SI9300038A - Novel imidazole compounds - Google Patents

Novel imidazole compounds Download PDF

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SI9300038A
SI9300038A SI9300038A SI9300038A SI9300038A SI 9300038 A SI9300038 A SI 9300038A SI 9300038 A SI9300038 A SI 9300038A SI 9300038 A SI9300038 A SI 9300038A SI 9300038 A SI9300038 A SI 9300038A
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alkyl
pyridyl
imidazole
formula
hydrogen
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SI9300038A
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Slovenian (sl)
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Timothy Francis Gallagher
Jerry Leroy Adams
John C Lee
John Richard White
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Smithkline Beecham Corp
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Abstract

Opisane so nove 2,4,5-triarilimidazolne spojine s splošno formulo: postopki za njihovo pripravo in farmacevtski sestavki za uporabo pri zdravljenju bolezenskih stanj, ki so povezana s prekomerno ali neuravnano proizvodnjo citokinov.New 2,4,5-triarylimidazole compounds are described with the general formula: processes for their preparation and pharmaceutical compositions for use in the treatment of conditions which are associated with overproduction or unbalanced production cytokines.

Description

SMITHKLINE BEECHAM CORPORATIONSMITHKLINE BEECHAM CORPORATION

NOVE SPOJINE NA OSNOVI IMIDAZOLNIH SPOJINNEW COMPOUNDS BASED ON IMIDAZOLE COMPOUNDS

Predloženi izum se nanaša na novo skupino imidazolnih spojin, na postopke za njihovo pripravo, na njihovo uporabo pri zdravljenju citokinsko posredovanih bolezni in farmacevtske sestavke za uporabo pri takšnem zdravljenju.The present invention relates to a new group of imidazole compounds, to methods for their preparation, to their use in the treatment of cytokine-mediated diseases, and to pharmaceutical compositions for use in such treatment.

Ozadje izumaBACKGROUND OF THE INVENTION

V zadnjih nekaj letih je bilo veliko zanimanja za spojine, ki so citokinski inhibitorji, za uporabo pri zdravljenju bolezenskih stanj, ki so povezana s prekomerno ali neuravnano proizvodnjo citokinov.In the last few years, there has been a great deal of interest in cytokine inhibitor compounds for use in the treatment of disease states associated with cytokine overproduction or disorder.

Spojine s splošno formulo (Α):Compounds of general formula (Α):

kjer je Ra piridil, Rb je v danem primeru substituiran fenil in je W delno ali popolno nenasičen kondenziran 5- ali 6-členski heterocikličen obroč, kot je pirolil, piridil, dihidropirolil, dihidropiridinil, dihidrotiazolil ali tetrahidro-triazinil, so inhibitorji citokinov IL-1 in TNF (glej WO88/01169, WO90/15534, W091/00092, W092/10190, WO92/10498 in WO92/12154, objavljeno po vložitvi te prijave). Poleg tega so te spojine tudi inhibitorji encima 5-lipoksigenaze. Sedaj smo presenetljivo ugotovili, da se, če obroč W zamenjamo z določenimi substituenti na položaju - 2, citokinsko inhibitorska aktivnost ohrani. Takšne spojine so generično 2-substituirani 4-aril-5heteroaril-imidazoli. Spojine znotraj tega razreda so že široko raziskovali kot protivnetna sredstva, ki delujejo kot inhibitorji ciklo-oksigenaze, kot je opisano v npr. US patentih 3,707,405 in 3,929,807. Zadnji opisuje spojine s splošno formulo (Β):where R a is pyridyl, R b is optionally substituted phenyl and W is a partially or completely unsaturated condensed 5- or 6-membered heterocyclic ring, such as pyrrolyl, pyridyl, dihydropyrrolyl, dihydropyridinyl, dihydrotiazolyl or tetrahydro-triazinyl, being cytokine inhibitors IL-1 and TNF (see WO88 / 01169, WO90 / 15534, W091 / 00092, W092 / 10190, WO92 / 10498 and WO92 / 12154, published after filing this application). In addition, these compounds are also inhibitors of the enzyme 5-lipoxygenase. We have now surprisingly found that when the W ring is replaced by certain substituents at position - 2, cytokine inhibitory activity is maintained. Such compounds are generally 2-substituted 4-aryl-5heteroaryl-imidazoles. Compounds within this class have already been widely studied as anti-inflammatory agents that act as cyclo-oxygenase inhibitors, as described in e.g. US Patents 3,707,405 and 3,929,807. The latter describes compounds of the general formula (Β):

kjer je eden izmed Ra in Rb v danem primeru substituiran fenil in je drugi 6-členski heterocikličen obroč z 1 ali 2 dušikovima atomoma in Rc predstavlja nižji alkil, cikloalkil ali fenil, v danem primeru substituiran s halogenom, nižjim alkilom ali nižjim alkoksi, še posebno spojino 2-(4-klorofenil)-4-(4-metoksifenil)-5-(4-piridil)-imidazol. Za te spojine je rečeno, da imajo protivnetno analgetično in antipiretično delovanje. Seveda pa tu ni omenjeno, da bi te spojine lahko bile citokinski inhibitorji.wherein one of R a and R b is optionally substituted phenyl and the other is a 6-membered heterocyclic ring of 1 or 2 nitrogen atoms and R c represents lower alkyl, cycloalkyl or phenyl optionally substituted by halogen, lower alkyl or lower alkoxy, in particular compound 2- (4-chlorophenyl) -4- (4-methoxyphenyl) -5- (4-pyridyl) -imidazole. These compounds are said to have anti-inflammatory analgesic and antipyretic activity. Of course, it is not mentioned here that these compounds could be cytokine inhibitors.

Popolen opis izumaA complete description of the invention

Torej, predloženi izum se nanaša na spojino s formulo (I):Thus, the present invention relates to a compound of formula (I):

RR

RR

R2 R 2

(I) kjerje(I) where

R1 4-piridil, pirimidinil, kinolil, izokinolinil, 1-imidazolil ali 1-benzimidazolil, ki je v danem primeru substituiran z enim ali dvema substituentoma, vsakega izmed njiju pa neodvisno izberemo izmed CM alkila, halo, CM alkoksi, C14 alkiitio, NHg, mono- ali di-C^-alkilamino ali N-heterociklilnega obroča, ta obroč pa ima od 5 do 7 členov in v danem primeru vsebuje dodatni heteroatom, izbran izmed kisika, žvepla ali NR22;R 1 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl, which is optionally substituted by one or two substituents, each of which is independently selected from C 1-4 alkyl, halo, C 1-4 alkoxy, C 14 an alkylthio, NHg, mono- or di-C 1-6 alkylamino or N-heterocyclyl ring, this ring having from 5 to 7 members and optionally containing an additional heteroatom selected from oxygen, sulfur or NR 22 ;

R2 Rg ali -OR12;R 2 R g or -OR 12 ;

R3 -XaP(Z)(XbR13)2 ali Ο-(Υχ)·R 3 -X a P (Z) (X b R 13 ) 2 or Ο- (Υ χ ) ·

Q aril ali heteroarilna skupina;Q is an aryl or heteroaryl group;

t celo število od 1 do 3;t is an integer from 1 to 3;

Xa -NR8-, -0-, -S- ali C140 alkilenska veriga, v danem primeru substituirana s C14 alkilom in v danem primeru prekinjena z -NRg-, -O- ali -S-;X a -NR 8 -, -O-, -S- or C 140 alkylene chain optionally substituted by C 14 alkyl and optionally interrupted by -NR g -, -O- or -S-;

Xb (CR^R^jn,-NR8-,-O-ali-S-;X b (CR ^ R ^ jn, -NR 8 -, - O-or-S-;

Z kisik ali žveplo;With oxygen or sulfur;

n O ali celo število od 1 do 10;n O or an integer from 1 to 10;

Yx neodvisno izbran izmed vodika, C15 alkila, halo substituiranega C15 alkila, halogena, -Xa-P(Z)-(XbR13)2 ali -(CR10R20)nY2;Y x is independently selected from hydrogen, C 15 alkyl, halo substituted C 15 alkyl, halogen, -X a -P (Z) - (X b R 13 ) 2 or - (CR 10 R 20 ) n Y 2 ;

Y2 -OR8, -NO2, -S(O)m,Rn, -SRg, -S(O)m,ORg, -S(O)mNR8R9, -NRgR9, -O(CR10R20)nNR8R9, -C(O)Rg, -CO2R8, -CO2(CR10R20)n,CONRgR9, -ZC(O)Rg, -CN, -C(Z)NR8R9, -NRioC(Z)R8, -C(Z)NRg0R9, -NR1„qZ)NRgR9, -NR10S(O)mR11, -N(OR21)C(Z)NR8R9, -N(OR21)qZ)Rg, -C( = NOR21)R8, -NR10C( = NR15)SR11, -NR10C( = NR15)NR8R9, -NR1oC( = CR14R24)SR11, -NR10C( = CR14R24)NR8R9,Y 2 -OR 8 , -NO 2 , -S (O) m , R n , -SRg, -S (O) m , OR g , -S (O) m NR 8 R 9 , -NR g R 9 , -O (CR 10 R 20 ) n NR 8 R 9 , -C (O) Rg, -CO 2 R 8 , -CO 2 (CR 10 R 20 ) n , CONR g R 9 , -ZC (O) R g , -CN, -C (Z) NR 8 R 9 , -NR io C (Z) R 8 , -C (Z) NR g 0R 9 , -NR 1 'qZ) NR g R 9 , -NR 10 S ( O) m R 11 , -N (OR 21 ) C (Z) NR 8 R 9 , -N (OR 21 ) qZ) R g , -C (= NOR 21 ) R 8 , -NR 10 C (= NR 15 ) SR 11 , -NR 10 C (= NR 15 ) NR 8 R 9 , -NR 10 C (= CR 14 R 24 ) SR 11 , -NR 10 C (= CR 14 R 24 ) NR 8 R 9 ,

-NR10C(O)C(O)NR8R9, -NR10C(O)C(O)OR10, -C(=NR13)NR8R9,-NR 10 C (O) C (O) NR 8 R 9 , -NR 10 C (O) C (O) OR 10 , -C (= NR 13 ) NR 8 R 9 ,

-C(=NOR13)NR8R9, -C(=NR13)ZRn, -OC(Z)NR8R9, -NR10S(O)mCF3, -NR10C(Z)OR10, 5-(R18)-l,2,4-oksadiazol-3-il ali 4-(R12)-5-(RlgR19)-4,5dihidro-l,2,4-oksadiazol-3-iI;-C (= NOR 13 ) NR 8 R 9 , -C (= NR 13 ) ZR n , -OC (Z) NR 8 R 9 , -NR 10 S (O) m CF 3 , -NR 10 C (Z) OR 10 , 5- (R 18 ) -1,2,4-Oxadiazol-3-yl or 4- (R 12 ) -5- (R 1g R 19 ) -4,5-dihydro-1,2,4-oxadiazole- 3-iI;

m’ 1 ali 2;m '1 or 2;

n’ je celo število od 1 do 10;n 'is an integer from 1 to 10;

R4 fenil, naft-l-il ali naft-2-il, ki je v danem primeru substituiran z enim ali dvema substituentoma, vsakega izmed njiju pa neodvisno izberemo in je ta 4-fenilni, 4-naft-l-ilni ali 5-naft-2-ilni substituent, halo, ciano, -C(Z)NR7R17, -C(Z)OR23, -(CR10R20)mCOR36, -SR5, -SOR5, -OR^, halo-substituirani-C14 alkU, C14 alkil, -ZqZ)R36, -NR^ZjR^ ah -(CR10R20)mNR10R2<), in ki je, za ostale položaje substitucije halo, ciano, -C(Z)NR16R26, -C(Z)ORg, -(CR10R20)mCORg, -S(O)mRg, -ORg, halo-substituiran-CM alkil, -CM alkil, -(CR^^NR^Rg, -NR10S(O)mR11, -NR^O^NR^, kjer je m 1 ali 2,-ZqZ)R8ali-(CR10R20)mNR16R26;R 4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected and is 4-phenyl, 4-naphth-1-yl or 5 -naphth-2-yl substituent, halo, cyano, -C (Z) NR 7 R 17 , -C (Z) OR 23 , - (CR 10 R 20 ) m COR 36 , -SR 5 , -SOR 5 , - OR ^, halo-substituted-C 14 alkU, C 14 alkyl, -ZqZ) R 36 , -NR ^ ZjR ^ ah - (CR 10 R 20 ) m NR 10 R 2 <) , and which, for other substitution positions halo, cyano, -C (Z) NR 16 R 26 , -C (Z) OR g , - (CR 10 R 20 ) m COR g , -S (O) m R g , -OR g , halo-substituted- C M alkyl, -C M alkyl, - (CR ^^ NR ^ R 8, -NR 10 S (O) m R 11 , -NR ^ O ^ NR ^ where m is 1 or 2, -ZqZ) R 8 or - (CR 10 R 20 ) m NR 16 R 26 ;

m 0 ali celo število 1 ali 2;m 0 or an integer 1 or 2;

Rs vodik, C14 alkil, C24 alkenil, C24 alkinil ali NR7R17, brez delov -SR5, ki jeR is hydrogen, C 14 alkyl, C 24 alkenyl, C 24 alkynyl or NR 7 R 17 , excluding parts -SR 5 which is

-SNR^p in -SOR5, ki je -SOH;-SNR ^ p and -SOR 5 which is -SOH;

R6 Cm alkil, halo-substituirani-C14 alkil, C24 alkenil, C24 alkinil ali C3 5 cikloalkil;R 6 is C 1-4 alkyl, halo-substituted-C 14 alkyl, C 24 alkenyl, C 24 alkynyl or C 3-5 cycloalkyl;

R? in R17 vsakega neodvisno izberemo izmed vodika ali CM alkila ali R? in R1? skupaj z dušikom, na katerega so vezani, tvorijo heterocikličen obroč s 5 do 7 členi, ta obroč pa v danem primeru vsebuje dodatni heteroatom izbran izmed kisika, žvepla ali NR22;R ? and R 17 are each independently selected from hydrogen or a C M alkyl, or R? and R 1? together with the nitrogen to which they are attached, form a heterocyclic ring of 5 to 7 members, this ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR 22 ;

Rg vodik, heterociklil, heterociklilalkil ali Rn;R g is hydrogen, heterocyclyl, heterocyclylalkyl or R n ;

R9 vodik, Cj 1θ alkil, C210 alkenil, C21θ alkinil, C3 7 cikloalkil, C5 7 cikloalkenil, aril, arilalkil, heteroaril ali heteroarilalkil ali pa lahko Rg in R? skupaj z dušikom, na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč pa v danem primeru vsebuje dodatni heteroatom izbran izmed kisika, žvepla ali nr12; R 9 is hydrogen, C 1-10 alkyl, C 210 alkenyl, C 21θ alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or can R g and R ? together with the nitrogen to which they are attached, form a heterocyclic ring of 5 to 7 members, this ring optionally containing an additional heteroatom selected from oxygen, sulfur or nr 12;

R10 in R^ vsakega neodvisno izberemo izmed vodika ali C14 alkila;R 10 and R 4 are each independently selected from hydrogen or C 14 alkyl;

Rn Cj 1θ alkil, halo-substituirani Cx 10 alkil, C21θ alkenil, C21θ alkinil, C37 cikloalkil, C5 7 cikloalkenil, aril, arilalkil, heteroaril ali heteroarilalkil;R 11 is C 1-10 alkyl, halo-substituted C x 10 alkyl, C 21θ alkenyl, C 21θ alkynyl, C 37 cycloalkyl, C 5 7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

R12 vodik, -C(Z)R13 ali v danem primeru substituiran C14 alkil, v danem primeru substituiran aril ali v danem primeru substituiran aril-CM alkil;R 12 is hydrogen, -C (Z) R 13 or optionally substituted C 14 alkyl, optionally substituted aryl or optionally substituted aryl-C M alkyl;

R13 vodik, Cj 10 alkil, cikloalkil, heterociklil, aril, arilalkil, heteroaril ali heteroarilalkil;R 13 is hydrogen, C 10 alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;

R14 in R^ vsakega neodvisno izberemo izmed vodika, alkila, nitro ali ciano;R 14 and R 4 are each independently selected from hydrogen, alkyl, nitro or cyano;

Rj5 je vodik, ciano, Cj4 alkil, C3 7 cikloalkil ali aril;R 5 is hydrogen, cyano, C 1-4 alkyl, C 3-7 cycloalkyl or aryl;

Rj6 in R^ vsakega neodvisno izberemo izmed vodika ali v danem primeru substituiranega Cj_4 alkila, v danem primeru substituiranega arila, ali v danem primeru substituiranega aril-C14 alkila, ali skupaj z dušikom, na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč pa v danem primeru vsebuje dodaten heteroatom, izbran izmed kisika, žvepla ali NR12;R 6 and R 6 are each independently selected from hydrogen or optionally substituted C 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 14 alkyl, or together with the nitrogen to which they are attached, form a heterocyclic ring with 5 to 7, this ring optionally containing an additional heteroatom selected from oxygen, sulfur or NR 12 ;

R18 in R19 vsakega neodvisno izberemo izmed vodika, C14 alkila, substituiranega alkila, v danem primeru substituiranega arila, v danem primeru substituiranega arilalkila ali skupaj pomenita kisik ali žveplo;R 18 and R 19 are each independently selected from hydrogen, C 14 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, or together represent oxygen or sulfur;

R2j vodik, farmacevtsko sprejemljiv kation, Cj 10 alkil, C3 7 cikloalkil, aril, aril C14 alkil, heteroaril, heteroarilalkil, heterociklil, aroil ali Cj 10 alkoil;R 2 is hydrogen, a pharmaceutically acceptable cation, C 10 alkyl, C 3-7 cycloalkyl, aryl, aryl C 14 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl or C 10 alkyl;

R^2 Rio QZ)-Cj^ alkil;R 2 is R 10 C 1 -C 5 -C 1 alkyl;

R^ ClJ( alkil, halo-substituiran-C14 alkil ali C3 5 cikloalkil;R 1 is C 1-10 ( alkyl, halo-substituted-C 14 alkyl or C 3-5 cycloalkyl;

R^ vodik ali R^;R 4 is hydrogen or R 4;

ali njeno farmacevtsko sprejemljivo sol;or a pharmaceutically acceptable salt thereof;

in brez 2-(4-klorofenil)-4-(4-metoksifenil)-5-(4-piridil)imidazola.and free of 2- (4-chlorophenyl) -4- (4-methoxyphenyl) -5- (4-pyridyl) imidazole.

Primerni Rj deli vključujejo 4-piridil, 4-pirimidinil, 4-kinolil, 6-izokinolinil,Suitable R 1 moieties include 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl,

1-imidazolil in 1-benzimidazolil, izmed katerih so 4-piridil, 4-pirimidinil in 4-kinolil, posebno 4-piridil, prednostni. Prednostni substituent za vse R7 dele je CM alkil, še posebno metil. Bolj prednosten je kot substituiran R7 del 4-piridilni derivat, substituiran na položaju -2 s CM alkilom, še posebno 2-metil-4-piridil. Tudi prednosten je 4-pirimidinilni derivat, substituiran na položaju 2 s CM alkilom ali NR^R^.1-imidazolyl and 1-benzimidazolyl, of which 4-pyridyl, 4-pyrimidinyl and 4-quinolyl, especially 4-pyridyl, are preferred. A preferred substituent for all R 7 parts of the C M alkyl, in particular methyl. More preferred as the substituted R 7 moiety is a 4-pyridyl derivative substituted at the -2 position by C 1-4 alkyl, in particular 2-methyl-4-pyridyl. Also preferred is the 4-pyrimidinyl derivative, substituted in position 2 with C M alkyl, or NR ^ R ^.

Prednostno je R2 vodik ali C1 alkil, bolj prednostno vodik ali metil.Preferably R 2 is hydrogen or C 1 alkyl, more preferably hydrogen or methyl.

Prednostno je R3 del (ne)substituirani arilni ali heteroarilni del Q, tudi naveden kot Q-(Yi)f Prednostno> kadar je Q aril, specifično fenil in kadar je Q heteroaril, prednostne skupine vključujejo pirol, piridin ali pirimidin. Bolj prednosten je Q kot fenil. Vsi prednostni deli so neodvisno substituirani z (Yj), kjer je t celo število od 1 do 3. Prednostno je 11 ali 2. Bolj prednostno je, kadar je R3 monosubstituiran fenil, substituent nameščen na položaju -4.Preferably R 3 is a (non) substituted aryl or heteroaryl portion of Q, also referred to as Q- (Y 1) f Preferably > when Q is aryl, specifically phenyl and when Q is heteroaryl, preferred groups include pyrrole, pyridine or pyrimidine. Q is preferred over phenyl. All preferred moieties are independently substituted by (Yj), where t is an integer from 1 to 3. Preferably, 11 or 2. More preferably, when R 3 is monosubstituted phenyl, the substituent is positioned at position -4.

Ustrezno je arilni ali heteroarilni del Q substituiran z do 3 substituenti Yp izmed katerih vsakega neodvisno izberemo izmed Cp5 alkila, halo-substituiranega C15 alkila, halogena, -XaP(Z)-(XbR13)2 ali -(CR^R^)^, kjer je Y2 -ORg, -NO2, -S(O)m.Rn, -SR8, -S(O)m.ORg, -S(O)mNR8R9, -NRgR9, -O(CR10R20) NRgR9, -C(O)Rg, -CO2R8, -CO2(CR10R20)n,CONR8R9, -ZC(O)Rg, -CN, -C(Z)NRgR9, -NR10C(Z)Rg, -C(Z)NRgOR9, -NR10C(Z)NRgR9, -NR10S(O)mR115 -N(OR21)C(Z)NR8R9, -N(OR21)C(Z)R8, -C(=NOR21)R8, -NR10C(=NR15)SRn, -NR10C(=NR15)NR8R9, -NR10C(=CR14R24SRn, -NR1oC(=CR14R24)NR8R9, -NR10C(O)C(O)R8R9, -NR10C(O)C(O)OR10, -C( = NR13)NR8R9, -C( = NOR13)NR8R9, -C(=NR13)ZRn, -OC(Z)NR8R9, -NR10S(O)mCF3, -NR10C(Z)OR1(), 5-(Rlg)-l,2,4-oksadiazol-3-il ali 4-(R12-5-(RlgR19)-4,5-dihidro-l,2,4oksadiazol-3-il; m’je 1 ali 2; R9 je vodik, C1W alkil, C21θ alkenil, C21θ alkinil, C3 7 cikloalkil, C5 7 cikloalkenil, aril, arilalkil, heteroaril ali heteroarilalkil ali pa lahko, Rg in R9 skupaj z dušikom na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč v danem primeru vsebuje dodaten heteroatom, izbran izmed kisika, žvepla ali NR12; R14 in R^ vsakega neodvisno izberemo izmed vodika, alkila, nitro ali ciano; RJ5 je vodik, ciano, C14 alkil, C3 7 cikloalkil ali aril; Rlg in R19 vsakega neodvisno izberemo izmed vodika, alkila, substituiranega alkila, v danem primeru substituiranega arila, arilalkila ali pa skupaj z ogljikom, na katerega sta vezana, pomenita dvojno vezani kisik ali žveplo, t.j. C=O ali C=S; in je R21 vodik, farmacevtsko sprejemljiv kation, alkil, cikloalkil, aril, arilalkil, heteroaril, heterocikličen, heteroarilalkil, aroil, alkoil.Accordingly, the aryl or heteroaryl portion of Q is substituted with up to 3 Y p substituents each of which are independently selected from C p5 alkyl, halo-substituted C 15 alkyl, halogen, -X a P (Z) - (X b R 13 ) 2 or - (CR ^ R ^) ^, where Y 2 is -OR g , -NO 2 , -S (O) m .R n , -SR 8 , -S (O) m .OR g , -S (O) m NR 8 R 9 , -NR g R 9 , -O (CR 10 R 20 ) NR g R 9 , -C (O) R g , -CO 2 R 8 , -CO 2 (CR 10 R 20 ) n , CONR 8 R 9 , -ZC (O) R g , -CN, -C (Z) NR g R 9 , -NR 10 C (Z) R g , -C (Z) NR g OR 9 , -NR 10 C ( Z) NR g R 9 , -NR 10 S (O) m R 115 -N (OR 21 ) C (Z) NR 8 R 9 , -N (OR 21 ) C (Z) R 8 , -C (= NOR 21 ) R 8 , -NR 10 C (= NR 15 ) SR n , -NR 10 C (= NR 15 ) NR 8 R 9 , -NR 10 C (= CR 14 R 24 SR n , -NR 10 C (= CR 14 R 24 ) NR 8 R 9 , -NR 10 C (O) C (O) R 8 R 9 , -NR 10 C (O) C (O) OR 10 , -C (= NR 13 ) NR 8 R 9 , -C (= NOR 13 ) NR 8 R 9 , -C (= NR 13 ) ZR n , -OC (Z) NR 8 R 9 , -NR 10 S (O) m CF 3 , -NR 10 C ( Z) oR 1 (), 5- (R lg) -l, 2,4-oxadiazol-3-yl or 4- (R12 -5- (R lg R 19) -4,5-dihydro-2 , 4oxadiazol-3-yl; m 'is 1 or 2; R 9 is hydrogen, C 1W alkyl, C 21θ alkenyl, C 21θ alkynyl, C 3 7 cycloalkyl, C 5 7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or may be, R g and R 9 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, this ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 12 ; R 14 and R 4 are each independently selected from hydrogen, alkyl, nitro or cyano; R J5 is hydrogen, cyano, C 14 alkyl, C 3 7 cycloalkyl or aryl; R LG and R 19 are each independently selected from hydrogen, alkyl, substituted alkyl, optionally substituted aryl, arylalkyl or together with the carbon to which they are attached denote a double bonded oxygen or sulfur, i.e. C = O or C = S; and R 21 is hydrogen, pharmaceutically acceptable cation, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclic, heteroarylalkyl, aroyl, alkyl.

Prednostni substituenti Υχ za uporabo v R3 vključujejo halogen, C15 alkil inPreferred Υ χ substituents for use in R 3 include halogen, C 15 alkyl and

oksadiazol-3-il in 4-(R12)-5-(RlgR19)-4,5-dihidro-l,2,4-oksadiazol-3-il.oxadiazol-3-yl and 4- (R12) -5- (R lg R 19) -4,5-dihydro-l, 2,4-oxadiazol-3-yl.

Prednostni substituenti Y1 za uporabo v R3, kadar je arilna ali heteroarilna skupina Q mono-substituirana, vključujejo -(CR10R20)nY2, kjer je: n 0,1,2 ali 3, prednostno 0 ali i; in je Y2 -ORg, posebno, kjer je Rg vodik ali C110 alkil; -NO2; -S(O)m,Rn, še posebno kjer je Rn C1W alkil; -SRg, še posebno, kjer je Rg C]10 alkil; S(O)mNRgR9, še posebno kjer sta Rg in R9 vsak vodik ali Cx alkil, ali Rg in R9 skupaj z dušikom, na katerega sta vezana, tvorita 5 do 7 členski obroč, ki v danem primeru vključuje še en heteroatom, izbran izmed kisika, žvepla ali NR12 in je m 2; n’ je 1 do 10; -NRgR9, še posebno kjer sta Rg in R9 vsak vodik, metil ali benzil, ali Rg in R9 skupaj z dušikom, na katerega sta vezana, tvorita 5 do 7 členski obroč, ki v danem primeru vključuje še en heteroatom, izbran izmed kisika, žvepla ali NR12; -O(CR10R20)nNR8R9, še posebno kjer sta Rg in R9 vsak Cx 1θ alkil, -C(O)Rg, še posebno kjer je Rg vodik ali C1W alkil; -CO2Rg, še posebno kjer je Rg vodik ali C]10 alkil; -CO2(CR10R20)n,CONRgR9, še posebno kjer sta Rg in R9 vodik ali C110 alkil; -CN; -C(Z)NRgR9, še posebno kjer sta Rg in R9 vodik ali C]10 alkil; -NR10S(O)mR11, še posebno kjer je R10 vodik ali C110 alkil in je Rn Cx 1θ alkil ali halosubstituiran; -NR10qZ)Rg, še posebno kjer je Rg C1W alkil in je Rlo vodik in je Z kisik; -C(Z)NRgOR9, še posebno kjer sta Rg in R9 vsak vodik in je Z kisik; NR10QZ)NRgR9, še posebno kjer sta Rg in R^ vsak vodik ali Cx 10 alkil in je Z kisik; -N(OR21)qZ)NRgR9, še posebno kjer je Rg, še posebno kjer so Rg, R9 in R21 vsak vodik ali C11Q alkil in je Z kisik; -C(=NOR13)NRgR9, še posebno kjer so Rg, R9 in R13 vsak vodik; -NRloq=NR15)NRgR9, še posebno kjer sta Rg in R9 vodik, Cx 1θ alkil ali arilalkil in je R1S ciano; in 5-(Rlg)-l,2,4-oksadiazol-3-il in 4-(R12)-5-(RlgR19)-4,5dihidro-l,2,4-oksadiazol-3-il, še posebno kjer je R12 vodik in sta Rlg in R19 vsak vodik ali Cx alkil, ali sta skupaj okso.Preferred Y 1 substituents for use in R 3 when the aryl or heteroaryl group Q is mono-substituted include - (CR 10 R 20 ) n Y 2 where: n is 0,1,2 or 3, preferably 0 or i; and Y 2 is -OR g , in particular where R g is hydrogen or C 110 alkyl; -NO 2 ; -S (O) m , R n , especially where R n is C 1W alkyl; -SR g , especially where R g is C 1-10 alkyl; S (O) m NR g R 9 , especially where R g and R 9 are each hydrogen or C x alkyl, or R g and R 9 together with the nitrogen to which they are attached form a 5 to 7 membered ring which in this case includes another heteroatom selected from oxygen, sulfur or NR 12 and m 2; n 'is 1 to 10; -NR g R 9 , especially where R g and R 9 are each hydrogen, methyl or benzyl, or R g and R 9 together with the nitrogen to which they are attached form a 5 to 7 membered ring, which optionally includes one heteroatom selected from oxygen, sulfur or NR 12 ; -O (CR 10 R 20 ) n NR 8 R 9 , especially where R g and R 9 are each C x 1θ alkyl, -C (O) R g , especially where R g is hydrogen or C 1 W alkyl; -CO 2 R g , especially where R g is hydrogen or C 1-10 alkyl; -CO 2 (CR 10 R 20 ) n , CONR g R 9 , especially where R g and R 9 are hydrogen or C 110 alkyl; -CN; -C (Z) NR g R 9 , especially where R g and R 9 are hydrogen or C 10 alkyl; -NR 10 S (O) m R 11 , in particular where R 10 is hydrogen or C 110 alkyl and R n C x 1θ is alkyl or halosubstituted; -NR 10 qz), R g, and particularly where R g C 1W alkyl, and R lo is hydrogen and Z is oxygen; -C (Z) NR g OR 9 , especially where R g and R 9 are each hydrogen and Z is oxygen; NR 10 QZ) NR g R 9 , especially where R g and R 4 are each hydrogen or C 10 alkyl and Z is oxygen; -N (OR 21 ) qZ) NR g R 9 , especially where R is g , especially where R g , R 9 and R 21 are each hydrogen or C 11 Q alkyl and Z is oxygen; -C (= NOR 13 ) NR g R 9 , especially where R g , R 9 and R 13 are each hydrogen; -NR lo q = NR 15 ) NR g R 9 , especially where R g and R 9 are hydrogen, C 1 -C 1 alkyl or arylalkyl and R 1 S is cyano; and 5- (R 1g ) -1,2,4-oxadiazol-3-yl and 4- (R 12 ) -5- (R 1g R 19 ) -4,5-dihydro-1,2,4-oxadiazol-3- yl, especially where R 12 is hydrogen and R lg and R 19 are each hydrogen or C x -alkyl, or together are oxo.

Prednostni substituenti za uporabo v Rg, kadar je arilna ali heteroarilna skupina Q disubstituirana, vključujejo tiste, tu zgoraj našetete za uporabo, kadar je Q monosubstituiran, in kot nadaljne substituente halogen in Cx 1θ alkil. Kadar je R3 fenil substituiran z dvema ali tremi substituenti, imajo alkilni deli prednostno od enega do tri ogljike, bolj prednostno enega. Prednostna obročna položaja za dva substituenta sta položaj -3 in -4 in za tri substituente položaj: -3, -4 in -5. Substituent na položaju -3 in -5 je prednostno CJ2 alkil, kot je metil, ali halogen, kot je bromo, fluoro ali kloro, medtem koje substituent na položaju -4 prednostno hidroksil.Preferred substituents for use in R8 when the aryl or heteroaryl group of Q is disubstituted include those listed above for use when Q is monosubstituted, and as further substituents halogen and C x 1θ alkyl. When R 3 is phenyl substituted with two or three substituents, the alkyl moieties preferably have from one to three carbons, more preferably one. The preferred ring positions for the two substituents are positions -3 and -4 and for the three substituents the positions are -3, -4 and -5. The substituent at position -3 and -5 is preferably C1-12 alkyl, such as methyl, or a halogen, such as bromo, fluoro or chloro, while the substituent at position -4 is preferably hydroxyl.

Bolj prednostno, za substituente R3, kjer je Υχ (CR10R20)nY2, je n 0 ali 1 in je Y2 -OH, -S(O)m,Rn, še posebno kjer je Rn Ο11θ alkil; -SRg, še posebno kjer je Rg C110 alkil; -NRgR9, še posebno kjer sta Rg in R9 vodik, alkil, arilalkil ali aril, ali Rg in R9 skupaj z dušikom, na katerega sta vezana, tvorita pirolidinilni, piperidinilni ali morfolinilni obroč, bolj prednostno Rg in R9 označujeta v NRgR9 delu vodik, metil ali benzil; -CO2Rg, še posebno kjer je Rg vodik ali Ο11θ alkil; -S(O)m,NRgR9, še posebno kjer sta Rg in R9 vsak vodik ali C110 alkil; -NR10S(O)mR11, še posebno kjer je R10 vodik in je Rn C110 alkil ali 5-(Rlg)-l,2,4-oksadiazol-3-il in 4-(R12)-5-(RlgR19)-4,5dihidro-l,2,4-oksadiazol-3-il, še posebno kjer je R12 vodik in sta Rlg in R19 vodik ali Cj θ alkil, ali sta skupaj okso.More preferably, for the substituents R 3 , where Υ χ (CR 10 R 20 ) n Y 2 , n is 0 or 1 and Y 2 is -OH, -S (O) m , R n , especially where R n Ο 11θ alkyl; -SR g , especially where R g is C 110 alkyl; -NR g R 9 , especially where R g and R 9 are hydrogen, alkyl, arylalkyl or aryl, or R g and R 9 together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl or morpholinyl ring, more preferably R g and R 9 denotes hydrogen, methyl or benzyl in NR g of R 9 ; -CO 2 R g , especially where R g is hydrogen or Ο 11θ alkyl; -S (O) m , NR g R 9 , especially where R g and R 9 are each hydrogen or C 110 alkyl; -NR 10 S (O) m R 11, especially wherein R 10 is hydrogen and R is n C 110 alkyl or 5- (R lg) -l, 2,4-oxadiazol-3-yl and 4- (R12 ) -5- (R lg R 19) -4,5dihidro-l, 2,4-oxadiazol-3-yl, especially where R 12 is hydrogen and R lg and R 19 is hydrogen or a C θ alkyl, or taken together are oxo.

Najbolj prednostno je Υχ metiltio, etiltio, metilsulfinil, etilsulfinil, metilsulfonil, N,Ndimetilaminometil, N-benzil-N-metilaminometil, N-morfolinometil, metansulfonamido, sulfonamidometil, 5-metil-4,5-dihidro-l,2,4-oksadiazol-3-il ali 5,5dimetil-4,5-dihidro-l,2,4-oksadiazol-3-il.Most preferably, χ χ is methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, N, N-dimethylaminomethyl, N-benzyl-N-methylaminomethyl, N-morpholinomethyl, methanesulfonamido, sulfonamidomethyl, 5-methyl-4,5-dihydro-1,2,4 -oxadiazol-3-yl or 5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl.

V vseh primerih tu notri, kjer je alkenilni ali alkinilni del kot substituentna skupina, kot je v R5, Rg, R9 ali Rn nenasičena vezava, t.j. vinilenska ali acetilenska vezava prednostno ni direktno vezana na dušikove, kisikove ali žveplove dele, npr. v Y2 kot C(Z)NRgOR9, NR10C(Z)NRgR9 ali ORg. Kot uporabljamo tukaj, se substituiran v danem primeru, če ni določeno drugače, nanaša na takšne skupine kot halogen, hidroksil, alkoksi, S(O)m alkil, amino, mono in di-substituirani amino, kot je NR?R1? skupina, alkil ali cikloalkil, t.j. kot je pri, v danem primeru substituiranem arilu ali, v danem primeru substituiranem arilalkilu.In all cases herein, where the alkenyl or alkynyl moiety as a substituent group, such as in R 5 , R g , R 9 or R n, is unsaturated bonding, i.e. vinylene or acetylene bonding is preferably not directly bonded to the nitrogen, oxygen or sulfur moieties, e.g. in Y 2 as C (Z) NR g OR 9 , NR 10 C (Z) NR g R 9 or OR g . As used herein, substituted, unless otherwise indicated, refers to such groups as halogen, hydroxyl, alkoxy, S (O) m alkyl, amino, mono and di-substituted amino such as NR ? R 1? a group, alkyl or cycloalkyl, i.e. as in the case of optionally substituted aryl or optionally substituted arylalkyl.

Kadar R3 vključuje Xa-P(Z)XbR13)2 skupino vezano, ali neposredno na imidazolni obroč, ali posredno preko arilne ali heteroarilne skupine, je Xa ustrezno kisik ali alkilen, v danem primeru prekinjen s kisikom, -npr. -CH2OCH2- in sta Z in Xb vsak kisik, tako, da prednostne skupine vključujejo -OP(O)(OR13)2 in -0^0^(0)(0^^.When R 3 includes X a -P (Z) X b R 13 ) 2 a group attached, either directly to the imidazole ring, or indirectly via an aryl or heteroaryl group, X a is suitably oxygen or alkylene, optionally interrupted by oxygen, - e.g. -CH 2 OCH 2 - and Z and X b are each oxygen, such that the preferred groups include -OP (O) (OR 13 ) 2 and -0 ^ 0 ^ (0) (0 ^^.

Prednostne substitucije za R4, kadar je ta 4-fenilni, 4-naft-l-ilni ali 5-naft-2-ilni del, je eden ali dva substituenta, vsak neodvisno izbran izmed halogena, -SR5, -SOR5, -OR^ ali -(CR10R20)mNR10R20 in za ostale položaje substitucije na teh obročih je prednostna substitucija halogen, -S(O)mRg, -ORg, -(CR10R20)mNR16R26, -NR10C(Z)Rg in -NR10S(O)mRn. Bolj prednostni substituenti za položaj -4 v fenilu in naft-l-ilu in na položaju -5 v naft-2-ilu vključujejo halogen, posebno fluoro in kloro, in -SR5 in -SOR5, kjer je R5 prednostno Cj 2 alkil, bolj prednostno metil; izmed katerih je posebno prednosten fluoro. Prednostni substituenti za položaj -3 v fenilu in naft-l-ilu vključujejo: halogen, posebno kloro; -ORg, posebno C1-4 alkoksi; amino; -NR10C(Z)Rg, posebno -NHCO(C140 alkil); in -NR10S(O)mRn, posebno -NHSO2(C110 alkil). Prednostno je R4 del nesubstituiran ali substituiran fenilni del. Bolj prednostno je R4 fenil ali fenil substituiran na položaju -4 s fluoro in/ali substituiran na položaju -3 s fluoro, kloro, C14 alkoksi, metansulfonamido ali acetamido.Preferred substitutions for R 4 when this 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl moiety is one or two substituents, each independently selected from halogen, -SR 5 , -SOR 5 , -OR ^ or - (CR 10 R 20 ) m NR 10 R 20 and for other substitution positions on these rings, halogen substitution is preferred, -S (O) m R g , -OR g , - (CR 10 R 20 ) m NR 16 R 26 , -NR 10 C (Z) R g and -NR 10 S (O) m R n . More preferred substituents for position -4 in phenyl and naphth-1-yl and at position -5 in naphth-2-yl include halogen, especially fluoro and chloro, and -SR 5 and -SOR 5 , where R 5 is preferably C 2 alkyl, more preferably methyl; of which fluoro is particularly preferred. Preferred substituents for the -3 position in phenyl and naphth-1-yl include: halogen, especially chloro; -OR g , especially C 1-4 alkoxy; amino; -NR 10 C (Z) R g , in particular -NHCO (C 140 alkyl); and -NR 10 S (O) m R n , in particular -NHSO 2 (C 110 alkyl). Preferably R 4 is an unsubstituted or substituted phenyl moiety. More preferably, R 4 is phenyl or phenyl substituted at position -4 with fluoro and / or substituted at position -3 with fluoro, chloro, C 14 alkoxy, methanesulfonamido or acetamido.

V prednostni podvrsti spojin s formulo (I) je Rj 4-piridil, 2-alkil-4-piridil ali 4-kinolil; R2 je vodik ali metil; R3 je fenil ali fenil substituiran, prednostno na položaju -4, s substituentom, izbranim izmed -(CR10R20)nY2, kjer je Y2, kjer je n 0,1,2 ah 3 in je Y2 In a preferred subtype of compounds of formula (I), R1 is 4-pyridyl, 2-alkyl-4-pyridyl or 4-quinolyl; R 2 is hydrogen or methyl; R 3 is phenyl or phenyl substituted, preferably at position -4, with a substituent selected from - (CR 10 R 20 ) n Y 2 , wherein Y is 2 , where n is 0,1,2 ah 3 and Y 2

dihidro-l,2,4-oksadiazol-3-il, 3,5-dimetilna ali dibromo-4-hidroksilna grupacija; in je R4 fenil ali fenil substituiran na položaju -4 s fluoro in/ali substituiran na položaju 3 s fluoro, kloro, C14 alkoksi, metansulfonamido ali acetamido.a dihydro-1,2,4-oxadiazol-3-yl, 3,5-dimethyl or dibromo-4-hydroxyl group; and R 4 is phenyl or phenyl substituted at position -4 with fluoro and / or substituted at position 3 with fluoro, chloro, C 14 alkoxy, methanesulfonamido or acetamido.

V bolj prednostni podvrsti je Rj 4-piridil, 2-metil-4-piridil ali 4-kinolil; R2 je vodik ali metil; R3 je fenil substituiran na položaju -4 s C1 alkiltio, C140 alkilsulfinilom, Cl lo alkilsulfonilom, N,N-di(C110 alkil)amino C12 alkilom, N-aralkil-N-C110 alkilamino C12 alkilom, N-morofolino C12 alkilom, C1 alkilsulfonamido, sulfonamido C12 alkilom, 5-C110 alkil-4,5-dihidro-l,2,4-oksadiazol-3-ilom ali 5,5-di(C110 alkil)-4,5dihidro-l,2,4-oksadiazol-3-ilom; in je R4 fenil ali fenil substituiran na položaju -4 s fluoro in/ali substituiran na položaju -3 s fluoro, kloro, C14 alkoksi, metansulfonamido ali acetamido.In a more preferred subtype, R1 is 4-pyridyl, 2-methyl-4-pyridyl or 4-quinolyl; R2 is hydrogen or methyl; R 3 is phenyl substituted at the 4-position with C 1 alkoxy, C 140 alkylsulfinyl, C l lo alkylsulfonyl, N, N-di (C 110 alkyl) amino C 12 alkyl, N-aralkyl-NC 110 alkylamino, C 12 alkyl, N -morpholino C 12 alkyl, C 1 alkylsulfonamido, sulfonamido C 12 alkyl, 5-C 110 alkyl-4,5-dihydro-1,2,4-oxadiazol-3-yl or 5,5-di (C 110 alkyl) - 4,5-dihydro-1,2,4-oxadiazol-3-yl; and R 4 is phenyl or phenyl substituted at position -4 with fluoro and / or substituted at position -3 with fluoro, chloro, C 14 alkoxy, methanesulfonamido or acetamido.

Primerne farmacevtsko sprejemljive soli so dobro znane strokovnjakom in vključujejo bazične soli anorganskih in organskih kislin, kot je klorovodikova kislina, bromovodikova kislina, žveplova kislina, fosforna kislina, metan sulfonska kislina, etan sulfonska kislina, ocetna kislina, jabolčna kislina, vinska kislina, citronska kislina, mlečna kislina, oksalna kislina, jantarna kislina, fumama kislina, maleinska kislina, benzojska kislina, salicilna kislina, fenilocetna kislina in mandeljeva kislina. Poleg tega lahko farmacevtsko sprejemljive soli spojin s formulo (I) tvorimo tudi s farmacevtsko sprejemljivim kationom, npr. če substituent Yt v R3 vključuje karboksi skupino. Primerni farmacevtsko sprejemljivi kationi so dobro znani strokovnjakom in vključujejo alkalijske, zemljo alkalijske, amonijeve in kvarteme amonijeve katione.Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, acetic acid, citric acid, citric acid, citric acid , lactic acid, oxalic acid, succinic acid, fumama acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and almond acid. In addition, the pharmaceutically acceptable salts of the compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, e.g. if the substituent Y t in R 3 includes a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkali earth, ammonium and quaternary ammonium cations.

Naslednji pojmi, kot jih uporabljamo tukaj, se nanašajo na:The following terms, as used here, refer to:

- halo - vsi halogeni, to je kloro, fluoro, bromo in jodo;- halo - all halogens, ie chloro, fluoro, bromo and iodo;

- Cj 1θ alkil ali alkil - oba ravna in razvejena verižna radikala z 1 do 10 ogljikovimi atomi, razen če ni dolžina verige drugače omejena, vključno, toda neomejeno na metil, etil, n-propil, izo-propil, n-butil, sefc-butil, izo-butil, /erc-butil in podobno;- C 1θ alkyl or alkyl - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, SEFC -butyl, iso-butyl, / erc-butyl and the like;

- aril - fenii in naftil;- aryl - phenyl and naphthyl;

- heteroaril (sam ali v katerikoli kombinaciji, kot je heteroariloksi) - 5-10 členski aromatski obročni sistem v katerem eden ali več obročev vsebuje enega ali več heteroatomov, izbranih iz skupine, ki se sestoji iz N, O ali S, kot je, toda neomejeno, pirol, kinolin, izokinolin, piridin, pirimidin, oksazol, tiazol, tiadiazol, triazol, imidazol ali benzimidazol;- heteroaryl (alone or in any combination, such as heteroaryloxy) - a 5-10 membered aromatic ring system in which one or more rings contains one or more heteroatoms selected from the group consisting of N, O or S, such as, but unlimited, pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole;

- heterocikličen (sam ali v katerikoli kombinaciji, kot je heterociklilalktf) - nasičen ali popolno ali delno nenasičen 4-10 členski obročni sistem, v katerem eden ali več obročev vsebuje enega ali več heteroatomov, izbranih izmed skupine, ki se sestoji izmed N, O ali S; kot je, toda neomejeno, pirolidin, piperidin, piperazin, morfolin, imidazolidin ali pirazolidin;- heterocyclic (alone or in any combination, such as heterocyclylalctf) - a saturated or fully or partially unsaturated 4-10 membered ring system in which one or more rings contains one or more heteroatoms selected from the group consisting of N, O or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine;

- aroil - C(O)Ar, kjer je Ar kot fenilni, naftilni ali aril alkilni derivat, kot je benzil in podobno;- aroyl - C (O) Ar, wherein Ar is as a phenyl, naphthyl or aryl alkyl derivative such as benzyl and the like;

- alkoil - C(O)Cj 1θ alkil, kjer je alkil, kot je definirano zgoraj;- alkyl - C (O) C 1-10 alkyl, where alkyl is as defined above;

- sulfinil - oksid (SO) ustreznega sulfida, medtem ko se pojem tio nanaša na sulfid.- sulfinyl oxide (SO) of the corresponding sulfide, while the term thio refers to sulfide.

Spojine v smislu predloženega izuma lahko vsebujejo enega ali več asimetričnih ogljikovih atomov in lahko obstajajo v racemnih in optično aktivnih oblikah. Vse te spojine so vključene v obseg predloženega izuma.The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are within the scope of the present invention.

Za namene nomenklature v predloženem opisu, spojine s formulo (I) imenujemo po njihovem položaju glede na:For the purposes of the nomenclature herein, the compounds of formula (I) are named by their position with respect to:

Posebno prednostne spojine s formulo (I) vključujejo:Particularly preferred compounds of formula (I) include:

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol;4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole;

4-(4-fluorofenil)-2-(4-etiltiofenil)-5-(4-piridil)imidazol;4- (4-fluorophenyl) -2- (4-ethylthiophenyl) -5- (4-pyridyl) imidazole;

4-(4-fluorofenil)-2-(4-metilsulfonilfenil)-5-(4-piridil)imidazol;4- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) -5- (4-pyridyl) imidazole;

4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)imidazol;4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole;

4-(4-fluorofenil)-2-(4-etilsulfmilfenil)-5-(4-piridil)imidazol;4- (4-fluorophenyl) -2- (4-ethylsulfinylphenyl) -5- (4-pyridyl) imidazole;

4-(3-klorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)imidazol;4- (3-chlorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole;

2-[4-(N-metil-N-benzil)aminometilfenil]-4-(4-fluorofenil)-5-(4-piridil)imidazol; 4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metiltiofenil)imidazol; 4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metilsulfinilfenil)imidazol; 4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-kinolil)imidazol; 2-[4-(N-morfolino)metilfenil]-4-(4-fluorofenil)-5-(4-piridil)-imidazol; in in njihove farmacevtsko sprejemljive soli.2- [4- (N-methyl-N-benzyl) aminomethylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylthiophenyl) imidazole; 4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylsulfinylphenyl) imidazole; 4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-quinolyl) imidazole; 2- [4- (N-morpholino) methylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -imidazole; and and pharmaceutically acceptable salts thereof.

Ostale prednostne spojine s formulo (I) vključujejo:Other preferred compounds of formula (I) include:

2-[(4-N,N-dimetil)aminometilfenil]-4-(4-fluorofenil)-5-(4-piridil)imidazol;2 - [(4-N, N-dimethyl) aminomethylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole;

2- (4-metansulfonamidofenil)-4-(4-fluorofenil)-5-(4-piridil)imidazol;2- (4-methanesulfonamidophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole;

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-kinolil)imidazol;4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-quinolyl) imidazole;

4-(3-klorofenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol;4- (3-chlorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole;

4-(3-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol;4- (3-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole;

4-(3-metoksifenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)imidazol;4- (3-methoxyphenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole;

4-(3-metansulfonamidofenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol;4- (3-Methanesulfonamidophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole;

4-(3-metansulfonamidofenil)-2-(4-metilsulfmilfenil)-5-(4-piridil)imidazol;4- (3-Methanesulfonamidophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole;

3- [4-(4-fluorofenil)-5-(4-piridil)imidazol-2-il]fenil-5,5-dimetil-4,5-dihidro-l,2,4-oksadiazol; ali3- [4- (4-fluorophenyl) -5- (4-pyridyl) imidazol-2-yl] phenyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazole; or

3-[4-(4-fluorofenil)-5-(4-piridil)imidazol-2-il]fenil-5-metil-4,5-dihidro-l,2,4-oksadiazol; in njihove farmacevtsko sprejemljive soli.3- [4- (4-fluorophenyl) -5- (4-pyridyl) imidazol-2-yl] phenyl-5-methyl-4,5-dihydro-1,2,4-oxadiazole; and pharmaceutically acceptable salts thereof.

Spojine s formulo (I) so imidazolni derivati, ki jih zlahka pripravimo ob uporabi postopkov dobro znanih strokovnjakom in ki so opisani v npr. Comprehensive Heterocyclic Chemistry, ed Katritzky and Rees, Pergamon Press, 1984, 5, 457:497, iz izhodnih materialov, ki so ali komercialno razpoložljivi, ali pa jih lahko pripravimo iz le-teh z anologijo po dobro znanih postopkih. Ključni korak v mnogih takšnih sintezah je tvorba centralnega imidazolnega jedra, da dobimo spojine s formulo (I).The compounds of formula (I) are imidazole derivatives which are readily prepared using methods well known in the art and which are described in e.g. Comprehensive Heterocyclic Chemistry, ed. Katritzky and Rees, Pergamon Press, 1984, 5, 457: 497, from starting materials that are either commercially available or can be prepared from them by analogy according to well known methods. A key step in many such syntheses is the formation of a central imidazole nucleus to give compounds of formula (I).

Primerni postopki so opisani v ititer alia US patent št. 3,707,475 in 3,940,486, ki sta tu vključena kot referenca v celoti. Ta patenta opisujeta sinteza α-diketonov in α-hidroksiketonov (benzoinov) in njihovo nadaljnjo uporabo pri pripravi imidazolov in N-hidroksil imidazolov. Potemtakem lahko nadaljnje spojine s formulo (I) pridobimo s prikrojitvijo substituentov v katerikoli izmed skupin Rp R,, R3 in R4, ob uporabi običajnih postopkov notranje konverzije in funkcionalne skupine.Suitable procedures are described in ititer alia U.S. Pat. 3,707,475 and 3,940,486, which are incorporated herein by reference in their entirety. These patents describe the synthesis of α-diketones and α-hydroxyketones (benzoins) and their further use in the preparation of imidazoles and N-hydroxyl imidazoles. Thus, further compounds of formula (I) can be obtained by tailoring the substituents to any of the groups R p R 1, R 3 and R 4 using conventional internal conversion and functional group procedures.

Še posebno v prvem postopku, lahko spojine s formulo (I) pripravimo s kondenzacijo α-diketona s formulo (II):Particularly in the first process, the compounds of formula (I) can be prepared by condensation of the α-diketone of formula (II):

R1COCOR4 (II), kjer sta R1 in R4, kot je definirano preje, ali njun ekvivalent z aldehidom s formulo (ΠΙ):R 1 is COCOR 4 (II), wherein R 1 and R 4 are as defined in the yarn, or an aldehyde equivalent of formula (ΠΙ) thereof:

R3CHO (III), kjer je R3, kot je definirano zgoraj ali njegov ekvivalent, in če je potrebno z amoniakom ali njegovim virom, pod pogoji tvorbe imidazolnega obroča.R 3 is CHO (III), wherein R 3 is as defined above or equivalent, and if necessary with ammonia or its source, under the conditions of formation of the imidazole ring.

Primerni ekvivalenti α-diketona so dobro znani strokovnjakom in vključujejo ustrezen α-keto-oksim in a-dioksim.Suitable α-diketone equivalents are well known to those skilled in the art and include the corresponding α-keto-oxime and α-dioxime.

Primerni ekvivalenti aldehida s formulo (III) so dobro znani v stroki in vključujejo ustrezen oksim in acetal.Suitable equivalents of the aldehyde of formula (III) are well known in the art and include the corresponding oxime and acetal.

Amoniak ali njegov vir prednostno uporabimo v prebitku, pri čemer uporabimo najmanj dimolamo količino v primeru α-diketona in najmanj ekvimolamo količino v primeru a-keto-oksima.Ammonia or its source is preferably used in excess, using at least a dimolous amount in the case of α-diketone and at least an equimolar amount in the case of α-keto-oxime.

Primerni viri amoniaka vključujejo amonijeve soli organskih karboksilnih kislin, kot je amonijev C1>6 alkanoat, npr. amonijev acetat in amonijev format, prednostno amonijev acetat in karboksilne amide, še posebno formične kisline, kot je formamid. Amonijevo sol splošno uporabimo v velikem prebitku in v prisotnosti kisline, kot je karboksilna kislina, to kislino lahko tudi uporabimo kot topilo za reakcijo. Če uporabimo formamid, ga lahko uporabimo v prebitku, kot reakcijsko topilo.Suitable sources of ammonia include the ammonium salts of organic carboxylic acids, such as ammonium C 1-6 alkanoate, e.g. ammonium acetate and ammonium formate, preferably ammonium acetate and carboxylic amides, especially formic acids such as formamide. The ammonium salt is generally used in high excess and in the presence of an acid such as carboxylic acid, this acid can also be used as a reaction solvent. If formamide is used, it can be used in excess as a reaction solvent.

Uporabimo lahko tudi alternativno topilo, kot je etanol ali dimetil sulfoksid (Lantos et al, J Het Chem, 19,1375,1982). Poleg tega lahko uporabimo tudi dodatno topilo, npr. dimetilformamid lahko uporabimo s formamidom. Reakcijo splošno izvedemo pri povišanih temperaturah, npr. pod pogoji refluksa in če je želeno, v danem primeru v zapečateni bučki pod tlakom in/ali v atmosferi inertnega plina, npr. dušika.Alternative solvents such as ethanol or dimethyl sulfoxide may also be used (Lantos et al, J Het Chem, 19,1375,1982). In addition, an additional solvent may be used, e.g. dimethylformamide can be used with formamide. The reaction is generally carried out at elevated temperatures, e.g. under reflux conditions and, if desired, optionally in a sealed pressurized flask and / or in an inert gas atmosphere, e.g. nitrogen.

Nadaljnji primerni vir amoniaka je hidroksilamin, v takem primeru je prvotno formiran imidazol N-hidroksi-N-oksid imidazol. Tega lahko reduciramo do ustreznega N-hidroksi imidazola z obdelavo v primernem reducimem sredstvu, kot je natrijev borohidrid, v primernem topilu, kot je metanol, sledeč postopku Akange in Allan, Chem and Ind, 5 Jan 1975, 38. N-hidroksi imidazol lahko po vrsti pretvorimo v imidazol s formulo (I), v kateri je R2 vodik, z obdelavo z običajnim deoksigenacijskim sredstvom, kot je fosforjev triklorid ali trialkilfosfit, kot je trimetil- ali trietil-fosfit. N-hidroksi-N-oksid imidazole lahko zlahka pridobimo z obdelavo α-diketona s formulo (II) z aldehidom s formulo (II) z okoli dvema ekvivalentoma hidroksilamina ali ustreznega aldoksima in okoli enim ekvivalentom hidroksilamina, pod protonsko katalizo. Alternativno lahko N-oksid pridobimo s kislinsko katalizirano kondenzacijo ustrzenega α-dioksima ali α-keto-oksima z aldoksimom aldehida s formulo (III).Another suitable source of ammonia is hydroxylamine, in which case the imidazole N-hydroxy-N-oxide imidazole was originally formed. This can be reduced to the corresponding N-hydroxy imidazole by treatment with a suitable reducing agent such as sodium borohydride in a suitable solvent such as methanol following the procedure of Akange and Allan, Chem and Ind, 5 Jan 1975, 38. N-hydroxy imidazole can be is in turn converted to imidazole of formula (I) in which R 2 is hydrogen by treatment with a conventional deoxygenating agent such as phosphorus trichloride or trialkyl phosphite such as trimethyl or triethyl phosphite. The N-hydroxy-N-oxide imidazoles can be readily obtained by treating the α-diketone of formula (II) with an aldehyde of formula (II) with about two equivalents of hydroxylamine or the corresponding aldoxime and about one equivalent of hydroxylamine, under proton catalysis. Alternatively, the N-oxide can be obtained by acid-catalyzed condensation of the crushed α-dioxime or α-keto-oxime with the aldeoxide of the aldehyde of formula (III).

Kadar je spojina s formulo (II) α-keto-oksimski derivat, je želeno, da je prvotno pridobljeni produkt spojina s formulo (I), v kateri je R2 hidroksil, ki ga lahko pretvorimo v spojino s formulo (I), v kateri je R2 vodik, kot je opisano zgoraj.When the compound of formula (II) is an α-keto-oxime derivative, it is desirable that the initially obtained product is a compound of formula (I) in which R 2 is hydroxyl which can be converted to a compound of formula (I) in which R 2 is hydrogen as described above.

Strokovnjaki si v nekaterih primerih želijo, da ne bi bilo nujno zagotoviti ločenega vira amoniaka, ker lahko α-diketonski ali aldehidni ekvivalent že vsebuje takšen vir. Takšni primeri vključujejo α-dioksim ali α-keto-oksim in aldoksim.In some cases, experts wish it would not be necessary to provide a separate source of ammonia, since the α-diketone or aldehyde equivalent may already contain such a source. Such examples include α-dioxime or α-keto-oxime and aldoxime.

Spojine s formulo (II) lahko pridobimo z uporabo dobro znanih sinteznih postopkov, nekateri izmed njih so ponazorjeni na shemah I in II. Kljub temu, da te ponazarjajo sinteze, v katerih je R4 ali 4-piridil ali 4-kinolinil, jih lahko enakovredno uporabljamo pri katerih koli drugih heteroarilnih obročih s primerno definicijo R4, s primernim izborom izhodnega materiala.The compounds of formula (II) can be obtained using well-known synthesis methods, some of which are illustrated in Schemes I and II. Although these illustrate syntheses in which R is 4 or 4-pyridyl or 4-quinolinyl, they can be equally used in any other heteroaryl rings with the appropriate definition of R 4 , with a suitable choice of starting material.

V shemi I anion pripravljen iz 1, z obdelavo z močno bazo, kot je litijev di-izopropilamid, kondenziramo s substituiranim benz-aldehidom, da dobimo, po odstranitvi zaščitne skupine, diol 2. Tega lahko nato pretvorimo v a-diketon 3 s Swernovo oksidacijo, katere veliko število potencialno uporabnih variacij je znano in ki jih lahko uporabimo, a-diketon 3 je nato cikliziran v imidazol 4, spojino s formulo (I), s segrevanjem 3 s substituiranim benzaldehidom v zmesi amonijevega acetata, kot vira amoniaka, in v primernem topilu, nprm. ocetni kislini ali DMSO. Imidazol 4 lahko nato pretvorimo v ostale imidazole 5 s primernimi postopki notranje pretvorbe funkcionalne skupime. Shema I tudi ponazarja pripravo zaščitenega α-hidroksiketona 2a, s kondenzacijo aniona 1, s primerno aktiviranim karbonilnim derivatom substituiranega benzamida, kot je N-metoksi-N-metilamid, da dobimo zaščiten α-hidroksiketon. Ta adukt 2a, lahko nato direktno pretvorimo v imidazol 5, z uporabo kombinacije bakrove(II) soli, kot je bakrov(II) acetat kot oksidacijskega sredstva in amonijevega acetata, kot vira amoniaka, α-hidroksiketonu 2a lahko tudi odstranimo zaščito in ga nato oksidiramo, da dobimo a-diketon 3, npr. z uporabo Swemove oksidacije.In Scheme I, the anion prepared from 1, by treatment with a strong base such as lithium di-isopropylamide, is condensed with substituted benz aldehyde to give, after removal of the protecting group, diol 2. This can then be converted to α-diketone 3 by Swernova. oxidation, of which a large number of potentially useful variations are known and which can be used, a-diketone 3 is then cyclized to imidazole 4, a compound of formula (I), by heating 3 with substituted benzaldehyde in a mixture of ammonium acetate, as a source of ammonia, and in a suitable solvent, e.g. acetic acid or DMSO. Imidazole 4 can then be converted to other imidazoles 5 by suitable functional conversion functional groups. Scheme I also illustrates the preparation of protected α-hydroxyketone 2a by condensation of anion 1 with a suitably activated carbonyl derivative of substituted benzamide such as N-methoxy-N-methylamide to give protected α-hydroxyketone. This adduct 2a can then be directly converted to imidazole 5 using a combination of copper (II) salt such as copper (II) acetate as an oxidizing agent and ammonium acetate as a source of ammonia, α-hydroxyketone 2a can also be deprotected and then oxidized to give α-diketone 3, e.g. using Swem oxidation.

Shema IScheme I

Shema II ponazarja uporabo α-keto-oksima za pripravo spojine s formulo (I). Heterociklični keton 7 pripravimo z dodajanjem aniona 4-metil-kinolina (pripravljen z njegovo obdelavo z alkil litijem, kot je n-butil litij) k N-alkil-O-alkoksibenzamidu. Alternativno lahko anion kondenziramo z benzaldehidom, da dobimo alkohol, ki ga nato oksidiramo do ketona 7. a-keto-oksim 8, nato pripravimo iz 7, ob uporabi standardnih pogojev, kot je reakcija z natrijevim nitritom in to lahko nato presnovimo z benzaldehidom, da dobimo N-hidroksiimidazol 9, spojino s formulo (I), v kateri je R2 hidroksi. To lahko presnovimo v 10, nadaljnjo spojino s formulo (I), v kateri je R2 vodik, z njeno obdelavo z deoksigenacijskim sredstvom, kot je fosforjev triklorid ali trialkil fosfit, kot je trimetil ali trietilfosfit. Za spojine s formulo (I), kjer je R3 -(CR10R20)n-P(Z)-(XbR13)2, lahko uporabimo reagent OHC-(CR10R20)n-P(Z)(XbR13)2 namesto OHC-C6H4-X, da naredimo primerno substituirano spojino 9.Scheme II illustrates the use of α-keto-oxime for the preparation of a compound of formula (I). The heterocyclic ketone 7 is prepared by the addition of 4-methyl-quinoline anion (prepared by treating it with alkyl lithium such as n-butyl lithium) to N-alkyl-O-alkoxybenzamide. Alternatively, the anion may be condensed with benzaldehyde to give an alcohol, which is then oxidized to ketone 7. α-keto-oxime 8, then prepared from 7, using standard conditions such as reaction with sodium nitrite and this can then be reacted with benzaldehyde. to give N-hydroxyimidazole 9, a compound of formula (I) wherein R 2 is hydroxy. This can be reacted to 10, a further compound of formula (I) wherein R 2 is hydrogen, by treating it with a deoxygenating agent such as phosphorus trichloride or trialkyl phosphite, such as trimethyl or triethyl phosphite. For compounds of formula (I) wherein R 3 is - (CR 10 R 20 ) n -P (Z) - (X b R 13 ) 2 , OHC- (CR 10 R 20 ) n -P (Z) reagent can be used ) (X b R 13 ) 2 instead of OHC-C 6 H 4 -X to make suitably substituted compound 9.

Shema IIScheme II

V nadaljnjem postopku lahko pridobimo spojino s formulo (I) z obdelavo α-hidroksiketona, spojine s formulo (ΙΙΑ):In the following process, a compound of formula (I) can be obtained by treating α-hydroxyketone, a compound of formula (ΙΙΑ):

R’CHOHCOR” (HA), kjer je eden izmed R’ in R” Rx in je drugi R4, njen primerno zaščiten derivat ali njen a-hidroksi oksimski ali α-haloketonsld derivat, z oksidacijskim sredstvom, sposobnim pretvorbe omenjene spojine v ustrezen α-diketon, v prisotnosti aldehida s formulo (III) ali njegovega ekvivalenta in vira amoniaka. Primerna oksidacijska sredstva vključujejo npr. oksidacijsko težko kovinsko sol, prednostno organsko bakrovo(II) sol, kot je bakrov(II) acetat ali bakrov(II) citrat. Reakcijo lahko izvedemo v topilu, kot je ocetna kislina, pod pogoji refluksa. Alternativno lahko uporabimo nižje alkanolno topilo, kot je metanol ali etanol, prednostno pri temperaturi v območju od 30 do 100°C (glej The Chemistry of Heterocyclic Compounds, Imidazole and its derivatives, part I, ed. Weissberger, Interscience Publishers, Inc., New York, 1953, 38). Ta pristop je tudi ponazorjen v shemi I.R'CHOHCOR "(HA), wherein one of R 'and R" is R x and the other is R 4 , a suitably protected derivative thereof, or a α-hydroxy oxime or α-haloketonsld derivative, with an oxidizing agent capable of converting said compound to the corresponding α-diketone, in the presence of an aldehyde of formula (III) or its equivalent and source of ammonia. Suitable oxidizing agents include e.g. an oxidising heavy metal salt, preferably an organic copper (II) salt, such as copper (II) acetate or copper (II) citrate. The reaction can be carried out in a solvent such as acetic acid under reflux conditions. Alternatively, a lower alkanol solvent such as methanol or ethanol may be used, preferably at a temperature in the range of 30 to 100 ° C (see The Chemistry of Heterocyclic Compounds, Imidazole and its derivatives, part I, ed. Weissberger, Interscience Publishers, Inc., New York, 1953, 38). This approach is also illustrated in Scheme I.

V nadaljnjem postopku lahko pridobimo spojino s formulo (I) z obdelavo amidina s formulo (IV):In the following procedure, a compound of formula (I) can be obtained by treating an amidine of formula (IV):

R3C(=NH)NHR2 (IV), kjer sta R^ in R3 kot smo definirali preje, ali njeno sol z reaktivnim estrom α-hidroksiketona s formulo (IIA) ali ustreznim α-haloketonom, v inertnem topilu, kot je halogenirano ogljikovodikovo topilo, npr. kloroform, pri zmerno povišani temperaturi in če je potrebno, v prisotnosti primernega kondenzacijskega sredstva, kot je baza. Primerni reaktivni estri vključujejo estre močnih organskih kislin, kot je nižje alkanska sulfonska ali arilsulfonska kislina, npr. metan ali p-toluen sulfonska kislina. Prednostno uporabimo kot sol amidin s formulo (IV), ustrezno hidrokloridno sol, ki jo lahko nato pretvorimo v prosti amidin in situ z uporabo dvofaznega sistema, v katerem je reaktivni ester v inertnem organskem topilu, kot je kloroform, in je sol v vodni fazi, kateri počasi dodajamo raztopino vodne baze v dimolami količini ob močnem mešanju. Primerne amidine s formulo (IV) lahko pridobimo s standardnimi postopki, glej npr. Garigipati R, Tetrahedron Letters, 190,31,1989.R 3 C (= NH) NHR 2 (IV), wherein R 4 and R 3 are as defined above, or a salt thereof with the reactive ester of α-hydroxyketone of formula (IIA) or the corresponding α-haloketone, in an inert solvent, such as is a halogenated hydrocarbon solvent, e.g. chloroform, at a moderately elevated temperature and, if necessary, in the presence of a suitable condensing agent such as a base. Suitable reactive esters include esters of strong organic acids, such as lower alkane sulfonic or arylsulfonic acid, e.g. methane or p-toluene sulfonic acid. Preferably, the amidine of formula (IV) is used as a salt, an appropriate hydrochloride salt, which can then be converted to the free amidine in situ using a two-phase system in which the reactive ester is in an inert organic solvent such as chloroform and the salt is in the aqueous phase , which is slowly added to the aqueous base solution in dimolom volumes with vigorous stirring. Suitable amidines of formula (IV) can be obtained by standard procedures, see e.g. Garigipati R, Tetrahedron Letters, 190,31,1989.

V nadaljnjem postopku lahko pridobimo spojino s formulo (I) z obdelavo iminoetra s formulo (V):In the following procedure, a compound of formula (I) can be obtained by treating an iminoether of formula (V):

R3C=NOR (V), kjer je R3 kot je definirano preje in je R C110 alkil, aril ali aril C14 alkil, z α-aminoketonom s formulo (VI):R 3 C = NOR (V) wherein R 3 is as defined in yarn and RC 110 is alkyl, aryl or aryl C 14 alkyl, with an α-aminoketone of formula (VI):

R’CHNH2COR” (VI), kjer je eden izmed R’ in R” R3 in je drugi R4 v primernem topilu. V nadaljnjem postopku lahko pripravimo N-substituirane spojine s formulo (I) z obdelavo aniona amida s formulo (VII):R'CHNH 2 COR "(VI), wherein one of R 'and R" is R 3 and the other R 4 is in a suitable solvent. In the following procedure N-substituted compounds of formula (I) can be prepared by treating an amide anion of formula (VII):

R1CH2NR2COR3 (VII), kjer sta R7 in R3 kot je definirano preje in je R^ kot je definiran preje drugačen od vodika z:R 1 CH 2 NR 2 COR 3 (VII), wherein R 7 and R 3 are as defined yarn and R 1 as defined yarn is other than hydrogen by:

(a) nitritom s formulo (VIII):(a) nitrite of formula (VIII):

R4CN (VIII), kjer je R4 kot je definirano preje, ali (b) prebitkom acil halida, npr. acil klorida, s formulo (IX):R 4 is CN (VIII), where R 4 is as defined in yarn, or (b) an excess of acyl halide, e.g. acyl chloride of formula (IX):

R4COHal (IX), kjer je R4 kot je definirano preje in je Hal halogen ali ustrezen anhidrid, da dobimo bis-aciliran intermediat, ki ga nato obdelamo z virom amoniaka, kot je amonijev acetat.R 4 is COHal (IX), where R 4 is as defined in yarn and Hal is halogen or a suitable anhydride to give a bis-acylated intermediate, which is then treated with an ammonia source such as ammonium acetate.

Ta pristop dovoljuje regiospecifično pripravo spojine s formulo (I), substituirane na položaju -1, kot je ponazorjeno v shemi III. Primerni amin RNH2 obdelamo sThis approach allows the regiospecific preparation of a compound of formula (I) substituted at position -1, as illustrated in Scheme III. The suitable amine RNH 2 is treated with

4-klorometilpiridinom, da dobimo 11, ki ga nato pretvorimo do amida 12, s standardnimi tehnikami.4-chloromethylpyridine to give 11, which is then converted to amide 12 by standard techniques.

Deprotonacija 12 z močno amidno bazo, kot je litijev di-izo-propilamid ali natrijevDeprotonation of 12 with a strong amide base such as lithium di-iso-propylamide or sodium

Z>w-(trimetilsilil)amid, ki ji sledi adicija s prebitnim aroilkloridom, dobimo bisacilirano spojino· 13, ki jo nato zapremo v imidazolno spojino s formulo (I), 14, s segrevanjem v ocetni kislini, ki vsebuje amonijev acetat. Alternativno lahko presnovimo anion 12 s substituiranim aril nitrilom, da pridobimo imidazol 14 neposredno.The Z> w- (trimethylsilyl) amide, followed by addition with excess aroyl chloride, gives the bisacylated compound · 13, which is then enclosed in the imidazole compound of formula (I), 14, by heating in acetic acid containing ammonium acetate. Alternatively, anion 12 with substituted aryl nitrile can be reacted to obtain imidazole 14 directly.

V nadaljnjem postopku lahko spojino s formulo (I) pripravimo z obdelavo spojine s formulo (X):In the following process, a compound of formula (I) can be prepared by treating a compound of formula (X):

R’COCHR”XcCOR3 (X), kjer so R’, R” in R3 kot je definirano preje in je Xc O ali NH, z virom amoniaka, kot je opisan preje, pod pogoji tvorbe imidazolnega obroča, ali cikliziranjem ustrezne Schiffove baze, formirane z obdelavo spojine s formulo (X), v kateri je Xc NH, z aminom R2NH2, na npr. termično ali s pomočjo ciklizimega sredstva, kot je fosforjev oksiklorid ali fosfoijev pentaklorid (glej Engel in Steglich, Liebigs Ann Chem, 1978, 1916 in Strzybny et al., J Org Chem, 1963, 28, 3381). Spojine s formulo (X) lahko pridobimo z npr. aciliranjem ustreznega α-keto-oksima (Xc je NH) ali α-hidroksiketona (Xc je O) z acil halidom s formulo R3COHal, kjer je R3, kot je definirano preje ali ustreznim anhidridom, pod standamimi acilimimi pogoji.R'COCHR "X c COR 3 (X), wherein R ', R" and R 3 are as defined yarn and X c is O or NH, with an ammonia source as described yarn, under the conditions of imidazole ring formation, or cyclization of the appropriate Schiff base, formed by treating the compound of formula (X), wherein X c is NH, with an amine R2NH2, for example. thermally or by a cyclizimic agent such as phosphorus oxychloride or phosphoic pentachloride (see Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and Strzybny et al., J Org Chem, 1963, 28, 3381). Compounds of formula (X) can be obtained by e.g. by acylating the corresponding α-keto-oxime (X c is NH) or α-hydroxyketone (X c is O) with an acyl halide of the formula R 3 COHal, wherein R 3 , as defined by yarn or the corresponding anhydride, is under standard acyl conditions.

V nadaljnjem postopku lahko spojine s formulo (I) pripravimo s pripajanjem primernega derivata spojine s formulo (XI):In the following procedure, compounds of formula (I) can be prepared by coupling a suitable derivative of a compound of formula (XI):

4 (XI) kjer je: T2 dušik zaščitna skupina ali je R2 drugačen kot vodik; in je Tj vodik, T3 je Q in T4 je R4; Tj je Rj, T3 je vodik in T4 je R4; ali je Tj je Rj, T3 je Q in T4 je vodik, v kateri so Rj, R2, R3, R4 in Q kot smo definirali zgoraj; s (i) kadar je Tj vodik, primernim derivatom heteroarilnega obroča RjH, pod obroč pripajalnimi pogoji, da izvedemo pripajanje heteroarilnega obroča Rj k imidazolnemu jedru na položaju 5; 4 (XI) wherein: T 2 is a nitrogen protecting group or R 2 is other than hydrogen; and Tj is hydrogen, T 3 is Q and T 4 is R 4 ; I.e. R 1, T 3 is hydrogen and T 4 is R 4 ; or T 1 is R 1, T 3 is Q and T 4 is hydrogen, in which R 1, R 2 , R 3 , R 4 and Q are as defined above; s (i) when Tj is hydrogen, a suitable derivative of the heteroaryl ring RjH, under ring coupling conditions, in order to attach the heteroaryl ring Rj to the imidazole nucleus at position 5;

(ii) kadar je T3 vodik, primernim derivatom arilnega ali heteroarilnega obroča QH, pod obroč pripajalnimi pogoji, da izvedemo pripajanje obroča Q k imidazolnemu jedru na položju 2; ali (iii) kadar je T4 vodik, primernim derivatom arilnega obroča R4H, pod obroč pripajalnimi pogoji, da izvedemo pripajanje arilnega obroča R4 k imidazolnemu jedru na položaju 4.(ii) when T 3 is hydrogen, a suitable derivative of the aryl or heteroaryl ring QH, under ring coupling conditions, in order to attach ring Q to the imidazole nucleus at position 2; or (iii) when T 4 is hydrogen, a suitable derivative of the aryl ring R 4 H, under ring coupling conditions, in order to attach the aryl ring R 4 to the imidazole nucleus at position 4.

Takšne arilne/heteroarilne pripajalne reakcije so dobro znane strokovnjakom. Splošno, organokovinski sintezni ekvivalent aniona ene komponente sklopimo z reaktivnim derivatom druge komponente v prisotnosti primernega katalizatorja. Anionski ekvivalent lahko tvorimo iz, ali imidazola s formulo (XI), v tem primeru arilna/heteroarilna spojina zagotavlja reaktivni derivat, ali iz arilne/heteroarilne spojine, v tem primeru imidazol zagotavlja reaktivni derivat. Potemtakem primerni derivati spojine s formulo (XI) ali arilni/heteroarilni obroči vključujejo organokovinske derivate, kot so organomagnezijevi, organocinkovi, organostanatni derivati in derivati boronske kisline, in primerni reaktivni derivati vključujejo bromo, jodo, fluorosulfonatne in trifluorometansulfonatne derivate. Primerni postopki so opisani v WO 91/19497, katerega opis je vključen tu notri.Such aryl / heteroaryl coupling reactions are well known in the art. In general, the organometallic synthesis equivalent of the anion of one component is coupled to the reactive derivative of the other component in the presence of a suitable catalyst. The anionic equivalent may be formed from either imidazole of formula (XI), in which case the aryl / heteroaryl compound provides the reactive derivative, or from the aryl / heteroaryl compound, in which case imidazole provides the reactive derivative. Suitable derivatives of the compound of formula (XI) or aryl / heteroaryl rings therefore include organometallic derivatives such as organomagnesium, organocin, organostanate derivatives and boronic acid derivatives, and suitable reactive derivatives include bromo, iodine, fluorosulfonate and trifluoromethanesulfonate. Suitable procedures are described in WO 91/19497, the description of which is incorporated herein.

Ustrezne organomagnezijeve in organocinkove derivate spojine s formulo (XI) lahko presnovimo s halogenskim, fluorosulfonatnim ali triflatnim derivatom heteroarilnega ali arilnega obroča, v prisotnosti obroč pripajalnega katalizatorja, kot je paladijev(O) ali paladijev(II) katalizator, po postopku Kumada et al., Tetrahedron Letters, 22,Suitable organomagnesium and organotin zinc derivatives of the compound of formula (XI) may be reacted with a halogen, fluorosulfonate or triflate derivative of a heteroaryl or aryl ring, in the presence of a catalyst ring, such as palladium (O) or palladium (II) catalyst, by the method of Kumad. , Tetrahedron Letters, 22,

5319 (1981). Ustrezni takšni katalizatorji vključujejo te/rafcw-(trifenilfosfin)paladij in PdCl2[l,4-Z>iy-(difenilfosfino)-butan], v danem primeru v prisotnosti litijevega klorida in baze, kot je trietilamin. Poleg tega lahko tudi uporabimo za pripajanje arilnega obroča nikljev(II) katalizator, kot je Ni(II)Cl2(l,2-bifenilfosfino)etan, po postopku Pridgen, J Org Chem, 1982, 47, 4319. Ustrezna reakcijska topila vključujejo heksametilfosfor-amid. Kadar je heteroarilni obroč 4-piridil, ustrezni derivati vključujejo 4-bromo- in 4-jodo-piridin in fluorosulfonatne in triflatne estre 4-hidroksi piridina. Podobno, ustrezni derivati, kadar je arilni obroč fenil, vključujejo bromo, fluorosulfonatne, triflatne in prednostno jodo derivate. Ustrezne organomagnezijeve in organocinkove derivate lahko pridobimo z obdelavo spojine s formulo (XI) ali njenega bromo derivata z alkillitijevo spojino, da dobimo ustrezen litijev reagent z deprotoniranjem oz. transmetalacijo. Ta litijev intermediat lahko nato obdelamo s prebitkom magnezijevega halida ali cinkovega halida, da dobimo ustrezen organokovinski reagent.5319 (1981). Suitable catalysts include these / rafcw- (triphenylphosphine) palladium and PdCl 2 [1,4-Z> iy- (diphenylphosphino) -butane], optionally in the presence of lithium chloride and a base such as triethylamine. In addition, a catalyst such as Ni (II) Cl 2 (1,2-biphenylphosphino) ethane may be used to attach the aryl ring of the nickel (II) ring, by the method of Pridgen, J Org Chem, 1982, 47, 4319. Suitable reaction solvents include hexamethylphosphoramide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives, when the aryl ring is phenyl, include bromo, fluorosulfonate, triflate and preferably iodine derivatives. Suitable organomagnesium and organotin zinc derivatives can be obtained by treating a compound of formula (XI) or a bromo derivative thereof with an alkyllithium compound to obtain the corresponding lithium reagent by deprotonation or. transmetalation. This lithium intermediate can then be treated with excess magnesium halide or zinc halide to give the appropriate organometallic reagent.

Trialkilcinkov derivat spojine s formulo (XI) lahko obdelamo z bromidnim, fluorosulfonatnim, triflatnim ali prednostno, jodidnim derivatom arilne ali heteroarilne obročaste spojine, v inertnem topilu, kot je tetrahidrofuran, prednostno vsebujoč 10% heksametilfosforamida, v prisotnosti primernega pripajalnega katalizatorja, kot je paladijev(O) katalizator, npr. ie/rafcw-(trifenilfosfm)paladij, po postopku, ki ga je opisal Stille, J Amer Chem Soc, 1987, 109, 5478, US patenti 4,719,218 in 5,002,942, ali z uporabo paladijevega(II) katalizatorja v prisotnosti litijevega klorida, v danem primeru z dodano bazo, kot je trietilamin, v inertnem topilu, kot je dimetilformamid. Trialkilcinkove derivate lahko ustrezno pridobimo z metalacijo ustrezne spojine s formulo (XI) z litiacijskim sredstvom, kot je s-butil-litij ali n-butillitij, v eterskem topilu, kot je tetrahidrofuran ali obdelavo bromo derivata ustrezne spojine s formulo (XI) z alkil litijem, ki mu sledi, v vsakem primeru, obdelava s trialkil cinkovim halidom. Alternativno lahko bromo-derivate spojine s formulo (XI) obdelamo s primerno heteroarilno ali arilno trialkil cinkovo spojino v prisotnosti katalizatoqa, kot je /e/rafcw-(trifenilfosfin)-paladij, pod pogoji podobnimi tistim, ki so opisani zgoraj.The trialkyl zinc derivative of the compound of formula (XI) may be treated with a bromide, fluorosulfonate, triflate, or preferably iodide derivative of an aryl or heteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of a catalysis adduct (O) catalyst, e.g. IU / rafcw- (triphenylphosphine) palladium, according to the procedure described by Stille, J Amer Chem Soc, 1987, 109, 5478, US Patents 4,719,218 and 5,002,942, or using a palladium (II) catalyst in the presence of lithium chloride, as given in the case of an added base such as triethylamine in an inert solvent such as dimethylformamide. Trialkyl zinc derivatives can be suitably obtained by metallizing a suitable compound of formula (XI) with a lithiation agent, such as s-butyl lithium or n-butyllithium, in an ether solvent such as tetrahydrofuran or treating a bromo derivative of the corresponding compound of formula (XI) with alkyl lithium followed, in each case, by treatment with trialkyl zinc halide. Alternatively, the bromo derivatives of the compound of formula (XI) may be treated with a suitably heteroaryl or aryl trialkyl zinc compound in the presence of a catalyst, such as / e / rafcw- (triphenylphosphine) palladium, under conditions similar to those described above.

Uporabni so tudi derivati boronske kisline. Zato lahko ustrezne derivate spojine s formulo (XI), kot je bromo, jodo, triflatni ali fluorosulfonatni derivat, presnovimo s heteroarilno ali arilno boronsko kislino, v prisotnosti paladijevega katalizatorja, kot je tefra&£s-(trifenilfosfm)-paladij ali PdCl2[l,4-biy-(difenilfosfino)-butanj v prisotnosti baze, kot je natrijev bikarbonat, pod pogoji refluksa, v topilu, kot je dimetok20 sietan (glej Fischer in Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439,1965, Snieckus, V., Tetrahedron Lett., 29, 2135, 1988 in Terashimia, M., Chem., Pharm. Buli., 11, 4755,1985). Uporabimo lahko tudi nevodne pogoje, npr. topilo kot je DMF, pri temperaturi okoli 100°C, v prisotnosti Pd(II) katalizatorja (glej Thompson W J et al, J Org Chem, 49, 5237, 1984). Ustrezne derivate boronske kisline lahko pripravimo z obdelavo magnezijevega ali litijevega derivata s trialkilboratnim estrom, kot je trietil, tri-izo-propil ali tributilborat, po standardnih postopkih.Boronic acid derivatives are also useful. Therefore, suitable derivatives of the compound of formula (XI), such as the bromo, iodo, triflate or fluorosulfonate derivative, is reacted with a heteroaryl or aryl boronic acid, in the presence of a palladium catalyst such as tefra & £ s- (triphenylphosphine) -palladium or PdCl 2 [ 1,4-biy- (diphenylphosphino) -butane in the presence of a base, such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethok20 sietan (see Fischer and Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439). 1965, Snieckus, V., Tetrahedron Lett., 29, 2135, 1988, and Terashimia, M., Chem., Pharm. Buli., 11, 4755, 1985). Non-aqueous conditions can also be used, e.g. a solvent such as DMF, at a temperature of about 100 ° C, in the presence of Pd (II) catalyst (see Thompson WJ et al, J Org Chem, 49, 5237, 1984). Suitable boronic acid derivatives can be prepared by treating a magnesium or lithium derivative with a trialkylborate ester such as triethyl, tri-iso-propyl or tributylborate, according to standard procedures.

V takšnih pripajalnih reakcijah moramo ustrezno upoštevati funkcionalne skupine, ki so prisotne v spojinah s formulo (XI). Tako naj bodo, splošno, amino in žveplo substituenti ne-oksidirani ali zaščiteni, in N-l dušik spojine s formulo (XI) zaščiten, če je končno zahtevana NH spojina. Nitro, bromo, jodo in hidroksilnim skupinam se moramo prednostno izogibati v spojinah s formulo (XI), v kateri je Tx vodik.In such coupling reactions, the functional groups present in the compounds of formula (XI) must be properly considered. Thus, in general, the amino and sulfur substituents should be non-oxidized or protected, and the N1 nitrogen of the compound of formula (XI) protected if the NH compound is finally required. Nitro, bromo, iodine and hydroxyl groups should preferably be avoided in compounds of formula (XI) in which T x is hydrogen.

Spojine s formulo (XI) so imidazoli in jih lahko pridobimo s katerimikoli postopki, ki so tu notri preje opisani za pripravo spojin s formulo (I). Še posebno lahko a-haloketon R4COCH2Hal (za spojine s formulo (XI), v katerih je Tj vodik) ali RjCOCI^Hal (za spojine s formulo (XI), v katerih je T4 vodik) presnovimo z amidinom s formulo (IV) ali njegovo soljo, v inertnem topilu, kot je halogenirano ogljikovodikovo topilo, npr. kloroform, pri zmerno povišani temperaturi in, če je potrebno, v prisotnosti primernega kondenzacijskega sredstva, kot je baza. Priprava primernih α-halo-ketonov je opisana v WO 91/19497. Za spojino s formulo (XI), v kateri je T3 vodik, lahko α-diketon s formulo (II) kondenziramo s formaldehidom ali njegovim ekvivalentom, v prisotnosti vira amoniaka. Primerne bromo derivate spojine s formulo (XI) lahko pridobimo z bromiranjem ustrezne spojine s formulo (XI) pod standardnimi bromimimi pogoji, npr. bromom v topilu, kot je diklormetan ali THF.The compounds of formula (XI) are imidazoles and can be obtained by any of the processes described herein for the preparation of compounds of formula (I). In particular, the α-haloketone R 4 COCH 2 Hal (for compounds of formula (XI) in which Tj is hydrogen) or RjCOCl ^ Hal (for compounds of formula (XI) in which T 4 is hydrogen) can be reacted with amidine with formula (IV), or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, e.g. chloroform, at a moderately elevated temperature and, if necessary, in the presence of a suitable condensing agent such as a base. The preparation of suitable α-halo-ketones is described in WO 91/19497. For a compound of formula (XI) in which T 3 is hydrogen, the α-diketone of formula (II) can be condensed with formaldehyde or its equivalent, in the presence of an ammonia source. Suitable bromo derivatives of the compound of formula (XI) can be obtained by bromination of the corresponding compound of formula (XI) under standard bromine conditions, e.g. bromine in a solvent such as dichloromethane or THF.

Spojine s formulo (I) lahko tudi pripravimo s postopkom, ki vključuje presnovitev spojine s formulo (XI), v kateri je Tj vodik, z N-acil heteroarilno soljo, po postopku opisanem v US patentih 4,803,279, 4,719,218 in 5,002,942, da dobimo intermediat, v katerem je heteroarilni obroč vezan na imidazolno jedro in je prisoten kot njegovCompounds of formula (I) may also be prepared by a process involving the digestion of a compound of formula (XI) in which Tj is hydrogen with an N-acyl heteroaryl salt according to the process described in US patents 4,803,279, 4,719,218 and 5,002,942 to give an intermediate , in which the heteroaryl ring is attached to the imidazole nucleus and is present as its

1,4-dihidro derivat, ta intermediat lahko nato izpostavimo oksidativno-deacilacijskim pogojem. Heteroarilno sol, npr. piridinijevo sol, lahko ali napravimo ali, bolj prednostno, pripravimo in situ z dodajanjem substituiranega karbonil halida (kot je acil halid, aroil halid, arilakil haloformatni ester ali prednostno, alkil haloformatni ester, kot je acetil bromid, benzoilklorid, benzil kloroformat ali prednostno, etil klorofor21 mat) k raztopini spojine s formulo (XI) v heteroarilni spojini R^H ali v inertnem topilu, kot je metilen klorid, h kateremu dodamo heteroarilno spojino. Primerni deacilacijski in oksidacijski pogoji so opisani v U.S. patentu št. 4,803,279, 4,719,218 in 5,002,942, katerih navedbe so tu notri vključene v njihovi celoti. Primerni oksidacijski sistemi vključujejo žveplo v inertnem topilu ali inertni zmesi, kot je dekalin, dekalin in diglyme, p-cimen, ksilen ali mezitilen, pod pogoji refluksa ali prednostno, kalijev f-butoksid in ί-butanol s suhim zrakom ali kisikom.1,4-dihydro derivative, this intermediate can then be subjected to oxidative-deacylation conditions. Heteroaryl salt, e.g. the pyridinium salt may either be made or, more preferably, prepared in situ by the addition of a substituted carbonyl halide (such as acyl halide, aroyl halide, arylalkyl haloformate ester or preferably, alkyl haloformate ester such as acetyl bromide, benzoyl chloride, benzyl chloroformate, or ethyl chlorofor21 mat) to a solution of a compound of formula (XI) in a heteroaryl compound R1H or in an inert solvent such as methylene chloride to which a heteroaryl compound is added. Suitable deacylation and oxidation conditions are described in U.S. Pat. patent no. No. 4,803,279, 4,719,218 and 5,002,942, all of which are incorporated herein by reference in their entirety. Suitable oxidation systems include sulfur in an inert solvent or inert mixture such as decalin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions or preferably, potassium f-butoxide and ί-butanol with dry air or oxygen.

Ko je enkrat imidazolno jedro izoblikovano, lahko nadaljnje spojine s formulo (I) pripravimo z uporabo standardnih tehnik za notranjo pretvorbo funkcionalnih skupin, npr. -C(O)NRgR9 iz -CO2CH3 s segrevanjem z ali brez katalitskega kovinskega cianida, t.j. NaCN in HNRgR9 v CH3OH; OC(O)Rg iz -OH z t.j. ClC(O)Rg v piridinu; -NR10-C(S)NRgR9 iz -NHR10 z alkilizotiocianatom ali tiocianatno kislino; NR6C(O)OR6 iz -NHR6 z alkil kloroformatom, -NR10C(O)NRgR9 iz -NHR10 z obdelavo z izocianatom, t.j. HN=C=O ali R10N=C=O; -NR10-C(O)Rg iz -NHR10 z obdelavo s Cl-C(O)Rg v piridinu; -C(=NR10)NRgR9 iz -C(NRgR9)SRg z HjNRg+OAc s segrevanjem v alkoholu; -C(NRgR9)SRg iz -C(S)NRgR9 z R6-J v inertnem topilu, t.j. acetonu; -C(S)NRgR9 (kjer Rg ali R9 nista vodik) iz -C(S)NH2 z HNRgR9, -C(=NCN)-NRgR9 iz -C(=NRgR9)-SRg z NH2CN s segrevanjem v brezvodnem alkoholu, alternativno iz -q=NH)-NRgR9 z obdelavo z BrCN in NaOEt v EtOH; -NR10-C(=NCN)SRg iz -NHR10 z obdelavo z (RgS)2C=NCN; -NR1QSO2Rg iz -NHR10 z obdelavo s ClSO2Rg s segrevanjem v piridinu; -NR10C(S)Rg iz -NR10C(O)Rg z obdelavo z Lawessonovim reagentom [2,4-h«(4-metoksifenil)-l,3,2,4-ditiadifosfetan-2,4-disulfid]; -NR1()SO2CF3 iz -NHR6 s trifličnim anhidridom in bazo; -NR1QC(O)-C(O)-OR8 iz -NHR10 z, t.j. metiloksalil kloridom in bazo, kot je trietilamin; -NR10C(O)-C(O)-NRgR9 iz -NR10C(O)-C(O)-ORg z HNRgR9; in l-(NR10)-2imidazolila iz -C(=NH)NHR10 s segrevanjem z 2-kloroacetaldehidom v kloroformu (kjer so R6, Rg, R9 in R10, kot smo definirali preje).Once the imidazole nucleus is formed, further compounds of formula (I) can be prepared using standard techniques for the internal conversion of functional groups, e.g. -C (O) NR g R 9 from -CO 2 CH 3 by heating with or without catalytic metal cyanide, i.e. NaCN and HNR g R 9 in CH 3 OH; OC (O) R g from -OH with i.e. ClC (O) R g in pyridine; -NR 10 -C (S) NR g R 9 from -NHR 10 with alkylisothiocyanate or thiocyanic acid; NR 6 C (O) OR 6 from -NHR 6 with alkyl chloroformate, -NR 10 C (O) NR g R 9 from -NHR 10 by isocyanate treatment, ie HN = C = O or R 10 N = C = O ; -NR 10 -C (O) R g from -NHR 10 by treatment with Cl-C (O) R g in pyridine; -C (= NR 10 ) NR g R 9 from -C (NR g R 9 ) SR g with HjNRg + OAc by heating in alcohol; -C (NR g R 9 ) SR g from -C (S) NR g R 9 with R 6 -J in an inert solvent, i.e. acetone; -C (S) NR g R 9 (where R g or R 9 is not hydrogen) from -C (S) NH 2 with HNR g R 9 , -C (= NCN) -NR g R 9 from -C (= NR g R 9 ) -SR g with NH 2 CN by heating in anhydrous alcohol, alternatively from -q = NH) -NR g R 9 by treatment with BrCN and NaOEt in EtOH; -NR 10 -C (= NCN) SR g from -NHR 10 by treatment with (R g S) 2 C = NCN; -NR 1Q SO 2 R g from -NHR 10 by treatment with ClSO 2 R g by heating in pyridine; -NR 10 C (S) R g from -NR 10 C (O) R g by treatment with Lawesson's reagent [2,4-h (4-methoxyphenyl) -1,3,2,4-dithiadiphosphane-2,4 -disulfide]; -NR 1 () SO 2 CF 3 from -NHR 6 with triflic anhydride and base; -NR 1Q C (O) -C (O) -OR 8 from -NHR 10 z, i.e. methyloxalyl chloride and a base such as triethylamine; -NR 10 C (O) -C (O) -NR g R 9 from -NR 10 C (O) -C (O) -OR g with HNR g R 9 ; and 1- (NR 10 ) -2-imidazolyl from -C (= NH) NHR 10 by heating with 2-chloroacetaldehyde in chloroform (where R 6 , R g , R 9 and R 10 are as defined in the yarns).

Spojine s formulo (I), v katerih je R2 vodik, zlahka pretvorimo v nadaljnje spojine s formulo (I), v katerih je R2 drugačen kot vodik, npr. alkil, z običajnimi postopki, kot je alkilacija ali acilacija, ki ji sledi redukcija. Takšni postopki so v splošnem relativno neučinkoviti zaradi pomanjkanja regiospecifičnosti in moramo želeni N-l-produkt ločiti od zmesi N-l in N-3 produktov npr. s kromatografijo ali frakcionimo kristalizacijo.Compounds of formula (I) in which R 2 is hydrogen can be easily converted to further compounds of formula (I) wherein R 2 is other than hydrogen, e.g. alkyl, by conventional processes such as alkylation or acylation followed by reduction. Such processes are generally relatively inefficient due to a lack of regiospecificity and the desired N1 product must be separated from a mixture of N1 and N-3 products e.g. by chromatography or fractional crystallization.

Ustrezne zaščitne skupine za uporabo s hidroksilnimi skupinami in imidazolnim dušikom so dobro znane v stroki in opisane v številnih referencah, npr. Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. Ustrezni primeri hidroksil zaščitnih skupin vključujejo silil etre, kot je t-butildimetil ali t-butildifenil, in alkil etre, kot je metil vezan z alkilno verigo ali variabilno vezjo (CR10R20)n. Ustrezni primeri zaščitnih skupin imidazolnega dušika vključujejo tetrahidropiranil.Suitable protecting groups for use with hydroxyl groups and imidazole nitrogen are well known in the art and have been described in numerous references, e.g. Protecting Groups and Organic Synthesis, Greene TW, Wiley-Interscience, New York, 1981. Relevant examples of hydroxyl protecting groups include silyl ethers such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers such as methyl linked by alkyl chain or variable circuit (CR 10 R 20 ) n . Relevant examples of imidazole nitrogen protecting groups include tetrahydropyranyl.

Farmacevtske kislinske adicijske soli spojine s formulo (I) lahko pridobimo na znan način npr. z njihovo obdelavo s primemo količino kisline v prisotnosti primernega topila.The pharmaceutical acid addition salts of the compounds of formula (I) can be obtained in a known manner e.g. treating them with a suitable amount of acid in the presence of a suitable solvent.

POSTOPKI ZDRAVLJENJATREATMENT PROCEDURES

Spojine s formulo (I) ali njihovo farmacevtsko sprejemljivo sol lahko uporabimo pri izdelavi zdravila za profilaktično in terapevtsko zdravljenje kateregakoli bolezenskega stanja pri človeku ali drugem sesalcu, ki je poslabšano ali povzročeno s prekomerno ali neuravnano citokinsko produkcijo takšnih celic sesalcev, ki so, toda neomejeno, monociti in/ali makrofagi.The compounds of formula (I) or a pharmaceutically acceptable salt thereof may be used in the manufacture of a medicament for the prophylactic and therapeutic treatment of any disease condition in a human or other mammal that is impaired or caused by the excessive or unregulated cytokine production of such mammalian cells which are, but are not limited to , monocytes and / or macrophages.

Spojine s formulo (I) so sposobne inhibiranja proinflamatomih citokinov, kot so IL-1, IL-6, IL-8 in TNF in so zato uporabne pri zdravljenju IL-1, IL-8 in TNF vplivajo na širok izbor celic in tkiv, in ti citokini, kakor tudi ostalicitokini, ki izhajajo iz levkocitov, so pomembni in kritični inflamatomi posredniki širokega izbora bolezenskih stanj in pogojev. Inhibicija teh pro-inflamatomih citokinov je koristna pri nadzorovanju, zmanjševanju in blažitvi teh bolezenskih stanj.The compounds of formula (I) are capable of inhibiting proinflammatory cytokines such as IL-1, IL-6, IL-8 and TNF and are therefore useful in the treatment of IL-1, IL-8 and TNF, affecting a wide variety of cells and tissues, and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. Inhibition of these pro-inflammatory cytokines is useful in controlling, reducing and ameliorating these disease states.

Potemtakem se predloženi izum nanaša na postopek za zdravljenjenje citokinskoposredovane bolezni, ki vključuje dajanje učinkovite citokinsko-moteče količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli.Thus, the present invention relates to a method for treating a cytokine-mediated disease, which comprises administering an effective cytokine-disrupting amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Še posebno so spojine s formulo (I) ali njihova farmacevtsko sprejemljiva sol uporabne pri profilaksi ali zdravljenju kateregakoli bolezenskega stanja pri človeku ali drugemu sesalcu, ki je poslabšano ali povzročeno s prekomerno ali neuravnano IL-1, IL-8 ali TNF produkcijo takšnih celic sesalcev, kot so, toda neomejeno, monociti in/ali makrofagi.In particular, the compounds of formula (I) or a pharmaceutically acceptable salt thereof are useful in the prophylaxis or treatment of any disease condition in a human or other mammal that is impaired or caused by excessive or unregulated IL-1, IL-8 or TNF production of such mammalian cells , such as, but not limited to, monocytes and / or macrophages.

Potemtakem se v drugem pogledu predloženi izum nanaša na postopek inhibicije produkcije IL-1 v sesalcu, ki ga potrebuje, ki vključuje dajanje omenjenemu sesalcu učinkovite količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli.Thus, in another aspect, the present invention relates to a method of inhibiting the production of IL-1 in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Obstajajo številna bolezenska stanja, v katerih je prekomerna ali neuravnana IL-1 produkcija vključena v poslabšanje in/ali povzročanje bolezni. Ta vključujejo reumatoidni artritis, osteoartritis, endotoksemijo in/ali sindrom toksičnega šoka, ostala akutna ali kronična inflamatoma bolezenska stanja, kot je inflamatoma reakcija povzročena z endotoksinom ali inflamatoma črevesna bolezen, tuberkulozo, aterosklerozo, mišično degeneracijo, multiplo sklerozo, hiranje, kostno resorpcijo, psoriatični artritis, Reiteijev sindrom, revmatični artritis, protin, traumatični artritis, rubella artritis in akutni sinovitis. Nedavni dokazi tudi povezujejo IL·! aktivnost z diabetesom, pankreasnimi β celicami in Alzheimeijevo boleznijo.There are a number of disease states in which excessive or unregulated IL-1 production is involved in exacerbation and / or induction of disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock syndrome, other acute or chronic inflammatory disease states, such as endotoxin or inflammatory inflammatory bowel reaction, tuberculosis, atherosclerosis, muscular degeneration, multiple sclerosis, multiple sclerosis, scorpion psoriatic arthritis, Reite's syndrome, rheumatic arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL ·! activity with diabetes, pancreatic β cells, and Alzheimer's disease.

V nadaljnjem pogledu se predloženi izum nanaša na postopek inhibicije produkcije TNF v sesalcu, ki ga potrebuje, ki vključuje dajanje omenjenemu sesalcu učinkovite količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli.In a further aspect, the present invention relates to a method of inhibiting the production of TNF in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Prekomerna ali neuravnana TNF produkcija je vključena v posredovanje ali poslabšanje številnih bolezni, vključno z revmatoidnim artritisom, revmatoidnim spondilitisom, osteoartritisom, protinskim artritisom in ostalimi stanji artritisa, sepso, septičnim šokom, endotoksičnim šokom, gram negativno sepso, sindromom toksičnega šoka, sindromom odrasle respiratorne izčrpanosti, cerebralno malarijo, kronično pljučno inflamatorno boleznijo, silikozo, pljučno sarkoidozo, boleznimi kostne resorpcije, kot je osteoporoza, reperfuzijsko poškodbo, transplantacijo t.j. gostiteljsko reakcijo, transplantantnimi zavrnitvami, vročica in mialgijami zaradi infekcije, kotje influenca, hiranjem, ki je posledica infekcije ali malignosti, hiranjem, ki je posledica sindroma pridobljene imunske nezadostnosti (AIDS), AIDS, ARC (AIDS povezan kompleks), tvorbo keloida, tvorbo brazgotinastega tkiva, Crohnovo boleznijo, ulkusnim kolitisom in pirezo.Excessive or unbalanced TNF production is involved in the transmission or exacerbation of many diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, syndrome of toxic shock depletion, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, reperfusion injury, transplantation ie host reaction, transplant rejections, fever and myalgia due to infection, such as influenza, infection-related malignancy, malignancy resulting from acquired immunodeficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, formation scar tissue, Crohn's disease, ulcerative colitis and pyrex.

Spojine s formulo (I) so tudi uporabne pri zdravljenju virusnih infekcij, kjer so takšni virusi oblčutljivi na zgornjo regulacijo s TNF ali izsilijo TNF produkcijo in vivo. Virusi, ki smo jo opazovali za zdravljenje v smislu izuma, so tisti, ki proizvajajo TNF kot rezultat infekcije, ali tisti, ki so občutljivi na inhibicijo, kot je z zmanjšanjem odgovora, neposredno ali posredno, s TNF inhibicijskimi-spojinami s formulo (I). Takšni virusi vključujejo, toda neomejeno, HIV-1, HIV-2 in HIV-3, citomegalovirus (CMV), Influenza, adenovirus in viruse herpesne skupine, kot, toda neomejeno, Herpes Zoster in Herpes Simplex. Potemtakem se v nadaljnjem pogledu predloženi izum nanaša na postopek za zdravljenje sesalca prizadetega z virusom človeške imunske nezadostnosti (HIV), ki vključuje dajanje takšnemu sesalcu učinkovite TNF inhibirajoče količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli.The compounds of formula (I) are also useful in the treatment of viral infections, where such viruses are susceptible to up-regulation by TNF or suppress TNF production in vivo. The viruses observed for treatment according to the invention are those that produce TNF as a result of infection, or those that are susceptible to inhibition, such as by reducing the response, directly or indirectly, with TNF inhibitory compounds of formula (I ). Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and herpes group viruses, such as, but not limited to, Herpes Zoster and Herpes Simplex. Accordingly, the invention further provides a method of treating a mammal afflicted with a human immunodeficiency virus (HIV) comprising administering to such a mammal an effective TNF inhibitory amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Spojine s formulo (I) lahko tudi uporabimo v povezavi z veterinarskim zdravljenjem sesalcev, drugih kot ljudi, ki potrebujejo inhibicijo TNF produkcije. TNF posredovane bolezni za zdravljenje, terapevtsko ali profilaktično, pri živalih vključujejo bolezenska stanja, kot so tista navedena zgoraj, toda še posebno virusne infekcije. Primeri takšnih virusov vključujejo, toda neomejeno, lentivirusne infekcije, kot je virus konjske infekcijske anemičnosti, virus kozjega artrisa, visna virus ali maedi virus, ali retrovirusi, kot je virus mačje imunske nezadostnosti (FIV), virus volovske imunske nezadostnosti, ali virus pasje imunske nezadostnosti.The compounds of formula (I) may also be used in conjunction with the veterinary treatment of mammals other than humans in need of inhibition of TNF production. TNF-mediated diseases for treatment, therapeutic or prophylactic, in animals include conditions such as those listed above, but especially viral infections. Examples of such viruses include, but are not limited to, lentiviral infections such as equine infectious anemia virus, goat arthritis virus, visna virus or maedi virus, or retroviruses such as feline immunodeficiency virus (FIV), volitional immunodeficiency virus, or canine immunodeficiency virus insufficiency.

Spojine s formulo (I) lahko tudi uporabimo lokalno pri zdravljenju ali profilaksi lokalnih bolezenskih stanj posredovanih ali poslabšanih s prekomerno citokinsko produkcijo, kot z IL-1 oz. TNF, kot so vneti sklepi, ekscemi, psorioze in ostala inflamatoma kožna stanja, kot so sončne oplekline; inflamatoma očesna stanja vključujejo konjuktivitis; pireza, bolečina in ostala stanja povezana z vnetjem.The compounds of formula (I) may also be used topically in the treatment or prophylaxis of local disease states mediated or exacerbated by cytokine overproduction, such as IL-1 or. TNF, such as inflamed joints, eczema, psoriasis, and other inflammatory skin conditions such as sunburn; inflammatory eye conditions include conjunctivitis; pyresis, pain and other conditions associated with inflammation.

Spojine s formulo (I) so tudi pokazale, da inhibirajo produkcijo IL-8 (Interleukin-8, NAP). Potemtakem, se v nadaljem pogledu predloženi izum nanaša na postopek za inhibiranje produkcije IL-8 v sesalcu, ki ga potrebuje, ki vključuje dajanje omenjenemu selsalcu učinkovite količine spojine s formulo (I) ali njene farmacevtsko sprejemljive soli.The compounds of formula (I) have also been shown to inhibit the production of IL-8 (Interleukin-8, NAP). Thus, in the following view, the present invention relates to a method for inhibiting the production of IL-8 in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Obstaja veliko bolezenskih stanj, v katerih je prekomerna ali neuravnana IL-8 produkcija vključena v poslabšanje in/ali povzročanje bolezni. Te bolezni so označene z masivno nevtrofilno infiltracijo, kot je psorioza, inflamatoma črevesna bolezen, astma, srčna in ledvična reperfuzijska poškodba, sindrom odrasle respiratorne izčrpanosti, tromboza in glomerulonefritis. Vse te bolezni so povezane s povečano IL-8 produkcijo, ki je odgovorna za kemotakso nevtrofilov v inflamatorno mesto. V nasprotju z ostalimi inflamatomimi citokini (IL-1, TNF in IL-6), ima IL-8 enkratno lastnost pospeševanja nevtrofilne kemotakse in aktivacije. Potemtakem inhibicija IL-8 produkcije vodi do neposredne redukcije v nevtrofilni infiltraciji.There are many disease states in which excessive or unregulated IL-8 production is involved in exacerbation and / or inducing disease. These diseases are characterized by massive neutrophilic infiltration, such as psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory exhaustion syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased IL-8 production, which is responsible for the neutrophil chemotaxis in the inflammatory site. Unlike other inflammatory cytokines (IL-1, TNF and IL-6), IL-8 has a unique property of promoting neutrophil chemotaxis and activation. Thus, inhibition of IL-8 production leads to a direct reduction in neutrophil infiltration.

Spojine s formulo (I) dajemo v količini, dovoljšnji da inhibira citokin, še posebno IL-1, IL-8 ali TNF produkcijo, tako da je uravnavana navzdol do normalnih nivojev, ali v nekem primeru do subnormalnih nivojev, tako da izboljšamo ali preprečimo bolezensko stanje. Abnormalne nivoje IL-1, IL-8 ali TNF, npr. v smislu predloženega izuma, določajo:The compounds of formula (I) are administered in an amount sufficient to inhibit the cytokine, in particular IL-1, IL-8 or TNF production, so that it is regulated down to normal levels, or in some cases to subnormal levels, to improve or prevent disease state. Abnormal levels of IL-1, IL-8 or TNF, e.g. according to the present invention, provide:

(i) nivoji prostih (necelično vezanih) EL-1, IL-8 ali TNF večji od ali enaki 1 Pg/ml;(i) levels of free (non-cell bound) EL-1, IL-8 or TNF greater than or equal to 1 Pg / ml;

(ii) katerakoli celica povezana z IL-1, IL-8 ali TNF; ali (iii) prisotnost IL-1, IL-8 ali TNF mRNA nad osnovnimi nivoji v celicah ali tkivih v katerih se producirajo IL-1, IL-8 oz. TNF.(ii) any cell associated with IL-1, IL-8 or TNF; or (iii) the presence of IL-1, IL-8, or TNF mRNA above baseline levels in cells or tissues in which IL-1, IL-8, or TNF.

Odkritje, da so spojine s formulo (I) inhibitorji citokinov, specifično IL-1, IL-8 inThe discovery that the compounds of formula (I) are cytokine inhibitors, specifically IL-1, IL-8 and

TNF, temelji na učinkih spojin s formulami (I) na produkcijo IL·!, IL-8 in TNF v in vitro preizkušanjih, ki so opisana tu notri.TNF is based on the effects of compounds of formulas (I) on the production of IL · 1, IL-8 and TNF in the in vitro assays described herein.

Kot uporabljamo tukaj, se pojem inhibiranje produkcije IL-1 (IL-8 ali TNF) nanaša na:As used herein, the term inhibition of IL-1 production (IL-8 or TNF) refers to:

a) zmanjšanje prekomernih in vivo nivojev citokina (IL-1, IL-8 ali TNF) v človeku, do normalnih in sub-normalnih nivojev, z inhibicijo in vivo sproščanja citokina z vsemi celicami, vključno, toda neomejeno, z monociti ali makrofagi;a) reducing excessive in vivo cytokine levels (IL-1, IL-8 or TNF) in man, to normal and sub-normal levels, by inhibiting in vivo cytokine release by all cells, including but not limited to, monocytes or macrophages;

b) spodnjo regulacijo, na genomskem nivoju, prekomernih in vivo nivojev citokina (IL-1, IL-8 ali TNF) v človeku, do normalnih ali sub-normalnih nivojev;b) down-regulation, at the genomic level, of excessive in vivo cytokine levels (IL-1, IL-8 or TNF) in man, up to normal or sub-normal levels;

c) spodnjo regulacijo z inhibicijo neposredne sinteze citokinov (IL-1, IL-8 ali TNF) kot postranskega dogodka; alic) down-regulation by inhibition of direct synthesis of cytokines (IL-1, IL-8 or TNF) as a side event; or

d) spodnjo regulacijo, na translantacijski nivo, prekomernih in vivo nivojev citokina (IL-1, IL-8 ali TNF) v človeku do normalnih ali sub-normalnih nivojev.d) down-regulation, at translational level, of excessive in vivo cytokine levels (IL-1, IL-8 or TNF) in man to normal or sub-normal levels.

Kot uporabljamo tukaj, se pojem 'TNF posredovana bolezen ali bolezensko stanje nanaša na katerokoli in vsa bolezenska stanja v katerih TNF igra vlogo, ali s produkcijo samega TNF ali s TNF, ki povzroča, da se sprosti drugi citokin, kot je, toda neomejeno z, EL-1, IL-6 ali IL-8. Bolezensko stanje v katerem je npr. IL-1 glavna komponenta in katerega produkcija ali delovanje je poslabšano ali izločeno v odzivu na TNF, potemtakem smatramo kot bolezensko stanje posredovano s TNF.As used herein, the term 'TNF mediated disease or disease state refers to any and all disease states in which TNF plays a role, or by the production of TNF itself or by TNF, which causes the release of another cytokine such as, but not limited to , EL-1, IL-6, or IL-8. A medical condition in which e.g. IL-1 is a major component and whose production or function is impaired or eliminated in response to TNF, is therefore considered to be a TNF-mediated disease condition.

Kot uporabljamo tukaj, se pojem citokin nanaša na katerikoli izločen polipeptid, ki prizadane funkcije celic in je molekula, ki uravnava interakcije med celicami v imunskem, inflamatornem ali hematopoetskem odzivu. Citokin vključuje, toda neomejeno, monokine in limfokine, ne glede na to, katere celice jih proizvajajo. Npr. monokin se splošno nanaša, kot da ga proizvaja in izloča mononukleama celica, kot je makrofag in/ali monocit. Seveda tudi mnoge ostale celice proizvajajo monokine, kot so naravne ubijalske celice, fibroblasti, bazofili, nevtrofili, endotelialne celice, možganski astrociti, stromalne celice kostnega mozga, epideralni keratinociti in B-limfociti. Limfokini se splošno nanašajo, kot da jih proizvajajo limfocitne celice. Primeri citokinov vključujejo, toda neomejeno, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8, Tumor Necrosis Factor-alpha (TNF-α) in Tumor Necrosis Factor beta (TNF-j8).As used herein, the term cytokine refers to any secreted polypeptide that affects cell function and is a molecule that regulates cell interactions in an immune, inflammatory, or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. E.g. monokine is generally referred to as being produced and secreted by a mononuclear cell such as a macrophage and / or monocyte. Of course, many other cells also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and B lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8, Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF) -j8).

Kot uporabljamo tukaj, se pojem, citokinsko moteča ali citokinsko supresivna količina nanaša na učinkovito količino spojine s formulo (I), ki povzroči, v in vivo nivojih, citokina do normalnih ali sub-normalnih nivojev, kadar jo dajemo pacientom za profilakso ali zdravljenje bolezenskega stanja, ki je poslabšano ali povzročeno s prekomerno ali neuravnano citokinsko produkcijo.As used herein, the term cytokine disruptive or cytokine suppressant refers to an effective amount of a compound of formula (I) that causes, in in vivo levels, cytokines to normal or sub-normal levels when administered to patients for prophylaxis or treatment of a disease conditions that are exacerbated or induced by overburdened or unbalanced cytokine production.

Kot uporabljamo tukaj, je citokin naveden v frazi inhibicija citokina za uporabo pri zdravljenju s HlV-inficiranega človeka citokin, kije vključen v (a) iniciacijo in/ali ohranjanje T celične aktivacije in/ali T celično-posredovan HIV genski izraz in/ali odgovor in/ali (b) katerikoli citokinsko-posredovan bolezensko povezan problem, kot je hiranje ali mišična degeneracija.As used herein, a cytokine is referred to in the phrase inhibition of a cytokine for use in the treatment of an HlV-infected human cytokine involved in (a) initiation and / or maintenance of T cell activation and / or T cell-mediated HIV gene expression and / or response and / or (b) any cytokine-mediated disease-related problem, such as choking or muscle degeneration.

Ker ima TNF-jS (tudi znan kot limfotoksin) tesno strukturno homologijo s TNF-a (tudi znan kot katektin) in ker vsak vključuje podobne biološke odzive in se veže na enak celični receptor, sta oba, TNF-α in TNF-jS inhibirana s spojinami predloženega izuma in sta tako tu notri navedena skupno kot *TNF', v kolikor ni specifično opisano drugače.Because TNF-jS (also known as lymphotoxin) has close structural homology to TNF-α (also known as catectin) and because each involves similar biological responses and binds to the same cellular receptor, both TNF-α and TNF-jS are inhibited with the compounds of the present invention and are thus referred to herein collectively as * TNF ', unless specifically described otherwise.

Z namenom uporabiti spojino (I) ali njeno farmacevtsko sprejemljivo sol pri zdravljenju, jo običajno formuliramo v farmacevtski sestavek v skladu s standardno farmacevtsko prakso. Ta izum se zaradi tega tudi nanaša na farmacevtski sestavek, ki vključuje učinkovito, ne-toksično količino spojine s formulo (I) in farmacevtsko sprejemljiv nosilec ali diluent.In order to use compound (I) or a pharmaceutically acceptable salt thereof in the treatment, it is usually formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention therefore also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

Spojine s formulo (I), njihove farmacevtsko sprejemljive soli in farmacevtske sestavke, ki takšne vključujejo, lahko primemo dajemo po katerihkoli poteh običajno uporabljenih za dajanje zdravila, npr. oralno, lokalno, parenteralno ali z inhalacijo. Spojine s formulo (I) lahko dajemo v običajnih dozirnih oblikah, pripravljenih s kombiniranjem spojine s formulo (I) s standardnimi farmacevtskimi nosilci glede na običajne postopke. Spojine s formulo (I) lahko tudi dajemo v običajnih odmerkih v kombinaciji z znano, drugo terapevtsko aktivno spojino. Ti postopki lahko obsegajo mešanje, granuliranje in stiskanje ali raztapljanje sestavin, kot je primemo glede na želen pripravek. Želeno je, daje oblika in značaj farmacevtsko sprejemljivega nosilca ali diluenta predpisana s količino aktivne sestavine, s katero bo kombiniran, s potjo dajanja in drugimi dobro znanimi variablami. Nosilec(ci), mora biti sprejemljiv v smislu, da je kompatibilen z ostalimi sestavinami sestavka in ne škoduje njegovemu koristniku.The compounds of formula (I), their pharmaceutically acceptable salts and pharmaceutical compositions including such may be administered via any of the routes commonly used for administration of the drug, e.g. orally, topically, parenterally or by inhalation. The compounds of formula (I) may be administered in conventional dosage forms prepared by combining a compound of formula (I) with standard pharmaceutical carriers according to conventional methods. The compounds of formula (I) may also be administered at conventional doses in combination with a known, other therapeutically active compound. These processes may include mixing, granulating, and compressing or dissolving the ingredients as appropriate with respect to the desired preparation. It is desirable that the form and character of the pharmaceutically acceptable carrier or diluent be prescribed by the amount of active ingredient with which it will be combined, the route of administration and other well-known variables. The carrier (s) must be acceptable in the sense that it is compatible with the other constituents of the composition and does not harm its user.

Uporabljeni farmacevtski nosilec je lahko, npr. ali trden ali tekoč. Primeri trdnih nosilcev so laktoza, terra alba, sukroza, talk, želatina, agar, pektin, akacija, magnezijev stearat, stearinska kislina in podobno. Primeri tekočih nosilcev so sirup, arašidovo olje, olivno olje, voda in podobno. Podobno lahko nosilec ali diluent vključuje časovno zakasnitveni material, dobro znan v stroki, kot je gliceril monostearat ali gliceril distearat sam ali z voskom.The pharmaceutical carrier used may be e.g. whether solid or fluid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delayed material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with wax.

Uporabimo lahko širok izbor farmacevtskih oblik. Tako lahko, če uporabimo trden nosilec, pripravek tabletiramo, spravimo v trdo želatinasto kapsulo v obliki praška ali pilule, ali v obliki majhne tablete ali pastile. Količina trdnega nosilca široko variira, toda prednostno naj bo od okoli 25 mg do okoli 1 g. Kadar uporabimo tekoč nosilec, je pripravek v obliki sirupa, emulzije, mehke želatinaste kapsule, sterilne injekcijske tekočine, kot je ampula ali nevodna tekoča suspenzija.A wide variety of pharmaceutical forms can be used. Thus, when a solid carrier is used, the preparation can be tableted, put into a hard gelatin capsule in powder or pill form, or in the form of a small tablet or lozenge. The amount of solid carrier varies widely, but preferably should be from about 25 mg to about 1 g. When a liquid carrier is used, the preparation is in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable fluid such as an ampoule or a non-aqueous liquid suspension.

Spojine s formulo (I) lahko dajemo lokalno, t.j. z ne-sistemskim dajanjem. To vključuje uporabo spojine s formulo (I) zunanje na koži ali ustni votlini in instilacijo takšne spojine v uho, oko in nos, tako da spojina bistveno ne vstopi v krvni tok. Nasprotno, se sistemsko dajanje nanaša na oralno, intravenozno, intrapertonealno in intramuskularno dajanje.The compounds of formula (I) may be administered topically, i.e. with non-systemic administration. This involves the use of a compound of formula (I) externally on the skin or oral cavity and the instillation of such compound into the ear, eye and nose so that the compound does not enter substantially into the blood stream. In contrast, systemic administration refers to oral, intravenous, intrapertoneal, and intramuscular administration.

Sestavki, primerni za lokalno dajanje, vključujejo tekoče in pol-tekoče pripravke primerne za penetracijo skozi kožo do mesta vnetja, kot so mazila, losioni, kreme ali paste, in kapljice primerne za dajanje v oko, uho ali nos. Aktivna sestavina lahko vsebuje, za lokalno dajanje, od 0,001 % do 10 % m/m, npr. od 1 mas.% do 2 mas.% sestavka. Seveda lahko vsebuje do 10 % m/m, toda prednostno bo vsebovala manj kot 5 % m/m, bolj prednostno od 0,1 % do 1 % m/m sestavka.Ingredients suitable for topical administration include liquid and semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as ointments, lotions, creams or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may contain, for topical administration, from 0.001% to 10% w / w, e.g. from 1% to 2% by weight of the composition. Of course, it may contain up to 10% w / w, but preferably it will contain less than 5% w / w, more preferably from 0.1% to 1% w / w of the composition.

Losioni v smislu predloženega izuma vključujejo tiste, primerne za uporabo na koži ali očesu. Očesni losion lahko vsebuje sterilno vodno raztopino, v danem primeru vsebujočo baktericid in jo lahko pripravimo po postopkih, podobnim tistim, za pripravo kapljic. Losioni ali mazila za uporabo na koži, lahko tudi vključujejo sredstvo, ki pospeši sušenje in hladi kožo, kot je alkohol ali aceton, in/ali vlažilo, kot je glicerol ali olje, kot je ricinovo olje ali arašidovo olje.Lotions of the present invention include those suitable for use on the skin or the eye. The eye lotion may contain a sterile aqueous solution, optionally containing a bactericide, and may be prepared by procedures similar to those used for the preparation of droplets. Lotions or ointments for use on the skin may also include an agent that accelerates drying and cools the skin, such as alcohol or acetone, and / or a moisturizer such as glycerol or an oil such as castor oil or peanut oil.

Kreme, mazila ali paste v smislu predloženega izuma so pol-trdni sestavki učinkovite sestavine za zunanjo uporabo. Pripravimo jih lahko z mešanjem učinkovite sestavine v fino porazdeljeni ali praškasti obliki, same ali v raztopini ali suspenziji, v vodno ali nevodno tekočino s pomočjo primernih strojev, z oljnato ali ne-oljnato podlago. Podlaga lahko vsebuje ogljikovodike, kot je trd, mehek ali tekoč parafin, glicerol, čebelji vosek, kovinsko milo; rastlinska sluz, olje naravnega izvora kot je mandeljevo, koruzno, arašidovo, ricinovo ali olivno olje; volnena maščoba ali njeni derivati ali maščobna kislina, kot je Sterna ali oljna kislina skupaj z alkoholom, kot je propilenglikol ali makrogel. Sestavek lahko vključuje katerokoli primerno površinsko aktivno sredstvo, kot je anionsko, kationsko ali ne-ionsko površinsko aktivno sredstvo, kot je sorbitan ester ali njegov polioksietilenski derivat. Vključimo lahko tudi suspendirna sredstva, kot so naravni gumiji, celulozni derivati ali anorganski materiali, kot so silikazirane silike in ostale sestavine, kot je lanolin.The creams, ointments or pastes of the present invention are semi-solid compositions of an effective ingredient for external use. They can be prepared by mixing the effective ingredient in a finely divided or powdered form, alone or in solution or suspension, in aqueous or non-aqueous liquid using suitable machines, with an oily or non-oily base. The substrate may contain hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, metal soap; vegetable mucilage, oil of natural origin such as almond, corn, peanut, castor or olive oil; wool fat or its derivatives or fatty acid such as Sterne or oleic acid together with an alcohol such as propylene glycol or macrogel. The composition may include any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or its polyoxyethylene derivative. Suspension agents such as natural gums, cellulose derivatives or inorganic materials such as silicified silicas and other constituents such as lanolin may also be included.

Kapljice v smislu predloženega izuma lahko vključujejo sterilne vodne ali oljnate raztopine ali suspenzije in jih lahko pripravimo z raztapljanjem učinkovite sestavine v primerni vodni raztopini baktericidnega in/ali fungicidnega sredstva in/ali katerega koli drugega primernega konzervansa in prednostno vključujejo povšinsko aktivno sredstvo. Nastalo raztopino lahko nato prečistimo s filtracijo, prenesemo v primerno embalažo, ki jo nato zapečatimo in steriliziramo z avtoklaviranjem ali vzdrževanjem pri 98-100 °C pol ure. Alternativno lahko raztopino steriliziramo s filtracijo in jo prenesemo v embalažo z antiseptično tehniko. Primeri baktericidnih in fungicidnih sredstev primernih za inkluzijo v kapljice so fenil živosrebrov nitrat ali acetat (0,0002 %), benzalkonijev klorid (0,01 %) in kloroheksidinijev acetat (0,01 %). Primerna topila za pripravo oljnate raztopine vključujejo glicerol, razredčen alkohol in propilen glikol.The droplets of the present invention may include sterile aqueous or oily solutions or suspensions and may be prepared by dissolving an effective ingredient in a suitable aqueous solution of a bactericidal and / or fungicidal agent and / or any other suitable preservative and preferably include a surfactant. The resulting solution can then be purified by filtration, transferred to suitable packaging, which is then sealed and sterilized by autoclaving or maintaining at 98-100 ° C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to the packaging by antiseptic technique. Examples of bactericidal and fungicidal agents suitable for droplet inclusion are phenyl mercury nitrate or acetate (0.0002%), benzalkonium chloride (0.01%) and chlorohexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, dilute alcohol and propylene glycol.

Spojine s formulo (I) lahko dajemo parenteralno, to je z intravenoznim, intramuskularnim, podkožnim intranazalnim, intrarektalnim, intravaginalnim ali intraperitonealnim dajanjem. Podkožne in intramuskularne oblike paranteralnega dajanja so splošno prednostne. Primerne dozirne oblike za takšno dajanje lahko pripravimo z običajnimi tehnikami. Spojine s formulo (I) lahko tudi dajemo z inhalacijo, t.j. z bintranazalnim in oralnim inhalacijskim dajanjem. Primerne dozirne oblike za takšno dajanje, kot je aerosolni pripravek ali odmerjen dozni inhalator, lahko pripravimo z običajnimi tehnikami.The compounds of formula (I) may be administered parenterally, i.e. by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of paranteral administration are generally preferred. Suitable dosage forms for such administration may be prepared by conventional techniques. The compounds of formula (I) may also be administered by inhalation, i.e. with bintranasal and oral inhalation administration. Suitable dosage forms for such administration as aerosol preparation or metered dose inhaler can be prepared by conventional techniques.

Za vse postopke uporabe, opisane v predloženem izumu, za spojine s formulo (I), je dnevni oralni dozirni režim prednostno od okoli 0,1 do okoli 80 mg/kg celokupne telesne teže, prednostno od okoli 0,2 do 30 mg/kg, bolj prednostno od okoli 0,5 mg do 15 mg. Dnevni parenteralni dozirni režim je okoli 0,1 do okoli 80 mg/kg celokupne telesne teže, prednostno od okoli 0,2 do okoli 30 mg/kg, in bolj prednostno od okoli 0,5 mg do 15 mg/kg. Dnevni lokalni dozirni režim je prednostno od 0,1 mg do 150 mg, dajemo enkrat do štirikrat, prednostno dvakrat do trikrat na dan. Dnevni inhalacijski dozirni režim je prednostno od okoli 0,01 mg/kg do okoli 1 mg/kg na dan. Strokovnjak bo upošteval, da je optimalna količina in razmeščanje posameznih doziranj spojine s formulo (I) ali njene farmacevtsko sprejemljive soli določeno z naravo in obsegom stanja, ki ga zdravimo, oblike, poti in mesta dajanja, in še posebno pacienta, ki ga zdravimo in da takšne optimume lahko določimo z običajnimi tehnikami. Od strokovnjaka je želeno, da zna določiti optimalni postopek zdravljenja, t.j. število odmerkov spojine s formulo (I) ali njene farmacevtsko sprejemljive soli dane na dan, za določeno število dni, z uporabo običajnega postopka testov za določanje zdravljenja.For all the application methods described in the present invention for compounds of formula (I), the daily oral dosage regimen is preferably from about 0.1 to about 80 mg / kg of total body weight, preferably from about 0.2 to 30 mg / kg , more preferably from about 0.5 mg to 15 mg. The daily parenteral dosage regimen is about 0.1 to about 80 mg / kg of total body weight, preferably from about 0.2 to about 30 mg / kg, and more preferably from about 0.5 mg to 15 mg / kg. The daily topical dosage regimen is preferably from 0.1 mg to 150 mg, administered once to four times, preferably twice to three times daily. The daily inhalation dosage regimen is preferably from about 0.01 mg / kg to about 1 mg / kg per day. The person skilled in the art will appreciate that the optimal amount and placement of individual dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof is determined by the nature and extent of the condition being treated, the form, route and site of administration, and in particular the patient being treated and that such optimisms can be determined by conventional techniques. The skilled person is required to be able to determine the optimal treatment procedure, i.e. the number of doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered per day for a specified number of days, using the usual test procedure for determining treatment.

Izum bomo opisali z navedbo naslednjih primerov, ki so samo ponazoritveni in jih ne gre razlagati kot omejitev obsega predloženega izuma.The invention will be described with reference to the following examples which are merely illustrative and should not be construed as limiting the scope of the present invention.

PRIMERI SINTEZEEXAMPLES OF SYNTHESIS

PRIMER 1EXAMPLE 1

2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini 2,(4-cianofenil)-4-(4-fluorofenil)-N-l-hidroksi-5-(4-piridil)imidazola (4,5g, 13,2 mmol) [glej primer 10 spodaj] v DMF (50 ml) dodamo trietil fosfit (3,4ml, 20 mmol) in nastalo zmes segrevamo na 100 °C 2 h Po ohladitvi, zmes zlijemo v Ef2O in trdno snov, kije nastala, zberemo s filtracijo, speremo z H2O in posušimo in vacuo, da dobimo naslovno spojino (4,0 g, 89 %). S prekristalizacijo iz CH2Cl2/MeOH dobimo belo trdno snov s tal. 268-269 °C.To a solution of 2, (4-cyanophenyl) -4- (4-fluorophenyl) -N1-hydroxy-5- (4-pyridyl) imidazole (4.5g, 13.2 mmol) [see example 10 below] in DMF (50 ml) was added triethyl phosphite (3.4ml, 20 mmol) and the resulting mixture was heated to 100 ° C for 2 h. After cooling, the mixture was poured into Ef 2 O and the resulting solid was collected by filtration, washed with H 2 O and dried. in vacuo to give the title compound (4.0 g, 89%). Recrystallization from CH 2 Cl 2 / MeOH gives a white solid from the ground. 268-269 ° C.

PRIMER 2 l-metil-2-(4-metoksifenil)-4-fenil-5-(4-piridil)-imidazol (a) N-metil-N-(4-pikolil)aminEXAMPLE 2 1-methyl-2- (4-methoxyphenyl) -4-phenyl-5- (4-pyridyl) -imidazole (a) N-methyl-N- (4-picolyl) amine

K 4-pikolil kloridu, hidrokloridu (10 g, 0,06 mol) dodamo metilamin (50 ml 40 %-ne vodne raztopine, 0,58 mol) in nastalo vijolično raztopino mešamo pri sobni temperaturi 30 min., nato zlijemo v H2O. Zmes ekstrahiramo z CH2C12 (6x) in združene organske ekstrakte uparevamo. Ostanek filtriramo pod znižanim tlakom preko silikagelne kolone, eluiramo s topnostnim gradientom 0-10 % MeOH)CHCl3, da zagotovimo naslovno spojino, kot rahlo rumeno olje (4,8 g, 66 %): NMR (CDC13): δ 8,50 (dd, 2H); 7,20 (dd, 2H); 3,70 (S, 2H); 2,40 (s, 3H); 1,70 (širok, IH).Methylamine (50 ml of 40% aqueous solution, 0.58 mol) was added to 4-picolyl chloride, hydrochloride (10 g, 0.06 mol) and the resulting purple solution was stirred at room temperature for 30 min, then poured into H 2 A. The mixture was extracted with CH 2 C1 2 (6x) and the combined organic extracts were evaporated. The residue was filtered under reduced pressure over a silica gel column, eluting with a solubility gradient of 0-10% MeOH) CHCl 3 to provide the title compound as a slightly yellow oil (4.8 g, 66%): NMR (CDCl 3 ): δ 8. 50 (dd, 2H); 7.20 (dd, 2H); 3.70 (S, 2H); 2.40 (s, 3H); 1.70 (broad, 1H).

(b) 4-metoksi-N-metil-N-(4-pikolil)benzamid(b) 4-Methoxy-N-methyl-N- (4-picolyl) benzamide

K raztopini N-metil-N-(pikolil)amina (0,40 g, 3,3 mmol) in trietilamina (1,5 ml, 10,8 mmol) v CH2C12 (15 ml) dodamo 4-metoksibenzoil klorid (1,2 g, 7,3 mmol). Nastalo zmes mešamo na sobni temperaturi 15 min., in nato porazdelimo med 2,5N NaOH in Et2O. Organski ekstrakt speremo z nasičenim vodnim NaCI in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4 % MeOH/CHCl3. Material, ki smo ga izolirali, trituriramo z Et2O, da dobimo naslovno spojino kot rahlo rumeno trdno snov (0,18 g, 21 %): Ή NMR (CDC13): δ 8,60 (d, 2H); 7,43 (širok d, 2H); 7,20 (širok s, 2H); 6,90 (širok d, 2H); 4,66 (širok s, 2H); 3,80 (s, 3H); 3,00 (s, 3H).To a solution of N-methyl-N- (picolyl) amine (0.40 g, 3.3 mmol) and triethylamine (1.5 ml, 10.8 mmol) in CH 2 Cl 2 (15 ml) was added 4-methoxybenzoyl chloride (1.2 g, 7.3 mmol). The resulting mixture was stirred at room temperature for 15 min, and then partitioned between 2.5N NaOH and Et 2 O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with a solubility gradient of 2-4% MeOH / CHCl 3 . The material isolated was triturated with Et 2 O to give the title compound as a slightly yellow solid (0.18 g, 21%): Ή NMR (CDCl 3 ): δ 8.60 (d, 2H); 7.43 (broad d, 2H); 7.20 (broad s, 2H); 6.90 (broad d, 2H); 4.66 (broad s, 2H); 3.80 (s, 3H); 3.00 (s, 3H).

(c) l-metil-2-(4-metoksifenil-4-fenil-5-(4-piridil)-imidazol(c) 1-methyl-2- (4-methoxyphenyl-4-phenyl-5- (4-pyridyl) -imidazole

K raztopini diizopropilamina (0,16 ml, 1,1 mmol) v THF pri -78 °C dodamo n-butillitij (0,38 ml 2,5 M raztopine, 0,95 mmol). K nastali raztopini dodamo raztopino 4-metoksi-N-metil-N-(4-pikolil)benzamida (0,16 g, 0,62 mmol) V THF. Nastalo temno rdečo raztopino segrejemo na -40 °C in mešamo 15 min., pri tem času dodamo benzonitril (0,13 ml, 1,2 mmol). Zmes segrejemo na sobno temperaturo in mešamo 10 h. Dodamo vodni NH4C1 (0,5 ml) in zmes koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4 % MeOH/CHCl3. Material, ki ga izoliramo, trituriramo z Et2O in prekristaliziramo iz EtOAc, da zagotovimo naslovno spojino kot sivobelo trdno snov (35 mg, 17 %): tal. 193-194 °C.To the solution of diisopropylamine (0.16 ml, 1.1 mmol) in THF at -78 ° C was added n-butyllithium (0.38 ml 2.5 M solution, 0.95 mmol). To the resulting solution was added a solution of 4-methoxy-N-methyl-N- (4-picolyl) benzamide (0.16 g, 0.62 mmol) in THF. The resulting dark red solution was warmed to -40 ° C and stirred for 15 min, at which time benzonitrile (0.13 ml, 1.2 mmol) was added. The mixture was warmed to room temperature and stirred for 10 h. Aqueous NH 4 C1 (0.5 ml) was added and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solubility gradient of 2-4% MeOH / CHCl 3 . The material to be isolated was triturated with Et 2 O and recrystallized from EtOAc to provide the title compound as a off-white solid (35 mg, 17%): m.p. Mp 193-194 ° C.

PRIMER 3EXAMPLE 3

2-(4-cianofenil)- l-metil-4-fenil-5 (4-piridil)imidazol (a) 4-ciano-N-metil-N-(4-pikolil)benzamid2- (4-cyanophenyl) -1-methyl-4-phenyl-5 (4-pyridyl) imidazole (a) 4-cyano-N-methyl-N- (4-picolyl) benzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 2, korak (b), razen da uporabimo 4-cianobenzoil klorid !H NMR (CDC13): δ 8,49 (dd, 2H); 7,86-7,04 (m, 6H); 4,70 in 4,43 (dva široka s, 2H); 3,08 in 2,89 (dva široka s, 3H).The title compound was prepared using the same procedure as described in Example 2, step (b), except that 4-cyanobenzoyl chloride was used ! H NMR (CDCl 3 ): δ 8.49 (dd, 2H); 7.86-7.04 (m, 6H); 4.70 and 4.43 (two broad s, 2H); 3.08 and 2.89 (two broad s, 3H).

(b) 4-ciano-N-[N”-a-dibenzoil-l,4-dihidropiridil-metilenil]-N-metilbenzamid(b) 4-cyano-N- [N ”-a-dibenzoyl-1,4-dihydropyridyl-methylenyl] -N-methylbenzamide

K raztopini diizopropilamina (2,8 ml, 20 mmol) v THF pri -78 °C dodamo n-butillitij (6,7 ml 2,5 M raztopine, 17 mmol). K nastali zmesi dodamo raztopino 4-ciano-Nmetil-N-(4-pikolil)benzamida (3,5 g, 14 mmol) v THF. Nastalo temno vijolično raztopino mešamo pri -78 °C 10 min., pri tem času dodamo benzoilklorid (4,1 ml, 35 mmol). Zmes segrevamo pri sobni temperaturi 30 min., nato zlijemo v vodni NH4C1. Zmes ekstrahiramo z Et2O in organski ekstrakt uparevamo pod znižanim tlakom. Ostanek trituriramo z Et2O, da zagotovimo oranžno trdno snov, ki jo rahlo speremo z acetonom in obilno z Et2O. Dobimo naslovno spojino, kot rahlo rumeno trdno snov (1,6 g, 25 %): Ή NMR (CDC13): δ 7,81-7,09 (m, 16H); 6,49 (m, 2H); 3,32 (s, 3H).To a solution of diisopropylamine (2.8 ml, 20 mmol) in THF at -78 ° C was added n-butyllithium (6.7 ml of a 2.5 M solution, 17 mmol). To the resulting mixture was added a solution of 4-cyano-N-methyl-N- (4-picolyl) benzamide (3.5 g, 14 mmol) in THF. The resulting dark purple solution was stirred at -78 ° C for 10 min, with benzoyl chloride (4.1 ml, 35 mmol) being added. The mixture was warmed to room temperature for 30 minutes, then poured into aqueous NH 4 Cl. The mixture was extracted with Et 2 O and the organic extract was evaporated under reduced pressure. The residue was triturated with Et 2 O to provide an orange solid, which was slightly washed with acetone and copious with Et 2 O. To give the title compound as a slightly yellow solid (1.6 g, 25%): Ή NMR (CDC1 3 ): δ 7.81-7.09 (m, 16H); 6.49 (m, 2H); 3.32 (s, 3H).

(c) 2-(4-cianofenil)-l-metil-4-fenil-5-(4-piridil)imidazol(c) 2- (4-cyanophenyl) -1-methyl-4-phenyl-5- (4-pyridyl) imidazole

K raztopini 4-ciano-N-[N”-a-dibenzoil-l,4-dihidropiridilmetilenil]-N-metilbenzamida (1,5 g, 3,3 mmol) v ocetni kislini (50 ml) dodamo amonijev acetat (1,5 g, 19,5 mmol). Nastalo zmes segrevamo pri refluksu 18 h, nato pustimo, da se ohladi in koncentriramo. Ostanek suspendiramo v CH2C12 in filtriramo. Filtrat uparimo in ostanek trituriramo z MeOH, da dobimo naslovno spojino kot belo kristalinično trdno snov (0,72 g, 64 %): tal. 176-177 °C.To a solution of 4-cyano-N- [N ”-a-dibenzoyl-1,4-dihydropyridylmethylenyl] -N-methylbenzamide (1.5 g, 3.3 mmol) in acetic acid (50 ml) was added ammonium acetate (1, 5 g, 19.5 mmol). The resulting mixture was refluxed for 18 h, then allowed to cool and concentrate. The residue was suspended in CH 2 Cl 2 and filtered. The filtrate was evaporated and the residue triturated with MeOH to give the title compound as a white crystalline solid (0.72 g, 64%): mp. 176-177 ° C.

PRIMER 4EXAMPLE 4

2-(4-aminometilfenil)-l-metil-4-fenil-5-(4-piridil)-imidazol2- (4-Aminomethylphenyl) -1-methyl-4-phenyl-5- (4-pyridyl) -imidazole

K raztopini 2-(4-cianofenil)-l-metil-4-fenil-5-(4-piridil)imidazola (0,20 g, 0,6 mmol) [glej primer 3 zgoraj] v THF (10 ml) dodamo LiAlH4 (0,60 ml 1,0 M raztopine v THF, 0,6 mmol), in nastalo raztopino mešamo pri sobni temperaturi 1 h. Zmes nato zlijemo v 2,5 N NaOH in ekstrahiramo z Et2O. Organski ekstrakt uparimo in ostanek prečistimo s flash kromatografijo, eluiramo najprej z topnostnim gradientom 0-10 % MeOH/CHCl3, ki mu sledi 1:10:90 NH4OH/MeOH/CHCl3. S trituracijo z etrom dobimo naslovno spojino kot belo trdno snov (66 mg, 32 %): CIMS (NH3, m/z): 341 (M++H).To a solution of 2- (4-cyanophenyl) -1-methyl-4-phenyl-5- (4-pyridyl) imidazole (0.20 g, 0.6 mmol) [see Example 3 above] in THF (10 ml) was added LiAlH 4 (0.60 ml of 1.0 M solution in THF, 0.6 mmol), and the resulting solution was stirred at room temperature for 1 h. The mixture was then poured into 2.5 N NaOH and extracted with Et 2 O. The organic extract was evaporated and the residue was purified by flash chromatography, eluting first with a solubility gradient of 0-10% MeOH / CHCl 3 followed by 1:10:90 NH 4 OH / MeOH / CHCl 3 . Trituration with ether gave the title compound as a white solid (66 mg, 32%): CIMS (NH 3 , m / z): 341 (M + + H).

PRIMER 5EXAMPLE 5

Natrijeva sol 4-[l-metil-4-fenil-5(4-piridil)-imidazol-2-il]benzojske kisline4- [1-Methyl-4-phenyl-5 (4-pyridyl) -imidazol-2-yl] benzoic acid sodium salt

Zmes 2-(4-cianofenil)-l-metil-4-fenil-5(4-piridil)imidazola (0,10 g, 0,3 mmol) [glej primer 3 zgoraj] v 6 N HC1 (3 ml) segrevamo pri refluksu 24 h, nato pustimo da se ohladi. pH naravnamo na 7 in trdno snov, ki je nastala, zberemo s filtracijo in speremo zaporedno z H2O, acetonom in Et2O, da zagotovimo naslovno spojino kot belo trdno snov (25 mg, 23 %): CIMS (NH3, m/z): 356 (M+ + H).A mixture of 2- (4-cyanophenyl) -1-methyl-4-phenyl-5 (4-pyridyl) imidazole (0.10 g, 0.3 mmol) [see Example 3 above] was heated in 6 N HCl (3 ml). at reflux for 24 h, then allow to cool. The pH was adjusted to 7 and the resulting solid was collected by filtration and washed sequentially with H 2 O, acetone and Et 2 O to provide the title compound as a white solid (25 mg, 23%): CIMS (NH 3 , m / z): 356 (M + + H).

PRIMER 6EXAMPLE 6

2-(4-acetamidometifenil)-l-metil-4-fenil-5-(4-piridil)imidazo]2- (4-acetamidometiphenyl) -1-methyl-4-phenyl-5- (4-pyridyl) imidazo]

K raztopini 2-(4-aminometilfenil)-l-metil-4-fenil-5-(4-piridil)imidazola (30 mg, 0,09 mmol) [glej primer 4 zgoraj] v piridinu (3 ml) dodamo acet anhidrid (0,30 ml, 3,18 mmol). Nastalo raztopino mešamo pri sobni temperaturi 30 min., nato koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 0-2 % MeOH/CHCI3. Izolirani material trituriramo z Et2O, da dobimo sivo belo trdno snov (10 mg, 28 %), ki jo prekristaliziramo iz EtOAc, da dobimo naslovno spojino: tal. 210-211 °C.To a solution of 2- (4-aminomethylphenyl) -1-methyl-4-phenyl-5- (4-pyridyl) imidazole (30 mg, 0.09 mmol) [see Example 4 above] acetyl anhydride was added in pyridine (3 ml). (0.30 ml, 3.18 mmol). The resulting solution was stirred at room temperature for 30 min, then concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solubility gradient of 0-2% MeOH / CHCl 3 . The isolated material was triturated with Et 2 O to give a gray-white solid (10 mg, 28%), which was recrystallized from EtOAc to give the title compound: m.p. 210-211 ° C.

PRIMER 7EXAMPLE 7

Metil-4-[l-metil-4-fenil-5-(4-piridil)-imidazol-2-il]benzoatMethyl-4- [1-methyl-4-phenyl-5- (4-pyridyl) -imidazol-2-yl] benzoate

K suspenziji natrijeve soli 4-[l-metil-4-fenil-5(4-piridil)-imidazol-2-il]benzojske kisline (20 mg, 0,06 mmol) [glej primer 5 zgoraj] v CH2C12 (2 ml) dodamo trietilamin (24 ml, 0,17 mmol), ki mu sledi tionil klorid (10 ml, 0,14 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 30 min., pri tem času dodamo MeOH (0,5 ml). Zmes mešamo pri sobni temperaturi še dodatni 2 h in koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 0-1 % MeOH/CHCl3 in prekristaliziramo iz EtOAc, da dobimo naslovno spojino kot sivo belo kristalinično trdno snov (1,6 mg, 8 %): tal. 208-209 °C.To a suspension of the sodium salt of 4- [1-methyl-4-phenyl-5 (4-pyridyl) -imidazol-2-yl] benzoic acid (20 mg, 0.06 mmol) [see example 5 above] in CH 2 C1 2 (2 ml) was added triethylamine (24 ml, 0.17 mmol) followed by thionyl chloride (10 ml, 0.14 mmol). The reaction mixture was stirred at room temperature for 30 min, at which time MeOH (0.5 ml) was added. The mixture was stirred at room temperature for an additional 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solubility gradient of 0-1% MeOH / CHCl 3 and recrystallized from EtOAc to give the title compound as a gray-white crystalline solid (1.6 mg, 8%): mp. Mp 208-209 ° C.

PRIMER 8aEXAMPLE 8a

4-(4-fluorofenil)-N-l-hidroksi-2-(4-hidroksifenil)-5-(4-piridil)imidazol4- (4-fluorophenyl) -N-1-hydroxy-2- (4-hydroxyphenyl) -5- (4-pyridyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 4-hidroksi-benzaldehid.The title compound was prepared using the same procedure as described in Example 10, step (d), except that 4-hydroxy-benzaldehyde was used.

PRIMER 8bEXAMPLE 8b

4-(4-fluorofenil)-2-(4-hidroksifenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-hydroxyphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo 4-(4-fluorofenil)-N-l-hidroksi-2-(4-hidroksifenil)-5-(4piridiljimidazol (glej primer 8a): tal. 214-215 °C.The title compound was prepared using the same procedure as described in Example 1 except that 4- (4-fluorophenyl) -N1-hydroxy-2- (4-hydroxyphenyl) -5- (4-pyridylimidazole (see Example 8a) was used: m.p. 214-215 ° C.

PRIMER 9EXAMPLE 9

4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzojska kislina4- [4- (4-Fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzoic acid

Raztopino, ki vsebuje 2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol (9,6 g, 28 mmol) [glej primer 1 zgoraj] v koncentrirani HC1 (100 ml) segrevamo pri refluksu 18 h. Po ohladitvi pH naravnamo na nevtralno z dodajanjem 50 %-ne vodne NaOH. Trdno snov, ki je nastala, zberemo s filtracijo in speremo zaporedno z H2O, acetonom in Et2O. Del trdne snovi (5 g) raztopimo v MeOH in filtriramo pod znižanim tlakom skozi blazinico silikagela, eluiramo s topnostnim gradientom 4-10 % MeOH/CHCl3, sledi 2:20:80 H2O/MeOH/CHCl3. Naslovno spojino izoliramo kot rumeno trdno snov, ki jo prekristaliziramo iz MeOH/CH2Cl2 (1,2 g, 30 % naravnan dobitek): tal. 289-290 °C.A solution containing 2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (9.6 g, 28 mmol) [see example 1 above] in concentrated HCl ( 100 ml) was heated at reflux for 18 h. After cooling, the pH was adjusted to neutral by the addition of 50% aqueous NaOH. The resulting solid was collected by filtration and washed successively with H 2 O, acetone and Et 2 O. Part of the solid (5 g) was dissolved in MeOH and filtered under reduced pressure through a pad of silica gel, eluting with a solubility gradient of 4-10 % MeOH / CHCl 3 , followed by 2:20:80 H 2 O / MeOH / CHCl 3 . The title compound was isolated as a yellow solid, which was recrystallized from MeOH / CH 2 Cl 2 (1.2 g, 30% yield): m.p. 289-290 ° C.

PRIMER 10EXAMPLE 10

2-(4-cianofenil)-4-(4-fluorofenil)-l-N-hidroksi-5-(4-piridil)imidazol (a) 4-fluoro-N-metoksi-N-metilbenzamid2- (4-cyanophenyl) -4- (4-fluorophenyl) -1-N-hydroxy-5- (4-pyridyl) imidazole (a) 4-fluoro-N-methoxy-N-methylbenzamide

K zmesi, ki vsebuje metoksimetilamin hidroklorid (44 g, 0,45 mol) in trietilamin (138 ml, 0,99 mol) v CH2C12 (500 ml) pri 0 °C dodamo preko 30 min. 4-fluorobenzoil klorid (50 ml, 0,41 mol). Nastalo zmes pustimo, da se segreje na sobno temperaturo in mešanje nadaljujemo 30 minut, pri tem času zmes zlijemo v H2O in ekstrahiramo z Et2O. Organski ekstrakt speremo z nasičenim vodnim NaCl in posušimo (MgSOJ. Odstranitev topila in vacuo da naslovno spojino (80 g, 100 %), ki jo uporabimo brez nadaljnjega čiščenja: XH NMR (CDC13): δ 7,72 (dd, 2H); 7,06 (jasen t, 2H); 3,52 (s, 3H); 3,43 (s, 3H).To a mixture containing methoxymethylamine hydrochloride (44 g, 0.45 mol) and triethylamine (138 ml, 0.99 mol) in CH 2 Cl 2 (500 ml) at 0 ° C was added over 30 min. 4-Fluorobenzoyl chloride (50 ml, 0.41 mol). The resulting mixture was allowed to warm to room temperature and stirring was continued for 30 minutes, at which time the mixture was poured into H 2 O and extracted with Et 2 O. The organic extract was washed with saturated aqueous NaCl and dried (MgSOJ. Removal of the solvent and vacuo gave the title compound (80 g, 100%) used without further purification: X H NMR (CDCl 3 ): δ 7.72 (dd, 2H); 7.06 (clear t, 2H); 3.52 (s, 3H); 3.43 (s, 3H).

(b) 4-fluoro-2-(4-piridil)acetofenon(b) 4-Fluoro-2- (4-pyridyl) acetophenone

Raztopino litijevega diizopropilamida pripravimo pri -78 °C na običajen način iz diizopropilamina (21 ml, 0,15 mol) in n-butillitija (54 ml 2,5 M raztopine v heksanih, 0,135 mol) in k tej dodamo pri -78 °C 4-pikolin (10 g, 0,108 mol). Po mešanju nadaljnjih 15 min. pri -78 °C dodamo 4-fluoro-N-metoksi-N-metilbenzamid (20 g, 0,109 mol) in zmes pustimo, da se počasi segreje na sobno temperaturo. Reakcijsko zmes zlijemo v nasičen vodni NaCl in ekstrahiramo s 4:1 THF/CH2C12 in organski ekstrakt posušimo (MgSO4). Topilo odstranimo in vacuo in k oljnatem rjavem ostanku dodamo Et2O. Naslovno spojino dobimo kot rjavo trdno snov (16,8 g, 72 %), ki jo prekristaliziramo iz Et2O/Heks: Ή NMR (CDC13): d 8,55 (d, 2H); 8,03 (dd, 2H); 7,16 (m, 4H); 4,24 (s, 2H).A solution of lithium diisopropylamide was prepared at -78 ° C in the usual manner from diisopropylamine (21 ml, 0.15 mol) and n-butyllithium (54 ml of a 2.5 M solution in hexanes, 0.135 mol) and added at -78 ° C. 4-picoline (10 g, 0.108 mol). After stirring for a further 15 min. at -78 ° C, 4-fluoro-N-methoxy-N-methylbenzamide (20 g, 0.109 mol) was added and the mixture was allowed to warm slowly to room temperature. The reaction mixture was poured into saturated aqueous NaCl and extracted with 4: 1 THF / CH 2 Cl 2 and the organic extract dried (MgSO 4 ). The solvent was removed in vacuo and Et 2 O was added to the oily brown residue. The title compound was obtained as a brown solid (16.8 g, 72%) recrystallized from Et 2 O / Hex: Ή NMR (CDCl 3 ): d 8 , 55 (d, 2H); 8.03 (dd, 2H); 7.16 (m, 4H); 4.24 (s, 2H).

(c) 4-fluoro-2-hidroksiimino-2-(4-piridil)acetofenon(c) 4-fluoro-2-hydroxyimino-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka (US 3,940,486) uporabljenega za pripravo 2-hidroksiimino-2-(4-piridil)acetofenona, razen da uporabimo 4-fluoro-2-(4-piridil)acetofenon.The title compound was prepared using the same process (US 3,940,486) used for the preparation of 2-hydroxyimino-2- (4-pyridyl) acetophenone except that 4-fluoro-2- (4-pyridyl) acetophenone was used.

(d) 2-(4-cianofenil)-4-(4-fluorofenil)-N-l-hidroksi-5-(4-piridil)imidazol(d) 2- (4-cyanophenyl) -4- (4-fluorophenyl) -N-1-hydroxy-5- (4-pyridyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka (US 3,940,486) uporabljenega za pripravo 2-(t-butil)-4-(fenil)-N-l-hidroksi-5-(4-piridil)imidazola, razen da uporabimo 4-fluoro-2-hidroksiimino-2-(4-piridil)acetofenona in 4-cianobenzaldehid: Ή NMR (CDC13): δ 8,27 (d, 2H); 7,94 (d, 2H); 7,72 (d, 2H);The title compound was prepared using the same process (US 3,940,486) used for the preparation of 2- (t-butyl) -4- (phenyl) -N 1 -hydroxy-5- (4-pyridyl) imidazole, except that 4-fluoro-2- hydroxyimino-2- (4-pyridyl) acetophenone and 4-cyanobenzaldehyde: Ή NMR (CDCl 3 ): δ 8.27 (d, 2H); 7.94 (d, 2H); 7.72 (d, 2H);

7,35 (d, 2H); 7,30 (dd, 2H); 6,96 (t, 2H).7.35 (d, 2H); 7.30 (dd, 2H); 6.96 (t, 2H).

PRIMER 11EXAMPLE 11

2-(4-aminometilfenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-Aminomethylphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini 2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (2,5 g, 7,3 mmol) [glej primer 1 zgoraj] v THF (50 ml) dodamo LiAlH4 (7,3 ml 1 M raztopine v THF, 7,3 mmol) in nastalo zmes segrevamo pri refluksu 2 h, pri tem času tenkoplastno tekočinske kromatografske analize kažejo, da je reakcija nepopolna. Dodamo dodatni LiAlH4 (4,0 ml, 4,0 mmol) in segrevanje nadaljujemo 30 min. Zmes pustimo, da se ohladi, jo nato zlijemo v 2,5 N NaOH in ekstrahiramo z THF. Organski ekstrakt speremo z nasičenim vodnim NaCl in koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo z 9:1 CHCl3/MeOH, sledi 90:10:1 CHCl3)MeOH/NH3. Material, ki smo ga izolirali, trituriramo z Et2O, da dobimo naslovno spojino (1,5 g, 60 %): tal. 214-215 °C.To a solution of 2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (2.5 g, 7.3 mmol) [see example 1 above] in THF (50 ml) was added LiAlH 4 (7.3 ml of 1 M solution in THF, 7.3 mmol) and the resulting mixture was heated at reflux for 2 h, during which time thin-layer chromatographic analyzes indicated that the reaction was incomplete. Additional LiAlH 4 (4.0 mL, 4.0 mmol) was added and heating was continued for 30 min. The mixture was allowed to cool, then poured into 2.5 N NaOH and extracted with THF. The organic extract was washed with saturated aqueous NaCl and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with 9: 1 CHCl 3 / MeOH followed by 90: 10: 1 CHCl 3 ) MeOH / NH 3 . The isolated material was triturated with Et 2 O to give the title compound (1.5 g, 60%): m.p. 214-215 ° C.

PRIMER 12aEXAMPLE 12a

2-(4-cianofenil)-4-(4-fluorofenil)-N-l-hidroksi-5-(4-kinolil)imidazol (a) 4-fluoro-2-(4-kinolil)acetofenon2- (4-cyanophenyl) -4- (4-fluorophenyl) -N-1-hydroxy-5- (4-quinolyl) imidazole (a) 4-fluoro-2- (4-quinolyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 4-metilkinolin: lH NMR (CDC13): δ 8,87 (d, IH); 8,13 (m, 3H); 7,86 (d, IH); 7,73 Qasen širok t, IH); 7,56 (jasen širok t, IH); 7,28 (d, IH); 7,20 (t, 2H); 4,71 (s, 2H).The title compound was prepared using the same procedure as described in Example 10, step (b), except that 4-methylquinoline was used: 1 H NMR (CDCl 3 ): δ 8.87 (d, 1H); 8.13 (m, 3H); 7.86 (d, 1H); 7.73 Qasen wide t, 1H); 7.56 (clear broad t, 1H); 7.28 (d, 1H); 7.20 (t, 2H); 4.71 (s, 2H).

(b) 4-fluoro-2-hidroksiimino-2-(4-kinolil)acetofenon(b) 4-Fluoro-2-hydroxyimino-2- (4-quinolyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 4-fluoro-2-(4-kinolil)acetofenon: *H NMR (DMSO-dJ: δ 9,00 (d, IH); 8,15 (m, 3H); 7,78 (m, IH); 7,61 (m, 2H); 7,50 (d, IH);The title compound was prepared using the same procedure as described in Example 10, step (c), except that 4-fluoro-2- (4-quinolyl) acetophenone was used: * H NMR (DMSO-dJ: δ 9.00 (d 1H); 8.15 (m, 3H); 7.78 (m, 1H); 7.61 (m, 2H); 7.50 (d, 1H);

7,42 (t, 2H).7.42 (t, 2H).

(c) 2-(4-cianofenil)-4-(4-fluorofenil)-N-l-hidroksi-5-(4-kinolil)imidazol(c) 2- (4-cyanophenyl) -4- (4-fluorophenyl) -N-1-hydroxy-5- (4-quinolyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 4-fluoro-2-hidroksiimino-2-(4-kinolil)acetofenon in 4-cianobenzaldehid: XH NMR (CDC13): δ 8,30 (d, 2H); 7,80 (D, IH); 7,70 (dva prekrivajoča d, 3H); 7,46 (m, 2H); 7,36 (m, IH); 7,11 (m, 2H); 7,01 (m, IH); 6,75 (t, 2H).The title compound was prepared using the same procedure as described in Example 10, step (d), except that 4-fluoro-2-hydroxyimino-2- (4-quinolyl) acetophenone and 4-cyanobenzaldehyde were used: X H NMR (CDC1 3 ): δ 8.30 (d, 2H); 7.80 (D, 1H); 7.70 (two overlapping d, 3H); 7.46 (m, 2H); 7.36 (m, 1H); 7.11 (m, 2H); 7.01 (m, 1H); 6.75 (t, 2H).

PRIMER 12bEXAMPLE 12b

2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-kinolil)-lH-imidazol2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-quinolyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo 2-(4-cianofenil)-4-(4-fluorofenil)-N-l-hidroksi-5-(4kinolil)imidazol [glej primer 12a]: tal. 294-295 °C.The title compound was prepared using the same procedure as described in Example 1 except that 2- (4-cyanophenyl) -4- (4-fluorophenyl) -N1-hydroxy-5- (4quinolyl) imidazole was used [see Example 12a]: m.p. 294-295 ° C.

PRIMER 13EXAMPLE 13

2-(3,5-dibromo-4-hidroksifenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol (a) l-(4-fluorofenil)-2-(4-piridil)-etandiol2- (3,5-dibromo-4-hydroxyphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (a) 1- (4-fluorophenyl) -2- (4-pyridyl) ) -ethanediol

K mešani raztopini 2,0 g (11,2 mmol) 4-(t-butildimetilsililoksi)metil piridina v 8 ml THF pri -20 °C dodamo 14,7 mmol litijevega di-izo-propil amida v THF. 30 minut kasneje dodamo 4-fluoro-benzaldehid (1,66 g, 13,4 mmol), na tej točki raztopino pustimo, da se počasi segreje na sobno temperaturo. Reakcijo pogasimo z NH4C1 in ekstrahiramo z etrom, da dobimo surovi zaščiteni diol, katerega s sledečo koncentracijo raztopimo v THF in obdelamo s 17 ml 1 molarne raztopine tetrabutilamonijevega iluorida v THF preko noči. Standarna vodna dodelava da sirovi diol, ki ga nadalje prečistimo s kolonsko kromatografijo (hex/EtOAc), da dobimo 1,6 g (62 %) naslovnega materiala.To a stirred solution of 2.0 g (11.2 mmol) of 4- (t-butyldimethylsilyloxy) methyl pyridine in 8 ml of THF at -20 ° C was added 14.7 mmol of lithium di-iso-propyl amide in THF. 30 minutes later, 4-fluoro-benzaldehyde (1.66 g, 13.4 mmol) was added, at which point the solution was allowed to slowly warm to room temperature. The reaction was quenched with NH 4 Cl and extracted with ether to give the crude protected diol, which was dissolved in THF at the following concentration and treated with 17 ml of 1 molar solution of tetrabutylammonium iloride in THF overnight. Standard aqueous finishing gave the crude diol, which was further purified by column chromatography (hex / EtOAc) to give 1.6 g (62%) of the title material.

(b) l-(4-fluorofenil)-2-(4-piridil)etandion(b) 1- (4-fluorophenyl) -2- (4-pyridyl) ethanedione

Oksidacija l-(4-fluorofenil)-2-(4-piridil)etandiola po oksalil kloridnem postopku Swern [J. org. Chem., 44, str. 4148,1979) da naslovni dion, sledi ekstrakcija dodelava in prekristalizacija iz heksanov, tal. 85-86,5 °C.Oxidation of 1- (4-fluorophenyl) -2- (4-pyridyl) ethanediol by the oxalyl chloride process Swern [J. org. Chem., 44, p. 4148,1979) to the title dione, followed by extraction finishing and recrystallization from hexanes, m.p. 85-86.5 ° C.

(c) 2-(3,5-dibromo-4-hidroksifenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol(c) 2- (3,5-dibromo-4-hydroxyphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini l-(4-fluorofenil)-2-(4-piridil)etandiona (0,25 g, 1,1 mmol) in 3,5dibromo-4-hidroksi-benzaldehida (0,37 g, 1,3 mmol) v ledocetni kislini (5 ml) dodamo amonijev acetat (0,50 g, 6,5 mmol) in nastalo zmes segrevamo pri refluksuTo a solution of 1- (4-fluorophenyl) -2- (4-pyridyl) ethanedione (0.25 g, 1.1 mmol) and 3.5dibromo-4-hydroxy-benzaldehyde (0.37 g, 1.3 mmol) ammonium acetate (0.50 g, 6.5 mmol) was added in glacial acetic acid (5 ml) and the resulting mixture was heated at reflux.

h. Po ohladitvi, zmes zlijemo v H2O in pH naravnamo na nevtralno z dodajanjemh. After cooling, the mixture was poured into H 2 O and the pH adjusted to neutral by addition

2,5 N NaOH. Trdno snov, ki nastane, zberemo s filtracijo, speremo s H2O, posušimo in vacuo in prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4% MeOH/CHCl3. Naslovno spojino dobimo kot rumeno rjavo trdno snov (15 mg, 3 %): ESMS (m/z)·. 488 (M++H).2.5 N NaOH. The resulting solid was collected by filtration, washed with H 2 O, dried in vacuo and purified by flash chromatography, eluting with a solubility gradient of 2-4% MeOH / CHCl 3 . The title compound was obtained as a yellow-brown solid (15 mg, 3%): ESMS (m / z) ·. 488 (M + + H).

PRIMER 14EXAMPLE 14

Etil-4[4-(4-fluorofenil)-5-(4-piridil)]-lH-imidazol-2-il]-benzoatEthyl-4 [4- (4-fluorophenyl) -5- (4-pyridyl)] -1H-imidazol-2-yl] -benzoate

Raztopino 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzojske kisline (30 mg, 0,08 mmol) [glej primer 9 zgoraj] v 20 %-ni etanolni HC1 (5 ml) segrevamo pri refluksu 24 h, ohladimo na sobno temperaturo in nevtraliziramo s 50 %-no NaOH. Ostanek zberemo in prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 4-10 % MeOH/CHCl3. Trituracija z Et2O da naslovno spojino kot belo trdno snov (3,2 g, 66 %): XH NMR (CDCl3/MeOH-d4): δ 8,45 (d, 2H); 8,12 (m, 4H); 7,52 (m, 4H); 7,15 (t, 2H); 4,42 (k, 2H); 1,43 (t, 3H).A solution of 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzoic acid (30 mg, 0.08 mmol) [see Example 9 above] in 20% - non-ethanol HCl (5 ml) was heated at reflux for 24 h, cooled to room temperature and neutralized with 50% NaOH. The residue was collected and purified by flash chromatography, eluting with a solubility gradient of 4-10% MeOH / CHCl 3 . Trituration with Et 2 O gave the title compound as a white solid (3.2 g, 66%): X H NMR (CDCl 3 / MeOH-d 4 ): δ 8.45 (d, 2H); 8.12 (m, 4H); 7.52 (m, 4H); 7.15 (t, 2H); 4.42 (k, 2H); 1.43 (t, 3H).

PRIMER 15EXAMPLE 15

2-[3,5-dimetil-4-hidroksi(fenil)]-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- [3,5-dimethyl-4-hydroxy (phenyl)] - 4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 3,5-dimetil-4-hidroksibenzaldehid: ESMS (m/z): 360 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that 3,5-dimethyl-4-hydroxybenzaldehyde was used: ESMS (m / z): 360 (M + + H).

PRIMER 16EXAMPLE 16

4-(4-fluorofenil-2-(2-hidroksifenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl-2- (2-hydroxyphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo salicilaldehid: ESMS (m/z): 332 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that salicylaldehyde was used: ESMS (m / z): 332 (M + + H).

PRIMER 17EXAMPLE 17

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-(metiltio)-benzaldehid: ESMS (m/z): 362 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that 4- (methylthio) -benzaldehyde was used: ESMS (m / z): 362 (M + + H).

PRIMER 18EXAMPLE 18

Metil 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzoatMethyl 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzoate

Zmes, ki vsebuje natrijevo sol 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2iljbenzojske kisline (0,20 g, 0,5 mmol) [glej primer 9 zgoraj] in koncentrirano HCI (10 kapljic) v MeOH (5 ml) segrevamo pri refluksu 8 h. Po ohladitvi naravnamo pH na nevtralno z dodajanjem 2,5 N NaOH in trdno snov, ki je nastala, zberemo s filtracijo, speremo z H2O in posušimo in vacuo. Naslovno spojino pridobimo kot rumeno trdno snov (0,14 g, 76 %) in prekristaliziramo iz EtOAc/CH2Cl2: XH NMR (CDCl3/MeOH-d4): δ 8,36 (d, 2H); 8,03 (m, 4H); 7,60-7,30 (m, 4H); 7,07 (t, 2H); 3,84 (s,3H).Mixture containing 4- [4- (4-Fluorophenyl) -5- (4-pyridyl) -1H-imidazole-2ylbenzoic acid sodium salt (0.20 g, 0.5 mmol) [see Example 9 above] and concentrated HCl (10 drops) in MeOH (5 ml) was heated at reflux for 8 h. After cooling, the pH was adjusted to neutral by the addition of 2.5 N NaOH and the resulting solid was collected by filtration, washed with H 2 O and dried in vacuo. The title compound was obtained as a yellow solid (0.14 g, 76%) and recrystallized from EtOAc / CH 2 Cl 2 : X H NMR (CDCl 3 / MeOH-d 4 ): δ 8.36 (d, 2H); 8.03 (m, 4H); 7.60-7.30 (m, 4H); 7.07 (t, 2H); 3.84 (s, 3H).

PRIMER 19EXAMPLE 19

4-(4-fluorofenil)-2-(4-metilsulfonilfenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini 4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazola (3,7 g,To a solution of 4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole (3.7 g,

9,8 mmol) [glej primer 20 spodaj] v 1:10 3 N HC1/H2O (88 ml) dodamo raztopino KMnO4 (1,5 g, 9,8 mmol) v H2O (15 ml). Po mešanju pri sobni temperaturi 1 h, dodamo dodaten KMnO4 (0,15 g, 0,9 mmol) in mešanje nadaljujemo 15 min. Zmes nato zlijemo v nasičen vodni Na2SO3 (200 ml) in pH naravnamo na rahlo kisel z dodajanjem 3 N HCI, nato na nevtralno z dodajanjem 2,5 N NaOH. Trdno snov, ki je nastala, zberemo s filtracijo, speremo zaporedno z H2O in MeOH in prekristaliziramo trikrat iz MeOH, da dobimo naslovno spojino (0,63 g, 16 %): tal. 148149°C.9.8 mmol) [see example 20 below] in 1:10 3 N HCl / H 2 O (88 ml) was added a solution of KMnO 4 (1.5 g, 9.8 mmol) in H 2 O (15 ml). After stirring at room temperature for 1 h, additional KMnO 4 (0.15 g, 0.9 mmol) was added and stirring was continued for 15 min. The mixture was then poured into saturated aqueous Na 2 SO 3 (200 ml) and the pH adjusted to slightly acidic by the addition of 3 N HCl, then to neutral by the addition of 2.5 N NaOH. The resulting solid was collected by filtration, washed sequentially with H 2 O and MeOH and recrystallized three times from MeOH to give the title compound (0.63 g, 16%): mp. 148149 ° C.

PRIMER 20EXAMPLE 20

4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini 4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazola (0,80 g, 2,2 mmol) [glej primer 17 zgoraj] v ledocetni kislini (15 ml) dodamo raztopino K^Og (0,72 g, 2,6 mmol) v H2O (20 ml). Dodamo dodatno ledocetno kislino (15 ml), da zagotovimo homogenost in nastalo raztopino mešamo pri sobni temperaturi 18 h. Zmes nato zlijemo v H2O in pH naravnamo na nevtralno z dodajanjem konc. NH4OH. Trdno snov, ki je nastala, zberemo s filtracijo, da dobimo naslovno spojino (0,65 g, 78 %) kot rumeno rjavo trdno snov, ki jo prekristaliziramo iz MeOH: tal. 250-252 °C.To a solution of 4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole (0.80 g, 2.2 mmol) [see example 17 above] in glacial acetic acid ( 15 ml) was added a solution of K ^ Og (0.72 g, 2.6 mmol) in H 2 O (20 ml). Additional glacial acetic acid (15 ml) was added to ensure homogeneity and the resulting solution was stirred at room temperature for 18 h. The mixture was then poured into H 2 O and the pH adjusted to neutral by the addition of conc. NH 4 OH. The resulting solid was collected by filtration to give the title compound (0.65 g, 78%) as a yellow-brown solid, which was recrystallized from MeOH: m.p. 250-252 ° C.

PRIMER 21EXAMPLE 21

N, N-dimetil-4-[4(4-fluorofenil-5-(4-piridil)-lH-imidazol-2-il]benzamidN, N-dimethyl-4- [4 (4-fluorophenyl-5- (4-pyridyl) -1H-imidazol-2-yl] benzamide

K dimetilamino(metil)aluminijevem kloridu (0,60 ml 0,67 M raztopine v toluenu,To dimethylamino (methyl) aluminum chloride (0.60 ml of 0.67 M solution in toluene,

O, 40 mmol) dodamo raztopino metil-4[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2iljbenzoata (50 mg, 0,13 mmol) [glej primer 18 zgoraj] v 1,2-dikloroetanu (5ml). Nastalo zmes segrevamo pri refluksu 4 h, nato pustimo da se ohladi in jo zlijemo v 2,5 N NaOH. Zmes ekstrahiramo z EtOAc in organski ekstrakt speremo z nasičenim vodnim NaCl in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4 % MeOH/CHCl3, da dobimo naslovno spojino (25 mg, 50 %) kot belo trdno snov: CIMS (NH3, m/z): 387 (M++H).O, 40 mmol) was added a solution of methyl-4 [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole-2ylbenzoate (50 mg, 0.13 mmol) [see example 18 above] in 1. 2-dichloroethane (5ml). The resulting mixture was refluxed for 4 h, then allowed to cool and poured into 2.5 N NaOH. The mixture was extracted with EtOAc and the organic extract was washed with saturated aqueous NaCl and dried (MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with a solubility gradient of 2-4% MeOH / CHCl 3 to give the title compound (25 mg, 50%) as a white solid: CIMS (NH 3 , m / z): 387 (M + + H).

PRIMER 22EXAMPLE 22

2-[(4-N,N-dimetil)aminometilfenil]-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2 - [(4-N, N-dimethyl) aminomethylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 11, razen da uporabimo N,N-dimetil-4-[4-(4-fluorofenil-5-(4-piridil)-lH-imidazol-2iljbenzamid: CIMS (NH3, miz)·. 373 (M++H).The title compound was prepared using the same procedure as described in Example 11 except that N, N-dimethyl-4- [4- (4-fluorophenyl-5- (4-pyridyl) -1H-imidazol-2ylbenzamide: CIMS ( NH 3 , mass) ·. 373 (M + + H).

PRIMER 23EXAMPLE 23

2-[4-(dimetilamino)fenil]-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- [4- (dimethylamino) phenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-(N,N-dimetilamino)benzaldehid: ESMS (m/z): 359 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that 4- (N, N-dimethylamino) benzaldehyde was used: ESMS (m / z): 359 (M + + H).

PRIMER 24EXAMPLE 24

4-(4-fluorofenil)-2-fenil-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2-phenyl-5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo benzaldehid: ESMS (m/z): 316 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that benzaldehyde was used: ESMS (m / z): 316 (M + + H).

PRIMER 25EXAMPLE 25

2-[4(3-dimetilaminopropoksi)fenil]-4-(4-fluorofenil)-5-(4-piridiI)-lH-imidazol2- [4 (3-dimethylaminopropoxy) phenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-(3-dimetilamino-propoksi)benzaldehid: ESMS (m/z): 417 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that 4- (3-dimethylamino-propoxy) benzaldehyde was used: ESMS (m / z): 417 (M + + H).

PRIMER 26EXAMPLE 26

4-(4-fluorofenil)-2-(4-nitrofenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-nitrophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-nitrobenzaldehid: ESMS (m/z): 359 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that 4-nitrobenzaldehyde was used: ESMS (m / z): 359 (M + + H).

PRIMER 27EXAMPLE 27

N,N-dimetil-4-[2-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzoil-oksiacetamid (a) Metil benzilglikolatN, N-dimethyl-4- [2- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzoyl-oxyacetamide (a) Methyl benzyl glycolate

K raztopini, ki vsebuje metilglikoiat (2,5 ml, 32 mmol) in trifluorometil-sulfonsko kislino (150 ml) v CHgClg (10 ml) dodamo benzil 2,2,2-trikloro-acetimidat (7,0 ml, 37 mmol). Po mešanju nekaj minut, zmes zlijemo v vodni NaHCO3 in ekstrahiramo z Et2O. Organski ekstrakt speremo z nasičenim vodnim NaCl, posušimo (MgSO4) in koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 9-17 % EtOAc/Heks da dobimo naslovno spojino: Ή NMR (CDC13); δ 7,34 (m, 5H); 4,62 (s, 2H); 4,11 (s, 2H); 3,78 (s, 3H).To a solution containing methylglycoiate (2.5 ml, 32 mmol) and trifluoromethylsulfonic acid (150 ml) in CHgClg (10 ml) was added benzyl 2,2,2-trichloro-acetimidate (7.0 ml, 37 mmol). . After stirring for a few minutes, the mixture was poured into aqueous NaHCO 3 and extracted with Et 2 O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solubility gradient of 9-17% EtOAc / Hex to give the title compound: Ή NMR (CDCl 3 ); δ 7.34 (m, 5H); 4.62 (s, 2H); 4.11 (s, 2H); 3.78 (s, 3H).

(b) Benzil-N,N-dimetilglikolamid(b) Benzyl-N, N-dimethylglycolamide

K dimetil-amino(metil)aluminijevem kloridu [pripravljenem iz dimetilamin hidroklorida (3,4 g, 42 mmol) in trimetil aluminija (21 ml 2 M raztopine, 42 mmol)] v toluenu (40 ml) dodamo metil benzilglikolat (3,0 g, 17 mmol). Po mešanju na sobni temperaturi 1,5 h, zmes zlijemo v 3 N HCI in ekstrahiramo z Et2O. Organski ekstrakt speremo z nasičenim vodnim NaCl, posušimo (MgSO4) in koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 9-50 % EtOAc/Heks. Naslovno spojino pridobimo kot brezbarvno olje (1,2 g, 37 %): Ή NMR (CDC13): δ 7,4-7,1 (m, 5H); 4,61 (s, 2H); 4,18 (s, 2H); 2,98 (s, 3H); 2,95 (s, 3H).To methyl dimethylamino (methyl) aluminum chloride [prepared from dimethylamine hydrochloride (3.4 g, 42 mmol) and trimethyl aluminum (21 ml 2 M solution, 42 mmol)] in toluene (40 ml) was added methyl benzyl glycolate (3.0 g, 17 mmol). After stirring at room temperature for 1.5 h, the mixture was poured into 3 N HCl and extracted with Et 2 O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solubility gradient of 9-50% EtOAc / Hex. The title compound was obtained as a colorless oil (1.2 g, 37%): Ή NMR (CDCl 3 ): δ 7.4-7.1 (m, 5H); 4.61 (s, 2H); 4.18 (s, 2H); 2.98 (s, 3H); 2.95 (s, 3H).

(c) N,N-dimetilglikolamid(c) N, N-dimethylglycolamide

K raztopini benzil-N,N-dimetilglikolamida (0,28 g, 1,5 mmol) v MeOH (5 ml) dodamo 10 % paladija na aktiviranem ogljiku (0,15 g) in nastalo zmes mešamo pod atmosfero H2. Po 1 h, zmes filtriramo skozi blazinico Celitea in filtrat koncentriramo pod znižanim tlakom, da dobimo naslovno spojino, ki jo uporabimo brez nadaljnjega čiščenja: TH NMR (CDC13); δ 4,13 (s, 2H); 3,01 (s, 3H); 2,89 (s, 3H).To a solution of benzyl-N, N-dimethylglycolamide (0.28 g, 1.5 mmol) in MeOH (5 ml) was added 10% palladium on activated carbon (0.15 g) and the resulting mixture was stirred under an H 2 atmosphere. After 1 h, the mixture was filtered through a Celitea pad and the filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification: T H NMR (CDCl 3 ); δ 4.13 (s, 2H); 3.01 (s, 3H); 2.89 (s, 3H).

(d) N,N-dimetil-4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzoil-oksiacetamid(d) N, N-dimethyl-4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzoyl-oxyacetamide

K raztopini 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzojske kisline (0,15 g, 0,42 mmol) [glej primer 9 zgoraj] v DMF (10 ml) dodamo karbonildiimidazol (0,34 g, 2,1 mmol). Po mešanju 18 h na sobni temperaturi, dodamo N,Ndimetilglikolamid (0,43 g, 4,2 mmol) in mešanje nadaljujemo dodatne 3 h na sobni temperaturi. Reakcijsko zmes zlijemo v H2O, ekstrahiramo z EtOAc in uparimo. Ost tanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2 % MeOH/CHCl3, da dobimo naslovno spojino: CIMS (NH3, m/z)·. 445 (M++H).To a solution of 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzoic acid (0.15 g, 0.42 mmol) [see Example 9 above] in DMF (10 ml) was added carbonyldiimidazole (0.34 g, 2.1 mmol). After stirring for 18 h at room temperature, N, N-dimethylglycolamide (0.43 g, 4.2 mmol) was added and stirring was continued for an additional 3 h at room temperature. The reaction mixture was poured into H 2 O, extracted with EtOAc and evaporated. The residue was purified by flash chromatography eluting with a solubility gradient of 2% MeOH / CHCl 3 to give the title compound: CIMS (NH 3 , m / z) ·. 445 (M + + H).

PRIMER 28EXAMPLE 28

2-(4-aminofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-aminophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Zmes, ki vsebuje 4-(4-fluorofenil)-2-(4-nitrofenil)-5-(4-piridil)-lH-imidazol (2,0 g, 5,6 mmol) [glej primer 26 zgoraj] in 10 % paladij na aktiviranem ogljiku (0,4 g) mešamo pod atmosfero H2 4 h, nato filtriramo skozi blazinico Celitea. Filtrat koncentriramo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 1-10 % MeOH/CHCl3. Naslovno spojino pridobimo kot rahlo oranžno trdno snov (0,50 g, 27 %): ΧΗ NMR (DMSO-dJ: δ 8,40 (d, 2H); 7,73 (d, 2H); 7,57 (m, 2H); 7,35 (m, 4H); 6,62 (t, 2H).Mixture containing 4- (4-fluorophenyl) -2- (4-nitrophenyl) -5- (4-pyridyl) -1H-imidazole (2.0 g, 5.6 mmol) [see Example 26 above] and 10 % palladium on activated carbon (0.4 g) was stirred under an atmosphere of H 2 for 4 h, then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a solubility gradient of 1-10% MeOH / CHCl 3 . The title compound is obtained as a slightly orange solid (0.50 g, 27%): Χ Η NMR (DMSO-dJ: δ 8.40 (d, 2H), 7.73 (d, 2H), 7.57 (m , 2H); 7.35 (m, 4H); 6.62 (t, 2H).

PRIMER 29EXAMPLE 29

4-(4-fluorofenil)-2-(4-metansulfonamidofenil-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methanesulfonamidophenyl-5- (4-pyridyl) -1H-imidazole

K suspenziji 2-(4-aminofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (80 mg, 0,24 mmol) [glej primer 28 zgoraj] in trietilamina (0,12 ml, 0,86 mmol) v CH2C12 (5 ml) dodamo metansulfonil klorid (55 ml, 0,72 mmol). Po mešanju na sobni temperaturi 1 h, zmes zlijemo v vodni NaHCO3 in ekstrahiramo z EtOAc. Organski ekstrakt speremo z nasičenim vodnim NaCl, posušimo (MgSO4) in koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-10 % MeOH/CHCl3, da dobimo naslovno spojino kot rumeno rjavo trdno snov (35 mg, 36 %): ESMS (m/z)·. 409 (M++H).To a suspension of 2- (4-aminophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (80 mg, 0.24 mmol) [see example 28 above] and triethylamine (0.12 ml, 0.86 mmol) in CH 2 Cl 2 (5 ml) was added methanesulfonyl chloride (55 ml, 0.72 mmol). After stirring at room temperature for 1 h, the mixture was poured into aqueous NaHCO 3 and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl, dried (MgSO 4 ) and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solubility gradient of 2-10% MeOH / CHCl 3 to give the title compound as a yellow-brown solid (35 mg, 36%): ESMS (m / z) ·. 409 (M + + H).

PRIMER 30EXAMPLE 30

4-[4-(4-fluorofenil)-5-(4-piridil)lH-imidazol-2-il]fenil-sulfonamid (a) Etil 4-sulfonamidobenzoat4- [4- (4-Fluorophenyl) -5- (4-pyridyl) 1H-imidazol-2-yl] phenyl sulfonamide (a) Ethyl 4-sulfonamidobenzoate

K raztopini 4-karboksibenzensulfonamida (5,0 g, 0,025 mol) v 20 %-ni etanolni HC1 (20 ml) segrevamo pri refluksu 18 h, nato pustimo, da se ohladi in jo koncentriramo pod znižanim tlakom, da dobimo naslovno spojino: XH NMR (CDC13): δ 8,20 (jasen d, 2H); 8,00 (jasen d, 2H); 4,88 (širok s, 2H); 4,43 (q, 2H); 1,43 (t, 3H).To a solution of 4-carboxybenzenesulfonamide (5.0 g, 0.025 mol) in 20% ethanol HCl (20 ml) was heated at reflux for 18 h, then allowed to cool and concentrated under reduced pressure to give the title compound: X H NMR (CDCl 3 ): δ 8.20 (clear d, 2H); 8.00 (clear d, 2H); 4.88 (broad s, 2H); 4.43 (q, 2H); 1.43 (t, 3H).

(b) N-metoksi-N-metil-4-sulfonamidobenzamid(b) N-methoxy-N-methyl-4-sulfonamidobenzamide

K raztopini metoksimetilamino(metil)aluminijevega klorida [pripravljenega iz metoksimetilamin hidroklorida (4,8g, 50 mmol) in trimetil aluminija (25 ml 2 M raztopine, 50 mmol)] v toluenu (50 ml) pri 0 °C dodamo etil 4-sulfonamidobenzoat (3,8 g, 17 mmol). Zmes pustimo, da se segreje na sobno temperaturo in mešamo 3 h, jo nato zlijemo v suspenzijo silikagela (50 g) v CHC13 (200 ml). Zmes filtriramo in filtrat koncentriramo pod znižanim tlakom. Ostanek zlijemo v H2O in trdno snov, ki je nastala, zberemo s filtracijo, speremo z H2O in posušimo in vacuo, da dobimo naslovno spojino (1,7 g, 42 %): Ή NMR (CDCl3/MeOH-d4): δ 7,86 (d, 2H); 7,66 (d, 2H); 3,43 (s, 3H); 3,29 (s, 3H).To a solution of methoxymethylamino (methyl) aluminum chloride [prepared from methoxymethylamine hydrochloride (4.8 g, 50 mmol) and trimethyl aluminum (25 ml 2 M solution, 50 mmol)] in toluene (50 ml) was added ethyl 4-sulfonamidobenzoate at 0 ° C. (3.8 g, 17 mmol). The mixture was allowed to warm to room temperature and stirred for 3 h, then poured into a suspension of silica gel (50 g) in CHCl 3 (200 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was poured into H 2 O and the resulting solid was collected by filtration, washed with H 2 O and dried in vacuo to give the title compound (1.7 g, 42%): Ή NMR (CDCl 3 / MeOH- d 4 ): δ 7.86 (d, 2H); 7.66 (d, 2H); 3.43 (s, 3H); 3.29 (s, 3H).

(c) 4-formilbenzensulfonamid(c) 4-Formylbenzenesulfonamide

K raztopini N-metoksi-N-metil-4-sulfonamidobenzamida (1,0 g, 4,1 mmol) v THF (25 ml) na -78 °C dodamo LiAlH4 (6,1 ml 1 M raztopine v THF, 6,1 mmol). Po mešanju pri -78 °C 30 min., zmes zlijemo v suspenzijo silikagela (50 g) v CHC13 (200 ml). Zmes filtriramo in filtrat koncentriramo pod znižanim tlakom. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-10 % MeOH/CHCl3. Naslovno spojino pridobimo kot belo trdno snov (0,12 g, 16 %): JH NMR (CDCl3/MeOH-d4); δ 10,3 (s, IH); 8,02 (d, 2H); 7,95 (d, 2H).To a solution of N-methoxy-N-methyl-4-sulfonamidobenzamide (1.0 g, 4.1 mmol) in THF (25 ml) at -78 ° C was added LiAlH 4 (6.1 ml of 1 M solution in THF, 6 , 1 mmol). After stirring at -78 ° C for 30 min, the mixture was poured into a suspension of silica gel (50 g) in CHCl 3 (200 ml). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solubility gradient of 2-10% M e OH / CHCl 3 . The title compound was obtained as a white solid (0.12 g, 16%): 1 H NMR (CDCl 3 / MeOH-d 4 ); δ 10.3 (s, 1H); 8.02 (d, 2H); 7.95 (d, 2H).

(d) 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]sulfonamid(d) 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] sulfonamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeruThe title compound is prepared using the same procedure as described in the example

13, razen da uporabimo 4-formilbenzen-sulfonamid: ESMS (m/z): 395 (M++H).13 except using 4-formylbenzene sulfonamide: ESMS (m / z): 395 (M + + H).

PRIMER 31EXAMPLE 31

N’-ciano-N-4-[4-(fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzilgvanidinN'-cyano-N-4- [4- (fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzylguanidine

K suspenziji 2-(4-aminometilfenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (0,10 g, 0,29 mmol) [glej primer 11 zgoraj] v CH3CN dodamo difenil cianokarbonimidat (83 mg, 0,35 mmol). Po mešanju na sobni temperaturi 18 h, trdno snov, ki je nastala, zberemo s filtracijo in speremo s CH3CN. Trdno snov raztopimo v MeOH nasičenem z NH3 in mešamo 72 h. Zmes koncentriramo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 4-10 % MeOH/CHCl3. Naslovno spojino izoliramo kot bledo rumeno trdno snov (22 mg, 18 %): tal. 280-281 °C.To a suspension of 2- (4-aminomethylphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (0.10 g, 0.29 mmol) [see Example 11 above] in CH 3 CN diphenyl cyanocarbonimidate (83 mg, 0.35 mmol) was added. After stirring at room temperature for 18 h, the resulting solid was collected by filtration and washed with CH 3 CN. The solid was dissolved in MeOH saturated with NH 3 and stirred for 72 h. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography, eluting with a solubility gradient of 4-10% MeOH / CHCl 3 . The title compound was isolated as a pale yellow solid (22 mg, 18%): m.p. 280-281 ° C.

PRIMER 32EXAMPLE 32

2-[4-(metansulfonamido)metilfenil]-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- [4- (methanesulfonamido) methylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 29, razen da uporabimo 2-(4-aminometilfenil)-4-(4-fluorofenil)-5-(4-piridil)-lHimidazol [glej primer 11 zgoraj]: ESMS (m/z): 423 (M++H).The title compound was prepared using the same procedure as described in Example 29 except that 2- (4-aminomethylphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1Himidazole was used [see Example 11 above]: ESMS (m / z): 423 (M + + H).

PRIMER 33EXAMPLE 33

4-(4-fluorofenil)-2-(4-metoksifenil)-5-(4-piridil)-lH-imidazol (a) l-ciano-l-(4-piridil)metil-4-metoksibenzoat4- (4-fluorophenyl) -2- (4-methoxyphenyl) -5- (4-pyridyl) -1H-imidazole (a) 1-cyano-1- (4-pyridyl) methyl-4-methoxybenzoate

Naslovno spojino pripravimo z uporabo enakega postopka Lantos, I. et al., (J. Med. Chem. 1984, 27, 72-75) uporabljenega za pripravo l-ciano-l(4-piridil)-metil benzoata, razen da uporabimo 4-metoksibenzoil klorid: NMR (CDC13): δ 8,81 (d,The title compound is prepared using the same procedure Lantos, I. et al. (J. Med. Chem. 1984, 27, 72-75) used for the preparation of 1-cyano-1 (4-pyridyl) -methyl benzoate, except that 4-methoxybenzoyl chloride: NMR (CDCl 3 ): δ 8.81 (d,

2H); 8,10 (d, 2H); 7,57 (d, 2H); 7,01 (d, 2H); 6,74 (s, IH); 3,93 (s, 3H).2H); 8.10 (d, 2H); 7.57 (d, 2H); 7.01 (d, 2H); 6.74 (s, 1H); 3.93 (s, 3H).

(b) l-(4-fluorofenil)-2-(4-piridil)-2-oksoetil 4-metoksibenzoat in 2-(4-fluorofenil)-l4-piridil)-2-oksoetil 4-metoksibenzoat(b) 1- (4-fluorophenyl) -2- (4-pyridyl) -2-oxoethyl 4-methoxybenzoate and 2- (4-fluorophenyl) -14-pyridyl) -2-oxoethyl 4-methoxybenzoate

Naslovne spojine pripravimo z uporabo enakega postopka Lantos et al. (J. Med. Chem. 1984, 27, 72-75) uporabljenega za pripravo l-(4-fluorofenil)-2-(4-piridil)-2oksoetil benzoata in 2-(4-fluorofenil)-l-(4-piridil)-2-oksoetil benzoata, razen da uporabimo l-ciano-l-(4-piridil)metil-4-metoksibenzoat: NMR (hitreje topni izomer, CDC13): S 8,78 (d, 2H); 8,03 (širok d, 2H); 7,73 (d, 2H); 7,53 (dd, 2H); 7,10 (jasen t, 2H); 6,93 (prekrivajoča s in d, 3H); 3,85 (s, 3H); 1H NMR (počasneje topni izomer, CDC13); δ 8,66 (d, 2H); 8,04 (m, 4H); 7,46 (d, 2H); 7,15 (jasen t, 2H); 6,95 (prekrivajoča s in d, 3H); 3,87 (s, 3H).The title compounds are prepared using the same procedure of Lantos et al. (J. Med. Chem. 1984, 27, 72-75) used to prepare 1- (4-fluorophenyl) -2- (4-pyridyl) -2-oxoethyl benzoate and 2- (4-fluorophenyl) -1- (4- pyridyl) -2-oxoethyl benzoate except using 1-cyano-1- (4-pyridyl) methyl-4-methoxybenzoate: NMR (faster soluble isomer, CDCl 3 ): S 8.78 (d, 2H); 8.03 (broad d, 2H); 7.73 (d, 2H); 7.53 (dd, 2H); 7.10 (clear t, 2H); 6.93 (overlapping s and d, 3H); 3.85 (s, 3H); 1 H NMR (slower soluble isomer, CDCl 3 ); δ 8.66 (d, 2H); 8.04 (m, 4H); 7.46 (d, 2H); 7.15 (clear t, 2H); 6.95 (overlapping s and d, 3H); 3.87 (s, 3H).

(c) 4-(4-fluorofenil)-2-(4-metoksifenil)-5-(4-piridil)-lH-imidazol(c) 4- (4-fluorophenyl) -2- (4-methoxyphenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini, ki vsebuje zmes l-(4-fluorofenil)-2-(4-piridil)-2-oksoetil 4-metoksibenzoat in 2-(4-fluorofenil)-l-(4-piridil)-2-oksoetil 4-metoksi-benzoat (0,35 g, 0,96 mmol) v ledocetni kislini (7,5 ml) dodamo amonijev acetat (0,35 g, 4,5 mmol). Nastalo zmes segrevamo pri refluksu 18 h, nato pustimo, da se ohladi. Zmes koncentriramo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 33-60 % EtOAc/Heks. Material, ki ga izoliramo, prekristaliziramo iz MeOH/CH2Cl2, da zagotovimo naslovno spojino (65 mg, 20 %) kot sivo belo trdno snov: tal. 264-265 °C.To a solution containing a mixture of 1- (4-fluorophenyl) -2- (4-pyridyl) -2-oxoethyl 4-methoxybenzoate and 2- (4-fluorophenyl) -1- (4-pyridyl) -2-oxoethyl 4- methoxy-benzoate (0.35 g, 0.96 mmol) in glacial acetic acid (7.5 ml) was added ammonium acetate (0.35 g, 4.5 mmol). The resulting mixture was refluxed for 18 h, then allowed to cool. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography eluting with a solubility gradient of 33-60% EtOAc / Hex. The material to be isolated was recrystallized from MeOH / CH 2 Cl 2 to provide the title compound (65 mg, 20%) as a gray-white solid: m.p. 264-265 ° C.

PRIMER 34EXAMPLE 34

2-(4-amino-3-jodofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-amino-3-iodophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini 2-(4-aminofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (50 mg, 0,15 mmol) [glej primer 28 zgoraj] v ledocetni kislini (5 ml) dodamo raztopino JC1 (24 mg, 0,15 mmol) v ledocetni kislini (1,5 ml). Nastalo zmes mešamo na sobni temperaturi 1 uro, nato jo zlijemo v nasičen vodni Na2S2O5. pH naravnamo na nevtralno z dodajanjem 2,5 N NaOH in ekstrahiramo z EtOAc. Organski ekstrakt koncentriramo pod znižanim tlakom in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-10 % MeOH/CHCl3. Material, ki ga izoliramo, prekristaliziramo iz Et2O/Heks, da dobimo naslovno spojino: XH NMR (CDC13): δTo a solution of 2- (4-aminophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (50 mg, 0.15 mmol) [see example 28 above] in glacial acetic acid (5 ml ) was added a solution of JC1 (24 mg, 0.15 mmol) in glacial acetic acid (1.5 ml). The resulting mixture was stirred at room temperature for 1 hour, then poured into saturated aqueous Na 2 S 2 O 5 . The pH was adjusted to neutral by the addition of 2.5 N NaOH and extracted with EtOAc. The organic extract was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with a solubility gradient of 2-10% MeOH / CHCl 3 . The material to be isolated was recrystallized from Et 2 O / Hex to give the title compound: X H NMR (CDCl 3 ): δ

8,42 (d, 2H); 8,18 (d, IH); 7,68 (dd, 2H); 7,42 (m, 4H); 7,09 (t, 2H); 6,77 (d, IH).8.42 (d, 2H); 8.18 (d, 1H); 7.68 (dd, 2H); 7.42 (m, 4H); 7.09 (t, 2H); 6.77 (d, 1H).

PRIMER 35EXAMPLE 35

N-benzil-N-metil-4-[4-(4-fluorofenil-5-(4-piridil)-lH-imidazol-2-il]benzamidN-benzyl-N-methyl-4- [4- (4-fluorophenyl-5- (4-pyridyl) -1H-imidazol-2-yl] benzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 21, razen da uporabimo benzilmetil-aminodimetil aluminij in metil 4-[4-(4fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzoat [glej primer 18 zgoraj]: tal. 233-234 °C.The title compound was prepared using the same procedure as described in Example 21 except that benzylmethyl-aminodimethyl aluminum and methyl 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] was used - benzoate [see example 18 above]: m.p. 233-234 ° C.

PRIMER 36EXAMPLE 36

2-[4-(N-benzil-N-metil)aminometilfenil]-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- [4- (N-Benzyl-N-methyl) aminomethylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 11, razen da uporabimo N-benzil-N-metil-4-[4-(4-fluorofenil)-5-(4-piridil)-lHimidazol-2-il]benzamid [glej primer 35 zgoraj]: ESMS (zn/z): 449 (M++H).The title compound was prepared using the same procedure as described in Example 11 except that N-benzyl-N-methyl-4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1Himidazol-2-yl was used ] benzamide [see Example 35 above]: ESMS (zn / z): 449 (M + + H).

PRIMER 37aEXAMPLE 37a

4-(4-fluorofenil)-N-l-hidroksi-2-(4-metiltiofenil)-5-(4-kinolil)imidazol (a) 4-fluoro-2-(4-kinolil)acetofenon4- (4-fluorophenyl) -N-1-hydroxy-2- (4-methylthiophenyl) -5- (4-quinolyl) imidazole (a) 4-fluoro-2- (4-quinolyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 4-metilkinolin: *H NMR (CDC13): δ 8,87 (d, IH); 8,10 (m, 3H); 7,88 (d, IH); 7,74 (širok t, IH); 7,57 (širok t, IH); 7,20 (m, 3H); 4,73 (s, 2H).The title compound was prepared using the same procedure as described in Example 10, step (b), except that 4-methylquinoline was used: 1 H NMR (CDCl 3 ): δ 8.87 (d, 1H); 8.10 (m, 3H); 7.88 (d, 1H); 7.74 (broad t, 1H); 7.57 (broad t, 1H); 7.20 (m, 3H); 4.73 (s, 2H).

(b) 4-fluoro-2-hidroksiimino-2-(4-kinolil)acetofenon(b) 4-Fluoro-2-hydroxyimino-2- (4-quinolyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 4-fluoro-2-(4-kinolil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c), except that 4-fluoro-2- (4-quinolyl) acetophenone was used.

(c) 4-(4-fluorofenil)-N-l-hidroksi-2-(4-metiltiofenil)-5-(4-kinolil)imidazol(c) 4- (4-fluorophenyl) -N-1-hydroxy-2- (4-methylthiophenyl) -5- (4-quinolyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 4-fluoro-2-hidroksiimino-2-(4-kinolil)acetofenon in 4-(metiltio)benzaldehid: *H NMR (CDC13): δ 8,03 (m, IH); 7,80 (širok d, 2H); 7,52 (d, IH); 7,40-7,10 (m, 5H); 6,81 (širok m, 3H); 6,61 (jasen t, 2H), 2,48 (s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (d), except that 4-fluoro-2-hydroxyimino-2- (4-quinolyl) acetophenone and 4- (methylthio) benzaldehyde were used: * H NMR (CDCl 3 ): δ 8.03 (m, 1H); 7.80 (broad d, 2H); 7.52 (d, 1H); 7.40-7.10 (m, 5H); 6.81 (broad m, 3H); 6.61 (clear t, 2H), 2.48 (s, 3H).

PRIMER 37bEXAMPLE 37b

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-kinolil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-quinolyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo 4-(4-fluorofenil)-N-l-hidroksi-2-(4-metiltiofenil)-5-(4kinolil)imidazol: ESMS (m/z): 412 (M++H).The title compound was prepared using the same procedure as described in Example 1 except that 4- (4-fluorophenyl) -Nl-hydroxy-2- (4-methylthiophenyl) -5- (4quinolyl) imidazole was used: ESMS (m / z ): 412 (M + + H).

PRIMER 38EXAMPLE 38

4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-kinolil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-quinolyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(4-fluoro-fenil)-2-(4-metiltiofenil)-5-(4-kinolil)-lHimidazol: ESMS (m/z): 428 (M++H).The title compound was prepared using the same procedure as described in Example 20 except that 4- (4-fluoro-phenyl) -2- (4-methylthiophenyl) -5- (4-quinolyl) -1Himidazole was used: ESMS (m / a z): 428 (M + + H).

PRIMER 39EXAMPLE 39

4-(3-klorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazol4- (3-chlorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(4-kluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lHimidazol [glej primer 40 spodaj]: ESMS (m/z): 394 (M++H).The title compound was prepared using the same procedure as described in Example 20 except that 4- (4-chlorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1Himidazole was used [see example 40 below]: ESMS (m / z): 394 (M + + H).

PRIMER 40aEXAMPLE 40a

4-(3-klorofenil)-N-l-hidroksi-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol (a) 3-kloro-N-metoksi-N-metilbenzamid4- (3-chlorophenyl) -N-1-hydroxy-2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole (a) 3-chloro-N-methoxy-N-methylbenzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10 (a), razen da uporabimo 3-klorobenzoil klorid: 1H NMR (CDC13): δ 7,69 (širok s, IH); 7,58 (širok d, IH); 7,42 (širok d, IH); 7,31 (dd, IH); 3,55 (s, 3H); 3,34 (s, 3H).The title compound was prepared using the same procedure as described in Example 10 (a) except that 3-chlorobenzoyl chloride was used: 1 H NMR (CDCl 3 ): δ 7.69 (broad s, 1H); 7.58 (broad d, 1H); 7.42 (broad d, 1H); 7.31 (dd, 1H); 3.55 (s, 3H); 3.34 (s, 3H).

(b) 3-kloro-2-(4-piridil)acetofenon(b) 3-chloro-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10 korak (b), razen da uporabimo 4-pikolin in 3-kloro-N-metoksi-N-metilbenzamid: *H NMR (CDC13): δ 8,60 (d, 2H); 8,00 (širok s, IH); 7,60 (širok d, IH); 7,45 (t, IH); 7,21 (d, 2H); 4,27 (s, 2H).The title compound was prepared using the same procedure as described in Example 10 step (b) except that 4-picoline and 3-chloro-N-methoxy-N-methylbenzamide were used: * H NMR (CDCl 3 ): δ 8.60 (d, 2H); 8.00 (broad s, 1H); 7.60 (broad d, 1H); 7.45 (t, 1H); 7.21 (d, 2H); 4.27 (s, 2H).

(c) 3-kloro-2-hidroksiimino-2-(4-piridil)acetofenon(c) 3-chloro-2-hydroxyimino-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 3-kloro-2-(4-piridil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c), except that 3-chloro-2- (4-pyridyl) acetophenone was used.

(d) 4-(3-klorofenil)-N-l-hidroksi-2-(4-metiltiofenil-5-(4-piridil)-lH-imidazol(d) 4- (3-chlorophenyl) -N-1-hydroxy-2- (4-methylthiophenyl-5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 3-kloro-2-hidroksiimino-2-(4-piridil)acetofenon in 4-metiltiobenzaldehid: Ή NMR (CDC13): δ 8,04 (d, 2H); 7,70 (d, 2H); 7,21-6,91 (m, 8H); 2,47 (s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (d), except that 3-chloro-2-hydroxyimino-2- (4-pyridyl) acetophenone and 4-methylthiobenzaldehyde were used: Ή NMR (CDC1 3 ) : δ 8.04 (d, 2H); 7.70 (d, 2H); 7.21-6.91 (m, 8H); 2.47 (s, 3H).

PRIMER 40bEXAMPLE 40b

4-(3-klorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (3-chlorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kotje opisan vprimeru 1, razen da uporabimo 4-(3-klorofenil)-N-l-hidroksi-2-(4-metiltiofenil)-5-(4piridil)imidazol: ESMS (m/z): 378 (M++H).The title compound was prepared using the same procedure as described in example 1 except that 4- (3-chlorophenyl) -N 1 -hydroxy-2- (4-methylthiophenyl) -5- (4pyridyl) imidazole was used: ESMS (m / z): 378 (M + + H).

PRIMER 41EXAMPLE 41

4-(4-fluorofenil-2-(4-formamidometilfenil)-5-(4-piridil)-lH-imidazol4- (4-Fluorophenyl-2- (4-formamidomethylphenyl) -5- (4-pyridyl) -1H-imidazole

Formilno kislino (10 ml) dodamo k acet anhidridu (20 ml) in zmes segrevamo na 50 °C 15 min. Dodamo 2-(4-aminometilfenil)-4-(4-fluorofenil)-5-4-(piridil)imidazol (0,25 g, 0,73 mmol) [glej primer 11] in reakcijsko zmes segrevamo na 50 °C 2h. Topilo uparimo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 4-10 % MeOH/CHCl3. Naslovno spojino izoliramo kot rumeno rjavo trdno snov (0,15 g, 55 %): ESMS (zn/z): 373 (M++H).Formic acid (10 ml) was added to acetal anhydride (20 ml) and the mixture was heated to 50 ° C for 15 min. 2- (4-Aminomethylphenyl) -4- (4-fluorophenyl) -5-4- (pyridyl) imidazole (0.25 g, 0.73 mmol) was added [see Example 11] and the reaction mixture was heated to 50 ° C for 2 h . The solvent was evaporated and the residue purified by flash chromatography eluting with a solubility gradient of 4-10% MeOH / CHCl 3 . The title compound was isolated as a yellow-brown solid (0.15 g, 55%): ESMS (zn / z): 373 (M + + H).

PRIMER 42EXAMPLE 42

4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzohidroksamna kislina4- [4- (4-Fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzohydroxamic acid

K raztopini 0-benzil-4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzohidroksamne kisline (0,10 g, 0,22 mmol) [glej primer 43 spodaj] v etanolu (10 ml) dodamo 10 % paladij na ogljiku. Po mešanju pod atmosfero H218 h, reakcijsko zmes filtriramo preko Celitea in trdne snovi speremo z etanolom. Združene filtrate uparimo in ostanek prekristaliziramo iz 2-propanola, da dobimo naslovno spojino (0,040 g, 50 %): ESMS (m/z): 375 (M++H).To a solution of 0-benzyl-4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzohydroxamic acid (0.10 g, 0.22 mmol) [see Example 43 below] in ethanol (10 ml) was added 10% palladium on carbon. After stirring under an atmosphere of H 2 for 18 h, the reaction mixture was filtered through Celite and the solids were washed with ethanol. The combined filtrates were evaporated and the residue was recrystallized from 2-propanol to give the title compound (0.040 g, 50%): ESMS (m / z): 375 (M + + H).

PRIMER 43EXAMPLE 43

0-benzil-4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzohidroksamna kislina0-Benzyl-4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzohydroxamic acid

K mešani suspenziji )-benzil-hidroksilamin hidroklorida (1,2 g, 7,8 mmol) v toluenu (20 ml) pri 0 °C dodamo trimetilaluminij (2,0 M v toluenu, 3,9 ml, 7,8 mmol). Reakcijsko zmes segrejemo na sobno temperaturo in mešanje nadaljujemo pri tej temperaturi 1 h. Etil 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzoat (1,0 g,To a mixed suspension) of benzyl-hydroxylamine hydrochloride (1.2 g, 7.8 mmol) in toluene (20 ml) at 0 ° C was added trimethylaluminum (2.0 M in toluene, 3.9 ml, 7.8 mmol). . The reaction mixture was warmed to room temperature and stirring was continued at this temperature for 1 h. Ethyl 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzoate (1.0 g,

2,6 mmol) [glej primer 14 zgoraj] dodamo in reakcijsko zmes segrevamo pri refluksu 3 h. Po ohladitvi, reakcijsko zmes zlijemo v 10 % MeOH/CHCl3, ki vsebuje silikagel. Trdne snovi odstranimo s filtracijo in speremo z 10 % MeOH/CHCl3. Združena spirala uparimo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 1-10 % MeOH/CHCl3. Trituracija z etrom da naslovno spojino kot belo trdno snov (0,25 g, 21 %): 1H NMR (CDCl3//MeOH-d4): δ 8,16 (d, 2H); 7,77 (d, 2H); 7,53 (d, 2H); 7,23 (m, 5H); 7,10 (m, 4H); 6,88 (t, 2H).2.6 mmol) [see Example 14 above] was added and the reaction mixture was heated at reflux for 3 h. After cooling, the reaction mixture was poured into 10% MeOH / CHCl 3 containing silica gel. The solids were removed by filtration and washed with 10% MeOH / CHCl 3 . The combined helix was evaporated and the residue purified by flash chromatography eluting with a solubility gradient of 1-10% MeOH / CHCl 3 . Trituration with ether gave the title compound as a white solid (0.25 g, 21%): 1 H NMR (CDCl 3 // MeOH-d 4 ): δ 8.16 (d, 2H); 7.77 (d, 2H); 7.53 (d, 2H); 7.23 (m, 5H); 7.10 (m, 4H); 6.88 (t, 2H).

PRIMER 44EXAMPLE 44

4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzamid oksim4- [4- (4-Fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzamide oxime

K zmesi 2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (3,0 g, 8,7 mmol) [glej primer 1 zgoraj] in K^COg (2,4 g, 17 mmol) v EtOH (120 ml) in H2O (6 ml) dodamo hidroksilamin hidroklorid (1,2 g, 17 mmol). Po segrevanju pri refluksu 24 h reakcijsko zmes zlijemo v H2O. Precipitat ohladimo, speremo z H2O in zračno posušimo. Surovi produkt raztopimo v acetonu, dodamo silikagel in topilo uparimo. Impregnirani silikagel dodamo na vrh flash kolone in kolono eluiramo s topnostnim gradientom 2-10 % MeOH/CHCl3, da dobimo naslovno spojino kot belo trdno snov (3,0 g, 91 %): ESMS (m/z); 374 (M++H).To a mixture of 2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (3.0 g, 8.7 mmol) [see example 1 above] and K ^ COg (2.4 g, 17 mmol) in EtOH (120 ml) and H 2 O (6 ml) was added hydroxylamine hydrochloride (1.2 g, 17 mmol). After heating at reflux for 24 h, the reaction mixture was poured into H 2 O. The precipitate was cooled, washed with H 2 O and air-dried. The crude product was dissolved in acetone, silica gel was added and the solvent was evaporated. Impregnated silica gel was added to the top of the flash column and the column eluted with a solubility gradient of 2-10% MeOH / CHCl 3 to give the title compound as a white solid (3.0 g, 91%): ESMS (m / z); 374 (M + + H).

PRIMER 45EXAMPLE 45

N”-metil-N’-ciano-N-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzilgvanidinN ”-methyl-N'-cyano-N- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzylguanidine

K suspenziji 2-(4-aminometilfenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazola (2,5 g,To a suspension of 2- (4-aminomethylphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (2.5 g,

7,3 mmol) [glej primer 11 zgoraj] v CH3CN (250 ml) dodamo difenil cianokarbonimidat (,8,8 g, 7,3 mmol). Po mešanju na sobni temperaturi 18 h, trdno snov, kije nastala, zberemo s filtracijo in speremo s CH3CN (2,1 g, 59 %). Brez nadaljnjega čiščenja ta material dodamo k metanolu (100 ml), nasičenim z metilaminom. Bučko zamašimo in reakcijsko zmes mešamo 18 h pri sobni temperaturi. Topilo in prebitni metilamin uparimo in ostanek trituriramo z etrom, da dobimo rjavo trdno snov, ki jo nadalje prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 4-10 % MeOH/CHCl3, da dobimo naslovno spojino, kot rumeno rjavo trdno snov (0,33 g, 78 %): CIMS (NHy m/z)·. 426 (M++H).7.3 mmol) [see Example 11 above] in CH 3 CN (250 ml) was added diphenyl cyanocarbonimidate (, 8.8 g, 7.3 mmol). After stirring at room temperature for 18 h, the resulting solid was collected by filtration and washed with CH 3 CN (2.1 g, 59%). This material was added to methanol (100 ml) saturated with methylamine without further purification. The flask was stoppered and the reaction mixture was stirred for 18 h at room temperature. The solvent and excess methylamine were evaporated and the residue triturated with ether to give a brown solid, which was further purified by flash chromatography, eluting with a solubility gradient of 4-10% MeOH / CHCl 3 to give the title compound as a yellow brown solid (0 , 33 g, 78%): CIMS (NH y m / z) ·. 426 (M + + H).

PRIMER 46aEXAMPLE 46a

N-l-hidroksi-4-(3-metoksifenil-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol (a) 3-metoksi-N-metoksi-N-metilbenzamidN-1-hydroxy-4- (3-methoxyphenyl-2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole (a) 3-methoxy-N-methoxy-N-methylbenzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (a), razen da uporabimo m-anizoil klorid: XH NMR (CDC13): δ 7,27 (m, 3H); 7,01 (m, IH); 3,82 (s, 3H); 3,57 (s, 3H); 3,36 (s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (a) except using m-anisoyl chloride: X H NMR (CDCl 3 ): δ 7.27 (m, 3H); 7.01 (m, 1H); 3.82 (s, 3H); 3.57 (s, 3H); 3.36 (s, 3H).

(b) 3-metoksi-2-(4-piridil)acetofenon(b) 3-methoxy-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 3-metoksi-N-metoksi-N-metilbenzamid: ESMS (zn/z): 228,2 (M++H).The title compound was prepared using the same procedure as described in Example 10, step (b), except that 3-methoxy-N-methoxy-N-methylbenzamide was used: ESMS (zn / z): 228.2 (M + + H) ).

(c) 2-hidroksiimino-3-metoksi-2-(4-piridil)acetofenon(c) 2-hydroxyimino-3-methoxy-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 3-metoksi-2-(4-piridil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c) except that 3-methoxy-2- (4-pyridyl) acetophenone was used.

(d) N-l-hidroksi-4-(3-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol(d) N-1-hydroxy-4- (3-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 2-hidroksiimino-3-metoksi-2-(4-piridil)acetofenon in 4-(metiltio)-benzaldehid: ESMS (zzz/z): 390 (M++H).The title compound was prepared using the same procedure as described in Example 10, step (d) except that 2-hydroxyimino-3-methoxy-2- (4-pyridyl) acetophenone and 4- (methylthio) -benzaldehyde were used: ESMS ( zzz / z): 390 (M + + H).

PRIMER 46bEXAMPLE 46b

4-(3-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol4- (3-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo N-l-hidroksi-4-(3-metoksifenil)-2-(4-metiltiofenil)-5-(4piridil)imidazol; tal. 215,0-216,0 °C.The title compound was prepared using the same procedure as described in Example 1 except that N-1-hydroxy-4- (3-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4pyridyl) imidazole was used; m.p. 215.0-216.0 ° C.

PRIMER 47EXAMPLE 47

4-(3-metoksifenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazol4- (3-Methoxyphenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 38, razen da uporabimo 4-(3-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)-lHimidazol [glej primer 46 zgoraj]: tal.: 167-168,5 °C.The title compound was prepared using the same procedure as described in Example 38 except that 4- (3-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1Himidazole was used [see Example 46 above]: mp: 167-168.5 ° C.

PRIMER 48EXAMPLE 48

Morfolino-4-]4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzamidMorpholino-4-] 4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 21, razen da uporabimo dimetilamino(morfolino)aluminijev klorid in etil 4-[4-(4fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzoat [glej primer 14 zgoraj]: ESMS (m/z): 429 (M++H).The title compound was prepared using the same procedure as described in Example 21 except that dimethylamino (morpholino) aluminum chloride and ethyl 4- [4- (4fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl were used ] -Benzoate [see Example 14 above]: ESMS (m / z): 429 (M + + H).

PRIMER 49EXAMPLE 49

4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metiltiofenil)-lH-imidazol4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylthiophenyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da ne uporabimo 4-(4-fluorofenil)-l-hidroksi-5-[4-(2-metilpiridil)]-2-(4metiltiofenil)-imidazol [glej primer 66 spodaj]: ESMS (m/z): 376,2 (M++H).The title compound was prepared using the same procedure as described in Example 13 except that no 4- (4-fluorophenyl) -1-hydroxy-5- [4- (2-methylpyridyl)] - 2- (4methylthiophenyl) -imidazole was used [see example 66 below]: ESMS (m / z): 376.2 (M + + H).

PRIMER 50EXAMPLE 50

4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metilsulfinilfenil)-lH-imidazol4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylsulfinylphenyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(4-fluorofenil)-5-[4-(2-metipiridil)]-2-(4-metiltio- fenil)lH-imidazol [glej primer 49 zgoraj]: ESMS (m/z): 392,2 (M++H).The title compound was prepared using the same procedure as described in Example 20, except that 4- (4-fluorophenyl) -5- [4- (2-methypyridyl)] 2- (4-methylthiophenyl) 1H-imidazole was used [see example 49 above]: ESMS (m / z): 392.2 (M + + H).

PRIMER 51aEXAMPLE 51a

4-(4-fluorofenil)-N-l-hidroksi-5-(4-pirimidinil)-imidazol (a) 4-fluoro-2-(4-pirimidinil)acetofenon4- (4-fluorophenyl) -N-1-hydroxy-5- (4-pyrimidinyl) -imidazole (a) 4-fluoro-2- (4-pyrimidinyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 4-metilpirimidin.The title compound was prepared using the same procedure as described in Example 10, step (b) except that 4-methylpyrimidine was used.

(b) 4-fluoro-2-hidroksiimino-2-(4-pirimidinil)acetofenon(b) 4-fluoro-2-hydroxyimino-2- (4-pyrimidinyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 4-fluoro-2-(4-pirimidinil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c) except that 4-fluoro-2- (4-pyrimidinyl) acetophenone was used.

(c) 4-(4-fluorofenil)-N-l-hidroksi-5-(4-pirimidinil)imidazol(c) 4- (4-fluorophenyl) -N-1-hydroxy-5- (4-pyrimidinyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 4-fluorofenil-2-hidroksiimino-2-(4pirimidinil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (d), except that 4-fluorophenyl-2-hydroxyimino-2- (4pyrimidinyl) acetophenone was used.

PRIMER 51bEXAMPLE 51b

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-pirimidinil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyrimidinyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo 4-(4-fluorofenil)-N-l-hidroksi-5-(4-pirimidinil)imidazol: CIMS (NH3, m/z): 363 (M++H).The title compound was prepared using the same procedure as described in Example 1 except that 4- (4-fluorophenyl) -Nl-hydroxy-5- (4-pyrimidinyl) imidazole was used: CIMS (NH 3 , m / z): 363 (M + + H).

PRIMER 52EXAMPLE 52

4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-pirimidinil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyrimidinyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(4-fluorofenil)-2-(4-metiltio)fenil)-5-(4-pirimidinil)-lHimidazol: CIMS (NH3, m/z); 379 (M++H).The title compound was prepared using the same procedure as described in example 20 except that 4- (4-fluorophenyl) -2- (4-methylthio) phenyl) -5- (4-pyrimidinyl) -1Himidazole was used: CIMS (NH 3 , m / z); 379 (M + + H).

PRIMER 53EXAMPLE 53

4-(4-fluorofenil)-2-(4-metilsulfonilfenil)-5-(4-pirimidinil)-lH-imidazol4- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) -5- (4-pyrimidinyl) -1H-imidazole

K raztopini 4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-pirimidinil)-lH-imidazola (0,10 g, 0,28 mmol) [glej primer 51 zgoraj] dodamo 3-kloroperbenzojsko kislino (50 %, 0,15 g, 0,42 mmol). Po mešanju na sobni temperaturi 72 h, topilo uparimo in ostanek porazdelimo med EtOAc in 2,5 N NaOH. Organsko fazo speremo s slanico, posušimo (MgSO4) in uparimo. Ostanek trituriramo z EtOAc, da dobimo naslovno spojino kot belo trdno snov (0,50 g, 46 %). CIMS (NH3, m/z)·. 395 (M++H).To a solution of 4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyrimidinyl) -1H-imidazole (0.10 g, 0.28 mmol) [see Example 51 above] was added 3-chloroperbenzoic acid (50%, 0.15 g, 0.42 mmol). After stirring at room temperature for 72 h, the solvent was evaporated and the residue partitioned between EtOAc and 2.5 N NaOH. The organic phase was washed with brine, dried (MgSO 4 ) and evaporated. The residue was triturated with EtOAc to give the title compound as a white solid (0.50 g, 46%). CIMS (NH 3 , m / z) ·. 395 (M + + H).

PRIMER 54EXAMPLE 54

4-(4-fluorofenil)-2-(4-morfolinometilfenil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-morpholinomethylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 11, razen da uporabimo morfolino-4-[4-(4-fluorofenil)-5-(4-piridil_lH-imidazol-2il]benzamid: tal. 242-243 °C.The title compound was prepared using the same procedure as described in Example 11 except that morpholino-4- [4- (4-fluorophenyl) -5- (4-pyridyl-1H-imidazol-2yl) benzamide was used: mp 242-243 ° C.

PRIMER 55EXAMPLE 55

4-(4-fluorofenil)-2-(4-hidroksimetil)-5-(4-piridil)-lH-imidazol4- (4-fluorophenyl) -2- (4-hydroxymethyl) -5- (4-pyridyl) -1H-imidazole

K suspenziji etil 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzoata (1,0 g,To a suspension of ethyl 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzoate (1.0 g,

2,6 mmol) [glej primer 14 zgoraj] v THF (25 ml) dodamo LiAlH4 (IM v THF, 7,8 ml, 7,8 mmol). Po mešanju na sobni temperaturi 0,5 h, reakcijsko zmes zlijemo v 2,5 N NaOH in ekstrahiramo trikrat z 2:1 EtOAc/CH2Cl2. Združene ekstrakte speremo s lanico, posušimo (MgSO4) in uparimo, da dobimo naslovno spojino kot belo trdno snov (0,50 g, 54 %).2.6 mmol) [see Example 14 above] in THF (25 ml) was added LiAlH 4 (IM in THF, 7.8 ml, 7.8 mmol). After stirring at room temperature for 0.5 h, the reaction mixture was poured into 2.5 N NaOH and extracted three times with 2: 1 EtOAc / CH 2 Cl 2 . The combined extracts were washed with flax, dried (MgSO 4 ) and evaporated to give the title compound as a white solid (0.50 g, 54%).

SlFIG

PRIMER 56EXAMPLE 56

4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-benzaldehid4- [4- (4-Fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -benzaldehyde

K suspenziji 4-(4-fluorofenil)-2-(4-hidroksimetil)-5-(4-piridil)-lH-imidazola (0,40 g, 1,2 mmol) [glej primer 55 zgoraj] v CH2C12 (40 ml) dodamo piridinijev klorokromat (0,30 g, 1,4 mmol) pri sobni temperaturi. Reakcijsko zmes mešamo pri tej temperaturi 2 h, filtriramo skozi blazinico silikagela, eluiramo z 2 % MeOH/CHCl3 in filtrat uparimo. Ostanek prečistimo s flash kromatografijo, eluiramo s 4 % MeOH/CHCl3, sledi prekristaizacija iz CH2Cl2/MeOH, da dobimo naslovno spojino kot belo trdno snov (0,30 g, 7,3 %).To a suspension of 4- (4-fluorophenyl) -2- (4-hydroxymethyl) -5- (4-pyridyl) -1H-imidazole (0.40 g, 1.2 mmol) [see Example 55 above] in CH 2 C1 Pyridinium chlorochromate (0.30 g, 1.4 mmol) at room temperature was added to 2 (40 ml). The reaction mixture was stirred at this temperature for 2 h, filtered through a pad of silica gel, eluted with 2% MeOH / CHCl 3 and the filtrate evaporated. The residue was purified by flash chromatography, eluting with 4% MeOH / CHCl 3 followed by recrystallization from CH 2 Cl 2 / MeOH to give the title compound as a white solid (0.30 g, 7.3%).

PRIMER 57EXAMPLE 57

4-(2-metoksifenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazol4- (2-Methoxyphenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(2-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)-lHimidazol [glej primer 58 spodaj]: CIMS (NH3, m/z): 390 (M++H).The title compound was prepared using the same procedure as described in Example 20 except that 4- (2-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1Himidazole was used [see example 58 below]: CIMS (NH 3 , m / z): 390 (M + + H).

PRIMER 58aEXAMPLE 58a

N-l-hidroksi-4-(2-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol (a) 2-metoksi-N-metoksi-N-metilbenzamidN-1-hydroxy-4- (2-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole (a) 2-methoxy-N-methoxy-N-methylbenzamide

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (a), razen da uporabimo 0-anizoil klorid: NMR (CDC13): δ 7,36 (m, 3H); 6,98 (dd, IH); 3,84 (s, 3H); 3,56 (širok s, 3H); 3,32 (širok s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (a) except using 0-anisoyl chloride: NMR (CDCl 3 ): δ 7.36 (m, 3H); 6.98 (dd, 1H); 3.84 (s, 3H); 3.56 (broad s, 3H); 3.32 (broad s, 3H).

(b) 2-metoksi-2-(4-piridil)acetofenon(b) 2-methoxy-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 2-metoksi-N-metoksi-N-metilbenzamid.The title compound was prepared using the same procedure as described in Example 10, step (b), except that 2-methoxy-N-methoxy-N-methylbenzamide was used.

(c) 2-hidroksiimino-2-metoksi-2-(4-piridil)acetofenon(c) 2-hydroxyimino-2-methoxy-2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 2-metoksi-2-(4-piridil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c), except that 2-methoxy-2- (4-pyridyl) acetophenone was used.

(d) N-l-hidroksi-4-(2-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazol(d) N-1-hydroxy-4- (2-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 2-hidroksiimino-2-metoksi-2-(4-piridil)acetofenon in 4-(metiltio)benzaldehid: ESMS (m/z)·. 390,0 (M++H).The title compound was prepared using the same procedure as described in Example 10, step (d) except that 2-hydroxyimino-2-methoxy-2- (4-pyridyl) acetophenone and 4- (methylthio) benzaldehyde were used: ESMS (m / z) ·. 390.0 (M + + H).

PRIMER 58bEXAMPLE 58b

4-(2-metoksifenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (2-Methoxyphenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo N-l-hidroksi-4-(2-metoksifenil)-2-(4-metiltiofenil)-5-(4piridil)imidazol: CIMS (NHy m/z)·. 374,2 (M++H).The title compound was prepared using the same procedure as described in Example 1 except that N1-hydroxy-4- (2-methoxyphenyl) -2- (4-methylthiophenyl) -5- (4pyridyl) imidazole was used: CIMS (NH y m / z) ·. 374.2 (M + + H).

PRIMER 59EXAMPLE 59

3-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]fenil-5-metil-4,5-dihidro-l,2,4-oksadiazol3- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] phenyl-5-methyl-4,5-dihydro-1,2,4-oxadiazole

Raztopino 4-[4-(4-fluorofenil)-5-(4-piridil-lH-imidazol-2-il]benzamid oksima (0,50 g, 1,3 mmol) [glej primer 44 zgoraj] in acetaldehida (25 ml) v etanolu (100 ml) in H2O (100 ml) mešamo pri sobni temperaturi sedem dni. Topilo uparimo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4 % CHCl3MeOH. Prekristalizacija iz EtOAc da naslovno spojino kot rumeno trdno snov (0,11 g, 21 %): CIMS (NH3, m/z)·. 400 (M++H).A solution of 4- [4- (4-fluorophenyl) -5- (4-pyridyl-1H-imidazol-2-yl] benzamide oxime (0.50 g, 1.3 mmol) [see example 44 above] and acetaldehyde (25 ml) in ethanol (100 ml) and H 2 O (100 ml) was stirred at room temperature for seven days, the solvent was evaporated and the residue was purified by flash chromatography, eluting with a solubility gradient of 2-4% CHCl 3 MeOH Recrystallization from EtOAc to give the title compound as a yellow solid (0.11 g, 21%): CIMS (NH 3 , m / z) · .400 (M + + H).

PRIMER 60EXAMPLE 60

3-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]fenil-5-metil-l,2,4-oksadiazol3- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] phenyl-5-methyl-1,2,4-oxadiazole

K raztopini 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzamid oksima (0,10 g, 0,27 mmol) [glej primer 44 zgoraj] v piridinu (10 ml) dodamo acet anhidrid (1,0 ml) pri sobni temperaturi. Po mešanju na tej temperaturi 18 h, reakcijsko zmes zlijemo v H2O in precipitat zberemo, speremo s H2O in posušimo in vacuo. Brez nadaljnjega čiščenja surovi o-acilamid oksim raztopimo v ocetni kislini (5 ml) in segrevamo pri refluksu 3h. Topilo uparimo, dodamo H2O in zmes nevtraliziramo z vodnim NaHCO3. Precitipitat zberemo, speremo s H2O, zračno posušimo in prečistimo s flash kromatografijo, eluiramo s 4 % MeOH/CHCl3. Trituracija z etrom da naslovno spojino kot belo trdno snov (0,030 g, 28 %): CIMS (NH3, m/z): 398 (M++H).To a solution of 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzamide oxime (0.10 g, 0.27 mmol) [see example 44 above] in pyridine (10 ml) was added acetyl anhydride (1.0 ml) at room temperature. After stirring at this temperature for 18 h, the reaction mixture was poured into H 2 O and the precipitate was collected, washed with H 2 O and dried in vacuo. Without further purification, the crude o-acylamide oxime was dissolved in acetic acid (5 ml) and refluxed for 3h. The solvent was evaporated, H 2 O was added and the mixture was neutralized with aqueous NaHCO 3 . The precipitate was collected, washed with H 2 O, air-dried and purified by flash chromatography, eluting with 4% MeOH / CHCl 3 . Trituration with ether gave the title compound as a white solid (0.030 g, 28%): CIMS (NH 3 , m / z): 398 (M + + H).

PRIMER 61EXAMPLE 61

4-(3-aminofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (3-aminophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Raztopino 0,161 g (0,41 mmol) 2-(4-metiltiofenil)-4-(3-nitrofenil)-5-(4-piridil)-lHimidazola [glej primer 62 spodaj] v 3,4 ml HOAc-H2O (1:1) obdelamo z 1,81 ml (2,87 mmol) 20 %-nega vodnega titanijevega(III) klorida v enem samem dodatku. Zmes mešamo na sobni temperaturi 20 min., nato jo naalkalimo s 10 %-nim NaOH. Vodno zmes ekstrahiramo s 95:5 Ch2Cl2/MeOH. Organske ekstrakte speremo s H2O in nasičenim NaCl. Uparjevanje topila in vacuo da rumeno trdno snov, ki jo filtriramo skozi zamašek silikagela, eluiramo s 90:10 Ch2Cl/MeOH. Naslovno spojino izoliramo kot bledo rumeno trdno snov (0,129 g, 78 %): CIMS (NH3, m/z): 359,1 (M++H).A solution of 0.161 g (0.41 mmol) of 2- (4-methylthiophenyl) -4- (3-nitrophenyl) -5- (4-pyridyl) -1Himidazole [see example 62 below] in 3.4 ml of HOAc-H 2 O (1: 1) is treated with 1.81 ml (2.87 mmol) of 20% aqueous titanium (III) chloride in a single additive. The mixture was stirred at room temperature for 20 min, then basified with 10% NaOH. The aqueous mixture was extracted with 95: 5 Ch 2 Cl 2 / MeOH. The organic extracts were washed with H 2 O and saturated NaCl. Evaporation of the solvent in vacuo gave a yellow solid which was filtered through a silica gel plug eluting with 90:10 Ch 2 Cl / MeOH. The title compound was isolated as a pale yellow solid (0.129 g, 78%): CIMS (NH 3 , m / z): 359.1 (M ++ H).

PRIMER 62aEXAMPLE 62a

N-l-hidroksi-2-(4-metiltiofenil)-4-(3-nitrofenil-5-(4-piridil)imidazol (a) l-(3-nitrofenil)-2-(4-piridil)etanolN-1-hydroxy-2- (4-methylthiophenyl) -4- (3-nitrophenyl-5- (4-pyridyl) imidazole (a) 1- (3-nitrophenyl) -2- (4-pyridyl) ethanol

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 3-nitrobenzaldehid: 1H NMR (CDC13): δ 8,41 (d, 2H); 8,23 (s, IH); 8,15 (d, IH); 7,67 (d, IH); 7,54 (t, IH); 7,19 (d, 2H); 5,05 (t, IH); 4,41 (s, 2H).The title compound was prepared using the same procedure as described in Example 10, step (b) except that 3-nitrobenzaldehyde was used: 1 H NMR (CDCl 3 ): δ 8.41 (d, 2H); 8.23 (s, 1H); 8.15 (d, 1H); 7.67 (d, 1H); 7.54 (t, 1H); 7.19 (d, 2H); 5.05 (t, 1H); 4.41 (s, 2H).

(b) l-(3-nitrofenil)-2-(4-piridil)acetofenon(b) 1- (3-nitrophenyl) -2- (4-pyridyl) acetophenone

K raztopini 1,0 ml (14,3 mmol) DMSO v 55 ml suhega CH2C12 dodamo 1,82 ml (12,9 mmol) trifluoro ocetnega anhidrida pri -78 °C. Zmes mešamo 30 min., nato po kapljicah dodamo raztopino l-(3-nitrofenil)-2-(4-piridil)etanola (1,09 g, 4,46 mmol) v DMSO/CH2C12 (3/11 ml). Zmes mešamo pri -78 °C 2 h, nato po kapljicah dodamo 4,1 ml (29,4 mmol) trietilamina. Ledeno kopel odstranimo in zmes segrejemo na sobno temperaturo. Zmes zlijemo v nasičen NH4C1 in ekstrahiramo s CH2C12. Organske ekstrakte speremo z nasičenim NH4C1 in nasičenim NaCI, nato posušimo preko MgSO4. Odstranitev topila in vacuo, da rdeče olje, ki ga prečistimo s flash kromatografijo, eluiramo z gradientom 0-3 % MeOH/CHCl3. Naslovno spojino izoliramo kot oranžno olje (0,65 g, 60 %): *H NMR (CDC13): δ 8,83 (s, IH); 8,60 (d, 2H); 8,46 (d, IH); 8,32 (d, IH); 7,72 (t, IH); 7,23 (d, 2H); 4,38 (s, 2H).To a solution of 1.0 ml (14.3 mmol) of DMSO in 55 ml of dry CH 2 Cl 2 was added 1.82 ml (12.9 mmol) of trifluoro acetic anhydride at -78 ° C. The mixture was stirred for 30 min, then a solution of 1- (3-nitrophenyl) -2- (4-pyridyl) ethanol (1.09 g, 4.46 mmol) in DMSO / CH 2 C1 2 (3/11 ml) was added dropwise. ). The mixture was stirred at -78 ° C for 2 h, then 4.1 ml (29.4 mmol) of triethylamine were added dropwise. The ice bath was removed and the mixture warmed to room temperature. The mixture was poured into saturated NH 4 Cl and extracted with CH 2 Cl 2 . The organic extracts were washed with saturated NH 4 Cl and saturated NaCl, then dried over MgSO 4 . Removal of solvent in vacuo to elute the red oil, which was purified by flash chromatography, with a gradient of 0-3% MeOH / CHCl 3 . The title compound was isolated as an orange oil (0.65 g, 60%): 1 H NMR (CDCl 3 ): δ 8.83 (s, 1H); 8.60 (d, 2H); 8.46 (d, 1H); 8.32 (d, 1H); 7.72 (t, 1H); 7.23 (d, 2H); 4.38 (s, 2H).

(c) 2-hidroksiimino-l-(3-nitrofenil)-2-(4-piridil)acetofenon(c) 2-hydroxyimino-1- (3-nitrophenyl) -2- (4-pyridyl) acetophenone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo l-(3-nitrofenil)-2-(4-piridil)acetofenon.The title compound was prepared using the same procedure as described in Example 10, step (c), except that 1- (3-nitrophenyl) -2- (4-pyridyl) acetophenone was used.

(d) N-l-hidroksi-2-(4-metiltiofenil)-4-(3-nitrofenil)-5-(4-piridil)imidazol(d) N-1-hydroxy-2- (4-methylthiophenyl) -4- (3-nitrophenyl) -5- (4-pyridyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 2-hidroksiimino-l-(3-nitrofenil)-2-(4piridil)acetofenon in 4-(metiltio)benzaldehid: JH NMR (CDCl3/MeOH-D4): δ 8,55 (d, 2H); 8,43 (m, IH); 8,15 (dd, IH); 8,06 (d, 2H(; 7,78 (d, IH); 7,51 (m, IH); 7,45 (d, 2H); 7,32 (m, 2H); 2,57 (s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (d) except that 2-hydroxyimino-1- (3-nitrophenyl) -2- (4pyridyl) acetophenone and 4- (methylthio) benzaldehyde were used: J H NMR (CDCl3 / MeOH-d 4): δ 8.55 (d, 2H); 8.43 (m, 1H); 8.15 (dd, 1H); 8.06 (d, 2H (; 7.78 (d, 1H); 7.51 (m, 1H); 7.45 (d, 2H); 7.32 (m, 2H); 2.57 (s , 3H).

PRIMER 62bEXAMPLE 62b

2-(4-metiltiofenil)-4-(3-nitrofenil)-5-(4-piridil)-lH-imidazol2- (4-methylthiophenyl) -4- (3-nitrophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 1, razen da uporabimo N-l-hidroksi-2-(4-metiltiofenil)-4-(3-nitrofenil)-5-(4piridil)imidazol: CIMS (NH3, m/z); 389,1 (M++H).The title compound was prepared using the same procedure as described in Example 1 except that N1-hydroxy-2- (4-methylthiophenyl) -4- (3-nitrophenyl) -5- (4pyridyl) imidazole was used: CIMS (NH 3 , m / z); 389.1 (M + + H).

PRIMER 63EXAMPLE 63

4-(3-metansulfonamidofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (3-Methanesulfonamidophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 29, razen da uporabimo 4-(3-aminofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol [glej primer 61 zgoraj]: ESMS (ra/z): 437,0 (M++H).The title compound was prepared using the same procedure as described in Example 29 except that 4- (3-aminophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole was used [see example 61 above ]: ESMS (ra / z): 437.0 (M + + H).

PRIMER 64EXAMPLE 64

3-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]fenil-l,2,4-oksadiazol-5(4H).on3- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] phenyl-1,2,4-oxadiazol-5 (4H).

K zmesi 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzamid oksima (0,25 g, 0,67 mmol) [glej primer 44 zgoraj v CH2C12 (5,0 ml in Et3N (0,19 ml, 1,3 mmol) dodamo etil kloroformat (0,076 ml, 0.80 mmol na sobni temperaturi. Po 0,5 h na tej temperaturi reakcijsko zmes zlijemo v H2O, jo štirikrat ekstrahiramo s CH2C12 in enkrat z 10 % MeOH/CH2Cl2. Organske ekstrakte združimo in uparimo. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-4 % MeOH/CHCl3. Trituracija z etrom da belo trdno snov (0,22 g, 73 %). Del te spojine (0,10 g, 0,22 mmol) raztopimo v HOAc (2,5 ml) in segrevamo pri refluksu 18 h. Reakcijsko zmes zlijemo v H2O, nevtraliziramo s kocentriranim NH4OH, ekstrahiramo z EtOAc in uparimo. Ostanek trituriramo z majhno količino hladnega EtOAc, da dobimo naslovno spojino kot rumeno trdno snov (0,020 g, 23 %): CIMS (NH3 zn/z): 400 (M++H).To a mixture of 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzamide oxime (0.25 g, 0.67 mmol) [see example 44 above in CH 2 C1 2 (5.0 ml and Et 3 N (0.19 ml, 1.3 mmol) was added ethyl chloroformate (0.076 ml, 0.80 mmol at room temperature). After 0.5 h at this temperature, the reaction mixture was poured into H 2 O , extracted four times with CH 2 C1 2 and once with 10% MeOH / CH 2 Cl 2. The organic extracts were combined and evaporated The residue was purified by flash chromatography eluting with a solubility gradient of 2-4% MeOH / CHCl 3 . a white solid (0.22 g, 73%). A portion of this compound (0.10 g, 0.22 mmol) was dissolved in HOAc (2.5 ml) and refluxed for 18 h. The reaction mixture was poured into H 2 O. , neutralized with concentrated NH 4 OH, extracted with EtOAc and evaporated The residue was triturated with a small amount of cold EtOAc to give the title compound as a yellow solid (0.020 g, 23%): CIMS (NH 3 zn / z): 400 (M + + H).

PRIMER 65EXAMPLE 65

4-(3-acetamidofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol4- (3-acetamidophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 6, razen da uporabimo 4-(3-aminofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol [glej primer 61 zgoraj]: ESMS (m/z): 401 (M++H).The title compound was prepared using the same procedure as described in Example 6 except that 4- (3-aminophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole was used [see example 61 above ]: ESMS (m / z): 401 (M + + H).

PRIMER 66EXAMPLE 66

4-(4-fluorofenil)-l-N-hidroksi-5-[4-(2-metilpiridil)]-2-(4-metiltiofenil)imidazol (a) 2-metil izonikotinska kislina4- (4-Fluorophenyl) -1-N-hydroxy-5- [4- (2-methylpyridyl)] - 2- (4-methylthiophenyl) imidazole (a) 2-methyl isonicotinic acid

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v Liebigs Ann. Chem., 1958, 613,153: ESMS (miz)·. 138,0 (M++H).The title compound is prepared using the same procedure as described in Liebigs Ann. Chem., 1958, 613,153: ESMS (mass) ·. 138.0 (M + + H).

(b) Metil 2-metilizonikotinat(b) Methyl 2-methylisonicotinate

K ledeno ohlajeni suspenziji 1,32 g (9,62 mmol) 2-metilizonikotinske kisline v 20 ml MeOH dodamo 1,47 ml (20,2 mmol) tionil klorida. Ledeno kopel odstranimo in reakcijsko zmes mešamo na sobni temperaturi. Po 22 h, uparimo MeOH in ostanek prenesemo v H2O. Vodno zmes nevtraliziramo z nasičenim NaHCO3, nato ekstrahiramo s Et2O. Organske ekstrakte speremo z nasičenim NaCl, posušimo preko MgSO4, nato filtriramo preko sloja Celitea. Uparevanje topila in vacuo da naslovno spojino kot rumeno tekočino (0,89 g, 61 %): 1H NMR (CDC13): δ 8,66 (d, IH);To an ice-cooled suspension of 1.32 g (9.62 mmol) of 2-methylisonicotinic acid in 20 ml of MeOH was added 1.47 ml (20.2 mmol) of thionyl chloride. The ice bath was removed and the reaction mixture was stirred at room temperature. After 22 h, the MeOH was evaporated and the residue was taken up in H 2 O. The aqueous mixture was neutralized with saturated NaHCO 3 , then extracted with Et 2 O. The organic extracts were washed with saturated NaCl, dried over MgSO 4 , then filtered through a pad of Celite. Evaporation of the solvent in vacuo gave the title compound as a yellow liquid (0.89 g, 61%): 1 H NMR (CDCl 3 ): δ 8.66 (d, 1H);

7,72 (s, IH); 7,64 (d, IH); 3,98 (s, 3H); 2,64 (s, 3H).7.72 (s, 1H); 7.64 (d, 1H); 3.98 (s, 3H); 2.64 (s, 3H).

(c) Metil 4-fluorofenilacetat(c) Methyl 4-fluorophenyl acetate

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 66, korak (b), razen da uporabimo 4-fluorofenilocetno kislino: *H NMR (CDC13): δThe title compound was prepared using the same procedure as described in Example 66, step (b), except that 4-fluorophenylacetic acid was used: * H NMR (CDC1 3 ): δ

7,25 (dd, 2H); 7,02 (t, 2H); 3,71 (s, 3H); 3,61 (s, 2H).7.25 (dd, 2H); 7.02 (t, 2H); 3.71 (s, 3H); 3.61 (s, 2H).

(d) 2-(4-fluorofenil)-l-[2-metil-(4-piridil)]etanon(d) 2- (4-fluorophenyl) -1- [2-methyl- (4-pyridyl)] ethanone

K sveže pripravljeni raztopini NaOMe (3,0 M v MeOH) dodamo raztopino metil 2-metilizonikotinata (6,81 g, 45,1 mmol) v MeOH (10 ml). Temu sledi dodajanje po kapljicah raztopine metil 4-fluorofenilacetata (8,34 g, 49,6 mmol) v MeOH (10 ml). MeOH oddestiliramo medtem ko reakcijsko zmes grejemo na 95 °C. Po 17,5 h trdni ostanek ohladimo. Dodamo koncentrirano HC1 (15 ml) in zmes segrevamo pri refluksu. Po 4 h zmes ohladimo, nato razredčimo z H2O. Vodno zmes speremo z Et2O, naravnamo pH na 5 z IN NaOH, nato naravnamo pH na 8 z nasičenim NaHCO3. Alkalno vodno zmes ekstrahiramo z EtOAc. EtOAc ekstrakte speremo z nasičenim NaCl, nato posušimo preko Na2SO4. Uparevanje topila in vacuo da rdeče olje, ki ga prečistimo s kolonsko kromatografijo, eluiramo z gradientom 0-3 % MeOH/CHCl3. Naslovno spojino izoliramo kot rdeče olje (1,5 g, 15 %).To a freshly prepared NaOMe solution (3.0 M in MeOH) was added a solution of methyl 2-methylisonicotinate (6.81 g, 45.1 mmol) in MeOH (10 ml). This was followed by the dropwise addition of a solution of methyl 4-fluorophenyl acetate (8.34 g, 49.6 mmol) in MeOH (10 ml). The MeOH was distilled off while the reaction mixture was heated to 95 ° C. After 17.5 h, the solid residue was cooled. Concentrated HCl (15 ml) was added and the mixture was heated at reflux. After 4 h, the mixture was cooled, then diluted with H 2 O. The aqueous mixture was washed with Et 2 O, pH adjusted to 5 with IN NaOH, then adjusted to pH 8 with saturated NaHCO 3 . The alkaline aqueous mixture was extracted with EtOAc. The EtOAc extracts were washed with saturated NaCl, then dried over Na 2 SO 4 . Evaporation of the solvent in vacuo gave the red oil, which was purified by column chromatography, eluted with a gradient of 0-3% MeOH / CHCl 3 . The title compound was isolated as a red oil (1.5 g, 15%).

(e) 2-(4-fluorofenil)-2-hidroksiimino-l-[2-metil-(4-piridil)etanon(e) 2- (4-fluorophenyl) -2-hydroxyimino-1- [2-methyl- (4-pyridyl) ethanone

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (c), razen da uporabimo 2-(4-fluorofenil)-l-[2-metil-(4-piridil)etanon: ESMS (miz): 259 (M++H).The title compound was prepared using the same procedure as described in Example 10, step (c), except using 2- (4-fluorophenyl) -1- [2-methyl- (4-pyridyl) ethanone: ESMS (mass): 259 (M + + H).

(f) 4-(4-fluorofenil)-l-hidroksi-5-[4-(2-metilpiridil)]-2-(4-metiltiofenil)imidazol(f) 4- (4-fluorophenyl) -1-hydroxy-5- [4- (2-methylpyridyl)] - 2- (4-methylthiophenyl) imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (d), razen da uporabimo 2-(4-fluorofenil)-2-hidroksiimino-l-[2-metil-(4piridil)]etanon in 4-(metiltio)benzaldehid: ESMS (m/z): 392 (M++H).The title compound was prepared using the same procedure as described in Example 10, step (d), except that 2- (4-fluorophenyl) -2-hydroxyimino-1- [2-methyl- (4pyridyl)] ethanone and 4- (methylthio) benzaldehyde: ESMS (m / z): 392 (M + + H).

PRIMER 67EXAMPLE 67

3- [4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]-fenil-5,5-dimetil-4,5-dihidro-l,2,4- oksadiazol3- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] -phenyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazole

K raztopini 4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzamid oksima (0,25 g, 0,67 mmol) [glej primer 44 zgoraj] v acetonu (10 ml) dodamo piridinijev trifluoroacetat (0,39 g, 2,0 mmol). Po segrevanju pri refluksu 18 h, reakcijsko zmes zlijemo v nasičen vodni NaHCO3, ekstrahiramo s EtOAc in organsko fazo uparimo. Ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 2-10 % MeOH/CHCl3, da dobimo naslovno spojino kot belo trdno snov (0,12 g, 43 %):To a solution of 4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzamide oxime (0.25 g, 0.67 mmol) [see example 44 above] in acetone (10 ml) was added pyridinium trifluoroacetate (0.39 g, 2.0 mmol). After refluxing for 18 h, the reaction mixture was poured into saturated aqueous NaHCO 3 , extracted with EtOAc and the organic phase evaporated. The residue was purified by flash chromatography, eluting with a solubility gradient of 2-10% MeOH / CHCl 3 to give the title compound as a white solid (0.12 g, 43%):

CIMS (NH3, m/z): 414 (M++H).CIMS (NH 3 , m / z): 414 (M + + H).

PRIMER 68EXAMPLE 68

N-hidroksi-N-l-[4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]fenil]etil]urea (a) a-metil-4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]benzil alkoholN-hydroxy-N1- [4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] phenyl] ethyl] urea (a) a-methyl-4- [4 - (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] benzyl alcohol

K zmesi 2-(4-cianofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazoIa (1,0 g, 2,9 mmol) [glej primer 1 zgoraj] dodamo MeMgBr (3 M v Et2O, 4,0 ml, 12 mmol) pri sobni temperaturi. Reakcijsko zmes segrevamo pri refluksu 1 h, zlijemo v nasičen vodni NH4C1, ekstrahiramo s THF in organsko fazo uparimo. Ostanek raztopimo v MeOH (20 ml) in dodamo NaBH4 (1,0 g, 26 mmol). Po 0,5 h na sobni temperaturi, topilo uparimo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 1-10 % MeOH/CHCl3, da dobimo naslovno spojino kot belo trdno snov (0,26 g, 25 %): Ή NRM (CDCl3/MeOH-D4): δ 8,37 (d, 2H); 7,79 (d, 2H); 7,4-7,2 (m, 6H); 6,99 (t, 3H); 4,76 (k, IH); 1,35 (d, 3H).To the mixture of 2- (4-cyanophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (1.0 g, 2.9 mmol) [see example 1 above] was added MeMgBr (3 M in Et 2 O, 4.0 mL, 12 mmol) at room temperature. The reaction mixture was heated at reflux for 1 h, poured into saturated aqueous NH 4 Cl, extracted with THF and the organic phase evaporated. The residue was dissolved in MeOH (20 ml) and NaBH 4 (1.0 g, 26 mmol) was added. After 0.5 h at room temperature, the solvent was evaporated and the residue purified by flash chromatography, eluting with a solubility gradient of 1-10% MeOH / CHCl 3 to give the title compound as a white solid (0.26 g, 25%): Ή NRM (CDCl 3 / MeOH-D 4 ): δ 8.37 (d, 2H); 7.79 (d, 2H); 7.4-7.2 (m, 6H); 6.99 (t, 3H); 4.76 (k, 1H); 1.35 (d, 3H).

(b) N-hidroksi-N-[l-[4-[4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol-2-il]fenil]etil]urea(b) N-hydroxy-N- [1- [4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazol-2-yl] phenyl] ethyl] urea

K zmesi a-metil-4-[4-(4-fluorofenil)-5-(4-piridil)imidazol-2-il]benzil akohola (0,25 g, 0,70 mmol), P(Ph)3 (0,46 g, 1,75 mmol) in N,O-bis(benziloksikarbonil)hidroksilamina (0,48 g, 1,75 mmol) v THF (15 ml) dodamo DEAD (0,28 ml, 1,75 mmol) pri sobni temperaturi. Reakcijsko zmes mešamo pri tej temperaturi 3 h in topilo uparimo. Ostanek delno prečistimo s flash kromatografijo, eluiramo z 1 % MeOH/CHCl3. K temu materialu dodamo metanol (25 ml) in zmes ohladimo na -78 °C. Pri tej temperaturi vpihujemo v mehurčkih amoniak 15 min. Reakcijsko zmes počasi segrejemo na sobno temperaturo, zamašimo in mešamo na sobni temperaturi 2 dni. Topilo uparimo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 1-10 % MeOH/CHCl3. Dobimo naslovno spojino kot sivo belo trdno snov (),43 g, 14 %): FABMS (m/z): 418 (M++H).To a mixture of? -Methyl-4- [4- (4-fluorophenyl) -5- (4-pyridyl) imidazol-2-yl] benzyl ether (0.25 g, 0.70 mmol), P (Ph) 3 ( 0.46 g, 1.75 mmol) and N, O-bis (benzyloxycarbonyl) hydroxylamine (0.48 g, 1.75 mmol) in THF (15 ml) were added DEAD (0.28 ml, 1.75 mmol) at room temperature. The reaction mixture was stirred at this temperature for 3 h and the solvent was evaporated. The residue was partially purified by flash chromatography eluting with 1% MeOH / CHCl 3 . Methanol (25 ml) was added to this material and the mixture was cooled to -78 ° C. At this temperature, the ammonia was bubbled for 15 min. The reaction mixture was slowly warmed to room temperature, capped and stirred at room temperature for 2 days. The solvent was evaporated and the residue purified by flash chromatography eluting with a solubility gradient of 1-10% MeOH / CHCl 3 . Obtained the title compound as a gray-white solid (), 43 g, 14%): FABMS (m / z): 418 (M + + H).

PRIMER 69EXAMPLE 69

N-hidroksi-N-[4-[4-(4-fluorofenil)-5-(4-piridil)-lH-irnidazol-2-il]fenil]metil ureaN-hydroxy-N- [4- [4- (4-fluorophenyl) -5- (4-pyridyl) -1H-iridazol-2-yl] phenyl] methyl urea

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 68, razen da uporabimo 4-(4-fluorofenil)-2-(4-hidroksimetil)-5-(4-piridil)-lHimidazol: FABMS (m/z)·. 418 (M++H).The title compound was prepared using the same procedure as described in Example 68 except that 4- (4-fluorophenyl) -2- (4-hydroxymethyl) -5- (4-pyridyl) -1Himidazole was used: FABMS (m / z) ·. 418 (M + + H).

PRIMER 70EXAMPLE 70

4-(3-metiltiofenil)-2-(4-morfolinometilfenil)-5-(4-piridil)-lH-imidazol (a) 3-metiltiobenzaldehid4- (3-methylthiophenyl) -2- (4-morpholinomethylphenyl) -5- (4-pyridyl) -1H-imidazole (a) 3-methylthiobenzaldehyde

Naslovno spojino pripravimo z uporabo enakega postopka, kot ga je opisal Campbell, J.R. v J. Org Chem., 1962, 27,2207: Ή NMR (CDC13); δ 9,95 (s, IH); 7,72 (s, IH); 7,61 (d, IH); 7,45 (m, 2H); 2,53 (s, 3H).The title compound was prepared using the same procedure as described by Campbell, JR, J. Org Chem. 1962, 27.2207: Ή NMR (CDC1 3); δ 9.95 (s, 1H); 7.72 (s, 1H); 7.61 (d, 1H); 7.45 (m, 2H); 2.53 (s, 3H).

(b) l-(3-metiltiofenil)-2-(4-piridil)etanol(b) 1- (3-methylthiophenyl) -2- (4-pyridyl) ethanol

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 10, korak (b), razen da uporabimo 3-(metiltio)benzaldehid: 1 H NMR (CDC13): δ 8,33 (d, 2H); 7,0-7,5 (m, 6H); 4,87 (m, IH); 2,96 (m, 2H); 2,45 (s, 3H).The title compound was prepared using the same procedure as described in Example 10, step (b), except that 3- (methylthio) benzaldehyde was used: 1 H NMR (CDCl 3 ): δ 8.33 (d, 2H); 7.0-7.5 (m, 6H); 4.87 (m, 1H); 2.96 (m, 2H); 2.45 (s, 3H).

(c) l-(3-metiltiofenil)-2-(4-piridil)etandion(c) 1- (3-methylthiophenyl) -2- (4-pyridyl) ethanedione

K raztopini l-(3-metiltiofenil)-2-(4-piridil)etanola (2,5 g, 10,2 mmol) v CH2C12 (150 ml) dodamo zmes Celitea (4,4 g) in piridinijevega dikromata (4,4 g), 20,4 mmol). Po mešanju 12 h zmes filtriramo skozi Celite. Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s topnostnim gradientom 40-50 % EtOAc/Heks, da zagotovimo naslovno spojino (144 mg, 5,5 %): TH NMR (CDC13: δ 8,88 (širok d, 2H); 7,85 (s, IH); 7,78 (d, 2H); 7,67 (d, IH); 7,56 (d, IH); 7,44 (t, IH); 2,55 (s, 3H).To a solution of 1- (3-methylthiophenyl) -2- (4-pyridyl) ethanol (2.5 g, 10.2 mmol) in CH 2 Cl 2 (150 ml) was added a mixture of Celite (4.4 g) and pyridinium dichromate (4.4 g), 20.4 mmol). After stirring for 12 h, the mixture was filtered through Celite. The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with a solubility gradient of 40-50% EtOAc / Hex to provide the title compound (144 mg, 5.5%): T H NMR (CDCl 3 : δ 8.88 (broad d, 2H); 7.85 (s, 1H); 7.78 (d, 2H); 7.67 (d, 1H); 7.56 (d, 1H); 7.44 (t, 1H); 2.55 (s, 3H).

(d) 4-morfolinometilbenzaldehid dietil acetal(d) 4-morpholinomethylbenzaldehyde diethyl acetal

Naslovno spojino pripravimo z uporabo enakega postopka, kot so ga opisali Borch,The title compound is prepared using the same procedure as described by Borch,

L.F., Bernstein, M. D., in Durst, H. D. v J. Am. Chem. Soc., 1971, 93, 2897, razen da uporabimo dietil acetal: Ή NMR (CDC13: δ 7,41 (d, 2H); 7,32 (d, 2H); 5,48 (s, IH); 3,3-3,8 (m, 10H); 2,43 (širok s, 4H); 1,25 (t, 6H).LF, Bernstein, MD, and Durst, HD in J. Am. Chem. Soc., 1971, 93, 2897 except to use diethyl acetal: Ή NMR (CDCl 3 : δ 7.41 (d, 2H); 7.32 (d, 2H); 5.48 (s, 1H); 3 , 3-3.8 (m, 10H); 2.43 (broad s, 4H); 1.25 (t, 6H).

(e) 4-(3-metiltiofenil)-2-(4-morfolinometilfenil)-5-(4-piridil)-lH-imidazol(e) 4- (3-methylthiophenyl) -2- (4-morpholinomethylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo l-(3-metiltiofenil)-2-(4-piridil)-etandion in 4-morfolinometilbenzaldehid dietil acetal *H NMR (CDC13: δ 8,47 (d, 2H); 8,02 (d, 2H); 7,3-7,9 (m, 8H); 3,72 (t, 4H); 3,54 (s, 2H); 2,44 (širok s, 4H); 2,38 (s, 3H).The title compound was prepared using the same procedure as described in Example 13 except using 1- (3-methylthiophenyl) -2- (4-pyridyl) -etanedione and 4-morpholinomethylbenzaldehyde diethyl acetal * H NMR (CDCl 3 : δ 8 , 47 (d, 2H); 8.02 (d, 2H); 7.3-7.9 (m, 8H); 3.72 (t, 4H); 3.54 (s, 2H); 2. 44 (broad s, 4H); 2.38 (s, 3H).

PRIMER 71EXAMPLE 71

4-(3-metilsulfinilfenil)-2-(4-morfolinometilfenil)-5-(4-piridil)-lH-imidazol4- (3-methylsulfinylphenyl) -2- (4-morpholinomethylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(3-metiltiofenil-2-(4-morfolinometilfenil)-5-(4-piridil)-lHimidazol [glej primer 70 zgoraj]: Ή NMR (CDC13: δ 8,38 (d, 2H); 7,92 (d, 2H); 7,1-7,6 (m, 8H); 3,76 (t, 4H); 3,59 (s, 2H); 2,73 (s, 3H); 2,52 (širok s, 4H).The title compound was prepared using the same procedure as described in Example 20 except using 4- (3-methylthiophenyl-2- (4-morpholinomethylphenyl) -5- (4-pyridyl) -1Himidazole [see example 70 above]: Ή NMR (CDCl 3 : δ 8.38 (d, 2H); 7.92 (d, 2H); 7.1-7.6 (m, 8H); 3.76 (t, 4H); 3.59 ( s, 2H); 2.73 (s, 3H); 2.52 (broad s, 4H).

PRIMER 72EXAMPLE 72

4-(3-metansulfonamidofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)-lH-imidazol4- (3-Methanesulfonamidophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 4-(3-metansulfonamido-fenil)-2-(4-metiltiofenil)-5-(4piridil-lH-imidazol [glej primer 63 zgoraj]: CIMS (NH3, m/z): 453,3 (M++H).The title compound was prepared using the same procedure as described in Example 20 except that 4- (3-methanesulfonamido-phenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl-1H-imidazole was used [see example 63 above] : CIMS (NH 3 , m / z): 453.3 (M + + H).

PRIMER 73EXAMPLE 73

2-(4-etiltiofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-ethylthiophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-etiltiobenzaldehid: tal. 203-205 °C.The title compound was prepared using the same procedure as described in Example 13 except that 4-ethylthiobenzaldehyde: m.p. 203-205 ° C.

PRIMER 74EXAMPLE 74

2-(4-etilsulfinilfenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol2- (4-ethylsulfinylphenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 20, razen da uporabimo 2-(4-etiltiofenil)-4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol [glej primer 73 zgoraj]: tal. 240 °C.The title compound was prepared using the same procedure as described in Example 20 except that 2- (4-ethylthiophenyl) -4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole was used [see Example 73 above ]: m.p. 240 ° C.

PRIMER 75EXAMPLE 75

4-(4-fluorofenil)-2-[(4-(4-metil-l-piperazinil)-sulfonil-fenil]-5-(4-piridil)-lH-imidazol (a) Etil [4-(4-metil piperazinil) sulfonamido] benzoat4- (4-fluorophenyl) -2 - [(4- (4-methyl-1-piperazinyl) -sulfonyl-phenyl] -5- (4-pyridyl) -1H-imidazole (a) Ethyl [4- (4- methyl piperazinyl) sulfonamido] benzoate

Zmes 4-klorosulfonil benzojske kisline (5,0 g, 22,67 mmol), N-metilpiperazina (25 ml) in MeOH (5 ml) mešamo 18 h in k zmesi dodamo eter (200 ml). Kristaliničen trden precipitat filtriramo in speremo z etrom (200 ml). Trdno snov suspendiramo v 20 %-ni etanolni HCl in zmes grejemo pri refluksu dokler ne dobimo homogene raztopine (okoli 2 h). Raztopino ohladimo na sobno temperaturo, koncentriramo in ostanek porazdelimo med nas. NaHCO3 in EtOAc. Organski ekstrakt posušimo in koncentriramo, da dobimo naslovno spojino (5,8 g, 80 %).A mixture of 4-chlorosulfonyl benzoic acid (5.0 g, 22.67 mmol), N-methylpiperazine (25 ml) and MeOH (5 ml) was stirred for 18 h and ether (200 ml) was added to the mixture. The crystalline solid precipitate was filtered off and washed with ether (200 ml). The solid was suspended in 20% ethanol HCl and the mixture was heated at reflux until a homogeneous solution (about 2 h) was obtained. The solution was cooled to room temperature, concentrated and the residue partitioned between us. NaHCO 3 and EtOAc. The organic extract was dried and concentrated to give the title compound (5.8 g, 80%).

(b) 4-(4-metil piperazinil) sulfonamido benzil alkohol(b) 4- (4-Methyl piperazinyl) sulfonamido benzyl alcohol

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 78, korak (b), razen da uporabimo etil [4-(4-metil piperazinil) sulfonamido] benzoat.The title compound was prepared using the same procedure as described in Example 78, step (b), except that ethyl [4- (4-methyl piperazinyl) sulfonamido] benzoate was used.

(c) 4-(4-metil piperazinil) sulfonamido benzaldehid(c) 4- (4-Methyl piperazinyl) sulfonamido benzaldehyde

K raztopini oksalil klorida (1,06 ml, 12,1 mmol) v CH2C12 (20 ml) dodamo DMSO (1,8 ml, 25,4 mmol) pri -60 °C in zmes mešamo 25 min. Dodamo raztopino 4-(4-metil piperazinil) sulfonamido benzil alkohola (3,0 g, 10,5 mmol) v CH2Cl2 (25 ml) in DMSO (5 ml) in zmes mešamo 1,5 h na -60 °C. DOdamo trietilamin (7,4 ml) in zmes porazdelimo med slanico in EtOAc. Organski ekstrakt koncentriramo, nato prečistimo s flash kromatografijo, da dobimo naslovno spojino (1,0 g, 33 %).To a solution of oxalyl chloride (1.06 ml, 12.1 mmol) in CH 2 Cl 2 (20 ml) was added DMSO (1.8 ml, 25.4 mmol) at -60 ° C and the mixture was stirred for 25 min. A solution of 4- (4-methyl piperazinyl) sulfonamido benzyl alcohol (3.0 g, 10.5 mmol) in CH 2 Cl 2 (25 ml) and DMSO (5 ml) was added and the mixture was stirred for 1.5 h at -60 ° C. Triethylamine (7.4 ml) was added and the mixture partitioned between brine and EtOAc. The organic extract was concentrated, then purified by flash chromatography to give the title compound (1.0 g, 33%).

(d) 4-(4-fluorofenil)-2-[4-(4-metil piperazinil) sulfonamido fenil]-5-(4-piridil)-lHimidazol(d) 4- (4-fluorophenyl) -2- [4- (4-methylpiperazinyl) sulfonamido phenyl] -5- (4-pyridyl) -1Himidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-(4-metil piperazinil) sulfonamido benzaldehid: tal. 74-76 °C.The title compound was prepared using the same procedure as described in Example 13 except that 4- (4-methyl piperazinyl) sulfonamido benzaldehyde: m.p. 74-76 ° C.

PRIMER 76EXAMPLE 76

4-(4-fluorofenil)-2-[4-(N-metilmetansulfonamido)-metilfenil]-5-(4-piridil)-lH-imidazol (a) Metil 4-[(metansulfonamido)metil]benzoat4- (4-fluorophenyl) -2- [4- (N-methylmethanesulfonamido) -methylphenyl] -5- (4-pyridyl) -1H-imidazole (a) Methyl 4 - [(methanesulfonamido) methyl] benzoate

K suspenziji 4-(aminometil)benzojske kisline (10 g, 66 mmol) v MeOH (100 ml) pri 0 °C dodamo po kapljicah SOC12 (5,3 ml, 73 mmol). Ledeno kopel odstranimo in reakcijsko zmes mešamo na sobni temperaturi preko noči. Po gretju reakcijske zmesi pri refluksu 4 h, topilo uparimo. Ostanek suspendiramo v CH2C12 (100 ml) pri 0 °C in dodamo trietilamin (25 ml), sledi dodajanje po kapljicah metansulfonil klorida (7,75 ml, 100 mmol). Reakcijsko zmes mešamo na sobni temperaturi 1 h, zlijemo v ledeno H2O, ekstrahiramo z CH2C12, posušimo preko anhidridnega Na2SO4, filtriramo in uparimo. Surovi produkt flash kromatografiramo na silikagelu, eluiramo z 1 % MeOH/CHCl3. Naslovno spojino izoliramo kot belo trdno snov (11,8 g, 74 %): !H NMR (CDC13: δ 8,03 (d, 2H); 7,42 (d, 2H); 4,9 (širok t, IH); 4,38 (d, 2H); 3,92 (s, 3H); 2,89 (s, 3H).To a suspension of 4- (aminomethyl) benzoic acid (10 g, 66 mmol) in MeOH (100 ml) at 0 ° C was added dropwise SOCl 2 (5.3 ml, 73 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. After the reaction mixture was heated at reflux for 4 h, the solvent was evaporated. The residue was suspended in CH 2 Cl 2 (100 ml) at 0 ° C and triethylamine (25 ml) was added followed by dropwise addition of methanesulfonyl chloride (7.75 ml, 100 mmol). The reaction mixture was stirred at room temperature for 1 h, poured into ice H 2 O, extracted with CH 2 Cl 2 , dried over anhydrous Na 2 SO 4 , filtered and evaporated. The crude product was flash chromatographed on silica gel, eluting with 1% MeOH / CHCl 3 . The title compound was isolated as a white solid (11.8 g, 74%) :! H NMR (CDCl 3 : δ 8.03 (d, 2H); 7.42 (d, 2H); 4.9 (broad t, 1H); 4.38 (d, 2H); 3.92 (s, 3H); 2.89 (s, 3H).

(b) Metil 4-[(N-metilmetansulfonamido)metil]benzoat(b) Methyl 4 - [(N-methylmethanesulfonamido) methyl] benzoate

K zmesi metil 4-[(metansulfonamido)metil]benzoata (5 g, 20,6 mmol) v MeOH (100 ml) na sobni temperaturi dodamo I^COj (2,9 g, 21 mmol). DOdamo metil jodid (7 ml, 16 g, 112 mmol) in zmes mešamo preko noči. Reakcijsko zmes filtriramo in trdno snov speremo z CHCl3/MeOH. Združene filtrate uparimo in ostanek prečistimo s flash kromatografijo, eluiramo z 0-5 % MeOH/CHCl3. Naslovno spojino izoliramo kot belo trdno snov (4,9 g, 94 %): 2H (CDC13: δ 8,08 (d, 2H); 7,48 (d, 2H); 4,41 (s, IH); 3,97 (s, 3H); 3,91 (s, 3H); 2,83 (s, 3H).To a mixture of methyl 4 - [(methanesulfonamido) methyl] benzoate (5 g, 20.6 mmol) in MeOH (100 ml) at room temperature was added 1 N CO 2 (2.9 g, 21 mmol). Methyl iodide (7 ml, 16 g, 112 mmol) was added and the mixture stirred overnight. The reaction mixture was filtered and the solid was washed with CHCl 3 / MeOH. The combined filtrates were evaporated and the residue purified by flash chromatography eluting with 0-5% MeOH / CHCl 3 . The title compound was isolated as a white solid (4.9 g, 94%): 2 H (CDCl 3 : δ 8.08 (d, 2H); 7.48 (d, 2H); 4.41 (s, 1H) 3.97 (s, 3H); 3.91 (s, 3H); 2.83 (s, 3H).

(c) 4-[(N-metilmetansulfonamido)metil]benzil alkohol(c) 4 - [(N-methylmethanesulfonamido) methyl] benzyl alcohol

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 78, korak (b), razen da uporabimo 4-[(N-metilmetansulfon- amido)metil]ben- zoat: Ή NMR (CDC13: d 7,34 (m, 4H); 4,68 (s, 2H); 4,29 (s, 2H); 2,83 (s, 3H); 2,74 (s, 3H).The title compound was prepared using the same procedure as described in Example 78, step (b), except using 4 - [(N-methylmethanesulfonamido) methyl] benzoate: Ή NMR (CDCl 3 : d 7.34 ( m, 4H); 4.68 (s, 2H); 4.29 (s, 2H); 2.83 (s, 3H); 2.74 (s, 3H).

(d) 4-[(N-metilmetansulfonamido)metil]benzaldehid(d) 4 - [(N-methylmethanesulfonamido) methyl] benzaldehyde

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 78, korak (c), razen da uporabimo 4-[(N-metilmetansulfonamido)-metil]benzil alkohol: Ή NMR (CDC13: δ 10,02 (s, IH); 7,9 (d, 2H); 7,54 (d, 2H); 4,4 (s, 2H); 2,9 (s, 3H); 2,81 (s, 3H).The title compound was prepared using the same procedure as described in Example 78, step (c), except that 4 - [(N-methylmethanesulfonamido) -methyl] benzyl alcohol was used: Ή NMR (CDCl 3 : δ 10.02 (s, 1H); 7.9 (d, 2H); 7.54 (d, 2H); 4.4 (s, 2H); 2.9 (s, 3H); 2.81 (s, 3H).

(e) 4-(4-fluorofenil)-2-[4-(N-metilmetansulfonamido)-metilfenil]-5-(4-piridil)-lHimidazol(e) 4- (4-fluorophenyl) -2- [4- (N-methylmethanesulfonamido) -methylphenyl] -5- (4-pyridyl) -1Himidazole

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-[(N-metilmetansulfonamido)metil]benzaldehid: tal. 222224 °C.The title compound was prepared using the same procedure as described in Example 13 except that 4 - [(N-methylmethanesulfonamido) methyl] benzaldehyde: m.p. 222224 ° C.

PRIMER 77EXAMPLE 77

Dietil [l-metil-4-fenil-5-(4-piridil)-imidazol-2-il]metoksi]metilfosfonat (a) N-metil-N-[4-pikolil]formamidDiethyl [1-methyl-4-phenyl-5- (4-pyridyl) -imidazol-2-yl] methoxy] methylphosphonate (a) N-methyl-N- [4-picolyl] formamide

K raztopini 4-pikolil klorida HC1 (15 g, 91,4 mmol) in N-metilformamida (53,4 ml, 914 mmol) v 300 ml THF dodamo 80 % NaH v mineralnem olju (5,48 g, 183 mmol). Po mešanju na sobni temperaturi 18 h, zmes pogasimo z ledeno vodo in porazdelimo med CHC12 in H2O. Organski ekstrakt speremo z vodnim NaCI in posušimo preko MgSO4. Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s 50:1 CH2Cl2/MeOH. Naslovno spojino pridobimo kot bledo rumeno olje (10,5 g, 76 %): ESMS (m/z): 151 (M++H).To a solution of 4-picolyl chloride HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml THF was added 80% NaH in mineral oil (5.48 g, 183 mmol). After stirring at room temperature for 18 h, the mixture was quenched with ice water and partitioned between CHCl 2 and H 2 O. The organic extract was washed with aqueous NaCl and dried over MgSO 4 . The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 50: 1 CH 2 Cl 2 / MeOH. The title compound was obtained as a pale yellow oil (10.5 g, 76%): ESMS (m / z): 151 (M + + H).

(b) l-metil-4-fenil-5-[4-piridil]imidazol(b) 1-methyl-4-phenyl-5- [4-pyridyl] imidazole

K raztopini di-zzo-propil-amina (11,2 ml, 79,9 mmol) v 150 ml THF pri -78 °C dodamo n-butillitij (31,9 ml 2,5 M raztopine, 79,9 mmol). K nastali zmesi dodamo raztopino N-metil-N-[4-pikolil]formamida (10 g, 66,5 mmol) v THF. Nastalo oranžno-rjavo raztopino mešamo pri -78 °C 20 min., pri tem času dodamo benzonitril (13,6 ml, 133 mmol). Nastalo temno rjavo zmes pustimo, da se segreje na sobno temperaturo in jo mešamo 1 h, segrevamo do refluksa 4 h in nato ohladimo na sobno temperaturo in porazdelimo med CH2C12 in H2O. Organski ekstrakt speremo z vodnim NaCI in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s 50:1 CH2Cl2/MeOH. Naslovno spojino pridobimo kot rahlo rumeno rjavo trdno snov (5,83 g, 37 %); tal. 158-159 °C.To the solution of di-iso-propyl-amine (11.2 ml, 79.9 mmol) in 150 ml THF at -78 ° C was added n-butyllithium (31.9 ml 2.5 M solution, 79.9 mmol). To the resulting mixture was added a solution of N-methyl-N- [4-picolyl] formamide (10 g, 66.5 mmol) in THF. The resulting orange-brown solution was stirred at -78 ° C for 20 min, at which time benzonitrile (13.6 ml, 133 mmol) was added. The resulting dark brown mixture was allowed to warm to room temperature and stirred for 1 h, heated to reflux for 4 h and then cooled to room temperature and partitioned between CH 2 C1 2 and H 2 O. The organic extract was washed with aqueous NaCl and dried ( MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 50: 1 CH 2 Cl 2 / MeOH. The title compound was obtained as a slightly yellow-brown solid (5.83 g, 37%); m.p. Mp 158-159 ° C.

(c) 2-formil-l-metil-4-fenil-5-[4-piridil]imidazol(c) 2-Formyl-1-methyl-4-phenyl-5- [4-pyridyl] imidazole

K raztopini l-metil-4-fenil-5-[4-piridinil]imidazola (0,275 g, 1,17 mmol) v THF pri -78 °C dodamo n-butillitij (0,56 ml 2,5 M raztopine, 1,40 mmol). Nastalo rdečeoranžno raztopino pustimo mešati pri -78 °C 0,5 h, ko dodamo DMF (0,18 ml, 2,34 mmol). Dopustimo, da se zmes segreje na sobno temperaturo in mešamo 4 h, nato jo pogasimo z ledeno vodo in porazdelimo med CH2C12 in H2O. Organski ekstrakt speremo z vodnim NaCI in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s 50:1 CH2Cl2/MeOH. Naslovno spojino pridobimo kot belo trdno snov (0,187 g, 61 %): tal. 167-168 °C.To a solution of 1-methyl-4-phenyl-5- [4-pyridinyl] imidazole (0.275 g, 1.17 mmol) in THF at -78 ° C was added n-butyllithium (0.56 ml of 2.5 M solution, 1 , 40 mmol). The resulting red-orange solution was allowed to stir at -78 ° C for 0.5 h when DMF (0.18 ml, 2.34 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 4 h, then quenched with ice water and partitioned between CH 2 Cl 2 and H 2 O. The organic extract was washed with aqueous NaCl and dried (MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 50: 1 CH 2 Cl 2 / MeOH. The title compound was obtained as a white solid (0.187 g, 61%): m.p. Mp 167-168 ° C.

(d) 2-hidroksimetil-l-metil-4-fenil-5-(4-piridil)imidazol(d) 2-hydroxymethyl-1-methyl-4-phenyl-5- (4-pyridyl) imidazole

K raztopini 2-formil-l-metil-4-fenil-5-[4-piridil]imidazola (0,830 g, 3,15 mmol) v MeOH pri 0 °C dodamo NaBH4 (0,143 g, 3,78 mmol). Zmes mešamo na sobni temperaturi 0,5 h, nakar topilo uparimo in vacuo in ostanek porazdelimo med CH2C12 in H2O. Organski ekstrakt speremo z vodnim NaCl in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s 25:1 CH2Cl2/MeOH. Naslovno spojino pridobimo kot belo trdno snov (0,608 g, 73 %): tal. 236-238 °C.To a solution of 2-formyl-1-methyl-4-phenyl-5- [4-pyridyl] imidazole (0.830 g, 3.15 mmol) in MeOH at 0 ° C was added NaBH 4 (0.143 g, 3.78 mmol). The mixture was stirred at room temperature for 0.5 h, then the solvent was evaporated in vacuo and the residue partitioned between CH 2 Cl 2 and H 2 O. The organic extract was washed with aqueous NaCl and dried (MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 25: 1 CH 2 Cl 2 / MeOH. The title compound was obtained as a white solid (0.608 g, 73%): m.p. 236-238 ° C.

(e) Dietil [l-metil-4-fenil-5-(4-piridil)-imidazol-2-il]metoksi]-metil-fosfonat(e) Diethyl [1-methyl-4-phenyl-5- (4-pyridyl) -imidazol-2-yl] methoxy] -methyl-phosphonate

K suspenziji 80 %-nega NaH v mineralnem olju (0,013 g, 0,452 mmol) v DMF pri 0 °C dodamo l-metil-2-hidroksimetil-4-fenil-5-[4-piridinil]imidazoIa (0,100 g, 0,377 mmol) v DMF. Nastalo bistro rumeno raztopino mešamo pri 0 °C 0,5 h, nakar dodamo dietil klorometilfosfonat (0,070 ml, 0,452 mmol) raztopljen v 0,079 ml HMPA. Nastalo zmes mešamo pri 0 °C 15 min. in nato segrejemo na sobno temperaturo. Po 5 h raztopino porazdelimo med CHjClj in H2O. Organski ekstrakt speremo z vodnim NaCl in posušimo (MgSO4). Topilo odstranimo in vacuo in ostanek prečistimo s flash kromatografijo, eluiramo s 50:1 CH2Cl2/MeOH. Naslovno spojino pridobimo kot rahlo rumenkasto rjavo olje (0,08 g, 56 %): ESMS (m/z): 416 (M++H).To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0 ° C was added 1-methyl-2-hydroxymethyl-4-phenyl-5- [4-pyridinyl] imidazole (0.100 g, 0.377 mmol) ) in the DMF. The resulting clear yellow solution was stirred at 0 ° C for 0.5 h, then diethyl chloromethyl phosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL of HMPA was added. The resulting mixture was stirred at 0 ° C for 15 min. and then warmed to room temperature. After 5 h, the solution was partitioned between CH 2 Cl 2 and H 2 O. The organic extract was washed with aqueous NaCl and dried (MgSO 4 ). The solvent was removed in vacuo and the residue purified by flash chromatography, eluting with 50: 1 CH 2 Cl 2 / MeOH. The title compound was obtained as a slightly yellowish brown oil (0.08 g, 56%): ESMS (m / z): 416 (M + + H).

PRIMER 78EXAMPLE 78

4-(4-fluorofenil)-2-[4-metansulfonamido)-metilfenil]-5-(4-piridil)-lH-imidazol (a) Metil 4-[(metansulfonamido)metil]-benzoat4- (4-Fluorophenyl) -2- [4-methanesulfonamido) -methylphenyl] -5- (4-pyridyl) -1H-imidazole (a) Methyl 4 - [(methanesulfonamido) methyl] -benzoate

Naslovno spojino pripravimo z uporabo enakega postopka, kot je opisan v primeru 76, korak (a).The title compound was prepared using the same procedure as described in Example 76, step (a).

(b) 4-[(nietansulfonamido)metil]benzil alkohol(b) 4 - [(Niethanesulfonamido) methyl] benzyl alcohol

K zmesi metil 4-[(metansulfonamdiometil]benzoata (3,6 g, 15 mmol) v THF (150 ml) dodamo LiAlH4 (1 M v THF, 30 ml, 30 mmol). Reakcijsko zmes mešamo na sobni temperaturi 1 h in zlijemo v 10 % MeOH/CHCl3, ki vsebuje silikagel. Trdne snovi odstranimo s filtracijo, speremo z 10 % MeOH/CHCl3 in združena spirala uparimo, da dobimo naslovno spojino kot belo trdno snov (2,6 g, 80 %).To a mixture of methyl 4 - [(methanesulfonamidiomethyl] benzoate (3.6 g, 15 mmol) in THF (150 mL) was added LiAlH 4 (1 M in THF, 30 mL, 30 mmol). The reaction mixture was stirred at room temperature for 1 h and poured into 10% MeOH / CHCl₂ is 3, which contains the silica gel. the solids were removed by filtration, washed with 10% MeOH / 3 of CHCl₂ and the combined coil is evaporated to give the title compound as a white solid (2.6 g, 80%).

(c) 4-[(metansulfonamido)metil]benzaldehid(c) 4 - [(methanesulfonamido) methyl] benzaldehyde

K raztopini 4-[(metansulfonamido)metil]benzil alkohola (1,0 g, 4,6 mmol) v CH2C12 (25 ml) dodamo piridinijev klorokromat (1,5 g, 7,0 mmol). Reakcijsko zmes mešamo 1 h na sobni temperaturi in zlijemo preko blazinice silikagela, eluiramo z 2 % MeOH/CHCl3. Naslovno spojino izoliramo kot rumeno rjavo trdo snov (1,0 g, 100 %): Ή NMR (CDC13): δ 10,03 (s, IH); 7,88 (d, 2H); 7,57 (d, 2H); 4,79 (širok s, IH);To a solution of 4 - [(methanesulfonamido) methyl] benzyl alcohol (1.0 g, 4.6 mmol) in CH 2 Cl 2 (25 ml) was added pyridinium chlorochromate (1.5 g, 7.0 mmol). The reaction mixture was stirred for 1 h at room temperature and poured over a pad of silica gel, eluting with 2% MeOH / CHCl 3 . The title compound was isolated as a yellow-brown solid (1.0 g, 100%): Ή NMR (CDCl 3 ): δ 10.03 (s, 1H); 7.88 (d, 2H); 7.57 (d, 2H); 4.79 (broad s, 1H);

4,43 (d, 2H); 2,93 (s, 3H).4.43 (d, 2H); 2.93 (s, 3H).

(d) 4-(4-fluorofenil)-2-[4-(metansulfonamido)metilfenil]-5-(4-piridil)-lH-imidazol(d) 4- (4-fluorophenyl) -2- [4- (methanesulfonamido) methylphenyl] -5- (4-pyridyl) -1H-imidazole

Naslovno spojino [tudi pripravljeno v primeru 32] pripravimo z uporabo enakega postopka, kot je opisan v primeru 13, razen da uporabimo 4-[(metansulfonamido)metil]benzaldehid.The title compound [also prepared in Example 32] was prepared using the same procedure as described in Example 13 except that 4 - [(methanesulfonamido) methyl] benzaldehyde was used.

PRIMER 79EXAMPLE 79

4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol (a) l-(t-butildimetilsililoksi)-2-(4-fluorofenil)-l-(4-piridil)etanon4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole (a) 1- (t-butyldimethylsilyloxy) -2- (4-fluorophenyl) -1- (4 -pyridyl) ethanone

K -20 °C raztopini diizopropilamina (64,4 ml, 0,46 mol) in THF (120 ml) dodamoTo -20 ° C to a solution of diisopropylamine (64.4 ml, 0.46 mol) and THF (120 ml) was added

207,8 ml (0,52 mol, 2,5 M raztopini v heksanih) po kapljicah n-butilitij preko 15 min. Temperaturo znižamo na -15 °C in zmes mešamo 0,5 h. Raztopino ohladimo na - 20 °C in po kapljicah dodamo 98,14 g (0,44 mol) 4-(t-butildimetilsililoksi)metil piridina preko 20 min. Po mešanju pri -20 °C 45 min. po kapljicah dodamo preko 0,5 h raztopino 4-fluoro-N-metoksi-N-metilbenzamida (84,5 g, 0,46 mol) [glej primer 10, korak (a)] v THF (90 ml). Ko je dodajanje končano, odstranimo ledeno kopel in reakcijsko zmes grejemo na 0 °C 1 h, nato mešamo pri sobni temperaturi 1,5 h. Zmes zlijemo v raztopino NH4C1 (98 g) in H2O (500 ml), nato ekstrahiramo s EtOAc (3 x207.8 ml (0.52 mol, 2.5 M solution in hexanes) dropwise with n-butyllithium over 15 min. The temperature was lowered to -15 ° C and the mixture was stirred for 0.5 h. The solution was cooled to -20 ° C and 98.14 g (0.44 mol) of 4- (t-butyldimethylsilyloxy) methyl pyridine were added dropwise over 20 min. After stirring at -20 ° C for 45 min. A solution of 4-fluoro-N-methoxy-N-methylbenzamide (84.5 g, 0.46 mol) was added dropwise over 0.5 h [see Example 10, step (a)] in THF (90 ml). After the addition is complete, the ice bath is removed and the reaction mixture is heated to 0 ° C for 1 h, then stirred at room temperature for 1.5 h. The mixture was poured into a solution of NH 4 C1 (98 g) and H 2 O (500 ml), then extracted with EtOAc (3 x

250 ml). EtOAc ekstrakte speremo s H2O in nasičenim NaCl, nato posušimo preko250 ml). The EtOAc extracts were washed with H 2 O and saturated NaCl, then dried over

MgSO4. Uparevanje topila in vacuo da naslovno spojino kot rumenkasto rjavo olje (114,2 g, 75%).MgSO 4 . Evaporation of the solvent in vacuo gave the title compound as a yellowish brown oil (114.2 g, 75%).

(b) 4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)-lH-imidazol(b) 4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) -1H-imidazole

K raztopini l-(t-butildimetilsililoksi)-2-(4-fluorofenil)-l-(4-piridil)etanona (6,3 g, 18,3 mmol) v ledocetni kislini (125 ml) dodamo brezvoden bakrov (II) acetat (6,6 g, 36,5 mmol), amonijev acetat (14 g, 183 mmol) in 4-(metiltio)benzaldehid (3,5 g, 22,9 mmol) in zmes segrevamo pri refluksu. Po 1 h reakcijsko zmes ohladimo, nato zlijemo v zmes konc. NH4OH (175 ml), ledu (100 ml) in EtOAc (100 ml). Nastalo zmes mešamo 15 min., nato se plasti ločijo. Vodno plast ekstrahiramo z EtOAc (2 x 50 ml). Združene EtOAc ekstrakte speremo z nasičenim NaCl in posušimo preko MgSO4. Uparevanje topila in vacuo da olje, ki ga prevzamemo v aceton. 3 N HC1 dodamo po kapljicah, da naravnamo pH na 2-3 in nastalo trdno snov filtriramo. Naslovno spojino [tudi pripravljena v primeru 17 kot prosta baza] izoliramo kot rumeno hidrokloridno sol (3,7 g, 51 %).To a solution of 1- (t-butyldimethylsilyloxy) -2- (4-fluorophenyl) -1- (4-pyridyl) ethanone (6.3 g, 18.3 mmol) in glacial acetic acid (125 ml) was added anhydrous copper (II) acetate (6.6 g, 36.5 mmol), ammonium acetate (14 g, 183 mmol) and 4- (methylthio) benzaldehyde (3.5 g, 22.9 mmol) and the mixture was heated at reflux. After 1 h, the reaction mixture was cooled, then poured into a conc. NH 4 OH (175 ml), ice (100 ml) and EtOAc (100 ml). The resulting mixture was stirred for 15 min, then the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO 4 . Evaporation of the solvent in vacuo gives the oil which is taken up in acetone. 3 N HCl was added dropwise to adjust the pH to 2-3 and the resulting solid filtered. The title compound [also prepared in Example 17 as the free base] was isolated as a yellow hydrochloride salt (3.7 g, 51%).

PRIMER 80EXAMPLE 80

2-[4-[(N-benzil-N-metil) aminometil]fenil]4-(4-fluorofenil)-5-(4-piridil)-lH-imidazol (a) 4-[(N-benzil-N-metil)aminometil]benzaldehid dietilacetal2- [4 - [(N-benzyl-N-methyl) aminomethyl] phenyl] 4- (4-fluorophenyl) -5- (4-pyridyl) -1H-imidazole (a) 4 - [(N-benzyl-N -methyl) aminomethyl] benzaldehyde diethyl acetal

K 62,4 g (0,30 mol) tereftalaldehid monodietil acetala dodamo 32,1 g (0,30 mol) benzil amina in 500 ml toluena. Nastalo raztopino segrevamo pri refluksu ob uporabi Dean-Stark pasti. Po 1 uri raztopino ohladimo in koncentriramo, da dobimo rahlo rumeno olje (89,1 g). Olje raztopimo v 900 ml EtOAc in dodamo 2,0 g 5 %-nega paladija na aktivnem oglju. Zmes hidrogeniramo na Parr hidrogenacijskih aparaturah pod 255106,12 Pa (37 psi) vodikovega tlaka. Zmes tresemo 1 uro na sobni temperaturi. Steklenico odpremo in dodamo 34,4 ml (0,42 mol) 37,5 %-ne formaldehidne raztopine (vodne). V steklenici ponovno vzpostavimo tlak s 227527,08 Pa (33 psi) vodika in zmes tresemo 17 ur na sobni temperaturi. Steklenico odpremo in reakcijsko zmes filtriramo in filtrat kondenziramo do skoraj brezbarvnega olja (93,9 g). Vakumska destilacija da 71,4 g (76 %) 4-(N-metil-N-benzil)aminometil74 benzaldehid dietilacetala: vr. (3,99966 kPa) (30 torr) 212-234 °C.To 62.4 g (0.30 mol) of terephthalaldehyde monodiethyl acetal was added 32.1 g (0.30 mol) of benzyl amine and 500 ml of toluene. The resulting solution was heated at reflux using a Dean-Stark trap. After 1 hour, the solution was cooled and concentrated to give a slightly yellow oil (89.1 g). Dissolve the oil in 900 ml of EtOAc and add 2.0 g of 5% palladium on activated charcoal. The mixture was hydrogenated on Parr hydrogenation apparatus at 255106.12 Pa (37 psi) hydrogen pressure. The mixture was shaken for 1 hour at room temperature. The bottle was opened and 34.4 ml (0.42 mol) of a 37.5% formaldehyde solution (aqueous) was added. The bottle was re-pressurized with 227527.08 Pa (33 psi) of hydrogen and the mixture was shaken for 17 hours at room temperature. The bottle was opened and the reaction mixture was filtered and the filtrate was condensed to near colorless oil (93.9 g). Vacuum distillation to give 71.4 g (76%) of 4- (N-methyl-N-benzyl) aminomethyl74 benzaldehyde diethyl acetal: m.p. (3.99966 kPa) (30 torr) 212-234 ° C.

(b) 2-[4-[(N-benzil-N-metil) aminometil]fenil]4-(4-fluorofenil)-5-(4-piridil)-lHimidazol(b) 2- [4 - [(N-benzyl-N-methyl) aminomethyl] phenyl] 4- (4-fluorophenyl) -5- (4-pyridyl) -1Himidazole

Naslovno spojino [tudi pripravljeno v primeru 36] pripravimo, kot je opisano v primeru 13, razen da uporabimo 4-[(N-benzil-N-metil)aminometil]benzaldehid dietilacetal.The title compound [also prepared in example 36] was prepared as described in example 13 except that 4 - [(N-benzyl-N-methyl) aminomethyl] benzaldehyde diethyl acetal was used.

BIOLOŠKI PRIMERIBIOLOGICAL EXAMPLES

Citokin-inhibicijske učinke spojin v smislu predloženega izuma določamo z naslednjimi in vitro analizami:The cytokine inhibitory effects of the compounds of the present invention are determined by the following in vitro assays:

1. IL-1 Človeške periferalne krvne monocite izoliramo in prečistimo iz ali svežih krvnih pripravkov prostovoljnih krvodajalcev ali iz krvne banke levkocitov po postopku Colotta et al, J Immunol 132, 936 (1984). Te monocite (lxl06) namažemo v 24-vdolbinske plošče v koncentraciji 1-2 milijon/ml na vdolbino. Celice pustimo dve uri, da prirastejo, nakar časovno ne-prirasle celice odstranimo z nežnim spiranjem. Nato dodamo k celicam testne spojine 1 h pred dodatkom lipopolisaharida (50 ng/mp) in kulture inkubiramo na 37 °C nadaljnjih 24 h. Na koncu tega obdobja kulturne supernatante odstranimo in očistimo od celic in vseh razkrojkov. Kulturne supernatante nato takoj analiziramo na IL-1 biološko aktivnost, ali po postopku Simon et al., J. Immunol. Methods, 84, 85, (1985) (ki temelji na sposobnosti IL-1, da stimulira Interleukin 2 proizvodno celično linijo (EL-4), da izloča IL-2, sporazumno z A23187 ionoforom) ali s postopkom Lee et al., J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA analiza). Pokazali smo, da so spojine s formulo (I) inhibitorji in vitro IL-1 proizvedenih s človeškimi monociti.1. IL-1 Human peripheral blood monocytes are isolated and purified from either fresh blood products from voluntary blood donors or from the leukocyte blood bank by the procedure of Colotta et al, J Immunol 132, 936 (1984). These monocytes (lxl0 6 ) were lubricated in 24-well plates at a concentration of 1-2 million / ml per well. The cells were allowed to grow for two hours, then the non-adherent cells were removed by gentle washing. The test compound was then added to the cells for 1 h before the addition of lipopolysaccharide (50 ng / mp) and the cultures were incubated at 37 ° C for a further 24 h. At the end of this period, the culture supernatants are removed and purified from cells and all decompositions. The culture supernatants were then immediately analyzed for IL-1 biological activity, or following the procedure of Simon et al., J. Immunol. Methods, 84, 85, (1985) (based on the ability of IL-1 to stimulate the Interleukin 2 production cell line (EL-4) to secrete IL-2 in concert with the A23187 ionophore) or by the method of Lee et al. J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA analysis). The compounds of formula (I) have been shown to be inhibitors of in vitro IL-1 produced by human monocytes.

2. TNFČloveške periferalne krvne monocite izoliramo in prečistimo iz ali krvne banke levkocitov ali plateletfereznih ostankov po postopku Colotta, R. et al., J Immunol, 132(2), 936 (1984). Monocite nanesemo z gostoto lxl06 celic/ml medij/vdolbina v 24-vdolbinske multi-krožnike. Celice pustimo, da priraščajo 1 uro, po tem času supernatant izsesamo in dodamo svež medij (1 ml, RPMI1640, Whitaker Biomedical Products Whitaker, CA), ki vsebuje 1 % zarodkovega govejega seruam plus penicilin in streptomicin (10 enot/ml). Celice inkubiramo 45 minut v prisotnosti ali odsotnosti testne spojine pri ΙηΜ-ΙΟμΜ dozirnih območjih (spojine solubiliziramo v dimetil sulfoksidu/etanolu, tako da je končna koncentracija dobila v kulturnem mediju 0,5 % dimetil sulfoksida/0,5 % etanola). Nato dodamo bakterijski lipopolisaharid (E. coli 055:B5 [LPS], Sigma Chemicals Co.) (100 ng/ml v 10 ml fosfatni napufrani slanici) in kulture inkubiramo 16-18 ur na 37 °C v 5 %-nem CO2 inkubatorju. Na koncu inkubacijskega obdobja kulturne supernatante odstranimo od celic, centrifugiramo pri 3000 obratih na minuto, da odstranimo celične razkrojke. Supernatante nato analiziramo za TNF aktivnost, ob uporabi ali radio-imuno ali ELISA analize, kot je opisano v WO 92/10190 in Becker et al, J Immunol, 1991, 147, 4307. Spojine s formulo (I) so pokazale, da so inhibitorji in vitro TNF produkcije.2. TNFHuman peripheral blood monocytes are isolated and purified from or leukocyte blood bank or plateletpheresis residues according to the procedure of Colotta, R. et al., J Immunol, 132 (2), 936 (1984). Monocytes were loaded at a density of lxl0 6 cells / ml medium / well into 24-well multi-well plates. The cells were allowed to grow for 1 hour, after which time the supernatant was aspirated and fresh medium (1 ml, RPMI1640, Whitaker Biomedical Products Whitaker, CA) containing 1% embryonic bovine serum plus penicillin and streptomycin (10 units / ml) was added. The cells were incubated for 45 minutes in the presence or absence of the test compound at ΙηΙ-ΙΟμΜ dosing ranges (the compounds were solubilized in dimethyl sulfoxide / ethanol to give a final concentration in culture medium of 0.5% dimethyl sulfoxide / 0.5% ethanol). The bacterial lipopolysaccharide (E. coli 055: B5 [LPS], Sigma Chemicals Co.) (100 ng / ml in 10 ml phosphate-filled brine) was then added and the cultures were incubated for 16-18 hours at 37 ° C in 5% CO 2 incubator. At the end of the incubation period, the culture supernatants were removed from the cells, centrifuged at 3000 rpm to remove cellular debris. The supernatants were then analyzed for TNF activity using either radio-immunoassay or ELISA as described in WO 92/10190 and Becker et al, J Immunol, 1991, 147, 4307. Compounds of formula (I) have shown that inhibitors of in vitro TNF production.

IL-1 in TNF inhibitorsko delovanje navidezno ne kolerira z lastnostjo spojin s formulo (I) v posredovalni arahidonski kislini metabolizemske inhibicije, nadalje sposobnost inhibiranja produkcije prostaglandinske in/ali levkotrienske sinteze, z nesteroidnimi proti-vnetnimi zdravili s potentno ciklooksigenazo in/ali lipoksigenazo, inhibitorsko delovanje ne pomeni, da bo spojina nujno tudi inhibirala TNF ali IL-1 produkcijo, pri ne-toksičnih odmerkih.IL-1 and TNF inhibitory activity do not seem to be choleric with the properties of the compounds of formula (I) in mediated arachidonic acid metabolism inhibition, further the ability to inhibit the production of prostaglandin and / or leukotriene synthesis, by non-steroidal anti-inflammatory drugs by potent cyclooxygenase and / or lipoxygenase the inhibitory activity does not mean that the compound will necessarily inhibit TNF or IL-1 production, at non-toxic doses.

3. IL-8 Primarne človeške popkovinske endotelialne celice (HUVEC) (Celi Systems, Kirland, Wa) vzdržujemo v kulturnem mediju, dopolnjenem s 15 %-nem zarodkovnem volovskem serumu in 1 % CS-HBGF, ki se sestoji iz FGF in heparina. Nato celice razredčimo 20-krat, predno jih nanesemo (250 μΐ) v z želatino prevlečene 96-vdolbinske plošče. Pred uporabo kulturni medij nadomestimo s svežim medijem (200 μΐ). K vsaki vdolbini v kvadroduplikatnih vdolbinah dodamo nato pufer ali testno spojino (25 μΐ, pri kocentracijah med 1 in 10 μΜ) in plošče inkubiramo 6 h v navlaženem inkubatorju pri 37 °C in atmosferi 5 %-nega CO2. Na koncu inkubacijskega obodobja supernatant odstranimo in analiziramo na IL-8 koncentracijo, ob uporabi IL-8 ELISA opreme, nabavljene pri R&D Systems (Minneapolis, MN). Vsi podatki so predstavljeni kot srednja vrednost (ng/ml) mnogokratnih vzorcev, ki temelji na standardni krivulji. IC50 smo primerno dobili z ne-linearnimi regresijskimi analizami. Spojine s formulo (I), primeri 5, 8b in 9, ponazarjajo od odmerka odvisno znižanje v produkciji IL-8 (50-65 % inhibicijo IL-8).3. IL-8 Primary human umbilical cord endothelial cells (HUVEC) (Whole Systems, Kirland, Wa) were maintained in culture medium supplemented with 15% embryonic ox serum and 1% CS-HBGF consisting of FGF and heparin. The cells were then diluted 20-fold before being applied (250 μΐ) to a gelatin-coated 96-well plate. The culture medium is replaced with fresh medium (200 μ 200) before use. To each well in quad-duplicate wells, a buffer or test compound (25 μΐ, at concentrations between 1 and 10 μΜ) was added and the plates were incubated for 6 h in a humidified incubator at 37 ° C and an atmosphere of 5% CO 2 . At the end of the incubation period, the supernatant was removed and analyzed for IL-8 concentration using the IL-8 ELISA equipment purchased from R&D Systems (Minneapolis, MN). All data are presented as the mean (ng / ml) of multiple samples based on the standard curve. IC 50 was appropriately obtained by non-linear regression analyzes. The compounds of formula (I), Examples 5, 8b and 9 illustrate a dose-dependent decrease in IL-8 production (50-65% inhibition of IL-8).

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Claims (15)

1. Spojina s formulo (I) (I) kjer jeA compound of formula (I) (I) wherein R3 4-piridil, pirimidinil, kinolil, izokinolinil, 1-imidazolil ali 1-benzimidazolil, ki je nesubstituiran ali substituiran z enim ali dvema substituentoma, vsakega izmed njiju neodvisno izberemo izmed CM alkil, halo, C14 alkoksi, CM alkiltio, NH2, mono- ali di-C^-alkilamino ali N-heterociklilnega obroča, ta obroč pa ima od 5 do 7 členov in v danem primeru vsebuje dodatni heteroatom, izbran izmed kisika, žvepla ali NR22;R 3 is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, 1-imidazolyl or 1-benzimidazolyl which is unsubstituted or substituted with one or two substituents, each of which are independently selected from a C M alkyl, halo, C 14 alkoxy, C M alkoxy , NH 2 , mono- or di-C 1-6 -alkylamino or N-heterocyclyl ring, this ring having from 5 to 7 members and optionally containing an additional heteroatom selected from oxygen, sulfur or NR 22 ; R2 R8ali-°Ri2;R 2 R 8 or 1 - R 2 ; R3 -XaP(Z)(XbR13)2 ali v danem primeru substituirana arilna ali heteroarilna skupina Q;R 3 -X a P (Z) (X b R 13 ) 2 or optionally substituted aryl or heteroaryl group Q; Xa NRg·, -O-, -S- ali C} alkilenska veriga, v danem primeru substituirana z CM alkilom in v danem primeru prekinjena z -NRg-, -O- ali -S-;X a NR g ·, -O-, -S- or C } alkylene chain optionally substituted by C M alkyl and optionally interrupted by -NR g -, -O- or -S-; xb '(CR^R^jnj-NRg-,-O-ali-S-; x b '(CR ^ R ^ jnj-NRg -, - O-or-S-; Z kisik ali žveplo;With oxygen or sulfur; n 0 ali celo število od 1 do 10;n is 0 or an integer from 1 to 10; R4 fenil, naft-l-il ali naft-2-il, ki je v danem primeru substituiran z enim ali dvema substituentoma, vsakega izmed njiju pa neodvisno izberemo in je, ta 4-fenilni, 4-naft-l-ilni ali 5-naft-2-ilni substituent halo, ciano, -C(Z)NR7R17, -C(Z)OR23, -(CR10R20)mCOR36, -SR5, -SOR5, -OR^, halo-substituirani-C14 alkil, alkil, -ZCiZjR^, -NR^ZjR^ ali -(CR10R20)mNR10R20, in ki je, za ostale položaje substitucije halo, ciano, -C(Z)NR16R26, -C(Z)ORg, -(CR10R20)mCORg, -S(O)mRg, -ORg, halo-substituiran-C^ alkil, -C14 alkil, NR1oC(Z)R8, -NR10S(O)mRn, -ZqZ)Rg ali -(CRJ^NRJ^;R 4 is phenyl, naphth-1-yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected and is, this 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent halo, cyano, -C (Z) NR 7 R 17 , -C (Z) OR 23 , - (CR 10 R 20 ) m COR 36 , -SR 5 , -SOR 5 , - OR 4, halo-substituted-C 14 alkyl, alkyl, -ZC 1 Z 2 R 4 , -NR 4 Z 1 R 4 or - (CR 10 R 20 ) m NR 10 R 20 , and which, for other substitution positions, is halo, cyano, -C (Z) NR 16 R 26 , -C (Z) OR g , - (CR 10 R 20 ) m COR g , -S (O) m Rg, -ORg, halo-substituted-C 1-6 alkyl, -C 14 alkyl , NR 10 C (Z) R 8 , -NR 10 S (O) m R n , -ZqZ) R g or - (CR 2 NR 5); m 0,1 ali 2;m is 0,1 or 2; R5 vodik, C14 alkil, C24 alkenil, C24 alkinil ali NR7R17, brez delov -SRs, pri čemer je -SNR?R17 in -SORs, pri čemer je -SOH; aliR 5 is hydrogen, C 14 alkyl, C 24 alkenyl, C 24 alkynyl or NR 7 R 17 , excluding parts -SR s , wherein -SNR ? R 17 and -SOR s wherein -SOH; or R6 alkil, halo-substituiran-C1-4 alkil, alkenil, alkinil ali C3 5 cikloalkil;R 6 alkyl, halo-substituted C 1-4 alkyl, alkenyl, alkynyl or C 3-5 cycloalkyl; R, in R17 vsakega neodvisno izberemo izmed vodika ali CM alkila ali R7 in R17 skupaj z dušikom, na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč pa v danem primeru vsebuje dodatni heteroatom izbran izmed kisika, žvepla ali NR22;R, and R 17 are each independently selected from hydrogen or a C M alkyl, or R 7 and R 17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen , sulfur or NR 22 ; Rg vodik, heterociklil, heterociklilalkil ali Rn;R g is hydrogen, heterocyclyl, heterocyclylalkyl or R n ; R10 in R20 je vsake neodvisno izbran izmed vodika ali C1M alkila;R 10 and R 20 are each independently selected from hydrogen or C 1 M alkyl; Rn CJ40 alkil, halo-substituirani C11θ alkil, C210 alkenil, C21() alkinil, C3 7 cikloalkil, C5 _7 cikloalkenil, aril, arilalkil, heteroaril ali heteroarilalkil;Rn C J40 alkyl, halo-substituted C 11θ alkyl, C 210 alkenyl, C 21 () alkynyl, C 3 7 cycloalkyl, C 5 _ 7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R12 vodik, -C(Z)R13 ali v danem primeru substituiran CM alkil, aril ali aril-C14 alkil;R 12 is hydrogen, -C (Z) R 13 or optionally substituted C M alkyl, aryl or aryl-C 14 alkyl; R13 vodik, Cj alkil, cikloalkil, heterociklil, aril, arilalkil, heteroaril ali heteroarilalkil;R 13 is hydrogen, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R16 in R26 vsak neodvisno izbran izmed vodika in v danem primeru substituiranega C^ alkila, arila, ali aril-C]4 alkila ali skupaj z dušikom, na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč pa v danem primeru vsebuje dodaten heteroatom, izbran izmed kisika, žvepla ali NR12;R 16 and R 26 are each independently selected from hydrogen and optionally substituted C 1-4 alkyl, aryl, or aryl-C 1-4 alkyl, or together with the nitrogen to which they are attached, form a heterocyclic ring of 5 to 7 members, this ring being optionally containing an additional heteroatom selected from oxygen, sulfur or NR 12 ; R22 R10 ali C(Z)-C14 alkil; R 22 R 10 or C (Z) -C 14 alkyl; R^ C14 alkil, halo-substituiran Cw alkil ali C3 5 cikloalkil;R 1 is C 14 alkyl, halo-substituted C w alkyl or C 3-5 cycloalkyl; R36 vodik ali R^;R 36 is hydrogen or R 16; ali njena farmacevtsko sprejemljiva sol;or a pharmaceutically acceptable salt thereof; in brez 2-(4-klorofenil)-4-(4-metoksifenil)-5-(4-piridil)imidazola in 2-fenil-4-fenil-5(4-piridil)imidazola.and free of 2- (4-chlorophenyl) -4- (4-methoxyphenyl) -5- (4-pyridyl) imidazole and 2-phenyl-4-phenyl-5 (4-pyridyl) imidazole. 2. Spojina po zahtevku 1, označena s tem, da je Rt v danem primeru substituiran 4-piridil, 4-pirimidinil, 4-kinolil, 6-izokinolil, 1-imidazolil ali 1-benzimidazolil.A compound according to claim 1, wherein R t is optionally substituted 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolyl, 1-imidazolyl or 1-benzimidazolyl. 3. Spojina po zahtevku 1 ali 2, označena s tem, daje R2 vodik ali C1]Q alkil.A compound according to claim 1 or 2, wherein R 2 is hydrogen or C 1 -C 5 alkyl. 4. Spojina po katerem koli od zahtevkov 1 do 3, označena s tem, da v R3 skupina Q vključuje v danem primeru substituiran fenilni, pirolilni, piridilni ali primidilni del.A compound according to any one of claims 1 to 3, characterized in that in R 3 the group Q includes optionally substituted phenyl, pyrrolyl, pyridyl or primidyl moiety. 5. Spojina, po katerem koli od zahtevkov 1 do 4, označena s tem, daje Q substituiran z do tremi substituenti Yp vsak izmed njih pa je neodvisno izbran izmed C15 alkila, halo-substituiranega C15 alkila, halogena, -XaP(Z)-(XbR13)2 ali -(CR10R20)nY2, kjer je Y2 -OR8, -NO2, -S(O)m,Rn, -SRg, -S(O)m.OR8, -S(O)mNR8R9, -NRgR9, -OCCRj^NRgR,, -C(O)R8, -CO2R8, -CO^CRj^CONR^, -ZC(O)RS, -CN, -C(Z)NR8R9, -NR10C(Z)R8, -C(Z)NR8OR9, -NR10C(Z)NR8R9, -NR10S(O)mRlp -N(OR21)C(Z)NR8R9, -N(OR21)C(Z)Rg, -C(=NOR21)R8, -NR10C(=NR15)SRn, -NR1oC(=NR15)NR8R9, -NR1oC(=CR14R24SR11, -NR1oC(=CR14R24)NR8R9, -NR10C(O)C(O)NR8R9, -NR10C(O)C(O)OR10, -C( = NR13)NRgR9,A compound according to any one of claims 1 to 4, characterized in that Q is substituted with up to three substituents Y p each of which is independently selected from C 15 alkyl, halo-substituted C 15 alkyl, halogen, -X a P (Z) - (X b R 13 ) 2 or - (CR 10 R 20 ) n Y 2 where Y 2 is -OR 8 , -NO 2 , -S (O) m , R n , -SRg, - S (O) m .OR 8 , -S (O) m NR 8 R 9 , -NR g R 9 , -OCCRj ^ NRgR ,, -C (O) R 8 , -CO 2 R 8 , -CO ^ CRj ^ CONR ^, -ZC (O) R S , -CN, -C (Z) NR 8 R 9 , -NR 10 C (Z) R 8 , -C (Z) NR 8 OR 9 , -NR 10 C ( Z) NR 8 R 9 , -NR 10 S (O) m R lp -N (OR 21 ) C (Z) NR 8 R 9 , -N (OR 21 ) C (Z) R g , -C (= NOR 21 ) R 8 , -NR 10 C (= NR 15 ) SR n , -NR 10 C (= NR 15 ) NR 8 R 9 , -NR 10 C (= CR 14 R 24 SR 11 , -NR 10 C (= CR 14 R 24 ) NR 8 R 9 , -NR 10 C (O) C (O) NR 8 R 9 , -NR 10 C (O) C (O) OR 10 , -C (= NR 13 ) NRgR 9 , -C( = NOR13)NR8R9, -C( = NOR13)NR8R9, -C(=NR13)ZR11, -OC(Z)NRgR9, -NR10S(O)mCF3, -NR10C(Z)OR10, 5-(R18)-l,2,4-oksadiazol-3-il ali 4-(R12-5(RlgRig)-4,5-dihidro-l,2,4-oksadiazol-3-il; m’ je 1 ali 2; n’ je 1 do 10; R9 je vodik, C110 alkil, C21θ alkenil, C21θ alkinil, C37 cikloalkil, C5 7 cikloalkenil, aril, arilalkil, heteroaril ali heteroarilalkil ali pa lahko, Rg in R9, skupaj z dušikom na katerega sta vezana, tvorita heterocikličen obroč s 5 do 7 členi, ta obroč v danem primeru vsebuje dodaten heteroatom, izbran izmed kisika, žvepla ali NR12; R14 in R24 pa vsakega neodvisno izberemo izmed vodika, alkila, nitro ali ciano; R15 je vodik, ciano, ClJ( alkil, C3 7 cikloalkil ali aril; Rlg in R19 vsakega neodvisno izberemo izmed vodika, C14 alkila, substituiranega alkila, v danem primeru substituiranega arila, v danem primeru substituiranega arilalkila ali skupaj pomenita kisik ali žveplo; in je R21 vodik, farmacevtsko sprejemljiv kation, alkil, cikloalkil, aril C^alkil, heteroaril, heteroaril^ 4 alkil, heterociklil, aroil, C140alkoil.-C (= NOR 13 ) NR 8 R 9 , -C (= NOR 13 ) NR 8 R 9 , -C (= NR 13 ) ZR 11 , -OC (Z) NRgR 9 , -NR 10 S (O) m CF 3 , -NR 10 C (Z) OR 10 , 5- (R 18 ) -1,2,4-Oxadiazol-3-yl or 4- (R 12 -5 (R 1g R ig ) -4,5- dihydro-1,2,4-oxadiazol-3-yl; m 'is 1 or 2; n' is 1 to 10; R 9 is hydrogen, C 110 alkyl, C 21θ alkenyl, C 21θ alkynyl, C 37 cycloalkyl, C 5 7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or may be, R g and R 9, together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen , sulfur or NR 12 ; R 14 and R 24 are each independently selected from hydrogen, alkyl, nitro or cyano; R 15 is hydrogen, cyano, C 1-10 ( alkyl, C 3-7 cycloalkyl or aryl; R 1g and R 19 each independently is selected from hydrogen, C 14 alkyl, substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, or together represent oxygen or sulfur, and R 21 is hydrogen, pharmaceutically acceptable iv cation, alkyl, cycloalkyl, aryl, C ^ alkyl, heteroaryl, heteroaryl ^ 4 alkyl, heterocyclyl, aroyl, C 140 Alko. 6. Spojina po zahtevku 5, označena s tem, da substituent Υχ izberemo izmed vodika, C15 alkila in -(CR10R20)nY2, kjer je Y2 -ORg, -NO2, -S(O)m.Rn, -SRg, -S(O)mNRgR9; -NRgR9, -O(CR10R20)nNRgR9, -C(O)Rg, -CO2Rg, -CO2(CR10R20)n.CONRgR9, -CN; -C(Z)NR8R9, -NR10S(O)mR11, -NR10C(Z)Rg, -NR10C(Z)NRgRg, -N(OR21)C(Z)NRgR9, -C(Z)NR8OR9, -NR1oC(=NR15)NR8R9, -C(=NOR13)NR8R9,Compound according to claim 5, characterized in that the substituent Υ χ is selected from hydrogen, C 15 alkyl and - (CR 10 R 20 ) n Y 2 , where Y 2 is -OR g , -NO 2 , -S (O ) m .R n , -SR g , -S (O) m NR g R 9 ; -NR g R 9 , -O (CR 10 R 20 ) n NR g R 9 , -C (O) R g , -CO 2 R g , -CO 2 (CR 10 R 20 ) n .CONR g R 9 , -CN; -C (Z) NR 8 R 9 , -NR 10 S (O) m R 11 , -NR 10 C (Z) R g , -NR 10 C (Z) NR g R g , -N (OR 21 ) C (Z) NR g R 9 , -C (Z) NR 8 OR 9 , -NR 10 o C (= NR 15 ) NR 8 R 9 , -C (= NOR 13 ) NR 8 R 9 , 5-(Rlg)-l,2,4-oksadiazol-3-il ali 4-(R12)-5-(RlgR19)-4,5-dihidro-l,2,4-oksadiazol-3-il.5- (R lg) -l, 2,4-oxadiazol-3-yl or 4- (R12) -5- (R lg R 19) -4,5-dihydro-l, 2,4-oxadiazol-3 -il. 7. Spojina po zahtevku 6, označena s tem, da ima skupina Q en substituent Yp ki je izbran izmed -(CR1QR20)nY2, kjer je: n 0, 1, 2 ali 3 in je Y2 -ORg, -NO2, -S(O)m,R11, -SRg, -S(O)mNR8R9; -NRgR9, -O(CR10R20) NRgR9, -C(O)Rg, -CO2Rg, -CO2(CR10R20)n,CONR8R9, -CN; -C(Z)NRgR9, -NR10S(O)mRu, -NR10C(Z)Rg, -C(Z)NR8OR9, -NR1oC(Z)NR8R9, -N(OR21)C(Z)NR8R9, -C(=NOR13NR8R9, -NR10C(=NR15)NR8R9, 5-(Rlg)-l,2,4-oksadiazol-3-il in 4-(R12)-5-(RlgR19)-4,5dihidro-l,2,4-oksadiazol-3-il.A compound according to claim 6, characterized in that the group Q has one substituent Y p selected from - (CR 1Q R 20 ) n Y 2 , wherein: n is 0, 1, 2 or 3 and Y 2 - OR g , -NO 2 , -S (O) m , R 11 , -SR g , -S (O) m NR 8 R 9 ; -NR g R 9 , -O (CR 10 R 20 ) NR g R 9 , -C (O) R g , -CO 2 R g , -CO 2 (CR 10 R 20 ) n , CONR 8 R 9 , - CN; -C (Z) NR g R 9 , -NR 10 S (O) m R u , -NR 10 C (Z) R g , -C (Z) NR 8 OR 9 , -NR 10 C (Z) NR 8 R 9 , -N (OR 21 ) C (Z) NR 8 R 9 , -C (= NOR 13 NR 8 R 9 , -NR 10 C (= NR 15 ) NR 8 R 9 , 5- (R 1g ) - l, 2,4-oxadiazol-3-yl and 4- (R12) -5- (R lg R 19) -4,5dihidro-l, 2,4-oxadiazol-3-yl. 8. Spojina po zahtevku 7, označena s tem, da je v Υχ n 0 ali 1 in je Y2 -OH, -S(O)m.R11, -SRg, -NRgR9, -CO2Rg, -S(O)m,NRgR9, -NR10S(O)mRlx, 5-(Rlg)-l,2,4oksadiazol-3-il ali 4-(R12)-5-(RlgR19)-4,5-dihidro-l,2,4-oksadiazol-3-il.Compound according to claim 7, characterized in that v Υ χ n is 0 or 1 and Y 2 is -OH, -S (O) m .R 11 , -SR g , -NR g R 9 , -CO 2 R g , -S (O) m , NR g R 9 , -NR 10 S (O) m R 1x , 5- (R 1g ) -1, 2,4oxadiazol-3-yl or 4- (R 12 ) - 5- (R 1g R 19 ) -4,5-dihydro-1,2,4-oxadiazol-3-yl. 9. Spojina po katerem koli izmed zahtevkov 1 do 8, označena s tem, da je v R4 4-fenilni, 4-naft-l-ilni ali 5-naft-2-ilni substituent halogen, -SRs, -SORs, -OR36, -(CR10R20)mNR16R26 ali -NR10C(Z)Rg in je substituent za druge položaje substitucije izbran izmed halogena, -S(O)mRg, -ORg, -(CR10R20)mNR16R26, -NR10C(Z)Rg aliA compound according to any one of claims 1 to 8, wherein in R 4 the 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent is halogen, -SR s , -SOR s , -OR 36 , - (CR 10 R 20 ) m NR 16 R 26 or -NR 10 C (Z) R g and the substituent for the other substitution positions is selected from halogen, -S (O) m R g , -OR g , - (CR 10 R 20 ) m NR 16 R 26 , -NR 10 C (Z) R g or 10. Spojina po katerem koli izmed zahtevkov 1 do 9, označena s tem, da je Rx 10. A compound according to any one of claims 1 to 9, characterized in that R x 4-piridil, 2-alkil-4-piridil ali 4-kinolil; R2 je vodik ali metil; R3 je fenil ali fenil substituiran, prednostno na položaju -4 s substituentom, izbranim izmed -(CR^R^)nY2,4-pyridyl, 2-alkyl-4-pyridyl or 4-quinolyl; R 2 is hydrogen or methyl; R 3 is phenyl or phenyl substituted, preferably at position -4 with a substituent selected from - (CR 2 R 4) n Y 2 , 4-(R12)-5-(RlgR19)-4,5-dihidro-l,2,4-oksadiazol-3-il ali 3,5-dimetil- ali 3,5-dibromo-4hidroksilna grupacija; in je R4 fenil ali fenil substituiran na položaju -4 s fluoro in/ali substituiran na položaju -3, s fluoro, kloro, CM alkoksi, metan-sulfonamido ali acetamido.4- (R 12 ) -5- (R 1g R 19 ) -4,5-dihydro-1,2,4-oxadiazol-3-yl or 3,5-dimethyl- or 3,5-dibromo-4-hydroxyl group; and R 4 is phenyl or phenyl substituted at the 4-position with fluoro and / or substituted in position -3 with a fluoro, chloro, C M alkoxy, methane-sulfonamido or acetamido. 11. Spojina s formulo (I) po zahtevku 1, označena s tem, dajo izberemo izmed: 4-(4-fluorofenil)-2-(4-metiltiofenil)-5-(4-piridil)imidazola; 4-(4-fluorofenil)-2-(4-etiltiofenil)-5-(4-piridil)imidazola; 4-(4-fluorofenil)-2-(4-metilsulfonilfenil)-5-(4-piridil)imidazola; 4-(4-fluorofenil)-2-(4-metilsulfinilfenil)-5-(4-piridil)imidazola; 4-(4-fluorofenil)-2-(4-etilsulfinilfenil)-5-(4-piridil)imidazola; 4-(3-klorofenil)-2-(4-metilsulfmilfenil)-5-(4-piridil)imidazola; 2-[4-(N-metil-N-benzil)aminometilfenil]-4-(4-fluorofenil)-5-(4-piridil)imidazola; 4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metiltiofenil)imidazola; 4-(4-fluorofenil)-5-[4-(2-metilpiridil)]-2-(4-metilsulfmilfenil)imidazola; 4-(4-fluorofenil)-2-(4-metilsulfmilfenil)-5-(4-kinolil)imidazola; 2-[4-(N-morfolino)metilfenil]-4-(4-fluorofenil)-5-(4-piridil)-imidazola;A compound of formula (I) according to claim 1, characterized in that it is selected from: 4- (4-fluorophenyl) -2- (4-methylthiophenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (4-ethylthiophenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (4-methylsulfonylphenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -2- (4-ethylsulfinylphenyl) -5- (4-pyridyl) imidazole; 4- (3-chlorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole; 2- [4- (N-methyl-N-benzyl) aminomethylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) imidazole; 4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylthiophenyl) imidazole; 4- (4-fluorophenyl) -5- [4- (2-methylpyridyl)] - 2- (4-methylsulfinylphenyl) imidazole; 4- (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-quinolyl) imidazole; 2- [4- (N-morpholino) methylphenyl] -4- (4-fluorophenyl) -5- (4-pyridyl) -imidazole; ali njena farmacevtsko sprejemljiva sol.or a pharmaceutically acceptable salt thereof. 12. Postopek za pripravo spojine s formulo (I) kot je definirana po kateremkoli izmed zahtevkov 1 do 11, označen s tem, da ta postopek vljučuje:A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 11, characterized in that the process involves: (i) kondenzacijo α-diketona s formulo (II):(i) Condensation of α-diketone of formula (II): R1COCOR4 (II), kjer sta Rj in R4, kot je definirano preje, ali njun ekvivalent, z aldehidom s formulo (III):R 1 is COCOR 4 (II) wherein R 1 and R 4 are as defined yarns or their equivalent, with an aldehyde of formula (III): R3CHO (III), kjer je R3 kot je definirano zgoraj ali njegov ekvivalent, in če je potrebno, z amoniakom ali njegovim virom, pod imidazol-obroč tvorbenimi pogoji;R 3 is CHO (III), wherein R 3 is as defined above or equivalent and, if necessary, with ammonia or its source, under imidazole ring formation conditions; (ii) obdelavo α-hidroksiketonske spojine s formulo (ΙΙΑ):(ii) treating an α-hydroxyketone compound of formula (ΙΙΑ): R’CHOHCOR” (IIA), kjer je eden izmed R’ in R” Rj in je drugi R4, njen primerno zaščiten derivat ali njen α-hidroksi oksimski ali α-haloketonski derivat, z oksidacijskim sredstvom, sposobnim pretvorbe omenjene spojine v ustrezen α-diketon, v prisotnosti aldehida s formulo (III) ali njegovega ekvivalenta in vira amoniaka;R'CHOHCOR "(IIA), wherein one of R 'and R" is Rj and the other is R 4 , its suitably protected derivative or its α-hydroxy oxime or α-haloketone derivative, with an oxidizing agent capable of converting said compound to the corresponding α-diketone, in the presence of an aldehyde of formula (III) or its equivalent and source of ammonia; (iii) obdelavo amidina s formulo (IV):(iii) treating the amidine of formula (IV): R3C(=NH)NHR2 (IV), kjer sta R2 in R3, kot sta definirana preje ali njegove soli, z reaktivnim estrom α-hidroksiketona s formulo (IIA) ali ustreznim α-haloketonom v inertnem topilu, pri blago povišani temperaturi in, če je potrebno, v prisotnosti primernega kondenzacijskega sredstva;R 3 C (= NH) NHR 2 (IV), wherein R 2 and R 3 are as defined yarns or salts thereof, with the reactive ester of α-hydroxyketone of formula (IIA) or the corresponding α-haloketone in an inert solvent, at mildly elevated temperature and, if necessary, in the presence of a suitable condensing agent; (iv) obdelavo iminoetra s formulo (V):(iv) treatment of the iminoether of formula (V): R3C=NOR (V), kjer je R3 kot je definirano preje in je R C110 alkil, aril ali aril C14 alkil, z α-aminoketonom s formulo (VI):R 3 C = NOR (V) wherein R 3 is as defined in yarn and RC 110 is alkyl, aryl or aryl C 14 alkyl, with an α-aminoketone of formula (VI): R’CHNH2COR” (VI), kjer je eden izmed R’ in R” Rj in je drugi R4, v primernem topilu;R'CHNH 2 COR '(VI), wherein one of R' and R 'is Rj and the other is R 4 , in a suitable solvent; (v) obdelavo aniona amida s formulo (VII):(v) Treatment of an amide anion of formula (VII): RjCH2NR2COR3 (VII), kjer sta Rj in R3 kot je definirano preje in je R2 kot je definiran preje drugačen od vodika, z:RjCH 2 NR 2 COR 3 (VII), wherein Rj and R 3 are as defined yarns and R 2 as defined yarns is other than hydrogen, with: (a) nitril s formulo (VIII):(a) Nitrile of formula (VIII): R4CN (VIII), kjer je R4 kot je definirano preje, ali (b) prebitkom acil halida, npr. acil klorida, s formulo (IX):R 4 is CN (VIII), where R 4 is as defined in yarn, or (b) an excess of acyl halide, e.g. acyl chloride of formula (IX): R4COHal (IX), kjer je R4 kot je definirano preje in je Hal halogen ali ustrezen anhidrid, da dobimo δΰ-aciliran intermediat, ki ga nato obdelamo z virom amoniaka;R 4 is COHal (IX), where R 4 is as defined in yarn and Hal is halogen or a suitable anhydride to give a δΰ-acylated intermediate, which is then treated with an ammonia source; (vi) obdelavo spojine s formulo (X)(vi) treating a compound of formula (X) R’COCHR”XcCOR3 (X), kjer so R’, R” in R4, kot je definirano preje in je Xc O ali NH, z virom amoniaka ali cikliziranje ustrezne Schiffove baze, pridobljene za obdelavo spojine s formulo (X) z aminom R2NH2;R'COCHR "X c COR 3 (X) wherein R ', R" and R 4 are as defined in yarn and X c is O or NH, with an ammonia source or cyclization of a suitable Schiff base obtained for treating a compound of formula (X) with the amine R2NH2; (vii) pripajanje primernega derivata spojine s formulo (XI):(vii) coupling a suitable derivative of a compound of formula (XI): _ 72 (xi) kjer je: T2 dušik zaščitna skupina ali R2 drugačen kot vodik; in je Tj vodik, T3 Q in T4 R4; Tj je Rj, T3 je vodik in T4 je R4; ali Tj je Rj, T3 je Q in T4 je vodik, v kateri so Rj, R2, R3, R4 in Q kot smo definirali zgoraj; s (i) kadar je Tj vodik, primernim derivatom heteroarilnega obroča RjH, pod obroč pripajalnimi pogoji, da izvedemo pripajanje heteroarilnega obroča Rj k imidazolnemu jedru na položaju 5;_ 72 (xi) wherein: T 2 is a nitrogen protecting group or R 2 is other than hydrogen; and Tj is hydrogen, T 3 Q and T 4 R 4 ; I.e. R 1, T 3 is hydrogen and T 4 is R 4 ; or T 1 is R 1, T 3 is Q and T 4 is hydrogen, in which R 1, R 2 , R 3 , R 4 and Q are as defined above; s (i) when Tj is hydrogen, a suitable derivative of the heteroaryl ring RjH, under ring coupling conditions, in order to attach the heteroaryl ring Rj to the imidazole nucleus at position 5; (ii) kadar je T3 vodik, primernim derivatom arilnega ali heteroarilnega obroča QH, pod obroč pripajalnimi pogoji, da izvedemo pripajanje obroča Q k imidazolnemu jedru na položju 2; ali (iii) kadar je T4 vodik, primernim derivatom arilnega obroča R4H, pod obroč pripajalnimi pogoji, da izvedemo pripajanje arilnega obroča R4 k imidazolnemu jedru na položaju 4;(ii) when T 3 is hydrogen, a suitable derivative of the aryl or heteroaryl ring QH, under ring coupling conditions, in order to attach ring Q to the imidazole nucleus at position 2; or (iii) when T 4 is hydrogen, a suitable derivative of the aryl ring R 4 H, under ring coupling conditions, to attach the aryl ring R 4 to the imidazole nucleus at position 4; (viii) obdelava spojine s formulo (XI), kjer je Τχ vodik z N-acil heteroarilno soljo, da dobimo intermediat, v katerem je heteroarilni obroč vezan k imidazolnemu jedru in je prisoten kot njegov 1,4-dihidro derivat, ta intermediat nato izpostavimo oksidativno-deacilacijskim pogojem; in nato, če je potrebno, izvedemo vse ali katerekoli dodatne korake odstranitve zaščitne skupine, pretvorbe prvotno pridobljene spojine s formulo (I) v nadaljnjo spojino s formulo (I) ali tvorbe farmacevtsko sprejemljive soli.(viii) treating a compound of formula (XI) wherein Τ χ is hydrogen with an N-acyl heteroaryl salt to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as its 1,4-dihydro derivative, this intermediate then exposed to oxidative-deacylation conditions; and then, if necessary, perform all or any additional steps of removing the protecting group, converting the initially obtained compound of formula (I) to a further compound of formula (I), or forming a pharmaceutically acceptable salt. 13. Spojina s formulo (I), kot je definirana po kateremkoli izmed zahtevkov 1 do 11, ali njena farmacevtsko sprejemljiva sol, označena s tem, da jo uporabimo pri zdravljenju.A compound of formula (I) as defined in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in treatment. 14. Uporaba spojine s formulo (I), kot je definirano po katerem koli od zahtevkov 1 do 11 ali njene farmacevtsko sprejemljive soli pri pridobivanju zdravila za zdravljenje citokinsko-posredovanega bolezenskega stanja.Use of a compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a cytokine-mediated disease state. 15. Farmacevtski sestavek, označen s tem, da vključuje učinkovito ne-toksično količino spojine s formulo (I) po katerem koli od zahtevkov 1 do 11 ah njene farmacevtsko sprejemljive soli, in farmacevtsko sprejemljivi nosilec ali diluent.15. A pharmaceutical composition comprising an effective non-toxic amount of a compound of formula (I) according to any one of claims 1 to 11 ah its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.
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