SK12002003A3 - Novel tyrosine kinase inhibitors - Google Patents

Novel tyrosine kinase inhibitors Download PDF

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SK12002003A3
SK12002003A3 SK12002003A SK12002003A SK12002003A3 SK 12002003 A3 SK12002003 A3 SK 12002003A3 SK 12002003 A SK12002003 A SK 12002003A SK 12002003 A SK12002003 A SK 12002003A SK 12002003 A3 SK12002003 A3 SK 12002003A3
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Slovakia
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methyl
pyridin
benzoimidazol
group
hydroxy
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SK12002003A
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Slovak (sk)
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Mark WITTMAN
Neelakantan Balasubramanian
Upender Velaparthi
Kurt Zimmermann
Mark G Saulnier
Peiying Liu
Xiaopeng Sang
David B Frennesson
Karen M Stoffan
James G Tarrant
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Bristol Myers Squibb Co
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Publication of SK12002003A3 publication Critical patent/SK12002003A3/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The present invention provides compounds of formula I[ ] and pharmaceutically acceptable salts thereof. The formula I compounds inhibit tyrosine kinase enzymes thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases which can be treated by inhibiting tyrosine kinase enzymes.

Description

Vynález sa vzťahuje na oblasť inhibície tyrozínkinázy s použitím nových nízkomolekulárnych inhibítorov.The invention relates to the field of tyrosine kinase inhibition using novel low molecular weight inhibitors.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Tyrozínkinázy tvoria triedu enzýmov, ktoré katalyzujú prenos terminálneho fosfátu z adenozíntrifosfátu na fenolovú hydroxylovú skupinu tyrozínového zvyšku obsiahnutého v cielenom proteine. Tyrozínkinázy majú rozhodujúcu úlohu v prenose signálu v niekoľkých bunkových funkciách zahrňujúcich proliferáciu buniek, karcinogenézu, apoptózu a diferenciáciu buniek (Plowman G.D.; Ullrich A.; Shawver L.K.; Receptor Tyrosine Kinases As Targets For Drug Intervention. DN a P (1994) 7:334-339). Preto by inhibítory vyššie uvedených enzýmov mohli byť vhodnými prostriedkami na liečenie alebo prevenciu proliferatívnych chorôb závislých od uvedených enzýmov. Z epidemiologických zistení vyplýva, že nadmerná expresia alebo aktivácia proteínových receptorov tyrozínkináz vedúca k signalizácii konštitučnej mitogenity je významným faktorom zahrnutým v rastúcom počte maligných ochorení ľudí. Tyrozínkinázy, u ktorých bolo zistené, že sú zahrnuté vo vyššie uvedených procesoch zahrňujú Abl, CDK, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src, a VEGF (Traxler P.M., Proteín Tyrosine Kinase Inhibitors in Cancer Treatment, Exp.Opin.Ther.Patents (1997), 7:571-588; uvedená práca je včlenená do tohto opisu odkazom). Preto stále pokračuje potreba vývoja nových zlúčenín vhodných na reguláciu alebo na inhibíciu enzýmov zo skupiny tyrozínkináz.Tyrosine kinases constitute a class of enzymes that catalyze the transfer of terminal phosphate from adenosine triphosphate to the phenolic hydroxyl group of the tyrosine residue contained in the targeted protein. Tyrosine kinases play a critical role in signal transduction in several cellular functions including cell proliferation, carcinogenesis, apoptosis and cell differentiation (Plowman GD; Ullrich A .; Shawver LK; Tyrosine Kinases As Targets For Drug Intervention. DN and P (1994) 7: 334 -339). Therefore, inhibitors of the above-mentioned enzymes could be suitable means for treating or preventing proliferative diseases dependent on said enzymes. Epidemiological findings suggest that overexpression or activation of protein receptor tyrosine kinases leading to constitutional mitogenicity signaling is an important factor involved in the increasing number of human malignancies. Tyrosine kinases that have been found to be involved in the above processes include Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src. , and VEGF (Traxler PM, Protein Tyrosine Kinase Inhibitors in Cancer Treatment, Exp.Opin.Ther.Patents (1997), 7: 571-588; the disclosure of which is incorporated herein by reference). Accordingly, there is a continuing need for the development of novel compounds suitable for the regulation or inhibition of tyrosine kinase enzymes.

Podstata vynálezuSUMMARY OF THE INVENTION

Vynález sa vzťahuje na zlúčeniny, ktoré sú inhibítory enzýmov zo skupiny tyrozinkináz, na kompozície obsahujúce uvedené inhibítory tyrozínkináz a na spôsoby použitia inhibítorov tyrozínkináz na liečbu chorôb charakterizovaných nadmernou expresiou alebo nadmernou produkciou aktivity tyrozinkinázy, ako je rakovina, diabetes, restenóza, artérioskleróza, psoriáza, angiogénne choroby a imunologické choroby (Powis G.; Workman P., Signaling Targets for The Development of Cancer Drugs., Anti-Cancer Drug Design (1994), 9:263-277; Merenmies J.; Parada L.F.; Henkemeyer M., Receptor Tyrosine Kinase Signaling in Vascular Development, Celí Growth Differ (1997) 8:3-10; Shawver L.K.; Lipsosn K.E.; Fong T.A.T.; McMahon G.; Plowman G.D.; Strawn L.M., Receptor Tyrosine Kinases As Targets For Inhibition of Angiogenesis, Drug Discovery Today (1997) 2:50-63; kde všetky uvedené publikácie sú do tohto textu včlenené odkazom.The invention relates to compounds which are inhibitors of enzymes of the tyrosine kinase family, to compositions comprising said tyrosine kinase inhibitors and to methods of using tyrosine kinase inhibitors for the treatment of diseases characterized by overexpression or overproduction of tyrosine kinase activity such as cancer, diabetes, restenosis, arteriosclerosis, psoriasis, angiogenic diseases and immunological diseases (Powis G .; Workman P., Signaling Targets for Development of Cancer Drugs., Anti-Cancer Drug Design (1994), 9: 263-277; Merenmies J .; Parada LF; Henkemeyer M., Receptor Tyrosine Kinase Signaling in Vascular Development, Cell Growth Differ (1997) 8: 3-10; Shawver LK; Lipsosn KE; Fong TAT; McMahon G .; Plowman GD; Strawn LM; Receptor Tyrosine Kinases As Targets For Inhibition Of Angiogenesis, Drug Discovery Today (1997) 2: 50-63, all of which are incorporated herein by reference.

Okrem použitia prostriedkov podlá vynálezu ako samostatných prostriedkov sa dálej predpokladá, že inhibítory tyrozinkinázy podľa vynálezu môžu zvyšovať účinnosť liečby cytotoxickými alebo cytostatickými prostriedkami pri ich použití v kombinácii so štandardnými terapeutickými spôsobmi známymi v odbore.In addition to using the compositions of the invention as separate compositions, it is further contemplated that the tyrosine kinase inhibitors of the invention may increase the effectiveness of treatment with cytotoxic or cytostatic agents when used in combination with standard therapeutic methods known in the art.

Vynález sa vzťahuje na zlúčeniny všeobecného vzorca (I) a na ich enantioméry, diastereoméry, farmaceutický prijateľné soli, hydráty, proliečivá a solváty;The invention relates to compounds of formula (I) and to enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs and solvates thereof;

kdewhere

X znamená skupinu zvolenú zo skupiny zahrňujúcej N, C, Ci-C3alkyl, Cr C3alkyl substituovaný jedným alebo viacerými substituentami R7 a priamu väzbu;X is selected from the group consisting of N, C, C 3 alkyl, C r C 3 alkyl substituted by one or more substituents R 7, and a direct bond;

Y znamená O alebo S;Y is O or S;

W má význam zvolený zo skupiny zahrňujúcej N, C, O a S s tou výhradou, že keď W znamená O alebo S, R9 nemá žiadny význam;W has the meaning selected from the group consisting of N, C, O and S, provided that when W is O or S, R 9 has no meaning;

R1, R2, R3, R4, R5, R5, R7, R8, R9 každý nezávisle znamená skupinu nezávisle zvolenú zo skupiny zahrňujúcej H, Ci-Cealkyl, alkenyl, alkinyl, cykloalkyl, heterocykloalkyl, halogén, amino, OR50, NO2, OH, SR60, NR60R51, CN, CO2R60, CONR60R61, C02NR60R51, NR62CONR60R51, NR60SO2R61, SO2NR60R61,R 1 , R 2 , R 3 , R 4 , R 5 , R 5 , R 7 , R 8 , R 9 each independently represent a group independently selected from H, C 1 -C 6 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogen , amino, OR 50 , NO 2, OH, SR 60 , NR 60 R 51 , CN, CO 2 R 60 , CONR 60 R 61 , CO 2 NR 60 R 51 , NR 62 CONR 60 R 51 , NR 60 SO 2 R 61 , SO 2 NR 60 R 61 ,

C(NR62)NR50R61, aryl, heteroaryl, (CH2)nOR60, (CH2)nNR60R61, (CH2)nSR60, (CH2)naryl, (CH2)nheteroaryl, (CH2)nheterocykloalkyl, NH-Z-aryl a NH-Z-heteroaryl;C (NR 62) NR 50 R 61, aryl, heteroaryl, (CH 2) n OR 60, (CH 2) n NR 60 R 61, (CH 2) n SR 60, (CH 2) n -aryl, (CH 2) n Heteroaryl, (CH 2 n- heterocycloalkyl, NH-Z-aryl and NH-Z-heteroaryl;

kde n znamená 1 až 3; awherein n is 1 to 3; and

Z znamená skupinu zvolenú zo skupiny zahrňujúcej CrCAalkyl, alkenyl a alkinyl; Z obsahujúcich jednu alebo viac skupín zvolených zo skupiny zahrňujúcej hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, NRsoS02R51; Z skupín s prípadne včlenenou jednou alebo viac skupinou zvolenou zo skupiny zahrňujúcej CO, CNOH, CNOR50, CNNR60, CNNCOR60 a CNNSO2R50;Z represents a group selected from the group consisting of C 1 -C 4 alkyl, alkenyl and alkynyl; Z having one or more groups selected from hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, NR a S02R 51; Among the groups optionally incorporated by one or more selected from the group consisting of CO, CNOH, CNOR 50 , CNNR 60 , CNNCOR 60, and CNNSO 2 R 50 ;

R50, R61 a R62 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej H, alkyl, alkenyl, alkinyl, cykloalkyl, cykloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl a alkyl-R25, kdeR 50 , R 61 and R 62 each independently represent a group selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25 wherein:

R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, kyano, halogén, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; aR 25 represents a group selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halogen, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O ) R 31, -NR 30 SO 2 R 31, -C (O) NR 30 R 31, heteroaryl or heterocycloalkyl; and

R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

Vo výhodných uskutočneniach R1, R7, R8 a R9 znamenajú vodík;In preferred embodiments, R 1 , R 7 , R 8 and R 9 are hydrogen;

R2 a R4 znamenajú H alebo F;R 2 and R 4 are H or F;

Y znamená O:Y stands for O:

X znamená skupinu zvolenú zo skupiny zahrňujúcej N a CH;X represents a group selected from the group consisting of N and CH;

W znamená N;W is N;

R5 znamená skupinu zvolenú zo skupiny zahrňujúcej H, metyl, etyl, izopropyl, sek-butyl, cyklopropyl, F a CF3;R 5 represents a group selected from H, methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, F and CF 3 ;

gg

R znamená skupinu zvolenú zo skupiny zahrňujúcej H, 2-aminometylpyridín, NHCH(CH2OH)CH2Ph, NHCH2CH(OH)aryl, a NHCH(CH2OH)CH2aryl; aR is selected from the group consisting of H, 2-aminomethylpyridine, NHCH (CH 2 OH) CH 2 Ph, NHCH 2 CH (OH) aryl, and NHCH (CH 2 OH) CH 2 aryl; and

R3 znamená skupinu zvolenú zo skupiny zahrňujúcej OR60, C(NH)NHR60, 60R 3 is selected from the group consisting of OR 60 , C (NH) NHR 60 , 60

C(O)NHR , imidazol, imidazolín, tetrahydropyrimidín, piperazín, morfolín, homomorfolín, piperidin, pyrolidín, homopiperazin a amino; kdeC (O) NHR, imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino; where

RORO

R znamená skupinu zvolenú zo skupiny zahrňujúcej H, alkyl, cykloalkyl, heterocykloalkyl, a alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, tioalkoxy, alkoxy, tioalkoxy, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, alebo heteroalkyl alebo heterocykloalkyl; aR represents a group selected from H, alkyl, cycloalkyl, heterocycloalkyl, and alkyl-R 25 , wherein R 25 represents a group selected from hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , or heteroalkyl or heterocycloalkyl; and

3131

R a R každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R and R each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

Vynález taktiež poskytuje farmaceutickú kompozíciu obsahujúcu zlúčeninu všeobecného vzorca (I) opísanú vyššie a farmaceutický prijateľný nosič.The invention also provides a pharmaceutical composition comprising a compound of formula (I) described above and a pharmaceutically acceptable carrier.

Vynález ďalej poskytuje farmaceutickú kompozíciu obsahujúcu zlúčeninu všeobecného vzorca (I) opísanú vyššie v spojení s farmaceutický prijateľným nosičom a s najmenej jedným ďalším antikancerogénnym prostriedkom prípadne vo forme jedného prípravku vo zvolených dávkach.The invention further provides a pharmaceutical composition comprising a compound of formula (I) described above in association with a pharmaceutically acceptable carrier and at least one other anticancer agent, optionally in the form of a single preparation at selected doses.

Okrem toho vynález poskytuje spôsob liečenia stavu majúceho spojitosť s najmenej jedným enzýmom zo skupiny tyrozínkináz, ktorý zahrňuje podávanie účinného množstva zlúčeniny všeobecného vzorca (I) opísanej vyššie subjektu patriacemu medzi cicavce, ktorého je potrebné liečiť. Ďalej vynález poskytuje spôsob liečenia stavu majúceho spojitosť s najmenej jedným enzýmom zo skupiny tyrozínkináz, ktorý zahrňuje podávanie najmenej jedného ďalšieho antikancerogénneho prostriedku v spojení so zlúčeninou všeobecného vzorca (I) opísanou vyššie, subjektu patriacemu medzi cicavce, ktorého je potrebné liečiť.In addition, the invention provides a method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering to a mammal in need of treatment an effective amount of a compound of formula (I) described above. Further, the invention provides a method of treating a condition having an association with at least one enzyme from the group of tyrosine kinases, which comprises administering at least one additional anticancer agent in conjunction with a compound of formula (I) described above to a mammalian subject in need of treatment.

Opisdescription

Vynález poskytuje zlúčeniny všeobecného vzorca (I) opísané vyššie, farmaceutické kompozície obsahujúce uvedené zlúčeniny a spôsoby použitia vyššie uvedených zlúčenín.The invention provides the compounds of formula (I) described above, pharmaceutical compositions comprising said compounds, and methods of using the above compounds.

Nižšie nasleduje opis významov rôznych výrazov použitých k opisu zlúčenín podľa vynálezu. Uvedené definície sa vzťahujú na výrazy použité v opise vynálezu (pokiaľ v špecifických prípadoch nie je uvedené iné obmedzenie) tak samostatne, ako aj na uvedené výrazy tvoriace súčasť väčšej skupiny.The following describes the meanings of the various terms used to describe the compounds of the invention. The foregoing definitions apply to the terms used in the description of the invention (unless otherwise specified in specific cases), both separately and to those terms forming part of a larger group.

Výraz alkyl” použitý tak samostatne, ako aj súčasť inej skupiny znamená monovalentnú od alkánu (uhľovodíka) odvodenú skupinu obsahujúcu 1 až 12 atómov uhlíka pokiaľ nie je uvedené inak. Alkylová skupina môže byť prípadne substituovaná priamou, rozvetvenou alebo cyklickou nasýtenou uhľovodíkovou skupinou. Pokiaľ je alkylová skupina substituovaná, môže byť substituovaná až štyrmi definovanými substitučnými skupinami R v ktoromkoľvek možnom mieste pripojenia. Pokiaľ je alkylová skupina substituovaná alkylovou skupinou je možné použiť alternatívny výraz rozvetvená alkylová skupina. Príklady nesubstituovaných alkylových skupín zahrňujú metyl, etyl, propyl, izopropyl, butyl, terc-butyl, izobutyl, pentyl, hexyl, izohexyl, heptyl, 4,4-dimetylpentyl, oktyl, 2,2,4-trimetylpentyl, nonyl, decyl, undecyl, dodecyl a podobne. Príklady substitučných skupín zahrňujú, ale nie sú obmedzené len na ne, nasledujúce skupiny: hydroxy, halogén (ako F, Cl, Br, I), halogénalkyl (ako CCI3 alebo CF3), alkoxy, alkyltio, kyano, karboxy (-COOH), alkylkarbonyl (-C(O)R), alkoxykarbonyl (-OCOR), amino, karbamoyl (-NHCOOR alebo -OCONHR), skupinu odvodenú od močoviny (-NHCONHR), tiol, (-SH), sulfoxy, sulfonyl, aryl, heteroaryl a heterocykloalkyl. Alkylové skupiny opísané vyššie môžu tiež obsahovať jednu alebo viac dvojitých väzieb uhlík-uhlík alebo jednu alebo viac trojitých väzieb uhlík-uhlík. Alkylové skupiny je rovnako možné znázorniť všeobecným vzorcom alkyl-R25. Vo výhodných uskutočneniach alkylová skupina znamená skupinu zo skupiny zahrňujúcej metyl, etyl, propyl alebo butyl a zahrňuje substituované metylové, etylové, propylové alebo butylové skupiny.The term alkyl, used alone and as part of another group, means a monovalent alkane (hydrocarbon) derived group having 1 to 12 carbon atoms unless otherwise indicated. The alkyl group may be optionally substituted by a straight, branched, or cyclic saturated hydrocarbon group. When an alkyl group is substituted, it may be substituted by up to four defined substituent groups R at any possible point of attachment. When an alkyl group is substituted with an alkyl group, an alternative term branched alkyl group may be used. Examples of unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl , dodecyl, and the like. Examples of substituent groups include, but are not limited to, the following groups: hydroxy, halogen (such as F, Cl, Br, I), haloalkyl (such as CCl 3 or CF 3 ), alkoxy, alkylthio, cyano, carboxy (-COOH) , alkylcarbonyl (-C (O) R), alkoxycarbonyl (-OCOR), amino, carbamoyl (-NHCOOR or -OCONHR), a urea-derived group (-NHCONHR), thiol, (-SH), sulfoxy, sulfonyl, aryl, heteroaryl and heterocycloalkyl. The alkyl groups described above may also contain one or more carbon-carbon double bonds or one or more carbon-carbon triple bonds. Alkyl groups can also be represented by the formula alkyl-R 25 . In preferred embodiments, alkyl is methyl, ethyl, propyl, or butyl, and includes substituted methyl, ethyl, propyl, or butyl groups.

Výraz alkenyl” použitý tak samostatne, ako aj súčasť inej skupiny znamená uhľovodíkovú skupinu s priamym, rozvetveným alebo cyklickým reťazcom obsahujúcu 2 až 12 atómov uhlíka a najmenej jednu dvojitú väzbu uhlík-uhlík. Alkenylová skupina môže byť substituovaná rovnakým spôsobom, ako je spôsob opísaný pre alkylovú skupinu.The term alkenyl, used alone and as part of another group, means a straight, branched or cyclic hydrocarbon group having 2 to 12 carbon atoms and at least one carbon-carbon double bond. The alkenyl group may be substituted in the same manner as described for the alkyl group.

Výraz alkinyl” použitý tak samostatne, ako aj súčasť inej skupiny znamená uhľovodíkovú skupinu s priamym, rozvetveným alebo cyklickým reťazcom obsahujúcu 2 až 12 atómov uhlíka a najmenej jednu trojitú väzbu uhlík-uhlík. Alkinylová skupina môže byť substituovaná rovnakým spôsobom, ako je spôsob opísaný pre alkylovú skupinu.The term alkynyl, used alone and as part of another group, means a straight, branched or cyclic hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may be substituted in the same manner as described for the alkyl group.

Výraz alkoxy” použitý tak samostatne, ako aj súčasť inej skupiny znamená alkylovú skupinu s priamym alebo s rozvetveným reťazcom obsahujúcu jeden až desať atómov uhlíka kovalentne pripojenú k materskej molekule cez atóm kyslíka, a výrazy ”Ci-C6alkoxy a nižší alkoxy” sa vzťahujú na vyššie uvedené skupiny obsahujúce jeden až šesť atómov uhlíka pričom ako príklady uvedených skupín, ale bez obmedzenia len na ne, je možné uviesť metoxy, etoxy, propoxy, izopropoxy, tercbutoxy a podobne. Výraz prípadne substituovaný” použitý v súvislosti s alkoxylovou skupinou znamená, že jeden až dva atómy vodíka, výhodne na rôznych atómoch uhlíka, sú nahradené substitučnou skupinou zvolenou zo skupiny zahrňujúcej nižší alkyl, fenyl, kyano, halogén, trifluórmetyl, nitro, hydroxy, alkanoyl, amino, monoalkylamino a dialkylamino. Alkoxylová skupina môže byť substituovaná rovnakým spôsobom, ako je spôsob opísaný pre alkylovú skupinu.The term "alkoxy" used alone and as part of another group means a straight or branched chain alkyl group containing one to ten carbon atoms covalently attached to the parent molecule via an oxygen atom, and the terms "C 1 -C 6 alkoxy and lower alkoxy" refer to to the aforementioned groups having one to six carbon atoms, examples of which include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, and the like. The term optionally substituted as used in connection with an alkoxy group means that one to two hydrogen atoms, preferably at different carbon atoms, are replaced by a substituent group selected from the group consisting of lower alkyl, phenyl, cyano, halogen, trifluoromethyl, nitro, hydroxy, alkanoyl, amino, monoalkylamino and dialkylamino. The alkoxy group may be substituted in the same manner as described for the alkyl group.

Výraz sulfoxy” použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená skupinu -SO, ktorá môže byť pripadne substituovaná napríklad alkylovou alebo arylovou skupinou.The term "sulfoxy" as used herein alone or as part of another group means -SO, which may optionally be substituted, for example, by an alkyl or aryl group.

Výraz sulfonyl” použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená skupinu -SO2, ktorá môže byť prípadne substituovaná napríklad alkylovou alebo arylovou skupinou.The term "sulfonyl" as used herein alone or as part of another group means -SO 2 , which may be optionally substituted, for example, by an alkyl or aryl group.

Výraz amino použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená skupinu -NH2. Uvedená aminoskupina môže byť pripadne substituovaná jednou alebo dvoma substitučnými skupinami, ktoré môžu byť rovnaké alebo rôzne a zahrňujú skupiny, ako je alkyl, aryl, arylalkyl, alkenyl, alkinyl, heteroaryl, heteroarylalkyl, cykloheteroalkyl, cykloheteroalkylalkyl, cykloalkyl, cykloalkylalkyl, halogénalkyl, hydroxyalkyl, alkoxyalkyl alebo tioalkyl. Výhodne substituované aminoskupiny zahrňujú alkylamino a dialkylamino, ako je metylamino, etylamino, dimetylamino, a dietylamino. Uvedené substituenty môžu byť ďalej substituované karboxylovou kyselinou alebo ktorýmkoľvek z alkylových alebo arylových substituentov uvedených v tomto opise. Okrem toho sa substituenty na aminoskupine môžu spojiť a spoločne s atómom dusíka, ku ktorému sú pripojené tvoriť skupiny zo skupiny zahrňujúcej pyrolidín-1 -yl, piperidín-1-yl, azepín-1-yl, morfolín-4-yl, 4tiamorfolinyl, 4-sulfoxymorfolín, 4-sulfonylmorfolín, piperazín-1 -yl, 4-alkylpiperazín-1 yl, 4-arylalkylpiperazín-1 -yl, 4-diarylalkylpiperazín-1 -yl, homopiperazín-1-yl, 4alkylhomopiperazín-1-yl, 4-arylalkylhomopiperazin-1-yl, 4-diarylalkylhomopiperazín-1yl; pyrolidín-1 -yl, piperidín-1-yl alebo azepin-1-yl prípadne substituované skupinou zvolenou zo skupiny zahrňujúcej alkyl, alkoxy, alkyltio, halogén, trifluórmetyl alebo hydroxy.The term amino used herein alone or as part of another group means -NH 2 . Said amino group may optionally be substituted by one or two substituent groups, which may be the same or different and include groups such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. Preferred substituted amino groups include alkylamino and dialkylamino such as methylamino, ethylamino, dimethylamino, and diethylamino. Said substituents may be further substituted with carboxylic acid or any of the alkyl or aryl substituents mentioned herein. In addition, the substituents on the amino group may be combined and together with the nitrogen atom to which they are attached to form a group selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, azepin-1-yl, morpholin-4-yl, 4-thiamorpholinyl, 4 -sulfoxymorpholine, 4-sulfonylmorpholine, piperazin-1-yl, 4-alkylpiperazin-1-yl, 4-arylalkylpiperazin-1-yl, 4-diarylalkylpiperazin-1-yl, homopiperazin-1-yl, 4alkylhomopiperazin-1-yl, 4- arylalkylhomopiperazin-1-yl, 4-diarylalkylhomopiperazin-1-yl; pyrrolidin-1-yl, piperidin-1-yl or azepin-1-yl optionally substituted with a group selected from alkyl, alkoxy, alkylthio, halogen, trifluoromethyl or hydroxy.

Výraz aryl použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená monocyklickú alebo bicyklickú aromatickú skupinu, ako je napríklad fenylová skupina, substituovaná fenylová skupina a podobne a tiež kondenzované skupiny, ako je napr. naftyl, fenantrenyl a podobne. Arylová skupina teda obsahuje najmenej jeden kruh obsahujúci najmenej 6 atómov, pričom môže obsahovať až päť kruhov s až 22 atómami, so striedavými (rezonujúcimi) dvojitými väzbami medzi susediacimi atómami uhlíkov alebo vhodnými heteroatómami. Arylové skupiny môžu byť pripadne substituované jednou alebo viacerými skupinami zahrňujúcimi, ale bez obmedzenia len na uvedené skupiny, halogén, alkyl, alkenyl, alkinyl, alkoxy, hydroxy, karboxy, karbamoyl, aikyloxykarbonyl, alkylaminokarbonyi, nitro, trifluórmetyl, amino, cykloalkyl, kyano, alkyiS(O)m (m = 0, 1, 2) alebo tiol. Arylové skupiny môžu byť taktiež substituované heterocyklolalkylovými alebo heterocykloarylovými skupinami a môžu tak tvoriť kondenzované kruhy, ako je dihydrobenzofuranyl, oxindolyl, indolyl, indolinyl, oxindolyl, benzoxazolidinonyl, benzoxazolinyl a benzoxazolidinón.The term aryl as used herein alone or as part of another group means a monocyclic or bicyclic aromatic group such as a phenyl group, a substituted phenyl group, and the like, as well as condensed groups such as e.g. naphthyl, phenanthrenyl and the like. Thus, an aryl group contains at least one ring containing at least 6 atoms and may contain up to five rings of up to 22 atoms, alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to, halogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, alkylaminocarbonyl, nitro, trifluoromethyl, amino, cycloalkyl, cyano, alkyl (S) m (m = 0, 1, 2) or thiol. Aryl groups may also be substituted with heterocyclolalkyl or heterocycloaryl groups and may thus form fused rings such as dihydrobenzofuranyl, oxindolyl, indolyl, indolinyl, oxindolyl, benzoxazolidinonyl, benzoxazolinyl and benzoxazolidinone.

Výraz cykloalkyl použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená plne nasýtené a čiastočne nenasýtené uhľovodíkové kruhy s 3 až 9 výhodne 3 až 7 atómami uhlíka. Uvedená cykloalkylová skupina môže byť substituovaná. Substituovaný cykloalkyl znamená kruhy obsahujúce jeden, dva alebo tri substitučné skupiny, výhodne jednu, zvolenú zo skupiny zahrňujúcej halogén, alkyl, substituovaný alkyl, alkenyl, alkinyl, nitro, kyano, oxo (=0), hydroxy, alkoxy, tioalkyl, -CO2H, -OC(=O)H, CO2-alkyl, -OC(=O)alkyl, = N-OH, =N-O-alkyl, aryl, heteroaryl, heterocyklyl, päť alebo šesťčlenný ketal (t.j. 1,3-dioxolán alebo 1,3dioxán), -NR'R, -C(=O)NR'R”, -OC(=O)NR'R, -NR'CO2NR, -NR'C(=0)R, -SO2NR'R a -NR'SO2R, kde každý z R' a R nezávisle od seba znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, substituovaný alkyl a cykloalkyl, alebo R' a R spoločne tvoria heterocyklický alebo heteroarylový kruh. Uvedené cykloalkylové skupiny môžu byť tiež substituované heteroatómami ako je O, N a S a tvoriť tak heterocyklolalkylové skupiny. Výhodné heterocykloalkylové skupiny zahrňujú skupiny odvodené od prípadne substituovaného morfolínu, homomorfolínu (7-členný kruh), tiomorfolínu, piperazínu, homopiperazínu (7-členný kruh) a piperidínu.The term cycloalkyl used herein alone or as part of another group means fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atoms. Said cycloalkyl group may be substituted. Substituted cycloalkyl means rings containing one, two or three substituent groups, preferably one, selected from the group consisting of halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo (= O), hydroxy, alkoxy, thioalkyl, -CO 2 H, -OC (= O) H, CO 2 -alkyl, -OC (= O) alkyl, = N-OH, = NO-alkyl, aryl, heteroaryl, heterocyclyl, five or six-membered ketal (ie, 1,3-dioxolane) or 1,3dioxane), -NR'R, -C (= O) NR'R ', -OC (= O) NR'R, -NR'CO 2 NR, -NR'C (= O) R, - SO 2 NR'R and -NR'SO 2 R, wherein each of R 'and R independently represents a group selected from the group consisting of hydrogen, alkyl, substituted alkyl and cycloalkyl, or R' and R together form a heterocyclic or heteroaryl ring. Said cycloalkyl groups may also be substituted with heteroatoms such as O, N and S to form heterocyclolalkyl groups. Preferred heterocycloalkyl groups include those derived from optionally substituted morpholine, homomorpholine (7-membered ring), thiomorpholine, piperazine, homopiperazine (7-membered ring), and piperidine.

Výraz heteroaryl použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená substituované a nesubstituovaná aromatické 5- aleboThe term heteroaryl as used herein, both alone and as part of another group, means substituted and unsubstituted aromatic 5- or

6-členné monocyklické skupiny, 9- alebo 10-členné bicyklické skupiny a 11- až 14členné tricyklické skupiny obsahujúce v najmenej jednom z kruhov najmenej jeden heteroatóm (O, S alebo N). Každý kruh heteroarylovej skupiny obsahujúci heteroatóm môže obsahovať jeden alebo dva atómy kyslíka alebo síry a/alebo jeden až štyri atómy dusíka s výhradou, že celkový počet heteroatómov v jednotlivom kruhu je štyri alebo menej a každý kruh obsahuje najmenej jeden atóm uhlíka. Kondenzované kruhy, tvoriace bicyklické a tricyklické skupiny môžu obsahovať len atómy uhlíka a môžu byť nasýtené, čiastočne nasýtené alebo nenasýtené. Atómy dusíka a síry môžu byť pripadne oxidované a atómy dusíka môžu byť prípadne kvarternizované. Heteroarylové skupiny, ktoré sú bicyklické alebo tricyklické musia obsahovať najmenej jeden plne aromatický kruh, ale ostatné kruhy alebo ďalšie kruhy môžu byť aromatické alebo nearomatické. Heteroarylová skupina môže byť pripojená väzbou cez ktorýkoľvek atóm dusíka alebo uhlíka v ktoromkoľvek z kruhov. Uvedený heteroarylový kruhový systém nemusí obsahovať žiadnu substitučnú skupinu alebo môže obsahovať jednu, dve alebo tri substitučné skupiny zvolené zo skupiny zahrňujúcej halogén, alkyl, substituovaný alkyl, alkenyl, alkinyl, nitro, kyano, hydroxy, alkoxy, tioalkyl, -CO2H, -OC(=O)H, -CO2-alkyl, -OC(=O)alkyl, fenyl, benzyl, fenyletyl, fenyloxy, fenyltío, cykloalkyl, substituovaný cykloalkyl, heterocyklo, heteroaryl, NR'R ', -C(=O)NR'R, -OC(=O)NR'R, -NR'CO2NR'', -NR'C(=O)R, -SO2NR'R a -NR'SO2R, kde každá zo skupín R' a R nezávisle od seba znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, substituovaný alkyl a cykloalkyl, alebo R' a R spoločne tvoria heterocyklický alebo heteroarylový kruh.6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11- to 14-membered tricyclic groups containing at least one heteroatom (O, S or N) in at least one of the rings. Each ring of a heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. Fused rings forming bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must contain at least one fully aromatic ring, but the other rings or other rings may be aromatic or non-aromatic. The heteroaryl group may be attached via a bond through any nitrogen or carbon atom in any of the rings. Said heteroaryl ring system may not contain any substituent group or may contain one, two or three substituent groups selected from the group consisting of halogen, alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, hydroxy, alkoxy, thioalkyl, -CO 2 H, - OC (= O) H, -CO 2 -alkyl, -OC (= O) alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclo, heteroaryl, NR'R ', -C (= O) ) NR'R, -OC (= O) NR'R, -NR'CO 2 NR '', -NR'C (= O) R, -SO 2 NR'R and -NR'SO 2 R, each R 'and R' independently of one another are selected from hydrogen, alkyl, substituted alkyl and cycloalkyl, or R 'and R together form a heterocyclic or heteroaryl ring.

Príkladné monocyklické heteroarylové skupiny zahrňujú pyrolyl, pyrolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, izoxazolyl, tiazolyl, tiadiazolyl, izotiazolyl, furanyl, tienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl a podobne.Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrrolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazinyl, triazinyl, triazinyl, triazinyl.

Príkladné bicyklické heteroarylové skupiny zahrňujú indolyl, indolinyl, oxindolyl, benzoxazolidinón, benzotiazolyl, benzodioxolyl, benzoxazolyl, benzotienyl, chinolyl, tetrahydroizochinolyl, izochinolyl, benzoimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, kumarinyl, benzopyranyl, cinolinyl, chinoxalinyl, indazolyl, pyrolopyridyl, furopyridinyl, dihydroizoindolyl, tetrahydrochinolyl a podobne.Exemplary bicyclic heteroaryl groups include indolyl, indolinyl, oxindolyl, benzoxazolidinone, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, benzoimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chrominyl, furinyl, chrominyl, cinxinyl, chromxyl, cinxinyl, chromx, , dihydroisoindolyl, tetrahydroquinolyl and the like.

Príkladné tricyklické heterocyklické skupiny zahrňujú karbazolyl, benzoindolyl, fenantrolinyl, akridinyl, fenantridinyl, xantenyl a podobne.Exemplary tricyclic heterocyclic groups include carbazolyl, benzoindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Výraz halogén” alebo halo použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená nezávisle zvolený atóm zo skupiny zahrňujúcej chlór, bróm, fluór alebo jód.The term "halogen" or "halo" as used herein alone or as part of another group means an independently selected atom from the group consisting of chlorine, bromine, fluorine or iodine.

Výraz hydroxy” použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená skupinu -OH.The term "hydroxy" as used herein alone or as part of another group means -OH.

Výraz tioalkoxy” použitý v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny znamená alkylovú skupinu opísanú v tomto opise pripojenú k materskej molekule cez atóm síry. Príklady tioalkoxylových skupín zahrňujú, ale bez obmedzenia len na uvedené skupiny, tiometoxy, tioetoxy a podobne.The term "thioalkoxy" as used herein, both alone and as part of another group, means an alkyl group described herein attached to the parent molecule through a sulfur atom. Examples of thioalkoxy groups include, but are not limited to, thiomethoxy, thioethoxy and the like.

Skratky: Ph” znamená fenylovú skupinu; Me” znamená metylovú skupinu; a ”Et” znamená etylovú skupinu.Abbreviations: Ph 'stands for phenyl; Me "represents a methyl group; and "Et" means ethyl.

Výraz antikancerogénny prostriedok” použitý v tomto texte je použitý v súvislosti so známymi spôsobmi liečenia rakoviny ako je radiačná terapia alebo terapia cytostatickými alebo cytotoxickými prostriedkami ako sú napríklad, ale bez obmedzenia len na uvedené prostriedky, prostriedky interagujúce s DNA ako je cisplatina alebo doxorubicín; inhibítory topoizomerázy II ako je etoposid; inhibítory topoizomerázy I ako je CPT-11 alebo topotekan; prostriedky interagujúce s tubulínom ako paklitaxel, docetaxel alebo epotilóny; hormonálne prostriedky ako je tamoxifen; inhibítory tymidilátsyntázy ako je 5-fluóruracil; antimetabolity ako je metotrexat; inhibítory tyrozínkinázy ako je Iressa a OSI-774; inhibítory angiogenézy; inhibítory EGF; inhibítory VEGF; inhibítory CDK; inhibítory Her1/2 a monoklonálne protilátky pôsobiace na receptory rastového faktora akými sú erbitux (EGF) a herceptín (Her2).The term anticancer agent "as used herein is used in connection with known methods of treating cancer such as radiation therapy or therapy with cytostatic or cytotoxic agents such as, but not limited to, DNA interacting agents such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents such as paclitaxel, docetaxel or epothilones; hormonal agents such as tamoxifen; thymidilate synthase inhibitors such as 5-fluorouracil; antimetabolites such as methotrexate; tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDK inhibitors; Her1 / 2 inhibitors and monoclonal antibodies acting on growth factor receptors such as erbitux (EGF) and herceptin (Her2).

Ak je pri funkčnej skupine uvedené, že je chránená”, znamená to, že uvedená funkčná skupina je modifikovaná do formy zabraňujúcej nežiaducim reakciám tejto skupiny. Vhodné chrániace skupiny zlúčenín podlá vynálezu budú pracovníkom v odbore zrejmé na základe ich skúsenosti a z opisu vynálezu a taktiež z literárnych údajov ako je napríklad práca autorov Greene T.W. a sp., Protective Groups in Organic Synthesis”, Wiley, N.Y. (1991).When a functional group is said to be protected, it is meant that said functional group is modified to prevent unwanted reactions of that group. Suitable protecting groups of the compounds of the invention will be apparent to those skilled in the art based on their experience and description of the invention, as well as literature data such as those of Greene T.W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

Ak skupina zo skupiny zahrňujúcej CrCgalkyl, alkenyl, alkinyl a cykloalkyl je substituovaná, potom je výhodne substituovaná jednou alebo viacerými skupinami zvolenými zo skupiny zahrňujúcej hydroxy, kyano, karbamoyl, hydroxy, alkoxy, tiol, alkenyl, tioalkoxy, amino, alkylamino, amido, sulfonyl, sulfonylamido, halogén, heterocykloalkyl, aryl alebo heteroaryl.When a C 1 -C 6 alkyl, alkenyl, alkynyl and cycloalkyl group is substituted, it is preferably substituted with one or more groups selected from the group consisting of hydroxy, cyano, carbamoyl, hydroxy, alkoxy, thiol, alkenyl, thioalkoxy, amino, alkylamino, amido, sulfonyl , sulfonylamido, halogen, heterocycloalkyl, aryl or heteroaryl.

Ak skupina zo skupiny zahrňujúcej aryl a heteroaryl je substituovaná, potom je výhodne substituovaná jednou alebo viacerými skupinami zvolenými zo skupiny zahrňujúcej alkyl, alkenyl, alkinyl, kyano, karbamoyl, hydroxy, alkoxy, tioalkoxy, amino. amido, sulfonylamido, halogén, alebo R', R, kde R' a R tvoria kruh kondenzovaný na arylovú skupinu. Ak skupina zo skupiny zahrňujúcej CH2aryl alebo heteroaryl je substituovaná, tak je výhodne substituovaná jednou alebo viacerými skupinami zvolenými zo skupiny zahrnujúcej alkyl, alkenyl, alkinyl, kyano, karbamoyl, hydroxy, alkoxy, tioalkoxy, amino, amido, sulfonylamido alebo halogén.When the aryl and heteroaryl group is substituted, it is preferably substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino. amido, sulfonylamido, halogen, or R ', R, wherein R' and R form a ring fused to an aryl group. If the group from the group of CH 2 aryl or heteroaryl is substituted, it is preferably substituted by one or more groups selected from alkyl, alkenyl, alkynyl, cyano, carbamoyl, hydroxy, alkoxy, thioalkoxy, amino, amido, sulfonamido or halo.

Ak skupina zo skupiny zahrňujúcej NH-Z-aryl a NH-Z-heteroaryl je substituovaná, potom je výhodne substituovaná jednou alebo viacerými skupinami zvolenými zo skupiny zahrňujúcej alkyl, alkenyl, alkinyl, hydroxy, alkoxy, tioalkoxy, amino halogén, nitro, nitril, karboxylát, alkoxykarbonyl, karbamoyl, ester, amid, aryl alebo heteroaryl.When a group selected from NH-Z-aryl and NH-Z-heteroaryl is substituted, it is preferably substituted by one or more of alkyl, alkenyl, alkynyl, hydroxy, alkoxy, thioalkoxy, amino halogen, nitro, nitrile, carboxylate, alkoxycarbonyl, carbamoyl, ester, amide, aryl or heteroaryl.

Index uvedený pod symbolom ”C” znamená počet atómov uhlíka, ktoré môže konkrétna skupina obsahovať. Napríklad výraz ’’Ci-C6alkyl” znamená priamy alebo rozvetvený nasýtený reťazec atómov uhlíka obsahujúci jeden až šesť atómov uhlíka; príklady uvedených skupín zahrňujú metyl, etyl, propyl, izopropyl, butyl, sek-butyl, izobutyl, terc-butyl, pentyl, sek-pentyl, izopentyl a hexyl. Podľa okolností výraz Cp C6alkyl” taktiež znamená Ci-Cealkylénovú skupinu spájajúcu dve skupiny; príklady alkylénových skupín zahrňujú propán-1,3-diyl, bután-1,4-diyl, 2-metylbután-1,4-diyl atď. Výraz ”C2-C6alkenyľ znamená priamy alebo rozvetvený reťazec atómov uhlíka obsahujúci najmenej jednu dvojitú väzbu uhlík-uhlik a majúci dva až šesť atómov uhlíka; príklady alkenylových skupín zahrňujú etenyl, propenyl, izopropenyl, butenyl, izobutenyl, pentenyl a hexenyl. Podľa okolností výraz Cí-Csalkenyl” taktiež znamená C2-C6alkéndiylovú skupinu spájajúcu dve skupiny; príklady alkéndiylových skupín zahrňujú etylén-1,2-diyl (vinylén), 2-metyl-2-butén-1,4-diyl, 2-hexén-1,6-diyl atď.The index below the symbol "C" indicates the number of carbon atoms a particular group may contain. For example, the term '' C 1 -C 6 alkyl "means a straight or branched saturated chain of carbon atoms containing one to six carbon atoms; examples of said groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, sec-pentyl, isopentyl and hexyl. Accordingly, the term C 1 -C 6 alkyl "also means a C 1 -C 6 alkylene group joining two groups; examples of alkylene groups include propane-1,3-diyl, butane-1,4-diyl, 2-methylbutane-1,4-diyl, and the like. The term "C 2 -C 6 alkenyl" means a straight or branched chain of carbon atoms containing at least one carbon-carbon double bond and having two to six carbon atoms; examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and hexenyl. According to circumstances, the term C 1 -C 6 alkenyl "also means a C 2 -C 6 alkenyldiyl group joining two groups; examples of the alkenediyl groups include ethylene-1,2-diyl (vinylene), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl, and the like.

Výraz ”C2-C6alkinyl” znamená priamy alebo rozvetvený reťazec atómov uhlíka obsahujúci najmenej jednu trojitú väzbu uhlík-uhlik a majúci dva až šesť atómov uhlíka; príklady alkinylových skupín zahrňujú etinyl, propinyl, butinyl a hexinyl.The term "C 2 -C 6 alkynyl" means a straight or branched chain of carbon atoms containing at least one carbon-carbon triple bond and having two to six carbon atoms; examples of alkynyl groups include ethynyl, propynyl, butynyl and hexynyl.

Výraz ”alkyl-R25’’ znamená prípadne substituované alkylové skupiny ako je metyl, etyl, propyl a butyl pripojené na skupinu R25. R25 všeobecne znamená skupiny zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, kyano, halogén, sulfoxy, sulfonyl, NHCOOH, -NHC(O)-, NHSO2-, -C(O)NH2, heteroarylovú alebo heterocykloalkylovú skupinu ako je morfolinyl alebo skupina vzorca:The term "alkyl-R 25 " means optionally substituted alkyl groups such as methyl, ethyl, propyl, and butyl attached to the R 25 group. R 25 generally represents a group selected from hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halogen, sulfoxy, sulfonyl, NHCOOH, -NHC (O) -, NHSO 2 -, -C (O) NH 2, a heteroaryl or heterocycloalkyl group such as morpholinyl or a group of the formula:

Výrazy imidazol” a imidazolín použité v tomto texte tak samostatne, ako aj vo forme súčasti inej skupiny zahrňujú substituované imidazoly a substituované imidazolíny. Podobne výraz tetrahydropyrimidín” zahrňuje substituované tetrahydropyrimidíny. Podobne výrazy piperazín’1, piperidín”, morfolíny”, homopiperaziny, homomorfolíny a pyrolidin” zahrňujú substituované piperazíny, substituované piperidíny, substituované morfolíny, substituované homomorfolíny a substituované pyrolidíny.The terms imidazole and imidazoline used herein alone and as part of another group include substituted imidazoles and substituted imidazolines. Similarly, the term tetrahydropyrimidine ”includes substituted tetrahydropyrimidines. Similarly, the terms piperazine ' 1 , piperidine', morpholines ', homopiperazines, homomorpholines and pyrrolidine' include substituted piperazines, substituted piperidines, substituted morpholines, substituted homomorpholines, and substituted pyrrolidines.

Vynález zahrňuje zlúčeniny všeobecného vzorca (I):The invention includes compounds of formula (I):

diastereoméry, farmaceutický prijateľné soli, hydráty, a ich enantioméry, proliečivá a ich solváty, kdediastereomers, pharmaceutically acceptable salts, hydrates, and enantiomers, prodrugs, and solvates thereof, wherein:

X znamená skupinu zvolenú zo skupiny zahrňujúcej N, C, Ci-Csalkyl, Cr X is selected from the group consisting of N, C, Cl-Cg alkyl, C r

C3alkyl substituovaný jedným alebo viacerými substituentami R7 a priamu väzbu;C 3 alkyl substituted with one or more R 7 's and a direct bond;

Y znamená O alebo S;Y is O or S;

W má význam zvolený zo skupiny zahrňujúcej N, C, O a S s tou výhradou, že keď W znamená O alebo S, R9 nemá žiadny význam;W has the meaning selected from the group consisting of N, C, O and S, provided that when W is O or S, R 9 has no meaning;

R1, R2, R3, R4, R5, Rs, R7, R8, R9 každý nezávisle znamená skupinu nezávisle zvolenú zo skupiny zahrňujúcej H, Ci-Cgalkyl, alkenyl, alkinyl, cykloalkyl, heterocykloalkyl, halogén, amino, OR60, NO2, OH, SR60, NR60R61, CN, CO2R50, CONR60R61, CO2NR60R61, NR62CONR60R61, NR60SO2R61, SO2NR60Rs1, C(NR62)NR60R51, aryl, heteroaryl, (CH2)nOR60 (CH2)nNR60R51, (CH2)nSR60, (CH2)naryl, (CH2)nheteroaryl, (CH2)nheterocykloalkyl, NH-Z-aryl a NH-Z-heteroaryl;R 1, R 2, R 3, R 4, R 5, R s, R 7, R 8, R 9 independently is independently selected from H, Ci-Cgalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogen , amino, OR 60 , NO 2, OH, SR 60 , NR 60 R 61 , CN, CO 2 R 50 , CONR 60 R 61 , CO 2 NR 60 R 61 , NR 62 CONR 60 R 61 , NR 60 SO 2 R 61 , SO 2 NR 60 R s1 , C (NR 62 ) NR 60 R 51 , aryl, heteroaryl, (CH 2) n OR 60 (CH 2 ) n NR 60 R 51 , (CH 2) n SR 60 , (CH 2 ) n aryl, (CH 2 ) n heteroaryl, ( CH 2 ) n heterocycloalkyl, NH-Z-aryl and NH-Z-heteroaryl;

kde n znamená 1 až 3; awherein n is 1 to 3; and

Z znamená skupinu zvolenú zo skupiny zahrňujúcej Ci-C4alkyl, alkenyl a alkinyl; Z obsahujúcich jednu alebo viac skupín zvolených zo skupiny zahrňujúcej hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, NR60SO2R51; Z skupín s prípadne včlenenou jednou alebo viac skupinou zvolenou zo skupiny zahrňujúcej CO, CNOH, CNOR60, CNNR60, CNNCOR60 a CNNSO2R60;Z is selected from the group consisting of Cl-C4 alkyl, alkenyl, and alkynyl; Z containing one or more groups selected from the group consisting of hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, NR 60 SO 2 R 51 ; Among the groups optionally incorporated by one or more selected from the group consisting of CO, CNOH, CNOR 60 , CNNR 60 , CNNCOR 60, and CNNSO 2 R 60 ;

R50 a R61 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej H, alkyl, alkenyl, alkinyl, cykloalkyl, cykloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl a alkyl-R25, kdeR 50 and R 61 each independently represent a group selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25 wherein:

R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, kyano, halogén, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R3', heteroaryl alebo heterocykloalkyl; aR 25 represents a group selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halogen, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 3 ', heteroaryl or heterocycloalkyl; and

R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

V niektorých uskutočneniach vynálezu R3 znamená -OR50. R'° znamená skupinu zvolenú zo skupiny zahrňujúcej alkyl a alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, alkylsulfoxy, alkylsulfonyl, -R30COOR31, -NR3QC(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkylR25. Vo výhodných uskutočneniach R50 znamená skupinu zvolenú zo skupiny zahrňujúcej metyl, -(CH2)PCH2OH alebo -(CH2)nCH2N(CH2CH2)2O, a n znamená 0, 1 alebo 2.In some embodiments, R 3 is -OR 50 . R 10 represents a group selected from the group consisting of alkyl and alkyl-R 25 , wherein R 25 represents a group selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, alkylsulfoxy, alkylsulfonyl, -R 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkylR 25 . In preferred embodiments, R 50 is selected from the group consisting of methyl, - (CH 2 ) p CH 2 OH, or - (CH 2 ) n CH 2 N (CH 2 CH 2 ) 2 O, and n is 0, 1 or 2.

oabout

V niektorých uskutočneniach vynálezu R znamená piperazín, homopiperazín,In some embodiments, R is piperazine, homopiperazine,

3-metylpiperazin alebo 3,5-dimetylpiperazín prípadne substituovaný v polohe 4-N skupinou zvolenou zo skupiny zahrňujúcej alkyl, aryl, cykloalkyl, cykloalkylalkyl, heterocykloalkyl, alkyl-R25, -C(O)-R15, alebo -CO2R15, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl, alkyl-R25, amino alebo aryl; a R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamíno, dialkylamino, kyano, halogén, sulfoxy, sulfonyl, arylsulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25. Vo výhodných uskutočneniach je piperazín substituovaný skupinou zo skupiny zahrňujúcej Me, CH2cyklopropyl, CH2CH2NMe2, CH2CH2NEt2, CH2CH2NH2, CH2CH2NHMe, CH2CH2NHEt, NCH2CH2N(CH2CH2)2O, (CH2)nCH2-R25, kde R25 znamená OH, OMe, F, CN, CF3, SOCH3 alebo SO2CH3 a kde n je 0, 1 alebo 2.3-methylpiperazine or 3,5-dimethylpiperazine optionally substituted in the 4-position by a group selected from the group consisting of alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, alkyl-R 25 , -C (O) -R 15 , or -CO 2 R 15 , wherein R 15 represents a group selected from the group consisting of hydrogen, alkyl, aryl, alkyl-R 25 , amino or aryl; and R 25 represents a group selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halogen, sulfoxy, sulfonyl, arylsulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 . In preferred embodiments, piperazine substituted by the group consisting of Me, CH2cyklopropyl, CH2CH2NMe2, CH2CH2NEt2, CH2CH2NH2, CH2CH2NHMe, CH2CH2NHEt, NCH2CH2N (CH2CH2) 2O, (CH2) nCH2-R25 wherein R25 is OH, OMe, F, CN, CF 3 , SOCH 3 or SO 2 CH 3 and wherein n is 0, 1 or 2.

V niektorých uskutočneniach vynálezu R3 znamená aminoskupinu. Výhodné aminoskupiny zahrňujú NHCH2CH2OH, NMeCH2CH2OH, NEtCH2CH2OHt NHCH2CH2NH2, NMeCH2CH2NH2, NEtCH2CH2NH2, NHCH2CH2NMe2, NMeCH2CH2NMe2, NEtCH2CH2NMe2, NHCH2CH2NEt2, NMeCH2CH2NEt2, NEtCH2CH2NEt2, NHCH2CH2N(CH2CH2)2O, NMeCH2CH2N(CH2CH2)2O,In some embodiments of the invention, R 3 is amino. Preferred amino groups include NHCH 2 CH 2 OH, NMeCH 2 CH 2 OH, NEtCH 2 CH 2 OH t NHCH 2 CH 2 NH 2 , NMeCH 2 CH 2 NH 2 , NEtCH 2 CH 2 NH 2 , NHCH 2 CH 2 NMe 2 , NMeCH 2 CH 2 NMe 2 , NEtCH 2 CH 2 NMe 2 , NHCH 2 CH 2 NEt 2 , NMeCH 2 CH 2 NEt 2 , NEtCH 2 CH 2 NEt 2 , NHCH 2 CH 2 N (CH 2 CH 2 ) 2 O, NMeCH 2 CH 2 N (CH 2 CH 2 ) 2 O .

ΝΕίΟΗ2ΟΗ2Ν(ΟΗ2θΗ2)2θ.ΟΗΕίΟΗ 2 ΟΗ 2 Ν (ΟΗ 2θΗ 2 ) 2θ.

V niektorých uskutočneniach vynálezu R3 znamená prípadne substituovaný piperidín. Výhodné substituenty zahrňujú skupiny zvolené zo skupiny zahrňujúcej hydroxy, tiol, amino, alkylamino, dialkylamino, alkoxy, tioalkoxy, 1,3-dioxolán(OCHR15)2, 1,3-dioxán(-OCHR15CHR15CHR15O-)-NHC(O)R15, -NHCO2R15, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, alkylsulfoxy, alkylsulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.In some embodiments of the invention, R 3 is optionally substituted piperidine. Preferred substituents include groups selected from the group consisting of hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3-dioxolane (OCHR 15 ) 2, 1,3-dioxane (-OCHR 15 CHR 15 CHR 15 O -) - NHC (O) R 15 , -NHCO 2 R 15 , wherein R 15 is selected from the group consisting of hydrogen, alkyl or alkyl-R 25 , wherein R 25 is selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, alkylsulfoxy, alkylsulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

V niektorých uskutočneniach vynálezu R3 znamená prípadne substituovaný morfolin, homomorfolín, tiomorfolín, sulfoxymorfolin alebo sulfonylmorfolín. Výhodné substituenty zahrňujú skupiny zvolené zo skupiny zahrňujúcej hydroxy, tiol, amino, alkylamino, dialkylamino, alkoxy, tioalkoxy, alkyl-R25, -NHC(O)R15, NHCO2R15, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, alkylsulfoxy, alkylsulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.In some embodiments of the invention, R 3 is optionally substituted morpholine, homomorpholine, thiomorpholine, sulfoxymorpholine or sulfonylmorpholine. Preferred substituents include groups selected from the group consisting of hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-R 25 , -NHC (O) R 15 , NHCO 2 R 15 , wherein R 15 is selected from hydrogen, alkyl or alkyl-R 25 , wherein R 25 is selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, alkylsulfoxy, alkylsulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

V niektorých uskutočneniach vynálezu R3 znamená pyrolidín. Výhodné pyrolidíny zahrňujú 3-hydroxypyrolidín, 3-alkoxypyrolidín a 3-alkylaminopyrolidín.In some embodiments, R 3 is pyrrolidine. Preferred pyrrolidines include 3-hydroxypyrrolidine, 3-alkoxypyrrolidine and 3-alkylaminopyrrolidine.

V jednom uskutočnení vynálezu R3 znamená prípadne substituovaný Ntetrahydropyrimídín alebo N-imidazolín, kde substitučné skupiny výhodne znamenajú skupiny zvolené zo skupiny zahrňujúcej alkyl, hydroxyalkyl, alkoxyalkyl, halogénalkyl, kyanoalkyl, karboxy alebo karboxamid.In one embodiment of the invention, R 3 is optionally substituted N-tetrahydropyrimidine or N-imidazoline, wherein the substituent groups are preferably selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanoalkyl, carboxy or carboxamide.

V niektorých uskutočneniach vynálezu R6 znamená skupinu zvolenú zo skupiny zahrňujúcej H, 2-aminometylpyridín, NHCH2CH(OH)aryl a NHCH(CH2OH)CH2aryl, kde arylová skupina je prípadne substituovaná. Vo výhodných uskutočneniach je arylová skupina substituovaná skupinami zvolenými zo skupiny zahrňujúcej Br, Cl, F a metoxy. V niektorých uskutočneniach R6 znamená skupinu majúcu niektorý z nasledujúcich všeobecných vzorcov:In some embodiments, R 6 is a group selected from H, 2-aminomethylpyridine, NHCH 2 CH (OH) aryl and NHCH (CH 2 OH) CH 2 aryl, wherein the aryl group is optionally substituted. In preferred embodiments, the aryl group is substituted with a group selected from the group consisting of Br, Cl, F and methoxy. In some embodiments, R 6 is a group having any of the following formulas:

kde R40 znamená vodík alebo alkylovú skupinu, výhodne metylovú skupinu a R17 znamená vodík alebo halogén ako je Br, Cl alebo F.wherein R 40 is hydrogen or alkyl, preferably methyl, and R 17 is hydrogen or halogen such as Br, Cl or F.

Výhodné zlúčeniny podľa vynálezu majú niektorý z nasledujúcich všeobecných vzorcov:Preferred compounds of the invention have any of the following general formulas:

kde každý z R12 a R13 nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25;wherein each of R 12 and R 13 independently represents a group selected from hydrogen, alkyl or alkyl-R 25 ;

R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkylR25;R 15 represents a group selected from hydrogen, alkyl or alkyl R 25 ;

swith

R nezávisle znamená vodík alebo metylovú skupinu;R is independently hydrogen or methyl;

každý z R17, R18 a R19 nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén alebo alkoxy, alebo R18 a R19 spoločne tvoria heterocykloalkylovú alebo heteroarylovú skupinu;each of R 17 , R 18 and R 19 independently represents a group selected from hydrogen, halogen or alkoxy, or R 18 and R 19 together form a heterocycloalkyl or heteroaryl group;

R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; aR 25 represents a group selected from hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and

R30 a R31 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 .

Vo výhodných uskutočneniach R12 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, metyl, hydroxymetyl, metoxymetyl, CH2F, CH2CN, CO2H alebo -CONR30R31, kde R30 a R31 nezávisle od seba znamenajú vodík alebo skupinu alkylR25;In preferred embodiments, R 12 is a group selected from the group consisting of hydrogen, methyl, hydroxymethyl, methoxymethyl, CH 2 F, CH 2 CN, CO 2 H or -CONR 30 R 31 , wherein R 30 and R 31 independently of one another are hydrogen or a group alkylR 25 ;

R13 znamená H;R 13 is H;

R17 znamená Br, Cl alebo F;R 17 is Br, Cl or F;

R znamená skupinu zvolenú zo skupiny zahrňujúcej halogén a metoxy; aR is selected from the group consisting of halogen and methoxy; and

R19 znamená H.R 19 stands for H.

Príklady vhodných solí zlúčenín podľa vynálezu zahrňujú soli anorganických alebo organických kyselín. Uvedené soli zahrňujú, ale nie sú obmedzené len na ne, hydrochlorid, hydrobromid, síran, metánsulfonát, maleát, fumarát, fosforečnan a ďalšie farmaceutický prijateľné soli. Vynález taktiež zahrňuje soli síce nevhodné na farmaceutické použitie, ale ktoré je možné použiť na izoláciu alebo prečistenie zlúčenín všeobecného vzorca (I) alebo ich farmaceutický prijateľných solí.Examples of suitable salts of the compounds of the invention include inorganic or organic acid salts. Said salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, methanesulfonate, maleate, fumarate, phosphate, and other pharmaceutically acceptable salts. The invention also encompasses salts which are unsuitable for pharmaceutical use, but which can be used to isolate or purify the compounds of formula (I) or pharmaceutically acceptable salts thereof.

Vynález taktiež zahrňuje všetky stereoizoméry zlúčenín podľa vynálezu ako vo forme ich zmesí alebo v ich čistých alebo v podstate čistých formách. Definícia zlúčenín podľa vynálezu zahrňuje všetky možné stereoizoméry a ich zmesi. Predovšetkým vynález zahrňuje racemické formy a izolované optické izoméry majúce špecifikovanú aktivitu. Racemické formy je možné rozštiepiť fyzikálnymi spôsobmi ako je napríklad frakčná kryštalizácia, separácia alebo kryštalizácia diastereomérnych derivátov alebo separácia chromatografiou na chirálnych kolónach. Jednotlivé optické izoméry je možné z racemátu získať napríklad prípravou soli s opticky aktívnou kyselinou s následnou kryštalizáciou.The invention also encompasses all stereoisomers of the compounds of the invention as in the form of mixtures thereof or in pure or substantially pure forms thereof. The definition of compounds of the invention includes all possible stereoisomers and mixtures thereof. In particular, the invention includes racemic forms and isolated optical isomers having the specified activity. Racemic forms can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chromatography on chiral columns. The individual optical isomers can be obtained from the racemate, for example, by preparing a salt with an optically active acid followed by crystallization.

Vynález je tiež nutné chápať tak, že poskytuje proliečivá zlúčenín všeobecného vzorca (I). Rôzne formy proliečiv sú v odbore všeobecne známe. Príklady foriem proliečiv sú opísané v nižšie uvedených prácach:The invention is also to be understood as providing prodrugs of the compounds of formula (I). Various forms of prodrugs are generally known in the art. Examples of prodrug forms are described in the following:

a) Design of Prodrugs”, ed. H. Bundgaard (Elsevier 1985); a Methods ina) Design of Prodrugs ”, ed. H. Bundgaard (Elsevier 1985); and Methods in

Enzymology”, Vol. 42, str. 309-396, ed. K.Widder a sp. (Academic Press, 1985);Enzymology ”, Vol. 42, p. 309-396, ed. K.Widder et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development”, ed. Krosgaard-Larsen a H. Bundgaard, kapitola 5 Design and Application of Prodrugs” H. Bundgaard, str. 113191 (1991);b) A Textbook of Drug Design and Development ”, ed. Krosgaard-Larsen and H. Bundgaard, Chapter 5 Design and Application of Prodrugs ”H. Bundgaard, p. 113,191 (1991);

c) H. Bundgaard, Advanced Drug Deliver Rewievs, 8, str. 1-38 (1992);c) H. Bundgaard, Advanced Drug Deliver Rewievs, 8, p. 1-38 (1992);

d) H. Bundgaard a sp., Journal of Pharmaceutical Sciences, 77, 285 (1988); ad) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and

e) N. Kayeka a sp., Chem.Phar.Bull., 32, 692 (1984).e) N. Kayeka et al., Chem.Phar.Bull., 32, 692 (1984).

Vynález taktiež poskytuje farmaceutickú kompozíciu obsahujúcu zlúčeninu všeobecného vzorca (I) opísanú vyššie a farmaceutický prijateľný nosič a najmenej jeden ďalší antikancerogénny prostriedok v jednom prípravku. Výhodné antikancerogénne prostriedky sú prostriedky zvolené zo skupiny zahrňujúcej: tamoxifen, toremifen, raloxifen, droloxifen, jodoxyfen, megestrol-acetát, anastrazol, letrazol, borazol, exemestan, flutamid, nilutamid, bikalutamid, cyproteron-acetát, goserelin-acetát, luprolid, finasterid, herceptin, metotrexat, 5-fluóruracil, cytozínarabinozid, doxorubicin, daunorubicín, epirubicin, idarubicín, mitomycín-C, daktinomycín, mitramycin, cisplatina, karboplatina, melfalan, chlorambucil, busulfán, cyklofosfamid, ifosfamid, nitrózomočovina, tiotefan, vinkristin, taxol, taxoter, etoposid, teniposid, amsakrin, irinotekan, topotekan, epotilón; inhibitor tyrozínkinázy ako je Iressa alebo OSI-774; inhibitor angiogenézy; inhibitor EGF; inhibitor VEGF; inhibitor CDK; inhibitor Her1/2 a monoklonálne protilátky cielené na receptory rastového faktora ako je erbitux (EGF) a herceptin (Her2).The invention also provides a pharmaceutical composition comprising a compound of formula (I) described above and a pharmaceutically acceptable carrier and at least one other anticancer agent in a single composition. Preferred anticancer agents are those selected from the group consisting of: tamoxifen, toremifene, raloxifene, droloxifene, iodoxyphene, megestrol acetate, anastrazole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, goserelin, goserelin herceptin, methotrexate, 5-fluorouracil, cytosine arabinoside, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, carboplatin, melphalan, chlorambucil, taxosulfolide, busulfotomide, cyclulfotomide, cyclofuran, cyclofuran, cyclofuran, cyclofuran, cyclofuran etoposide, teniposide, amsacrine, irinotecan, topotecan, epothilone; a tyrosine kinase inhibitor such as Iressa or OSI-774; angiogenesis inhibitor; an EGF inhibitor; a VEGF inhibitor; a CDK inhibitor; a Her1 / 2 inhibitor and monoclonal antibodies directed to growth factor receptors such as erbitux (EGF) and herceptin (Her2).

Vynález ďalej poskytuje spôsob liečenia ochorení prostredníctvom modulácie najmenej jedného enzýmu zo skupiny tyrozínkináz, kde uvedený spôsob zahrňuje podávanie účinného množstva zlúčeniny všeobecného vzorca (I) opísanej vyššie cicavcovi, ktorého je potrebné liečiť.The invention further provides a method of treating diseases by modulating at least one enzyme from the group of tyrosine kinases, said method comprising administering to a mammal in need of treatment an effective amount of a compound of formula (I) described above.

Okrem toho vynález poskytuje spôsob liečenia ochorení prostredníctvom modulácie najmenej jedného enzýmu zo skupiny tyrozínkináz, kde uvedený spôsob zahrňuje podávanie účinného množstva zlúčeniny všeobecného vzorca (I) opísanej vyššie v spojení (v súčasnom alebo sekvenčnom podávaní) s najmenej jedným antikancerogénnym prostriedkom cicavcovi, ktorého je potrebné liečiť.In addition, the invention provides a method of treating diseases by modulating at least one enzyme from the group of tyrosine kinases, said method comprising administering an effective amount of a compound of formula (I) described above in conjunction (concurrent or sequential) with at least one anticancer agent to a mammal in need thereof. to heal.

Stavy, kde liečenie spôsobmi podľa vynálezu je výhodné zahrňujú rakovinu. Enzýmy zo skupiny tyrozínkináz zahrňujú (ale nie sú obmedzené len na ne): Abl, CDK, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src a VEGF.Conditions where treatment with the methods of the invention is preferred include cancer. Enzymes from the family of tyrosine kinases include (but are not limited to): Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src and VEGF.

Vynález taktiež poskytuje spôsob liečenia rakoviny, kde uvedený spôsob zahrňuje podávanie terapeuticky účinného množstva najmenej jednej farmaceutickej kompozície opísanej vyššie cicavcovi, ktorého je potrebné liečiť.The invention also provides a method of treating cancer, said method comprising administering to a mammal in need of treatment a therapeutically effective amount of at least one pharmaceutical composition described above.

Vynález taktiež poskytuje spôsob liečenia proliferativnych chorôb, kde uvedený spôsob zahrňuje podávanie terapeuticky účinného množstva najmenej jednej farmaceutickej kompozície opísanej vyššie cicavcovi, ktorého je potrebné liečiť.The invention also provides a method of treating proliferative diseases, said method comprising administering to a mammal in need thereof a therapeutically effective amount of at least one pharmaceutical composition described above.

Niektoré zlúčeniny všeobecného vzorca (I) je všeobecne možné pripraviť spôsobmi znázornenými v nižšie uvedených schémach a na základe skúseností pracovníkov v odbore. Vynález tiež zahrňuje solváty zlúčenín všeobecného vzorca (I) (napríklad hydráty). Spôsoby solvatácie sú v odbore všeobecne známe. Podľa vyššie uvedeného, zlúčeniny podľa vynálezu môžu byť vo voľnej alebo hydratovanej forme a je možné ich pripraviť spôsobmi znázornenými v nižšie uvedených schémach vo forme príkladov spôsobov príprav zlúčenín podľa vynálezu.Certain compounds of formula (I) may generally be prepared by the methods depicted in the schemes below and based on the experience of those skilled in the art. The invention also includes solvates of the compounds of formula (I) (e.g. hydrates). Methods of solvation are generally known in the art. Accordingly, the compounds of the invention may be in free or hydrated form and may be prepared by the methods depicted in the schemes below as examples of methods for preparing the compounds of the invention.

Špecifickejšie sú v schémach l-VII znázornené spôsoby prípravy zlúčenín podlá vynálezu. Príklady, ktoré sú v opise vynálezu zaradené za uvedenými schémami slúžia na opis prípravy konkrétnych zlúčenín podľa uvedených schém. Použitie uvedených schém však nie je obmedzené len na uvedené príklady alebo na zvolené substituenty, ktoré sú uvedené len na znázornenie vynálezu.More specifically, Schemes 1-VII show methods for preparing compounds of the invention. The examples that follow the Schemes are intended to describe the preparation of particular compounds of the Schemes. However, the use of the above schemes is not limited to the examples given or the selected substituents, which are given only to illustrate the invention.

Schéma I znázorňuje prípravu benzoimidazolov. Východiskové diamíny vzorca (1) je možné ľahko pripraviť na základe údajov z literatúry alebo sú obchodne dostupné. Diamín sa kondenzuje s aldehydom (2) na benzoimidazol (3). Následne je možná ďalšia modifikácia funkčných skupín na arylovej skupine alebo na heterocyklickej skupine zlúčeniny (3).Scheme I illustrates the preparation of benzoimidazoles. The starting diamines of formula (1) can easily be prepared from literature data or are commercially available. The diamine is condensed with the aldehyde (2) to the benzoimidazole (3). Subsequently, further modification of the functional groups on the aryl group or on the heterocyclic group of compound (3) is possible.

Schéma IScheme I

Alternatívne je možné uvedený benzoimidazol pripraviť postupne (pozri schému II) prípravou amidu s použitím chloridu kyseliny zlúčeniny (5) alebo s použitím ktoréhokoľvek z dostupných kondenzačných činidiel na syntézu peptidov ako je DCC (dicyklohexylkarbodiimid), EDCI (1-(3-dimetylaminopropyl)-3etylkarbodiimid-hydrochlorid), atď. Po príprave amidu (6) je možné nitroskupinu redukovať katalytickou hydrogenáciou, prenosovou hydrogenáciou alebo chemickou redukciou ako je reakcia s SnCI2 alebo s práškovým železom alebo inými spôsobmi známymi pre redukciu arylnitroskupin. Spracovaním anilínu s kyselinou sa potom získa benzoimidazol.Alternatively, said benzoimidazole can be prepared sequentially (see Scheme II) by preparing an amide using the acid chloride of compound (5) or using any of the available peptide synthesis coupling reagents such as DCC (dicyclohexylcarbodiimide), EDCI (1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride), etc. After preparation of the amide (6), the nitro group can be reduced by catalytic hydrogenation, transfer hydrogenation or chemical reduction such as reaction with SnCl 2 or with iron powder or other methods known for reducing aryl nitro groups. Treatment of the aniline with the acid then affords the benzoimidazole.

Schéma IIScheme II

Napríklad v schéme III je znázornené použitie 4-jód-2-metoxypyridín-3karbaldehydu (7) na prípravu funkcionalizovaného benzoimidazolu (8). Hydrolýzou metoxylovej skupiny s použitím protickej kyseliny, TMSI (trimetylsilyljodidu), BBr3 alebo za iných podmienok známych v odbore vedúcich k štiepeniu metyléteru sa získa halogénpyridón (9). Prídavkom nukleofilného heteroatómu vo forme amínov, alkoholov alebo tiolov sa potom pripravia substituované pyridóny (10). Cez aldehydovú skupinu je možné včleniť ďalšie funkčné skupiny; vyššie uvedený spôsob je uvedený len na účely znázornenia.For example, Scheme III illustrates the use of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (7) for the preparation of functionalized benzoimidazole (8). Hydrolysis of the methoxy group using a protic acid, TMSI (trimethylsilyl iodide), BBr 3 or other conditions known in the art leading to the cleavage of methyl ether yields halopyridone (9). Substituted pyridones (10) are then prepared by addition of a nucleophilic heteroatom in the form of amines, alcohols or thiols. Additional functional groups may be incorporated via the aldehyde group; the above method is given for illustration purposes only.

Schéma IIIScheme III

Podobne je možné modifikovať arylový kruh benzoimidazolu pripraveného spôsobmi znázornenými v schémach I alebo II. Napríklad zavedenie kyanovej skupiny do polohy R benzoimidazolu umožňuje tvorbu heterocyklov ako je imidazol, imidazolíny, oxazolíny, tiazolíny, amidy alebo amidíny. Transformácie tohto typu znázorňuje schéma IV. Heterocyklický kruh východiskového kyanovou skupinou substituovaného benzimidazolu (11) sa modifikuje spôsobom znázorneným v schéme IV a získa sa zlúčenina (12). Imidátový medziprodukt (13) sa výhodne pripraví s použitím etanolu a kyseliny. Imidát (13) je možné previesť pomocou diamínov na imidazolíny, pomocou aminoalkoholov na oxazolíny, pomocou aminoacetalov na imidazoly a pomocou aminotiolov na tiazolíny (14). Alternatívne je možné uvedený imidát hydrolyzovať na kyselinu a kondenzovať s amínmi s použitím štandardných činidiel na prípravu amidov (DCC, EDCI atď.) a pripraviť tak amidy (15). Imidát (13) je tiež vhodný medziprodukt na prípravu amidínov (16) reakciou s amínmi.Similarly, it is possible to modify the aryl ring of benzoimidazole prepared by the methods shown in Schemes I or II. For example, the introduction of a cyano group at the R-position of benzoimidazole allows the formation of heterocycles such as imidazole, imidazolines, oxazolines, thiazolines, amides or amidines. Transformations of this type are shown in Scheme IV. The heterocyclic ring of the starting cyano-substituted benzimidazole (11) is modified as shown in Scheme IV to give compound (12). The imidate intermediate (13) is preferably prepared using ethanol and an acid. The imidate (13) can be converted by diamines to imidazolines, by amino alcohols to oxazolines, by aminoacetals to imidazoles and by aminothiols to thiazolines (14). Alternatively, said imidate can be hydrolyzed to acid and condensed with amines using standard amide preparation reagents (DCC, EDCI, etc.) to prepare amides (15). The imidate (13) is also a suitable intermediate for the preparation of amidines (16) by reaction with amines.

Schéma IVScheme IV

X=NH,O, SX = NH, O, S

Schéma V znázorňuje ďalšiu transformáciu benzoimidazolov substituovaných atómom halogénu s použitím reakcie katalyzovanej paládiom podľa Suzukiho (Yang a sp., Acta Chem. Scand. (1993) 221; Suzuki a sp., Synth. Commun. (1981) 11:513) alebo podľa Buchwald/Hartwiga (Buchwald a sp., J. Am. Chem. Soc. (1994) 116:7901; Hartwig a sp., J. Am. Chem. Soc (1994) 116:5969; Hartwig, Angew. Chem. Int. Ed. Engl. (1998) 37:2046) alebo variáciami vyššie uvedených spôsobov. Najprv sa predpokladá príprava brómom substituovaného benzimidazolu (17) ako substrátu pre Suzukiho kondenzáciu s aryl-, vinyl- a heterocyklyl- derivátmi borónovej kyseliny (dihydroxyborán), kde sa uvedenou kondenzáciou pripravia benzoimidazoly (18). Podobne je možné pripraviť aminy a heterocykly ako sú piperazínové a morfolínové deriváty (19) s použitím rovnakého východiskového bromidu za podmienok reakcie opísaných Buchwaldom a Hartwigom alebo variáciami tejto reakcie.Scheme V shows a further transformation of halogen-substituted benzoimidazoles using a palladium catalyzed reaction according to Suzuki (Yang et al., Acta Chem. Scand. (1993) 221; Suzuki et al., Synth. Commun. (1981) 11: 513) or according to Buchwald / Hartwiga (Buchwald et al., J. Am. Chem. Soc. (1994) 116: 7901; Hartwig et al., J. Am. Chem. Soc. (1994) 116: 5969; Hartwig, Angew. Chem. Int. (Ed. Engl. (1998) 37: 2046) or variations of the above methods. It is initially envisaged to prepare bromo substituted benzimidazole (17) as a substrate for Suzuki condensation with aryl, vinyl and heterocyclyl boronic acid derivatives (dihydroxyborane), whereby benzoimidazoles (18) are prepared by said condensation. Similarly, amines and heterocycles such as piperazine and morpholine derivatives (19) can be prepared using the same starting bromide under the reaction conditions described by Buchwald and Hartwig or variations thereof.

Schéma VScheme V

X = NH, O, SX = NH, O, S

Alternatívne je možné pripraviť aminoderiváty a heterocyklické deriváty, ako je zlúčenina (19) s použitím medziproduktu (6) opísaného v schéme II. Ak skupina R3 v zlúčenine (6) znamená halogén, výhodne F, je možné halogén nahradiť amínmi, alkoholmi, heterocyklickými aminmi a ďalšími dusík obsahujúcimi heterocyklami, ako je piperazín, piperidín, 4-aminopiperidin, morfolin, imidazol atď. (schéma VI). Terminálny dusík piperazínu alebo 4-aminopiperidínu je možné alkylovať štandardnými spôsobmi alkylácie alebo podrobiť reakcii s aldehydmi v redukčnej aminácii a získať tak alkylované deriváty. Alternatívne je možné terminálny atóm dusíka piperazínu alebo 4-aminopiperidínu acylovať alebo karbamoylovať množstvom spôsobov, ktoré sú známe pracovníkom v odbore organickej syntézy. V nadväznosti na spôsob podľa schémy II je tak možné pripraviť zlúčeniny ako je zlúčenina (19).Alternatively, amino derivatives and heterocyclic derivatives such as compound (19) can be prepared using intermediate (6) described in Scheme II. When R 3 in compound (6) is halogen, preferably F, halogen may be replaced with amines, alcohols, heterocyclic amines and other nitrogen-containing heterocycles such as piperazine, piperidine, 4-aminopiperidine, morpholine, imidazole, etc. (Scheme VI). The terminal nitrogen of piperazine or 4-aminopiperidine can be alkylated by standard alkylation methods or reacted with aldehydes in reductive amination to provide alkylated derivatives. Alternatively, the terminal nitrogen atom of piperazine or 4-aminopiperidine can be acylated or carbamoylated by a number of methods known to those skilled in the art of organic synthesis. Thus, following the process of Scheme II, compounds such as compound (19) can be prepared.

Schéma VIScheme VI

HNYZ redukciaHNYZ reduction

H*H *

Alternatívne je možné zaviesť amíny, heterocykly a alkoholy do polohy R3 nukleofilnou aromatickou substitučnou reakciou s použitím medziproduktu (20), v ktorom R3 znamená halogén, výhodne fluór, kde uvedenou reakciou je možné halogén nahradiť amínmi, alkoholmi, heterocyklickými amínmi a ďalšími dusík obsahujúcimi heterocyklami ako je piperazín, piperidín, 4-aminopiperidín, morfolín, imidazol atď. (schéma VII). Terminálny dusík piperazínu alebo 4-aminopiperidínu je možné alkylovať štandardnými spôsobmi alkylácie alebo podrobiť redukčnej aminácii s aldehydmi a získať tak alkylované deriváty. Alternatívne je možné terminálny atóm dusíka piperazínu alebo 4-aminopiperidínu acylovať alebo karbamoylovať množstvom spôsobov, ktoré sú známe odborníkom v odbore organickej syntézy. Získaný nitroanilín je potom možné redukovať na diamín (21) a spracovať spôsobom znázorneným v schéme III.Alternatively, amines, heterocycles and alcohols may be introduced at the R 3 position by a nucleophilic aromatic substitution reaction using intermediate (20) wherein R 3 represents halogen, preferably fluorine, wherein said reaction may replace halogen with amines, alcohols, heterocyclic amines and other nitrogen containing heterocycles such as piperazine, piperidine, 4-aminopiperidine, morpholine, imidazole, etc. (Scheme VII). The terminal nitrogen of piperazine or 4-aminopiperidine can be alkylated by standard alkylation methods or subjected to reductive amination with aldehydes to provide alkylated derivatives. Alternatively, the terminal nitrogen atom of piperazine or 4-aminopiperidine can be acylated or carbamoylated by a number of methods known to those skilled in the art of organic synthesis. The obtained nitroaniline can then be reduced to the diamine (21) and treated as shown in Scheme III.

Schéma VIIScheme VII

R2 R 2 -NH2 -NH 2 Nu Nu Nik Nik R R A A -NH NH R5 R 5 'no2 'no 2 redukcia reduction r r 'NH; 'NH; 20 20 21 21

Využitieexploitation

Zlúčeniny podľa vynálezu majú farmakologické vlastnosti; predovšetkým sú zlúčeniny všeobecného vzorca (I) inhibitormi enzýmov zo skupiny tyrozínkináz. Nové zlúčeniny podľa vynálezu sú teda vhodné na terapiu rôznych proliferatívnych chorôb (zahrňujúcich choroby súvisiace s enzýmami zo skupiny tyrozínkináz, ale bez obmedzenia len na ne) ako je rakovina, autoimunitné choroby, vírusové ochorenia, plesňové ochorenia, neurodegeneratívne choroby a kardiovaskulárne choroby.The compounds of the invention have pharmacological properties; in particular, the compounds of formula (I) are inhibitors of the enzymes of the tyrosine kinase family. Thus, the novel compounds of the invention are useful in the treatment of various proliferative diseases (including but not limited to diseases related to enzymes of the tyrosine kinase family) such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurodegenerative diseases and cardiovascular diseases.

Špecifickejšie sú zlúčeniny všeobecného vzorca (I) vhodné na liečenie rôznych druhov rakoviny zahrňujúcich, ale bez obmedzení len na uvedené choroby nasledujúce:More specifically, the compounds of formula (I) are useful in the treatment of various cancers including, but not limited to, the following diseases:

a) karcinómy zahrňujúce karcinóm močového mechúra, prsníka, hrubého čreva, obličiek, pečene, plúc vrátane malobunkového karcinómu pľúc, pažeráka, žlčníka, vaječníkov, pankreasu, žalúdka, maternicového krčka, štítnej žľazy, prostaty a kože vrátane karcinómu dlaždicových buniek;(a) cancers including bladder, breast, colon, kidney, liver, lung, including small cell lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin cancer, including small cell carcinoma;

b) lymfoproliferatívne krvné tumory zahrňujúce leukémiu, akútnu lymfocytárnu leukémiu, akútnu lymfoblastickú leukémiu, B-lymfocytárny lymfóm, T-lymfocytárny lymfóm, Hodgkinov lymfóm, ne-Hodgkinov lymfóm, vlasatobunkový lymfóm a Burkettov lymfóm;b) lymphoproliferative blood tumors including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-lymphocytic lymphoma, T-lymphocytic lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma;

c) myeloproliferatívne krvné tumory zahrňujúce myeloidné' leukémie, myelodysplastický syndróm a promyelocytické leukémie;c) myeloproliferative blood tumors including myeloid leukemias, myelodysplastic syndrome and promyelocytic leukemias;

d) tumory mezenchymálneho pôvodu zahrňujúce fibrosarkóm a rabdomyosarkóm;d) tumors of mesenchymal origin including fibrosarcoma and rhabdomyosarcoma;

e) tumory centrálneho a periférneho nervového systému zahrňujúce astrocytóm, neuroblastóm, glióm a Schwanómy; ae) tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma and Schwwanomas; and

f) ostatné tumory zahrňujúce sarkóm, melanóm, seminóm, teratokarcinóm, osteosarkóm, xeroderma pigmentosum, keratoakantóm, tyroidný folikulárny karcinóm a Kaposiho sarkóm.f) other tumors including sarcoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma, and Kaposi's sarcoma.

Vzhľadom na všeobecnú kľúčovú úlohu tyrozínkináz v riadení proliferácie buniek, inhibítory týchto enzýmov môžu pôsobiť ako reverzibilné cytotoxické prostriedky, ktoré je možné použiť na liečenie ľubovoľného chorobného procesu vykazujúceho rysy abnormálnej proliferácie buniek ako je napr. benígna hyperplázia prostaty, familiárna adenomatózna polypóza, neurofibromatóza, ateroskleróza, pľúcna fibróza, artritída, psoriáza, glomerulonefritída, restenóza po angioplastike alebo cievnej operácii, tvorba hypertrofujúcich jaziev, zápalové ochorenia čriev, rejekcia po transplantácii, endotoxický šok a infekcia plesňami.In view of the general key role of tyrosine kinases in controlling cell proliferation, inhibitors of these enzymes can act as reversible cytotoxic agents that can be used to treat any disease process exhibiting abnormal cell proliferation features such as e.g. benign prostate hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, formation of hypertrophic scars, inflammatory bowel disease, transplant rejection, rejection after transplantation.

Zlúčeniny všeobecného vzorca (I) môžu indukovať apoptózu. Apoptická odozva je pri rôznych ochoreniach ľudí aberantná. Zlúčeniny všeobecného vzorca (I) ako modulátory apoptózy môžu byť vhodné na liečenie rakoviny (foriem uvedených vyššie, ale neobmedzených len na ne), vírusových infekcií (zahrnujúcich infekcie vyvolané vírusmi zo skupiny herpesvirus, vírus Epstein-Barrovej, Sindbis vírus a adenovírus, ale neobmedzených len na uvedenú skupinu vírusov), na prevenciu vývoja AIDS u jedincov infikovaných HIV, na liečenie autoimunitných chorôb (zahrňujúcich ale neobmedzených len na uvedené choroby, systémový lupus erythematosus, autoimunitne podmienenú glomerulonefritídu, reumatoidnú artritídu, psoriázu, zápalové ochorenia čriev, a autoimunitný diabetes mellitus), neurodegenerativnych chorôb (zahrňujúcich ale neobmedzených len na uvedené choroby, Alzheimerovu chorobu, demenciu spojenú s AIDS, Parkinsonovu chorobu, amyotrofickú laterálnu sklerózu, retinitis pigmentosa, spinomuskulárnu atrofiu a cerebrálnu degeneráciu), myelodisplastického syndrómu, aplastickéj anémie, ischemických poškodení spojených s infarktami myokardu a reperfúzneho poškodenia, chorôb pečene spojených s účinkami toxínov alebo alkoholu, hematologických ochorení (zahrňujúcich, ale bez obmedzenia len na uvedené choroby, chronickú anémiu a aplastickú anémiu), degeneratívne choroby muskuloskeletámeho systému (zahrňujúce, ale bez obmedzenia len na uvedené choroby, osteoporózu a artritídu), aspirín-senzitívne rinosinusitídy, cystické fibrózy, roztrúsené sklerózy, ochorenia obličiek a bolesti pri rakovine.The compounds of formula (I) may induce apoptosis. The apoptotic response is aberrant in various human diseases. Compounds of formula (I) as apoptosis modulators may be useful in the treatment of cancer (but not limited to those listed above), viral infections (including infections caused by herpesvirus, Epstein-Barr virus, Sindbis virus and adenovirus, but not limited to only to the aforementioned group of viruses), to prevent the development of AIDS in HIV-infected individuals, to treat autoimmune diseases (including but not limited to systemic lupus erythematosus, autoimmune-related glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory diabetes mellitus, inflammatory autoimmune diseases) ), neurodegenerative diseases (including but not limited to, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinomuscular atrophy, and cerebral degeneration), myelodisplastic syndrome, aplastic anemia, ischemic injury associated with myocardial infarction and reperfusion injury, liver diseases associated with toxin or alcohol effects, haematological diseases (including but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to but not limited to the aforementioned diseases, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

Zlúčeniny všeobecného vzorca (I) môžu modulovať úroveň syntézy bunkovej RNA a DNA. Uvedené prostriedky podľa vynálezu sú preto vhodné na liečenie vírusových infekcií (zahrňujúcich infekcie vyvolané vírusmi zo skupiny HIV, ľudský papiloma vírus, herpesvirus, poxvírus, vírus Epstein-Barrovej, Sindbis vírus a adenovírus, ale neobmedzených len na uvedenú skupinu vírusov).Compounds of formula (I) may modulate the level of cellular RNA and DNA synthesis. The compositions of the invention are therefore suitable for the treatment of viral infections (including but not limited to those caused by HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

Zlúčeniny všeobecného vzorca (I) môžu byť takisto vhodné na chemoprevenciu rakoviny. Chemoprevenciou sa rozumie inhibícia vývoja invazívnej rakoviny buď blokovaním iniciujúceho mutagénneho javu alebo blokovaním progresie premalignych buniek, u ktorých už došlo k určitému zásahu alebo inhibície relapsu tumoru.The compounds of formula (I) may also be useful for cancer chemoprevention. By chemoprevention is meant the inhibition of the development of invasive cancer either by blocking the initiating mutagenic event or by blocking the progression of premalignant cells that have already had some intervention or inhibition of tumor relapse.

Zlúčeniny všeobecného vzorca (I) môžu byť takisto vhodné na inhibíciu angiogenézy tumorov alebo šírenia ich metastáz.The compounds of formula (I) may also be useful for inhibiting tumor angiogenesis or spreading their metastases.

Zlúčeniny podľa vynálezu môžu byť takisto vhodné na použitie v spojení (pri súčasnom alebo sekvenčnom podávaní) so známymi antikancerogénnymi spôsobmi liečenia, ako je radiačná terapia alebo liečenie cytostatickými alebo cytotoxickými prostriedkami ako sú napríklad prostriedky zo skupiny zahrňujúcej, ale neobmedzené len na ne, prostriedky interagujúce s DNA, ako je cisplatina alebo doxorubicín; inhibitory topoizomerázy II, ako je etoposid; inhibitory topoizomerázy I, ako je CPT-11 alebo topotekan; prostriedky interagujúce s tubulinom, ako je paklitaxel, docetaxel alebo epotilóny; hormonálne prostriedky, ako je tamoxifen; inhibitory tymidilátsyntázy, ako je 5-fluórouracil; a antimetabolity, ako je metotrexat; inhibitory tyrozinkinázy, ako je Iressa a OSI-774; inhibitory angiogenézy; inhibitory VEGF; inhibitory CDK; inhibitory Her1/2 a monoklonálne protilátky cielené na receptory rastového faktora, ako je erbitux (EGF) a herceptín (Her2).The compounds of the invention may also be suitable for use in conjunction (concurrent or sequential) with known anti-cancerogenic therapies, such as radiation therapy or treatment with cytostatic or cytotoxic agents such as but not limited to agents interacting with DNA such as cisplatin or doxorubicin; topoisomerase II inhibitors such as etoposide; topoisomerase I inhibitors such as CPT-11 or topotecan; tubulin interacting agents such as paclitaxel, docetaxel or epothilones; hormonal agents such as tamoxifen; thymidilate synthase inhibitors such as 5-fluorouracil; and antimetabolites such as methotrexate; tyrosine kinase inhibitors such as Iressa and OSI-774; angiogenesis inhibitors; VEGF inhibitors; CDK inhibitors; Her1 / 2 inhibitors and monoclonal antibodies targeted to growth factor receptors such as erbitux (EGF) and herceptin (Her2).

Pri spracovaní do prípravkov so zvoleným obsahom účinných zložiek obsahujú uvedené kombinované produkty zlúčeninu podľa vynálezu v rozmedzí dávok opísanom nižšie a ďalší farmaceutický účinný prostriedok alebo spôsob liečenia v povolenom rozmedzí dávok. Zlúčeniny všeobecného vzorca (I) je možné tiež podávať v prípadoch, keď príprava kombinovaného prípravku nie je vhodná, sekvenčne. Vynález poradie sekvencie neobmedzuje: zlúčeniny všeobecného vzorca (I) je možné podávať buď pred alebo po podaní známeho antikancerogénneho alebo cytotoxického prostriedku (prostriedkov).When formulated into the formulations of the selected active ingredients, said combination products comprise a compound of the invention in the dosage range described below and another pharmaceutical active agent or method of treatment within the permitted dosage range. The compounds of formula (I) may also be administered sequentially when the preparation of the combination preparation is not suitable. The invention does not limit sequence order: the compounds of formula (I) may be administered either before or after administration of the known anticancer or cytotoxic agent (s).

Vynález taktiež zahrňuje liečivá určené na použitie opísané vyššie, zahrňujúce liečenie rakoviny, zápalu, artritídy, ktoré obsahujú najmenej jednu zlúčeninu všeobecného vzorca (I) opísanú vyššie alebo najmenej jednu z jej farmaceutický prijateľných solí a na použitie zlúčeniny všeobecného vzorca (I) opísanej vyššie na prípravu liečiva účinného na liečbu proliferatívnych chorôb opísaných vyššie zahrňujúcich rakovinu, zápal a/alebo artritídu.The invention also includes medicaments for use as described above, including the treatment of cancer, inflammation, arthritis, comprising at least one compound of formula (I) described above or at least one of its pharmaceutically acceptable salts, and for use of a compound of formula (I) described above for preparing a medicament effective for treating the proliferative diseases described above, including cancer, inflammation and / or arthritis.

Farmakologické vlastnosti zlúčenín podľa vynálezu je možné potvrdiť viacerými možnými farmakologickými stanoveniami. Zlúčeniny podlá vynálezu a ich soli beli ohodnotené nižšie uvedenými farmakologickými skúškami.The pharmacological properties of the compounds of the invention can be confirmed by several possible pharmacological assays. The compounds of the invention and their salts are evaluated by the pharmacological tests below.

Biologické stanoveniaBiological assays

A. Stanovenie s CDK 2/cyklín E kinázouA. CDK 2 / Cyclin E Kinase Assay

Reakčné zmesi obsahujú 5 ng bakulovirusom exprimovaného GSTCDK2/cyklín E komplexu, 0,5 pg GST-RB fúzneho proteínu (aminokyseliny 776-928 retinoblastómového proteínu), 0,2 pCi 33Ργ-ΑΤΡ, 25 pM ATP v 50 pl kinázového pufra (50 mM Hepes, pH 8,0, 10 mM MgCI2, 1 mM EGTA, 2 mM DTT). Reakčné zmesi sa potom inkubujú 45 minút pri 30 °C a potom sa reakcia ukonči pridaním chladnej kyseliny trichlóroctovej (TCA) s obsahom kyseliny v konečnej zmesi 15 %. Zrazeniny vzniknuté s TCA sa oddelia na filtračných doskách GF/C (Packard Inštrument Co., Meriden, CT) s použitím univerzálneho zberného systému Filtermate (Packard Inštrument Co., Meriden, CT) a filtre sa potom kvantitatívne vyhodnotia na scintilačnom počítači s tekutým scintilátorom TopCount, 96 jamiek (Packard Inštrument Co., Meriden, CT). Koncentrácia zlúčenín potrebná k 50 % inhibícii aktivity kinázy (IC50) sa vyhodnotí z kriviek dávka-odozva. Zlúčeniny sa pred stanovením rozpustia na koncentráciu 10 mM v dimetylsulfoxide (DMSO) a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 2 %. Hodnoty IC50 boii zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 14 %.Reaction mixtures contain 5 ng baculovirus-expressed GSTCDK2 / cyclin E complex, 0.5 µg GST-RB fusion protein (amino acids 776-928 retinoblastoma protein), 0.2 µCi 33 γ-ΤΡΤΡ, 25 µM ATP in 50 µl kinase buffer (50 µg). mM Hepes, pH 8.0, 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT). The reaction mixtures are then incubated for 45 minutes at 30 ° C and then quenched by addition of cold trichloroacetic acid (TCA) containing an acid content of 15% in the final mixture. The TCA precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a universal Filtermate collection system (Packard Instrument Co., Meriden, CT), and the filters were then quantitatively evaluated on a liquid scintillation scintillation counter. TopCount, 96 wells (Packard Instrument Co., Meriden, CT). The concentration of compounds required to inhibit 50% of kinase activity (IC 50) is evaluated from dose-response curves. Compounds are dissolved to a concentration of 10 mM in dimethylsulfoxide (DMSO) prior to assay and then evaluated at six concentrations in triplicate. The final DMSO concentration in the reaction mixture was 2%. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 14%.

B. Stanovenie s EMT-kinázouB. EMT-Kinase Assay

Na stanovenie inhibičnej aktivity zlúčenín voči Emt bolo použité stanovenie s použitím filtrácie, v ktorom sa hodnotí fosforylácia Gst-SLP76 pomocou Gst-Emtk. Reakcia s kinázou sa uskutoční v 96 jamkovej doštičke pri teplote miestnosti, nechá sa prebiehať 15 minút a potom sa ukončí pridaním 100 pl 20 % kyseliny trichlóroctovej (TCA) obsahujúcej 0,1 mol/l pyrofosforečnanu sodného. Reakčná zmes na reakciu s kinázou (60 μΙ) obsahuje 25 mM HEPES, pH 7,0, 0,1 mg/ml BSA, 5 mM MgCI2, 5 mM MnCI2, 8 ng enzýmu (Gst-Emtk), 5 pg substrátového proteínu (Gst-SLP76), 1pM ATP, 0,4 pCi [γ-Ρ33]ΑΤΡ a hodnotenú zlúčeninu (v rôznych koncentráciách). Po ukončení reakcie sa proteíny vyzrážajú v priebehu 1 h prostredníctvom TCA pri 4 ’C. Vyzrážané proteíny sa potom prevedú na filtre (UniFilter-96, GF/C, Packard Inštrument) a nadbytok [-/-P33]ATP sa odstráni premytím. Rádioaktivita sa zmeria na prístroji TopCount NXT (Packard Inštrument) po pridaní 35 μΙ prostriedku Microscint 20 (Packard Inštrument).To determine the inhibitory activity of the compounds against Emt, a filtration assay was used to assess the phosphorylation of Gst-SLP76 by Gst-Emtk. The kinase reaction is carried out in a 96-well plate at room temperature, allowed to proceed for 15 minutes and then terminated by the addition of 100 µl of 20% trichloroacetic acid (TCA) containing 0.1 mol / l sodium pyrophosphate. The kinase reaction mixture (60 μΙ) contains 25 mM HEPES, pH 7.0, 0.1 mg / ml BSA, 5 mM MgCl 2 , 5 mM MnCl 2 , 8 ng enzyme (Gst-Emtk), 5 µg substrate protein (Gst-SLP76), 1 µM ATP, 0.4 pCi [γ-Ρ 33 ] ΑΤΡ, and the compound of interest (at various concentrations). Upon completion of the reaction, proteins are precipitated within 1 h by TCA at 4 ° C. The precipitated proteins are then transferred to filters (UniFilter-96, GF / C, Packard Instrument) and excess [- / - P 33 ] ATP is removed by washing. Radioactivity is measured on a TopCount NXT (Packard Instrument) after adding 35 μΙ of Microscint 20 (Packard Instrument).

C. Stanovenie s FAK tyrozínkinázouC. FAK Tyrosine Kinase Assay

Aktivita fokálnej adhéznej tyrozínkinázy sa hodnotí s použitím syntetického polyméru poly(Glu/Tyr) (Sigma Chemicals) ako fosfoakceptorového substrátu. Reakčná zmes má v jednotlivých prípadoch vždy celkový objem 50 μΙ a obsahuje 100 ng bakulovirusom exprimovaného enzýmu, 2 pg poly(Glu/Tyr), 1 μΜ ATP, a 0,2 μθί [v-P33]ATP. Reakčná zmes tiež obsahuje 40 mM tris-HCI, pH 7,4, 1 mM MnCI2, 0,5 mM DTT a 0,1 mg/ml hovädzieho sérového albumínu. Reakčné zmesi sa inkubujú 1 h pri 26 °C a potom sa vyhodnotí aktivita kinázy ako množstvo rádioaktívneho fosfátu prevedeného do poly(GluZTyr) substrátu. Inkorporácia fosfátu sa stanoví po pridaní chladnej kyseliny trichlóroctovej (TCA), ktorou sa proteiny vyzrážajú a prevedú sa filtrami, GF/C unifilter (Packard Inštrument Co., Meriden, CT) pomocou univerzálneho zberného zariadenia Filtermate a potom sa filtre kvantitatívne vyhodnotia na 96 jamkovom scintilačnom počítači s tekutým scintilátorom TopCount (Packard Inštrument Co., Meriden, CT). Hodnotené zlúčeniny sa najprv rozpustia v dimetylsulfoxide na koncentráciu 10 mM a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 0,5 %, kde pre uvedenú koncentráciu bolo preukázané, že neovplyvňuje aktivitu kinázy. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.Focal adhesion tyrosine kinase activity is evaluated using a synthetic poly (Glu / Tyr) polymer (Sigma Chemicals) as a phosphoacceptor substrate. The reaction mixture in each case has a total volume of 50 μΙ and contains 100 ng baculovirus-expressed enzyme, 2 µg poly (Glu / Tyr), 1 μΜ ATP, and 0.2 μθί [vP 33 ] ATP. The reaction mixture also contains 40 mM Tris-HCl, pH 7.4, 1 mM MnCl 2 , 0.5 mM DTT, and 0.1 mg / ml bovine serum albumin. The reaction mixtures are incubated for 1 hour at 26 ° C and then kinase activity is evaluated as the amount of radioactive phosphate transferred to the poly (GluZTyr) substrate. Phosphate incorporation is determined by the addition of cold trichloroacetic acid (TCA) to precipitate proteins and pass through filters, a GF / C unifilter (Packard Instrument Co., Meriden, CT) using a Universal Filtermate Harvester, and then quantitate the filters in a 96 well assay. a TopCount liquid scintillation counter (Packard Instrument Co., Meriden, CT). The compounds to be evaluated are first dissolved in dimethylsulfoxide at a concentration of 10 mM and then evaluated at six concentrations in triplicate. The final concentration of DMSO in the reaction mixture was 0.5%, where it was shown to have no effect on kinase activity at the indicated concentration. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

D. Stanovenie s HER-1/HER-2 kinázouD. HER-1 / HER-2 Kinase Assay

Na sledovanie aktivity kinázy sa použijú reakčné zmesi obsahujúce 10 ng bakulovirusom exprimovaného GST-HER1, 100 ng HER2, 100 ng/ml poly(Glu/Tyr) (Sigma), 0,2 pCi 33Ργ-ΑΤΡ, 1 μΜ ATP v 50 μΙ pufra pre kinázu (50 mM tris, pH 7,5, 10 mM MnCI2. 0,5 mM DTT). Reakčné zmesi sa potom inkubujú 1 h pri 27 °C a potom sa reakcia ukonči pridaním chladnej kyseliny trichlóroctovej (TCA) s obsahom kyseliny v konečnej zmesi 15 %. Zrazeniny vzniknuté s TCA sa oddelia na filtračných doskách GF/C (Packard Inštrument Co., Meriden, CT) s použitím univerzálneho zberného systému Filtermate (Packard Inštrument Co., Meriden, CT) a filtre sa potom kvantitatívne vyhodnotia na scintilačnom počítači s tekutým scintilátorom TopCount, 96 jamiek (Packard Inštrument Co., Meriden, CT). Koncentrácia zlúčenín potrebná k 50 % inhibícii aktivity kinázy (IC50) sa vyhodnotí z kriviek dávka-odozva. Zlúčeniny sa pred stanovením rozpustia na koncentráciu 10 mM v dimetylsulfoxide (DMSO) a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 1 %. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.Reaction mixtures containing 10 ng baculovirus-expressed GST-HER1, 100 ng HER2, 100 ng / ml poly (Glu / Tyr) (Sigma), 0.2 pCi 33 Ργ-ΑΤΡ, 1 μΜ ATP at 50 μΙ are used to monitor kinase activity. kinase buffer (50 mM tris, pH 7.5, 10 mM MnCl 2 , 0.5 mM DTT). The reaction mixtures are then incubated for 1 hour at 27 ° C and then quenched by addition of cold trichloroacetic acid (TCA) containing an acid content of 15% in the final mixture. The TCA precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a universal Filtermate collection system (Packard Instrument Co., Meriden, CT), and the filters were then quantitatively evaluated on a liquid scintillation scintillation counter. TopCount, 96 wells (Packard Instrument Co., Meriden, CT). The concentration of compounds required to inhibit 50% of kinase activity (IC 50 ) is evaluated from dose-response curves. Compounds are dissolved to a concentration of 10 mM in dimethylsulfoxide (DMSO) prior to assay and then evaluated at six concentrations in triplicate. The final DMSO concentration in the reaction mixture is 1%. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

E. Stanovenie s IGF-receptorovou tyrozinkinázouE. IGF-Receptor Tyrosine Kinase Assay

Aktivita IGF-1 receptorovej tyrozínkinázy sa hodnotí s použitím syntetického polyméru poly(Glu/Tyr) (Sigma Chemicals) ako fosfoakceptorového substrátu. Reakčná zmes má v jednotlivých prípadoch vždy celkový objem 50 μΙ a obsahuje 125 ng bakulovírusom exprimovaného enzýmu, 2,5 ng poly(Glu/Tyr), 25 μΜ ATP a 0,1 μθί [γ-33Ρ]ΑΤΡ. Reakčná zmes tiež obsahuje 20 mM MOPS, pH 7,0, 5 mM MnCI2, 0,5 mM DTT a 0,1 mg/ml hovädzieho sérového albumínu. Reakčné zmesi sa inkubujú 45 min pri 30 °C a potom sa vyhodnotí aktivita kinázy ako množstvo rádioaktívneho fosfátu prevedeného do poly(Glu/Tyr) substrátu. Inkorporácia fosfátu sa stanoví po pridaní chladnej kyseliny trichlóroctovej (TCA), ktorou sa proteíny vyzrážajú a prevedú sa filtrami, GF/C unifilter (Packard Inštrument Co., Meriden, CT) pomocou univerzálneho zberného zariadenia Filtermate a potom sa filtre kvantitatívne vyhodnotia na 96 jamkovom scintilačnom počítači s tekutým scintilátorom TopCount (Packard Inštrument Co., Meriden, CT). Hodnotené zlúčeniny sa najprv rozpustia v dimetylsulfoxide na koncentráciu 10 mM a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 0,5 %, kde pre uvedenú koncentráciu bolo preukázané, že neovplyvňuje aktivitu kinázy. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.IGF-1 receptor tyrosine kinase activity is evaluated using a synthetic poly (Glu / Tyr) polymer (Sigma Chemicals) as a phosphoacceptor substrate. The reaction mixture always has a total volume of 50 μ 50 and contains 125 ng baculovirus-expressed enzyme, 2.5 ng poly (Glu / Tyr), 25 μΜ ATP and 0.1 μθί [γ- 33 Ρ] ΑΤΡ. The reaction mixture also contains 20 mM MOPS, pH 7.0, 5 mM MnCl 2 , 0.5 mM DTT, and 0.1 mg / ml bovine serum albumin. The reaction mixtures were incubated for 45 min at 30 ° C and then kinase activity was evaluated as the amount of radioactive phosphate transferred to the poly (Glu / Tyr) substrate. Phosphate incorporation is determined by the addition of cold trichloroacetic acid (TCA) to precipitate proteins and pass through filters, a GF / C unifilter (Packard Instrument Co., Meriden, CT) using a Universal Filtermate collection device, and then quantitatively evaluate the filters to 96 wells. a TopCount liquid scintillation counter (Packard Instrument Co., Meriden, CT). The compounds to be evaluated are first dissolved in dimethylsulfoxide at a concentration of 10 mM and then evaluated at six concentrations in triplicate. The final concentration of DMSO in the reaction mixture was 0.5%, where it was shown to have no effect on kinase activity at the indicated concentration. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

F. Stanovenie s receptorovou tyrozinkinázou inzulínuF. Insulin receptor tyrosine kinase assay

Aktivita receptorovej tyrozínkinázy inzulínu sa hodnotí s použitím syntetického polyméru poly(Glu/Tyr) (Sigma Chemicals) ako fosfoakceptorového substrátu.Insulin receptor tyrosine kinase activity is evaluated using a synthetic poly (Glu / Tyr) polymer (Sigma Chemicals) as a phosphoacceptor substrate.

Reakčná zmes má v jednotlivých prípadoch vždy celkový objem 50 μΙ a obsahuje 90 ng bakulovírusom exprimovaného enzýmu, 2,5 ^ig poly(Glu/Tyr), 25 μΜ ATP, a 0,1 μθί [γ-33Ρ]ΑΤΡ. Reakčná zmes tiež obsahuje 20 mM tris-HCI, pH 7,4, 5 mM MnCI2, 0,5 mM DTT a 0,1 mg/ml hovädzieho sérového albumínu. Reakčné zmesi sa inkubujú 1 h pri 26 °C a potom sa vyhodnotí aktivita kinázy ako množstvo rádioaktívneho fosfátu prevedeného do poly(Glu/Tyr) substrátu. Inkorporácia fosfátu sa stanoví po pridaní chladnej kyseliny trichlóroctovej (TCA), ktorou sa proteíny vyzrážajú a prevedú sa filtrami, GF/C unifilter (Packard Inštrument Co., Meriden, CT) pomocou univerzálneho zberného zariadenia Filtermate a potom sa filtre kvantitatívne vyhodnotia na 96 jamkovom scintilačnom počítači s tekutým scintilátorom TopCount (Packard Inštrument Co., Meriden, CT). Hodnotené zlúčeniny sa najprv rozpustia v dimetylsulfoxide na koncentráciu 10 mM a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 0,5 %, kde pre uvedenú koncentráciu bolo preukázané, že neovplyvňuje aktivitu kinázy. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.The reaction mixture in each case has a total volume of 50 μΙ and contains 90 ng baculovirus-expressed enzyme, 2.5 μg poly (Glu / Tyr), 25 μΜ ATP, and 0.1 μθί [γ- 33 Ρ] ΑΤΡ. The reaction mixture also contains 20 mM Tris-HCl, pH 7.4, 5 mM MnCl 2 , 0.5 mM DTT, and 0.1 mg / ml bovine serum albumin. The reaction mixtures are incubated for 1 hour at 26 ° C and then kinase activity is evaluated as the amount of radioactive phosphate transferred to the poly (Glu / Tyr) substrate. Phosphate incorporation is determined by the addition of cold trichloroacetic acid (TCA) to precipitate proteins and pass through filters, a GF / C unifilter (Packard Instrument Co., Meriden, CT) using a Universal Filtermate collection device, and then quantitatively evaluate the filters to 96 wells. a TopCount liquid scintillation counter (Packard Instrument Co., Meriden, CT). The compounds to be evaluated are first dissolved in dimethylsulfoxide at a concentration of 10 mM and then evaluated at six concentrations in triplicate. The final concentration of DMSO in the reaction mixture was 0.5%, where it was shown to have no effect on kinase activity at the indicated concentration. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

G. Stanovenie s LCK kinázouG. LCK Kinase Assay

Na sledovanie aktivity kinázy sa použijú reakčné zmesi obsahujúce 10 ng bakulovírusom exprimovanej GST-Lck, 100 ng/ml poly(Glu/Tyr) (Sigma), 0,2 pCi 33ΡγATP, 1 μΜ ATP v 50 μΙ pufra pre kinázu (50 mM tris, pH 7,5, 10 mM MnCh, 0,5 mM DTT). Reakčné zmesi sa potom inkubujú 1 h pri 27 °C a potom sa reakcia ukončí pridaním chladnej kyseliny trichlóroctovej (TCA) s obsahom kyseliny v konečnej zmesi 15 %. Zrazeniny vzniknuté s TCA sa oddelia na filtračných doskách GF/C (Packard Inštrument Co., Meriden, CT) s použitím univerzálneho zberného systému Filtermate (Packard Inštrument Co., Meriden, CT) a filtre sa potom kvantitatívne vyhodnotia na scintilačnom počítači s tekutým scintilátorom TopCount, 96 jamiek (Packard Inštrument Co., Meriden, CT). Koncentrácia zlúčenín potrebná k 50 % inhibícii aktivity kinázy (IC5o) sa vyhodnotí z kriviek dávka-odozva. Zlúčeniny sa pred stanovením rozpustia na koncentráciu 10 mM v dimetylsulfoxide (DMSO) a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 1 %. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.Reaction mixtures containing 10 ng baculovirus-expressed GST-Lck, 100 ng / ml poly (Glu / Tyr) (Sigma), 0.2 pCi 33 ΡγATP, 1 μΜ ATP in 50 μΙ kinase buffer (50 mM) are used to monitor kinase activity. tris, pH 7.5, 10 mM MnCl 2, 0.5 mM DTT). The reaction mixtures are then incubated for 1 h at 27 ° C and then quenched by addition of cold trichloroacetic acid (TCA) containing an acid content of 15% in the final mixture. The TCA precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a universal Filtermate collection system (Packard Instrument Co., Meriden, CT), and the filters were then quantitatively evaluated on a liquid scintillation scintillation counter. TopCount, 96 wells (Packard Instrument Co., Meriden, CT). The concentration of compounds required to inhibit 50% of kinase activity (IC 50 ) is evaluated from dose-response curves. Compounds are dissolved to a concentration of 10 mM in dimethylsulfoxide (DMSO) prior to assay and then evaluated at six concentrations in triplicate. The final DMSO concentration in the reaction mixture is 1%. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

H. Stanovenie s MET kinázouH. MET kinase assay

Na sledovanie aktivity kinázy sa použijú reakčné zmesi obsahujúce 10 ng bakulovírusom exprimovanej GST-Met, 2,5 pg/ml poly(Glu/Tyr) (Sigma), 0,2 pCi 33ΡγATP, 10 μΜ ATP v 50 μΙ pufra pre kinázu (40 mM tris, pH 7,5, 1 mM MnCI2, 0,5 mM DTT). Reakčné zmesi sa potom inkubujú 1 h pri 27 °C a potom sa reakcia ukončí pridaním chladnej kyseliny trichlóroctovej (TCA) s obsahom kyseliny v konečnej zmesi 3,5 %. Zrazeniny vzniknuté s TCA sa oddelia na filtračných doskách GF/C (Packard Inštrument Co., Meriden, CT) s použitím univerzálneho zberného systému Filtermate (Packard Inštrument Co., Meriden, CT) a filtre sa potom kvantitatívne vyhodnotia na scintilačnom počítači s tekutým scintilátorom TopCount, 96 jamiek (Packard Inštrument Co., Meriden, CT). Koncentrácia zlúčenín potrebná k 50 % inhibícií aktivity kinázy (IC50) sa vyhodnotí z kriviek dávka-odozva Zlúčeniny sa pred stanovením rozpustia na koncentráciu 10 mM v dimetylsulfoxide (DMSO) a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 1 %. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.Reaction mixtures containing 10 ng baculovirus-expressed GST-Met, 2.5 µg / ml poly (Glu / Tyr) (Sigma), 0.2 µCi 33 ΡγATP, 10 µΜ ATP in 50 µΙ kinase buffer () are used to monitor kinase activity. 40 mM tris, pH 7.5, 1 mM MnCl 2 , 0.5 mM DTT). The reaction mixtures were then incubated for 1 hour at 27 ° C and then quenched by addition of cold trichloroacetic acid (TCA) containing an acid content of 3.5% in the final mixture. The TCA precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a universal Filtermate collection system (Packard Instrument Co., Meriden, CT), and the filters were then quantitatively evaluated on a liquid scintillation scintillation counter. TopCount, 96 wells (Packard Instrument Co., Meriden, CT). Compound concentration required for 50% inhibition of kinase activity (IC 50) is evaluated from dose-response curves Compounds are dissolved to a concentration of 10 mM in dimethylsulfoxide (DMSO) prior to assay and then evaluated at six concentrations in triplicate. The final DMSO concentration in the reaction mixture is 1%. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

I. Stanovenie s PDGF receptorovou kinázouI. Assay with PDGF receptor kinase

Na sledovanie aktivity kinázy sa použijú reakčné zmesi obsahujúce 70 ng bakulovírusom exprimovanej GST-PDGFbR, 0,3 pg biotinylovaného poly(Glu/Tyr) (Sigma) v 50 μΙ pufra pre kinázu (20 mM Hepes, 0,7 μΜ ATP, 10 mM MnCI2, 0,5 mM DTT, 0,15 mM NaCI, 0,1 mg/ml BSA). Reakčné zmesi sa potom inkubujú 30 min pri teplote miestnosti za trepania a potom sa reakcia ukončí pridaním 10 μΙ 0,2 M EDTA, pH 8,0. Potom sa pridá 150 μΙ HTRF detekčného pufra a reakčná zmes sa inkubuje 1 hodinu 30 minút pri teplote miestnosti. Počet signálov sa kvantitatívne vyhodnotí na zariadení Discovery HTRF Packard Inštrument.Reaction mixtures containing 70 ng baculovirus-expressed GST-PDGFbR, 0.3 µg biotinylated poly (Glu / Tyr) (Sigma) in 50 μΙ kinase buffer (20 mM Hepes, 0.7 μΜ ATP, 10 mM) are used to monitor kinase activity. MnCl 2 , 0.5 mM DTT, 0.15 mM NaCl, 0.1 mg / ml BSA). The reaction mixtures are then incubated for 30 min at room temperature with shaking and then quenched by the addition of 10 μΙ 0.2 M EDTA, pH 8.0. Then 150 μΙ of HTRF detection buffer is added and the reaction mixture is incubated for 1 hour 30 minutes at room temperature. The number of signals is quantitatively evaluated on a Discovery HTRF Packard Instrument.

J. Stanovenie s VEGFR-2 (KDR) kinázouJ. Assay with VEGFR-2 (KDR) kinase

Na sledovanie aktivity kinázy sa použijú reakčné zmesi obsahujúce 7,5 ng bakulovírusom exprimovanej GST-KDR, 1,5 pg/ml poly(Glu/Tyr) (Sigma), 0,4 pCi 33Py-ATP, 2,5 μΜ ATP v 50 μΙ pufra pre kinázu (25 mM tris, pH 7,5, 1,8 mM MnCI2, 0,625 mM DTT). Reakčné zmesi sa potom inkubujú 1 h pri 27 °C a potom sa reakcia ukončí pridaním chladnej kyseliny trichlóroctovej (TCA) s obsahom kyseliny v konečnej zmesi 15 %. Zrazeniny vzniknuté s TCA sa oddelia na filtračných doskách GF/C (Packard Inštrument Co., Meriden, CT) s použitím univerzálneho zberného systému Filtermate (Packard Inštrument Co., Meriden, CT) a filtre sa potom kvantitatívne vyhodnotia na scintilačnom počítači s tekutým scintilátorom TopCount, 96 jamiek (Packard Inštrument Co., Meriden, CT). Koncentrácia zlúčenín potrebná k 50 % inhibícii aktivity kinázy (ICso) sa vyhodnotí z kriviek dávka-odozva. Zlúčeniny sa pred stanovením rozpustia na koncentráciu 10 mM v dimetylsulfoxide (DMSO) a potom sa hodnotia pri šiestich koncentráciách vždy trikrát. Konečná koncentrácia DMSO v reakčnej zmesi je 1 %. Hodnoty IC50 boli zistené nelineárnou regresnou analýzou a mali koeficient variancie (SD/priemer, n=6) = 16 %.Reaction mixtures containing 7.5 ng baculovirus-expressed GST-KDR, 1.5 µg / ml poly (Glu / Tyr) (Sigma), 0.4 µCi 33 Py-ATP, 2.5 µΜ ATP in 50 μΙ kinase buffer (25 mM tris, pH 7.5, 1.8 mM MnCl 2 , 0.625 mM DTT). The reaction mixtures are then incubated for 1 h at 27 ° C and then quenched by addition of cold trichloroacetic acid (TCA) containing an acid content of 15% in the final mixture. The TCA precipitates were collected on GF / C filter plates (Packard Instrument Co., Meriden, CT) using a universal Filtermate collection system (Packard Instrument Co., Meriden, CT), and the filters were then quantitatively evaluated on a liquid scintillation scintillation counter. TopCount, 96 wells (Packard Instrument Co., Meriden, CT). The concentration of compounds required to inhibit 50% of kinase activity (IC 50) is evaluated from dose-response curves. Compounds are dissolved to a concentration of 10 mM in dimethylsulfoxide (DMSO) prior to assay and then evaluated at six concentrations in triplicate. The final DMSO concentration in the reaction mixture is 1%. IC 50 values were determined by non-linear regression analysis and had a coefficient of variation (SD / mean, n = 6) = 16%.

K. Stanovenie cytotoxicity (ΗΤ-29-hrubé črevo; Colo205, MCF-7-prsnik).K. Determination of cytotoxicity (ΗΤ-29-colon; Colo205, MCF-7-breast).

Tumorové bunkové línie sa kultivujú v médiu McCoy 5A (GIBCO) s 10 % teplom inaktivovaného fetálneho hovädzieho séra (GIBCO). Cytotoxicita in vitro bola na uvedených tumorových bunkách hodnotená kolorimetrickým stanovením s tetrazóliovým derivátom, MTS, s využitím metabolickej konverzie MTS (3-(4,5dimetyltiazol-2-yl)-5-(3-karboxymetoxyfenyl)-2-(4-sulfenyl)-2H-tetrazólium, vnútorná soľ) (Promega) na jej redukovanú formu, ktorá absorbuje svetlo pri 492 nm (1). Bunky sa naočkujú 24 hodín pred pridaním liečiva. Po inkubácii pri 37 °C po 72 hodín s postupne zriedenou testovanou zlúčeninou sa k bunkám pridá MTS (Riss T.L. a sp., Comparison of MTT, XTT and novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays, Mol. Biol. Celí 3 (Suppl.):184a, 1992) v spojení s prostriedkom pre vytvorenie elektrónovej väzby, fenazínmetosulfátom. V inkubácii sa pokračuje ďalšie 3 hodiny a potom sa spektrometrom zmeria absorbancia média pri 492 nm na získanie hodnoty umožňujúcej stanoviť počet prežívajúcich buniek vzhľadom na kontrolnú populáciu buniek. Výsledky sú vyjadrené vo forme priemerných cytotoxických koncentrácií (v hodnotách IC50).Tumor cell lines are cultured in McCoy 5A medium (GIBCO) with 10% heat inactivated fetal bovine serum (GIBCO). In vitro cytotoxicity was evaluated on the tumor cells by a tetrazolium derivative colorimetric assay, MTS, utilizing the metabolic conversion of MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfenyl)) -2H-tetrazolium inner salt (Promega) to its reduced form which absorbs light at 492 nm (1). Cells are seeded 24 hours prior to drug addition. After incubation at 37 ° C for 72 hours with successively diluted test compound, MTS (Riss TL et al., Comparison of MTT, XTT and novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assays, Mol. Biol.) Is added to the cells. (Suppl.): 184a, 1992) in conjunction with an electron-bonding agent, phenazine metosulfate. Incubation is continued for a further 3 hours and then the absorbance of the medium at 492 nm is measured with a spectrometer to obtain a value allowing the number of surviving cells to be determined relative to the control cell population. Results are expressed as mean cytotoxic concentrations (IC 50 values).

Tabuľka 1 - Biologická aktivita (μΜ); pri všetkých zlúčeninách uvedených v tabuľke bola zistená účinnosť pri koncentrácii menšej ako 25 μΜ voči jednej alebo viacerým z kináz zahrňujúcich CDK, EMT, FAK, Her1, Her2, IGF, IR, LCK, MET, PDGF, VEGF. HT-29 a Colo205 sú ľudské bunkové línie tumoru hrubého čreva a MCF-7 je ľudská bunková línia tumoru prsníka.Table 1 - Biological activity (μΜ); for all compounds listed in the table, efficacy was found to be less than 25 μΜ against one or more of the kinases including CDK, EMT, FAK, Her1, Her2, IGF, IR, LCK, MET, PDGF, VEGF. HT-29 and Colo205 are human colon tumor cell lines and MCF-7 is a human breast tumor cell line.

Príklad Example HT-29 HT-29 MCF-7 MCF-7 Colo205 Colo205 1 1 1,0 1.0 3 3 2,0 2.0 399 399 0,4 0.4 0,8 0.8 400 400 0,8 0.8 0,9 0.9 411 411 0,7 0.7 0,9 0.9 517 517 0,3 0.3 519 519 0,3 0.3 0,6 0.6 520 520 0,6 0.6 0,2 0.2 521 521 0,5 0.5 522 522 0,7 0.7 0,1 0.1 0,1 0.1 523 523 0,6 0.6 524 524 0,6 0.6 525 525 1,1 1.1 526 526 1,4 1.4 527 527 1,3 1.3 0,1 0.1 0,3 0.3 534 534 0,4 0.4 538 538 0,9 0.9 544 544 0,3 0.3 0,6 0.6 553 553 0,9 0.9 0,3 0.3 0,2 0.2 554 554 0,7 0.7 0,2 0.2 0,3 0.3 555 555 0,2 0.2 0,1 0.1 0,2 0.2 559 559 0,6 0.6 0,3 0.3 574 574 0,2 0.2 581 581 0,2 0.2 0,3 0.3 582 582 0,1 0.1 0,2 0.2

583 583 0,1 0.1 0,2 0.2 584 584 0,3 0.3 0,2 0.2 585 585 0,7 0.7 0,3 0.3 590 590 0,8 0.8 0,2 0.2 0,2 0.2 593 593 0,7 0.7

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Všeobecný spôsob prípravy 2-hydroxy-2-(substituovaný fenyl)-etylamínov:General process for the preparation of 2-hydroxy-2- (substituted phenyl) -ethylamines:

OHOH

-(3-chlórfenyl)-2-nitroetanol:- (3-chlorophenyl) -2-nitroethanol:

K roztoku 3-chlórbenzaldehydu (20 g, 0,142 mmol) v nitrometáne (100 ml) sa pridá síran horečnatý (37,6 g, 0,312 mol) a fosfazénová báza, Pi-tercbutyltris(tetrametylén) (4,43 g, 0,014 mol). Reakčná zmes sa mieša pri teplote miestnosti 2 h. Po zahustení za zníženého tlaku sa zvyšok prečisti rýchlou chromatografiou (25 % EtOAc/hexán) a titulná zlúčenina sa získa (26,4 g, 100 %) vo forme zelenožltého oleja. 1H NMR (300 MHz, DMSO-dg) Ô 7,53 (1H, s), 7,35-7,42 (3H, m), 6,23 (1H, široký s), 5,32-5,33 (1H, m), 4,90 (1H, dd, J = 3,2, 12,4 Hz), 4,60 (1H, dd, J = 1,2, 12,4 Hz).To a solution of 3-chlorobenzaldehyde (20 g, 0.142 mmol) in nitromethane (100 mL) was added magnesium sulfate (37.6 g, 0.312 mol) and a phosphazene base, Pi-tert-butyltris (tetramethylene) (4.43 g, 0.014 mol). . The reaction mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, the residue was purified by flash chromatography (25% EtOAc / hexane) to give the title compound (26.4 g, 100%) as a greenish-yellow oil. 1 H NMR (300 MHz, DMSO-d 6) δ 7.53 (1H, s), 7.35-7.42 (3H, m), 6.23 (1H, broad s), 5.32-5, 33 (1H, m), 4.90 (1H, dd, J = 3.2, 12.4 Hz), 4.60 (1H, dd, J = 1.2, 12.4 Hz).

OTESOTES

(1 -(3-chlórfenyl)-2-nitroetoxy)trietylsilán:(1- (3-chlorophenyl) -2-nitroethoxy) triethylsilane:

K roztoku 1-(3-chlórfenyl)-2-nitroetanolu (26 g, 0,14 mol) v DMF (50 ml) sa pridá imidazol (28,6 g, 0,42 mol) a chlóretylsilán (25,3 g, 0,17 mol). Reakčná zmes sa mieša 2 h pri teplote miestnosti. Po zaliati vodou sa reakčná zmes extrahuje etylacetátom. Spojené organické vrstvy sa premyjú vodou a soľným roztokom, vysušia saTo a solution of 1- (3-chlorophenyl) -2-nitroethanol (26 g, 0.14 mol) in DMF (50 mL) was added imidazole (28.6 g, 0.42 mol) and chloroethylsilane (25.3 g, 0.17 mol). The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried

Na2SO4 a prefiltrujú sa. Po odstránení rozpúšťadla sa surový produkt prečisti rýchlou chromatografiou (2 % EtOAc/hexán) na titulnú zlúčeninu (37 g, 91 %) vo forme bezfarebného oleja. 1H NMR (300 MHz, CDCI3) δ 7,40 (1H, s), 7,27-7,32 (3H, m),Na 2 SO 4 and filtered. After removal of the solvent, the crude product was purified by flash chromatography (2% EtOAc / hexanes) to give the title compound (37 g, 91%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 (1H, s), 7.27-7.32 (3H, m),

5,40 (1H, dd, J = 3,2, 9,5 Hz), 4,51 (1H, dd, J = 9,5, 12,1 Hz), 4,36 (1H, dd, J = 3,3, 12,1 Hz), 0,85 (9H, t, J = 7,5 Hz), 0,54 (6H, q, J = 7.5 Hz).5.40 (1H, dd, J = 3.2, 9.5 Hz), 4.51 (1H, dd, J = 9.5, 12.1 Hz), 4.36 (1H, dd, J = 3.3, 12.1 Hz), 0.85 (9H, t, J = 7.5 Hz), 0.54 (6H, q, J = 7.5 Hz).

OTESOTES

2-(3-chlórfenyl)-2-trietylsilanyloxyetylamín:2- (3-chlorophenyl) -2-trietylsilanyloxyetylamín:

Raneyov nikel (1 g) sa päťkrát premyje vodou a trikrát metanolom. Potom [1(3-chlórfenyl)-2-nitroetoxy]trietylsilán (10 g, 0,032 mol) hydrogenuje s Raneyovým niklom v metanole pri teplote miestnosti a tlaku 35 psi (241 kPa) 14 h. Potom sa reakčná zmes prefiltruje cez vrstvu celitu a premyje sa metanolom. Zahustením filtrátu do sucha sa získa vo forme bezfarebného oleja titulná zlúčenina (5,6 g, 62 %), ktorá sa použije v nasledujúcom stupni bez ďalšieho čistenia. 1H NMR (300 MHz, CDCI3) δ 7,32 (1H, s), 7,18-7,26 (3H, m), 4,70 (1H, t, J = 5,8 Hz), 2,86 (2H, m), 0,89 (9H, t, J = 7,9 Hz), 0,56 (6H, q, J = 7,8 Hz). LRMS (M+H)+ m/z 286.The Raney nickel (1 g) was washed five times with water and three times with methanol. Then [1- (3-chlorophenyl) -2-nitroethoxy] triethylsilane (10 g, 0.032 mol) was hydrogenated with Raney nickel in methanol at room temperature and 35 psi pressure for 14 h. The reaction mixture was then filtered through a pad of celite and washed with methanol. Concentration of the filtrate to dryness gave the title compound as a colorless oil (5.6 g, 62%), which was used in the next step without further purification. 1 H NMR (300 MHz, CDCl 3 ) δ 7.32 (1H, s), 7.18-7.26 (3H, m), 4.70 (1H, t, J = 5.8 Hz), 2 86 (2H, m), 0.89 (9H, t, J = 7.9Hz), 0.56 (6H, q, J = 7.8Hz). LRMS (M + H) < + > m / z 286.

Všeobecný spôsob prípravy 2-hydroxy-2-(substituovaný fenyl)-etylamínov:General process for the preparation of 2-hydroxy-2- (substituted phenyl) -ethylamines:

oabout

4-metoxy-3-brómfenylchlóracetofenôn:4-methoxy-3-brómfenylchlóracetofenôn:

K suspenzii AICI3 (13,4 g, 0,10 mol) v dichlórmetáne (40 ml) sa pridá pri 0 °C roztok 2-brómanizolu (12,5 ml, 0,10 mol) a chlóracetylchloridu (8 ml, 0,10 mol). Roztok sa nechá v priebehu dvoch hodín ohriať na teplotu miestnosti, vyleje sa na ľad a extrahuje sa dichlórmetánom, premyje sa nasýteným roztokom hydrogenuhličitanu sodného, soľným roztokom, a vysuší sa MgSO4. Potom sa roztok prefiltruje, zahustí sa a kryštalizáciou z EtOH sa získa 15,37 g bielej tuhej hmoty.To a suspension of AlCl 3 (13.4 g, 0.10 mol) in dichloromethane (40 mL) was added a solution of 2-bromoanisole (12.5 mL, 0.10 mol) and chloroacetyl chloride (8 mL, 0.10) at 0 ° C. mol). The solution was allowed to warm to room temperature over two hours, poured out on ice and extracted with dichloromethane, washed with saturated sodium bicarbonate solution, brine, and dried over MgSO 4 . The solution was then filtered, concentrated and crystallized from EtOH to give 15.37 g of a white solid.

LRMS [M-H]' 260,8; IR (KBr): 1697, 1048, 1255 cm’1; 1H NMR (300 MHz, CDCI3) δLRMS [MH] - 260.8; IR (KBr): 1697, 1048, 1255 cm < -1 >; 1 H NMR (300 MHz, CDCl 3 )?

8,18 (s, 1H), 7,94 (dd, J = 8.67 Hz, 1H), 6,96 (d, J = 8,67 Hz, 1H), 4,62 (s, 2H), 3,98 (s, 3H); 13C NMR (CDCI3, 75.5 Hz) δ 188,8, 160,3, 134,1, 129,9, 128,2, 112,4, 111,3,8.18 (s, 1H), 7.94 (dd, J = 8.67Hz, 1H), 6.96 (d, J = 8.67Hz, 1H), 4.62 (s, 2H), 3, 98 (s, 3 H); 13 C NMR (CDCl 3 , 75.5 Hz) δ 188.8, 160.3, 134.1, 129.9, 128.2, 112.4, 111.3,

56,6, 45,3.56.6, 45.3.

Všeobecný spôsob chirálnej redukcie chlórketónov a amonolýzy:General method of chiral reduction of chloroketones and ammonolysis:

OHOH

(S)-1-[4-metoxy-3-brómfenyl]-2-cľilóretanol;(S) -1- [4-methoxy-3-bromophenyl] -2-cľilóretanol;

K roztoku (S)-metyl-CBS-oxaborolidínu (1 mol/l v toluéne, 0,745 mmol) a BH3THF (8 ml, 8 mmol) sa súčasne pridá roztok BH3-THF (19 ml, 19 mmol) a roztok chlórketónu (10,03 g, 37,98 mmol) v 19 ml THF. Oba roztoky sa pridávajú po kvapkách v priebehu 30 minút. Roztok sa potom mieša a potom sa reakcia preruší pomalým zaliatím metanolom (50 ml). Potom sa roztok zahustí a prečistením zvyšku chromatografiou na krátkej kolóne silikagélu (hexán/etylacetát 1:1) sa získa v kvantitatívnom výťažku (10,0 g) chlórhydrín vo forme číreho oleja. IR (KBr); 1053, 1258, 3406 cm1; 1H NMR (300 MHz, CDCI3) δ 7,59 (s, 1H), 7,30 (dd, J = 2,16 Hz, 1H), 6,90 (d, J = 8,46 Hz, 1H), 4,83 (dd, J = 3,57 Hz, 1H), 3,90 (s, 3H), 3,64 (ddd, J =To a solution of (S) -methyl-CBS-oxaborolidine (1 mol / L in toluene, 0.745 mmol) and BH 3 THF (8 mL, 8 mmol) was added simultaneously a solution of BH 3 -THF (19 mL, 19 mmol) and a chloroketone solution. (10.03 g, 37.98 mmol) in 19 mL THF. Both solutions are added dropwise over 30 minutes. The solution was then stirred and then quenched by slowly quenching with methanol (50 mL). Thereafter, the solution was concentrated and purification of the residue by short silica gel column chromatography (hexane / ethyl acetate 1: 1) gave chlorohydrin as a clear oil in quantitative yield (10.0 g). IR (KBr); 1053, 1258, 3406 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 (s, 1H), 7.30 (dd, J = 2.16 Hz, 1H), 6.90 (d, J = 8.46 Hz, 1H 4.83 (dd, J = 3.57 Hz, 1H), 3.90 (s, 3H), 3.64 (ddd, J

3,6, 11,1, 8,7, 2H), 2,04 (b s. 1H). 13C NMR (CDCI3, 75,5 Hz) δ 155,9, 133,5, 131,1, 126,3, 11 1,9, 73,1, 60,4, 56,3, 50,7.3.6, 11.1, 8.7, 2H), 2.04 (bs, 1H). 13 C NMR (CDCl 3 , 75.5 Hz) δ 155.9, 133.5, 131.1, 126.3, 11 1.9, 73.1, 60.4, 56.3, 50.7.

(S)-2-amino-1-[3-chlór-4-metoxyfenyl]etanolhydrochlorid:(S) -2-Amino-1- [3-chloro-4-methoxyphenyl] ethanol hydrochloride:

K roztoku chlórhydrinu (10,0 g, 37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahustí. Kryštalizáciou zvyšku zo zmesi etanol/etylacetát sa získa 3,83 g bielej tuhej hmoty (35 %). Získaný produkt sa nechá reagovať s Boc2O v etyl-acetáte a nasýtenom hydrogenuhličitane sodnom a analýzou chirálnou HPLC na stĺpci Chiracel OJ s použitím mobilnej fázy 95 % hexán/etanol bol zistený 98 % ee (enantiomérny nadbytok). Oddelením ďalších podielov - 2,96 g a 1,41 g sa získa celkovo 75 % výťažok. LRMS [M+H]+ 246; IR (cm-1, KBr) 1055, 1261, 3001, 2948, 3356; 1H NMR (500 MHz, DMSO) ô 8,09 (b s, 2H), 7,58 (s, 1H), 7,36 (dd, J = 2,05,To a solution of chlorohydrin (10.0 g, 37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and stirred at room temperature for 48 hours. The solution was cooled and the flask opened. The ammonia was evaporated and the solution was concentrated. Crystallization of the residue from ethanol / ethyl acetate gave 3.83 g of a white solid (35%). The product obtained was treated with Boc 2 O in ethyl acetate and saturated sodium bicarbonate and 98% ee (enantiomeric excess) was detected by chiral HPLC on a Chiracel OJ column using a 95% hexane / ethanol mobile phase. Separation of the other fractions - 2.96 g and 1.41 g gave a total yield of 75%. LRMS [M + H] < + >246; IR (cm -1 , KBr) 1055, 1261, 3001, 2948, 3356; 1 H NMR (500 MHz, DMSO) δ 8.09 (bs, 2H), 7.58 (s, 1H), 7.36 (dd, J = 2.05,

6,45 Hz, 1H), 7,11 (d, J = 8,5 Hz, 1H), 6,10 (s, 1H), 4,80 (m, 1H), 3,84 (s, 3H), 3,00 (ddd, J = 2,7, 12,6, 9,5 Hz, 2H); 13C NMR (DMSO, 75,5 Hz) δ 154,8, 135,4, 130,4,6.45 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.10 (s, 1H), 4.80 (m, 1H), 3.84 (s, 3H) 3.00 (ddd, J = 2.7, 12.6, 9.5 Hz, 2H); 13 C NMR (DMSO, 75.5 Hz) δ 154.8, 135.4, 130.4,

126,6, 112,4, 110,4, 67,9, 56,2, 45,4.126.6, 112.4, 110.4, 67.9, 56.2, 45.4.

OH (S)-2-amino-1-[3-chlórfenyl]etanolhydrochlorid:OH (S) -2-amino-1- [3-chlorophenyl] ethanol hydrochloride:

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [M+H]+ 172; IR (KBr, cm’1) 3048, 3351, 2952; 1H NMR (300 MHz, MeOD) δ 7,48 (s, 1H), 7,35 (m, 3H), 3.31 (ddd, J = 1,5, 3,12, 9,15 Hz, 2H).Prepared in the general manner described above. LRMS [M + H] < + >172; IR (KBr, cm -1 ) 3048, 3351, 2952; 1 H NMR (300 MHz, MeOD) δ 7.48 (s, 1H), 7.35 (m, 3H), 3.31 (ddd, J = 1.5, 3.12, 9.15 Hz, 2H).

OHOH

Br NHrHCI (S)-2-amino-1-[3-brómfenyl]etanol-hydrochlorid:Br NH HCI r (S) -2-Amino-1- [3-bromophenyl] ethanol Hydrochloride:

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [MH]+ 217,9; IR (KBr, cm'1) 3025, 3443, 2891; 1H NMR (500 MHz, DMSO) δ 7,93 (b s, 2H), 7,60 (s, 1H), 7,52 (d, 1H), 7,41 (s, 1H), 7,35 (d, J = 7,7 Hz, 1H), 6,17 (s, 1H), 4,82 (m, 1H), 3,08 (ddd, J = 2,6, 12,7, 9,6 Hz, 2H); 13C NMR (DMSO, 75,5 MHz) δ 144,4, 130,5,Prepared in the general manner described above. LRMS [MH] + 217.9; IR (KBr, cm -1 ) 3025, 3443, 2891; 1 H NMR (500 MHz, DMSO) δ 7.93 (bs, 2H), 7.60 (s, 1H), 7.52 (d, 1H), 7.41 (s, 1H), 7.35 (s) d, J = 7.7 Hz, 1H), 6.17 (s, 1H), 4.82 (m, 1H), 3.08 (ddd, J = 2.6, 12.7, 9.6 Hz) , 2H); 13 C NMR (DMSO, 75.5 MHz) δ 144.4, 130.5,

128,7, 125,0, 121,6, 68,3, 45,1.128.7, 125.0, 121.6, 68.3, 45.1.

MeS (S)-2-amino-1-[3-chlór-4-metyltiofenyl]etanol-hydrochlorid:MeS (S) -2-amino-1- [3-chloro-4-methylthiophenyl] ethanol hydrochloride:

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [M+H]+ 217,9; IR (KBr, cm'1) 3007, 3358; M NMR (500 MHz, DMSO) δ 8,12 (b s, 2H), 7,46 (s, 1H),Prepared in the general manner described above. LRMS [M + H] + 217.9; IR (KBr, cm -1 ) 3007, 3358; 1 H NMR (500 MHz, DMSO) δ 8.12 (bs, 2H), 7.46 (s, 1H),

7,37 (s, 1H), 7,35 (d, 1 H), 6,19 (d, 1H), 4,83 (m, 1H), 3,01 (ddd, J = 3,2, 12,8, 9,3 Hz, 2H); 13C NMR (DMSO, 75,5 MHz) δ 139,6, 136,5, 129,8, 126,6, 125,4, 68,0, 45,2,7.37 (s, 1H), 7.35 (d, 1H), 6.19 (d, 1H), 4.83 (m, 1H), 3.01 (ddd, J = 3.2, 12) 8, 9.3 Hz, 2H); 13 C NMR (DMSO, 75.5 MHz) δ 139.6, 136.5, 129.8, 126.6, 125.4, 68.0, 45.2,

14.2.14.2.

OHOH

(S)-2-amino-1-[3-chlór-4-fluórfenyl]etanol-hydrochlorid:(S) -2-Amino-1- [3-chloro-4-fluoro-phenyl] -ethanol hydrochloride:

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [M+H]+ 189,9; IR (KBr, cm’1) 1509, 3008, 3359; 1H NMR (500 MHz, DMSO) δ 8,21 (b s, 2H), 7,61 (d, J = 7,85 Hz, 1H), 7,42 (m, 2H), 6,29 (s, 1H), 4,88 (m, 1H), 3,03 (ddd, J = 3,4, 12,8, 9,2 Hz, 2H); 13C NMR (DMSO, 75,5 MHz) δ 157,5, 155,5, 139,7, 128,1, 126,7, 119,3.Prepared in the general manner described above. LRMS [M + H] + 189.9; IR (KBr, cm -1 ) 1509, 3008, 3359; 1 H NMR (500 MHz, DMSO) δ 8.21 (bs, 2H), 7.61 (d, J = 7.85 Hz, 1H), 7.42 (m, 2H), 6.29 (s, 1H), 4.88 (m, 1H), 3.03 (ddd, J = 3.4, 12.8, 9.2 Hz, 2H); 13 C NMR (DMSO, 75.5 MHz) δ 157.5, 155.5, 139.7, 128.1, 126.7, 119.3.

116,7, 109,0, 67,8,45,2.116.7, 109.0, 67.8, 45.2.

(S)-2-amino-1-[3-chlór-4-metoxyfenyl]etanolhydrochlorid:(S) -2-Amino-1- [3-chloro-4-methoxyphenyl] ethanol hydrochloride:

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [M+Hf 202; IR (KBr, cm'1) 3354, 3003, 2949, 1288, 1064; 1H NMR (500 MHz, DMSO) δ 8,18 (br s. 3H), 7,43 (d, J = 2,0 Hz, 1H), 7,31 (dd, J = 8,5, 2,0 Hz, 1H), 7,14 (d, J = 5,1 Hz, 1H). 6,11 (s, 1H), 4.81 (m, 1H), 3,84 (s, 3H), 2,99 (dd, J = 13, 3,5 Hz, 1H), 2,83 (dd, J = 12.5, 9 Hz, 1H); 13C NMR (DMSO, 125 MHz) δ 153,9, 135,0, 127,3, 125,8, 120,8.Prepared in the general manner described above. LRMS [M + H] + 202; IR (KBr, cm -1 ) 3354, 3003, 2949, 1288, 1064; 1 H NMR (500 MHz, DMSO) δ 8.18 (br s, 3H), 7.43 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.5, 2, 0 Hz, 1H), 7.14 (d, J = 5.1 Hz, 1H). 6.11 (s, 1H), 4.81 (m, 1H), 3.84 (s, 3H), 2.99 (dd, J = 13, 3.5 Hz, 1H), 2.83 (dd, J) = 12.5.9 Hz, 1H); 13 C NMR (DMSO, 125 MHz) δ 153.9, 135.0, 127.3, 125.8, 120.8.

112,6, 68,0, 56,1, 45,5. Elementárna analýza: pre C9H12CINO2.HCI vypočítané C 45,39, H 5,50, N 5,88; nájdené C 45,38, H 5,43, N 5.70.112.6, 68.0, 56.1, 45.5. Elemental analysis: for C 9 H 12 ClNO 2 .HCl calculated C 45.39, H 5.50, N 5.88; found C 45.38, H 5.43, N 5.70.

(S)-2-amino-1-(7-bróm-2,3-dihydrobenzofurán-5-yl)-2-aminoetanol;(S) -2-Amino-1- (7-bromo-2,3-dihydrobenzofuran-5-yl) -2-aminoethanol;

Pripraví sa všeobecným spôsobom opísaným vyššie. LRMS [M+H]+ 258: IR (KBr, cm’1) 3349, 3006, 2928, 1485, 1045, 983; 1H NMR (500 MHz, DMSO) δ 8,13 (br s, 3H), 7,29 (s, 1H), 7,23 (s, 1 H). 6,08 (d, J=4,0 Hz, 1 H), 4,76 (m, 1H), 4,61 (t, J=9 Hz, 2H), 3,29 (t, J=9 Hz, 2H), 2,96 (dd, J=13, 3,5 Hz, 1H), 2,82 (dd, J=13, 9,5 Hz, 1H); 13C NMR (DMSO, 125 MHz) δ 156,3, 135,9, 129,1, 128.1, 122,1, 100,9, 71,5,Prepared in the general manner described above. LRMS [M + H] + 258: IR (KBr, cm -1 ) 3349, 3006, 2928, 1485, 1045, 983; 1 H NMR (500 MHz, DMSO) δ 8.13 (br s, 3H), 7.29 (s, 1H), 7.23 (s, 1H). 6.08 (d, J = 4.0 Hz, 1H), 4.76 (m, 1H), 4.61 (t, J = 9 Hz, 2H), 3.29 (t, J = 9 Hz) 2H), 2.96 (dd, J = 13, 3.5 Hz, 1H), 2.82 (dd, J = 13, 9.5 Hz, 1H); 13 C NMR (DMSO, 125 MHz) δ 156.3, 135.9, 129.1, 128.1, 122.1, 100.9, 71.5,

68,2, 45,6, 29,9;68.2, 45.6, 29.9;

Elementárna analýza: pre CioHi2BrN02.HCI vypočítané C 40,77, H 4,44, N 4,75; nájdené C 40,77, H 4,63, N 4,63.For C 10 H 12 BrNO 2 .HCl requires C 40.77, H 4.44, N 4.75; found C 40.77, H 4.63, N 4.63.

Všeobecný spôsob prípravy 2-amino-3-(substituovaný fenyl)-propanoluGeneral process for the preparation of 2-amino-3- (substituted phenyl) -propanol

Terc-butylester kyseliny (S)-[2-(3-brómfenyl)-1-hydroxymetyletyl]karbámovej:(S) - [2- (3-Bromo-phenyl) -1-hydroxy-methyl-ethyl] -carbamic acid tert-butyl ester:

K roztoku kyseliny (S)-3-(3-brómfenyl)-2-terc-butoxykarbonylaminopropiónovej (500 mg, 1,45 mmol) v THF (30 ml) sa pridá komplex bóran-tetrahydrofurán (roztok 1 mol/l) (4,35 ml, 4,35 mmol). Reakčná zmes sa mieša 14 h pri teplote miestnosti a potom sa reakcia preruší zaliatím kyselinou octovou (1 ml). Po odstránení väčšiny rozpúšťadla sa zvyšok extrahuje EtOAc, premyje sa soľným roztokom a vysuší sa Na2SO4. Po zahustení sa surový produkt (400 mg, 83 %) použije v nasledujúcom stupni bez ďalšieho čistenia. ĽCMS [M+Hf m/z 330 (t=1,61 min).To a solution of (S) -3- (3-bromophenyl) -2-tert-butoxycarbonylaminopropionic acid (500 mg, 1.45 mmol) in THF (30 mL) was added borane-tetrahydrofuran complex (1M solution) (4). , 35 mL, 4.35 mmol). The reaction mixture was stirred at room temperature for 14 h and then quenched with acetic acid (1 mL). After removing most of the solvent, the residue was extracted with EtOAc, washed with brine and dried over Na 2 SO 4 . After concentration, the crude product (400 mg, 83%) was used in the next step without further purification. LCMS [M + H] + m / z 330 (t = 1.61 min).

OH (S)-2-amino-3-(3-brómfenyl)propán-1-ol:OH (S) -2-amino-3- (3-bromophenyl) propan-1-ol:

K roztoku terc-butylesteru kyseliny (S)-[2-(3-brómfenyl)-1-hydroxymetyletyl]karbámovej (400 mg. 1.21 mmol) v metanole (30 ml) sa pridá HCI 4 mol/l v dioxáne (2 ml, v nadbytku). Reakčná zmes sa mieša 14 h pri teplote miestnosti. Potom sa zahustí pri zníženom tlaku a zvyšok sa použije v ďalšom stupni bez ďalšieho čistenia.To a solution of (S) - [2- (3-bromo-phenyl) -1-hydroxy-methyl-ethyl] -carbamic acid tert-butyl ester (400 mg, 1.21 mmol) in methanol (30 mL) was added 4 mol / L HCl in dioxane (2 mL, v). excess). The reaction mixture was stirred at room temperature for 14 h. It is then concentrated under reduced pressure and the residue is used in the next step without further purification.

LCMS [M+H]+ m/z 230 (t=0.78 min).LCMS [M + H] + m / z 230 (t = 0.78min).

5-chlóracetyl-7-chlóroxindol:5-Chloroacetyl-7-chlorooxindole:

K suspenzii AICI3 (13,4 g, 0.10 mol) v dichlórmetáne (40 ml) sa pridá pri 0 °C roztok 7-chlóroxindolu (0,10 mol) a chlóracetylchloridu (8 ml, 0,10 mol). Potom sa roztok nechá v priebehu dvoch hodín zohriať na teplotu miestnosti, vyleje sa na ľad a extrahuje sa dichlórmetánom, premyje sa nasýteným roztokom hydrogenuhličitanu, soľným roztokom, a vysušením MgSO4 sa potom získa požadovaný chlórketón.To a suspension of AlCl 3 (13.4 g, 0.10 mol) in dichloromethane (40 mL) was added at 0 ° C a solution of 7-chloroindole (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol). The solution was allowed to warm to room temperature over two hours, poured out on ice and extracted with dichloromethane, washed with saturated bicarbonate solution, brine, and dried over MgSO 4 to give the desired chloroketone.

(S)-7-chlór-5-(2-chlór-1-hydroxyetyl)-2-oxoindol:(In) 7-chloro-5- (2-chloro-1-hydroxyethyl) -2-oxoindole:

K roztoku (S)-metyl-CBS-oxazaborolidínu (1 mol/l v toluéne, 0,745 ml, 0,745 mmol) a BH3-THF (8 ml, 8 mmol) sa súčasne pridá roztok BH3-THF (19 ml, 19 mmol) a roztok 5-chlóracetyl-7-chlóroxindolu (37,98 mmol) v 19 ml THF. Obidva roztoky sa pridajú po kvapkách v priebehu 30 minút. Získaný roztok sa mieša 1 hodinu a potom sa reakcia preruší pomalým pridaním metanolu (50 ml). Roztok sa potom zahustí a zvyšok sa prečistí chromatografiou na krátkom stĺpci silikagélu (hexán/etylacetát,To a solution of (S) -methyl-CBS-oxazaborolidine (1 mol / L in toluene, 0.745 mL, 0.745 mmol) and BH 3 -THF (8 mL, 8 mmol) was added simultaneously a solution of BH 3 -THF (19 mL, 19 mmol). ) and a solution of 5-chloroacetyl-7-chloro-indole (37.98 mmol) in 19 mL of THF. Both solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and then quenched by the slow addition of methanol (50 mL). The solution was then concentrated and the residue purified by silica gel short column chromatography (hexane / ethyl acetate,

NHj-HCIN H-HCl

O (S)-amino-1-(7-chlóroxindol-5-yl)-etanol-hydrochlorid:O (S) -amino-1- (7-chloroindol-5-yl) -ethanol hydrochloride:

K roztoku chlórhydrínu (37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín. Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahustí na hydrochloridovú soľ, ktorá sa nechá vykryštalizovať zo zmesi etanol/etylacetát.To a solution of chlorohydrin (37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and allowed to warm to room temperature for 48 hours. The solution was then cooled and the flask opened. The ammonia was evaporated and the solution was concentrated to the hydrochloride salt which was crystallized from ethanol / ethyl acetate.

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6-chlóracetyl-4-chlór-2-benzoxazolinón:6-Chloroacetyl-4-chloro-2-benzoxazolinone:

K suspenzii AICI3 (13,4 g, 0,10 mol) v dichlórmetáne (40 ml) sa pridá pri 0 °C roztok 4-chlór-2-benzoxazolinónu (0,10 mol) a chlóracetylchloridu (8 ml, 0,10 mol). Potom sa roztok nechá v priebehu dvoch hodín ohriať na teplotu miestnosti, vyleje sa na ľad a extrahuje sa dichlórmetánom, premyje sa nasýteným roztokom hydrogenuhličitanu, soľným roztokom, a vysušením MgSO4 sa potom získa požadovaný chlórketón.To a suspension of AlCl 3 (13.4 g, 0.10 mol) in dichloromethane (40 mL) at 0 ° C was added a solution of 4-chloro-2-benzoxazolinone (0.10 mol) and chloroacetyl chloride (8 mL, 0.10 mol). ). The solution was allowed to warm to room temperature over two hours, poured out on ice and extracted with dichloromethane, washed with saturated bicarbonate solution, brine, and dried over MgSO 4 to give the desired chloroketone.

(S)-6-(2-chlór-1-hydroxyetyl)-4-chlór-2-benzoxazolinón:(S) -6- (2-chloro-1-hydroxyethyl) -4-chloro-2-benzoxazolinone:

K roztoku (S)-metyl-CBS-oxazaborolidínu (1 mol/l v toluéne, 0,745 ml, 0,745 mmol) a BH3-THF (8 ml, 8 mmol) sa súčasne pridá roztok BH3-THF (19 ml, 19 mmol) a roztok 6-chlóracetyl-4-chlór-2-benzoxazolinónu (37,98 mmol) v 19 ml THF. Oba roztoky sa pridajú po kvapkách v priebehu 30 minút. Získaný roztok sa mieša 1 hodinu a potom sa reakcia preruší pomalým pridaním metanolu (50 ml). Roztok sa potom zahustí a zvyšok sa prečistí chromatografiou na krátkom stĺpci silikagélu (hexán/etylacetát, 1:1).To a solution of (S) -methyl-CBS-oxazaborolidine (1 mol / L in toluene, 0.745 mL, 0.745 mmol) and BH3-THF (8 mL, 8 mmol) was added simultaneously a solution of BH3-THF (19 mL, 19 mmol) and solution of 6-chloroacetyl-4-chloro-2-benzoxazolinone (37.98 mmol) in 19 mL of THF. Both solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and then quenched by the slow addition of methanol (50 mL). The solution was then concentrated and the residue was purified by silica gel short column chromatography (hexane / ethyl acetate, 1: 1).

NHrHCI (S)-2-amino-1-(4-chlór-2-benzoxazolinón-6-yl)etanol-hydrochlorid:NH HCI r (S) -2-Amino-1- (4-chloro-2-benzoxazolinone-6-yl) ethanol hydrochloride:

K roztoku chlórnydrinu (37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín. Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahustí na hydrochloridovú soľ, ktorá sa nechá vykryštalizovať zo zmesi etanol/etylacetát.To a solution of chlornydrin (37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and allowed to warm to room temperature for 48 hours. The solution was then cooled and the flask opened. The ammonia was evaporated and the solution was concentrated to the hydrochloride salt which was crystallized from ethanol / ethyl acetate.

N-metyl-7-chlórindolín:N-Methyl-7-chloroindoline:

K roztoku 7-chlórindolu (0,10 mol) v 500 ml acetónu sa pridá K2CO3 (0,15 mol) a Mel (0,15 mol) a zahrieva sa pri teplote spätného toku až do spotreby východiskových zložiek. Potom sa reakčná zmes prefiltruje, premyje sa vodou a nasýteným roztokom hydrogenuhličitanu, a vysušením MgSO4 sa získa N-Me-7chlórindolín.To a solution of 7-chloroindole (0.10 mol) in 500 mL acetone was added K 2 CO 3 (0.15 mol) and MeI (0.15 mol) and heated to reflux until consumption of the starting components. Then the reaction mixture was filtered, washed with water and saturated bicarbonate solution, and dried over MgSO 4 to give N-Me-7-chloroindoline.

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N-metyl-5-chlóracetyl-7-chlórindolín:N-Methyl-5-chloroacetyl-7-chloroindoline:

K suspenzii AICI3 (13,4 g, 0,10 mol) v dichlórmetáne (40 ml) sa pridá pri 0 °C roztok N-Me-7-chlórindolínu (0,10 mol) a chlóracetylchloridu (8 ml, 0,10 mol). Potom sa roztok nechá v priebehu dvoch hodín ohriať na teplotu miestnosti, vyleje sa na ľad a extrahuje sa dichlórmetánom, premyje sa nasýteným roztokom hydrogenuhličitanu, soľným roztokom, a vysušením MgSO4 sa potom získa požadovaný chlórketón.To a suspension of AlCl 3 (13.4 g, 0.10 mol) in dichloromethane (40 mL) was added a solution of N-Me-7-chloroindoline (0.10 mol) and chloroacetyl chloride (8 mL, 0.10) at 0 ° C. mol). The solution was allowed to warm to room temperature over two hours, poured out on ice and extracted with dichloromethane, washed with saturated bicarbonate solution, brine, and dried over MgSO 4 to give the desired chloroketone.

OHOH

(S)-N-metyl-5-(2-chlór-1-hydroxyetyl)-7-chlórindolín:(S) -N-methyl-5- (2-chloro-1-hydroxyethyl) -7-chloroindoline:

K roztoku (S)-metyl-CBS-oxazaborolidínu (1 mol/l v toluéne, 0,745 ml, 0.745 mmol) a BH3-THF (8 ml, 8 mmol) sa súčasne pridá roztok BH3-THF (19 ml, 19 mmol) a roztok N-metyl-5-chlóracetyl-7-chlórindolínu (37,98 mmol) v 19 ml THF. Oba roztoky sa pridajú po kvapkách v priebehu 30 minút. Získaný roztok sa mieša 1 hodinu a potom sa reakcia preruší pomalým pridaním metanolu (50 ml). Roztok sa potom zahustí a zvyšok sa prečistí chromatografiou na krátkom stĺpci silikagélu (hexán/etylacetát, 1:1).To a solution of (S) -methyl-CBS-oxazaborolidine (1 mol / L in toluene, 0.745 mL, 0.745 mmol) and BH 3 -THF (8 mL, 8 mmol) was added simultaneously a solution of BH 3 -THF (19 mL, 19 mmol). ) and a solution of N-methyl-5-chloroacetyl-7-chloroindoline (37.98 mmol) in 19 mL of THF. Both solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and then quenched by the slow addition of methanol (50 mL). The solution was then concentrated and the residue was purified by silica gel short column chromatography (hexane / ethyl acetate, 1: 1).

(S)-2-amino-1-(7-chlór-N-metylindolín-5-yl)etanol-hydrochlorid:(S) -2-Amino-1- (7-chloro-N-methylindoline-5-yl) ethanol hydrochloride:

K roztoku chlórhydrinu (37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín. Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahusti na hydrochloridovú soľ, ktorá sa nechá vykryštalizovať zo zmesi etanol/etylacetát.To a solution of chlorohydrin (37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and allowed to warm to room temperature for 48 hours. The solution was then cooled and the flask opened. The ammonia was evaporated and the solution was concentrated to the hydrochloride salt which was crystallized from ethanol / ethyl acetate.

OHOH

(S)-2-chlór-1-(7-chlór-N-metylindol-5-yl)etanol:(S) -2-chloro-1- (7-chloro-N-methyl-indol-5-yl) ethanol:

Roztok (S)-N-metyl-5-(2-chlór-1-hydroxyetyi)-7-chlórindolín (0,10 mmol) v 100 ml terc-butyl(metyl)éteru sa spracuje s o-chlóranilom (0,10 mmol) pri teplote miestnosti. Roztok sa potom zahustí a chromatografiou zvyšku na silikagéli (hexán/etylacetát, 1:1) sa získa zodpovedajúci indol.A solution of (S) -N-methyl-5- (2-chloro-1-hydroxyethyl) -7-chloroindoline (0.10 mmol) in 100 mL of tert-butyl (methyl) ether was treated with o-chloroanil (0.10). mmol) at room temperature. The solution was then concentrated and chromatography of the residue on silica gel (hexane / ethyl acetate, 1: 1) afforded the corresponding indole.

(S)-2-amino-1-(7-chlór-N-metylindol-5-yl)eianol-hydrochlorid:(S) -2-Amino-1- (7-chloro-N-methyl-indol-5-yl) Eiane hydrochloride:

K roztoku chlórhydrínu (37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín. Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahustí na hydrochloridovú soľ, ktorá sa nechá vykryštalizovať zo zmesi etanol/etyiacetát.To a solution of chlorohydrin (37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and allowed to warm to room temperature for 48 hours. The solution was then cooled and the flask opened. The ammonia was evaporated and the solution was concentrated to the hydrochloride salt which was crystallized from ethanol / ethyl acetate.

4-chlór-2-metylbenzoxazol:4-chloro-2-methyl-benzoxazol:

K roztoku 4-chlór-2-benzoxazolinónu (0.10 mol) v 200 ml etanolu sa pridá LiOH (0,20 mol) v 100 ml vody. Roztok sa potom zahrieva 8 hodín pri teplote spätného toku a potom sa ochladí. Potom sa roztok zneutralizuje HCI 1 mol/l a extrahuje sa etylacetátom, ktorý sa potom vysuší MgSO4. Roztok sa potom zahustí, zvyšok sa vyberie do 200 ml toluénu a s 0,10 mol kyseliny octovej. Získaný produkt sa potom zahrieva pri teplote spätného toku s použitím Dean-Starkovho odlučovača 12 hodín, potom sa zahusti a prečistí sa rýchlou chromatografiou.To a solution of 4-chloro-2-benzoxazolinone (0.10 mol) in 200 mL ethanol was added LiOH (0.20 mol) in 100 mL water. The solution was then heated at reflux for 8 hours and then cooled. The solution was neutralized with 1N HCl and extracted with ethyl acetate, which was then dried over MgSO 4 . The solution is then concentrated, the residue is taken up in 200 ml of toluene and with 0.10 mol of acetic acid. The product obtained is then heated at reflux using a Dean-Stark trap for 12 hours, then concentrated and purified by flash chromatography.

6-chlóracetyl-4-chlór-2-metylbenzoxazol:6-Chloroacetyl-4-chloro-2-methyl-benzoxazol:

K suspenzii AICI3 (13,4 g, 0,10 mol) v dichlórmetáne (40 ml) sa pridá pri 0 °C roztok 2-metyl-4-chlórbenzoxazolu (0,10 mol) a chlóracetylchloridu (8 ml, 0,10 mol).To a suspension of AlCl 3 (13.4 g, 0.10 mol) in dichloromethane (40 mL) at 0 ° C was added a solution of 2-methyl-4-chlorobenzoxazole (0.10 mol) and chloroacetyl chloride (8 mL, 0.10). mol).

Potom sa roztok nechá v priebehu dvoch hodín ohriať na teplotu miestnosti, vyleje sa na ľad a extrahuje sa dichlórmetánom. premyje sa nasýteným roztokom hydrogenuhličitanu, soľným roztokom, a vysušením MgSC>4 sa potom získa požadovaný chlórketón.The solution was allowed to warm to room temperature over two hours, poured out on ice and extracted with dichloromethane. it is washed with saturated bicarbonate solution, brine, and dried over MgSO 4 to give the desired chloroketone.

OH (S)-6-(2-chlór-1-hydroxyetyl)-4-chlór-2-metylbenzoxazol:OH (S) -6- (2-chloro-1-hydroxyethyl) -4-chloro-2-methylbenzoxazole:

K roztoku (S)-metyl-CBS-oxazaborolidínu (1 mol/l v toluéne, 0,745 ml, 0,745 mmol) a BH3-THF (8 ml, 8 mmol) sa súčasne pridá roztok BH3-THF (19 ml, 19 mmol) a roztok 6-chlóracetyl-4-chlór-2-metylbenzoxazolu (37,98 mmol) v 19 m! THF. Oba roztoky sa pridajú po kvapkách v priebehu 30 minút. Získaný roztok sa mieša 1 hodinu a potom sa reakcia preruší pomalým pridaním metanolu (50 ml). Roztok sa potom zahusti a zvyšok sa prečistí chromatografiou na krátkom stĺpci silikagélu (hexán/etylacetát, 1:1).To a solution of (S) -methyl-CBS-oxazaborolidine (1 mol / L in toluene, 0.745 mL, 0.745 mmol) and BH 3 -THF (8 mL, 8 mmol) was added simultaneously a solution of BH 3 -THF (19 mL, 19 mmol). ) and a solution of 6-chloroacetyl-4-chloro-2-methylbenzoxazole (37.98 mmol) in 19 ml. THF. Both solutions were added dropwise over 30 minutes. The resulting solution was stirred for 1 hour and then quenched by the slow addition of methanol (50 mL). The solution was then concentrated and the residue was purified by silica gel short column chromatography (hexane / ethyl acetate, 1: 1).

(S)-2-amino-1-(4-chlór-2-metylbenzoxazol-6-yl)etanol-hydrochlorid:(S) -2-Amino-1- (4-chloro-2-methyl-benzoxazol-6-yl) ethanol hydrochloride:

K roztoku chlórhydrínu (37,9 mmol) v 120 ml metanolu sa pri -40 °C pridá 100 g amoniaku. Potom sa roztok uzavrie v tlakovej banke a ohriaty na teplotu miestnosti sa mieša 48 hodín. Potom sa roztok ochladí a banka sa otvorí. Amoniak sa odparí a roztok sa zahustí na hydrochloridovú soľ, ktorá sa nechá vykryštalizovať zo zmesi etanol/etylacetát.To a solution of chlorohydrin (37.9 mmol) in 120 mL of methanol at -40 ° C was added 100 g of ammonia. The solution was sealed in a pressure flask and allowed to warm to room temperature for 48 hours. The solution was then cooled and the flask opened. The ammonia was evaporated and the solution was concentrated to the hydrochloride salt which was crystallized from ethanol / ethyl acetate.

Príprava 3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-4-jód-1H-pyridín-2-ónu:Preparation of 3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4-iodo-1H-pyridin-2-one:

-(3-metyl-4-nitrofenyl)-1 H-imidazol:- (3-Methyl-4-nitrophenyl) -1H-imidazole:

,N=\, N = \

K roztoku 4-fluór-2-metyl-1-nitrobenzénu (300 mg, 1,84 mmol) v DMSO (2 ml) sa pridá KOH (20 mg, 3.87 mmol) a imidazol (263 mg, 3,88 mmol). Reakčná zmes sa potom zahrieva 3.5 h pri 100 °C, potom sa ochladí na teplotu miestnosti a zriedi sa ľadovo chladnou vodou. Vzniknutá zrazenina sa odfiltruje, premyje sa ľadovo chladnou vodou a vysušením za zníženého tlaku sa vo forme žltého prášku získa titulná zlúčenina (310 mg, 80 %).To a solution of 4-fluoro-2-methyl-1-nitrobenzene (300 mg, 1.84 mmol) in DMSO (2 mL) was added KOH (20 mg, 3.87 mmol) and imidazole (263 mg, 3.88 mmol). The reaction mixture was then heated at 100 ° C for 3.5 h, then cooled to room temperature and diluted with ice-cold water. The resulting precipitate was filtered off, washed with ice-cold water and dried under reduced pressure to give the title compound as a yellow powder (310 mg, 80%).

1H NMR (300 MHz, DMSO-d6) δ 8,46 (1H, s), 8,16 (1H, d, J = 8,9 Hz), 7,90-7,92 (2H, m). 7,78 (1H, dd, J = 2,5, 8,9 Hz), 7,17 (1H, s), 2,61 (3H, s). LRMS (M+H)+ m/z 204. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.46 (1H, s), 8.16 (1H, d, J = 8.9 Hz), 7.90-7.92 (2H, m) . 7.78 (1H, dd, J = 2.5, 8.9 Hz), 7.17 (1H, s), 2.61 (3H, s). LRMS (M + H) < + > m / z 204.

N:N:

4-imidazol-1-yl-2-metylfenylamín:4-imidazol-1-yl-2-methyl-:

K 1-(3-metyl-4-nitrofenyl)-1H-imidazolu (200 mg, 0,98 mmol) a 10 % paládia na uhlíku (35 mg) sa pridá odplynený metanol (3 ml). Potom sa suspenzia prepláchne a evakuuje pomocou prívodov vodík/vákuum. Potom sa suspenzia mieša 14 h pri teplote miestnosti v atmosfére vodíka (balón s vodíkom). Tmavá reakčná zmes sa potom prefiltruje cez vrstvu celitu a premyje sa metanolom. Zahustením filtrátu sa získa titulná zlúčenina (166 mg, 98 %), ktorá sa použije v ďalšom stupni bez ďalšieho čistenia. 1H NMR (300 MHz, DMSO-d5) δ 7,95 (1H, s), 7,48 (1H, s), 7,16 (1H, úzky d, J = 2,5 Hz), 7,09 (1H, dd, J = 2,5, 8,4 Hz), 7,01 (1H, s), 6,67 (1H, d, J = 8,4 Hz), 5,03 (2H, široký s), 2,10 (3H. s).To 1- (3-methyl-4-nitrophenyl) -1H-imidazole (200 mg, 0.98 mmol) and 10% palladium on carbon (35 mg) was added degassed methanol (3 mL). Then, the suspension is rinsed and evacuated using hydrogen / vacuum inlets. The suspension was then stirred at room temperature for 14 h under a hydrogen atmosphere (balloon with hydrogen). The dark reaction mixture was then filtered through a pad of celite and washed with methanol. Concentration of the filtrate gave the title compound (166 mg, 98%), which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d 5 ) δ 7.95 (1H, s), 7.48 (1H, s), 7.16 (1H, narrow d, J = 2.5 Hz), 7, 09 (1H, dd, J = 2.5, 8.4 Hz), 7.01 (1H, s), 6.67 (1H, d, J = 8.4 Hz), 5.03 (2H, broad) s), 2.10 (3H, s).

N-(4-imidazol-1-yl-2-metyl-6-nitrofenyl)acetamid:N- (4-imidazol-1-yl-2-methyl-6-nitrophenyl) acetamide:

K roztoku 4-imidazol-1-yl-2-metylfenylamínu (1 g, 5,78 mmol) v CH2CI2 (20 ml) sa pridá pri 0 °C Ac2O (0,7 ml, 7,28 mmol). Reakčná zmes sa potom mieša 14 h pri teplote miestnosti a potom sa zriedi vodou. Vodná vrstva sa potom extrahuje CH2CI2 a spojené organické vrstvy sa premyjú nasýteným NaHCO3 a soľným roztokom, vysušia sa Na2SO4 a zahustením za zníženého tlaku sa získa biela tuhá hmota.To a solution of 4-imidazol-1-yl-2-methylphenylamine (1 g, 5.78 mmol) in CH 2 Cl 2 (20 mL) at 0 ° C was added Ac 2 O (0.7 mL, 7.28 mmol). ). The reaction mixture was then stirred at room temperature for 14 h and then diluted with water. The aqueous layer was then extracted with CH 2 Cl 2 and the combined organic layers were washed with saturated NaHCO 3 and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give a white solid.

Získaná biela tuhá hmota sa suspenduje v H2SO4 (koncentrovanej) (15 ml). Potom sa k suspenzii pri 0 °C pridá HNO3 (koncentrovaná) (0,312 ml). Reakčná zmes sa potom pomaly ohreje na teplotu miestnosti a mieša sa 4 h pri teplote miestnosti. Po ochladení na -10 °C sa reakčná zmes zneutralizuje hydroxidom amónnym a extrahuje sa etyl-acetátom. Spojené organické vrstvy sa premyjú soľným roztokom, vysušia sa Na2SO4 a zahustia sa. Prečistením zvyšku rýchlou chromatografiou (MeOH/THF/hexán 1:9:5) sa získa titulná zlúčenina (0,61 g, 41 %). 1H NMR (300 MHz, CD3OD) δ 8,11 (1H, s), 7,45-7,56 (2H, m), 7,38 (1H, dd, J = 2,4, 8,4 Hz), 7,14 (1H, s), 2,33 (3H, s), 2,18 (3H, s).The resulting white solid was suspended in H 2 SO 4 (concentrated) (15 mL). HNO 3 (concentrated) (0.312 mL) was then added to the suspension at 0 ° C. The reaction mixture was then slowly warmed to room temperature and stirred for 4 h at room temperature. After cooling to -10 ° C, the reaction mixture was neutralized with ammonium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. Purification of the residue by flash chromatography (MeOH / THF / hexane 1: 9: 5) gave the title compound (0.61 g, 41%). 1 H NMR (300 MHz, CD 3 OD) δ 8.11 (1H, s), 7.45-7.56 (2H, m), 7.38 (1H, dd, J = 2.4, 8, 4 Hz), 7.14 (1H, s), 2.33 (3H, s), 2.18 (3H, s).

4-imidazol-1-yl-2-metyl-6-nitrofenylamín:4-imidazol-1-yl-2-methyl-6-nitro-phenylamine:

K suspenzii N-(4-imidazol-1-yl-2-metyl-6-nitrofenyl)-acetamidu (279 mg, 1,07 mmol) v etanole (3 ml) sa pridá HCI 2 mol/l (2 ml). Reakčná zmes sa zahrieva 14 h pri teplote spätného toku, ochladí sa na teplotu miestnosti a zneutralizuje sa nasýteným NaHCO3. Výsledná jasne oranžová tuhá hmota sa odfiltruje a vysuší sa za zníženého tlaku. Titulná zlúčenina sa získa vo forme oranžovej tuhej hmoty. 1H NMR (300 MHz, CD3OD) δ 8,78 (1H, s), 8,24 (1H, s), 7,78 (1H, s), 7,64 (1H, s), 7,46 (1H, s), 2,36 (3H, s).To a suspension of N- (4-imidazol-1-yl-2-methyl-6-nitrophenyl) -acetamide (279 mg, 1.07 mmol) in ethanol (3 mL) was added 2 N HCl (2 mL). The reaction mixture was heated at reflux for 14 h, cooled to room temperature and neutralized with saturated NaHCO 3 . The resulting bright orange solid was filtered off and dried under reduced pressure. The title compound is obtained as an orange solid. 1 H NMR (300 MHz, CD 3 OD) δ 8.78 (1H, s), 8.24 (1H, s), 7.78 (1H, s), 7.64 (1H, s), 7, 46 (1H, s); 2.36 (3H, s).

5-imidazol-1-yl-3-metylbenzén-1,2-diamín:5-imidazol-1-yl-3-methyl-benzene-1,2-diamine:

K 4-imidazol-1-yl-2-metyl-6-nitrofenylaminu (350 mg, 1,61 mmol) a 10 % paládia na uhlíku (40 mg) sa pridá odplynený metanol (5 ml) a TFA (5 kvapiek). Reakčná zmes sa potom prepláchne a evakuuje pomocou prívodu vodik/vákuum a potom sa mieša 14 h pri teplote miestnosti v atmosfére vodíka (balón s vodíkom). Tmavá reakčná zmes sa potom prefiltruje cez vrstvu celitu a premyje sa metanolom. Zahustením filtrátu sa získa zvyšok, ktorý sa zriedi vodou a extrahuje sa etyl acetátom. Spojené organické vrstvy sa premyjú nasýteným NaHCO3, soľným roztokom a vysušia sa Na2SO4. Zahustením do sucha sa vo forme tuhej hmoty získa titulná zlúčenina (275 mg, 91 %). 1H NMR (300 MHz, CD3OD) δ 7,87 (1H, s), 7,34 (1H, s), 7,05 (1 H, s), 6,72 (1H, d, J = 2,4 Hz), 6,65 (1H, d, J = 2,4 Hz), 2,21 (3H, s). LCMS (M+H)+ m/z 189 (t = 0,23 min).To 4-imidazol-1-yl-2-methyl-6-nitrophenylamine (350 mg, 1.61 mmol) and 10% palladium on carbon (40 mg) was added degassed methanol (5 mL) and TFA (5 drops). The reaction mixture was then purged and evacuated via hydrogen / vacuum and then stirred for 14 h at room temperature under a hydrogen atmosphere (hydrogen balloon). The dark reaction mixture was then filtered through a pad of celite and washed with methanol. Concentration of the filtrate yielded a residue which was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 , brine and dried over Na 2 SO 4 . Concentration to dryness gave the title compound as a solid (275 mg, 91%). 1 H NMR (300 MHz, CD 3 OD) δ 7.87 (1H, s), 7.34 (1H, s), 7.05 (1H, s), 6.72 (1H, d, J = 2.4 Hz), 6.65 (1H, d, J = 2.4 Hz), 2.21 (3H, s). LCMS (M + H) < + > m / z 189 (t = 0.23 min).

MeOMeO

4-jód-2-metoxypyridín-3-karbaldehyd (WO 95/29917):4-Iodo-2-methoxypyridine-3-carbaldehyde (WO 95/29917):

Do päťlitrovej trojhrdlovej banky s guľatým dnom vybavenej zhora zavedeným miešadlom s atmosférou dusíka sa vnesie THF (1 I) a banka sa ochladí na -78 °C. K miešanému roztoku sa pri -78 °C kanylou pridá terc-butyllítium (roztok 1,7 mol/l v pentáne) (800 ml, 1,36 mol) a potom 2-metoxypyridín (132,2 g, 1,21 mol). Zmes sa potom mieša 1 h pri -78 °C. K zmesi sa potom po kvapkách pri -78 °C pridá N-formylΝ,Ν',Ν'-trimetyletylén-diamin (176 ml, 1,37 mol). Reakčná zmes a potom pri -78 °C mieša asi 30 minút a potom sa v priebehu asi 30 minút ohreje na -23 °C. K zmesi sa potom pridá pri -23 °C etylénglykoldimetyléter (1 I) a potom butyllítium (2,5 mol/l v hexáne) (800 ml, 2,0 mol). Výsledná zmes sa mieša asi 2 h, v priebehu ktorých sa reakčná zmes sfarbí do tmavozelená. Do štvorhrdlovej banky s guľatým dnom s objemom 12 I sa vnesie jód (571 g, 2,25 mol) a etylénglykoldimetyléter (2 I) a výsledný roztok sa ochladí na -78 °C. Obsah päťlitrovej banky sa potom kanylou prevedie ku zmesi s teplotou -78 °C obsahujúcej jód a etylénglykoldimetyléter umiestnenej v dvanásťlitrovej banke. Po ukončení prídavku sa reakčná zmes mieša pri teplote -78 °C ďalšiu 1 hodinu. Potom sa chladiaci kúpeľ odstráni a zmes sa nechá ohriať na asi 0 °C a spracuje sa s 2 I vody a 2 I kyseliny chlorovodíkovej 1 mol/l. Potom sa pridá metyl(terc-butyl)éter (2 I) a vrstvy sa oddelia. Vodná vrstva sa extrahuje 2x11 metyl(terc-butyl)éteru. Spojené organické vrstvy sa premyjú nasýteným Na2S2O3 (1,2 I), soľným roztokom (1,2 I) a vysušia sa Na2SC>4· Po zahustení za zníženého tlaku sa hustá kaša zriedi hexánom (1 I). Zmes sa potom ochladí v kúpeli ľad/voda asi 30 min. Zrazenina sa odfiltruje a vysušením za zníženého tlaku sa vo forme svetložltej tuhej hmoty získa titulná zlúčenina. 1H NMR (300 MHz, CDCI3) δ 10,22 (s, 1H), 7,86 (1H, d, J = 5,3 Hz), 7,54 (1H, d, J = 5,3 Hz),THF (1 L) was charged to a five-liter three-necked round-bottomed flask equipped with an overhead stirrer under a nitrogen atmosphere and cooled to -78 ° C. To the stirred solution was added tert-butyllithium (1.7 mol / L in pentane) at -78 ° C (800 mL, 1.36 mol) followed by 2-methoxypyridine (132.2 g, 1.21 mol). The mixture was then stirred at -78 ° C for 1 h. N-formyl-,-', Ν'-trimethylethylenediamine (176 mL, 1.37 mol) was then added dropwise at -78 ° C. The reaction mixture was then stirred at -78 ° C for about 30 minutes and then warmed to -23 ° C over about 30 minutes. Ethylene glycol dimethyl ether (1 L) was then added at -23 ° C followed by butyllithium (2.5 mol / L in hexane) (800 mL, 2.0 mol). The resulting mixture was stirred for about 2 hours, during which time the reaction mixture turned dark green. Iodine (571 g, 2.25 mol) and ethylene glycol dimethyl ether (2 L) were charged to a 12 L 4-neck round bottom flask and the resulting solution was cooled to -78 ° C. The contents of the five-liter flask were then transferred via cannula to a mixture of -78 ° C containing iodine and ethylene glycol dimethyl ether placed in a twelve-liter flask. After the addition was complete, the reaction mixture was stirred at -78 ° C for an additional 1 hour. Then the cooling bath was removed and the mixture was allowed to warm to about 0 ° C and treated with 2 L of water and 2 L of 1 mol / L hydrochloric acid. Then methyl (tert-butyl) ether (2 L) was added and the layers were separated. The aqueous layer was extracted with 2 x 11 methyl (tert-butyl) ether. The combined organic layers were washed with saturated Na 2 S 2 O 3 (1.2 L), brine (1.2 L) and dried over Na 2 SO 4. After concentration under reduced pressure, the thick slurry was diluted with hexane (1 L). . The mixture was then cooled in an ice / water bath for about 30 min. The precipitate was filtered off and dried under reduced pressure to give the title compound as a pale yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ 10.22 (s, 1H), 7.86 (1H, d, J = 5.3 Hz), 7.54 (1H, d, J = 5.3 Hz) )

4,06 (3Η, s). LCMS (M+H)+ m/z 364 (t = 2,26 min).4.06 (3Η, s). LCMS (M + H) < + > m / z 364 (t = 2.26 min).

6-imidazol-1-yl-2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-1H-benzoimidazol:6-imidazol-1-yl-2- (4-iodo-2-methoxy-pyridin-3-yl) -4-methyl-1 H-benzoimidazole:

K roztoku 5-imidazol-1-yl-3-metylbenzén-1,2-diamínu (175 mg, 0,93 mmol) v metanole (8 ml) sa pridá pri teplote 0 °C roztok 4-jód-2-metoxypyridin-3-karbaldehydu (245 mg, 0,93 mmol) v metanole (5 ml). Reakčná zmes sa mieša pri 0’°C 1,5 h a potom 2 h pri teplote miestnosti. Po zahustení sa prečistením zvyšku rýchlou chromatografiou na stĺpci (10 % MeOH/CH2CI2) získa titulná zlúčenina (291 mg, 60 %). 1H NMR (300 MHz, CD3OD) δ 8,13 (1H, s), 7,98 (1H, d, J = 5,4 Hz), 7,62 (1H, d, J = 5,4 Hz), 7,59 (2H, s), 7.33 (1H, s), 7,16 (1H, s), 3,90 (3H, s), 2,67 (3H, s). LCMS (M+H)+ m/z 432 (t = 0,99 min).To a solution of 5-imidazol-1-yl-3-methylbenzene-1,2-diamine (175 mg, 0.93 mmol) in methanol (8 mL) at 0 ° C was added a solution of 4-iodo-2-methoxypyridine- Of 3-carbaldehyde (245 mg, 0.93 mmol) in methanol (5 mL). The reaction mixture was stirred at 0 ° C for 1.5 h and then at room temperature for 2 h. After concentration, purification of the residue by flash column chromatography (10% MeOH / CH 2 Cl 2 ) gave the title compound (291 mg, 60%). 1 H NMR (300 MHz, CD 3 OD) δ 8.13 (1H, s), 7.98 (1H, d, J = 5.4 Hz), 7.62 (1H, d, J = 5.4 Hz), 7.59 (2H, s), 7.33 (1H, s), 7.16 (1H, s), 3.90 (3H, s), 2.67 (3H, s). LCMS (M + H) < + > m / z 432 (t = 0.99 min).

3-(6-imidazol-1-yl-4-metyl-1 H-benzoimidazol-2-yl)-4-jód-1H-pyridín-2-ón:3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4-iodo-1H-pyridin-2-one:

Suspenzia 6-imidazol-1 -yl-2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-1 Hbenzoimidazolu v HCI 1 mol/l (6 ml) sa zahrieva 3 dni pri 70 °C, potom sa ochladí na teplotu miestnosti a zriedi sa etyl-acetátom. Po extrakcii sa spojené organické vrstvy premyjú soľným roztokom, vysušia sa Na2SO4 a zahustia sa. Prečistením zvyšku rýchlou chromatografiou (10 % MeOH/CH2CI2) sa získa vo forme tuhého produktu titulná zlúčenina (78 mg, 81 %). 1H NMR (300 MHz. CD3OD) δ 8.12 (1H, s), 7,58 (2H. s), 7,29-7,31 (2H, m). 7,16 (1 H, s), 7.01 (1 H, J = 6,8 Hz), 2.66 (3H, s). LCMS (M+H)+ m/z 418 (t = 0,75 min).A suspension of 6-imidazol-1-yl-2- (4-iodo-2-methoxy-pyridin-3-yl) -4-methyl-1H-benzimidazole in 1N HCl (6 mL) was heated at 70 ° C for 3 days, then cooled to room temperature and diluted with ethyl acetate. After extraction, the combined organic layers are washed with brine, dried over Na 2 SO 4 and concentrated. Purification of the residue by flash chromatography (10% MeOH / CH 2 Cl 2 ) gave the title compound as a solid (78 mg, 81%). 1 H NMR (300 MHz, CD 3 OD) δ 8.12 (1H, s), 7.58 (2H, s), 7.29-7.31 (2H, m). 7.16 (1H, s), 7.01 (1H, J = 6.8 Hz), 2.66 (3H, s). LCMS (M + H) < + > m / z 418 (t = 0.75 min).

Príprava 2-(4-chlór-2-oxo-1,2-dihydropyridín-3-yl)-7-metyl-3H-benzoimidazol-5karbonitrilu: .Preparation of 2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazole-5-carbonitrile:.

4-amino-3-metylbenzonitril:4-amino-3-methyl-benzonitrile:

K roztoku 3-metyl-4-nitrobenzonitrilu (20 g, 0,123 mol) v HOAc (200 ml) sa pridá práškové železo (17,55 g, 0,309 mol). Po 10 minútach začne prebiehať exotermická reakcia a zmes sa zafarbí na tmavo. Reakčná zmes sa mieša pri teplote miestnosti 14 h a potom sa zriedi EtOAc (200 ml). Hnedá zrazenina sa odfiltruje cez vrstvu celitu a filtračný koláč sa premyje EtOAc. Filtrát sa zahustí za zníženého tlaku a prečistením zvyšku rýchlou chromatografiou (40 % EtOAc/hexán) sa získa titulná zlúčenina (15,3 g, 92 %). 1H NMR (300 MHz, CDCI3) δ 7,30-7,34 (2H, m), 6,64 (1H, d, J = 8,7 Hz), 2,16 (3H, s). LCMS (M+H)* m/z 133 (t = 0,93 min).To a solution of 3-methyl-4-nitrobenzonitrile (20 g, 0.123 mol) in HOAc (200 mL) was added iron powder (17.55 g, 0.309 mol). After 10 minutes, an exothermic reaction started and the mixture turned dark. The reaction mixture was stirred at room temperature for 14 h and then diluted with EtOAc (200 mL). The brown precipitate was filtered through a pad of celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and purification of the residue by flash chromatography (40% EtOAc / hexane) gave the title compound (15.3 g, 92%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.34 (2H, m), 6.64 (1H, d, J = 8.7 Hz), 2.16 (3H, s). LCMS (M + H) + m / z 133 (t = 0.93 min).

N-(4-kyano-2-metyl-6-nitrofenyl)-2,2,2-trifluóracetamid:N- (4-cyano-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide:

K ľadom chladenému anhydridu kyseliny trifluóroctovej (60 ml) sa po častiach pridá 4-amino-3-metylbenzonitril (14,33 g, 0,108 mol). Získaná kaša sa mieša 30 min pri 0 °C. Potom sa pridá dusičnan amónny (17,28 g, 0,216 mol). Reakčná zmes sa potom mieša 1 h pri 0 °C a 14 h pri teplote miestnosti. Po odstránení väčšiny rozpúšťadla sa reakčná zmes ochladí ľadom a prevrstvi sa ľadom. Zrazenina žltej farby sa odfiltruje, premyje sa chladnou vodou a vysuší sa za zníženého tlaku. Surový produkt (15,5 g, 52 % výťažok s približne 80 % čistotou) sa použije v ďalšom stupni bez ďalšieho čistenia. 1H NMR (300 MHz, CD3OD) δ 8,05 (1H, s), 7,74 (1H, s), 2,30 (3H, s). LRMS (neg.ESI, M-H)' m/z 272.4-Amino-3-methylbenzonitrile (14.33 g, 0.108 mol) was added portionwise to ice-cooled trifluoroacetic anhydride (60 mL). The resulting slurry was stirred at 0 ° C for 30 min. Ammonium nitrate (17.28 g, 0.216 mol) was then added. The reaction mixture was then stirred at 0 ° C for 1 h and at room temperature for 14 h. After most of the solvent was removed, the reaction mixture was cooled with ice and overlaid with ice. The yellow precipitate is filtered off, washed with cold water and dried under reduced pressure. The crude product (15.5 g, 52% yield with approximately 80% purity) was used in the next step without further purification. 1 H NMR (300 MHz, CD 3 OD) δ 8.05 (1H, s), 7.74 (1H, s), 2.30 (3H, s). LRMS (neg. ESI, MH) m / z 272.

4-amino-3-metyl-5-nitrobenzonitril:4-amino-3-methyl-5-nitrobenzonitrile:

Zmes N-(4-kyano-2-metyl-6-nitrofenyl)-2,2,2-trifluóracetamidu (5 g, 18,3 mmol) a amoniak 2 mol/l v metanole (80 ml) sa zahrieva 14 h pri teplote spätného toku a potom sa ochladí na teplotu miestnosti. Po zahustení za zníženého tlaku sa prečistením zvyšku rýchlou chromatografiou (20 % EtOAc/hexán) získa titulná zlúčenina (3,24 mg 100 %, asi 80 % čistoty). 1H NMR (300 MHz, CDCI3) δ 8,40 (1H, s), 7,47 (1H, s), 6,6-6,8 (2H, široký s), 2,89 (3H, s).A mixture of N- (4-cyano-2-methyl-6-nitrophenyl) -2,2,2-trifluoroacetamide (5 g, 18.3 mmol) and 2M ammonia in methanol (80 mL) was heated at room temperature for 14 h. and then cooled to room temperature. After concentration under reduced pressure, purification of the residue by flash chromatography (20% EtOAc / hexane) gave the title compound (3.24 mg of 100%, about 80% purity). 1 H NMR (300 MHz, CDCl 3 ) δ 8.40 (1H, s), 7.47 (1H, s), 6.6-6.8 (2H, broad s), 2.89 (3H, s) ).

3,4-diamino-5-metylbenzonitril:3,4-diamino-5-methyl-benzonitrile:

K roztoku 4-amino-3-metyl-5-mtrobenzonitrilu (3,24 g, 18,3 mmol) v etanole (80 ml) sa pridá dihydrát chloridu cínatého (8,67 g, 49,75 mmol). Reakčná zmes sa zahrieva 14 h pri teplote spätného toku, potom sa ochladí na teplotu miestnosti a zahustí sa za zníženého tlaku. Zvyšok sa potom zriedi etyl-acetátom (100 ml) a spracuje sa s trietylamínom (20 ml). Získaná kaša sa prefiltruje cez vrstvu celitu a filtračný koláč sa premyje troma podielmi acetátu (50 I). Filtrát sa premyje nasýteným NaHCO3, vodou a soľným roztokom, potom sa vysuší Na2SO4 a prefiltruje sa. Po odstránení rozpúšťadla sa prečistením zvyšku rýchlou chromatografiou na silikagéli (30 % - 50 % EtOAc/hexán) získa vo forme svetložltého tuhého produktu (2,17 g, 81 %) titulná zlúčenina. 1H NMR (300 MHz, CDCI3) δ 6,94 (1H, s), 6,85 (1H, s), 2,16 (3H, s). LCMS (M+Hf m/z 148 (t = 0,67 min).To a solution of 4-amino-3-methyl-5-nitrobenzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added stannous chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was heated at reflux for 14 h, then cooled to room temperature and concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 mL) and treated with triethylamine (20 mL). The resulting slurry was filtered through a pad of celite and the filter cake was washed with three portions of acetate (50 L). The filtrate was washed with saturated NaHCO 3, water, and brine, then dried over Na 2 SO 4 and filtered. After removal of the solvent, purification of the residue by flash chromatography on silica gel (30% - 50% EtOAc / hexane) gave the title compound as a pale yellow solid (2.17 g, 81%). 1 H NMR (300 MHz, CDCl 3 ) δ 6.94 (1H, s), 6.85 (1H, s), 2.16 (3H, s). LCMS (M + H + m / z 148 (t = 0.67 min)).

2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5-karbonitril:2- (4-iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile:

K roztoku 3.4-díamino-5-metylbenzonitrilu (2,00 g, 13,6 mmol) v MeOH (40 ml) sa pridá pri 0 °C 4-jód-2-metoxypyridín-3-karbaldehyd (3,6 g, 13,6 mmol) v MeOH (20 ml). Vzniknutá kaša sa mieša 1 h pri 0 °C. Potom sa k reakčnej zmesi pri 0 °C pridá dávkovacím lievikom po kvapkách jód (1,73 g, 8,8 mmol) v MeOH (10 ml). Reakčná zmes sa potom mieša 14 hodín pri teplote miestnosti. Po odstránení MeOH sa zvyšok zriedi nasýteným Na2S2O3 a extrahuje sa EtOAc. Spojené organické vrstvy sa premyjú vodu a soľným roztokom a vysušia sa Na2SO4. Prečistením surového produktu rýchlou chromatografiou na stĺpci (3 % MeOH/CH2CI2) sa získa titulná zlúčenina (1,81 g, 46 %). 1H NMR (300 MHz, CDCI3) δ 7,90 (1H, s), 7,49 (1H, d, J =To a solution of 3,4-diamino-5-methylbenzonitrile (2.00 g, 13.6 mmol) in MeOH (40 mL) at 0 ° C was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (3.6 g, 13 mL). , 6 mmol) in MeOH (20 mL). The resulting slurry was stirred at 0 ° C for 1 h. Iodine (1.73 g, 8.8 mmol) in MeOH (10 mL) was then added dropwise via addition funnel to the reaction mixture at 0 ° C. The reaction mixture was then stirred at room temperature for 14 hours. After removal of MeOH, the residue was diluted with saturated Na 2 S 2 O 3 and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na 2 SO 4 . Purification of the crude product by flash column chromatography (3% MeOH / CH 2 Cl 2 ) gave the title compound (1.81 g, 46%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.90 (1H, s), 7.49 (1H, d, J =

5,4 Hz), 7,46 (1H, s), 7,41 (1H, d, J = 5,3 Hz), 3,78 (3H, s), 2.68 (3H, s). LCMS (M+Hf m/z 391 (t = 1,27 min).5.4 Hz), 7.46 (1H, s), 7.41 (1H, d, J = 5.3 Hz), 3.78 (3H, s), 2.68 (3H, s). LCMS (M + H + m / z 391 (t = 1.27 min)).

2-(4-chlór-2-oxo-1,2-dihydropyridin-3-yl)-7-metyl-3H-benzoimidazol-5karbonitril:2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzimidazole-5-carbonitrile:

Suspenzia 2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5karbonitrilu (1,8 g, 4,63 mmol) v HCI 4 mol/l v dioxáne (40 ml) sa zahrieva 6 h pri 80 °C a potom sa ochladí na teplotu miestnosti. Zrazenina sa odfiltruje a vysuší sa. Surový produkt (1,08 g, 82 %) sa použije v ďalšom stupni bez ďalšieho čistenia. LRMS (neg.ESI, M-H)' m/z 283.A suspension of 2- (4-iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazole-5-carbonitrile (1.8 g, 4.63 mmol) in 4 N HCl in dioxane (40 mL) was heated. 6 h at 80 ° C and then cooled to room temperature. The precipitate was filtered off and dried. The crude product (1.08 g, 82%) was used in the next step without further purification. LRMS (neg.ESI, M-H) m / z 283.

Príprava (S)-4-(1-benzyl)-2-trityloxyetylamino)-3-(6-bróm-4-metyl-1H-benzoimidazol2-yl)-1 H-pyridín-2-ónu:Preparation of (S) -4- (1-benzyl) -2-trityloxyethylamino) -3- (6-bromo-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

5-bróm-3-metylbenzén-1,2-diamín:5-bromo-3-methyl-benzene-1,2-diamine:

K suspenzii 4-bróm-2-metyl-6-nitrofenylamínu (20 g, 0,086 mol) v etanole (200 ml) sa pridá chlorid cinatý - dihydrát (49,2 g, 0,258 mol). Reakčná zmes sa zahrieva 14 h pri teplote spätného toku, potom sa ochladí na teplotu miestnosti a zahustí sa za zníženého tlaku. Zvyšok sa potom zriedi etyl-acetátom (150 ml) a spracuje sa s trietylamínom (40 ml). Získaná kaša sa prefiltruje cez vrstvu celitu a filtračný koláč sa premyje troma podielmi acetátu (50 ml). Filtrát sa premyje nasýteným NaHCO3, vodou a soľným roztokom, potom sa vysuší Na2SO4 a prefiltruje sa. Po odstránení rozpúšťadla sa prečistením zvyšku rýchlou chromatografiou na stĺpci silikagélu (30 % - 50 % EtOAc/hexán, potom 5 % MeOH/CH2CI2) získa vo forme žltého oleja (10,26 g, 59 %) titulná zlúčenina. 1H NMR (300 MHz, CDCI3) δ 6,77 (1H, d, J = 2,0 Hz), 6,74 (1H, d, J = 2,0 Hz), 2,16 (3H, s). LCMS (M+Hf m/z 201 (t = 0,83 min).To a suspension of 4-bromo-2-methyl-6-nitrophenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin (II) chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated at reflux for 14 h, then cooled to room temperature and concentrated under reduced pressure. The residue was then diluted with ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of Celite and the filter cake was washed with three portions of acetate (50 mL). The filtrate was washed with saturated NaHCO 3 , water, and brine, then dried over Na 2 SO 4 and filtered. After removal of the solvent, purification of the residue by flash chromatography on silica gel (30% - 50% EtOAc / hexane, then 5% MeOH / CH 2 Cl 2 ) gave the title compound as a yellow oil (10.26 g, 59%). 1 H NMR (300 MHz, CDCl 3 ) δ 6.77 (1H, d, J = 2.0 Hz), 6.74 (1H, d, J = 2.0 Hz), 2.16 (3H, s) ). LCMS (M + H + m / z 201 (t = 0.83 min).

Br.Br.

MeOMeO

6-bróm-2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-1H-benzoimidazol:6 bromo-2- (4-iodo-2-methoxy-pyridin-3-yl) -4-methyl-1 H-benzoimidazole:

K roztoku 5-bróm-3-metyl-1,2-fenyldiamínu (4 g, 19,9 mmol) v MeOH (80 ml) sa pridá po kvapkách pri 0 °C 4-jód-2-metoxypyridín-3-karbaldehyd (5,23 g, 19,9 mmol) v MeOH (20 ml). Vzniknutá kaša sa mieša 30 min pri teplote miestnosti. Potom sa k reakčnej zmesi pridá dávkovacím lievikom po kvapkách jód (2,53 g, 9,95 mmol) v MeOH (20 ml). Po 14 hodinách sa reakčná zmes zahustí za zníženého tlaku, zriedi sa 5 % Na2S2O3 a extrahuje sa etyl-acetátom. Spojené organické vrstvy sa premyjú vodou a soľným roztokom a vysušia sa Na2SO4. Po odstránení rozpúšťadla sa opatrným prečistením surového produktu rýchlou chromatografiou (20 % EtOAc/hexán) získa vo forme žltej peny titulná zlúčenina (4,05 g, 46 %). 1H NMR (300 MHz, CDCI3) δ 7,86 (1H, d, J = 5,31 Hz), 7,53 (1H, d, J = 5,3 Hz), 7,26 (2H, široký s). 3,91 (3H, s), 2,63 (3H, s). LCMS (M+H)+ m/z 444 (t = 1,39 min).To a solution of 5-bromo-3-methyl-1,2-phenyldiamine (4 g, 19.9 mmol) in MeOH (80 mL) was added dropwise at 0 ° C 4-iodo-2-methoxy-pyridine-3-carbaldehyde ( 5.23 g, 19.9 mmol) in MeOH (20 mL). The resulting slurry was stirred at room temperature for 30 min. Iodine (2.53 g, 9.95 mmol) in MeOH (20 mL) was then added dropwise via addition funnel. After 14 hours, the reaction mixture was concentrated under reduced pressure, diluted with 5% Na 2 S 2 O 3 and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over Na 2 SO 4. After removal of the solvent, the crude product was carefully purified by flash chromatography (20% EtOAc / hexane) to give the title compound as a yellow foam (4.05 g, 46%). 1 H NMR (300 MHz, CDCl 3 ) δ 7.86 (1H, d, J = 5.31 Hz), 7.53 (1H, d, J = 5.3 Hz), 7.26 (2H, broad) with). 3.91 (3H, s); 2.63 (3H, s). LCMS (M + H) < + > m / z 444 (t = 1.39 min).

3-(6-bróm-4-metyl-1H-benzoimidazol-2-yl)-4-chlór-1H-pyridín-2-ón:3- (6-bromo-4-methyl-1 H-benzoimidazol-2-yl) -4-chloro-1 H-pyridin-2-one;

Suspenzia 6-bróm-2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-1 H-benzoimidazolu (4 g, 9,03 mmol) s HCI 4 mol/l v dioxáne (60 ml) sa zahrieva 6 h pri 80 °C a potom sa ochladí na teplotu miestnosti. Zrazenina sa odfiltruje a vysušením sa získa vo forme hnedého prášku titulná zlúčenina (3,0 g, 100 %). Surový produkt sa použije v ďalšom stupni bez ďalšieho čistenia. 1H NMR (300 MHz. CD3OD) δ 7,55 (1H, s), 7,42 (1H, d, J = 6,0 Hz), 7,17 (1H, s), 6.91 (1H, d, J = 6,0 Hz), 2,55 (3H, s). LCMS (M+H)+ m/z 338 (t = 1.33 min).A suspension of 6-bromo-2- (4-iodo-2-methoxypyridin-3-yl) -4-methyl-1H-benzoimidazole (4 g, 9.03 mmol) with 4 N HCl in dioxane (60 mL) was added. was heated at 80 ° C for 6 h and then cooled to room temperature. The precipitate was filtered off and dried to give the title compound (3.0 g, 100%) as a brown powder. The crude product was used in the next step without further purification. 1 H NMR (300 MHz, CD 3 OD) δ 7.55 (1H, s), 7.42 (1H, d, J = 6.0 Hz), 7.17 (1H, s), 6.91 (1H, s, d, J = 6.0 Hz), 2.55 (3H, s). LCMS (M + H) < + > m / z 338 (t = 1.33 min).

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-(6-bróm-4-metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón:(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (6-bromo-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

K roztoku 3-(6-bróm-4-metyl-1 H-benzoimidazol-2-yl)-4-chlór-1 H-pyridín-2-ónu (1,42 g, 3,78 mmol) v DMF (15 ml) sa pridá (S)-(-)-2-amino-3-fenyl-1-propanol (1,43 g, 9,45 mmol) a N-metylmorfolín (1,5 ml). Reakčná zmes sa potom zahrieva 6 h pri 80 °C a potom sa ochladí na teplotu miestnosti. Potom sa rozpúšťadlo odstráni za vysoko zníženého tlaku a prečistením zvyšku rýchlou chromatografiou (5 % MeOH/CH2Cl2) sa vo forme žltej peny získa titulná zlúčenina (1,26 g, 74 %). 1H NMR (300 MHz, CDCI3) δ 6,9-7,2 (8H, m), 5,86 (1 H, d, J = 7,1 Hz), 3,7-3,9 (3H, m), 2,9-3,1 (2H, m), 2,57 (3H, s). LCMS (M+H)+ m/z 453 (t = 2,03 min).To a solution of 3- (6-bromo-4-methyl-1H-benzoimidazol-2-yl) -4-chloro-1H-pyridin-2-one (1.42 g, 3.78 mmol) in DMF (15 (S) - (-) - 2-amino-3-phenyl-1-propanol (1.43 g, 9.45 mmol) and N-methylmorpholine (1.5 mL) were added. The reaction mixture was then heated at 80 ° C for 6 h and then cooled to room temperature. Then, the solvent was removed under high vacuum and purification of the residue by flash chromatography (5% MeOH / CH 2 Cl 2) gave the title compound (1.26 g, 74%) as a yellow foam. 1 H NMR (300 MHz, CDCl 3 ) δ 6.9-7.2 (8H, m), 5.86 (1H, d, J = 7.1 Hz), 3.7-3.9 (3H) , m), 2.9-3.1 (2H, m), 2.57 (3H, s). LCMS (M + H) < + > m / z 453 (t = 2.03 min).

(S)-4-(1-benzyl-2-trityloxyetylamino)-3-(6-bróm-4-metyl-1H-benzoimidazol-2yl)-1 H-pyridín-2-ón:(S) -4- (1-Benzyl-2-trityloxyethylamino) -3- (6-bromo-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

K roztoku (S)-4-(1 -benzyl-2-hydroxyetylamino)-3-(6-bróm-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ónu (0,9 g, 1,98 mmol) v THF (30 ml), pridá sa CS2CO3 (1,29 g, 3,96 mmol) a potom trifenylmetylchlorid (1,10 g, 3,96 mmol). Potom sa reakčná zmes zahrieva 14 h v atmosfére dusíka pri teplote spätného toku a potom sa ochladí na teplotu miestnosti. Po odstránení rozpúšťadla sa zvyšok zriedi etylacetátom a premyje sa vodou. Vodná frakcia sa extrahuje etyl-acetátom a spojené organické vrstvy sa premyjú vodou a soľným roztokom a vysušia sa Na2SO4. Po zahustení za zníženého tlaku sa prečistením zvyšku rýchlou chromatografiou na stĺpci (30 % EtOAc/hexán) získa vo forme bieleho tuhého produktu titulná zlúčenina (1 g, 73 %). 1H NMR (300 MHz, DMSO-de) δ 11,77 (1H, široký s), 11,73 (1H, d, J =To a solution of (S) -4- (1-benzyl-2-hydroxyethylamino) -3- (6-bromo-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (0.9 g, 1.98 mmol) in THF (30 mL), CS 2 CO 3 (1.29 g, 3.96 mmol) was added followed by triphenylmethyl chloride (1.10 g, 3.96 mmol). The reaction mixture was then heated to reflux for 14 h under nitrogen and then cooled to room temperature. After removal of the solvent, the residue was diluted with ethyl acetate and washed with water. The aqueous fraction was extracted with ethyl acetate and the combined organic layers were washed with water and brine and dried over Na 2 SO 4 . After concentration under reduced pressure, purification of the residue by flash column chromatography (30% EtOAc / hexane) gave the title compound (1 g, 73%) as a white solid. 1 H NMR (300 MHz, DMSO-d e) δ 11.77 (1H, br s), 11.73 (1 H, d, J =

5,2 Hz), 11,46 (1H, široký s). 7,13-7,54 (23H, m), 5.87 (1H, d, J = 4,5 Hz), 4,09-4,14 (1 H, m), 3,07-3,42 (4H, m), 2,54 (3H, s). LCMS (M+H)+ m/z 695 (t = 2.79 min).5.2 Hz), 11.46 (1H, broad s). 7.13-7.54 (23H, m), 5.87 (1H, d, J = 4.5Hz), 4.09-4.14 (1H, m), 3.07-3.42 (4H) , m), 2.54 (3H, s). LCMS (M + H) < + > m / z 695 (t = 2.79 min).

Príprava 3-[6-(4-acety I p i perazín-1 -yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-chlór-1 H pyridin-2-ónu:Preparation of 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one:

1-[4-(4-amino-3-metyl-5-nitrofenyl)piperazín-1-yl]-etanón:1- [4- (4-amino-3-methyl-5-nitrophenyl) piperazin-1-yl] -ethanone:

Zmes 4-bróm-2-metyl-6-nitrofenylaminu (5 g, 21,64 mmol), 1-acetylpiperazínu (4,2 g, 32,46 mmol) paládium-acetátu (244 mg, 1,08 mmol), tri-terc-butylfosfínu (440 mg, 2,16 mmol) a nátrium-terc-butoxidu (4,2 g, 43,29 mmol) v toluéne (70 ml) sa zahrieva 14 h v atmosfére dusíka pri 100 °C. Potom sa reakčná zmes ochladí na teplotu miestnosti a zriedi sa etyl-acetátom. Po extrakcii sa spojené organické vrstvy premyjú vodou, soľným roztokom a vysušia sa Na2SO4. Zahustením sa získa hnedastý zvyšok, prečistením ktorého rýchlou chromatografiou na stĺpci (10 % MeOH/CH2Cl2) sa získa titulná zlúčenina (4,21 g, 70 %). 1H NMR (400 MHz, CD3OD) δ 7,42 (1H, d, J = 2,8 Hz), 7,23 (1H, d, J = 2,8 Hz), 3,71 (2H, t, J = 5,1 Hz), 3,67 ( 2H, t, J = 5,1 Hz), 3,04 (2H, t, J = 5,2 Hz), 2,98 (2H, t, J = 5,2 Hz), 2,24 (3H, s), 2,13 (3H, s). LCMS (M+H)+ m/z 279 (t = 1,46 min).A mixture of 4-bromo-2-methyl-6-nitrophenylamine (5 g, 21.64 mmol), 1-acetylpiperazine (4.2 g, 32.46 mmol), palladium acetate (244 mg, 1.08 mmol), three tert -butylphosphine (440 mg, 2.16 mmol) and sodium tert -butoxide (4.2 g, 43.29 mmol) in toluene (70 mL) was heated under nitrogen at 100 ° C for 14 h. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. After extraction, the combined organic layers are washed with water, brine and dried over Na 2 SO 4 . Concentration gave a brownish residue which was purified by flash column chromatography (10% MeOH / CH 2 Cl 2) to give the title compound (4.21 g, 70%). 1 H NMR (400 MHz, CD 3 OD) δ 7.42 (1H, d, J = 2.8 Hz), 7.23 (1H, d, J = 2.8 Hz), 3.71 (2H, t, J = 5.1 Hz), 3.67 (2H, t, J = 5.1 Hz), 3.04 (2H, t, J = 5.2 Hz), 2.98 (2H, t, J = 5.2 Hz), 2.24 (3H, s), 2.13 (3H, s). LCMS (M + H) < + > m / z 279 (t = 1.46 min).

oabout

-[4-(3,4-diamino-5-metylfenyl)piperazín-1 -yljetanón:- [4- (3,4-Diamino-5-methylphenyl) piperazin-1-yl] ethanone:

K 1-[4-(4-amino-3-metyl-5-nitrofenyl)piperazin-1-yl]etanónu (4,5 g, 16,2 mmol) a 10 % paládia na uhlíku (400 mg) sa v atmosfére dusíka pridá metanol (50 ml) a kyselina octová (5 ml). Reakčná zmes sa mieša v atmosfére vodíka (balón s vodíkom) 14 h. Tmavý roztok sa prefiltruje cez vrstvu celitu a filtračný koláč sa premyje metanolom. Zahustením filtrátu sa získa titulná zlúčenina (4.00 g, 100 %), ktorá sa použije v nasledujúcom stupni bez ďalšieho čistenia. LCMS (M+H)+ m/z 207 (t = 0,41 min).To 1- [4- (4-amino-3-methyl-5-nitrophenyl) piperazin-1-yl] ethanone (4.5 g, 16.2 mmol) and 10% palladium on carbon (400 mg) under an atmosphere Methanol (50 mL) and acetic acid (5 mL) were added under nitrogen. The reaction mixture was stirred under a hydrogen atmosphere (balloon with hydrogen) for 14 h. Filter the dark solution through a pad of celite and wash the filter cake with methanol. Concentration of the filtrate gave the title compound (4.00 g, 100%), which was used in the next step without further purification. LCMS (M + H) < + > m / z 207 (t = 0.41 min).

OABOUT

1-{4-[2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5-yl]piperazín1-yl}etanón.1- {4- [2- (4-iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazin-1-yl} -ethanone.

K roztoku 1-[4-(3,4-diamino-5-metylfenyl)piperazín-1-yl]etanónu (4,00 g, 16,18 mmol) v metanole (100 ml) sa pridá 4-jód-2-metoxypyridín-3-karbaldehyd (4,25 g,To a solution of 1- [4- (3,4-diamino-5-methylphenyl) piperazin-1-yl] ethanone (4.00 g, 16.18 mmol) in methanol (100 mL) was added 4-iodo-2- methoxypyridine-3-carbaldehyde (4.25 g,

16,18 mmol). Reakčná zmes sa mieša 14 hodín pri teplote miestnosti. Po zahustení, sa prečistením zvyšku rýchlou chromatografiou na stĺpci (10 % MeOH/CH2Cl2) získa titulná zlúčenina (5,25 g, 66 %). 1H NMR (400 MHz, CD3OD) δ 7,81 (1H, d, J = 5,4 Hz), 7,48 (1H, d, J = 5,4 Hz), 7,26 (1H, s), 6,85 (1H, s), 3,85 (3H. s), 3,78 (2H, t, J = 5,0 Hz), 3,64 (2H, t, J = 5,0 Hz), 3,16 (2H, t, J = 5,2 Hz), 3,11 (2H, t, J = 2,5 Hz), 2,62 (3H, s), 2,13 (3H, s). LCMS (M+H)* m/z 492 (t = 1,71 min).16.18 mmol). The reaction mixture was stirred at room temperature for 14 hours. After concentration, purification of the residue by flash column chromatography (10% MeOH / CH 2 Cl 2) gave the title compound (5.25 g, 66%). 1 H NMR (400 MHz, CD 3 OD) δ 7.81 (1H, d, J = 5.4 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.26 (1H, s), 6.85 (1H, s), 3.85 (3H, s), 3.78 (2H, t, J = 5.0Hz), 3.64 (2H, t, J = 5.0) Hz), 3.16 (2H, t, J = 5.2 Hz), 3.11 (2H, t, J = 2.5 Hz), 2.62 (3H, s), 2.13 (3H, with). LCMS (M + H) + m / z 492 (t = 1.71 min).

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3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-chlór-1Hpyridín-2-ón:3- [6- (4-Acetyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one:

K roztoku 1 -; 4-[2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5yl]piperazín-1 -yl}etanónu (5,2 g, 10,6 mmol) v HCI 4 mol/l v dioxáne (60 ml) sa pridá voda (5 ml). Reakčná zmes sa potom mieša 14 h pri teplote miestnosti. Zahustením reakčnej zmesi sa získa titulná zlúčenina (4,02 g, 100 %), ktorá sa použije v ďalšom stupni bez ďalšieho čistenia. LCMS (M+H)* m/z 486 (t = 1,55 min).To solution 1-; 4- [2- (4-Iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazin-1-yl} -ethanone (5.2 g, 10.6 mmol) in HCl 4 In dioxane (60 mL), water (5 mL) was added. The reaction mixture was then stirred at room temperature for 14 h. Concentration of the reaction mixture afforded the title compound (4.02 g, 100%), which was used in the next step without further purification. LCMS (M + H) + m / z 486 (t = 1.55 min).

Príprava (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-(4-metyl-6-piperazín-1-yl-1H59 benzoimidazol-2-yl)-1H-pyridín-2-ón:Preparation of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl-1H-59-benzoimidazol-2-yl) -1H-pyridin-2-one:

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(S)-3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1H-pyridín-2-ón:(S) -3- [6- (4-Acetyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one :

K roztoku 3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-chlór1H-pyridín-2-ónu (1 g, 2,6 mmol) v DMF (10 ml) sa pridá (S)-(-)-2-amino-3fenylpropanol (0,78 mg, 5,2 mmol) a N-metylmorfolín (2 ml). Reakčná zmes sa potom zahrieva 12 h pri 80 °C, potom sa ochladí na teplotu miestnosti a zahustí sa za vysoko zníženého tlaku. Prečistením zvyšku rýchlou chromatografiou na stĺpci (10 % MeOH/CH2CI2) sa získa titulná zlúčenina (0,90 g, 69 %), 1H NMR (400 MHz, CD3OD) δ 7,36 (1H, s), 7,02-7.23 (6H, m), 6,80 (1H, s), 5,98 (1H, d, J = 7,5 Hz), 4,10-4,12 (3H, m), 3,67-3,78 (6H, m), 3,06-3,11 (3H, m), 2,90 (1 H, dd, J = 7,8, 13,6 Hz), 2,54 (3H, s), 2,12 (3H, s). LCMS (M+H)’ m/z 501 (t = 1,30 min).To a solution of 3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S) - (-) - 2-amino-3-phenylpropanol (0.78 mg, 5.2 mmol) and N-methylmorpholine (2 mL). The reaction mixture was then heated at 80 ° C for 12 h, then cooled to room temperature and concentrated under high vacuum. Purification of the residue by flash column chromatography (10% MeOH / CH 2 Cl 2 ) gave the title compound (0.90 g, 69%), 1 H NMR (400 MHz, CD 3 OD) δ 7.36 (1H, s), 7 02-7.23 (6H, m), 6.80 (1H, s), 5.98 (1H, d, J = 7.5Hz), 4.10-4.12 (3H, m), 3, 67-3.78 (6H, m), 3.06-3.11 (3H, m), 2.90 (1H, dd, J = 7.8, 13.6 Hz), 2.54 (3H) , s), 2.12 (3 H, s). LCMS (M + H) + m / z 501 (t = 1.30 min).

(S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazoi-2-yl)-1H-pyridín-2-ón.·(S) -4- (1-hydroxymethyl-2-phenyl-ethylamino) -3- (4-methyl-6-piperazin-1-yl-1Hbenzoimidazoi-2-yl) -1 H-pyridin-2-one. ·

K roztoku (S)-3-[6-(4-acetylpiperazín-1 -yl)-4-metyl-1 H-benzoimidazol-2-yl]-4(1-hydroxymetyl-2-fenyletylamino)-1H-pyridin-2-ónu (900 mg, 18 mmol) v HCI 4 mol/l v dioxáne (10 ml) sa pridá voda (1 ml). Reakčná zmes sa zahrieva 14 h pri teplote miestnosti a potom sa ochladí na teplotu miestnosti. Zahustením za vysoko zníženého tlaku sa získa titulná zlúčenina (0,83 g, 100 %), ktorá sa použije v ďalšom stupni oez ďalšieho čistenia. LCMS (M+H)+ m/z 459 (t = 1.13 min).To a solution of (S) -3- [6- (4-acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4 (1-hydroxymethyl-2-phenylethylamino) -1H-pyridine- 2-one (900 mg, 18 mmol) in 4 N HCl in dioxane (10 mL) was added water (1 mL). The reaction mixture was heated at room temperature for 14 h and then cooled to room temperature. Concentration under high vacuum gave the title compound (0.83 g, 100%), which was used in the next step without further purification. LCMS (M + H) < + > m / z 459 (t = 1.13 min).

Príprava 2-(4,6-dichlórpyrimidín-5-yl)-6-imidazol-1-yl-4-metyl-1 H-benzoimidazolu:Preparation of 2- (4,6-dichloropyrimidin-5-yl) -6-imidazol-1-yl-4-methyl-1H-benzoimidazole:

ClCl

4,6-dichlórpyrimidín-5-karbaldehyd:4,6-dichloropyrimidine-5-carbaldehyde:

K POCI3 (21 ml, 0,23 mol) sa pri 0 °C pridá DMF (7 ml, 0,09 mol). Reakčná zmes sa potom mieša 0,5 h pri teplote miestnosti. Potom sa po malých podieloch pridá 4,6-dihydroxypyrimidín-5-karbaldehyd (5 g, 0,045 mol). Reakčná zmes sa potom zahrieva 6 h pri 90 °C a potom sa ochladí na teplotu miestnosti. Potom sa k reakčnej zmesi umiestnenej v ľadovom kúpeli veľmi pomaly pridá vo veľkom nadbytku drvený ľad. Zmes sa potom extrahuje CH2CI2. Spojené organické vrstvy sa premyjú vodu, soľným roztokom a vysušia sa Na2SO4. Po zahustení sa prečistením chromatografiou na stĺpci (20 % EtOAc/hexán) získa titulná zlúčenina (4 g, 50 %).To POCl 3 (21 mL, 0.23 mol) at 0 ° C was added DMF (7 mL, 0.09 mol). The reaction mixture was then stirred at room temperature for 0.5 h. Then 4,6-dihydroxypyrimidine-5-carbaldehyde (5 g, 0.045 mol) was added in small portions. The reaction mixture was then heated at 90 ° C for 6 h and then cooled to room temperature. Crushed ice is then added very slowly to the reaction mixture placed in the ice bath. The mixture was then extracted with CH 2 Cl 2. The combined organic layers were washed with water, brine and dried over Na 2 SO 4 . After concentration, purification by column chromatography (20% EtOAc / hexane) gave the title compound (4 g, 50%).

’H NMR (400 MHz, CDCI3) δ 8,91 (1H, s), 7,87 (1H, s). LRMS (M+Hf m/z 177.Δ H NMR (400 MHz, CDCl 3) δ 8.91 (1H, s), 7.87 (1H, s). LRMS (M + H + m / z 177).

2-(4,6-dichlórpyrimidín-5-yl)-6-imidazol-1-yl-4-metyl-1 H-benzoimidazolu:2- (4,6-Dichloropyrimidin-5-yl) -6-imidazol-1-yl-4-methyl-1H-benzoimidazole:

K roztoku 5-imidazol-1-yl-3-metylbenzén-1,2-diamínu (180 mg, 0,96 mmol) v metanole (4 ml) sa pridá roztok 4,6-dichlórpyrimidín-5-karbaldehydu (183 mg. 0.96 mmol) v metanole (1 ml). Reakčná zmes sa potom mieša 14 h pri teplote miestnosti. Po zahustení, sa prečistením rýchlou chromatografiou na stĺpci (5 % metanol/C^Ch) získa titulná zlúčenina (180 mg, 55 %). LCMS (M+H)’ m/z 344 (t = 1,31 min).To a solution of 5-imidazol-1-yl-3-methylbenzene-1,2-diamine (180 mg, 0.96 mmol) in methanol (4 mL) was added a solution of 4,6-dichloropyrimidine-5-carbaldehyde (183 mg). 0.96 mmol) in methanol (1 mL). The reaction mixture was then stirred at room temperature for 14 h. After concentration, purification by flash column chromatography (5% methanol / CH 2 Cl 2) afforded the title compound (180 mg, 55%). LCMS (M + H) m / z 344 (t = 1.31 min).

Spôsob prípravy 2-amino-4-fluór-6-metylnitrobenzénu:Method for the preparation of 2-amino-4-fluoro-6-methylnitrobenzene:

Di-terc-butylester kyseliny 2-(3,5-difluór-2-nitrofenyl)malónovej:2- (3,5-Difluoro-2-nitrophenyl) malonic acid di-tert-butyl ester:

K suspenzii NaH (54,6 g, 60 %, 1,365 mol) v 600 ml DMF sa pri O ’C pridá diterc-butyl-malonát (118 g, 0,546 mol) a zmes sa mieša 30 min. Potom sa pridá v priebehu 3 hodín roztok 2,4,6-trifluórnitrobenzénu v 400 ml DMF (75 g, 0,42 mol) a roztok sa mieša 12 hodín pri teplote miestnosti. Reakčná zmes sa potom extrahuje etyl-acetátom (3x). Etylacetát sa potom premyje vodu (3x) a soľným roztokom, vysuší sa MgSO4 a zahustením sa získa 62 g surového produktu. LCMS [M+Naj- 396; 1H NMR (500 MHz, DMSO) δ 7,81 (m, 1H), 7,27 (m, 1H), 5,00 (s, IH), 1,41 (m, 18H).To a suspension of NaH (54.6 g, 60%, 1.365 mol) in 600 mL DMF at 0 ° C was added di-tert-butyl malonate (118 g, 0.546 mol) and the mixture was stirred for 30 min. A solution of 2,4,6-trifluoronitrobenzene in 400 mL DMF (75 g, 0.42 mol) was then added over 3 hours and the solution was stirred at room temperature for 12 hours. The reaction mixture was then extracted with ethyl acetate (3x). The ethyl acetate was then washed with water (3x) and brine, dried over MgSO 4 and concentrated to give 62 g of crude product. LCMS [M + Na] + - 396; 1 H NMR (500 MHz, DMSO) δ 7.81 (m, 1H), 7.27 (m, 1H), 5.00 (s, 1H), 1.41 (m, 18H).

Di-terc-butylester kyseliny 2-(3-amino-5-fluór-2-nitrofenylimalónovej:2- (3-Amino-5-fluoro-2-nitrophenylimalonic acid di-tert-butyl ester):

K surovému di-terc-butylesteru kyseliny 2-(3,5-difluór-2-nitrofenyl)maiónovej (62 g, 0,42 mol) sa v tlakovej banke pridá 700 ml amoniakj 2 mol/l v metanole. Banka sa potom uzavrie a zahrieva sa 18 hodín pri 85 ’C. Potom sa reakčná zmes ochladí, nádobka sa opatrne otvorí a zahustením metanolového roztoku sa získa 140 g surového produktu. LCMS [M+Na]- 393; 1H NMR (500 MHz. DMSO) δ 6,76 (dd, J = 10,8, 2,8 Hz. 1H), 6,29 (dd, J = 10,8, 2,8 Hz, 1H), 4,99 (br s, 2H), 4.80 (s, 1H), 1,40 (m, 18H).To the crude 2- (3,5-difluoro-2-nitrophenyl) -thionic acid di-tert-butyl ester (62 g, 0.42 mol) in a pressure flask was added 700 mL of 2M ammonia in methanol. The flask was then sealed and heated at 85 ° C for 18 hours. The reaction mixture was then cooled, the vial was carefully opened and the methanol solution was concentrated to give 140 g of crude product. LCMS [M + Na] - 393; 1 H NMR (500 MHz, DMSO) δ 6.76 (dd, J = 10.8, 2.8 Hz, 1H), 6.29 (dd, J = 10.8, 2.8 Hz, 1H), 4.99 (br s, 2H); 4.80 (s, 1H); 1.40 (m, 18H).

3-amino-5-fluór-2-nitrofenyloctová kyselina:3-Amino-5-fluoro-2-nitrophenylacetic acid:

K di-terc-butylesteru kyseliny 2-(3-amino-5-fluór-2-nitrofenyl)malónovej (140 g) v 500 ml HCI 4 mol/l v dioxáne sa pridá 50 ml vody a reakčná zmes sa zahrieva 2 dni pri 40 °C. Roztok sa potom extrahuje etyl-acetátom (3x) a etylacetát sa potom premyje vodou (3x) a soľným roztokom. Organická fáza sa vysuší MgSO4 a zahustením sa získa 78 g surového produktu (s čistotou zistenou LC/MS 66 %). 1H NMR (500 MHz, DMSO) δ 12,40 (br s, 1H), 7,04 (s, 2H), 6,68 (dd, J = 10,9, 2,8 Hz, 1H), 3,80 (s, 2H).To 2- (3-amino-5-fluoro-2-nitrophenyl) malonic acid di-tert-butyl ester (140 g) in 500 mL of 4M HCl in dioxane was added 50 mL of water and the reaction mixture was heated at 40 ° C for 2 days. C. The solution was then extracted with ethyl acetate (3x) and the ethyl acetate was then washed with water (3x) and brine. The organic phase was dried over MgSO 4 and concentrated to give 78 g of crude product (66% pure by LC / MS). 1 H NMR (500 MHz, DMSO) δ 12.40 (br s, 1H), 7.04 (s, 2H), 6.68 (dd, J = 10.9, 2.8 Hz, 1H), 3 .80 (s, 2H).

2-amino-4-fluór-6-metylnitrobenzén:2-amino-4-fluoro-6-methyl-nitrobenzene:

K surovej 3-amino-5-fluór-2-nitrofenyloctovej kyseline (3,6 g, 16,8 mmol) sa pridá Cu2O (10,1 g, 70,6 mmol) v 120 ml acetonitrilu s 120 μΙ metanolu a suspenzia sa zahrieva 12 hodín pri teplote spätného toku. Reakčná zmes sa potom prefiltruje cez celit a vrstva celitu sa potom premyje vodu a etyl-acetátom. Filtrát sa extrahuje etyl-acetátom, premyje sa vodou a soľným roztokom, vysuší sa Na2SO4 a zahustením sa získa 2,95 g produktu s čistotou zistenou 1H NMR 80 %. ESI-MS [M+Na]-193; 1H NMR (500 MHz, DMSO) δ 6,67 (s, 2H), 6,56 (dd, J = 11, 2,8 Hz. 1H), 6,39 (dd, J = 11, 2,8 Hz, 1H), 2,50 (s, 3H).To the crude 3-amino-5-fluoro-2-nitrophenylacetic acid (3.6 g, 16.8 mmol) was added Cu 2 O (10.1 g, 70.6 mmol) in 120 mL of acetonitrile with 120 μΙ of methanol and the suspension is heated at reflux for 12 hours. The reaction mixture was then filtered through celite and the celite pad was washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated to give 2.95 g of the product with a 80% purity by 1 H NMR. ESI-MS [M + Na] - 193; 1 H NMR (500 MHz, DMSO) δ 6.67 (s, 2H), 6.56 (dd, J = 11, 2.8 Hz, 1H), 6.39 (dd, J = 11, 2.8 Hz, 1H), 2.50 (s, 3H).

Spôsob prípravy 4-chlór-3-(4-metyl-6-morfolín-4-yl-1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ónu a 4-jód-3-(4-metyl-6-morfolín-4-yl-1 H-benzoimidazcl-2-yl)-1 H-pyridín-2ónu.Process for preparing 4-chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one and 4-iodo-3- (4-methyl-6) -morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one.

2-metyl-4-morfolín-4-yl-6-nitrofenylamín:2-methyl-4-morpholin-4-yl-6-nitro-phenylamine:

Do tlakovej banky s objemom 800 ml sa vnesie tris(dibenzylidénacetónjdipaládium (2,64 g, 2,88 mmol). 2-(di-terc-butylr'osfino)bifenyl (1,42 g, 4,75 mmol) a nátrium-terc-butoxid (17,5 g, 182 mmol). Potom sa pridá suchý THF (500 ml), 4-bróm-2-metyl-6-nitroanilín (30,0 g, 130 mmol) a morfolín (34 ml, 390 mmol). Roztokom sa nechá 1 minútu prebublávať argón a potom sa banka uzavrie. Reakčná zmes sa mieša 3 dni pri 85 CC. Potom sa THF odparí za zníženého tlaku a surový produkt sa najprv absorbuje na oxid kremičitý, ktorý sa prevedie na vrchol stĺpca silikagélu. Elúciou pomocou zmesí hexán-(etylacetát) (gradient 6:4 až 6:6 až 0:1) sa po odparení rozpúšťadiel získa titulná zlúčenina (červenohnedý tuhý produkt,Tris (dibenzylideneacetone) dipalladium (2.64 g, 2.88 mmol), 2- (di-tert-butylphosphino) biphenyl (1.42 g, 4.75 mmol) and sodium- tert-butoxide (17.5 g, 182 mmol) then dry THF (500 mL), 4-bromo-2-methyl-6-nitroaniline (30.0 g, 130 mmol) and morpholine (34 mL, 390 mL) were added. Argon was bubbled through the solution for 1 minute, then the flask was sealed, and the reaction mixture was stirred at 85 ° C for 3 days. Elution with hexane- (ethyl acetate) mixtures (gradient 6: 4 to 6: 6 to 0: 1) gave the title compound (red-brown solid, after evaporation of the solvents).

49,3 %). LCMS (M+H)+ m/z 238 (t = 0,64 min). 1H NMR (500 MHz. DMSO-ds) δ 7,32 (1H, s), 7,22 (1H, s), 6,96 (2H, s), 3,72 (4H. široký s), 2,96 (4H, široký s), 2,21 (3H, s).49.3%). LCMS (M + H) < + > m / z 238 (t = 0.64 min). 1 H NMR (500 MHz. DMSO-ds) δ 7.32 (1 H, s), 7.22 (1H, s), 6.96 (2H, s), 3.72 (4H. Br s). 2.96 (4H, broad s), 2.21 (3H, s).

2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-6-morfolín-4-yl-1 H-benzoimidazol:2- (4-Iodo-2-methoxy-pyridin-3-yl) -4-methyl-6-morpholin-4-yl-1H-benzoimidazole:

V Paarovej banke sa 2-metyl-4-morfolin-4-yl-6-nitrofenylamin (15,2 g, 64 mmol) uvedie do suspenzie s metanolom (200 ml). Potom sa pridá paládium na uhlíku (1,0 g, 10 % Pd) a suspenzia sa pretrepáva cez noc pri tlaku vodíka 60 psi (413,7 kPa). Potom sa zmes prefiltruje cez vrstvu celitu (v atmosfére argónu) do trojhrdlovej banky a celit sa premyje metanolom tak, aby celkový objem filtrátu a metanolu predstavoval 500 ml a roztok sa ochladí na 0° C. Potom sa pomaly (v priebehu 3 hodín) pridá roztok 4-jód-2-metoxypyridín-3-karbaldehyd (14,6 g, 55,5 mmol). Po pridaní približne štvrtinového množstva vyššie uvedeného roztoku sa systém otvorí a cez víkend sa mieša za dosiahnutia teploty miestnosti. Potom sa reakčná zmes zahustí za zníženého tlaku, prefiltruje sa cez vrstvu oxidu kremičitého (elučný prostriedok: dichlórmetán.etylacetát:metanol, 55:40:5) roztok sa nechá kryštalizovať z etyl-acetátu. Titulná zlúčenina sa izoluje vo forme hnedého tuhého produktu (12,67 g, 51 %). Rýchlou chromatografiou matečného roztoku sa získa ďalší podiel, 2,90 g (12 %) (nástrek pomocou dichlórmetánu, elúcia pomocou dichlórmetánu:etyl-acetátu 6:4 a potom dichlórmetánu:etyl-acetátu:metanolu, 58:40:2). LCMS (Μ+ΗΓ m/z 451 (t = 1,03 min). Ή NMR (500 MHz, CDCI3) δ 7,76 (1H, d, J = 5,3 Hz). 7,42 (1H, d, J = 5,3 Hz), 6.85 (1H, široký s), 6,82 (1H, s). 3,86 (4H, t, J = 4,5 Hz), 3,79 (3H, s), 3,12 (4H, t. J = 4.5 Hz), 2,60 (3H, s), 2,21 (3H, s).In a Paar flask, 2-methyl-4-morpholin-4-yl-6-nitrophenylamine (15.2 g, 64 mmol) was suspended in methanol (200 mL). Palladium on carbon (1.0 g, 10% Pd) was then added and the suspension was shaken overnight at 60 psi of hydrogen. The mixture was then filtered through a pad of celite (under argon) into a three neck flask and the celite was washed with methanol until the total volume of filtrate and methanol was 500 ml and the solution was cooled to 0 ° C. solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (14.6 g, 55.5 mmol). After adding about a quarter of the above solution, the system is opened and stirred over the weekend to reach room temperature. The reaction mixture was then concentrated under reduced pressure, filtered through a pad of silica (eluent: dichloromethane: ethyl acetate: methanol, 55: 40: 5) and the solution was crystallized from ethyl acetate. The title compound was isolated as a brown solid (12.67 g, 51%). Flash chromatography of the mother liquor yielded an additional crop, 2.90 g (12%) (feed using dichloromethane, eluting with dichloromethane: ethyl acetate 6: 4 and then dichloromethane: ethyl acetate: methanol, 58: 40: 2). LCMS (Μ + ΗΓ m / z 451 (t = 1.03 min). Ή NMR (500 MHz, CDCl 3 ) δ 7.76 (1H, d, J = 5.3 Hz). d, J = 5.3 Hz), 6.85 (1H, broad s), 6.82 (1H, s), 3.86 (4H, t, J = 4.5 Hz), 3.79 (3H, s) ), 3.12 (4H, t. J = 4.5 Hz), 2.60 (3H, s), 2.21 (3H, s).

4-chlór-3-(4-metyl-6-morfolín-4-yl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón a 4jód-3-(4-metyl-6-morfolín-4-yl-1 H-benzoimidazol-2-y!)-1 H-pyridín-2-ón:4-chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one and 4-iodo-3- (4-methyl-6-morpholine) 4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

2-(4-jód-2-metoxypyridín-3-yl)-4-metyl-6-morfolín-4-yl-1 H-benzoimidazol (15,58 g, 34,6 mmol) sa suspenduje v 1,4-dioxáne (300 ml) a pridá sa koncentrovaná vodná HCI (50 ml). Zmes sa mieša cez noc pri teplote miestnosti a potom 3 hodiny pri 50 °C. Potom sa zmes ochladí na teplotu miestnosti, vleje sa do ľadovo chladného roztoku NaHCO3 (67 g, 0,8 mol) a prefiltruje sa. Vodná fáza sa extrahuje etylacetátom. Tuhé zložky sa rozpustia v menšom množstve metanolu a potom sa uskutoční extrakcia medzi vodu a CH2CI2. Spojené organické vrstvy sa vysušia Na2SO4 a zahustením vo vákuu sa získa neseparovateľná zmes 4-chlórôvanej a 4jódovanej titulnej zlúčeniny. Produkt sa použije bez ďalšieho čistenia. LCMS (M+H)+ m/z 437 a m/z 345 (obe zlúčeniny majú t = 0,92 min).2- (4-Iodo-2-methoxy-pyridin-3-yl) -4-methyl-6-morpholin-4-yl-1H-benzoimidazole (15.58 g, 34.6 mmol) was suspended in 1,4- dioxane (300 mL) and concentrated aqueous HCl (50 mL) was added. The mixture was stirred at room temperature overnight and then at 50 ° C for 3 hours. The mixture was cooled to room temperature, poured into ice-cold NaHCO 3 (67 g, 0.8 mol) and filtered. The aqueous phase is extracted with ethyl acetate. The solids were dissolved in a smaller amount of methanol and then extracted between water and CH 2 Cl 2. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give an unseparable mixture of 4-chlorinated and 4-iodinated title compound. The product was used without further purification. LCMS (M + H) + m / z 437 and m / z 345 (both compounds have t = 0.92 min).

Spôsob prípravy terc-butylesteru 4-[2-(4-chlór-2-oxo-1,2-dihydropyridín-3-yl)-7-metyl3H-benzoimidazol-5-yl]-piperazín-1-karboxylovej kyseliny a terc-butylesteru 4-(2-(4jód-2-oxo-1,2-dihydropyridin-3-yl)-7-metyl-3H-benzoimídazol-5-yl]piperazín-1karboxylovej kyseliny4- [2- (4-Chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazine-1-carboxylic acid tert-butyl ester and tert- 4- (2- (4-Iodo-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl) piperazine-1-carboxylic acid butyl ester

OABOUT

Terc-butylester 4-(3-amino-5-metyl-4-nitrofenyl)piperazín-1-karboxylovej kyseliny:4- (3-Amino-5-methyl-4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester:

K miešanému roztoku 3-fluór-5-amino-6-nitrotoluénu (10 g, 58,79 mmol) v bezvodom NMP (160 ml) sa v atmosfére dusíka pridá BOC-piperazin (39 g, 209,4 mmol) a 4-metylmorfolín (25,9 ml). Vzniknutý tmavý roztok sa zahrieva 72 h pri teplote spätného toku, potom sa ochladí na teplotu miestnosti a zriedi s etyl-acetátom (4000 ml). Organická vrstva sa premyje vodou (8x1500 ml), soľným roztokom (1x1500 ml), vysuší sa síranom sodným a zahustí sa za zníženého tlaku. Výsledný tmavý olej sa rozpustí vo vriacom absolútnom etanole (800 ml), potom sa objem upraví zahustením na 400 ml a nechá sa cez noc pri teplote miestnosti. Potom sa roztok ešte viac ochladí na teplotu -20 °C na 5 hodín a vzniknutý tuhý produkt sa odfiltruje a vysušením za zníženého tlaku sa získa 16,3 g (83 %) svetložltého tuhého produktu. Ή NMR (500 MHz, CDCI3) δ 6,16 (br s, 1H), 6,04 (br s, 1H), 3,70-3,60 (m, 4H), 3,38-3,25 (m, 4H), 2,53 (s, 3H), 1.48 (s, 9H); LCMS (M+H)* m/z 337.To a stirred solution of 3-fluoro-5-amino-6-nitrotoluene (10 g, 58.79 mmol) in anhydrous NMP (160 mL) under N 2 was added BOC-piperazine (39 g, 209.4 mmol) and 4- methyl morpholine (25.9 mL). The resulting dark solution was heated at reflux for 72 h, then cooled to room temperature and diluted with ethyl acetate (4000 mL). The organic layer was washed with water (8x1500 mL), brine (1 x 1500 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting dark oil was dissolved in boiling absolute ethanol (800 mL), then the volume was adjusted to 400 mL by concentration and left overnight at room temperature. Then the solution was cooled further to -20 ° C for 5 hours and the resulting solid product was filtered off and dried under reduced pressure to give 16.3 g (83%) of a pale yellow solid. Ή NMR (500 MHz, CDCl 3 ) δ 6.16 (br s, 1H), 6.04 (br s, 1H), 3.70-3.60 (m, 4H), 3.38-3.25 (m, 4H), 2.53 (s, 3H), 1.48 (s, 9H); LCMS (M + H) < + > m / z 337.

OABOUT

Terc-butylester 4-(3,4-diamino-5-metylfenyl)piperazín-1 -karboxylovej kyseliny:4- (3,4-Diamino-5-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester:

K miešanému roztoku terc-butylesteru 4-(3-amino-5-metyl-4-nitrofenyl)piperazín-1-karboxylovej kyseliny (15 g, 44,6 mmol) v metanole (2200 ml) sa pridá 20 % Pd(OH)2/C (1.6 g), suspenzia sa dôkladne premyje dusíkom a potom vodíkom. Získaná suspenzia sa mieša cez noc pri teplote miestnosti v atmosfére vodíka (asi 1 atm t.j. 101,325 kPa). Potom sa suspenzia prefiltruje v atmosfére dusíka cez vrstvu Celitu a premyje sa metanolom (400-500 ml). Získaný produkt sa okamžite použije v ďalšom stupni. LCMS (M+H)+ m/z 307.To a stirred solution of 4- (3-amino-5-methyl-4-nitrophenyl) piperazine-1-carboxylic acid tert-butyl ester (15 g, 44.6 mmol) in methanol (2200 mL) was added 20% Pd (OH). 2 / C (1.6 g), the suspension is thoroughly purged with nitrogen and then with hydrogen. The resulting suspension is stirred overnight at room temperature under a hydrogen atmosphere (about 1 atm). Then, the suspension was filtered under a Celite pad under a nitrogen atmosphere and washed with methanol (400-500 mL). The product obtained is used immediately in the next step. LCMS (M + H) < + > m / z 307.

OABOUT

Terc-butylester 4-[2-(4-jód-2-metoxypyridin-3-yl)-7-metyl-3H-benzoimidazol-5yl]piperazín-1-karboxylovej kyseliny:4- [2- (4-Iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazine-1-carboxylic acid tert-butyl ester:

K miešanému roztoku terc-butylesteru 4-(3,4-diamino-5-metylfenyl)piperazín-1karboxylovej kyseliny (44,6 mmol pri predpokladanej 100 % konverzii v predchádzajúcom stupni) v metanole (asi 2700 ml) sa pri 0 “C v atmosfére dusíka pomaly pridá (2 h) dávkovacím lievikom roztok 4-jód-2-metoxypyridín-3-karbaldehydu (15,0 g, 57,1 mmol) v bezvodom metanole (225 ml). Získaný produkt sa potom mieša ďalších 30 min pri 0 °C, potom sa chladiaci kúpeľ odstráni a reakčná zmes sa mieša na vzduchu pri teplote miestnosti 72 h. Výsledný roztok sa zahusti za zníženého tlaku, zvyšok sa rozpustí v dichlórmetáne (1500 ml) a rozpúšťadlo sa odstráni vo vákuu (postup sa 3x opakuje). Získaná tmavá tuhá pena sa vysuší za vysoko zníženého tlaku. 1H NMR (500 MHz, CDCI3) δ 7,82 (d, 1H, J = 5,4 Hz), 7,50 (d, 1H, J = 5,4 Hz). 6,98 (br s, 1H), 6,90 (br s, 1H), 4,05 (s, 3H), 3,67-3,58 (m, 4H), 3,18-3,09 (m, 4H), 2,63 (s, 3H), 1,49 (s, 9H); LCMS (M+H)+ m/z 550.To a stirred solution of 4- (3,4-diamino-5-methylphenyl) piperazine-1-carboxylic acid tert-butyl ester (44.6 mmol assuming 100% conversion in the previous step) in methanol (about 2700 mL) at 0 ° C in A solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (15.0 g, 57.1 mmol) in anhydrous methanol (225 mL) was added slowly (2 h) via a addition funnel under nitrogen atmosphere. The product obtained is then stirred for an additional 30 min at 0 ° C, then the cooling bath is removed and the reaction mixture is stirred in air at room temperature for 72 h. The resulting solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane (1500 mL) and the solvent was removed in vacuo (procedure was repeated 3 times). The dark solid foam obtained is dried under high vacuum. 1 H NMR (500 MHz, CDCl 3 ) δ 7.82 (d, 1H, J = 5.4 Hz), 7.50 (d, 1H, J = 5.4 Hz). 6.98 (br s, 1H), 6.90 (br s, 1H), 4.05 (s, 3H), 3.67-3.58 (m, 4H), 3.18-3.09 ( m, 4H), 2.63 (s, 3H), 1.49 (s, 9H); LCMS (M + H) < + > m / z 550.

4-jód-3-(4-metyl-6-piperazín-1-yl-1H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:4-Iodo-3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

K miešanému roztoku terc-butylesteru 4-[2-(4-jód-2-metoxypyridín-3-yl)-7metyl-3H-benzoimidazol-5-yl]piperazin-1 -karboxylovej kyseliny (24 g, 43,7 mmol) sa pridá 1,4-dioxán (750 ml), vodná HCI 6 mol/l (30 ml) a zmes sa zahrieva cez noc pri 75 °C. Potom sa roztok ochladí na teplotu miestnosti, supernatant sa zleje, a tmavý gumovitý zvyšok sa premyje bezvodým dietyléterom (3x500 ml) a vysušením za zníženého tlaku sa získa vo forme tmavej tuhej hmoty 17,7 g (93 %) titulnej zlúčeniny, ktorá sa použije na prípravu terc-butylesteru 4-[2-(4-chlór-2-oxo-1,2-dihydropyridín-3yl)-7-metyl-3H-benzoimidazol-5-yl]piperazín-1-karboxylovej kyseliny a terc-butylesteruTo a stirred solution of 4- [2- (4-iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperazine-1-carboxylic acid tert-butyl ester (24 g, 43.7 mmol) 1,4-dioxane (750 mL), 6 N aqueous HCl (30 mL) were added and the mixture was heated at 75 ° C overnight. Then the solution was cooled to room temperature, the supernatant was decanted, and the dark gummy residue was washed with anhydrous diethyl ether (3 x 500 mL) and dried under reduced pressure to give 17.7 g (93%) of the title compound as a dark solid. for the preparation of 4- [2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid tert-butyl ester and tert-butyl ester

4-[2-(4-jód-2-oxo-1,2-dihydropyridín-3-yl)-7-metyl-3H-benzoimidazol-5-yl]piperazin-1karboxylovej kyseliny; LCMS (M+Hf m/z 436 (malý pík (4-chlór-pyridín-2-ón) v LC/MS má m/z 344, 346.4- [2- (4-Iodo-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid; LCMS (M + H + m / z 436 (small peak (4-chloro-pyridin-2-one)) in LC / MS has m / z 344, 346.

Terc-butylester 4-[2-(4-chlór-2-oxo-1,2-dihydropyridin-3-yl)-7-metyl-3Hbenzoimidazol-5-yl]piperazín-1-karboxylovej kyseliny a terc-butylester 4-[2-(4-jód-2oxo-1,2-dihydropyridín-3-yl)-7-metyl-3H-benzoimidazol-5-yl]piperazín-1-karboxylovej kyseliny:4- [2- (4-Chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid tert-butyl ester and 4- [2- (4-Iodo-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxylic acid:

K miešanej suspenzii 4-jód-3-(4-metyl-6-piperazín-1-yl-1H-benzoimidazol-2-yl)1H-pyridín-2-ónu (17,7 g. 40,7 mmol) v dichlórmetáne (750 ml) sa pridá di-(tercbutyl)-dikarbonát (9,8 g, 44,8 mmol) a trietylamín (67,4 ml, 483,6 mmol). Zmes sa mieša 30 min pri teplote miestnosti a prečistí sa rýchlou chromatografiou na silikagéli. Elúcia sa uskutoční najprv dichlórmetánom a potom zmesou 2,5 % metanol/etylacetát, homogénne frakcie sa spoja a čiastočným odparením vo vákuu sa po filtrácii získa žltý tuhý produkt (8,9 g, asi 41 %, 2 podiely). 1H NMR (500 MHz, CD3OD) δ 7,25 (d. 1 H, J = 6,9 Hz), 6,97 (d, 1H, J = 6,9 Hz), 6.97 (br s, 1H). 6,89 (br s. 1H), 3,65-3,56 (m, 4H), 3,16-3,07 (m, 4H), 2,55 (s, 3H), 1,49 (s, 9H); LCMS (M+H)+ m/z 536 (malý pík (4-chlórpyridίη-2-όη) v LC/MS zodpovedá m/z 444, 446).To a stirred suspension of 4-iodo-3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (17.7 g, 40.7 mmol) in dichloromethane (750 mL) was added di- (tert-butyl) dicarbonate (9.8 g, 44.8 mmol) and triethylamine (67.4 mL, 483.6 mmol). The mixture was stirred at room temperature for 30 min and purified by flash chromatography on silica gel. Elution was carried out first with dichloromethane and then with 2.5% methanol / ethyl acetate, the homogeneous fractions were combined and partially evaporated in vacuo to give a yellow solid after filtration (8.9 g, about 41%, 2 fractions). 1 H NMR (500 MHz, CD 3 OD) δ 7.25 (d, 1H, J = 6.9 Hz), 6.97 (d, 1H, J = 6.9 Hz), 6.97 (br s, 1H). 6.89 (br s, 1H), 3.65-3.56 (m, 4H), 3.16-3.07 (m, 4H), 2.55 (s, 3H), 1.49 (s 9H); LCMS (M + H) + m / z 536 (small peak (4-chloropyridin-2-one) in LC / MS corresponds to m / z 444, 446).

Spôsob prípravy 3-[6-(4-aminopiperidín-1-yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-jód1 H-pyridín-2-ónu a 3-[6-(4-aminopiperidin-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4chlór-1H-pyridín-2-ónu.Process for preparing 3- [6- (4-aminopiperidin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-iodo-1H-pyridin-2-one and 3- [6- (4- Amino-piperidin-1-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4-chloro-1 H-pyridin-2-one.

HH

Terc-butylester [1-(3-amino-5-metyl-4-nitrofenyl)piperidín-4-yl]karbámovej kyseliny:[1- (3-Amino-5-methyl-4-nitrophenyl) piperidin-4-yl] carbamic acid tert-butyl ester:

5-fluór-3-metyl-2-nitrofenylamin (0,97 g, 5,7 mmol), sa spojí s 4-N-BOCaminopiperidinom (1,60 g, 8,0 mmol), diizopropyletylaminom (2,5 ml, 14 mmol) a s DMSO (10 ml) a spojené zložky sa miešajú 3 hodiny pri 85 =C. Potom sa reakčná zmes vleje do nasýteného vodného roztoku NaHCO3 a extrahuje sa etyl-acetátom. Organické vrstvy sa premyjú vodou (3x) a soľným roztokom, vysušia sa Na2SO4 a zahustia sa. Rýchlou chromatografiou na oxide kremičitom (elúcia zmesou hexány: etyl-acetát:trietylamin, 50:50:1 a následne v pomere 33:66:1) sa vo forme žltého tuhého produktu získa titulná zlúčenina (1,57 g, 79 %). LCMS (M+H)' m/z 351 (t =5-fluoro-3-methyl-2-nitrophenylamine (0.97 g, 5.7 mmol) was combined with 4-N-BOCaminopiperidine (1.60 g, 8.0 mmol), diisopropylethylamine (2.5 mL, 14 mmol) and DMSO (10 ml) and the contents were stirred for 3 hours at 85 = C. the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layers were washed with water (3x) and brine, dried over Na 2 SO 4 and concentrated. Flash chromatography on silica (eluting with hexanes: ethyl acetate: triethylamine, 50: 50: 1 followed by 33: 66: 1) gave the title compound as a yellow solid (1.57 g, 79%). LCMS (M + H) + m / z 351 (t

I, 55 min). 1H NMR (500 MHz, CD3OD) δ 6,70 (1H, široký s), 6.22 (1H. d, J = 2,5 Hz),(55 min). 1 H NMR (500 MHz, CD 3 OD) δ 6.70 (1H, broad s), 6.22 (1H, d, J = 2.5 Hz),

6.13 (1H, d. J = 2,5 Hz), 3,88 (2H, d, J = 13,3 Hz), 3,58 (1H, široký s). 2,98 (2H, t, J =6.13 (1H, d, J = 2.5 Hz), 3.88 (2H, d, J = 13.3 Hz), 3.58 (1H, broad s). 2.98 (2 H, t, J =

II, 8 Hz), 2,48 (3H, s), 1,92 (2H, d, J = 11,3 Hz), 1,48 (2H, m), 1.45 (9H, s).II, 8 Hz), 2.48 (3H, s), 1.92 (2H, d, J = 11.3 Hz), 1.48 (2H, m), 1.45 (9H, s).

HH

Terc-butylester [ 1-[2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5yl]pjperidín-4-yl}karbámovej kyseliny:[1- [2- (4-Iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperidin-4-yl} -carbamic acid tert-butyl ester:

Terc-butylester [1-(3-amino-5-metyl-4-nitrofenyl)piperidín-4-yl]karbámovej kyseliny (1,54 g, 4,4 mmol) sa rozpustí v metanole (100 ml). Potom sa pridá paládium na uhlíku (0,3 g, 10 % Pd) a suspenzia sa intenzívne mieša v atmosfére vodíka pri tlaku v balóne cez noc. Potom sa zmes prefiltruje cez vrstvu celitu (v atmosfére argónu) do trojhrdlovej banky, celit sa premyje metanolom a filtrát sa ochladí na 0 °C. Potom sa pomaly (v priebehu 2 hodín) pridá roztok 4-jód-2-metoxypyridín-3karbaldehydu (1,21 g, 4,6 mmol) v metanole (50 ml). Zmes sa potom mieša cez noc za prístupu vzduchu pri teplote miestnosti a potom sa zahustí za zníženého tlaku. Rýchlou chromatografiou na stĺpci oxidu kremičitého (elúcia zmesou hexány:etylacetátmetanol, 5:4:1) sa získa titulná zlúčenina (0,79 g, 32 %). LCMS (M+H)+ m/z 564 (t = 1,31 min).[1- (3-Amino-5-methyl-4-nitrophenyl) piperidin-4-yl] carbamic acid tert -butyl ester (1.54 g, 4.4 mmol) was dissolved in methanol (100 mL). Palladium on carbon (0.3 g, 10% Pd) was then added and the suspension was vigorously stirred under hydrogen at balloon pressure overnight. The mixture was then filtered through a pad of celite (under argon) into a three neck flask, the celite was washed with methanol, and the filtrate was cooled to 0 ° C. A solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (1.21 g, 4.6 mmol) in methanol (50 mL) was then added slowly (over 2 hours). The mixture was then stirred overnight at room temperature and then concentrated under reduced pressure. Flash chromatography on silica (hexanes: ethyl acetate: methanol, 5: 4: 1) gave the title compound (0.79 g, 32%). LCMS (M + H) < + > m / z 564 (t = 1.31 min).

3-[6-(4-aminopiperidín-1 -y l)-4-mety I-1 H-benzoimidazol-2-yl]-4-jód-1 H-pyridín2-ón a 3-[6-(4-aminopiperidín-1 -yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-chlór-1 Hpyridín-2-ón:3- [6- (4-Amino-piperidin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-iodo-1H-pyridin-2-one and 3- [6- (4-Amino-piperidin) -1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4-chloro-1H-pyridin-2-one:

Terc-butylester [ 1-[2-(4-jód-2-metoxypyridín-3-yl)-7-metyl-3H-benzoimidazol-5yljpiperidίη-4-yl| karbámovej kyseliny (330 mg, 0,59 mol) sa suspenduje v HCI 4 mol/l v dioxáne (20 ml) a pridá sa voda (3 ml) (exotermický priebeh reakcie). Zmes sa mieša cez noc pri teplote miestnosti a zahustením za zníženého tlaku sa získa neseparovateľná zmes 4-chlórovanej a 4-jódovanej titulnej zlúčeniny. Produkt sa použije bez ďalšieho čistenia. LCMS (M+H)+ m/z 450 a m/z 358 (u oboch t = 0,69 min).[1- [2- (4-Iodo-2-methoxy-pyridin-3-yl) -7-methyl-3H-benzoimidazol-5-yl] -piperidin-4-yl | carbamic acid (330 mg, 0.59 mol) was suspended in 4M HCl in dioxane (20 mL) and water (3 mL) was added (exothermic reaction). The mixture was stirred overnight at room temperature and concentrated under reduced pressure to give an unseparable mixture of 4-chloro and 4-iodo-title compound. The product was used without further purification. LCMS (M + H) + m / z 450 and m / z 358 (both t = 0.69 min).

3-metyl-5-(2-morfolín-4-etoxy)-2-nitrofenylamín:3-methyl-5- (2-morpholin-4-ethoxy) -2-nitro-phenylamine:

K roztoku 2-morfolín-4-yletanolu (5 g, v nadbytku) v THF (30 ml) sa pridá NaH (0,21 g, 8,82 mmol) v dávke chladenej v ľadovom kúpeli. Reakčná zmes sa potom mieša 30 minút pri teplote miestnosti. Potom sa pridá 5-fluór-3-metyl-2nitrofenylamín. Reakčná zmes sa potom zohrieva 6 h pri teplote spätného toku, potom sa ochladí na teplotu miestnosti a zahusti sa. Zvyšok sa zriedi vodou a extrahuje sa EtOAc. Spojené organické vrstvy sa premyjú vodou, soľným roztokom a vysušia sa Na2SO4. Po zahustení sa zvyšok prečistí chromatografiou na stĺpci (20 % EtOAc/hexán) s výťažkom titulnej zlúčeniny (0,70 g, 85 %). 1H NMR (400 MHz, CD3OD) δ 6,10 (1H, s), 6,09 (1H, s), 4,38-4,42 (2H, m), 3,92-4,08 (4H, m), 3,72 (1H, d, J = 12 Hz), 3,53-3,56 (2H, m), 3,05-3,10 (2H, m), 2,48 (3H. s). LCMS (M+H)+ m/z 282 (t = 0,73 min).To a solution of 2-morpholin-4-yl-ethanol (5 g, in excess) in THF (30 mL) was added NaH (0.21 g, 8.82 mmol) in a portion cooled in an ice bath. The reaction mixture was then stirred at room temperature for 30 minutes. 5-Fluoro-3-methyl-2-nitrophenylamine is then added. The reaction mixture was then heated at reflux for 6 h, then cooled to room temperature and concentrated. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over Na 2 SO 4 . After concentration, the residue was purified by column chromatography (20% EtOAc / hexane) to yield the title compound (0.70 g, 85%). 1 H NMR (400 MHz, CD 3 OD) δ 6.10 (1H, s), 6.09 (1H, s), 4.38-4.42 (2H, m), 3.92-4.08 (4H, m), 3.72 (1H, d, J = 12Hz), 3.53-3.56 (2H, m), 3.05-3.10 (2H, m), 2.48 ( 3H (s). LCMS (M + H) < + > m / z 282 (t = 0.73 min).

OHC (S)-7-bróm-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1.2dihydropyridín-3-ylj -3H-benzoimidazol-5-karbaldehyd:OHC (S) -7-Bromo-2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzoimidazole-5-carbaldehyde:

K roztoku (S)-7-bróm-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl’-3H-benzoimidazol-5-karbonitrilu (150 mg, 0,31 mmol) v THF (50 ml) sa pridá pri -78 °C DIBAL-H (roztok 1 mol/l v toluéne, 1,55 ml, 1,55 mmol). Reakčná zmes sa mieša 10 h pri -40 °C a potom sa ochladí na -78 °C. Potom sa pridá EtOAc (0.5 ml). Reakčná zmes sa mieša 30 min pri -78 °C a potom sa pridá voda (1 ml). Potom sa reakčná zmes ohreje na teplotu miestnosti a zahustí sa. Zvyšok sa prefiltruje cez nízku vrstvu celitu. Filtrát sa zahustí a prečistením preparatívnej HPLC sa získa titulná zlúčenina (67 mg, 43 %). 1H NMR (400 MHz, CD3OD) δ 9,45 (1H, s), 7,62 (1H, s), 7,56 (1 H, úzky d, J = 1,6 Hz), 7.44 (1H, úzky d, J = 1,0 Hz), 7,32-7.42 (2H, m), 7,24-7.30 (3H, m), 6,24 (1H, d, J = 7.6 Hz), 5,01 (1H, m), 3,65-3,76 (2H. m). LCMS (M+H)+ m/z 487 (t = 1,76 min).To a solution of (S) -7-bromo-2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl'-3H-benzoimidazole-5-carbonitrile ( 150 mg, 0.31 mmol) in THF (50 mL) was added at -78 ° C DIBAL-H (1M solution in toluene, 1.55 mL, 1.55 mmol). The reaction mixture was stirred at -40 ° C for 10 h and then cooled to -78 ° C. EtOAc (0.5 mL) was then added. The reaction mixture was stirred at -78 ° C for 30 min and then water (1 mL) was added. The reaction mixture was then warmed to room temperature and concentrated. The residue was filtered through a low pad of celite. The filtrate was concentrated and purified by preparative HPLC to give the title compound (67 mg, 43%). 1 H NMR (400 MHz, CD 3 OD) δ 9.45 (1H, s), 7.62 (1H, s), 7.56 (1H, narrow d, J = 1.6 Hz), 7.44 (1H, s, narrow d, J = 1.0 Hz), 7.32-7.42 (2H, m), 7.24-7.30 (3H, m), 6.24 (1H, d, J = 7.6 Hz), 5.01 (1H, m), 3.65-3.76 (2H, m). LCMS (M + H) < + > m / z 487 (t = 1.76 min).

5-(1,4,5,6-tetrahydropyrimid ín-1 -yl)-3-metyl-2-nitroanilín:5- (1,4,5,6-tetrahydropyrimidin-1-yl) -3-methyl-2-nitroaniline:

K miešanému roztoku 2,0 g (11,76 mmol) 5-fluór-3-metyl-2-nitroanilínu v 10 ml DMSO sa pridá 1,2 g (14,11 mmol) 1,4,5,6-tetrahydropyrimidínu a 2,43 g (17,64 mmol) uhličitanu draselného a zmes sa zahrieva 10 h pri 100 °C, potom sa ochladí, zriedi sa vodou a extrahuje sa etyl-acetátom obsahujúcim 5 % metanolu. Spojené organické extrakty sa premyjú vodou, soľným roztokom a vysušia sa (Na2SO4). Odparením rozpúšťadla sa získa zvyšok, ktorého spracovaním chromatografiou (20 % amoniaku 2 mol/l v metanole a dichlórmetáne) sa získa 1,85 g (67 %) produktu vo forme červenej tuhej hmoty. 1H NMR (400 MHz, CD3OD) δ 7,89 (1H, s), 6,53 (1H, d, J = 2,57 Hz), 6,44 (1H, d, J = 2,1 Hz), 7,04 (1H, d, J = 2,1 Hz), 3,70 (2H, t, J = 6,0 Hz),To a stirred solution of 2.0 g (11.76 mmol) of 5-fluoro-3-methyl-2-nitroaniline in 10 mL of DMSO was added 1.2 g (14.11 mmol) of 1,4,5,6-tetrahydropyrimidine and 2.43 g (17.64 mmol) of potassium carbonate and the mixture was heated at 100 ° C for 10 h, then cooled, diluted with water and extracted with ethyl acetate containing 5% methanol. The combined organic extracts were washed with water, brine and dried (Na 2 SO 4 ). Evaporation of the solvent gave a residue which was chromatographed (20% 2M ammonia in methanol and dichloromethane) to give 1.85 g (67%) of the product as a red solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.89 (1H, s), 6.53 (1H, d, J = 2.57 Hz), 6.44 (1H, d, J = 2.1) Hz), 7.04 (1H, d, J = 2.1Hz), 3.70 (2H, t, J = 6.0Hz),

3,41 (2H, t, J = 5,65 Hz), 2,43 (3H, s), 2,05 (2H, m). LCMS (M+H)+ m/z 235 (t = 0,78 min).3.41 (2H, t, J = 5.65 Hz), 2.43 (3H, s), 2.05 (2H, m). LCMS (M + H) < + > m / z 235 (t = 0.78 min).

Príklad 1 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 1-21)Example 1 (General Preparation of Compounds of Examples 1-21)

(S)-4-(2-hydroxy-1-fenyletylamino)-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridin-2-ón:(S) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

K roztoku 3-(6-imidazol-1 -yl-4-metyl-1 H-benzoimidazol-2-yl)-4-jód-1 H-pyridín2-ónu (30 mg, 0,072 mmol) v DMF (1 ml) sa pridá (S)-(-)-2-fenylglycinol (26 mg, 0,18 mmol) a N-metylmorfolín (0,1 ml). Reakčná zmes sa zahrieva 6 h pri 80 °C a potom sa ochladí na teplotu miestnosti. Potom sa rozpúšťadlo odstráni za zníženého tlaku a prečistením zvyšku preparatívnou HPLC sa získa titulná zlúčenina (16 mg. 52 %). 1H NMR (300 MHz, CD3OD) δ 8,07 (1H, úzky t, J = 1,7 Hz), 7,76 (2H, s), 7,27-7,48 (7H. m), 7,21 (1H, d, J = 7,5 Hz), 6,11 (1H, d, J = 7,5 Hz), 4,92 (1H, m), 4,03 (1H, dd, J = 4,5, 11,2 Hz), 3;95 (1H. dd, J = 6,2, 11,2 Hz), 2,75 (3H, s). LCMS (M+H)+ m/z 427 (t = 1,44 min).To a solution of 3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4-iodo-1H-pyridin-2-one (30 mg, 0.072 mmol) in DMF (1 mL) (S) - (-) - 2-phenylglycinol (26 mg, 0.18 mmol) and N-methylmorpholine (0.1 mL) were added. The reaction mixture was heated at 80 ° C for 6 h and then cooled to room temperature. Then, the solvent was removed under reduced pressure and purification of the residue by preparative HPLC gave the title compound (16 mg, 52%). 1 H NMR (300 MHz, CD 3 OD) δ 8.07 (1H, narrow t, J = 1.7 Hz), 7.76 (2H, s), 7.27-7.48 (7H, m) 7.21 (1H, d, J = 7.5Hz), 6.11 (1H, d, J = 7.5Hz), 4.92 (1H, m), 4.03 (1H, dd, J = 4.5, 11.2 Hz), 3.95 (1H, dd, J = 6.2, 11.2 Hz), 2.75 (3H, s). LCMS (M + H) < + > m / z 427 (t = 1.44 min).

Príklad 2Example 2

(±)-4-[2-hydroxy-2-(3-jódfenyl)etylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2-hydroxy-2- (3-iodophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one :

1H NMR (300 MHz, CD3OD) δ 9,41 (1H, s), 8,06 (1H, s), 7,88 (1H, s), 7,76 (1H, s), 7,71 (1H, s), 7,59 (1H, d, J = 7,8 Hz), 7,47 (1H, d, J = 7,8 Hz), 7,32 (1H, s), 7,29 (1H, d. J = 7,6 Hz), 7,09 (1H, t. J = 7.8 Hz), 6,24 (1H, d, J = 7,6 Hz), 4,97 (1H, dd, J = 5,0, 6,0 Hz), 3,75 (1H, dd, J = 5,0, 13,5 Hz), 3,67 (1H, dd, J = 6,0, 13,5 Hz), 2,68 (3H, s). LCMS (M+H)+ m/z 553 (t = 1,43 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.88 (1H, s), 7.76 (1H, s), 7, 71 (1H, s), 7.59 (1H, d, J = 7.8Hz), 7.47 (1H, d, J = 7.8Hz), 7.32 (1H, s), 29 (1H, d, J = 7.6Hz), 7.09 (1H, t, J = 7.8Hz), 6.24 (1H, d, J = 7.6Hz), 4.97 (1H, dd, J = 5.0, 6.0 Hz), 3.75 (1H, dd, J = 5.0, 13.5 Hz), 3.67 (1H, dd, J = 6.0, 13, 5 Hz), 2.68 (3H, s). LCMS (M + H) < + > m / z 553 (t = 1.43 min).

Príklad 3Example 3

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 9,39 (1H, úzky t, J = 1,4 Hz), 8,04 (1H, úzky t, J = 1,7 Hz), 7,76 (1H, úzky t, J = 1,7 Hz), 7,69 (1H, úzky d, J = 1,9 Hz), 7,55 (1H, s), 7,23-7,42 (5H, m), 6,25 (1H, d. J = 7,6 Hz), 5,01 (1H, dd, J = 4,8, 6,4 Hz), 3,76 (1H, dd, J = 4,8, 13,4 Hz), 3,66 (1H. dd, J = 6,4, 13,4 Hz), 2,67 (3H, s). LCMS (M+Hf m/z 461 (t = 1,46 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.39 (1H, narrow t, J = 1.4 Hz), 8.04 (1H, narrow t, J = 1.7 Hz), 7.76 ( 1H, narrow t, J = 1.7 Hz), 7.69 (1H, narrow d, J = 1.9 Hz), 7.55 (1H, s), 7.23-7.42 (5H, m 6.25 (1H, d, J = 7.6 Hz), 5.01 (1H, dd, J = 4.8, 6.4 Hz), 3.76 (1H, dd, J = 4, Δ, 13.4 Hz), 3.66 (1H, dd, J = 6.4, 13.4 Hz), 2.67 (3H, s). LCMS (M + H + m / z 461 (t = 1.46 min).

Príklad 4Example 4

(±)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón:(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one:

1H NMR (300 MHz, CD3OD) δ 9,38 (1H, s), 8,02 (1H, s), 7.74 (1H, s), 7,69 (1H, s). 7,66 (1H, úzky d, J = 1,4 Hz), 7,20-7,48 (5H, m), 6,21 (1H, d, J = 7,6 Hz), 4,99 (1H, dd, J = 6,3 Hz), 3,73 (1H, dd, J = 4,8, 13.5 Hz), 3,64 (1H, dd, J = 6,3, 13,5 Hz), 2,65 (3H, s). LCMS (M+H)+ m/z 505 (t = 1,47 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.38 (1H, s), 8.02 (1H, s), 7.74 (1H, s), 7.69 (1H, s). 7.66 (1H, narrow d, J = 1.4 Hz), 7.20-7.48 (5H, m), 6.21 (1H, d, J = 7.6 Hz), 4.99 ( 1H, dd, J = 6.3 Hz), 3.73 (1H, dd, J = 4.8, 13.5 Hz), 3.64 (1H, dd, J = 6.3, 13.5 Hz), 2.65 (3 H, s). LCMS (M + H) < + > m / z 505 (t = 1.47 min).

Príklad 5Example 5

(±)-N-(2-chlór-4-{1-hydroxy-2-[3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyridin-4-ylamino]etyl}fenyl)iTietánsulfónamid:(±) -N- (2-chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1 H-benzoimidazol-2-yl) -2-oxo-1,2 dihydropyridin-4-ylamino] ethyl} phenyl) iTietánsulfónamid:

1H NMR (300 MHz, CD3OD) δ 9,39 (1H, s), 8,05 (1 H, s), 7,76 (1H, s), 7.86 (1H. s), 7,62 (1H, úzky d, J = 1,5 Hz), 7,52 (1H, s). 7,42-7,49 (2H, m), 7,31 (1H, s), 7,30 (1H. d, J = 7,6 Hz), 6,26 (1H, d, J = 7,6 Hz), 5,01 (1H, dd, J = 5,0, 5,6 Hz), 3,76 (1H. d, J = 5,0, 13,4 Hz), 3,74 (1H, dd, J = 5,6, 13,4 Hz), 2,98 (3H, s), 2,68 (3H, s). LCMS (M-Hf m/z 554 (t = 1,11 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.39 (1H, s), 8.05 (1H, s), 7.76 (1H, s), 7.86 (1H, s), 7.62 (1H, narrow d, J = 1.5Hz), 7.52 (1H, s). 7.42-7.49 (2H, m), 7.31 (1H, s), 7.30 (1H, d, J = 7.6 Hz), 6.26 (1H, d, J = 7, 6 Hz), 5.01 (1H, dd, J = 5.0, 5.6 Hz), 3.76 (1H, d, J = 5.0, 13.4 Hz), 3.74 (1H, dd, J = 5.6, 13.4 Hz), 2.98 (3H, s), 2.68 (3H, s). LCMS (M-H + m / z 554 (t = 1.11 min).

Príklad 6Example 6

3-brómbenzo-N'-[3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-2-oxo-1,2dihydropyridin-4-yl)hydrazid:3-bromo-benzo-N '- [3- (6-imidazol-1-yl-4-methyl-1 H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine-4-yl) hydrazide:

NMR (300 MHz, CD3OD) δ 9,40 (1H, úzky t, J = 1,4 Hz), 8,14 (1H, úzky t, J = 1,7 Hz), 8,05 (1H, úzky t, J = 1,7 Hz), 7,95 (1H, d, J = 7,9 Hz), 7,81 (1H, d, J = 7,9 Hz), 7,74-7,77 (2H, m), 7,49 (1H, t, J = 7,9 Hz), 7,41 (1H, d, J = 7,4 Hz), 7,34 (1H, s),NMR (300 MHz, CD 3 OD) δ 9.40 (1H, narrow t, J = 1.4 Hz), 8.14 (1H, narrow t, J = 1.7 Hz), 8.05 (1H, narrow t, J = 1.7 Hz), 7.95 (1H, d, J = 7.9 Hz), 7.81 (1H, d, J = 7.9 Hz), 7.74-7.77 (2H, m), 7.49 (1H, t, J = 7.9Hz), 7.41 (1H, d, J = 7.4Hz), 7.34 (1H, s),

6.38 (1H, d, J = 7,4 Hz), 2,70 (3H, s). LCMS (M+H)+ m/z 504 (t = 1,44 min).6.38 (1H, d, J = 7.4Hz), 2.70 (3H, s). LCMS (M + H) < + > m / z 504 (t = 1.44 min).

Príklad 7Example 7

4-aminobenzo-N'-[3-(6-imidazol-1-yl-4-metyl-1 H-benzoimidazol-2-yl)-2-oxo-4-Aminobenzo-N '- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-

1,2-dihydropyridín-4-yl)hyd razid:1,2-dihydropyridin-4-yl) hydrazide:

1H NMR (300 MHz. CD3OD) δ 9,41 (1H, s), 8,06 (1H, s), 7,76-7,79 (4H, m), 1 H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.76-7.79 (4H, m),

7.39 (1H. d, J = 7,4 Hz), 7.36 (1H, s), 6,81 (2H, d, J = 8,6 Hz), 6,36 (1H, d. J = 7,4 Hz), 2,70 (3H. s). LCMS (M+Hf m/z 441 (t = 0,96 min).7.39 (1H, d, J = 7.4Hz), 7.36 (1H, s), 6.81 (2H, d, J = 8.6Hz), 6.36 (1H, d, J = 7.4Hz) Hz), 2.70 (3H, s). LCMS (M + H + m / z 441 (t = 0.96 min).

Príklad 8Example 8

(S)-4-[2-(2-chlórfenyl)-1-hydroxymetyletylamino-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- [2- (2-Chloro-phenyl) -1-hydroxy-methylethylamino-3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 9,41 (1H, s), 8,05 (1H, úzky t, J = 1,7 Hz), 7,76 (1H, úzky t, J = 1,7 Hz), 7,72 (1H, úzky d, J = 1,9 Hz), 7,08-7,36 (6H, m), 6,10 (1H, d, J = 7,7 Hz), 3,98-4,24 (1H, m), 3,84 (1H, dd, J = 4,4, 11,2 Hz), 3,79 (1H, dd, J = 4,8, 11,2 Hz), 3,35 (1H, dd, J = 5,4, 13,6 Hz), 3,09 (1H, dd, J = 7,8, 13,6 Hz), 2,72 (3H, s). LCMS (M+H)+ m/z 475 (t = 1,56 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.05 (1H, narrow t, J = 1.7 Hz), 7.76 (1H, narrow t, J = 1) 7 Hz), 7.72 (1H, narrow d, J = 1.9 Hz), 7.08-7.36 (6H, m), 6.10 (1H, d, J = 7.7 Hz) 3.98-4.24 (1H, m), 3.84 (1H, dd, J = 4.4, 11.2 Hz), 3.79 (1H, dd, J = 4.8, 11, 2 Hz), 3.35 (1H, dd, J = 5.4, 13.6 Hz), 3.09 (1H, dd, J = 7.8, 13.6 Hz), 2.72 (3H, with). LCMS (M + H) < + > m / z 475 (t = 1.56 min).

Príklad 9Example 9

(S)-4-[2-(3-chlórfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- [2- (3-Chloro-phenyl) -1-hydroxy-methylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one :

1H NMR (300 MHz, CD3OD) δ 9,42 (1H, s), 8,07 (1H, úzky t, J = 1,7 Hz), 7,75- 1 H NMR (300 MHz, CD 3 OD) δ 9.42 (1H, s), 8.07 (1H, narrow t, J = 1.7 Hz), 7.75-

7,78 (2H, m), 7,14-7,37 (6H. m), 6,18 (1H, d, J = 7,7 Hz), 4,07-4,11 (1H, m), 3,763,77 (2H, m), 3,17 (1H, dd, J = 5,1, 13,7 Hz), 2,98 (1H, dd, J = 8,2, 13,7 Hz), 2,71 (3H, s). LCMS (M+H)T m/z 475 (t = 1,57 min).7.78 (2H, m), 7.14-7.37 (6H, m), 6.18 (1H, d, J = 7.7Hz), 4.07-4.11 (1H, m) 3.763.77 (2H, m), 3.17 (1H, dd, J = 5.1, 13.7 Hz), 2.98 (1H, dd, J = 8.2, 13.7 Hz), 2.71 (3 H, s). LCMS (M + H) + m / z 475 (t = 1.57 min).

Príklad 10Example 10

(S)-4-[2-(4-chlórfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- [2- (4-chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 9,42 (1H, s), 8,07 (1H, úzky t, J = Í.6 Hz), 7,77 (1H, úzky t, J = 1,6 Hz), 7,73 (1H, úzky d, J = 1,9 Hz), 7,16-7,37 (6H, m), 6,19 (1H, d, J = 7,7 Hz), 4,06-4,10 (1H, m), 3,72-3,77 (2H, m), 3,14 (1H. dd, J = 5,3, 13,8 Hz), 2,98 (1H, dd, J = 7.8, 13,8 Hz), 2,69 (3H, s). LCMS (M+H)+ m/z 475 (t = 1,61 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.42 (1H, s), 8.07 (1H, narrow t, J = 1.6 Hz), 7.77 (1H, narrow t, J = 1) 6 Hz), 7.73 (1H, narrow d, J = 1.9 Hz), 7.16-7.37 (6H, m), 6.19 (1H, d, J = 7.7 Hz) 4.06-4.10 (1H, m), 3.72-3.77 (2H, m), 3.14 (1H, dd, J = 5.3, 13.8 Hz), 2.98 (1H, dd, J = 7.8, 13.8 Hz), 2.69 (3H, s). LCMS (M + H) < + > m / z 475 (t = 1.61 min).

Príklad 11Example 11

(S)-4-[2-(2-brómfenyl)-1 -hydroxymetyletylamino]-3-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- [2- (2-Bromophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one :

1H NMR (300 MHz, CD3OD) δ 9,41 (1H, s), 8,06 (1H, s), 7,75-7,77 (2H. m), 1 H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.75-7.77 (2H, m),

7,52 (1H, dd, J = 1,5, 7,5 Hz), 7,36 (1H, d, J = 1,9 Hz), 7,34 (1H, s), 7,03-7,16 (3H, m), 6,09 (1H, d, J = 7,7 Hz), 4,15-4,27 (1H, m), 3,82 (2H, m). 3,35 (1 H, dd, J = 5,0,7.52 (1H, dd, J = 1.5, 7.5 Hz), 7.36 (1H, d, J = 1.9 Hz), 7.34 (1H, s), 7.03-7 16 (3H, m), 6.09 (1H, d, J = 7.7Hz), 4.15-4.27 (1H, m), 3.82 (2H, m). 3.35 (1H, dd, J = 5.0,

13,6 Hz), 3,10 (1H, dd, J = 9,0, 13,6 Hz), 2,74 (3H, s). LCMS (M+H)+ m/z 519 (t =13.6 Hz), 3.10 (1H, dd, J = 9.0, 13.6 Hz), 2.74 (3H, s). LCMS (M + H) < + > m / z 519 (t =

1,56 min).1.56 min).

Príklad 12Example 12

(S)-4-[2-(3-brómfenyl)-1 -hydroxymetyletylamino]-3-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- [2- (3-Bromophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2- one:

1H NMR (300 MHz, CD3OD) δ 9,41 (1H, s), 8,06 (1H, s), 7,74-7,77 (2H, m), 1 H NMR (300 MHz, CD 3 OD) δ 9.41 (1H, s), 8.06 (1H, s), 7.74-7.77 (2H, m),

7,47 (1H, s), 7,24-7,31 (4H, m), 7,11 (1H, d, J = 7,7 Hz), 6,16 (1H, d, J = 7,7 Hz). 4,05-4,11 (1H, m), 3,76 (2H, m), 3,15 (1H, dd, J = 5,0, 13,6 Hz), 2,96 (1H, dd, J = 8,3,7.47 (1H, s), 7.24-7.31 (4H, m), 7.11 (1H, d, J = 7.7Hz), 6.16 (1H, d, J = 7, 7 Hz). 4.05-4.11 (1H, m), 3.76 (2H, m), 3.15 (1H, dd, J = 5.0, 13.6 Hz), 2.96 (1H, dd, J = 8.3,

13,6 Hz), 2,70 (3H, s). LCMS (M+H)+ m/z 519 (t = 1,54 min).13.6 Hz), 2.70 (3H, s). LCMS (M + H) < + > m / z 519 (t = 1.54 min).

Príklad 13Example 13

(+)-4-[1-hydroxymetyl-2-pentafluórfenylamino]-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 H-py rid ίη-2-όη:(+) - 4- [1-Hydroxymethyl-2-pentafluorophenylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 9,40 (1H, s), 8,06 (1H, úzky t, J = 1,8 Hz), 7,77 (1H, úzky t, J = 1,7 Hz), 7,74 (1H, úzky d, J = 1,8 Hz), 7,35 (1H, s), 7,29 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 9.40 (1H, s), 8.06 (1H, narrow t, J = 1.8 Hz), 7.77 (1H, narrow t, J = 1.7) Hz), 7.74 (1H, narrow d, J = 1.8 Hz), 7.35 (1H, s), 7.29 (1H, d, J =

7,6 Hz), 6,22 (1H, d, J = 7,6 Hz), 4,24 (1H, m), 3,82 (2H, dd, J = 2,6, 4,5 Hz), 3,23 (2H, t, J = 6,5 Hz), 2,70 (3H, s). LCMS (M+H)+ m/z 531 (t = 1,61 min).7.6 Hz), 6.22 (1H, d, J = 7.6 Hz), 4.24 (1H, m), 3.82 (2H, dd, J = 2.6, 4.5 Hz) 3.23 (2H, t, J = 6.5Hz), 2.70 (3H, s). LCMS (M + H) < + > m / z 531 (t = 1.61 min).

Príklad 14Example 14

(S)-4-( 1 -hydroxymetyl-2-pyridín-4-etylamino)-3-(6-imidazol-1 -yl-4-metyl-1 Ηbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- (1-Hydroxymethyl-2-pyridin-4-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one :

1H NMR (300 MHz, CD3OD) δ 9,42 (1H, s), 8,67 (2H, d, J = 6,6 Hz), 8,07 (2H, d, J = 6,6 Hz), 8,06 (1H, s), 7,77 (2H, s), 7.36 (1H, s), 7,28 (1H, d, J = 7,6 Hz), 6,24 (1H, d, J = 7,6 Hz), 4,35 (1H, m), 3,82 (2H, d, J = 4,4 Hz), 3,50 (1H, dd, J = 4,4, 13,6 Hz), 3,40 (1H, dd, J = 8,7, 13,6 Hz), 2,71 (3H, s). LCMS (M+H)* m/z 442 (t = 0,96 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.42 (1H, s), 8.67 (2H, d, J = 6.6 Hz), 8.07 (2H, d, J = 6.6) Hz), 8.06 (1H, s), 7.77 (2H, s), 7.36 (1H, s), 7.28 (1H, d, J = 7.6 Hz), 6.24 (1H, s, d, J = 7.6 Hz), 4.35 (1H, m), 3.82 (2H, d, J = 4.4 Hz), 3.50 (1H, dd, J = 4.4, 13) 6 Hz), 3.40 (1H, dd, J = 8.7, 13.6 Hz), 2.71 (3H, s). LCMS (M + H) + m / z 442 (t = 0.96 min).

Príklad 15Example 15

(S)-4-(1-hydroxymetyl-2-naftalén-2-yletylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- (1-Hydroxymethyl-2-naphthalen-2-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,99 (1H, úzky t, J = 1,7 Hz), 7,26-7,75 (11H, m), 7,15 (1H, d, J = 7,6 Hz), 6,19 (1H, d, J = 7,6 Hz), 4,16-4,20 (1H, m), 3,75-3,86 (2H, m), 3,30 (1H, dd, J = 5,4, 13,6 Hz), 3,15 (1H, dd, J = 7,6, 13,6 Hz), 2,60 (3H, s). LCMS (M+H)* m/z 491 (t = 1,71 min). 1 H NMR (300 MHz, CD 3 OD) δ 7.99 (1H, narrow t, J = 1.7 Hz), 7.26-7.75 (11H, m), 7.15 (1H, d, J = 7.6 Hz), 6.19 (1H, d, J = 7.6 Hz), 4.16-4.20 (1H, m), 3.75-3.86 (2H, m), 3.30 (1H, dd, J = 5.4, 13.6 Hz), 3.15 (1H, dd, J = 7.6, 13.6 Hz), 2.60 (3H, s). LCMS (M + H) + m / z 491 (t = 1.71 min).

Príklad 16Example 16

(S)-4-(2-cyklohexyl-1-hydroxymetyletylamino)-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- (2-Cyclohexyl-1-hydroxymethylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 9,40 (1H, s), 8,06 (1 H, úzky t, J = 1,7 Hz), 7,76 (1H, úzky t, s= 1,7 Hz), 7,73 (1H, úzky d, J = 1,7 Hz), 7,34 (1H, d, J = 7,6 Hz), 7,33 (1 H, s), 6,34 (1H, d, J = 7,6 Hz), 3,89-3,94 (1H, m), 3,68 (2H, d, J = 4,9 Hz), 2,68 (3H, s), 1,62-1,83 (7H, m), 0,95-1,26 (6H, m). LCMS (M+H)+ m/z 447 (t = 1,71 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.40 (1H, s), 8.06 (1H, narrow t, J = 1.7 Hz), 7.76 (1H, narrow t, s = 1.7 Hz), 7.73 (1H, narrow d, J = 1.7 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.33 (1H, s), 6 34 (1H, d, J = 7.6Hz), 3.89-3.94 (1H, m), 3.68 (2H, d, J = 4.9Hz), 2.68 (3H, s), 1.62-1.83 (7H, m), 0.95-1.26 (6H, m). LCMS (M + H) < + > m / z 447 (t = 1.71 min).

Príklad 17Example 17

(3S,4R)-4-(3-hydroxy-2,2-dimetylchromán-4-ylamino)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2-yl)-1 H-pyridin-2-ón:(3S, 4R) -4- (3-Hydroxy-2,2-dimethylchroman-4-ylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one;

Ή NMR (300 MHz, CD3OD) δ 9,36 (1H, s), 8,02 (1H, úzky t, J = 1,7 Hz), 7,73 (1H, úzky t, J = 1,7 Hz), 7,69 (1H, úzky d, J = 2,0 Hz), 7,37 (1H, d, J = 7,6 Hz), 7,18-Ή NMR (300 MHz, CD 3 OD) δ 9.36 (1H, s), 8.02 (1H, narrow t, J = 1.7 Hz), 7.73 (1H, narrow t, J = 1, 7 Hz), 7.69 (1H, narrow d, J = 2.0 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.18-

7,30 (3H, m), 6,89 (1H, t, J = 7,6 Hz), 6,85 (1H, d, J = 8,4 Hz), 6,61 (1H, d, J = 7,6 Hz), 4,93 (1H, d, J = 8,2 Hz), 3,80 (1H, d, J = 8,2 Hz), 2,46 (3H, s), 1,48 (3H, s), 1,35 (3H, s). LCMS (M+H)+ m/z 483 (t = 1,70 min).7.30 (3H, m), 6.89 (1H, t, J = 7.6Hz), 6.85 (1H, d, J = 8.4Hz), 6.61 (1H, d, J = 7.6 Hz), 4.93 (1H, d, J = 8.2 Hz), 3.80 (1H, d, J = 8.2 Hz), 2.46 (3H, s), 1, 48 (3H, s); 1.35 (3H, s). LCMS (M + H) < + > m / z 483 (t = 1.70 min).

Príklad 18Example 18

3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-4-(2-tiofén-2-yletylamino)-3- (6-imidazol-1-yl-4-methyl-1 H-benzoimidazol-2-yl) -4- (2-thiophen-2-yl-ethylamino) -

H-pyridín-2-ón:H-pyridin-2-one;

1H NMR (500 MHz, DMSO-dg) δ 13,17 (1H, široký s), 11,32 (1H, široký s), 11,03 (1H, široký s), 9,59 (1H, široký s), 8,22 (1H, široký s), 7,91 (1H. s), 7,82 (1H, d, J = 2,0 Hz), 7,41 (1H, t, J = 6,9 Hz), 7,36 (1H. dd, J = 1,0, 5,1 Hz), 7,30-7,40 (1H, m), 7,05 (1H, široký s), 7,01 (1H, t, J = 4,2 Hz), 6,23 (1H, d, J = 7,5 Hz), 3,74 (2H, t, J = 1 H NMR (500 MHz, DMSO-d 6) δ 13.17 (1H, broad s), 11.32 (1H, broad s), 11.03 (1H, broad s), 9.59 (1H, broad s) 8.22 (1H, broad s), 7.91 (1H, s), 7.82 (1H, d, J = 2.0 Hz), 7.41 (1H, t, J = 6.9) Hz), 7.36 (1H, dd, J = 1.0, 5.1 Hz), 7.30-7.40 (1H, m), 7.05 (1H, broad s), 7.01 (1H) 1H, t, J = 4.2Hz, 6.23 (1H, d, J = 7.5Hz), 3.74 (2H, t, J =

6,5 Hz), 3,25 (2H, t, J = 6,5 Hz), 2,58 (3H, s).6.5 Hz), 3.25 (2H, t, J = 6.5 Hz), 2.58 (3H, s).

Príklad 19Example 19

3-(6-imidazol-1-yl-4-metyl-1 H-benzoimidazol-2-yl)-4-[2-(1 H-indol-3-yl)etylamino]-1 H-pyridín-2-ón:3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- [2- (1H-indol-3-yl) ethylamino] -1H-pyridin-2- one:

1H NMR (500 MHz, DMS0-d6) δ 13,17 (1H, široký s), 11,27 (1H, široký s), 11,00 (1H, široký s), 10,89 (1H, s), 9,58 (1H, široký s), 8,30 (1H, široký s), 7,91 (1H, s), 7,80 (1H, s), 7,63 (1H, d, J = 7,9 Hz), 7,40 (1H, t, J = 6,9 Hz), 7,34 (1H, d, J = 8,0 Hz), 7,30-7,40 (2H, m), 7,07 (1H, t, J = 7,5 Hz), 6,99 (1H, t, J = 7,6 Hz), 6,23 (1H, dd, J = 0,8, 7,2 Hz), 3,76 (2H, široký s), 3,17 (2H, t, J = 6,7 Hz), 2,50 (3H, s). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.17 (1H, broad s), 11.27 (1H, broad s), 11.00 (1H, broad s), 10.89 (1H, s 9.58 (1H, broad s), 8.30 (1H, broad s), 7.91 (1H, s), 7.80 (1H, s), 7.63 (1H, d, J = 7.9 Hz), 7.40 (1H, t, J = 6.9 Hz), 7.34 (1H, d, J = 8.0 Hz), 7.30-7.40 (2H, m) 7.07 (1H, t, J = 7.5Hz), 6.99 (1H, t, J = 7.6Hz), 6.23 (1H, dd, J = 0.8, 7.2 Hz), 3.76 (2H, broad s), 3.17 (2H, t, J = 6.7 Hz), 2.50 (3H, s).

Príklad 20Example 20

3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-4-(pyridín-2-ylmetoxy)-1H pyridín-2-όπ:3- (6-Imidazol-1-yl-4-methyl-1 H -benzoimidazol-2-yl) -4- (pyridin-2-ylmethoxy) -1 H -pyridin-2-one:

K roztoku 3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-4-jód-1H-pyridín2-ónu (25 mg, 0,06 mmol) v DMF sa pridá pyridínmetanol (26 mg, 0,24 mmol) a fluorid cézny (36 mg, 0,24 mmol). Reakčná zmes sa potom zahrieva 14 h pri 130 °C a potom sa ochladí na teplotu miestnosti. Po zahustení za zníženého tlaku sa prečistením zvyšku preparatívnou HPLC získa titulná zlúčenina (8,2 mg, 34 %). 1H NMR (300 MHz, CD3OD) δ 9,58 (1H, úzky d, J = 1,2 Hz), 8,92 (1H, d, J = 4,9 Hz),To a solution of 3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4-iodo-1H-pyridin-2-one (25 mg, 0.06 mmol) in DMF was added pyridine methanol ( 26 mg, 0.24 mmol) and cesium fluoride (36 mg, 0.24 mmol). The reaction mixture was then heated at 130 ° C for 14 h and then cooled to room temperature. After concentration under reduced pressure, purification of the residue by preparative HPLC gave the title compound (8.2 mg, 34%). 1 H NMR (300 MHz, CD 3 OD) δ 9.58 (1H, narrow d, J = 1.2 Hz), 8.92 (1H, d, J = 4.9 Hz),

8,19 (1H, úzky t, J = 1,2 Hz), 8,12 (1H, s), 7,97-8,02 (2H, m), 7,85 (1H, úzky t, J = 1,8 Hz), 7,81 (1H, úzky t, J = 1,0 Hz), 7.63 (1H, d, J = 7,9 Hz), 7.54 (1H, t, J = 6,2 Hz),8.19 (1H, narrow t, J = 1.2 Hz), 8.12 (1H, s), 7.97-8.02 (2H, m), 7.85 (1H, narrow t, J = 1.8 Hz), 7.81 (1H, narrow t, J = 1.0 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.54 (1H, t, J = 6.2 Hz) .

6,81 (1H, J = 7,5 Hz), 5,86 (2H, s), 2,86 (3H, s). LCMS (M+H)+ m/z 399 (t = 1,07 min).6.81 (1H, J = 7.5Hz), 5.86 (2H, s), 2.86 (3H, s). LCMS (M + H) < + > m / z 399 (t = 1.07 min).

Príklad 21Example 21

(+)-4-[2-(3-brómfenyl)-2-fluóretylamino]-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 H-pyridin-2-ón:(+) - 4- [2- (3-Bromophenyl) -2-fluoroethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one:

1H NMR (300 MHz, CD3OD) δ 9,40 (1H, t, J = 1,4 Hz), 8,06 (1H, t, J = 1,9 Hz), 7,76 (1H, t, J = 1,7 Hz), 7,72 (1H, d, J = 1,9 Hz), 7,66 (1H, s), 7,27-7,50 (5H, m), 6,29 (1H, d, J = 7,6 Hz), 5,75-5,94 (1H, m), 3,86-4,06 (2H, m), 2,64 (3H, s). LCMS (M+H)+ m/z 507 (t = 1,70 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.40 (1H, t, J = 1.4Hz), 8.06 (1H, t, J = 1.9Hz), 7.76 (1H, t, J = 1.7 Hz), 7.72 (1H, d, J = 1.9 Hz), 7.66 (1H, s), 7.27-7.50 (5H, m), 6, 29 (1H, d, J = 7.6Hz), 5.75-5.94 (1H, m), 3.86-4.06 (2H, m), 2.64 (3H, s). LCMS (M + H) < + > m / z 507 (t = 1.70 min).

Príklad 22 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 22-28)Example 22 (General Preparation of Compounds of Examples 22-28)

(S)-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7metyl-3H-benzoimidazol-5-karbonitril:(S) -2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile:

K roztoku 2-(4-chlór-2-oxo-1,2-dihydropyridín-3-yl)-7-metyl-3H-benzoimidazol-To a solution of 2- (4-chloro-2-oxo-1,2-dihydropyridin-3-yl) -7-methyl-3H-benzoimidazole-

5-karbonitrilu (0,7 g, 2,19 mmol) v DMF (15 ml) sa pridá N-metylmorfolín (0,66 g, 6,57 mmol) a (S)-(-)-2-amino-3-fenyl-1-propanol (0,40 g, 2,63 mmol). Reakčná zmes sa zahrieva 6 h pri 80 °C a potom sa ochladí na teplotu miestnosti. Po zahustení za zníženého tlaku sa prečistením zvyšku rýchlou chromatografiou (3 % MeOH/CH2CI2) vo forme žltej peny získa titulná zlúčenina (0,59 g, 68 %). 1H NMR (400 MHz, CD3OD) δ 7,74 (1H, s), 7,63 (1H, s), 7,12-7,27 (6H, m), 6,07 (1H, dd, J = 7,5 Hz),Of 5-carbonitrile (0.7 g, 2.19 mmol) in DMF (15 mL) is added N-methylmorpholine (0.66 g, 6.57 mmol) and (S) - (-) - 2-amino-3 -phenyl-1-propanol (0.40 g, 2.63 mmol). The reaction mixture was heated at 80 ° C for 6 h and then cooled to room temperature. Concentration in vacuo afforded the residue by flash chromatography (3% MeOH / CH 2 Cl 2 ) as a yellow foam to give the title compound (0.59 g, 68%). 1 H NMR (400 MHz, CD 3 OD) δ 7.74 (1H, s), 7.63 (1H, s), 7.12-7.27 (6H, m), 6.07 (1H, dd) , J = 7.5Hz),

3,97 (1H, m), 3,74 (2H, t, J = 5 Hz), 3,14 (1 H, dd, J = 5,5, 14,0 Hz), 2,94 (1H, dd, J = 7,9, 14,0 Hz), 2,60 (3H, s). LCMS (M+H)+ m/z 400 (t = 1,71 min).3.97 (1H, m), 3.74 (2H, t, J = 5Hz), 3.14 (1H, dd, J = 5.5, 14.0 Hz), 2.94 (1H, dd, J = 7.9, 14.0 Hz), 2.60 (3H, s). LCMS (M + H) < + > m / z 400 (t = 1.71 min).

Príklad 23Example 23

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihyd ropyrid ín-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril:(±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbonitrile:

1H NMR (300 MHz, DMSO-de) δ 7,92 (1H, s), 7,59 (1H. s), 7,28-7,47 (5H, m), 1 H NMR (300 MHz, DMSO-d e) δ 7.92 (1 H, s), 7.59 (1H. S), 7.28-7.47 (5H, m),

6,19 (1H, d, J = 7,3 Hz), 4,92-4,96 (1H, m), 3,53-3,73 (2H, m), 2,58 (3H, s). LCMS (M+H)+ m/z 420 (t = 1,99 min).6.19 (1H, d, J = 7.3Hz), 4.92-4.96 (1H, m), 3.53-3.73 (2H, m), 2.58 (3H, s) . LCMS (M + H) < + > m / z 420 (t = 1.99 min).

Príklad 24Example 24

(S)-2-{4-[2-(3-chlórfenyl)-2-hydroxymetyletylamino]-2-oxo-1,2-dihydropyridín-3yl}-7-metyl-3H-benzoimidazol-5-karbonitril:(S) -2- {4- [2- (3-chlorophenyl) -2-hydroxymethyl-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile:

1H NMR (400 MHz, CD3OD) δ 7,86 (1H, s), 7,10-7,33 (6H, m), 6,12 (1H, d, J = 1 H NMR (400 MHz, CD 3 OD) δ 7.86 (1H, s), 7.10-7.33 (6H, m), 6.12 (1H, d, J =

7,6 Hz), 4,01-4,05 (1H, m), 3,75 (2H, d, J = 4,9 Hz), 3,15 (1 H, dd, J = 4,9, 13,5 Hz), 2,86-3,00 (1H, m), 2,63 (3H, s). LCMS (M+Hf m/z 434 (t = 1,81 min).7.6 Hz), 4.01-4.05 (1H, m), 3.75 (2H, d, J = 4.9 Hz), 3.15 (1H, dd, J = 4.9, 13.5 Hz), 2.86-3.00 (1H, m), 2.63 (3H, s). LCMS (M + H + m / z 434 (t = 1.81 min).

Príklad 25Example 25

(±)-2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karbonitril:(±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-methyl-3H-benzimidazole-5 carbonitrile:

1H NMR (300 MHz, CD3OD) δ 7,86 (1H, s), 7,75 (1H, s), 7,67 (1H, s), 7.28- 1 H NMR (300 MHz, CD 3 OD) δ 7.86 (1H, s), 7.75 (1H, s), 7.67 (1H, s), 7.28-

7,40 (2H, m), 6,95 (1H, d, J = 8,5 Hz), 6,24 (1H, d, J = 7,4 Hz), 4,93 (1H, m), 3,65-7.40 (2H, m), 6.95 (1H, d, J = 8.5Hz), 6.24 (1H, d, J = 7.4Hz), 4.93 (1H, m), 3,65-

3,97 (2H, m), 3,82 (3H, s), 2,57 (3H, s). LCMS (M+Hf m/z 494 (t = 2,10 min).3.97 (2H, m), 3.82 (3H, s), 2.57 (3H, s). LCMS (M + H + m / z 494 (t = 2.10 min).

Príklad 26Example 26

(±)-2-{4-[2-(3-fluórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril:(±) -2- {4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile:

1H NMR (400 MHz, CD3OD) δ 7,10 (1H, s), 7,49 (1H, s), 7,22-7,32 (4H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.10 (1H, s), 7.49 (1H, s), 7.22-7.32 (4H, m),

6,92 (1H, d, J = 8,9 Hz), 6,17 (1H, d, J = 7,2 Hz), 4,92 (1 H, t, J = 6,3 Hz), 3,66 (2H, d,6.92 (1H, d, J = 8.9 Hz), 6.17 (1H, d, J = 7.2 Hz), 4.92 (1H, t, J = 6.3 Hz), 3 66 (2H, d)

J = 5,9 Hz), 2,56 (3H, s). LCMS (M+H)+ m/z 404 (t = 1,65 min).J = 5.9 Hz), 2.56 (3H, s). LCMS (M + H) < + > m / z 404 (t = 1.65 min).

Príklad 27Example 27

(±)-2-{4-[2-(3-brómfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril:(±) -2- {4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile:

1H NMR (300 MHz, CD3OD) ô 7,92 (1H, s), 7,72 (1 H, s), 7,26-7,50 (5H, m). 1 H NMR (300 MHz, CD 3 OD) δ 7.92 (1H, s), 7.72 (1H, s), 7.26-7.50 (5H, m).

6,19 (1H, d, J = 7,1 Hz), 4,93 (1H, t, J = 4,3 Hz), 3,47-3,73 (2H, m), 2,58 (3H, s). LCMS (M+H)+ m/z 464 (t = 2,00 min).6.19 (1H, d, J = 7.1Hz), 4.93 (1H, t, J = 4.3Hz), 3.47-3.73 (2H, m), 2.58 (3H) , with). LCMS (M + H) < + > m / z 464 (t = 2.00 min).

Príklad 28Example 28

(S)-2-[4-(2-hydroxy-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7-metyl3H-benzoimidazol-5-karbonitril:(S) -2- [4- (2-hydroxy-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile:

1H NMR (400 MHz, CD3OD) δ 8,04 (1H, s), 7,74 (1H, s), 7,24-7,51 (6H, m). 1 H NMR (400 MHz, CD 3 OD) δ 8.04 (1H, s), 7.74 (1H, s), 7.24-7.51 (6H, m).

6,22 (1H, d, J = 7,5 Hz), 5,00 (1H, m), 3,64-3,74 (2H, m), 2,60 (3H, s). LCMS (M+H)’ m/z 386 (t = 1,65 min).6.22 (1H, d, J = 7.5Hz), 5.00 (1H, m), 3.64-3.74 (2H, m), 2.60 (3H, s). LCMS (M + H) m / z 386 (t = 1.65 min).

Príklady 29-35Examples 29-35

Zlúčeniny podlá vyššie uvedených príkladov sa pripravia z obchodne dostupných alebo ľahko dostupných diamínov, ktoré sa potom kondenzujú s 4-jód-2metoxypyridín-3-karbaldehydom spôsobom znázorneným v schéme III.The compounds of the above examples are prepared from commercially available or readily available diamines, which are then condensed with 4-iodo-2-methoxy-pyridine-3-carbaldehyde as shown in Scheme III.

Príklad 29Example 29

(±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4.5,6-trifluór-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 13,26 (1H, široký s), 10,93 (1H, široký s), 10,27 (1H, široký s), 7,76 (1H, s), 7,54-7,56 (2H, m), 7,41-7,42 (1H, m), 7,06 (1H, d, J = 8,2 Hz), 6,29 (1H, d, J = 7,5 Hz), 5,05-5,07 (1H, m), 3,87 (3H, s), 3,74-3,79 (1H, m), 1 H NMR (500 MHz, CD 3 COCD 3) δ 13.26 (1H, broad s), 10.93 (1H, broad s), 10.27 (1H, broad s), 7.76 (1H, s), 7 54-7.56 (2H, m), 7.41-7.42 (1H, m), 7.06 (1H, d, J = 8.2 Hz), 6.29 (1H, d, J = 7.5 Hz), 5.05-5.07 (1H, m), 3.87 (3H, s), 3.74-3.79 (1H, m),

3,65-3,69 (1H, m).3.65-3.69 (1 H, m).

Príklad 30Example 30

(±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4.6-dibróm-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4,6-dibromo-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

1H NMR (500 MHz, CD3COCD3) δ 13,18 (1H, široký s). 11,18 (1H, široký s), 10,20 (1H, široký s), 7,92 (1H, s), 7,78 (1H, s), 7,52-7,55 (3H, m), 7,03 (1H, d, J = 8,5 Hz), 6,28 (1H, d, J = 7,4 Hz), 5,06-5,08 (1H, m), 3,86 (3H, s), 3,73-3,77 (1H, m), 3,66- 1 H NMR (500 MHz, CD 3 COCD 3) δ 13.18 (1H, broad s). 11.18 (1H, broad s), 10.20 (1H, broad s), 7.92 (1H, s), 7.78 (1H, s), 7.52-7.55 (3H, m) 7.03 (1H, d, J = 8.5Hz), 6.28 (1H, d, J = 7.4Hz), 5.06-5.08 (1H, m), 3.86 (1H 3H, s), 3.73-3.77 (1 H, m), 3.66-

3,70 (1H, m).3.70 (1 H, m).

Príklad 31Example 31

(±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(5,6-dichlór-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (5,6-dichloro-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 7,79 (3H, m), 7,53 (1H, dd, J = 2,0, 8,4 Hz), 7,41-7,44 (1H, m), 7,08 (1H, d, J = 8,4 Hz), 6.29 (1H, d, J = 7,5 Hz), 5,05-5,08 (1H, m), 3,89 (3H, s), 3,74-3,78 (1H, m), 3,70-3,72 (1H, m). 1 H NMR (500 MHz, CD 3 COCD 3) δ 7.79 (3H, m), 7.53 (1H, dd, J = 2.0, 8.4 Hz), 7.41-7.44 (1H, m 7.08 (1H, d, J = 8.4Hz), 6.29 (1H, d, J = 7.5Hz), 5.05-5.08 (1H, m), 3.89 (3H) s, 3.74-3.78 (1 H, m), 3.70-3.72 (1 H, m).

Príklad 32Example 32

(±)-3-(1 H-benzoimidazol-2-yl)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-1 Hpyridín-2-ón:(±) -3- (1H-Benzoimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 7,80 (1H, s), 7,64-7,69 (2H, m), 7,60 (1H, d, J = 7,7 Hz), 7,46-7,48 (2H, m), 7,33 (1H, t, J = 7,8 Hz), 7,19-7,22 (2H. m), 6,59 (1H, d, J - 4,5 Hz), 5,12-5,14 (1H, m), 5,13 (1H, dd. J = 4,5. 7,2 Hz), 3,82 (1H, dd, J = 4,5, 1 H NMR (500 MHz, CD 3 COCD 3) δ 7.80 (1H, s), 7.64-7.69 (2H, m), 7.60 (1H, d, J = 7.7 Hz), 7, 46-7.48 (2 H, m), 7.33 (1 H, t, J = 7.8 Hz), 7.19-7.22 (2 H, m), 6.59 (1 H, d, J - 4.5 Hz), 5.12-5.14 (1H, m), 5.13 (1H, dd, J = 4.5, 7.2 Hz), 3.82 (1H, dd, J = 4) 5.

13,6 Hz), 3,71 (1H, dd, J = 7,2, 13,6 Hz).13.6 Hz), 3.71 (1H, dd, J = 7.2, 13.6 Hz).

Príklad 33Example 33

3-(1H-benzoimidazol-2-yl)-4-[(pyridín-2-ylmetyl)amino]-1 H-pyridín-2-ón:3- (1H-benzoimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 8,96-8,98 (1H, m), 8,46-8,49 (1H, m), 8,03 (1H, d, J = 8,0 Hz), 7,93 (1H, t, J = 6,4 Hz), 7,69-7,73 (2H, m), 7,53 (1H, d, J = 7,5 Hz), 7,28-7,32 (2H. s), 6,34 (1H, d, J = 7,5 Hz), 5,29 (2H, m). 1 H NMR (500 MHz, CD 3 COCD 3) δ 8.96-8.98 (1H, m), 8.46-8.49 (1H, m), 8.03 (1H, d, J = 8.0 Hz) 7.93 (1H, t, J = 6.4 Hz), 7.69-7.73 (2H, m), 7.53 (1H, d, J = 7.5 Hz), 7.28 -7.32 (2H, s), 6.34 (1H, d, J = 7.5Hz), 5.29 (2H, m).

Príklad 34Example 34

(S)-3-(1 H-benzoimidazol-2-yl)-4-(1-hydroxymetyl-2-fenyletylamino)-1H-pyridin2-ón:(S) -3- (1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 7,67-7,69 (2H, m), 7,15-7,44 (8H, m), 6,31 (1H, d, J = 7,5 Hz), 4,10-4,13 (1H, m), 3,76-3,82 (2H, m), 3,23 (1H, dd, J = 5,6, 13,7 Hz), 3,04 (1H, dd, J = 8.1, 13,7 Hz). 1 H NMR (500 MHz, CD 3 COCD 3) δ 7.67-7.69 (2H, m), 7.15-7.44 (8H, m), 6.31 (1H, d, J = 7.5 Hz) 4.10-4.13 (1H, m), 3.76-3.82 (2H, m), 3.23 (1H, dd, J = 5.6, 13.7 Hz), 3, 04 (1H, dd, J = 8.1, 13.7 Hz).

Príklad 35Example 35

(±)-3-(1 H-benzoimidazol-2-yl)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-1 H-pyridin-2-ón:(±) -3- (1H-Benzoimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one:

1H NMR (500 MHz, CD3COCD3) δ 7,78 (1H, s), 7,68 (2H, s), 7.50-7,55 (2H. m), 7,21-7,24 (2H, m), 7,06 (1H, d, J = 8,4 Hz), 6,44 (1H, d, J = 7,5 Hz), 5,08 (1H, dd. J = 1 H NMR (500 MHz, CD 3 COCD 3) δ 7.78 (1H, s), 7.68 (2H, s), 7.50-7.55 (2H, m), 7.21-7.24 (2H, m) 7.06 (1H, d, J = 8.4Hz), 6.44 (1H, d, J = 7.5Hz), 5.08 (1H, dd, J =

4,6, 7,2 Hz), 3,87 (3H, s), 3,79 (1H, dd, J = 4,6, 13,4 Hz), 3,71 (1H. dd, J = 7,2, 13,44.6, 7.2 Hz), 3.87 (3H, s), 3.79 (1H, dd, J = 4.6, 13.4 Hz), 3.71 (1H, dd, J = 7 , 2, 13.4

Hz).Hz).

Príklady 36 až 43Examples 36 to 43

Zlúčeniny podľa vyššie uvedených príkladov sa pripravia spôsobom znázorneným v schéme V.The compounds of the above examples were prepared as shown in Scheme V.

Príklad 36 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 36 až 43).Example 36 (General procedure for preparing the compounds of Examples 36 to 43).

Izopropylamid (S)-4-{2-[4-( 1 -hydroxymetyl-2-fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl-3H-benzoimidazol-5-yl}piperazin-1 -karboxylovej kyseliny:(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazol-5-yl} piperazine- 1-carboxylic acid:

K roztoku (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-(4-metyl-6-piperazin-1-yl1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (30 mg, 0,063 mmol) v metanole (2 ml) sa pridá izopropylizokyanát (2 kvapky). Reakčná zmes sa mieša 5 min pri teplote miestnosti. Zahustením sa získa zvyšok, ktorého prečistením preparatívnou HPLC sa získa titulná zlúčenina (23,8 mg, 69 %). 1H NMR (400 MHz, CD3OD) δ 7,55 (1H, s),To a solution of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl) -1H-benzoimidazol-2-yl) -1H-pyridin-2-one (30 mg) , 0.063 mmol) in methanol (2 mL) was added isopropyl isocyanate (2 drops). The reaction mixture was stirred at room temperature for 5 min. Concentration gave a residue which was purified by preparative HPLC to give the title compound (23.8 mg, 69%). 1 H NMR (400 MHz, CD 3 OD) δ 7.55 (1H, s),

7,14-7,28 (7H, m), 6,12 (1H, d, J = 7,8 Hz), 4,01-4,03 (1H, m), 3,92 (kvintet, J = 6,67.14-7.28 (7H, m), 6.12 (1H, d, J = 7.8 Hz), 4.01-4.03 (1H, m), 3.92 (quintet, J = 6.6

Hz), 3,80 (4H, m), 3,76 (1H. dd, J = 4,8, 11,2 Hz), 3,70 (1H, dd, J = 5,2, 11,2 Hz),Hz), 3.80 (4H, m), 3.76 (1H, dd, J = 4.8, 11.2 Hz), 3.70 (1H, dd, J = 5.2, 11.2 Hz) )

3,61-3,64 (4H, m), 3,09 (1H, dd, J = 5,6, 13,7 Hz), 2,91 (1H, dd, J = 8,0, 13,7 Hz),3.61-3.64 (4H, m), 3.09 (1H, dd, J = 5.6, 13.7 Hz), 2.91 (1H, dd, J = 8.0, 13.7 Hz);

2,64 (3H, s), 1,19 (6H, d, J = 6.8 Hz). LCMS (M+H)+ m/z 545 (t = 1,99 min).2.64 (3H, s), 1.19 (6H, d, J = 6.8Hz). LCMS (M + H) < + > m / z 545 (t = 1.99 min).

Príklad 37Example 37

Etylamid (S)-4-{2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7-metyl-3H-benzoimidazol-5-yl}piperazín-1-karboxylovej kyseliny:(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazol-5-yl} ethylamide piperazine-1-carboxylic acid:

'H NMR (400 MHz, CD3OD) δ 7,55 (1H, s), 7,12-7,28 (7H, m), 6,12 (1H, d, J = 7,8 Hz), 4,01-4,05 (1H, m), 3,62-3,81 (10H, m), 3,24 (2H, q, J = 7,2 Hz), 3,08 (1H, dd, J = 5,6, 13,7 Hz), 2,91 (1H, dd, J = 8,0, 13,7 Hz), 2,65 (3H, s), 1,14 (3H, t, J = 7,2 Hz). LCMS (M+H)+ m/z 531 (t = 1,93 min).1 H NMR (400 MHz, CD 3 OD) δ 7.55 (1H, s), 7.12-7.28 (7H, m), 6.12 (1H, d, J = 7.8 Hz), 4.01-4.05 (1H, m), 3.62-3.81 (10H, m), 3.24 (2H, q, J = 7.2 Hz), 3.08 (1H, dd, J = 5.6, 13.7 Hz), 2.91 (1H, dd, J = 8.0, 13.7 Hz), 2.65 (3H, s), 1.14 (3H, t, J = 7.2 Hz). LCMS (M + H) < + > m / z 531 (t = 1.93 min).

Príklad 38Example 38

(S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-{4-metyl-6-[4-(1-fenylmetanoyl)piperazín-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:(S) -4- (1-hydroxymethyl-2-phenyl-ethylamino) -3- {4-methyl-6- [4- (1-fenylmetanoyl) piperazin-1-yl] -1 H-benzimidazol-2-yl} -1 pyridin-2-one;

K roztoku (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-(4-metyl-6-piperazín-1-yl1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ónu (30 mg, 0,063 mmol) v metanole (2 ml) sa pridá benzoylchlorid (1 kvapka). Reakčná zmes sa potom mieša 5 min a zahustí sa. Prečistením zvyšku preparatívnou HPLC sa získa titulná zlúčenina (11 mg, 33 %). 1H NMR (400 MHz, CD3OD) δ 7,48-7,54 (5H, m), 7,37 (1H, s), 7,13-7,26 (7H, m), 6,08 (1H, d, J = 7,7 Hz), 3,79-4,02 (5H, m), 3,76 (1H, dd, J = 4,7, 11,2 Hz), 3,67 (1H, dd, J = 5,7, 11,2 Hz), 3,54 (4H, m), 3,03 (1H, dd, J = 5,7, 13,7 Hz), 2,89 (1H, dd, J = 8,0,To a solution of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl) -1H-benzoimidazol-2-yl) -1H-pyridin-2-one ( 30 mg, 0.063 mmol) in methanol (2 mL) was added benzoyl chloride (1 drop). The reaction mixture was then stirred for 5 min and concentrated. Purification of the residue by preparative HPLC gave the title compound (11 mg, 33%). 1 H NMR (400 MHz, CD 3 OD) δ 7.48-7.54 (5H, m), 7.37 (1H, s), 7.13-7.26 (7H, m), 6.08 (1H, d, J = 7.7Hz), 3.79-4.02 (5H, m), 3.76 (1H, dd, J = 4.7, 11.2 Hz), 3.67 ( 1 H, dd, J = 5.7, 11.2 Hz), 3.54 (4H, m), 3.03 (1H, dd, J = 5.7, 13.7 Hz), 2.89 (1H , dd, J = 8.0

13,7 Hz), 2,62 (3H, s). LCMS (M+H)+ m/z 563 (t = 2,19 min).13.7 Hz), 2.62 (3H, s). LCMS (M + H) < + > m / z 563 (t = 2.19 min).

Príklad 39 (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[6-(4-izopropylpiperazin-1-yl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:Example 39 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H-pyridine- 2-one:

K roztoku (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-(4-metyl-6-piperazín-1-yl1H-benzoimidazol-2-yl)-1H-pyridin-2-ónu (25 mg, 0,054 mmol) v metanole (0,5 ml) sa pridá acetón (0,5 ml) a NaCNBH3 1 mol/l v THF. Reakčná zmes sa potom mieša 1 h pri teplote miestnosti a zahustí sa za zníženého tlaku. Prečistením zvyšku preparatívnou HPLC sa získa titulná zlúčenina (12 mg, 44 %). 1H NMR (400 MHz, CD3OD) δ 7,10-7,24 (6H, m), 7,08 (1H, s), 7,06 (1H, s), 6,06 (1H, d, J = 7,9 Hz), 3,584,01 (10H, m), 3,34 (1H, m), 3,13 (1H, m), 2,98 (1H, dd, J = 5,9, 13,7 Hz), 2,83 (1H, dd, J = 7,9, 13,7 Hz), 2,60 (3H, s), 1,44 (6H, d, J = 6,7 Hz). LCMS (M+H)+ m/z 501 (t = 1,80 min).To a solution of (S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- (4-methyl-6-piperazin-1-yl) -1H-benzoimidazol-2-yl) -1H-pyridin-2-one (25 mg) , 0.054 mmol) in methanol (0.5 mL) was added acetone (0.5 mL) and NaCNBH 3 1M in THF. The reaction mixture was then stirred at room temperature for 1 h and concentrated under reduced pressure. Purification of the residue by preparative HPLC afforded the title compound (12 mg, 44%). 1 H NMR (400 MHz, CD 3 OD) δ 7.10-7.24 (6H, m), 7.08 (1H, s), 7.06 (1H, s), 6.06 (1H, d) J = 7.9 Hz), 3.584.01 (10H, m), 3.34 (1H, m), 3.13 (1H, m), 2.98 (1H, dd, J = 5.9, 13.7 Hz), 2.83 (1H, dd, J = 7.9, 13.7 Hz), 2.60 (3H, s), 1.44 (6H, d, J = 6.7 Hz) . LCMS (M + H) < + > m / z 501 (t = 1.80 min).

Príklad 40Example 40

(S)-3-[6-(4-benzylpiperazin-1-yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridin-2-ón:(S) -3- [6- (4-Benzyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2- one:

1H NMR (400 MHz, CD3OD) δ 7,50-7,57 (6H, m), 7,04-7,27 (7H, m), 6,07 (1H, d, J = 7,8 Hz), 4,22 (2H, s), 3,97-4,00 (1H, m), 3,34-3,77 (2H, m), 2,82-3,04 (10H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.50-7.57 (6H, m), 7.04-7.27 (7H, m), 6.07 (1H, d, J = 7, 8 Hz), 4.22 (2H, s), 3.97-4.00 (1H, m), 3.34-3.77 (2H, m), 2.82-3.04 (10H, m) )

2,58 (3H, s). LCMS (M+H)+ m/z 549 (t = 1,93 min).2.58 (3 H, s). LCMS (M + H) < + > m / z 549 (t = 1.93 min).

HNHN

Príklad 41Example 41

(±)-3-[6-(4-acetylpiperazín-1 -yl)-4-metyl-1 H-benzoimidazol-2-yl]-4-[2-(3chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón:(±) -3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H- pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,50 (1H, s), 7,25-7,49 (5H, m), 7,20 (1H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.50 (1H, s), 7.25-7.49 (5H, m), 7.20 (1H, s),

6,25 (1 H, d, J = 8,0 Hz), 4,94 (1H, dd, J = 4,6, 7,1 Hz), 3,88-3,92 (4H, m), 3,50-3,65 (6H, m), 2,62 (3H, s), 2,20 (3H, s). LCMS (M+H)* m/z 521 (t = 2,13 min).6.25 (1H, d, J = 8.0 Hz), 4.94 (1H, dd, J = 4.6, 7.1 Hz), 3.88-3.92 (4H, m), 3.50-3.65 (6H, m), 2.62 (3H, s), 2.20 (3H, s). LCMS (M + H) + m / z 521 (t = 2.13 min).

Príklad 42Example 42

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one :

1H NMR (400 MHz, CD3OD) δ 7,47 (1H, s), 7,25-7,38 (4H, m), 7,07 (2H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.07 (2H, s),

6,25 (1H, d, J = 7,6 Hz), 4,90 (1H, m), 3,42-3,66 (10H, m), 2,59 (3H, s). LCMS (M+H)* m/z 479 (t = 1,90 min).6.25 (1H, d, J = 7.6Hz), 4.90 (1H, m), 3.42-3.66 (10H, m), 2.59 (3H, s). LCMS (M + H) + m / z 479 (t = 1.90 min).

Príklad 43Example 43

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(4-izopropylpiperazín-1-yl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H- pyridin-2-one;

’H NMR (400 MHz, CD3OD) δ 7,47 (1H, s), 7,25-7,38 (4H, m), 7,06 (2H, s),1 H NMR (400 MHz, CD 3 OD) δ 7.47 (1H, s), 7.25-7.38 (4H, m), 7.06 (2H, s),

6,26 (1H, d, J = 7,6 Hz), 4,91-4,93 (1H, m), 3.89-3,92 (2H, m), 3.51-3,64 (5H, m),6.26 (1H, d, J = 7.6Hz), 4.91-4.93 (1H, m), 3.89-3.92 (2H, m), 3.51-3.64 (5H, m) .

3,31-3,37 (2Η, m), 3,09-3,30 (2H, m), 2,59 (3H, s), 1,44 (6H, d, J = 6,6 Hz). LCMS (M+H)* m/z 521 (t = 1,95 min).3.31-3.37 (2Η, m), 3.09-3.30 (2H, m), 2.59 (3H, s), 1.44 (6H, d, J = 6.6 Hz) . LCMS (M + H) + m / z 521 (t = 1.95 min).

Príklad 44Example 44

(S)-6-(1 -hydroxymetyl-2-fenyletylamino)-5-(6-imidazol-1 -yl-4-metyl-í Hbenzoimidazol-2-yl)-3H-pyrimidín-4-ón:(S) -6- (1-Hydroxymethyl-2-phenylethylamino) -5- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -3H-pyrimidin-4-one:

(S)-2-[6-chlór-5-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)pyrimidin-4ylamino]-3-fenylpropán-1-ol:(S) -2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1 H-benzoimidazol-2-yl) -pyrimidin-4-ylamino] -3-phenyl-propan-1-ol:

K roztoku 2-(4,6-dichlórpyrimidín-5-yl)-6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazolu (40 mg, 0,16 mmol) v izopropanole (5 ml) sa pridá (S)-(-)-2-amino-3fenylpropanol (35 mg, 0,23 mmol) a trietylamin (0,5 ml). Reakčná zmes sa zahrieva 4 h pri 80 °C a potom sa ochladí na teplotu miestnosti a zahustí sa za vysoko zníženého tlaku. Surový produkt sa použije v ďalšom stupni bez ďalšieho čistenia. LCMS (M+H)’ m/z 460 (t = 2,13 min).To a solution of 2- (4,6-dichloropyrimidin-5-yl) -6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 mL) was added (S). - (-) - 2-Amino-3-phenylpropanol (35 mg, 0.23 mmol) and triethylamine (0.5 mL). The reaction mixture was heated at 80 ° C for 4 h and then cooled to room temperature and concentrated under high vacuum. The crude product was used in the next step without further purification. LCMS (M + H) m / z 460 (t = 2.13 min).

(S)-6-(1-hydroxymetyl-2-fenyletylamino)-5-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-3H-pyrimidín-4-ón:(S) -6- (1-hydroxymethyl-2-phenyl-ethylamino) -5- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -3H-pyrimidin-4-one;

K roztoku (S)-2-[6-chlór-5-(6-imidazol-1-yl-4-metyl-1 H-benzoimidazol-2yl)pyrimidin-4-ylamino]-3-fenylpropán-1-olu v HCI 4 mol/l (0,5 ml) a kyseline octovej (0,5 ml) sa pridajú dve kvapky vody. Reakčná zmes sa potom zahrieva 8 h pri 100 °C, ochladí sa na teplotu miestnosti a zneutralizuje sa amoniakom v metanole. Po zahustení, prečistením zvyšku preparatívnou HPLC sa získa titulná zlúčenina (26 mg, 37 % v oboch stĺpcoch). 1H NMR (400 MHz, CD3OD) δ 9,41 (1H, úzky t, J = 1,5 Hz), 8,06 (1H, úzky dd, J = 1,6, 1,9 Hz), 7,93 (1H, s), 7,77 (1H, úzky dd, J = 1,6, 1,8 Hz),To a solution of (S) -2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) pyrimidin-4-ylamino] -3-phenylpropan-1-ol in Two drops of water were added to 4 mol / L HCl (0.5 mL) and acetic acid (0.5 mL). The reaction mixture was then heated at 100 ° C for 8 h, cooled to room temperature and neutralized with ammonia in methanol. After concentration, purification of the residue by preparative HPLC afforded the title compound (26 mg, 37% in both columns). 1 H NMR (400 MHz, CD 3 OD) δ 9.41 (1H, narrow t, J = 1.5 Hz), 8.06 (1H, narrow dd, J = 1.6, 1.9 Hz), 7.93 (1H, s), 7.77 (1H, narrow dd, J = 1.6, 1.8 Hz),

7,73 (1Η, úzky d, J = 1,9 Hz), 7,11-7,21 (6H, m), 4,70-4,74 (1H, m), 3,74 (2H, d, J =7.73 (1Η, narrow d, J = 1.9 Hz), 7.11-7.21 (6H, m), 4.70-4.74 (1H, m), 3.74 (2H, d) , J =

4,7 Hz), 3,11 (1H, dd, J = 6,1, 13,5 Hz), 3,00 (1H, dd, J = 7,8, 13,5 Hz), 2,70 (3H, s). LCMS (M+H)+ m/z 442 (t = 2,17 min).4.7 Hz), 3.11 (1H, dd, J = 6.1, 13.5 Hz), 3.00 (1H, dd, J = 7.8, 13.5 Hz), 2.70 ( 3H, s). LCMS (M + H) < + > m / z 442 (t = 2.17 min).

Príklady 45 až 383Examples 45 to 383

Zlúčeniny podľa vyššie uvedených príkladov sa pripravia všeobecnými spôsobmi prípravy opísanými vyššie (schéma III).The compounds of the above examples were prepared by the general preparation methods described above (Scheme III).

Podmienky LCMS:LCMS conditions:

a) YMC C18 S5 4,6x50 mm; gradient 0-100 % v priebehu 4 min*; prietoková rýchlosť 4 ml/mina) YMC C18 S5 4.6x50mm; 0-100% gradient over 4 min *; flow rate 4 ml / min

b) YMC ODS-A C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 2 min*; prietoková rýchlosť 5 ml/minb) YMC ODS-A C18 S7 3.0x50mm; 0-100% gradient over 2 min *; flow rate 5 ml / min

c) YMC C18 S5 4,6x50 mm; gradient 0-100 % v priebehu 8 min*; prietoková rýchlosť 2,5 ml/minc) YMC C18 S5 4.6x50mm; 0-100% gradient over 8 min *; flow rate 2.5 ml / min

d) YMC C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 3 min*; prietoková rýchlosť 5 ml/mind) YMC C18 S7 3.0x50mm; 0-100% gradient over 3 min *; flow rate 5 ml / min

e) YMC ODSA S3 6,0x150 mm; gradient 0-100 % v priebehu 5 min*; prietoková rýchlosť 1,5 ml/mine) YMC ODSA S3 6.0 x 150 mm; 0-100% gradient over 5 min *; flow rate 1.5 ml / min

f) PHS-PRIMESPHERE C18 4,6x30 mm; gradient 0-100 % v priebehu 2 min*; prietoková rýchlosť 5 ml/minf) PHS-PRIMESPHERE C18 4.6x30mm; 0-100% gradient over 2 min *; flow rate 5 ml / min

g) YMC C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 4 min*; prietoková rýchlosť 5 ml/min(g) YMC C18 S7 3,0x50mm; 0-100% gradient over 4 min *; flow rate 5 ml / min

h) YMC ODS-A C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 2 min*; prietoková rýchlosť 5 ml/minh) YMC ODS-A C18 S7 3.0x50mm; 0-100% gradient over 2 min *; flow rate 5 ml / min

i) YMC ODS-A C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 1,5 min*; prietoková rýchlosť 5 ml/mini) YMC ODS-A C18 S7 3.0x50mm; 0-100% gradient over 1.5 min *; flow rate 5 ml / min

j) YMC Xterra C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 2 min*; prietoková rýchlosť 5 ml/min(j) YMC Xterra C18 S7 3.0x50mm; 0-100% gradient over 2 min *; flow rate 5 ml / min

k) YMC Pro-ODS C18 S5 4,6x33 mm; gradient 0-100 % v priebehu 3 min*; prietoková rýchlosť 4 ml/mink) YMC Pro-ODS C18 S5 4.6x33mm; 0-100% gradient over 3 min *; flow rate 4 ml / min

l) YMC ODS-A C18 S7 3,0x50 mm; gradient 0-100 % v priebehu 4 min*; prietoková rýchlosť 4 ml/min */ gradient začína zmesou 10 % metanol/90 % voda (0,1 % TFA) a končí zmesou 90 % metanol/10 % voda (0,1 % TFA).l) YMC ODS-A C18 S7 3.0x50mm; 0-100% gradient over 4 min *; flow rate 4 ml / min * / gradient starts with 10% methanol / 90% water (0.1% TFA) and ends with 90% methanol / 10% water (0.1% TFA).

Pr. č. Pr. no. Názov Title Vzorec formula T (min) T (min) Hmotnosť (M+H)+ m/zMass (M + H) + m / z 45 45 4-(2-fluórbenzylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (2-Fluorobenzylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Oh H V V- * M V—NM I M N Oh H V V- * M V — NM I M N 1,43 (I) 1.43 (I) 415 415 46 46 4-(3,4-dimetoxybenzylamino-3-(6-imidazol-4-metyl1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (3,4-Dimethoxybenzylamino-3- (6-imidazol-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one I HN á bUO OM· I HN á bUO OM · 1,37 (I) 1.37 (I) 457 457 47 47 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(pyridín-2-ylmetyl)amino-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino-1H-pyridin-2-one Ä H A | HN á Ä H A | HN á 2,17 (a) 2.17 (a) 398 398 48 48 (S)-4-(1-hydroxymetyl-2fenyletylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /=1 H % N ySsx n y—nh l / OH O/ = 1 H% N ySsx ny-nh 1 / OH 0 1,48 (b) 1.48 (b) 441 441 49 49 (R)-4-(1 -hydroxymetyl-2fenyletylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / u 0, F-NH 1 HN / OH O / u 0, F-NH 1 HN / OH ABOUT 1,48 (b) 1.48 (b) 441 441 50 50 N-(2-[3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihyd ropyridi n4-ylamino]etyl}acetamid N- (2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} acetamide Ο^γ^,Ν /-NH IAn-^v 1 HN \---v O HN— Ο ^ γ ^, Ν / -NH ^ In Ian- 1 HN \ --- in O HN- 1,55 (I) 1.55 (I) 392 392

51 51 4-(3,4-dihydroxybenzylamino)-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón 4- (3,4-dihydroxybenzylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one N NH I HN ď HO OH N NH I HN d OH OH 1,97 (I) 1.97 (I) 429 429 52 52 4-[2-(3H-imidazol-4-yl)etylamino]-3-(6-imidazol-1 -yl4-metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón 4- [2- (3H-imidazol-4-yl) ethylamino] -3- (6-imidazol-1-yl4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one Ογγί V.. V—ίί | HN Ογγί V .. V — ίί | HN 1,91 (a) 1.91 (a) 401 401 53 53 4-(3,4-dihydro-2H-chinolín-1yl)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón 4- (3,4-dihydro-2H-quinolin-1-yl) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one /S H Qo / S H QO 1,88 (a) 1.88 (a) 423 423 54 54 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4- [(pyridin-3-ylmetyl)amino]- 1H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [(Pyridin-3-ylmethyl) amino] - 1 H-pyridin-2-one ČL m V V—NH I HN ď Λ- NARTICLE W W m-NH H N I N d Λ- 1,83 (a) 1.83 (a) 398 398 55 55 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(pyridín-4-ylmetyl)amino-1 Hpyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(pyridin-4-ylmethyl) amino-1H-pyridin-2-one N===ľ| 0 V-NH I HN á N === ¾ | 0 V-NH I HN a 1,74 (a) 1.74 (a) 398 398 56 56 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(2pyridín-2-yletylamino)-1 Hpyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4- (2-pyridin-2-ylethylamino) -1H-pyridin-2-one /1 0 V-nh HN/ 10 V-nh HN 1,99 (a) 1.99 (a) 412 412 57 57 4-[benzyl-(2-hydroxyetyl)amino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimídazol-2yl)-1H-pyridín-2-ón 4- [benzyl- (2-hydroxyethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one θγ-^N V-NH \^^N 'J θγ- ^ N V-NH \ ^^ N 'J 1,86 (a) 1.86 (a) 441 441

58 58 (±)-4-[1-(4-chlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [1- (4-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one H V« Π r- WH Vnú I HM ClH V «Π r- WH Outer I HM Cl 3,3 (a) 3.3 (a) 461 461 59 59 (±)-4-[(1 -etylpyrolidín-2- ylmetyl)amino]-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4 - [(1-Ethylpyrrolidine-2-) ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /N=l 0 V- NH XXrp | HN/ N = 10 V - NH XXrp | HN 1,88 (a) 1.88 (a) 418 418 60 60 (1 R,2S)-4-(2-hydroxy-1 rnetyl-2-fenyletylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (1R, 2S) -4- (2-Hydroxy-1-methyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V-NH I HN OH In NH I HN OH 3,01 (a) 3.01 (a) 441 441 61 61 (±)-4-(2-hydroxy-2fenyletylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ν==ί o ϊΧφ | HN OH ν == ί o ϊΧφ | HN OH 2,96 (a) 2.96 (a) 427 427 62 62 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(3imidazol-1 -ylpropylamino)1H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- (3imidazol-1-ylpropylamino) 1H-pyridin-2-one I HN '' \ Λν I HN '' \ Λν 1,94 (a) 1.94 (a) 415 415 63 63 (S)-4-(2-hydroxy-2-fenyletylamino]-3-(6-imidazol-1 -yl4-metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón (S) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one /H „ A LazAJ I HN OH Έ / H „A Lazaj I HN OH Έ 1,27 (b) 1.27 b 427 427 64 64 (R)-4-(2-hydroxy-2fenyletylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one H % r-NH ςΪΛ'ν I HN ^OHH% r - NH 2 is HN 4 OH 1,27 (b) 1.27 b 427 427

65 65 (±)-4-(1-benzylpyrolidín-3ylamino)-3-(6-imidazol-1 -yl4-metyl-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (±) -4- (1-Benzylpyrrolidin-3-ylamino) -3- (6-imidazol-1-yl4-methyl-1H-benzoimidazol-2- yl) -1H-pyridin-2-one Ch h ΧΧφ h n Ch h ΧΧφ h n 1,19 (b) 1.19 b 466 466 66 66 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-[2(5-nitropyridín-2-ylamino)etylamino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [2- (5-nitropyridin-2-ylamino) ethylamino] -1H-pyridin-2-one I ___________ m-θ-Ηθ, I ___________ m-θ-Ηθ, 1,37 (b) 1.37 b 472 472 67 67 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(2morfolín-4-yletylamino)-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4- (2-morpholin-4-ylethylamino) -1H-pyridin-2-one N V-NH LXZy? | HN '—\ Q N, N-NH LXZy? | HN '- \ Q 0,98 (b) 0.98 b 420 420 68 68 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-[2(2-metyl-5-nitro-1 H-imidazol1-yl)etylamino]-1H-pyridín-2ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethylamino] -1H-pyridin-2-one tu '7— NH I HN ^N-Z d T ο2ν-%,νtu 7 7 - NH 1 HN 4 NZ d T ο 2 ν -%, ν 1,31 (b) 1.31 b 460 460 69 69 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-[2(3-metyl-3H-imidazol-4yl)etylamino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [2- (3-methyl-3H-imidazol-4-yl) ethylamino] -1H-pyridin-2-one n y—nh I HN >.í N' n y — nh I HN > .í N ' 0,97 (b) 0.97 b 415 415 70 70 (±)-4-(4-dietylamino-1metylbutylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-όη (±) -4- (4-Diethylamino-1-methylbutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one a *^_ž-nh I HN _h—ŕand * Z _ ^ NH HN I t-_h 1,13 (b) 1.13 b 448 448 71 71 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(2pyrolidín-1 -yletylamino)-1 Hpyridin-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- (2-pyrrolidin-1-ylethylamino) -1H-pyridin-2-one I HN s—s 0I HN s— s 0 0,87 (b) 0.87 b 404 404

72 72 (±)-4-(1,2-difenyletylamino)3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (1,2-Diphenyl-ethylamino) -3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -1H-pyridin-2-one N Ä / H y—NH | HyN R / H s-NH | Hy 1,72 (b) 1.72 b 487 487 73 73 4-benzylamino-3-(6-imidazol- 1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4-benzylamino-3- (6-imidazol 1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2-one /X H T V—NH 1 HN /=—. / X H T In NH 1 HN / = -. 1,49 (b) 1.49 b 397 397 74 74 4-(3-dimetylaminopropylamino)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón 4- (3-dimethylaminopropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one /=) h T y—NH ΙΛΝ ζ>~ν 1 HN \—H \/ =) h T y — NH ΙΛ Ν ζ> ~ ν 1 HN \ —H \ Í03 (b) I03 (b) 392 392 75 Ί 75 Ί 4-[(adamantán-1 -ylmetyl)amino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón 4 - [(adamantan-1-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one /Ν=Ά 0 V- N xN xxz-p 1 NH/ Ν = Ά 0 V- N xN xxz-p 1 NH 1,87 (b) 1.87 b 455 455 76 76 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4(indán-2-ylamino)-1 Hpyridin-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4 (indan-2-ylamino) -1H-pyridin-2-one ,NX h 0 Vnh 1 NH X, N X h 0 V nh 1 NH X 1,57 (b) 1.57 b 423 423 77 77 4-(3,5-bis(trifluórmetyl- benzylamino)-3'(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (3,5-Bis (trifluoromethyl benzylamino) -3 '(6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 'ú-NH T -0 CP,0 'ú-NH T -0 CP, 1,68 (b) 1.68 b 533 533 78 78 (±)-4-(1,1-dioxotetrahydro1 X6-tiofén-3-ylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón(±) -4- (1,1-dioxotetrahydro1 X 6 -thiophene-3-ylamino) -3- (6imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 Hpyridín-2-one H 0 y—NH xxHj I NH oz so H 0 y — NH x x H i NH o zs 1,03 (b) 1.03 b 425 425

79 79 3-(6-imid azol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4(3,4,5-trimetoxybenzylamino)-1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 (3,4,5-trimethoxybenzylamino) -1H-pyridin-2-one HH lAO-? I HN 0M« HH lAO-? I HN 0M ' 1,33 (b) 1.33 (b) 487 487 80 80 4-[(furán-2-ylmetyl)amino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(furan-2-ylmethyl) amino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O N I HN 0 O N I HN 0 1,34 (b) 1.34 b 387 387 81 81 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(tiofén-2-ylmetyl)amino]-1 Hpyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 [(thiophen-2-ylmethyl) amino] -1H-pyridin-2-one N=-, Z I u °Λ V-NH HN S^, = N -, Z I u ° Λ In NH HN S ^, 1,42 (b) 1.42 b 403 403 82 82 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-[3(2-oxopyrolidín-1 -yl)p ropy Iamino]-1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4- [3- (2-oxopyrrolidin-1-yl) -amino] -1H-pyridin-2-one ζΝ=η H o. L-NH 1 hn Qζ Ν = η H o. L-NH 1 1,15 (b) 1.15 b 432 432 83 83 4-[(1 H-benzoimidazol-2ylmetyl)amino]-3-(6-imidazol1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(1H-benzoimidazol-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one νγ-γ y-NH Ufy HN '-VO Hνγ-γ y -NH Ufy HN '-VO H 0,98 (b) 0.98 b 437 437 84 84 4-[2-(6-fluór-1 H-indol-2yl)etylamino]-3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol2-yl)-1H-pyridín-2-ón 4- [2- (6-fluoro-1H-indol-2-yl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one .XXhy? 1 HN .XXhy? 1 HN 1,53 (b) 1.53 b 468 468 85 85 benzylester {2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo1,2-dihydropyridín-4ylamino]etyl}karbámovej kyseliny {2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -ethyl} -carbamic acid benzyl ester O 1 HN X____ KN— b ABOUT 1 HN X____ KN— b 1,31 (b) 1.31 b 484 484

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86 86 (1S,2R)-4-(2-hydroxy-1,2- difenyletylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (1 S, 2 R) -4- (2-hydroxy-1,2- Diphenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one I HN /=x HO >7 I HN / = x HO> 7 1,42 (b) 1.42 b 503 503 87 87 (±)-4-(2-[1,3]dioxolán-2- yletylamino)-3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol2-yl)-1 H-pyridín-2-ón (±) -4- (2- [1,3] dioxolan-2 ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one Αγφ I Y Αγφ I Y 1,24 (b) 1.24 b 407 407 88 88 metylester (±)-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyrídín-4ylamino]-3-fenylpropiónovej kyseliny (±) -2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-methyl ester 1,2-dihydropyridin-4-ylamino] -3-phenylpropionic acid HN MeOOC ff~~\ HN MeOOC ff 1,44 (b) 1.44 (b) 469 469 89 89 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(2- 2H-[1,2,3]-triazol-2- yletylamino)-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- (2- 2H- [1,2,3] triazol-2 ylethylamino) -1H-pyridin-2-one ,N=i | HN '---\ H-N, N = i | HN '--- \ HN 1,05 (b) 1.05 b 402 402 90 90 (±)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-4-[( 1 -fény I-1 -pyridín-2ylmetyl)amino-1 H-pyrid i n-2ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4 - [(1-phenyl-1-pyridin-2-ylmethyl) amino-1H-pyridin-2-one Λ1 H ý~NH LAh-HU I HN^Λ1 H ý ~ NH LAh-HU I HN ^ 1,35 (b) 1.35 b 474 474 91 91 (1 R,2S)-4-(1 -hydroxyindán- 2-ylamino)-3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol- 2-yl)-1 H-pyridín-2-ón (1R, 2S) -4- (1-Hydroxyindan- 2-ylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole- 2-yl) -1H-pyridin-2-one I % I % 1,35 (b) 1.35 b 439 439 92 92 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4(fenetylamino-1 H-pyrid ín-2ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 (phenethylamino-1H-pyridin-2-one) ιΖγΎ 1 HN A ιΖγΎ 1 HN A 1,51 (b) 1.51 b 411 411

101101

93 93 (±)-4-[2-hydroxy-2-(3hyd roxyfe nyl)ety lam ino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-Hydroxy-2- (3-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ý—NH IZrv KN OH M OH NH— NH IZrv KN OH M OH 1,15 (a) 1.15 (a) 443 443 94 94 (S)-4-[1-hydroxymetyl-2-(4hydroxyfenyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [1-Hydroxymethyl-2- (4-hydroxy-phenyl) -ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ΙΛΛν I HO-~--S OH ΙΛΛν I HO - ~ - OH 1,1 (b) 1,1 b 457 457 95 95 (R)-4-(2-hydroxy-2-pyridin-2yl-etylamino)-3-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol- 2-yl)-1 H-pyridin-2-ón (R) -4- (2-Hydroxy-2-pyridin-2-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole- 2-yl) -1H-pyridin-2-one LXoÚ I HH OH Έ LXoÚ I HH OH Έ 1,09 (a) 1.09 (a) 428 428 96 96 (S)-4-(2-hydroxy-2-pyridín-2yl-etylamino)-3-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol2-yl)-1 H-pyridin-2-ón (S) -4- (2-Hydroxy-2-pyridin-2-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one N Λ /1 H m\ z~ | HH -OH v)N Λ / 1 H m \ z ~ | HH -OH v) 1,09 (a) 1.09 (a) 428 428 97 97 (S)-4-(2-benzylsulfanyl-1 hydoxymetyletylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyrid ίη-2-όη (S) -4- (2-Benzylsulfanyl-1-hydroxymethylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1 H -pyridin-2-one ΙΛΛν JH ---- S-7 OH CPJν JH ---- S- 7 OH CP 1,4 (b) 1.4 b 487 487 98 98 4-(2-hydroxyetylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (2-hydroxyethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 7=1 h 0. y-NH I HH X\ OH7 = 1 h 0. y-NH 1 HH X 1 OH 0,93 (b) 0.93 b 351 351 99 99 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)[metyl-(2-pyridín-2-yletylamino]-1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) [methyl- (2-pyridin-2-ylethylamino) -1H-pyridin-2-one ,H=1 O V-s^U W 1X, H = 1 0 Vs ^ UW 1X 0,43 (b) 0.43 b 426 426

102102

100 100 (S)-4-( 1 -hyd roxymetyl-2pyridín-2-yletylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- (1-Hydroxymethyl-2-pyridin-2-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one x Γ° x xz^z ir\ x Γ ° x ^ x of the ir \ 0,93 (f) 0.93 f 442 442 101 101 (R)-4-(1-hydroxymetyl-2pyridín-2-yletylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- (1-Hydroxymethyl-2-pyridin-2-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one S-NH I HN qAh S-NH I HN qAh 0,94 (f) 0.94 f 442 442 102 102 dimetylamino-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol2-yl)-1 H-pyridín-2-ón dimethylamino- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one 'ý—NH \ The Y-NH \ 0,70 (f) 0.70 (f) 335 335 103 103 (1S,2S)-4-(2-hydroxy-1hydroxymetyl-2-fenyletylamino)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-όπ (1S, 2S) -4- (2-Hydroxy-1-hydroxymethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one H ° I HN. OH H ° I HN. OH 1,10 (b) 1.10 (b) 457 457 104 104 (±)-4-[2-hydroxy-3-(naftalén- 1-yloxy)propylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2-hydroxy-3- (naphthalene 1-Yloxy) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one C* a Y- HN OH A C * and Y- HN OH A 1,53 (b) 1.53 b 507 507 105 105 (1R,2R)-4-(2-benzyloxy-1hydroxymetylpropylamino)-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (1R, 2R) -4- (2-Benzyloxy-1-hydroxymethyl-propylamino) -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one (A « v I Hŕj, (And in I Hŕj, 3,14 (a) 3.14 (a) 485 485 106 106 benzylester (S)-3-hydroxy-2[3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-2oxo-1,2-dihydropyridí n-4ylaminojpropiónovej kyseliny (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-) -benzyl ester 1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino-propionic acid V'NvXX^N V-NH I HN °H \ /—' 0 V'NvXX N ^ V-NH H N ° I H \ / - '0 2,95 (a) 2.95 (a) 485 485

103103

107 107 metylester (S)-3-hydroxy-2[3-(6-imidazol-1 -yl-4-metyl1 H-benzoimidazol-2-yl)-2oxo-1,2-dihydropyrid í n-4ylamino]propiónovej kyseliny (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -propionic acid methyl ester C1VÄ I HN O-< OH / Λ C1 VÄ HN O- <OH / Λ 2,29 (a) 2.29 (a) 409 409 108 108 (S)-2-[3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihyd ropy rid i n4-ylamino]-3-pyridín-2-ylpropiónová kyselina (S) -2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-4-ylamino] -3-pyridin-2 -ylpropionic acid Λα °. I HN^ OH Λα °. 1 HN 4 OH 0,94 (f) 0.94 f 456 456 109 109 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4(pyridín-4-ylamino)-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4 (pyridin-4-ylamino) -1H-pyridin-2-one Yhh I HM b YHH I HM b 1,15 (a) 1.15 (a) 384 384 110 110 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4(pyridín-4-ylamino)-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4 (pyridin-4-ylamino) -1H-pyridin-2-one y- HN b y- HN b 0,65 (f) 0.65 f 384 384 111 111 (S)-4-[2-(3,4-dihydroxyfenyl)-2-hydroxyetylamino]-3(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-4-1 Hpyridín-2-ón (S) -4- [2- (3,4-Dihydroxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4-1-pyridin-2 -one Za „ a Αγ'-Α V-HH I HN OH Q- OH OH After 'a Αγ'-Α V-HH I HN OH Q- OH OH 1,04 (b) 1.04 b 459 459 112 112 (S)-4-[ 1 -hydroxymetyl-2-(3metylbenzylsulfanyl)etylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (S) -4- [1-Hydroxymethyl-2- (3-methylbenzylsulfanyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one I HN I HN 1,49 (b) 1.49 b 501 501 113 113 (S)-4-[1 -hydroxymetyl-2-(4metylbenzylsulfanyl)etylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1H-pyridin-2-ón (S) -4- [1-Hydroxymethyl-2- (4-methylbenzylsulfanyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one b Vbp l HN y~\ ,___, S-A OH b VBP l HN y ~ \ , S-A OH 1,49 (b) 1.49 b 501 501

104104

114 114 (±)-4-[2-hydroxy-2-(4hydroxy-3-metoxyfenyl)etylamino]-3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (±) -4- [2-Hydroxy-2- (4-hydroxy-3-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2 -one Oyyí J-NH I HN OH OMo OH Oyyi J-NH I HN OH OMO OH 1.10 (b) 1.10 b 473 473 115 ! 4-(2-hydroxy-2-naftalén-1 -yl- I etylamino)-3-(6-imidazol-1 -yl- 4-metyl-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón115 ! 4- (2-hydroxy-2-naphthalen-1-yl-1-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2 -one /~NH | H Ν' ^CH/ ~ NH | HΝΝ ^ CH 1,49(b) 1.49 (b) 477 477 116 116 (S)-N-(1 -karbamoyl-2fenyletyl)-3-hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridín-4ylaminojpropiónamid (S) -N- (1-Carbamoyl-2-phenylethyl) -3-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4ylaminojpropiónamid V«h HO—7 HH-< --' y-NH, 0V H 2 H - 7 H H -? - NH 3 O 1.07 (b) 1.07 b 541 541 117 117 (±)-N-(4'-{1-hydroxy-2-[3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropy rid í η-4-y Iamino]etyl}bifenyl-2yl)metánsulfónamid (±) - N - (4 '- {1-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - 1,2-Dihydropyridin-4-ylamino] ethyl} biphenyl-2-yl) methanesulfonamide ΟγΛγΰ NH | KN HO—/ HHSOjCHj O ΟγΛγΰ NH | KN HO / HHSOjCHj ABOUT 1,34 (b) 1.34 b 596 596 118 118 (±)-N-(4-{1-hydroxy-2-[3-(6- ímidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridi η-4-ylamino]etyl}fenyl)metánsulfónamid (±) -N- (4- {1-hydroxy-2- [3- (6- imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide íl Vnh I HN OH Έ NKSOCH, íl Vnh I HN OH Έ NKSOCH. 1,11 (b) 1.11 b 520 520 119 119 (±)-N-(3-{1 -hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2*dihydropyridin-4-ylamino]etyl}fenyl)metánsulfónamid (±) -N- (3- {1-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - * 1,2 dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide ,H»I O V ] HH OH V Py- NHSG,CHj H , OH, PyNHSG, CH3 1,14 (b) 1.14 b 520 520

105105

120 120 (±)-N-(5-{1-hydroxy-2-[3-(6- imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-d ihydropyrid i η-4-ylamino]etyl}-2-metoxyfenyl)metánsulfónamid (±) -N- (5- {1-hydroxy-2- [3- (6- imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo- 1,2-Dihydropyridin-4-ylamino] ethyl} -2-methoxyphenyl) methanesulfonamide J- XH I HM OH Sk OM· J- XH I HM OH sk OM · 1,12 (b) 1.12 b 550 550 121 121 (±)-N-(2-{1-hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyrid in-4-ylamino]etyl}fenyl)metánsulfónamid (±) -N- (2- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide /=*1 O HN OH f mmsojCH, o / = * 1 O HN OH f mmsojCH, about 1,19 (b) 1.19 b 520 520 122 122 (±)-N-(3-{1-hydroxy-2-[3-(6- imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-d i hyd ropyrid i η-4-ylamino]etyl}fenyl)-4-metylbenzénsulfónamid (±) -N- (3- {1-hydroxy-2- [3- (6- imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) -4-methylbenzenesulfonamide 1 MN OM 1 MN OM 1,33 (b) 1.33 (b) 596 596 123 123 (±)-2,2,2-trifluór-N-(3-{1hydroxy-2-[3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol2-yl)-2-oxo-1,2- dihyd ropyrid í η-4-ylamino]etyl}fenyl)acetamid (±) -2,2,2-Trifluoro-N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1) , 2- dihydrochloride (4-ylamino) ethyl} phenyl) acetamide I HN OH Sk / V-NHCOC*, I HN OH sk / V-NHCOC * 2,97 (a) 2.97 (a) 538 538 124 124 (±)-N-(2-chlór-5-{1 -hydroxy2-[3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-2oxo-1,2-d ihydropyridín-4ylamino]etyl}fenyl)metánsulfónamid (±) -N- (2-Chloro-5- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl) methanesulfonamide | MM OH Sk Cl | MM OH sk Cl 2,75 (a) 2.75 (a) 554 554

106106

125 125 (±)-N-(5-{1 -hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-d ihydropyrid ίη-4-ylamino]etyl}-2-metylfenyl)metánsulfónamid (±) -N- (5- {1-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - 1,2-Dihydropyridin-4-ylamino] ethyl} -2-methylphenyl) methanesulfonamide HM OH H fl hhso,ch> HM OH H fl hhso, ch> 2,73 (a) 2.73 (a) 534 534 126 126 (S)-2-[3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyridín- 4-ylamino]-3-fenyl- propiónová kyselina (S) -2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine- 4-ylamino] -3-phenyl- propionic acid V-NH I HN COOH In NH I HN COOH 1,50 (f) 1.50 f 455 455 127 127 (S)-2-[3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d i hyd ropy rid í n4-ylamino]-N-metyl-3fenylpropiónamid (S) -2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-4-ylamino] -N-methyl- 3fenylpropiónamid ,Ν=η o Vnh XX+p I z5 / ”n— , Ν = η o Vnh XX + p I of 5 / ” n— 1,43 (f) 1.43 (f) 468 468 128 128 (S)-2-[3-(6-imidazol-1-yl-4- metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyridín4-ylamino]-3- fenylpropiónamid (S) -2- [3- (6-imidazol-1-yl-4- methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -3- propionamide ,Ν=η <3 ý-NH ' //° fí' nh2 , Ν = η <3 γ-NH '// ° phi' nh 2 1,39 (f) 1.39 (f) 454 454 129 129 (S)-2-[3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d i hyd ropyrid in4-ylamino]-N,N-dimetyl-3fenylpropiónamid (S) -2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -N, N-dimethyl- 3fenylpropiónamid H % >-NH I ti //° - H% > -NH I ti // ° - 1,48 (f) 1.48 (f) 482 482 130 130 (R)-4-(2-hydroxy-1fenyletylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one y- x y- x 1,44 (f) 1.44 (f) 427 427

107107

131 131 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(3pyridín-2-ylpropylamino)-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-Benzoimidazol-2-yl) -4- (3-pyridin-2-ylpropylamino) -1H-pyridin-2-one ΙλαΡ I HN ΙλαΡ I HN 1,0 (b) 1,0 b 426 426 132 132 (S)-4-(1-benzyl-4-hydroxy-2oxobutylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Benzyl-4-hydroxy-2-oxobutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V- NH | H N, 0 \=/ OH V- NH | H N, O = OH 1,41 (f) 1.41 (f) 483 483 133 133 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(4- pyridín-2-yl-n-butylamino)- 1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- (4- pyridin-2-yl-n-butylamino) - 1H-pyridin-2-one O LXAp HN >> ABOUT LXAp HN >> 1,06 (d) 1.06 d 440 440 134 134 (S)-4-(1-aminometyl-2fenyletylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Aminomethyl-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one A H O. N N V-NH 1 Jl ? x^~n y— 1 H N.A H O. N N V-NH 1 Jl? x ^ ~ ny— 1 H N. 1,27 (f) 1.27 f 440 I 440 I 135 135 (S)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-4-(1-metylaminometyl-2fenyletylamino)-1 H-py ridín-2ón (S) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (1-methylaminomethyl-2-phenylethylamino) -1H-pyridin-2-one N^ / » 0 1 HN,N ^ / 0 0 1 HN, 1,27 (f) 1.27 f 454 454 136 136 (S)-4-(1-dimetylaminometyl- 2-fenyletylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-dimetylaminometyl- 2-Phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 νΝγγΝ >-nh LArO-? HN,0 ν Ν γγΝ> NH LArO-? HN 1,25 (f) 1.25 f 468 468

108108

137 137 4-(4-hydroxybutylamino)-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (4-hydroxybutylamino) -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one T—NH I HN OH T-NH I HN OH 1,19 (f) 1.19 f 379 379 138 138 (±)-4-[2-hydroxy-2-(3trifluórmetylfenyl)etylamino]3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-hydroxy-2- (3-trifluoromethylphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -1H-pyridin-2-one O I HH OH K- ABOUT I HH OH K- 1,40 (b) 1.40 b 495 495 139 139 (±)-4-[2-hydroxy-2-(3,4,5trimetoxyfenyl)etylamino]-3- (6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-hydroxy-2- (3,4,5-trimethoxyphenyl) ethylamino] -3 (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 1 H y— NH 1 HN OH x-7 DU. P*0· ΟΜ»1 H y — NH 1 HN OH x-7 DU . P * 0 · ΟΜ » 1,18 (b) 1.18 b 517 517 140 140 (S)-4-(1-benzyl-2metoxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyrid ίη-2-όη (S) -4- (1-Benzyl-2-methoxyethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 ΙλρΡ 0 ΙλρΡ 1,67 (f) 1.67 (f) 455 455 141 141 4-(3-hydroxypropylamino)-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón 4- (3-hydroxypropylamino) -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ,NSa 0 y™ I )—Z 1 HN OH, N Sa (y) (I) - Z 1 HN OH 0,95 (f) 0.95 (f) 365 365 142 142 (±)-4-[2-hydroxy-1 -(4nitrobenzyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-Hydroxy-1- (4-nitrobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one y- I HN o^yy^'°m γ-1 HN o γ y y m 1,51 (a) 1.51 (a) 486 486

109109

143 143 (±)-4-[1-(2-fluórbenzyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [1- (2-Fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Vhh I HN x0H FVhh I HN x0H F 1,57 (a) 1.57 (a) 459 459 144 144 (±)-4-[1-(3-fluórbenzyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [1- (3-Fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V- « \ NM | HN FV - « NM | HN F 1,57 (a) 1.57 (a) 459 459 145 145 (S)-4-[2-hyd roxy-1 -(4metoxybenzyl)etylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2-Hydroxy-1- (4-methoxybenzyl) ethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one N VhH Lx/yý I HN, MbO—OH N VhH Lx digits / year I HN, MbO-OH 1.54 (a) 1.54 (a) 471 471 146 146 (±)-4-[2-hydroxy-1 -(3hydroxybenzyl)etylamino-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-Hydroxy-1- (3-hydroxybenzyl) ethylamino-3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one Λι H v y—NH IXrV ] HN °H HOΛι H γ - NH IXrV] HN ° H HO 1,38 (a) 1.38 (a) 457 457 147 147 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(izochinolín-3-ylmetyl)amino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 [(isoquinolin-3-ylmethyl) amino] -1H-pyridin-2-one 1,15 (d) 1.15 (d) 448 448 148 148 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4{[4-(3-fenylpropyl)-pyridín-2ylmetyl]amino}-1 H-pyridín-2ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 {[4- (3-phenylpropyl) -pyridin-2-ylmethyl] amino} -1H-pyridin-2-one 1,31 (d) 1.31 (d) 516 516

110110

149 149 3-(6-i midazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(3-metylpyridín-2-ylmetyl)amino]-1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(3-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one Νζ=ί Vnh I HN N=\ •p Νζ = ί Vnh I HN N = \ • p 1,00 (d) 1.00 (d) 412 412 150 150 4-[(3,5-dimetylpyridin-2ylmetyl)amino]-3-(6-ímidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(3,5-Dimethyl-pyridin-2-ylmethyl) -amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V” HH LAMA HN Ύ V ”HH LAMA HN Ύ 1,00 (d) 1.00 (d) 426 426 151 151 4-[(3-hydroxymetylpyridin-2ylmetyl)amino]-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(3-Hydroxymethyl-pyridin-2-ylmethyl) -amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one <Q H % V— NH I hn n== Yl./ HOH2C&Lt; QH% V-NH1Hn == Y1 / HOH 2 C 0,93 (d) 0.93 (d) 428 428 152 152 (S)-4-[2-hydroxy-1-(4hydroxy-3-nitrobenzyl)etylamino]-3-(6-imidazol-1 -yl4-metyl-1 H-benzoimidazol-2yl)-1 H-pyrid ίη-2-όη (S) -4- [2-hydroxy-1- (4-hydroxy-3-nitrobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridyl- 2-όη N’·*, Z H o V-H^yy^n ý—NH N ý—V I H°—OH O2NN '· *, Z H o VH ^ yy ^ n — NH N — — V H H — OH O 2 N 1,47 (a) 1.47 (a) 486 486 153 153 (S)-4-[2-hydroxy-1 -(4jódbenzyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1Hpyridín-2-ón (S) -4- [2-Hydroxy-1- (4-iodobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one /N=n 0 TXyV I HN, O”/ N = n 0 TXyV I HN, O ” 1,73 (a) 1.73 (a) 567 567 154 154 (S)-4-[2-hydroxy-1 -(4hydroxy-3-jódbenzyl)etylamino]-3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-1H-pyridín-2-ón (S) -4- [2-Hydroxy-1- (4-hydroxy-3-iodobenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2- one ,Ν=η o Vnh ΧΧΎ 1 HO-H^y*--í 1, Ν = η o V nh ΧΧΎ 1 HO-H ^ y * - i 1 1,44 (a) 1.44 (a) 583 583

111111

155 155 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(6-metylpyridín-2-ylmetyl)amino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(6-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one /H=1 h °w y-NH V-Φ // H = 1 h ° w y -NH V-Φ / 0.71 (b) 0.71 b 412 412 156 156 4-[2-(5-etylpyridín-2yl)etylamino]-3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol- 2-y l)-1 H-pyridín-2-ón 4- [2- (5-ethylpyridin-2-yl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole- 2-yl) -1H-pyridin-2-one s O 0 '«N s O 0 '«N 1,01 (b) 1.01 b 440 440 157 157 (±)-4-(2,3-dihydroxypropylamino)-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (±) -4- (2,3-Dihydroxypropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one Y H o LArty? | HN ON —OHY H o LArty? | HN ON — OH 1,11 (a) 1.11 (a) 381 381 158 158 (S)-4-[2-hydroxy-1-(4hydroxy-3-metoxybenzyl)etylamino]-3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (S) -4- [2-hydroxy-1- (4-hydroxy-3-methoxybenzyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole-2- yl) -1H-pyridin-2-one I ΗΝ^ HO—/ \>H MeO I ΗΝ ^ HO— / \> H MeO 1,29 (f) 1.29 f 491 491 159 159 (S)-4-[1-(4-fluórbenzyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [1- (4-Fluorobenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /y 0 NN ^~NH F_£yA^0H/ y 0 N N - ~ NH F - R yA ^ O H 1,57 (a) 1.57 (a) 459 459 160 160 (S)-4-[2-hydroxy-1 -(naftalén1-ylmetyl)etylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2-Hydroxy-1- (naphthalen-1-ylmethyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one I OH I OH 1,71 (a) 1.71 (a) 491 491 161 161 4-(2-hydroxy-1 -hydroxymetyletylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (2-hydroxy-1-hydroxymethylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2-one Y H °A y—NH χχγ HN OH HO—7 YH ° A y — NH χχγ HN OH HO— 7 1,00 (f) 1.00 (f) 381 381

112112

162 162 4-(2-hydroxy-1,1-bishydroxymetyletylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- (2-Hydroxy-1,1-bis-hydroxymethylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 7*^ ~ H /-nh I HN ?Voh OH OH7 * ~ ^ H / I H N NH? OH OH OH W 0,89 (f) 0.89 f 411 411 163 163 (±)-4-[2-(3-fluórfenyl)-2- hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-fluorophenyl) -2- hydroxyethylamino] -3- (6imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2-one M H ý-HH HN OH M H Y HH HN OH 1,38 (b) 1.38 b 445 445 164 164 (±)-4-[2-hydroxy-2-(3metoxyfenyl)etylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1Hpyridín-2-ón (±) -4- [2-Hydroxy-2- (3-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one 0 VN ηργ HN OH OM· 0 V N ηργ HN OH OM · 1,35 (b) 1.35 b 457 457 165 165 (±)-4-[2-hydroxy-2-(4metoxyfenyl)etylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazo!-2-yl)-1Hpyridín-2-ón (±) -4- [2-Hydroxy-2- (4-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one ,ν=Ί 0 T HN OH OMé, ν = Ί 0 T HN OH OMe 1,35 (b) 1.35 b 457 457 166 166 (±)-4-(2-hydroxy-3fenylpropylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (2-Hydroxy-3-phenylpropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ti y- 1 HN OH ti y- 1 HN OH 1,44 (b) 1.44 (b) 441 441 167 167 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(3-trifluórmetylpyridín-2ylmetyl)amino]-1 H-pyridín-2ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(3-trifluoromethylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one /Ν=η h °a V-γΑ^Ν VWH HN N=\ /Ž) F,C/ Ν = η h ° and V-γΑ ^ Ν VWH HN N = \ /)) F, C 1,53 (d) 1.53 (d) 466 466

113113

168 168 4-[(6-etoxypyridín-2-ylmetyl)amino]-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón 4 - [(6-ethoxypyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one y- o-/ | HN y- about-/ | HN 1,51 (d) 1.51 (d) 442 442 169 169 4-[(4-chlórpyridín-2-ylmetyl)amino]-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón 4 - [(4-chloropyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one Ύ ““-Q Cl Q ““ -Q Cl 1,38 (d) 1.38 (d) 432 432 170 170 3-(6-imidazol-1 -yl-4-metyl1 H-benzoimidazol-2-yl)-4[(4-fenylpyridín-2-ylmetyl)amino]-1 H-pyrid í n-2ón 3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4 - [(4-phenylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one HZ) HZ) 1,24 (d) 1.24 d 474 474 171 171 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(4-benzyloxypyridín-2ylmetyl)amino]-1 H-pyridi n-2ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(4-benzyloxypyridin-2-ylmethyl) amino] -1H-pyridin-2-one W-p O_H T About Wp _H T 1,14 (d) 1.14 d 504 504 172 172 benzylester (2S,3S)-{2hydroxy-3-[3-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol2-yl)-2-oxo-1,2dihydropyridín-4-ylamino]-4fenylbutylj-karbámovej kyseliny (2S, 3S) - {2-Hydroxy-3- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-pyridin-4-ylamino] -4-phenyl-butyl] -carbamic acid benzyl ester of Z *1 H % V * ? | OH ZXVV-HH Z * 1 H% IN * ? | OH ZXVV-HH 1,59 (f) 1.59 f 604 604 173 173 (S)-4-[ 1 -(4-benzyloxybenzyl)-2-hydroxyetylamino]3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [1- (4-Benzyloxybenzyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -1H-pyridin-2-one Vnh 1 . . 0—V 7 f OH IGB 1 . . 0 — V 7 f OH 1,74 (f) 1.74 (f) 547 547

114114

174 174 3-(6-i m id azo I-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(4-metylpyridín-2-ylmetyl)amino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(4-methylpyridin-2-ylmethyl) amino] -1H-pyridin-2-one S H V—NH LAŕmJ1 , 1 HN /=<SH V - NH Lmr 1 , 1 HN / = < 0,95 (d) 0.95 (d) 412 412 175 175 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(4-metoxypyridín-2-ylmetyl)amino]-1 H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(4-methoxypyridin-2-ylmethyl) amino] -1H-pyridin-2-one o 1 HN /=/ about 1 HN / = / 0,92 (d) 0.92 (d) 428 428 176 176 4-{[6-(3-hydroxypropyl)pyridín-2-ylmetyl]amino}-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón 4 - {[6- (3-Hydroxypropyl) pyridin-2-ylmethyl] amino} -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1H-pyridin-2-one V- HH 1 HN N==\V- HH 1 HN N == \ 0,96 (d) 0.96 (d) 456 456 177 177 4-[(6-aminometylpyridín-2ylmetyl)amino]-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón 4 - [(6-Aminomethyl-pyridin-2-ylmethyl) -amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O j-J /-NH, ABOUT j-J / -NH, 0,99 (b) 0.99 b 427 427 178 178 N-(6-{[3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropy ridín4-ylamino]metyl}pyridín-2ylmetyl)formamid N- (6 - {[3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] methyl} pyridin-2-ylmethyl) formamide .NÄ 0, h' S y—HHCHO. N 0 0, h 'S y — HHCHO 1,02 (b) 1.02 b 455 455 179 179 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4- [(chinolín-2-ylmetyl)aminoJ- 1H-pyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [(Quinolin-2-ylmethyl) aminoJ- 1 H-pyridin-2-one / w N ) Y HH\ \N==// w N) Y HH \ \ N == / 1,16 (b) 1.16 b 448 448 180 180 4-(2-cyklohex-1-enyletylamino)-3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-1 H-pyrid ίη-2-όπ 4- (2-Cyclohex-1-enylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-yl V-NH j HN In NH j HN 1,61 (b) 1.61 b 415 415

115115

181 181 (S)-4-[2-(4-terc-butoxyfenyl)- 1-hydroxymetyletylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [2- (4-butoxyphenyl) - 1-Hydroxymethylethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /N=i o GNH ΐΑφ HN. 0—c 7-- OH/ N = io GNH ΐΑφ HN. O — C 7-- OH 1,61 (f) 1.61 (f) 513 513 182 182 (±)-4-[2-(2,3-dichlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (2,3-Dichloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / 1 H °x\ V” MM I HN OH K» / 1 H ° x \ In ”MM I HN OH K » 1,52 (b) 1.52 b 495 495 183 183 (±)-4-[2-(3,4-difluórfenyl)-2hydroxyetylamino]“3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3,4-Difluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V- j HN OH F IN- j HN OH F 1,34 (b) 1.34 b 463 463 184 184 (S)-4-[2-(3,4-dichlórfenyl)-1 hydroxymetyletylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (3,4-Dichloro-phenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one NH I HN. Cl—OH Cl NH I HN. C-OH Cl 1,67 (f) 1.67 (f) 509 509 185 185 (S)-4-[1 -hydroxymetyl-2-(4hydroxy-2-trifluórmetylfenyl)etylamino]-3-(6-imidazol-1 -yl4-metyl-1 H-benzoimidazol-2yl)-1H-pyridín-2-ón (S) -4- [1-Hydroxymethyl-2- (4-hydroxy-2-trifluoromethylphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2- one HN, HO—oh CF, HN HO-OH CF, 1,46 (f) 1.46 (f) 525 525 186 186 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4- [(izochinolin-1-ylmetyl)- amino]-1 H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [(Isoquinolin-1-ylmethyl) - amino] -1H-pyridin-2-one XaZv XaZv 1,14 (d) 1.14 d 448 448

116116

187 187 (S)-4-[2-(3,4-difluórfenyl)-1hydroxymetyletylamíno]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-όπ (S) -4- [2- (3,4-Difluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one N=ň o I KM. F N = n o I KM. F 1,52 (f) 1.52 (f) 477 477 188 188 4-[(4-hydroxypyridín-2ylrnetyl)amino]-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(4-Hydroxy-pyridin-2-ylmethyl) -amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ’ 0 Ύ T )—f I HN OH'0 Ύ T) - I H N OH F 0,91 (d) 0.91 (d) 414 414 189 189 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-(2piperidín-1-yletylamino)-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- (2-piperidin-1-ylethylamino) -1-pyridin-2-one ,N=-| 0 Ú—N H I HN o, N = - | 0 I — NH I HN o 0,92 (b) 0.92 b 418 418 190 190 (±)-4-(2-hydroxy-2-ptolyletylamino)-3-(6-imidazol1-yl-4-metyl-1H- benzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (2-hydroxy-2-ptolyletylamino) -3- (6-imidazol-1-yl-4-methyl-1 H benzoimidazol-2-yl) -1H-pyridin-2-one T HN OH T HN OH 5,74 (c) 5.74 (c) 441 441 191 191 4-[2-(3,5-bis-trifluórmetylfenyl)-2-hydroxyetylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- [2- (3,5-bis-trifluoromethylphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /=1 H X V N n y-NH 1 HN OH F,C/ = 1 HX V N y-NH 1 HN OH F, C 6,40 (c) 6.40 (c) 563 563 192 192 (±)-4-[2-(3-chlórfenyl)-2metoxyetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyrid ίη-2-όη (±) -4- [2- (3-Chloro-phenyl) -2-methoxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one H % 1 HN OMe H% 1 HN OMe 6,5 (c) 6.5 (c) 475 475

117117

193 193 4-[(4-hydroxymetylpyridin-2ylmetyl)amino]-3-(6-imidazol1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(4-hydroxymethylpyridin-2-ylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 'I HN N=y CH2OH1 H N N = y CH 2 OH 0,9 (b) 0,9 b 428 428 194 194 (+)-4-(2-(3,5-dichlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-όπ (+) - 4- (2- (3,5-Dichloro-phenyl) -2-hydroxy-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /NA h | HN OH ct/ N A h | HN OH ct 1,54 (b) 1.54 b 495 495 195 195 (±)-4-[(4-terc-butyl-1 hydroxycyklohexylmetyl)amino]-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (±) -4 - [(4-tert-Butyl-1-hydroxycyclohexylmethyl) amino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one O H % NH PA/pJ W O H% NH PA / pJ W 3,82 (a) 3.82 (a) 475 475 196 196 terc-butylester (+)-{2hydroxy-3-[3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol2-yl)-2-oxo-1,2dihydropyridín-4ylamino]propyl}karbámovej kyseliny (+) - {2-Hydroxy-3- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-pyridin-4-ylamino] -propyl} -carbamic acid tert-butyl ester 1 HN OH H b-NH 0 k1 HN OH H b-NH 0 k 1,23 (b) 1.23 b 480 480 197 197 (±)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-(3,3,3-trifluór-2hydroxypropylamino)-1 Hpyridín-2-ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (3,3,3-trifluoro-2-hydroxypropylamino) -1-pyridin-2-one /b 0 1 HH OH 'Ά CF3 / b 0 1 HH OH 'Ά CF 3 1,17 (b) 1.17 b 419 419 198 198 (±)-4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2 -one 1 HN OH Py F 1 HN OH Py F 1,40 (b) 1.40 b 479 479

118118

199 199 (±)-4-(2-hydroxy-2-mtolyletylamino)-3-(6-imidazol- 1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (2-hydroxy-2-mtolyletylamino) -3- (6-imidazol 1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one / 1 y—NH 1 HN OH K / 1 Y-NH 1 HN OH The 1,37 (b) 1.37 b 441 441 200 200 (S)-4-(1-hydroxymetyl-3fenylpropylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-3-phenylpropylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 1 HN, cT 0 1 HN, cT 1,56 (f) 1.56 (f) 455 455 201 201 (S)-4-( 1 -hydroxymetyl-2-ρ- tolyletylamino)-3-(6-irnidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-r- tolylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 —NH iXhu 1 HN, 0 —NH iXhu 1 HN, 1,57 (f) 1.57 f 455 455 202 202 (S)~4-[2-(3-fluórfenyl)-1 hydroxymetyletylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [2- (3-Fluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Ϊ HN, OH F Ϊ HN, OH F 1,48 (f) 1.48 (f) 459 459 203 203 (1S,2R)-4-(1-benzyl-2,4dihydroxybutylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (1S, 2R) -4- (1-Benzyl-2,4-dihydroxybutylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one o oh 1 HN, f---' —J *3H about oh 1 HN, f --- ' —J * 3H 1,39 (f) 1.39 (f) 485 485 204 204 (S)-4-[1-hydroxymetyl-2-(3trifluórmetylfenylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [1-Hydroxymethyl-2- (3-trifluoromethyl-phenylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ,N^ 0 XXHu 1 HN, OH F3C N , O XXHu 1 HN, OH F 3 C 1,56 (f) 1.56 (f) 509 509

119119

205 205 3-(6-ím idazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(pyrimidín-2-ylmetyl)amino]1H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(pyrimidin-2-ylmethyl) amino] 1H-pyridin-2-one HN N=\ M. J N— HN N = \ M. J N— 1,16 (b) 1.16 b 399 399 206 206 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(pyrazín-2-ylmetyl)amino]- 1 H-pyridin-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(pyrazin-2-ylmethyl) amino] - 1H-pyridin-2-one NÄ / \ H °Λ NH nAn f HN N=\N R / \ H ° f Λ n A H N NH N = \ 1,14 (b) 1.14 b 399 399 207 207 (±)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-(2-fenyl-1-pyridín-2-yletylamino)-1 H-pyridín-2-ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (2-phenyl-1-pyridin-2-ylethylamino) -1H-pyridin-2-one V- NH LAAy? 1 HN^ V- NH LAAy? 1 HN ^ 1,26 (b) 1.26 b 488 488 208 208 (±)-3-(6-imidazo!-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-(3-fenyl-1-pyridín-2-ylpropylamino)-1 H-pyrid ín-2ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (3-phenyl-1-pyridin-2-ylpropylamino) -1H-pyridin-2-one O {j V-NH L A }—? ý—z ABOUT {N-NH L} -? Y-Z 1,34 (d) 1.34 (d) 502 502 209 209 (±)-4-[2-(3-fluórfenyl)-1 pyridín-2-yletylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Fluorophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one H % N / ý1y 1 HN^ FH% N / Y 1 s ^ 1 HN F 1,31 (d) 1.31 (d) 506 506 210 210 (±)-4-[2-(3-chlórfenyl)-1 pyridin-2-yletylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one On h V 7~NH 1 HN^ /N=\) ClOn h V 7 -NH 1 HN ( N = Cl) 1,39 (d) 1.39 (d) 522 522 211 211 4-[2-(2-fluórfenyl)-1 -pyridín- 2-yletylamino]-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-ľ-yO-l Hpyridín-2-ón 4- [2- (2-fluorophenyl) -1-pyridine- 2-Ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-1'-yl-1-pyridin-2-one Y™ IZn>_V Hŕ/ FY ™ IZn > H / F 1,33 (d) 1.33 (d) 506 506

120120

212 212 (±)-4-[2-(3-brómfenyl)-1 pyridín-2-yletylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromophenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one I HN Br I HN br 1,40 (d) 1.40 (d) 566 566 213 213 (±)-4-[2-(2-brómfenyl)-1 pyridín-2-yletylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (2-Bromo-phenyl) -1-pyridin-2-ylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /Nä1 0 N ý—NH MN/ Sf/ Na 1 0 Na — NH MN / Sf 1,45 (d) 1.45 (d) 566 566 214 214 (±)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-[2-(2-jódfenyl)-1 pyridín-2-yl-etylamino]-1 Hpyridín-2-όη (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- [2- (2-iodophenyl) -1-pyridin-2-yl-ethylamino] -1-pyridin-2 -όη /i θ ý—NH ϊχΗμ* HN/ 1/ i θ ý — NH ϊχΗμ * HN / 1 1,47 (d) 1.47 (d) 614 614 215 215 (±)-4-[2-(2-chlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyrid ίη-2-όη (±) -4- [2- (2-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 1 HN OH 1 HN OH 1,21 (i) 1.21 i 461 461 216 216 4-[3-(4-cyklopentylamino-6propoxy-[1,3,5]triazín-2yloxy)propylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4- [3- (4-Cyclopentylamino-6-propoxy- [1,3,5] triazin-2yloxy) propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridine- 2-one | HN G-0 , L7- | HN G-0, L7- 1,67 (b) 1.67 b 585 585 217 217 (±)-3-{1 -hydroxy-2-[3-(6- imidazol-yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridín-4ylaminojetyljbenzonitril (±) -3- {1-Hydroxy-2- [3- (6- imidazol-yl-4-methyl-1H-benzimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4ylaminojetyljbenzonitril n z n z 1,20 (b) 1.20 b 452 452

121121

218 218 (±)-4-(2-bifenyl-3-yl-2hydroxyetylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- (2-Biphenyl-3-yl-2-hydroxy-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 1,51 (b) 1.51 b 503 503 219 219 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 7 Π M 0. N V—NH HN OH K-7 Π M 0. NV — NH HN OH K- 1,35 (f) 1.35 (f) 447 447 220 220 (S )-4-[ 1 -hydroxymetyl-2-(2metoxyfenyl)etylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [1-Hydroxymethyl-2- (2-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / 1 H ΟΛ y—NH 1 KN^ (Qh-XXh OMe/ 1 H Ο Λ y — NH 1 KN ^ (Qh-XXh OMe 1,52 (f) 1.52 (f) 471 471 221 221 (S)-4-[ 1 -hydroxymetyl-2-(3metoxyfenyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [1-Hydroxymethyl-2- (3-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Q V- NH 1 HN. OH MoO Q V - NH 1 HN. OH MoO 1,42 (f) 1.42 (f) 471 471 222 222 (S)-4-[1-hydroxymetyl-2-(3nitrofenyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [1-Hydroxymethyl-2- (3-nitrophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O°XNH I hn, OH o3n0 ° X NH 1 hn, OH o 3 n 1,27 (f) 1.27 f 486 486 223 223 (S)-4-[3-(2-benzotiazol-2ylfenoxy)-2-hyd roxypropylamino]-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (S) -4- [3- (2-Benzothiazol-2-yl-phenoxy) -2-hydroxy-propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine- 2-one (=1 H v T HN -pH ccX (= 1 H at T HN -pH CCX 1.47 (j) 1.47 j 590 590

122122

224 224 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2 -one I HN OH OMe I HN OH OMe 1,35 (j) 1.35 (j) 535 535 225 225 (S)-4-(1-benzyl-2-hydroxy-2metyl-propylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- (1-Benzyl-2-hydroxy-2-methyl-propylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / | H 0 X-Nxŕx^Sx<-N V— NH I HN, ./ | X @ H 0 N x S x t x ^ <-NV- NH I HN. 22,07 22,07 HPLC HPLC 226 226 (R)-4-( 1 -benzyl-2-hyd roxy-2metyl-propylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- (1-Benzyl-2-hydroxy-2-methyl-propylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /N=l h V^nx^x,n y— NH XXHu I HN ,/ N = 1h V ^ n x ^ x, ny - NH XXHu I HN, 22,09 22,09 HPLC HPLC 227 227 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4- [(5-metylpyridín-2-ylmetyl)amino-1 H-pyridin-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [(5-methylpyridin-2-ylmethyl) amino-1H-pyridin-2-one Ό^^^Ν 'V-NH I HN Ν» V-NH I HN Ν » 0,99 (d) 0.99 (d) 412 412 228 228 (±)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-(2-fenyl-2-pyridín-2-ylpent-4-enylamino-1 Hpyridin-2-ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (2-phenyl-2-pyridin-2-ylpent-4-enylamino-1H-pyridin-2-one /T H % \^Nxy^x--N y—NH/ TH% \ ^ N xy ^ x - N y — NH 1,41 (d) 1.41 (d) 528 528 229 229 (±)-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-4-(2-fenyl-2-pyridín-2-yletylamino)-1 H-pyridín-2-ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (2-phenyl-2-pyridin-2-ylethylamino) -1H-pyridin-2-one X- N NH T HN j) wX - N NH T HN j) w 1,22 (d) 1.22 d 488 488

123123

230 230 6-{[3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d ihydropyrid ín- 4-ylamino]metyl}nikotínonitril 6 - {[3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine- 4-ylamino] -methyl} -nicotinonitrile 'U- N N NH I HN N=X CN NH-NHN HNN = X CN 1,22 (d) 1.22 d 423 423 231 231 (±)-4-[2-(5-bróm-2-metoxyfenyl)-2-hydroxyetylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (5-Bromo-2-methoxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2 -one o 1— NH LAAV 1 HN OH μ·°Ο^βγ o 1 - NH LAAV 1 HN OH µ · ° Ο ^ βγ 1,27 (i) 1.27 i 535 535 232 232 (±)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl) -4-(1 -pyridín-2-yletylamino)-1 H-pyridin-2-ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (1-pyridin-2-ylethylamino) -1H-pyridin-2-one Λ=ι 0 TXrp HNTX = ι 0 TXrp HN 1,12 (d) 1.12 d 412 412 233 233 (±)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-4-(1 -pyridín-2-ylpropylamino)-1 H-pyridín-2ón (±) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (1-pyridin-2-ylpropylamino) -1H-pyridin-2-one 1 HN N=\ /O 1 HN /ABOUT 1,17 (d) 1.17 d 426 426 234 234 (±)-4-[2-(3-bróm-4-fluórfenyl)-2-hydroxyetylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-fluorophenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridine-2- one 1 HN OH Q- F 1 HN OH Q- F 1,24 (i) 1.24 i 523 523 235 235 (±)-4-[2-(5-bróm-2-fluórfenyl)-2-hyd roxyetylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (5-Bromo-2-fluorophenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2 -one O NH HN OH F—Br NH NH OH F — Br 1,15 (i) 1.15 i 523 523

124124

236 236 (±)-4-[2-(3,5-dibrómfenyl)-2hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3,5-Dibromophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one NH U'-Z'V I HN OH Br NH U'-Z'V I HN OH br 1,30 (i) 1.30 i 583 583 237 237 (±)-4-[2-(3-brómfenyl)-2hydroxypropylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-Bromo-phenyl) -2-hydroxy-propylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Λη H --N y-NH HN I \__L.OH CH Λη H --N y-NH HN I \ __ L.OH CH 1,90 (d) 1.90 (d) 519 519 238 238 (E)-4-[2-(3-brómfenyl)-2hydroxyiminoetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazoi-2-yl)-1 Hpyridín-2-ón (E) -4- [2- (3-Bromophenyl) -2-hydroxyiminoethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Ο'γ-ΐ^Ν V- NH I HN N—OH -'Γ-ΐ ^ Ν V-NH 1 HN N — OH 7,81 (e) 7.81 e 518 518 239 239 (Z)-4-[2-(3-brómfenyl)-2hydroxyiminoetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (Z) -4- [2- (3-Bromophenyl) -2-hydroxyiminoethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one | HN HOv ) H“| HN HO v) H ' 7,91 (e) 7.91 e 518 518 240 240 (R)-4-(3-hydroxy-1fenylpropylamino)-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (R) -4- (3-Hydroxy-1-phenyl-propylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O ΧχΝ-γ-xb VNK LAHp I hn.O ΧχΝ-γ-xb in NK LAHp I hn. 1,48 (f) 1.48 (f) 441 441 241 241 (S)-4-(3-hydroxy-1fenylpropylamino)-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (3-Hydroxy-1-phenyl-propylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / A u % V-Ν^ΧγΝ V—NH ch™ / A u% V-Ν ^ ΧγΝ V-NH ch ™ 1,48 (f) 1.48 (f) 441 441

125125

242 242 (S)-4-(3-hydroxy-1-(2jódfenyl)propylamino)-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- (3-Hydroxy-1- (2-iodophenyl) propylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 'V-NH —V ' 1 HN "W-NH -IN 1 HN 1.61 (f) 1.61 f 567 567 243 243 (S)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (S) -4- [2- (3-bromophenyl) -2- hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V-NH 1 HN .OH In NH 1 HN .OH 1.35 (b) 1.35 b 505 505 244 244 (S)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one LA AM 1 HN OH LA AM 1 HN OH 1,30 (b) 1.30 b 461 461 245 245 (R)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /=1 H °\\ >-NH LAAM | HN OH / = 1 H ° \\ > NH LAAM | HN OH 1,37 (b) 1.37 b 461 461 246 246 (R)-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (R) -4- [2- (3-Bromo-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /1 H °Λ 1 HN OH A·' / 1 H ° Λ 1 HN OH · A ' 1,35 (b) 1.35 b 505 505 247 247 4-[2-(3-chlórfenyl)etylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón 4- [2- (3-chlorophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one M IX AM 1 HN y. M IX AM 1 HN y. 1,53 (b) 1.53 b 445 445

126126

248 248 (±)-4-[2-(3-chlór-4-hydroxyfenyl)-2-hydroxyetylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-4-hydroxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one y h v V-NH | HN pH P OH y h in V-NH | HN pH P OH 1,15 (b) 1.15 b 477 477 249 249 (±)-4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2 -one I KN OH OMa I CN OH OMe 1,24 (b) 1.24 b 491 491 250 250 (±)-4-{2-[3-chlór-4-(2-metylalyloxy)fenyl]-2-hydroxyetylamino}-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (±) -4- {2- [3-chloro-4- (2-methylalyloxy) phenyl] -2-hydroxyethylamino} -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) - 1H-pyridin-2-one 7=1 H >—HH Xzyy? I HN OH P“ 7 = 1 H > —HH Xzyy? I HN OH P " 1,46 (b) 1.46 b 531 531 251 251 (±)-[2-(3-brómbifenyl-3-yl-2hydroxyetylamino]-3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) - [2- (3-Bromobiphenyl-3-yl-2-hydroxyethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one o | HN OH about | HN OH 1,44 (i) 1.44 (i) 581 581 252 252 (±)-4-(2-hydroxy-2- [1 ,ľ,3',1 )terfenyl-5-yletylamino)-3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol- 2-yl)-1 H-pyridin-2-ón(±) -4- (2-hydroxy-2- [1,1 ', 3', 1) terphenyl-5 - ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole-2) -yl) -1H-pyridin-2-one Q - v cx/y? 1 KM OH Q - v cx / y? 1 KM OH 1,48 (i) 1.48 (i) 579 579 253 253 (±)-4-[2-(3-chlór-4-propoxyfenyl)-2-hydroxyetylamino]-3- (6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-chloro-4-propoxy-phenyl) -2-hydroxy-ethylamino] -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one y * v >-NH 1 HN OH P o— y * v > NH 1 HN OH After- 1,76 (b) 1.76 b 519 519

127127

254 254 3-[3-(6-i mid azol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-2oxo-1,2-dihydropyridín-4ylamino]-N-fenylpropiónamid 3- [3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -N-phenylpropionamide H ° N ς NH I HN ÓH ° N ς NH I HN Ó 1,13 (i) 1.13 i 454 454 255 255 (±)-4-[2-hydroxy-2-(3nitrofenyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2-Hydroxy-2- (3-nitrophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0«^» V I HN OH HO, 0 «^» V I HN OH HO 1,20 (i) 1.20 i 472 472 256 256 4-[2-(5-bróm-2-metoxyfenyl)etylamino]-3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-1H-pyridín-2-ón 4- [2- (5-bromo-2-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one NH I HN \< OMe fi NH I HN \ <OMe Fiction 1,51 (i) 1.51 (i) 519 519 257 257 2-[3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-2oxo-1,2-dihyd ropyrid ín-4ylamino]-N-fenyl-acetamid 2- [3- (6-Imidazol-1-yl) -4-methyl- 1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -N-phenyl-acetamide Λη H o V-N \ I HN 0Hη H o V - N \ I HN 0 1.25 (i) 1.25 i 440 440 258 258 (R)-N-{2-[3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d ihyd ropy rid ín4-ylamino]-2-fenyletyl}metánsulfónamid (R) -N- {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-4-ylamino] -2- phenyl-ethyl} methanesulfonamide Cyyi! V* J/=\ NHSOjCH, W Cyyi! IN* J / = \ NHSOjCH, W 1,35 (h) 1.35 (h) 504 504 259 259 (S)-N-{2-[3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d ihyd ropy rid ín4-ylami no]-1 -fenylety l}~ metánsulfónamid (S) -N- {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydro-pyridin-4-ylamino] -1 Phenylethyl 1-methanesulfonamide T HN NHSOjCHj o T HN NHSOjCHj about 1,32 (h) 1.32 (h) 504 504

128128

260 260 (±)-N-(2-chlór-4-{1 -f I uór-2-[3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridin-4ylamino]etyl}fenyl)-2,2,2trifluóracetamid (±) - N- (2-Chloro-4- {1-fluoro-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) -2,2,2trifluóracetamid 0 A-N H I HN F Á- NHCOCF, 0 A-N H I HN F Á- NHCOCF. 1,30 (b) 1.30 b 574 574 261 261 3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-4[(piperidín-4-ylmetyl)amino]1H-pyridín-2-ón 3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4 - [(piperidin-4-ylmethyl) amino] 1H-pyridin-2-one Z > H °Λ V— NH IX'HJ γ H>Z> H ° Λ V - NH IX'HJ γ H> 0,90 (b) 0.90 (b) 404 404 262 262 (±)-4-[2-(3-bróm-5-pyridín-3ylfenyl)-2-hydroxyetylamino]3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-bromo-5-pyridin-3ylfenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -1H-pyridin-2-one V·* I HN OH O~B' o* HN OH O ~ B 'o 1.18 (a) 1.18 a 582 582 263 263 etylester (±)-(2-chlór-4-{1hydroxy-2-[3-(6-imidazol-1 yl-4-metyl-1 H-benzoimidazol2-yl)-2-oxo-1,2dihydropyridín-4-ylamino]etyl}fenyl)karbámovej kyseliny (±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine-4-) ethyl ester ylamino] ethyl} phenyl) carbamic acid I HN OH Ä;· I HN OH R, · 1.36 (b) 1.36 b 548 548 264 264 (±)-N-(2-chlór-4-{1-hydroxy2-[3-(6-imidazol-1-yl-4-metyl- 1 H-benzoimidazol-2-yl)-2oxo-1,2-d ihyd ropyrid í n-4ylamino]etyl}fenyl)-2,2dimetylpropiónamid (±) -N- (2-chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl) -2,2-dimethylpropionamide | HH OH CH | HH OH CH 1,42 (b) 1.42 b 560 560 265 265 (S)-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-4-(1-hydroxymetyl-2pyridin-3-yl-etylamino)-1 Hpyridín-2-ón (S) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-pyridin-3-yl-ethylamino) -1H-pyridin-2-one o I OH about I OH 0,78 (b) 0.78 b 442 442

129129

266 266 (S)-3-hydroxy-2-[3-(6imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridín-4ylamino]-N-naftalén-1ylpropiónamid (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] -N-naphthalen-1ylpropiónamid y-yQ KO—7 HN—k /]y-yQ KO— 7 HN — k /] 1,41 (b) 1.41 b 520 520 267 267 (S)-3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-4-[1-(1 H-indol-3-ylmetyl)2-hydroxyetylamino]-1 Hpyridín-2-ón (S) -3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -4- [1- (1H-indol-3-ylmethyl) 2-hydroxyethylamino] -1H-pyridin-2- one ov y Η I HN,o v y Η I HN, 1.22 (b) 1.22 b 480 480 268 268 (S)-4-[3-hydroxy-1-(1Himidazol-4-yl)propylamino]-3(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [3-Hydroxy-1- (1H-imidazol-4-yl) -propylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O * v N\ NH T HN, n __/ HO*O * in N \ NH T HN, n __ / HO * 0,75 (b) 0.75 b 431 431 269 269 (±)-4-[2-(3,4-dichlórfenyl)-2hydroxyetylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3,4-Dichloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one / “1 U 0A V- H N /~HH 1 HH OH Cl/ “1 U 0 A V- H N / ~ HH 1 HH OH Cl 1.48 (b) 1.48 b 495 495 270 270 (±)-1 -(2-ch lórety l)-3-(2-ch lór- 4-{1 -hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridin-4- ylamino]etyl}fenylmočovina (±) -1- (2-chloroethyl) -3- (2-chloro- 4- {1-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4 ylamino] ethyl} phenyl urea O Z-**4 HH OH Ίο--. HN—·. '—aOZ - ** 4 HH OH Ίο--. · HN. 's 1,26 (b) 1.26 b 581 581

130130

271 271 izopropylester (±)-(2-chlór-4{1 -hyd roxy-2-[3-(6-imidazol1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-d i hydropyridín-4-ylamino]etyl}fenyl)karbámovej kyseliny (±) - (2-Chloro-4 {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - isopropyl ester 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid 7^ u HN OH Λ j °Λ 7 ^ u HN OH Λ j ° Λ 1,41 (b) 1.41 b 562 562 272 272 izobutylester (±)-(2-chlór-4{1-hydroxy-2-[3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridín-4ylamino]etyl}fenyl)karbámovej kyseliny (±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] -butyl ester 1,2-dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid ä, 0 7 HH OH ä, 0 7 HH OH 1,49 (b) 1.49 b 576 576 273 273 (S)-3-hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridin-4- ylamino]-N-naftalén-2ylpropiónamid (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo- 1,2-dihydropyridin-4 ylamino] -N-naphthalen-2ylpropiónamid N-. I HN, 0 HO—f—V N. I HN, 0 HO-F-W 1,36 (b) 1.36 b 520 520 274 274 (S)-3-hydroxy-2-[3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyrid ín-4ylamino]-N-(4-metoxynaftalén-2-yl)propiónamid (S) -3-Hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo- 1,2-Dihydropyridin-4-ylamino] -N- (4-methoxynaphthalen-2-yl) propionamide ho—l OMe it-l OMe 1,45 (b) 1.45 b 550 550 275 275 (S)-{2-[3-(6-imidazol-1 -yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihyd ropyridín4-ylamino]-1-fenyletyl}etánsulfónamid (S) - {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} ethanesulfonamide W | HK MMSOjCHjCHj W | HK MMSOjCHjCHj 1,47 (b) 1.47 b 518 518

131131

276 276 metylester (±)-(2-chlór-4-{1hydroxy-2-[3-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol- 2-yl)-2-oxo-1,2- dihydropyridír>-4ylamino]etyl}fenylkarbámovej kyseliny (±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazole) - 2-yl) -2-oxo-1,2- dihydropyridir-4-ylamino] ethyl} phenylcarbamic acid HH I HN OH ¥ c— HH I HN OH ¥ c- 1.23 (b) 1.23 b 534 534 277 277 (±)-4-[ 1 -hydroxymetyl-2-(2hydroxy-3-metylfenyl)etylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón (±) -4- [1-Hydroxymethyl-2- (2-hydroxy-3-methylphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2 -one O H V Y-N N\ N H I HN ' OHOHV Y - NN \ NH I HN 'OH 1,29 (b) 1.29 b 471 471 278 278 (S)-4-[2-(5-bróm-2-metoxyfenyl)-1hydroxymetyletylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (5-Bromo-2-methoxyphenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 Br 0 br 1,48 (b) 1.48 (b) 549 549 279 279 4-(2S-hydroxy-1-indán-1yletylamino)-3-(6-imidazol-1yl-4-metyl-1 H-benzoimidazol2-yl)-1 H-pyridín-2-ón 4- (2S-Hydroxy-1-indan-1-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one I HN /r, -/ W I HN / R, - / W 1,42 (b) 1.42 b 467 467 280 280 (±)-4-[2-(3-bróm-4-metylfenyl)-2-hydroxyetylamino]-3(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methylphenyl) -2-hydroxyethylamino] -3 (6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl) -1-pyridin-2 -one VnH LXYp | HN OH Q- V HH LXYp | HN OH Q- 1,43 (b) 1.43 b 519 519 281 281 3-(6-imidazol-1 -yl-4-metyl- 1 H-benzoimidazol-2-yl)-4-[2- (1 H-indol-5-yl)etylamino]-1 Hpyridín-2-ón 3- (6-Imidazol-1-yl-4-methyl- 1H-benzoimidazol-2-yl) -4- [2- (1H-Indol-5-yl) ethylamino] -1H-pyridin-2-one /~NH ΙΑΛήΑ HN Ύ N H/ ~ NH ΙΑΛήΑ HN Ύ N H 1,54 (b) 1.54 b 450 450

132132

282 282 (S)-3-(5-bróm-2-metoxyfenyl)-2-[3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyrid í n4-ylamino]propiónová kyselina (S) -3- (5-Bromo-2-methoxyphenyl) -2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine] n-4-ylamino] propionic acid ,N=i Ox ' P^VcOOH čr Br, N = O and x '^ P cr Br VcOOH 1,09 (b) 1.09 b 563 563 283 283 (S)-{2-[3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-di hydropyrid í n4-ylamino]-1 -fenyletyl}amid kyseliny propán-2-sulfónovej (S) - {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} propane-2-sulfonic acid amide J. H MU I HN HN-S. Έ J. H MU I HN HN-S. Έ 1,34 (b) 1.34 b 532 532 284 284 (S)-{2-[3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyrid í n4-ylamino]-1 -fenyletyl}amid kyseliny tiofén-2-sulfónovej (S) - {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} amide thiophene-2-sulfonic acid 1 HN HN-S, Έ 1 HN HN-S Έ 2,45 (a) 2.45 (a) 572 572 285 285 (S)-N-{2-[3-(6-imidazol-1-yl- 4-metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d ihydropyrid í n4-ylamino]-1 -fenyletyl}metánsulfonylbenzénsulfónamid (S) -N- {2- [3- (6-imidazol-1-yl 4-Methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} methanesulfonylbenzenesulfonamide | HN HN-SV | HN HN-S V 1,34 (b) 1.34 b 644 644 286 286 (S)-N-{2-[3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-dihydropyrid in4-ylamino]-1 -fenyletyl}benzénsulfónamid (S) -N- {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylethyl} benzenesulfonamide ΟνΛ.» S-NH 1 HN NHSOjPh S-NH 1 HN NHSOjPh 1,60 (b) 1.60 b 566 566 287 287 (S)-2-{3-hydroxy-[3-(6- imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridín-4ylamino]propyl}benzonitril (S) -2- {3-hydroxy [3- (6- imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -2-oxo- 1,2-dihydropyridin-4-ylamino] -propyl} -benzonitrile °··α:φ· I HN <^~OH CN ° · · α: φ · I HN <^ -OH CN 1,16 (b) 1.16 b 466 466

133133

288 288 (S)-4-(1 -hydroxymetyl-2-o- tolyletylamino)-3-(6-imidazol1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-o-) tolylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one o I HN Q_AOho I HN Q_A O h 1.33 (b) 1.33 b 455 455 289 289 (S)-5-bróm-3-[6-(2-brómimidazol-1-yl)-4-metyl-1Hbenzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -5-Bromo-3- [6- (2-bromoimidazol-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2 -one Br /-f V NH | HN Br br / f In NH | HN Br 1,36 (b) 1.36 b 597 597 290 290 (S)-4-[2-(2-chlór-6-fluórfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1 -y I-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (S) -4- [2- (2-chloro-6-fluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine -2-one /=1 H % I F HN, ~OH Cl / = 1 H% I F HN, -OH Cl 1,40 (a) 1.40 (a) 493 493 291 291 (S)-4-[2-(2,5-difluórfenyl)-1 hydroxymetyletylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (2,5-Difluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one «3 h v I F HN, F «3 hrs I F HN, F 1,44 (a) 1.44 (a) 477 477 292 292 (S)-4-[1-hydroxymetyl-2-(2metoxyfenyl)etylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [1-Hydroxymethyl-2- (2-methoxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Vy<yN VNH 1 HN, °H OMeVy <yN VNH 1 HN, ° H OMe 1.52 (f) 1.52 f 471 471 293 293 (S)-4-[2-(2,6-difluórfenyl)-1hydroxymetyletylamino]-3-(6imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (2,6-Difluorophenyl) -1-hydroxymethylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Vy^N V- NH 1 F HN, <0-)~\h F You N, N-NH 1 F HN, <0-) ~ \ h F 1,42 (a) 1.42 (a) 477 477

134134

294 294 (S)-4-[2-(2,6-dichlórfenyl)-1 hydroxymetyletylamino]-3-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- [2- (2,6-Dichloro-phenyl) -1-hydroxy-methylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one /=) o 't- -N —NH I CIHN, OH Cl / =) o 1 --N - NH I CIHN, OH Cl 1,42 (a) 1.42 (a) 509 509 295 295 (S)-4-[1-hydroxymetyl-(2trifluórmetoxyfenyl)etylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (S) -4- [1-Hydroxymethyl- (2-trifluoromethoxy-phenyl) -ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one V-NH I Hlí; Xoh OCFjV-NH 1 H 1; X oh OCFj 1,48 (a) 1.48 (a) 525 525 296 296 (S)-N-{2-[3-(6-imidazol-1-yl4-metyl-1 H-benzoimidazol-2yl)-2-oxo-1,2-d ihydropyridin4-ylamino]-1-fenylpropyl}metánsulfónamid (S) -N- {2- [3- (6-Imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] -1-phenylpropyl} methanesulfonamide Ό NH I HN. £yV^NHso2eH3 Ό NH I HN. N, N 2 O 5 2 eH 3 1,31 (a) 1.31 (a) 518 518 297 297 (S)-2-{4-[2-(2-chlórfenyl)-1hydroxymetyletylamino]-2oxo-1,2-dihydropy rid í η-3-y I}7-metyl-3H-benzoimidazol-5karbonitril (S) -2- {4- [2- (2-Chloro-phenyl) -1-hydroxy-methylethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbonitrile 0 NC<.zZ^ N V-NH XXht? | HN Cl0 NC <.zZ ^ N V-NH XXht? | HN Cl 1,80 (b) 1.80 b 434 434 298 298 (S)-2-[4-( 1 -hyd roxymetyl-2pyridín-3-yletylamino)-2-oxo- 1,2-dihydropyridín-3-yl]-7metyl-3H-benzoimidazol-5karbonitril (S) -2- [4- (1-Hydroxymethyl-2-pyridin-3-ylethylamino) -2-oxo- 1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carbonitrile n /—NH ΧΧ'Χ? I HN Q-ľ-y n / —NH ΧΧ'Χ? I HN Q-D-yl 1,07 (b) 1.07 b 401 401 299 299 (S)-2-[4-(1-hydroxymetyl-2pyridín-4-yletylamino)-2-oxo1,2-d ihyd ropyrid ín-3-yl}-7metyl-3H-benzoimidazol-5karbonitril (S) -2- [4- (1-Hydroxymethyl-2-pyridin-4-ylethylamino) -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbonitrile V-NH OcHu I HN /z___ N^^--/ OH In NH OcHu I HN /from___ N 1 - / OH 1,16 (b) 1.16 b 401 401

135135

300 300 (S)-2-[4-(1 -hydroxymetyl-2tiofén-2-yletylamino)-2-oxo1,2-di hydropy rid ίη-3-y l]-7metyl-3H-benzoimidazol-5karbonitril (S) -2- [4- (1-Hydroxymethyl-2-thiophen-2-ylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile N c I HN N c I HN 1,73 (b) 1.73 b 406 406 301 301 (S)-2-[4-(2-benzo[b]-tiofén-3yl-1 -hydroxymetyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7-metyl-3Hbenzoimidazol-5-karbonitril (S) -2- [4- (2-Benzo [b] -thiophen-3-yl-1-hydroxymethylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile V °x\ /-NH I HN S/,_____ 7%—/\°H In ° C, -NH 1 HN S, _____ 7% - / ° C 1,84 (b) 1.84 b 456 456 302 302 7-metyl-2-{2-oxo-4-[(pyridín- 2-ylmetyl)amino]-1,2dihydropyridin-3-yl}-3Hbenzoimidazol-5-karbonitril 7-Methyl-2- {2-oxo-4 - [(pyridin 2-ylmethyl) amino] -1,2dihydropyridin-3-yl} -3Hbenzoimidazol-5-carbonitrile H '0 *γ%-Ν)-ΚΗ HN N=\ H '0 * γ% -Ν) -ΚΗ HN N = \ 1,30 (b) 1.30 b 357 357 303 303 (±)-2-{4-[2-(3-bróm-4- metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7-chlór-3Hbenzoimidazol-5-karbonitril (±) -2- {4- [2- (3-bromo-4- methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-chloro-3H-benzoimidazol-5-carbonitrile H °x\ R V—NH 1, HN OH Cl \___Z Q- OMeH ° x \ R H = NH 1, HN OH Cl \ ___ From Q-OMe 1,74 (d) 1.74 (d) 514 514 304 304 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-chlór3H-benzoimidazol-5karbonitril (±) -2- {4- [2- (3-chlorophenyl) -2hydroxyetylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-chlór3H-benzoimidazol-5-carbonitrile 0 1. HN OH C’ \___Z0 1. HN OH C '\ ___ Z 1,78 (d) 1.78 (d) 440 440 305 305 (±)-2-{4-[2-(3-brómfenyl)-2hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-chlór3H-benzoimidazol-5karbonitril (±) -2- {4- [2- (3-bromophenyl) -2hydroxyetylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-chlór3H-benzoimidazol-5-carbonitrile 0 jA HN OH (>·' 0 jA HN OH (> · ' 1,77 (d) 1.77 (d) 484 484

136136

306 306 (±)-2-{4-[2-(3-brómfenyl)-2- hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-etyl3H-benzoimidazol-5karbonitril (±) -2- {4- [2- (3-bromophenyl) -2- hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-ethyl-3H-benzoimidazol-5-carbonitrile V-nh J X- In NH J X- 1,82 (d) 1.82 (d) 478 478 307 307 (±)-2-{4-[2-(3-bróm-4- metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-etyl3H-benzoimidazol-5karbonitril (±) -2- {4- [2- (3-bromo-4- methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-ethyl-3H-benzoimidazol-5-carbonitrile ‘OXp HN OH X OMe 'oXP HN OH X OMe 1,76 (d) 1.76 (d) 508 508 308 308 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-etyl3H-benzoimidazol-5karbonitril (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-ethyl-3H-benzoimidazol-5-carbonitrile xxpx HN ,0H X’ xxpx HN, OH X ' 1,80 (d) 1.80 (d) 434 434 309 309 izobutylester (±)-(2-chlór-4{2-[3-(6-kyano-4-metyl-1 Hbenzoimidazol-2-yl)-2-oxo- 1,2-dihydropyridin-4ylamino]-1 -hydroxyetyl}fenyl)karbámovej kyseliny (±) - (2-Chloro-4 {2- [3- (6-cyano-4-methyl-1H-benzoimidazol-2-yl) -2-oxo] - isobutyl ester 1,2-dihydropyridin-4-ylamino] -1-hydroxyethyl} phenyl) carbamic acid 0 I H\ /0H Qx HH-<0 I H \ / 0H Qx HH- < 1,93 (b) 1.93 b 535 535 310 310 (S)-7-etyl-2-[4-(1 -hydroxymetyl-2-fenyletylamino)-2oxo-1,2-dihyd ropy rid ίη-3-yl]3H-benzoimidazol-5karbonitril (S) -7-Ethyl-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] 3H-benzoimidazole-5-carbonitrile ncV'%>--n X-nh X Ηχ nc V '%> - n X-nh X Η χ 1,75 (d) 1.75 (d) 414 414 311 311 (S)-7-bróm-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2oxo-1,2-d ihyd ropy ridín-3-yll3H-benzoimidazol-5karbonitril (S) -7-Bromo-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -3H-benzoimidazole-5-carbonitrile 0 ΧαλΡ B' 0 ΧαλΡ B ' 1,91 (b) 1.91 b 464 464

137137

312 312 (S)-4-( 1 -hydroxymetyl-2fenyletylamino)-3-[4-metyl-6(4-metylpiperazín-1-yl)-1Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -1H-pyridin-2-one O h N NH 1 HN ,______ -ŕ. O^°h O h N NH 1 HN, ______ -r. The h ° ^ 1,08 (f) 1.08 f 473 473 313 313 (S)-4-( 1 -hydroxymetyl-2fenyletylamino)-3-[4-metyl-6(4-n-butylpiperazín-1 -yl)-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-n-butylpiperazin-1-yl) -1 H -benzoimidazol-2-yl] -1 H -pyridin-2-one M 0 Vmh 1 KN M 0 Vmh 1 KN 1,29 (k) 1.29 (k) 515 515 314 314 (S)-3-{6-[4-(2-hyd roxyetyl)piperazín-1-yl]-4-metyl-1Hbenzoimidazol-2-yl}-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- {6- [4- (2-Hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridine -2-one ho____ Cl H NH 1 HNho____ Cl H NH 1 HN 1,62 (k) 1.62 (k) 503 503 315 315 (S)-3-[6-(4-cyklohexylpiperazín-1 -yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4-Cyclohexyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one θΌ h v I A Λ—4, '/) y— 1 HN Q-AAhθΌ h in IA Λ — 4,) y — 1 HN Q-AAh 1,34 (f) 1.34 (f) 541 541 316 316 (S)-3-[6-(4-benzylpiperazín- 1-yl)-4-metyl-1Hbenzoimidazol-2-yl]-4-(1 hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4-benzylpiperazin 1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one ΟΌγγΐ: V* ΙΑΛ$-? 1 KN ^^-4 'OH ΟΌγγΐ: V * ΙΑΛ $ -? 1 KN ^^ - 4 'OH 1,93 (f) 1.93 (f) 549 549 317 317 (S)-4-{2-[4-(1-hydroxymetyl- 2-fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl3H-benzoimidazol-5yl]piperazín-1 -karboxamid (S) -4- {2- [4- (1-hydroxymethyl- 2-Phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazol-5-yl] piperazine-1-carboxamide O A'-'i „ o LA?V 1 HN ABOUT And '-' i 'o LA? In 1 HN 1,26 (f) 1.26 f 502 502

138138

318 318 (S)-3-[6-(4-benzénsulfonylpiperazin-1 -yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4-Benzenesulfonyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one Ph°2SO o k. N MM 4 0H Ph ° 2S O o k. N MM 40H 2,30 (k) 2.30 k 599 599 319 319 (S)-4-(1 -hydroxymetyl-2fenyletylamino)-3-[6-(4metánsulfonylpiperazin-1-yl)4-metyl-1 H-benzoimidazo)-2yl]-1 H-pyrid ίη-2-όη (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-methanesulfonylpiperazin-1-yl) 4-methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2-one m.°2s 1 1 H °* 1 HN J OHm. ° 2 s 1 1 H ° * 1 HN J OH 1,93 (k) 1.93 (k) 537 537 320 320 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(4metyl-6-piperazín-1-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one 0 XX .rv HN ON 0 XX .rv HN ON 1,90 (f) 1.90 (f) 479 479 321 321 (+)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-[6-(4cyklopropylmetylpiperazín-1- yl)-4-metyl-1 H- benzoimidazol-2-yl]-1 Hpyridín-2-ón (+) - 4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -3- [6- (1- 4cyklopropylmetylpiperazín yl) -4-methyl-1H- benzoimidazol-2-yl] -1H-pyridin-2-one V'Yj H T W KN OHV'Yj H T W KN OH 1,97 (k) 1.97 (k) 533 533 322 322 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-{6-[4(2,2-dimetylpropyl)piperazín- 1 -yl]-4-metyl-1 Hbenzoimidazol-2-yl}-1 Hpyridín-2-ón (±) -4- [2- (3-chlorophenyl) -2hydroxyetylamino] -3- {6- [4- (2,2-dimethylpropyl) piperazine 1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1-pyridin-2-one ΑΟγ,ϋ V-HH UŕV 1 HN OH X-· ΑΟγ, ϋ V-HH UrV 1 HN OH · X- 2,06 (k) 2.06 k 549 549 323 323 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(4cyklobutylpiperazín-1 -y l)-4metyl-1 H-benzoimidazol-2yl]-1 H-pyridin-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (4-cyclobutyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2-one - v XXaX 1 HN OH Ah - in XXAX 1 HN OH Ah 1,97 (k) 1.97 (k) 533 533

139139

324 324 (±)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-[6-(4etylpiperazín-1-yl)-4-metyl- 1 H-benzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -3- [6- (4-ethylpiperazin-1-yl) -4-methyl- 1H-benzoimidazol-2-yl] -1H-pyridin-2-one | HN OH | HN OH 1,88 (k) 1.88 (k) 507 507 325 325 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-{6-[4-(2hydroxyetyl)piperazín-1-yl]-4metyl-1 H-benzoimidazol-2yl}-1H-pyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine- 2-one o | KH OH o | KH OH 1,82 (k) 1.82 (k) 524 524 326 326 etylester (±)-[4-(2-{4-[2-(3chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7-metyl-3Hbenzoimidazol-5yl)piperazín-1 -yljoctovej kyseliny (±) - [4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) -piperazine ethyl ester -1-yl-acetic acid | OH A- | OH A- 2,03 (k) 2.03 (k) 565 565 327 327 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-{6-[4-(3dimetylamino-2,2dimetylpropyl)piperazín-1 -yl]4-metyl-1 H-benzoimidazol-2yl}-1H-pyridin-2-ón (±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-dimethylamino-2,2-dimethylpropyl) piperazin-1-yl] 4-methyl-1H-benzoimidazol-2-yl} 1H-pyridin-2-one T H. « O-’ T H. « ABOUT-' 1,84 (k) 1.84 (k) 592 592 328 328 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(4metyl-6-morfolín-4-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one y.. I HN OH y .. I HN OH 1,19 (a) 1.19 (a) 480 480

140140

329 329 (±)-4-[2-(3-brómfenyl-2hydroxyetylamino]-3-(4metyl-6-morfolín-4-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromophenyl-2-hydroxyethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one O * %_ V—·Η·χ^^χ--Ν V—NH Učy 1 HN OHO *% _ V— · Η · χ ^^ χ - Ν V - NH Učy 1 HN OH 1,21 (a) 1.21 (a) 524 524 330 330 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(4-metyl-6-morfolín-4-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1-pyridin-2 -one V-HH 1 HN OH MQ-9r OMeV-HH 1 HN OH M Q- 9r OMe 1.16 (a) 1.16 a 554 554 331 331 (±)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-{4metyl-6-[4-(tetrahydropyrán4-yl)piperazín-1-yl]-1 Hbenzoimidazol-2-yl}-1 Hpyridín-2-ón (±) -4- [2- (3-chloro-phenyl) -2- hydroxyethylamino] -3- {4-methyl-6- [4- (tetrahydropyran-4-yl) piperazin-1-yl] -1-benzoimidazol-2-yl} -1-pyridin-2-one O-H-X L i « V y? 1 HN OH Έ- O-H-X L i «V y? 1 HN OH Έ- 1,19 (f) 1.19 f 563 563 332 332 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(4imidazol-2-ylmetylpiperazin- 1-yl)-4-metyl-1H- benzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-chlorophenyl) -2hydroxyetylamino] -3- [6- (2-4imidazol ylmetylpiperazin- 1-yl) -4-methyl-1H- benzoimidazol-2-yl] -1H-pyridin-2-one HN OH V HN OH IN 1,19 (f) 1.19 f 559 559 333 333 (±)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-[4metyl-6-(4-propylpiperazín-1 yl)-1 H-benzoimidazol-2-yl]- 1 H-pyridín-2-ón (±) -4- [2- (3-chloro-phenyl) -2- hydroxyethylamino] -3- [4-methyl-6- (4-propylpiperazin-1-yl) -1H-benzoimidazol-2-yl] - 1H-pyridin-2-one H v 1 HN OH H v 1 HN OH 1,19 (f) 1.19 f 521 521

141141

334 334 (±)-4-[2-(3-chlórfenyl)-2hyd roxyetylam i no]-3-{4metyl-6-[4-( 1 -metylpiperidín4-y l)p iperazí n-1 -yl]-1 Hbenzoimidazol-2-yl}-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -1-benzoimidazole -2-yl} -1H-pyridin-2-one HN OH Ä- HN OH a- 1,08 (f) 1.08 f 576 576 335 335 (±)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-{6-[4-(2hydroxyetyl)piperazín-1-yl)-4metyl-1 H-benzoimidazol-2yl}-1 H-pyridín-2-ón (±) -4- [2- (3-bromophenyl) -2- hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one y T^T V-A? HN OH Y y T ^ T V-A? HN OH Y 1,79 (f) 1.79 (f) 567 567 336 336 (±)-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(4metyl-6-piperazín-1-yl)-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl) -1-benzoimidazol-2-yl) -1-pyridin-2-one HN 1 o t 1 M V\ n ΙΑΖήΑ 1 HN OH Y HN 1 o t 1 M V n ΙΑΖήΑ 1 HN OH Y 1,83 (f) 1.83 (f) 523 523 337 337 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(4-metyl-6-piperazín-1 -yl)- 1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4-methyl-6-piperazin-1-yl) - 1H-benzoimidazol-2-yl) -1H-pyridin-2-one ΗΝ'ΖΥ Q LA/qA 1 HN OH Q-- OM·LA Ζ Υ Υ LA LA LA LA LA · · · · 1,72 (f) 1.72 (f) 553 553 338 338 (±)-3-[6-(4-acetylpiperazin-1yl)-4-metyl-1Hbenzoimidazol-2-yl]-4-[2-(3brómfenyl)-2-hyd roxyetylamino]-1 H-pyridín-2-ón (±) -3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2- one A 1 HH OH Br A 1 HH OH br 1,90 (f) 1.90 (f) 565 565 339 339 (±)-3-(6-amino-5-metyl-1 Hbenzoimidazol-2-yl]-4-[2-(3brómfenyl)-2-hyd roxyetylamino]-1 H-pyridín-2-ón (±) -3- (6-amino-5-methyl-1H-benzimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one 0 HN OH Ύ·· 0 HN OH Ύ · · 1.41 G) 1.41 G) 454 454

142142

340 340 (±)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-(6pyrazol-1-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-chloro-phenyl) -2- hydroxyethylamino] -3- (6-pyrazol-1-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one V- NH lA-Ay? HN OH V- NH 1a-Ay? HN OH 1,86 (f) 1.86 (f) 447 447 341 341 (±)-3-(6-amino-4-metyl-1 Hbenzoimidazol-2-yl]-4-[2-(3chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (±) -3- (6-amino-4-methyl-1H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one I HN OH I HN OH 1,51 (f) 1.51 (f) 410 410 342 342 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(6[1,2,3]triazol-1-yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6 [1,2,3] triazol-1-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ,=N o HN OH X“ , = N o HN OH X " 2,04 (f) 2.04 f 448 448 343 343 (+)-N-(2-{4-[2-(3-chlórfenyl)2-hydroxyetylamino]-2-oxo1,2-d ihyd ropy rid ín-3-yl}-7metyl-3H-benzoimidazol-5yl)acetamid (+) - N- (2- {4- [2- (3-Chloro-phenyl) 2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) acetamide H H °Λ ° lAXp I HN OH X H H ° Λ ° lAXp I HN OH X 1,62 (f) 1.62 (f) 452 452 344 344 (±)-(2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo-1,2dihydropyrid ín-3-yl}-7-metyl3H-benzoimidazol-5yl)močovina (±) - (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) -urea Vnh τΐΧφ HN OH X IGB τΐΧφ HN OH X 1,49 (f) 1.49 (f) 453 453 345 345 (±)-1-(2-{4-[2-(3-chlórfenyl)- 2-hydroxyetylamino]-2-oxo- 1,2-d i hyd ropyrid ín-3-yl}-7metyl-3H-benzoimidazol-5yl)-3-etylmočovina (±) -1- (2- {4- [2- (3-chlorophenyl) - 2-hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) -3-ethylurea __V- H 0 U/y I HN pH-V - H 0 U / y 1 HN pH 1,64 (f) 1.64 (f) 481 481

143143

346 346 (±)-1-(2-{4-[2-(3-chlórfenyl)- 2-hydroxyetylamino]-2-oxo- 1,2-dihydropy ridi η-3-y l}-7metyl-3H-benzoimidazol-5yl)-3-izopropylmočovina (±) -1- (2- {4- [2- (3-chlorophenyl) - 2-hydroxy-ethylamino] -2-oxo- 1,2-Dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) -3-isopropylurea H H „ 0 ý-KH ° < X *—? I MM OH Y· H H 'O y-KH ° <X * -? I MM OH Y · 1,71 (f) 1.71 f 495 495 347 347 (S)-4-(1-hydroxymetyl-2fenyletylamino)-3-[4-metyl-6(2-morfolín-4-yletylamino)- 1 H-benzoimidazol-2-yl]-1 Hpyridín-2-ón (S) -4- (1-hydroxymethyl-2-phenylethylamine) -3- [4-methyl-6- (2-morpholin-4-yl-ethylamino) - 1H-benzoimidazol-2-yl] -1H-pyridin-2-one O ABOUT 1,05 (f) 1.05 f 503 503 348 348 (±)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-(4,5,6trifluór-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón (±) -4- [2- (3-bromophenyl) -2- hydroxyethylamino] -3- (4,5,6-trifluoro-1H-benzoimidazol-2-yl) -1H-pyridin-2-one H °Λ V NH é HN OH M' H ° Λ In NH HN OH M ' 1,76 (d) 1.76 (d) 479 479 349 349 4-[(pyridín-2-ylmetyl)amino]- 3-(4,5,6-trifluór-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(pyridin-2-ylmethyl) amino] - 3- (4,5,6-Trifluoro-1H-benzoimidazol-2-yl) -1H-pyridin-2-one H °x\ H N N=\ H ° x \ H N N = \ 1,36 (d) 1.36 (d) 372 372 350 350 (S)-4-( 1 -hydroxymetyl-2- fenyletylamino)-3-(4,5,6trifluór-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (S) -4- (1-Hydroxymethyl-2- phenylethylamino) -3- (4,5,6-trifluoro-1H-benzoimidazole-2- yl) -1H-pyridin-2-one χτφ F ΗΊ-χτφ F Η Ί- 1,73 (d) 1.73 (d) 415 415 351 351 3-(4,6-dibróm-1Hbenzoimidazol-2-yl)-4[(pyridín-2-ylmetyl)amino]1H-pyridín-2-ón 3- (4,6-dibromo-1 H -benzoimidazole-2-yl) -4 [(pyridin-2-ylmethyl) amino] -1H-pyridin-2-one o V~NH L ΗΝχ/Ν=ΛV V ~ NH L ΗΝ χ / Ν = Λ 1,66 (d) 1.66 (d) 474 474

144144

352 352 (± )-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(4,6dibróm-1 H-benzoimidazol-2- yl)-1 H-pyridin-2-ón (±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4,6-dibromo-1H-benzoimidazole-2- yl) -1H-pyridin-2-one H °Λ y— NH LAo? 1. HN OH ΒΓ \___/ O-H ° Λ y— NH LAo? 1. HN OH ΒΓ \ ___ / O- 1.95 (d) 1.95 d 581 581 353 353 (S)-3-(4,6-dibróm-1Hbenzoimidazol-2-yl)-4-(1 hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- (4,6-Dibromo-1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one 0 N ý— NH B, 0 NH B 1,92 (d) 1.92 (d) 517 517 354 354 (±)-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(5,6dichlór-1 H-benzoimidazol-2yl)-1 H-pyridín-2-ón (±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (5,6-dichloro-1H-benzoimidazol-2-yl) -1H-pyridin-2-one H °VK HN OH H ° VK HN OH 1,85 (d) 1.85 (d) 493 493 355 355 3-(5,6-dichlór-1 H- benzoimidazol-2-yl)-4[(pyridin-2-ylmetyl)aminoJ- 1 H-pyridin-2-ón 3- (5,6-dichloro-1H- benzimidazol-2-yl) -4 [(pyridin-2-ylmethyl) aminoJ- 1H-pyridin-2-one o Cl HN N=S Cl Cl HN N = S 1,48 (d) 1.48 (d) 386 386 356 356 (S)-3-(5,6-dichlór-1H- benzoimidazol-2-yl)-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- (5,6-dichloro-1 H benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one H y—NH .Χΐ-Φ H y — NH 1,82 (d) 1.82 (d) 429 429 357 357 (±)-3-(4,6-bis-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-[2(3-brómfenyl)-2-hydroxyetylamino]-1 H-pyridin-2-ón (±) -3- (4,6-bis-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one 0 kn ,°h CF’ X___/ b-*0 kn , ° h CF 'X ___ / b- * 1,56 (b) 1.56 b 561 561 358 358 3-(4,6-bis-trifluórmety 1-1Hbenzoimidazol-2-yl)-4[(pyridin-2-ylmetyl)amino]- 1 H-pyridín-2-ón 3- (4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino] - 1H-pyridin-2-one 0 X-NK XXhu CF3 H ,N=\ mm0 X-NK XXhu CF 3 H, N = \ mm 1,39 (b) 1.39 b 454 454

145145

359 I 359 I (5)-3-(4,6-bis-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-(1 hydroxymetyl-2-fenyletylamino)-1H-pyridín-2-ón (5) -3- (4,6-bis-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one H SF, j; 0-0,« H SF, j; 0-0, « 1,53 (b) 1.53 b 497 497 360 360 (±)-3-(4,6-bis-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-[2(3-bróm-4-metoxyfenyl)-2hydroxyetylamino]-1 Hpyridín-2-ón (±) -3- (4,6-bis-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one f e h V L HN OH CFa \___/ Q- OMefeh V L HN OH CFα \ ___ / Q-OMe 1,51 (b) 1.51 b 591 591 361 361 (±)-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(4chlór-6-trifl uórmety I-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one FC H V LAZy? Cl HN Z OH FC H V LAZy? C H N Z OH 1,54 (b) 1.54 b 527 527 362 362 3-(4-chlór-6-trifluó rm ety I-1Hbenzoimidazol-2-yl)-4[(pyridín-2-ylmetyl)amino]- 1 H-pyridín-2-όπ 3- (4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl) -4 - [(pyridin-2-ylmethyl) amino] - 1H-pyridin-2-ol F C H V r. HN N=\ F C H V r. HN N = \ 1.34 (b) 1.34 b 420 420 363 363 (S)-3-(4-chlór-6-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- (4-chloro-6-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one H °Λ F3° N) ζ NH a OHH ° Λ F 3 ° N ) ζ NH and OH 1,51 (b) 1.51 b 463 463 364 364 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino)-3(4-chlór-6-trif luórmetyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino) -3 (4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one H /~nJ HN OH Cl Q·· OMeH / ~ n HN OH Cl Q ·· OMe 1,50 (b) 1.50 b 557 557 365 365 (±)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-(5trifluórmetyl-1 Hbenzoimidazol-2-yl)-1 Hpyrid ίη-2-όη (±) -4- [2- (3-bromophenyl) -2- hydroxyethylamino] -3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one « v V—NH HN OH " in In NH HN OH 1,42 (b) 1.42 b 493 493

146146

366 366 4-[(pyridín-2-ylmetyl)amino]- 3-(5-trifluórmetyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón 4 - [(pyridin-2-ylmethyl) amino] - 3- (5-Trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one Y-NH yy HN N=\ Y-NH yy HN N = \ 1,16 (b) 1.16 b 386 386 367 367 (S)-4-(1-hydroxymetyl-2fenyletylamino)-3-(5trifluórmetyl-1Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one ^^N y NH ..Cuu H N, θ-Ρ'οΗ N, NH ..Cuu H N, θ-Ρ'οΗ 1,41 (b) 1.41 b 429 429 368 368 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(5-trifluórmetyl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1-pyridin-2-one P HN OH Q^·· OMe P HN OH Q ^ ·· OMe 1,38 (b) 1.38 b 523 523 369 369 (±)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-(5-fluór6-imidazol-1-yl-1Hbenzoimidazol-2-yl)-1 Hpyridin-2-ón (±) -4- [2- (3-bromophenyl) -2- hydroxyethylamino] -3- (5-fluoro-6-imidazol-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one HN OH P- HN OH P- 1,10 (b) 1.10 (b) 509 509 370 370 3-(5-fluór-6-imidazol-1 -yl-1 H- benzoimidazol-2-yl)-4[(pyridín-2-ylmetyl)amino]- 1 H-pyridín-2-ón 3- (5-fluoro-6-imidazol-1-yl-1 H- benzimidazol-2-yl) -4 [(pyridin-2-ylmethyl) amino] - 1H-pyridin-2-one 0 F HN N=\0 F HN N = \ 0,73 (b) 0.73 b 402 402 371 371 (S)-3-(5-fluór-6-imidazol-1 -yl- 1 H-benzoimidazol-2-yl)-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- (5-Fluoro-6-imidazol-1-yl- 1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one OH OH 1,04 (b) 1.04 b 445 445 372 372 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(5-fluór-6-imidazol-1 -yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (5-fluoro-6-imidazol-1-yl-1H-benzimidazol-2-yl) -1-pyridin-2 -one HN OH Q- OMe HN OH Q- OMe 1,05 (b) 1.05 b 539 539

147147

373 373 (±)-3-(4-bróm-6-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-[2(3-brómfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (±) -3- (4-bromo-6-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one H V y—NH L HN OH Bľ \___/HV y — NH L HN OH Bl'_ / 1,97 (d) 1.97 (d) 571 571 374 374 (±)-3-(4-bróm-6-trifluórmetyl- 1 H-benzoimidazol-2-yl)-4-[2(3-chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (±) -3- (4-bromo-6-trifluoromethyl- 1H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one FC ” V FaCVz^r-N y— NH LAZyJ á. HN OH Ί>.FC ”V FaC V z ^ r -Ny— NH LAZyJ. HN OH Ί>. 1,95 (d) 1.95 (d) 527 527 375 375 (±)-4-[2-(3-brómfenyl)-2hydroxyetylamino]-3-(4,6difluór-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4,6-difluoro-1H-benzoimidazole-2- yl) -1H-pyridin-2-one fwv_¥nh F ΗΝχ pH O- f wv_ ¥ nh F ΗΝ χ pH O- 1,72 (d) 1.72 (d) 461 461 376 376 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(4,6difluór-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- (4,6-difluoro-1H-benzoimidazole-2- yl) -1H-pyridin-2-one F V I HN OH F V I HN OH 1,70 (d) 1.70 (d) 417 417 377 377 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3(4,6-difluór-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3 (4,6-difluoro-1H-benzoimidazol-2-yl) -1-pyridin-2-one H 7—NH I HN OH p- OMe H 7-NH I HN OH p- OMe 1,65 (d) 1.65 (d) 491 491 378 378 (±)-4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-3-[4metyl-6-(2-rnetylimidazol-1 yl]-1 H-benzoimidazol-2-yl)1H-pyridín-2-ón (±) -4- [2- (3-chloro-phenyl) -2- hydroxyethylamino] -3- [4-methyl-6- (2-methylimidazol-1-yl) -1H-benzoimidazol-2-yl) 1H-pyridin-2-one Y H o LXYp* I HN OHY H o LXYp * I HN OH 1,38 (d) 1.38 (d) 475 475

148148

379 379 (±)-4-[2-(3-bróm-4-metoxy- fenyl)-2-hydroxyetylamino]-3[4-metyl-6-(4-metyl-imidazol1 -y I]-1 H-benzoimidazol-2-yl)1H-pyridín-2-ón (±) -4- [2- (3-bromo-4-methoxy- phenyl) -2-hydroxyethylamino] -3 [4-methyl-6- (4-methyl-imidazol-1-yl) -1H-benzoimidazol-2-yl) 1H-pyridin-2-one H*-, - J M 0 [ HN OH OM·H * -, - J M 0 1,35 (d) 1.35 (d) 549 549 380 380 (±)-4-[2-(3-brómfenyl)-2- hydroxyetylamino]-3-(5,6- difluór-1 H-benzoimidazol-2- yl)-1 H-pyridín-2-ón (±) -4- [2- (3-bromophenyl) -2- ethylamino] -3- (5,6- Difluoro-1H-benzoimidazole-2- yl) -1H-pyridin-2-one H °Λ Y-NH HN OH H ° Λ Y-NH HN OH 1,67 (b) 1.67 b 461 461 381 381 3-(5,6-difluór-1H- benzoimidazol-2-yl)-4[(pyridín-2-ylmetyl)amino]- 1 H-pyridin-2-ón 3- (5,6-Difluoro-1 H benzimidazol-2-yl) -4 [(pyridin-2-ylmethyl) amino] - 1H-pyridin-2-one HN N=\ HN N = \ 1,18 (b) 1.18 b 354 354 382 382 6-hydroxy-5-(6-imidazol-1 -yl- 4-metyl-1 H-benzoimidazol-2- yl)-3H-pyrimidín-4-ón 6-Hydroxy-5- (6-imidazol-1-yl) 4-Methyl-1H-benzoimidazole-2- yl) -3H-pyrimidin-4-one 4 }| H °Λ 1 HO 4} | H ° Λ 1 HO 0,96 (f) 0.96 f 309 309 383 383 (±)-6-[2-(3-chlórfenyl)-2- hydroxyetylamino]-5-(6imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-3Hpyrimidín-4-ón (±) -6- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -5- (6imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -3Hpyrimidín-4-one p T />~A T HN OH p T /> ~ A T HN OH 2,30 (f) 2.30 f 462 462

Spôsob prípravy medziproduktového imidátu (schéma IV, (13))Method for preparation of intermediate imidate (Scheme IV, (13))

149149

Etylester (S)-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridine-

3-yl]-7-metyl-3H-benzoimidazol-5-karboximidovej kyseliny:3-yl] -7-methyl-3H-benzoimidazole-5-carboximidic acid:

Suspenzia (S)-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl-3H-benzoimidazol-5-karbonitrilu (0,8 g, 2,0 mmol) v etanole (bezvodom, 80 ml) sa prebubláva HCI (bezvodým) pri 0 °C až do nasýtenia. Po niekoľkých minútach prebublávania dôjde k vyčireniu roztoku a roztok sa potom mieša 14 h pri teplote miestnosti. Po zahustení za zníženého tlaku sa surový produkt (0,89 g, 100 %) hneď použije v ďalšom stupni bez ďalšieho čistenia. LCMS (M+H)+ m/z 446 (t = 1,55 min).(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile (0.8 g, 2.0 mmol) in ethanol (anhydrous, 80 mL) was bubbled with HCl (anhydrous) at 0 ° C until saturation. After a few minutes of bubbling, the solution became clear and the solution was then stirred at room temperature for 14 h. After concentration under reduced pressure, the crude product (0.89 g, 100%) was used immediately in the next step without further purification. LCMS (M + H) &lt; + &gt; m / z 446 (t = 1.55 min).

Etylester (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboximidovej kyseliny:(±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboximidic acid ethyl ester:

Titulná zlúčenina sa pripraví všeobecným spôsobom pre prípravu imidátu. LCMS (M+H)+ m/z 466 (t = 1,43 min).The title compound is prepared in a general manner for the preparation of the imidate. LCMS (M + H) &lt; + &gt; m / z 466 (t = 1.43 min).

Všeobecný spôsob prípravy zlúčenín podľa príkladov 384-397 - príprava imidazolínov (schéma IV (14))General Preparation of the Compounds of Examples 384-397 - Preparation of Imidazolines (Scheme IV (14))

Príklad 384Example 384

(S)-3-[6-(4,5-dihydro-1H-imidazol-2-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1H-pyridín-2-ón:(S) -3- [6- (4,5-dihydro-1 H-imidazol-2-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4- (1hydroxymetyl-2-phenyl-ethylamino) -1 H pyridin-2-one;

150150

Surový imidátový ester (60 mg, 0,135 mmol) sa zriedi metanolom a potom sa pridá etyléndiamín (24 mg, 0,40 mmol). Reakčná zmes sa zahrieva 6 hodín pri teplote spätného toku. Po zahustení za zníženého tlaku sa prečistením zvyšku preparatívnou HPLC získa titulná zlúčenina (37 mg, 62 %). 1H NMR (300 MHz, CD3OD) δ 7,94 (1H, s), 7,50 (1H, s), 7,12-7,30 (6H, m), 6,16 (1H, d, J = 7,7 Hz), 4,044,10 (5H, m), 3,75-3,77 (2H, m), 3,15 (1H, dd, J = 5,2, 13,6 Hz), 2,96 (1H, dd, J = 8,1,The crude imidate ester (60 mg, 0.135 mmol) was diluted with methanol and then ethylenediamine (24 mg, 0.40 mmol) was added. The reaction mixture was heated at reflux for 6 hours. After concentration under reduced pressure, purification of the residue by preparative HPLC gave the title compound (37 mg, 62%). 1 H NMR (300 MHz, CD 3 OD) δ 7.94 (1H, s), 7.50 (1H, s), 7.12-7.30 (6H, m), 6.16 (1H, d) J = 7.7 Hz), 4.044.10 (5H, m), 3.75-3.77 (2H, m), 3.15 (1H, dd, J = 5.2, 13.6 Hz) 2.96 (1H, dd, J = 8.1,

13,6 Hz), 2,67 (3H, s). LCMS (M+H)+ m/z 443 (t = 1,50 min).13.6 Hz), 2.67 (3H, s). LCMS (M + H) &lt; + &gt; m / z 443 (t = 1.50 min).

Príklad 385Example 385

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(4,5-dihydro-1H-imidazol-2-yl)-(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4,5-dihydro-1 H-imidazol-2-yl) -

4-metyl-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:4-Methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,93 (1H, s), 7,54 (1H, s), 7,23-7,45 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.93 (1H, s), 7.54 (1H, s), 7.23-7.45 (5H, m),

6,26 (1H, d, J = 7,6 Hz), 5,01 (1H, t, J = 6,3 Hz), 4,01 (4H, s), 3,78 (1H, dd, J = 4,7,6.26 (1H, d, J = 7.6Hz), 5.01 (1H, t, J = 6.3Hz), 4.01 (4H, s), 3.78 (1H, dd, J = 4.7,

13,5 Hz), 3,67 (1H, dd, J = 6,6, 13,5 Hz), 2,66 (3H, s). LCMS (M+H)+ m/z 463 (t =13.5 Hz), 3.67 (1H, dd, J = 6.6, 13.5 Hz), 2.66 (3H, s). LCMS (M + H) &lt; + &gt; m / z 463 (t =

1,54 min).1.54 min).

Príklad 386Example 386

4-[2-(3-chlórfenyl)-2R-hydroxyetylamino]-3-[4-metyl-6-(4S-metyl-4,5-dihydro-4- [2- (3-chloro-phenyl) -2R-hydroxy-ethylamino] -3- [4-methyl-6- (4S-methyl-4,5-dihydro-

H-imidazol-2-yl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-2Shydroxyetylamino]-3-[4-metyl-6-(4S-metyl-4,5-dihydro-1H-imidazol-2-yl)-1 Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:1H-imidazol-2-yl) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) -2Shydroxyethylamino] -3- [4-methyl-6] - (4S-Methyl-4,5-dihydro-1 H -imidazol-2-yl) -1 H -benzoimidazol-2-yl] -1 H -pyridin-2-one:

151 1H NMR (300 MHz, CD3OD) δ 7,90 (2H, s), 7,53 (2H, s), 7,22-7,47 (10H, m),151 1 H NMR (300 MHz, CD 3 OD) δ 7.90 (2H, s), 7.53 (2H, s), 7.22-7.47 (10H, m),

6,23 (2H, d, J = 7,5 Hz), 5,00 (1H, t, J = 6,4 Hz), 4,49-4,57 (2H, m), 4,21 (2H, t, J = 11,0 Hz), 3,67-3,78 (6H, m), 2,63 (6H, s), 1,48 (6H, d, J = 6,3 Hz). LCMS (M+H)+ m/z 477 (t= 1,71 min).6.23 (2H, d, J = 7.5Hz), 5.00 (1H, t, J = 6.4Hz), 4.49-4.57 (2H, m), 4.21 (2H t, J = 11.0 Hz), 3.67-3.78 (6H, m), 2.63 (6H, s), 1.48 (6H, d, J = 6.3 Hz). LCMS (M + H) &lt; + &gt; m / z 477 (t = 1.71 min).

Príklad 387Example 387

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(1-rnetyl-4,5-dihydro1 H-imidazol-2-yl)-1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H -benzoimidazol-2-yl] -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,94 (1H, s), 7,57 (1H, s), 7,23-7,52 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.94 (1H, s), 7.57 (1H, s), 7.23-7.52 (5H, m),

6,22 (1H, d, J = 7,5 Hz), 4,99 (1H, m), 4,00-4,15 (2H, m), 3,57-3,75 (4H, m), 3,57-6.22 (1H, d, J = 7.5Hz), 4.99 (1H, m), 4.00-4.15 (2H, m), 3.57-3.75 (4H, m) , 3,57-

3,75 (4H, m), 2,77 (3H, s), 2,61 (3H, s). LCMS (M+H)* m/z 477 (t = 1,60 min).3.75 (4H, m), 2.77 (3H, s), 2.61 (3H, s). LCMS (M + H) + m / z 477 (t = 1.60 min).

Príklad 388Example 388

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(4,4-dimetyl-4,5-dihydro-1Himidazol-2-yl)-4-metyl-1H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1 H -benzoimidazol-2-yl] -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,89 (1H, s), 7,52 (1H, s), 7,22-7,45 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.89 (1H, s), 7.52 (1H, s), 7.22-7.45 (5H, m),

6,19 (1H, d, J = 7,4 Hz), 4,99 (1H, t, J = 6,2 Hz), 3,84 (2H, s), 3,78 (1H, dd, J = 4,4,6.19 (1H, d, J = 7.4Hz), 4.99 (1H, t, J = 6.2Hz), 3.84 (2H, s), 3.78 (1H, dd, J = 4.4,

13,4 Hz), 3,60 (1H, dd, J = 6,7, 13,4 Hz), 2,61 (3H, s), 1,55 (6H, s). LCMS (M+H)* m/z 491 (t = 1,73 min).13.4 Hz), 3.60 (1H, dd, J = 6.7, 13.4 Hz), 2.61 (3H, s), 1.55 (6H, s). LCMS (M + H) + m / z 491 (t = 1.73 min).

Príklad 389Example 389

152152

2-(2-{4-[2-(3-chlórfenyl)-2R-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-yl)-4,5-dihydro-1H-imidazol-4S-karboxylová kyselina a 2(2-{4-[2-(3-chlórfenyl)-2S-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7-metyl3H-benzoimidazol-5-yl)-4,5-dihydro-1H-imidazol-4S-karboxylová kyselina:2- (2- {4- [2- (3-chloro-phenyl) -2R-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) -4, 5-Dihydro-1H-imidazole-4S-carboxylic acid and 2 (2- {4- [2- (3-chlorophenyl) -2S-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7 -methyl-3H-benzoimidazol-5-yl) -4,5-dihydro-1H-imidazole-4S-carboxylic acid:

1H NMR (300 MHz, CD3OD) δ 7,88 (2H, s), 7,52 (2H, s), 7,22-7,44 (1OH, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.88 (2H, s), 7.52 (2H, s), 7.22-7.44 (1OH, m),

6,17 (2H, d, J = 7,4 Hz), 5,05 (2H, m), 4,23-4,38 (4H, m), 3,56-3,72 (6H, m), 2,58 (6H, s). LCMS (M+H)+ m/z 507 (t = 1,64 min).6.17 (2H, d, J = 7.4Hz), 5.05 (2H, m), 4.23-4.38 (4H, m), 3.56-3.72 (6H, m) 2.58 (6H, s). LCMS (M + H) &lt; + &gt; m / z 507 (t = 1.64 min).

Príklad 390Example 390

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(1,4,5,6tetrahydropyrimidín-2-yl)-1H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (1,4,5,6-2-yl) -1 H-benzimidazol-2-yl -1 H-Pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,90 (1H, s), 7,53 (1H, s), 7,22-7,47 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.90 (1H, s), 7.53 (1H, s), 7.22-7.47 (5H, m),

6,23 (1H, d, J = 7,6 Hz), 5,00 (1H, t, J = 6,3 Hz), 4,49-4,57 (1H, m), 3,60-3,77 (5H,6.23 (1H, d, J = 7.6Hz), 5.00 (1H, t, J = 6.3Hz), 4.49-4.57 (1H, m), 3.60-3 77 (5H,

m), 3,24-3,34 (2H, m), 2,63 (3H, s). LCMS (M+H)* m/z 477 (t = 1,59 min).m), 3.24-3.34 (2H, m), 2.63 (3H, s). LCMS (M + H) + m / z 477 (t = 1.59 min).

OMeOMe

Príklad 391Example 391

153 (±)-4-[2-(3-chlór-4-metoxyfenyl)-2-metoxyetylamino]-3-[6-(4,5-dihydro-1Himidazol-2-yl)-4-metyl-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:153 (±) -4- [2- (3-chloro-4-methoxyphenyl) -2-methoxyethylamino] -3- [6- (4,5-dihydro-1 H -imidazol-2-yl) -4-methyl-1 H- benzimidazol-2-yl] -1-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,88 (1H, s), 7,46 (1H, s), 7,44 (1H, s), 7,31 (1H, d, J = 6,4 Hz), 7,28 (1H, d, J = 5,6 Hz), 7,01 (1H, d, J = 6,4 Hz), 6,19 (1H, d, J = 5,6 Hz), 4,49 (1H, dd, J = 3,4, 5,0 Hz), 4,09 (4H, s), 3,82 (3H, s), 3,36 (3H, s), 3,63-3,67 (2H, m), 2,62 (3H, s). LCMS (M+H)+ m/z 507 (t = 1,72 min). 1 H NMR (300 MHz, CD 3 OD) δ 7.88 (1H, s), 7.46 (1H, s), 7.44 (1H, s), 7.31 (1H, d, J = 6) 4 Hz), 7.28 (1H, d, J = 5.6 Hz), 7.01 (1H, d, J = 6.4 Hz), 6.19 (1H, d, J = 5.6 Hz), 4.49 (1H, dd, J = 3.4, 5.0 Hz), 4.09 (4H, s), 3.82 (3H, s), 3.36 (3H, s), 3.63-3.67 (2H, m); 2.62 (3H, s). LCMS (M + H) &lt; + &gt; m / z 507 (t = 1.72 min).

Príklad 392Example 392

(±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-[6-(4,5-dihydro-1Himidazol-2-yl)-4-metyl-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:(±) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazole 2-yl] -1-pyridin-2-one;

Titulná zlúčenina sa pripraví hydrolýzou benzylchloridu na hydroxylovú skupinu. 1H NMR (400 MHz, CD3OD) δ 7,90 (1H, s), 7,67 (1H, s), 7,48 (1H, s), 7,38 (1H, dd, J = 2,0, 8,5 Hz), 7,31 (1H, d, J = 7,6 Hz), 6,95 (1H, d, J = 8,5 Hz), 6,26 (1H, d, J = 7,6 Hz), 4,94 (1H, m), 4,10 (4H, s), 3,80 (3H, s), 3,62-3,74 (2H, m), 2,62 (3H, s). LCMS (M+H)+ m/z 537 (t = 1,49 min).The title compound was prepared by hydrolyzing benzyl chloride to a hydroxyl group. 1 H NMR (400 MHz, CD 3 OD) δ 7.90 (1H, s), 7.67 (1H, s), 7.48 (1H, s), 7.38 (1H, dd, J = 2) 0.88 Hz, 7.31 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.5 Hz), 6.26 (1H, d, J = 7.6 Hz), 4.94 (1H, m), 4.10 (4H, s), 3.80 (3H, s), 3.62-3.74 (2H, m), 2.62 (3 H, s). LCMS (M + H) &lt; + &gt; m / z 537 (t = 1.49 min).

Príklad 393Example 393

(S)-3-[6-(4,4-dimetyl-4,5-dihydro-1H-imidazol-2-yl)-4-metyl-1H-benzoimidazol2-yl]-4-(1-hydroxymetyl-2-fenyletylamino)-1H-pyridín-2-ón:(S) -3- [6- (4,4-dimethyl-4,5-dihydro-1 H-imidazol-2-yl) -4-methyl-1H-benzoimidazol2-yl] -4- (1-hydroxymethyl-2 phenyl-ethylamino) -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,94 (1H, s), 7,50 (1H, s), 7,12-7,30 (6H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.94 (1H, s), 7.50 (1H, s), 7.12-7.30 (6H, m),

154154

6,15 (1 H, dd, J = 7,7 Hz), 4,02-4,10 (1H, m), 3,85 (2H, s), 3,75-3,77 (2H, m), 2,96-6.15 (1H, dd, J = 7.7 Hz), 4.02-4.10 (1H, m), 3.85 (2H, s), 3.75-3.77 (2H, m) ), 2,96-

3,17 (2H, m), 2,67 (3H, s), 1,56 (6H, s). LCMS (M+H)+ m/z 471 (t = 1,62 min).3.17 (2H, m), 2.67 (3H, s), 1.56 (6H, s). LCMS (M + H) &lt; + &gt; m / z 471 (t = 1.62 min).

Príklad 394Example 394

(S)-2-{2-[4-(1S-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihyd ropyridín-3-yl]-(S) -2- {2- [4- (1S-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -

7-metyl-3H-benzoimidazol-5-yl}-4,5-dihydro-1H-imidazol-4S-karboxylová kyselina:7-Methyl-3H-benzoimidazol-5-yl} -4,5-dihydro-1H-imidazole-4S-carboxylic acid:

1H NMR (300 MHz, CD3OD) δ 8,03 (1H, s), 7,60 (1H, s), 7,11-7,29 (6H, m), 1 H NMR (300 MHz, CD 3 OD) δ 8.03 (1H, s), 7.60 (1H, s), 7.11-7.29 (6H, m),

6,15 (1H, d, J = 7,3 Hz), 5,07 (1H, dd, J = 6,9, 11,8 Hz), 4,25-4,41 (2H, m), 4,05-4,07 (1H, m), 3,70-3,82 (2H, m), 3,12 (1H, dd, J = 5,5, 13,6 Hz), 2,95 (1H, dd, J = 8,0, 13,6 Hz), 2,69 (3H, s). LCMS (M+H)+ m/z 487 (t = 1,35 min).6.15 (1H, d, J = 7.3 Hz), 5.07 (1H, dd, J = 6.9, 11.8 Hz), 4.25-4.41 (2H, m), 4 0.04-4.07 (1H, m), 3.70-3.82 (2H, m), 3.12 (1H, dd, J = 5.5, 13.6 Hz), 2.95 (1H δ d, J = 8.0, 13.6 Hz), 2.69 (3H, s). LCMS (M + H) &lt; + &gt; m / z 487 (t = 1.35 min).

Príklad 395Example 395

(S)-4-(1 -hydroxymetyl-2 -fenyletylamino)-3-[4-metyl-6-(1,4,5,6tetrahydropyrimid ín-2-yl]-1 H-pyridín-2-ón:(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-2-yl) -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,76 (1H, s), 7,32 (1H, s), 7,09-7,29 (6H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.76 (1H, s), 7.32 (1H, s), 7.09-7.29 (6H, m),

6,15 (1H, d, J = 7,6 Hz), 4,02-4,07 (1H, m), 3,71-3,79 (2H, m), 3,61 (4H, t, J = 5,6 Hz), 3,14 (1H, dd, J = 5,3, 13,6 Hz), 2,95 (1H, dd, J = 8,1, 13,6 Hz), 2,65 (3H, s), 2,09-2,16 (2H, m). LCMS (M+H)+ m/z 457 (t = 1,49 min).6.15 (1H, d, J = 7.6Hz), 4.02-4.07 (1H, m), 3.71-3.79 (2H, m), 3.61 (4H, t, J = 5.6 Hz), 3.14 (1H, dd, J = 5.3, 13.6 Hz), 2.95 (1H, dd, J = 8.1, 13.6 Hz), 2, 65 (3H, s), 2.09-2.16 (2 H, m). LCMS (M + H) &lt; + &gt; m / z 457 (t = 1.49 min).

Príklad 396Example 396

155155

(S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[4-metyl-6-(1-metyl-4,5-dihydro-1H imidazol-2-yl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (1-methyl-4,5-dihydro-1H-imidazol-2-yl) -1H-benzoimidazole-2 -yl] -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,77 (1H, s), 7,10-7,30 (7H, m), 6,16 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 7.77 (1H, s), 7.10-7.30 (7H, m), 6.16 (1H, d, J =

7.6 Hz), 3,97-4,20 (5H, m), 3,73-3,77 (2H, m), 3,26 (3H, s), 3,15 (1H, dd, J = 5,3,7.6 Hz), 3.97-4.20 (5H, m), 3.73-3.77 (2H, m), 3.26 (3H, s), 3.15 (1H, dd, J = 5) 3.

13.6 Hz), 2,96 (1H, dd, J = 8,0, 13,6 Hz), 2,68 (3H, s). LCMS (M+H)+ m/z 457 (t =13.6 Hz), 2.96 (1H, dd, J = 8.0, 13.6 Hz), 2.68 (3H, s). LCMS (M + H) &lt; + &gt; m / z 457 (t =

1,53 min).1.53 min).

Príklad 397Example 397

(S)-3-[6-(4,5-dihydro-1H-imidazol-2-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-(2hydroxy-2-fenyletylamino)-1H-pyridín-2-ón:(S) -3- [6- (4,5-dihydro-1 H-imidazol-2-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4- (2-hydroxy-2-phenyl-ethylamino) -1 H pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,91 (1H, s), 7,50 (1H, s), 7,48 (2H, s), 7,24- 1 H NMR (400 MHz, CD 3 OD) δ 7.91 (1H, s), 7.50 (1H, s), 7.48 (2H, s), 7.24-

7,35 (4H, m), 6,25 (1H, d, J = 7,6 Hz), 5,01 (1H, dd, J = 4,6, 7,0 Hz), 4,10 (4H, s),7.35 (4H, m), 6.25 (1H, d, J = 7.6Hz), 5.01 (1H, dd, J = 4.6, 7.0Hz), 4.10 (4H) , with),

3,65-3,76 (2H, m), 2,64 (3H, s). LCMS (M+H)+ m/z 429 (t = 1,48 min).3.65-3.76 (2 H, m), 2.64 (3 H, s). LCMS (M + H) &lt; + &gt; m / z 429 (t = 1.48 min).

Príklad 398Example 398

OHOH

156 (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[6-(1H-imidazol-2-yl)-4-metyl-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:156 (S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2-one :

K roztoku imidát-esteru (150 mg, 0,31 mmol) v metanole (10 ml) sa pridá aminoacetaldehyd-dietylacetal (97 mg, 0,93 mmol). Zmes sa mieša 14 h pri teplote miestnosti. Potom sa rozpúšťadlo odstráni vo vákuu a zvyšok sa spracuje pri teplote miestnosti počas 14 h s 60 % HCIO4 (5 ml). Potom sa reakčná zmes zneutralizuje s hydroxidom amónnym (koncentrovaným). Anorganická soľ sa odfiltruje. Filtrát sa zahustí a prečistením preparatívnou HPLC sa získa vo forme bieleho tuhého produktu titulná zlúčenina (37 mg, 27 %). 1H NMR (300 MHz, CD3OD) δ 7,94 (1H, úzky d, J = 1,3 Hz), 7,58 (2H, s), 7,53 (1H, úzky d, J = 0,6 Hz), 7,12-7,31 (6H, m),To a solution of the imidate ester (150 mg, 0.31 mmol) in methanol (10 mL) was added aminoacetaldehyde diethyl acetal (97 mg, 0.93 mmol). The mixture was stirred at room temperature for 14 h. Then the solvent was removed in vacuo and the residue was treated at room temperature for 14 h with 60% HClO 4 (5 mL). The reaction mixture is then neutralized with ammonium hydroxide (concentrated). The inorganic salt is filtered off. The filtrate was concentrated and purified by preparative HPLC to give the title compound (37 mg, 27%) as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ 7.94 (1H, narrow d, J = 1.3 Hz), 7.58 (2H, s), 7.53 (1H, narrow d, J = 0) 6 Hz), 7.12-7.31 (6 H, m),

6,16 (1H, d, J = 7,7 Hz), 4,04-4,08 (1H, m), 3,76-3,79 (2H, m), 3,16 (1H, dd, J = 5,4,6.16 (1H, d, J = 7.7Hz), 4.04-4.08 (1H, m), 3.76-3.79 (2H, m), 3.16 (1H, dd, J = 5.4,

13,6 Hz), 3,97 (1H, dd, J = 8,1, 13,6 Hz), 2,69 (3H, s). LCMS (M+H)+ m/z 441 (t =13.6 Hz), 3.97 (1H, dd, J = 8.1, 13.6 Hz), 2.69 (3H, s). LCMS (M + H) &lt; + &gt; m / z 441 (t =

1,60 min).1.60 min).

Všeobecný spôsob prípravy amidínov, zlúčenín podľa príkladov 399-412 (schéma IV (16))General Method for Preparation of Amidines, Compounds of Examples 399-412 (Scheme IV (16))

Príklad 399Example 399

(S)-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7,Ndimetyl-3H-benzoimidazol-5-karboxamidín:(S) -2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7, N-dimethyl-3H-benzimidazole-5-carboxamidine:

Surový imidát-ester (60 mg, 0,135 mmol) sa zriedi v metanole (10 ml) a potom sa k roztoku pridá metylamin (2,0 mol/l v metanole, nadbytok 0,5 mí). Reakčná zmes sa mieša 2 hodiny, potom sa zahustí a prečistením preparatívnou HPLC sa získa vo forme bieleho tuhého produktu titulná zlúčenina (32 mg, 55 %). 1H NMR (300 MHz, CD3OD) δ 7,82 (1H, s), 7,38 (1H, s), 7,10-7,30 (6H, m), 6,15 (1H, J = 7,7 Hz), 4,034,07 (1H, m), 4,72-4,76 (2H, m), 3,06-3,18 (1H, m), 3,12 (3H, s), 2,96 (1H, dd, J =The crude imidate ester (60 mg, 0.135 mmol) was diluted in methanol (10 mL) and then methylamine (2.0 M in methanol, excess 0.5 mL) was added to the solution. The reaction mixture was stirred for 2 hours, then concentrated and purified by preparative HPLC to give the title compound as a white solid (32 mg, 55%). 1 H NMR (300 MHz, CD 3 OD) δ 7.82 (1H, s), 7.38 (1H, s), 7.10-7.30 (6H, m), 6.15 (1H, J) = 7.7 Hz), 4.034.07 (1H, m), 4.72-4.76 (2H, m), 3.06-3.18 (1H, m), 3.12 (3H, s) 2.96 (1H, dd, J =

157157

8,0, 13,5 Hz), 2,67 (3H, s). LCMS (M+H)* m/z 431 (t = 1,34 min).8.0, 13.5 Hz), 2.67 (3H, s). LCMS (M + H) + m / z 431 (t = 1.34 min).

Príklad 400Example 400

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} 7, N-dimethyl-3H-benzimidazole-5-carboxamidine :

1H NMR (300 MHz, CD3OD) δ 7,81 (1H, s), 7,54 (1H, s), 7,23-7,54 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.81 (1H, s), 7.54 (1H, s), 7.23-7.54 (5H, m),

6,26 (1H, d, J = 7,6 Hz), 5,01 (1H, t, J = 4,8 Hz), 3,77 (1H, dd, J = 4,5, 13,4 Hz), 3,67 (1H, dd, J = 6,6, 13,4 Hz), 3,12 (3H, s), 2,66 (3H, s). LCMS (M+H)* m/z 451 (t = 1,32 min).6.26 (1H, d, J = 7.6Hz), 5.01 (1H, t, J = 4.8Hz), 3.77 (1H, dd, J = 4.5, 13.4Hz ), 3.67 (1H, dd, J = 6.6, 13.4 Hz), 3.12 (3H, s), 2.66 (3H, s). LCMS (M + H) + m / z 451 (t = 1.32 min).

Príklad 401Example 401

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridin-3-yl}-7metyl-3H-benzoimidazol-5-karboxamidín:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamidine:

1H NMR (300 MHz, CD3OD) δ 7,90 (1H, s), 7,26-7,57 (6H, m), 6,25 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 7.90 (1H, s), 7.26-7.57 (6H, m), 6.25 (1H, d, J =

7,6 Hz), 5,01 (1H, t, J = 6,4 Hz), 3,75 (1H, dd, J = 4,8, 13,4 Hz), 3,66 (1H, dd, J = 6,7,7.6 Hz), 5.01 (1H, t, J = 6.4 Hz), 3.75 (1H, dd, J = 4.8, 13.4 Hz), 3.66 (1H, dd, J = 6.7,

13,4 Hz), 2,62 (3H, s). LCMS (M+H)* m/z 437 (t = 1,59 min).13.4 Hz), 2.62 (3H, s). LCMS (M + H) + m / z 437 (t = 1.59 min).

Príklad 402Example 402

158158

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyrid ίη-3-yl}7,N,N-trimetyl-3H-benzoimidazol-5-karboxamidín:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} 7, N, N-trimethyl-3H-benzoimidazole- 5-carboxamidine:

1H NMR (300 MHz, CD3OD) δ 7,63 (1H, s), 7,54 (1H, s), 7,18-7,41 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.63 (1H, s), 7.54 (1H, s), 7.18-7.41 (5H, m),

6,26 (1H, d, J = 7,6 Hz), 5,01 (1H, t, J = 6,3 Hz), 3,77 (1H, dd, J = 4,7, 13,5 Hz), 3,67 (1H, dd, J = 6,6, 13,5 Hz), 3,34 (6H, s), 2,66 (3H, s). LCMS (M+H)+ m/z 465 (t = 1,57 min).6.26 (1H, d, J = 7.6Hz), 5.01 (1H, t, J = 6.3Hz), 3.77 (1H, dd, J = 4.7, 13.5Hz ), 3.67 (1H, dd, J = 6.6, 13.5 Hz), 3.34 (6H, s), 2.66 (3H, s). LCMS (M + H) &lt; + &gt; m / z 465 (t = 1.57 min).

Príklad 403Example 403

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7cyklopropyl-3H-benzoimidazol-5-karboxamidín:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7cyklopropyl-3H-benzimidazole-5-carboxamidine:

1H NMR (300 MHz, CD3OD) δ 7,78 (1H, s), 7,54 (1H, s), 7,22-7,41 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.78 (1H, s), 7.54 (1H, s), 7.22-7.41 (5H, m),

6,25 (1H, d, J = 7,6 Hz), 5,01 (1H, t, J = 6,4 Hz), 3,76 (1H, dd, J = 4,7, 13,5 Hz), 3,67 (1H, dd, J = 6,6, 13,5 Hz), 2,77-2,83 (1H, m), 2,65 (3H, s), 1,03-1,10 (2H, m), 0,860,92 (2H, m). LCMS (M+H)+ m/z 477 (t = 1,43 min).6.25 (1H, d, J = 7.6Hz), 5.01 (1H, t, J = 6.4Hz), 3.76 (1H, dd, J = 4.7, 13.5Hz 1.67 (1H, dd, J = 6.6, 13.5 Hz), 2.77-2.83 (1H, m), 2.65 (3H, s), 1.03-1, 10 (2H, m), 0.860.92 (2H, m). LCMS (M + H) &lt; + &gt; m / z 477 (t = 1.43 min).

Príklad 404Example 404

OMeOMe

159 (±)-2-{4-[2-(3-chlór-4-metoxyfenyl)-2-metoxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:159 (±) -2- {4- [2- (3-Chloro-4-methoxy-phenyl) -2-methoxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzoimidazole 5-carboxamidine:

1H NMR (300 MHz, CD3OD) δ 7,79 (1H, úzky d, J = 1,0 Hz), 7,45 (1H, úzky d, J = 1,5 Hz), 7,38 (1H, s), 7,28-7,31 (2H, m), 7,02 (1H, d, J = 6,4 Hz), 6,22 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 7.79 (1H, narrow d, J = 1.0 Hz), 7.45 (1H, narrow d, J = 1.5 Hz), 7.38 ( 1H, s), 7.28-7.31 (2H, m), 7.02 (1H, d, J = 6.4Hz), 6.22 (1H, d, J =

5,7 Hz), 4,52 (1H, t, J = 5,9 Hz), 3,83 (3H, s), 3,60-3,71 (2H, m), 3,36 (3H, s), 3,13 (3H, s), 2,65 (3H, s). LCMS (M+H)+ m/z 495 (t = 1,64 min).5.7 Hz), 4.52 (1H, t, J = 5.9 Hz), 3.83 (3H, s), 3.60-3.71 (2H, m), 3.36 (3H, s) s), 3.13 (3H, s), 2.65 (3H, s). LCMS (M + H) &lt; + &gt; m / z 495 (t = 1.64 min).

Príklad 405Example 405

(±)-2-{4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:(±) -2- {4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7, N-dimethyl-3H-benzoimidazol 5-carboxamidine:

K roztoku 2-{4-[2-(3-chlór-4-metoxyfenyl)-2-metoxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidínu (40 mg, 0,08 mmol) v metanole (5 ml) sa pridá NaOH 2 mol/l (0,5 ml) a reakčná zmes sa mieša 14 h pri teplote miestnosti. Po zahustení za zníženého tlaku sa prečistením zvyšku preparatívnou HPLC získa vo forme oleja titulná zlúčenina (7,2 mg, 19 %). 1H NMR (300 MHz, CD3OD) δ 7,78 (1H, úzky d, J = 1,6 Hz), 7,52 (1H, úzky d, J = 2,1 Hz),To a solution of 2- {4- [2- (3-chloro-4-methoxyphenyl) -2-methoxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzoimidazole-5- carboxamidine (40 mg, 0.08 mmol) in methanol (5 mL) was added 2M NaOH (0.5 mL) and the reaction mixture was stirred at room temperature for 14 h. After concentration under reduced pressure, the residue was purified by preparative HPLC to give the title compound as an oil (7.2 mg, 19%). 1 H NMR (300 MHz, CD 3 OD) δ 7.78 (1H, narrow d, J = 1.6 Hz), 7.52 (1H, narrow d, J = 2.1 Hz),

7,30-7,36 (3H, m), 6,99 (1H, d, J = 8,5 Hz), 6,27 (1 H, d, J = 7,6 Hz), 4,94 (1H, t, J = 5,9 Hz), 3,82 (3H, s), 3,68-3,72 (2H, m), 3,13 (3H, s), 2,63 (3H, s). LCMS (M+H)+ m/z 481 (t = 1,44 min).7.30-7.36 (3H, m), 6.99 (1H, d, J = 8.5 Hz), 6.27 (1H, d, J = 7.6 Hz), 4.94 (1H 1H, t, J = 5.9 Hz), 3.82 (3H, s), 3.68-3.72 (2H, m), 3.13 (3H, s), 2.63 (3H, s) ). LCMS (M + H) &lt; + &gt; m / z 481 (t = 1.44 min).

Príklad 406Example 406

OMeOMe

160 (±)-2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:160 (±) -2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzoimidazole 5-carboxamidine:

1H NMR (400 MHz, CD3OD) δ 7,77 (1H, s), 7,67 (1H, s), 7,29-7,39 (3H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.77 (1H, s), 7.67 (1H, s), 7.29-7.39 (3H, m),

6,95 (1H, d, J = 8,4 Hz), 6,23 (1 H, d, J =4,4 Hz), 4,92 (1H, m), 3,80 (3H, s), 3,69 (2H, m), 3,13 (3H, s), 2,61 (3H, s). LCMS (M+H)+ m/z 525 (t = 1,44 min).6.95 (1H, d, J = 8.4Hz), 6.23 (1H, d, J = 4.4Hz), 4.92 (1H, m), 3.80 (3H, s) 3.69 (2H, m), 3.13 (3H, s), 2.61 (3H, s). LCMS (M + H) &lt; + &gt; m / z 525 (t = 1.44 min).

Príklad 407Example 407

(S)-N-cyklopropyl-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl-3H-benzoimidazol-5-karboxamidín:(S) -N-cyclopropyl-2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridine-3-yl] -7-methyl-3H-benzimidazole-5-carboxamidine:

1H NMR (300 MHz, CD3OD) δ 7,81 (1H, s), 7,37 (1H, s), 7,10-7,30 (6H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.81 (1H, s), 7.37 (1H, s), 7.10-7.30 (6H, m),

6,16 (1H, d, J = 7,6 Hz), 4,03-4,08 (1H, m), 3,74-3,76 (2H, m), 3,15 (1H, dd, J = 5,3,6.16 (1H, d, J = 7.6Hz), 4.03-4.08 (1H, m), 3.74-3.76 (2H, m), 3.15 (1H, dd, J = 5.3,

13,6 Hz), 2,96 (1H, dd, J = 8,1, 13,6 Hz), 2,78-2,84 (1H, m), 2,67 (3H, s), 1,03-1,10 (2H, m), 0,87-0,92 (2H, m). LCMS (M+H)+ m/z 457 (t = 1,51 min).13.6 Hz), 2.96 (1H, dd, J = 8.1, 13.6 Hz), 2.78-2.84 (1H, m), 2.67 (3H, s), 1, O 3 - 1.10 (2H, m), 0.87-0.92 (2H, m). LCMS (M + H) &lt; + &gt; m / z 457 (t = 1.51 min).

Príklad 408Example 408

(S)-N-etyl-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3yl]-7-metyl-3H-benzoimidazol-5-karboxamidín:(S) -N-ethyl-2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzimidazole-5-carboxamidine:

1H NMR (400 MHz, CD3OD) δ 7,82 (1H, s), 7,38 (1H, s), 7,12-7,30 (6H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.82 (1H, s), 7.38 (1H, s), 7.12-7.30 (6H, m),

6,15 (1H, d, J = 7,8 Hz), 4,04-4,07 (1H, m), 3,75-3,77 (2H, m), 3,51 (2H, q, J = 7,36.15 (1H, d, J = 7.8Hz), 4.04-4.07 (1H, m), 3.75-3.77 (2H, m), 3.51 (2H, q, J = 7.3

Hz), 3,15 (1H, dd, J = 5,4, 13,7 Hz), 2,96 (1H, dd, J = 8,1, 13,7 Hz), 2,67 (3H, s), 1,40Hz), 3.15 (1H, dd, J = 5.4, 13.7 Hz), 2.96 (1H, dd, J = 8.1, 13.7 Hz), 2.67 (3H, s) ), 1.40

161 (3Η, t, J = 7,3 Hz). LCMS (M+H)+ m/z 445 (t = 1,44 min).161 (3Η, t, J = 7.3Hz). LCMS (M + H) &lt; + &gt; m / z 445 (t = 1.44 min).

Príklad 409Example 409

(S)-2-{4-[2-(3-chlórfenyl)-1-hydroxymetyletylamino]-2-oxo-1,2-dihydropyridín-3yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:(S) -2- {4- [2- (3-chlorophenyl) -1-hydroxymethyl-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzimidazole-5-carboxamidine:

1H NMR (400 MHz, CD3OD) δ 7,83 (1H, s), 7,38 (1H, s), 7,31 (1H, s), 7,10- 1 H NMR (400 MHz, CD 3 OD) δ 7.83 (1H, s), 7.38 (1H, s), 7.31 (1H, s), 7.10-

7,24 (4H, m), 6,16 (1H, d, J = 7,6 Hz), 4,06-4,09 (1H, m), 3,72-3,77 (2H, m), 3,16 (3H, s), 3,15 (1H, m), 2,96 (1H, dd, J = 8,2, 13,7 Hz), 2,67 (3H, s). LCMS (M+H)+ m/z 465 (t = 1,49 min).7.24 (4H, m), 6.16 (1H, d, J = 7.6Hz), 4.06-4.09 (1H, m), 3.72-3.77 (2H, m) 3.16 (3H, s), 3.15 (1H, m), 2.96 (1H, dd, J = 8.2, 13.7 Hz), 2.67 (3H, s). LCMS (M + H) &lt; + &gt; m / z 465 (t = 1.49 min).

Príklad 410Example 410

(S)-2-{4-[2-(2-chlórfenyl)-1-hydroxymetyletylamino]-2-oxo-1,2-dihydropyridín-3yl}-7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:(S) -2- {4- [2- (2-chlorophenyl) -1-hydroxymethyl-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzimidazole-5-carboxamidine:

1H NMR (400 MHz, CD3OD) δ 7,84 (1H, s), 7,41 (1H, s), 7,32-7,35 (2H, s), 7,06-7,18 (3H, m), 6,10 (1H, d, J = 7,5 Hz), 4,20-4,24 (1H, m), 3,76-3,85 (2H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.84 (1H, s), 7.41 (1H, s), 7.32-7.35 (2H, s), 7.06-7.18 (3H, m), 6.10 (1H, d, J = 7.5Hz), 4.20-4.24 (1H, m), 3.76-3.85 (2H, m),

3,30-3,34 (1H, m), 3,06-3,14 (1H, m), 3,13 (3H, s), 2,64 (3H, s). LCMS (M+H)+ m/z 465 (t = 1,48 min).3.30-3.34 (1H, m), 3.06-3.14 (1H, m), 3.13 (3H, s), 2.64 (3H, s). LCMS (M + H) &lt; + &gt; m / z 465 (t = 1.48 min).

Príklad 411Example 411

162162

(+)-2-{4-[2-(2-brómfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}7,N-dimetyl-3H-benzoimidazol-5-karboxamidín:(+) - 2- {4- [2- (2-bromophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} 7, N-dimethyl-3H-benzimidazole-5-carboxamidine :

1H NMR (300 MHz, CD3OD) δ 7,80 (1H, s), 7,61 (1H, s), 7,20-7,45 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.80 (1H, s), 7.61 (1H, s), 7.20-7.45 (5H, m),

6,25 (1H, d, J = 7,3 Hz), 5,00 (1H, t, J = 5,9 Hz), 3,64-3,80 (2H, m), 3,12 (3H, s), 2,66 (3H, s). LCMS (M+H)+ m/z 495 (t = 1,49 min).6.25 (1H, d, J = 7.3Hz), 5.00 (1H, t, J = 5.9Hz), 3.64-3.80 (2H, m), 3.12 (3H) , s), 2.66 (3H, s). LCMS (M + H) &lt; + &gt; m / z 495 (t = 1.49 min).

Príklad 412Example 412

(S)-2-[4-(2-hydroxy-2-fenyletylamino]-2-oxo-1,2-dihydropyridín-3-yl]-7,Ndimetyl-3H-benzoimidazol-5-karboxamidín:(S) -2- [4- (2-hydroxy-2-phenyl-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl] -7, N-dimethyl-3H-benzimidazole-5-carboxamidine:

1H NMR (400 MHz, CD3OD) δ 7,78 (1H, s), 7,24-7,49 (7H, m), 6,21 (1H, d, J = 7,0 Hz), 4,00-5,05 (1H, m), 3,61-3,74 (2H, m), 3,12 (3H, s), 2,63 (2H, s). LCMS (M+H)+ m/z 417 (t = 1,28 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.78 (1H, s), 7.24-7.49 (7H, m), 6.21 (1H, d, J = 7.0 Hz), 4.00-5.05 (1 H, m), 3.61-3.74 (2 H, m), 3.12 (3 H, s), 2.63 (2 H, s). LCMS (M + H) &lt; + &gt; m / z 417 (t = 1.28 min).

Pr. č. Pr. no. Názov Title Vzorec formula T (min) T (min) Hmotnosť (M+H)+m/zMass (M + H) + m / z 413 413 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(1imino-1-morfolín-4-ylmetyl)4-metyl-1 H-benzoimidazol2-yl]-1 H-pyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (1-amino-1-morpholin-4-ylmethyl) -4-methyl-1H-benzoimidazol-2-yl] -1H-pyridine -2-one NM 0 oW HN OH NM 0 oW HN OH 1,55 (f) 1.55 (f) 507 507

163163

414 414 (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]3-[6-(4,5-dihydro-1 Himidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] 3- [6- (4,5-dihydro-1 H -imidazol-2-yl) -4-methyl-1H-benzimidazole- 2-yl] -1H-pyridin-2-one .Vrá* H. Returns * H 1,49 (b) 1.49 b 537 537 415 415 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-di hydropyrid í n-3-yl}-N(2,2-d ietoxyetyl)-7-mety I3H-benzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N (2,2-diethoxyethyl) -7-methyl I3H-benzimidazole-5-carboxamidine Γ m 0. r-*4 T s ITm I KN OH G 0 m 0 . r - * 4 T with ITm I KN OH G 1,77 (f) 1.77 (f) 553 553 416 416 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(1 Himidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [6- (1 H -imidazol-2-yl) -4-methyl-1H-benzimidazol-2-yl] -1 H -pyridin-2-one Οι H N N H h j HN OH ΉΟι H NNH h j HN OH Ή 1,71 (f) 1.71 f 461 461 417 417 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(7'metyl-1 H,3'H-[2,5']-bibenzoimidazol-2'-yl)-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (7'-methyl-1H, 3'H- [2,5 '] - bibenzoimidazol-2'-yl) -1H-pyridine- 2-one G T G T 1,82 (b) 1.82 b 511 511 418 418 (+)-cis-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(7 metyl-3a,4,5,6,7,7ahexahydro-1 H,3'H-[2,5']-bibenzoimidazol-2 -yI)-1Hpyridín-2-ón (+) - cis-4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (7-methyl-3a, 4,5,6,7,7ahexahydro-1H, 3'H- [2,5 ' 1-Bibenzoimidazol-2-yl) -1H-pyridin-2-one Qi.... | HN Of Qi .... | HN Of 1,75 (b) 1.75 b 517 517

164164

419 419 (±)-trans-4-[2-(3-chlórfenyl)- 2-hydroxyetylamino]-3-(7'metyl-3a,4,5,6,7,7ahexahydro-1 H,3'H-[2,5']-bibenzoimidazol-2'-yl)-1 Hpyridín-2-ón (±) -trans-4- [2- (3-chlorophenyl) - 2-hydroxyethylamino] -3- (7'methyl-3a, 4,5,6,7,7ahexahydro-1H, 3'H- [2,5 '] - bibenzoimidazol-2'-yl) -1H-pyridin-2 -one CA B 0 lA/ylI, j-’“ MH OH A-CA B 0.1A / yl, MH + OH 1,75 (b) 1.75 b 517 517 420 420 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-dihydropy ridí n-3-yl}-Ncyklopentyl-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N-cyclopentyl-7-methyl-3-benzoimidazole-5-carboxamidine ZA 0 | VM OH A- ZA 0 | VM OH A- 1,55 (b) 1.55 b 505 505 421 421 (+)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-dihydropyridín-3-yl}-Ncyklohexyl-7-metyl-3Hbenzoimidazol-5karboxamidín (+) - 2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -Ncyklohexyl-7-methyl-3H-benzoimidazol-5-carboxamidine 1 oh A· 1 oh A · 1.61 (b) 1.61 b 519 519 422 422 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-d i hyd ropyrid í n-3-yl}-7metyl-N-propyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-N-propyl-3-benzoimidazole-5-carboxamidine NH, 0 HN OH Ή-NH, 0 HN OH Ή- 1,48 (b) 1.48 (b) 479 479 423 423 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-d i hydropyridí η-3-y l}-7metyl-N,N'-dipropyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-N, N'-dipropyl-3H-benzoimidazole-5-carboxamidine \ o A·\ o A · 1,61 (b) 1.61 b 521 521

165165

424 424 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-dihydropyrid í n-3-yl}-Nizopropyl-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -Nisopropyl-7-methyl-3Hbenzoimidazole-5-carboxamidine / HH1 0 w I b-/ HH 1 0 w I b- 1,41 (b) 1.41 b 479 479 425 425 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-d ihyd ropyrid í n-3-yl}-7metyl-N-(2-morfolín-4yletyl)-3H-benzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-N- (2-morpholin-4-yl-ethyl) - 3H-benzimidazole-5-carboxamidine I HK OH I HK OH 1,27 (b) 1.27 b 550 550 426 426 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo- 1,2-dihydropyrid í n-3-yl}-7metyl-N,N'-bis-(2-morfolín- 4- yletyl)-3H-benzoimidazol- 5- karboxamidín (±) -2- {4- [2- (3-chlorophenyl) -2hydroxyetylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -7-methyl-N, N'-bis- (2-morpholine- 4-ylethyl) -3H-benzoimidazole- 5-carboxamidine r? n Aj y- r? n Aj y- 1,22 (b) 1.22 b 663 663 427 427 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-d ihydropyrid in-3-yl}-N(2-hydroxyetyl)-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -N (2-hydroxy-ethyl) -7-methyl-3H-benzoimidazole-5-carboxamidine ľ*1 H y—KM | HW OH¾ * 1 H y — KM | HW OH 1,38 (b) 1.38 b 481 481 428 428 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[4metyl-6-(5-metyl-1 Himidazol-2-yl-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-όπ (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (5-methyl-1 H -imidazol-2-yl-1-benzoimidazol-2-yl) -1-pyridin-2- όπ B χιά KM\__ζ°Η B χιά KM \ __ ζ ° Η 1,62 (b) 1.62 b 475 475

166166

429 429 (±)-2-{4-[2-(3-chlórfenyl)-2hyd roxyety lam i no]-2-oxo1,2-dihydropyridín-3-yl}-4metyl-1 H-benzoimidazol-6karboximid-amidhydrazid (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -4-methyl-1H-benzoimidazole-6-carboximide-amide hydrazide 0 ^'πΆ^χ NH T HH OH o-* 0 ^ 'πΆ ^ χ NH T HH OH about-* 1,44 (f) 1.44 (f) 452 452 430 430 (±)-2-{4-[2-(3-ch)órfenyl)-2hydroxyetylamino]-2-oxo1,2-dihyd ropy ridin-3-yl}-4metyl-1 H-benzoimidazol-6karboximid-amid-(Nformyl)hydrazid (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -4-methyl-1H-benzoimidazole-6-carboximide-amide ( Nformyl) hydrazide „CHO O H^ľx^cx D NH 1 HN OH "CHO ABOUT NH4 1 HN OH 1,58 (f) 1.58 (f) 480 480 431 431 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[4metyl-6-(4H-[1,2,4]triazol-3yl]-1 H-benzoimidazol-2-yl]1H-pyridín-2-ón (±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4H- [1,2,4] triazol-3-yl] -1H-benzoimidazol-2-yl] 1H pyridin-2-one 1 MN OH 1 MN OH 1,82 (f) 1.82 (f) 462 462 432 432 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-d ihyd ropyrid ín-3-yl}-Nhydroxy-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -Nhydroxy-7-methyl-3H-benzoimidazole-5-carboxamidine NKj O h0-h ] HN OHThe NKI h0-h] H N OH 1,34 (f) 1.34 (f) 453 453 433 433 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-dihyd ropyrid ín-3-yl}-Nmetoxy-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -N-methoxy-7-methyl-3-benzoimidazole-5-carboxamidine 7hj o M»OX Λ M V- NH I HN OH7 h y M »O X Λ M V - NH I HN OH 1,41 (f) 1.41 (f) 467 467

167167

434 434 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-dihyd ropyrid ín-3-yl}-Nhydroxy-7,N-dimetyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -N-hydroxy-7, N-dimethyl-3H-benzoimidazole-5-carboxamidine x o n x o n 1,39 (f) 1.39 (f) 467 467 435 435 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-dihydropyridin-3-yl}-Netyl-7-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -N-ethyl-7-methyl-3H-benzoimidazol-5-carboxamidine HH, ' D I HN OHHH, D HN OH 1,62 (f) 1.62 (f) 465 465 436 436 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo- 1,2-dihydropy rid ίη-3-y l}-7metyl-N-(2,2,2-trifluóretyl)3H-benzoimidazol-5karboxamidín (±) -2- {4- [2- (3-chlorophenyl) -2hydroxyetylamino] -2-oxo- 1,2-Dihydropyridin-3-yl} -7-methyl-N- (2,2,2-trifluoroethyl) 3H-benzoimidazole-5-carboxamidine o FjC HH I HN OH about FjC HH I HN OH 1.75 (f) 1.75 f 519 519 437 437 (±)-2-{4-[2-(3-chlórfenyl)-2hyd roxyetylam i no]-2-oxo1,2-d ihydropyrid ίη-3-y I}7,N,N'-trimetyl-3Hbenzoimidazol-5karboxamidin (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N, N'-trimethyl-3H-benzoimidazole- 5-carboxamidine ΰ IZ^Z /z / ΰ IZ ^ Z / z / 1,58 (f) 1.58 (f) 465 465 438 438 (±)-2-{4-[2-(3-fluórfenyl)-2hydroxyetylamino]-2-oxo1,2-dihyd ropyrid í n-3-yl}-7, Ndimetyl-3H-benzoimidazol5-karboxamidín (±) -2- {4- [2- (3-Fluorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7, N-dimethyl-3H-benzoimidazole-5-carboxamidine ««2 0 I HN OH «« 1 0 I HN OH 1,28 (b) 1.28 b 435 435

168168

439 439 (±)-3-[6-(4,5-dihydro-1 Ηimidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-[2-(3fluórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (±) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- [2- (3-fluorophenyl) -2-hydroxyethylamino] - 1H-pyridin-2-one HH OH A HH OH A 1,46 (b) 1.46 b 447 447 440 440 (±)-3-[6-(5,5-dimetyl-4,5dihydro-1 H-imidazol-2-yl)-4metyl-1 H-benzoimidazol-2yl]-4-[2-(3-fluórfenyl)-2hydroxyetylamino]-1 Hpyridín-2-ón (±) -3- [6- (5,5-Dimethyl-4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- [2- (3-fluorophenyl)] -2-hydroxyethylamino] -1H-pyridin-2-one /“•yH o HN OH Ä/ “• y H o HN OH NO 1,59 (b) 1.59 b 475 475 441 441 (S)-3-[6-(4,5-dihydro-1Himidazol-2-yl)-4-fenyl-1 Hbenzoimidazol-2-yl]-4-(1 hyd roxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-phenyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H- pyridin-2-one H V ΐΓγψ N y-NH jl OH O H V ΐΓγψ N y-NH jl OH ABOUT 2,90 (b) 2.90 b 505 505 442 442 (S)-3-[4-bróm-6-(4,5- dihydro-1 H-imidazol-2-yl)- 1 H-benzoimidazol-2-yl]-4(1-hydroxymetyl-2-fenyletylamino)-1 H-pyridín-2-ón (S) -3- [4-bromo-6- (4,5- dihydro-1H-imidazol-2-yl) - 1H-benzoimidazol-2-yl] -4 (1-hydroxymethyl-2-phenylethylamino) -1H-pyridin-2-one Br br 1,57 (b) 1.57 b 507 507 443 443 izobutyl ester (±)-[2-chlór-4(1-hydroxy-2-[3-[4-metyl-6(N-metyl-karbamimidoyl)- 1 H-benzoimidazol-2-yl]-2oxo-1,2-d ihydropyrid í n-4ylamino}etyl)fenyl]karbámovej kyseliny (±) - [2-Chloro-4- (1-hydroxy-2- [3- [4-methyl-6 (N-methyl-carbamimidoyl)) - isobutyl ester] - 1H-benzoimidazol-2-yl] -2-oxo-1,2-dihydropyridin-4-ylamino} ethyl) phenyl] carbamic acid 0 í HN OH Ä 0 HN OH Ä 1,64 (b) 1.64 b 566 566

169169

444 444 (S)-2-[4-( 1 -hydroxymetyl-2fenyletylamino)-2-oxo-1,2d ihydropyridí n-3-y I ]-7-metylN-(2-morfolín-4-yletyl)-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-N- (2-morpholin-4-ylethyl) -3H-benzoimidazole-5-carboxamidine Π Γ « v N NH I HNΠ Γ «in N NH I HN 1.33 (b) 1.33 b 530 530 445 445 (S)-2-[4-(1-hydroxyrnetyl-2- fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl- N-(2-tiofén-2-yletyl)-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (1-hydroxymethyl-2- phenyl-ethylamino) -2-oxo-1,2-dihydropyridine-3-yl] -7-methyl- N- (2-thiophen-2-yl-ethyl) -3Hbenzoimidazol-5-carboxamidine n r « v I HN n r «v I HN 1,62 (b) 1.62 b 527 527 446 446 (S)-2-[4-(1-hydroxymetyl-2- fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metyl- N-(2-pyridín-2-yletyl)-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (1-hydroxymethyl-2- phenyl-ethylamino) -2-oxo-1,2-dihydropyridine-3-yl] -7-methyl- N- (2-pyridin-2-yl-ethyl) -3Hbenzoimidazol-5-carboxamidine Z' * NH; o I HNZ 'NH; o I HN 1,40 (b) 1.40 b 522 522 447 447 (S)-2-[4-( 1 -hyd roxymetyl-2fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metylN-(2-pyridín-3-yletyl)-3Hbenzoimidazol-5karboxamidin (S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-N- (2-pyridin-3-ylethyl) -3H-benzoimidazole-5-carboxamidine rNii ľ”3 h v Μ-Λγ/ j HNr N ii ¾ ” 3 hv Μ-Λγ / j HN 1.37 (b) 1.37 b 522 522 448 448 (S)-2-[4-(1-hydroxymetyl-2- fenyletylamino)-2-oxo-1,2- dihydropyridín-3-yl]-7-metyl- N-(2-pyridín-4-yletyl)-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (1-hydroxymethyl-2- phenyl-ethylamino) -2-oxo-1,2- dihydro-pyridin-3-yl] -7-methyl- N- (2-pyridin-4-yl-ethyl) -3Hbenzoimidazol-5-carboxamidine 0-X 0-X 1.25 (b) 1.25 b 522 522

170170

449 449 (S)-2-[4-(1 -hydroxymetyl-2fenyletylamino)-2-oxo-1,2dihydropyridin-3-yl]-7-metylN,N'-bis-(2-pyridín-3-yletyl)3H-benzoimidazol-5karboxamidín (S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-N, N'-bis- (2-pyridin-3-ylethyl) 3H- benzoimidazole-5-carboxamidine Λ v | HN Λ v | HN 1,24 (b) 1.24 b 627 627 450 450 (S)-2-[4-( 1 -hydroxymetyl-2- fenyletylamino)-2-oxo-1,2dihydropyridín-3-yl]-7-metylN, N '-bis-( 2-py rid í n -4-y lety I )3H-benzoimidazol-5karboxamidín (S) -2- [4- (1-hydroxymethyl-2-) phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-N, N'-bis- (2-pyridin-4-y) I) 3H-benzoimidazole-5-carboxamidine ;; • HN ;; • HN 1,16 (b) 1.16 b 627 627 451 451 (S)-4-[2-(2-chlórfenyl)-1- hydroxymetyletylamino]-3[6-(4,5-dihydro-l H-imidazol2-yl)-4-metyl-1Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (S) -4- [2- (2-Chlorophenyl) -1- hydroxymethyl-ethylamino] -3 [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -1-pyridin-2-one Γ~ NH 0 I HN <Q-Moh ClΓ ~ NH 0 I HN <QM oh Cl 1,53 (b) 1.53 b 477 477 452 452 (S)-2-[4-( 1 -hydroxymetyl-2pyridín-3-yl-etylamino)-2oxo-1,2-d i hyd ropyrid ίη-3-yl]7,N-dimetyl-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (1-Hydroxymethyl-2-pyridin-3-yl-ethylamino) -2-oxo-1,2-dihydro-pyridin-3-yl] 7, N-dimethyl-3H-benzoimidazole-5-carboxamidine 0 'w I HN /“A 2--' OH 0 'w I HN / "A 2-- 'OH 0,80 (b) 0.80 b 432 432 453 453 (S)-3-(6-(4,5-dihydro-1Himidazol-2-yl)-4-metyl-1Hbenzoimidazol-2-yl]-4-(1hydroxymety l-2-pyrid í n - 3yletylamino)-1 H-pyridín-2-ón (S) -3- (6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-pyridin-3-ylethylamino) -1 H-pyridin-2-one M I —j °M M I — M ° M 0,98 (b) 0.98 b 444 444

171171

454 454 (S)-2-[4-(1 -hydroxymetyl-2pyridín-4-yletylamino)-2oxo-1,2-dihydropyridín-3-yl]7,N-dimetyl-3Hbenzoimidazol-5karboxamidin (S) -2- [4- (1-Hydroxymethyl-2-pyridin-4-ylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] 7, N-dimethyl-3H-benzoimidazole-5-carboxamidine NH, Q 'φφ I HN __ 4, v?—' 0H NH, Q 'φφ I HN __ 4, v? -' 0H 0,73 (b) 0.73 b 432 432 455 455 (S)-3-[6-(4,5-dihydro-1Himidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-(1hydroxymetyl-2-pyridín-4yletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-pyridin-4-ylethylamino) -1H- pyridin-2-one Φχφ I HfL —t °H Iχφ I Hf L —t ° H 0,98 (b) 0.98 b 444 444 456 456 (S)-2-[4-( 1 -hydroxymetyl-2tifén-2-yletylamino)-2-oxo- 1,2-dihydropyridín-4-yl]-7,Ndimetyl-5-karboxamidín (S) -2- [4- (1-Hydroxymethyl-2-thiphen-2-ylethylamino) -2-oxo- 1,2-dihydropyridin-4-yl] -7, N-dimethyl-5-carboxamidine NH, 'ΦΦ I HN OH NH, 'ΦΦ I HN OH 1,24 (b) 1.24 b 437 437 457 457 (S)-3-[6-(4,5-dihydro-1H- imidazol-2-yl)-4-metyl-1 H- benzoimidazol-2-yl]-4-(1hydroxymetyl-2-tiofén-2yletylamino)-1 H-pyridín-2-ón (S) -3- [6- (4,5-dihydro-1H- imidazol-2-yl) -4-methyl-1H- benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-thiophen-2-ylethylamino) -1H-pyridin-2-one Γ™ o ΦΦ 1 HN, Ο-Φ* Γ ™ o ΦΦ 1 HN, Ο-Φ * 1,46 (b) 1.46 b 449 449 458 458 (S)-2-[4-(2-benzo[b]tiofén- 3-yl-1 -hydroxymetyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7,N-dimetyl-3Hbenzoimidazol-5karboxamidín (S) -2- [4- (2-benzo [b] thiophene 3-yl-1-hydroxymethylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7, N-dimethyl-3H-benzoimidazole-5-carboxamidine ΝΜ» e ( ON Qp5 Q » e (ON Qp 5 1,47 (b) 1.47 b 487 487 459 459 7,N-dimetyl-2-[2-oxo-4-(2pyridín-2-yletylamino)-1,2dihydropyridín-3-yl]-3Hbenzoimidazol-5karboxamidín 7, N-dimethyl-2- [2-oxo-4- (2-pyridin-2-yl-ethylamino) -1,2dihydropyridín-3-yl] -3Hbenzoimidazol-5-carboxamidine Γ’ H % 7~\h | HN bΓ 'H% 7 ~ \ h | HN b 0,86 (b) 0.86 b 402 402

172172

460 460 3-(6-(4,5-dihydro-1Himidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-(2pyridín-2-yletylamino)-1 Hpyridín-2-ón 3- (6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (2-pyridin-2-ylethylamino) -1-pyridin-2-one I HN H I HN H 0,91 (b) 0.91 b 414 414 461 461 (S)-7-bróm-2-[4-(1-hydroxymetyl-2-fenyletylamino)-2oxo-1,2-dihydropyrid ίη-3-yl]- N-metyl-3H-benzoimidazol- 5-karboxamidín (S) -7-Bromo-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] - N-methyl-3H-benzoimidazol 5-carboxamidine Rr HN qXRr HN qX 1,47 (b) 1.47 b 495 495 462 462 (±)-2-{4-[2-(3-chlórfenyl)-2hydroxyetylamino]-2-oxo1,2-dihyd ropyrid ín-3-yl}-7etyl-N-metyl-3Hbenzoimidazol-5karboxamidín (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-ethyl-N-methyl-3H-benzoimidazole-5-carboxamidine •M* o J HN OH • M * o J HN OH 1,51 (d) 1.51 (d) 465 465 463 463 7, N-d imetyl-2-[2-oxo-4-(2pyridín-2-ylmetylamino)-1,2dihydropyridín-3-yl]-3Hbenzoimidazol-5karboxamidín 7, N-Dimethyl-2- [2-oxo-4- (2-pyridin-2-ylmethylamino) -1,2-dihydropyridin-3-yl] -3H-benzoimidazole-5-carboxamidine T hn n=\ m“) T hn n = \ m ') 0,98 (b) 0.98 b 388 388 464 464 3-(6-(4,5-dihydro-1 Himidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4[(pyridín-2-ylmetyl)amino]1H-pyridín-2-ón 3- (6- (4,5-dihydro-1 H -imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4 - [(pyridin-2-ylmethyl) amino] 1H-pyridin-2-one Γ~ΝΗ g γ~ Ν Η g γ 1,07 (b) 1.07 b 400 400 465 465 7,N-dimetyl-2-[2-oxo-4-(2tiofén-2-yletylamino)-1,2dihydropyridín-3-yl]-3Hbenzoimidazol-5karboxamidin 7, N-dimethyl-2- [2-oxo-4- (2-thiophen-2-yl-ethylamino) -1,2dihydropyridín-3-yl] -3Hbenzoimidazol-5-carboxamidine «Hj 0 I HN H «Hj 0 I HN H 1,53 (b) 1.53 b 407 407

173173

466 466 3-[6-(4,5-dihydro-l Ηimidazol-2-yl)-4-metyl-1 Hbenzoimidazol-2-yl]-4-(2tiofén-2-yletylamino)-1 Hpyridín-2-ón 3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (2-thiophen-2-ylethylamino) -1-pyridin-2-one I HN y I HN y 1,62 (b) 1.62 b 419 419 467 467 (±)-2-{4-[2-(3-chlórfenyl)- etylamino]-2-oxo-1,2dihydro-pyridín-3-yl}-7,Ndimetyl-3H-benzoimidazol5-karboxamidín (±) -2- {4- [2- (3-chlorophenyl) - ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7, N-dimethyl-3H-benzoimidazole-5-carboxamidine H y/y I HN H y / y I HN 1,57 (b) 1.57 b 435 435 468 468 (±)-4-[2-(3-chlórfenyl)etylamino]-3-[6-(4,5-dihydro1 H-imidazol-2-yl)-4-metyl- 1 H-benzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-chlorophenyl) ethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-methyl- 1H-benzoimidazol-2-yl] -1H-pyridin-2-one Λ’!“ h 3- | HN K“ H ’!" H 3 | HN K " 1,66 (b) 1.66 b 447 447 469 469 (+)-3-[4-chlór-6-(4,5- dihydro-1 H-imidazol-2-yl)- 1 H-benzoimidazol-2-yl]-4[2-(3-chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (+) - 3- [4-chloro-6- (4,5- dihydro-1H-imidazol-2-yl) - 1H-benzoimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one /-NH o N / S / -NH o N / S 1,40 (d) 1.40 (d) 483 483 470 470 (±)-3-[4-chlór-6-(5,5-dimetyl- 4,5-dihydro-l H-imidazol-2yl)-1 H-benzoimidazol-2-yl]- 4-[2-(3-chlórfenyl)-2- hydroxyetyl-amino]-1 Hpyridin-2-ón (±) -3- [4-chloro-6- (5,5-dimethyl- 4,5-dihydro-1H-imidazol-2-yl) -1H-benzoimidazol-2-yl] - 4- [2- (3-chloro-phenyl) -2- hydroxyethylamino] -1H-pyridin-2-one 7-KH 0 < Vnh N^ÍjL ) \ ? oH V7-KH 0 (Vnh N ^ j L) \? oH V 1,52 (d) 1.52 (d) 511 511 471 471 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(5,5dimetyl-4,5-dihydro-l Himidazol-2-yl)-4-etyl-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (5,5-dimethyl-4,5-dihydro-1 H -imidazol-2-yl) -4-ethyl-1H-benzoimidazole-2 -yl] -1H-pyridin-2-one T hm' oh K- T hm 'oh K- 1,57 (d) 1.57 d 505 505

174174

472 472 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(4,5dihydro-1 H-imidazol-2-yl)-4etyl-1 H-benzoimidazol-2-yl]1H-pyridín-2-ón (±) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- [6- (4,5-dihydro-1H-imidazol-2-yl) -4-ethyl-1H-benzoimidazol-2-yl] 1H pyridin-2-one Z'-NM Q ] HM OH ΫZ'-NM Q ] HM OH Ϋ 1,49 (d) 1.49 (d) 477 477 473 473 (S)-3-[6-(4,5-dihydro-l Himidazol-2-yl)-4-etyl-1 Hbenzoimidazol-2-yl]-4-(1 hydroxymetyl-2-fenyletamino)-1 H-pyridín-2-ón (S) -3- [6- (4,5-Dihydro-1H-imidazol-2-yl) -4-ethyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H- pyridin-2-one y—NH 0 Αχφ Jy — NH 0 Αχφ J 1,47 (d) 1.47 (d) 457 457 474 474 (S)-7-etyl-2-[4-(1 -hydroxymetyl-2-fenyletylamino)-2oxo-1,2-dihyd ropyrid ίη-3-yl]N-metyl-3H-benzoimidazol5-karboxamidín (S) -7-Ethyl-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] N-methyl-3H-benzoimidazole-5-carboxamidine NHj o ΥΦ J h Q-Aoh NHj o ΥΦ J h Q-Aoh 1,42 (d) 1.42 (d) 445 445

Príprava amiduPreparation of the amide

Príprava medziproduktuPreparation of intermediate

Etylester (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboxylovej kyseliny(±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester

Roztok etylesteru (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboximidovej kyseliny (400 mg, 0,90 mmol) sa zriedi roztokom HCI 2 mol/l (20 ml) a zmes sa mieša 14 h pri teplote miestnosti. Po zahustení do sucha sa surový produkt (419 mg, 100 %) použije v ďalšom stupni bez ďalšieho čistenia. Malé množstvo produktu bolo prečistené(±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboximidic acid ethyl ester solution (400 mg, 0.90 mmol) was diluted with 2 N HCl (20 mL) and the mixture was stirred at room temperature for 14 h. After concentration to dryness, the crude product (419 mg, 100%) was used in the next step without further purification. A small amount of product was purified

175 preparativnou HPLC za získania titulnej zlúčeniny. 1H NMR (300 MHz, CD3OD) δ 8,11 (1H, s), 7,74 (1H, s), 7,25-7,54 (5H, m), 6,25 (1H, d, J = 7,6 Hz), 4,99 (1H, t, J = 7,2 Hz). 4,38 (2H, q, J = 7,1 Hz), 3,61-3,76 (2H, m), 2,61 (3H, s), 1,42 (3H, q, J = 7,1 Hz). LCMS (M+H)+ m/z 467 (t = 2,23 min).175 by preparative HPLC to give the title compound. 1 H NMR (300 MHz, CD 3 OD) δ 8.11 (1H, s), 7.74 (1H, s), 7.25-7.54 (5H, m), 6.25 (1H, d) J = 7.6 Hz), 4.99 (1H, t, J = 7.2 Hz). 4.38 (2H, q, J = 7.1 Hz), 3.61-3.76 (2H, m), 2.61 (3H, s), 1.42 (3H, q, J = 7, 1 Hz). LCMS (M + H) &lt; + &gt; m / z 467 (t = 2.23 min).

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karboxylová kyselina(±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid

Etylester (419 mg, 0,90 mmol) pripravený vyššie uvedeným spôsobom sa zriedi metanolom (15 ml) a vodou (5 ml) a potom sa pridá hydroxid sodný (180 mg, 4,5 mmol). Zmes sa mieša 14 h pri teplote miestnosti. Po odstránení metanolu sa zvyšok zneutralizuje roztokom HCI 2 mol/l. Výsledná kaša sa prefiltruje a premyje sa ľadovo chladnou vodu. Tuhý podiel sa oddelí a vysuší sa za vysoko zníženého tlaku. Surový produkt (395 mg, 100 % výťažok, 80 % čistota) sa použije v ďalšom stupni bez ďalšieho čistenia. 1H NMR (300 MHz, CD3OD) δ 8,20 (1H, s), 7,92 (1 H, s), 7,27-The ethyl ester (419 mg, 0.90 mmol) prepared as above was diluted with methanol (15 mL) and water (5 mL) and then sodium hydroxide (180 mg, 4.5 mmol) was added. The mixture was stirred at room temperature for 14 h. After removal of the methanol, the residue was neutralized with 2M HCl solution. The resulting slurry was filtered and washed with ice-cold water. The solid was collected and dried under high vacuum. The crude product (395 mg, 100% yield, 80% purity) was used in the next step without further purification. 1 H NMR (300 MHz, CD 3 OD) δ 8.20 (1H, s), 7.92 (1H, s), 7.27-

7,47 (5H, m), 6,27 (1H, d, J = 7,6 Hz), 4,85 (1H, m), 3,63 (2H, m), 2,67 (3H, s). LCMS (M+H)+ m/z 439 (t = 1,88 min).7.47 (5H, m), 6.27 (1H, d, J = 7.6Hz), 4.85 (1H, m), 3.63 (2H, m), 2.67 (3H, s) ). LCMS (M + H) &lt; + &gt; m / z 439 (t = 1.88 min).

Príklad 475Example 475

Etylester (S)-2-[4-(1-hydroxymetyl-2-fenyletyl-amino)-2-oxo-1,2-dihydropyridín-(S) -2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridine-

3-yl]-7-metyl-3H-benzoimidazol-5-karboxylovej kyseliny3-yl] -7-methyl-3H-benzoimidazole-5-carboxylic acid

Imidátester (30 mg, 0,067 mmol) sa zriedi metanolom (10 ml) a pridajú sa dve kvapky vody. Reakčná zmes sa potom mieša 20 h pri teplote miestnosti. PoThe imidate ester (30 mg, 0.067 mmol) was diluted with methanol (10 mL) and two drops of water were added. The reaction mixture was then stirred at room temperature for 20 h. After

176 zahustení za zníženého tlaku sa prečistením preparatívnou HPLC získa vo forme bielej tuhej hmoty titulná zlúčenina. 1H NMR (300 MHz, CD3OD) δ 7,74 (1H, s), 7,11-Purification by preparative HPLC afforded the title compound as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ 7.74 (1H, s), 7.11-

7,30 (7H, m), 6,10 (1H, d, J = 6,9 Hz), 4,37 (2H, q, J = 6,6 Hz), 4,02 (1H, široký s), 3,69-3,81 (2H, m), 3,10 (1H, dd, J = 4,8, 13,5 Hz), 2,93 (1H, dd, J = 7,8, 13,5 Hz), 2,62 (3H, s), 1,41 (3H, t, J = 6,6 Hz). LCMS (M+H)+ m/z 447 (t = 1,95 min).7.30 (7H, m), 6.10 (1H, d, J = 6.9Hz), 4.37 (2H, q, J = 6.6Hz), 4.02 (1H, broad s) 3.69-3.81 (2H, m), 3.10 (1H, dd, J = 4.8, 13.5 Hz), 2.93 (1H, dd, J = 7.8, 13, 5 Hz), 2.62 (3H, s), 1.41 (3H, t, J = 6.6 Hz). LCMS (M + H) &lt; + &gt; m / z 447 (t = 1.95 min).

Príprava amidov s použitím (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboxylovej kyseliny ako východiskovej zložky, príklady 476-504, schéma IV (15).Preparation of amides using (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5- carboxylic acid starting material, examples 476-504, Scheme IV (15).

Príklad 476Example 476

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-metylamid:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamide N methylamide:

K roztoku uvedenej kyseliny (50 mg, 0,11 mmol) v DMF (5 ml) sa pridá difenylfosforylazid (38 mg, 0,14 mmol). Zmes sa mieša 5 min. Potom sa pridá roztok metylamínu (2,0 mol/l v THF) (0,11 ml, 0,22 mmol). Zmes sa mieša pri teplote miestnosti 14 h. Po odstránení DMF za vysoko zníženého tlaku sa prečistením zvyšku preparatívnou HPLC získa vo forme bieleho tuhého produktu titulná zlúčenina (18 mg, 36 %). 1H NMR (300 MHz, CD3OD) δ 7,89 (1H, s), 7,18-7,53 (6H, m), 6,23 (1H, d, J = 7,6 Hz), 4,98 (1H, m), 3,70 (1H, dd, J = 4,7, 13,5 Hz), 3,61 (1H, dd, J = 7,0, 13,5 Hz), 2,94 (3H, s), 2,61 (3H, s). LCMS (M+H)+ m/z 452 (t = 1,57 min).To a solution of said acid (50 mg, 0.11 mmol) in DMF (5 mL) was added diphenylphosphoryl azide (38 mg, 0.14 mmol). The mixture was stirred for 5 min. A solution of methylamine (2.0 M in THF) (0.11 mL, 0.22 mmol) was then added. The mixture was stirred at room temperature for 14 h. After removal of DMF under high vacuum, purification of the residue by preparative HPLC afforded the title compound (18 mg, 36%) as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ 7.89 (1H, s), 7.18-7.53 (6H, m), 6.23 (1H, d, J = 7.6 Hz), 4.98 (1H, m), 3.70 (1H, dd, J = 4.7, 13.5 Hz), 3.61 (1H, dd, J = 7.0, 13.5 Hz), 2 94 (3H, s); 2.61 (3H, s). LCMS (M + H) &lt; + &gt; m / z 452 (t = 1.57 min).

Príklad 477Example 477

NN

177 (±)-2-{4-[2-(3-chlórŤenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridin-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-dimetylamid:177 (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbox-N -dimetylamid:

1H NMR (300 MHz, CD3OD) δ 7,52 (1H, s), 7,24-7,40 (5H, m), 7,15 (1H, s), 1 H NMR (300 MHz, CD 3 OD) δ 7.52 (1H, s), 7.24-7.40 (5H, m), 7.15 (1H, s),

6,25 (1H, d, J = 7,6 Hz), 4,98 (1H, dd, J = 5,0, 6,9 Hz), 3,70 (1H, dd, J = 4,8, 13,56.25 (1H, d, J = 7.6Hz), 4.98 (1H, dd, J = 5.0, 6.9Hz), 3.70 (1H, dd, J = 4.8, 13.5

Hz), 3,62 (1H, dd, J = 7,0, 13,5 Hz), 3,3 (3H, s), 3,08 (3H, s), 2,62 (3H, s) . LCMS (M+H)+ m/z 466 (t = 1,84 min).Hz), 3.62 (1H, dd, J = 7.0, 13.5 Hz), 3.3 (3H, s), 3.08 (3H, s), 2.62 (3H, s). LCMS (M + H) &lt; + &gt; m / z 466 (t = 1.84 min).

Príklad 478 (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-(terc-butyl)amid:Example 478 (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbox- N- (tert-butyl) amide;

1H NMR (300 MHz, CD3OD) δ 7,82 (1H, s), 7,53 (1H, s), 7,48 (1H, s), 7,24- 1 H NMR (300 MHz, CD 3 OD) δ 7.82 (1H, s), 7.53 (1H, s), 7.48 (1H, s), 7.24-

7,40 (4H, m), 6,25 (1H, d, J = 7,6 Hz), 5,00 (1H, m), 3,64-3,70 (2H, m), 2,62 (3H, s),7.40 (4H, m), 6.25 (1H, d, J = 7.6Hz), 5.00 (1H, m), 3.64-3.70 (2H, m), 2.62 (3H, s)

1,49 (9H, s). LCMS (M+H)+ m/z 494 (t = 1,79 min).1.49 (9 H, s). LCMS (M + H) &lt; + &gt; m / z 494 (t = 1.79 min).

Príklad 479 (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridin-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-butyl(metyl)amid:Example 479 (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbox- N-butyl (methyl) amide;

1H NMR (300 MHz, CD3OD) δ 7,51 (1H, s), 7,48 (1H, s), 7,24-7,39 (4H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.51 (1H, s), 7.48 (1H, s), 7.24-7.39 (4H, m),

178178

7,13 (1Η, s), 6,22 (1H, d, J = 7,6 Hz), 4,95 (1H, m), 3,55-3,70 (3H, m), 3,34 (1H, m),7.13 (1H, s), 6.22 (1H, d, J = 7.6Hz), 4.95 (1H, m), 3.55-3.70 (3H, m), 3.34 (LH, m),

3,05 (3H, s), 2,62 (3H, s), 0,79-1,69 (7H, m). LCMS (M+H)+ m/z 508 (t = 1,88 min).3.05 (3H, s), 2.62 (3H, s), 0.79-1.69 (7H, m). LCMS (M + H) &lt; + &gt; m / z 508 (t = 1.88 min).

Príklad 480Example 480

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-(2-morfolín-4-yletyl)amid.(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamide N (2-morpholin-4-yl-ethyl) -amide.

1H NMR (300 MHz, CD3OD) δ 7,58 (1H, s), 7,52 (1H, s), 7,05-7,42 (5H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.58 (1H, s), 7.52 (1H, s), 7.05-7.42 (5H, m),

6,22 (1H, d, J = 7,6 Hz), 4,97 (1H, dd, J = 4,9, 6,7 Hz), 2,60-4,07 (14H, m), 2,61 (3H, s). LCMS (M+H)+ m/z 551 (t = 1,49 min).6.22 (1H, d, J = 7.6Hz), 4.97 (1H, dd, J = 4.9, 6.7Hz), 2.60-4.07 (14H, m), 2 61 (3H, s). LCMS (M + H) &lt; + &gt; m / z 551 (t = 1.49 min).

Príklad 481Example 481

Terc-butylester (±)-4-[1-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)metanoyl]piperazín-1-karboxylovej kyseliny:(±) -4- [1- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-tert-butyl ester -benzoimidazol-5-yl) methanoyl] piperazine-1-carboxylic acid:

1H NMR (300 MHz, CD3OD) δ 7,52 (1H, s), 7,50 (1H, s), 7,24-7,38 (4H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.52 (1H, s), 7.50 (1H, s), 7.24-7.38 (4H, m),

7,18 (1H, m), 6,22 (1H, d, J = 7,6 Hz), 4,97 (1H, m), 3,49-3,69 (1 OH, m), 2,62 (3H, s),7.18 (1H, m), 6.22 (1H, d, J = 7.6Hz), 4.97 (1H, m), 3.49-3.69 (10H, m), 2, 62 (3 H, s),

1,47 (9H, s). LCMS (M+H)+ m/z 607 (t = 1,90 min).1.47 (9 H, s). LCMS (M + H) &lt; + &gt; m / z 607 (t = 1.90 min).

Príklad 482Example 482

179179

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(1-piperazín-1ylmetanoyl)-1 H-benzoimidazo)-2-yl]-1 H-pyridin-2-ón:(±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (1-piperazin-1-ylmethanoyl) -1H-benzoimidazol-2-yl] -1H pyridin-2-one;

K roztoku terc-butylu (±)-4-[1-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2oxo-1,2-dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)metanoyl]piperazín-1karboxylovej kyseliny (40 mg, 0,06 mmol) v metanole (5 ml) sa pridá roztok HCI 4 mol/l v dioxáne (0,1 ml, v nadbytku). Reakčná zmes sa potom mieša 14 h pri teplote miestnosti. Reakčná zmes sa potom zahustí za zníženého tlaku a prečistením zvyšku preparatívnou HPLC sa vo forme bielej peny získa titulná zlúčenina (16 mg, 63 %). 1H NMR (300 MHz, CD3OD) δ 7,56 (1H, s), 7,53 (1H, s), 7,23-7,41 (4H, m), 7,17 (1H, m),To a solution of tert-butyl (±) -4- [1- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl -3H-Benzoimidazol-5-yl) methanoyl] piperazine-1-carboxylic acid (40 mg, 0.06 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (0.1 mL, in excess). The reaction mixture was then stirred at room temperature for 14 h. The reaction mixture was then concentrated under reduced pressure and purification of the residue by preparative HPLC gave the title compound (16 mg, 63%) as a white foam. 1 H NMR (300 MHz, CD 3 OD) δ 7.56 (1H, s), 7.53 (1H, s), 7.23-7.41 (4H, m), 7.17 (1H, m),

6,26 (1H, d, J = 7,6 Hz), 4,99 (1H, dd, J = 4,7, 6,4 Hz), 3,91 (4H, široký s), 3,74 (1H, dd, J = 4,7, 13,5 Hz), 3,65 (1H, dd, J = 6,4, 13,5 Hz), 3,31 (4H, široký s, 2,63 (3H, s). LCMS (M+H)+ m/z 507 (t = 1,38 min).6.26 (1H, d, J = 7.6 Hz), 4.99 (1H, dd, J = 4.7, 6.4 Hz), 3.91 (4H, broad s), 3.74 ( 1H, dd, J = 4.7, 13.5 Hz), 3.65 (1H, dd, J = 6.4, 13.5 Hz), 3.31 (4H, broad s, 2.63 (3H) LCMS (M + H) &lt; + &gt; m / z 507 (t = 1.38 min).

Príklad 483Example 483

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-cyklopropylamid:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamide N cyclopropylamide:

1H NMR (300 MHz, CD3OD) δ 7,80 (1H, s), 7,21-7,53 (6H, m), 6,22 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 7.80 (1H, s), 7.21-7.53 (6H, m), 6.22 (1H, d, J =

7,6 Hz), 4,99 (1H, t, J = 6,4 Hz), 3,59-3,76 (2H, m), 2,83-2,90 (1H, m), 2,60 (3H, s), 0,81-0,89 (2H, m), 0,64-0,73 (2H, m). LCMS (M+H)+ m/z 478 (t = 1,60 min).7.6 Hz), 4.99 (1H, t, J = 6.4 Hz), 3.59-3.76 (2H, m), 2.83-2.90 (1H, m), 2, 60 (3H, s), 0.81-0.89 (2H, m), 0.64-0.73 (2H, m). LCMS (M + H) &lt; + &gt; m / z 478 (t = 1.60 min).

180180

Príklad 484Example 484

(±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridin-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-cyklopentylamid:(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamide N cyclopentylamide:

1H NMR (300 MHz, CD3OD) δ 7,97 (1H, s), 7,16-7,60 (6H, m), 6,22 (1H, d, J = 1 H NMR (300 MHz, CD 3 OD) δ 7.97 (1H, s), 7.16-7.60 (6H, m), 6.22 (1H, d, J =

7,6 Hz), 4,35 (1H, m), 4,35 (1H, m), 3,58-3,68 (2H, m), 2,62 (3H, s), 1,29-2,07 (9H, m). LCMS (M+H)+ m/z 506 (t = 1,86 min).7.6 Hz), 4.35 (1H, m), 4.35 (1H, m), 3.58-3.68 (2H, m), 2.62 (3H, s), 1.29- 2.07 (9 H, m). LCMS (M + H) &lt; + &gt; m / z 506 (t = 1.86 min).

Príklad 485Example 485

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-( 1 -piperidín-1 ylmetanoyl)-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1-piperidin-1-ylmethanoyl) -1H-benzoimidazol-2-yl] -1H-pyridine 2-one;

1H NMR (300 MHz, CD3OD) δ 7,53 (1H, s), 7,46 (1H, s), 7,18-7,41 (4H, m), 7,07 (1H, s), 6,23 (1H, d, J = 7,6 Hz), 4,98 (1H, dd, J = 4,8, 6,6 Hz), 3,60-3,74 (5H, m), 3,18-3,24 (1H, m), 2,60 (3H, m), 1,43-1,7 (6H, m). LCMS (M+H)+ m/z 506 (t = 1 H NMR (300 MHz, CD 3 OD) δ 7.53 (1H, s), 7.46 (1H, s), 7.18-7.41 (4H, m), 7.07 (1H, s) 6.23 (1H, d, J = 7.6Hz), 4.98 (1H, dd, J = 4.8, 6.6Hz), 3.60-3.74 (5H, m) 3.18-3.24 (1H, m), 2.60 (3H, m), 1.43-1.7 (6H, m). LCMS (M + H) &lt; + &gt; m / z 506 (t =

1,78 min).1.78 min).

Príklad 486Example 486

181 (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbox-N-cyklohexylamid:181 (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbox-N -cyclohexylamide:

'H NMR (300 MHz, CD3OD) δ 7,88 (1H, s), 7,54 (1H, s), 7,52 (1 H, s), 7,16-1 H NMR (300 MHz, CD 3 OD) δ 7.88 (1H, s), 7.54 (1H, s), 7.52 (1H, s), 7.16-

7,40 (4H, m), 6,22 (1H, d, J = 7,6 Hz), 4,97 (1H, dd, J = 4,7, 6,9 Hz), 3,89 (H, m),7.40 (4H, m), 6.22 (1H, d, J = 7.6Hz), 4.97 (1H, dd, J = 4.7, 6.9Hz), 3.89 (H , m),

3,69 (1H, dd, J = 4,7, 13,5 Hz), 3,61 (1H, dd, J = 6,9, 13,5 Hz), 2,61 (3H, s), 1,192,00 (1 OH, m). LCMS (M+H)+ m/z 520 (t = 1,93 min).3.69 (1H, dd, J = 4.7, 13.5 Hz), 3.61 (1H, dd, J = 6.9, 13.5 Hz), 2.61 (3H, s), 1.192 .00 (10H, m). LCMS (M + H) &lt; + &gt; m / z 520 (t = 1.93 min).

Príklad 487Example 487

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[1-(4-metylpiperidín-1yl)metanoyl]-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón:(±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [1- (4-methyl-piperidin-1-yl) -methanoyl] -1H-benzoimidazol-2-yl -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,51 (1H, s), 7,49 (1H, s), 7,21-7,39 (4H, m), 1 H NMR (300 MHz, CD 3 OD) δ 7.51 (1H, s), 7.49 (1H, s), 7.21-7.39 (4H, m),

7,14 (1H, s), 6,24 (1H, d, J = 7,6 Hz), 4,96 (1H, dd, J = 4,7, 7,0 Hz), 3,68 (1H, dd, J =7.14 (1H, s), 6.24 (1H, d, J = 7.6Hz), 4.96 (1H, dd, J = 4.7, 7.0Hz), 3.68 (1H , dd, J =

4,7, 13,6 Hz), 3,60 (1H, dd, J = 7,0, 13,6 Hz), 2,62 (3H, m), 1,93-1,72 (9H, m), 1,00 (3H, d, J = 6,3 Hz). LCMS (M+H)+ m/z 520 (t = 1,97 min).4.7, 13.6 Hz), 3.60 (1H, dd, J = 7.0, 13.6 Hz), 2.62 (3H, m), 1.93-1.72 (9H, m 1.00 (3H, d, J = 6.3 Hz). LCMS (M + H) &lt; + &gt; m / z 520 (t = 1.97 min).

Príklad 488Example 488

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(4,5-dihydrotiazol-2-yl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (4,5-dihydrothiazol-2-yl) -4-methyl-1H-benzoimidazol-2-yl] -1 H-pyridin-2-one;

182182

K roztoku (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karbonitrilu (100 mg, 0,24 mmol) v metanole (20 ml) sa pridá 2-aminoetanoltiol-hydrochlorid (41 mg, 0,36 mmol) a trietylamín (0,1 ml, nadbytok). Reakčná zmes sa zahrieva 14 h pri teplote spätného toku a potom sa ochladí na teplotu miestnosti. Po zahustení sa prečistením preparatívnou HPLC vo forme žltého tuhého produktu získa titulná zlúčenina (76 mg, 66 %). 1H NMR (300 MHz, CD3OD) δ 8,10 (1H, s), 7,71 (1H, s), 7,66 (1H, s), 7,25-To a solution of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbonitrile ( 100 mg, 0.24 mmol) in methanol (20 mL) was added 2-aminoethanolthiol hydrochloride (41 mg, 0.36 mmol) and triethylamine (0.1 mL, excess). The reaction mixture was heated at reflux for 14 h and then cooled to room temperature. After concentration, purification by preparative HPLC as a yellow solid gave the title compound (76 mg, 66%). 1 H NMR (300 MHz, CD 3 OD) δ 8.10 (1H, s), 7.71 (1H, s), 7.66 (1H, s), 7.25-

7,53 (4H, m), 6,33 (1H, d, J = 7,6 Hz), 5,01 (1H, dd, J = 4,2, 7,0 Hz), 4,58 (2H, t, J =7.53 (4H, m), 6.33 (1H, d, J = 7.6 Hz), 5.01 (1H, dd, J = 4.2, 7.0 Hz), 4.58 (2H , t, J =

8,6 Hz), 3,91 (2H, t, J = 8,6 Hz), 3,73 (1H, dd, J = 4,2, 13,7 Hz), 3,63 (1H, dd, J = 7,0,8.6 Hz), 3.91 (2H, t, J = 8.6 Hz), 3.73 (1H, dd, J = 4.2, 13.7 Hz), 3.63 (1H, dd, J = 7.0,

13,7 Hz), 2,64 (3H, s). LCMS (M+H)+ m/z 480 (t = 1,70 min).13.7 Hz), 2.64 (3H, s). LCMS (M + H) &lt; + &gt; m / z 480 (t = 1.70 min).

Príklad 489 (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbaldehyd:Example 489 (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbaldehyde:

K suspenzii (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karbonitrilu (76 mg, 0,18 mmol) v toluéne (bezvodý, 20 ml) sa pridá pri teplote -78 °C v atmosfére dusíka diizobutylaluminium (roztok v toluéne 1,4 mol/l) (0,65 ml, 0,97 mmol). Zmes sa mieša 6 h pri -78 °C. Potom sa pridá etylacetát (1 ml) a potom voda (0,5 ml). Zmes sa mieša pri teplote miestnosti 20 minút. Potom sa zmes prefiltruje cez vrstvu celitu a filtrát sa zahustí. Prečistením surového produktu preparatívnou HPLC sa vo forme hnedého tuhého produktu získa titulná zlúčenina (4 mg, 2,5 %). 1H NMR (300 MHz, CD3OD) δ 7,65 (1H, s), 7,57 (1H, s), 7,24-7,50 (5H, m), 6,26 (1H, d, J = 7,6 Hz), 5,49 (1H, s), 4,96 (1H, m), 3,53-3,79 (2H, m), 2,62 (3H, s). LCMS (M+H)+ m/z 423 (t = 1,79 min).To a suspension of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carbonitrile ( 76 mg, 0.18 mmol) in toluene (anhydrous, 20 mL) was added diisobutylaluminum (solution in toluene 1.4 mol / l) (0.65 mL, 0.97 mmol) at -78 ° C under nitrogen. . The mixture was stirred at -78 ° C for 6 h. Ethyl acetate (1 mL) was added followed by water (0.5 mL). The mixture was stirred at room temperature for 20 minutes. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification of the crude product by preparative HPLC afforded the title compound (4 mg, 2.5%) as a brown solid. 1 H NMR (300 MHz, CD 3 OD) δ 7.65 (1H, s), 7.57 (1H, s), 7.24-7.50 (5H, m), 6.26 (1H, d) J = 7.6 Hz), 5.49 (1H, s), 4.96 (1H, m), 3.53-3.79 (2H, m), 2.62 (3H, s). LCMS (M + H) &lt; + &gt; m / z 423 (t = 1.79 min).

183183

Príklad 490Example 490

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(1-hydroxy-1-metyletyl)-4metyl-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [6- (1-hydroxy-1-methylethyl) -4-methyl-1 H-benzoimidazol-2-yl] -1 H-pyridine 2-one:

K roztoku etylesteru (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboxylovej kyseliny (40 mg, 0,08 mmol) v THF (5 ml) sa pri -78 °C v atmosfére dusíka pridá metyllítium (roztok v THFTo a solution of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester of acid (40 mg, 0.08 mmol) in THF (5 mL) at -78 ° C under a nitrogen atmosphere is added methyl lithium (a solution in THF

1,4 mol/l, 0,57 ml, 0,8 mmol). Reakčná zmes sa postupne cez noc ohreje na teplotu miestnosti. Po zaliatí vodou sa reakčná zmes rozdelí medzi etylacetát a vodu. Organické vrstvy sa premyjú soľným roztokom, vysušia sa Na2SO4 a zahustia sa vo vákuu. Prečistením zvyšku preparatívnou HPLC sa vo forme bezfarebného oleja získa titulná zlúčenina (13 mg, 36 %). 1H NMR (300 MHz, CD3OD) δ 7,66 (1H, s),1.4 mol / L, 0.57 mL, 0.8 mmol). The reaction mixture was gradually warmed to room temperature overnight. After quenching with water, the reaction mixture was partitioned between ethyl acetate and water. The organic layers were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. Purification of the residue by preparative HPLC gave the title compound (13 mg, 36%) as a colorless oil. 1 H NMR (300 MHz, CD 3 OD) δ 7.66 (1H, s),

7,47 (1 H, s), 7,26-7,41 (5H, m), 6,26 (1H, d, J = 7,6 Hz), 4,92 (1H, m), 3,54-3,61 (2H, m), 2,62 (3H, s), 1,60 (6H, s). LCMS (M+H)+ m/z 453 (t = 1,46 min).7.47 (1H, s), 7.26-7.41 (5H, m), 6.26 (1H, d, J = 7.6 Hz), 4.92 (1H, m), 3, 54-3.61 (2H, m), 2.62 (3H, s), 1.60 (6H, s). LCMS (M + H) &lt; + &gt; m / z 453 (t = 1.46 min).

Príklad 491Example 491

(±)-3-(6-aminometyl-4-metyl-1H-benzoimidazol-2-yl)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-1H-pyridín-2-ón:(±) 3- (6-Aminomethyl-4-methyl-1 H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) -2hydroxyetylamino] -1 H-pyridin-2-one;

K roztoku (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2To a solution of (±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2

184 dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-karboxamidu (20 mg, 0,046 mmol) v THF (1 ml) sa pridá komplex borán-tetrahydrofurán (1 mol/l) (0,45 ml, 0,45 mmol). Reakčná zmes sa mieša pri teplote miestnosti 10 h a potom sa reakcia preruší pridaním kyseliny octovej (2 kvapky). Po odstránení väčšiny rozpúšťadla sa zvyšok extrahuje EtOAc, premyje sa soľným roztokom a vysuší sa Na2SO4. Po zahustení, prečistením surového produktu preparatívnou HPLC sa získa titulná zlúčenina (11,5 mg, 60 %). 1H NMR (400 MHz, CD3OD) δ 7,53 (1H, s), 7,50 (1H, s), 7,39 (1H, d, J =184 dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxamide (20 mg, 0.046 mmol) in THF (1 mL) was added borane-tetrahydrofuran complex (1 mol / l) (0.45 mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 10 h and then quenched by the addition of acetic acid (2 drops). After removing most of the solvent, the residue was extracted with EtOAc, washed with brine and dried over Na 2 SO 4 . After concentration, purification of the crude product by preparative HPLC gave the title compound (11.5 mg, 60%). 1 H NMR (400 MHz, CD 3 OD) δ 7.53 (1H, s), 7.50 (1H, s), 7.39 (1H, d, J =

7,5 Hz), 7,24-7,32 (3H, m), 7,13 (1H, s), 6,26 (1H, d, J = 7,5 Hz), 4,99 (1H, dd, J =7.5 Hz), 7.24-7.32 (3H, m), 7.13 (1H, s), 6.26 (1H, d, J = 7.5 Hz), 4.99 (1H, dd, J =

4,8, 6,8 Hz), 4,19 (2H, s), 3,72 (1H, dd, J = 4,8, 13,6 Hz), 3,64 (1H, dd, J = 6,8, 13,6 Hz), 2,62 (3H, s). LCMS (M+H)+ m/z 424 (t = 2,10 min).4.8, 6.8 Hz), 4.19 (2H, s), 3.72 (1H, dd, J = 4.8, 13.6 Hz), 3.64 (1H, dd, J = 6) , 8, 13.6 Hz), 2.62 (3H, s). LCMS (M + H) &lt; + &gt; m / z 424 (t = 2.10 min).

Príklad 492Example 492

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-hydroxymetyl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-hydroxymethyl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

K roztoku etylesteru (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3H-benzoimidazol-5-karboxylovej kyseliny (25 mg, 0,054 mmol) v metanole (2 ml) a kyseline octovej (1 ml) sa pri -20 °C pridá NaBH4 (10 mg, 0,27 mmol). Reakčná zmes sa mieša 30 min pri -20 °C a potom sa zaleje izopropanolom (5 kvapiek). Po odstránení väčšiny rozpúšťadla sa zvyšok extrahuje EtOAc, premyje sa vodou a soľným roztokom a vysuší sa Na2SO4. Po zahustení sa prečistením surového produktu preparatívnou HPLC získa titulná zlúčenina (18 mg, 62 %). 1H NMR (300 MHz, CD3OD) δ 7,50 (1H, s), 7,48 (1H, s), 7,25-7,38 (4H, m), 7,22 (1H, s),To a solution of (±) -2- {4- [2- (3-chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzoimidazole-5-carboxylic acid ethyl ester (25 mg , 0.054 mmol) in methanol (2 mL) and acetic acid (1 mL) at -20 ° C was added NaBH 4 (10 mg, 0.27 mmol). The reaction mixture was stirred at -20 ° C for 30 min and then quenched with isopropanol (5 drops). After removing most of the solvent, the residue was extracted with EtOAc, washed with water and brine and dried over Na 2 SO 4 . After concentration, the crude product was purified by preparative HPLC to give the title compound (18 mg, 62%). 1 H NMR (300 MHz, CD 3 OD) δ 7.50 (1H, s), 7.48 (1H, s), 7.25-7.38 (4H, m), 7.22 (1H, s) )

6,25 (1H, d, J = 7,6 Hz), 4,89-4,94 (1H, m), 4,76 (2H, s), 3,51-3,62 (2H, m), 2,62 (3H, s). LCMS (M+H)+ m/z 425 (t = 1,64 min).6.25 (1H, d, J = 7.6Hz), 4.89-4.94 (1H, m), 4.76 (2H, s), 3.51-3.62 (2H, m) 2.62 (3H, s). LCMS (M + H) &lt; + &gt; m / z 425 (t = 1.64 min).

185185

Pr. č. Pr. no. Názov Title Vzorec (BMS č.) formula (BMS #) T (min) T (min) Hmotnosť (M+H)+ m/zMass (M + H) + m / z 493 493 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5karboxamid (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carboxamide S H ‘k >-hh —ý· 7 ' HH OH A S H ‘k > -hh —H · 7'HH OH A 1,68 (f) 1.68 (f) 437 437 494 494 etylester (±)-2-{4-[2-(3fluórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7-metyl-3Hbenzoimidazol-5karboxylovej kyseliny (±) -2- {4- [2- (3-Fluoro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester y*'!! 6,0 ιΧΜμ j HN OH Έ-·y * '!! 6.0 ιΧΜμ j HN OH Έ- · 1,90 (b) 1.90 b 451 451 495 495 etylester (±)-7-chlór-2-{4-[2(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3Hbenzoimidazol-5karboxylovej kyseliny (±) -7-Chloro-2- {4- [2- (3-chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -3-benzoimidazole-5-carboxylic acid ethyl ester 2 c y— nh 1, HN OH A- 2 c y— nh 1, HN OH A- 2,06 (d) 2.06 d 487 487 496 496 (±)-7-chlór-2-{4-[2-(3chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3Hbenzoimidazol-5karboxamid (±) -7-chloro-2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -3Hbenzoimidazol-5-carboxamide 2 O HN OH ''-'ty* 2 O HN OH '' -'Ty * 1,54 (d) 1.54 d 458 458 497 497 (±)-7-chlór-2-{4-[2-(3- chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3Hbenzoimidazol-5karboxylová kyselina (±) -7-chloro-2- {4- [2- (3- chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3Hbenzoimidazole-5-carboxylic acid Á H V λ HN OH A Á H V λ HN OH A 1,69 (d) 1.69 (d) 459 459

186186

498 498 etylester (±)-2-{4-[2-(3chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridin-3-yl}-7-etyl3H-benzoimidazol-5karboxylovej kyseliny (±) -2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-ethyl-3H-benzoimidazole-5-carboxylic acid ethyl ester J HN OH J HN OH 1,98 (d) 1.98 (d) 481 481 499 499 (±)-2-{4-[2-(3-chlórfenyl)-2- hydroxyetylamino]-2-oxo- 1,2-dihydropyridin-3-yl}-7etyl-3H-benzoimidazol-5karboxamid (±) -2- {4- [2- (3-chloro-phenyl) -2- hydroxy-ethylamino] -2-oxo- 1,2-dihydropyridin-3-yl} -7etyl-3H-benzimidazole-5-carboxamide J K N* pn X” J K N * pn X " 1,51 (d) 1.51 (d) 452 452 500 500 etylester (S)-7-bróm-2-[4-(1hydroxymetyl-2-fenyletylamino]-2-oxo-1,2dihydropyridín-3-yl]-3Hbenzoimidazol-5karboxylovej kyseliny (S) -7-Bromo-2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -3H-benzoimidazole-5-carboxylic acid ethyl ester “Χφ Br___ OH“Χφ Br ___ OH 2,06 (b) 2.06 b 511 511 501 501 etylester (±)-2-{4-[2-(3brómfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl3H-benzoimidazol-5karboxylovej kyseliny (±) -2- {4- [2- (3-Bromo-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester HN OH X” HN OH X " 1,99 (b) 1.99 b 511 511 502 502 etylester (S)-2-{4-[2-(2chlórfenyl)-1 -hydroxymetyletylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl3H-benzoimidazol-5karboxylovej kyseliny (S) -2- {4- [2- (2-Chloro-phenyl) -1-hydroxy-methylethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester I HN OH Ct I HN OH Ct 1,89 (b) 1.89 b 481 481

187187

503 503 etylester (S)-2-[4-(2hydroxy-2-fenyletylamino)-2oxo-1,2-dihydropy ridí η-3-yl]7-metyl-3H-benzoimidazol5-karboxylovej kyseliny (S) -2- [4- (2-Hydroxy-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carboxylic acid ethyl ester 0 0 I HN OH O 0 0 I HN OH ABOUT 1.84 (b) 1.84 b 433 433 504 504 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[4mety l-6-( 1 H-tetrazol-5-yl)- 1 H-benzoimidazol-2-yl]-1 Hpyridin-2-ón (±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (1H-tetrazol-5-yl) - 1H-benzoimidazol-2-yl] -1H-pyridin-2-one '«H 0 LAryy I HN OH'' 0 H OH H N I Lary 1,92 (f) 1.92 (f) 463 463

Všeobecný spôsob uskutočnenia kondenzácií podľa Suzukiho, príklady 505-509 (schéma V, (18))General Conduct of Suzuki Condensations, Examples 505-509 (Scheme V, (18))

Príklad 505Example 505

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6-fenyl-1H-benzoimidazol-2-yl)1H-pyridin-2-ón:(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-phenyl-1 H-benzoimidazol-2-yl) -1H-pyridin-2-one;

K roztoku (S)-4-(1-benzyl-2-trityloxyetylamino)-3-[6-bróm-4-metyl-1 Hbenzoimidazol-2-yl]-1H-pyridín-2-ónu (50 mg, 0,072 mmol), kyseliny fenylborónovej (dihydroxyfenylborán) (13 mg, 0,11 mmol) a K2CO3 2 mol/l (0,108 ml, 0,22 mmol) v THF (5 ml) sa pridá Pd(PPh3)4 (8,3 mg, 0,007 mmol). Zmes sa zahrieva pri teplote spätného toku 1 h. Pri chladení sa reakčná zmes zriedi CH2CI2, premyje sa nasýteným NaHCO3, vysuší sa Na2SO4 a zahusti sa za zníženého tlaku. Zvyšok sa použije v ďalšom stupni bez ďalšieho čistenia. LCMS (M+H)+ m/z 693 (t = 2,82 min). Surový produkt sa pri teplote miestnosti po 6 h spracuje s roztokom HCI 4 mol/l v dioxáne (5 ml). Po zahustení za zníženého tlaku sa prečistením zvyšku preparatívnouTo a solution of (S) -4- (1-benzyl-2-trityloxyethylamino) -3- [6-bromo-4-methyl-1H-benzimidazol-2-yl] -1H-pyridin-2-one (50 mg, 0.072 mmol) ), phenylboronic acid (dihydroxyphenylborane) (13 mg, 0.11 mmol) and K 2 CO 3 2M (0.108 mL, 0.22 mmol) in THF (5 mL) were added Pd (PPh 3 ) 4 (8 , 3 mg, 0.007 mmol). The mixture was heated at reflux for 1 h. On cooling, the reaction mixture was diluted with CH 2 Cl 2 , washed with saturated NaHCO 3 , dried over Na 2 SO 4, and concentrated under reduced pressure. The residue was used in the next step without further purification. LCMS (M + H) &lt; + &gt; m / z 693 (t = 2.82 min). The crude product was treated with 4N HCl in dioxane (5 mL) for 6 h at room temperature. After concentration under reduced pressure, the residue is purified by preparative purification

188188

HPLC vo forme bieleho tuhého produktu získa titulná zlúčenina (17 mg, 34 %). 1H NMR (300 MHz, CD3OD) δ 7,13-7,67 (13H, m), 6,15 (1H, d, J = 7,4 Hz), 3,99-4,11 (1H, m), 3,74-3,77 (2H, m), 3,16 (1H, dd, J = 5,4, 13,6 Hz), 2,97 (1H, dd, J = 7,8, 13,6 Hz), 2,69 (3H, s). LCMS (M+H)+ m/z 451 (t = 2,04 min).HPLC to give the title compound as a white solid (17 mg, 34%). 1 H NMR (300 MHz, CD 3 OD) δ 7.13-7.67 (13H, m), 6.15 (1H, d, J = 7.4 Hz), 3.99-4.11 (1H m, 3.74-3.77 (2H, m), 3.16 (1H, dd, J = 5.4, 13.6 Hz), 2.97 (1H, dd, J = 7.8) , 13.6 Hz), 2.69 (3H, s). LCMS (M + H) &lt; + &gt; m / z 451 (t = 2.04 min).

Príklad 506Example 506

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-1H-benzoimidazol-2-yl)-1 Hpyridí η-2-όη:(S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-1 H -benzoimidazol-2-yl) -1 H -pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 6,98-7,46 (9H, m), 6,15 (1H, d. J = 7,5 Hz), 3,99-4,04 (1H, m), 3,75 (1H, d, J = 5,1 Hz), 3,16 (1H, dd, J = 5,1, 13,6 Hz), 2,95 (1H, dd, J = 8,1, 13,6 Hz), 2,61 (3H, s). LCMS (M+H)+m/z 375 (t = 1,72 min). 1 H NMR (300 MHz, CD 3 OD) δ 6.98-7.46 (9H, m), 6.15 (1H, d J = 7.5 Hz), 3.99-4.04 (1H m), 3.75 (1H, d, J = 5.1 Hz), 3.16 (1H, dd, J = 5.1, 13.6 Hz), 2.95 (1H, dd, J = 8.1, 13.6 Hz), 2.61 (3H, s). LCMS (M + H) &lt; + &gt; m / z 375 (t = 1.72 min).

Príklad 507Example 507

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-[6-(2-metoxyfenyl)-4-metyl-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- [6- (2-methoxyphenyl) -4-methyl-1 H -benzoimidazole-2-yl] -1-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 6,99-7,59 (12H, m), 6,16 (1H, d, J = 7,5 Hz), 4,04 (1H, m), 3,81 (3H, s), 3,76 (2H, d, J = 4,1 Hz), 2,96-3,20 (2H, m), 2,66 (3H, s). LCMS (M+H)+ m/z 481 (t = 2,00 min). 1 H NMR (300 MHz, CD 3 OD) δ 6.99-7.59 (12H, m), 6.16 (1H, d, J = 7.5 Hz), 4.04 (1H, m), 3.81 (3H, s), 3.76 (2H, d, J = 4.1 Hz), 2.96-3.20 (2H, m), 2.66 (3H, s). LCMS (M + H) &lt; + &gt; m / z 481 (t = 2.00 min).

Príklad 508Example 508

189189

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-[6-(4-fluórfenyl)-4-metyl-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- [6- (4-fluorophenyl) -4-methyl-1 H -benzoimidazole-2-yl] -1-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,10-7,66 (12H, m), 6,13 (1H, d, J = 7,6 Hz), 3,99-4,04 (1H, m), 3,76 (2H, d, J = 5,0 Hz), 3,16 (1H, dd, J = 5,0, 13,6 Hz), 2,96 (1H, dd, J = 8,1, 13,6 Hz), 2,65 (3H, s). LCMS (M+H)+ m/z 469 (t = 2,07 min). 1 H NMR (300 MHz, CD 3 OD) δ 7.10-7.66 (12H, m), 6.13 (1H, d, J = 7.6 Hz), 3.99-4.04 (1H m), 3.76 (2H, d, J = 5.0 Hz), 3.16 (1H, dd, J = 5.0, 13.6 Hz), 2.96 (1H, dd, J = 8.1, 13.6 Hz), 2.65 (3H, s). LCMS (M + H) &lt; + &gt; m / z 469 (t = 2.07 min).

Príklad 509Example 509

(S)-4-(1-benzyl-2-hydroxyetylamino)-3-[6-(4-metoxyfenyl)-4-metyl-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- [6- (4-methoxyphenyl) -4-methyl-1 H -benzoimidazole-2-yl] -1-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 6,97-7,65 (12H, m), 6,14 (1H, d, J = 7,6 Hz), 4,00-4,04 (1H, m), 3,83 (3H, s), 3,76 (2H, d, J = 5,0 Hz), 2,95-3,19 (2H, m), 2,67 (3H, s). LCMS (M+H)+ m/z 481 (t = 2,01 min). 1 H NMR (300 MHz, CD 3 OD) δ 6.97-7.65 (12H, m), 6.14 (1H, d, J = 7.6 Hz), 4.00-4.04 (1H , m), 3.83 (3H, s), 3.76 (2H, d, J = 5.0 Hz), 2.95-3.19 (2H, m), 2.67 (3H, s) . LCMS (M + H) &lt; + &gt; m / z 481 (t = 2.01 min).

Príklad 510Example 510

OHOH

190 (S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6-morfolín-4-yl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:190 (S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one:

Zmes (S)-4-(1-benzyl-2-trityloxyetylamino)-3-[6-bróm-4-metyl-1Hbenzoimidazol-2-yl]-1H-pyridin-2-ónu (150 mg, 0,216 mmol), morfolínu (28,2 mg, 0,324 mmol), paládium-acetátu (2,4 mg, 0,01 mmol), tri-(terc-butyl)fosfínu (4,4 mg, 0,02 mmol) a nátrium-terc-butoxidu (104 mg, 1,08 mmol) v toluéne sa zahrieva v atmosfére dusíka 14 h pri 100 °C. Reakčná zmes sa potom ochladí na teplotu miestnosti a zriedi sa EtOAc. Po extrakcii sa spojené organické vrstvy premyjú vodou, soľným roztokom a vysušia sa Na2SO4. Zahustením sa získa hnedastý zvyšok, ktorý sa spracuje počas 6 hodín s roztokom HCI 4 mol/l v dioxáne (3 ml). Po odstránení rozpúšťadla sa prečistením zvyšku preparatívnou HPLC získa titulná zlúčenina (18 mg, 18 %). 1H NMR (400 MHz, CD3OD) δ 7,59 (1H, s), 7,12-7,28 (7H, m), 6,12 (1H, d, J = 7,6 Hz), 4,01-4,08 (5H, m), 3,76 (1H, dd, J = 4,8, 11,1 Hz), 3,71 (1H, d, J = 5,2,A mixture of (S) -4- (1-benzyl-2-trityloxyethylamino) -3- [6-bromo-4-methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2-one (150 mg, 0.216 mmol), morpholine (28.2 mg, 0.324 mmol), palladium acetate (2.4 mg, 0.01 mmol), tri- (tert-butyl) phosphine (4.4 mg, 0.02 mmol) and sodium tert- of butoxide (104 mg, 1.08 mmol) in toluene was heated under nitrogen at 100 ° C for 14 h. The reaction mixture was then cooled to room temperature and diluted with EtOAc. After extraction, the combined organic layers are washed with water, brine and dried over Na 2 SO 4 . Concentration gave a brownish residue which was treated for 6 hours with a 4 M HCl solution in dioxane (3 mL). After removal of the solvent, purification of the residue by preparative HPLC gave the title compound (18 mg, 18%). 1 H NMR (400 MHz, CD 3 OD) δ 7.59 (1H, s), 7.12-7.28 (7H, m), 6.12 (1H, d, J = 7.6 Hz), 4.01-4.08 (5H, m), 3.76 (1H, dd, J = 4.8, 11.1 Hz), 3.71 (1H, d, J = 5.2,

11,1 Hz), 3,32-3,10 (4H, m), 3,09 (1H, dd, J = 5,6, 13,7 Hz), 2,92 (1H, dd, J = 8,0,11.1 Hz), 3.32-3.10 (4H, m), 3.09 (1H, dd, J = 5.6, 13.7 Hz), 2.92 (1H, dd, J = 8 , 0,

13,7 Hz), 2,65 (3H, s). LCMS (M+H)+ m/z 460 (t = 1,30 min).13.7 Hz), 2.65 (3H, s). LCMS (M + H) &lt; + &gt; m / z 460 (t = 1.30 min).

Príklad 511Example 511

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-1H-benzoimidazol-2-yl)1H-pyridín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-1 H-benzoimidazol-2-yl) -1H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,17-7,64 (8H, m), 6,23 (1H, d, J = 10,2 Hz), 4,94 (1H, m), 3,61 (1H, dd, J = 4,8, 13,8 Hz), 3,54 (1H, dd, J = 7,4. 13,8 Hz), 2,61 (3H, s). LCMS (M+H)+ m/z 395 (t = 1,65 min). 1 H NMR (300 MHz, CD 3 OD) δ 7.17-7.64 (8H, m), 6.23 (1H, d, J = 10.2 Hz), 4.94 (1H, m), 3.61 (1H, dd, J = 4.8, 13.8 Hz), 3.54 (1H, dd, J = 7.4, 13.8 Hz), 2.61 (3H, s). LCMS (M + H) &lt; + &gt; m / z 395 (t = 1.65 min).

Príklad 512Example 512

191191

(±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-pyridin-3-yl-1Hbenzoimidazol-2-yl)-1H-pyndín-2-ón:(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-pyridin-3-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 9,14 (1H, s), 8,88 (1H, d, J = 8,2 Hz), 8,72 (1H, d, J = 5,4 Hz), 8,08 (1H, dd, J = 5,8, 8,2 Hz), 7,82 (1H, s), 7,56 (1H. s), 7,24-7,45 (5H, m), 6,25 (1H, d, J = 7,6 Hz), 5,02 (1H, dd, J = 5,0, 6,5 Hz), 3,77 (1H, dd, J = 5,0, 13,5 Hz), 3,68 (1H, dd, J = 6,5, 13,5 Hz), 2,68 (3H, s). LCMS (M+H)+ m/z 472 (t = 1,66 min). 1 H NMR (300 MHz, CD 3 OD) δ 9.14 (1H, s), 8.88 (1H, d, J = 8.2 Hz), 8.72 (1H, d, J = 5.4 8.08 (1H, dd, J = 5.8, 8.2 Hz), 7.82 (1H, s), 7.56 (1H, s), 7.24-7.45 (5H) , m), 6.25 (1H, d, J = 7.6Hz), 5.02 (1H, dd, J = 5.0, 6.5Hz), 3.77 (1H, dd, J = 5.0, 13.5 Hz), 3.68 (1H, dd, J = 6.5, 13.5 Hz), 2.68 (3H, s). LCMS (M + H) &lt; + &gt; m / z 472 (t = 1.66 min).

Pr. č. Pr. no. Názov Title Vzorec formula T (min) T (min) Hmotnosť (M+H)+m/zMass (M + H) + m / z 513 513 (±)-3-(6-bróm-4-metyl-1 Hbenzoimidazol-2-yl)-4-[2-(3chlórfenyl)-2-hyd roxyetylamino]-1 H-pyridín-2-ón (±) -3- (6-Bromo-4-methyl-1H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one 0 HH OH CM 0 HH OH CM 2,08 (f) 2.08 f 473 473 514 514 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-[6-(4metoxyfenyl)-4-metyl-1 Hbenzoimidazol-2-yl]-1 Hpyridín-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (4-methoxy-phenyl) -4-methyl-1H-benzoimidazol-2-yl] -1-pyridin-2-one | HN OH Έ- | HN OH Έ- 1.96 (f) 1.96 f 501 501 515 515 (±)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-3-(4metyl-1 H-benzoimidazol-2yl)-1 H-pyridin-2-ón (±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one | HN OH M | HN OH M 1,65 (f) 1.65 (f) 395 395

192192

516 (S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6piperidín-1 -yl-1 Hbenzoimidazol-2-yl)-1 Hpyridín-2-ón516 (S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzoimidazol-2-yl) -1-pyridin-2-one

1,39 (b)1.39 b

458458

Zlúčeniny podľa príkladov 517-519 sa pripravia spôsobmi znázornenými v schémachThe compounds of Examples 517-519 were prepared by the methods depicted in the Schemes

VII a III.VII and III.

Príklad 517Example 517

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one :

1H NMR (500 MHz, CD3OD) δ 7,54 (br s, 1H), 7,40-7,20 (m, 4H), 7,03 (br s, 1H), 6,84 (br s, 1H), 6,25 (d, 1H, J = 7,60 Hz), 5,01-4,91 (m, 1H), 3,73 (dd, 1H), 3,65 (dd, 1H), 3,45-3,25 (m, 8H), 2,56 (s, 3H); LCMS (M+H)+ m/z 479, 481. 1 H NMR (500 MHz, CD 3 OD) δ 7.54 (br s, 1H), 7.40-7.20 (m, 4H), 7.03 (br s, 1H), 6.84 (br s) s, 1H), 6.25 (d, 1H, J = 7.60 Hz), 5.01-4.91 (m, 1H), 3.73 (dd, 1H), 3.65 (dd, 1H) 1.45-3.25 (m, 8H), 2.56 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 479, 481.

Príklad 518Example 518

(±)-4-[2-(3-chlór-metylsulfanylfenyl)-2-hydroxyetylamino]-3-(4-metyl-6p iperazi n-1 -yl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:(±) -4- [2- (3-chloromethylsulfanylphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one;

193 1H NMR (500 MHz, CD3OD) δ 7,47 (br s, 1H), 7,38-7,29 (m, 2H), 7,19 (d, 1H, J = 8,3 Hz), 7,03 (br s, 1H), 6,98 (br s, 1H), 6,26 (d, 1H, J = 7,7 Hz), 4,90-4,81 (m, 1H),193 1 H NMR (500 MHz, CD 3 OD) δ 7.47 (br s, 1H), 7.38-7.29 (m, 2H), 7.19 (d, 1H, J = 8.3 Hz) 7.03 (br s, 1H), 6.98 (br s, 1H), 6.26 (d, 1H, J = 7.7 Hz), 4.90-4.81 (m, 1H) .

3,65-3,35 (m, 10H), 2,56 (s, 3H), 2,42 (s, 3H); LCMS (M+H)+ m/z 525, 527.3.65-3.35 (m, 10H), 2.56 (s, 3H), 2.42 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 525, 527.

Príklad 519Example 519

(S)-4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl) -1H-benzoimidazol-2-yl) -1H- pyridin-2-one;

1H NMR (500 MHz, CD3OD) δ 7,61 (dd, 1H, J = 2,1, 7,2 Hz), 7,40 (ddd, 1H), 7,28 (d, 1H, J = 7,5 Hz), 7,17 (dd, 1H, J = 8,9, 8,8 Hz), 7,02 (br s, 1H), 6,87 (br s, 1H), 6,25 (d, 1H, J = 7,6 Hz), 4,99-4,90 (m, 1H), 3,73-3,60 (m, 2H), 3,45-3,30 (m, 8H), 2,54 (s, 3H); LCMS (M+H)+ m/z 497, 499. 1 H NMR (500 MHz, CD 3 OD) δ 7.61 (dd, 1H, J = 2.1, 7.2 Hz), 7.40 (ddd, 1H), 7.28 (d, 1H, J = 7.5 Hz), 7.17 (dd, 1H, J = 8.9, 8.8 Hz), 7.02 (br s, 1H), 6.87 (br s, 1H), 6.25 (d, 1H, J = 7.6Hz), 4.99-4.90 (m, 1H), 3.73-3.60 (m, 2H), 3.45-3.30 (m, 8H) 2.54 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 497, 499.

Na prípravu zlúčenín podľa nižšie uvedených príkladov 520-522 sa použije spôsob znázornený v schéme VII a uvedené príklady znázorňujú alkyláciu derivátov piperazínu.To prepare the compounds of Examples 520-522 below, the method outlined in Scheme VII is used and the examples below illustrate the alkylation of piperazine derivatives.

Príklad 520 (všeobecný spôsob prípravy zlúčenín podľa príkladov 520-522)Example 520 (general method for preparing compounds of Examples 520-522)

(S)-3-[4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-yl]propionitril:(S) -3- [4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol 5-yl) piperazin-1-yl] -propionitrile:

194194

K miešanému roztoku 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6piperazín-1-yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (17 mg, 0,021 mmol) v bezvodom metanole (1 ml) sa pridá Hunigova báza (36 μΙ). Výsledný roztok sa ochladí na 0 °C a po častiach sa pridáva akrylonitril (5 μΙ) pokým podľa výsledkov LCMS reakcia neprebehne kvantitatívne. Reakčná zmes sa potom ohreje na teplotu miestnosti a rozpúšťadlo sa odparí za zníženého tlaku. Získaný zvyšok sa prečistí preparatívnou HPLC na reverznej fáze s použitím gradientovej elúcie fázou metanol/voda/0,1 % kyselina trifluóroctová. Odparením frakcií sa získa titulná zlúčenina vo forme soli s kyselinou trifluóroctovou: 1H NMR (500 MHz, CD3OD) δ 7,49 (brs, 1H), 7,39-7,23 (m, 4H), 7,15 (brs, 1H), 7,06 (brs, 1H), 6,25 (d, 1H, J = 7,7 Hz), 4,97-4,88 (m, 1H), 3,70-3,40 (m, 12H), 3,06 (t, 2H, J = 7,0 Hz), 2,59 (s, 3H); LCMS (M+H)+ m/z 532, 534. Získaná soľ čistej titulnej zlúčeniny s kyselinou trifluóroctovou sa rozpustí v metanole a nanesie sa na kolónku Varian Mega Bond-Elute SCX. Elúciou metanolom a potom NH3 2,0 mol/l/MeOH sa získa voľná báza. Získaný produkt sa suspenduje v MeOH a pridá sa vodná HCI 1,00 mol/l (2 ekv.). Získaný roztok sa prefiltruje cez filter 45 pm a odparením sa získa bis-HCI soľ titulnej zlúčeniny: : 1H NMR (300 MHz, CD3OD) δ 7,50-7,25 (m, 5H), 7,16 (br s, 1H), 7,13 (br s, 1H), 6,27 (d, 1H, J = 7,7 Hz), 4,95-4,87 (m, 1H), 3,70-3,40 (m, 12H), 3,13 (t, 2H, J = 7,0 Hz), 2,62 (s, 3H); LCMS (M+H)+ m/z 532, 534.To a stirred solution of 4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (17 mg, 0.021 mmol) in anhydrous methanol (1 mL) was added Hunig's base (36 μΙ). The resulting solution is cooled to 0 ° C and acrylonitrile (5 μΙ) is added in portions until the reaction is quantitative according to LCMS results. The reaction mixture was then warmed to room temperature and the solvent was evaporated under reduced pressure. The residue obtained is purified by reverse phase preparative HPLC using a gradient of methanol / water / 0.1% trifluoroacetic acid. Evaporation of fractions gave the title compound as the trifluoroacetic acid salt: 1 H NMR (500 MHz, CD 3 OD) δ 7.49 (brs, 1H), 7.39-7.23 (m, 4H), 7.15 (brs) 1 H, 7.06 (brs, 1 H), 6.25 (d, 1 H, J = 7.7 Hz), 4.97-4.88 (m, 1 H), 3.70-3.40 ( m, 12H), 3.06 (t, 2H, J = 7.0 Hz), 2.59 (s, 3H); LCMS (M + H) + m / z 532, 534. The obtained trifluoroacetic acid salt of the pure title compound was dissolved in methanol and applied to a Varian Mega Bond-Elute SCX column. Elution with methanol and then NH3 2.0M / MeOH gave the free base. The obtained product was suspended in MeOH and aqueous HCl 1.00 M (2 eq) was added. The resulting solution was filtered through a 45 µm filter and evaporated to give the bis-HCl salt of the title compound: 1 H NMR (300 MHz, CD 3 OD) δ 7.50-7.25 (m, 5H), 7.16 (br s, 1H), 7.13 (br s, 1H), 6.27 (d, 1H, J = 7.7 Hz), 4.95-4.87 (m, 1H), 3.70-3, 40 (m, 12H), 3.13 (t, 2H, J = 7.0 Hz), 2.62 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 532, 534.

Príklad 521Example 521

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metánsulfonyletyl)piperazin-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonylethyl) -piperazin-1-yl] -4-methyl-1H-benzoimidazol-2 -yl} -1H-pyridin-2-one:

1H NMR (500 MHz, CD3OD) δ 7,53 (br s, 1H), 7,41-7,20 (m, 4H), 7,13 (br s, 1H), 6,92 (br s, 1H), 6,24 (d, 1H, J = 7,6 Hz), 45,00-4,92 (m, 1H), 3,80-3,25 (m, 14H), 3,13 (s, 3H), 2,57 (s, 3H); LCMS (M+H)+ m/z 585, 587. 1 H NMR (500 MHz, CD 3 OD) δ 7.53 (br s, 1H), 7.41-7.20 (m, 4H), 7.13 (br s, 1H), 6.92 (br s, 1H), 6.24 (d, 1H, J = 7.6Hz), 45.00-4.92 (m, 1H), 3.80-3.25 (m, 14H), 3.13 (s, 3H), 2.57 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 585, 587.

195195

Príklad 522Example 522

(S)-3-[4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-yl]propionitril·.(S) -3- [4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-methyl- 3H-benzoimidazol-5-yl) piperazin-1-yl] -propionitrile ·.

1H NMR (500 MHz, CD3OD) δ 7,59 (br s, 1H), 7,41 (d, 1H, J = 7,5 Hz), 7,34 (dd, 1H, J = 2,0, 8,5 Hz), 7,17 (br s, 1H), 7,12 (br s, 1H), 7,00 (d, 1H, J = 8,5 Hz), 1 H NMR (500 MHz, CD 3 OD) δ 7.59 (br s, 1H), 7.41 (d, 1H, J = 7.5 Hz), 7.34 (dd, 1H, J = 2, 0, 8.5 Hz), 7.17 (br s, 1H), 7.12 (br s, 1H), 7.00 (d, 1H, J = 8.5 Hz),

6,25 (d, 1H, J = 7,5 Hz), 4,85-4,76 (m, 1H), 3,85 (s, 3H), 3,80-3,30 (m, 12H), 3,16 (t, 2H, J = 7,0 Hz), 2,55 (s, 3H); LCMS (M+H)+ m/z 606, 608.6.25 (d, 1H, J = 7.5Hz), 4.85-4.76 (m, 1H), 3.85 (s, 3H), 3.80-3.30 (m, 12H) 3.16 (t, 2H, J = 7.0 Hz); 2.55 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 606, 608.

Zlúčeniny podľa príkladov 523-528 sa pripravia spôsobom znázorneným v schémach VII a III a uvedené príklady znázorňujú karbamoyláciu piperazínových derivátov.The compounds of Examples 523-528 were prepared as shown in Schemes VII and III, and the examples shown illustrate the carbamoylation of piperazine derivatives.

Príklad 523 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 523-528)Example 523 (General Preparation of Examples 523-528)

Etylester (S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny.(S) -4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazole-5- ethyl ester yl) piperazine-1-carboxylic acid.

196196

K miešanému roztoku 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6piperazín-1-yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (soľ s asi 2 TFA, 80 mg, asi 0,1 mmol) v metanole (2 ml) sa pri 0 °C pridá N,N-diizopropyletylamín (170 μΙ) a 2fluóretyl-chlórmravčan (37 mg). Potom sa odstráni chladiaci kúpeľ a roztok sa mieša pri teplote miestnosti 30 minút, kde po uvedenom čase podľa výsledkov LC/MS dochádza k úplnému prebehnutiu reakcie. Reakčná zmes sa potom prečistí preparatívnou HPLC na reverznej fáze s použitím gradientovej elúcie mobilnou fázou metanol/voda/0,1 % kyseliny trifluóroctovej. Odparením frakcií sa získa titulná zlúčenina vo forme soli s kyselinou trifluóroctovou, ktorá sa rozpustí v metanole a nanesie sa na kolónku Varian Mega Bond-Elute SCX. Elúciou metanolom a potom NH3 2,0 mol/l/MeOH sa získa voľná báza (46,2 g). Získaný produkt sa suspenduje v MeOH a pridá sa vodná HCI 1,00 mol/l (1 ekv.). Získaný roztok sa prefiltruje cez filter 45 pm a odparením sa získa mono-HCI soľ titulnej zlúčeniny (46 mg): 1H NMR (500 MHz, CD3OD) δ 7,50 (br s, 1H), 7,45-7,20 (m, 6H), 6,26 (d, 1 H, J = 7,7 Hz), 4,98-4,91 (m, 1H), 4,64 (dm, 2H, J = 47,9 Hz), 4,39 (dm, 2H, J = 29 Hz), 3,95-3,50 (m, 10H), 2,63 (s, 3H); LCMS (M+H)+ m/z 569, 571.To a stirred solution of 4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (salt) with about 2 TFA, 80 mg, about 0.1 mmol) in methanol (2 mL) at 0 ° C, add N, N-diisopropylethylamine (170 µΙ) and 2-fluoroethyl chloroformate (37 mg). The cooling bath was then removed and the solution was stirred at room temperature for 30 minutes, after which time the reaction was complete according to LC / MS results. The reaction mixture was then purified by reverse phase preparative HPLC using a gradient elution of methanol / water / 0.1% trifluoroacetic acid mobile phase. Evaporation of the fractions gave the title compound as the trifluoroacetic acid salt, which was dissolved in methanol and applied to a Varian Mega Bond-Elute SCX column. Elution with methanol and then NH 3 2.0 M / MeOH gave the free base (46.2 g). The obtained product was suspended in MeOH and aqueous HCl 1.00 mol / L (1 eq) was added. The resulting solution was filtered through a 45 µm filter and evaporated to give the mono-HCl salt of the title compound (46 mg): 1 H NMR (500 MHz, CD 3 OD) δ 7.50 (br s, 1H), 7.45-7 20 (m, 6H), 6.26 (d, 1H, J = 7.7 Hz), 4.98-4.91 (m, 1H), 4.64 (dm, 2H, J = 47, 9 Hz), 4.39 (dm, 2H, J = 29 Hz), 3.95-3.50 (m, 10H), 2.63 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 569, 571.

Príklad 524Example 524

2-metoxyetylester (S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny:(S) -4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole- 2-methoxy-ethyl ester- 5-yl) piperazine-1-carboxylic acid:

1H NMR (500 MHz, CD3OD) δ 7,53-7,22 (m, 7H), 6,26 (d, 1H, J = 7,6 Hz), 4,96 (dd, 1H, J = 7,0, 4,6 Hz), 4,31-4,27 (m, 2H), 4,05-3,55 (m, 12H), 3,39 (s, 3H), 2,64 (s, 3H); LCMS (M+H)+ m/z 581, 583. 1 H NMR (500 MHz, CD 3 OD) δ 7.53-7.22 (m, 7H), 6.26 (d, 1H, J = 7.6 Hz), 4.96 (dd, 1H, J) = 7.0, 4.6 Hz), 4.31-4.27 (m, 2H), 4.05-3.55 (m, 12H), 3.39 (s, 3H), 2.64 ( s, 3H); LCMS (M + H) &lt; + &gt; m / z 581, 583.

Príklad 525Example 525

197197

Terc-butylester (S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl)-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny:(S) -4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl) -7-methyl-3H-benzoimidazole- 5-yl) piperazine-1-carboxylic acid:

1H NMR (500 MHz, CD3OD) δ 7,51 (br s, 1H), 7,40-7,22 (m, 6H), 6,26 (d, 1H, J = 7,7 Hz), 4,96-4,90 (m, 1H), 3,90-3,30 (m, 10H), 2,64 (s, 3H), 1,51 (s,’9H); LCMS (M+H)+ m/z 579, 581. 1 H NMR (500 MHz, CD 3 OD) δ 7.51 (br s, 1H), 7.40-7.22 (m, 6H), 6.26 (d, 1H, J = 7.7 Hz) 4.96-4.90 (m, 1H), 3.90-3.30 (m, 10H), 2.64 (s, 3H), 1.51 (s, 9H); LCMS (M + H) &lt; + &gt; m / z 579, 581.

Príklad 526Example 526

Prop-2-inylester (S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridin-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1 -karboxylovej kyseliny:(S) -4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H- benzoimidazol-5-yl) piperazine-1-carboxylic acid:

1H NMR (500 MHz, CD3OD) δ 7,50 (br s, 1H), 7,43-7,20 (m, 5H), 7,19 (br s, 1H), 6,25 (d, 1H, J = 7,6 Hz), 4,98-4,90 (m, 1H), 4,78 (d, 2H, J = 2,5 Hz), 3,95-3,30 (m, 10H), 2,97 (t, 1H, J = 2,5 Hz), 2,62 (s, 3H); LCMS (M+H)+ m/z 561, 563. 1 H NMR (500 MHz, CD 3 OD) δ 7.50 (br s, 1H), 7.43-7.20 (m, 5H), 7.19 (br s, 1H), 6.25 (d 1H, J = 7.6Hz), 4.98-4.90 (m, 1H), 4.78 (d, 2H, J = 2.5Hz), 3.95-3.30 (m, 10H), 2.97 (t, 1H, J = 2.5 Hz), 2.62 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 561, 563.

Príklad 527Example 527

198198

Terc-butylester (S)-4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2oxo-1,2-dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny:(S) -4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl- 3H-Benzoimidazol-5-yl) piperazine-1-carboxylic acid:

1H NMR (300 MHz, CD30D) δ 7,65 (br s, 1H), 7,48-7,28 (m, 6H), 7,25 (br s, 1H), 6,97 (d, 1H, J = 8,5 Hz), 6,25 (d, 1H, J = 7,7 Hz), 4,94-4,86 (m, 1H), 3,90-3,45 (m, 10H), 3,82 (s, 3H), 2,61 (s, 3H), 1,52 (s, 9H); LCMS (M+H)+ m/z 653, 655. 1 H NMR (300 MHz, CD 3 OD) δ 7.65 (br s, 1H), 7.48-7.28 (m, 6H), 7.25 (br s, 1H), 6.97 (d 1 H, J = 8.5 Hz), 6.25 (d, 1H, J = 7.7 Hz), 4.94-4.86 (m, 1H), 3.90-3.45 (m, 10H), 3.82 (s, 3H), 2.61 (s, 3H), 1.52 (s, 9H); LCMS (M + H) &lt; + &gt; m / z 653, 655.

Príklad 528Example 528

Etylester (S)-4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny:(S) -4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H- benzoimidazol-5-yl) piperazine-1-carboxylic acid:

1H NMR (400 MHz, CD3OD) δ 7,80 (1H, s), 7,63 (1H, úzky d, J = 1,8 Hz), 7,52 (1H, s), 7,42 (1H, d, J = 7,5 Hz), 7,37 (1H, dd, J = 1,8, 8,4 Hz), 7,00 (1H, d, J = 8,4 Hz), 6,31 (d, 1H, J = 7,5 Hz), 4,89 (1H, m), 4,22 (2H, q, J = 7,1 Hz), 3,98 (4H, br s), 3,84 (3H, s), 3,70-3,72 (4H, m), 3,59-3,60 (2H, m), 2,67 (3H, s), 1,31 (3H, t, J = 7,1 Hz). LCMS (M+H)+ m/z 625 (t = 1,45 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.80 (1H, s), 7.63 (1H, narrow d, J = 1.8 Hz), 7.52 (1H, s), 7.42 (1H, d, J = 7.5Hz), 7.37 (1H, dd, J = 1.8, 8.4Hz), 7.00 (1H, d, J = 8.4Hz), 6 31 (d, 1H, J = 7.5Hz), 4.89 (1H, m), 4.22 (2H, q, J = 7.1Hz), 3.98 (4H, brs), 3.84 (3H, s), 3.70-3.72 (4H, m), 3.59-3.60 (2H, m), 2.67 (3H, s), 1.31 (3H, s) t, J = 7.1 Hz). LCMS (M + H) &lt; + &gt; m / z 625 (t = 1.45 min).

Zlúčeniny podľa nasledujúcich príkladov (529-540) sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú alternatívny spôsob alkylácie piperazínových derivátov.The compounds of the following examples (529-540) were prepared according to the methods depicted in Schemes VII and III, and the examples shown illustrate an alternative method of alkylating piperazine derivatives.

Príklad 529 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 529-540)Example 529 (General Preparation of Examples 529-540)

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(S)-4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-(6-[4-(3-fluórpropyl)piperazin-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón:(S) -4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H benzoimidazol-2-yl} -1 H-pyridin-2-one;

K miešanému roztoku 4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4metyl-6-piperazín-1-yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (100 mg, 0,162 mmol) v 1,4-dioxáne (4,0 ml), etanole (0,8 ml), metanole (0,8 ml) sa pridá N,Ndiizopropyletylamín (0,30 ml) a 1-bróm-3-fluór-propán (85 μΙ), Reakčná zmes sa potom zahrieva 12 h pri 80 °C. Reakčná zmes sa potom prečistí preparatívnou HPLC na reverznej fáze s použitím gradientovej elúcie mobilnou fázou metanol/voda/0,1 % kyseliny trifluóroctovej. Odparením frakcií sa získa titulná zlúčenina vo forme soli s kyselinou trifluóroctovou, ktorá sa rozpustí v metanole a nanesie sa na kolónku Varian Mega Bond-Elute SCX. Elúciou metanolom a potom NH3 2,0 mol/l/MeOH sa získa voľná báza (39,3 g). Získaný produkt sa suspenduje v MeOH a pridá sa vodná HCI 1,00 mol/l (2 ekv.). Získaný roztok sa prefiltruje cez filter 45 pm a odparením sa získa bis-HCI sof titulnej zlúčeniny (43,5 mg): 1H NMR (400 MHz, CD3OD) δ 7,43-7,37 (m, 2H), 7,28 (dd', 1H, J = 2,0, 8,6 Hz), 7,16 (br s, 1H), 7,08 (d, 1H, J = 1,7 Hz), 7,01 (d, 1H, J = 8,5 Hz), 6,24 (d, 1H, J = 7,7 Hz), 4,84-4,78 (m, 1H), 4,60 (dt, 2H, J = 5,7,To a stirred solution of 4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2 -one (100 mg, 0.162 mmol) in 1,4-dioxane (4.0 mL), ethanol (0.8 mL), methanol (0.8 mL) were added N, N-diisopropylethylamine (0.30 mL) and 1 N -Bromo-3-fluoro-propane (85 μΙ), The reaction mixture is then heated at 80 ° C for 12 h. The reaction mixture was then purified by reverse phase preparative HPLC using a gradient elution of methanol / water / 0.1% trifluoroacetic acid mobile phase. Evaporation of the fractions gave the title compound as the trifluoroacetic acid salt, which was dissolved in methanol and applied to a Varian Mega Bond-Elute SCX column. Elution with methanol and then NH 3 2.0 M / MeOH gave the free base (39.3 g). The obtained product was suspended in MeOH and aqueous HCl 1.00 M (2 eq) was added. The resulting solution was filtered through a 45 µm filter and evaporated to give the bis-HCl salt of the title compound (43.5 mg): 1 H NMR (400 MHz, CD 3 OD) δ 7.43-7.37 (m, 2H), 7.28 (dd ', 1H, J = 2.0, 8.6 Hz), 7.16 (br s, 1H), 7.08 (d, 1H, J = 1.7 Hz), 7.01 (d, 1H, J = 8.5Hz), 6.24 (d, 1H, J = 7.7Hz), 4.84-4.78 (m, 1H), 4.60 (dt, 2H, J = 5.7,

47,1 Hz), 3,95-3,88 (m, 2H), 3,83 (s, 3H), 3,78-3,71 (m, 2H), 3,53-3,14 (m, 8H), 2,59 (s, 3H), 2,31-2,16 (m, 2H); LCMS (M+H)+ m/z 569, 571.47.1 Hz), 3.95-3.88 (m, 2H), 3.83 (s, 3H), 3.78-3.71 (m, 2H), 3.53-3.14 (m 8H), 2.59 (s, 3H), 2.31-2.16 (m, 2H); LCMS (M + H) &lt; + &gt; m / z 569, 571.

Príklad 530Example 530

-2 HCI-2 HCl

200 (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóretyl)piperazín-1 -ylj-200 (S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-fluoro-ethyl) -piperazin-1-yl] -

4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón.' 1H NMR (400 MHz, CD3OD) δ 7,45-7,20 (m, 5H), 7,16 (br s, 1H), 7,09 (br s, 1H), 6,25 (d, 1H, J = 7,6 Hz), 5,00-4,92 (m, 1H), 4,92-4,78 (m, 2H), 3,98-3,15 (m, 12H), 2,60 (s, 3H); LCMS (M+H)+ m/z 525, 527.4-Methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one. 1 H NMR (400 MHz, CD 3 OD) δ 7.45-7.20 (m, 5H), 7.16 (br s, 1H), 7.09 (br s, 1H), 6.25 (d 1 H, J = 7.6 Hz), 5.00-4.92 (m, 1H), 4.92-4.78 (m, 2H), 3.98-3.15 (m, 12H), 2.60 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 525, 527.

Príklad 531Example 531

(S)-4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:(S) -4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H- benzimidazol-2-yl} -1 H-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,52 (dd, 1H, J = 2,1, 7,2 Hz). 7,40 (d, 1H, J = 1 H NMR (400 MHz, CD 3 OD) δ 7.52 (dd, 1H, J = 2.1, 7.2 Hz). 7.40 (d, 1 H, J =

7,6 Hz), 7,35-7,12 (m, 3H), 7,08 (d, 1H, J = 1,7 Hz), 6,25 (d, 1H, J = 7,7 Hz), 4,90-7.6 Hz), 7.35-7.12 (m, 3H), 7.08 (d, 1H, J = 1.7 Hz), 6.25 (d, 1H, J = 7.7 Hz) , 4,90-

4,82 (m, 1H), 4,60 (dt, 2H, J = 5,4, 47,1 Hz), 3,96-3,10 (m, 12H), 2.60 (s, 3H), 2,282,13 (m, 2H); LCMS (M+H)+ m/z 557, 559.4.82 (m, 1H), 4.60 (dt, 2H, J = 5.4, 47.1 Hz), 3.96-3.10 (m, 12H), 2.60 (s, 3H), 2.282 13 (m, 2H); LCMS (M + H) &lt; + &gt; m / z 557, 559.

Príklad 532Example 532

(S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(6-[4-(3-fluórpropyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:(S) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H- benzimidazol-2-yl} -1 H-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,58 (d, 1H, J = 2,0 Hz), 7,43 (d, 1H, J = 7,6 1 H NMR (400 MHz, CD 3 OD) δ 7.58 (d, 1H, J = 2.0 Hz), 7.43 (d, 1H, J = 7.6)

201201

Hz), 7,34 (dd, 1H, J = 2,0, 8,5 Hz), 7,19 (br s, 1H), 7,11 (br s. 1H), 7,00 (d, 1H, J =Hz), 7.34 (dd, 1H, J = 2.0, 8.5 Hz), 7.19 (br s, 1H), 7.11 (br s, 1H), 7.00 (d, 1H) , J =

8,5 Hz), 6,26 (d, 1H, J = 7,7 Hz), 5,90-4,82 (m, 1H), 4,61 (dt, 2H, J = 5,4, 47,1 Hz), 3,95-3,12 (m, 12H), 3,85 (s, 3H), 2,62 (s, 3H), 2,30-2,14 (m, 2H); LCMS (M+H)+ m/z 613.8.5 Hz), 6.26 (d, 1H, J = 7.7 Hz), 5.90-4.82 (m, 1H), 4.61 (dt, 2H, J = 5.4, 47) 1 Hz), 3.95-3.12 (m, 12H), 3.85 (s, 3H), 2.62 (s, 3H), 2.30-2.14 (m, 2H); LCMS (M + H) &lt; + &gt; m / z 613.

Príklad 533Example 533

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(3,3.3trifluórpropyl)piperazin-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,3.3trifluórpropyl) piperazin-1-yl] -1 H-benzimidazol-2 yl} -1 H-pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,50-7,10 (m, 7H), 6,26 (d, 1H, J = 7,5 Hz), 4,96-4,88 (m, 1H), 4,00-3,15 (m, 12H), 3,00-2,82 (m, 2H), 2,61 (s, 3H); LCMS (M+H)+ m/z 575, 577. 1 H NMR (300 MHz, CD 3 OD) δ 7.50-7.10 (m, 7H), 6.26 (d, 1H, J = 7.5 Hz), 4.96-4.88 (m 1 H, 4.00-3.15 (m, 12H), 3.00-2.82 (m, 2H), 2.61 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 575, 577.

Príklad 534Example 534

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazin-1y l]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole-2- yl} -1H-pyridin-2-one:

1H NMR (300 MHz, CD3OD) δ 7,46-7,25 (m, 5H), 7,19 (br s, 1H), 7,11 (br s, 1H), 6,27 (d, 1H, J = 7,7 Hz), 4,95-4,86 (m, 1H), 4,62 (dt, 2H, J = 5,4. 47,1 Hz), 3,98- 1 H NMR (300 MHz, CD 3 OD) δ 7.46-7.25 (m, 5H), 7.19 (br s, 1H), 7.11 (br s, 1H), 6.27 (d 1 H, J = 7.7 Hz), 4.95-4.86 (m, 1H), 4.62 (dt, 2H, J = 5.4, 47.1 Hz), 3.98-

3.15 (m, 12H), 2,62 (s, 3H), 2,35-2,12 (m, 2H); LCMS (M+H)+ m/z 539. 541.3.15 (m, 12H); 2.62 (s, 3H); 2.35-2.12 (m, 2H); LCMS (M + H) &lt; + &gt; m / z 539. 541.

Príklad 535Example 535

202202

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(3,4,4-trifluórbut-3enyl)piperazín-1-yl]-1H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,4,4-trifluoro-3-enyl) piperazine-1-yl] - 1H-Benzoimidazol-2-yl} -1H-pyridin-2-one:

LCMS (M+H)* m/z 587, 589.LCMS (M + H) + m / z 587, 589.

Príklad 536Example 536

4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-{6-[4-(3-fluór-2-hydroxypropyl)- piperazín-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- {6- [4- (3-fluoro-2-hydroxypropyl) piperazin-1-yl] -4-methyl-1H benzoimidazol-2-yl} -1 H-pyridin-2-one;

LCMS (M+H)* m/z 555, 553.LCMS (M + H) + m / z 555, 553;

Príklad 537 HcExample 537 H c

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxy-2-metylpropyl)piperazín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,44-7,22 (m, 5H), 7,15 (br s, 1H), 7,08 (br s, 1 H NMR (400 MHz, CD 3 OD) δ 7.44-7.22 (m, 5H), 7.15 (br s, 1H), 7.08 (br s,

203203

1Η), 6,25 (d, 1H, J = 7,6 Hz), 4,88-4,80 (m, 1H), 3,86-3,81 (m, 4H), 3,55-3,32 (m, 6H), 3,28 (s, 2H), 2,60 (s, 3H), 1,38 (s, 6H); LCMS (M+H)+ m/z 551, 553.1 H), 6.25 (d, 1H, J = 7.6 Hz), 4.88-4.80 (m, 1H), 3.86-3.81 (m, 4H), 3.55-3 32 (m, 6H), 3.28 (s, 2H), 2.60 (s, 3H), 1.38 (s, 6H); LCMS (M + H) &lt; + &gt; m / z 551, 553.

Príklad 538Example 538

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,50 (1H, s), 7,25-7,35 (4H, m), 7,04 (1H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.50 (1H, s), 7.25-7.35 (4H, m), 7.04 (1H, s),

6,97 (1H, s), 6,22 (1H, d, J = 6,8 Hz), 4,93-4,95 (1H, m), 3,21-3,96 (14H, m), 2,57 (3H, s); LCMS (M+H)+ m/z 523 (t = 1,11 min).6.97 (1H, s), 6.22 (1H, d, J = 6.8Hz), 4.93-4.95 (1H, m), 3.21-3.96 (14H, m) 2.57 (3H, s); LCMS (M + H) &lt; + &gt; m / z 523 (t = 1.11 min).

Príklad 539Example 539

(S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,60 (1H, úzky d, J = 2,0 Hz), 7,40 (1H, d, J = 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, d, J =

7,6 Hz), 7,35 (1H, dd, J = 2,0, 8,4 Hz), 7,13 (1H, s), 7,09 (1H, s), 6,99 (1H, d, J = 8,4 Hz), 6,25 (1H, d, J = 7,6 Hz), 4,82-4,87 (1H, m), 3,76-3,97 (6H, m), 3,84 (3H, s), 3,243,52 (8H, m), 2,60 (3H, s). LCMS (M+H)+ m/z 597 (t = 1,09 min).7.6 Hz), 7.35 (1H, dd, J = 2.0, 8.4 Hz), 7.13 (1H, s), 7.09 (1H, s), 6.99 (1H, d, J = 8.4 Hz), 6.25 (1H, d, J = 7.6 Hz), 4.82-4.87 (1H, m), 3.76-3.97 (6H, m 1.84 (3H, s), 3.243.52 (8H, m), 2.60 (3H, s). LCMS (M + H) &lt; + &gt; m / z 597 (t = 1.09 min).

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Príklad 540Example 540

(S)-4-[2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-yl]acetonitril:(S) -4- [2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl ) piperazin-1-yl] acetonitrile:

1H NMR (400 MHz, CD3OD) δ 7,50-7,25 (m, 7H), 6,28 (d, 1H, J = 8,0 Hz), 4,95-4,88 (m, 1H), 4,32 (s, 2H), 3,75-3,62 (m, 4H), 3,60-3,35 (m, 6H), 2,63 (s, 3H); LCMS (M+H)+ m/z 518, 520. 1 H NMR (400 MHz, CD 3 OD) δ 7.50-7.25 (m, 7H), 6.28 (d, 1H, J = 8.0 Hz), 4.95-4.88 (m 1 H, 4.32 (s, 2H), 3.75-3.62 (m, 4H), 3.60-3.35 (m, 6H), 2.63 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 518, 520.

Zlúčeniny podľa nižšie uvedených príkladov 541-553 sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú acyláciu piperazínových derivátov.The compounds of Examples 541-553 below were prepared according to the methods outlined in Schemes VII and III, and the examples illustrate the acylation of piperazine derivatives.

Príklad 541 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 541-553)Example 541 (General Preparation of Examples 541-553)

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(4-fluórbutyryl)piperazin-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (4-fluoro-butyryl) -piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl -1H-pyridin-2-one:

K miešanému roztoku 4-[2-(3-chlórfenyl)hydroetylamino]-3-(4-metyl-6piperazín-1-yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (70 mg, 0,136 mmol) v bezvodom N,N-dimetylformamide (750 μΙ) sa pridá 1-(3-dimetylaminopropyl)-3etylkarbodiimid-hydrochlorid (112 mg, 0,584 mmol), hydrát 1-hydroxybenzotriazoluTo a stirred solution of 4- [2- (3-chlorophenyl) hydroethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (70 mg, 0.136 mmol) in anhydrous N, N-dimethylformamide (750 μΙ) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (112 mg, 0.584 mmol), 1-hydroxybenzotriazole hydrate

205 (59 mg, 0,438 mmol), N-metylmorfolín (0,048 ml, 0,438 mmol) a kyselina 4fluórmaslová (31 mg, 0,291 mmol); (vid’O'Hagan D., J. Fluorine Chem., 43, (1989), 371-377) a zmes sa zahrieva 3 h pri 80 °C. Reakčná zmes sa potom prečistí preparatívnou HPLC na reverznej fáze s použitím gradientovej elúcie mobilnou fázou metanol/voda/0,1 % kyseliny trifluóroctovej, Odparením frakcií sa získa titulná zlúčenina vo forme soli s kyselinou trifluóroctovou, ktorá sa rozpustí v metanole a nanesie sa na kolónku Varian Mega Bond-Elute SCX. Elúciou metanolom a potom NH3 2,0 mol/l/MeOH sa získa voľná báza (35,9 g). Získaný produkt sa suspenduje v MeOH a pridá sa vodná HCI 1,00 mol/l (2 ekv.). Získaný roztok sa prefiltruje cez filter 45 μηη a odparením sa získa bis-HCl soľ titulnej zlúčeniny (37,6 mg): 1H NMR (400 MHz, CD3OD) δ 7,61 (br s, 1H), 7,47 (br s, 1H), 7,44-7,20 (m, 5H), 6,27 (d, 1H, J =205 (59 mg, 0.438 mmol), N-methylmorpholine (0.048 mL, 0.438 mmol) and 4-fluorobutyric acid (31 mg, 0.291 mmol); (see O'Hagan D., J. Fluorine Chem., 43, (1989), 371-377) and heated at 80 ° C for 3 h. The reaction mixture was then purified by reverse phase preparative HPLC using a gradient elution of methanol / water / 0.1% trifluoroacetic acid mobile phase. Evaporation of fractions gave the title compound as the trifluoroacetic acid salt, which was dissolved in methanol and applied to a column. Varian Mega Bond - Elute SCX. Elution with methanol and then NH 3 2.0 M / MeOH gave the free base (35.9 g). The obtained product was suspended in MeOH and aqueous HCl 1.00 M (2 eq) was added. The resulting solution was filtered through a 45 μη filter and evaporated to give the bis-HCl salt of the title compound (37.6 mg): 1 H NMR (400 MHz, CD 3 OD) δ 7.61 (br s, 1H), 7.47 (br s, 1H), 7.44-7.20 (m, 5H), 6.27 (d, IH, J =

7,6 Hz), 4,92 (dd, 1H, J = 4,4, 7,3 Hz), 4,50 (dt, 2H, J = 5,9, 47,3 Hz), 4,05-3,40 (m, 10H), 2,64 (s, 3H), 2,63 (t, 2H, J = 7,6 Hz), 2,09-1,95 (m, 2H); LCMS (M+H)+ m/z 567, 569.7.6 Hz), 4.92 (dd, 1H, J = 4.4, 7.3 Hz), 4.50 (dt, 2H, J = 5.9, 47.3 Hz), 4.05- 3.40 (m, 10H), 2.64 (s, 3H), 2.63 (t, 2H, J = 7.6 Hz), 2.09-1.95 (m, 2H); LCMS (M + H) &lt; + &gt; m / z 567, 569.

Príklad 542Example 542

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2,2-difluóracetyl)piperazin-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón: LCMS (M+H)* m/z 557, 559.(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2,2-difluoroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole -2-yl} -1H-pyridin-2-one: LCMS (M + H) + m / z 557, 559.

Príklad 543Example 543

• HCI• HCl

HO(I>HO (I>

206 (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metánsijlfonylacetyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridin-2-ón: LCMS (M+H)+ m/z 599, 601.206 (S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-methanesulfonyl-acetyl) -piperazin-1-yl] -4-methyl-1H-benzoimidazol-2 -yl} -1H-pyridin-2-one: LCMS (M + H) &lt; + &gt; m / z 599, 601.

Príklad 544Example 544

(S)-3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-[2-(3chlórfenyl)-2-hydroxyetylamino]-1H-pyridín-2-ón:(S) -3- [6- (4-acetyl-1-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1-pyridine 2-one:

’H NMR (500 MHz, CD3OD) δ 7,57 (br s, 1H), 7,49 (br s, 1H), 7,40-7,20 (m, 5H), 6,29 (d, 1H, J = 7,6 Hz), 4,98-4,90 (m, 1H), 4,02-3,91 (m, 4H), 3,70-3,50 (m, 6H), 2,66 (s, 3H), 2,21 (s, 3H); LCMS (M+Hf m/z 521, 523.1 H NMR (500 MHz, CD 3 OD) δ 7.57 (br s, 1H), 7.49 (br s, 1H), 7.40-7.20 (m, 5H), 6.29 (d 1H, J = 7.6 Hz), 4.98-4.90 (m, 1H), 4.02-3.91 (m, 4H), 3.70-3.50 (m, 6H), 2.66 (s, 3H); 2.21 (s, 3H); LCMS (M + H + m / z 521, 523).

Príklad 545Example 545

OABOUT

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-{4-[2-(1-oxo-1tiomorfolín-4-yl)acetyl]piperazín-1-yl}-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón: LCMS (M+H)+ m/z 638, 640.(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6- {4- [2- (1-oxo-1tiomorfolín-4-yl) acetyl] piperazine 1-yl} -1H-benzoimidazol-2-yl) -1H-pyridin-2-one: LCMS (M + H) + m / z 638, 640.

Príklad 546Example 546

207 (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-{4-[2-(1,1 -dioxo-1 -tiomorfolín-207 (S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6- {4- [2- (1,1-dioxo-1-thiomorpholine-

4-yl)acetyl]piperazín-1 -yl}-4-metyl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón: LCMS (M+H)+ m/z 654, 656.4-yl) acetyl] piperazin-1-yl} -4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one: LCMS (M + H) + m / z 654, 656.

Príklad 547Example 547

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-rnetyl-6-[4-(2-tiomorfolín-4ylacetyl)piperazín-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridin-2-ón: LCMS (M+H)+ m/z 622, 624.(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (2-thiomorpholin-4ylacetyl) piperazin-1-yl] -1H-benzoimidazol 2-yl} -1H-pyridin-2-one: LCMS (M + H) &lt; + &gt; m / z 622, 624.

Príklad 548Example 548

4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-{6-[4-(2-metánsulfinylacetyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón: LCMS (M+H)+ m/z 583, 585.4- [2- (3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- {6- [4- (2-metánsulfinylacetyl) piperazin-1-yl] -4-methyl-1 H-benzoimidazol-2-yl 1 H-Pyridin-2-one: LCMS (M + H) + m / z 583, 585.

• HCtHCt

HOIHOI

208 (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metoxyacetyl)piperazin1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:208 (S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole-2- yl} -1H-pyridin-2-one:

1H NMR (500 MHz, CD3OD) δ 7,49 (br s, 1H), 7,40-7,18 (m, 6H), 6,26 (d, 1H, J = 7,7 Hz), 4,98-4,90 (m, 1H), 4,25 (s, 2H), 3,95-3,46 (m, 10H), 3,44 (s, 3H), 2,63 (s, 3H); LCMS (M+Hf m/z 551,553. 1 H NMR (500 MHz, CD 3 OD) δ 7.49 (br s, 1H), 7.40-7.18 (m, 6H), 6.26 (d, 1H, J = 7.7 Hz) 4.98-4.90 (m, 1H), 4.25 (s, 2H), 3.95-3.46 (m, 10H), 3.44 (s, 3H), 2.63 (s 3H); LCMS (M + H + m / z 551.553).

Príklad 550Example 550

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(2-metylsulfanylacetyl)piperazín-1 -yl]-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón:(S) -4- [2- (3-Chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylacetyl) piperazin-1-yl] -1H-benzoimidazol-2 -yl} -1H-pyridin-2-one:

1H NMR (500 MHz, CD3OD) δ 7,49 (br s, 1H), 7,45-7,20 (m, 6H), 6,26 (d, 1H, J = 7,60 Hz), 4,98-4,90 (m, 1H), 3,97-3,40 (m, 12H), 2,63 (s, 3H), 2,20 (s, 3H); LCMS (M+H)+ m/z 567, 569. 1 H NMR (500 MHz, CD 3 OD) δ 7.49 (br s, 1H), 7.45-7.20 (m, 6H), 6.26 (d, 1H, J = 7.60 Hz) 4.98-4.90 (m, 1H), 3.97-3.40 (m, 12H), 2.63 (s, 3H), 2.20 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 567, 569.

Príklad 551Example 551

(S)-3-{6-[4-(2-chlóracetyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-4-[2(3-chlórfenyl)-2-hyd roxyetylamino]-1 H-pyridín-2-όη:(S) -3- {6- [4- (2-chloroacetyl) piperazine-1-yl] -4-methyl-1 H-benzoimidazol-2-yl} -4- [2- (3-chlorophenyl) -2-hydroxy roxyethylamino] -1H-pyridin-2-one:

1H NMR (500 MHz, CD3OD) δ 7,49 (br s, 1H), 7,38-7,20 (m, 5H), 7,15 (br s, 1H), 6,25 (d, 1H, J = 7,6 Hz), 4,98-4,90 (m, 1H), 4,35 (s, 2H), 3,90-3,80 (m, 4H), 1 H NMR (500 MHz, CD 3 OD) δ 7.49 (br s, 1H), 7.38-7.20 (m, 5H), 7.15 (br s, 1H), 6.25 (d (1H, J = 7.6 Hz), 4.98-4.90 (m, 1H), 4.35 (s, 2H), 3.90-3.80 (m, 4H),

209209

3,66-3,30 (m, 6H), 2,61 (s, 3H); LCMS (M+H)+ m/z 555, 557.3.66-3.30 (m, 6H); 2.61 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 555, 557.

Príklad 552Example 552

(S)-4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hyd roxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karbaldehyd:(S) -4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H- benzoimidazol-5-yl) -piperazine-1-carbaldehyde:

1H NMR (400 MHz, CD3OD) δ 8,18 (1H, s), 7,65 (1H, s), 7,61 (1H, úzky d, J = 2,0 Hz), 7,46 (1H, s), 7,43 (1H, d, J = 7,6 Hz), 7,36 (1H, dd, J = 2,0, 8,5 Hz), 7,00 (1H, d, J = 8,5 Hz), 6,32 (1H, d, J = 7,6 Hz), 4,86-4,89 (1H, m), 3,91-3,96 (4H, m), 3,84 (3H, s), 3,57-3,67 (7H, m), 2,66 (3H, s). LCMS (M+H)+ m/z 581 (t = 1,24 min). 1 H NMR (400 MHz, CD 3 OD) δ 8.18 (1H, s), 7.65 (1H, s), 7.61 (1H, narrow d, J = 2.0 Hz), 7.46 (1H, s), 7.43 (1H, d, J = 7.6Hz), 7.36 (1H, dd, J = 2.0, 8.5Hz), 7.00 (1H, d, J = 8.5 Hz), 6.32 (1H, d, J = 7.6 Hz), 4.86-4.89 (1H, m), 3.91-3.96 (4H, m), 3.84 (3H, s), 3.57-3.67 (7H, m), 2.66 (3H, s). LCMS (M + H) &lt; + &gt; m / z 581 (t = 1.24 min).

Príklad 553 oExample 553 o

(S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karbaldehyd:(S) -4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl ) piperazine-1-carbaldehyde:

1H NMR (400 MHz, CD3OD) δ 8,12 (1H, s), 7,50 (1H, s), 7,24-7,38 (6H, m), 1 H NMR (400 MHz, CD 3 OD) δ 8.12 (1H, s), 7.50 (1H, s), 7.24-7.38 (6H, m),

6,23 (1H, d, J = 7,6 Hz), 4,93-4,96 (1H, m). 3,54-3,79 (10H, m), 2,58 (3H, s). LCMS (M+H)+ m/z 507 (t = 1,29 min).6.23 (1H, d, J = 7.6Hz); 4.93-4.96 (1H, m). 3.54-3.79 (10H, m); 2.58 (3H, s). LCMS (M + H) &lt; + &gt; m / z 507 (t = 1.29 min).

210210

Zlúčeniny opísané v nižšie uvedených príkladoch (554-575) sa pripravia spôsobmi znázornenými v schémach VII a IIIThe compounds described in the examples below (554-575) were prepared by the methods shown in Schemes VII and III

Príklad 554Example 554

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one;

K suspenzii 4-chlór-3-(4-metyl-6-morfolín-4-yl-1 H-benzoimidazol-2-yl)-1 Hpyridín-2-ónu a zodpovedajúceho jódovaného derivátu, 4-jód-3-(4-metyl-6-morfolín-4yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ónu (4,43 g, približne 11 mmol) v acetonitrile (100 ml) sa pridá trietylamín (7,0 ml, 50 mmol) a 2-(S)-2-(3-chlórfenyl)-2hydroxyetylamin-hydrochlorid (2,55 g, 12,2 mmol). Zmes sa mieša pri 85 °C cez noc. Po tomto čase analýza LCMS ešte stále preukazuje podiel východiskových pyridónov v reakčnej zmesi. Pridá sa 2-(S)-2-(3-chlórfenyl)-2-hydroxyetylamín-hydrochlorid (0,22 g, 1,06 mmol) a zmes sa mieša pri 85 °C ďalších 24 hodín. Po odparení prchavých zložiek sa pridá vodný roztok CS2CO3 (200 ml, 10 %) a suspenzia sa podrobí spracovaniu ultrazvukom počas 5 minút a potom sa mieša cez noc. Produkt sa odfiltruje, premyje sa vodou a rekryštalizuje sa z metanolu-chloroformu. Titulná zlúčenina sa izoluje vo forme žltých kryštálov (3,951 g, 75 %). LCMS (M+H)+ m/z 480 (t - 1,31 min). HPLC t = 4,93 min, YMC-Pack ODS-A 3,0 x 50 mm; gradientová elúcia 0-100 % v priebehu 8 min; prietoková rýchlosť 2,5 ml/min. 1H NMR mono-HCI soli (500 MHz, DMSO-de) δ 13,3 (1H, široký s), 11,22 (1H, s), 10,9 (1H, široký s), 7,65 (1H, široký s), 7,60 (1H, s), 7,45 (d, J = 7,6 Hz), 7,38-7,30 (4H, m), 6,19 (1H, d, J =To a suspension of 4-chloro-3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one and the corresponding iodinated derivative, 4-iodo-3- (4 -methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one (4.43 g, approximately 11 mmol) in acetonitrile (100 mL) is added triethylamine (7.0 mL, 50 mmol) and 2- (S) -2- (3-chlorophenyl) -2-hydroxyethylamine hydrochloride (2.55 g, 12.2 mmol). The mixture was stirred at 85 ° C overnight. After this time, LCMS analysis still showed the proportion of starting pyridones in the reaction mixture. 2- (S) -2- (3-chlorophenyl) -2-hydroxyethylamine hydrochloride (0.22 g, 1.06 mmol) was added and the mixture was stirred at 85 ° C for an additional 24 hours. After evaporation of the volatiles, aqueous CS 2 CO 3 solution (200 mL, 10%) was added and the suspension was sonicated for 5 minutes and then stirred overnight. The product was filtered off, washed with water and recrystallized from methanol-chloroform. The title compound was isolated as yellow crystals (3.951 g, 75%). LCMS (M + H) + m / z 480 (t = 1.31 min). HPLC t = 4.93 min, YMC-Pack ODS-A 3.0 x 50 mm; gradient elution 0-100% over 8 min; flow rate 2.5 ml / min. 1 H NMR of mono-HCl salt (500 MHz, DMSO-d 6) δ 13.3 (1H, broad s), 11.22 (1H, s), 10.9 (1H, broad s), 7.65 (1H , broad s), 7.60 (1H, s), 7.45 (d, J = 7.6 Hz), 7.38-7.30 (4H, m), 6.19 (1H, d, J =

7,5 Hz), 4,92 (1H, t, J = 5,3 Hz), 4,00 (6H, široký), 3,67 (1H, m), 3,52 (5H, m), 2,58 (3H, s).7.5 Hz), 4.92 (1H, t, J = 5.3 Hz), 4.00 (6H, broad), 3.67 (1H, m), 3.52 (5H, m), 2 58 (3H, s).

Všeobecný spôsob prípravy mono- a bis-HCI solí;General process for the preparation of mono- and bis-HCl salts;

Roztok alebo suspenzia voľnej bázy v metanole sa spracuje s 1,00 (alebo vA solution or suspension of the free base in methanol is treated with 1.00 (or

211 druhom prípade s 2,00) ekvivalentom vodnej HCI 1,00 mol/l. Pokiaľ významné množstvo zlúčeniny zostane nerozpustené, pridá sa na zlepšenie rozpustnosti rovnaký objem dichlóretánu. Zmes sa potom prefiltruje a zahustí sa vo vákuu. Malé podiely pripravených zlúčenín sa získajú zahustením do sucha, pri príprave vo väčších množstvách, ako na štúdie in vivo, sa uskutoční zahustenie až na objem, pri ktorom dochádza ku kryštalizácii a zlúčeniny sa izolujú filtráciou.211 the second case with 2.00) aqueous HCl equivalent of 1.00 mol / l. If a significant amount of the compound remains undissolved, an equal volume of dichloroethane is added to improve solubility. The mixture was then filtered and concentrated in vacuo. Small portions of the prepared compounds are obtained by concentration to dryness, in larger quantities than for in vivo studies, the concentration is performed up to the crystallization volume and the compounds are isolated by filtration.

Príklad 555Example 555

(S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4yl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,68-7,60 (m, 2H), 7,43-7,28 (m, 3H), 6,98 (d, 1H, J = 8,50 Hz), 6,26 (d, 1H, J = 7,7 Hz), 4,97-4,89 (m, 1H), 4,18-4,04 (m, 4H), 3,82 (s, 3H), 3,73-3,55 (m, 6H), 2,63 (s, 3H); LCMS (M+H)+ m/z 554, 556. 1 H NMR (300 MHz, CD 3 OD) δ 7.68-7.60 (m, 2H), 7.43-7.28 (m, 3H), 6.98 (d, 1H, J = 8, 50 Hz), 6.26 (d, 1H, J = 7.7 Hz), 4.97-4.89 (m, 1H), 4.18-4.04 (m, 4H), 3.82 ( s, 3H), 3.73-3.55 (m, 6H), 2.63 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 554, 556.

Príklad 556Example 556

(S)-4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:(S) -4- [2- (3-chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl) -1H-benzoimidazol-2-yl) -1H- pyridin-2-one;

1H NMR (300 MHz, CD3OD) δ 7,65-7,50 (m, 2H), 7,43-7,20 (m, 3H), 7,18 (dd, 1 H NMR (300 MHz, CD 3 OD) δ 7.65-7.50 (m, 2H), 7.43-7.20 (m, 3H), 7.18 (dd,

1H, J = 8,9, 8,8 Hz), 6,27 (d, 1 H, J = 7,6 Hz), 5,00-4,91 (m, 1H), 4,15-4,02 (m, 4H), 3,75-3,60 (m, 6H), 2,64 (s, 3H); LCMS (M+H)+ m/z 498, 500.1H, J = 8.9, 8.8 Hz), 6.27 (d, 1H, J = 7.6 Hz), 5.00-4.91 (m, 1H), 4.15-4, O 2 (m, 4H), 3.75-3.60 (m, 6H), 2.64 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 498, 500.

212212

Príklad 557Example 557

o— (S)-4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4y I-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón:o- (S) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) - 1 H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,67 (br s, 1H), 7,45 (br s, 1H), 7,40-7,28 (m, 3H), 7,00 (d, 1H, J = 8,4 Hz), 6,27 (d, 1H. J = 7,6 Hz), 4,95-4,84 (m, 1H), 4,15-4,05 (m, 4H), 3,82 (s, 3H), 3,75-3,55 (m, 6H). 2.64 (s, 3H); LCMS (M+H)+ m/z 510, 512. 1 H NMR (400 MHz, CD 3 OD) δ 7.67 (br s, 1H), 7.45 (br s, 1H), 7.40-7.28 (m, 3H), 7.00 (d 1 H, J = 8.4 Hz), 6.27 (d, 1H, J = 7.6 Hz), 4.95-4.84 (m, 1H), 4.15-4.05 (m, 4H), 3.82 (s, 3H), 3.75-3.55 (m, 6H). 2.64 (s. 3H); LCMS (M + H) &lt; + &gt; m / z 510, 512.

Príklad 558Example 558

(S)-4-[2-(7-bróm-2,3-dihydrobenzofurán-5-yl)-2-hydroxyetylamino]-3-(4-metyl-(S) -4- [2- (7-bromo-2,3-dihydrobenzofuran-5-yl) -2-hydroxy-ethylamino] -3- (4-methyl-

6-morfolin-4-yl-1 H-benzoimidazol-2-yl)-1 H-pyrid í η-2-όη:6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-yl:

1H NMR (400 MHz, CD3OD) δ 7,54 (br s, 1H), 7,35-7,30 (m, 2H), 7,27 (br s, 1H), 7,22 (br s, 1H), 6,27 (d, 1H, J = 7,6 Hz), 4,95-4,87 (m, 1H), 4,60-4,50 (m, 2H), 4,10-4,00 (m, 4H), 3,75-3,60 (m, 6H), 3,25-3,13 (m, 2H), 2,62 (s, 3H); LCMS (M+H)+ m/z 566, 568. 1 H NMR (400 MHz, CD 3 OD) δ 7.54 (br s, 1H), 7.35-7.30 (m, 2H), 7.27 (br s, 1H), 7.22 (br s) s, 1H), 6.27 (d, 1H, J = 7.6Hz), 4.95-4.87 (m, 1H), 4.60-4.50 (m, 2H), 4.10 -4.00 (m, 4H), 3.75-3.60 (m, 6H), 3.25-3.13 (m, 2H), 2.62 (s, 3H); LCMS (M + H) &lt; + &gt; m / z 566, 568.

Príklad 559Example 559

• HCI• HCl

213213

4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-[2(S),6(R)-dimetylmorfolín-4-yl]-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- [2 (S), 6 (R) -dimethylmorpholin-4-yl] -1H-benzoimidazole -2-yl] -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,23-7,57 (7H, m), 6,22 (d, 1H, J = 7,6 Hz), 4,97 (m, 1H), 4,06 (2H, m), 3,62-3,68 (4H, m), 3,20-3,34 (2H, m), 2,63 (3H, s), 1,30 (6H, d, J = 6,28 Hz). LCMS (M+H)+ m/z 508 (t = 2,12 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.23-7.57 (7H, m), 6.22 (d, 1H, J = 7.6 Hz), 4.97 (m, 1H), 4, 06 (2H, m), 3.62-3.68 (4H, m), 3.20-3.34 (2H, m), 2.63 (3H, s), 1.30 (6H, d, J = 6.28 Hz). LCMS (M + H) &lt; + &gt; m / z 508 (t = 2.12 min).

Príklad 560Example 560

4-[2-(3-bróm-4-metoxyfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-[2(S),6(R)dimetylmorfolín-4-yl]-1 H-benzoimidazol-2-yl]-1 H-pyrid í η-2-όη:4- [2- (3-bromo-4-methoxy-phenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- [2 (S), 6 (R) dimethyl-morpholin-4-yl] -1 H-benzoimidazol-2-yl] -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,73 (1H, s), 7,63 (1H, s), 7,42 (1H, s), 7,34 (2H, m), 6,96 (1H, d, J = 8,48 Hz), 6,21 (1H, d, J = 7,48 Hz), 4,87 (1H, m), 4,23 (2H, m), 3,57-3,67 (4H, m), 3,34 (3H, s), 3,30-3,32 (2H, m), 2,60 (1 H, s), 1,30 (6H, d, J = 6,2 Hz). LCMS (M+H)* m/z 582 (t = 2,03 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.73 (1H, s), 7.63 (1H, s), 7.42 (1H, s), 7.34 (2H, m), 6.96 ( 1H, d, J = 8.48Hz), 6.21 (1H, d, J = 7.48Hz), 4.87 (1H, m), 4.23 (2H, m), 3.57- 3.67 (4H, m), 3.34 (3H, s), 3.30-3.32 (2H, m), 2.60 (1H, s), 1.30 (6H, d, J = 6.2 Hz). LCMS (M + H) + m / z 582 (t = 2.03 min).

Príklad 561Example 561

4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-fluórmetylmorfolín-4-yl]-4- [2- (3-chlorophenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-fluórmetylmorfolín-4-yl] -

4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-24-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) 2-fluórmetylmorfolín-4-yl] -4-methyl-1 H-benzoimidazol-2

214 yl}-1 H-pyridín-2-ón:214 yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,47 (6H, m), 6,22 (d, 1H, J = 7,2 Hz), 4,87-4,94 (1H, m), 4,60 (1H, d, J = 3,4 Hz), 4,48 (1H, d, J = 3,4 Hz), 4,04-4,15 (3H, m), 3,283,62 (6H, m), 2,56 (3H, s). LCMS (M+H)* m/z 512 (t = 1,35 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.47 (6H, m), 6.22 (d, 1H, J = 7.2 Hz), 4.87-4.94 (1H, m), 4.60 (1H, d, J = 3.4Hz), 4.48 (1H, d, J = 3.4Hz), 4.04-4.15 (3H, m), 3.283.62 (6H) , m), 2.56 (3H, s). LCMS (M + H) + m / z 512 (t = 1.35 min).

Príklad 562Example 562

4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-fluórmetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1H-pyridín-2-ón:4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- fluórmetylmorfolín-4-yl] -4-methyl-1 H -benzoimidazole-2-yl} -1 H-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,60 (1H, úzky d, J = 2,0 Hz), 7,56 (1H, s), 7,39 (1H, br s), 7,34 (1H, dd, J = 2,0, 8,4 Hz), 6,97 (1H, d, J = 8,4 Hz), 6,27 (d, 1H, J = 6,4 Hz), 4,86 (1H, m), 4,61 (1H, m), 4,50 (1H, m), 4,77-4,19 (3H, m), 3,82 (3H, s), 3,38- 1 H NMR (400 MHz, CD 3 OD) δ 7.60 (1H, narrow d, J = 2.0 Hz), 7.56 (1H, s), 7.39 (1H, br s), 34 (1H, dd, J = 2.0, 8.4 Hz), 6.97 (1H, d, J = 8.4 Hz), 6.27 (d, 1H, J = 6.4 Hz), 4.86 (1H, m), 4.61 (1H, m), 4.50 (1H, m), 4.77-4.19 (3H, m), 3.82 (3H, s), 3 , 38-

3,74 (8H, m), 2,63 (3H, s). LCMS (M+H)* m/z 586 (t = 1,31 min).3.74 (8H, m); 2.63 (3H, s). LCMS (M + H) + m / z 586 (t = 1.31 min).

Príklad 563Example 563

4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-fluórmetyl215 morfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1H-pyridín-2-óri:4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-fluoromethyl-2H-morpholin-4-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- fluórmetylmorfolín-4-yl] -4-methyl-1 H -benzoimidazole-2-yl} -1 H-pyridin-2-Ori

1H NMR (400 MHz, CD3OD) δ 7,45 (1H, s), 7,28-7,30 (3H, m), 7,10 (1H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.45 (1H, s), 7.28-7.30 (3H, m), 7.10 (1H, s),

6,97 (1H, d, J = 8,0 Hz), 6,20 (d, 1H, J = 6,4 Hz), 4,85 (1H, m), 4,58 (1H, br s), 4,46 (1H, br s), 3,93-4,10 (3H, m), 3,80 (3H, s), 3,59 (4H, m), 3,07-3,29 (2H, m), 2,55 (3H, s). LCMS (M+H)+ m/z 542 (t = 1,28 min).6.97 (1H, d, J = 8.0Hz), 6.20 (d, 1H, J = 6.4Hz), 4.85 (1H, m), 4.58 (1H, br s) 4.46 (1H, br s), 3.93-4.10 (3H, m), 3.80 (3H, s), 3.59 (4H, m), 3.07-3.29 ( 2H, m), 2.55 (3H, s). LCMS (M + H) &lt; + &gt; m / z 542 (t = 1.28 min).

Príklad 564Example 564

4-[2-(7-bróm-2,3-dihydrobenzofurán-5-yl)-(S)-2-hydroxyetylamino]-3-[6-[(R)-2fluórmetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyrid í η-2-όη a 4-[2-(7bróm-2,3-dihydrobenzofurán-5-yl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2fluórmetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-2-yl}-1 H-pyrid in-2-ón:4- [2- (7-bromo-2,3-dihydrobenzofuran-5-yl) - (S) -2-hydroxy-ethylamino] -3- [6 - [(R) -2fluórmetylmorfolín-4-yl] -4-methyl- -1H-benzoimidazol-2-yl} -1H-pyridin-2-yl and 4- [2- (7-bromo-2,3-dihydrobenzofuran-5-yl) - (S) -2-hydroxyethylamino] - 3- {6 - [(S) -2-Fluoromethyl-morpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,26-7,40 (4H, m), 7,19 (1H, s), 6,24 (1H, d, J = 1 H NMR (400 MHz, CD 3 OD) δ 7.26-7.40 (4H, m), 7.19 (1H, s), 6.24 (1H, d, J =

7,6 Hz), 4,81-4,82 (1H, m), 4,49-4,61 (4H, m), 3,18-4,18 (11H, m), 2,59 (3H, s). LCMS (M+H)+ m/z 598 (t = 1,32 min).7.6 Hz), 4.81-4.82 (1H, m), 4.49-4.61 (4H, m), 3.18-4.18 (11H, m), 2.59 (3H) , with). LCMS (M + H) &lt; + &gt; m / z 598 (t = 1.32 min).

Príklad 565Example 565

216216

4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxymetylmorfolín-4yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-[6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- [6 - [(S) -2-hydroxymethylmorpholin-4-yl] -4-methyl -1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,49 (1H, s), 7,23-7,37 (6H, m), 7,10 (1H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.49 (1H, s), 7.23-7.37 (6H, m), 7.10 (1H, s),

6,24 (d, 1H, J = 7,6 Hz), 4,95-4,96 (1H, m), 4,19 (1H, m), 3,94-4,80 (2H, m), 3,59-6.24 (d, 1H, J = 7.6Hz), 4.95-4.96 (1H, m), 4.19 (1H, m), 3.94-4.80 (2H, m) , 3,59-

3,71 (8H, m), 2,63 (3H, s). LCMS (M+H)+ m/z 510 (t = 1,21 min).3.71 (8H, m); 2.63 (3H, s). LCMS (M + H) &lt; + &gt; m / z 510 (t = 1.21 min).

Príklad 566Example 566

4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón:4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,62 (1H, úzky d, J = 2,0 Hz), 7,54 (1H, s), 7,29- 1 H NMR (400 MHz, CD 3 OD) δ 7.62 (1H, narrow d, J = 2.0 Hz), 7.54 (1H, s), 7.29-

7,36 (3H, m), 6,95 (1H, d, J = 8,4 Hz), 6,23 (d, 1H, J = 7,6 Hz), 4,88-4,89 (1H, m), 3,56-4,19 (11H, m), 3,80 (3H, s), 2,60 (3H, s). LCMS (M+H)+ m/z 584 (t = 1,16 min).7.36 (3H, m), 6.95 (1H, d, J = 8.4 Hz), 6.23 (d, 1H, J = 7.6 Hz), 4.88-4.89 (1H , m), 3.56-4.19 (11H, m), 3.80 (3H, s), 2.60 (3H, s). LCMS (M + H) &lt; + &gt; m / z 584 (t = 1.16 min).

Príklad 567Example 567

OMeOMe

217217

4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxymetylmorfolín-4-yl]-4-rnetyl-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyrid ίη-2-όη:4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-yl:

1H NMR (400 MHz, CD3OD) δ 7,68 (1H, s), 7,54 (1 H, s), 7,45 (1H, s), 7,39 (1H, s), 7,30-7,32 (2H, m), 6,98 (1H, d, J = 8,4 Hz), 6,22 (d, 1H, J = 7,6 Hz), 4,89 (1H, m), 4,11-4.19 (3H, m), 3,80 (3H, s), 3,49-3,72 (8H, m), 2,60 (3H, s). LCMS (M+H)+ m/z 540 (t - 1,09 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.68 (1H, s), 7.54 (1H, s), 7.45 (1H, s), 7.39 (1H, s), 7 30-7.32 (2H, m), 6.98 (1H, d, J = 8.4 Hz), 6.22 (d, 1H, J = 7.6 Hz), 4.89 (1H, m), 4.11-4.19 (3H, m), 3.80 (3H, s), 3.49-3.72 (8H, m), 2.60 (3H, s). LCMS (M + H) + m / z 540 (t = 1.09 min).

Príklad 568Example 568

4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metylrriorfolín-4-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2ón:4- [2- (3-Chloro-phenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-methyl-trifluorolin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-methylmorpholin-4-yl] -4 methyl-1 H-benzoimidazol-2-yl} -1 H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,75 (1H, s), 7,48 (1H, s), 7,42 (1H, s), 7,23- 1 H NMR (400 MHz, CD 3 OD) δ 7.75 (1H, s), 7.48 (1H, s), 7.42 (1H, s), 7.23-

7,37 (4H, m), 6,24 (d, 1H, J = 7,2 Hz), 4,94-4,97 (1H, m), 4,11-4,16 (3H, m), 3,614,68 (5H, m), 3,38 (1H, m), 2,64 (3H, s), 1,29 (3H, d, J = 6,4 Hz). LCMS (M+H)+ m/z 494 (t = 1,32 min).7.37 (4H, m), 6.24 (d, 1H, J = 7.2 Hz), 4.94-4.97 (1H, m), 4.11-4.16 (3H, m) , 3.614.68 (5H, m), 3.38 (1H, m), 2.64 (3H, s), 1.29 (3H, d, J = 6.4 Hz). LCMS (M + H) &lt; + &gt; m / z 494 (t = 1.32 min).

Príklad 569Example 569

218218

4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metylmorfolín-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,63 (1H, s), 7,62 (1H, s), 7,30-7,61 (3H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.63 (1H, s), 7.62 (1H, s), 7.30-7.61 (3H, m),

6,95 (1H, d. J = 8,4 Hz), 6,22 (1H, d, J = 7,6 Hz), 4,88-4,90 (1H, m), 4,08-4,18 (3H, m), 3,80 (3H. s), 3,61-3,67 (5H, m), 3,32-3,34 (1H, m), 2,60 (3H, s), 1,28 (3H, d, J = 6,0 Hz). LCMS (M+H)+ m/z 568 (t = 1,31 min).6.95 (1H, d, J = 8.4 Hz), 6.22 (1H, d, J = 7.6 Hz), 4.88-4.90 (1H, m), 4.08-4 18 (3H, m), 3.80 (3H, s), 3.61-3.67 (5H, m), 3.32-3.34 (1H, m), 2.60 (3H, s) 1.28 (3H, d, J = 6.0 Hz). LCMS (M + H) &lt; + &gt; m / z 568 (t = 1.31 min).

Príklad 570Example 570

4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metylmorfolin-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-py ridín-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metylmorfolin-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1H-pyridín-2-ón:4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2 -methyl morpholine-4-yl] -4-methyl-1 H -benzoimidazole-2-yl} -1 H-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,48 (1H, úzky d, J = 2,0 Hz), 7,40 (1H, br s), 1 H NMR (400 MHz, CD 3 OD) δ 7.48 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, br s),

7,31 (1H, úzky d, J = 2,0 Hz), 7,29 (1H. úzky d, J = 2,0 Hz), 6,97 (1H, d, J = 8,4 Hz),7.31 (1H, narrow d, J = 2.0 Hz), 7.29 (1H, narrow d, J = 2.0 Hz), 6.97 (1H, d, J = 8.4 Hz),

6,22 (d, 1H, J = 7,6 Hz), 4,87-4,90 (1H, m), 4,11 (1H, m), 3,95-4,01 (2H, m), 3,806.22 (d, 1H, J = 7.6Hz), 4.87-4.90 (1H, m), 4.11 (1H, m), 3.95-4.01 (2H, m) , 3.80

219 (3Η, s), 3,47 (4H, m), 3,32 (1H, m), 3,25 (1H, m), 2,57 (3H, s), 1,27 (3H, d, J = 6,4 Hz). LCMS (M+H)+ m/z 525 (t = 1,27 min).219 (3Η, s), 3.47 (4H, m), 3.32 (1H, m), 3.25 (1H, m), 2.57 (3H, s), 1.27 (3H, d) , J = 6.4 Hz). LCMS (M + H) &lt; + &gt; m / z 525 (t = 1.27 min).

Príklad 571Example 571

4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metoxymetylmorfolín-4yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-methoxymethylmorpholin-4-yl] -4-methyl -1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,49 (1H, úzky d, J = 2,0 Hz), 7,23-7,36 (6H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.49 (1H, narrow d, J = 2.0 Hz), 7.23-7.36 (6H, m),

6,22 (d, 1H, J = 7,2 Hz), 4,93-4,96 (1H, m), 4,08-4,21 (11H, m), 3,38 (3H, s), 2,60 (3H, s), 1,27 (3H, d, J = 6,4 Hz). LCMS (M+H)+ m/z 524 (t = 1,35 min).6.22 (d, 1H, J = 7.2Hz), 4.93-4.96 (1H, m), 4.08-4.21 (11H, m), 3.38 (3H, s) 2.60 (3H, s), 1.27 (3H, d, J = 6.4 Hz). LCMS (M + H) &lt; + &gt; m / z 524 (t = 1.35 min).

Príklad 572Example 572

4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metoxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolin-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

220 1H NMR (400 MHz, CD3OD) δ 7,63 (1H, úzky d, J = 2,0 Hz), 7,40 (1H, br s),220 1 H NMR (400 MHz, CD 3 OD) δ 7.63 (1H, narrow d, J = 2.0 Hz), 7.40 (1H, br s),

7,30-7,36 (3H, m), 7,19 (1H, br s), 6,95 (1H, d, J = 8,4 Hz), 6,23 (d, 1H, J = 7,2 Hz), 4,87-4,89 (1H, m), 4,18 (1H, m), 3,97-4,03 (3H, m), 3,80 (3H, s), 3,54-3,66 (7H, m), 3,39 (3H, s), 2,59 (3H, s). LCMS (M+H)+ m/z 598 (t = 1,31 min).7.30-7.36 (3H, m), 7.19 (1H, br s), 6.95 (1H, d, J = 8.4 Hz), 6.23 (d, 1H, J = 7) 2 Hz), 4.87-4.89 (1H, m), 4.18 (1H, m), 3.97-4.03 (3H, m), 3.80 (3H, s), 3 54-3.66 (7H, m), 3.39 (3H, s), 2.59 (3H, s). LCMS (M + H) &lt; + &gt; m / z 598 (t = 1.31 min).

Príklad 573Example 573

4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metoxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,52 (1H, s), 7,46 (1H, úzky d, J = 1,6 Hz), 7,29- 1 H NMR (400 MHz, CD 3 OD) δ 7.52 (1H, s), 7.46 (1H, narrow d, J = 1.6 Hz), 7.29-

7,34 (3H, m), 6,99 (1H, d, J = 8,4 Hz), 6,24 (d, 1H, J = 7,2 Hz), 4,89 (1H, m), 4,06-7.34 (3H, m), 6.99 (1H, d, J = 8.4Hz), 6.24 (d, 1H, J = 7.2Hz), 4.89 (1H, m), 4,06-

4,17 (3H, m), 3,81 (3H, s), 3,54-3,68 (8H, m), 3,38 (3H, s), 2,60 (3H, s). LCMS (M+H)+ m/z 554 (t = 1,28 min).4.17 (3H, m), 3.81 (3H, s), 3.54-3.68 (8H, m), 3.38 (3H, s), 2.60 (3H, s). LCMS (M + H) &lt; + &gt; m / z 554 (t = 1.28 min).

Príklad 574Example 574

4-[2-(3-chlórfenyl-2(S)-hydroxyetylamino]-3-[4-metyl-6-(4-metylpiperazín-1-yl)1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón:4- [2- (3-chlorophenyl-2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyridine 2-one;

1H NMR (400 MHz, CD3OD) δ 7,46 (1H, s), 7,24-7,36 (m, 4H), 7,04 (2H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.46 (1H, s), 7.24-7.36 (m, 4H), 7.04 (2H, s),

221221

6,22 (1 H, d, J = 7,64 Hz), 4,89 (1H, m), 3,30-3,82 (1 OH, m), 2,97 (3H, s), 2,57 (3H, s). LCMS (M+H)* m/z 493 (t = 1,56 min).6.22 (1H, d, J = 7.64 Hz), 4.89 (1H, m), 3.30-3.82 (1H, m), 2.97 (3H, s), 2 57 (3H, s). LCMS (M + H) + m / z 493 (t = 1.56 min).

Príklad 575Example 575

4-[2-(3-bróm-4-metoxyfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(4metylpiperazín-1-yl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:4- [2- (3-bromo-4-methoxyphenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] - 1 H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,61 (1H, d, J = 2,0 Hz), 7,32-7,37 (2H, m), 7,05 (2H, s), 6,97 (1H, d, J = 8,52 Hz), 6,24 (1H, d, J = 7,64 Hz), 4,82 (1H, m), 3,82 (3H, s), 3,30-3,64 (10H, m), 2,98 (3H, s), 2,56 (3H, s). LCMS (M+H)* m/z 567 (t = 1,53 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.61 (1H, d, J = 2.0 Hz), 7.32-7.37 (2H, m), 7.05 (2H, s), 6.97 (1H, d, J = 8.52Hz), 6.24 (1H, d, J = 7.64Hz), 4.82 (1H, m), 3.82 (3H, s), 3.30-3.64 (10H, m), 2.98 (3H, s), 2.56 (3H, s). LCMS (M + H) + m / z 567 (t = 1.53 min).

Zlúčeniny podľa príkladov 576-581 sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú acyláciu 4-aminopiperidínových derivátov.The compounds of Examples 576-581 were prepared according to the methods depicted in Schemes VII and III, and the examples shown show the acylation of 4-aminopiperidine derivatives.

Príklad 576 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 576-581)Example 576 (General Preparation of Compounds of Examples 576-581)

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(acetamido)piperidín-1-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine 2-one;

Roztok 4-aminopiperidínového derivátu (asi 50-100 pmol) v 5 ml MeOH sa ochladí na 0 °C. Potom sa pridá približne 10 ekvivalentov Huenigovej bázy a asi 3A solution of the 4-aminopiperidine derivative (about 50-100 pmol) in 5 mL of MeOH was cooled to 0 ° C. About 10 equivalents of Huenig base and about 3

222 ekvivalenty acylchloridu. Fľaštička sa pretrepe a nechá sa v pokoji 1 hodinu pri teplote miestnosti. Po odparení prchavých zložiek sa prečistením preparatívnou HPLC získa požadovaný 4-acylaminopiperidínový derivát. 1H NMR (500 MHz, CD3OD) δ 8,06 (1H, s), 7,68 (1H, s), 7,49 (1H, s), 7,44 (1H, d, J = 7,6), 7,27-7,38 (4H, m), 6,33 (1H, d, J = 7,6 Hz), 4,96 (1H, dd, J = 4,1, 7,6 Hz), 4,17 (1H, m), 3,87 (4H, m), 3,65 (1H, dd, J = 4,2, 14 Hz), 3,58 (1H, dd, J = 7,8, 13,8 Hz), 2,72 (3H, s), 2,31 (2H, m), 2,19 (2H, m), 2,02 (3H, s). LCMS (M+H)+ m/z 535 (t = 1,03 min, YMC Xterra C18 S7 3,0 x 50 mm; gradientová elúcia 0-100 % v priebehu 1,5 min; prietoková rýchlosť 5 ml/min).222 equivalents of acyl chloride. The vial was shaken and allowed to stand at room temperature for 1 hour. After evaporation of the volatiles, purification by preparative HPLC yields the desired 4-acylaminopiperidine derivative. 1 H NMR (500 MHz, CD 3 OD) δ 8.06 (1H, s), 7.68 (1H, s), 7.49 (1H, s), 7.44 (1H, d, J = 7) 6), 7.27-7.38 (4H, m), 6.33 (1H, d, J = 7.6Hz), 4.96 (1H, dd, J = 4.1, 7.6) Hz), 4.17 (1H, m), 3.87 (4H, m), 3.65 (1H, dd, J = 4.2, 14 Hz), 3.58 (1H, dd, J = 7) , 8, 13.8 Hz), 2.72 (3H, s), 2.31 (2H, m), 2.19 (2H, m), 2.02 (3H, s). LCMS (M + H) + m / z 535 (t = 1.03 min, YMC Xterra C18 S7 3.0 x 50 mm; gradient elution 0-100% over 1.5 min; flow rate 5 mL / min) .

Príklad 577Example 577

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyacetamido)piperidín1 -y l]-4-m ety I-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-ethyl-1H-benzoimidazol-2-yl} - 1 H-pyridin-2-one:

LCMS (M+Hf m/z 551 (t = 1,27 min). HPLC t = 5,01 min, Waters Xterra C18LCMS (M + H + m / z 551 (t = 1.27 min), HPLC t = 5.01 min, Waters Xterra C18

S5 4,6 x 30 mm; gradientová elúcia 0-100 % v priebehu 12 min; prietoková rýchlosť 5 ml/min.S5 4.6 x 30 mm; gradient elution 0-100% over 12 min; flow rate 5 ml / min.

Príklad 578Example 578

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóracetamido)piperidin-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyrid ίη-2-όη:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H -pyrid-2-όη:

223223

LCMS (M+H)+ m/z 597 (t = 1,31 min). HPLC t = 6,90 min, YMC-Pack ODS-A 3.0 x 50 mm; gradientová elúcia 0-100 % v priebehu 12 min; prietoková rýchlosť 2,5 ml/min.LCMS (M + H) &lt; + &gt; m / z 597 (t = 1.31 min). HPLC t = 6.90 min, YMC-Pack ODS-A 3.0x50mm; gradient elution 0-100% over 12 min; flow rate 2.5 ml / min.

Príklad 579Example 579

4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(acetamido)piperidín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (acetamido) -piperidin-1-yl] -4-methyl-1 H-benzoimidazol-2-yl} -1-pyridin-2-one;

LCMS (M+H)+ m/z 609 (t = 1,27 min). HPLC t = 5,00 min, Waters Xterra C18 S5 4,6 x 30 mm; gradientová elúcia 0-100 % v priebehu 12 min; prietoková rýchlosť 5 ml/min.LCMS (M + H) &lt; + &gt; m / z 609 (t = 1.27 min). HPLC t = 5.00 min, Waters Xterra C18 S5 4.6x30mm; gradient elution 0-100% over 12 min; flow rate 5 ml / min.

Príklad 580Example 580

4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyacetamido)piperidín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 H-pyridin-2-one:

LCMS (M+H)+ m/z 595 (t = 1,30 min). HPLC t = 5,09 min, Waters Xterra C18 S5 4,6 x 30 mm; gradientová elúcia 0-100 % v priebehu 12 min; prietoková rýchlosť 5 ml/min.LCMS (M + H) &lt; + &gt; m / z 595 (t = 1.30 min). HPLC t = 5.09 min, Waters Xterra C18 S5 4.6x30mm; gradient elution 0-100% over 12 min; flow rate 5 ml / min.

Príklad 581Example 581

224224

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóracetamido)piperid ín-1 yl]-4-mety I-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1 H-pyridin-2-one:

LCMS (M+H)+ m/z 553 (t = 1,35 min). HPLC t = 5,90 min, YMC-Pack ODS-A 3,0 x 50 mm; gradientová elúcia 0-100 % v priebehu 12 min; prietoková rýchlosť 2,5 ml/min.LCMS (M + H) &lt; + &gt; m / z 553 (t = 1.35 min). HPLC t = 5.90 min, YMC-Pack ODS-A 3.0x50mm; gradient elution 0-100% over 12 min; flow rate 2.5 ml / min.

Zlúčeniny podľa príkladov 582-584 sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú karbamoyláciu 4-aminopiperidínových derivátov.Examples 582-584 were prepared according to the methods depicted in Schemes VII and III, and the examples shown illustrate the carbamoylation of 4-aminopiperidine derivatives.

Všeobecný spôsob prípravy zlúčenín podľa príkladov 582-584General process for preparing the compounds of Examples 582-584

Roztok 4-aminopiperidinového derivátu (asi 50-100 pmol) v 5 ml MeOH sa ochladí na 0 °C. Potom sa pridá približne 10 ekvivalentov Huenigovej bázy a asi 3 ekvivalenty karbamoylchloridu. Fľaštička sa pretrepe a nechá sa v pokoji cez noc pri teplote miestnosti. Po odparení prchavých zložiek sa prečistením preparatívnou HPLC získa požadovaný 4-karbamoyl-derivát aminopiperidínu.A solution of the 4-aminopiperidine derivative (about 50-100 pmol) in 5 mL of MeOH was cooled to 0 ° C. About 10 equivalents of Huenig base and about 3 equivalents of carbamoyl chloride are then added. The vial is shaken and left to stand overnight at room temperature. After evaporation of the volatiles, purification by preparative HPLC affords the desired 4-carbamoyl derivative of aminopiperidine.

Príklad 582Example 582

-HCI-HCl

HOlh·Holhol ·

225225

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metoxyetoxykarbamoyl)piperidín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-metoxyetoxykarbamoyl) piperidin-1-yl] -4-methyl-1 H-benzoimidazol-2-yl} -1 pyridin-2-one;

1H NMR (500 MHz, CD3OD) č 7,90 (1H, s), 7,26-7,52 (6H, m), 6,29 (1H, d, J = 1 H NMR (500 MHz, CD 3 OD) δ 7.90 (1H, s), 7.26-7.52 (6H, m), 6.29 (1H, d, J =

7,5 Hz), 4,97 (1H, dd, J = 4,1, 7,0 Hz), 4,20 (2H, m), 3,93 (1H, m), 3,60-3,84 (8H, m),7.5 Hz), 4.97 (1H, dd, J = 4.1, 7.0 Hz), 4.20 (2H, m), 3.93 (1H, m), 3.60-3, 84 (8 H, m),

3,37 (3H, s), 2,69 (3H, s), 2,33 (2H, m), 2,13 (2H, m). LCMS (M+H)+ m/z 595 (t = 1,09 min, YMC Xterra C18 S7 3,0 x 50 mm; gradientová elúcia 0-100 % v priebehu 1,5 min; prietoková rýchlosť 5 ml/min).3.37 (3H, s), 2.69 (3H, s), 2.33 (2H, m), 2.13 (2H, m). LCMS (M + H) + m / z 595 (t = 1.09 min, YMC Xterra C18 S7 3.0 x 50 mm; gradient elution 0-100% over 1.5 min; flow rate 5 mL / min) .

Príklad 583Example 583

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-[4-(metoxykarbamoyl)piperidín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- [4- (methoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine 2-one;

1H NMR (500 MHz, CD3OD) δ 8,0 (1H, s), 7,63 (1H, s), 7,26-7,49 (5H, m), 6,32 (1H, d, J = 7,6 Hz), 4,96 (1H, dd, J = 4,2, 7,6 Hz), 3,93 (1H, m), 3,79-3,88 (4H, m), 3,67 (3H, s), 3,56-3,65 (2H, m), 2,71 (3H, s), 2,32 (2H, m), 2,17 (2H, m). LCMS (M+H)+ m/z 551 (t = 1,07 min, YMC Xterra C18 S7 3,0 x 50 mm; gradientová elúcia 0100 % v priebehu 1,5 min; prietoková rýchlosť 5 ml/min). 1 H NMR (500 MHz, CD 3 OD) δ 8.0 (1H, s), 7.63 (1H, s), 7.26-7.49 (5H, m), 6.32 (1H, d) J = 7.6 Hz), 4.96 (1H, dd, J = 4.2, 7.6 Hz), 3.93 (1H, m), 3.79-3.88 (4H, m) 3.67 (3H, s), 3.56-3.65 (2H, m), 2.71 (3H, s), 2.32 (2H, m), 2.17 (2H, m). LCMS (M + H) + m / z 551 (t = 1.07 min, YMC Xterra C18 S7 3.0 x 50 mm; gradient elution 0100% over 1.5 min; flow rate 5 mL / min).

Príklad 584Example 584

HCIHCl

226226

4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóretoxykarbamoyl)piperidín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 H-pyridin-2-one:

1H NMR (500 MHz, CD3OD) δ 7,92 (1H, s), 7,26-7,54 (6H, m), 6,3 (1H, d. J = 1 H NMR (500 MHz, CD 3 OD) δ 7.92 (1H, s), 7.26-7.54 (6H, m), 6.3 (1H, d, J =

7,5 Hz), 4,97 (1H, dd, J = 4,5, 7,5 Hz), 4,63 (1H, široký s), 4,53 (1H, d, J = 2,5 Hz),7.5 Hz), 4.97 (1H, dd, J = 4.5, 7.5 Hz), 4.63 (1H, broad s), 4.53 (1H, d, J = 2.5 Hz) )

4,32 (1H, široký s), 4,27 (1H, široký s), 3,93 (1H, m), 3,79-3,85 (4H, m), 3,58-3,72 (2H, m), 2,70 (3H, s), 2,33 (2H, m), 2,15 (2H, m). LCMS (M+H)+ m/z 583 (t = 1,29 min, YMC Xterra C18 S7 3,0 x 50 mm; gradientová elúcia 0-100 % v priebehu 2 min; prietoková rýchlosť 5 ml/min).4.32 (1H, broad s), 4.27 (1H, broad s), 3.93 (1H, m), 3.79-3.85 (4H, m), 3.58-3.72 ( 2H, m), 2.70 (3H, s), 2.33 (2H, m), 2.15 (2H, m). LCMS (M + H) + m / z 583 (t = 1.29 min, YMC Xterra C18 S7 3.0 x 50 mm; gradient elution 0-100% over 2 min; flow rate 5 mL / min).

Zlúčeniny podľa nižšie uvedených príkladov 585-590 sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú použitie alkoholu ako nukleofilného prostriedku podľa schémy VIIThe compounds of Examples 585-590 below were prepared by the methods depicted in Schemes VII and III, and the examples illustrate the use of an alcohol as a nucleophilic agent according to Scheme VII

Príklad 585 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 585-590) (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín-4-yletoxy)1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:Example 585 (General Preparation of Examples 585-590) (S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) ) 1H-benzoimidazol-2-yl] -1H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,53 (1H, s), 7,37-7,39 (1H, m), 7,23-7,30 (3H, m), 7,01 (1H, s), 6,75 (1H, s), 6,21 (1H, d, J = 7,2 Hz), 4,98 (1H, t, J = 5,6 Hz), 4,40 (2H, br s), 3,97 (4H, br s), 3,45-3,73 (8H, m), 2,54 (3H, s). LCMS (M+H)+ m/z 524 (t = 1 H NMR (400 MHz, CD 3 OD) δ 7.53 (1H, s), 7.37-7.39 (1H, m), 7.23-7.30 (3H, m), 7.01 (1H, s), 6.75 (1H, s), 6.21 (1H, d, J = 7.2Hz), 4.98 (1H, t, J = 5.6Hz), 4.40 (2H, br s), 3.97 (4H, br s), 3.45-3.73 (8H, m), 2.54 (3H, s). LCMS (M + H) &lt; + &gt; m / z 524 (t =

1,24 min).1.24 min).

Príklad 586Example 586

227227

(S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín4-yletoxy)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzoimidazol-2-yl] -1 H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,67 (1H, úzky d, J = 1,6 Hz), 7,36 (1H, dd, J = 1 H NMR (400 MHz, CD 3 OD) δ 7.67 (1H, narrow d, J = 1.6 Hz), 7.36 (1H, dd, J =

1,6, 8,4 Hz), 7,25 (1H, d, J = 7,2 Hz), 6,98 (1H, s), 6,92 (1H, d, J = 8,4 Hz), 6,75 (1H, s), 6,22 (1H, d, J = 7,2 Hz), 4,89-4,92 (1H, m), 4,41 (2H, br s), 3,97 (4H, br s), 3,79 (3H, s), 3,34-3,66 (8H, m), 2,51 (3H, s). LCMS (M+H)+ m/z 598 (t =1,22 min).1.6, 8.4 Hz), 7.25 (1H, d, J = 7.2 Hz), 6.98 (1H, s), 6.92 (1H, d, J = 8.4 Hz) 6.75 (1H, s), 6.22 (1H, d, J = 7.2 Hz), 4.89-4.92 (1H, m), 4.41 (2H, br s), 3 97 (4H, br s), 3.79 (3H, s), 3.34-3.66 (8H, m), 2.51 (3H, s). LCMS (M + H) &lt; + &gt; m / z 598 (t = 1.22 min).

Príklad 587Example 587

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-metoxyetoxy)-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-methoxyethoxy) -1Hbenzoimidazol-2-yl] -1-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 7,48 (1H, s), 7,25-7,36 (4H, m), 6,96 (1H, s), 1 H NMR (400 MHz, CD 3 OD) δ 7.48 (1H, s), 7.25-7.36 (4H, m), 6.96 (1H, s),

6,81 (1H, s), 6,20 (1H, d, J = 7,4 Hz), 4,90-4,93 (1H, m), 4,13-4,14 (2H, m), 3,76-3,77 (2H, m), 3,50-3,61 (2H, m), 3,43 (3H, s), 2,53 (3H, s). LCMS (M+H)+ m/z 469 (t = 1,52 min).6.81 (1H, s), 6.20 (1H, d, J = 7.4Hz), 4.90-4.93 (1H, m), 4.13-4.14 (2H, m) 3.76-3.77 (2H, m), 3.50-3.61 (2H, m), 3.43 (3H, s), 2.53 (3H, s). LCMS (M + H) &lt; + &gt; m / z 469 (t = 1.52 min).

Príklad 588Example 588

228228

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-hydroxyetoxy)-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-hydroxyethoxy) -1Hbenzoimidazol-2-yl] -1-pyridin-2-one;

’H NMR (400 MHz, CD3OD) δ 7,43-7,45 (2H, m), 7,27-7,34 (3H, m), 7,08 (1H, s), 7,04 (1H, úzky d, J = 1,0 Hz), 6,28 (1H, d, J = 7,6 Hz), 4,87 (1H, m), 4,13 (2H, t, J = 4,6 Hz), 3,92 (2H, t, J = 4,6 Hz), 3,45-3,54 (2H, m), 2,60 (3H, s). LCMS (M+H)+ m/z 455 (t = 1,35 min).1 H NMR (400 MHz, CD 3 OD) δ 7.43-7.45 (2H, m), 7.27-7.34 (3H, m), 7.08 (1H, s), 7.04 (1H, narrow d, J = 1.0Hz), 6.28 (1H, d, J = 7.6Hz), 4.87 (1H, m), 4.13 (2H, t, J = 4) 6 Hz), 3.92 (2H, t, J = 4.6 Hz), 3.45-3.54 (2H, m), 2.60 (3H, s). LCMS (M + H) &lt; + &gt; m / z 455 (t = 1.35 min).

Príklad 589Example 589

(S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(3-morfolin4-ylpropoxy)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (3-morpholin-4-ylpropoxy) -1H-benzoimidazol-2-yl] -1 H-pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 7,66 (1 H, s), 7,35 (1H, dd, J = 1,6, 7,9 Hz), 7,25 (1H, br s), 6,93 (1H, s), 6,91 (1H, s), 6,68 (1H, s), 6,19 (1H, br s), 4,86 (1H, m), 4,054,10 (4H, br s), 3,79 (3H, s), 3,17-3,73 (12H, m), 2,50 (3H, s). LCMS (M+H)+ m/z 612 (t = 1.16 min). 1 H NMR (400 MHz, CD 3 OD) δ 7.66 (1H, s), 7.35 (1H, dd, J = 1.6, 7.9 Hz), 7.25 (1H, br s ), 6.93 (1H, s), 6.91 (1H, s), 6.68 (1H, s), 6.19 (1H, br s), 4.86 (1H, m), 4.054, 10 (4H, br s), 3.79 (3H, s), 3.17-3.73 (12H, m), 2.50 (3H, s). LCMS (M + H) &lt; + &gt; m / z 612 (t = 1.16 min).

Príklad 590Example 590

229229

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6~(3-morfolín-4ylpropoxy)-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (3-morpholin-4ylpropoxy) -1 H-benzimidazol-2-yl] -1 H-pyridine 2-one:

1H NMR (400 MHz, CD3OD) δ 7,36-7,38 (1H, m), 7,23-7,30 (3H, m), 6,92 (1H, s), 6,67 (1H, s), 6,18 (1H, d, J = 6,9 Hz), 4,96 (1H, t, J = 5,9 Hz), 4,04-4,08 (4H, m), 1 H NMR (400 MHz, CD 3 OD) δ 7.36-7.38 (1H, m), 7.23-7.30 (3H, m), 6.92 (1H, s), 6.67 (1H, s), 6.18 (1H, d, J = 6.9Hz), 4.96 (1H, t, J = 5.9Hz), 4.04-4.08 (4H, m) .

3,82 (2H, m), 3,56-3,65 (8H, m), 3,15-3,18 (2H, m), 2,52 (3H, s). LCMS (M+H)+ m/z 538 (t= 1,19 min).3.82 (2H, m), 3.56-3.65 (8H, m), 3.15-3.18 (2H, m), 2.52 (3H, s). LCMS (M + H) &lt; + &gt; m / z 538 (t = 1.19 min).

Zlúčeniny podľa nižšie uvedených príkladov sa pripravia spôsobmi opísanými v schémach VII a III, kde kyanová skupina (schéma IV) sa prevedie na aldehyd, ktorý sa podrobí reduktívnej aminácii s amínom.The compounds of the examples below are prepared by the methods described in Schemes VII and III, wherein the cyano group (Scheme IV) is converted to an aldehyde which is subjected to reductive amination with an amine.

Príklad 591 (Všeobecný spôsob prípravy zlúčenín podľa príkladov 591-593)Example 591 (General Preparation of Examples 591-593)

(S)-3-(4-bróm-6-morfolín-4-ylmetyl-1H-benzoimidazol-2-yl)-4-[2-(3-chlórfenyl)2-hydroxyetylamino]-1H-pyridín-2-ón:(S) -3- (4-bromo-6-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) 2-hydroxy-ethylamino] -1 H-pyridin-2-one :

K roztoku (S)-7-bróm-2-{4-[2-(3-chlórfenyl)-2-ľiydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3H-benzoimidazol-5-karbaldehydu (130 mg, 0,27 mmol) v metanole (60 ml) sa pridá morfolín (0,2 ml, v nadbytku). Reakčná zmes sa mieša 1 hTo a solution of (S) -7-bromo-2- {4- [2- (3-chlorophenyl) -2-yl-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -3H-benzoimidazole-5-carbaldehyde ( 130 mg, 0.27 mmol) in methanol (60 mL) was added morpholine (0.2 mL, in excess). The reaction mixture was stirred for 1 h

230 pri teplote miestnosti. Potom sa pridá NaCNBH3 (roztok 1 mol/l v THF, 1,35 ml, 1,35 mmol). Reakčná zmes sa potom mieša cez noc pri teplote miestnosti a zahustí sa za zníženého tlaku. Prečistením zvyšku preparatívnou HPLC sa získa titulná zlúčenina (68 mg. 45 %). 1H NMR (400 MHz, CD3OD) δ 7,83 (1H, s), 7,69 (1H, s), 7,68 (1H, s), 7,24-7,54 (4H, m), 6,30 (1H, d, J = 7,6 Hz), 4,89-5,02 (1H, m), 4,50 (2H, s), 3,66-3,71 (4H, m). 3,17-3,43 (6H, m). LCMS (M+H)+ m/z 558 (t = 1,41 min).230 at room temperature. Then NaCNBH 3 (1M solution in THF, 1.35 mL, 1.35 mmol) was added. The reaction mixture was then stirred overnight at room temperature and concentrated under reduced pressure. Purification of the residue by preparative HPLC afforded the title compound (68 mg, 45%). 1 H NMR (400 MHz, CD 3 OD) δ 7.83 (1H, s), 7.69 (1H, s), 7.68 (1H, s), 7.24-7.54 (4H, m) 6.30 (1H, d, J = 7.6Hz), 4.89-5.02 (1H, m), 4.50 (2H, s), 3.66-3.71 (4H, m). 3.17-3.43 (6 H, m). LCMS (M + H) &lt; + &gt; m / z 558 (t = 1.41 min).

Príklad 592Example 592

(S)-3-[4-bróm-6-(4-metylpiperazín-1-ylmetyl)-1H-benzoimidazol-2-yl]-4-[2-(3chlórfenyl-2-hydroxyetylamino]-1H-pyridín-2-ón:(S) -3- [4-bromo-6- (4-methylpiperazin-1-ylmethyl) -1 H-benzimidazol-2-yl] -4- [2- (3-Chloro-2-hydroxy-ethylamino] -1 H -pyridin-2 -one

Ή NMR (400 MHz, CD3OD) δ 7,70 (1H, s), 7,55 (2H, s), 7,42 (1H, d, J = 7,6 Hz), 7,24-7,32 (3H, m), 6,22 (1H, d, J = 7,6 Hz), 5,01 (1H, t, J = 6,2 Hz), 4,35 (2H, br s), 3,48-3,71 (10H, m), 2,98 (3H, s). LCMS (M+H)+ m/z 571 (t = 1,37 min).Ή NMR (400 MHz, CD 3 OD) δ 7.70 (1H, s), 7.55 (2H, s), 7.42 (1H, d, J = 7.6 Hz), 7.24-7 32 (3H, m), 6.22 (1H, d, J = 7.6Hz), 5.01 (1H, t, J = 6.2Hz), 4.35 (2H, br s), 3.48-3.71 (10H, m); 2.98 (3H, s). LCMS (M + H) &lt; + &gt; m / z 571 (t = 1.37 min).

Príklad 593Example 593

(S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(4-metylpiperazín-1ylmetyl)-1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón:(S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-ylmethyl) -1H-benzoimidazol-2-yl] -1H- pyridin-2-one;

Zmes obsahujúca (S)-3-[4-bróm-6-(4-metylpiperazin-1-ylmetyl)-1 Hbenzoimidazol-2-yl]-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón (80 mg,(S) -3- [4-Bromo-6- (4-methylpiperazin-1-ylmethyl) -1-benzoimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1 H-pyridin-2-one (80 mg,

231231

0,14 mmol), tetrametylcín (2,5 ml, nadbytok), PdCl2(PPh3)4 (10 mg, 0,014 mmol) a KF (40 mg, 0,7 mmol) v DMF (2 ml) sa vo fľaštičke prebublá dusíkom, potom sa fľaštička uzavrie a zahrieva sa dva dni pri 100 °C. Potom sa reakčná zmes nechá prejsť vrstvičkou celitu. Po zahustení, prečistením zvyšku preparativnou HPLC sa získa titulná zlúčenina (34 mg, 48 %). 1H NMR (400 MHz, CD3OD) δ 7,53 (1H, s), 7,45 (1H, s), 7,24-7,40 (4H, m), 7,09 (1H, s), 6,22 (1H, d, J = 7,6 Hz), 4,99 (1H, t, J = 6,4 Hz), 4,04 (2H, br s), 3,61-3,74 (2H, m), 2,98-3,34 (8H, m), 2,80 (3H, s), 2,58 (3H, s). LCMS (M+Hf m/z 507 (t = 1,29 min).0.14 mmol), tetramethyltin (2.5 mL, excess), PdCl 2 (PPh 3) 4 (10 mg, 0.014 mmol) and KF (40 mg, 0.7 mmol) in DMF (2 mL) were purged with nitrogen in a vial , then the vial is capped and heated at 100 ° C for two days. The reaction mixture was then passed through a pad of celite. After concentration, purification of the residue by preparative HPLC gave the title compound (34 mg, 48%). 1 H NMR (400 MHz, CD 3 OD) δ 7.53 (1H, s), 7.45 (1H, s), 7.24-7.40 (4H, m), 7.09 (1H, s) 6.22 (1H, d, J = 7.6Hz), 4.99 (1H, t, J = 6.4Hz), 4.04 (2H, br s), 3.61-3, 74 (2H, m), 2.98-3.34 (8H, m), 2.80 (3H, s), 2.58 (3H, s). LCMS (M + H + m / z 507 (t = 1.29 min).

Zlúčeniny podľa nižšie uvedených príkladov 594-595 sa pripravia spôsobmi znázornenými v schémach VII a III a uvedené príklady znázorňujú použitie tetrahydropyrimidínového nukleofilného prostriedku podľa schémy VIIThe compounds of Examples 594-595 below were prepared by the methods shown in Schemes VII and III, and the examples illustrate the use of the tetrahydropyrimidine nucleophilic composition of Scheme VII

Príklad 594Example 594

4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(1,4,5,6tetrahydropyrimidin-1 -yl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón:4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H-benzoimidazol-2-yl] -1 H-Pyridin-2-one:

1H NMR (400 MHz, CD3OD) δ 8,38 (1H, s), 7,52 (1H, s), 7,21-7,41 (5H, m), 7,04 (1H, d, J = 1,2 Hz), 6,21 (1H, d, J = 7,6 Hz), 4,97 (1H, t, J = 4,9 Hz), 3,97 (2H, m), 3,60-3,73 (2H, m), 3,52 (2H, t, J = 5,74 Hz), 2,60 (3H, s), 2,25 (2H, m). LCMS (M+H)+ m/z 477 (t = 1,79 min). 1 H NMR (400 MHz, CD 3 OD) δ 8.38 (1H, s), 7.52 (1H, s), 7.21-7.41 (5H, m), 7.04 (1H, d) J = 1.2 Hz), 6.21 (1H, d, J = 7.6 Hz), 4.97 (1H, t, J = 4.9 Hz), 3.97 (2H, m), 3.60-3.73 (2H, m), 3.52 (2H, t, J = 5.74 Hz), 2.60 (3H, s), 2.25 (2H, m). LCMS (M + H) &lt; + &gt; m / z 477 (t = 1.79 min).

Príklad 595Example 595

o—about-

232232

4-[2-(4-metoxy-3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(1,4,5,6tetrahydropyrimidín-1-yl)-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón:4- [2- (4-methoxy-3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- (1,4,5,6-1-yl) -1H-benzoimidazol 2-yl] -1-pyridin-2-one;

1H NMR (400 MHz, CD3OD) δ 8,37 (1H, s), 7,52 (1H, s), 7,04-7,52 (5H, m), 7,04 (1H, d, J = 1,2 Hz), 6,21 (1H, d, J = 7,6 Hz), 4,98 (1H, t, J = 4,92 Hz), 3,97 (5H, m), 3,60-3,73 (2H, m), 3,52 (2H, t, J = 5,74 Hz), 2,60 (3H, s), 2,26 (2H, m). LCMS (M+H)+ m/z 507 (t = 1,67 min). 1 H NMR (400 MHz, CD 3 OD) δ 8.37 (1H, s), 7.52 (1H, s), 7.04-7.52 (5H, m), 7.04 (1H, d) J = 1.2 Hz), 6.21 (1H, d, J = 7.6 Hz), 4.98 (1H, t, J = 4.92 Hz), 3.97 (5H, m), 3.60-3.73 (2H, m), 3.52 (2H, t, J = 5.74 Hz), 2.60 (3H, s), 2.26 (2H, m). LCMS (M + H) &lt; + &gt; m / z 507 (t = 1.67 min).

Je potrebné si uvedomiť, že príklady opísané vyššie sú uvedené len na znázornenie vynálezu a rozsah vynálezu nijako neobmedzujú. Všetky citácie uvedené v tomto opise sú do vyššie uvedeného textu plne včlenené odkazom.It is to be understood that the examples described above are given only to illustrate the invention and do not limit the scope of the invention in any way. All references cited herein are incorporated by reference in their entirety.

Claims (57)

1. Zlúčenina všeobecného vzorca (I):1. A compound of formula (I): a jej enantioméry, diastereoméry, farmaceutický prijateľné soli, hydráty, proliečivá a solváty;and enantiomers, diastereomers, pharmaceutically acceptable salts, hydrates, prodrugs, and solvates thereof; kdewhere X znamená skupinu zvolenú zo skupiny zahrňujúcej N, C, Ci-C3alkyl, CiC3alkyl substituovaný jedným alebo viacerými substituentami R7 a priamu väzbu;X represents a group selected from the group consisting of N, C, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted with one or more substituents R 7 and a direct bond; Y znamená O alebo S;Y is O or S; W má význam zvolený zo skupiny zahrňujúcej N, C, O a S s tou výhradou, že keď W znamená O alebo S, R9 nemá žiadny význam;W has the meaning selected from the group consisting of N, C, O and S, provided that when W is O or S, R 9 has no meaning; R1, R2, R3, R4, R5, R6, R7, R8, R9 každý nezávisle znamená skupinu nezávisle zvolenú zo skupiny zahrňujúcej H, Ci-Csalkyl, alkenyl, alkinyl, cykloalkyl, heterocykloalkyl, halogén, amino, OR50, NO2, OH, SR50, NR50R61, CN, CO2R60, CONRS0R61, OCONRsoR61, NR62CONRsoR61, NRsoS02R61, S02NRsoR61, C(NR62)NR60R61, aryl, heteroaryl, (CH2)nOR60 (CH2)nNR60R61, (CH2)nSR60, (CH2)naryl, (CH2)nheteroaryl, (CH2)nheterocykloalkyl, NH-Z-aryl a NH-Z-heteroaryl;R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 each independently represent a group independently selected from H, C 1 -C 8 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogen , amino, OR 50 , NO 2, OH, SR 50 , NR 50 R 61 , CN, CO 2 R 60 , CONR S 0 R 61 , OCONR with R 61 , NR 62 CONR with R 61 , NR with SO 2 R 61 , SO 2 NR with R 61 , C (NR 62) NR 60 R 61, aryl, heteroaryl, (CH 2) n OR 60 (CH 2) n NR 60 R 61, (CH 2) n SR 60, (CH 2) n -aryl, (CH 2) n -heteroaryl, (CH 2 n- heterocycloalkyl, NH-Z-aryl and NH-Z-heteroaryl; kde n znamená 1 až 3; awherein n is 1 to 3; and Z znamená skupinu zvolenú zo skupiny zahrňujúcej Ci-C4alkyl, alkenyl a alkinyl; Z skupinu obsahujúcu jednu alebo viacej skupín zvolených zo skupiny Z is selected from the group consisting of Cl-C4 alkyl, alkenyl, and alkynyl; Z is a group comprising one or more groups selected from the group 234 zahrňujúcej hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, NR60SO2R61; Z skupinu s prípadne včlenenou jednou alebo viac skupinou zvolenou zo skupiny zahrňujúcej CO, CNOH, CNOR60, CNNR60, CNNCOR50 a CNNSO2R6°;234 including hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, NR 60 SO 2 R 61 ; Z optionally incorporating one or more selected from CO, CNOH, CNOR 60 , CNNR 60 , CNNCOR 50, and CNNSO 2 R 6 °; R60 a R61 každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej H, alkyl, alkenyl, alkinyl, cykloalkyl, cykloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl a alkyl-R25, kdeR 60 and R 61 each independently represent a group selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, heteroaryl, heteroarylalkyl and alkyl-R 25 , wherein: R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, kyano, halogén, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; aR 25 represents a group selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, aryl, heteroaryl, cyano, halogen, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O ) R 31, -NR 30 SO 2 R 31, -C (O) NR 30 R 31, heteroaryl or heterocycloalkyl; and R a R každý nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R and R each independently represent a group selected from hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 2. Zlúčenina podľa nároku 1, kdeThe compound of claim 1, wherein R1, R7, R8 a R9 znamená H;R 1 , R 7 , R 8 and R 9 are H; R2 a R4 znamená H alebo F;R 2 and R 4 is H or F; Y znamená O;Y is O; X znamená skupinu zvolenú zo skupiny zahrňujúcej N a CH;X represents a group selected from the group consisting of N and CH; W znamená N;W is N; R5 znamená skupinu zvolenú zo skupiny zahrňujúcej H, metyl, etyl, izopropyl, sek-butyl, cyklopropyl, F a CF3;R 5 represents a group selected from H, methyl, ethyl, isopropyl, sec-butyl, cyclopropyl, F and CF 3 ; R6 sa zvolí zo skupiny zahrňujúcej H, 2-aminometylpyridín, NHCH2CH(OH)Ph,R 6 is selected from the group consisting of H, 2-aminomethylpyridine, NHCH 2 CH (OH) Ph, NHCH2CH(OH)(3-CI-Ph), NHCH2CH(OH)(3-Br-Ph), NHCH2CH(OH)(3-Br-4-OMe-Ph),NHCH 2 CH (OH) (3-Cl-Ph), NHCH 2 CH (OH) (3-Br-Ph), NHCH 2 CH (OH) (3-Br-4-OMe-Ph), NHCH(CH2OH)CH2Ph, NHCH2CH(OH)aryl a NHCH(CH2OH)CH2aryl; aNHCH (CH 2 OH) CH 2 Ph, NHCH 2 CH (OH) aryl and NHCH (CH 2 OH) CH 2 aryl; and 235235 R3 sa zvolí zo skupiny zahrňujúcej OR60, C(NH)NHR60, C(O)NHR60, imidazol, imidazolín, tetrahydropyrimidín, piperazín, morfolín, homomorfolín, piperidín, pyrolidín, homopiperazín a amino; kdeR 3 is selected from the group consisting of OR 60 , C (NH) NHR 60 , C (O) NHR 60 , imidazole, imidazoline, tetrahydropyrimidine, piperazine, morpholine, homomorpholine, piperidine, pyrrolidine, homopiperazine and amino; where R znamená skupinu zvolenú zo skupiny zahrňujúcej H, alkyl, cykloalkyl, heterocykloalkyl, a alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, tioalkoxy, alkoxy, tioalkoxy, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, alebo heteroaryl alebo heterocykloalkyl; a každý zR represents a group selected from H, alkyl, cycloalkyl, heterocycloalkyl, and alkyl-R 25 , wherein R 25 represents a group selected from hydrogen, alkenyl, hydroxy, thiol, thioalkoxy, alkoxy, thioalkoxy, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , or heteroaryl or heterocycloalkyl; and each of them R a R nezávisle od seba znamena skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R and R independently of one another are selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 3. Zlúčenina podľa nároku 2, kde R3 znamená -OR60 a Rso znamená skupinu zvolenú zo skupiny zahrňujúcej alkyl alebo -alkyl-R , kde R znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a každý z3. The compound of claim 2, wherein R 3 is -OR 60 and R a is selected from alkyl or alkyl-R, wherein R is selected from hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and each of them R30 a R31 nezávisle od seba znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 independently of one another are selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 4. Zlúčenina podľa nároku 3, kde R60 znamená skupinu zvolenú zo skupiny zahrňujúcej metyl, -(CH2)nCH2OH alebo -(CH2)nCH2N(CH2CH2)2O, a n znamená 0, 1 alebo 2.4. The compound of claim 3, wherein R 60 is selected from methyl, - (CH 2) n CH 2 OH or - (CH 2) n CH 2 N (CH 2 CH 2) 2 O, n is 0, 1 or 2 . 5. Zlúčenina podľa nároku 3, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej morfolín,A compound according to claim 3, wherein R 25 represents a group selected from the group consisting of morpholine, O oO o 236 kde R33 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo substituovaný alkyl.236 wherein R 33 represents a group selected from the group consisting of hydrogen, alkyl or substituted alkyl. 6. Zlúčenina podľa nároku 2, kde R3 sa zvolí zo skupiny zahrňujúcej piperazin, homopiperazín, 3-metylpiperazín alebo 3,5-dimetylpiperazín prípadne substituovaný v polohe 4-N skupinou zvolenou zo skupiny zahrňujúcej alkyl, cykloalkyl, cykloalkylalkyl, alkyl-R25, -C(O)-R15, alebo -CO2R15, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl, alkyl-R25, amino alebo aryl; aA compound according to claim 2 wherein R 3 is selected from the group consisting of piperazine, homopiperazine, 3-methylpiperazine or 3,5-dimethylpiperazine optionally substituted in the 4-N position with a group selected from alkyl, cycloalkyl, cycloalkylalkyl, alkyl-R 25 , -C (O) -R 15 , or -CO 2 R 15 , wherein R 15 represents a group selected from the group consisting of hydrogen, alkyl, aryl, alkyl-R 25 , amino or aryl; and R25 znamená skupinu zvolenú zo skupiny zahrnujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, alkylamino, dialkylamino, kyano, halogén, sulfoxy, sulfonyl, arylsulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a každý zR 25 is selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, cyano, halogen, sulfoxy, sulfonyl, arylsulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and each of them R30 a R31 nezávisle od seba znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 independently of one another are selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 7. Zlúčenina podľa nároku 6, kde uvedený piperazin je substituovaný skupinou zvolenou zo skupiny zahrňujúcej metyl, etyl, CH2-cyklopropyl, hydroxyetyl, 2dimetylaminoetyl, 2-dietylaminoetyl, 2-aminoetyl, 2-metylaminoetyl, 2-etylaminoetyl, metoxyetyl, etoxyetyl, morfolin a morfolinyletyl.The compound of claim 6, wherein said piperazine is substituted with a group selected from methyl, ethyl, CH 2 -cyclopropyl, hydroxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-aminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl, methoxyethyl, ethoxyethyl, morpholine and morpholinylethyl. 8. Zlúčenina podľa nároku 2, kde R3 znamená aminoskupinu zvolenú zo skupiny zahrňujúcej hydroxyalkylamino, aminoalkylamino, dialkylaminoalkylamino a heterocykloalkylamino.A compound according to claim 2 wherein R 3 is an amino group selected from the group consisting of hydroxyalkylamino, aminoalkylamino, dialkylaminoalkylamino and heterocycloalkylamino. 9. Zlúčenina podľa nároku 8, kde uvedená aminoskupina znamená skupinu zvolenú zo skupiny zahrňujúcej NHCH2CH2OH, NMeCH2CH2OH, NEtCH2CH2OH, NHCH2CH2NH2, NMeCH2CH2NH2, NEtCH2CH2NH2, NHCH2CH2NMe2, NMeCH2CH2NMe2, NEtCH2CH2NMe2, NHCH2CH2NEt2, NMeCH2CH2NEt2, NEtCH2CH2NEt2, NHCH2CH2N(CH2CH2)2O, NMeCH2CH2N(CH2CH2)2O,The compound of claim 8, wherein said amino group is selected from the group consisting of NHCH 2 CH 2 OH, NMeCH 2 CH 2 OH, NEtCH 2 CH 2 OH, NHCH 2 CH 2 NH 2 , NMeCH 2 CH 2 NH 2 , NEtCH 2 CH 2 NH 2 , NHCH 2 CH 2 NMe 2 , NMeCH 2 CH 2 NMe 2 , NEtCH 2 CH 2 NMe 2 , NHCH 2 CH 2 NEt 2 , NMeCH 2 CH 2 NEt 2 , NEtCH 2 CH 2 NEt 2 , NHCH 2 CH 2 N (CH 2 CH 2 ) 2 O, NMeCH 2 CH 2 N (CH 2 CH 2 ) 2 O, NEtCH2CH2N(CH2CH2)2O.NEtCH 2 CH 2 N (CH 2 CH 2 ) 2 O. 10. Zlúčenina podľa nároku 2, kde R3 znamená piperidín prípadne substituovanýThe compound of claim 2, wherein R 3 is piperidine optionally substituted 237 skupinou zvolenou zo skupiny zahrňujúcej hydroxy, tiol, amino, alkylamino, dialkylamino, alkoxy, tioalkoxy, 1,3-dioxolán, 1,3-dioxán, -NHC(O)R15, -NHCO2R15 kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo ne TC alkyl-R , kde R znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR3CCOOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a každý z237 a group selected from the group consisting of hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, 1,3-dioxolane, 1,3-dioxane, -NHC (O) R 15 , -NHCO 2 R 15 wherein R 15 represents a group selected from the group consisting of hydrogen, alkyl, aryl or not TC alkyl-R, wherein R is selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 3C COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and each of them R30 a R31 nezávisle od seba znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 independently of one another are selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 11. Zlúčenina podľa nároku 2, kde R3 znamená morfolín, tiomorfolin, sulfoxymorfolín, sulfonylmorfolín alebo homomorfolín alebo substituovaný morfolín, tiomorfolin, sulfoxymorfolín, sulfonylmorfolín alebo homomorfolín.The compound of claim 2, wherein R 3 is morpholine, thiomorpholine, sulfoxymorpholine, sulfonylmorpholine or homomorpholine or substituted morpholine, thiomorpholine, sulfoxymorpholine, sulfonylmorpholine or homomorpholine. 12. Zlúčenina podľa nároku 11, kde uvedený morfolín, tiomorfolin, sulfoxymorfolín, sulfonylmorfolín alebo homomorfolín je substituovaný skupinou zvolenou zo skupiny zahrňujúcej hydroxy, tiol, amino, alkylamino, dialkylamino, alkoxy, tioalkoxy, alkyl-R25, -NHC(O)R15, NHCO2R15, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo alkyl-R25, kde R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkenyl, hydroxy, tiol, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl; a každý zThe compound of claim 11, wherein said morpholine, thiomorpholine, sulfoxymorpholine, sulfonylmorpholine or homomorpholine is substituted with a group selected from hydroxy, thiol, amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, alkyl-R 25 , -NHC (O) R 15 , NHCO 2 R 15 , wherein R 15 is selected from the group consisting of hydrogen, alkyl, aryl or alkyl-R 25 , wherein R 25 is selected from the group consisting of hydrogen, alkenyl, hydroxy, thiol, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; and each of them R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 13. Zlúčenina podľa nároku 2, kde R3 znamená (CH2)n-morfolín alebo (CH2)npiperazín, kde n znamená 1 až 3.The compound of claim 2 wherein R 3 is (CH 2 ) n -morpholine or (CH 2 ) n piperazine wherein n is 1 to 3. 14. Zlúčenina podľa nároku 2, kde R3 znamená prípadne substituovaný Ntetrahydropyrimidín alebo N-imidazolín.The compound of claim 2, wherein R 3 is optionally substituted N-tetrahydropyrimidine or N-imidazoline. 15. Zlúčenina podľa nároku 14, kde najmenej jedna z uvedených substitučnýchThe compound of claim 14, wherein at least one of said substitution 238 skupín je zo skupiny zahrňujúcej alkyl, hydroxyalkyl, alkoxyalkyl, halogénalkyl, kyanoalkyl, karboxylovú skupinu alebo karboxamid.238 groups are selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cyanoalkyl, carboxyl, or carboxamide. 16. Zlúčenina podľa nároku 2, kde R3 je pyrolidin.The compound of claim 2, wherein R 3 is pyrrolidine. 17. Zlúčenina podľa nároku 2, kde uvedený pyrolidin je zvolený zo skupiny zahrňujúcej 3-hydroxypyrolidín, 3-alkoxypyrolidín a 3-alkylaminopyrolidín a 3dialkylaminopyrolidín.The compound of claim 2, wherein said pyrrolidine is selected from the group consisting of 3-hydroxypyrrolidine, 3-alkoxypyrrolidine, and 3-alkylaminopyrrolidine, and 3-dialkylaminopyrrolidine. 18. Zlúčenina podľa nároku 2, kde R6 znamená skupinu zvolenú zo skupiny zahrňujúcej H, 2-aminometylpyridín, NHCH2CH(OH)aryl a NHCH(CH2OH)CH2aryl.The compound of claim 2, wherein R 6 is selected from the group consisting of H, 2-aminomethylpyridine, NHCH 2 CH (OH) aryl and NHCH (CH 2 OH) CH 2 aryl. 19. Zlúčenina podľa nároku 18, kde uvedená arylová skupina je prípadne substituovaná fenylová skupina.The compound of claim 18, wherein said aryl group is an optionally substituted phenyl group. 20. Zlúčenina podľa nároku 19, kde uvedená fenylová skupina je substituovaná skupinou zvolenou zo skupiny zahrňujúcej Br, Cl, F, alkoxy alebo -NHSO2CH3.The compound of claim 19, wherein said phenyl group is substituted with a group selected from the group consisting of Br, Cl, F, alkoxy or -NHSO 2 CH 3 . 21. Zlúčenina podľa nároku 19, kde uvedená substitučná skupina je 3-Br, 3-CI aleboThe compound of claim 19, wherein said substituent group is 3-Br, 3-Cl or 3-F.3-F. 22. Zlúčenina podľa nároku 19, kde uvedená substitučná skupina je 4-F alebo 4m etoxy.The compound of claim 19, wherein said substituent group is 4-F or 4m ethoxy. 23. Zlúčenina podľa nároku 19, kde R6 znamená aleboThe compound of claim 19, wherein R 6 is or 239 kde R17 znamená skupinu zvolenú zo skupiny zahrňujúcej H, Br, Cl alebo F a R40 znamená H alebo alkylovú skupinu.239 wherein R 17 is H, Br, Cl or F and R 40 is H or alkyl. 24. Zlúčenina všeobecného vzorca kde R12 a R13 vzájomne nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25, kdeA compound of the formula wherein R 12 and R 13 independently of each other represent a group selected from hydrogen, alkyl or alkyl-R 25 , wherein: R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, amino, alkoxy, tioalkoxy, halogén, kyano, sulfoxy, sulfonyl, -CO2H, -C(O)NR30R31, -NR30SO2R31, -NR30C(O)R31, -NR30C(O)OR31, heteroaryl alebo heterocykloalkyl;R 25 represents a group selected from hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halogen, cyano, sulfoxy, sulfonyl, -CO 2 H, -C (O) NR 30 R 31 , -NR 30 SO 2 R 31 , - NR 30 C (O) R 31 , -NR 30 C (O) OR 31 , heteroaryl or heterocycloalkyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy, alebo R18 a R19 spoločne tvoria heterocykloalkylovú alebo heteroarylovú skupinu;R 17 , R 18 and R 19 independently of each other represent a group selected from the group consisting of hydrogen, halogen and alkoxy, or R 18 and R 19 together form a heterocycloalkyl or heteroaryl group; R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25.R 30 and R 31 independently of each other represent a group selected from the group consisting of hydrogen, alkyl or alkyl-R 25 . 25. Zlúčenina podľa nároku 24, kde R25znamená morfolínovú skupinu,The compound of claim 24, wherein R 25 is a morpholine group, Rn R31Rn R31 240 kde R33 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo substituovaný alkyl.240 wherein R 33 represents a group selected from the group consisting of hydrogen, alkyl or substituted alkyl. 26. Zlúčenina podľa nároku 24, kde R12 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, metyl, hydroxymetyl, metoxymetyl, CH2F, CH2CN, CO2H alebo -CONR30R31, kde R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík alebo alkyl-R25.A compound according to claim 24, wherein R 12 is selected from the group consisting of hydrogen, methyl, hydroxymethyl, methoxymethyl, CH 2 F, CH 2 CN, CO 2 H or -CONR 30 R 31 , wherein R 30 and R 31 independently of one another each represents a group selected from the group consisting of hydrogen or alkyl-R 25 . 27. Zlúčenina podľa nároku 24, obsahujúca vedľajší reťazec zvolený zo skupiny zahrňujúcejA compound according to claim 24, comprising a side chain selected from the group consisting of O kde R40 znamená vodík alebo alkylovú skupinu a R70 znamená vodík alebo halogén.Wherein R 40 is hydrogen or alkyl and R 70 is hydrogen or halogen. 28. Zlúčenina podľa nároku 24, kde R12 a R13 znamenajú H; R17 znamená Br, F alebo Cl; R18 znamená metoxylovú skupinu alebo fluór; R19 znamená H; alebo R18 a R19 spoločne tvoria 4-0,5-dihydrofuranyl.The compound of claim 24, wherein R 12 and R 13 are H; R 17 is Br, F or Cl; R 18 is methoxy or fluoro; R 19 is H; or R 18 and R 19 together form 4-0,5-dihydrofuranyl. 29. Zlúčenina podľa nároku 24, kde R12 a R13 znamenajú metylovú skupinu; R17 znamená Br, F alebo Cl, R18 znamená vodík alebo metoxylovú skupinu; a R19 znamená H.The compound of claim 24, wherein R 12 and R 13 are methyl; R 17 is Br, F or Cl, R 18 is hydrogen or methoxy; and R 19 is H. 30. Zlúčenina všeobecného vzorcaA compound of formula 241 kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo -alkyl-R25, kde241 wherein R 15 represents a group selected from hydrogen, alkyl, aryl or -alkyl-R 25 wherein R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, amino, alkoxy, tioalkoxy, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl;R 25 represents a group selected from the group consisting of hydrogen, hydroxy, thiol, alkenyl, amino, alkoxy, thioalkoxy, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; 1R každý R nezávisle znamená vodík alebo metylovú skupinu;1R each R is independently hydrogen or methyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy; alebo R18 a R19 spoločne tvoria heterocykloalkylovú alebo heteroarylovú skupinu; aR 17, R 18 and R 19 each independently is selected from hydrogen, halogen and alkoxy; or R 18 and R 19 together form a heterocycloalkyl or heteroaryl group; and R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R .R 30 and R 31 independently of one another are selected from the group consisting of hydrogen, alkyl or alkyl-R. 31. Zlúčenina podľa nároku 30, kde R25 znamená morfolín, tiomorfolín, o oThe compound of claim 30, wherein R 25 is morpholine, thiomorpholine, oo 32. Zlúčenina podľa nároku 30, ktorej vedľajší reťazec má nižšie uvedenú štruktúru:The compound of claim 30, wherein the side chain has the following structure: 242242 NHNH NHNH NHNH OABOUT NH kde R40 znamená vodík alebo alkylovú skupinu a R17 znamená vodík alebo halogén.NH wherein R 40 is hydrogen or alkyl and R 17 is hydrogen or halogen. 33. Zlúčenina podľa nároku 30, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, metyl, etyl alebo (CH2)nCH2-R25, kde R25 znamená OH, OMe, F, CN, CF3, SOCH3 alebo SO2CH3, kde n znamená 0 alebo 1.The compound of claim 30, wherein R 15 is selected from the group consisting of hydrogen, methyl, ethyl or (CH 2 ) n CH 2 -R 25 , wherein R 25 is OH, OMe, F, CN, CF 3 , SOCH 3 or SO 2 CH 3 , wherein n is 0 or 1. 34. Zlúčenina podľa nároku 30, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej kyanoetyl, hydroxyetyl, CH2CH2SOCH3, CH2CH2CH2F, CH2CH2CH2CN alebo CH2CH2CF3; R15 a R19 znamenajú H; R17 znamená Br alebo Cl; a R18 znamená vodík alebo metoxylovú skupinu.The compound of claim 30, wherein R 15 is selected from the group consisting of cyanoethyl, hydroxyethyl, CH 2 CH 2 SOCH 3 , CH 2 CH 2 CH 2 F, CH 2 CH 2 CH 2 CN or CH 2 CH 2 CF 3 ; R 15 and R 19 are H; R 17 is Br or Cl; and R 18 is hydrogen or methoxy. 35. Zlúčenina všeobecného vzorca35. A compound of formula 243 kde243 where R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo alkyl-R25;R 15 represents a group selected from the group consisting of hydrogen, alkyl, aryl or alkyl-R 25 ; R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl;R 25 represents a group selected from hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; každý R16 nezávisle znamená vodík alebo metylovú skupinu;each R 16 is independently hydrogen or methyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy; alebo R18 a R19 spoločne tvoria heterocykloalkylovú alebo heteroarylovú skupinu; aR 17, R 18 and R 19 each independently is selected from hydrogen, halogen and alkoxy; or R 18 and R 19 together form a heterocycloalkyl or heteroaryl group; and R a R nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, alebo alkyl-R25. 36 R and R independently represent a group selected from the group consisting of hydrogen, alkyl, or alkyl-R 25 . 36 36. Zlúčenina podľa nároku 35, kde R25 znamená morfolín, tiomorfolin, kde R33 znamená vodík, alkylovú alebo substituovanú alkylovú skupinu.The compound of claim 35, wherein R 25 is morpholine, thiomorpholine, wherein R 33 is hydrogen, alkyl or substituted alkyl. 37. Zlúčenina podľa nároku 35, ktorá obsahuje vedľajší reťazec nižšie uvedenej štruktúry:A compound according to claim 35, which comprises a side chain of the following structure: 244 \244 \ NH \NH \ NH kde R40 znamená vodík alebo alkylovú skupinu a R17 znamená vodík alebo halogén.NH wherein R 40 is hydrogen or alkyl and R 17 is hydrogen or halogen. 38. Zlúčenina podľa nároku 35, kde R15 znamená vodík alebo metylovú skupinu; R17 znamená bróm, chlór alebo fluór; R18 znamená vodík alebo metoxylovú skupinu; a R19 znamená vodík. 39 The compound of claim 35, wherein R 15 is hydrogen or methyl; R 17 is bromo, chloro or fluoro; R 18 is hydrogen or methoxy; and R 19 is hydrogen. 39 39. Zlúčenina všeobecného vzorca kdeA compound of the formula wherein R25;R 25 ; R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, alebo alkyl245R 15 represents a group selected from the group consisting of hydrogen, alkyl, or alkyl 244 R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl;R 25 represents a group selected from hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; každý R16 nezávisle znamená vodík alebo metylovú skupinu;each R 16 is independently hydrogen or methyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy; alebo R18 a R19 spoločne tvoria heterocyklickú alebo heteroarylovú skupinu; aR 17, R 18 and R 19 each independently is selected from hydrogen, halogen and alkoxy; or R 18 and R 19 together form a heterocyclic or heteroaryl group; and R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl alebo alkyl-R25.R 30 and R 31 independently of each other represent a group selected from the group consisting of hydrogen, alkyl or alkyl-R 25 . 40. Zlúčenina podľa nároku 39, ktorá obsahuje vedľajší reťazec nižšie uvedenej štruktúry:A compound according to claim 39, which comprises a side chain of the following structure: kde R40 znamená vodík alebo alkylovú skupinu a R17 znamená vodík alebo halogén.wherein R 40 is hydrogen or alkyl and R 17 is hydrogen or halogen. 41. Zlúčenina podľa nároku 39, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, metyl, etyl alebo -(CH2)n(CH2)-R25, kde n znamená 0, 1 alebo 2; a R25 znamená OH, OMe, F, CN, CF3, SOCH3 alebo SO2CH3, -NR“°COR31, -NR30COOR31, -NR30SO2R31, -C(O)NR30R31, alebo má nižšie uvedený štruktúrny vzorec:The compound of claim 39, wherein R 15 is selected from the group consisting of hydrogen, methyl, ethyl or - (CH 2) n (CH 2) -R 25 , wherein n is 0, 1 or 2; and R 25 is OH, OMe, F, CN, CF 3, SOCH 3 or SO 2 CH 3 , -NR 30 COR 31 , -NR 30 COOR 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 or having the following structural formula: 246246 FLji R,31 kde R33 znamená vodík, alkylovú alebo substituovanú alkylovú skupinu.F 1 R 31, wherein R 33 represents hydrogen, alkyl or substituted alkyl. 42. Zlúčenina podľa nároku 39, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej etyl, metoxyetyl, CH2CH2F a CH2CH2CN; R17 znamená bróm alebo chlór; R18 znamená metoxylovú skupinu alebo vodík: a R19 znamená vodík.The compound of claim 39, wherein R 15 is selected from the group consisting of ethyl, methoxyethyl, CH 2 CH 2 F and CH 2 CH 2 CN; R 17 is bromo or chloro; R 18 is methoxy or hydrogen; and R 19 is hydrogen. 43. Zlúčenina všeobecného vzorca kdeA compound of the formula wherein R15 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo alkyl-R25;R 15 represents a group selected from the group consisting of hydrogen, alkyl, aryl or alkyl-R 25 ; R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol,R 25 represents a group selected from the group consisting of hydrogen, hydroxy, thiol, 30 31 alkenyl, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR COOR , -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl;Alkenyl, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR COOR, -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy; alebo R18 a R19 spoločne tvoria heterocyklickú alebo heteroarylovú skupinu; aR 17, R 18 and R 19 each independently is selected from hydrogen, halogen and alkoxy; or R 18 and R 19 together form a heterocyclic or heteroaryl group; and 247247 R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 44. Zlúčenina podľa nároku 43, kde R15 znamená -(CH2)n(CH2)R25, n znamená 0, 1, 2 alebo 3 a R25 znamená OH, OMe, F, CN, CF3, SOCH3 alebo SO2CH3, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, alebo má nižšie uvedený štruktúrny vzorec:The compound of claim 43, wherein R 15 is - (CH 2) n (CH 2) R 25 , n is 0, 1, 2 or 3 and R 25 is OH, OMe, F, CN, CF 3, SOCH 3 or SO 2 CH 3 , -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , or has the following structural formula: o o kde R37 znamená vodík, alkylovú alebo substituovanú alkylovú skupinu.oo wherein R 37 is hydrogen, alkyl or substituted alkyl. 45. Zlúčenina podľa nároku 43, kde R15 znamená skupinu zvolenú zo skupiny zahrňujúcej metyl, etyl, CH2F, metoxyetyl, CH2CH2F alebo CH2CH2CH2SOCH3; R17 znamená bróm; R18 znamená vodík, metoxylovú skupinu alebo fluór; R19 znamená H.The compound of claim 43, wherein R 15 is selected from the group consisting of methyl, ethyl, CH 2 F, methoxyethyl, CH 2 CH 2 F, or CH 2 CH 2 CH 2 SOCH 3 ; R 17 is bromo; R 18 is hydrogen, methoxy or fluoro; R 19 stands for H. 46. Zlúčenina podľa nároku 45, ktorá obsahuje vedľajší reťazec nižšie uvedenej štruktúry:A compound according to claim 45, which comprises a side chain of the following structure: ^NH^ NH HN' aleboHN 'or 248 kde R40 znamená vodík alebo alkylovú skupinu a R17 znamená vodík alebo halogén.248 wherein R 40 is hydrogen or alkyl and R 17 is hydrogen or halogen. 43. Zlúčenina všeobecného vzorca kde každý R15 nezávisle znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, aryl alebo alkyl-R25;A compound of the formula wherein each R 15 is independently selected from the group consisting of hydrogen, alkyl, aryl or alkyl-R 25 ; R25 znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, hydroxy, tiol, alkenyl, alkoxy, tioalkoxy, amino, halogén, kyano, sulfoxy, sulfonyl, -NR30COOR31, -NR30C(O)R31, -NR30SO2R31, -C(O)NR30R31, heteroaryl alebo heterocykloalkyl;R 25 represents a group selected from hydrogen, hydroxy, thiol, alkenyl, alkoxy, thioalkoxy, amino, halogen, cyano, sulfoxy, sulfonyl, -NR 30 COOR 31 , -NR 30 C (O) R 31 , -NR 30 SO 2 R 31 , -C (O) NR 30 R 31 , heteroaryl or heterocycloalkyl; R17, R18 a R19 vzájomne nezávisle každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, halogén a alkoxy; alebo R18 a R19 spoločne tvoria heterocyklickú alebo heteroarylovú skupinu; aR 17, R 18 and R 19 each independently is selected from hydrogen, halogen and alkoxy; or R 18 and R 19 together form a heterocyclic or heteroaryl group; and R30 a R31 nezávisle od seba každý znamená skupinu zvolenú zo skupiny zahrňujúcej vodík, alkyl, cykloalkyl alebo alkyl-R25.R 30 and R 31 each independently represent a group selected from the group consisting of hydrogen, alkyl, cycloalkyl or alkyl-R 25 . 48. Zlúčenina podľa nároku 1, ktorou je zlúčenina zvolená zo skupiny zlúčenín zahrňujúcich:The compound of claim 1 which is a compound selected from the group consisting of: zlúčeninu podľa nároku 1 vzorca:a compound according to claim 1 of the formula: 249 (S)-4-(2-hydroxy-1-fenyletylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;249 (S) -4- (2-Hydroxy-1-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (±)-4-[2-hydroxy-2-(3-jódfenyl)etylamino]-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2-Hydroxy-2- (3-iodophenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]“3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] "3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-rnetyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (S)-4-[2-(2-ch lórfenyl)-1 -hydroxymetyletylamino]-3-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (2-Chloro-phenyl) -1-hydroxy-methylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2- one; (S)-4-[2-(3-chlórfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-chlorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (S)-4-[2-(4-chlórfenyl)-1 -hydroxymetyletylamino]-3-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (4-Chloro-phenyl) -1-hydroxy-methylethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one ; (S)-4-[2-(2-brómfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridin-2-ón;(S) -4- [2- (2-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (S)-4-[2-(3-brómfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-bromophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-(1-hydroxymetyl-2-pentafluórfenyletylamino)-3-(6-imidazol-1-yl-4-metyl1 H-benzoimidazol-2-yl)-1 H-pyrid í η-2-όη;(±) -4- (1-hydroxymethyl-2-pentafluorophenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (S)-4-(1-hydroxymetyl-2-pyridín-4-yletylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- (1-hydroxymethyl-2-pyridin-4-yl-ethylamino) -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (S)-4-[1-hydroxymetyl-2-(2-naftyl)etylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [1-hydroxymethyl-2- (2-naphthyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one ; 3-(6-imidazol-1-yl-4-metyl-1H-benzoimidazol-2-yl)-4-(pyridín-2-ylmetoxy)-1Hpyridín-2-ón;3- (6-imidazol-1-yl-4-methyl-1 H-benzoimidazol-2-yl) -4- (pyridin-2-ylmethoxy) -1Hpyridín-2-one; (±)-4-[2-(3-brómfenyl)-2-fluóretylamino]-3-(6-imidazol-1-yl-4-metyl-1H* benzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-Bromophenyl) -2-fluoroethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one; (S)-2-[4-(1 -hydroxymetyl-2-fenyletylamino)-2 -oxo-1,2-dihydropyridín-3-yl]-7metyl-3H-benzoimidazol-5-karbonitril;(S) -2- [4- (1-hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile; (±)-2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril;(±) -2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile; (±)-2-{4-[2-(3-chlórfenyl)-1-hydroxymetyletylamino]-2-oxo-1,2-dihydropyridín-3(±) -2- {4- [2- (3-chlorophenyl) -1-hydroxymethyl-ethylamino] -2-oxo-1,2-dihydropyridine-3 250 yl}-7-metyl-3H-benzoimidazol-5-karbonitril;250 yl} -7-methyl-3H-benzoimidazole-5-carbonitrile; (±)-2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridin-3-yl}-7-metyl-3H-benzoimidazol-5-karbonitril;(±) -2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-methyl-3H-benzimidazole-5 carbonitrile; (±)-2-{4-[2-(3-fluórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridin-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril;(±) -2- {4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile; (±)-2-{4-[2-(3-brómfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-karbonitril;(±) -2- {4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzimidazole-5-carbonitrile; (S)-2-[4-(2-hydroxy-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7-metyl3H-benzoimidazol-5-karbonitril; (±)-3-(1H-benzoimidazol-2-yl)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-1Hpyridín-2-ón;(S) -2- [4- (2-hydroxy-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazole-5-carbonitrile; (±) -3- (1 H-benzoimidazol-2-yl) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -1Hpyridín-2-one; (S)-3-(1H-benzoimidazol-2-yl)-4-(1-hydroxymetyl-2-fenyletylamino)-1H-pyridín2-ón;(S) -3- (1H-benzoimidazol-2-yl) -4- (1-hydroxymethyl-2-phenyl-ethylamino) -1 H-pyridin-2-one; (+)-3-(1 H-benzoimidazol-2-yl)-4-[2-(3-bróm-4-metoxyfenyl)-2hydroxyetylamino]-1H-pyridín-2-ón;(+) - 3- (1H-benzoimidazol-2-yl) -4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -1H-pyridin-2-one; (S)-4-{2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihyd ropyridín-3-yl]-7metyl-3H-benzoimidazol-5-yl}-piperazín-karbox(izopropyl)amid;(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7methyl-3H-benzoimidazol-5-yl} -piperazine -carboxamide (isopropyl) amide; (S)-4-{2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1, 2-dihyd ropyridin-3-yl]-7metyl-3H-benzoimidazol-5-yl}-piperazín-karbox(etyl)amid;(S) -4- {2- [4- (1-Hydroxymethyl-2-phenylethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazol-5-yl} -piperazine -carboxamide (ethyl) amide; (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-{4-metyl-6-[4-(1fenylmetanoyl)piperazín-1-yl]-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- {4-methyl-6- [4- (1-phenylmethanoyl) piperazin-1-yl] -1H-benzoimidazol-2-yl} -1H pyridin-2-one; (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[6-(4-izopropylpiperazin-1-yl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón;(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [6- (4-isopropylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H-pyridin-2- one; (S)-3-[6-(4-benzylpiperazín-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-(1hydroxymetyl-2-fenyletylamino)-1 H-pyrid ίη-2-όη;(S) -3- [6- (4-Benzyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (1-hydroxymethyl-2-phenylethylamino) -1H-pyridine-2- όη; (±)-3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-[2-(3chlórfenyl)-2-hydroxyetylamino]-1H-pyridín-2-ón;(±) -3- [6- (4-acetyl-1-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -1-pyridine 2-one; (+)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazol-2-yl)-1 H-pyrid in-2-ón;(+) - 4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridine-2- one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(4-izopropylpiperazín-1-yl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-όη;(±) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [6- (4-isopropyl-piperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H- pyridin-2-όη; (S)-6-(1-hydroxymetyl-2-fenyletylamino)-5-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-3H-pyrimidín-4-ón;(S) -6- (1-hydroxymethyl-2-phenyl-ethylamino) -5- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -3H-pyrimidin-4-one; 251 (S)-2-[6-chlór-5-(6-imidazol-1 -yl-4-metyl-1 H-benzoimidazol-2-yl)pyrimidín-4ylamino]-3-fenylpropán-1-ol;251 (S) -2- [6-chloro-5- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) pyrimidin-4-ylamino] -3-phenylpropan-1-ol; (S)-4-(2-hydroxy-2-fenyletylamino)-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- (2-hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (R) -4-(2-hydroxy-2-fenyletylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(R) -4- (2-Hydroxy-2-phenylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (1S,2R)-4-(1-hydroxyindán-2-ylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(1 S, 2 R) -4- (1-Hydroxy-indan-2-ylamino) -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-hydroxy-2-(3-hydroxyfenyl)etylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2-hydroxy-2- (3-hydroxyphenyl) ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one ; (S) -4-(2-hydroxy-2-pyridín-2-yletylamino)-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- (2-Hydroxy-2-pyridin-2-ylethylamino) -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (±)-N-(3-{1-hydroxy-2-[3-(6-imidazol-1-yl-4-metyl-1 H-benzoimidazol-2-yl)-2oxo-1,2-dihydropyridín-4-ylamino]etyl}fenyl)metánsulfónamid;(±) -N- (3- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridine- 4-ylamino] ethyl} phenyl) methanesulfonamide; (±)-4-[2-(3-fluórfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-fluorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;(±) -4- [2- (3-Chloro-4-fluorophenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one; (S)-4-[2-(3-fluórfenyl)-1-hydroxymetyletylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-fluorophenyl) -1-hydroxymethyl-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one; (S)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylarriino]-3-(6-imidazol-1-yl-4-metyl-1 Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one ; (R)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4-metyl-1Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón;(R) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one ; (±)-4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-(6-imidazol-1-yl-4metyl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;(±) -4- [2- (3-Chloro-4-methoxyphenyl) -2-hydroxyethylamino] -3- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -1H- pyridin-2-one; Metylester (±)-(2-chlór-4-{1 -hydroxy-2-[3-(6-imidazol-1 -yl-4-metyl-1 H(±) - (2-Chloro-4- {1-hydroxy-2- [3- (6-imidazol-1-yl-4-methyl-1H) -ethyl] - methyl ester 252 benzoimidazol-2-yl)-2-oxo-1,2-dihydropyridin-4-ylamino]etyl}fenyl)karbámovej kyseliny;252 benzoimidazol-2-yl) -2-oxo-1,2-dihydropyridin-4-ylamino] ethyl} phenyl) carbamic acid; (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[4-metyl-6-(4-metylpiperazín-1-yl)1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón;(S) -4- (1-hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyridin-2 one; (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[4-metyl-6-(4-butylpiperazin-1-yl)1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (4-butylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H-pyridin-2 one; (S)-3-{6-[4-(2-hydroxyetyl)piperazín-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-4-(1hydroxymetyl-2-fenyletylamina)-1H-pyridín-2-ón;(S) -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -4- (1-hydroxymethyl-2-phenylethylamine) -1H- pyridin-2-one; (S)-4-{2-[4-(1-hydroxymetyl-2-fenyletylamino)-2-oxo-1,2-dihydropyridín-3-yl]-7metyl-3H-benzoimidazol-5-yl}-piperazín-1-karboxamid;(S) -4- {2- [4- (1-hydroxymethyl-2-phenyl-ethylamino) -2-oxo-1,2-dihydropyridin-3-yl] -7-methyl-3H-benzoimidazol-5-yl} -piperazine 1-carboxamide; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3’[6-(4-etylpiperazín-1-yl)-4-metyl1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3 '[6- (4-ethylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -1H- pyridin-2-one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-'lyl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole-2- yl} -1H-pyridin-2-one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-brómfenyl-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-1 Hbenzoimidazol-2-yl)-1 H-;(±) -4- [2- (3-bromophenyl-2-hydroxyethylamino) -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H-; (±)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4yl-1 H-benzoimidazol-2-yl)-1 H-pyrid ίη-2-όη;(±) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1H- pyrid-2-ol; (±)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl 1 H-pyridin-2-one; (±)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(±) -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; (±)-4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón;(±) -4- [2- (3-Bromophenyl) -2-hydroxyethylamino] -3- (4-methyl-6-piperazin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one ; (±)-3-[6-(4-acetylpiperazín-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-[2-(3brómfenyl)-2-hydroxyetylamino]-1H-pyridín-2-ón;(±) -3- [6- (4-acetyl-1-yl) -4-methyl-1 H-benzoimidazol-2-yl] -4- [2- (3-bromophenyl) -2-hydroxy-ethylamino] -1-pyridine 2-one; (S)-4-(1-hydroxymetyl-2-fenyletylamino)-3-[4-metyl-6-(2-morfolín-4yletylamino)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(S) -4- (1-Hydroxymethyl-2-phenylethylamino) -3- [4-methyl-6- (2-morpholin-4-ylethylamino) -1H-benzoimidazol-2-yl] -1H-pyridin-2- one; 253 (+)-6-[2-(3-chlórfenyl)-2-hydroxyetylarnino]-5-(6-imidazol-1 -yl-4-metyl-1 Hbenzoimidazol-2-yl)-3H-pyrimidín-4-ón;253 (+) - 6- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -5- (6-imidazol-1-yl-4-methyl-1H-benzoimidazol-2-yl) -3H-pyrimidin-4- one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[6-(1-hydroxy-1-metyletyl)-4metyl-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [6- (1-hydroxy-1-methylethyl) -4-methyl-1H-benzoimidazol-2-yl] -1H- pyridin-2-one; (±)-3-(6-aminometyl-4-metyl-1H-benzoimidazol-2-yl)-4-[2-(3-chlórfenyl)-2hydroxyetylamino]-1H-pyridín-2-ón;(±) 3- (6-Aminomethyl-4-methyl-1 H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) -2hydroxyetylamino] -1 H-pyridin-2-one; (±)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-hydroxymetyl)-4-metyl-1Hbenzoimidazol-2-yl)-1 H-pyridín-2-ón;(±) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (6-hydroxymethyl) -4-methyl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one; (S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6-morfolín-4-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón; a (S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6-piperidín-1-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón.(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-morpholin-4-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; and (S) -4- (1-Benzyl-2-hydroxyethylamino) -3- (4-methyl-6-piperidin-1-yl-1H-benzoimidazol-2-yl) -1H-pyridin-2-one. 49. Zlúčenina podľa nároku 2 zvolená zo skupiny zlúčenín zahrňujúcich:A compound according to claim 2 selected from the group consisting of: (S)-4-(1-benzyl-2-hydroxyetylamino)-3-(4-metyl-6-piperidín-1-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- (1-benzyl-2-hydroxy-ethylamino) -3- (4-methyl-6-piperidin-1-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlór-4-metylsulfanylfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín1-yl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ón;4- [2- (3-chloro-4-methylsulfanyl-phenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1 H-benzoimidazol-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-piperazín-1-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-piperazin-1-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; 3- [4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-3- [4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} - 7-metyl-3H-benzoimidazol-5-yl)-piperazín-1-yl]propionitril;7-methyl-3H-benzoimidazol-5-yl) -piperazine-1-yl] -propionitrile; 4- [2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metánsulfonyletyl)piperazín1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfonylethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine 2-one; 3-[4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-3H-benzoimidazol-5-yl)-7-metylpiperazín-1-yl]propionitril;3- [4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -3H-benzoimidazol-5-yl) 7-methyl-piperazin-1-yl] -propionitrile; 2-fluóretylester 4-(2-{4’[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1 -karboxylovej kyseliny;4- (2- {4 '[2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) 2-fluoroethyl ester piperazine-1-carboxylic acid; 2-metoxyetylester 4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1 -karboxylovej kyseliny;4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) 2-methoxy-ethyl ester piperazine-1-carboxylic acid; Terc-butylester 4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny;4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) tert-butyl ester piperazine-1-carboxylic acid; 254254 Prop-2-inylester 4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1 -karboxylovej kyseliny;4- (2- {4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H-benzoimidazole-5- prop-2-ylester yl) piperazine-1-carboxylic acid; Terc-butylester 4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-4- (2- {4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -2-oxo-tert-butyl ester 1,2-dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1 -karboxylovej kyseliny;1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) piperazine-1-carboxylic acid; Etylester (S)-4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karboxylovej kyseliny;(S) -4- (2- {4- [2- (3-Bromo-4-methoxy-phenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydro-pyridin-3-yl} -7-methyl-3H- benzoimidazol-5-yl) piperazine-1-carboxylic acid; 4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1 H-benzoimidazol-2 yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóretyl)piperazín-1-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H pyridin-2-one; 4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1 H-benzoimidazol-2 yl} -1 H-pyridin-2-one; 4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridin-2-ón;4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1 H-benzoimidazol-2 yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(3,3,3-trifluórpropyl)piperazín-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,3,3-trifluoropropyl) piperazin-1-yl] -1 H-benzimidazol-2- yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fluórpropyl)piperazín-1-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-py ridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoropropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H -pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(3,4,4-trifluórbut-3enyl)piperazin-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (3,4,4-trifluoro-3-enyl) -piperazin-1-yl] -1H-benzoimidazol 2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(3-fliiór-2-hydroxypropyl)piperazin-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (3-fluoro-2-hydroxypropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2 yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxy-2-metylpropyl)piperazí n-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-py rid ίη-2-ό n;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxy-2-methylpropyl) piperazin-1-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;(S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl 1 H-pyridin-2-one; (S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyetyl)piperazín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-py rid í η-2-όη;(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-yl; [4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3-yl}-7metyl-3H-benzoimidazol-5-yl)piperazín-1-yl]acetonitril;[4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl) piperazine 1-yl] acetonitrile; 4-[2-(3-chlórfenyl)-2-ľiydroxyetylamino]-3-{6-[4-(4-fluórbutyryl)piperazín-1-yl]-44- [2- (3-chlorophenyl) -2-ľiydroxyetylamino] -3- {6- [4- (4-trifluorobutyryl) piperazin-1-yl] -4 255 metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;255 methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2,2-difluóracetyl)piperazín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2,2-difluoroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metánsulfonylacetyl)piperazín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfonylacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; 3- [6-(4-acetylpiperazín-1-yl)-4-metyl-1H-benzoimidazol-2-yl]-4-(2-(3- chlórfenyl)-2-hydroxyetylamino]-1H-pyridín-2-ón;3- [6- (4-Acetylpiperazin-1-yl) -4-methyl-1H-benzoimidazol-2-yl] -4- (2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2- one; 4- [2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-{4-[2-(1-oxo-114tiomorfolín-4-yl)acetyl]piperazín-1-yl}-1H-benzoimidazol-2-yl)-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- (4-methyl-6- {4- [2- (1-oxo-114-thiomorpholin-4-yl) acetyl] piperazin-1-yl} -1 H-benzimidazol-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(6-{4-[2-(1,1-dioxo-116-tiamorfolín-4yl)acetyl]piperazín-1-yl}-4-metyl-1H-benzoimidazol-2-yl)-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (6- {4- [2- (1,1-dioxo-116-thiamorpholine-4-yl) acetyl] piperazine-1-yl} -4 methyl-1 H-benzoimidazol-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(2-tiomorfolin-4ylacetyl)piperazin-1-yl]-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {4-methyl-6- [4- (2-thiomorpholin-4ylacetyl) piperazin-1-yl] -1 H-benzimidazol-2-yl} -1-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metánsulfinylacetyl)piperazín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methanesulfinylacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metoxyacetyl)piperazín-1-yl]4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{4-metyl-6-[4-(2-metylsulfanylacetyl)piperazin-1 -y I]-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {4-methyl-6- [4- (2-methylsulfanylacetyl) piperazin-1-yl] -1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 3- {6-[4-(2-chlóracetyl)piperazín-1-yl]-4-metyl-1H-benzoimidazol-2-yl}-4-[2-(3chlórfenyl)-2-hydroxyetylamino]-1H-pyridín-2-ón;3- {6- [4- (2-Chloroacetyl) piperazin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -1H-pyridine 2-one; (S)-4-(2-{4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-2-oxo-1,2dihydropyridín-3-yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karbaldehyd;(S) -4- (2- {4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxy-ethylamino] -2-oxo-1,2-dihydropyridine-3-yl} -7-methyl-3H-benzimidazole 5-yl) -piperazine-1-carbaldehyde; (S)-4-(2-{4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-2-oxo-1,2-dihydropyridín-3yl}-7-metyl-3H-benzoimidazol-5-yl)piperazín-1-karbaldehyd;(S) -4- (2- {4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -2-oxo-1,2-dihydropyridin-3-yl} -7-methyl-3H-benzoimidazol-5-yl ) piperazine-1-carbaldehyde; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; 4- [2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl) 1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;1H-benzoimidazol-2-yl) -1H-pyridin-2-one; 4-[2-(3-chlór-4-fluórfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl-1Hbenzoimidazol-2-yl)-1H-pyridín-2-ón;4- [2- (3-chloro-4-fluorophenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl-1 H -benzoimidazole-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlór-4-metoxyfenyl)-2-hydroxyetylamino]-3-(4-metyl-6-morfolín-4-yl2564- [2- (3-chloro-4-methoxyphenyl) -2-hydroxy-ethylamino] -3- (4-methyl-6-morpholin-4-yl256 1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;1H-benzoimidazol-2-yl) -1H-pyridin-2-one; 4-[2-(7-bróm-2,3-dihydrobenzofurán-5-yl)-2-hydroxyetylamino]-3-(4-metyl-6morfolín-4-yl-1 H-benzoimidazol-2-yl)-1 H-pyridín-2-ón;4- [2- (7-bromo-2,3-dihydrobenzofuran-5-yl) -2-hydroxyethylamino] -3- (4-methyl-6-morpholin-4-yl-1H-benzoimidazol-2-yl) -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-[2(S),6(R)dimetylmorfolín-4-yl]-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- [2 (S), 6 (R) dimethylmorpholin-4-yl] -1H-benzoimidazole- 2-yl] -1H-pyridin-2-one; 4-[2-(3-bróm-4-metoxyfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-[2(S),6(R)dimetylmorfolín-4-yl]-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón;4- [2- (3-bromo-4-methoxy-phenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- [2 (S), 6 (R) dimethyl-morpholin-4-yl] -1 benzoimidazol-2-yl] -1-pyridin-2-one; 4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-fluórmetylmorfolín-4-ylJ4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl-(S)-2hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-2yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one and 4- [2- (3-chlorophenyl- (S) -2-hydroxyethylamino) -3- {6 - [(S) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H -benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-(6-[(R)-2fluórmetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- (6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-fluoromethylmorpholine- 4-yl] -4-methyl-1 H-benzoimidazol-2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2fluórmetylmorfolin-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-fluórmetylmorfolín-4-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-fluoromethylmorpholin-4-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-fluoromethylmorpholine- 4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(7-bróm-2,3-dihydrobenzofurán-4-yl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2fluórmetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(7bróm-2,3-dihydrobenzofurán-4-yl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2fluórmetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (7-bromo-2,3-dihydrobenzofuran-4-yl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2fluórmetylmorfolín-4-yl] -4-methyl- -1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (7-bromo-2,3-dihydrobenzofuran-4-yl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2fluórmetylmorfolín-4-yl] -4-methyl-1 H-benzoimidazol-2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxymetylmorfolín-4y l]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-py ridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-{6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl-1H-benzoimidazol2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl } -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-hydroxymethylmorpholin-4-yl] -4 -methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-bróm-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-hydroxy4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxy-ethylamino] -3- {6 - [(R) -2-hydroxy 257 metylmorfolin-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-hydroxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;257 methylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2- hydroxyethylamino] -3- {6 - [(S) -2-hydroxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metylmorfolín-4-yl]-4metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-{6-[(S)-2-metylmorfolín-4-yl]-4-metyl-1H-benzoimidazol-2-yl}-1Hpyridín-2-ón;4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-methylmorpholin-4-yl] -4-methyl -1 H-benzimidazol-2-yl} -1Hpyridín-2-one; 4-[2-(3-bróm-4-rnetoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metylmorfolin-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metylmorfolín-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methyl-morpholin-4-yl] -4-methyl-1 H -benzoimidazole-2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2metylmorfolín-4-yl]-4-rnetyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metylmorfolín-4-yl]-4-metyl-1Hbenzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methylmorpholin-4-yl] -4-methyl-1H-benzoimidazole- 2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-methylmorpholine- 4-yl] -4-methyl-1 H -benzoimidazole-2-yl} -1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-(S)-2-hydroxyetylairiino]-3-{6-[(R)-2-metoxymetylmorfolín-4yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlórfenyl)-(S)-2hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolin-4-yl]-4-metyl-1 H-benzoimidazol2-yl}-1 H-pyridin-2-ón;4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylairino] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chlorophenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2-methoxymethylmorpholin-4-yl] -4-methyl -1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-bróm-4-rnetoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(R)-2-metoxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-bróm-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolin-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-bromo-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlór-4-metoxyfenyl)-(S)-2-hydroxyetylamirio]-3-{6-[(R)-2-metoxymetylmorfolín-4-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón a 4-[2-(3-chlór-4metoxyfenyl)-(S)-2-hydroxyetylamino]-3-{6-[(S)-2-metoxymetylmorfolín-4-yl]-4-metyl1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamirio] -3- {6 - [(R) -2-methoxymethylmorpholin-4-yl] -4-methyl-1H- benzoimidazol-2-yl} -1H-pyridin-2-one and 4- [2- (3-chloro-4-methoxyphenyl) - (S) -2-hydroxyethylamino] -3- {6 - [(S) -2- methoxymethylmorpholin-4-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(4-metylpiperazín-1-yl)1 H-benzoimidazol-2-yl]-1 H-py rid í η-2-όη;4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] -1H- pyridine η-2-όη; 4-[2-(3-bróm-4-metoxyfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(4metylpiperazín-1 -yl)-1 H-benzoimidazol-2-yl]-1 H-pyridin-2-ón;4- [2- (3-bromo-4-methoxyphenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-yl) -1H-benzoimidazol-2-yl] - 1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(acetamido)piperidín-'l-yl]-44- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- {6- [4- (acetamido) -piperidin-'l-yl] -4 258 metyl-1 H-benzoimidazol-2-yl}-1 H-py ridí η-2-όη;258 methyl-1H-benzoimidazol-2-yl} -1H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyacetamido)piperidín1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóracetamido)piperidin-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridin-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H pyridin-2-one; 4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-{6-[4-(acetamido)piperidín-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- {6- [4- (acetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl } -1 H-pyridin-2-one; 4-[2-(3-brómfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-hydroxyacetamido)piperidín-1-yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-bromophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-hydroxyacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóracetamido)piperidín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyrid í η-2-όη;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-fluoroacetamido) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H -pyridine η-2-όη; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-metoxyetoxykarbamoyl)piperidín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (2-methoxyethoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1 H-pyridin-2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(metoxykarbamoyl)piperidín-1yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- {6- [4- (methoxycarbamoyl) piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} -1H-pyridine 2-one; 4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-{6-[4-(2-fluóretoxykarbarnoyl)piperidín-1 -yl]-4-metyl-1 H-benzoimidazol-2-yl}-1 H-pyridín-2-ón;4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- {6- [4- (2-fluoro-ethoxycarbnoyl) -piperidin-1-yl] -4-methyl-1H-benzoimidazol-2-yl} - 1H-pyridin-2-one; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín-4-yletoxy)1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzoimidazol-2-yl] -1H pyridin-2-one; (S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín4-yletoxy)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón;(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylethoxy) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one; (S)-4-[2-(3-chlórfenyl)-2-hyd roxyetylamino]-3-[4-metyl-6-(2-metoxyetoxy)-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón;(S) -4- [2- (3-Chloro-phenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-methoxy-ethoxy) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one ; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-hydroxyetoxy)-1Hbenzoimidazol-2-yl]-1H-pyridín-2-ón;(S) -4- [2- (3-chlorophenyl) -2-hydroxy-ethylamino] -3- [4-methyl-6- (2-hydroxyethoxy) -1Hbenzoimidazol-2-yl] -1-pyridin-2-one; (S)-4-[2-(3-bróm-4-metoxyfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín4-ylpropoxy)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón, (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(2-morfolín-4ylpropoxy)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-όπ;(S) -4- [2- (3-Bromo-4-methoxyphenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H-benzoimidazol-2-yl] -1H-pyridin-2-one, (S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (2-morpholin-4-ylpropoxy) -1H- benzoimidazol-2-yl] -1H-pyridin-2-one; (S)-3-(4-bróm-6-morfolín-4-ylmetyl-1H-benzoimidazol-2-yl)-4-[2-(3-chlórfenyl)2-hydroxyetylamino]-1H-pyridin-2-ón;(S) -3- (4-bromo-6-morpholin-4-ylmethyl-1 H-benzoimidazol-2-yl) -4- [2- (3-chlorophenyl) 2-hydroxy-ethylamino] -1 H-pyridin-2-one ; (S)-3-(4-bróm-6-(4-metylpiperazín-1-ylmetyl-1H-benzoimidazol-2-yl)-4-[2-(3(S) -3- (4-bromo-6- (4-methylpiperazin-1-ylmethyl-1 H-benzoimidazol-2-yl) -4- [2- (3 259 chlórfenyl)-2-hydroxyetylamino]-1 H-pyridín-2-ón;259 chlorophenyl) -2-hydroxyethylamino] -1H-pyridin-2-one; (S)-4-[2-(3-chlórfenyl)-2-hydroxyetylamino]-3-[4-metyl-6-(4-metylpiperazín-1ylmetyl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón; a(S) -4- [2- (3-chlorophenyl) -2-hydroxyethylamino] -3- [4-methyl-6- (4-methylpiperazin-1-ylmethyl) -1H-benzoimidazol-2-yl] -1H- pyridin-2-one; and 4-[2-(3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(1,4,5,6tetrahydropyrimidín-1 -yl)-1 H-benzoimidazol-2-yl]-1 H-pyridín-2-ón; a4- [2- (3-chlorophenyl) -2 (S) -hydroxyethylamino] -3- [4-methyl-6- (1,4,5,6-tetrahydropyrimidin-1-yl) -1H-benzoimidazol-2-yl] 1 H-pyridin-2-one; and 4-[2-(4-metoxy-3-chlórfenyl)-2(S)-hydroxyetylamino]-3-[4-metyl-6-(1,4,5,6tetrahydropyrimidín-1-yl)-1H-benzoimidazol-2-yl]-1H-pyridín-2-ón.4- [2- (4-methoxy-3-chlorophenyl) -2 (S) -hydroxy-ethylamino] -3- [4-methyl-6- (1,4,5,6-1-yl) -1H-benzoimidazol 2-yl] -1-pyridin-2-one. 50. Farmaceutická kompozícia vyznačujúca sa tým, že obsahuje zlúčeninu podľa nároku 1 a farmaceutický prijateľný nosič.50. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 51. Farmaceutická kompozícia podľa nároku 50, vyznačujúca sa tým, že obsahuje najmenej jeden ďalší antikancerogénny prostriedok vo zvolenej dávke.51. The pharmaceutical composition of claim 50 comprising at least one additional anticancer agent at a selected dose. 52. Farmaceutická kompozícia podľa nároku 51, vyznačujúca sa tým, že uvedený antikancerogénny prostriedok sa zvolí zo skupiny zahrňujúcej tamoxifen, toremifen, raloxifen, droloxifen, jodoxyfen, megestrol-acetát, anastrazol, letrazol, borazol, exemestan, flutamid, nilutamid, bikalutamid, cyproteron-acetát, goserelin-acetát, luprolid, finasterid, herceptin, metotrexat, 5-fluóruracil, cytozin-arabinozid, doxorubicín, epirubicín, idarubicín, mitomycín-C, daktinomycín, mitramycín, cisplatinu, melfalan, chlórambucil, busulfán, cyklofosfamid, ifosfamid, nitrozómočoviny, tiotefan, vinkristin, taxol, taxoter, etoposid, teniposid, amsakrin, irinotekan, topotekan, epotilón, Iressa, OSI-774, inhibítory angiogenézy, inhibítory EGF, inhibítory VEGF, inhibítory CDK, inhibítory Her1 a Her2 a monoklonálne protilátky.52. The pharmaceutical composition of claim 51, wherein said anticancer agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxyphene, megestrol acetate, anastrazole, letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide, bicalutamide, bicaloteramide. -acetate, goserelin acetate, luprolide, finasteride, herceptin, methotrexate, 5-fluorouracil, cytosine-arabinoside, doxorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mitramycin, cisplatin, cyclosporamide, melphoramide, melphosulfofluoramide, melfalan, busphenamide, melphorofilane, chlorphosulfofluoride, , tiotefan, vincristine, taxol, taxoter, etoposide, teniposide, amsacrine, irinotecan, topotecan, epothilone, Iressa, OSI-774, angiogenesis inhibitors, EGF inhibitors, VEGF inhibitors, CDK inhibitors, Her1 and Her2 antibody inhibitors and monoclonal. 53. Spôsob liečby stavu spojeného s najmenej jedným enzýmom zo skupiny tyrozínkináz, vyznačujúci sa tým, že zahrňuje podávanie účinného množstva zlúčeniny podľa vynálezu cicavcovi, ktorého je potrebné liečiť.53. A method of treating a condition associated with at least one tyrosine kinase enzyme comprising administering an effective amount of a compound of the invention to a mammal in need of treatment. 54. Spôsob podľa nároku 53, vyznačujúci sa tým, že uvedená tyrozínkináza je zo skupiny enzýmov zahrňujúcich Abl, skupinu CDK, EGF, EMT, FGF, FAK, Flk-1/KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src alebo VEGF.54. The method of claim 53, wherein said tyrosine kinase is from the group of enzymes including Abl, CDK, EGF, EMT, FGF, FAK, Flk-1 / KDR, HER-2, IGF-1R, IR, LCK, MET, PDGF, Src or VEGF. 260260 55. Spôsob podľa nároku 53, vyznačujúci sa tým, že uvedenému cicavcovi sa podáva v kombinácii so zlúčeninou podľa vynálezu najmenej jeden ďalší antikancerogénny prostriedok.55. The method of claim 53, wherein said mammal is administered in combination with a compound of the invention at least one additional anticancer agent. 56. Spôsob podľa nároku 53, vyznačujúci sa tým, že uvedený stav je rakovina.56. The method of claim 53, wherein said condition is cancer. 57. Spôsob liečenia rakoviny, vyznačujúci sa tým, že zahrňuje podávanie terapeuticky účinného množstva kompozície podľa nároku 50 alebo 51 cicavcovi, ktorého je potrebné liečiť.57. A method of treating cancer comprising administering to a mammal in need thereof a therapeutically effective amount of a composition according to claim 50 or 51. 58. Spôsob liečenia proliferatívnej choroby, vyznačujúci sa tým, že zahrňuje podávanie terapeuticky účinného množstva kompozície podľa nároku 50 alebo 51 cicavcovi, ktorého je potrebné liečiť.58. A method of treating a proliferative disease, comprising administering to a mammal in need of treatment a therapeutically effective amount of a composition of claim 50 or 51.
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Families Citing this family (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7081454B2 (en) * 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
AU2003218236B2 (en) 2002-03-01 2007-12-06 Bristol-Myers Squibb Company Transgenic non-human mammals expressing constitutively activated tyrosine kinase receptors
EP1534703A2 (en) * 2002-06-12 2005-06-01 Abbott Laboratories Antagonists of melanin concentrating hormone receptor
WO2004050033A2 (en) * 2002-12-02 2004-06-17 Arqule, Inc. Method of treating cancers
EP1581539A4 (en) * 2003-01-03 2007-09-19 Bristol Myers Squibb Co Novel tyrosine kinase inhibitors
US7329678B2 (en) * 2003-01-28 2008-02-12 Smithkline Beecham Corporation Chemical compounds
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
JP5010917B2 (en) * 2003-08-29 2012-08-29 エグゼリクシス， インコーポレイテッド c-Kit Regulator and Method of Use
US20050075358A1 (en) * 2003-10-06 2005-04-07 Carboni Joan M. Methods for treating IGF1R-inhibitor induced hyperglycemia
DE102004010207A1 (en) * 2004-03-02 2005-09-15 Aventis Pharma S.A. New 4-benzimidazolyl-3(2H)-pyridazinone derivatives are kinase inhibitors, especially useful for treatment of cancer
DK1740591T3 (en) 2004-04-02 2009-10-26 Osi Pharm Inc Heterobicyclic protein kinase inhibitors substituted with a 6,6-biocyclic ring
EP1831168B1 (en) * 2004-12-16 2014-07-02 Vertex Pharmaceuticals Inc. Pyrid-2-ones useful as inhibitors of tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases.
WO2006130657A2 (en) 2005-05-31 2006-12-07 Bristol-Myers Squibb Company Stereoselective reduction process for the preparation of pyrrolotriazine compounds
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7345178B2 (en) 2005-08-04 2008-03-18 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
AU2006284900A1 (en) * 2005-08-29 2007-03-08 Vertex Pharmaceuticals Incorporated 3, 5-disubstituted pyrid-2-ones useful as inhibitors of Tec family of non-receptor tyrosine kinases
US7786120B2 (en) 2005-08-29 2010-08-31 Vertex Pharmaceuticals Incorporated Pyridones useful as inhibitors of kinases
WO2007027594A1 (en) 2005-08-29 2007-03-08 Vertex Pharmaceuticals Incorporated 3,5-disubstituted pyrid-2-ones useful as inhibitors of tec family of non-receptor tyrosine kinases
WO2007026720A1 (en) * 2005-08-31 2007-03-08 Taisho Pharmaceutical Co., Ltd. Ring-fused pyrazole derivative
US8575164B2 (en) 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
WO2007145203A1 (en) * 2006-06-13 2007-12-21 Daiichi Fine Chemical Co., Ltd. Optically active 2-amino-1-(4-fluorophenyl)ethanol
US8063225B2 (en) * 2006-08-14 2011-11-22 Chembridge Corporation Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders
WO2008022747A1 (en) * 2006-08-21 2008-02-28 F. Hoffmann-La Roche Ag Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents
WO2008025526A1 (en) * 2006-08-31 2008-03-06 F. Hoffmann-La Roche Ag Indole derivatives, their manufacture and use as pharmaceutical agents
WO2008144345A2 (en) 2007-05-17 2008-11-27 Bristol-Myers Squibb Company Biomarkers and methods for determining sensitivity to insulin growth factor-1 receptor modulators
TW200916472A (en) 2007-06-20 2009-04-16 Sirtris Pharmaceuticals Inc Sirtuin modulating compounds
EP2170859A1 (en) 2007-06-25 2010-04-07 F. Hoffmann-Roche AG Benzimidazole amido derivatives as kinase inhibitors
EP2065380A1 (en) * 2007-08-22 2009-06-03 F.Hoffmann-La Roche Ag Pyridoneamide derivatives as focal adhesion kinase (FAK) inhibitors and their use for the treatment of cancer
US7816540B2 (en) * 2007-12-21 2010-10-19 Hoffmann-La Roche Inc. Carboxyl- or hydroxyl-substituted benzimidazole derivatives
CA2712959C (en) 2008-01-22 2015-06-23 Vernalis (R & D) Ltd Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity
ES2396613T3 (en) 2008-05-19 2013-02-22 OSI Pharmaceuticals, LLC Imidazopyrazines and substituted imidazotriazines
EA021424B1 (en) 2008-12-19 2015-06-30 Сертрис Фармасьютикалз, Инк. Thiazolopyridine sirtuin modulating compounds
DE102010001064A1 (en) * 2009-03-18 2010-09-23 Bayer Schering Pharma Aktiengesellschaft Substituted 2-acetamido-5-aryl-1,2,4-triazolones and their use
CA2752826A1 (en) 2009-04-20 2010-10-28 OSI Pharmaceuticals, LLC Preparation of c-pyrazine-methylamines
CA2763624A1 (en) * 2009-05-27 2010-12-02 Abbott Laboratories Pyrimidine inhibitors of kinase activity
EP2494070A2 (en) 2009-10-30 2012-09-05 Bristol-Myers Squibb Company Methods for treating cancer in patients having igf-1r inhibitor resistance
EA022623B1 (en) * 2010-10-06 2016-02-29 ГЛАКСОСМИТКЛАЙН ЭлЭлСи Benzimidazole derivatives as pi3 kinase inhibitors
US8772304B2 (en) * 2010-11-01 2014-07-08 Boehringer Ingelheim International Gmbh Benzimidazole inhibitors of leukotriene production
US20140309229A1 (en) 2011-10-13 2014-10-16 Bristol-Myers Squibb Company Methods for selecting and treating cancer in patients with igf-1r/ir inhibitors
EP3674300B1 (en) 2013-06-21 2022-10-12 Zenith Epigenetics Ltd. Novel bicyclic bromodomain inhibitors
EP3010918B1 (en) * 2013-06-21 2018-08-15 Zenith Epigenetics Ltd. Novel substituted bicyclic compounds as bromodomain inhibitors
KR20160038008A (en) 2013-07-31 2016-04-06 제니쓰 에피제네틱스 코포레이션 Novel quinazolinones as bromodomain inhibitors
CN103936719A (en) * 2014-05-14 2014-07-23 中国药科大学 Preparation method and application of benzimidazoles derivatives
CN108064274A (en) 2014-07-30 2018-05-22 耶达研究及发展有限公司 For cultivating the culture medium of multipotential stem cell
WO2016087936A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Corp. Substituted pyridinones as bromodomain inhibitors
WO2016092375A1 (en) 2014-12-11 2016-06-16 Zenith Epigenetics Corp. Substituted heterocycles as bromodomain inhibitors
CN107406438B (en) 2014-12-17 2021-05-14 恒翼生物医药科技(上海)有限公司 Inhibitors of bromodomains
ES2766835T3 (en) * 2015-04-16 2020-06-15 Merck Patent Gmbh Derivatives of 3- (1H-benzimidazol-2-yl) -1H-pyridin-2-one
EP3914698A1 (en) 2019-01-23 2021-12-01 Yeda Research and Development Co. Ltd Culture media for pluripotent stem cells
CN117069696B (en) * 2023-08-17 2024-04-26 中国药科大学 Double-target small molecule inhibitor and preparation method and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6162804A (en) * 1997-09-26 2000-12-19 Merck & Co., Inc. Tyrosine kinase inhibitors
EP1194425B1 (en) * 1999-06-23 2005-08-10 Aventis Pharma Deutschland GmbH Substituted benzimidazole
US7081454B2 (en) * 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors

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