuhvaćenih.

Ovaj pronalazak će sada biti dalje opisan pomoću sledećih primera koji ga ne ograničavaju. U primeni opisa iz ovih primera, mora biti jasno da će se druga i različita ostvarenja postupaka obuhvaćenih ovim pronalasku same nametnuti stručnjacima iz ove oblasti. U prethodnom i sledećim primerima, sve temperature su date nekorigovane u stepenima celzijusa; i ukoliko nije drugačije naznačeno, svi udeli i procenti su maseni.

Celokupni opisi svih patentnih prijava, patenata i publikacija citiranih u prethodnom i daljem tekstu su ovde navedeni kao referenca.

PRIMERIA

l-CiklopentiIoksi-2-metoksi-5-nitrobenzen

U suspenziju 2-metoksi-5-nitrofenola (525 g, 3,104 mol.) i kalijum karbonata (643,5 g, 4,66 mol.) u dimetilformamidu (1 L), u atmosferi N2, doda se ciklopentil bromid (499,2 ml, 4,66 mol.). Suspenzija se zagreva na 100°C u toku od 6 h. Kalijum karbonat (85,8g, 0,62 mol.) i ciklopentil bromid (50 ml, 0,46 mol.) se dodaju. Suspenzija se zagreva na 100°C u toku od 4 h. TLC (tanko slojna hromatografija) ukazuje daje reakcija kompletna (9:1 DCM.:MeOH). Reakciona smeša se ohladi na sobnu temperaturu i razblaži sa vodom (3L) i etrom (3L). Slojevi se odvoje i vodeni sloj se re-ekstrahuje sa etrom (2L). Spojeni organski slojevi se isperu sa IN NaOH (2L), i slanim rastvorom (2L). Organski sloj osuši se preko natrijum sulfata, i upari. Dobijena čvrsta materija azeotropno se destiluje sa toluenom (2 x 300 ml), pa se dobija736,7g (99,6%-ni prinos) u obliku žute čvrste marterije.

Jedinjenja koja slede su dobijena na sličan način kao što je gore opisano:

a) l-ciklopropilmetoksi-2-metoksi-5.nitrobenzen

b) l-ciklopentoksi-2-difiuorometoksi 5-nitrobenzen

c) 1 -cikIopropilmetoksi-2-difluorometoksi-5-nitrobenzen

PRIMER 1B

2-Metoksi-5-nitro-l-((3R)-tetrahidrofuriloksi)benzen

U smešu 2-metoksi-5-nitrofenola (1.69 g, 10 mmol.), trifenilfosfina (5,24 g, 20 mmol.) i 3-(ft)-hidroksitetrahidrofurana (1,80 g, 20 mmol.) u anhidrovanom tetrahidrofuranu (40 ml) doda se kap po kap, pri mešanju, diizopropilazodikarboksilata (4,0 ml, 20 mmol.) i smeša se ostavi da meša na sobnoj sobnoj temperaturi u toku 16 h. Smeša se razblaži sa 150 ml etra i ispere sa 2N NaOH (3 x 50 ml) i sa 50 ml slanog rastvora, (MgS04) i koncentruje u vakumu. Sirov ostatak se prečisti brzom-jednokratnom hromatografijom ("fleš") na koloni sa silika gelom (Biotage Flash 40M) eluiranjem sa 20%-nim etil acetatom u heksanu, pa se dobija 1,05 g proizvoda.

Sledeća jedinjenja se dobijaju na sličan način kao što je gore opisano:

a) 2-metoksi-5-nitro-l-(3-tetrahidrofuriloksi)benzen

b) 2-metoksi-5-nitro-l-((319)-tetrahidrofuriloksi)benzen

c) 2-difluorometoksi-5-nitro-l-(3-tetrahidrofuriloksi)benzen

d) 2-difluorometoksi-5-nitro-l -((3ii')-tetrahidrofuriloksi)benzen

e) 2-difluorometoksi-5-nitro-l-((35)-tetrahidrofuriloksi)benzen

f) 2-metoksi-5-nitro-l-(3-fenpropiloksi)benzen

g) 1 -(2-indaniloksi)-4-metoksi-5-nitrobenzen

PRIMER 1C

l-(fm\-ButildimetiIsiliI)oksi-2-metoksi-5-nitrobenzen

U smešu 2-metoksi-5-nitrofenola (1,53 g, 9,0 mmol.) i imidazola (1,08 g, 15,9 mmol.) u anhidrovanom DMF (40 ml) doda se pri mešanju,terc. -butildimetilsililhlorid (2,05 g, 13,6 mmol,) i smeša se ostavi da mesa na sobnoj temperaturi u toku 16 sati. Rastvarač se udalji u vakumu i ostatak se rastvori u 40 ml 50%-nog etil acetata u heksanu i filtruje preko 10 g silika gela. Silika gel se ispere sa dodatnim 200 ml 50%-nim etil acetatom u heksanu i filtrati se spoje i konccntruju u vakumu, pa se dobija 2,01 g proizvoda u obliku kristalne materije žutomrke boje. "H NMR (CDCI3) 8 7,89 (dd, IH. J = 9,0 Hz, 2,8 Hz), 7,69 (d, IH, J = 2,8 Hz), 6,88 (d, IH, J = 9,0), 3,90 (s,3H), 1,00 (s, 9H), 0,18 (s, 6H).

PRIMER 2

3-CikIopentiIoksi-4-metoksianilin

U suspenziju 10%-nog Pd na aktivnom uglju (25 g u etanolu (4L), u atmosferi azota, doda se l-ciklopentiloksi-2-metoksi-5-nitrobenzen (250 g. 1,054 mola). Reakciona smeša se degazira u vakumu tri puta. Reakciona smeša se snažno meša za koje vreme se vodonik uvodi preko reakcione smeše. Posle 4 h reakciona smeša je kompletna (TLC , 5:1 heksan:EA). Reakciona smeša se filtruje preko sloja celita i celit se ispere sa dodatnim etanolom. Rasrvarač se udalji u vakumu, pa se dobija 208,38 g (95%-ni prinos 3-ciklopentiloksi-4-metoksianilina u obliku tečnosti crvene boje. 'HNMR(CDC13)8 6,85(d, J = 8,4Hz, IH), 6,29 (s,lH), 6,19(dd, J =2,8, 8,4, IH), 4,69(p,J= 4,4 Hz, IH), 3,75 (s, 3H), 3,44 (š.s, 2H), 1,90-1,81 (m, 6H), 1,61-1,55 (m, 2H).

Sledeća jedinjenja su dobijena na sličan način kao što je gore opisano:

a) 3-ciklopentiloksi-4-difluorometoksianilin

b) 3-ciklopropilmetoksi-2-metoksianilin

c) 3-ciklopropilmetoksi-4-difluorometoksianilin

d) 4-metoksi-3-((3i?)-tetrahidrofuriloksi)anilin

e) 4-metoksi-3-(tetrahidrofuriloksi)anilin

f) 4-metoksi-3-((35)-tetrahidrofuriloksi)anilin

g) 4-difIuorometoksi-3-(3-tetrahidrofuriloksi)anilin

h) 4-difluorometoksi-3-((3i?)-tetrahidrofuriloksi)anilin

i) 4-difluorometoksi-3-((3Sj-tetrahidrofuriloksi)anilin

j) 3-(terc-butildimetilsilil)oksi-4-metoksianlin

k) 4-metoksi-3-(3-fenpropiloksi)anilin

1) 3-(2-indaniloksi)-4-metoksianilin

PRIMER 3

3-CiklopentiI-4-metoksi-A<r->(3-piridiImetil)anilin

U smešu 3-piridinkarboksaldehida (106,55g, 0,995 molova u metanolu (5L) doda se 3-toluensulfonsa kiselina monohidrat (200 mg). Reakciona smeša se meša u toku 4 sata. Balon se zatim ohladi na 0° C i natrijum borhidrid (37,64g, 2,3 mol.) doda se u porcijama u toku 4 h. Reakciona smeša se ostavi da zauzme sobnu temperaturu u toku od 16 h upri mešanju. TLC ukazuje daje reakcija kompletna (1:3 heksan:EA). Rastvarač je uparen do oko 0,5 L u obliku suspenzije. Suspenzija- kaša razblaži se vodom (1L) i ekstrahuje sa etil acetatom (2 x 2L). Spojeni organski slojevi isperu se sa slanim rastvorom (500 ml), osuše preko natrijum sulfata i koncetruju, pa se dobija 300g

(100%-ni prinos) željenog proizvoda u obliku viskozne tečnosti braon boje. 'H NMR (CDCI3) 5 8,61-8,48 (m, 2H), 7,69-7,67 (m,lH), 7,24-7,21 (m,lH), 6,72 (d, J = 8,4Hz, IH), 6,23 (s,lH), 6,13 (dd, J = 2,6, 8,6, IH), 4,65 (š.s, IH), 4,27 (s,2H), 4,0 (š.s,lH), 3,73 (s,3H), 1,88-1,70 (m,6H), 1,65-1,45 (m,2H).

Sledeća jedinjenja dobijena su na sličan način kao stoje gore opisano:

a) 3-ciklopentiloksi-4-metoksi-A^-(3-tienilmetil)anilin

b) 3-ciklopentiloksi-4-metoksi-A^-(4-piridilmetil)anilin

c) 3-ciklopentiloksi-jV-(2,6-dihloro-4-piridilmetil)-4-metoksianilin

d) 3-ciklopentiloksi-4-metoksi-A^-(2-hinolinilmetil)anilin

e) 3-ciklopentiloksi-4-metoksi-A<f->(3-hinolinilmetil)anilin

f) 3-ciklopentiloksi-4-metoksi-jV-(4-hinolinilmctil)anilin

g) 3-ciklopentiloksi-4-metoksi-A<f->(2-pirazinilmetil)anilin

h) 4-metoksi-A<f->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)anilin

i) 4-metoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)anilin

j) 4-metoksi-A'-(3-piridilmetil)-3-((35)-tetrahidrofuriloksi)anilin k) 3-ciklopropilmetoksi-4-difluorometoksi-7/-(3-piridilmetil)anilin 1) 3-ciklopentiloksi-4-difluorometoksi-7/-(3-piridilmetil)anilin m) 4-difluorometoksi-A^-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)anilin n) 4-difluorometoksi-A<r->(3-piridilmetil)-3-((3/?)-tetrahidrofuriloksi)anilin o) 3,4-bis(difluorometoksi)-jV-(3-piridilmetil)anilin p) 3-terc-butildimetilsililoksi-4-metoksi-A<f->(3-piridilmetil)anilin q) 3-ciklopentiloksi-4-metoksi-A^-(2-piridilmetil)anilin r) 3-ciklopentiloksi-4-metoksi-A^-[l-(2-fenetil)]anilin s) N-benzil-S-ciklopentiloksM-metoksianilin

t) A^-[(cikloheks-l-en-l-il)metil]-3-ciklopentiloksi-4-metoksianilin u) 3-ciklopentiloksi-4-metoksi-jV-(3,4,5-trimetoksibenzil)anilin v) A^-[(cikloheks-3-en-l-il)metil]-3-ciklopentiloksi-4-metoksianilin

\v) 3-cikIopentiloksi-4-metoksi-A<r->(2,4,6-trimetilbenzil)anilin x) 3-ciklopentiloksi-4-metoksi-A<r->(2-metiibenzil)aniIin y) 3-ciklopentiloksi-4-metoksi-A<L>(2-trifluorometilbenzil)anilin z) S-ciklopentiloksi^-rnetoksi-A^-^S^-metilendioksObenzi^anilin aa) 3-ciklopentiloksi-4-metoksi-A<L>(2-hidroksi-3-metoksilbenzil)anilin bb) 3-ciklopentiloksi-A/-(3-furilmetil)-4-metoksianilin cc) 3-ciklopentiloksi-4-metoksi-A^-(3-metilbenzil)anilin dd) S-ciklopentiloksi^-metoksi-A^^-metoksibenziOanilin ee) 3-ciklopentiioksi-4-metoksi-A^-(3-hlorobenzil)anilin ff) 3-ciklopentiloksi-4-metoksi-A<f->(3-metoksibenzil)anilin gg) 3-ciklopentiloksi-4-metoksi-Ar-(2-hlorobenzil)anilin hh) 3-ciklopentiloksi-4-metoksi-Af-(3-metilbenzil)anilin ii) 4-metoksi-3-(3-fenpropiIoksi)-A<?->(4-piridilmetil)anilin jj) A^-(2,6-dihloro-4-piridilrnetil)-3-(2-indaniloksi)-4-metoksianiIin kk) 4-metoksi-3-(3-fenpropiloksi)-Ar-(2-piridilmetil)anilin 11) A<r->(2,6-dihloro-4-piridilrnetil)-4-metoksi-3-(3-fenpropiloksi)anilin mm) 4-metoksi-3-(3-fenpropiloksi)-A</->(3-piridilmetil)anilin nn)3-ciklopentiloksi-4-metoksi-//-(2-tienilmetil)anilin oo) 3-(2-indaniloksi)-4-metoksi-A/-(3-tienilmetiI)anilin pp)4-metoksi-3-(3-fenpropiloksi)-A/-(3-tienilmetil)anilin qq) 3-(2-indaniloksi)-4-metoksi-A7-(2-piridilmetil)anilin rr) 3-(2-indaniloksi)-4-metoksi-A<r->(3-piridilmetil)anilin ss) 3-(2-indaniloksi)-4-metoksi-A^-(4-piridilmetil)anilin tt) 3-ciklopentiloksi-4-metoksi-A<r->(3-piperidinmetil)anilin uu) 3-ciklopentiloksi-4-metoksi-Af-(3-(l-/erc-butiloksikarbonil)piperidinmetil)anilin vv) 3-ciklopentiloksi-4-metoksi-Af-(6-metil-2-piridilmetil)anilin ww) A/-(2-hloro-3-piridilmetil)-3-ciklopentiloksi-4-metoksianilin xx) A/-(2-hloro-5-piridilmetil)-3-ciklopentiloksi-4-metoksianilin yy) 3-ciklopentiloksi-4-metoksi-A/-(2-tiazolilmetil)anilin

PRIMER 4

3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin

U argonom ispranu posudu od 100 ml prethodno osušenoj u sušnici je dodato sledećim redom 0,59 g (6,10 mmol) NaOtBu, 360 mg Pd2dba3, 20 ml toluena, 0,14 ml P(tBu)3, i 20 ml rastvora koji se sastoji od 1,3 g (4,36 mmol) N-(3-piridilmetil)-3-ciklopentiloksi-4-metoksianilina u toluenu. Uz mešanje, dodato je 3,1 g (15 mmol) jodbenzena ukapljavanjem i mešavina je mešana tokom 18 časova. Reakciona smeša je razblažena sa EtOAc i isprana dva puta sa H2O i ekstrahovana sa 3 x 15 ml 3./VHC1. Spojeni kiseli ekstrakti su isprani sa 15 ml EtOAc i zatim pažljivo neutralisani sa6NNaOH do vrednosti pH veće od 12. Bazni rastvor je ekstrahovan sa 2 x 15 ml EtOAc i spojene organske frakcije su posle toga isprane sa 15 ml H2O i slanog rastvora, osušene (MgSO<i) i koncentrisane. Ostatak je prečišćen hromatografijom preko silika gela

(Biotage Flash 40M) eluiranjem sa 25% EtOAc u heksanu. Materijal je dalje prečišćen kristalizacijom iz heksana i dobilo se 550 mg čvrste bele supstance. 'H NMR (CDCI3) 8 8,61 (s,IH), 8,49 (d, IH, J = 4,2 Hz), 7,67 (d, IH, 7,9 Hz), 7,30-7,10 (m, 3H), 6,90-6,80 (m, 4H), 6,80-6,60 (m, 2H), 4,94 (s, 2H), 4,64 (p, IH, J = 4,1 Hz), 3,84 (s, 3H), 1,86-1,70 (m, 6H), 1,65-1,45 (m, 2H).

Sledeće jedinjenja su dobijena na sličan način kao što je gore opisano:

a) S-ciklopentiloksi^-metoksi^'-metil-A^^-piridilmetiOdifenilamin

b) 3-ciklopentiloksi-4-metoksi-3'-metil-A<r->(3-piridilmetil)difenilamin

c) 3-ciklopentiloksi-4-metoksi-4'-metil-A</->(3-piridilmetil)difenilamin

d) S-ciklopentiloksi^'-etil^-metoksi-A^^-piridilmetiOdifenilamin

e) S'-hloro^-ciklopentiloksi^-metoksi-^S-piridilmetiOdifenilamin

f) 4'-hloro-3-ciklopentiloksi-4-metoksi-A</->(3-piridilmetil)difenilamin

g) 3-ciklopentiloksi-2',4-dimetoksi-A^-(3-piridilmetil)difenilamin

h) 3-ciklopentiloksi-3',4-dimetoksi-A<r->(3-piridilmetil)difenilamin i) 3-ciklopentiloksi-4\4-dimetoksi-A;-(3-piridilmetil)diferiilarnin j) 3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)-3'-trifluorornetildifenilarnin k) 3-ciklopentiloksi-4-metoksi-Af-(3-iridilmetil)-<4>'4rifluorometildifenilamin 1) 3-ciklopentiloksi-3'-fluoro-4-metoksi-A^-(3-piridilmetil)difenilarnin m) 3-ciklopentiloksi-4'-fluoro-4-metoksi-Af-(3-piridilrnetil)difenilamin n) 3-ciklopentiloksi-4-metoksi-3'-fenil-Af-(3-piridilrnetil)difenilamin o) S-ciklopentiloksi^-metoksi^'-fenil-A^^S-piridilrnetiOdifenilarnin p) 3'-cijano-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilarnin q) 4'-cijano-3-ciklopentiloksi-4-metoksi-Ar-(3-piridiIrnetil)difenilarnin r) etil A^^-ciklopentiloksi^-metoksifeniO-A^^S-piridilmeti^^-arninobenzoat s) etil A<f->(3-ciklopentiloksi-4-metoksifenil)-A<r->(3-piridilmetil)-4-arninobenzoat t) 3-ciklopentiloksi-4-metoksi-3'-nitro-A<f->(3-piridilmetil)difenilamin u) 3-ciklopentiloksi-4-metoksi-4'-nitro-A^-(3-piridilrnetil)difenilarnin v) ^-(S-ciklopentiloksi^-metoksifeni^-A^^-piridilmeti^-l-naftilamin w) 3-cikIopentiloksi-2\3'-dimetil-4-metoksi-A<r->(3-piridilmetil)difenilarnin x) 3-ciklopentiloksi-2\4'-dimetil-4-metoksi-Ar-(3-piridilmetil)difenilarnin y) 3-ciklopentiloksi-2\5'-dimetil-4-metoksi-A/-(3-piridilmetil)difenilamin z) 3-ciklopentiloksi-3\4'-dimetil-4-metoksi-A<f->(3-piridilmetil)difenilamin aa) S-ciklopentilok^i^^S'-dihloro^-metoksi-A^-CS-piridilmetiOdifenilarnin bb)3-ciklopentiloksi-3\4'-dihloro-4-metoksi-A^-(3-piridilmetil)difenilarnin cc) 3-ciklopentiloksi-3\5'-dihloro-4-metoksi-Af-(3-piridilmetil)difenilarnin dd) 3'-hloro-3-ciklopentiloksi-4'-fluoro-4-metoksi-A^-(3-piridilmetil)difenilamin ee) 4'-hloro-3-ciklopentiloksi-3'-fluoro-4-metoksi-A^-(3-piridilmetil)difenilarnin ff) 4'-hloro-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)-3'-trifluorometildifenilamin

gg) S-ciklopentiloksi^-metoksi-A^^-tienilmetiOdifenilamin h^A^^S-ciklopentiloksi^-metoksifeniO-A^^S^ienilmeti^-l-naftilamin ii) 3-ciklopentiloksi-2\3'-dihloro-4-metoksi-A^-(3-tienilmetil)difenilamin jj) 3-ciklopentiloksi4-metoksi-4'-metil-A^-(4-piridilmetil)difenilarriin kk) 3-ciklopentiloksi-A^-(2,6-dihloro-4-piridilmetil)-4-metoksi-3'-metildifenilarnin

11) 2'-hloro-3-ciklopentiloksi-A?-(2,6-dihloro-4-piridilmetil)-4-metoksidifenilam mm) 3-ciklopentiloksi-//-(2,6-dihloro-4-piridilmetil)-4-metoksidifenilamin nn) 3-ciklopentiloksi-4-metoksi-A^-(6-metil-2-piridilmetil)metildifenilamin oo) 3-ciklopentiloksi-4-metoksi-A^-(3-hinolinmetil)difenilamin pp) 3-ciklopentiloksi-4-metoksi-A/-(4-hinolinmetil)difenilamin qq) 3-ciklopentiloksi-4-metoksi-A'-(2-pirazinolmetil)difenilamin rr) 4-metoksi-3'-metil-A^-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin ss) 4-metoksi-4'-metil-A<f->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin tt) 4,4'-dimetoksi-Ar-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin uu) 3'-hloro-4-metoksi-Ar-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin vv) 4-metoksi-4'-(4-metilpiperazin-l-ilkarbonil)-Ar-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin

ww) 3'-cijano-4-metoksi-jV-(3-piridilmetil)-3-((3/?)-tetrahidrofuriloksi)difenilamin

xx)3'-cijano-4-metoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)difenilamin yy) 3-ciklopropilmetoksi-4-difluorometoksi-A?-(3-piridilmetil)difenilamin zz) 3-ciklopentiloksi-4-difluorometoksi-A'-(3-piridilmetil)difenilamin aaa) 4-difluorometoksi-A<r->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin bbb) 3,4-bis(difluorometoksi)-A<r->(3-piridilmetil)difenilamin ccc) 4-difluorometoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)difenilamin

ddd) 3'-cijano-4-difluorometoksi-A^-(3-piridilmetil)-3-((3/?)-tetrahidrofuriloksi)difenilamin

eee) 3'-hloro-4-difluorometoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)difenilamin

fff) etil A<r->(3-ciklopropilmetoksi-4-difluorometoksifenil)-A<7>^-(3-piridilmetil)-3-aminobenzoat

ggg) 3-ciklopentiloksi-4-metoksi-3'-(4-metilpiperazin-l-ilkarbonil)-A^-(3-piridilmetil)difenilamin

hhh) 3-ciklopentiloksi-4-metoksi-4'-(4-rnetilpiperazin-l-ilkarbonil)-iV-(3-piridilmetil)difenilamin

iii) 3'-terc-butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)difenilamin

jjj) 4'-terc-butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin

kkk) 4'-terc-A<r->(3-ciklopentiloksi-4-metoksifenil)-A<r->(3-piridilmetil)aminobenzoat

111) etil ^-(S-ciklopentiloksi^-difluorometoksifeniO-A^^-piridilmetiO-S-aminobenzoat

mmm) etil A<r->(4-difluorometoksi-3-(3-tetrahidrofuriloksi)fenil)-A^-(3-piridilmetil)-3-aminobenzoat

nnn) etil A<r->(3,4-bis(difluorometoksi)fcnil)-A<r->(3-piridilrnetil)-3-arninobcnzoat ooo) etil A^-(4-metoksi-3-((3^)-tetrahidrofuriloksi)fenil)-A<r->(3-piridilmetil)-3-aminobenzoat

ppp) etil A^^-ciklopropilmetoksi^-rnetoksifeniO-A^^S-piridilrnetil)^-aminobenzoat

qqq) 3-ciklopentiloksi-4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-^-piridilmetiOdifenilamin

rrr) 3-ciklopentiloksi-4-metoksi-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A/-(3-piridilmetil)difenilamin

sss) 4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A<f->(3-piridilrnetil)-3-((3i?)-tetrahidrofuriloksi)difenilarnin

ttt) 3-ciklopropilrnetoksi-4-metoksi-4,-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A<f->

(3-piridilmetil)difenilamin

uuu) 4-difluorornetoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A<f->(3-piridilrnetil)-3-((3R)-tetrahidrofuriloksi)difenilamin

vvv) 3-ciklopropilrnetoksi-4-dilfuorometoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-N-(3-piridilmetil)difenilamin

www) 3-ciklopentiloksi-4-difluorornetoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A^-(3-piridilmetil)difenilamin

xxx) 3-ciklopropilmetoksi-4-difluorometoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A<?->(3-piridilmetil)difenilamin

yyy) bis-(3,4-difluorornetoksi)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A<L>

(3-piridilmetil)difenilamin

zzz) 3-/erc-butildimetiIsililoksi-4-metoksi-A<r->(3-piridilrnetil)difenilamin aaaa) 3-/erc-butildimetiIsiIiloksi-3'-hloro-4-metoksi-A-(3-piridilmetil)difenilamin

bbbb) etil A<A->(34erc-butiIdimetilsililoksi-4-rnetoksifenil)-A<f->(3-piridilmetil)-3-aminobenzoat

cccc) S-ciklopentiloksi^'-hloro^-metoksi-A^^-piridilmetiOdifenilarnin dddd) 3-(2-indaniloksi)-4-metoksi-Ar-(3-piridilmetil)difenilarnin

PRIMER 5

A<7->(3-ciklopentiloksi-4-metoksifenil)-A'<L>(3-piridilmetil)-3-aminobenzoeva kiselina Rastvor napravljen od 6,5 g etil A^-ciklopentiloksM-metoksifeniO-A<7->^-piridilmetil)-3-aminobenzoata u 50 ml EtOH je tretiran sa 10 ml 6N NaOH. Smeša je ostavljena da stoji 6 sati, koncentrisana i razblažena sa 50 ml H2O. Vodena smeša je ekstrahovana sa 2 x 50 ml etra, zakišeljena sa AcOH do pH 3, i ekstrahovana sa 2 x 50 ml EtOAc. Spojene EtOAc frakcije su isprane sa 25 ml H2O i 25 ml slanog rastvora (MgS04) i koncentrisan. Ostatak je prečišćen hromatografijom preko Si02(35 g RediSep® kolona) upotrebom linearnog gradijenta EtOAc i heksana kao eluenta (50% EtOAc prema 70% EtOAc tokom 20 minuta) radi dobijanja 4,8 g žutog čvrstog proizvoda posle sušenja u vakuumu tokom 12 h na 60°C.<*>H NMR (CDCI3) 5 11,15 (šs,lH), 8,70-8,55 (m, 2H), 7,77-6,71 (m, 9H), 4,99 (s, 2H), 4,65 (p, J = 3,8 Hz, IH), 3,84 (s, 3H), 1,86-1,70 (m, 6H), 1,65-1,45 )m, 2H).

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) ^-(S-ciklopentiloksi^-metoksifeniO-^S-piridilmetiO^-arninobenzoeva kiselina b) ^-(S-ciklopentiloksi^-difluorometoksifeniO-A^-CS-piridilmetiO-S-aminobenzoeva kiselina c) A^-[4-difluorometoksi-3-(3-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina d) Af-3,4-bis(difluorometoksi)fenil)-A/-(3-piridilmetil)-3-aminobenzoeva kiselina e) A<f->[4-metoksi-3-((3R)-tctrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina f) A^^-ciklopropilmetoksi^-metoksifeni^-A^^-piridilmetiO^-aminobenzoeva kiselina g) A<r->(3-ciklopropilmetoksi-4-difluorometoksifenil)-A<?->(3-piridilmetil)-3-aminobenzoeva kiselina h) ^-(3-ciklopentiloksi-4-metoksifenil)-3-aminobenzoeva kiselina i) A^-[3-(4-hlorofenil)prop-1 -iloksi-4-metoksifenil]-A^3-piridilmetil)-3-aminobenzoeva kiselina

j) A<r->(3-ciklopropilmetoksi-4-metoksifenil)-A/-(3-piridilmetil)-3-aminobenzoeva

kiselina

k) //-[3-(2-indaniloksi)-4-metoksifenil]-A<r->(3-piridilmetil)-3-aminobenzoeva

kiselina

1) Ar-[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A/-(3-piridilmetil)-3-aminobenzoeva

kiselina

m) A<f->[4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-A<r->(3-piridiImetil)-3-aminobenzoeva kiselina

n) A</->[3-(2-metoksietoksi)-4-metoksifenil]-Af-(3-piridilmetil)-3-aminobenzoeva

kiselina

o) A</->[4-metoksi-3-(2-(2-piridil)etil)oksifenil]-A</->(3-piridilmetil)-3-aminobenzoeva kiselina

PRIMER 6

A^-(3-ciklopentiloksi-4-metoksifenil)-A</->(3-piridilrnetil)-2-aniinobenzoeva kiselinaTerc- but\\^-(S-ciklopentiloksi^-metoksifeniO-^S-piridilmetil)^-aminobenzoat (60 mg, 0,13 mmol) je dodato u 2 ml 98% mravlje kiseline i grejano na 40°C tokom 4 sata. Mravlja kiselina je uklonjenain vacuoi ostatak je premešten u kolonu sa silika gelom (RediSep, 4,2 g). Proizvod je eluiran sa linearnim gradijentom od 40% EtOAc u heksanu do 60% EtOAc u heksanu tokom 15 minuta radi dobijanja 16 mg proizvoda kao čvrste braon supstance. 'H NMR (CDCb) 5 8,47 (d, IH, J = 4,9), 8,43 (s, IH), 8,10 (d, IH, J = 7,8), 7,67 (d, IH, J = 7,8 Hz), 7,56 (m, IH), 7,40-7,20 (m, 3H), 6,75 (d, IH, J = 8,7), 6,57 (d, IH, J = 8,7), 6,47 (s, IH), 4,72 (s, 2H), 4,54 (p, IH, J = 4,3), 3,77 (s,3H), 1,80-1,60 (m, 6H), 1,60-1,40 (m, 2H).

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) A<r->(3-ciklopentiloksi-4-metoksifenil)-A<r->(3-piridilmetil)-3-aminobenzoeva kiselina b) A<f->(3-ciklopentiloksi-4-metoksifenil)-A/-(3-piridilmetil)-6-aminonikotinska kiselina

PRIMER 7

3-ciklopropilmetiloksi-4-difluorometoksi-A'-)3-piridilmetil)-4'-(2H-tetrazol-5-il)đifenilamin

S-ciklopropilmetoksi^-difluorometoksi-A^^-piridilmetil^'-p^-tetrahidropiranil)-2H-tetrazol-5-il]difenilamin (1,5 g, 0,26 mmol) je rastvoreno u THF (5 ml) i dodato je 3 ml IN HC1. Posle 6 sati na sobnoj temperaturi, smeša je neutralisana do pH = 5 zasićenim vodenim rastvorom natrijum bikarbonata i ekstrahovana sa EtOAc (3 x 50 ml). EtOAc ekstrakti su spojeni, isprani slanim rastvorom (50 ml), osušeni (MgS04) i koncentrisaniin vacuo.Sirovi ostatak je prebačen u RediSep kolonu (10 g, silika gel) i proizvod je eluiram upotrebom linearnog gradijenta od 0% MeOH u EtOAc do 5% MeOH u EtOAc tokom 20 minuta radi dobijanja 0,96 g proizvoda u obliku belog praha.

'H NMR (CD3OD) 5 8,55 (s, IH), 8,43 (d, IH, J = 4,9 Hz), 7,65 (d, IH, J = 8,0 Hz), 7,21 (dd, IH, J = 4,9 Hz, 8,0 Hz), 7,18 (d, IH, J = 8,9 Hz), 7,10-6,90 (m, 3H), 6,87 (dd, IH, J = 8,6 Hz, 2,5 Hz), 6,75 (t, IH, J = 75,5 Hz), 5,14 (s, 2H), 3,82 (d, 2H, J = 6,9 Hz), 1,23 (m, IH), 0,60 (m, 2H), 0,33 (m, 2H).

Sledeća jedinjenja su dobijana na sličan način kao stoje gore opisano:

a) S-ciklopentiloksi^-metoksi-A^^-piridilmetiO^'^H-tetrazol-S-iOdifenilamin b) 3-ciklopentiloksi-4-difluorometoksi-A/-(3-piridilmetil)-3'-(2H-tetrazol-5-il)difenilamin c) 4-metoksi-Af-(3-piridilmeti))-3-((3/?)-tetrahidrofuriloksi) -4'-(2H-tetrazol-5-il)difenilamin d) 3-ciklopropilmetiloksi-4-metoksi-A/-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin e) 4-difluorometoksi-Af-(3-piridilmetil)-3-((3^)-tetrahidrofuriloksi) -4'-(2H-tetrazol-5-il)difenilamin f) 3-ciklopentiloksi-4-difluorometoksi-A<f->(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin g) S-ciklopropilmetiloksi^-dilfuorometoksi-^S-piridilmetiO-S'^H-tetrazol-S-il)difenilamin h) bis^^-difluorometoksi-A^^-piridilmetiO^'^H-tetrazol-S-iOdifenilamin

PRIMER8 (postupak A)

3-cikIopentiloksi-4-metoksidifenilamin

Postupak A. (ref. Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P.,Tetrahedron Lett., 1998, 39,2933-2936.). Kaša od 207 mg 4-metoksi-3-ciklopentiloksianilina, 280 mg fenilborne kiseline, 182 mg Cu(OAc)2, 280 u.1 Et3N i 4,0 ml CH2CI2 je mešana tokom 20 h na sobnoj temperaturi. Crna smeša je filtrirana preko silike eluiran sa CH2C12, koncentrisana, i prečišćena hromatografijom preko Si02

upotrebom EtOAc/heksan (15/85) kao eluenta radi dobijanja 75 mg željenog proizvoda.

'H NMR (CDCI3) 5 7,26-7,20 (m, 2H), 6,94-6,63 (m, 6H), 5,50 (s, IH), 4,71 (m, IH), 3,82 (s,3H), 1,89-1,54 (m, 8H).

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) 3-ciklopentiloksi-3',4-dimetoksidifenilamin

b) 3'-hloro-3-ciklopentiloksi-4-metoksidifenilamin

c) 3-ciklopentiloksi-4-metoksi-3'-metildifenilamin

d) 3-ciklopentiloksi-4'-lfuro-metoksidifenilamin

e) 3-ciklopentiloksi-4-metoksi-4'-vinildifenilamin

f) 3'-cijano-3-ciklopentiloksi-4-metoksidifenilamin

g) 4'-hloro-3-ciklopentiloksi-4-metoksidifenilamin

h) 3-ciklopentiloksi-4',4-dimetoksidifenilamin

i) 3-ciklopentiloksi-4-metoksi-2'-metildifenilamin

j) 3-ciklopentiloksi-4-metoksi-4'-metildifenilamin

k) 2'-hloro-3-ciklopentiloksi-4-metoksidifenilamin

1) 3-ciklopentiloksi-2',4-dimetoksidifenilamin

m) 3-ciklopentiloksi-4-metoksi-3'-trifluorometildifenilamin n) 3-ciklopentiloksi-4-metoksi-4'-trifluorometildifenilamin o) 3-ciklopentiloksi-2',5'-4-metoksidifenilamin

PRIMER 8 (postupak B)

3-ciklopentiloksi-4-metoksidifenilamin

Postupak B( Angenv Chem Int. Ed,1995, 34( 11), 1348-1351.) Napravljena je smeša od 207 mg 3- ciklopentiloksi-4-metoksianilina, 204 mg jodobenzena, 115 mg NaOtBu, 9 mg Pd2(dba)3, 12 mg P(o-tol)3i 7 ml toluena i zagrevana na 100°C uz mešanje tokom 4 sata. Smeša je ohlađena na sobnu temperaturu, razblažena sa 25 ml EtOAc i isprana sa 10 ml H20, 10 ml slanog rastvora, osušena (MgS04) i koncentrisana. Ostatak je prečišćen hromatografijom preko Si02upotrebom EtOAc/heksan (5/95) kao eluenta radi dobijanja 84 mg željenog proizvoda.

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) 3-cikIopentiloksi-4-metoksi-2',4'-dimetildifenilamin

b) 3-ciklopentiloksi-2',5'-dimetil-4-metoksidifenilamin

c) 3-ciklopentiloksi-2',3'-dimetil-4-metoksidifenilamin

d) 3-ciklopentiloksi-3',4'-dimetil-4-metoksidifenilamin

e) 3-ciklopentiloksi-3',4'-metilendioksidifenilamin

f) 4'-terc-butil-3-ciklopentiloksi-4-metoksidifenilamin

g) 3-ciklopentiloksi-3',4'-dihloro-4-metoksidifenilamin

h) 3-ciklopentiloksi-2',3'-dihloro-4-metoksidifenilamin

PRIMER 8 (postupak C)

3-ciklopentiloksi-2',4,5'-trimetoksidifenilamin

Postupak C. U smešu od Pd(dppf)Cl2(0,025 mmol, 5mol%), dppf (0,075 mmol, 3dppf/Pd) i NaOtBu (0,70 mmol, 1,4 ekvivalenta) i 1,0 ml THF je dodat l-bromo-2,5-dimetoksibenzen (0,55 mmol, 1,1 ekvivalenta) a zatim 1,0 ml 0,5 M rastvora 3-ciklopentiloksi-4-metoksianilina u THF. Smeša je zagrevana na 60°C tokom 3 sata i razblažena etrom i isprana sa H20 i slanim rastvorom, osušena (MgSC>4) i koncentrisana. Sirovi ostatak je prečišćen hromatografijom preko silika gela (Biotage Flash 12) eluiranjem sa 15% EtOAc u heksanu.

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) A^3-ciklopentiIoksi-4-metoksifenil)-3-piridilamin

b) 3-ciklopentiloksi-2',4',4-trimetoksidifenilamin

c) N-p-ciklopentiloksM-metoksifenil^-piridilamin

d) A^-(3-ciklopentiIoksi-4-metoksifenil)-8-hinolinilamin

e) A^-(3-ciklopentiloksi-4-metoksifenil)-2-naftilamin

f) Af-(3-ciklopentiloksi-4-metoksifenil)-l-naftilamin

g) 3-ciklopentiloksi-4'-etil-metoksidifenilamin

h) 3-ciklopentiloksi-2'-fluoro-4-metoksi-5'-metildifenilamin

i) 3-ciklopentiloksi-3'-fluoro-4-metoksi-4'-metildifenilamin

j) A^-(3-ciklopentiloksi-4-metoksifenil)-2-pirimidinilamin k) 3-ciklopentiloksi-3',5'-dihloro-4-metoksidifenilamin 1) 3-ciklofeniloksi-2'-etil-4-metoksidifenilamin

m) 4'-hloro-3-ciklopentiloksi-3'-fluoro-4-metoksidifenilamin n) A^3-ciklopentiloksi-4-metoksifenil)-4-isohinolinilamin o) A<r->(3-ciklopentiloksi-4-metoksifenil)-2-pirazinilamin p) A^3-ciklopentiloksi-4-metoksifenil)-5-pirimidinilamin q) A^-(3-ciklopentiloksi-4-metoksifenil)-l-izohinolinilamin r) A^-(3-ciklopentiloksi-4-metoksifenil)-3-hinolinilamin s) A^3-ciklopentiloksi-4-metoksifenil)-4-piridilamin t) A^^-ciklopentiloksi^-difluorometoksifeniO-S-piridilamin u) A^^-ciklopropilmetiloksi^-metoksifeni^-S-piridilamin v) A^-(3-ciklopropilmetiloksi-4-difluorometoksifenil)-3-piridilamin w) //-(4-metoksi-3-(3/?)-tetrahidrofuriloksifenil)-3-piridilamin x) A</->(4-difluorometoksi-3-(3^)-tetrahidrofuriloksifenil)-3-piridilamin

y) Etil A^-(3-ciklopentiIoksi-4-metoksifenil)-3-arninobenzoat z) 3- ciklopentiloksi-4'-(A?,A^-dimetilamino)-4-metoksidifenilamin aa) A^-(3-ciklopentiloksi-4-metoksifenil)-3-(6-metoksipiridil)arnin bb) metil AM3-ciklopentiloksi-4-metoksifenil)-2-aminonikotinat cc)terc-buiUAM3-ciklopentiloksi-4-metoksifenil)-6-aminonikotinat dd) 2'-amino-3-ciklopentiloksi-4-metoksidifenilamin

ee) 3-ciklopentiloksi-4-metoksi-3'-(l-ftalimido)difenilamin ff) 3-ciklopentiloksi-4-metoksi-3'-[2-(2-tetrahidropiranil)-2H-tetrazol-5-iljdifenilamin

PRIMER 9 (postupak A)

3-ciklopentiloksi-4-metoksi-A<r->metiIdifenilamin

U rastvor 3-ciklopentiloksi-4-metoksidifenilamina (70 mg, 0,25 mmol) u 3 ml THF na temperaturi od 0°C je dodato 0,55 ml 0,5 M KN(TMS)2u toluenu. Rastvor je mešan na temperaturi od 0°C tokom 0,5 h i dodato je 2,0 ekvivalenta jodometana i reakciona smeša je zagrejana na sobnu temperaturu. Po završetku reakcije što je indicirano pomoću TLC, dodato je 10 ml EtOAc i smeša je isprana sa 3 ml H20, 3 ml slanog rastvora, osušena (MgSO,)) i koncentrisana. Sirovi ostatak je prečišćen hromatografijom na koloni (Biotage flash 12) upotrebom 5% EtOAc u heksanu kao eluenta.

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) 3-ciklopentiloksi-A'-etil-4-metoksidifenilamin

b) 3-ciklopentiloksi-4-metoksi-A^l-propil)difenilamin

c) 3-ciklopentiloksi-4-metoksi-A^-[l-(3-fenpropil)]difenilamin

d) A</->benzil-3-ciklopentiloksi-4-metoksidifenilamin

e) 3-ciklopentiloksi-4-metoksi-Ar-(4-piridilmetil)difenilamin

f) 3-ciklopentiloksi-4-metoksi-A^-(2-piridilrnetil)difenilamin

g) 3-ciklopentiloksi-4-rnetoksi-A/-(3-piridilrnetil)difenilarniri

h) 3-ciklopentiloksi-4-metoksi-A^-[3-(3-piridil)-l-propil]difenilamin

i) ^-(S-ciklopentiloksi^-metoksifeniO-A^-etil^-izohinolinilarnin

j) A^-(3-ciklopentiloksi-4-metoksifenil)-A^-benzil-4-izohinolinilarnin k) A^-(3-cikIopentiloksi-4-metoksifenil)-A<A->metil-4-izohinolinilarnin 1) A<f->(3-cikIopentiloksi-4-metoksifenil)-A^-propil-4-izohinolinilamin

m) A^-(3-ciklopentiloksi-4-metoksifenil)-A<r->(4-izohinolinil)-A<?->(4-piridilmetil)amin n) A^-(3-ciklopentiloksi-4-metoksifeniI)-A<A->(4-izohinolinil)-A</->(3-piridilmetil)arnin o) ^-(S-ciklopentiloksi^-metoksifeniO-A^^S-izohinoliniO-A^-CS-piridimidiOamin p) A^-(3-ciklopentiloksi-4-metoksifenil)-A^-(2-pirazinil)-A^-(3-piridilmetil)amin

q) A^-(3-ciklopentiloksi-4-metoksifenil)-A^-(2-piridil)-A^-(3-piridilmetil)arnin r) A^-(3-ciklopentiIoksi-4-metoksifenil)-A^-(3-piridil)-A^-(3-piridilmetil)arniri s) A<r->(3-ciklopentiloksi-4-metoksifenil)-A</->(4-piridil)-A<?->(3-piridilmetil)arnin t)terc- but\\^-(S-ciklopentiloksi^-rnetoksifeniO-T/^-piridilmeti^-ć-aminonikotinat

u) A<f->(3-ciklopropilmetoksi-4-metoksifeniI)-A<r->(3-piridil)-A^-(3-piridilmetil)arnin v) A<r->(4-metoksi-3-(3/?)-tetrahidrofuriloksifenil)-A</->(3-piridil)-A<r->(3-piridilmetil)amin

w) A<r->(3-ciklopentiloksi-4-difluorometoksifenil)-A^-(3-piridil)-7V-(3-piridilmetil)amin

x) A^-(3-ciklopropilmetoksi-4-difluorometoksifenil)-A/-(3-piridil)-A<?->(3-piridilmetil)amin

y) A<f->(4-difluorometoksi-3-(3/?)-tetrahidrofuriloksifenil)-^-(3-piridiI)-A<f->(3-piridilmetil)amir)

z) 7V-(4-hloro-3-piridilmetil)-A<r->(3-ciklopentiloksi-4-rnetoksifenil)-A<f->(2-piridil)amin

aa) A^-(3-ciklopentiloksi-4-metoksifenil)-A^-(4-metil-3-piridilmetil)-A<r->(2-piridil)amin

bb) 3-ciklopentiloksi-4-rnetoksi-A^-(2-tiazolilmetil)difenilamin

cc) iV-(2-hloro-3-piridilmetil)-3-ciklopentiloksi-4-metoksidifenilamin dd) A<f->(6-hloro-3-piridilmetil)-3-ciklopentiloksi-4-metoksidifenilamin

PRIMER 9 (postupak B)

A^-4-hIoro-3-piridilmetil)-Ar-(3-ciWopentil-4-metoksifenil)-Ar-(2-piridil)amin

U rastvor (3-ciklopentiloksi-4-metoksifenil)-2-piridilamina (30 mg, 0,10 mmol) i 4-hloropikolil hlorid hidrohlorida (50 mg, 0,25 mmol) rastvoreno u DMF (1 ml) dodavanje u malim količinama natrijum hidrid (50 mg 60% -ne disperzije u mineralnom ulju, 1,3 mmol). Posle mešanja tokom 1 sata na sobnoj temperaturi, smeša je usuta u 25 ml ledene vode. Smeša je ekstrahovana sa EtOAc (2x15 ml) i EtOAc ekstrakti su spojeni, isprani slanim rastvorom (15 ml), osušeni (MgS04) i koncentrisaniin vacuo.Sirovi ostatak je prebačen u RediSep kolonu (4,2 g, slika gel) i proizvod je eluiran sa 15% EtOAc u heksanu radi dobijanja proizvoda kao žute kristalne čvrste supstance. 'H NMR (CDC13) 5 8,61 (s, IH), 8,34 (d, IH, J = 5,3 Hz), 8,17 (d, IH, J = 5,0 Hz), 7,33 (m, IH), 7,25 (m, IH), 6,83 (d, IH, J = 8,5), 6,75 (d, IH, J = 8,5), 6,71 (s, IH), 6,62 (m, IH), 6,42 (d, IH, J = 8,6), 5,31 (s, 2H), 4,63 (p, IH, J = 4,12 Hz), 3,83 (s,3H), 1,86-1,70 (m,6H), 1,65-1,45 (m, 2H).

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) 3,4-bis(diflorometoksi)-A^-(4-hloro-3-piridilmetil)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)difenilamin b) 3,4-bis(difluorometoksi)-//-(4-metil-3-piridilmetil)-3'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)difenilamin

PRIMER10

S-ciklopentiloksM-metoksianilino-A^^S-piridilmetiO-N-S^-piridilJbenzarnid

U rastvor Af-(3-ciklopentiloksi-4-metoksifenil)-Af-(3-piridilmetil)-3-aminobenzoeve kiseline (20 mg, 0,05 mmol) i pyBOP (40 mg, 0,08 mmol) u CH2CI2(2 ml) na sobnoj temperature je dodat diizopropiletilamin (20 ml, 0,11 mmol). Posle mešanja tokom 15 minuta, dodat je 4-aminopiridin (15 mg, 0,15 mmol) i smeša je mešana još 16 h. Smeša je razblažena sa EtOAc (25 ml) i isprana vodom (2x15 ml) i slanim rastvorom (15 ml),osušena(MgS04) i koncentrisanain vacuo.Sirovi ostatak je prebačen u RediSep kolonu (4,2 g, silikagel) i proizvod je eluiran sa linearnim gradijentom od 40% EtOAc u heksanu do 60% EtOAc u heksanu tokom 22 minuta radi dobijanja 22 mg proizvoda.'HNMR(CDC13) 8 8,70-8,40 (m, IH), 8,24 (s,IH), 7,72 (d, IH, 9,0 Hz), 7,68-7,55 (m, 2H), 7,30-7,20 (m, IH), 6,88 (d, 2H, J = 8,5), 6,80-6,65 (m, 3H), 4,98 (s, 2H), 4,66 (p, IH, J = 4,1 Hz), 3,86 (s, 3H), 1,86-1,70 (m, 6H), 1,65-1,45 (m, 2H).

Sledeća jedinjenja su dobijana na sličan način kao što je gore opisano:

a) 3-(3-ciklopentiloksi-4-metoksianilino)-//-(3-piridilmetil)-A<r->3-[3-(A^,A<f->dimetilamino)prop-l -iljbenzamid b) S-ciklopentiloksM-metoksi-S'^-metilpiperazin-l-ilkarbonil)-^^-piridilmetil)difenilamin c) 3-ciklopentiloksi-4-difluorometoksi-4'-(4-metilpiperazin-l-ilkarbonil)-A^-(3-piridilmetil)difenilamin d) 3-ciklopentiloksi-4-metoksi-4'-(4-metilpiperazin-l-ilkarbonil)-A<r->(3-piridilmetil)-3-(3-tetrahidrofuraniloksi)-difenilamin

PRIMER 11

Sledeća jedinjenja su dobijena na sličan način kao što je opisano u primeru 2:

a) 4'-amino-3-cikIopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin

b) 3'-amino-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin

c) 3'-amino-3-ciklopropilmetoksi-4-metoksi-A'-(3-piridilmetil)difenilamin

d) 3'-amino-4-metoksi-A</->(3-piridiImetil)-3-[(3R)-tetrahidrofuriloksi]difenilamin

PRIMER 12

3-ciklopentiIoksi-4'-metansulfonilaniino-4-metoksi-A^-(3-piridiIrnetil)-difeniIamin

U rastvor 4'-amino-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamina

(47 mg, 0,12 mmol) u CH2CI2(2 ml) na sobnoj temperature je dodat piridin (20

mikrolitara, 0,24 mmol) a zatim metan sulfonil hlorid (15 mikrolitara, 0,18 mmol) i smeša je ostavljena na sobnoj temperaturi tokom 16 h. Smeša je razblažena etrom (50

ml) i isprana sa vodom (25 ml) i slanim rastvorom (25 ml), osušena (MgSC>4) i koncentrisana. Sirovi ostatak je prečišćen fleš hromatografijom u koloni (4,2 g RediSep kolona, silika gel), eluiran sa linearnim gradijentom od 45% EtOAc u heksanu do 60%

EtOAc u heksanu tokom 20 minuta radi dobijanja 41 mg proizvoda.<*>H NMR (CDCI3) 5 ' 8,51 (s, IH), 8,41 (d, IH, J = 4,8 Hz), 7,56 (d, IH, 7,9 Hz), 7,16 (m, IH), 6,98 (d, 2H,

J = 9,0 Hz), 6,80-6,60 (m, 6H), 4,82 (s, 2H), 4,56 (p, IH, J = 4,0 Hz), 3,75 (s, 3H),

1,86-1,70 (m, 6H), 1,65-1,45 (m, 2H).

Sledeća jedinjenja su dobijena na sličan način kao što je gore opisano :

a) 3-ciklopentiloksi-3'-etansulfonilamino-4-metoksi-A^-(3-piridilmetil)difenilamin

b) 3-ciklopentiloksi-4-metoksi-3'-(l-propansulfonilarnino)-A^-(3-piridilmetil)difenilamin c) 3'-(I-butansuIfoniIamino)-3-cikloperitiIoksi-4-rnetoksi-Ar-(3-piridilmetil)difenilamin d) 3'-benziIsulfonilamino-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)difenilamin

e) S'-acetamido-S-ciklopentiloksi^-metoksi-A^^S-piridilmetiOdifenilarnin

f) 3-ciklopentiloksi-4'-etansulfonilamino-4-metoksi-A^-(3-piridilmetil)difenilamin g) 3-ciklopentiloksi-4-rnetoksi-4'-(l-propansulfonilarnino)-Ar-(3-piridilmetil)difenilamin h) S-ciklopropilmetoksi-S'-etansulfonilarnino^-metoksi-A^-CS-piridilmetil)difenilamin

i) 4-difluorometoksi-3'-etansulfonilamino-Af-(3-pindilmetil)-3-[(3R)-tetrahidrofuriloksi]difenilamin

PRIMER 13

3-ciklopentiloksi-4-metoksi-3'-hidroksimetil-AL(3-piridilmetil)difenilaniin

U rastvor etil A<f->(3-ciklopentiloksi-4-metoksifenil)-iV-(3-piridilmetil)-3-aminobenzoat (50 mg, 0,11 mmol) u THF na 0°C dodato je ukapljavanjem, uz mešanje, 2,5 M diizobutilaluminum hidrida u toluenu (0,4 ml, 1,00 mmol). Smeša je mešana na 0°C tokom 1 h i višak diizobutilaluminum hidrida je ugašen dodavanjem smeši 5 kapi EtOAc. Smeša je koncentrisana i ostatak je raspodeljen između CH2CI2(50 ml) i vode (50 ml). Slojevi su odvojeni i vodeni sloj je ekstrahovan sa CH2CI2(2x10 ml). Organski ekstrakti su spojeni i isprani sa slanim rastvorom (50 ml), osušeni (MgSO<t) i koncentrisani. Sirovi ostatak je prečišćen fleš kolonskom hromatografijom (4,2 g RediSep kolona, silika gel) eluiran sa 300 ml 50% EtOAc u heksanu onda 100% EtOAc radi dobijanja 15 mg proizvoda.<*>H NMR (CDC13) 8 8,51 (s, IH), 8,40 (š, IH), 7,58 (d, IH, 7,9 Hz), 7,25-7,05 (m, 3H), 6,80-6,60 (m, 5H), 4,85 (s, 2H), 4,56 (p, IH, J = 4,1 Hz), 4,50 (s,2H), 3,76 (s,3H), 1,86-1,70 (m, 7H), 1,65-1,45 (m, 2H).

Sledeća jedinjenja su dobijena na sličan način kao stoje gore opisano :

a) 3-ciklopentiloksi-4-metoksi-4'-hidroksimetil-A<f->(3-piridilmetil)difenilamin

PRIMER 14

S-ciklopentiloksi^-metoksi-A'^-piridilrnetil^'^lH-tetrazol-S-iOdifenilarnin

U rastvor Ar-(3-ciklopentiloksi-4-metoksifenil)-Ar-(3-piridilmetil)-3-aminobenzonitrila (100 mg, 0,25 mmol) u DMF (3 ml) je dodat NaN3(163 mg, 2,5 mmol) i NH4CI (135 mg, 2,5 mmol) i smeša je mešana na temperaturi od 120°C tokom 6h. Smeša je ohlađena na sobnu temperaturu, razblažena sa vodom (50 ml) i ekstrahovana sa EtOAc (2x25 ml). EtOAc ekstrakti su spojeni, isprani sa vodom (25 ml) i slanim rastvorom (25 ml), osušeni (MgS04) i koncentrisaniin vacuo.Ostatak je prebačen u RediSep kolonu (4,2 g, silika gel) i eluirani sa linearnim gradijentom od 50% do 75% EtOAc u heksanu radi dobijanja 12 mg proizvoda. 'H NMR (CDC13) 5 12,50 (š, IH), 8,64 (s, IH), 8,54 (š, IH), 7,86 (d, 2H, J = 8,8 Hz), 7,75 (d, IH, 7,8 Hz), 7,36 (m, IH), 6,80-6,60 (m, 5H), 4,99 (p, IH, J = 4,1 Hz), 3,84 (s, 3H), 1,86-1,70 (m, 7H), 1,65-1,45 (m, 2H).

PRIMER 15

3-ciklopentiIoksi-4-metoksi-4'-(4-metiI-l-piperazinilmetil)-A<r->(3-piridilmetil)difenilamin

U rastvor 3-ciklopentiloksi-4-metoksi-4'-(4-metilpiperazin-l-ilkarboniljdifenilamina (100 mg, 0,20 mmol) u THF (5 ml) je pažljivo dodat litijum aluminijum hidrid (50 mg, 1,3 mmol). Smeša je mešana tokom 15 minuta i nekoliko kapi EtOAc je pažljivo dodato radi gašenja viška hidrida. Dodati su voda (50 ml) i CH2CI2(50 ml) i smeše su filtrirane kroz celit. CH2CI2sloj je odvojen, ispran slanim rastvorom (25 ml), osušen (MgSO^ i koncentrisanin vacuo.Sirovi ostatak je prečišćen ISCO RediSep kolonom (4,2 g, silicijum dioksid), eluiran sa gradijentom od 5% MeOH u EtOAc do 15% MeOHu EtOAc radi dobijanja 60 mg proizvoda kao blago žutog ulja.

'H NMR (CDCb) 5 8,59 (s, IH), 8,47 (d, IH, J = 4,8 Hz), 7,65 (d, IH, 7,9 Hz), 7,21

(dd, IH, J = 4,8 Hz, 7,9 Hz), 7,11 (d, 2H, J = 8,6 Hz), 6,82-6,73 (m, 3H), 6,70-6,65 (m, 2H), 4,91 (s, 2H), 4,62 (p, IH, J = 4,12 Hz), 3,82 (s, 3H), 3,41 (s, 2H), 2,75-2,20 (m, 8H), 2,27 (s,3H), 1,86-1,70 (m, 6H), 1,65-1,45 (m, 2H).

Sledeća jedinjenja su dobijena na sličan način kao što je gore opisano :

a) S-ciklopentiloksi^-metoksi-S'^-metil-l-piperazinilmetil)^^-piridilmetil)difenilamin

PRIMER 16

S'-aminometil-S-ciklopentiloksM-metoksi-A^^S-piridilmeti^difenilamin

U rastvor A^-(3-ciklopentiloksi-4-metoksifenil)-7^-(3-piridilmetil)-3-aminobenzonitrila (50 mg, 0,12 mmol) u THF (5 ml) je pažljivo dodat litijum aluminijum hidrid (20 mg, 0,52 mmol). Smeša je mešana tokom 4 h i nekoliko kapi vode je pažljivo dodato radi gašenja viška hidrida. Dodati su voda (50 ml) i CH2CI2(50 ml) i smeše su filtrirane kroz celit. CH2CI2sloj je odvojen, ispran slanim rastvorom (25 ml), osušen (MgSOi) i koncentrisanin vacuo.Sirovi ostatak je prečišćen ISCO RediSep kolonom (4,2 g, silicijum dioksid), eluiran sa 10% MeOH u EtOAc radi dobijanja 20 mg proizvoda.<]>H NMR (CDC13) 5 8,60(s, IH), 8,47 (š, IH), 7,65 (d, IH, 7,8 Hz), 7,26-7,10 (m, 2H), 6,90-6,54 (m, 6H), 4,94 (s, 2H), 4,63 (p, IH, J = 4,1 Hz), 3,83 (s, 3H), 3,75 (m, 2H), 2,29 (š, 2H), 1,86-1,70 (m, 6H), 1,65-1,45 (m, 2H).

PRIMER 17

3-hidroksi-4-metoksi-A^-(3-piridilmetil)difenilamin

U rastvor 3-(/erc-butildimetilsiloksi)-A?-(3-piridilmetil)-4-metoksidifenilamina (1,20 g, 2,85 mmol.) u THF (40 ml) na 0°C, dodat je 1,0M tetrabutilamonijum fluorid u THF (10 ml, 10 mmol.). Smeša je mešana na temperaturi od 0°C, tokom 30 min. Dodata je voda (50 ml) i smeša se ekstrahuje sa etrom (3 x 25 ml). Etarski ekstrakti se spoje i isperu sa vodom (3 x 25 ml) i slanim rastvorom (25 ml), osuše (MgSC>4) i koncentrujuin vacuo.Ostatak se trituriše sa heksanom i sakupi vakum filtrovanjem, pa se dobija 0,85 g proizvoda.<!>H NMR (CDCI3) 5 8,58 (s, IH), 8,46 (Š.,1H) 7,67 (d, IH, 7,8 Hz), 7,26-7,10 (m, 3H), 6,90-6,65 (m, 5H), 6,64 (dd, IH, J =8,6 Hz, 2,6 Hz), 6,53 (Š,1H), 4,92 (s, 2H), 3,86 (s, 3H).

Sledeća jedinjenja su dobijena na sličan način kao stoje opisano gore:

a) 3' -hloro-3-hidroksi-4-metoksi-AA-(3-piridilmetil)difenilamin

b) etil Ar-(3-hidroksi-4-metoksifenil)-A/-(3-piridilmetil)-3-aminobenzoat

PRIMER 18 (postupak B)

Sledeća jedinjenja su dobijena na sličan način kao što je opisano u primeru 1B:

a) 3-[3-(4-hlorofenil)prop-l-iloksi]-4-metoksi-7V-(3-piridilmetil)difenilamin

b) 3-[2-(4-hlorofenil)etoksi]-4-metoksi-A?-(3-piridilmetil)difenilamin

c) 4-metoksi-3-(4-fenoksibut-l-il)oksi-Ar-(3-piridilmetil)difenilamin

d) 4-metoksi-A<l>-(3-iridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin

e) 4-metoksi-3-[3-(4-metoksifenil)prop-l-il]oksi-A^-(3-piridilmetil)difenilamin

f) 4-metoksi-3-[3-(4-piridil)prop-l-il]oksi-A/-(3-piridilmetil)difenilamin

g) 4-metoksi-3-[2-(4-metoksifenil)etoksi]-AA-(3-piridilmetil)difenilamin

h) 4-metoksi-3-[4-fenilbut-l-il)oksi-A<r->(3-piridilmetil)difenilamin

i) 4-metoksi-3-[4-(4-metoksifenil)but-l-il]oksi-A<f->(3-piridilmetil)difenilamin

j) 4-metoksi-3-[4-(4-nitrofenil)but-l-il]oksi-A/-(3-piridilmetil)difenilamin k) 4-metoksi-3-[2-(2-piridil)etoksi]-A<r->(3-piridilmetil)difenilamin

1) 4-metoksi-3-[2-(4-piridil)etoksi]-A</->(3-piridilmetil)difenilamin m) 4-metoksi-3-[3-(2-piridil)prop-l-il]oksi-A/-(3-piridilmetil)difenilamin n) 4-metoksi-3-(2-metoksietoksi)-//-(3-piridilmetil)difenilamin o) 3-ciklopropilmetoksi-4-metoksi-A/-(3-piridilmetil)difenilamin p) 4-metoksi-3-(l-metilpirolidin-3-il)oksi-Af-(3-piridilmetil)difenilamin q) 4-metoksi-3-(l-metilpiperidin-4-il)oksi-A^-(3-piridilmetil)difenilamin r) 4-metoksi-A^-(3-piridilmetil)-3-[(3S)4etrahidrofuriloksi]difenilamin s) 4-metoksi-AA-(3-piridilmetil)-3-[(37?)-tetrahidromriloksi]difenilamin t) S'-hloro^-metoksi-S-p^I-piridi^etoksij-^-CS-piridilmeti^difenilamin u) 3,-hloro-4-metoksi-3-[2-(4-piridil)etoksi]-A/-(3-piridilmetil)difenilamin v) 3'-hloro-4-metoksi-3-(2-metoksietoksi)-A^-(3-piridilmetil)difenilarnin w) 3'-hloro-4-metoksi-A<L>(3-piridilmetil)-3-[(3i?)-tctrahidrofuriloksi]difenilamin x) 3 -cikloheksiloksi-4-metoksi-A/-(3 -piridilmetil)difenilamin y) 3-cikloheptiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin z) 3-(2-ciklopropiletoksi)-4-metoksi-A^-(3-piridilmetn)difenilamin aa) 3-ciklopentilmetoksi-4-metoksi-A</->(3-piridilrnetil)difenilamin bb) etil A^-[3-(4-hlorofenil)prop-l-iloksi-4-metoksifenil]-A^-(3-piridilmetil)-3-aminobenzoat

cc) etil Ar-(3-ciklopropilmetoksi-4-metoksifenil)-A^-(3-piridilmetil)-3-aminobenzoat dd) etil A^-(3-ciklopropilmetoksi-4-difluorometoksifenil)-7V-(3-piridilmetil)-3-aminobenzoat

ee) etilN-[3-(2-indaniloksi)-4-metoksifenil]-jV-(3-piridilmetil)-3-aminobenzoatff) etilA^-[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A/-(3-piridilmetil)-3-aminobenzoat

gg) etil A^-[4-metoksi-3-((3/?)-tetrahidroffiiriloksi)fenil]-(3-piridilmetil)-3-aminobenzoat

hh) etil A^-[3[(2-metoksietoksi)-4-metoksifenil]-A^-(3-piridilmetil)-3-aminobenzoat ii) etil Af-[4-metoksi-3-(2-(2-piridil)etil)oksifenil]-A^-(3-piridilmetil)-3-aminobenzoat

PRIMER 18 (Postupak C)

Sledeća jedinjenja su dobijena na sličan način kao stoje opisano u primeru 8 A kuplovanjem fenola sa bornom kiselinom radije nego kuplovanje anilina sa bornom kikselinom:

a) 4-metoksi-3-(4-metoksifenoksi)-A^-(3-piridilmetil)difenilamin

b) 4-metoksi-3-fenoksi-A<r->(3-piridilmetil)difenilamin

c) 4-metoksi-3-(4-metilfenoksi)-A<L>(3-piridilmetil)difenilamin

d) 3-(4-hlorofenoksi)-4-metoksi-A^-(3-piridilmetil)difenilamin

e) 3-[2-(4-hlorofenil)eteniloksi]-4-metoksi-A<f->(3-piridilmetil)difenilamin

PRIMER 19

Sledeća jedinjenja su dobijena na sličan naćin kao stoje opisano u primeru 17:

a) 3-ciklopentiloksi-3'-hidroksi-4-metoksi-A<r->(piridilmetil)difenilamin

b) 3-ciklopentiloksi)-4'-hidroksi-4-metoksi-Ar-(3-piridilmetil)difenilamin

c) 3-ciklopropilmetoksi-4,-hidroksi-4-metoksi-A<r->(3-piridilmetil)difenilamin

PRIMER 20 (Postupak A)

Sledeće jedinjenje je dobijeno na sličan način kao što je opisano u primeru IA:

a) 3,-(2-bromoetoksi)-3-cikIopentiloksi-4-metoksi-A<A->(3-piridilmetil)difenilamin

PRIMER 20 (Postupak B)

a) 3-ciklopentiloksi-4'-(2-metoksietoksi)-4-metoksi-Af-(3-piridilmetil)difenilamin b) S-ciklopentiloksi^'^S-metil-l-butoksi^-metoksi-A^^-piridilmetiOdifenilamin c) 3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)-4,-[(35)-tetrahidrofuraniloksijdifenilamin d) 3-ciklopentiloksi-4-metoksi-N-(3-piridilmetil)-4>-[(3^?)-tetrahidrofuraniloksijdifenilamin e) S-ciklopentiloksi-^-ciklopropilmeto f) 4<>->cikloheksiletoksi-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)difenilamin g) 4,-ciklopentiletoksi-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin h) 3-ciklopentiloksi-4-metoksi-4,-(l-metilpiperidin-4-iloksi)-Af-(3-piridilmetil)difenilamin

i) 3-ciklopentiloksi-4-metoksi-4'-(l-metilpirolidin-3-iloksi)-A/-(3-piridilmetil)difenilamin

j) 3-ciklopentiloksi-4-metoksi-4,-[2-(l-rnetilpirolidin-2-il)etoksi]-Ar-(3-piridilmetil)difenilamin

k) 3-cikIopentiloksi-4-metoksi-4,[-(l-piroIidiniIetoksi)-iV-(3-piridilmetil)difenilamin

1) 3-ciklopentiloksi-4-metoksi-4,-[2-(6-rnetilpiridil)rnetoksi)-Af-(3-piridilmetil)difenilamin

m) 3-ciklopentiloksi-4-metoksi-4'-[3-(l-rnetilpiperidinil)rnetoksi]-A/-(3-piridilmetil)difenilamin

n) 3-cik!opentiloksi-4-metoksi-4,-[2-(l-rnetiIpiperidinil)rnetoksi]-Af-(3-piridilmetil)difenilamin

o) 3-ciklopentiloksi-4-metoksi-4,-[2-(5oksopirolidinil)metoksi]-A</->(3-piridilmetil)difenilamin

P) 4,-[r(3-brornopropiI)oksi]-3-cikIopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin

q) 3-ciklopentiloksi-4-rnetoksi-4,-[2-(Ar-ftalirnido)etoksi]-A^-(3-piridilmetil)difenilamin

PRIMER 21

3-Ciklopcntiloksi-4-rnetoksi-3'-[2-(l-piperidinl)etoksi]-A<L>(piridilmetiI)-difenilamin

U rastvor 3'-(2-bromoetoksi)-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)dimetilamina (17 mg, 0,03 mmol.) u acetonitrilu (1L) doda se kalijum karbonat (25 mg, 0,18 mmol.) i piperidin (5 L, 0,05 mmol.) i smeša na 60 C u toku 4 h. Smeša se raspodeli izmedju vode (50 ml) i EtOAc (50 ml). Slojevi se odvoje i organski sloj se ispere sa vodom (25 ml) i slanim rastvorom (25 ml), osuši (MgSO ), i koncentruje u vakumu. Ostatak se nanese na ISCO RediSep kolonu (4,2 g, silikagela) i kolona eluira sa linearnim gradijentom od 5% MeOH u EtOAc do 15% MeOH u EtOAc, pa se dobija 11 mg proizvoda<]>H NMR (CDC13) 8,59 (s,lH) 8,48 (d,lH,J =4,7), 7,64 (d,lH, 8,2Hz), 7,26-7,20 (m,lH), 7,06 (t,lH,J = 8,6Hz), 6,81 (d,lH, J =9,2Hz), 6,75-6,68 (m,2H), 6,45-6,35 (m,3H), 4,91 (s,2H), 4,64 (p,lH, J = 4,1Hz), 4,00 (t,2H, J = 6,2Hz), 3,84 (s,3H), 2,71 (t,2H, J = 6,2Hz), 2,47 (m,4H), 1,90-1,70 (m,6H), 1,81-1,70 (m,6H), 1,65-1,45 (m,2H).

Sledeća jedinjenja su dobijena na sličan način kao što je opisano gore:

a) 3-ciklopentiloksi-3'-[2-(l-imidazolil)etoksi]-4-metoksi-<y>V-(3-piridilmetil)difenilamin b) 3-ciklopentiloksi-4-metoksi-3'-[2-(l-metilpiperazin-4-il)etoksi]-A<r->(3-piridilmetil)difeniamin c) 3-ciklopentiloksi-4-metoksi-4'-[3-(2-metilpiperazin-4-il)propokssi]-A<f->(3-piridilmetil)difenilamin d) 3-cikloopentiloksi-4-metoksi-4'-[3-(l-metilpiperazin-4-il)propoksi]-7^-(3-piridilmetil)difenilamin e) S-ciklopentiloksi^-metoksi^'-fS^-morfolin^-iletilaminoJpropoksij-^S-piridilmetil)difenilamin

f) 4-metoksi-3-(2-fenoksietoksi)-A<L>(3-piridlmetil)difenilamin

g) 3-[2-(4-hlorofenoksi)etoksi)-4-metoksi-A<f->(3-piridilmetil)difenilamin

h) 4-metoksi-3-(2-pirolidin-l-il)etoksi-A^-(3-piridilmetil)difenilamin i) 4-metoksi-3-(2-(4-metilpiperazin-l-il)etoksi)-A<?->(3-piridilmetil)difenilamin

j) 3-[2-(4-hlorofenilamino)etoksi]-4-metoksi-A^-(3-piridilmetil)difenilami

PRIMER 22

4'-aminoetoksi-3-ciklopentiloksi-4-metoksi-7V-(3-piridilmetil)difenilarnin

U rastvor Ar-(3-piridilmetil)-3'-[2-(2-tfalimido)etoksi]-3-ciklopentiloksi-4-metoksidifenilamina (o,39 g, 0,69 mmol.) u MeOH (5 ml) doda se hidrazin hidrat (1.0 ml, 20 mmol.). Posle 6 sati na sobnoj temperaturi, EtOAc se doda (50 ml) i talog se odvoji filtrovanjem. Filtrat se ispere sa vodom (25 ml) i slanim rastvorom (25 ml), osuši (MgS04), i koncentruje u vakumu. Ostatak se nanese na ISCO RediSep kolonu (10 g,silika gela). Kolona se ispere sa 10%-nim MeOH u EtOAc (200 ml) i proizvod se eluira sa 50%-nim MeOH u EtOAc, pa se dobija 0,21 g.<*>H NMR (CDCI3) 8,55 (s,lH), 8,42 (d,lH, J = 3,8 Hz), 7,62 (d,lH, 7,7 Hz), 7,20-7,10 (m,lH), 6,91 (d,2H, J = 9,0 Hz), 6,78 (d, 2H, J = 9,0 Hz), 6,70 (d,lH, J = 8,6 Hz), 6,50-6,35 (m,2H), 4,82 (s,2H), 4,54 (p,lH, J = 4,1 Hz), 3,90 (t,2H, J = 6,1 Hz), 3,74 (s,3H), 3,01 (m,2H),

PRIMER 23

Sledeća jedinjenja su dobijena na sličan način kao što je opisano u primeru 12:

a) 3-ciklopentiloksi-4'-(2-metansulfonilamino)etoksi-4-metoksi-A</->(3-piridilmetil)difenilamin b) 3'ciklopentiloksi-4'-(2-etansulfonilamino)etoksi-4-metoksi-A<7->(3-piridilmetil)difenilamin c)3-ciklopentiloksi-4-metoksi-4'-[2-(2-propansulfonilamino)etoksi]- N-( 3-piridilmetil)difenilamin d) 3-ciklopentiloksi-4-metoksi-4'-[2-(l-propansulfonilamino)etoksi]-A<f->(3-piridilmetil)difenilamin e) 4'-[2-(l-butansulfonilamino)etoksi]-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)difenilamin

PRIMER 24

In vitromerenje aktivnosti inhibicije fosfodiesteraze tip 4

Humana PDE 4 je dobijena iz Sf9 ćelija zaraženih bakulovirusom koje izražavaju rekombinovan enzim. CDNK koja kodira hPDE-4D6 je subklonirana u vektor bakulovirusa. Ćelije insekta (Sf9) su zaražene bakulovirusom i ćelije su kultivisane sve dok se protein nije izrazio. Ćelije zaražene bakulovirusom su lizirane i lizat je upotrebljen kao izvor hODE-4D6 enzima. Enzim je delimično prečišćen upotrebom DEAE jon izmenjivačke hromatografije. Ovaj postupak se može ponavljati upotrebom cDNK koja kodira druge PDE-4 enzime.

Ogled:

Fosfodiesteraze tipa 4 konvertuju ciklični adenozin monofosfat (cAMP) u 5'-adenozin monofosfat (5'-AMP). Nukleotidaza konvertuje 5'-AMP u adenozin. Stoga kombinovana aktivnost PDE 4 i nukleotidaze konvertuje cAMP u adenozin. Adenozin se lako izdvaja od cAMP pomoću neutralnih kolona sa aluminom. Inhibitori fosfodiesteraze blokiraju pretvaranje cAMP u adenozin u ovom ogledu; kao posledica, inhibitori PDE 4 dovode do smanjivanja adenozina.

Ćelijski lizati (40 ul) koji izražavaju hPDE-4D6 su kombinovani sa 50 u.1 mešavine iz ogleda i sa 10 ul inhibitora i inkubirane tokom 12 minuta na sobnoj temperaturi. Finalne koncentracije komponenata iz ogleda su: 0,4 ug, 10 mM Tris-HCl (pH 7,5), 10 mM MgCl2, 3 uM cAMP, 0,002 U 5'-nukleotidaze, i 3 x IO<4>cpm [3H]camp. Reakcija je zaustavljena dodavanjem 100 ul ključajuće 5mN HC1. Alikvot

od 75 ul reakcione smeše prebačen iz svakog udubljenja u kolone sa aluminom (Multiplate; Millipore). Označeni adenozin je eluiran u OptiPlate centrifugiranjem tokom 2 minuta; i u OptiPlate je dodato 150 ul scintilacionog fluida po udubljenju. Ploča je zadihtovana, mućkana tokom oko 30 minuta, i cpm [<3>H] adenozina je određena upotrebom Wallac Triflux®.

Sva test jedinjenja su rastvorena u 100%-om DMSO i u ogledu razblažena tako daje finalna koncentracija DMSO 0,1%. DMSO ne utiče na aktivnost enzima pri ovoj koncentraciji.

Smanjenje koncentracije adenozina je indikacija aktivnosti inhibicije PDE. pICsovrcdnosti su određene merenjem 6 do 12 koncentracija jedinjenja koje su u rasponu od 0,1 nM do 10 000 nM i crtanjem koncentracija leka prema koncentraciji<3>H-adenozina. Nelinearni regresivni program (Assay Explorer® je korišćen za utvrđivanje vrednosti pIC50.

PRIMER 25 (Postupak A)

Pasivno izbegavanje kod pacova, test učenja i memorije

Test je izveden kao što je ranije opisano (Zhang, H.-T, Crissman, A.M,

Dorairaj, N.R, Chandler, L.J, i O'Donnell, J.M,Neuropsychopharmacology,2000, 23, 198-204.). Aparat (model E10-16SC, Coulbourn Instruments, Allentovvn, PA) se satoji od komore sa dva odeljka pri čemu je osvetljeni odeljak povezan sa mračnim odeljkom padajućim vratima. Pod mračnog odeljka je napravljen od šipki od nerđajućeg čelika kroz koje može da se propusti električni šok u šape iz izvora jednosmerne struje. Sve eksperimentalne grupe su prvo naviknute na aparat dan pre početka eksperimenta. Tokom ispitivanja, pacov (mužjak Spraque-Dawley (Harlan) težine 250 do 350 g) je stavljen u osvetljeni odeljak tako da gleda suprotno od padajućih vrata tokom jednog minuta pre nego što su vrata podignuta. Vreme oklevanja ulaska u mračni odeljak je zabeleženo. Pošto je pacov ušao u mračni odeljak, vrata su zatvorena i električni šok od 0;5 mA je dat u trajanju od 3 sekunde. Dvadest četiri časa kasnije, pacovu ja dato mg/kg MK-801 ili slanog rastvora, 30 minuta pre ubrizgavanja slanog rastvora ili test jedinjenja ( u dozama od 0,1 do 2,5 mg/kg, i.p.) stoje urađeno 30 minuta pre početka retencionog testa. Pacov je ponovo stavljen u osvetljeni odeljak sa otvorenim padajućim vratima. Skklonost ulaska u mračni odeljak je beležena do 180 sekundi kada je proba završena.

Svi podaci su analizirani analizom varijacija (ANOVA); a individualna upoređivanja su izvršena primenom Kewman-Keuls-ovih testova. Neiskusnim pacovima je, u prošeku, trebalo manje od 30 sekundi da pređu iz osvetljenog odeljka u mračni odeljak. Međutim, 24 sata posle izlaganja elektičnom šoku, većina pacova prethodno tretiranih nosačem nije ponovila ulazak u mračni odeljak; prosečno oklevanje se povećalo do 175 sekundi (p < 0,001). Prethodno tretiranje sa MK-801 (0,1 mg/kg) značajno smanjuje ovo oklevanje kada se poredi sa nosačen (p<0,001). Ovaj efekat amnezije MK-801 je obrnut na statistički značajan način aktuelnim test jedinjenjem na način koji je zavisan od doze (npr, [3H]difenilamin, opseg efikasnih doza = 0,5 do 2,5 mg/kg, i.p.; i A</->(3-ciklopentiloksi-4-metoksifenil)-A<f->(3-piridilmetil)-3-aminobenzoeva kiselina, opseg efikasnih doza = 0,1 do 2,5 mg/kg, i.p.)

PRIMER 25 (Postupak B)

zadatak sa radijalnim krakastim lavirintom,in vivotest učenja i memorije

Test je izvršen kao što je prethodno opisano (Zhang, H.-T, Crissman, A.M, Dorairaj, N.R, Chandler, L.J, i O'Donnell, J.M,Neuropsychopharmacology,2000, 23, 198-204.). Pet dana posle početnog smeštanja, pacovi (mužjaci Spraque-Dawley (Harlan) težine 250 do 350 g) su stavljeni u osmokraki radijalni lavirint (svaki krak je 60x10x12 cm visine; lavirint je podignut 70 cm iznad poda) radi privikavanja tokom dva dana. Pacovi su zatim postavljani individualno u centar lavirinta tokom 5 minuta sa peletama hrane postavljenim blizu udubljenja za hranu, a zatim, sledećeg dana pelete hrane su postavljane u udubljenja na krajevima krakova; dnevno su vršene dve sesije. Sledeće, u četiri nasumice odabrana kraka su postavljene po jedna peleta hrane kao mamac. Pacov je ograničen na centralnu platformu (26 cm u prečnik) tokom 15 sekundi a zatim pušten da se slobodno kreće po lavirintu sve dok ne pokupi sve pelete hrane ili ne prođe 10 minuta, šta god se pre dogodi. Beležena su 4 parametra: 1) greške radne memorije, npr, ulasci u krakove sa mamcima koji su već bili posećeni tokom iste probe;

2) greške referentne memorije, npr, ulasci u krakove bez mamca; 3) ukupni ulasci u krakove; i 4) trajanje testa (u sekundama) vreme potrošeno na skupljanje peleta u

lavirintu. Ako je greška radne memorije bila nula i prosečna greška referentne memorije manja od jedan u pet uspešnih pokušaja , ti pacovi su započinjali test sa lekom. MK-801 ili slani rastvor su injektirani 15 minuta pre testa sa nosačen ili lekom. koji su davani 45 minuta pre testa. Eksperimenti su vršeni u osvetljenom prostoru, koji je sadržao

nekoliko ekstra lavirintskih otvora za posmatranje.

Svi podaci su analizirani analizom varijacija (ANOVA); a individualna upoređivanja su izvršena primenom Kewman-Keuls-ovih testova. U poređenju sa kontrolom, MK-801 (0,1 mg/kg, i.p.) povećava učestanost grešaka i radne i referentne memorije (p<0,01). Ovaj efekat amnezije MK-801 na radnu memoriju je obrnut na statistički značajan način davanjem aktuelnog test jedinjenja na način koji je zavisan od doze (npr, 3-ciklopentiloksi-4-metoksi-A/-(3-piridilmetil)difenilamin, efikasne doze = 2,5 mg/kg, i.p.;p<0,01)

Prethodni primeri mogu da se ponove sa sličnim rezultatima zamenom generično ili specifično opisanog reaktanta i/ili radnih uslova iz ovog pronalaska umesto onih upotrebljenih u prethodnim primerima.

Iako je ovaj pronalazak ilustrovan ceneći proizvodnju i određenim jedinjenjima, očigledno je da se varijacije i modifikacije ovog pronalska mogu izvršiti bez udaljivanja od suštine i opsega ovog pronalaska.

Claims

1. Jedinjenje formule I naznačeno t i m e što je: R1 alkil grupa sa 1 do 4 atoma ugljenika, koja se račva ili ne račva i koja nije supstituisana ili je supstituisana jedan ili više puta halogenom; R<2>je alkil grupa sa 1 dol2 atoma ugljenika, koja se račva ili ne račva i koja je nesupstituisana ili supstituisana jedan ili više puta halogenom, hidroksi, cijano, Ci^-alkoksi, okso grupom ili njihovom kombinacijom, i u kome je, opciono, jedna ili više -CH2CH2- grupa zamenjena u svakom slučaju sa -CH=CH- ili -C=C-; je cikloalkil grupa sa 3 do 10 atoma ugljenika, koja nije supstituisana ili je supstituisana jedan ili više puta halogenom, hidroksi, okso, cijano grupom, alkil grupom koja ima 1 do 4 ugljenikova atoma, ili njihovom kombinacijom; je cikloalkilalkil grupa koja ima 4 do 16 ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta halogenom, okso, cijano, hidroksi, Ci^-alkil, C1-4-alkoksi grupom ili njihovom kombinacijom; je aril grupa koja ima 6 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom; je arilalkil grupa u kojoj arilni deo ima 6 do 14 ugljenikovih atoma i u kojoj alkilni deo koji se račva ili nc račva ima 1 do 5 ugljenikovih atoma, gde je arilalkil radikal ne supstituisan ili supstituisan u arilnom delu jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom, i gde je u alkilnom delu jedna ili više -H2CH2- grupa svaka opciono zamenjena sa -CH=CH- ili -CsC- ijedna ili više -CH2-grupa je svaka opciono zamenjena sa -O- ili -NH- i/ili je alkilni deo opciono zamenjen sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom; je delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, hidroksi, nitro, cijano, okso grupom ili njihovom kombinacijom; je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso grupom ili njihovom kombinacijom; je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimični zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, OCF3, hidroksi, aril, alkil,cijano, trifluorometil, nitro, okso grupom ili njihovom kombinacijom, gde su u alkilnom delu jedna ili više-CH2CH2-grupa svaka opciono zamenjena sa-CH=CH- ili -C=C-, ijedna ili više -CH2- grupa je svaka opciono zamenjena sa -O- ili -NH- i/ili alkilni deo je opciono zamenjena sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom; R<3>je H, alkil grupa koja ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, cijano, Ci^-alkoksi grupom, ili njihovom kombinacijom; je delimično nezasićena karbocikl-alkil grupa u kojoj karbociklični udeo ima 5 do 14 ugljenikovih atoma, i alkilni deo koji je račvast ili nije račvast ima 1 do 5 ugljenikovih atoma, i koja je ne supstituisana ili supstituisana u karbocikličnom delu jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, i gde je alkilni deo opciono supstituisan halogenom, Ci_4-alkoksi, cijano grupom, ili njihovom kombinacijom; je arilalkil grupa koja ima 7 do 19 ugljenikovih atoma, gde arilni deo ima 6 do 14 ugljenikovih atoma i alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom ili je heteroarilalkil grupa, u kojoj heteroarilni deo može biti delimično ili potpuno zasićen i ima prsten sa 5 do 10 atoma pri čemu je najmanje jedan atom prstena N, O ili S atom, alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, heteroarilalkilna grupa nije supstituisana ili je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF3O, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; R<4>je H, aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkenil, alkinil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, OCF3, amino, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazoI-5-il, 2(-heterocikl)tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi (npr,ferc-butildimetilsilioksi), R5-L-, grupom ili njihovom kombinacijom, ili je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom prstena heteroatom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, fenoksi, trialkilsililoksi grupom ili njihovom kombinacijom; R<5>jeH, je alkil grupa koji ima 1 do 8, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Ci-4-alkil, Ci-4-aIkoksi, okso grupom ili njihovom kombinacijom, je alkilamino ili dialkilamino grupa gde svaki alkilni deo ima nezavisno 1 do 8, je delimično nezasićena karbociklično-alkilna grupa u kojoj karbociklični deo ima 5 do 14 ugljenikovih atoma i alkilni deo ima 1 do 5 ugljenikovih atoma, koja je ne supstituisana ili supstituisana, poželjno u karbocikličnom delu, jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, je cikloalkil grupa koja ima 3 do 10, koja je nesupstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, okso, cijano, alkoksi grupom, alkil grupom sa 1 do 4 ugljenikova atoma ili njihovom kombinacijom, je cikloalkilalkil grupa koja ima 4 do 16, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta sa halogenom, okso, cijano, hidroksi, alkil, alkoksi grupom ili njihovom kombinacijom, je aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil grupom ili njihovom kombinacijom. je arilalkil grupa koja sadrži 7 do 19 ugljenikovih atoma, gde u arilnom delu ima 6 do 14 ugljenikovih atoma i alkilni deo koji se račva ili ne račva, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom, je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi, dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom ili njihovom kombinacijom ili je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimično zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo koji je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF3O, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; L je jednostruka veza ili dvovalentni alifatični radikal koji ima 1 do 8 ugljenikovih atoma gde je jedna ili više -CH2-grupa svaka opciono zamenjena sa -O-, -S-, -NR<6->, -S02NH-, -NHS02-, -CO-, -NR<6>CO-, - CONR<6->, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH-, ili - NHCSNH-; i R<6>je H ili alkil grupa koja ima 1 do 8 ugljenikovih atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Ci-4-alkil, Ci-4-alkoksi, okso grupom ili njihovom kombinacijom; pri čemu je najmanje jedan od R3 i R4 različiti od H; i njihove farmaceutski prihvatljive soli.

2. Jedinjenje prema u zahtevu 1, naznačeno time što R<4>nije H

3. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil ili CHF2; R2 je alkil, alkenil, alkinil, cikloalkil, arilalkil, heterocikl-alkil, cikloalkilalkil, aril ili heterociklična grupa u svakom od slučaja supstituisana ili nesupstituisana; R3 je H, alkil, arilalkil ili heteroarilalkil grupa u svakom od slučaja supstituisana ili nesupstituisana; i R4 je aril ili heteroaril grupa, u svakom od slučaja supstituisana ili nesupstituisana;

4. Jedinjenje kao u zahtevu 1, naznačeno timeštojeRje heteroarilalkil grupa supstituisana ili nesupstituisana.

5. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil ili CHF2, R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili (3i?)-tetrahidrofuranil.

6. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil ili CHF2grupa, R2 je ciklopentil grupa; R3 je heteroarilalkil grupa, u svakom od slučaja supstituisana ili nesupstituisana i R4 je , supstituisana ili nesupstituisana, aril ili heteroaril grupa.

7. Jedinjenje kao u zahtevu 1, naznačeno time što je R I metil grupa, R<2>je ciklopentil grupa; R3 je arilalkil ili heteroarilalkil grupa, u svakom od slučaja supstituisana ili nesupstituisana i R4 je , supstituisana ili nesupstituisana, aril grupa.

8. Jedinjenje kao u zahtevu 1, naznačeno time što je R 1 metil grupa, R<2>je ciklopentil grupa; R3 je heteroarilalkil grupa, koja je supstituisana ili nesupstituisana.

9. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil grupa, R<2>je ciklopentil grupa; R je heteroarilalkil grupa, koja je supstituisana ili nesupstituisana i R4 je fenil grupa koja je supstituisana ili nesupstituisana.

10. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil grupa, R<2>je ciklopentil grupa; R3 je piridilmetil, pirimidinilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil ili pirazinilmetil grupa, u svakom od slučaja supstituisana ili nesupstituisana, ili metil, etil ili propil grupa, i R4 je fenil ili fenil grupa supstituisana sa 1 do 3 supstituenta.

11. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil grupa, R<2>je ciklopentil grupa; R3 je piridilmetil, pirimidinilmetil, fenetil, benzil, tienilmetil, piridilpropil, piperidinilmetil ili pirazinilmetil grupa u svakom od slučaja supstituisana ili nesupstituisana, ili metil, etil ili propil grupa i R4 je fenil, naftil, bifenil, piridil, pirimidinil, tiazolil, pirazinil, hinolinil ili izohinolinil grupa, u svakom od slučaja supstituisana ili nesupstituisana.

12. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil ili CHF2grupa, R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa; R3 je H; i R4 je fenil, naftil, piridil, hinolinil ili izohinolinil grupa, u svakom od slučaja supstituisana ili nesupstituisana.

13. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil ili CHF2grupa; R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa; R3 je H; i R4 je fenil grupa koja je nesupstituisana ili supstituisana sa metil, etil, metoksi, Cl, F, CF3, vinil, cijano, amino, karboksi, hidroksimetil ili etilsulfonamido grupom ili je 3-piridil grupa koja je nesupstituisana ili je supstituisana sa karboksi ili alkoksikarbonil grupom.

14. Jedinjenje kao u zahtevu 1, naznačeno time što je R 1 metil grupa, R2 je ciklopentil grupa; R3 je H; i R4 je fenil, naftil, piridil, hinolinil ili izohinolinil grupa, u svakom od slučaja supstituisana ili nesupstituisana.

15. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil grupa, R<2>je ciklopentil grupa; R<3>jeH; i R<4>je fenil grupa koja je nesupstituisana ili supstituisana sa metil, etil, metoksi, Cl, F, CF3, vinil, cijano, amino, karboksi, hidroksimetil ili etilsulfonamido grupom, ili je 3-piridil grupa koja je nesupstituisana ili je supstituisana sa karboksi ili alkoksikarbonil grupom.

16. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil ili CHF2grupa; R je ciklopentil, CHF2, ciklopropilmetil, piridiletil, ili tetrahidrofuranil grupa; R3 je benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, piridilmetil, hinolinilmetil, izohinolinilmetil, tiazolilmetil ili pirolilmetil grupa,u svakom od slučaja supstituisana ili nesupstituisana.; i R4 je H.

17. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil ili CHF2grupa; R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa; R3 je pirazinilmetil, pirimidinilmetil ili piridilmetil grupa u svakom od slučaja supstituisana ili nesupstituisana.; R4 je H.

18. Jedinjenje kao u zahtevu 1, naznačeno t i m e što je R<1>metil grupa; R<2>je ciklopentil grupa; R3 je benzil, fenetil, cikloheksenilmetil, furanilmetil, tienilmetil, pirazinilmetil, pirimidinilmetil, piridilmetil, hinolinilmetil, izohinolinilmetil, tiazolilmetil ili pirolilmetil grupa u svakom od slučaja supstituisana ili nesupstituisana.; R4 je H.

19. Jedinjenje kao u zahtevu 1, naznačeno time što je R1 metil grupa; R<2>je ciklopentil grupa; R3 je pirazinilmetil, piridilmetil grupa u svakom od slučaja supstituisana ili nesupstituisana.; i R4 je H.

20. Jedinjenje kao u zahtevu 1, naznačeno time što je pomenuto jedinjenje formule IV u kojoj su R I i R 2 kao što je definisano, najmanje jedan od A, B, C i D je N, a drugi su CH, i R4 je piridil ili fenil grupa grupa, u svakom od slučaja supstituisana ili nesupstituisana, i njegove farmaceutski prihvatljive soli.

21. Jedinjenje kao u zahtevu 20, n a z n a č e n o time što je R1 metil ili CHF2grupa.

22. Jedinjenje kao u zahtevu 21, naznačeno time što Bje N.

23. Jedinjenje kao u zahtevu 20, naznačeno time što je R1 metil ili CHF2grupa, i R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa.

24. Jedinjenje kao u zahtevu 23, n a z n a č e n 0 time što B je N.

25. Jedinjenje kao u zahtevu 19, naznačeno t i m e što je R<1>metil ili CHF2grupa, i R<4>je 3-piridil ili fenil grupa koja je u svakom od slučaja supstituisana ili nesupstituisana.

26. Jedinjenje kao u zahtevu 25, naznačeno time što Bje N.

27. Jedinjenje kao u zahtevu 20, naznačeno time što je R1 metil ili CHF2grupa, i R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa i R4 je 3-piridil ili fenil grupa koja je u svakom od slučaja supstituisana ili nesupstituisana.

28. Jedinjenje kao u zahtevu 27, n a z n a č e n o time što B je N.

29. Jedinjenje kao u zahtevu 20, naznačeno time što je R1 metil ili CHF2grupa, i R4 je fenil grupa koja je supstituisana u 3- ili 4- položaju.

30. Jedinjenje kao u zahtevu 29, naznačeno time što BjeN.

31. Jedinjenje kao u zahtevu 19, naznačeno time što je R1 metil ili CHF2grupa, i R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa, i R4 je fenil grupa koja je supstituisana u 3- ili 4- položaju.

32. Jedinjenje kao u zahtevu 31, naznačeno time što BjeN.

33. Jedinjenje kao u zahtevu 20, n a z n a č e n o time što je R1 metil ili CHF2grupa, i R4 je 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etil-sulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 3-nitro-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etil-sulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil-fenil grupa.

34. Jedinjenje kao u zahtevu 33, n a z n a č e n 0 time što B je N.

35. Jedinjenje kao u zahtevu 20, naznačeno time što je R1 metil ili CHF2grupa, R2 je ciklopentil, CHF2, ciklopropilmetil, piridiletil ili tetrahidrofuranil grupa, i R4 je 3-piridil, 3-COOH-fenil, 3-Cl-fenil, 3-cijano-fenil, 3-etil-sulfonamido-fenil, 3-tetrazol-5-il-fenil, 3-hidroksimetil-fenil, 3-nitro-fenil, 4-piridil, 4-COOH-fenil, 4-cijano-fenil, 4-etil-sulfonamido-fenil, 4-tetrazol-5-il-fenil, ili 4-hidroksimetil-fenil grupa.

36. Jedinjenje kao u zahtevu 35, n a z n a č e n o time što B je N.

37. Jedinjenje kao u zahtevu 1, naznačeno time što je pomenuto jedinjenje odabrano od: a) S-ciklopentiloksi^'-etil^-metoksi-A^^-piridilmeti^difenilamin b) 3-ciklopentiloksi-3',4-dimetoksi-A<r->(3-piridilmetil)difenilamin c) 3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)-3'-trifluorometildifenilamin d) 3-ciklopentiloksi-3'-fluoro-4-metoksi-Air-(3-piridilmetil)difenilamin e) 3-ciklopentiloksi-4'-fluoro-4-metoksi-A<r->(3-piridilmetil)difeniIamin f) 3-ciklopentiloksi-4-metoksi-3'-fenil-A'-(3-piridilmetil)difenilamin g) 4'-cijano-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin h) 3-ciklopentiloksi-4-metoksi-3'-nitro-A<f->(3-piridilmetil)difenilamin i) 4'-hloro-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)-3'-trifluorometildifenilamin j) 4-metoksi-3'-metil-A<f->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin k) 3-ciklopentiloksi-4-difluorometoksi-A/-(3-piridilmetil)difenilamin 1) Af-(3-ciklopentiloksi-4-metoksifenil)-Ar-(3-piridilmetil)-6-aminonikotinska kiselina m) Af-(3-ciklopentiloksi-4-metoksifenil)-Af-(2-pirazinil)-Ar-(3-piridilmetil)amin n) 3'-benzilsulfonilamino-3-ciklopentiloksi-4-metoksi-A'-(3-piridilmetil)difenilamin o) 3-[3-(4-hlorofenil)prop-l-iloksi-4-metoksi]-A<?->(3-piridilmetil)difenilamin p) 4-metoksi-3-[3-(4-metoksifenil)prop-l-il]oksi-A^-(3-piridilmetil)difenilamin q) 4-metoksi-3-[3-(2-piridil)prop-l-il]oksi-A<f->(3-piridilmetil)difenilamin r) 3-ciklopentiloksi-4'-(2-metoksietoksi)-4-metoksi-A^-(3-piridilmetil)difenilamin s) 3-ciklopentiloksi-4-metoksi-Af-(3-piridilmetil)-4'-[(3R)-tetrahidrofuraniloksijdifenilamin t) 3-ciklopentiIoksi-4-metoksi-4'-(l-rnetiIpiperidin-4-iloksi)-A^-(3-piridilmetil)difenilamin u) 3-ciklopentiloksi-4-rnetoksi-4'-(l-rnetilpirolidin-3-iloksi)-A^-(3-piridilmetil)difenilamin v) 3-ciklopentiloksi-4-metoksi-4'-[2-(l-pirolidiniletoksi)-A<r->(3-piridilmetil)difenilamin w) 3-ciklopentiloksi-4-metoksi-4'-[2-(6-metilpiridil)metoksi)-A'-(3-piridilmetil)difenilamin x) 3-ciklopentiloksi^-metoksi-4'-[2-(l-rnetilpiperidinil)rnetoksi]-A'-(3-piridilmctil)difenilamin y) 3-ciklopentiloksi-4-metoksi-3'-[2-(l-piperidinil)etoksi]-A<r->(3-piridilmetil)difenilamin z) 3-ciklopentiloksi-3'-[2-(l-imidazolil)etoksi]-4-metoksi-A<?->(3- piridilmetiljdifenilamin aa) 3-ciklopentiloksi-4-rnetoksi-4'-[3-(2-metilpiperazin-4-il)propoksi]-A^-(3- piridilmetil)difenilamin bb)3-ciklopentiloksi-4-metoksi-4'-[3-(2-morfolin-4-iletilamino)propoksi]-A^-(3- piridilmetil)difenilamin cc) 3-[2-(4-hlorofenoksi)etoksi]-4-metoksi-A^-(3-piridilmetil)difenilarnin dd) 3-[2-(4-hlorofenilamino)etoksi]-4-metoksi-A7-(3-piridilmetil)difenilamin ee) 3-ciklopentiloksi-4'-(2-metansulfonilamino)etoksi]-4-metoksi-A<r->(3- piridilmetil)difenilamin ff) 4'-[2-(l-butansulfonilamino)etoksi]- 3-ciklopentiloksi-4-metoksi-jV-(3- piridilmetil)difenilamin gg)3-ciklopentiloksi-4-metoksi-Ar-(3-piridilrnetil)difenilarnin hh)3-ciklopentiloksi-4-metoksi-3'-metil-A^-(3-piridilmetil)difenilarnin ii) 3-ciklopentiloksi-4-metoksi-4'-metil-A/-(3-piridilmetil)difenilarnin jj) 3-ciklopentiloksi-4-metoksi-4'-nitro-A?-(3-piridilrnetil)difenilarnin kk) 3-ciklopentiloksi-3',4'-dihloro-4-metoksi- -N-^-piridilmetiOdifenilamin 11) 3'-hloro-3-ciklopentiloksi-4'-fluoro-4-metoksi-A^-(3-piridilmetil)difenilarniri mm) 3-ciklopentiloksi-A</->(2,6-dihloro-4-piridilmetil)-4-metoksidifenilamin nn)4-metoksi-4'-metil-A^-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin oo)4,4'-dimetoksi-A</->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin pp)3-indaniloksi-4-metoksi-A^-(3-piridilmetil)difenilamin qq) A'-^-metoksi^^^-piridiOetiOoksifenill-A^^-piridilmetiO-S-aminobenzoeva kiselina rr) A<?->(3-ciklopentiloksi-4-metoksifenil)-Ar-(4-izohinolinil)-A^-(3-piridilmetil)amin ss) ^-(S-ciklopentiloksi^-metoksifeni^-A^^-piridilmeti^-A/^S-piridilmetiOamin tt) A</->(3-ciklopentiloksi-4-metoksifenil)-Ar-(2-piridil)-A^-(3-piridilmetil)amin uu)./V-(4-metoksi-3- (3R)-tetrahidrofuraniloksifenil)-A?-(3-piridil)-Af-(3- piridilmetil)amin vv) 3-ciklopentiloksi-4-metoksianilino-Ar-(3-piridilmetil)-A/-3-(4-piridil)benzamid ww) 3-ciklopentiloksi-4-metoksi-3'-(4-metilpiperazin-l-ilkarbonil)-Ar-(3- piridilmetil)difenilamin xx) 3-ciklopentiloksi-4-difluorometoksi-4'-(4-metilpiperazin-l-ilkarbonil)-A^-(3- piridilmetil)difenilamin yy)4-metoksi-4'-(4-metilpiperazin-l-ilkarbonil)-A<f->(3-piridilmetil)-(3-(3- tetrahidrofuriloksi)difenilamin zz) 3'-(l-butansulfonilamino)-3-ciklopentiloksi-4-metoksi-A</->(3- piridilmetil)difenilamin aaa) 3'-acetamido-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin bbb) 4-metoksi-A<r->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin ccc) 4-metoksi-3-[2-(4-piridil)etoksi]-A</->(3-piridilmetil)difenilamin ddd) 4-metoksi-3-(2-metoksietoksi)-A^-(3-piridilmetil)difenilamin eee) 3-ciklopropilmetoksi-4-metoksi-A^-(3-piridilmetil)difenilamin fff)4-metoksi-A<f->(3-piridilmetil)-3-[(35)-tetrahidrofuriloksi]difenilamin ggg) 3'-hloro-4-metoksi-3-[2-(4-piridil)etoksi]-A/-(3-piridilmetil)difenilamin hhh) 3-[2-(4-hlorofenil)eteniloksi] -4-metoksi-//-(3-piridilmetil)difenilamin iii) 3-ciklopentiloksi-3'-hidroksi-4-metoksi-Af-(3-piridilmetil)difenilamiri jjj) S-ciklopentiloksi^'-hidroksi^-metoksi-A^^-piridilmetiOdifenilarnin kkk) 4'-cikloheksiloksi-3-ciklopentiloksi-4-metoksi-A</->(3- piridilmetil)difenilamin 111) 3-ciklopentiloksi-4-metoksi-4'-[2-(l-rnetilpirolidin-2-il)etoksi]-A<f->(3- piridilmetil)difenilamin mmm) 3-ciklopentiloksi-4-metoksi-4'43-(l-rnetilpiperidinil)metoksi]-A^-(3- piridilmetil)difenilamin nnn) 3-ciklopentiloksi-4-metoksi-4'-[3-(l-rnetilpiperazin-4-il)propoksi]-A^-(3- piridilmetil)difenilamin ooo) 4-metoksi-3-(2-fenoksietoksi)-A^-(3-piridilmetil)difenilarnin ppp) 3-ciklopentiloksi-4-rnetoksi-4'-[2-(2-propansulfonilarnino)etoksi]-A^-(3- piridilmetil)difcnilamin qqq) 3'-cijano-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin rrr)4'-hloro-3-ciklopentiloksi-3'-fluoro-4-metoksi-Ar-(3-piridilmetil)difenilamin sss) 3-ciklopropilmetoksi-4-difluorometoksi-A^-(3-piridilmetil)difenilamin ttt) 3-ciklopentiloksi-4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il)-A'-(3- piridilmetil)difenilamin uuu) 3-ciklopentiloksi-4'-metansulfonilarnino-4-metoksi-A^-(3- piridilmetil)difenilamin vvv) S-ciklopentiloksi^-metoksi-S'-hidroksirnetil-A^-CS- piridilmetil)difenilamin www) S-ciklopentiloksi^-metoksi^'-hidroksimetil-A^-CS- piridilmetil)difenilamin xxx) 4-metoksi-3-[3-(4-piridil)prop-l-il]oksi-^-(3-piridilmetil)difeniIamin >'yy) 3'-hloro-4-metoksi-3-(2-metoksietoksi)-7Y-(3-piridilmetil)difenilarnin zzz) S-ciklopropilmetoksi^'-hidroksi^-metoksi-A^-CS- piridilmetil)difenilamin aaaa) 3-ciklopentiIoksi-4'-(2-etansulfonilarnino)etoksi-4-metoksi-A/-(3- piridilmetil)difenilamin bbbb) 3-ciklopropilmetoksi-4-metoksi-4-[2-(l-propansulfonilarnino)etoksi]-jV- (3-piridilmetil)difenilamin cccc) S'-hloro-S-ciklopentiloksi^-metoksi-^S-piridilmetiOdifenilarnin dddd) 3'-hloro-4-metoksi-A/-(3-piridilmetil)-3-(3- tetrahidrofuriloksi)difenilamin eeee) 3'-cijano-4-metoksi-N-(3-piridilmetil)-3-((3R)- tetrahidrofuriloksi)difenilamin ffff) 4-difluorometoksi-A<f->(3-piridilmetil)-3-(3- tetrahidrofuriloksi)difenilamin gggg) 3,4-bis(difluorometoksi)-A<f->(3-piridilrnetil)difenilamin hhhh) 4-difluorometoksi-A<f->(3-piridilmetil)-3-((3R)- tetrahidrofuriloksi)difenilamin iiiOS'-cijano^-difluorornetoksi-^S-piridilmetiO-S-^R)- tetrahidrofuriIoksi)difenilamin jjjj)3'-hloro-4-difluorometoksi-A<f->(3-piridilmetil)-3-((3R)- tetrahidrofuriloksi)difenilamin kkkk) 4'-rerc-butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-A<r->(3- piridilmetil)difenilamin llll)A<L>(3-ciklopentiloksi-4-metoksifenil)-A^-(3-piridilmetil)-3-arninobenzoeva kiselina mmmm) A^-(3-ciklopentiloksi-4-metoksifenil)-A<?->(3-piridilmetil)-4-aminobenzoeva kiselina nnnn) 7Y-(3-ciklopentiloksi-4-difluorometoksifenil)-A^-(3-piridilmetil)-3- aminobenzoeva kiselina oooo) A/-[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3- aminobenzoeva kiselina pppp) A<f->3,4-bis(difluorometoksi)fenil)-A<r->(3-piridilmetil)-3-aminobenzoeva kiselina qqqq) A<r->[4-metoksi-3-((3R)-tetrahidrofuriloksi)feniI]-A<r->(3-piridilrnetil)-3- aminobenzoeva kiselina rrrr) ^-(S-ciklopropilmetoksi^-inetoksifeniO-^S-piridilmetil)^- aminobenzoeva kiselina ssss) A^-(3-ciklopropilmetoksi-4-difluorometoksifenil)-A<?->(3-piridilmetil)-3- aminobenzoeva kiselina ttt^A^^S-ciklopentiloksi^-metoksifeni^-S-aminobenzoeva kiselina uuuu) A^-[3-(4-hlorofenil)prop-l-iloksi-4-metoksifenil]-A<f->(3-piridilmetil)-3- aminobenzoeva kiselina vvvv) A<f->(3-ciklopropiImetoksi-4-metoksifenil)-A<f->(3-piridilmetil)-3- aminobenzoeva kiselina wwww) A<f->[3-(2-indaniloksi)-4-metoksifenil]-A/-(3-piridilmetil)-3-aminobenzoeva kiselina xxxx) A<r->[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A/-(3-piridilmetil)-3- aminobenzoeva kiselina yyyy) iV-[4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-A<r->(3-piridilmetil)-3- aminobenzoeva kiselina zzzz) //-[3-(2-metoksietoksi)-4-metoksifenil]-A'-(3-piridilmetil)-3- aminobenzoeva kiselina aaaaa) 3-ciklopropilmetiloksi-4-difluorometoksi-A^-(3-piridilmetil)-4'-(2H- tetrazol-5-il)difenilamin bbbbb) 3-ciklopentiloksi-4-metoksi-Af-(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin ccccc) 3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)-3'-(2H-tetrazol-5- il)difenilamin ddddd) 4-metoksi-A^-(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)-4'-(2H-tetrazol- 5-il)difenilamin eeeee) S-ciklopropilmetiloksi^-metoksi-A^-CS-piridilmetiO^'^H-tetrazol-S- il)difenilamin fffff) 4-đifluorometoksi-A^-(3-piridilmetil)-3-((3/?)-tetrahidrofuriloksi)-4'-(2H tetrazol-5-il)difenilamin ggggg) S-ciklopentiloksi^-difluorometoksi-^S-piridilmetiO^'^H-tetrazol-S- il)difenilamin hhhhh) 3-ciklopropilmetiloksi-4-difluorometoksi-A<r->(3-piridilmetil)-3'-(2H- tetrazol-5-il)difenilamin iiiii) bis-3,4-difluorometoksi-A<?->(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin jjjjj) A^-(3-ciklopentiloksi-4-metoksifenil)-A^-(3-piridil)-A^-(3-piridilmetil)amin kkkkk) A<f->(3-ciklopentiloksi-4-diflLiorometoksifenil)-A<f->(3-piridil)-A<?->(3- piridilmetil)amin 11111) Af-(3-ciklopropilmetoksi-4-difluorornetoksifenil)-A/-(3-piridil)-Af-(3- piridilmetil)amin mmmmm) A<f->(difluorometoksi-3-(3R)-tetrahidrofuriloksifenil)-A^-(3-piridil)-//-(3- piridilmetil)amin nnnnn) 3-ciklopentiloksi-3'-etansulfonilarnino-4-metoksi-A<f->(3- piridilmetil)difenilamin ooooo) 3-ciklopentiloksi-4-rnetoksi-3'-(l-propansulfonilarnino)-A'-(3- piridilmetil)difenilamin ppppp) 3-ciklopentiloksi-4'-etansulfoniIamino-4-metoksi-jV-(3- piridilmetil)difenilamin qqqqq) S-ciklopentiloksi^-rnetoksi^'^l-propansulfonilamino)-^^- piridilmetil)difenilamin rrrrr) S-ciklopropilmetoksi-S'-etansulfonilarnino^-rnetoksi-A^^- piridilmetil)difenilamin sssss) 4-difluorometoksi-3'-etansulfonilamino-A<r->(3-piridilmetil)-3-[(3R)- tetrahidrofuriloksi]difenilamin ttttt) 4-metoksi-3-[2-(2-piridil)etoksi]-7V-(3-piridilmetil)difenilarnin uuuuu) 4-metoksi-A<r->(3-piridiImetil)-3-[(3/?)-tetrahidrofuriloksi]difenilamin vvvvv) 3'-hloro-4-metoksi-3-[2-(2-piridil)etoksi]-A^-(3-piridilmetil)difenilarnin iii) A^-metoksi-S-^-tetrahidro kiselina jjj) A/-3,4-bis(difluorometoksi)fenil)-A<f->(3-piridilmetil)-3-aminobenzoeva kiselina kkk) A<?->[4-metoksi-3-((3/?)-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3- aminobenzoeva kiselina 111) ^-(S-ciklopropilmetoksi^-metoksifeni^-A^S-piridilmetiO^-aminobenzoeva kiselina mmm) A^-(3-ciklopropilmetoksi-4-difluorometoksifenil)-A^-(3-piridilmetil)-3- aminobenzoeva kiselina nnn) A<?->(3-ciklopentiloksi-4-metoksifenil)-3-aminobenzoeva kiselina ooo) A^-[3-(4-hlorofenil)prop-l-iloksi-4-metoksifenil]-A/-(3-piridilmetil)-3- aminobenzoeva kiselina ppp) A<f->(3-ciklopropilmetoksi-4-metoksifenil)-A/-(3-piridilmetil)-3- aminobenzoeva kiselina qqq) A<f->[3-(2-indaniloksi)-4-metoksifenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina rrr) A/-[4-rnetoksi-3-(3-tetrahidrofuriloksi)fenil]-Ar-(3-piridilrnetil)-3-aminobenzoeva kiselina sss) A^-^-metoksi-S-^^-tetrahidrofuriloksOfenilJ-A^^-piridilmetiO-S- aminobenzoeva kiselina ttt) A<f->[3-(2-metoksietoksi)-4-metoksifenil]-A<r->(3-piridilmetil)-3-aminobenzoeva kiselina uuu) S-ciklopropilmetoksi^-difluorometoksi-A^^-piridilmetiO^'^H- tetrazol-5-il)difenilamin vvv) 3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetiI)-4'-(2H-tetrazol-5- il)difenilamin www) 3-ciklopentiloksi-4-metoksi-7/-(3-piridilmetil)-3'-(2H-tetrazol-5- il)difenilamin xxx) 4-metoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)-4'-(2H-tetrazol- 5-il)difenilamin yyy) 3-ciklopropilmetoksi-4-metoksi-A/-(3-piridilrnetil)-4'-(2H-tetrazol-5- il)difenilamin zzz) 4-difluorometoksi-JV-(3-piridilmetil)-3-((3^)-tetrahidrofuriloksi)-4'-(2H- tetrazol-5-il)difenilamin aaaa) 3-ciklopentiloksi-4-difluorometoksi-A<r->(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin bbbb) 3-cikIopropilmetoksi-4-difluorometoksi-A</->(3-piridilrnetil)-3'-(2H- tetrazoI-5-il)difenilamin cccc) bis-S^-difluorometoksi-A^^-piridilrnetiO^'^H-tetrazol-S- il)difenilamin dddd) ^-(S-ciklopentiloksi^-metoksifenil^^S-piridiO-A^^-piridilmetiOamin eeee) A<r->(3-ciklopentiloksi-4-difluorometoksifenil)-A<f->(3-piridiI)-A<r->(3- piridilmetil)amin ffff) A^-(3-ciklopropilmetoksi-4-difluorometoksifenil)-A<f->(3-piridil)-A<r->(3- piridilmetil)amin gggg) A<f->(4-dilfuorometoksi-3-(3/?)-tetrahidrofuriloksifenil)-A'-(3-piridil)-A/-(3- piridilmetil)amin hhhh) 3-ciklopentiloksi-3'-etansulfonilamino-4-metoksi-^-(3-piridilmetil) difenilamin iiii)3-ciklopentiloksi-4-metoksi-3'-(l-propansulfonilamino)-A<r->(3-piridilrnetil) difenilamin jjjj)3-ciklopentiloksi-4'-etansulfonilamino-4-metoksi-A</->(3-piridilmetil) difenilamin kkkk) 3-cikIopentiloksi-4-metoksi-4'-(l-propansulfonilamino)-A</->(3- piridilmefil) difenilamin llll)3-ciklopropilmetoksi -3'-(l-etansulfonilamino)-4-metoksi-A<r->(3-piridilmetil) difenilamin mmmm) 4-difluorometoksi-3'-etansulfonilamino-A<r->(3-piridilmetil)-3-[(3R)- tetrahidrofuriloksijdifenilamin nnnn) 4-metoksi-[2-(2-piridil)etoksi]-A</->(3-piridilmetil)difenilamin oooo) 4-metoksi-A<f->(3-piridilmetil)-3-[(3^)-tetrahidrofuriloksi]difenilamin pppp) 3'-hloro-4-metoksi-3-[2-(2-piridil)etoksi]-A/-(3-piridilmetil)difenilamin qqqq) 3'-hloro-4-metoksi-A<?->(3-piridilmetil)-3-[(3i?)- tetrahidrofuriloksi]difenilamin rrrr) S-ciklopentiloksi^-rnetoksi^'-p^S-oksopirolidiniOrnetoksij-A<1>^- piridilmetil)difenilamin i njegove farmaceutski prihvatljive soli.

39. Jedinjenje kao u zahtevu 1, naznačeno time što je pomenuto jedinjenje odabrano od: a) 3'-cijano-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin b) 4'-hloro-3-ciklopentiloksi-3'-fluoro-4-metoksi-A<r->(3-piridilmetil)difenilamin c) 3-ciklopropilmetoksi-4-difluorometoksi-A^-(3-piridilmetil)difenilamin d) 3-ciklopentiloksi-4-metoksi-4'-(2-(tetrahidropiran-2-il)-2H-tetrazol-5-il-A^-(3-piridilmetil)difenilamin e) 3-ciklopentiloksi-4'-metansulfonilamino-4-metoksi-A/-(3-piridilmetil)difcnilamin f) 3-ciklopentiloksi-4-metoksi-3'-hidroksimetil-//-(3-piridilmetil)difenilamin g) 3-ciklopentiloksi-4-metoksi-4'-hidroksimetil-A<f->(3-piridilmetil)difenilamin h) 4-metoksi-3-[3-(4-piridil)prop-l-il]oksi-7V-(3-piridilmetil)difenilamin i) 3'-hloro-4-metoksi-3-(2-metoksietoksi]-A'-(3-piridilmetil)difeniIamin j) 3-ciklopropilmetoksi-4'-hidroksi-4-metoksi-A<r->(3-piridilmetil)difenilamin k) 3-ciklopentiloksi-4'-(2-etansulfonilamino)etoksi-4-metoksi-A</->(3-piridilmetil)difenilamin

1) 3-ciklopentiloksi-4-metoksi-4'-[2-(l-propansulfonilamino)etoksi]-A^-(3-piridilmetil)difenilamin m) 3'-hloro-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin n) 3'-hloro-4-metoksi-7V-(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin o) 3'-cijano-4-metoksi-A<r->(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin p) 4-difluorometoksi-A<r->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin q) 3,4-bis(difluorometoksi)-A^-(3-piridilmetil)difenilamin r) 4-difluorometoksi-A^-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilamin s) 3'-cijano-4-dilfuorornetoksi-yV-(3-piridilrnetil)-3-((3R)- tetrahidrofuriloksi)difenilamin t) 3'-hloro-4-difluorometoksi-A^-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)difenilam u) 4'-/erc-butiIdimetilsililoksi-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin v) ^-(S-ciklopentiloksi^-metoksifeni^-^S-piridilmeti^-S-arninobenzoeva kiselina w) A<L>(3-cikIopentiloksi-4-metoksifenil)-A<A->(3-piridilmetiI)-4-aminobenzoeva kiselina x) A/-(3-ciklopentiloksi-4-difiuorometoksifenil)-A<f->(3-piridilmetil)-3-aminobenzoeva kiselina y) A<A->[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina z) A<f->3,4-bis(difluorometoksi)fenil)-A^-(3-piridilmetil)aminobenzoeva kiselina aa) A^-[4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina bb) ^-(S-ciklopropilmetoksi^-metoksifeni^-T/^-piridilmeti^^-aminobenzoeva kiselina cc) //^-ciklopropilmetoksi^-difluorometoksifeniO^^-piridilmetiO-S- aminobenzoeva kiselina dd) A^^-ciklopentiloksi^-metoksifeniO-S-aminobenzoeva kiselina ee) A^-fS^-hlorofeni^prop-l-iloksM-metoksifenilj-A<f>^-piridilmetil)^- aminobenzoeva kiselina ff) A/-(3-ciklopropilmetoksi-4-metoksifenil)-A<A->(3-piridilmetil)-3-aminobenzoeva kiselina gg) Ar-[3-(2-indaniloksi)-4-metoksifenil]-7vT-(3-piridilmetil)-3-aminobenzoeva kiselina hh) A''-[4-metoksi-3-(3-tetrahidrofuriloksi)feniI]-A;-(3-piridilmetil)-3-aminobenzoeva kiselina ii) A<r->[4-metoksi-3-((3R)-tetrahidrofuriloksi)fenil]-A^-(3-piridilmetil)-3-aminobenzoeva kiselina jj) Ar-[3-(2-metoksietoksi)-4-metoksifenil]-Af-(3-piridilmetil)-3-aminobenzoeva kiselina kk) 3-ciklopropilmetoksi-4-difluorometoksi-A^-(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin

11) 3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin mm) S-ciklopentiloksi^-metoksi-A^^-piridilmeti^-S'^H-tetrazol-S-i^difenilamin nn)4-metoksi-A^-(3-piridilmetil)-3-((3R)-tetrahidromriloksi-4'-(2ri-tetrazol-5-il)difenilamin oo) 3-ciklopropilmetoksi-4-metoksi-Af-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin pp)4-difluorometoksi-A/-(3-piridilmetil)-3-((3^)-tetrahidrofuriloksi-4'-(2H-tetrazol-5- il)difenilamin qq) 3-ciklopentiloksi-4-difluorometoksi-Ar-(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin rr) 3-ciklopropilmetoksi-4-difluorometoksi-A'r-(3-piirdilmetil)-3'-(2H-tetrazol-5- il)difenilamin ss) bis-3,4-difluorometoksi-A<A->(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin tt) A</->(3-ciklopentiloksi-4-metoksifenil)-A</->(3-piridil)-A^-(3-piridilmetil)amin uu) A^-(3-ciklopentiloksi-4-difluorometoksifenil)-A^-(3-piridil)-A^-(3-piridilmetil)amin vv) Ar-(3-ciklopropilmetoksi-4-difluorometoksifenil)-A/-(3-piridil)-A^-(3- piridilmetil)amin ww) A^-(4-dilfuorometoksi-3-(3R)-tetrahidrofuriloksifenil)-//-(3-piridil)-A^-(3- piridilmetil)amin xx) 3-ciklopentiloksi-3'-etansulfonilamino-4-metoksi-A^-(3-piridilmetil)difenilamin yy) 3 -ciklopentiloksi-4-metoksi-3'-(1 -propansulfonilamino)-A7-(3- piridilmetil)difenilamin zz) 3-ciklopentiloksi-4'-etansulfonilamino)-4-metoksi-A<r->(3-piridilmetil)difenilamin aaa) 3 -ciklopentiloksi-4-metoksi-4'-( 1 -propansulfonilamino)-./V-(3 - piridilmetil)difenilamin bbb) 3-ciklopropilmetoksi-3'-etansulfonilamino)-4-metoksi-A<r->(3- piridilmetil)difenilamin ccc) 4-difluorometoksi-3'-etansulfonilamino-7v<r->(3-piridilmetil)-3-[(3R)- tetrahidrofuriloksi] difenilamin ddd) 4-metoksi-3-[2-(2-piridil)etoksi]-A^-(3-piridilmetil)difenilarnin eee) 4-metoksi-Af-(3-piridilmetil)-3-[(3i?)4etrahidrofuriloksi]difenilamin fff) 3'-hloro-4-metoksi-3-[2-(2-piridil)etoksi]-A^-(3-piridilmetil)difenilarnin ggg) 3'-hloro-4-metoksi-A^-(3-piridilmetil)-3-[(3i?)-tetrahidrofuriloksi]difenilamin hhh) S-ciklopentiloksi^-metoksi^'-p^S-oksopirolidiniOmetoksij-A^^S- piridilmetil)difenilamin; i njegove farmaceutski prihvatljive soli.

40. Jedinjenje kao u zahtevu 1, naznačeno time što je pomenuto jedinjenje odabrano od: a) 3'-hloro-3-ciklopentiloksi-4-metoksi-A<f->(3-piridilmetil)difenilamin b) 3'-hloro-4-metoksi-A<r->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin c) 3'-cijano-4-metoksi-A</->(3-piridilmetil)-3-(37?)-tetrahidrofuriloksi)difenilamin d) 4-difluorometoksi-A<r->(3-piridilmetil)-3-(3-tetrahidrofuriloksi)difenilamin e) 3,4-bis(difluorometoksi)-<y>V-(3-piridilmetil)difenilamin f) 4-difluorometoksi-A<r->(3-piridilmetil)-3-((3i?)-tetrahidrofuriloksi)difenilamin g) 3'-cijano-4-difluorometoksi-A<r->(3-piridilmetil)-3-((3^)- tetrahidrofuriloksi)difenilamin h) 3'-hloro-4-difluorometoksi-A<7->(3-piridilmetil)-3-((3/?)-tetrahidrofuriloksi)difenilamin i) 4'-/erc-butildimetilsililoksi-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin j) ^-(S-ciklopentiloksi^-metoksifeni^-^S-piridilmetil^-aminobenzoeva kiselina k) A^-(3-ciklopentiloksi-4-metoksifenil)-A<r->(3-piridilmetil)-4-aminobenzoeva kiselina 1) A<?->(3-ciklopentiloksi-4-difluorometoksifenil)-A<r->(3-piridilmetil)-3-aminobenzoeva kiselina m) A</->[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-/V"-(3-piridilmetil)-3-aminobenzoeva kiselina n) A<f->3,4-bis(difluorometoksifenil)-A</->(3-piridilmetil)-3-aminobenzoeva kiselina o) Af-[4-metoksi-3-((3/?)-tetrahidro kiselina p) //-(3-ciklopropilmetoksi-4-metoksifenil)-//-(3-piridilmetil)-4-aminobenzoeva kiselina q) A<f->(3-ciklopropilmetoksi-4-difluorometoksifenil)-A<f->(3-piridilmetil)-3-aminobenzoeva kiselina r) //-(3-ciklopentiloksi-4-metoksifenil)-3-aminobenzoeva kiselina s) A<f->[3-(4-hlorofenil)prop-l-iloksi-4-metoksifenil]-A<f->(3-piridilmetil)-3-aminobenzoeva kiselina t) A<f->(3-ciklopropilmetoksi-4-metoksifenil)-A/-(3-piridilmetil)-3-aminobenzoeva kiselina u) A'-(3-(2-indaniloksi)-4-mctoksifenil)-A<r->(3-piridilmetil)-3-aminobcnzocva kiselina v) //-[4-metoksi-3-(3-tetrahidrofuriloksi)fenil]-A'-(3-piridilmetil)-3-aminobenzoeva kiselina w) A^-[4-metoksi-3-((37?)-tetrahidrofuriloksi)fenil]-A/-(3-piridilmetil)-3-aminobenzoeva kiselina x) A'-[3-(2-metoksietoksi)-4-metoksi fenil]-A<r->(3-piridilmetil)-3-aminobenzoeva kiselina y) 3-ciklopropilmetoksi-4-difluorometoksi-A^-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin z) 3-ciklopentiloksi-4-metoksi-Af-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin aa) S-ciklopentiloksi^-metoksi-^S-piridilmetiO-S'^H-tetrazol-S-iOdifenilamin bb) 4-metoksi-Af-(3-piridilmetil)-3-((3R)-tetrahidrofuriloksi)-4'-(2H-tetrazol-5-il)difenilamin cc) 3-ciklopropilmetoksi-4-metoksi-A/-(3-piridilmetil)-4'-(2H-tetrazol-5-il)difenilamin dd)4-difluorometoksi-A^3-piridilmet^ il)difenilamin ee) 3-ciklopentiloksi-4-difluorometoksi-A^-(3-piridilmetil)-4'-(2H-tetrazol-5- il)difenilamin ff) 3-ciklopropilmetoksi-4-dinuorometoksi-A<?->(3-piridilmetil)-3<i->(2H-tetrazol-5- il)difenilamin gg) bis-3,4-difluorometoksi-A-(3-piridilmetil)-4'-(2H-tetrazol-5-iI)difenilarnin hh)A<r->[3-ciklopentiloksi-4-metoksifenil]-A'-(3-piridil)-A<r->(3-piridilmetil)arnin ii) A<r->[3-ciklopeiitiloksi-4-difluorometoksifenil]-A^-(3-piridil)-A^-(3-piridilmetil)amin jj) A<r->[3-cikIopropilrnetoksi-4-difluorometoksifeniI]-A/-(3-piridil)-A^-(3- piridilmetil)amin kk)A<f->(4-difluorometoksi-3-(3/?)-tetrahidrofuriloksifenil)-A<r->(3-piridil)-A<f->(3- piridilmetil)amin U) 3-ciklopentiloksi-3'-etansulfonilamino-4-metoksi-Af-(3-p^ mm) 3-cikIopentiloksi-4-metoksi-3'-(l-propansulfonilamino)-A<r->(3- piridilmetil)difenilamin nn) 3-ciklopentiloksi-4'-etansulfonilamino-4-metoksi-A<f->(3-piridilmetil)difenilamin oo) 3-ciklopentiloksi-4-metoksi-4'-(l-propansulfonilamino)-Af-(3- piridilmetil)difenilamin pp)3-ciklopropilmetoksi-3'-etansulfonilamino-4-metoksi-A<r->(3-piridilmetil)difenilamin qq) 4-difluorometoksi-3'-etansulfonilamino-A^-(3-piridilmetil)-3-[(3i?)- tetrahidrofuriIoksi]difenilamin rr) 4-metoksi-3-[2-(2-piridil)etoksi]-A<f->(3-piridilmetil)difenilamin ss) 4-metoksi-A<f->(3-piridilmetiI)-3-[(3/?)-tetrahidrofuriloksi]difenilamin tt) 3'-hIoro-4-metoksi-3-[2-(2-piridil)etoksi]-A^-(3-piridiImetiI)difenilamin uu)3'-hloro-4-metoksi-A<r->(3-piridilmetiI)-3-[(3/?)-tetrahidrofuriloksi]difenilamin vv) 3-ciklopentiloksi-4-metoksi-4'-[2-(5-oksopirolidinil)metoksi]-Ar-(3- piridilmetil)difenilamin; i njegove farmaceutski prihvatljive soli.

41. Jedinjenje formule I': naznačeno time što: R<1>' je metoksi, F, Cl, CHF2ili CF3; R<2>' je alkil grupa koja ima 1 do 12 ugljenikovih atoma, alkil grupa koja ima 1 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom, alkenil grupa koja ima 2 do 12 ugljenikovih atoma, alkenil grupa koja ima 2 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom, alkinil grupa koja ima 2 do 12 ugljenikovih atoma, alkinil grupa koja ima 2 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom, cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma, cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, alkil grupom ili njihovom kombinacijom, cikloalkilalkil grupa koja ima 4 do 12 ugljenikovih atoma, cikloalkilalkil grupa koja ima 4 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, alkil grupom ili njihovom kombinacijom, delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma, delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkiloksi, nitro, cijano, okso grupom ili njihovom kombinacijom, arilalkil grupa koja ima 7 do 26 ugljenikovih atoma, arilalkil grupa koja ima 7 do 26 ugljenikovih atoma, koja je supstituisana jedan ili više puta sa halogenom, alkil, alkiloksi, nitro, cijano, okso, trifluorometil grupom ili njihovom kombinacijom, heteroalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu pri čemu je najmanje jedan atom prstena heteroatom, ili supstituisana heteroalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu pri čemu je najmanje jedan atom prstena heteroatom i koja je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, okso, cijano grupom ili njihovom kombinacijom; X jeOiliS R3 je aril grupa koja ima 6 do 14 ugljenikovih atoma je aril grupa koja ima 6 do 14 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, hidroksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom, heteroaril grupom koji je nesupstituisana ili supstituisana sa halogenom, alkil ili alkoksi grupom ili njihovom kombinacijom, je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom, ili je supstituisana heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom koja je supstituisana jedan ili više puta sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom; L je -NH-, -NR<4>'-, -NHCH2-, -NR<4>ĆH2- ili -CH2NR4 - i R<4>je alkil grupa koja ima 1 do 12 ugljenikovih atoma je alkil grupa koja ima 1 do 12 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, okso, cijano grupom ili njihovom kombinacijom, je aril grupa koja ima 6 do 14 ugljenikovih atoma koja nije supstituisana ili je supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, amino, alkilamino, dialkilamino, hidroksialkil, hidroksialkoksi, karboksi, cijano, acil, alkoksikarbonil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom ili njihovom kombinacijom, je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom, je supstituisana heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom i koja je supstituisana jedan ili više puta sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom, je arilalkil grupa koja sadrži 7 do 16 ugljenikovih atoma, je arilalkil grupa koja sadrži 7 do 16 ugljenikovih atoma koja je supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso, trifluorometil grupom ili njihovom kombinacijom je heteroarilalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom, je suspstituisana heteroarilalkil grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom heteroatom i koja je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, okso, cijano grupom ili njihovom kombinacijom; i njegove farmaceutski prihvatljive soli.

42. Postupak za poboljšavanje razumevanja kod pacijenata kod kojih je takvo poboljšavaje željeno n a z n a č e n time što podrazumeva davanje pacijentu efektivne količine jedinjenja kao u zahtevu 1.

43. Postupak kao u zahtevu 42 naznačen time što se pomenuto jedinjenje daje u količini od 0,01 - 100 mg/kg telesne težine/dan.

44. Postupak kao u zahtevu 42 naznačen time što je pomenuti pacijent ljudsko biće.

45. Postupak za tretiranje pacijenata koji pate od pogoršanja ili smanjenja razumevanja naznačen time što obuhvata davanje pomenutom pacijentu efektivnu količinu jedinjenja kao u zahtevu 1.

46. Postupak kao u zahtevu 45 naznačen time što je pomenuti pacijent ljudsko biće.

47. Postupak kao u zahtevu 46 naznačen time što pomenuti pacijent pati od umanjenja pamćenja.

48. Postupak kao u zahtevu 45 naznačen time što se pomenuto jedinjenje daje u količini od 0,01 - 100 mg/kg telesne težine/dan.

49. Postupak kao u zahtevu 47 naznačen time što pomenuti pacijent pati od Alchajmerove bolesti, šizofrenije, Parkinsonove bolesti, Hantingtonove bolesti, Pikove bolesti, Krojcfeld-Jakobsove bolesti, depresije, starenja, povreda glave, moždanog udara, CNS hipoksije, cerebralne senilnosti, multi infarktne demencije, HIV ili kardiovaskularnih bolesti.

50. Postupak za tretiranje pacijenata sa oboljenjem koje obuhvata smanjenje cAMP nivoa naznačen time što obuhvata davanje pomenutom pacijentu efektivnu količinu jedinjenja kao u zahtevu 1.

51. Postupak za inhibiranje aktivnosti PDE 4 enzima naznačen time što obuhvata davanje pomenutom pacijentu efektivnu količinu jedinjenja kao u zahtevu 1.

52. Farmaceutska kompozicija naznačena time što obuhvata jedinjenje kao u zahtevu 1 i farmaceutski prihvatljive nosače.

53. Kompozicija kao u zahtevu 51 naznačena time što pomenuta kompozicija sadrži 0,1 - 50 mg pomenutog jedinjenja.

54. Postupak za tretiranje pacijenta koji boluje od umanjenja pamćenja zbog neurodegenerativnog obolenja naznačen time što obuhvata davanje pomenutom pacijentu efektivnu količine jedinjenje kao u zahtevu 1.

55. Postupak za tretiranje pacijenta koji boluje od umanjenja pamćenja zbog akutnog neurodegenerativnog poremećaja naznačen time što obuhvata davanje pomenutom pacijentu efektivne količine jedinjenja kao u zahtevu 1.

56. Postupak za tretiranje pacijenta koji boluje alergijskog ili upalnog obolenja n a značen time što obuhvata davanje pomenutom pacijentu efektivne količine jedinjenja kao u zahtevu 1.

57. Jedinjenje formule u kojoj: R<1>je H, ferc-butildimetilsilil,<3>H3C-,<l4>CH3-,<n>CH3- grupa ili fenolna zaštitna grupa R<2>je alkil grupa sa 1 dol2, ugljenikovih atoma, koja se račva ili ne račva i koja je nesupstituisana ili supstituisana jedan ili više puta halogenom, hidroksi, cijano, Ci_4-alkoksi, okso grupom ili njihovom kombinacijom, i u kome je, opciono, jedna ili više -CH2CH2- grupa zamenjena u svakom slučaju sa-CH=CH- ili - C=C- grupom, je cikloalkil grupa sa 3 do 10, ugljenikovih atoma, koja nije supstituisana ili je supstituisana jedan ili više puta halogenom, hidroksi, okso, cijano grupom, alkil grupom koja ima 1 do 4 ugljenikova atoma, alkoksi grupom koja ima 1 do 4 ugljenikova atoma ili njihovom kombinacijom, je cikloalkilalkil grupa koja ima 4 do 16, ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta halogenom, okso, cijano, hidroksi, CM-alkil, Ci-4-alkoksi grupom ili njihovom kombinacijom, je aril grupa koja ima 6 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom, je arilalkil grupa u kojoj arilni deo ima 6 do 14 ugljenikovih atoma i u kojoj alkilni deo koji se račva ili ne račva ima 1 do 5 ugljenikovih atoma, gde je arilalkil radikal ne supstituisan ili supstituisan u arilnom delu jedan ili više puta sa halogenom, CF3, OCF3, alkil, hidroksi, alkoksi, nitro, metilendioksi, etilendioksi, cijano grupom ili njihovom kombinacijom, i gde je u alkilnom delu jedna ili više -CH2CH2- grupa svaka opciono zamenjena sa -CH=CH- ili - C=C- i jedna ili više -CH2- grupa je svaka opciono zamenjena sa -O- ili -NH-i/ili je alkilni deo opciono supstituisan sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom, je delimično nezasićena karbociklična grupa koja ima 5 do 14 ugljenikovih atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkoksi, hidroksi, nitro, cijano, okso grupom ili njihovom kombinacijom, je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, aril, alkil, alkoksi, nitro, cijano, trifluorometil, okso grupom ili njihovom kombinacijom, ili je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimični zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, OCF3, hidroksi, aril, alkil, alkoksi, cijano, trifluorometil, nitro, okso grupom ili njihovom kombinacijom, gde su u alkilnom delu jedna ili više -CH2CH2- grupa svaka opciono zamenjena sa -CH=CH- ili -C=C-, ijedna ili više -CH2- grupa je svaka opciono zamenjena sa -O- ili -NH- i/ili alkilni deo je opciono zamenjena sa halogenom, okso, hidroksi, cijano grupom ili njihovom kombinacijom; R<3>je H, alkil grupa koja ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, cijano, Q.4-alkoksi grupom, ili njihovom kombinacijom, je delimično nezasićena karbocikl-alkil grupa u kojoj karbociklični udeo ima 5 do 14 ugljenikovih atoma, i alkilni deo koji je račvast ili nije račvast ima 1 do 5 ugljenikovih atoma, i koja je ne supstituisana ili supstituisana u karbocikličnom delu jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, i gde je alkilni deo opciono supstituisan halogenom, Ci-4-alkoksi, cijano grupom, ili njihovom kombinacijom, je arilalkil grupa koja ima 7 do 19 ugljenikovih atoma, gde arilni deo ima 6 do 14 ugljenikovih atoma i alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom, ili je heteroarilalkil grupa, u kojoj heteroarilni deo može biti delimično ili potpuno zasićen i ima prsten sa 5 do 10 atoma pri čemu je najmanje jedan atom prstena N, O ili S atom, alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, heteroalkilna grupa nije supstituisana ili je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF3O, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; R<4>je H, aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkenil, alkinil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, OCF3, amino, aminoalkil, aminoalkoksi, dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, 2(-heterocikl)tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi, (npr,/erc-butildimetilsilioksi), R<5->L-, grupom ili njihovom kombinacijom ili je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom prstena heteroatom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi, dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi, R<5->L-, dialkilamino-L-, grupom ili njihovom kombinacijom; R<5>je H, je alkil grupa koji ima 1 do 8 ugljenikova atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Ci-4-alkil, Ci_4-alkoksi, okso grupa ili njihovom kombinacijom, je alkilamino ili dialkilamino grupa gde svaki alkilni deo ima nezavisno 1 do 8 ugljenikova atoma, je delimično nezasićena karbociklično-alkilna grupa u kojoj karbociklični deo ima 5 do 14 ugljenikovih atoma i alkilni deo ima 1 do 5 ugljenikovih atoma, koja je ne supstituisana ili supstituisana, poželjno u karbocikličnom delu, jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, je cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma, koja je nesupstituisana ili supstituisana jedan ili više puta sa halogenom, hidrokso, okso, cijano, alkoksi grupom, alkil grupom sa 1 do 4 ugljenikova atoma ili njihovom kombinacijom, je cikloalkilalkil grupa koja ima 4 do 16 ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta sa halogenom, okso, cijano, hidroksi, alkil, alkoksi grupom ili njihovom kombinacijom, je aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksi alkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil grupom ili njihovom kombinacijom, je arilalkil grupa koja sadrži 7 do 19 ugljenikovih atoma, gde u arilnom delu ima 6 do 14 ugljenikovih atoma i alkilni deo koji se račva ili ne račva, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom, je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom ili njihovom kombinacijom, ili je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimično zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo koji je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF30, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili susptituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; L je jednostruka veza ili dvovalentni alifatični radikal koji ima 1 do 8 ugljenikovih atoma gde je jedna ili više -CH2-grupa svaka opciono zamenjena sa -O-, -S-, - NR<6->, -S02NH-, -NHS02-, -CO-, -NR<6>CO-, -CONR<6->, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH-, ili -NHCSNH-; i R<6>je H ili alkil grupa koja ima 1 do 8 ugljenikovih atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Ci-4-alkil, C|.4-alkoksi, okso grupom ili njihovom kombinacijom; pri čemu je najmanje jedan od R<3>i R<4>različiti od II; i njegove farmaceutski prihvatljive soli.

58. Jedinjenje formule naznačeno time što: R1 je alkil grupa koja ima 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom; R<2>je H, rerobutildimetilsiloksi ili fenol zaštitna grupa; R<3>je H, alkil grupa koja ima 1 do 8, poželjno 1 do 4 ugljenikova atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, cijano, C|_4-alkoksi grupom, ili njihovom kombinacijom, je delimično nezasićena karbocikl-alkil grupa u kojoj karbociklični udeo ima 5 do 14 ugljenikovih atoma, i alkilni deo koji je račvast ili nije račvast ima 1 do 5 ugljenikovih atoma, i koja je ne supstituisana ili supstituisana u karbocikličnom delu jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, i gde je alkilni deo opciono supstituisan halogenom, Cj^-alkoksi, cijano grupom, ili njihovom kombinacijom, je arilalkil grupa koja ima 7 do 19 ugljenikovih atoma, gde arilni deo ima 6 do 14 ugljenikovih atoma i alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom, ili je heteroarilalkil grupa, u kojoj heteroarilni deo može biti delimično ili potpuno zasićen i ima prsten sa 5 do 10 atoma pri čemu je najmanje jedan atom prstena N, O ili S atom, alkilni deo, koji je račvast ili nije račvast, ima 1 do 5 ugljenikovih atoma, hcteroalkilna grupa nije supstituisana ili je supstituisana jedan ili više puta u heteroarilnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF3O, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili supstituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; R<4>je H, aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, alkenil, alkinil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, OCF3, amino, aminoalkil, aminoalkoksi, dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, 2(-heterocikl)tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi, (npr,terc-butildimetilsilioksi),R<5->L-, grupom ili njihovom kombinacijom ili je heteroaril grupa koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je najmanje jedan atom prstena heteroatom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi, dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi, trialkilsililoksi, R<5->L-, dialkilamino-L- grupom ili njihovom kombinacijom; R<5>je H, je alkil grupa koji ima 1 do 8 ugljenikova atoma, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, C|_4-alkil, Cj^-alkoksi, okso grupom ili njihovom kombinacijom, je alkilamino ili dialkilamino grupa gde svaki alkilni deo ima nezavisno 1 do 8 ugljenikova atoma, je delimično nezasićena karbociklično-alkilna grupa u kojoj karbociklični deo ima 5 do 14 ugljenikovih atoma i alkilni deo ima 1 do 5 ugljenikovih atoma, koja je ne supstituisana ili supstituisana, poželjno u karbocikličnom delu, jedan ili više puta sa halogenom, alkil, alkoksi, nitro, cijano, okso grupom ili njihovom kombinacijom, je cikloalkil grupa koja ima 3 do 10 ugljenikovih atoma, koja je nesupstituisana ili supstituisana jedan ili više puta sa halogenom, hidroksi, okso, cijano, alkoksi grupom, alkil grupom sa 1 do 4 ugljenikova atoma ili njihovom kombinacijom, je cikloalkilalkil grupa koja ima 4 do 16 ugljenikovih atoma, koja je ne supstituisana ili supstituisana u cikloalkilnom delu i/ili alkilnom delu jedan ili više puta sa halogenom, okso, cijano, hidroksi, alkil, alkoksi grupom ili njihovom kombinacijom, je aril grupa koja ima 6 do 14 ugljenikovih atoma i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil grupom ili njihovom kombinacijom, je arilalkil grupa koja sadrži 7 do 19 ugljenikovih atoma, gde u arilnom delu ima 6 do 14 ugljenikovih atoma i alkilni deo koji se račva ili ne račva, ima 1 do 5 ugljenikovih atoma, arilalkil radikal je ne supstituisan ili supstituisan, u arilnom delu, jedan ili više puta halogenom, CF3O, trifluorometil, nitro, amino, alkil, alkoksi, alkilamino, dialkilamino grupom i/ili supstituisan u alkilnom delu sa halogenom, cijano ili metil grupom, je heterociklična grupa, koja je zasićena, delimično zasićena ili nezasićena, koja ima 5 do 10 ugljenikovih atoma u prstenu u kome je bar jedan atom prstena N, O ili S atom, koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, alkil, hidroksi, alkoksi, alkoksialkoksi, nitro, metilendioksi, etilendioksi, trifluorometil, amino, aminometil, aminoalkil, aminoalkoksi dialkilamino, hidroksialkil grupom, hidroksamskom kiselinom, tetrazol-5-il, hidroksialkoksi, karboksi, alkoksikarbonil, cijano, acil, alkiltio, alkilsulfinil, alkilsulfonil, fenoksi grupom ili njihovom kombinacijom, ili je heterocikl-alkil grupa, u kojoj je heterociklični deo zasićen, delimično zasićen ili nezasićen, i ima 5 do 10 atoma u prstenu u kome je najmanje jedan atom prstena N, O ili S, i alkilni deo koji je račvast ili nije račvast i ima 1 do 5 ugljenikovih atoma, heterocikl-alkil grupa je nesupstituisana ili supstituisana jedan ili više puta u heterocikličnom delu sa halogenom, alkil, alkoksi, cijano, trifluorometil, CF3O, nitro, okso, amino, alkilamino, dialkilamino grupom ili njihovom kombinacijom i/ili susptituisana u alkilnom delu sa halogenom, cijano ili metil grupom ili njihovom kombinacijom; L je jednostruka veza ili dvovalentni alifatični radikal koji ima 1 do 8 ugljenikovih atoma gde je jedna ili više -CH2-grupa svaka opciono zamenjena sa -O-, -S-, -NR<6->, -S02NH-, -NHS02-, -CO-, -NR<6>CO-, - CONR<6->, -NHCONH-, -OCONH-, -NHCOO-, -SCONH-, -SCSNH-, ili - NHCSNH-; i R<6>jeH alkil grupa koja ima 1 do 8 ugljenikovih atoma, koja se račva ili ne račva i koja je ne supstituisana ili supstituisana jedan ili više puta sa halogenom, Ci.4-alkil, Ci-4-alkoksi, okso grupom ili njihovom kombinacijom; pri čemu je najmanje jedan od R<3>i R<4>različiti od H; i njegove farmaceutski prihvatljive soli.

59. Jedinjenje naznačeno time što je odabrano od sledećih jedinjenja: a) 3-ciklopentil-4-metoksi-AL(3-piridilmetiI)anilin; b) 3-?er/-butildimetilsililoksi-4-metoksi-A<f->(3-piridiImetil)anilin; c) 3-/err-butildimetilsililoksi-4-metoksi-A^-(3-piridilmetil)difenilamin; d) 3-/e/-/-butildimetilsiIiloksi-3'-hloro-4-metoksi-A<r->(3-piridilmetil)difenilamin; e) etil A<?->(3-?etr-butildimetilsililoksi-4-metoksifenil)-A^-(3-piridilmetil)-3-aminobenzoat f) 3-ciklopentiloksi-4-metoksidifenilamin; g) 3-hidroksi-4-metoksi-A<f->(3-piridilmetil)difenilamin; h) 3'-hloro-3-hidroksi-4-metoksi-A^-(3-piridilmetil)difenilamin; i) etil A<f->(3-hidroksi-4-metoksifenil)-A<r->(3-piridilmetil)-3-aminobenzoat; j) 3'-(2-bromoetoksi)-3-ciklopentiloksi-4-metoksi-A<r->(3-piridilmetil)difenilamin; k) 4'-[l-(3-bromopropil)oksi]-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin; i 1) 4-hidroksi-3-ciklopentiloksi-A<f->(3-piridilmetil)difenilamin; 59. Jedinjenje naznačeno time što je odabrano od sledećih jedinjenja: a) 3-đklopentil-4-metoksi-AL(3-piridilmetil)anilin; b) 3-/e/-^-butildimetilsililoksi-4-metoksi-A^-(3-piridilmetil)anilin; c) 3-/<?r/-butildimetilsililoksi-4-metoksi-A^-(3-piridilmetil)difenilamin; d) 3-/e//-butildimetilsililoksi-3'-hloro-4-metoksi-A</->(3-piridilmetil)difenilamin; e) etil A<f->(3-tetr-butildimetilsililoksi-4-metoksifenil)-A/-(3-piridilmetil)-3-aminobenzoat; f) 3-ciklopentiloksi-4-metoksidifenilamin; g) 3-hidroksi-4-metoksi-A<A->(3-piridilmetil)difenilamin; h) 3'-hloro-3-hidroksi-4-metoksi-A/-(3-piridilmetil)difenilamin; i) etil //-(3-hidroksi-4-mctoksifcnil)-A</->(3-piridilmetil)-3-aminobcnzoat; j) 3'-(2-bromoetoksi)-3-ciklopentiloksi-4-metoksi-<y>V-(3-piridilmetil)difenilamin; k) 4'-[ 1 -(3-bromopropil)oksi]-3-ciklopentiloksi-4-metoksi-A^-(3-piridilmetil)difenilamin; i 1) 4-hidroksi-3-ciklopentiloksi-vV-(3-piridilmetil)difenilamin. 60. Jedinjenje prema zahtevu 1 naznačeno time što je pomenuto jedinjenje A<L>3,4-bis(difluorometoksi)fenil-A/-(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 61. Jedinjenje prema zahtevu 1 naznačeno time što je pomenuto jedinjenje<y>V-(3-ciklopentiloksi-4-metoksifenil)-A^-(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 62. Postupak prema zahtevu 44 naznačen time što je pomenuto jedinjenje A</->3,4-bis(difluorometoksi)fenil-A^-(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 63. Postupak prema zahtevu 50 naznačen time što je pomenuto jedinjenje<y>V-3,4-bis(difluorometoksi)fenil-A/-(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 64. Postupak prema zahtevu 63 naznačen time što je pomenuta bolest depresija. 65. Postupak prema zahtevu 44 naznačen time što je pomenuto jedinjenje<y>V-(3-ciklopentiloksi-4-metoksifenil)-A</->(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 66. Sastav prema zahtevu 52 naznačen time što je pomenuto jedinjenjeAL3,4-bis(difluorometoksi)fenil-A/-(3-piridilmetil)-3-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 67. Sastav prema zahtevu 52 naznačen time što je pomenuto jedinjenjeAA-(S-ciklopentiloksi^-metoksifeniO-^^S-piridilmetiOO-aminobenzojeva kiselina ili njena farmaceutski prihvatljiva so. 68. Sastav prema zahtevu 52 naznačen time što pomenuti sastav dalje sadrži dodatni farmaceutski agens odabran od blokatora kalcijumovih kanala, kloinergičnih lekova, modulatora adenozin receptora, modulatora amfakina NMDA-R, modulatora mGluR, inhibitora holinesteraza, ili bilo koje njihove kombinacije. 69. Sastav prema zahtevu 66 naznačen time što navedeni sastav dalje sadrži dodatni farmaceutski agens odabran od blokatora kalcijumovih kanala, kloinergičnih lekova, modulatora adenozin receptora, modulatora amfakina NMDA-R, modulatora mGluR, inhibitora holinesteraza, ili bilo koje njihove kombinacije. 70. Sastav prema zahtevu 67 naznačen time što navedeni sastav dalje sadrži dodatni farmaceutski agens odabran od blokatora kalcijumovih kanala, kloinergičnih lekova, modulatora adenozin receptora, modulatora amfakina NMDA-R, modulatora mGluR, inhibitora holinesteraza, ili bilo koje njihove kombinacije.

1. A compound of Formula I wherein: R<1>is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen ; R<2>is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Cj-i-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH-or -OC-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, C|-4-alkyl, Cpa-alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3iOCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the ar<y>lalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or - C = C-, and one or more -CH2- groups are each optionally replaced by -O- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof, a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 nng atoms in which at least 1 nng atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof, or a heterocyclicalkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 nng atom is a N, 0 or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CILCHr groups are each optionally replaced by -CH=CH- or -C = C-, and one or more -CH2- groups are each optionally replaced by -0-or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof; R<3>is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci-4-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R<4>is H, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, OCF3, ammo, aminoalkyl, aminoaLkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbony], cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, tnalkylsilyloxy (eg.tert-butyldimethylsilyloxy), R<3->L-, or combinations thereof, or heteroaryl having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbon<y>l, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy, or combinations thereof; R<5>is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Ci-4-alkyl, Q-4-alkoxy, oxo, or combinations thereof, alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, a partially unsaturated carbocycle-alkyl group wherein the portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy,_oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CT3O, nitro, ammo, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyi, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or a heterocyclicalky! group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 nng atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF3O, nitro, oxo, ammo, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alky! portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -0-, -S-, -NR<6->, -SO2NH-, -NHSO2-, -CO-, -NR<6>CO-, -CONR<6->, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; andR6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, CV4-alkyl, C|-4-alkoxy, oxo, or combinations thereof; wherein at least one of R3 and R<4>is other than H; and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R<4>is other than H.

3. A compound according to claim 1, wherein R<1>is methyl or CHF2; R<2>is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloalkylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; R<J>is H, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R<4>is aryl or heteroaryl, in each case substituted or unsubstituted.

4. A compound according to claim 1, wherein R3 is heteroarylalkyl which is substituted or unsubstituted.

5. A compound according to claim 1, wherein R<1>is methyl or CHF:, and R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or (3R)-tetrahydrofuranyl.

6. A compound according to claim 1, wherein R<1>is methyl or CHF2; R<2>is cyclopentyl; R<3>is heteroarylalkyl, in each case substituted or unsubstituted; and R<4>is substituted or unsubstituted aryl or heteroaryl.

7. A compound according to claim 1, wherein R<l>is methyl; R: is cyclopentyl; R<J>is arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R<4>is substituted or unsubstituted aryl.

8. A compound according to claim 1, wherein R<1>is methyl; R<2>is cyclopentyl; and R<3>is heteroarylalkyl which is substituted or unsubstituted.

9. A compound according to claim 1. wherein R<1>is methyl; R<2>is cyclopentyi; R<J>is heteroarylalkyl which is substituted or unsubstituted; and R4 is phenyl which is substituted or unsubstituted.

10. A compound according to claim 1, wherein R<1>is methyl; R<2>is cyclopentyl; R<3>is pyridyimethyl, pynmidmylmethyl, phenethyl, benzyl, thienylmethyl, pyndylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R<4>is phenyl or phenyl substituted with 1 to 3 substituents.

11. A compound according to claim 1, wherein R1 is methyl; R<2>is cyclopentyl; R"is pyridyimethyl, pynmidinylmethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinyhnethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R<4>is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted.

12. A compound according to claim 1, wherein R<1>is methyl or CFFFY, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R<3>is H; and R4 is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.

13. A compound according to claim 1, R<1>is methyl or CHF?; R2 is cyclopentyl, CF£F2j cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R3 is H; and R4 is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.

14. A compound according to claim i, wherein R1 is methyl; R"is cyclopentyl; R<3>is H; and R<4>is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted.

15. A compound according to claim 1, wherein R<1>is methyl; R<2>is cyclopentyl; R<J>is H; and R<4>is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyl, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl.

16. A compound according to claim 1, wherein R<1>is methyl or CHF2; R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R<J>is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyridyimethyl, quinolinyrnethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted; and R4 is H.

17. A compound according to claim 1, wherein R<1>is methyl or CHF?; R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl; R<3>is pyrazinylmethyl, pyrimidinyimethyl, or pyridyimethyl, which in each is unsubstituted or substituted; and R<4>is H.

18. A compound according to claim 1, wherein R<1>is methyl; R." is cyclopentyl; RJ is benzyl, phenethyl, cyclohexenylmethyl, furanylmethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridyimethyl, quinolinyimethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted; and R<4>is H.

19. A compound according to claim 1, wherein R is methyl; R<*>is cyclopentyl; R<3>is pyrazinylmethyl or pyridyimethyl, which in each is unsubstituted or substituted; and R is H.

20. A compound according to claim 1, wherein said compound is of formula IV wherein R<1>and R<2>are as defined, at least one of A, B, and D is N and the others are CH, and R4 is pyridyl or phenyl which is each case is substituted or unsubstituted, and pharmaceutically acceptable salts thereof.

21. A compound according to claim 20, wherein R1 is methyl or CHF?.

22. A compound according to claim 21, wherein B is N.

23 A compound according to claim 20, wherein R1 is methyl or CHF2, and R<2>is cyclopentyl, CHF?, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl.

24. A compound according to claim 23, wherein B is N.

25. A compound according to claim 19, wherein R<1>is methyl or CHF2, and R<4>is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.

26. A compound according to claim 25, wherein B is N.

27. A compound according to claim 20, wherein R<1>is methyl or CHF2, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl or tetrahydrofuranyl, and RJ is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted.

28. A compound according to claim 27, wherein B is N.

29. A compound according to claim 20, wherein R<l>is methyl or CHP2, and R<4>is phenyl which is substituted in the 3- or 4- position.

30. A compound according to claim 29, wherein B is N.

31. A compound according to claim 19, wherein R<1>is methyl or CHF2, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R4 is phenyl which is substituted in the 3- or 4- position.

32. A compound according to claim 31, wherein B is N.

33. A compound according to claim 20, wherein R! is methyl or CHF2, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.

34. A compound according to claim 33, wherein B is N.

35. A compound according to claim 20, wherein R<1>is methyl or CHF?, R: is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl, or tetrahydrofuranyl, and R<4>is 3-pyndyl, 3-COOH-phenyI, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazol-5-yi-phenyl, 3-hydroxymethyl-phenyl, 3-nitro-phenyi, 4-pyndyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl.

36. A compound according to claim 35, wherein B is N.

37. A compound according to claim 1, wherein said compound is selected from: a) 3-Cyclopentyloxy-4'-ethyl-4-methoxy-jV-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-3' ,4-dimethoxy-yY-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-A/-(3-pyridylmethyl)-3'-tnfluoromethyldiphenylamine d) S-Cyclopentyloxy-S'-nuoro^-methoxy-^S-pyridylmethy^diphenylamine e) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-Ar-(3-pyridylmethyl)diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3'-phenyl-A</>'-(3-pyridylmethyl)diphenylamine g) 4'-Cyano-3-cyclopentyloxy-4-methoxy-iV-(3-pyTidylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-3'-nitro-A^-(3-pvridylmethyl)diphenylamine i) 4'-Chloro-3-cyclopentyloxy-4-methoxy-A/-(3-pyridylmethyl)-3 '-trifluoromethyldiphenylamine j) 4-Memox<y->3'-methyl-A/-(3-pyird<y>lmemyl)-3-(3-tetrahydrofuryloxy)diphenyIami^^k) 3-Cyclopentyloxy-4-difluoromethoxy-A</>'-(3-pyridyimethyl)diphenylamine 1) Ar<->(3-Cyclopentyloxy-4-methoxyphenyl)-A/-(3-pyridylmethyl)-6-aminonicotinic acid m) A^-(3-Cyclopentyloxy-4-methoxyphenyl)-/Y-{2-pyrazinyl)-A</->(3-pyridylmethyl)amine n) 3'-Ben2ylsulfonylamino-3-cyclopentyloxy-4-methoxy-A;-(3-pyridylmethyl)diphenylamine o) 3-[3-(4-Chlorophenyl)prop-l-yloxy]-4-methoxy-/V-{3-pyridylmethyl)diphenylamine p) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-/V-{3- pyridylmethyl)diphenylamme q) 4-Methoxy-3-[3-(2-pyridyl)prop4-yl]ox r) 3-Cyclopentyloxy-4'-(2-rnethoxyethoxy)-4-methoxy-.'V-(3- pyndyimethyl)dip'nenylamine s) 3-Cyclopentyloxy-4-methoxy-<V-(^^ diphenylamine t) 3-Cyclopentyloxy-4-rnethoxy-4'-(l-rnethylpiperidin-4-yloxy)-iV-(3-pyndylmethyl)diphenylarnine u) 3-Cyclopentyloxy-4-rnethoxy-4'-(l-raethylpyrrolidin-3-yloxy)-iV-(3-pyridylmethyl)diphenylarnine v) 3-CyclopentyIoxy-4-methoxy-4'-[2-(l-pyTTolidinylethoxy)-A/'-(3-pyTidylmethyl)diphenylamine w) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyn^yl)memoxy)-A/'-(3-pyridy!methyl)diphenylamine x) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpiperidinyI)methoxy]-A</->(3-pyridylmethyl)diphenylaraine y) 3-Cyclopentyloxy-4-methoxy-3'-[2-(l-piperidinyl)ethoxy]-A/'-(3-pyTidylmeth.yl)diphenylamine z) 3-Cyclopentyloxy-3'-[2-(l-irnidazolyl)ethoxy]-4-methoxy-iV-(3- pyn^yliriethyl)diphenylamine aa) 3 -Cyc lopentyloxy-4-methoxy-4' -[ 3 -(2 -methyip iperazin-4-yl)propoxy] -iV-(3 - pyridylmethyl)diphenylarnine bb) 3-Cyclopentyloxy-4-methoxy-4'-[3^ pyridylmethyl)diphenylamine cc) 3-[2-(4-Chlorophenoxy)ethoxy)-4-m dd) 3-[2-(4-Crdorophenylamino)ethoxy]-4-methoxy-A/-(3-pyirdyboieth ee) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-rnethoxy-A</->(3- pyridylmethyl)diphenylarnine ff) 4'-[2-(1 -Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-methoxy-A/-(3- pyTidylrnethyl)diphenylamine gg) 3-Cyclopentyloxy-4-methoxy-A^-(3-pyridylmemyl)diphenylamine hh) 3-Cyclopentyloxy-4-methoxy-3'-mem^ ii) 3-Cyclopentyloxy-4-memoxy-4'-m jj) 3-Cyclopentyloxy-4-methoxy-4'-nitro-/V-(3-pyndylmethyl)diphenylamjne kJc) 3-Cyclopentyioxy-3\4'-dichloro-4-m«^ 11) 3'-Chloro-3-cyclopentyloxy-4'-fluoro^ rnrn) 3-Cyciopentyloxy-/V-(2,6-dichloro-4-pyn^ nn) 4-Methoxy-4'-methyl-A/-(3-pyTidylmethyl)-3-(3-tetrahydrofuryb oo)4,4^Dimethoxy-A/-(3-pyndylmethyl)-3-(3-tetrahydrom^ pp) 3-mdanyloxy-4-methoxy-jV-(3-pyn^ylmethyl)diphenylamine qq)yV-[4-Methoxy-3-(2-{2-pyridyl)emyL^^ axrrinobenzoic acid rr)/V-(3-Cyclopentyloxy-4-raemoxyphenyl)-A</->(4-isoquinolinyl)-^-(3- pyridylmechyl)arrnne ss)<y>V-(3-Cyclopemyloxy-4-methoxyphenyl)wV-(3-pyndylrnemyl)-/V-(5- pyrirnidinyl)amine tt)yV-(3-Cyclopentyloxy-4-memoxyphe^uu) A/-(4-Methoxy-3-(3i?)-tetrahydrofuryloxyphenyl)-A/-(3-pyridyl)-A/-(3- pyridylmethyl)arnine w)3-Cyclopentyloxy-4-methoxyamlino-/V-(3-pyridylmethyl)-A/'-3-(4-pyTidyl)bww) 3-Cyclopentyloxy-4-methoxy-3'-(4-rnethylpiperazin-l-ylcarbonyl)-A</->(3-pyridylmemyt)diphenylamine xx)3-Cyclopentyloxy-4-difluorometh^ pyridylrn.ethyi)diphenylarnine yy) 4-Methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-A/-(3-pyridylmethyl)^ tetrahydrofuryloxy)diphenylamine zz) 3' -(1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-A/-(3- pyridylmethyl)diphenylamine aaa) 3'-Acetamido-3-cyclopentyloxy-4-mem^ bbb) 4-Methoxy-A/-(3-pyridylmethyl)-3-(3-tetrahydro ccc) 4-Methoxy-3-[2-(4-pyndyl)emoxy]-A</->(3-pyn^ylmethyl)diphenylamine ddd) 4-Memoxy-3-(2-methoxyethoxy^ eee) S-Cyclopropylmethoxy^-memoxy-^-CS-pyridylrnethyOdiphenylarame fff) 4-<Vlethoxy-A^(3-pyndyimemyO ggg) 3'-Chloro-4-methoxy-3-[2-(4-pyridyl)ethoxy]-/V-(3-pyridylmeth hlih) 3-[2-(4-Chlorophenyi)ethenyloxy]-4-iii) 3-Cyclopentyloxy-3'-hydroxy-4-metho jjj) 3-Cyclopentyloxy-4'-hydroxy-4-methoxy-jV-(3-pyridylmethyl)diphen kkk) 4'-Cyclohexylethoxy-3-cyclopentyioxy-4-methoxy-<y>V-(3- pyridylmethyl)diphenylamine 111) 3-Cyclopentyloxy-4-rnethoxy-4'-[2-(l-methylpyrrolidin-2-yl)ethoxy]-/V-(3- pyridylrnethyl)diphenylarni.ne mrrixn) 3-Cyclopentyloxy-4-methoxy-4' -[3-{ 1 -methylpiperidinyl)methoxy]-iV-(3- pyndylmethyl)diphenylamme rrnn) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yi)propoxy]-A</->(3- pyndylmethyl)diphenylamine ooo) 4-Methoxy-3-(2-phenoxyethoxy)^ ppp) 3-Cyclopentyloxy-4-methoxy-4,-[2-(2-propanesulfonylamino)ethoxy]-<y>V-(3- pvridylmethyl)diphenylamine qqq) 3'-Cyano-3-cyclopentyloxy-4-methoxy rrr) 4'-Chloro-3-cyclopentyloxy-3'-fluo^ sss) 3-Cyclopropylmethoxy-4-difluorom ttt) 3-Cyclopentyloxy-4-memoxy-4^(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-A</->(3- pyridylmethyl)diphenylamine uuu) 3-Cyclopentyloxy-4'-methanesulfonylam diphenylamine wv) 3-Cyclopentyloxy-4-methoxy-3'-hydroxyrnethyl-A</>'-(3- pyTidylrnethyl)diphenylamine www) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-/V-(3- pyndylmethyl)diphenylamme xxx) 4-Methoxy-3-(3-(4-pyndyl)prop-1 -yl]oxy-A^-{3-pyridylrnethyl)diphenylarnine yyy) 3'-Chloro-4-methoxy-3-(2-methox zzz) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-iV-(3- pvridylmeth<y>l)dihen<y>larnine aaaa) 3-Cyclopenty[oxy-4'-(2-ethanesulfo^ pyridylmethyl)diphenylamine bbbb) 3-Cyclopemyloxy-4-methoxy-4'-[2-(l-propanesulfo^ pyridylrnethyi)diphenylamine cccc) 3<:>-Chioro-3-cyclopentyloxy-4-methoxy-.V-(3-pyridylmethyl)diphenylam dddd) 3' -Chloro-4-methoxy-A/-(3-pyridylmethyl)-3-{3- terrahydrofuryloxy)diphenylarnine eeee) 3'-Cyano-4-methoxy-iV-(3-pyridylrnethyl)-3-{(3^)- tetrahydrofuryloxy)diphenylamine ffff) 4-Dinuoromemoxy-Af<->(3-pyndylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine gggg) 3,4-Bis(diiluoromethoxy)-iV-(3-pyndylrnethyl)diphenylaraine hhhh) 4-Difluoromethoxy-AA<->(3-pyridylmethyl)-3-((3/?)- tetrahydrofuryloxy)diphenylaniine iiii)3'-Cyano-4-difluoromethoxy-A</->(3-pyridylrnethyl)-3-{(3i?)- tetrahydrofuryloxy)diphenylamine '-Chloro-4-dilfuoromethoxy-A</->(3-pyridylmethyl)-3-((3j<!>?)- tetrahydrofuryloxy)diphenylamine kkkk) 4'-ferf-Butyldimemylsilyloxy-3-cyclopentyloxy-4-methoxy-A</->(3- pyridylrnethyl)diphenylamine llll)jV-(3-Cyclopentyloxy-4-methoxyphenyl)^ acid mmrnrn) Af-(3-Cyclopentyloxy-4-methoxypheny aminobenzoic acid nnnri) A</->(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-A</->(3-pyn^ylrnethyl)-3- aminobenzoic acid oooo)A/-[4-Memoxy-3-(3-tetrahydrofur7loxy)phenyl]-A^-(3-pyndylmem^ aminobenzoic acid pppp) A/-3,4-Bis(difluoromemoxy)phenyi)-A/-(3-pyridylmethyl)-3-aminobenzoic acid qqqq)A</->[4-methoxy-3-((3^)-tetrahydrofuryloxy)phenyl]-.V-{3-pyridylmethyl)-3- aminobenzoic acid rrrr) A</->(3-Cyclopropylmethoxy-4-methoxyphenyi)-A</->(3-pyridylmethyl)-4- aminobenzoic acid ssss)/V-(3-Cyclopropylmethoxy-4-dirluorom aminobenzoic acid tttt)A/'-(3-Cyclopentyloxy-4-methoxyphenyl)-3-ammobenzoic acid uuuu) yV-[3-(4-Chlorophenyl)prop-1 -yloxy-4-mechoxyphenyi]-/V-(3-pyndyLmethyl)-3- aminobenzoic acid ww) iV-(3-Cyclopropylmethoxy-4-methoxyphenyl)-.'V-(3-pyndylmethyl)-3- aminobenzoic acid wwww) yV-{3-(2-mdanyloxy)-4-methoxyphenyi]-iV-(3-pyirdylmethyl)-3- aminobenzoic acid xxxx) A</>"-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyi]-/V-(3-pyndylmethyi)-3- aminobenzoic acid yyyy) A/-[4-Methoxy-3-((3R)-tetrahycixofuryloxy)phenyl]-.V-(3-pyridylmethyl)-3- aminobenzoic acid zzzz) .'V-[3-(2-Methoxyethoxy)-4-methoxyphenyl]-7V-(3-pyridylmethyi)-3-aminobenzoic acid aaaaa) 3-Cyclopropylmethyloxy-4-difluoromethoxy-iV-(3-pyn^ybmethyl)-4'-(2H- tetrazol-5-yl)diphenylamine bbbbb) 3-Cyclopentyloxy-4-methoxy-yV-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine ccccc) 3-Cyclopentyloxy-4-methoxy-iV-(3-pyridyimethyl)-3'-(2H-tetrazol-5- yl)diphenylamine ddddd) 4-Methoxy-A43-pyndylmethyl)-3-^ yl)dip henylamine eeeee) 3-Cyclopropylmethyloxy-4-memoxy-iV-{3-pyridyimethyl)-4'-(2H-tetrazol-5- yl)diphenylamine fffff) 4-Difluoromethoxy-AH3-pyridylme^ tetrazol-5-yl)diphenyiamine ggggg) 3-Cyclopentyloxy-4-difluromethoxy-/V-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine hhhhh) 3-Cyclopropylmethyloxy-4-difluoromethoxy-iV-(3-pyirdylmethyi)-3'-(2H- tetrazol-5-yl)diphenylamine riin) Bis-3,4-difiuoromethoxy-iY-(3-pyridylmethyl)-4'-{2H-tetrazol-5- yl)diphenylamme JJJJj) yV-(3-Cyclopentyloxy-4-methoxyphenyi)-A^-(3-pyridyl)-;V-(3-py^kkkkk) /V'-(3-Cyciopentyloxy-4-dilfuoromechoxyphenyl)-/V-{3-pyTidy pyTidylmethyl)araine

11111) YV-(3-Cyclopropylmethoxy-4-difiuoromethoxy^ pyridylrnethyl)amine mrnrnmrn)iV-(4-Difluoromethoxy-3-(3i?)-tetrahydro iV-(3-pyridylmethyl)amine nnnnn) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-A'-(3- pyridylmethyl)diphenylamine ooooo) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-A/-(3- pyTidylmethyl)diphenylarnine ppppp) 3-Cyclopentyloxy-4'-ethanesulfonylajTiino-4-rnethoxy-A/-(3- pyndylmethyl)diphenylarrhne qqqqq) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-iV-(3- pyridylmethyl)diphenylarnine rrrrr) 3-Cyclopropylmethoxy-3'-ethanesuIfonylamino-4-methoxy-<y>V-(3- pyridylmethyl)diphenylarnine sssss) 4-Difiuoromethoxy-3'-emanesulfo tetrahydrofuryloxyjdiphenylamine ttttt) 4-Memoxy-3-[2-(2-pyndyl)ethoxy]-/V-(3-pyridy uuuuu) 4-Memoxy-/V-(3-pyridylmemyl)-3-[(3.ft)-tetr^ wwv) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-A/-(3-pyridylmethyl)diph www) 3'-Chloro-4-methoxy-A</->(3-pyridylrnethyl)-3-[(3iR)- tetrahydrofaiyloxyjdiphenylamine xxxxx)3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyrrolidinyl)metJioxy]-A</->(3- pyridylmethyl)diphenylamine; and pharmaceutical^ acceptable salts thereof.

38. A compound according to claim 1, wherein said compound is selected from: a) 3-Cyclopentyloxy-4-methoxy-./V-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-iV-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4'-methyl-iV-(3-pyridylmethyl)diphenylamme d) 3-Cyclopentyioxy-4-methoxy-4'-mtro-/V-(3-pyndylmethyl)diphenylamine e) 3-Cyclopentyloxy-3',4'-dichloro-4-methoxy-<y>V-(3-pyridylmethyl)diphenylamine f) 3'-Chloro-3-cyclopentyloxy-4'-fluoro-4-methoxy-.'V-(3-pyndylmethyl)diphenylamine g) 3-CyclopentyloxywV-(2,6-dichloro-4-pyridylmethyl)-4-methoxydiphenylamine h) 4-Methoxy-4'-methyl-A^-(3-pyndylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine i) 4,4'-Dimethoxy-/V-(3-pyridylmethyl)-3-(3-tetrahydrofiiryloxy)dipheriylamine j) 3-Indanyloxy-4-methoxy-jV-(3-pyridylmethyl)diphenylamine k) A</->[4-Methoxy-3-(2-(2-pyridyl)ethyl)oxyphenyl]-A</->(3-pyridylmethyl)-3-aminobenzoic acid

1)A</->(3-Cyclopentyloxy-4-methoxyphenyl)-A</>'-(4-isoquinolinyl)-A</->(3-pyridylmethyl)amine m)A</->(3-Cyclopentyloxy-4-methoxyphenyl)-/V-(3-pyridylmethyl)-/Y-(5-pyrimidinyl)amine n) A</->(3-Cyclopentyloxy-4-methoxyphenyl)-A</->(2-pyridyl)-iV-(3-pyridylmethyl)amine o) A/-(4-Methoxy-3-(3iR)-tetrahydrofhi7loxyphenyl)-yY-(3-pyridyl)-A/-(3-pyridylmethyl)amine p) 3-Cyclopentyloxy-4-memoxyanilino-/V-(3-pyri^ q) 3-Cyclopentyloxy-4-methoxy-3'-{4-methylpiperazm-1 -yicarbonyi)-/V-{3-pyridylmethyl)diphenylamine r) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-/V-{3-pyridylmethyl)diphenylamine s) 4-Memoxy-4'-{4-memylpiperazin-l-ylcarbonyl)-A</->(3-pyridylmethyl)-(3-(3-tetrahydrofuryloxy)diphenylamine t) 3'-(1 -Butanesulfonylamino)-3-cyclopentyloxy-4-methoxy-/Y-(3-pyridylmethyl)diphenylamine u) 3'-Acetamido-3-cyclopentyloxy-4-me v) 4-Methoxy-iV-(3-pyndyimethyl)o-(3-tetrahydroruryloxy)diph^ w) 4-Methoxy-3-[2-(4-pyndyl)ethoxy]-/V-(3-pyndyLmethyl)diphen x) 4-Methoxy-3-(2-methoxyethoxy)-yV-(3-pyridylraethyl)diphenyIam y) 3-CyclopropyImethoxy-4-methoxy^ z) 4-MethoxywV-(3-pyndylmethyl)o^ aa) 3'-Chloro-4-memoxy-3-[2-(4-pyridyl)eth^ bb) 3-[2-(4-Chloropheny!)ethenyloxy]-4-me cc) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-yY^^ dd) 3-Cyclopentyloxy-4'-hydroxy-4-merho^ ee) 4'-Cyclohexyiethoxy-3-cyclopentyloxy-4-methoxy-A</->(3- pyridylrnethyl)diphenylarnirie ff) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpyrTolidin-2-yl)ethoxy]-iV-(3 pyTidylmethyl)diphenylamine gg) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methyIpipendinyl)methoxy]-Ar<->(3- pyridylrnethyl)diphenylamine hh) 3-Cyclopentyioxy-4-memoxy-4'-[3-(l-memylpiperazin-4-yl)propoxy]-yV-(3- pyndylmethyl)diphenylamine ii) 4-Methoxy-3-(2-phenoxyefiioxy)-<y>V-(3-pyTidylmethyl)diphenylamine jj) 3-Cyclopentyloxy-4-methoxy-4'-[2-(2-propanesulfonylarnino)ethoxy]-<y>V-{3- pyridybriethyl)diphenylarriine kk)3'-Cyano-3-cyclopentyloxy-4-memo 11) 4'-Chloro-3-cyclopentyloxy-3'-fluo^ mm) 3-Cyclopropylmethoxy-4-difluoromethoxy-A</->(3-pyridylmethyl)diphenylamine nn) 3-Cyclopentyloxy-4-methoxy-4' -(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-yV-(3- pyridylmethyl)diphenylamine oo) 3-Cyclopentyloxy-4'-metlianesulfonylammo-4-methoxy-<y>V-(3-pyndylmethyl)- diphenylamine pp) 3-Cyclopentyloxy-4-methoxy-3'-hy qq) 3-Cyclopentyloxy-4-methoxy-4'-hydros rr) 4-Methoxy-3-[3-(4-pyridyl)prop-1 -yl]oxy-A^-(3-pyridylmethyl)diphenylamine ss) 3'-Chloro-4-methoxy-3-{2-meth^ tt) 3-Cyclopropylmethoxy-4'-hydroxy-4-methoxy-A/-(3-pyn^ylmeth uu) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-rnethoxy-Ar-(3- pyridylrnethyl)diphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-A/-(3- pyridylrnethyl)diphenylamine ww) 3'-Chloro-3-cycIopentyloxy-4-methoxy-A/-(3-py^ xx) 3'-Chloro-4-methoxy-/V-(3-pyridyl^ yy) 3'-Cyano-4-methoxy-A/-(3-pyridylmethyl)-3-((3/?)-tetrahydromryloxy^ zz) 4-Difluoromethoxy-A/-(3-pyridylrnethyI)-3-(3-tetrahydromry'lox aaa) 3,4-Bis(dilfuoromethoxy)-A/-(3-pyridylme bbb)4-Dinuoromethoxy-/V-(3-pyndylrnethyl)-3-((3i?)- tetrahydrofuryloxy)diphenyiamine ccc) 3'-Cyano-4-difluoromethoxy-A</->(3-pyridylrnethyl)-3-((3i?)- tetxahydromiyloxy)diphenylarriine ddd) 3'-Chloro-4-difluoromethoxy-A^-(3-pyndylmethyl)-3-((3^)- tetrahydxofuryloxy)diphenylamine eee) 4'-fe^Butyldimethylsilyloxy-3-cyclopentyloxy-4-rnethoxy-Ar-(3- pyridylmethyl)diphenylamine fff) iV-(3-Cyclopentyloxy-4-methoxyphenyl)-yV-(3-pyridylmethyl)-3-aminober^ acid goo)A-(3-Cyclopentyloxy-4-methoxyphenyl)-iV-{3-pyridylmethyl)-4-aminobenzoic acid hhh) AA-(3-Cyclopentyloxy-4-difluoromemoxyphenyl)-A-(3-pyridybieth aminobenzoic acid iii) Ar<->[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-A^-(3-pyndylmethyl)-3-aminobenzoic acid jjj) A</->3,4-Bis(difluoromethoxy)phenyl)-A</->(3-pyridylmethyl)-3-aminobenzoic acid kick) Ar<->(4-methoxy-3-((3i?)-tetrahydrofuryloxy)phenyl]-A</->(3-pyridyimethyl)-3- aminobenzoic acid 111)A</->(3-Cyclopropylmetxioxy-4-arethoxyphenyl)-/V-{3-pyridylmethyl)-4-aminobenzoicacid mmm) ;V-(3-Cyclopropylmetboxy-4-dinuoromethox aminobenzoic acid nnn)/V-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid ooo) A/-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-yV-(3-pyridylmethyl)-3- aminobenzoic acid ppp) A/-{3-Cyclopropylmethoxy-4-methoxyphenyl)-/V-(3-pyridyImethyl)-3- aminobenzoic acid qqq) A-[3-(2-mdanyloxy)-4-methoxyphenyl]-.Y-(3-pyridylmethyi)-3-arninobenzoic acid rrr) /V-[4-MemoxyO-(3-tetrahydrofuryloxy)phenyl]-A/-(3-pyridyLmethyl)-3-aminobenzoic acid sss) /V-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-Af-(3-pyndylmethyl)-3- aminobenzoic acid ttt)A</->[3-(2-Methoxyethoxy)-4-methoxyphenyl]-<y>V-(3-pyridylmethyl)-3-aminobenzoic acid uuu) 3-Cyclopropylmethyioxy-4-dinuoromethoxy-/V-(3-pyn^ylmethyI)-4'-(2H- tetrazol-5-yl)diphenylamine m)3-Cyclopentyloxy-4-methoxy-A/-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine www) 3-Cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyi)-3'-(2H-tetrazol-5- yl)diphenylamine xxx) 4-Methoxy-A/-(3-pyridylmethyl)-3-((3i?)^^^ y'l)diphenylamine yyy) ~ 3-Cyclopropymiethyioxy-4-methoxy-A/-{3--pyTidylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine zzz) 4~Difiuoromethoxy-A/-(3-pyridylm tetrazo 1-5-yl)dipheny 1 amine aaaa) 3-Cyclopentyloxy-4-difluromethoxy-/V-(3-pyridylmethyl)-4'-{2H-tetrazol-5- yl)diphenylamine bbbb) 3-Cyclopropylmethyloxy-4-difiuoromethoxy-/V-(3-pyridylmethyl)-3'-(2H- tetrazol-5-yl)diphenylamine cccc) Bis-3,4-difluoromethoxy-iV-(3-pyndylm yl)diphenylarnine dddd) /V-(3-Cyciopentyloxy-4-methoxyphenyl)-/^ eeee)/V-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-<y>V-(3-pyridyI)-/V-(3- pyridylmethyl)amine ffff) /Y-(3-Cyclopropylmethoxy-4-difluoromethoxy pyridylmethyl)arnine gggg) /V-(4-Difluoromethoxy-3-(3^)-tetrahydrofuryloxyphenyl)wV-(3-pyridy pyridylmethyl)amme hhhh) 3-Cyclopentyloxy-3'-ethanesulfonylarnino-4-methoxy-/V-(3- pyndylmethyl)diphenyiamine iiii)3-Cyclopentyloxy-4-methoxy-3'-(l-propajiesulfonylamirio)-/V-(3- pyridylmethyl)diphenylamine jjjj)3-CyclopentyIoxy-4'-ethanesulfonylamino-4-rnethoxy-<y>V-(3- pyridylmethyl)diphenylamine kkkk) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylarnino)-.'V-(3- pyridylmethyl)diphenylamine llll)3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-iV-(3- pyridylmetxiyl)diphenylarnine rrurirarn) 4-Difluoromethoxy-3' -ethanesulfonylamino-A/-(3-pyridylmethyl)-3-[(3R)- tetrahydromryloxy]diphenylamine nnnn) 4-Methoxy-3-[2-(2-pyndyl)ethoxy]-A</->(3-pyridylmethyl)diphenylamine oooo) 4-Memoxy-/V-(3-pyirdylmethyl)-3-[Q pppp) 3'-Chloro-4-memoxy-3-[2-(2-pyridyl)emoxy]-A/-(3-pyTidylmethyl)di qqqq) 3' -Chloro-4-methoxy-iV-(3-pyridylrnethyl)-3-[(3i?)- tetrahydro furyloxyjdiphenylamine rrrr) 3-Cyclopentyloxy-4-memoxy-4'-[2-(5-oxopyrrolidinyl)methoxy]-/V-(3- pyridylmethyl)diphenylamine; and pharmaceutically acceptable salts thereof.

39. A compound according to claim 1, wherein said compound is selected from: a) 3 ,-Cyano-3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyl)diphenylamine b) 4,-Chloro-3-cyclopentyloxy-3'-lfuoro-4-methoxy-A</->(3-pyridylmethyl)diphenylamine c) 3-Cyclopropylmethoxy-4-dilfuoromethoxy-A</->(3-pyndylmethyl)diphenylamme d) 3-Cyclopentyloxy-4-methoxy-4'-(2-(tetxahydrop>Tan-2-yl)-2H-tetrazol-5-yl)-/Vr-(3-pyndylmethyl)diphenylamme e) 3-Cyclopentyloxy-4'-methanesulfonylamino-4-methoxy-/V-(3-pyridylmethyl)-diphenylamine f) 3-Cyclopentyloxy-4-methoxy-3'-hydroxvmethyl-A</->(3-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4'-hyaxoxymethyi-A</>'-(3-pyTidyhnethyl)diphenylamine h) 4-Methoxy-3-[3-(4-pyridyl)prop-1 -y l]oxy-/V-(3-pyridylmethyl)diphenylamine i) 3 '-Chloro-4-methoxy-3-(2-methoxyethoxy)-A/-(3-pyridylmethyl)diphenylamine j) 3-CyclopropyLmethoxy-4'-hydroxy-4-methoxy-A</->(3-pyridylmethyl)diphenylamine k) 3-Cyclopentyloxy-4'-(2-ethanesulfonylamino)ethoxy-4-methoxy-A</>'-(3-pyridylmethyl)diphenylamine

1) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylamino)ethoxy]-A</->(3-pyridylmethyl)diphenylamine m) 3'-Chloro-3-cyclopentyloxy-4-methoxy-A</>'-(3-pyridylmethyl)diphenylamine n) 3'-Chloro-4-methoxy-iV-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine o) 3'-Cyano^-methoxywV-(3-pyirdylmethy p) 4-Difluoromethoxy-A</->(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine q) 3,4-Bis(difluoromethoxy)-A</->(3-pyTidylmethyl)diphenylamine r) 4-Difluoromethoxy-iV-{3-pyridylmethyl)-3-((3i?)-tetrahydrofuryloxy)diphenylamine s) 3 '-Cyano-4-difluoromethoxy-A/-{3-pyTidylmethyl)-3-{(3i?)- tetrahydrofuryloxy)diphenylamine t) 3'-Chloro-4-difluoromethoxy-/>/-(3-pyridylmethyl)-3-((3^)- tetrahydrofuryloxy)diphenylamine u) 4'-ferr-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-A</->(3-pyridylmethyl)diphenylamine v) /V-(3-Cyclopentyloxy-4-meth^ acid w) /V-(3-Cyclopentyloxy-4-methoxyphenyl)-/V-(3-pyndylmethyl)-4-am acid x)<y>V-(3-CycIopentyloxy-4-dilfuoromethoxyphenyl)-/V-{3-pvndylmethyl)-3-ammobenzoic acid y) A/"-[4-Methoxy-3-(3-tetrahydromryloxy acid z) ;V-3,4-Bis(difluoromethoxy)phenyl)-jV-(3-pyirdyimethyl)-3-arm^obenzoic acid aa) ;V-[4-methoxy-3-((3.K)-tetrahydr^ aminobenzoic acid bb) yV-(3-Cyclopropylmethoxy-4-methoxyphenyl)-/V-(3-pyridylmethyl)-4-aminobenzoic acid cc)<y>V-(3-C<y>clopropyuTiethoxy-4-difluoromethoxyphenyl)-/V-(3-pyTidylmethyl)-3- aminobenzoic acid dd)/V-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid ee) A</->[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-iV-(3-pyTidylmethyl)-3- ' aminobenzoic acid ff)^-(S-Cyclopropylmethoxy^-methoxypheny^-<y>V^S-pyridylmethyO^-aminobenzoic acid gg) yV-[3-(2-mdanyloxy)-4-methoxyphenyl]-/V-(3-pyridyh-nethyl)-3-aminobenzoic acid hh) A/-[4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-/V-(3-pyndybmethyl)-3-aminobenzoic acid ii) A^-(4-Methoxy-3-((3R)-tetrahydromi7loxy)phenyl]-<y>V-(3-pyTidyLmethyl)-3- aminobenzoic acid jj) A</->f3-(2-Methoxyethoxy)-4-methoxyphenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid kdc) 3-Cyclopropyimethyloxy-4-difluoromethoxy-A/-{3-pyndyumethyl)-4'-(2H-tetrazol-5- yi)diphenylamine

11) 3-Cyclopentyloxy-4-methoxy-A</->(3-pyridylmethyi)-4'-(2H-tetrazol-5- yl)diphenylamine mm) 3-Cyclopentyloxy-4-methoxy-A</,->{3-pyridylmethyl)-3'-(2H-tetrazol-5- yl)diphenylamine nn) 4-Methoxy-iV-(3-pyridylmethyl)-3^ yl)diphenylamine oo) 3-Cyclopropylmethyloxy-4-methoxy-/V-(3-pyridyimethyl)-4'-(2H- yl)diphenylarnme pp) 4-Dilfuoromethoxy-/V-(3-pyndyta 5-yl)diphenylamme qq) 3-CycIopentyloxy-4-dilfurometh^ yl)diphenylamine rr) 3-CyclopropyLmemyloxy-4-diiluorom yl)diphenylamine ss) Bis-3,4-difluoromethoxy-A-(3-pyridylmemyl)-4'-{2H-teurazol-5-yl) tt) A'-(3-CyclopentyIoxy-4-methoxypte uu)N-(3-Cyclopentyloxy-4-dinuoro pyndylmethyl)amine vv)N-(3-Cyclopropylmethoxy-4-^^ pyridylmemyl)amine ww)A^4-Difluoromethoxy-3-(3i?)-tetra^ pyndylmethyl)amine xx) 3-Cyclopentyloxy-3 *-ctliariesulfonylarriino-4-rnethoxy-A/-(3- pyridylmethyl)diphenylamine yy) 3-Cyclopentyloxy-4-methoxy-3'-(l-propanesulfonylamino)-jV-{3- pyndylrnethyi)diphenylarnine zz) 3-Cyclopentyloxy-4'-emanesulfonylamino-4-methoxy-iV-(3- pyridylrnethyl)diphenylamine aaa) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonyiamino)-JV-{3- pyridylrnethyl)diphenytamine bbb) 3-Cyciopropylmethoxy-3'-emanesulfonylamino-4-arethoxy-iV-(3- pyridylmethyl)diphenylamine ccc) 4-DifIuoromethoxyO'-ethanesulfo^ tetrahydrofuryloxyjdiphenylamine ddd) 4-Methoxy-3-{2-(2-pyndh/l)etho^ eee)4-Methoxy-/V-(3-pyridylmfff) 3'-Chloro-4-methoxy-3-[2-(2-pyndyl)ethoxy]-/V-(3-pyri ggg) 3'-Chloro-4-methoxywV-(3-pyridylmethyl)-3-[(3i?)- tetrahydrofuryioxyjdiphenylamme hhh) 3-Cyclopentyloxy-4-methoxy-4'-{2-{5-oxopyTrolidinyj)rnethoxy]-<y>V-(3- pyridyknethyl)diphenylarnine; and pharmaceutically acceptable salts thereof.

40. A compound according to claim 1, wherein said compound is selected from: a) 3'-Chloro-3-cyclopentyloxy-4-methoxy-<y>V-(3-pyridylmethyl)diphenylamme b) 3'-Chloro-4-methoxywV-(3-pyn^ylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine c) 3'-Cyano-4-methoxy-/V-(3-pyTidylmethyi)-3-^^ d) 4-Difluoromethoxy-<y>V-(3-pyridylmethyl)-3-(3-tetxahydrofuryloxy)diphenyiamine e) 3,4-Bis(difluoromethoxy)-/V-(3-pyridylmethyl)diphenylamine f) 4-Difluoromethoxy-<y>V-(3-pyridyimethyl)-3-{(37?)-tetrahydrofuryloxy)diphenylamine g) 3'-Cyano-4-difiuoromethoxy-iV-(3-pyridylmethyl)-3-((3i?)- tetrahydrofuryloxy)diphenylamine h) 3'-Chloro-4-difluoromethoxy-<y>Y-(3-pyridylmethyl)-3-((3i?)- tetrahydrofuryloxy)diphenylamine i) 4'-ferr-Butyldimethylsilyloxy-3-cyclopentyioxy-4-methoxy-/Y-(3-pyridylmethyl)diphenylamine j)<y>Y-{3-Cyclopentyloxy-4-methoxyphenyl)-<y>V-(3-pyridylmethyl)-3-aminobenzoic acid k) A</->{3-Cyclopentyloxy-4-methoxyphenyl)-A</->{3-pyridylmethyl)-4-aminoben2oic acid 1) A</->{3-Cyclopentyloxy-4-dilfuoromethoxyphenyl)-Ar<->(3-pyridylmethyi)-3-aminobenzoic acid m)<y>V-{4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-A</->(3-pyridyimethyl)-3-aminobenzoic acid n)/V-3,4-Bis(difluoromethoxy)phenyl)wV-(3-pyndylmethyl)-3-aminobenzoic acid o) /V-[4-methoxy-3-((3/?)-tetra^ aminobenzoic acid p)<y>V-(3-Cyclopropylmethoxy-4-memoxyphenyl)-/V-{3-pyridylmethyl)-4-aminobenzoic acid q)/V-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-/V-{3-pyndyLmethyi)-3-aminobenzoic acid r) A</->(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid s)<y>Y-[3-(4-Chlorophenyl)prop-l-yloxy-4-memoxyphenyl]-<y>V-{3-pyridylmethyl)-3-aminobenzoic acid t)<y>V-(3-Cyclopropylmethoxy-4-methoxyphenyl)-A</->(3-pyridylmethyl)-3-aminobenzoic acid u) A-[3-(2-mdanyloxy)-4-methoxyphenyl]-/V-{3-pyTidylmemyi)-3-aminobenzoic acid v) /V-[4-Methoxy-3-(3-tetrahydrofhryloxy)ph acid w)<y>V-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-iV-(3-pyridylmethyl)-3-aminobenzoic acid x) yV-[3-(2-Methoxyemoxy)-4-methoxyphenyn acid y) 3-Cyclopropylmemy1oxy-4-difluoromethoxy-.A/-(3-pyridylmethyi)-4'-(2H-tetrazol-5-yl)diphenylamine z) 3-Cyclopentyioxy-4-methoxy-<y>Y-(3-pyndyknethyl)-4'-{2H-tetTazol-5- yl)diphenylamine aa) 3-Cyclopentyloxy-4-methoxy-<y>Y-(3-pyridylmemyl)-3'-(2H-tetrazol-5- yl)diphenylamine bb) 4-Methoxy-/V-{3-pyridylmemyl)-3-((3^ yl)dipheny[amine cc) 3-Cyclopropyimethyloxy-4-memoxy-/V-(3-pyn^yuTiethyl)-4'-(2H-tetrazol-5- yl)diphenylamine dd) 4-Difluoromethoxy-yV-(3-pyndylmethyl)-3-{(3^)-tetrahydrofuryloxy)-4'-{2H-tetrazol- 5-yl)diphenylamine ee) 3-Cyclopentyloxy-4-difiuro yl)diphenylamine ff) 3-Cyclopropylmethyloxy-4-dilfuoromethoxy-/Y-(3-pyndylmeth yl)diphenylamine gg) Bis-3,4-difluoromethoxy-iV-(3-pyridyl^hh) A/-(3-Cyclopentyloxy-4-arethoxyphenyl)-/V-(3-pyridyl)-/V-(3-pyndyun ii)N-p-Cyclopentyloxy^-difluorom pyTidylrnethyl)arnrrie jj) A/-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-A/-(3-pyridyl)^ pyridylrnethyl)arriine kk)iV-(4-Difluoromemoxy-3-(3^ pyridylmethyl)amine

11) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-/Y-(3- pyridylmethyl)diphenylarnine rnrn) 3-Cyclopentyloxy-4-methoxy-3'-(1 -propanesulfonylamino)-/Y-(3- pyridylrnethyl)diphenylarnine nn) 3-Cyclopentyloxy-4'-ethanesulfonylamino-4-rnethoxy-Ar<->(3- pyridylrnethyl)diphenylamine oo) 3-Cyclopentyloxy-4-memoxy-4'-(l-propanesulfonylarnino)-Y-(3- pyridylmethyl)diphenylamine pp) 3-Cyclopropylmethoxy-3'-ethanesulfonylarm^o-4-methoxy-A</->(3- pyridylmethyl)diphenylamine qq) 4-Diifuoromethoxy-3'-emanesuifo^ tetrahydrofuryloxyjdiphenylamine rr) 4-Methoxy-3-[2-(2-pyndyl)ethoxy]-iV-{3-pyri^ ss) 4-Methoxy-A/-(3-pyirdylmethyl)-3-[(3^ tt) 3'-Chloro-4-methoxy-3-[2-(2-pyridyl)ethoxy]-A/-(3-pyridylmethyl)diph uu) 3'-Chloro-4-methoxy-A;-(3-pyridylmethyl)-3-[(3i?)- tetrahydrofuryloxyjdiphenylamine vv) 3-Cyclopentyloxy-4-methoxy-4,-[2-(5-oxopyn-olidinyl)methoxy]-/Y-(3- pyridylmethyl)diphenylamine; and pharmaceutical!y acceptable salts thereof.

41. A compound according to formula I': wherein R1 is methoxy, F, CI, CHF2or CF3; R<:>' is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, alkenyl having 2 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof, eye loaikytalkyl having 4 to 12 carbon atoms, cycloalkyialkyi having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, nitro, cyano, oxo, or combinations thereof, arylalkyl having 7 to 26 carbon atoms arylalkyl having 7 to 26 carbon atoms which is substituted one or more times .by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifiuoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; X isOorS; R3 is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, ammo, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof; L is -NH-, -NR<4>'-, -NHCH2-, -NR4CH2-, or -CH2NR<4>'-; and R<4>is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom- is a heteroatom, substituted heteroaryl having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, tnfluoromethyl, nitro, oxo, ammo, alkylamino, dialkylamino or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trfiuoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 nng atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and pharmaceutically acceptable salts thereof.

42. A method for enhancing cognition in a patient in whom such enhancement is desired comprising administering to said patient an effective amount of a compound according to claim 1.

43. A method according to claim 42, wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day.

44. A method according to claim 42, wherein said patient is a human.

45. A method of treating a patient suffering from cognition impairment or decline comprising administering to said patient an effective amount of a compound according to claim 1.

46. A method according to claim 45, wherein said patient is a human.

47. A method according to claim 46, wherein said patient is suffering from memory impairment.

48. A method according to claim 45, wherein said compound is administered in an amount of 0.01-100 mg/kg of body weight/day.

49. A method according to claim 47, wherein said patient is suffering from memory impairment due to Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia, HIV or cardiovascular disease.

50. A method for treating a patient having.a disease involving decreased cAMP levels comprising administering to said patient an effective amount of a compound according to claim 1.

51. A method of inhibiting PDE4 enzyme activity in a patient comprising administering to said patient an effective amount of a compound according to claim 1.

52. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 1 17

53. A composition according to ciaim 51, wherein said composition contains 0.1-50 mg of said compound.

54. A method of treating a patient suffering from memory impairment due to a neurodegenerative disease comprising administering to said patient an effective amount of a compound according to claim 1.

55. A method of treating a patient suffering from memory impairment due to an acute neurodegenerative disorder comprising administering to said patient an effective amount of a compound according to claim 1.

56. A method of treating a patient suffering from an allergic or inflammatory disease comprising administering to said patient an effective amount of a compound according to claim 1.

57. A compound of the Formula wherein: R<1>is H, tert-butydimethylsilyl, 3rFjC-,<14>CH3-, "CHj- or a phenolic protective group; R<2>is alkyl having 1 to 12 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CFLCH-- groups is replaced in each case by -CH=CH- or -OC-, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations. thereo f, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci-4-alkyl, Ci-4-alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof, arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CH-zCH^- groups are each I'll optionally replaced by -CH=CH- or -C = C-, and one or more -CHr groups are each optionally replaced by -0- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl. alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof, a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof, or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, 0 or S atom, and the alky! portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCF3, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH2- groups are each optionally replaced by -CH=CH- or -C^C-, and one or more -CH?- groups are each optionally replaced by -0-or -NH- and/or the alkyl pomon is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof; R<3>is H, alkyl having . 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, Ci-4-alkoxy, cyano or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF3O, nitro, amino, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF30, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R4 is H, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.tert-butyldimethylsilyloxy), Rs<->L-, or combinations thereof, or heteroaryl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, arkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R<3->L-, dialkylamino-L-, or combinations thereof; R<5>is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Ct-4-alkyl, Cro-alkoxy, oxo, or combinations thereof, alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy,_oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycioalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion anaVor the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF^O, nitro, ammo, alkyl, alkoxy, ammo, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 nng atoms in which at least 1 nng atom is a N, 0 or S ' atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 nng atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic • portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF30, nitro,. oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -0-, -S-, -NR<6->,-SO2NH-,-NHSO2-,-CO-,-NR<6>CO-, -CONR<6->, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; and R<6>is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, G-d-alkyl, Ci-4-alkoxy, oxo, or combinations thereof; wherein at least one of RJ and R<J>is other than H; and pharmaceuticaliy acceptable salts thereof.

58. A compound of the Formula wherein: R<1>is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen ; R<2>is H, tert-butyldimethylsilyloxy- or a phenolic protectibe group; R<3>is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo. or combinations thereof, and the alkyt portion is optionally substituted by halogen, G-4-alkoxy, cyano or combinations thereo f. arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF3O, nitro, ammo, alkyl, alkoxy, alkylamino, dialkylamino and/or substituted m the alkyl portion by halogen, cyano, or methyl, or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 nng atoms in which at least 1 ring atom is a N, 0 or S atom, the alky! portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; R<4>isH, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl. -2(-heterocycle)tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.tert-butyldimethylsilyloxy), R<5->L-, or combinations thereof, or heteroar<y>l having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy,, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, tnfluoromethyl, ammo, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy R<3->L-, dialkylamino-L-, or combinations thereof; R<5>is H, alkyl having 1 to 8 carbon atoms, which is unsubstituted or substituted one or more times with halogen, Ci-4-alkyl, C|-4-alkoxy, oxo, or combinations thereof, alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8 carbon atoms, a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has I to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy,_oxo, cyano, alkoxy, alkyl having 1 to 4 carbon atoms, or combinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano. hydroxy, alkyl, alkoxy or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, or combinations thereof, arylalkyl having 7 to 19 carbon atoms, wherein the aryl'portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl, a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring'atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl, hydroxamic acid, tetrazoie-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl, cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof, or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 nng atom is a N, 0 or S atom, and the alkyl portion which is branched or unbranched and has I to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, c<y>ano, trifiuoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof; L is a single bond or a divalent aliphatic radical having 1 to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -0-, -S-, -NR<6->, -S02NH-, -NKSOr, -CO-, -NR<6>CO-, -CONR<6->, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH-; andR6 is H, or alkyl having 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Q-4-alkyl, Ci-4-alkoxy, oxo, or combinations thereof; wherein at least one of R3 and R<4>is other than :H; and pharmaceutical^ acceptable salts thereof.

59. A compound sleeted from: a) 3-Cyclopentyl-4-methoxy-N-(3-pyridyLmethyl)aniline; • b) 3-/err-Butyldimethylsilyloxy-4-methoxy-N-(3-pyridylmethyl)aniline; c) 3-ferr-Butyldimethylsilyloxy-4-methoxy-JY-(3-pyridylmethyl)dipheny!amine; d) S-rerf-Butyldimethylsilyloxy-S'-chloro^-methoxy-Y^S-pyridylmethyl)diphenylamine e) Ethyl ^-{S-rerf-butyldimethylsilyloxy^-methoxyphenyO-.Y^S-pyridylmethyl)-3-aminobenzoate; f) 3-Cyclopentyloxy-4-methoxydiphenylamine; g) 3-Hydroxy-4-methoxy-N-(3-pyndylmethyl)diphenylamine; h) 3'-Chloro-3-hydroxy-4-methoxy-/Y-(3-pyridylmethyl)diphenylamine; i) Ethyl yV-(3-hydroxy<->4-methox<y>phen<y>l)-A/-(3-pyridylmethyl)-3-ammobenzoate; j) 3 '-{2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-N-{3-pyndylrnethyl)diphenylamine; k) 4'-[l-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-methoxy-/V-(3-pyndylrnethyl)diphenylamine; and 1) 4-hydroxy-3-cyclopenthloxy-N-(3 -pyndylmethyi)diphenlamine.. (57)Abstract:PDE4 inhibition is achieved by novel compounds, e.g.. N-substituted aniline and diphenylamine analous. The compounds of the presem invention are of Formula 1: wherein R<1>, R;, R<J>and R~are as defined herein. PHOSPHODIESTERASE 4 INHIBITORS This application claims benefit of U.S. Provisional application Senal No. 60/262,651, filed January 22, 2001, U.S. provisional application Senal No. 60/267,196, filed February 3, 2001, and U.S. Provisional application Senal No. 60/306,140, filed July 14,2001. FIELD OF THE INVENTION The present invention relates generally to the field of phosphodiesterase 4 (PDE4) enzyme inhibition. More specifically this invention relates to selective PDE4 inhibition by novel compounds, e.g., TV-substituted aniline and diphenylamine analogs, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof. BACKGROUND OF THE INVENTION The cyclic nucleotide specific phosphodiesterases (PDEs) represent a family of enzymes that catalyze the hydrolysis of various cyclic nucleoside monophosphates (including cAMP and cGMP). These cyclic nucleotides act as second messengers within cells, and as messengers, carry impulses from cell surface receptors having bound various hormones and neurotransmitters. PDEs act to regulate the level of cyclic nucleotides within cells and maintain cyclic nucleotide homeostasis by degrading such cyclic mononucleotides resulting in termination of their messenger role. PDE enzymes can be grouped into eleven families according to their specificity toward hydrolysis of cAMP or cGMP, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds. For example, PDE I is stimulated by Ca<2+>/calmodulin. PDE 2 is cGMP-dependent, and is found in the heart and adrenals. PDE 3 is cGMP -dependent, and inhibition of this enzyme creates positive inotropic activity. PDE 4 is cAMP specific, and its. inhibition causes airway . relaxation, antiinflammatory and antidepressant activity. PDE 5 appears to be important in regulating cGMP content in vascular smooth muscle, and therefore PDE 5 inhibitors may have cardiovascular activity. Since the PDEs possess distinct biochemical properties, it is likely that they are subject to a variety of different forms of regulation. PDE4 is distinguished by various kinetic properties including low Michaelis constant for cAMP and sensitivity to certain drugs. The PDE4 enzyme family consists of four genes, which produce 4 isoforms of the PDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [See: Wang et al. Expression, Punfication, and Characterization of human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D,Biochem. Biophys. Res. Comm.,234, 320-324 (1997)] In addition, various splice variants of each PDE4 isoform have been identified. PDE4 isoenzymes are localized in the cytosol of cells and are unassociated with any known membranous structures. PDE4 isoenzymes specifically inactivate cAMP by catalyzing its hydrolysis to adenosine 5'-monophosphate (AMP). Regulation of cAMP activity is important in many biological processes, including inflammation and memory. Inhibitors of PDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo are powerful antiinflammatory agents and therefore may be'useful in treating diseases where inflammation is problematic such as asthma or arthritis. Further, rolipram improves the cognitive performance of rats and mice in learning paradigms. In addition to such compounds as rolipram, xanthine derivatives such as pentoxifylline, denbufylline, and theophylline inhibit PDE4 and have received considerable attention of late for their cognition enhancing effects. cAMP and cGMP are second messengers that mediate cellular responses to many different hormones and neurotransmitters. Thus, therapeutically significant effects may result from PDE inhibition and the resulting increase in intracellular cAMP or cGMP in key cells, such as those located in the nervous system and elsewhere in the body. Rolipram, previously in development as an anti-depressant, selectively inhibits the PDE4 enzyme and has become a standard agent in the classification of PDE enzyme subtypes. Early work in the PDE4 field focused on depression and inflammation, and has subsequently been extended to include indications such as dementia, [see "The PDE TV Family Of Calcium-Phosphodiesterases Enzymes," John A. Lowe, III, et al., Drugs of the Future 1992, 17(9):799-807 for a general review). Further clinical developments of rolipram and other first-generation PDE4 inhibitors were terminated due to the side effect profile of these compounds. The primary side effect in primates is emesis, while the primary side effects in rodents are testicular degranulation, weakening of vascular smooth muscle, psychotrophic effects, increased gastric acid secretion and stomach erosion. SUMMARY OF THE INVENTION The present invention relates to novel compounds, e.g., novel TV-substituted aniline and diphenylamine compounds, that inhibit PDE4 enzymes, and especially have improved side effect profiles, e.g., are relatively non-emetic, (e.g., as compared to the previously discussed prior art compounds). Preferably, the compounds selectively inhibit PDE4 enzymes. The compounds of this invention at the same time facilitate entry into cells, especially cells of the nervous system. Still further, the present invention.provides methods for synthesizing compounds with such activity and selectivity as well as methods of (and corresponding pharmaceutical compositions for) treating a patient, e.g., mammals, including humans, requiring PDE inhibition, especially PDE4 inhibition, for a disease state that involves elevated intracellular PDE 4 levels or decreased cAMP levels, e.g., involving neurological syndromes, especially those states associated with memory impairment, most especially long term memory impairment, as where such memory impairment is dueinpan to catabolism of intracellular cAMP levels by PDE 4 enzymes, or where such memory impairment may be improved by effectively inhibiting PDE4 enzyme activity. In a preferred aspect, the compounds of the invention improve such diseases by inhibiting PDE4 enzymes at doses which do not induce emesis. The present invention includes compounds of Formula I: wherein R<1>is alkyl having 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen (e.g., CH3, CHF2, CF3, etc.); R<2>is alkyl having 1 to 12, preferably 1 to 8 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times by halogen, hydroxy, cyano, Ci-4-alkoxy, oxo or combinations thereof, and wherein optionally one or more -CH2CH2- groups is replaced in each case by -CH=CH- or -C = C- (e.g., CH3, CFfF2, CF3, methoxyethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion andVor the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, Ci-4-alkyl, C|-4-alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, cyano, or combinations thereof (e.g., methylphenyl, mefhoxyphenyl, chlorophenyl, etc.), arylalkyl in which the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, which the arylalkyl radical is unsubstituted or is substituted in the aryl portion one or more times by halogen, CF3, OCF3, alkyl, hydroxy, alkoxy, nitro, cyano, methylenedioxy, ethylenedioxy, or combinations thereof, and wherein in the alkyl portion one or more -CFkCHj- groups are each optionally replaced by -CH=CH- or -C = C-, and one or more -CHj- groups are each optionally rep laced by -0- or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., phenylethyl, phenylpropyl, phenylbutyl, methoxyphenylethyl, methoxyphenylpropyl, chlorophenylethyl, chlorophenylpropyl, phenylethenyi, phenoxyethyl, phenoxybutyl, chlorophenoxyethyl, chlorophenylaminoethyl, etc.), a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, which is unsubstituted or substituted one or more times by halogen, alkyl, alkoxy, hydroxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenyl, cyclohexadienyl, indanyl, tetrahydronaphthenyl, etc.), a heterocyclic group, which is saturated, partially saturated or unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, which is unsubstituted or substituted one or more times by halogen, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof (e.g., 3-thienyi, 3-tetrahydrofuranyi, 3-pyrrolyl, etc.), or a heterocycle-alkyl group, wherem the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 nng atom is a N, O or S atom, and the alkyl portion is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is - unsubstituted or substituted one or more times in the heterocyclic portion by halogen, OCFj, hydroxy, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, or combinations thereof, wherein in the alkyl portion one or more -CH2CH?- groups are each optionally replaced by -CH=CH- or ~ C = C-, and one or more -CH?- groups are each optionally replaced by -0-or -NH- and/or the alkyl portion is optionally substituted by halogen, oxo, hydroxy, cyano, or combinations thereof (e.g., pyridylethyl, pydridylpropyl, methylpiperazinylethyl, etc.); R<3>is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, cyano, Ci-4-alkoxy, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion which is branched or unbranched has 1 to 5 carbon atoms, and which is unsubstituted or substituted in the carbocyclic portion one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof, and the alkyl portion is optionally substituted by halogen, C|-4-alkoxy, cyano or combinations thereof (e.g., cyclohexenylmethyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF30, nitro, amino, alky!, alkoxy, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyl, etc.), or heteroarylalkyl group, wherein the heteroaryl portion may be partially or fully saturated and has 5 to 10 nng atoms in which at least 1 ring atom is a N, 0 or S atom, the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, the heteroarylalkyl group is unsubstituted or substituted one or more times in the heteroaryl portion by halogen, alkyl, alkoxy, cyano, tnfluoromethyl, CF3O, nitro, oxo, ammo, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridyimethyl, pyridylpropyl, methylpyrdylmethyl, chloropyndylmethyl, dichloropyndylmethyl, thienylmethyl, thiazolylmethyl, quinolinylmethyl, isoquinolinylmethyl, piperidinylmethyl, furanylmethyl, imidazolylmethyl, methylimidazolylmethyl, pyrrolylmethyl, etc.); R<4>isH, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, OCF3, amino, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg, hydroxymethyl), hydroxamic acid, tetrazole-5-yl, 2(-heterocycle)tetrazole-5-yl (eg, 2-(2-tetrahydropyranyl)tetrazole-5-yl)Jhydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.tert-butyldimethylsilyloxy), R<5->L-, or combinations thereof (e.g., substituted or unsubstituted phenyl, naphthyl, and biphenyl, such as phenyl, methylphenyl,_chlorophenyl, fiuorophenyi, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyi, ethoxycarbonylphenyi, dimeth<y>lphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), or heteroaryl having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg, hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy, trialkylsilyloxy (eg.tert-butyldimethylsilyloxy), R<3->L-, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyi, imidazoiyl, thiazolyl, etc.); R<5>isH, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is unsubstituted or substituted one or more times with halogen, G-4-alkyl, G-4-alkoxy,. oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.), alkylamino or dialkylamino wherein each alkyl portion has independently 1 to 8, preferably 1 to 4 carbon atoms (e.g., dimethylamino, etc.), a partially unsaturated carbocycle-alkyl group wherein the carbocyclic portion has 5 to 14 carbon atoms and the alkyl portion has 1 to 5 carbon atoms, which is unsubstituted or substituted, preferably in the carbocyclic portion, one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, or combinations thereof (e.g., cyclohexenylmethyl, etc.), cycloalkyl having 3 to 10, preferably 3 to 8 carbon atoms, which is unsubstituted or substituted one or more times by halogen, hydroxy, oxo, cyano, alkoxy, alkyl having ! to 4 carbon atoms, or combinations thereof (e.g., cyclopentyl), cycloalkylalkyl having 4 to 16, preferably 4 to 12 carbon atoms, which is unsubstituted or substituted in the cycloalkyl portion and/or the alkyl portion one or more times by halogen, oxo, cyano, hydroxy, alkyl, alkoxy or combinations thereof (e.g., cyclopentylmethyl, cyclopropylmethyl, etc.), aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, trifiuoromethyl, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg, hydroxymethyl), hydroxamic acid, tetrazole-5-yl, hydroxyalkoxy, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkyithio, alkylsulfinyl, alkylsulfonyl, (e.g., substituted or unsubstituted phenyl and naphthyl, methyfphenyi, chlorophenyl, fiuorophenyi, vinylphenyl, cyanophenyl, methylenedioxophenyl, ethylphenyl, dichlorophenyl, carboxyphenyl, ethoxycarbonylphenyl, dimethylphenyl, hydroxymethylphenyl, nitrophenyl, aminophenyl, etc.), arylalkyl having 7 to 19 carbon atoms, wherein the aryl portion has 6 to 14 carbon atoms and the alkyl portion, which is branched or unbranched, has 1 to 5 carbon atoms, arylalkyl radical is unsubstituted or substituted, in the aryl portion, one or more times by halogen, trifiuoromethyl, CF3O, nitro, amino, alkyl, alkoxy, amino, alkylamino, dialkylamino and/or substituted in the alkyl portion by halogen, cyano, or methyl (e.g., benzyl, phenethyl, phenpropyl, methylbenzyl, methoxybenzyl, trfluoromethyl, benzyl, methylenedioxobenzyi, etc.), a heteroc<y>clic group, which is saturated, partially saturated or unsaturated, having 5 to 10 nng atoms in which at least 1 nng atom is a N, 0 or S atom, which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, alkoxyalkoxy, nitro, methylenedioxy, ethylenedioxy, tnfluoromethyi, amino, aminomethyl, aminoalkyl, aminoalkoxy dialkylamino, hydroxyalkyl (eg, hydroxymethyi), hydroxamic acid, tetrazole-5-yl, h<y>droxyalkox<y>, carboxy, alkoxycarbonyl (e.g., tert-butyloxycarbonyl, ethoxycarbonyl), cyano, acyl, alkyithio, alk<y>lsulfinyl, alkylsulfonyl, phenoxy, or combinations thereof (e.g., pyridyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyrimidinyl, imidazolyl, thiazolyl, etc.), or a heterocycle-alkyl group, wherein the heterocyclic portion is saturated, partially saturated or unsaturated, and has 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and the alkyl portion which is branched or unbranched and has 1 to 5 carbon atoms, the heterocycle-alkyl group is unsubstituted or substituted one or more times in the heterocyclic portion by halogen, alkyl, alkoxy, cyano, trifiuoromethyl, CF3O, nitro, oxo, amino, alkylamino, dialkylamino, or combinations thereof and/or substituted in the alkyl portion by halogen, cyano, or methyl or combinations thereof (e.g., pyridyimethyl, pyridylpropyl, methylpridylmethyl, etc.); L is a single bond or a divalent aliphatic radical having I to 8 carbon atoms wherein one or more -CH2- groups are each optionally replaced by -0-, -S-, -NR<6->, -SO2NH-, -NHSO2-, -CO-, -NR<6>CO-, -CONR<6->, -NHCONH-, -OCONH, -NHCOO-, -SCONH-, -SCSNH-, or -NHCSNH- (e.g.,-0-, CH2-, -CO-, -CO-O-, -O-CO-, -CO-NH-, -NH-CO-, -CH2CH2CH2-NH-CO-, -CIVCH2-O-, -S02-NH-CH2CH2-0-, -0-CH2CH,-0-, -CH2-NH-CO-, -CO-NH-CH,-, -S02-NH-, -CH2-N<H>-S02-, -CH2CH2CH?-SOr NH-, etc.); and R • is H, alkyl having 1 to 8, preferably 1 to 4 carbon atoms, which is branched or unbranched and which is unsubstituted or substituted one or more times with halogen, Ci-4-alkyl, Ci-4-alkoxy, oxo, or combinations thereof (e.g., methyl, ethyl, propyl, etc.); wherein at least one of R3 and R<4>is other than H; and pharmaceutically acceptable salts thereof. According to a further aspect of the invention there is provided a genus of novel compounds according to the formulas II and III: wherein R<1>, R<2>, R<3>, and R<4>are as defined above. The compounds of this subgenus of formula I not only have PDE4 inhibitory activity, but also are useful as intermediates for preparing compounds of Formula I in which R<3>and R<4>are both other than H. In addition, preferred compounds of formula I are those of the subformula IV wherein R<1>, R<2>, and Rd are as defined in Formula I and one of A, B and D is N and the others are C. Preferably, B is N. Also, Ra is preferably pyridyl or phenyl which in each case is substituted or unsubstituted. The present invention also includes compounds of Formula I': wherein R<1>' is methoxy, F, CI, CHF; or CF3; R<2>' is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, alkenyl having 2 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, alkynyl having 2 to 12 carbon atoms, alkynyl having 2 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano or combinations thereof, cycloalkyl having 3 to 10 carbon atoms, cycloalkyl having 3 to 10 carbon atoms substituted one or more times by halogen, oxo, alkyl, or combinations thereof, cycioalkylalkyl having 4 to 12 carbon atoms, cycloalkylaikyl having 4 to 12 carbon atoms which is substituted one or more times by halogen, oxo, alkyl or combinations thereof, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms, a partially unsaturated carbocyclic group having 5 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, alkyloxy, mtro, cyano, oxo, or combinations thereof, arylalkyl having 7 to 26 carbon atoms arylalkyl having 7 to 26 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, mtro, cyano, oxo, trifiuoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; X isOorS, R<J>is aryl having 6 to 14 carbon atoms, aryl having 6 to 14 carbon atoms which is substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alk<y>ithio, alkylsulfinyl, alkylsulfonyl, phenoxy, heteroaryl which is unsubstituted or substituted by halogen, alkyl or alkoxy, or combinations thereof, heteroaryl having 5 to 10 nng atoms in which at least 1 ring atom is a heteroatom, or substituted heteroaryl having 5 to 10 nng atoms in which at least 1 ring atom is a heteroatom which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof;' L is -NH-, -NR<4>'-, -NHCH-2-, -NR<4>'CH2-, or -CH2NR<4>'-; and R4 is alkyl having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms which is substituted one or more times by halogen, oxo, cyano, or combinations thereof, aryl having 6 to 14 carbon atoms and which is unsubstituted or substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkyithio, alkylsulfinyl, alkylsulfonyl, phenoxy or combinations thereof, heteroaryl having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom, substituted heteroaryl having 5 to L0 nng atoms in which at least 1 nng atom is a heteroatom and which is substituted one or more times by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof, arylalkyl having 7 to 16 carbon atoms, arylalkyl having 7 to 16 carbon atoms which is substituted one or more times by halogen, alkyl, alkoxy, nitro, cyano, oxo, trifiuoromethyl, or combinations thereof, heteroarylalkyl having 5 to 10 ring atoms in which at least 1 nng atom is a heteroatom, or substituted heteroarylalkyl having 5 to 10 ring atoms in which at least 1 ring atom is a heteroatom and which is substituted one or more times in the heteroaryl portion by halogen, aryl, alkyl, alkoxy, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, dialkylamino or combinations thereof and/or substituted in the alkyl portion by halogen, oxo, cyano, or combinations thereof; and pharmaceutical^ acceptable salts thereof. The compounds of the present invention are effective in inhibiting, or modulating the activity of PDE4 in animals, e.g., mammals, especially humans. These compounds , exhibit neurological activity, especially where such activity affects cognition, including long term memory. These compounds will also be effective in treating diseases where decreased cAMP levels are involved. This includes but is not limited to inflammatory diseases. These compounds may also function as antidepressants, or be useful in treating cognitive and negative symptoms of schizophrenia. Assays for determining PDE inhibiting activity as well as selectivity of PDE 4 inhibiting activity and selectivity of inhibiting PDE 4 isoenzymes are known within the an. See, e.g., US 6,136,821, the disclosure of which is incorporated herein by reference. According to a further aspect of the invention there'are provided compounds useful as intermediates for the production of the PDE4 inhibitors described herein (e.g., PDE4 inhibitors of Formula I) and/or useful for the synthesis of radio-labeled analogs of the PDE4 inhibitors with in this application. Thus, there are provided intermediate compounds which correspond to compounds of Formula I, wherein R<2>, R<J>, and R<4>are as previously defined for Formula I, but R<1>is H, rerr-butyldimethylsilyl-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are described, for example'; in Greene, T.W. and Wuts, P.G.M, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. These intermediates are also useful for the synthesis of radio-labeled compounds, such as where R<1>is ^C-,<14>CH3- or "CHj-, for example by removing the protecting group and reacting the resultant compound in which R<1>is H with suitable radio-labelled reagents. Such radio-labeled compounds are useful for determining compound tissue distribution in animals, in PET imaging studies, and for in vivo, ex vivo, and in vitro binding studies. Also provided are intermediate compounds which correspond to compounds of Formula I, wherein R<l>, R<3>, and R<4>are as previously defined for Formula I, but R<2>is H,ferf-butyldimethylsilyloxy-, or a suitable phenolic protecting group. Suitable phenolic protecting groups are descnbed, for example, in Greene, T.W. and Wuts, P.G.M., • Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 246-293. Compounds in which R<2>is H are useful as intermediates, for example, as scaffolds for parallel or combinatorial chemistry applications. Further, these compounds are useful for the introduction of radio-labels such as 3H, l4C, or 1 'C. As previously described, compounds according to formula II, wherein R , R"and R<4>are as previously described are useful intermediates for the production of compounds according to formula I where in R<J>is other than H. Also, as previously described, compounds according to formula III, wherein R!, R<2>and R<J>are as previously described are useful intermediates for the production of compounds according to formula I where in R4 is other than H. Halogen herein refers to F, CI, Br, and I. Preferred halogens are F and CI. Alkyl, as a group or substituent per se or as pan of a group or substituent (e.g., alkylamino, trialkylsilyloxy, aminoalkyl, hydroxyalkyl), means a straight-chain or branched-chain aliphatic hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, especially 1 to 4 carbon atoms. Suitable alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples of suitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyi, 1- or 2-ethylbutyl, ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl, ethylpentyl, ethylmethylbutyl, dirnethylbutyl, and the like. Substituted alkyl groups are alkyl groups as described above which are substituted in one or more positions by halogens, oxo, hydroxyl, G-4-alkoxy and/or cyano.. Halogens are preferred substituents, especially F and CI. Alkoxy means alkyl-O- groups and alkoxyalkoxy means alkyl-O-alkyl-O- groups"in which the alkyl portions are in accordance with the previous discussion. Suitable alkoxy and alkoxyalkoxy groups include methoxy, ethoxy, propoxy, butoxy, peatoxy, hexoxy, heptoxy, octoxy methoxymethoxy ethoxymethoxy, propoxymethoxy, and methoxyethoxy. Preferred alkoxy groups are methoxy and ethoxy. Similarly, alkoxycarbonyl means alkyl -O-CO- in which the alkyl portion is in accordance with the previous discussion. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl. Cycloalkyl means a monocyclic, bicyclic or tricyclic nonaromatic saturated hydrocarbon radical having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, especially 3 to 6 carbon atoms. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, 1-decalin, adamant-1-yl, and adamant-2-yl. Other suitable cycloalkyl groups include spiropent<y>l, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, btcyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Preferred cycloalklyl groups are cyclopropyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be substituted, for example, substituted by halogens and/or alkyl groups. Cycloalkylalkyl refers to cycloalkyl-alkyl radicals in which the cycloalkyl and alkyl portions are in accordance with previous discussions. Suitable examples include cyclopropylmethyl and cyclopentylmethyl. Aryl, as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, especially 6 to 10 carbon atoms. Suitable aryl groups include phenyl, naphthyl and biphenyl. Substituted aryl groups include the above-described aryl groups ■ which are substituted one or more times by, for example, halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkyithio, alkylsulfinyl, alkylsulfonyl, and phenoxy. Arylalkyl refers to an aryl-alkyl-radica! in which the aryl and alkyl portions are in accordance with the previous descriptions. Suitable examples include benzyl, 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl, phenpentyl, and napthylmethyl. Heteroaryl refers to an aromatic heterocyclic group having one or two rings and a total number of 5 to 10 nng atoms wherein at least one of the ring atoms is a heteroatom. Preferably, the heteroaryl group contains 1 to 3, especially 1 or 2, hetero-ring atoms which are selected from N, O and S. Suitable heteroaryl groups include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tnazolyl, tetrazolyl, dithialyl, oxathialyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazoiyl, thiadiazolyl, pyridyl, pyridazmyl, pyrimidinyl, pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazmyl, oxadiazinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indolyl, isoindolyl, indazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzisothiazolyl, purinyl, benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyndinyl, and benzoxazinyl, e.g., 2-thienyl, 3-thienyl, 2-,

3- or 4-pyirdyl, 2-, 3-, 4-, 5-, 6-, 7- or 3-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7- or S-isoquinolinyl. Substituted heteroaryl refers to the heteroaryl groups described above which are substirued in one or more places by, for example, halogen, aryl, alkyl, alkoxy, carboxy, methylene, cyano, trifiuoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino. Heterocycles include heteroaryl groups as described above as well as non-aromatic cyclic groups containing at least one hetero-ring atom, preferably selected from N, S and O, for example, tetrahydrofuranyl, piperidinyl, and pyrrolidinyl. Heterocycle-alkyl refers to a heterocycle-alkyl-group wherein the heterocyclic and alkyl portions are in accordance with the previous discussions. Suitable examples are pyridyimethyl, thienylmethyl, pyrimidinylmethyl, pyrazinylmethyl, and isoqumolinylmethyl. Partially unsaturated carbocyclic structures are non-aromatic monocyclic or bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to 10 carbon atoms, wherein the nng structure(s) contains at least one C=C bond. Suitable examples are cyclopentenyl, cyclohexenyl, cyclohexadienyl, tetrahydronaphthenyl and indan-2-yl. Alkenyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures are each replaced by - CH=CH-. Suitable alkenyl groups are ethenyl, 1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and 2-pentenyl. Alkynyl refers to straight-chain or branched-chain aliphatic radicals containing 2 to 12 carbon atoms in which one or more -CH2-CH2- structures, are each replaced by • C = C-. Suitable alkynyl groups are ethynyl, propynyl, 1-butynyl, and 2-butynyl. Acyl refers to alkanoyl radicals having I to 13 carbon atoms in which the alkyl portion can be substituted by halogen, alkyl, aryl and/or alkoxy, or aroyl radicals having 7 to 15 carbon atoms in which the aryl portion can be substituted by, for example, halogen, alkyl and/or alkoxy. Suitable acyl groups include formyl, acetyl, propionyl, butanoyl and benzoyl. Substituted radicals preferably have 1 to 3 substituents, especially 1 to 2 substituents. In the compounds of Formula I, R<1>is an alkyl group having preferably 1 to 4 carbon atoms which is optionally substituted by halogen, preferably fluorine or chlorine. In particular, R1 is preferably methyl or difluoromethyl. R<2>is preferably cycloalkyl, particularly cyclopentyl. R<2>is also preferably aryl or arylalkyl, particularly substituted or unsubstituted phenyl or phenylalkyl, such as phenyl, methylphenyl, methoxyphenyl, chlorophenyl, phenethyl, phenpropyl, phenbutyl, phenylethenyl, phenoxyethyl, phenoxypropyl, phenoxybutyl, chlorophenylethyl, methoxyphenyl ethyl, chlorophenylethenyl, chlorophenoxyethyl, chlorophenypropyl, methoxyphenpropyl, methoxyphenbutyl, chiorophenbutyl, nitrophenbutyl, chlorophenylaminoethyl, and the like, R2 is also preferably a partially unsaturated carbocyclic groups, which is unsubstituted or substituted, particularly cyclohexenyi, cyclohexadienyl, indan-2-yl. R<2>is also preferably an alkyl group having 1 to 8 carbon atoms, especially 1 to 4 carbon atoms, which is substituted or unsubstituted, e.g., methyl, difluoromethyl, trifiuoromethyl, and methoxyethyl. R<2>is also preferably a heterocyclic or heterocycle-alkyl group, particularly radicals in which the heterocyclic group has 5 to 6 ring atoms and 1 to 2 hetero-ring atoms selected from N, 0 and S, e.g., tetrahydrofuranyl, pyrrolidinyl, pyrrolyl, pyridyimethyl, pyridylethyl, pyridylpropyl, piperazinylmethyl, piperazinyiethyl, methylpiperazinylethyl and the like. Preferred R<2>include cyclopentyl, tetrahydrofuranyl, CHF\, methoxyethyl, . cyclopropylmethyl, phenethyl, phenpropyl, phenylethenyl, phenoxyethyl, phenoxybutyl, phenylaminoethyl, indan-2-yl, pyridylethyl, and pyridylpropyl. R<3>is preferably hydrogen, alkyl having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, or n-butyl), arylalkyl (e.g., substituted or unsubstitituted benzyl, phenethyl, and phenpropyl), or a heteroarylalkyl group (e.g., substituted or unsubstituted pyridyimethyl, furanylmethyl, thienylmethyl, pyrrolylmethyl, pynmidinylmethyl, thiazolylmethyl, isoquinolinylmethyl and quinolinylmethyl). Preferred substituents for aryl and heteroaryl portions of RJ are F, CI, CH3, C2H5, OCH3, and CN. R4 is preferably aryl, or heteroaryl, especially phenyl, naphthyl, biphenyl, furanyl, pyrazinyl, pyrimidinyl, pyridyl, quinolin<y>l, and isoquinolinyl, which in each case is unsubstituted or is substituted one or more times. Preferred substituents are OH, F, CI, CF;,, alkyl (such as methyl or ethyl), alkoxy (such as methoxy and ethoxy), CN, vinyl, CH?OH, CONHOH, CONH2, methylenedioxy, COOH, and combinations thereof. In addition, when R<4>is aryl, especially, phenyl, preferred substituents include R<J->L-, e.g., R<5->, R<5->0-, R<5->CO-, R<5->NH-CO-, R<5->S02-NH-, R<5->S02-NH-alkvlene-0-, NH2-alkyl-NH-CO-, R<5->alkylene-NH-CO-, alkyl-CO-NH-alkyl- as well as methyl, ethyl, CI, F, CN, OCH2, CF3, ammo, nitro, HOCH2and COOH. When R<4>is aryl substituted by R:,-S02-NH- it is preferably a substituted phenyl group and R<3>is preferably methyl, ethyl, propyl or phenyl. When R<4>is aryl substituted by Ri<->S02-NH-alkylene-0- it is preferably a substituted phenyl. In such cases, R<5>is preferably methyl, ethyl, propyl or phenyl and alkylene is preferably -CH2-, -CH2CH2- or -CH2CH2CH2-. When R4 is aryl substituted by R<J->L- it is preferably substituted phenyl. In such cases, preferred R^ groups include tetrazolyl, oxazinyl, piperazinyl, methylpiperazinyl, pyridyl, methylpyridyl, pyrrolinyl, methylpyrrolinyl, piperadinyl, or methylpiperadinyl, and L is preferably a single bond, -0-, -CO-, -CHr, -CH2CH2-, -CH2CH2CH2-, -CH2-0-, -CH2CH2-O-, -CH2CH2CH2-0-, -CH2-NH-CH2CH2-0-, -CO-NH- or -NH-CO-. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by sub formulas Ia-Fh which correspond to formula I but exhibit the following preferred groups: la R1 is methyl or CHF2; R<2>is alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, heterocycle-alkyl, cycloaikylalkyl, aryl, or heterocyclic, in each case substituted or unsubstituted; R3 isH, alkyl, arylalkyl or heteroarylalkyl, in each case substituted or unsubstituted; and R4 is aryl or heteroaryl, in each case substituted or unsubstituted. lb R<3>is heteroarylalkyl which is substituted or unsubstituted. Ic R<1>is methyl or CHP2; and R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl). Id R1 is methyl or CHF2; R2 is cyclopentyl; R3 is heteroarylalkyl, in each case substituted or unsubstituted; and R4 is substituted or unsubstituted aryl or heteroaryl. Ie R<1>is methyl; R2 is cyclopentyl; and R<3>is heteroarylalkyl which is substituted or unsubstituted. If R<1>is methyl; R2 is cyclopentyl; R3 is heteroarylalkyl which is substituted or unsubstituted; and R4 is phenyl which is substituted or unsubstituted. Ig R<1>is methyl; R<2>is cyclopentyl; RJ is pyridyimethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, or pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R4 is phenyl or phenyl substituted with 1 to 3 substituents. Ih R<1>is methyl; R2 is cyclopentyl; RJ is pyridyimethyl, phenethyl, benzyl, thienylmethyl, pyridylpropyl, piperidinylmethyl, pyrazinylmethyl, which in each case is substituted or unsustituted, or methyl, ethyl, or propyl; and R<4>is phenyl, naphthyl, biphenyl, pyridyl, pyrimidinyl, thiazolyl, pyrazinyl, quinolinyl, or isoquinolinyl, in each case substituted or unsubstituted. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas lla-IId which correspond to formula II but exhibit the following preferred groups: ria R<1>is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridyiethyl), or tetrahydrofuranyl (particularly (3R)-tetxahydrofuranyl); and R<4>is phenyl, naphthyl, pyridyl, quinolinyl,"or isoquinolinyl, which in each case is substituted or unsubstituted. lib R' is methyl or CHFv, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyndylethyi (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and R<4>is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, amino, carboxy, hydroxymethyi, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. lie R<1>is methyl; R<2>is cyclopentyl; and R<4>is phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl, which in each case is substituted or unsubstituted. lid R<1>is methyl; R<2>is cyclopentyl; and R<4>is phenyl which is unsubstituted or substituted by methyl, ethyl, methoxy, CI, F, CF3, vinyl, cyano, ammo, carboxy, hydroxymethyi, or ethylsulfonamido, or is 3-pyridyl which is unsubstituted or substituted by carboxy or alkoxycarbonyl. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas Hla-IIId which correspond to formula III but exhibit the following preferred groups: Ilia R<1>is methyl or CHF2; R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyi), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl); and R3 isbenzyl, phenethyl, cyclohexenylmethyl, furanylrnethyl, thienylmethyl, pyridyimethyl, quinolinymethyl, isoquinolinylmethyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted. nib R' is methyl or CHF2; R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetTahydrofuranyl); and R3 is pyrazinylmethyl, pyrimidinylmethyi or pyndylmethyl, which in each is unsubstituted or substituted. Die R<l>is methyl; R2 is cyclopentyl; and R<J>is benzyl, phenethyl, cyclohexenylmethyl, furanylrnethyl, thienylmethyl, pyrazinylmethyl, pyrimidinylmethyl, pyridyimethyl, qumolinymethyl, isoqumolinylmethyl, isovmidazolyl, thiazolylmethyl, or pyrrolylmethyl, which in each case is substituted or unsubstituted. Did R<1>is methyl; R" is cyclopentyl; and R<J>is pyrazinylmethyl or pyridyimethyl, which in each is unsubstituted or substituted. In addition, preferred PDE4 inhibitors in accordance with the invention are compounds described by subformulas PVa-IVp which correspond to formula IV but exhibit the following preferred groups: rVa R<1>is methyl or CHF2. IVb R<1>is methyl or CHF2, and B is N. rVcR<1>is methyl or CHF2, and R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl). TVd R' is methyl or CHF2, B is N, and R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (jR)-tetrahydrofuranyl). IVe R<1>is methyl or CHF2, and R<4>is 3-pyndyl or phenyl, which in each case is substituted or unsubstituted. IVf R' is methyl or CHF2, B is N, and R<4>is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. rVg R<1>is methyl or CHF2, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R<4>is 3-pyridyl or phenyl, which in each case is substituted or unsubstituted. IVh R1 is methyl or CHF2l B is N, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyTidylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R"<1>is 3-pyridyt or phenyl, which in each case is substituted or unsubstituted. IVi R<l>is methyl or CHF2, and R" is phenyl which is substituted in the 3- or 4- position. rVj R' is methyl or CHF2, B is N\and R<4>is phenyl which is substituted in the 3- or 4- position. IVk R<1>is methyl or CHF2, R<2>is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R4 is phenyl which is substituted in the 3- or 4- position. IVI R<1>is methyl or CHF2, B isN, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyndylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R4 is phenyl which is substituted in the 3- or 4- position. rVm R<1>is methyl or CHF2, and R<4>is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetra2ol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. IVn R<1>is methyl or CFTF2, B is N, and R4 is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyl, 4-pyndyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. IVo R<1>is methyl or CHF2, R2 is cyclopentyl, CHF2, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R<4>is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phen<y>l, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyi, 4-pyridyl, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. rv"p R<1>is methyl or CHF:, B is N, R<2>is cyclopentyl, CHFj, cyclopropylmethyl, pyridylethyl (particularly 2-pyridylethyl), or tetrahydrofuranyl (particularly (3R)-tetrahydrofuranyl), and R<4>is 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano-phenyl, 3-ethylsulfonamido-phenyl, 3-tetrazol-5-yl-phenyl, 3-hydroxymethyl-phenyi, 3-nitro-phenyl, 4-pyridyi, 4-COOH-phenyl, 4-cyano-phenyl, 4-ethylsulfonamido-phenyl, 4-tetrazol-5-yl-phenyl, or 4-hydroxymethyl-phenyl. Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of inhibiting a PDE4 enzyme, especially an isoenzyme, e.g., as determined by a conventional assay or one described herein, eitherin vitroorin vivo(in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating neurological syndrome, e.g., loss of memory, especially long-term memory, cognitive impairment or decline, memory impairment, etc. a method of treating a disease state modulated by PDE4 activity, in a mammal, e.g., a human,.e.g., those mentioned herein. The compounds of the present invention may be prepared conventionally. Some of the processes which can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials. Starting nitrophenols of the type 1 are either commercially available (e.g., Rl = CH3) or prepared by published procedures (e.g., Rl = CHF2or both Rl and R2 = CHP2, see Mueller, Klaus-Helmut. Eur. Pat. Appl. (1994), 8 pp. CODEN: EPXXDW EP 626361A1; Touma, Toshihiko; Asai, Tomoyuki. Jpn. Kokai Tokkyo Koho (1999), 6 pp. CODEN: JKXXAP JP 11071319 A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokietov, Victor.Int. Symp. Wood. Pulping Chem.,1995, 8th,3,

295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M. PCT Int. Appl. (1996), 12 pp. CODEN: PLXXD2 WO 9623754 Al 19960808). Aniline intermediates 3' are produced in two steps; first, an addition reaction provides intermediate 2, followed by reduction of the nitro group. Intermediate mtro compounds 2 can be prepared by numerous published procedures, such as by Mitsunobu reactions or standard alkylation reactions. Compounds where R2 is aryl or heteroaryi can be prepared by copper catalyzed reactions with aryi or heteroaryl iodides under UHman conditions or by coupling aryl-, vinyl-, or heteroaryl- boromc acids with phenol 2 in the presence of a copper catalyst (e.g., Cu(OAc)2) and base such as TEA. Mitsunobu reaction between an appropriately substituted nitrophenol and a primary or secondary alcohol using an azodicarboxylate (e.g., DEAD, DIAD), and a suitable phosphine (e.g., Ph3P, Bu3P) provides alkylated rutrophenols 2. Mitsunobu reactions are general performed in aprocic solvents such as dichloromethane or THF. Alternatively, alkylation can be achieved by the reaction between an appropriately substituted nitrophenol and an alkyl haiide in the presence of a. base (e.g., K2C03or NaH) in a polar aprotic solvent (e.g., DMF or CH3CN). Nitrocatechols 2 are subsequently reduced to the corresponding anilines 3 by methods standard in the art such as by hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., MeOH or EtOH) under an atmosphere of hydrogen. Alternatively, nitrocatechols 3 can be reduced by using a hydride source (e.g., NaBH4) and a transition metal catalyst (e.g., NiCb, Pd on carbon) or by using metals (e.g., Zn, Sn, Fe) in mineral acid solutions (e.g., HC1) to produce the corresponding anilines. Generally polar protic solvents such as ethanol or methanol are used in these reactions. /V-Arylalkylanilines 4 are synthesized by standard methods in the art such as by reductive amination reaction, alkylation reaction, or by reduction of corresponding amides. For example, the reductive amination reaction of an aryl or arylalkyl aldehyde with appropriately substituted anilines in the presence of a borohydride reducing agent such as NaBH4or NaBH3CN with an acid catalyst such as acetic acid or pTsOH provides desired/V-arylalkylanilines. These reactions generally take place in polar protic solvents such as methanol, ethanol, isopropanol, n-propanol and the like.. iV-Arylalkylanilin.es 4 readily undergo A/'-arylation by methods standard to the art including Ullman coupling reaction, metal-catalyzed coupling, or aromatic nucleophilic substitution reaction. For example, the metal catalyzed reaction between an/V-benzylamline and an aryl halide using a palladium catalyst, (e.g., Pd2dba3), a bulky electron ncn phosphme ligand (e.g., tributylphosphine), and suitable base (e.g., NaOtBu) provides /V-Arylalkyldiphenylamines. Nickel and copper catalysts have been employed as well. Solvents useful in this reaction include non-polar aprotic solvents such as toluene, benzene, xylenes, tetrahydrofuran, and ether. When synthesizing compounds of the type 5 wherein R4 is an alkoxycarbonylphenyl, it is advantageous that-amine 4 is coupled with 1.1 equivalents of .'err-butyl 3-iodobenzene and that 22 mol % of (tBu)3P, 5.5 mol % of Pd2(dba)3 and 1.3 equivalents of tBuONa are used. Carboxylic ester intermediates 6 can be hydrolyzed under acidic or basic conditions to give the corresponding carboxylic acids 7. For example, an ethyl ester (R5 = Et) can be hydrolyzed using a mixture of aqueous base (e.g., NaOH, KOFI) and a water miscible solvent (e.g., EtOH, THF). While r-Butyl esters (R5 = f-butyl) can be hydrolyzed using an aqueous acid (e.g., HC1, formic acid, TFA) in a water miscible organic solvent, if necessary. Coupling of protected tetrazole bromo or iodobenzsnes (e.g., 5-(3-iodophenyl)-2-(2-tetrahydropyran)tetrazole) with^-substituted aniline derivatives 4 produce THP-protected tetrazoles 8. Hydrolysis of THP-protected tetrazoles 8 can be accomplished by using an aqueous acid, such as HC1 in water and a miscible solvent such as THF or EtOH to provide tetrazoles 9. Further, THP tetrazoles 8 can also be oxidatively cleaved using reagents such as CAN and DDQ in halognenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane and the like to yield tetrazoles 9. Alternatively, tetrazole analogs 9 can be prepared from the corresponding nitriles by treatment with azide ion (e.g., KN3, NaN3, etc.) and a proton source (e.g., NH4C1) in a polar aprotic solvent such as DMF. They also may be prepared by treatment with an azide ion and a Lewis acid (e.g., ZnBr2) in water, using a water miscible co-solvent such as isopropanol if necessary. Another method of preparation is by treatment of a nitrile with tin or silicon azides (e.g., Me3SiN3, Bu3SnN3) in an aprotic organic solvent such as benzene, toluene, dichloromethane, dichloroethane, ether, THF, and the like. SCHEME 4 Diphenylamin.es 10 can be prepared by coupling appropriately substituted anilines 3, such as 3-cyclopentyloxy-4-methoxyarhline, with arylboronic acids in the presence of a base such as triethylamine and a copper catalyst such as copper acetate (as descnbed by Chan et al,Tetrahedron Lett.,39, 2933-2936 (1998)). In general, halogenated solvents such as dichloromethane, chloroform, dichloroethane, and the like as well as nonpolar aprotic solvents such as benzene, toluene, or xylene are utilized. Such diphenylamines (e.g., 10) can more preferably be synthesized by metal catalyzed amination reactions. For example, reaction of an appropriately substituted aniline 3 with an arylhalide in the presence of a base (e.g., K3PO4, CsCO}, or NaOtBu) and a palladium or nickel catalyst, for example Pd(dppf)C!2, a ligand (e.g., dppf) and a base (e.g., NaOtBu)( JACS.1996,

7 75, 7217) or with Pd2dba3, a bulky electron rich phosphine such as P(tBu)3, and a base (e.g., NaOtBu)( J. Org. Chem. 1999, 64, 5575)provides the desired diphenylamines 10. Solvents most commonly utilized in this type of reaction include non-polar aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, and the like. Diphenylamines 10 can then be alkylated with various alkyl halides or arylalkyl halides such as, but not limited to iodomethane, ethylbromide, benzylchloride, 3-(chloromethyl)pyridine, 4-(chloromethyl)-2,6-dichloropyridine, and 4-(bromomethyl)-benzoic acid, or salts thereof, in the presence of a non-nucleophilic base such as sodium hydride, potassium hexamethyldisilazide or potassium diisopropylamide to provideTV-substituted diphenylamines 5. Solvents useful in this reaction include aprotic solvents such as benzene, toluene, tetrahydrofuran, ether, DMF, and the like. Carboxylic acids 7 can be further manipulated to form carboxamides 11 using methods standard in the art. For example, a carboxylic acid can be treated with a suitable primary or secondary amine, in the presence of a suitable coupling reagent such as BOP, pyBOP or DCC, and a base such as Et3N or DIEA to yield a carboxamide. These reactions generally take place in non-polar aprotic solvents such as dichloromethane, chloroform, or dichloroethane. Carboxylic esters 6 or acids 7 can be reduced using methods standard in the art to give the corresponding carboxaldehyde or hydroxymethyi analogs. For example, an aryl ethyl ester (e.g., structure 6, R5 = ethyl) can be treated with an appropriate reducing agent (e.g., LAH, DIBAL, etc.)'in an aprotic solvent such as ether or THF, to produce the corresponding carboxaldehydes or hydroxymethyi analogs. Such aldehydes and alcohols can be further derivatised by methods standard in the art. Similarly carboxamides (e.g., structure 11) and nitnles can be reduced using methods standard in the art to provide the corresponding substituted amines or1aminomethyl analogs. For example, an aryl carboxamide 11 can be reduced with an appropriate reducing agent (e.g., LAH) in an aprotic solvent (e.g., benzene, toluene, ether, THF, etc.) to give the corresponding substituted aminomethyl analog. Whereas reduction of an aryl nitrile yields the corresponding primary aminomethyl analog. Nitrobenzene compounds 12 can be reduced to the corresponding anilines 13 by methods standard in the art such as hydrogenation using a suitable catalyst (e.g., Pd on carbon) in a polar protic solvent (e.g., EtOH, MeOH, etc.). Nitrobenzenes 12 can also be reduced using a hydride source (e.g., NaBH4) and a transition metal catalyst (e.g., NiCh, Pd on carbon) in polar protic solvents such as EtOH, to produce the corresponding anilines 13. These anilines can then befurther substituted by methods standard in the art. For example, anilines of the type 13 can be alkylated, acylated, or sulfonylated to give the corresponding/V-alkyl amines, carboxamides (e.g., structure 15) or sulfonamides (e.g., structure 14) respectively. For example, a sulfonamide can be prepared from an aniline and an appropriate sulfonyl halide or sulfonic anhydride (e.g., MeSO^Cl, EtSOaCI, BnS02Cl, PhSOiCi, etc.) in the presence of abase (e.g., Et3N, pyridine, DEEA, etc.). Suitable solvents for this reaction include non-polar aprotic solvents such as dichloromethane, chloroform, ether, and the like. Trialkylsilylethers of the type 16 are prepared as described in Scheme 1. The terr-butyldimethylsilyl protected catechol intermediates 16 are readily deprotected by numerous literature methods (see Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999, pp. 273-276.) such as by using a fluoride ion source (e.g., BU4NF) in an aprotic solvent such as ether or TFfT; or under acidic conditions (e.g., KF, 48% HBr, DMF). The resultant phenol 17, which is a very useful synthetic intermediate, can then be alkylated by methods standard in the art and in a similar manner as described for the alkylation of nitrophenol 2 in Scheme 1. For example, by the Mitsunobu reaction, by reaction with an alkyl halide in the presence of a base, or by Ullman type aryl coupling or by reaction with vinyl-, aryl- or heteroaryl-boronic acids in the precence of a copper catalyst. Haloalkoxy intermediates 18, prepared by alkylation of the corresponding phenol, can be alkylated by reactions with substituted amines, alcohols, or thiols in the presence of a base to provide analogs such as 19. For example, an alkyl halide can be aminated with an appropriate primary or secondary amine and a base such as K?C03, in a polar aprotic solvent such as THF, DMF, or CHjCN. Many of these synthetic procedures are described more fully in the examples below. One of ordinary skill in the art will recognize that some of the compounds of Formulae (I) and (T) can exist in different geometrical isomeric forms. In addition, some of the compounds of the present invention possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers, as well as in the form of racemic ornonracemic mixtures thereof, and in the form of diastereomers and diastereomeric mixturesinter aha.All of these compounds, includingcisisomers,transisomers, diastereomic mixtures, racemates, nonracemic mixtures of enantiomers, and substantially pure and pure enantiomers, are within the scope of the present invention. Substantially pure enantiomers contain no more than 5% w/w of the corresponding opposite enantiomer, preferably no more than 2%, most preferably no more than 1%. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyttartanc, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomenc salts. - A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers. Suitable chirai HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without denvitization, are also useful. The optically active compounds of Formulae I and 1' can likewise be obtained by chiral syntheses utilizing optically active starting materials. The present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutical^ acceptable salts and prodrugs of all the compounds of the present invention. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, mangnesium, ammonium, and choline salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods. The following are further examples of acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesuifonat.es, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, mesylates and undecanoates. Preferably, the salts formed are pharmaceutically acceptable for administration to mammals. However, pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent. The free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt. The compounds of the invention can be administered alone or as an active ingredient of a formulation. Thus, the present invention also includes pharmaceutical compositions of compounds of Formulae I or I' containing, for example, one or more pharmaceutically acceptable carriers. Numerous standard references are available that describe procedures for preparing various formulations suitable for administering the compounds according to the invention. Examples of potential formulations and preparations are contained, for example, in the Handbook of Pharmaceutical Excipients, .American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition). In view of their high degree of PDE4 inhibition, the compounds of the present invention can be administered to anyone requiring or desiring PDE4 inhibition, and/or enhancement of cognition. Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, . intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration. Various solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders. The compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the an, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubncants and the like. Time release capsules, tablets and gels are also advantageous in admimstenng the compounds of the present invention. Various liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention. The compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible. Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols. Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art. For topical administration the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches. Aerosol formulations suitable for administering via inhalation also can be made. For example, for treatment of disorders of the respiratory tract, the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions. The aerosol formulation can be placed into a pressurized acceptable propellant. The compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines NIVLDA-R modulators, mGluR modulators, and cholmesterase inhibitors (e.g., donepezil, rivasti<g>imine, and glanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below its usual dosage range. The present invention further includes methods of treatment that involve inhibition of PDE4 enzymes. Thus, the present invention includes methods of selective inhibition of PDE4 enzymes in animals, e.g., mammals, especially humans, wherein such inhibition has a therapeutic effect, such as where such inhibition may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory. Such methods comprise administering to ah animal in need thereof, especially a mammal, most especially a human, an inhibitory amount of a compound, alone or as part of a formulation, as disclosed herein. The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. The present invention includes methods for treating patients suffering from memory impairment in all forms of dementia. Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus. The present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline. The present invention includes methods of treatment for memory impairment as a result of disease. In another application, the invention includes methods for dealing with memory loss resulting from the use of general anesthetics, chemotherapy, radiation treatment, post-surgical trauma, and therapeutic intervention. The compounds may be used to treat psychiatric conditions including schizophrenia, bipolar or manic depression, major depression, and drug addiction and morphine dependence. These compounds may enhance wakefulness. PDE4 inhibitors can be used to raise cAMP levels and prevent neurons from undergoing apoptosis. PDE4 inhibitors are also known to be anti-inflammatory. The combination of anti-apoptotic and anti-inflammatory properties make these compounds useful to treat neurodegeneration resulting from any disease or injury, including stroke, spinal cord injury, neurogenesis, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy (MSA). Thus, in accordance with a preferred embodiment, the present invention includes methods of treating patients suffering from memory impairment due to, for example, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formula (I) or (<V>) or pharmaceutically acceptable salts thereof. The compounds of the present invention can also be used in a method of treating patients suffering from disease statescharacterized bydecreased NMD A function, such as schizophrenia. The compounds can also be used to treat psychosischaracterized byelevated levels of PDE 4, for example, various forms of depression, such as manic depression, major depression, and depression associated with psychiatric and neurological disorders. As mentioned, the compounds of the invention also exhibit anti-inflammatory activity. As a result, the inventive compounds are useful in the treatment of a variety of allergic and inflammatory diseases, particularly disease statescharacterized bydecreased cyclic AMP levels and/or elevated phosphodiesterase 4 levels. Thus, in accordance with a further embodiment of the invention, there is provided a method of treating allergic and inflammatory disease states, comprising administering an effective amount of a compound according to Formulae (I) or (T) or a pharmaceutically acceptable salt thereof. Such disease states include: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilic granuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, artherosclerosis, keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, chronic obstructive airways disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, systemic lupus erythematosus, follicular and wide-area pyodermias, endogenous and exogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpura nephritis, inflammatory bowel disease, leukemia, multiple sclerosis, gastrointestinal diseases, autoimmune diseases and the like. PDE4 inhibitors for, treating asthma, chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatory diseases, and for inhibiting tumor necrosis factor are known within the an. See, e.g., WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651, and US 5,935,9778. These references also describe assays for determining PDE4 inhibition activity, and methods for synthesizing such compounds. The entire disclosures of these documents are hereby incorporated by reference. PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as an antibiotic, for treatment of cardiovascular disease by mobilizing cholesterol from atherosclerotic lesions, to treat rheumatoid arthritis (PA), for long-term inhibition of mesenchymal-cell proliferation after transplantation, for treatment of urinary obstruction secondary to benign prostatic hyperplasia, for suppression of chemotaxis and reduction of invasion of colon cancer cells, for treatment of B cell chronic lymphocytic leukemia (B-CLL), for inhibition of uterine contractions, to attenuate pulmonary vascular ischemia-reperfusion injury (IPJ) , for corneal hydration , for inhibition of IL-2R expression and thereby abolishing HIV-l DNA nuclear import into memory T cells, for augmentation of glucose-induced insulin secretion, in both the prevention and treatment of colitis, and to inhibit mast cell degranulation. The compounds of the present invention can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or in the treatment of psychosis, e.g., other PDE4 inhibitors, calcium channel blockers, chloinergic drugs, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, and cholinesterase inhibitors (e.g., donepezil, nvastigimine, and glanthanamine). In such combinations, each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range. The dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the seventy of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations. The compounds of the invention are typically administered at dosage levels and in a mammal customary for PDE4 inhibitors such as those known compounds mentioned above. For example, the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.01-100 mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg/day. Unit dosage forms can contain, for example, 0.1-50 mg of active compound. For intravenous administration, the compounds can be administered, in single or multiple dosages, at a dosage level of, for example, 0.001-50 mg/kg/day, preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosage forms can contain, for example, 0.1-10 mg of active compound. In carrying out the procedures of the present invention it is of course to be understood that reference to particular buffers, media,1 reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. The present invention will now be further descnbed by way of the following non-limiting examples. In applying the disclosure of these examples, it should be kept clearly in mihd.that other and different embodiments of the methods disclosed according to the present invention will no doubt suggest themselves to those of skill in the relevant art. In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. The entire disclosures of all applications, patents and publications, cited above and below, are hereby incorporated by reference. EXAMPLE 1A l-Cyclopentyloxy-2-methoxy-5-nitrobenzene To a suspension of 2-methoxy-5-nitrophenol (525g, 3.104 mol) and potassium carbonate (643.5g, 4.66 mol) in dimethylformamide (1 L), under N2protection, was added cyclopentyl bromide (499.2 mL, 4.66 mol). The suspension was heated to 100°C for 6h. Potassium carbonate (85.8g, 0.62 mol) and cyclopentyl bromide (50 mL, 0.46 mol) were added. The suspension was heated to 100°C for 4h. TLC indicated the reaction was complete (9:V DCM:MeOH). The reaction mixture was cooled to room temperature and diluted with water (3L) and ether (3L). The layers were separated and the aqueous layer was re-extracted with ether (2L). The combined organic layers were washed with IN NaOH (2L), water (2L), and brine (2L). The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting solid was azeotroped with toluene (2 x 300 mL) to obtain 736i7g (99.6% yield) as a yellow solid. The following compounds were prepared in a similar manner as described above: a) l-Cyclopropylmethoxy-2-methoxy-5-nitrobenzene b) l-Cyclopentoxy-2-difluoromethoxy-5-nitrobenzene c) l-Cyciopropylmethoxy-2-difiuoromethoxy-5-nitroberi2ene EXAMPLE IB 2-Methoxy-5-nitro-l-((37i')-tetratiydrofuryIoxy)benzene To a mixture of 2-Methoxy-5-nitrohenol (1.69 g, 10 rnmol), tnphenyiphosphine (5.24 g, 20 mmol) and 3-(i?)-hydroxytetrahydrofuran (1.80 g, 20 rnmol) m anhydrous tetrahydrofuran (40 mL) was added drop-wise, with stirring, diisopropylazocicarboxylate (4.0 mL, 20 mmol) and the mixture was allowed to stir at room temperature for 16 h. The mixture was diluted with ether (150 mL) and washed with 2N NaOH (3 x 50 mL) and bnne (50 mL), (MgSOa) and concentrated in vacuo. The crude residue was purified by flash column chromatography over silica gel (Biotage Flash 40M) eluting with 20% ethyl acetate in hexanes to give 1.05 g of product The following compounds were prepared in a similar manner as described above: a) 2-Methoxy-5-nitro-l-(3-tetrahydrofuryloxy)benzene b) 2-Methoxy-5-nitro-l-((35)-tetrahydrofuryloxy)benzene c) 2-Difluoromethoxy-5-nitro-l-(3-tetrahydrofuryloxy)benzene d) 2-Difluoromethoxy-5-nitro-1 -((3i?)-tetrahydrofuryloxy)benzene e) 2-Difluoromethoxy-5-nitro-1 -((3>S)-tetrahydrofuryloxy)benzene f) 2-Methoxy-5-nitro-1 -(3-phenpropyloxy)benzene g) 1 -(2-Indanyloxy)-4-methoxy-5-nitrobenzene EXAMPLE 1Cl-{r^rr-8utyIdimethyIsilyl)oxy-2-methoxy-5-aitrobenzeae To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DtVIF (40 mL) was added, with stirring,tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removedin vacuoand the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica-gel. The silica gel was washed with an additional"200 mL of 50% ethyl acetate in hexanes and the filtrates were combined and concentratedin vacuoto give 2.01 g of product as a tan crystalline solid. 'H NMR (CDC13) 5 7.89 (dd, 1H, J = 9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J = 2.8 Hz), 6.88 (d, 1H, J = 9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H). EXAMPLE 2 3-Cyclopentyloxy-4-methoxy aniline To a suspension of 10% Pd on activated carbon (25g) in ethanol (4L), under ~ N2 protection, was added l-cyclopentyloxy-2-methoxy-5-nitrobenzene (250g, 1.054 mol). The reaction mixture was degassed under vacuum three times. The reaction mixture was stirred vigorously while hydrogen gas was allowed to flow over the reaction mixture. After 4h the reaction was complete by TLC (5:1 hex:EA). The reaction mixture was filtered through a pad of celite and the celite was rinsed with additional ethanol. The solvent was removed in-vacuo to obtain 208.38g (95% yield) of 3-cyclopentyloxy-4-methoxyaniline as a red liquid.<l>H NMR (CDC13) 5 6.85 (d. J = 8.4Hz, 1H), 6.29 (s, 1H), 6.19 (dd, J = 2.8, 8.4, 1H), 4.69 (p, J = 4.4 Hz, 1H), 3.75 (s, 3H), 3.44 (bs, 2H), 1.90-1.81 (m, 6H), 1.61-1.55 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-dif!uoromethoxyaniline b) 3-Cyclopropylmethoxy-2-methoxyaniline c) 3-Cyclopropylmefhoxy-4-difluoromefhoxyaniline d) 4-Methoxy-3-((3T?)-tetrahydrofuryloxy)aniline e) 4-Methoxy-3-(tetjahydrofuryloxy)aniline f) 4-Methoxy-3-((3c7)-tetrahydrofuryioxy)aniline g) 4-Difiuoromethoxy-3-(3-tetrahydrofuryloxy)aniline h) 4-Difiuoromethoxy-3-((37?)-tetrahydrofuryloxy)aniline i) 4-Difluoromethoxy-3-((3o<7>)-tetrahydro fury loxy)ani line j) 3-(;err-Butyldimethylsilyl)oxy-4-methoxyaniline k) 4-Methoxy-3-(3-phenpropyloxy)aniline

1) 3-(2-Indanyloxy)-4-methoxyaniline EXAMPLE 3 5 3-Cyclopentyl-4-rnethoxy-A'-(3-pyridylmethyl)arji]iiie To a mixture of 3-pyridinecarboxaldehyde (106.55g, 0.995 mol) in methanol (5L) was added 3-cyclopentyloxy-4-methoxyaniline (208.38g, 1.005 mol) and p-toluenesulfonic acid monohydrate (200 mg). The reaction mixture was stirred for 4h. The flask was then cooled to 0°C and sodium borohydride (37.64g, 2.3 mol) was added ponionwise over 4h. 0 The reaction mixture was allowed to warm to room temperature over 16h with stirring. TLC indicated the reaction was complete (1:3 hex:EA). The solvent was evaporated until approximately 0.5L of slurry remained. The slurry was diluted with water (1L) and extracted with ethyl acetate (2 x 2L). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, and concentrated to yield 300g (100% yield) 5 of the desired product as a brown viscous liquid. 'H NMR (CDClj) 5 8.61 -8.48 (m, 2H), 7.69-7.67 (m, 1H), 7.24-7.21 (m, 1H), 6.72 (d. J = 8.4 Hz, 1H), 6.23 (s, 1H), 6.13 (dd, J = 2.6, 8.6, 1H), 4.65 (bs, 1H), 4.27 (s, 2H), 4.0 (bs, 1H), 3.73 (s, 3H), 1.88-1.70 (m, 6H), ■ 1.65-1.45 (m, 2H). '. Q The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-A/'-(3-thienylmethyl)aniline b) 3-CyclopentyIoxy-4-memoxy-A</->(4-pyridylmethyl)aniIine c) 3-Cyclopentylox<y->iV-(2,6-dichloro-4-pyridylmethyl)- 4-methoxyaniline 15 d) 3-Cyclopentyloxy-4-methoxy-/V-(2-quinolinylmethyl)aniline e) 3-Cyclopentyloxy-4-methoxy-Ar<->(3-quinolinylmethyl)aniline f) 3-Cyclopenryloxy-4-methoxy-/V-(4-quinolinylmethyl)aniline g) 3-Cyclopenryloxy-4-methoxy-A''-(2-pyrazinylmethyi)aniline h)4-Methoxy-<y>V-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)aniline;0 i) 4-Methoxy-/V-(3-pyndylmeth.yi)-3-((3/?)-tetrahydrofuryloxy)aniline j)4-Memoxy-/V-{3-pyridylmethyl)-3-{(36^-teti^ydrofuryloxy)anilinek) 3-Cyclopropylmethoxy-4-difluo^ I) 3-Cyclopentyloxy-4-difluoromethoxy-/V-(3-pyTidylmeth m) 4-Difluoromerhoxy-/Y-(3-pym n) 4-Difluoromethoxy-iV-(3-pyTidy o) 3,4-Bts(difluoromethoxy)-;V-(3-pyridylmechyl)amline p) 3-tert-Butyldimethylsilyloxy-4-memo q) 3-Cyclopentyloxy-4-methoxy-/vr-(2-pyndylmethy()aniline r) 3-CyclopenLyloxy-4-methoxy-/V-[l-(2-phenethyl)]aniline s)/Y-Benzyl-3-cyclopentyloxy-4-methoxyaniline t) /Y-[(Cyclohex-1 -en-1 -yl)methyI]-3-cyc lopentyloxy-4-methoxyani line ■ u) 3-Cyclopentyloxy-4-methoxy-.Y-(3,4,5-tnmethoxybenzyl)aniline v) .'V-[(Cyclohex-3-en-l-yl)methy!]-3-cyclopentyloxy-4-methoxyaniIine w) 3-Cyclopen[yloxy-4-met;rioxy-yV-(2,4,6-trirnethylbenzyl)aniline x) 3-Cyclopen:yloxy-4-methoxy-/V-(2-methyibenzyl)aniline y) 3-Cyc!opentyloxy-4-methoxy-/V-(2-tnfluoromethylbenzyl)aniline z) 3-Cylclopentyloxy-4-methoxy-A</>'-((3,4-methylenedioxy)benzyl)aniline aa) 3-Cyclopentyioxy-/V-(2-hydroxy-3-methoxylbenzyl)-4-methoxyaniline bb) 3-Cyc]opentyloxy-/V-(3-mrylmemyl)-4-rnethoxyaniline cc) 3-Cyclopentyloxy-4-methoxy-/v'-{3-med1ylbenzyl)aniline dd) 3-Cyciopentyloxy-4-methoxy-iV-(2-metiioxybenzyl)aniline ee) 3-Cyclopentyloxy-4-methoxy-A''-(3-chlorobenzyl)aniline ff) 3-Cyclopentyloxy-4-methoxy-/V-(3-rnethoxybenzyl)aniline gg) 3-Cyclopentyloxy-4-methoxy-/V-(2-chlorobenzyl)aniline hh) 3-Cyclopentyloxy-4-methoxy-/V-{3-methylbenzyl)ani]ine ii) 4-Methoxy-3-(3-phenpropyloxy)-iV-(4-pyndylrnethyl)aniline jj) A</->{2,6-Dichloro-4-pyridylmethyl)-3-(2-indanyloxy)-4-methoxyaniline kk) 4-Methoxy-3-(3-phenpropyloxy)-/V'-(2-pyn^ylrnethyl)aniline II)/Y-(2,6-Dichloro-4-pyridy(methyl)-4-metJioxy-3-(3-phenpropyloxy)aniline mm) 4-Methoxy-3-(3-phenpropyloxy)-Y-(3-pyridylmethyl)aniline nn) 3-Cyclopentyloxy-4-memoxy-/V-(2-thienylmethyl)aniline oo) 3-(2-Indanyloxy)-4-methoxy-Ar<->(3-thienylmethyl)aniline pp)4-Methoxyo-(3-phenpro qq) 3-(2-mdanyloxy)-4-methoxy-yV-(2-pyridylm rr) 3-(2-Indanyloxy)-4-methoxy-/V-(3-pyndylmethy!)aniline ss) 3-(2-mdanyloxy)-4-methoxy-/V-(4-pyndyuTiethyl)anihne tt) 3-Cyc[opentyloxy-4-methoxy-jV-(3-pipendinemethyl)aniIine uu) 3-Cyclopentyloxy-4-methoxy-Ar-(3-(l-ferr- butyloxycarbonyl)piperidinemefhyl)aniline vv) 3-Cyclopenty1oxy-4-methoxy-/V-(6-methyl-2-pyridylmemyl)aniline ww)<y>Y-(2-Chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-rnethoxyanilirie xx)yV-(2-Chloro-5-pyridylmethyl)-3-cyclopentyloxy-4-methoxyamlin yy) 3-Cyclopentyloxy-4-raethoxy-/V-(2-thia2olylmethyl)anilirie EXAMPLE 4 3-Cyclopentyloxy-4-methoxy-A</->(3-pyridylmethyl)diphenylarnine To a 100 mL oven dried, argon flushed flask was added in the following order 0.59 g (6.10 mmol) of NaOtBu, 360 mg of Pd2dba3, 20 mL of toluene, 0.14 mL of P(tBu)3, and a 20 mL solution of 1.3 g (4.36 mmol) of N-(3-pyridylmethyl)-3-cyclopentyloxy-4-methoxyaniline in toluene. With stirring, 3'.1 g (15 mmol) ofiodobenzene was added dropwise and the mixture was stirred for 18 hours. The reaction mixture was diluted with EtOAc and washed twice with H20 and extracted with 3x15 mLof 3/VHC1. The combined acid extracts were washed with 15 mL of EtOAc and then carefully neutralized with6NNaOH to pH greater than 12. The basic solution was extracted with 2 x 15 mL of EtOAc and the combined organic fractions were subsequently washed with 15 mL of H20 and brine, dried (MgSOO, and concentrated. The residue was purified by chromatography over silica gel (Biotage Flash 40M) eluting with 25% EtOAc in hexanes. The material was further purified by crystallization from hexanes to give 550 mg of a white solid.<l>H NMR (CDC13) 5 8.61 (s, 1H), 8.49 (d, 1H, J = 4.2 Hz), 7.67 (d, 1H, 7.9 Hz), 7.30-7.10 (m, 3H), 6.90-6.80 (m, 4H),6M- 6. 60(m, 2H), 4.94 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz),3.S4 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H)/ The following compounds were prepared in a similar manner as described above: a) 3-Cyc]opentyloxy-4-metho b) 3-Cyclopentyloxy-4-methoxy-3'-methyl-A^-(3-pyridylmethyl)diphenylarnine c) 3-Cyclopentyloxy-4-methoxy-4'-m d) 3-CycIopemyloxy-4'-ethyl-4-metho e) 3'-Chloro-3-cycLopentyloxy-4-mem^ f) 4'-Chloro-3-cyclopentyloxy-4-m g) 3-Cyclopentyloxy-2',4-dimethoxy-/V-(3-pyridylmechyl)diphenylamine h) 3-Cyc]opentyioxy-3',4-dirnem^ • i) 3-Cyclopentyloxy-4,4'-dimethoxy-/V-(3-pyridylmethyl)diphen j) 3-Cyclopentyloxy-4-methoxy-iV-(3-p k) 3-Cyclopentyioxy-4-methoxy-A/-(3-pyTidylmethyl)-4'-tnfluoromethy 1) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-/V-(3-pyridylmethyl)diphenyla m) 3-Cyclopentyloxy-4'-fluoro-4-methoxy-V-(3-pyrid<y>lmeth<y>l)dihen<y>lamine. n) 3-CycIopentyloxy-4-methoxy-3'-phenyI-iV-(3-pyndylm o) 3-Cyclopentyloxy-4-methoxy-4'-phen^^ p) 3'-Cyano-3-cyclopentyloxy-4-methoxy-iV-(3-pyndylmethyl)diphenylamine q) 4'-Cyano-3-cyclopentyloxy-4-methoxy-A/-^^ r) Ethyl Ar-{3-cyclopentyloxy-4-methoxyphenyl)-Ar-(3-pyridylmethyl)-3-aminobenzoate s) Ethyl N-Q-cyclopentyloxy^-metho t) 3-Cyclopentyloxy-4-methoxy-3'-nitro-<y>V-(3-pyridylmethyl)diphenylamine u) 3-Cyclopentyloxy-4-methoxy-4'-aitro-A</->(3-pyridylmethyl)diphenylamine v)A</->(3-Cyclopentyloxy-4-methoxyphenyl)-<y>Y-(3-pyridylmethyl)-l-naphthylarninew) 3-Cyclopentyloxy-2\3'-dimethyl-4-m x) 3-Cyclopentyloxy-2\4'-dimethyl-4-metho y) 3-Cyclopentyloxy-2\5'-dimethyl-4-meth^ z) 3-Cyclopentyloxy-3\4'-dimethyl-4-m aa) 3-Cyclopentyloxy-2\3'-dichloro-4-^ bb) 3-Cyclopentyloxy-3\4'-dichloro-4-m^ cc) 3-Cyclopentyloxy-3\5'-dichloro-4-m dd) 3'-Chloro-3-cyclopentyloxy-4'-fl ee) 4'-Chloro-3-cyclopentylo^ ff) 4'-Chloro-3-cyclopentyloxy-4-mem^ tnfluoromethyldiphenylamine gg) 3-Cyclopentyloxy-4-methoxy-;V-(3-th^ hh) /V-(3-Cyclopentyloxy-4-methoxypheny ii) 3-Cyclopentyloxy-2\3'-dichlo^ jj) 3-Cyciopentyloxy-4-methoxy-4'-methyl-/V-(4-pynd<y>lmeth<y>l)dihen<y>lamine kk) 3-Cyclopentyloxy-yV-(2,6-dichloro-4-pyridylmethyl)-4-methoxy-3'- methyldiphenylamine 11) 2'-Chloro-3-cyclopentyloxy-iV-(2,6-dichloro-4-pyndyImethyl)-4- methoxydiphenyl amine mm) 3-Cyclopentyloxy-A/-(2,6-dichloro-4-pvridylmethyl)-4-methoxydiphenylamine nn) 3-CyclopentyIoxy-4-methoxy-A/-(6-methyl-2-pyridylmethyl)diphenylamine oo) 3-CycIopentyloxy-4-methoxy-^/-(3-quinolinylmethyl)diphenylamine pp) 3-Cyclopentyloxy-4-methoxy-/V-(4-quinolinylmethyl)diphenylamine qq) 3-Cyclopentyloxy-4-methoxy-7v'-(2-pyrazinylmethyl)diphenylamine rr) 4-Methoxy-3'-methyl-/Y-(3-pyirdylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine ss) 4-Methoxy-4'-methyl-7V-(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine tt)4,4'-Dimethoxy-/\r<->(3-pyridylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamineuu) 3'-Chloro-4-methoxy-/V-(3-pyndylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine vv) 4-Methoxy-.4'-(4-methylpiperazin-l-ylcarbonyl)-/Y-(3-pyridylmethyl)-3-(3- tetrahydrofuryloxy)diphenylamine ww) 3'-Cyano-4-methoxy-iV-(3-pyridylmethyl)-3-((3/^)- tetrahydrofuryloxy)diphenylamine xx) 3'-Cyano-4-methoxy-/V-(3-pyTidylmemyl)-3-((3^)-tetrahydromryloxy)dipheny yy) 3-Cyclopropylmethoxy-4-difluoromethoxy-iV-(3-pyridyimethyl)diphenylamine zz) 3-Cyclopentyloxy-4-difiuoromethoxy-iV-{3-pyndylmethyl)diphenylamine aaa) 4-Difluoromethoxy-/V-{3-pyTidylmethyl)-3-(3-tetrahydrofuryloxy)diphenylamine bbb) 3,4-Bis(difluoromethoxy)-/V-(3-pyridylmethyl)diphenylamine ccc) 4-Difluoromethoxy-A/"-{3-pyndylmethyi)-3-((3i?)- tetrahydrofuryioxy)diphenylamine ddd) 3'-Cyano-4-difluoromethoxy-/V-(3-pyridylm tetrahydrofuryloxy)diphenylamine eee) 3'-Chloro-4-difiuoromethoxy-/V-(3-pym tetrahydrofuryloxy)diphenylarnine fff) Ethyl yV-(3-cyclopropylmethoxy-4-difluor^ aminobenzoate ggg) 3-Cyciopentyloxy-4-methoxy-3'-(4-methylpiperazin-l-ylcarbonyl)-<y>V-{3- pyndylrnethyl)diphenylaraine hhh) 3-Cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)-yV-(3- pyTidylmethyl)diphenylamine iii) 3'-ferr-Butyldirnethylsilyloxy-3-cyclopentyloxy-4-methoxy-.'V-(3- pyridylrnethyl)diphenylarnirie jjj) 4'-fen-Butyldimethylsilyloxy-3-cyclopentyloxy-4-methoxy-/V-(3- pyridylmethyl)diphenylamine kick)tert- Buty\A</->(3-cyclopentyloxy-4-methoxyphenyl)wV-(3-pyndylrnethyl)-3- arninobenzoate 111) Ethyl<y>V-(3-cycloper.tyloxy-4-difluoromethoxyphenyl)-/V-(3-pyn^ylmethyl)-3- aminobenzoate raram) Ethyl/Y-(4-difluoromethoxy-3-(3-tetrahydrofuryloxy)phenyl)-/V-(3- pyndylrnethyl)-3-arriinoberizoate nnn) Ethyl /V-{3,4-Bis(dilfuoromethoxy)phenyl)-/Y-(3-pyndylraemyl)-3-ami ooo) Ethyl yV-{4-methoxy-3-((3/x>tetrahydrom -3- arninobenzoate ppp) Ethyl /V-(3-cyclopropylmethoxy-4-m aminobenzoate qqq) 3-Cyclopentyloxy-4-memoxy-4'-(2-(tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-/V- (3-pyridylmethyl)diphenylamine rrr) 3-Cyclopentyloxy-4-memoxy-3'-{2-{tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-yV-{3- pyndylmethyl)diphenylamine sss) 4-Methoxy-4'-(2-{tetrahydropyran-2-yl)-2H-tetrazol-5-yl)-<y>V-(3-pyridylmethyl)-3-- ((3i?)-tetrahydrofuryloxy)diphenylamine ttt) j-Cyclopropylmemoxy-4-m^ (3-pyridylrnethyl)diphenylamirie uuu) 4-Difluoromethoxy-4,-(2-(tetrahydropvran-2-y^ pyridylmerhyl)-3-((3i^)-tetrahydrofuryloxy)diphenylarnine vvv) 3-Cyclopropylmethoxy-4-difluoromethoxy tetrazol-5-yl)-/V-{3-pyndylmechyl)diphenylamine ww) 3-Cyclopentyloxy-4-difluoromethoxy-4'-(2-(tetrahydropyran-2-yl)-2H yl)-/V-(3-pyridylmethyl)diphenylamine xxx) 3-CycIopropyImethoxy-4-dilfuoromethoxy-3 '-(2-(tetrahydTopyran-2-yl)-2H- tetrazol-5-yl)-/V-(3-pyridylmethyl)diphenylamine yyy) Bis-(3,4-difIuoromethoxy)-3'-(2-(tetxahydrop pyridylmethyl)diphenylarnine zzz) 3-rerr-Butyldimethylsilyloxy-4-methoxy aaaa) 3-/er/-Butyldirnethylsilyloxy-3'-ch]oro-4-methoxy-A</->(3- pyridylmethyl)diphenylarnine bbbb) Ethyl /V-(3-te^butyldimethy!silyloxy-4-methoxy^ aminobenzoate cccc) 3-Cyclopentyloxy-2'-chloro-4-methoxy-<y>V-(3-pyndylxnethyl)diphenylamine dddd) 3-(2-indanyloxy)-4-methoxy-/V-(3-pyridylmethyl)diphenylamine EXAMPLE 5 7V-(3-CycIopeatyIoxy-4-methoxyphenyl)-/V-{3-pyridyImethyl)-3-aminobenzoic acid A solution of 6.5 g of ethyl/V-(3-cyclopentyloxy-4-methoxyphen<y>l)-/V-(3-pyridylmethyl)-3-aminobenzoate in 50 mL of EtOH was treated with 10 mL of 6N NaOH. The mixture was allowed to stand for 6 hours, concentrated, and diluted with 50 mL of H2O. The aqueous mixture was extracted with 2 x 50 mL of ether, acidified with AcOH to pH 3, and extracted with 2 x 50 mL of EtOAc. The combined EtOAc fractions were washed with 25 mL of H20 and 25 mL of brine, dried (MgSO<i), and concentrated. The residue was punfied by chromatography over SiO?(35 g RediSep® column) using a linear gradient of EtOAc and hexanes as eluant (50% EtOAc to 70% EtOAc over 20 • minutes) to provide 4.8 g of a yellow solid product after drying in vacuo for 12 h at 60°C. 'HNMR (CDCI3) 5 11.15 (bs, 1H), 8.70-8.55 (m, 2H), 7.77-6.71 (m, 9H), 4.99 (s, 2H), 4.65 (p, J = 3.8 Hz, 1H), 3.84 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a)<y>V-(3-Cyc!openty!oxy-4-methoxyphenyl)-/V-(3-pyndylmethyl)-4-ammobenzoic acid b) /V-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-iV-(3-pyridylmethyl)-3-aminobenzoic acid c) A<f>T4-Difluoromethox<y>-3-(3-tetrah<y>drofur<y>lox<y>)phen<y>l]-/V-(3-pyridylmethyl)-3-aminobenzoic acid d)<y>V-3,4-Bis(dirluoromethoxy)phenyl)-A''-(3-pyirdylmethyl)-3-aminobenzoic acid e)/V-[4-Merhoxy-3-((3/^)-tetrahydrofuryloxy)phenyl]-/<Vr>-(3-p<y>ndylmethyl)-3-aminobenzoic acid f)/V-(3-Cyclopropylmethoxy-4-methoxyphenyl)-/V'-(3-pyridylmethyl)-4-aminobenzoic acid g)/V^S-Cyclopropylmethoxy^-difluoromethoxypheny^-A/^S-pyridylmethy^-S-aminobenzoic acid h) /Y'-(3-Cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoic acid i) /V'-[3-(4-Chlorophenyl)prop-l-yloxy-4-methoxyphenyl]-<y>Y-(3-pyridylmethyl)-3-aminobenzoic acid j)/^-(S-Cyclopropylmethoxy^-methoxyphenyO-<y>V^S-pyTidylmethy^-S-aminobenzoicacid k) /V-[3-(2-mdanyloxy)-4-methoxyphenyl]-/V-{3-pyridylmemylj acid 1) Ar-(4-Methoxy-3-(3-tetrahydrofuryloxy)phenyl]-/V-(3-pyridylmethyl)-3-aminobenzoic acid m) 7v'-[4-Methoxy-3-((3R)-tetrahydrofuryloxy)phenyl]-A/'-(3-pyridylmethy!)-3-aminobenzoic acid n) A^-{3-(2-Methoxyemoxy)-4-methoxyphenyl]-.V-(3-pyridylmethyl)-3-aminobenzoic acid0) Ar-[4-Methoxy-3-(2-(2-pyndyl)ethyl)oxyphenyl]-/V-(3-pyridylmethyl)-3-ammobenzoic acid EXLAMPLE 6 yV-(3-CyclopenrMoxy-4-methoxyphenyl)-/V-(3-pyridylmeth acid Ten- Butyl<y>Y-(3-cyclopentyloxy-4-methoxyphenyl)-/Y-(3-pyn^yImethyi)-2-ammobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL 98% formic acid and heated at 40 °C for 4 h. The formic acid was removedin vacuoand the residue was loaded onto a column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from 40%o EtOAc in hexanes to 60% EtOAc in hexanes over 15 mm to yield 16 mg of product as a brown solid. 'H NMR (CDC13) 5 8.47 (d, 1H, J = 4.9), 8.43 (s, 1H), 8.10 (d, 1H, J = 7.8), 7.67 (d, 1H, J = 7.8 Hz), 7.56 (m, 1H), 7.40-7.20 (m, 3H), 6.75 (d, 1H, J = 8.7), 6.57 (d, 1H, J = 8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J - 4.3), 3.77 (s, 3H), 1.80-1.60 (m, 6H), 1.60-1.40 (m,2H). The following compounds were prepared in a similar manner as described above: a) yY-(3-Cyclopentyloxy-4-methoxyphenyl)-yY-(3-pyridylmethyl)-3-aminobenzoic acid b) ■A,,<->(3-Cyclopentyloxy-4-methoxyphenyl)-A</>'-(3-p>Tidylmethyl)-6-aminonicotinic acid EXAMPLE 7 3-Cy clop ropy Imethyloxy-4-difluoromethoxy-yY-(3-pyridylmethyI)-4'- (2H-tetrazol-5-yl)diphenylamine 3-Cyclopropylmethoxy-4-difluoromethoxy-<y>V-(3-pyridylmethyl)-4'-[2-(2-tetrahydropyranyl)-2H-tetrazol-5-yl]diphenylamine (1.5 g, 0.26 mmol) was dissolved in THF (5 mL) and 3 mL of IN HC1 was added. After 6 h at room temperature, the mixture was neutralized to pH = 5 with saturated aqueous sodium bicarbonate and extracted with ■ EtOAc (3 x 50 mL). The EtOAc extracts were combined, washed with bnne (50 mL), dried (MgSO<}), and concentratedin vacuo.The crude residue was loaded onto a RediSep column (10 g, silica gel) and the product was eluted using a linear gradient from 0% MeOH in EtOAc to 5% MeOH in EtOAc over 20 min to give 0.96 g of product as a white powder. "H NMR (CD3OD) 5 8.55 (s, 1H), 8.43 (d, 1H, J = 4.9 Hz), 7.65 (d, 1H, 8.0 Hz), 7.21 (dd, 1H, J = 4.9 Hz, 8.0 Hz), 7.18 (d, 1H, J = 8.9 Hz), 7.10-6.90 (m, 3H), 6.87 (dd, 1H, J = 3.6 Hz, 2.5 Hz), 6.75 (t, 1H, J = 75.5 Hz), 5.14 (s, 2H), 3.82 (d, 2H, J = 6.9 Hz), 1.23 (m, 1H), 0.60 (m, 2H), 0.33 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-/V-(3-pyndylmethyl)-4<7->(2H-tetrazol-5-yl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-iV-(3-pyridylmethyl)-3'-(2H-tetrazol-5-yl)diphenylamine c) 4-Methoxy-/V'-(3-pyTidylmethyl)-3-((3/^)-tetrahydrofuryloxy)-4'-(2H-tetrazol-5-yl)diphenylamine d) 3-CyclopropylmethyIoxy-4-methoxy-<y>V-(3-p<y>ridyLmethyl)-4'-(2H-tetrazol-5-yl)diphenylamine e) 4-Difluoromethoxy-/V-(3-pyndylmethyl)-3-((37^)-tetrahydrofuryioxy)-4'-(2H-tetrazol-5-yl)diphenylamine f) 3-Cyclopentyloxy-4-difluromethoxy-Ar<->(3-pyridylmethyI)-4'-(2H-tetrazol-5-yl)diphenylamine g) 3-Cyclopropylmethyloxy-4-difluoromethoxywV-(3'-pyirdylmethyl)-3'-{2H-tetrazol-5-yl)diphenylamine h) Bis-3,4-difluoromethoxy-A/-(3-pyridylmethyl)-4'-(2H-tetrazol-5-yr)diphenylamine EXAMPLE 8 (Method A) 3-Cyclopentyloxy-4-methoxydiphenyIamiue Method A. (Ref. Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P,Tetrahedron Lett., 1998, 39, 2933-2936.).A slurry of 207 mg of 4-methoxy-3-cyclopentyloxyaniline, 280 mg of phenylboronic acid, 182 mg of Cu(OAc)2, 280 uL of EtoN and 4.0 mL of CH2CI2 was stirred for 20 h at room temp. The black mixture was filtered through silica eluting with CH2CI2, concentrated, and purified by chromatoghraphy over S1O2using EtOAc/Hexanes (15/85) as.eluant to provide 75 mg of the desired product. 'H NMR (CDCI3) 5 7.26-7.20 (m, 2H), 6.94-6.63 (m, 6H), 5.50 (s, 1H), 4.71 (m, 1H), 3.82 (s, 3H), 1.89-1.54 (m, 8H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-3\4-dimethoxydiphenylarnine b) 3'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamme c) 3-Cyclopentyloxy-4-methoxy-3methyldiphenylamine d) 3-Cyclopentyloxy-4'-fluoro-4-methoxydiphenylamine e) 3-Cyclopentyloxy-4-methoxy-4'-vinyldiphenylamine f) 3 '-Cyano-3-cyclopentyloxy-4-methoxydiphenylamine g) 4'-Chloro-3-cyclopentyloxy-4-methoxydiphenylarnine h) 3-Cyclopentyloxy-4,4'-dimethoxydiphenylamine i) 3-Cyclopentyloxy-4-methoxy-2 '-methyldiphenylamine j) 3-Cyclopentyloxy-4-methoxy-4'-methyldiphenylamine k) 2'-Chloro-3-cyclopentyloxy-4-methoxydiphenylamine

1) 3-Cyclopentyloxy-2!,4-dimethoxydiphenylamine m) 3-Cyclopentyloxy-4-methoxy-3'-trifluoromethyldiphenylamine n) 3-Cyclopentyloxy-4-methoxy-4'-trifluoromethyldiphenylamine o) 3-Cyclopentyloxy-2',5'-dimethyl-4-methbxydiphenylamine EXAMPLE 8 (Method B) 3-CyclopenryIoxy-4-methoxydiphenylarnine Method B{ Angerw Chem. Int. Ed., 1995, 34(17),1348-1351.) A mixture of 207 mg of 3-cyclopentyloxy-4-methoxyaniline, 204 mg of iodobenzene, 115 mg of NaOtBu, 9 mg of Pd2(dba);j, 12 mg of P(o-tol)3 and 7 mL of toluene was combined and wanned with stirring to 100 °C for 4h. The mixture was cooled to room temp, diluted with 25 mL of EtOAc and washed with 10 mL of H2O, 10 mL of brine, dried (MgSOa) and concentrated. The residue was punfied by chromatography over Si02using EtOAc/hexanes (5/95) as eluant to provide 84 mg of the desired product. The following compounds were prepared in a similar manner as descnbed above: a) 3-Cyclopentyloxy-4-merhoxy-2^4'-dimethyidiphenylamme b) 3-Cyclopentyloxy-2\5'-dimethyl-4-raethoxydipheny[amme c) 3-Cyclopentyloxy-2',3'-dimethyl-4-methoxydiphenylamine d) 3-Cyclopentyloxy-3\4'-dimethyl-4-methoxydiphenylamine e) 3-Cyclopentyloxy-3\4'-meth<y>lenedioxydiphenylamme f) 4'-ierr-Butyl-3-cyclopentyloxy-4-methoxydiphenylarnine g) 3-CyclopentyIoxy-3 \4'-dichloro-4-methoxydiphenylamine h) 3-Cyclopentyloxy-2',3'-dichloro-4-methoxydiphenylamine EXAMPLE 8 (Method C) 3-Cyclopentyloxy-2\4,5Mrimethoxy diphenylamine Method C. To a mixture of Pd(dppf)Cl2 (0.025 mmol, 5mol%), dppf (0.075 mmol, 3dppf/Pd) and NaOtBu (0.70 mmol, 1.4 equivalents) and 1.0 mL THF was added 1-bromo-2,5-dimethoxybenzene (0.55 mmol, 1.1 equivalents) followed by 1.0 mL of a0. 5Msolutionof 3-cyclopentyioxy-4-methoxyaniline in THF. The mixture was heated to 60 °C for 3 hours and diluted with ether and washed with H20 and brine, dried (MgS04), and concentrated. The crude residue was purified by chromatography over silica gel (Biotage Flash 12) eluting with 15% EtOAc in hexanes! The following compounds were prepared in a similar manner as described above: a) /V-(3-Cyclopentyloxy-4-methoxyphenyl)-3-pyridylamine b) 3-Cyclopentyloxy-2',4',4-trimethoxydiphenylamine c)<y>V-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine d) /V-(3-Cyclopentyloxy-4-methoxyphenyl)-8-quinolinylamine e)/V-(3'-Cyclopentyloxy-4-methoxyphenyl)-2-naphthylaminef)/V-(J-Cyclopentyloxy-4-methoxyphenyl)-l-naphthylamine g) 3-Cyclopentyloxy-4'-ethyl-4-methoxydiphenylamine h) 3-Cyclopentyioxy-2'-fluoro-4-methoxy-5'-methyldiphenylamine'i) 3-Cyclopentyloxy-3'-fluoro-4-methoxy-4'-methyldiphenyIamine j)<y>V-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyirmidinylamine k) 3-Cyclopentyioxy-3\5.'-dichloro-4-methoxydiphenylam

1) 3-Cyclopentyloxy-2'-ethyl-4-rnethox<y>dihen<y>lamme m) 4'-Chloro-3-cyclopentyloxy-3'-fluoro-4-methoxydiphenylamme n)<y>V-(3-Cyclopentyloxy-4-methoxyphenyl)-4-isoquinolinylammeo) yV-(3-Cycloper1tyloxy-4-methoxyphenyl)-2-pyrazinylamme p) iV-(3-Cyc[opentyloxy-4-methoxypheny[)-5-pynmidinylamine q) yV-(3-Cyclopentyloxy-4-methoxyphenyl)-l -isoquinolinyiamine r) Ar<->(3-Cyclopentyloxy-4-methoxyphenyl)-3-qumolinylamine s)/V-(3-Cyclopentyloxy-4-methoxyphenyl)-4-pyridylamine t) /v'-(3-Cyclopentyloxy-4-difluoro u)A-(3-CyclopropylniethyIoxy-4-methoxyphenyi)-3-pyridylaminev) Ar-(3-CyclopropylmethyIoxy-4-difluoromethoxyphenyl)-3-pyri w) yV-(4-Methoxy-3-(3.f<!)4etrahydrofuryloxy^ x) A'r-{4-Difluoromethoxy-3-(3^)-tetrahydromryloxyphen y) Ethyl<y>V-(3-cyclopentyloxy-4-methoxyphenyl)-3-aminobenzoate z) 3-Cyclopenty!oxy-4'-(/V^-dimethylarmno)-4-methoxydiphenylam aa) /Y-(3-Cyclopentyloxy-4-methoxyphenyl)-3-(6-methoxypyridyl)amm bb) Methyl yV-(3-cyclopentyloxy-4-memoxyphenyl)-21arninonicotinate cc)cert- Butyl Ar<->(3-cyclopentyloxy-4-methoxyphenyl)-6-aminonicotinatedd) 2'-Amino-3-cyclopentyloxy-4-memoxydiphenylamine ee) 3-Cyclopentyloxy-4-methoxy-3'-(l-phthaliraido)diphenylamirie ff) 3-Cyclopentyloxy-4-methoxy-3'-[2-(2-terjahydropyranyl)-2H-tetrazol-5- yljdiphenylamine EXAMPLE 9 (Method A) 3-Cyclopentyloxy-4-methoxy- iV-meth<y>ldih<e>nylamine To a solution of 3-cyclopentyloxy-4-methoxydiphenylamine (70 mg, 0.25 mmol) in 3 mL of THF at 0 °C was added 0.55 mL of 0.5 M KN(TMS)2in toluene. The solution was stirred at 0 °C for 0.5 h and 2.0 equivalents of iodomethane was added and the reaction mixture was warmed to room temperature. Upon reaction completion as indicated by TLC, 10 mL of EtOAc was added and the mixture was washed with 3 mL of H?0, 3 mL of brine, dried (MgSOn) and concentrated. The crude residue was purified by column chromatography (Biotage flash 12) using 5% EtOAc in hexanes as eluant. The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-iV-ethyl-4-methoxydiphenylamine b) 3-Cyclopentyloxy-4-methoxy-A-(l-propyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-iY-[l-(3-phenpropyl)]diphenylamine d) iV-Benzyl-3-cyclopentyloxy-4-methoxydiphenylamine e) 3-Cyclopentyloxy-4-methoxy-/V-(4-pyridylmethyl)diphenylamine 0 3-Cyclopentyloxy-4-mefhoxy-Ar<->(2-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxywV-(3-pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-.'V-[3-(3-pyridyl)-l-propyl]diphenylamine i) Ar-(3-Cyclopentyloxy-4-methoxyphenyI)-A'-ethyl-4-isoquinotinylamine j) A/-(3-Cyclopentyloxy-4-methoxyphenyl)-A/-benzyl-4-isoquinolinylamine k) 7V-(3-Cyclopentyloxy-4-memoxyphenyl)-7V-methyl-4-isoquinolinylamine 1) iV-(3-Cyclopentyloxy-4-methoxyphenyl)-A-propyl-4-isoqumolinylamine m) /v'-(3-Cyclopentyloxy-4-methoxyphenyl)-Ar<->(4-isoquinolinyl)-/v'-(4-pyridylmethyl)amine n) A^-{3-Cyclopentyloxy-4-methoxyphenyl)-Ar<->(4-isoquinolinyl)-A</->(3-pyridylmethyl)amine o) A</->(3-Cyclopentyloxy-4-methoxyphenyl)-A</>'-(3-pyridylmethyl)-A</->(5-pyrimidinyl)amine p)A</->(3-Cyclopentyloxy-4-methoxyphenyl)-<y>V-(2-pyrazinyl)-/V-(3-pyridylmethyl)amineq)<y>V-(3-Cyclopentyloxy-4-methoxyphenyl)-Ar<->(2-pyridyl)-AA<->{3-pyridylmethyl)amine r)<y>V-(3-Cyclopentyloxy-4-methoxyphenyl)-A</->(3-pyridyl)-A</->(3-pyndylmethyl)amine s) A^-(3-Cyclopentyloxy-4-methoxyphenyl)-A'-(4-pyTidyl)-/V-(3-pyridylmethyl)amine t)/erf-Butyl A'-(3-cyclopentyloxy-4-methoxyphenyl)-/V-(3-pyridylmethyl)-6-aminonicotinate u) A/-(3-Cydopropylmethoxy-4-methoxypheny pyndylmethyl)amine v)<y>V-(4-Methoxy-3-(3/^)-tetrahydrofuryioxyphenyl)-iV-(3-pyTidyl)-A'-(3-pyridylmethyl)amine w) A/-(3-Cyclopentyloxy-4-difluoromethoxyphenyl)-/V-(3-pyn^yl)-A/-(3-pyridylmethyl)amine x) /V-(3-Cyclopropylmethoxy-4-di^^ pyridylmethyl)amine y) /V-{4-Dilfuoromethoxy-3-{3jf?)-terjahydrofuryloxyphenyl)-A/-(3-pyrid pyridylrnethyl)aTTiine z) /V-(4-Chloro-3-pyridylmethyl)-/V-(3-cyclopentyloxy-4-merh pyridyl)amrne aa)/V-(3-cyclopentyloxy-4-methoxyphenyl)-/V-(4-methy]-3-pyndy pyridyl)amine bb) 3-CycIopentyloxy-4-raethoxy-A/-(2-tbiazolylraetiyl)diphenylamine cc) /V-(2-Chloro-3-pyridylmethyl)-3-cyclope dd) A^^-ChloroO-pyridylmemyl^ EXAMPLE 9 (MethodB) <y>V-4-Chloro-3-pyridylmethyi)-<y>V-(3-cyclopentyl-4- methoxy phenyl)-A/-(2-pyridyl)amineTo a solution of (3-cyclopentyloxy-4-methoxyphenyl)-2-pyridylamine (30 mg, 0.10 mmol) and 4-chloropicolyl chloride hydrochlonde (50 mg, 0.25 mmol) was dissolved in DMF (1 mL) and sodium hydride (50 mg of a 60% mineral oil dispersion, 1.3 mmol) was added in small portions. After stirring for lh at room temperature, the mixture was poured into 25 mL ice water. The mixture was extracted with EtOAc (2 x 15 mL) and the EtOAc extracts were combined, washed with brine (15 mL), dried (MgSOa), and concentratedin vacuo.The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with 15% EtOAc in hexanes to give 20 mg of product as a yellow crystalline solid. 'H NMR (CDCb) 5 8.61 (s, 1H), 8.34"(d, 1H, J = 5.3 Hz), 8.17 (d, 1H, 5.0 Hz), 7.33 (m, IH), 7.25 (m, 1H), 6.83 (d, 1H, J = 8.5), 6.75 (d, 1H, J = 8.5), 6.-71 (s, 1H), 6.62 (m. 1H), 6.42 (d, 1H, J = 8.6), 5.31 (s, 2H), ^.63 (p, 1H, J = 4.12 Hz), 3.83 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3,4-Bis(difluoromethoxy)-/V-(4-chloro-3-pyndylmethyl)-3'-(2-(tetrahydropyTan-2-yl)-2H-tetrazol-5-yl)diphenylamine b) 3,4-Bis(difluoromethoxy)-<y>V-(4-methyl-3-pyridylmethyl)-3'-{2-(tetrahydropyran-2-yi)-2H-tetrazoi-5-yI)diphenylamine EXAMPLE 10 3-Cyclopenryloxy-4-methoxyanilino-A'-{3-pyridylmethyl)-Ar<->3-(4-pyridyl)benzamide To a solution of /V-(3-cycIopentyloxy-4-methoxyphenyl)-A/-(3-pyridyimethyi)-3-aminobenzoic acid (20 mg, 0.05 mmol) and pyBOP (40 mg. 0.08 mmol) in CH2CI2(2 mL) at room temperature was added diisopropylethylamine (20 L, 0.11 mmol). After stirring for 15 min, 4-aminopyridine (15 mg, 0.15 mmol) was added and the mixture was allowed to stir 16 h. The mixture was diluted with EtOAc (25 mL) and washed with water (2x15 mL) and bnne (15 mL), dried (MgSO*),'and concentratedin vacuo.The crude residue was loaded onto a RediSep column (4.2 g, silica gel) and the product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 mm to give 22 mg of product.<l>H NMR (CDCI3) 5 8.70-8.40 (m, 3H), 3.24 (s, 1H), 7.72 (d, 1H, 9.0 Hz), 7.68-7.55 (m, 2H), 7.30-7.20 (m, 1H), 6.88 (d, 2H, J = 8.5), 6.80-

6.65 (m, 3H), 4.98 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.86 (s, 3H), 1.86-1.70 (m, 6H),

1.65-1.45 (m,2H). The following compounds were prepared in a similar manner as described above: a) 3-(3-Cyclopentyloxy-4-metJioxyanilino)-<y>V-(3-pyridytmemyl)-A^-J-[3-(A</>,A</->dimethylamino)prop-1 -yljbenzamide b) 3-Cyclopentyloxy-4-methoxy-3'-(4-methylpiperazm-l-ylcarbonyl)-/V-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyioxy-4-difluoromethoxy-4'-(4-m pyndylmethyljdrphenylamine d) 3-Cyc[opentyloxy-4-methoxy-4'-(4-methylpiperazin-l-yicarbonyl)-/V-(3-pyndyimethyl)-3-(3-tetrahydrofuranyioxy)-dihen<y>lamine EX.4MPLE 11 The following compounds were prepared in a similar fashion as described in Example a) 4'-.\mmo-3-cyclopentyloxy-4-methoxy-AA<->(3-pyridylmethyl)diphenylamine b) 3'-Amino-3-cyclopentyloxy-4-methoxy-A/-(3-pyridylmethyl)diphenylamine c) 3'-Amino-3-cyclopropylmethoxy-4-methoxy-AA-(3-pyridylmediyl)diphenylamine d)<3>'-Amino-4-methoxy-/V-(3-pyrid<y>lmeth<y>l)-3-[(3j'?)- tetrahydrofuryloxyjdiphenylamine EXAMPLE 12 3-CyclopentyIoxy-4'-methanesulfonyIamino-4-methoxy-Av- (3-pyridylmethyl)-diphenylamine To a solution of 4'-ammo-3-cyclopentyloxy-4-methoxywV-{3-pyridylmethyl)-diphenylamine (47 mg, 0.12 mmol) in CH2CI2(2 mL) at room temperature was added pyridine (20 microliters, 0.24 mmol) followed by methanesulfonyl chloride (15 microliters, 0.18 mmol) and the mixture was allowed to stand at room temperature for 16 h. The mixture was diluted with ether (50 mL) and washed with water (25 mL) and brine (25 mL), dried (MgSOf), and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with a linear gradient from 45% EtOAc in hexanes to 60% EtOAc in hexanes over 20 min to yield 41 mg of product.<l>H NMR (CDC13) 5 8.51 (s, 1H), 8.41 (d, 1H, J = 4.8 Hz), 7.56 (d, 1H, 7.9 Hz), 7.16 (m, 1H), 6.98 (d, 2H, J = 9.0 Hz), 6.80-6.60 (m, 6H), 4.82 (s, 2H), 4.56 (p, 1H, J =

4.0 Hz), 3.75 (s,3H), 2.86 (s,3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-3'-ethanesulfonylamino-4-methoxy-/V-(3-pyridylmethyl)diphenylamine b)S-Cyclopentyloxy^-methoxyo'^l-propanesulfonylaminoj-A</>^S-pyndyimethyl)diphenylamine c) 3'-(1 -Butanesulfonylammo)-3-cyclopentyioxy-4-methoxy-yV-(3-pyndylmethyl)diphenylamine d) 3'-Benzylsulfonylamino-3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyl)diphenylamine e) 3'-Acetamido-3-cyclopentyloxy-4-methoxy-Ar<->(3-pyridylmethyl)diphenylamine f) S-Cyclopentyloxy^'-ethanesulfonylammo^-methoxy-^S-pyridylmethyl)diphenylamine g) 3-Cyclopentyloxy-4-methoxy-4'-(l-propanesulfonylamino)-Ar<->(3-pyndylmethyl)diphenylamine h) 3-Cyclopropylmethoxy-3'-ethanesulfonylamino-4-methoxy-A</->(3-pyridylmethyl)diphenylamine i) 4-Difluoromethoxy-3'-ethanesulfonylamino-A^-(3-pyridylmethyl)-3-[(3R)-tetrah<y>drofuryloxyjdiphenylamine EXAMPLE 13 3-Cydopentyioxy-4-methoxy-3 '-hydroxy methyl^V^-pyridylmethyOdiphenylamine To a solution of Ethyl /Vr-{3-cyclopentyloxy-4-methoxyphenyi)-Ar-(3-pyridylmethyl)-3-aminobenzoate (50 mg, 0.11 mmol) in TFff (5 mL) at 0 °C was added drop-wise, with stirring, 2.5M diisobutylaluminum hydride in toluene (0.4 mL, 1.00 mmol). The mixture was stirred at 0 °C for 1 h and the excess diisobutylaluminum hydride was quenched by adding 5 drops of EtOAc to the mixture. The mixture was concentrated and the residue was partitioned between CH2CI2(50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with CH-CI2(2x10 mL). The organic extracts were combined and washed with brine (50 mL), dried (MgSOO, and concentrated. The crude residue was purified by flash column chromatography (4.2 g RediSep column, silica gel) eluting with 300 mL 50% EtOAc in hexanes then 100% EtOAc to give 15 mg of product. 'H NMR (CDC13>5 8.51 (s, 1H), - 8.40 (br, 1H), 7.58 (d, 1H, 7.9 Hz), 7.25-7.05 (m, 3H), 6.80-6.60 (m, 5H), 4.85 (s, 2H),

4.56 (p, 1H,J = 4.1 Hz), 4.50 (s, 2H), 3.76 (s, 3H), 1.86-1.70 (m, 7H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-4'-hydroxymethyl-.V-(3-pvndylmethyl)diphenylamine EXAMPLE 14 3-Cyclopentylo.\y-4-methoxy-/Y-(3-pyridylmethyl)-4'-(2H-tetrazol-5- yl)diphenylamine To a solution of/V-(3-cyclopentyloxy-4-methoxyphenyl)-/V-(3-pyridylmethyl)-3-ammobenzonitrile (100 mg, 0.25 mmol) in DMF (3 mL) was added NaN3(163 mg, 2.5 mmol) and NH4C1 (135 mg, 2.5 mmol) and the mixture was stirred at 120 °C for 6 h. The mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2 x 25 mL). ■ The EtOAc extracts were combined, washed with water (25 mL) and brine (25 mL), dried (MgS04), and concentratedin vacuo.The residue was loaded onto a RediSep column (4.2 g, silica gel) and eluted with a linear gradient from 50% to 75% EtOAc in hexanes to yield 12 mg of product. 'H NMR (CDC13) 8 12.50 (br, 1H), 8.64 (s, 1H), 8.54 (br, 1H), 7.86 (d, 2H, J = 8.8 Hz), 7.75 (d, 1H, 7.8 Hz), 7.36 (m, 1H),

6.80-6.60 (m, 5H), 4.99 (s, 2H), 4.66 (p, 1H, J = 4.1 Hz), 3.84 (s, 3H), 1.86-1.70 (m, 7H),

1.65-1.45 (m,2H). EXAMPLE 15 3-Cyclopentyloxy-4-methoxy-4'-(4-methyl-l-piperazinylmethyl)- A^-pyridylmethyOdiphenylamine To a solution of 3-cyclopentyloxy-4-methoxy-4'-(4-methylpiperazin-l-ylcarbonyl)dipheylamine (100 mg, 0.20 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (50 mg, 1.3 mmol). The mixture was stirred for 15 mm and a few drops of EtOAc was carefully added to quench the excess hydride. Water (50 mL) and CFLCL (50 mL) were added and the mixtures were filtered through Celite. The CH2CI2layer was separated, washed with brine (25 mL), dried (MgS04), and concentratedin vacuo.The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with a gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to yield 60 mg of product as a light yellow oil.<*>H NMR (CDC13) 5 8.59 (s, 1H), 8.47 (d, 1H, J = 4.8 Hz), 7.65 (d, 1H, 7.9 Hz), 7.21 (dd, 1H, J = 4.8 Hz, 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.82-6.73 (m, 3K), 6.70-6.65 (m, 2H), 4.91 (s, 2H), 4.62 (p, 1H, J = 4.12 Hz),

3.82 (s, 3H), 3.41 (s, 2H), 2.75-2.20 (m, 8H), 2.27 (s, 3H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-4-methoxy-3'-(4-methyl-l-piperazinylmethyl)A</->(3-pyridylmethyl)diphenylamine EXAMPLE 16 3'-Aminomethyl-3-cyclopentyloxy-4-methoxy-Ar<->(3-pyridylmethyl)diphenylamine To a solution of iV-(3-c<y>cloent<y>loxy-4-methoxyhen<y>l)-/V-(3-p<y>rid<y>lmethyl)-3-aminobenzonitrile (50 mg, 0.12 mmol) in THF (5 mL) was carefully added, with stirring, lithium aluminum hydride (20 mg, 0.52 mmol). The mixture was stirred for 4 h and a few drops of water were carefully added to quench the excess hydride. Water (50 mL) and CH2C12(50 mL) were added and the mixtures were filtered through Celite. The CH2CI2layer was separated, washed with brine (25 mL), dried (MgS04), and concentratedin vacuo.The crude residue was purified on an ISCO RediSep column (4.2 g, silica) eluting with 10% MeOH in EtOAc to yield 20 mg of product. 'H NMR (CDCI3) 5 8.60 (s, 1H), 8.47 (br, 1H), 7.65 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 2H), 6.90-6.65 (m, 6H), 4.94 (s, 2H), 4.63 (p, 1H, J = 4.1 Hz), 3.83 (s, 3H), 3.75 (m, 2H), 2.29 (br, 2H), 1.86-1.70 (m, 6H), 1.65-1.45 (m, 2H). EXAMPLE 17 3-Hydroxy-4-methoxy-/V-{3-pyridylmethyl)diphenylam To a solution of 3-(rerr-butyldimethylsiloxy)-/V-(3-p>Tidylrnethyi)-4-methoxydiphenylamme (1.20 g, 2.85 mmol) in THF (40 mL) at 0 °C, was added 1.0M tetrabutylammonium fluonde in TPEF (10 mL, 10 mmol). The mixture was stirred at 0 °C for 30 min. Water (50 mL) was added and the mixture was extracted with ether (3 x 25 mL). The ether extracts were combined and washed with water (3 x 25 mL) and brine (25 mL), dried (MgSCU), and concentratedin vacuo.The residue was triturated with hexanes and collected by vacuum filtration to give 0.85 g of product. 'H NMR (CDC13) S 8.58 (s, 1H), 8.46 (br, 1H), 7.67 (d, 1H, 7.8 Hz), 7.26-7.10 (m, 3H), 6.90-6.65 (m, 5H),

6.64 (dd, 1H, J = 8.6 Hz, 2.6 Hz), 6.53 (br, 1H), 4.92 (s, 2H), 3.86 (s, 3H). The following compounds were prepared in a similar manner as described above: a) 3'-Chloro-3-hydroxy-4-methoxy-/V-(3-pyTidylmethyl)diphenylamine b) Ethyl A/-(3-hydroxy-4-methoxyphenyl)-A-(3-pyridylmethyl)-3-aminobenzoate EXAMPLE 18 (Method B) The following compounds were prepared in a similar manner as described in Example IB: a) 3-[3-(4-Chlorophenyl)prop-1-<y>loxy]-4-methoxy-/V-(3-pyridylmethyl)diphenylamine b) 3-[2-(4-Chlorophenyl)ethoxy]-4-methoxy-/V"-(3-pyridylmethyl)diphenylamine c) 4-Methoxy-3-(4-phenoxybut-1 -yl)oxy-/Y-(3-pyridylmethyl)diphenylamine d) 4-Methoxy-A</->(3-pyndylmethyl)-3-(3-tehrmydrofuryloxy)diphenylamine e) 4-Methoxy-3-[3-(4-methoxyphenyl)prop-l-yl]oxy-Af<->(3- pyridylmethyl)diphenyiamine f) 4-Methoxy-3-[3-(4-pyridyl)prop-l-yl]oxy-.V-(3-pyridylmethyl)diphenylamine g) 4-Methoxy-3-[2-(4-methoxyphenyl)ethoxy]-A</->(3-pyndylmethyl)diphenylamine h) 4-Methoxy-3-(4-phenylbut-l-yl)oxy-A'r<->(3-pyridylmethyl)diphenylamine i) 4-Methoxy-3-[4-(4-methoxyphenyl)but-l-yl]oxy-A/-(3-pyridylmethyl)diphenylamihe j) 4-Methoxy-3-[4-(4-nitrophenyl)but-1 -yl]oxy-/V-(3-pyridylmethyl)diphenylamine k) 4-Methoxy-3-[2-(2-pyndyl)ethoxy]-/V-(3-pyndylm 1) 4-Methoxy-3-[2-(4-pyridyl)emoxy]-/V-(3-pyirdylmethyl)diph m) 4-Methoxy-3-[3-(2-pyndyl)prop-l-^^ n) 4-Methoxy-3-(2-methoxyethoxy)-iV-(3-pyridyImeth o) 3-Cyclopropylmethoxy-4-methoxy-/V-{3^ p) 4-MethoxyO-(l-methylpyrrolidm-3-yl)ox q) 4-Methoxy-3-(l-methylpipendin-4-yl)oxy-iV-(3-pyTidylm r) 4-Methoxy-/V-(3-pyndylmethyl)-3^ s) 4-Methoxy-/V-(3-pyirdylmethyl)-3-[(3j^ t) 3'-Chloro-4-methoxy-3-[2-(2-pyndyl)etho u) 3'-Chloro-4-methoxy-3-[2-(4-pyridy v) 3'-ChIoro-4-methoxy-3-(2-methoxyethoxy)-/V-(3-pyridyIm w) 3 '-Chloro-4-methoxy-/V-(3-pyridylrnethyl)-3-[(3J??)- tetrahydrofuryloxyjdiphenylamine x) 3-Cyclohexyloxy-4-methoxy-Af-(3-pyridylmem^ y) 3-Cycloheptyloxy-4-methoxy-^-(3-pyn^ylmemyl)diphenylamine z) 3-(2-Cyclopropylemoxy)-4-methoxy-/V-(3-pyTidylmethyl)diph aa) 3-Cyclopentylmemoxy-4-memoxy-yV-(3-pyridylmethyl)diphen bb) Ethyl yV-[3-(4-chlorophenyl)prop-l-yloxy-4-m arninobenzoate cc) Ethyl yV-(3-cyclopropy!memoxy-4-m aminobenzoate dd) Ethyl7V-(3-cyclopropylmethoxy-4-difluoro aminobenzoate ee) EthylyV-(3-(2-indanyloxy)-4-memoxyphenyl]-^ff) Ethyl A^-[4-methoxy-3-(3-tetrahydromryloxy)phenyl]-/V-(3-pyridylmethyl)-3- aminobenzoate gg) Ethyl A<L>(4-methoxy-3-((3R)-tetrahydrofnryloxy)phenyl]-A</->(3-pyridylmethyl)-3- aminobenzoate hh) Ethyl /V-[3-(2-methoxyemoxy)-4-methoxyph^ aminobenzoate h) Ethyi iV-[4-methoxy-3-(2-(2-pyndyl)ethyl)oxypheny[]-/V-(3-py^ aminobenzoate EXAMPLE 18 (Method C) The following compounds were prepared in a similar manner as described in Example 8A by coupling a phenol with a boronic acid rather than coupling an aniline with a boronic acid: a) 4-Methoxy-3-(4-methoxyphenoxy)-Af<->(3-pyridylmethyl)diphenylamme b) 4-Methoxy-3-phenoxy-/V-(3-pyridylmethyl)diphenylamme c) 4-Methoxy-3-(4-methylphenoxy)-/V-(3-pyridylmethyl)diphenylamine d) 3-(4-Chlorophenoxy)-4-methoxy-A/'-(3-pyridylmethyl)diphenylamine e) 3-[2-(4-Chlorophenyl)ethenyloxy]-4-methoxy-A/-(3-pyridylmetliyl)diphenylamine EXAMPLE 19 The following compounds were prepared in a similar manner as described in Example 17: a) 3-Cyclopentyloxy-3'-hydroxy-4-methoxy-A/-(3-pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-hydroxy-4-memox<y->A/-(3-pyridyLmethyl)diphenylamine c) 3-Cyclopropylmefhoxy-4'-hydroxy-4-methoxy-A</->(3-pyridylmemyl)diphenylamine EXAMPLE 20 (Method A) The following compounds were prepared in a similar manner as described in Example 1A: a) 3'-(2-Bromoethoxy)-3-cyclopentyloxy-4-methoxy-/V-(3- pyridylmethyl)diphenylamine EXAMPLE 20 (Method B) The following compounds were prepared in a similar manner as described in Example IB: a) 3-Cyclopentyloxy-4'-(2-methoxyethoxy)-4-methoxy-<y>V-(3-pyndylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-(3-methyl-l-butoxy)-4-methoxy-/V-(3-pyridylmethyl)diphenylarnine c) 3-Cyclopentyloxy-4-methoxy-/V-(3-pyn^ diphenylamine d) 3-Cyclopentyloxy-4-methoxy-iV-(3-pyndylmethyl)-4'-[(3^)-tetrahydrofuranyloxy]-diphenylamine e) 3-Cyclopentyloxy-4'-cyclopropylmethoxy-4-methoxy-/V-(3-pyndylmethyl)diphenylamine f) 4'-Cyclohexylethoxy-3-cyclopentyloxy-4-methoxy-<y>V-(3- pyridylmethyl)diphenylamine g) 4'-Cyclopentylethoxy-3-cyclopentyioxy-4-methoxy-/V-(3- pyridylmethyl)diphenylamine h) 3-Cyclopentyloxy-4-methoxy-4'-(l-methylpiperidin-4-yloxy)-Ar<->(3-pyridylmethyl)diphenylamine i) 3-Cyclopentyloxy-4-methoxy-4'-(l-mem<y>lyTrohdin-3-yloxy)-7/-(3-pyridylmethyl)diphenylamine j) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-memylpyrrolidm-2-yl)ethoxy]-/V-(3-pyridylmethyl)diphenylamine k) 3-Cyclopentyloxy-4-meriioxy-4'-[2-(l-pyTTolidinylethoxy)-/V-(3-pyridylmethyl)diphenylamine

1) 3-Cyclopentyloxy-4-methoxy-4'-[2-(6-methylpyridyl)methoxy)-<y>Y-(3-pyridylmethyl)diphenyiamine m) 3-Cyclopentyloxy-4-memox<y>-4'-[3-(l-mem<y>lpiperidin<y>l)methox<y>]-A/'-{3-pyridylmethyl)diphenylamine n) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-methylpipendinyl)methoxy]-iV-(3-pyndylmethyl)diphenylamine o) 3-Cyclopentyloxy-4-methoxy-4'-[2-(5-oxopyTTolidinyl)methoxy]-/Y-(3-pyndylmethyl)diphenylamine p) 4'-{l-(3-Bromopropyl)oxy]-3-cyclopentyloxy-4-rnethoxy-/V-{3- pyndylrnethyi)diphenylamine q) 3-Cyclopentyloxy-4-methoxy-4'42-(iV-phthaHmido)echoxy pyridylmethyl)diphenylarnine EXAMPLE 21 3-CycIopentyIoxy-4-rnethoxy-3'-[2-(l-piperidinyI)ethoxy]-'V-(3- pyridylmethyl)diphenylamine To a solution of<3>'-(2-bromoethoxy)-3-c<y>cloent<y>loxy-4-methoxy-/V-(3-pyridyLmethyl)diphenylamine (17 mg, 0.03 mmol) in acetonitrile (1 mL) was added potassium carbonate (25 mg, 0.18 mmol) and piperidine (5 u.L, 0.05 mmol) and the mixture was stirred at 60 °C for 4 h. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL), dried (MgSO-f), and concentratedin vacuo.The residue was loaded on an ISCO RediSep column (4.2g, silica) and the column was eluted with a linear gradient from 5% MeOH in EtOAc to 15% MeOH in EtOAc to give 11 mg of product. 'H NMR (CDCI3) 5 8.59 (s, 1H), 8.48 (d, 1H, J = 4.7), 7.64 (d, 1H, 8.2 Hz), 7.26-7.20 (m, 1H), 7.06 (t, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.75-6.68 (m, 2H),

6.45-6.35 (m, 3H), 4.91 (s, 2H), 4.64 (p, 1H, J = 4.1 Hz), 4.00 (t, 2H, J = 6.2 Hz), 3.S4 (s, . 3H), 2.71 (t, 2H,J = 6.2 Hz), 2.47 (m, 4H), 1.90-1.70 (m, 6H), 1.86-1.70(m, 6H), 1.65-1.45 (m, 2H). The following compounds were prepared in a similar manner as described above: a) 3-Cyclopentyloxy-3'-[2-(l-imidazolyl)ethoxy]-4-methoxy-A</>'-(3-pyridyLmethyl)diphenylamine b) 3-Cyclopentyloxy-4-methoxy-3 '-[2-( I -methylpiperazin-4-yl)ethoxy]-/Y-(3-pyridylmethyl)diphenylamine c) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-methylpiperazin-4-yl)propoxy]-/V-(3-pyridylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-[3-(l-methylpiperazin-4-yO pyndylmethyi)diphenylamine e) 3-Cyclopentyloxy-4-methoxy-4'-[3-(2-morpholm-4-ylethylammo)propoxy pyridylmethyl)diphenylarnirie f) 4-Methoxy-3-(2-phenoxyethoxy)-/V-(3-pyridyl^ g) 3-[2-(4-Chlorophenoxy)ethoxy)-4-memoxy-/V-(3-pyri h) 4-Memoxy-3-(2-pyrrolidin-l-yl)ethoxy-/^ i) 4-Methoxy-3-(2-(4-methylpiperazin-l-yl)em^ j) 3-[2-(4-Chlorophenylamm^ EXAMPLE 22 4'-Aminoethoxy-3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyl)diphenyiarnine To a solution of yV-(3-pyridylrnethyl)-3'-[2-(2-phthalirnido)ethoxy]-3-cyclopentyloxy-4-methoxydiphenylamine (0.39 g, 0.69 rnmol) in MeOH (5 mL) was added hydrazine hydrate (1.0 mL, 20 mmol). After 6 h at room temperature, EtOAc was added (50 mL) and the precipitate was filtered off. The filtrate was washed with water (25 mL) and brine (25 mL), dried (MgSCu), and concentratedin vacuo.The residue was loaded on an ISCO RediSep column (10 g, silica). The column was washed with 10% MeOH in EtOAc (200 mL) and the product was eluted with 50% MeOH in EtOAc to yield 0.21 g.<l>H iNMR (CDCI3) 5 8.55 (s, 1H), 8.42 (d, 1H, J = 3.8 Hz), 7.62 (d, 1H, 7.

7 Hz), 7.20-7.10 (m, 1H), 6.91 (d, 2H, J = 9.0 Hz), 6.78 (d, 2H, J - 9.0 Hz), 6.70 (d, 1H, J = 8.6 Hz), 6.50-6.35 (m, 2H), 4.82 (s, 2H), 4.54 (p, 1H, J = 4.1 Hz), 3.90 (t, 2H, J = 6.1 Hz), 3.74 (s, 3H), 3.01 (m, 2H), 1.86-1.70 (m, 8H), 1.65-1.45 (m, 2H). EXAMPLE 23 The following compounds were prepared in a similar manner as described in Example 12: a) 3-Cyclopentyloxy-4'-(2-methanesulfonylamino)ethoxy-4-methoxy-A'-(3-'pyridylmethyl)diphenylamine b) 3-Cyclopentyloxy-4'-(2-etha^ pyridylmethyl)diphenylamme c) 3-Cyclopentyloxy-4-methoxy-4'-[2-{2-propanesulfonylamino)ethoxy]-/V-(3-pyndylmethyl)diphenylamine d) 3-Cyclopentyloxy-4-methoxy-4'-[2-(l-propanesulfonylarnino)ethoxy]-/V-(3-pyndylmethyl)diphenylamine e) 4'-[2-(l-Butanesulfonylamino)ethoxy]-3-cyclopentyloxy-4-memoxy-/V-(3-pyridylmethyl)diphenylamine EXAMPLE 24 In Vitro Measurement of Type 4 Phosphodiesterase Inhibition Activity Human PDE4 was obtained from baculovirus-mfected Sf9 cells that expressed the recombinant enzyme. The cDNA encoding hPDE-4D6 was subcloned into a baculovirus vector. Insect cells (Sf9) were infected with the baculovirus and cells were cultured until protein was expressed. The baculovirus-infected cells were lysed and the lysate was used as source of hPDE-4D6 enzyme. The enzyme was partially purified using a DEAE ion exchange chromatography. This procedure can be repeated using cDNA encoding other PDE-4 enzymes. Assay: Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP) to 5'-adenosine monophosphate (5'-AMP). Nucleotidase converts 5'-AMP to adenosine. Therefore the combined activity of PDE4 and nucleotidase converts cAMP to adenosine. Adenosine is readily separated from cAMP by neutral alumina columns. Phosphodiesterase inhibitors block the conversion of cAMP to adenosine in this assay; consequently, PDE4 inhibitors cause a decrease in adenosine. Cell lysates (40 ul) expressing hPDE-4D6 were combined with 50 ul of assay mix and 10 ul of inhibitors and incubated for 12 min at room temperature. Final concentrations of assay components were: 0. 4 ug enzyme, lOrrfM Tris-HCl (pH 7.5), lOmiVl MgCl2, 3 uM cAMP, 0.002 U 5<?->nucleotidase, and 3 x 10<4>cpm of [3H]cAMP. The reaction was stopped by adding 100 ul of boiling 5mN HC1. An aliquot of 75 ul of reaction mixture was transferred from each well to alumina columns (Multiplate; Millipore). Labeled adenosine was eluted into an OptiPlate by spinning at 2000 rpm for 2 min; 150 pi per well of scintillation fluid was added to the OptiPlate. The plate was sealed, shaken for about 30 mm, and cpm of [<3>H]adenosine was determined using a Wallac Tnflux®. All test compounds are dissolved in 100% DMSO and diluted into the assay such that the final concentration of DMSO is 0.1%. DMSO does not affect enzyme activity at this concentration. A decrease in adenosine concentration is indicative of inhibition of PDE activity.. pICjovalues were determined by screening 6 to 12 concentrations of compound ranging from 0.1 nM to 10,000 nM and then plotting drug concentration versus<3>H-adenosine concentration. Nonlinear regression software (Assay Explorer®) was used to estimate pICso values. EXAMPLE 25 (Method A) Passive Avoidance in Rats, an in vivo Test for Learning and Memory The test was performed as previously described (Zhang, H.-T, Crissman, A.M., Dorairaj, N.R, Chandler, L.J, and O'Donnell, J.M.,Neuropsychopharmacology,2000,23, 198-204.).The apparatus (Model E10-16SC, Coulbourn Instruments, Allentown, PA) consisted of a two-compartment chamber with an illuminated compartment connected to a darkened compartment by a guillotine door. The floor of the darkened compartment consisted of stainless steel rods through which an electric foot-shock could be delivered from a constant current source. All experimental groups were first habituated to the apparatus the day before the start of the experiment. During the training, the rat (Male Spraque-Dawley (Harlan) weighing 250 to 350 g) was placed in the illuminated compartment facing away from the closed guillotine door for 1 minute before the door . was raised. The latency for entering the darkened compartment was recorded. After the rat entered the darkened compartment, the door was closed and a 0.5 mA electric shock was administered for 3 seconds. Twenty-four hours later, the rat was administered 0.1 mg/kg MK-801 or saline, 30 minutes pnor to the injection of saline or test compound (dosed from 0.1 to 2.5 mg/kg, i.p.), which was 30 minutes before the retention test started. The rat was again placed in the illuminated compartment with the guillotine door open. The latency for entering the darkened compartment was recorded for up to 180 seconds, at which time the trial was terminated. All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Naive rats required less than 30 seconds, on average, to cross from the illuminated compartment to the darkened compartment. However, 24 hours after the electric shock exposure, most rats pretreated with vehicle did not re-enter the darkened compartment; the average latency was increased up to 175 seconds (p < 0.001). Pretreatment with MK-801 (0.1 mg/kg) markedly reduced this latency when compared to the vehicle (p<0.001). This amnesic effect of MK-801 is reversed in a statistically significant manner by actual test compounds in a dose-dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyl) diphenylamine, Effective dose range = 0.5 to 2.5 mg/kg, i.p.; and^-(3-cyclopentyloxy-4-methoxyphenyl)-Ar<->(3-pyridyhnethyl)-3-aminobenzoic acid, effective dose range = 0.1 to 2.5 mg/kg, ip). EXAMPLE 25 (Method B) Radial arm maze task in Rats, an in vivo Test for Learning and Memory The test was performed as previously described (Zhang, H.-T, Crissman, A.M, Dorairaj, N.R, Chandler, L.J, and O'Donnell, J.M,Neuropsychopharmacology,2000,23,198-204.). Five days after initial housing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) were placed in the eight-arm radial maze (each arm was 60x10x12 cm high; the maze was elevated 70 cm above the floor) for acclimation for two days. Rats were then placed individually in the center of the maze for 5 minutes with food pellets placed close to the food wells, and then, the next day, in the wells at the end of the arms; 2 sessions a day were conducted. Next, four randomly selected arms were then baited with one pellet of food each. The rat was restricted to the center platform (26 cm in diameter) for 15 seconds and then allowed to move freely throughout the maze until it collected all pellets of food or 10 minutes passed, whichever came first. Four parameters were recorded: I) working memory errors, i.e., entries into baited arms that had already been visited during the same trial; 2) reference memory errors, i.e., entries into unbaited arms; 3) total arm entnes; and 4) the test duration (seconds), i.e., the time spent in the collection of all the pellets in the maze. If the working memory error was zero and the average reference memory error was less than.one in five successive trials, the rats began the drug tests. MK-801 or saline was injected 15 minutes prior to vehicle or test agent, which was given 45 minutes before the test. Experiments were performed in a lighted room, which contained several extra-maze visual cues. All data were analyzed by analyses of variance (ANOVA); individual comparisons were made using Kewman-Keuls tests. Compared to control, MK-801 (0.1 mg/kg, i.p.) increased the frequencies of both working and reference memory errors (p<0.01). This amnesic effect of MK-801 on working memory is reversed in a statistically significant manner by the administration of actual test compounds in a dose-dependent fashion (e.g., 3-cyclopentyloxy-4-methoxy-/V-(3-pyridylmethyljdiphenylamme, Effective dose = 2.5 mg/kg, i.p.; p<0.0l) The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. While the invention has been illustrated with respect to the production and of particular compounds, it is apparent that variations and modifications of the invention can be made without departing from the spirit or scope of the invention.