HRP20040898A2 - 4-(n-phenylamino)-quinazolines/quinolines as tyrosine kinase inhibitors - Google Patents

4-(n-phenylamino)-quinazolines/quinolines as tyrosine kinase inhibitors Download PDF

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HRP20040898A2
HRP20040898A2 HR20040898A HRP20040898A HRP20040898A2 HR P20040898 A2 HRP20040898 A2 HR P20040898A2 HR 20040898 A HR20040898 A HR 20040898A HR P20040898 A HRP20040898 A HR P20040898A HR P20040898 A2 HRP20040898 A2 HR P20040898A2
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alkyl
amino
morpholin
oxo
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Himmelsbach Frank
Jung Birgit
Solca Flavio
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Boehringer Ingelheim Pharma Gmbh & Co.Kg.
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Priority claimed from DE10214412A external-priority patent/DE10214412A1/en
Priority claimed from DE2002131711 external-priority patent/DE10231711A1/en
Application filed by Boehringer Ingelheim Pharma Gmbh & Co.Kg. filed Critical Boehringer Ingelheim Pharma Gmbh & Co.Kg.
Publication of HRP20040898A2 publication Critical patent/HRP20040898A2/en

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    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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    • A—HUMAN NECESSITIES
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Description

Predmet predloženog izuma su biciklički heterocikli opće formule The subject of the proposed invention are bicyclic heterocycles of the general formula

[image] [image]

njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli, posebno njihove fiziološki podnošljive soli s anorganskim ili organskim kiselinama, koji imaju dragocjena farmakološka svojstva, naročito inhibicijski učinak na prijenos signala posredovan s tirozin kinazom, njihova upotreba za liječenje bolesti, naročito tumorskih bolesti kao i benigne hiperplazije prostate (BPH), bolesti pluća i dišnih putova, i njihova proizvodnja. U gornjoj općoj formuli I their tautomers, their stereoisomers, their mixtures and their salts, especially their physiologically tolerable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular the inhibitory effect on signal transmission mediated by tyrosine kinase, their use for the treatment of diseases, especially tumor diseases as and benign prostatic hyperplasia (BPH), lung and respiratory diseases, and their production. In the general formula I above

Ra predstavlja vodikov atom ili C1-4-alkilnu skupinu, Ra represents a hydrogen atom or a C1-4-alkyl group,

Rbje fenilna ili 1-feniletilna skupina, u kojoj je fenilna jezgra supstituirana u svakom slučaju s radikalima R1 do R3, pri čemu Rbje is a phenyl or 1-phenylethyl group, in which the phenyl nucleus is substituted in each case with radicals R1 to R3, wherein

R1 i R2, koji mogu biti jednaki ili različiti, u svakom slučaju predstavljaju vodik, fluor, klor, brom ili atom joda, R1 and R2, which may be the same or different, in any case represent hydrogen, fluorine, chlorine, bromine or an iodine atom,

C1-4-alkil, hidroksi, C1-4-alkoksi, C2-3-alkenil ili C2-3-alkinilnu skupinu, C1-4-alkyl, hydroxy, C1-4-alkoxy, C2-3-alkenyl or C2-3-alkynyl group,

aril, ariloksi, arilmetil ili arilmetoksi skupinu, an aryl, aryloxy, arylmethyl or arylmethoxy group,

heteroaril, heteroariloksi, heteroarilmetil ili heteroarilmetoksi skupinu, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group,

metilnu ili metoksi skupinu supstituiranu s 1 do 3 atoma fluora, ili a methyl or methoxy group substituted with 1 to 3 fluorine atoms, or

cijano, nitro ili amino skupinu, i cyano, nitro or amino group, i

R3je vodik, fluor, klor ili atom broma, ili R 3 is hydrogen, fluorine, chlorine or a bromine atom, or

metilna ili trifluormetilna skupina, methyl or trifluoromethyl group,

Rc je ciklobutil, ciklopentil ili cikloheksilna skupina, koja je supstituirana u svakom slučaju sa skupinom R4-N-R5, pri čemu Rc is a cyclobutyl, cyclopentyl or cyclohexyl group, which is substituted in each case with the group R4-N-R5, wherein

R4je vodikov atom ili C1-3-alkilna skupina i R4 is a hydrogen atom or a C1-3-alkyl group and

R5 je vodikov atom ili C1-3-alkilna skupina, aminokarbonil-C1-3-alkil, C1-3-alkil amino karbonil-C1-3-alkil, di(C1-3-alkil)aminokarbonil-C1-3-alkil, pirolidin-1-ilkarbonil-C1-3-alkil, piperidin-1-ilkarbonil-C1-3-alkil, homopiperidin-1-ilkarbonil-C1-3-alkil, morfolin-4-ilkarbonil-C1-3-alkil, homomorfolin-4-ilkarbonil-C1-3-alkil, piperazin-1-il-karbonil-C1-3-alkil, 4-C1-3-alkil-piperazin-1-ilkarbonil-C1-3-alkil, homopiperazin-1-ilkarbonil-C1-3-alkil ili 4-C1-3-alkil-homopiperazin-1-il-karbonil-C1-3-alkilna skupina, R5 is a hydrogen atom or a C1-3-alkyl group, aminocarbonyl-C1-3-alkyl, C1-3-alkyl aminocarbonyl-C1-3-alkyl, di(C1-3-alkyl)aminocarbonyl-C1-3-alkyl, pyrrolidin-1-ylcarbonyl-C1-3-alkyl, piperidin-1-ylcarbonyl-C1-3-alkyl, homopiperidin-1-ylcarbonyl-C1-3-alkyl, morpholin-4-ylcarbonyl-C1-3-alkyl, homomorpholin- 4-ylcarbonyl-C1-3-alkyl, piperazin-1-yl-carbonyl-C1-3-alkyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl-C1-3-alkyl, homopiperazin-1-ylcarbonyl- C1-3-alkyl or 4-C1-3-alkyl-homopiperazin-1-yl-carbonyl-C1-3-alkyl group,

hidroksi-C2-4-alkil, C1-3-alkiloksi-C2-4-alkil, C1-4-alkiloksi-karbonilamino-C2-4-alkil, amino-C2-4-alkil, C1-3-alkilamino-C2-4-alkil, di-(C1-3-alkil) amino-C2-4-alkil, C1-3-alkilkarbonilamino-C2-4-alkil, aminokarbonilamino-C2-4-alkil, C1-3-alkilaminokarbonilamino-C2-4-alkil, di-(C1-3-alkil) amino-karbonilamino-C2-4-alkil, pirolidin-1-il-karbonilamino-C2-4-alkil, piperidin-1-ilkarbonilamino-C2-4-alkil, morfolion-4-ilkarbonilamino-C2-4-alkil, C1-3-alkilsulfonil-C2-4-alkil ili C1-3-alkilsulfonilamino-C2-4-alkilna skupina, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C1-4-alkyloxy-carbonylamino-C2-4-alkyl, amino-C2-4-alkyl, C1-3-alkylamino-C2- 4-alkyl, di-(C1-3-alkyl) amino-C2-4-alkyl, C1-3-alkylcarbonylamino-C2-4-alkyl, aminocarbonylamino-C2-4-alkyl, C1-3-alkylaminocarbonylamino-C2-4 -alkyl, di-(C1-3-alkyl) amino-carbonylamino-C2-4-alkyl, pyrrolidin-1-yl-carbonylamino-C2-4-alkyl, piperidin-1-ylcarbonylamino-C2-4-alkyl, morpholion- 4-ylcarbonylamino-C2-4-alkyl, C1-3-alkylsulfonyl-C2-4-alkyl or C1-3-alkylsulfonylamino-C2-4-alkyl group,

(2-okso-pirolidin-1-il)-C2-4-alkil, (2-oksopiperidin-1-il)-C2-4-alkil, (3-okso-morfolin-4-il)-C2-4-alkil, 2-okso-imidazolidin-1-il)-C2-4-alkil, 2-okso-3-C1-3-alkil-imidazolidin-1-il)-C2-4-alkil, (2-okso-heksahidropirimidin-1-il)-C2-4-alkil ili (2-okso-3-C1-3-alkil-heksahidropirimidin-1-il)-C2-4-alkilna skupina, (2-oxo-pyrrolidin-1-yl)-C2-4-alkyl, (2-oxopiperidin-1-yl)-C2-4-alkyl, (3-oxo-morpholin-4-yl)-C2-4- alkyl, 2-oxo-imidazolidin-1-yl)-C2-4-alkyl, 2-oxo-3-C1-3-alkyl-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-hexahydropyrimidine -1-yl)-C2-4-alkyl or (2-oxo-3-C1-3-alkyl-hexahydropyrimidin-1-yl)-C2-4-alkyl group,

C1-4-alkilsulfonil, klor-C1-4-alkilsulfonil, brom-C1-4-alkilsulfonil, amino-C1-4-alkilsulfonil, C1-3-alkilamino-C1-4-alkilsulfonil, di-(C1-3-alkil)amino-C1-4-alkilsulfonil, (pirolidin-1-il)-C1-4-alkilsulfonil, (piperidin-1-il)-C1-4-alkilsulfonil, (homopiperidin-1-il)-C1-4-alkilsulfonil, (morfolin-4-il)-C1-4-alkilsulfonil, (homomorfolin-4-il)-C1-4-alkilsulfonil, (piperazin-1-il)-C1-4-alkilsulfonil, (4-C1-3-alkil-piperazin-1-il)-C1-4-alkilsulfonil, (homo-piperazin-1-il)-C1-4-alkilsulfonil ili (4-C1-3-alkil-homo-piperazin-1-il)-C1-4-alkilsulfonilna skupina, C1-4-alkylsulfonyl, chloro-C1-4-alkylsulfonyl, bromo-C1-4-alkylsulfonyl, amino-C1-4-alkylsulfonyl, C1-3-alkylamino-C1-4-alkylsulfonyl, di-(C1-3-alkyl )amino-C1-4-alkylsulfonyl, (pyrrolidin-1-yl)-C1-4-alkylsulfonyl, (piperidin-1-yl)-C1-4-alkylsulfonyl, (homopiperidin-1-yl)-C1-4-alkylsulfonyl , (morpholin-4-yl)-C1-4-alkylsulfonyl, (homomorpholin-4-yl)-C1-4-alkylsulfonyl, (piperazin-1-yl)-C1-4-alkylsulfonyl, (4-C1-3- alkyl-piperazin-1-yl)-C1-4-alkylsulfonyl, (homo-piperazin-1-yl)-C1-4-alkylsulfonyl or (4-C1-3-alkyl-homo-piperazin-1-yl)-C1 -4-alkylsulfonyl group,

C1-4-alkiloksikarbonilna skupina, C1-4-alkyloxycarbonyl group,

formil, C1-4-alkil-karbonil, C1-3-alkiloksi-C1-4-alkil-karbonil, tetrahidrofuranilkarbonil, tetrahidropiranil-karbonil, amino-C1-4-alkil-karbonil, C1-3-alkilamino-C1-4-alkil-karbonil, di-(C1-3-alkil)amino-C1-4-alkil-karbonil, pirolidin-1-il-C1-4-alkil-karbonil, piperidin-1-il-C1-4-alkil-karbonil, (homopiperidin-1-il)-C1-4-alkil-karbonil, morfolin-4-il-C1-4-alkil-karbonil, (homomorfolin-4-il)-C1-4-alkil-karbonil, (piperazin-1-il)-C1-4-alkil-karbonil, (4-C1-3-alkil-piperazin-1-il)-C1-4-alkil-karbonil, (homo-piperazin-1-il)-C1-4-alkil-karbonil, (4-C1-3-alkil-homo-piperazin-1-il)-C1-4-alkil-karbonil ili C1-3-alkilsulfonil-C1-4-alkil-karbonilna skupina, formyl, C1-4-alkyl-carbonyl, C1-3-alkyloxy-C1-4-alkyl-carbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranyl-carbonyl, amino-C1-4-alkyl-carbonyl, C1-3-alkylamino-C1-4- alkyl-carbonyl, di-(C1-3-alkyl)amino-C1-4-alkyl-carbonyl, pyrrolidin-1-yl-C1-4-alkyl-carbonyl, piperidin-1-yl-C1-4-alkyl-carbonyl , (homopiperidin-1-yl)-C1-4-alkyl-carbonyl, morpholin-4-yl-C1-4-alkyl-carbonyl, (homomorpholin-4-yl)-C1-4-alkyl-carbonyl, (piperazine- 1-yl)-C1-4-alkyl-carbonyl, (4-C1-3-alkyl-piperazin-1-yl)-C1-4-alkyl-carbonyl, (homo-piperazin-1-yl)-C1-4 -alkyl-carbonyl, (4-C1-3-alkyl-homo-piperazin-1-yl)-C1-4-alkyl-carbonyl or C1-3-alkylsulfonyl-C1-4-alkyl-carbonyl group,

cijano, aminokarbonil, C1-3-alkil-aminokarbonil, di-(C1-3-alkil) amino-karbonil, (C1-3-alkiloksi-C2-4-alkil) aminokarbonil, N-(C1-3-alkil)-N-(C1-3-alkiloksi-C2-4-alkil)aminokarbonil, arilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, homopiperidin-1-ilkarbonil, morfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo-[3.2.1]okt-8-ilkarbonil, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarbonil, piperazin-1-ilkarbonil, 4-C1-3-alkil-piperazin-1-ilkarbonil, homopiperazin-1-ilkarbonil, 4-C1-3-alkil-homopiperazin-1-ilkarbonil, aminosulfonil, C1-3-alkil-aminosulfonil, di-(C1-3-alkil)amino-sulfoni1, pirolidin-1-il-sulfonil, piperidin-1-ilsulfonil, homopiperidin-1-il-sulfonil, morfolin-4-ilsulfonil, homomorfolin-4-ilsulfonil, piperazin-1-ilsulfonil, 4-C1-3-alkil-piperazin-1-il-sulfonil, homopiperazin-1-ilsulfonil ili 4-C1-3-alkil-homo-piperazin-1-ilsulfonilna skupina, cyano, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl) amino-carbonyl, (C1-3-alkyloxy-C2-4-alkyl) aminocarbonyl, N-(C1-3-alkyl)- N-(C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2 -oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[ 3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl, 4-C1-3-alkyl-homopiperazin-1-ylcarbonyl, aminosulfonyl, C1-3-alkyl-aminosulfonyl, di-(C1-3-alkyl)amino-sulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl, homopiperidin-1-yl-sulfonyl, morpholin-4-ylsulfonyl , homomorpholin-4-ylsulfonyl, piperazin-1-ylsulfonyl, 4-C1-3-alkyl-piperazin-1-yl-sulfonyl, homopiperazin-1-ylsulfonyl or 4-C1-3-alkyl-homo-piperazin-1-ylsulfonyl group,

ciklobutil, ciklopentil ili ciklohekslna skupina koja je supstituirana u svakom slučaju sa skupinom R6, gdje cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case with the group R6, where

R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-C1-3-alkil-imidazolidin-1-il, 2-okso-heksahidro-pirimidin-1-il ili 2-okso-3-C1-3-alkil-heksahidro-pirimidin-1-il skupina, R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-C1-3- alkyl-imidazolidin-1-yl, 2-oxo-hexahydro-pyrimidin-1-yl or 2-oxo-3-C1-3-alkyl-hexahydro-pyrimidin-1-yl group,

azetidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, an azetidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above,

pirolidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, a pyrrolidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above,

piperidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, a piperidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above,

piperidin-4-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, ili a piperidin-4-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above, or

tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd je vodikov atom ili fluor, klor ili atom broma, Rd is a hydrogen atom or a fluorine, chlorine or bromine atom,

hidroksi skupina, hydroxy group,

C1-4-alkiloksi skupina, C1-4-alkyloxy group,

metoksi skupina supstituirana s 1 do 3 atoma fluora, methoxy group substituted with 1 to 3 fluorine atoms,

etiloksi skupina supstituirana s 1 do 5 atoma fluora, ethyloxy group substituted with 1 to 5 fluorine atoms,

C2-4-alkiloksi skupina koja je supstituirana s radikalom R6 ili R7 , pri čemu C2-4-alkyloxy group which is substituted with the radical R6 or R7, wherein

R6 definiran kao ovdje gore, i R6 defined as above, i

R7 je hidroksi, C1-3-alkiloksi, C3-6-cikloalkiloksi, amino, C1-3-alkilamino, di-(C1-3-alkil)amino, bis-(2-metoksietil)amino, pirolidin-1-il, piperidin-1-il, homo-piperidin-1-il, morfolin-4-il, homomorfolin-4-il, 2-oksa-5-aza-biciklo[2.2.1]hept-5-il, 3-oksa-8-aza-biciklo[3.2.1]-okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il, 4-C1-3-alkil-piperazin-1-il, homopiperazin-1-il ili C1-3-alkil-homopiperazin-1-il skupina, ili R7 is hydroxy, C1-3-alkyloxy, C3-6-cycloalkyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-methoxyethyl)amino, pyrrolidin-1-yl, piperidin-1-yl, homo-piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa- 8-aza-bicyclo[3.2.1]-oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl, 4-C1-3-alkyl -piperazin-1-yl, homopiperazin-1-yl or C1-3-alkyl-homopiperazin-1-yl group, or

formilamino, C1-4-alkilkarbonilamino, C1-3-alkiloksi-C1-3-alkil-karbonilamino, C1-4-alkiloksikarbonil amino, aminokarbonilamino, C1-3-alkilaminokarbonilamino, di-(C1-3-alkil)aminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarboni1amino, piperazin-1-i1karboni1amino, 4-C1-4-alkil-piperazin-1-ilkarbonilamino-morfolin-4-il-karbonilamino ili C1-4-alkilsulfonilarainoskupina, formylamino, C1-4-alkylcarbonylamino, C1-3-alkyloxy-C1-3-alkylcarbonylamino, C1-4-alkyloxycarbonyl amino, aminocarbonylamino, C1-3-alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidine- 1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C1-4-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-yl-carbonylamino or C1-4-alkylsulfonylarino,

C3-7-cikloalkiloksi ili C3-7-cikloalkil-C1-4-alkiloksi skupina, C3-7-cycloalkyloxy or C3-7-cycloalkyl-C1-4-alkyloxy group,

tetrahidrofuran-3-iloksi, tetrahidropiran-3-iloksi ilitetrahidropiran-4-iloksi skupina, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group,

tetrahidrofuranil-C1-4-alkiloksi ili tetrahidro-piranil-C1-4-alkiloksi skupina, tetrahydrofuranyl-C1-4-alkyloxy or tetrahydro-pyranyl-C1-4-alkyloxy group,

C1-4-alkoksi skupina, supstituirana s pirolidinilnom, piperidinilnom ili s homopiperidinilnom skupinom, koja je u položaju 1 supstituirana s radikalom R8, pri čemu C1-4-Alkoxy group, substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group, which is substituted in position 1 with the radical R8, wherein

R8 je vodikov atom ili C1-3-alkilna skupina, ili C1-4-alkoksi skupina supstituirana s morfolinilnom skupinom koja je u položaju 4 supstituirana s ostatkom R8, pri čemu je R8 definiran kao gore, i R8 is a hydrogen atom or a C1-3-alkyl group, or a C1-4-alkoxy group substituted with a morpholinyl group which is substituted in position 4 with the residue R8, where R8 is defined as above, and

X je metinska skupina supstituirana sa cijano skupinom ili dušikov atom, X is a methine group substituted with a cyano group or a nitrogen atom,

pri čemu arilne skupine, koje su spomenute kod definicije gornjih radikala, znače u svakom slučaju fenilnu skupinu, koja je mono- ili disupstituirana s R9, pri čemu supstituenti mogu biti jednaki ili različiti i where the aryl groups, which are mentioned in the definition of the above radicals, mean in each case a phenyl group, which is mono- or disubstituted with R9, whereby the substituents can be the same or different and

R9 je vodikov atom, fluor, klor, brom ili atom joda ili C1-3-alkil, hidroksi, C1-3-alkiloksi, difluormetil, trifluormetil, difluormetoksi, trifluormetoksi ili cijano skupina, R9 is a hydrogen atom, fluorine, chlorine, bromine or iodine atom or a C1-3-alkyl, hydroxy, C1-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group,

heteroarilne skupine koje su spomenute kod definicije gornjih radikala znače piridil, piridazinil, pirimidinil ili pirazinilnu skupinu, pri čemu su gore spomenute heteroarilne skupine u svakom slučaju mono- ili disupstituirane s radikalom R i pri čemu supstituenti mogu biti jednaki ili različiti, a R9 je definiran kao gore, i the heteroaryl groups mentioned in the definition of the above radicals mean a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, wherein the above-mentioned heteroaryl groups are in each case mono- or disubstituted with the radical R and wherein the substituents may be the same or different, and R9 is defined as above, and

gore spomenuta pirolidinilna, piperidinilna, piperazinilna i morfolinilna skupina mogu biti u svakom slučaju supstituirane s jednom ili dvije C1-3-alkilne skupine, i the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may in each case be substituted with one or two C1-3-alkyl groups, and

ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, unless stated otherwise, the aforementioned alkyl groups may be straight or branched,

pod uvjetom da je isključen spoj 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-hidroksi-kinazolin. provided that the compound 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded.

Prednost se daje onim spojevima gornje opće formule I u kojoj Preference is given to those compounds of the above general formula I in which

Ra je vodikov atom, Ra is a hydrogen atom,

Rbje fenil skupina supstituirana s radikalima R1 do R3, pri čemu Rb is a phenyl group substituted with radicals R1 to R3, wherein

R1 je vodik, fluor, klor ili atom broma, R1 is hydrogen, fluorine, chlorine or bromine atom,

metil, trifluormetil ili etinilna skupina, a methyl, trifluoromethyl or ethynyl group,

feniloksi ili fenilmetoksi skupina, pri čemu fenilni dio u gore spomenutim skupinama je prema potrebi supstituiran s jednim atomom fluora ili klora, ili a phenyloxy or phenylmethoxy group, wherein the phenyl part in the aforementioned groups is optionally substituted with one fluorine or chlorine atom, or

piridiloksi ili piridinilmetoksi skupina, pri čemu piridinilni dio u gore spomenutim skupinama je prema potrebi supstituiran s metilnom ili trifluormetilnom skupinom, pyridyloxy or pyridinylmethoxy group, whereby the pyridinyl part in the above-mentioned groups is optionally substituted with a methyl or trifluoromethyl group,

R2 je vodik, fluor ili atom klora ili metilna skupina i R2 is hydrogen, fluorine or chlorine atom or methyl group and

R3 je vodikov atom, R3 is a hydrogen atom,

Rc je ciklopentilna skupina, koja je u položaju 3 supstituirana sa skupinom R4-N-R5, pri čemu Rc is a cyclopentyl group, which is substituted in position 3 with the group R4-N-R5, whereby

R4 je vodikov atom ili C1-3-alkilna skupina i R4 is a hydrogen atom or a C1-3-alkyl group and

R5 je vodikov atom ili C1-3-alkilna skupila, aminokarbonil-C1-3-alkil, C1-3-alkilaminokarbonil-C1-3-alkil, di-(C1-3-alkil)aminokarbonil-C1-3-alkil, pirolidin-1-ilkarbonil-C1-3-alkil, piperidin-1-il-karbonil-C1-3-alkil, piperazin-1-ilkarbonil-C1-3-alkil, 4-C1-3-alkil-piperazin-1-il-karbonil-C1-3-alkil ili morfolin-4-ilkarbonil-C1-3-alkilna skupina, R5 is a hydrogen atom or a C1-3-alkyl group, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, di-(C1-3-alkyl)aminocarbonyl-C1-3-alkyl, pyrrolidine -1-ylcarbonyl-C1-3-alkyl, piperidin-1-yl-carbonyl-C1-3-alkyl, piperazin-1-ylcarbonyl-C1-3-alkyl, 4-C1-3-alkyl-piperazin-1-yl -carbonyl-C1-3-alkyl or morpholin-4-ylcarbonyl-C1-3-alkyl group,

hidroksi-C2-4-alkil, C1-3-alkiloksi-C2-4-alkil, C1-4-alkiloksi-karbonilamino-C2-4-alkil, amino-C2-4-alkil, C1-3-alkilamino-C2-4-alkil, di-(C1-3-alkil) amino-C2-4-alkil, C1-3-alkilkarbonilamino-C2-4-alkil, aminokarbonilamino-C2-4-alkil, C1-3-alkilaminokarbonilamino-C2-4-alkil, di-(C1-3-alkil)amino-karbonilamino-C2-4-alkil, morfolin-4-il-karbonilamino-C2-4-alkil, C1-3-alkilsulfonil-C2-4-alkil ili C1-3-alkilsulfonilamino-C2-4-alkilna skupina, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C1-4-alkyloxy-carbonylamino-C2-4-alkyl, amino-C2-4-alkyl, C1-3-alkylamino-C2- 4-alkyl, di-(C1-3-alkyl) amino-C2-4-alkyl, C1-3-alkylcarbonylamino-C2-4-alkyl, aminocarbonylamino-C2-4-alkyl, C1-3-alkylaminocarbonylamino-C2-4 -alkyl, di-(C1-3-alkyl)amino-carbonylamino-C2-4-alkyl, morpholin-4-yl-carbonylamino-C2-4-alkyl, C1-3-alkylsulfonyl-C2-4-alkyl or C1- 3-alkylsulfonylamino-C2-4-alkyl group,

(2-okso-pirolidin-1-il)-C2-4-alkil, (2-oksopiperidin-1-il)-C2-4-alkil, (3-okso-morfolin-4-il)-C2-4-alkil, (2-okso-imidazolidin-1-il)-C2-4-alkil, (2-okso-3-metil-imidazolidin-1-il)-C2-4-alkil, (2-okso-heksahidropirimidin-1-il)-C2-4-alkil ili (2-okso-3-metil-heksahidropirimidin-1-il)-C2-4-alkilna skupina, (2-oxo-pyrrolidin-1-yl)-C2-4-alkyl, (2-oxopiperidin-1-yl)-C2-4-alkyl, (3-oxo-morpholin-4-yl)-C2-4- alkyl, (2-oxo-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-3-methyl-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-hexahydropyrimidin-1 -yl)-C2-4-alkyl or (2-oxo-3-methyl-hexahydropyrimidin-1-yl)-C2-4-alkyl group,

C1-3-alkilsulfonil, klor-C2-4-alkilsulfonil, brom-C2-4-alkilsulfonil, amino-C2-4-alkilsulfonil, C1-3-alkilamino-C2-4-alkilsulfonil, di-(C1-3-alkil)amino-C2-4-alkilsulfonil, (pirolidin-1-il)-C2-4-alkilsulfonil, (piperidin-1-il)-C2-4-alkilsulfonil ili (morfolin-4-il)-C2-4-alkilsulfonilna skupina, C1-3-alkylsulfonyl, chloro-C2-4-alkylsulfonyl, bromo-C2-4-alkylsulfonyl, amino-C2-4-alkylsulfonyl, C1-3-alkylamino-C2-4-alkylsulfonyl, di-(C1-3-alkyl )amino-C2-4-alkylsulfonyl, (pyrrolidin-1-yl)-C2-4-alkylsulfonyl, (piperidin-1-yl)-C2-4-alkylsulfonyl or (morpholin-4-yl)-C2-4-alkylsulfonyl group,

C1-4-alkiloksikarbonilna skupina, C1-4-alkyloxycarbonyl group,

formil, C1-3-alkilkarbonil, C1-3-alkiloksi-C1-3-alkil-karbonil, tetrahidrofuranilkarbonil, tetrahidropiranil-karbonil, amino-C1-3-alkilkarbonil, C1-3-alkilamino-C1-3-alkilkarbonil, di-(C1-3-alkil) amino-C1-3-alkilkarbonil, pirolidin-1-il-C1-3-alkilkarbonil, piperidin-1-il-C1-3-alkilkarbonil, piperazin-1-il-C1-3-alkil-karbonil, 4-C1-3-alkilpiperazin-1-il-C1-3-alkilkarboni1, morfolin-4-il-C1-3-alkilkarbonil ili C1-3-alkilsulfonil-C1-3-alkilkarbonilna skupina, ili formyl, C1-3-alkylcarbonyl, C1-3-alkyloxy-C1-3-alkylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranyl-carbonyl, amino-C1-3-alkylcarbonyl, C1-3-alkylamino-C1-3-alkylcarbonyl, di- (C1-3-alkyl) amino-C1-3-alkylcarbonyl, pyrrolidin-1-yl-C1-3-alkylcarbonyl, piperidin-1-yl-C1-3-alkylcarbonyl, piperazin-1-yl-C1-3-alkyl -carbonyl, 4-C1-3-alkylpiperazin-1-yl-C1-3-alkylcarbonyl, morpholin-4-yl-C1-3-alkylcarbonyl or C1-3-alkylsulfonyl-C1-3-alkylcarbonyl group, or

cijano, aminokarbonil, C1-3-alkilaminokarbonil, di-(C1-3-alkil)aminokarbonil, (C1-3-alkiloksi-C2-4-alkil)aminokarbonil, N-(C1-3-alkil)-N-(C1-3-alkiloksi-C2-4-alkil)aminokarbonil, fenilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, C1-3-alkil-morfolin-4-ilkarbonil, di-(C1-3-alkil)morfolin-4-il-karbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo-[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo[3.2.1]okt-8-ilkarboni1, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarboni1, piperazin-1-ilkarbonil, 4-(C1-3-alkil)-piperazin-1-il-karbonil, aminosulfonil, C1-3-alkil-aminosulfonil, di-(C1-3-alkil)aminosulfonil, pirolidin-1-il-sulfonil, piperidin-1-ilsulfonil ili morfolin-4-ilsulfonilna skupina, ili cyano, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)aminocarbonyl, (C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, N-(C1-3-alkyl)-N-(C1 -3-alkyloxy-C2-4-alkyl)aminocarbonyl, phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C1-3-alkyl-morpholin-4-ylcarbonyl, di-(C1- 3-Alkyl)morpholin-4-yl-carbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo-[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2 .1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-3-alkyl)-piperazin-1-yl -carbonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, di-(C1-3-alkyl)aminosulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl or morpholin-4-ylsulfonyl group, or

ciklopentilna skupina, koja je u položaju 3 supstituirana sa skupinom R6, pri čemu cyclopentyl group, which is substituted in position 3 with the group R6, wherein

R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metil-imidazolidin-1-il, 2-okso-heksahidro-pirimidin-1-il-ili 2-okso-3-metil-heksahidropirimidin-1-il skupina, R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin- 1-yl, 2-oxo-hexahydro-pyrimidin-1-yl-or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R4-N-R5, pri čemu su R4 i R5 definirani kao gore, cyclohexyl group, which is substituted in position 3 or in position 4 with the group R4-N-R5, wherein R4 and R5 are defined as above,

cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R6, pri čemu je R6 definiran kao gore, cyclohexyl group, which is substituted in the 3-position or in the 4-position with the group R6, wherein R6 is defined as above,

pirolidin-3-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, pyrrolidin-3-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above,

piperidin-3-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, piperidin-3-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above,

piperidin-4-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, ili piperidin-4-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above, or

tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd je vodikov atom, Rd is a hydrogen atom,

C1-3-alkiloksi skupina, C1-3-alkyloxy group,

metoksi skupina, koja je supstituirana s jednim do tri atoma fluora, methoxy group, which is substituted with one to three fluorine atoms,

etiloksi skupina, koja je u položaju 2 supstituirana s radikalom R6 ili R7, pri čemu ethyloxy group, which is substituted in position 2 with the radical R6 or R7, wherein

R6 je definiran kao gore i R6 is defined as above and

R7 je hidroksi, C1-3-alkil, amino, C1-3-alkilamino, di-(C1-3-alkil)amino, bis-(2-metoksietil)amino, pirolidin-1-il, piperidin-1-il, morfolin-4-il, 2-oksa-5-aza-biciklo-[2.2.1]hept-5-il, 3-oksa-8-aza[3.2.1]okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il ili 4-C1-3-alkil-piperazin-1-il skupina, ili R7 is hydroxy, C1-3-alkyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-methoxyethyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 2-oxa-5-aza-bicyclo-[2.2.1]hept-5-yl, 3-oxa-8-aza[3.2.1]oct-8-yl, 8-oxa-3 -aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl or 4-C1-3-alkyl-piperazin-1-yl group, or

formilamino, C1-4-alkilkarbonilamino, C1-3-alkiloksi-C1-3-alkil-karbonilamino, C1-4-alkiloksikarbonilamino, aminokarbonilamino, C1-3-alkilaminokarbonilamino, di-(C1-3-alkil)aminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarbonilamino, piperazin-1-ilkarbonilamino, 4-C1-3-alkil-piperazin-1-ilkarbonilamino-morfolin-4-il-karbonilamino ili C1-4-alkilsulfonilamino skupina, formylamino, C1-4-alkylcarbonylamino, C1-3-alkyloxy-C1-3-alkylcarbonylamino, C1-4-alkyloxycarbonylamino, aminocarbonylamino, C1-3-alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidine-1 -ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C1-3-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-yl-carbonylamino or C1-4-alkylsulfonylamino group,

propiloksi skupina, koja je u položaju 3 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, ili a propyloxy group, which is substituted in position 3 with the residue R6 or R7, wherein R6 and R7 are defined as above, or

butiloksi skupina, koja je u položaju 4 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, i a butyloxy group, which is substituted in position 4 with the residue R6 or R7, wherein R6 and R7 are defined as above, and

X je dušikov atom, X is a nitrogen atom,

pri čemu, ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, njihovim tautomerima, njihovim stereoizomerima, njihovim smjesama i njihovim solima. wherein, unless stated otherwise, the aforementioned alkyl groups may be straight or branched, their tautomers, their stereoisomers, their mixtures and their salts.

Posebnu prednost se daje onim spojevima gornje opće formule I u kojoj Particular preference is given to those compounds of the above general formula I in which

Ra je vodikov atom, Ra is a hydrogen atom,

Rbje 3-etinilfenil, 3-bromfenil, 3,4-difluorfenil ili 3-klor-4-fluor-fenilna skupina, 3-klor-4-benziloksi-fenil, 3-klor-4-[(3-fluor-benzil)-oksi]fenil, 4-(piridin-3-iloksi)-fenil, 4-[(6-metil-piridin-3-il)oksi]-fenil, 3-metil-4-(piridin-3-iloksi)-fenil, 3-metil-4-[(6-metil-piridin-3-il)oksi]-fenil, 3-klor-4-(piridin-3-iloksi)-fenil ili 3-klor-4-[(6-metil-piridin-3-il)oksi]-fenilna skupina, Rbje 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group, 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl) -oxy]phenyl, 4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-methyl-4-(pyridin-3-yloxy)- phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-chloro-4-(pyridin-3-yloxy)-phenyl or 3-chloro-4-[(6 -methyl-pyridin-3-yl)oxy]-phenyl group,

Rc je cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R4-N-R5, pri čemu Rc is a cyclohexyl group, which is substituted in position 3 or in position 4 with the group R4-N-R5, whereby

R4 je vodikov atom, metilna ili etilna skupina i R4 is a hydrogen atom, methyl or ethyl group and

R5 je vodikov atom, metil, aminokarbonilmetil, metilamino-karbonilmetil, dimetilaminokarbonilmetil, pirolidin-1-ilkarbonilmetil, piperidin-1-ilkarbonilmetil, piperazin-1-ilkarbonilmetil-, 4-metilpiperazin-1-il-karbonilmetil, morfolin-4-ilkarbonilmetil, 2-(morfolin-4-il-karbonil)etil ili 3-(morfolin-4-il-karbonil)propilna skupina, R5 is a hydrogen atom, methyl, aminocarbonylmethyl, methylamino-carbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidin-1-ylcarbonylmethyl, piperidin-1-ylcarbonylmethyl, piperazin-1-ylcarbonylmethyl-, 4-methylpiperazin-1-yl-carbonylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl)ethyl or 3-(morpholin-4-yl-carbonyl)propyl group,

etil, propil, 2-hidroksietil, 3-hidroksipropil, 2-metoksietil, 3-metoksipropil, 2-(butiloksikarbonilamino)-etil, 2-aminoetil, 3-aminopropil, 2-(acetilamino)etil, 3-(acetilamino)propil, 2-(etilkarbonilamino)etil, 3-(etil-karbonilamino)propil, 2-(propilkarbonilamino)etil, 3-(propilkarbonilamino)propil, 2-(etilaminokarbonilamino)-etil, 3-(etilaminokarbonilamino)propil, 2-(dimetilamino-karbonilamino)etil, 3-(dimetilamino-karbonilamino)propil, 2-(morfolin-4-ilkarbonilamino)etil, 3-(morfolin-4-il-karbonilamino)propil, 2-(metilsulfonil)etil, 3-(metil-sulfonil)propil, 2-(metilsulfonilamino)etil ili 3-(metil-sulfonilamino)propilna skupina, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(butyloxycarbonylamino)-ethyl, 2-aminoethyl, 3-aminopropyl, 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 2-(ethylcarbonylamino)ethyl, 3-(ethyl-carbonylamino)propyl, 2-(propylcarbonylamino)ethyl, 3-(propylcarbonylamino)propyl, 2-(ethylaminocarbonylamino)-ethyl, 3-(ethylaminocarbonylamino)propyl, 2-(dimethylamino- carbonylamino)ethyl, 3-(dimethylamino-carbonylamino)propyl, 2-(morpholin-4-ylcarbonylamino)ethyl, 3-(morpholin-4-yl-carbonylamino)propyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl) )propyl, 2-(methylsulfonylamino)ethyl or 3-(methylsulfonylamino)propyl group,

2-(2-okso-pirolidin-1-il)etil, 2-(2-okso-piperidin-1-il)etil, 2-(3-okso-morfolin-4-il)etil, 2-(2-okso-imidazolidin-1-il)etil, 2-(2-okso-3-metil-imidazolidin-1-il)-etil, 2-(2-okso-heksahidropiridin-1-il)etil ili 2-(2-okso-3-metil-heksahidropirimidin-1-il)etilna skupina, 2-(2-oxo-pyrrolidin-1-yl)ethyl, 2-(2-oxo-piperidin-1-yl)ethyl, 2-(3-oxo-morpholin-4-yl)ethyl, 2-(2- oxo-imidazolidin-1-yl)ethyl, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl, 2-(2-oxo-hexahydropyridin-1-yl)ethyl or 2-(2- oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group,

3-(2-okso-pirolidin-1-il)propil, 3-(2-oksopiperidin-1-il)propil, 3-(3-okso-morfolin-4-il)propil, 3-(2-okso-imidazolidin-1-il)propil, 3-(2-okso-3-metil-imidazolidin-1-il)-propil, 3-(2-okso-heksahidropiridin-1-il)propil ili 3-(2-okso-3-metil-heksahidropirimidin-1-il)propilna skupina, 3-(2-oxo-pyrrolidin-1-yl)propyl, 3-(2-oxopiperidin-1-yl)propyl, 3-(3-oxo-morpholin-4-yl)propyl, 3-(2-oxo- imidazolidin-1-yl)propyl, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl, 3-(2-oxo-hexahydropyridin-1-yl)propyl or 3-(2-oxo- 3-methyl-hexahydropyrimidin-1-yl)propyl group,

metilsulfonil, etilsulfonil, 3-klorpropilsulfonil, 2-(morfolin-4-il)-etilsulfonil ili 3-(morfolin-4-il)-propil-sulfonilna skupina, methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2-(morpholin-4-yl)-ethylsulfonyl or 3-(morpholin-4-yl)-propyl-sulfonyl group,

propiloksikarbonilna ili butiloksikarbonilna skupina, propyloxycarbonyl or butyloxycarbonyl group,

formil, acetil, etilkarbonil, propilkarbonil, metoksi-acetil, (2-metoksietil)karbonil, (3-metoksipropil)-karbonil, tetrahidrofuran-2-ilkarbonil, tetrahidropiran-4-ilkarbonil, aminoacetil, metilaminoacetil, dimetilamino-acetil, morfolin-4-ilacetil, [2-(morfolin-4-il)etil]-karbonil, [3-(morfolin-4-il)propil]-karbonil ili metil-sulfonilacetilna skupina, formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxy-acetyl, (2-methoxyethyl)carbonyl, (3-methoxypropyl)-carbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl, dimethylaminoacetyl, morpholine-4 -ylacetyl, [2-(morpholin-4-yl)ethyl]-carbonyl, [3-(morpholin-4-yl)propyl]-carbonyl or methyl-sulfonylacetyl group,

cijano, aminokarbonil, metilaminokarbonil, dimetil-aminokarbonil, etilaminokarbonil, dietilaminokarbonil, propilaminokarbonil, (2-metoksietiljaminokarbonil, N-metil-N-(2-metoksietil)-aminokarbonil, (3-metoksipropil)-aminokarbonil, N-metil-N-(3-metoksipropil)-aminokarbonil, fenil-aminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-il-karbonil, morfolin-4-ilkarbonil, 2-metilmorfolin-4-il-karbonil, 2,6-dimetilmorfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo[3.2.1]okt-8-i1karbonil, 8-oksa-3-azabiciklo[3.2.1]okt-3-i1karbonil, 4-metilpiperazin-1-il-karbonil, aminosulfonil, metilaminosulfonil, dimetil-amino-sulfonil ili morfolin-4-ilsulfonilna skupina, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2-methoxyethylaminocarbonyl, N-methyl-N-(2-methoxyethyl)-aminocarbonyl, (3-methoxypropyl)-aminocarbonyl, N-methyl-N-( 3-methoxypropyl)-aminocarbonyl, phenyl-aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-yl-carbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-yl-carbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl , homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa -3-azabicyclo[3.2.1]oct-3-ylcarbonyl, 4-methylpiperazin-1-yl-carbonyl, aminosulfonyl, methylaminosulfonyl, dimethyl-amino-sulfonyl or morpholin-4-ylsulfonyl group,

cikloheksilna skupina koja je supstituirana u položaju 3 ili u položaju 4 sa skupinom R6, dok cyclohexyl group which is substituted in position 3 or in position 4 with the group R6, doc

R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metil-imidazolidin-1-il, 2-okso-heksahidropirimidin-1-il ili 2-okso-3-metil-heksahidropirimidin-1-il skupina, R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin- 1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

pirolidin-3-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, a pyrrolidin-3-yl group which is substituted in position 1 with the group R5, while R5 is defined as above,

piperidin-3-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, piperidin-3-yl group which is substituted in position 1 with the group R5, while R5 is defined as above,

piperidin-4-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, piperidin-4-yl group which is substituted in position 1 with the group R5, while R5 is defined as above,

tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd je vodikov atom, Rd is a hydrogen atom,

metoksi, difluormetoksi ili etiloksi skupina, methoxy, difluoromethoxy or ethyloxy group,

etiloksi skupina, koja je suptituirana u položaju 2 s ostatkom R6 ili R7, pri čemu je R6 definiran kao gore, i an ethyloxy group, which is substituted in position 2 with a residue R6 or R7, where R6 is defined as above, and

R7 je hidroksi, metoksi, etoksi, amino, dimetilamino, dietilamino, bis-(2-metoksietil)-amino, pirolidin-1-il, piperidin-1-il, morfolin-4-il, homomorfolin-4-il, 2-oksa-5-aza-biciklo[2.2.1]hept-5-il, 3-oksa-8-aza-biciklo[3.2.1]-okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il, 4-metil-piperazin-1-il ili 4-etilpiperazin-1-il skupina, ili R7 is hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2- oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]-oct-8-yl, 8-oxa-3-aza-bicyclo[3.2 .1]oct-3-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl or 4-ethylpiperazin-1-yl group, or

acetilamino, etilkarbonilamino, propilkarbonilamino, butilkarbonilamino, metoksiacetilamino, butiloksikarbonil-amino, etilaminokarbonilamino, dimetilaminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarboni1amino, morfolin-4-ilkarbonilamino, metilsulfonilamino, etil-sulfonilamino ili butilsulfonilamino skupina, acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino, methylsulfonylamino, ethylsulfonylamino or butylsulfonylamino,

propiloksi skupina, koja je u položaju 3 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, ili a propyloxy group, which is substituted in position 3 with the residue R6 or R7, wherein R6 and R7 are defined as above, or

butiloksi skupina, koja je u položaju 4 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, i a butyloxy group, which is substituted in position 4 with the residue R6 or R7, wherein R6 and R7 are defined as above, and

X je dušikov atom, X is a nitrogen atom,

pri čemu, ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, njihovim tautomerima, njihovim stereoizomerima, njihovim smjesama i njihovim solima. wherein, unless stated otherwise, the aforementioned alkyl groups may be straight or branched, their tautomers, their stereoisomers, their mixtures and their salts.

Posve posebnu prednost se daje onim spojevima gornje opće formule I u kojoj Particular preference is given to those compounds of the above general formula I in which

Ra je vodikov atom, Ra is a hydrogen atom,

Rb je 3-bromfenil, 3,4-difluorfenil, 3-klor-4-fluor-fenil ili 3-etinilfenilna skupina, ili Rb is a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or 3-ethynylphenyl group, or

3-klor-4-benziloksi-fenil, 3-klor-4-[(3-fluorbenzil)-oksi]-fenil, 4-(piridin-3-iloksi)-fenil, 4-[(6-metil-piridin-3-il)oksi]-fenil, 3-metil-4-(piridin-3-iloksi)-fenil, 3-metil-4-[(6-metil-piridin-3-il)oksi]-fenil, 3-klor-4-(piridin-3-iloksi)-fenil ili 3-klor-4-[(6-metil-piridin-3-il)oksi]-fenilna skupina, 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluorobenzyl)-oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridine- 3-yl)oxy]-phenyl, 3-methyl-4-(pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3- chloro-4-(pyridin-3-yloxy)-phenyl or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group,

Rc je cikloheksilna skupina, koja je u položaju 3 supstituirana s amino, acetilamino, terc-butiloksikarbonil-amino ili metilsulfonilamino skupinom, Rc is a cyclohexyl group, which is substituted in position 3 with an amino, acetylamino, tert-butyloxycarbonyl-amino or methylsulfonylamino group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s amino, metilamino, etilamino, dimetilamino, aminokarbonilmetilamino, metilaminokarbonilmetilamino, dimetilaminokarbonilmetilamino, morfolin-4-ilkarbonil-metilamino, [3-(morfolin-4-ilkarbonil)propil]amino, [2-(metil-sulfonil)etil]amino, [3-(metilsulfonil)propil]amino ili [2-(metilsulfonilamino)etil]amino skupinom, cyclohexyl group, which is substituted in position 4 with amino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino, methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino, morpholin-4-ylcarbonyl-methylamino, [3-(morpholin-4-ylcarbonyl)propyl]amino, [2-( methylsulfonyl)ethyl]amino, [3-(methylsulfonyl)propyl]amino or [2-(methylsulfonylamino)ethyl]amino group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s [2-(2-okso-pirolidin-1-il)etil]amino, [2-(2-oksopiperidin-1-il)etil]amino, [2-(2-okso-imidazolidin-1-il)etil]amino, [2-(2-okso-3-metil-imidazolidin-1-il)-etil]amino, [2-(2-okso-heksahidropirimidin-1-il)etil]amino ili [2-(2-okso-3-metil-heksahidropirimidin-1-il)etil]amino skupinom, cyclohexyl group, which is substituted in position 4 with [2-(2-oxo-pyrrolidin-1-yl)ethyl]amino, [2-(2-oxopiperidin-1-yl)ethyl]amino, [2-(2- oxo-imidazolidin-1-yl)ethyl]amino, [2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl]amino, [2-(2-oxo-hexahydropyrimidin-1-yl)ethyl ]amino or [2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s [3-(2-okso-pirolidin-1-il)propil]amino, [3-(2-oksopiperidin-1-il)propil]amino, [3-(2-okso-imidazolidin-1-il)propil]amino, [3-(2-okso-3-metil-imidazolidin-1-il)propil]amino, [3-(2-okso-heksahidropirimidin-1-il)propil]amino ili [3-(2-okso-3-metil-heksahidro-pirimidin-1-il)propil]amino skupinom, cyclohexyl group, which is substituted in position 4 with [3-(2-oxo-pyrrolidin-1-yl)propyl]amino, [3-(2-oxopiperidin-1-yl)propyl]amino, [3-(2- oxo-imidazolidin-1-yl)propyl]amino, [3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl]amino, [3-(2-oxo-hexahydropyrimidin-1-yl)propyl] amino or [3-(2-oxo-3-methyl-hexahydro-pyrimidin-1-yl)propyl]amino group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s acetilamino, N-(acetil)-metilamino, amino-metilkarbonilamino, metilaminometilkarbonilamino, dimetil-aminometilkarbonilamino, morfolin-4-ilmetilkarbonilamino, metoksiacetilamino, N-(metoksiacetil)-metilamino, tetrahidropiran-4-ilkarbonilamino, N-(tetrahidropiran-4-il-karbonil)-metilamino, terc-butiloksikarbonilamino, N-(terc-butiloksikarbonil)-metilamino, aminokarbonilamino, metil-aminokarbonilamino, N-(etilaminokarbonil)-metilamino, di-metilaminokarbonilamino, N-(dimetilaminokarbonil)-metilamino, N-(piperidin-1-ilkarbonil)-metilamino, morfolin-4-ilkarbonilamino, N-(morfolin-4-ilkarbonil)-metilamino ili N-(4-metilpiperazin-1-ilkarbonil)-metilamino skupinom, cyclohexyl group, which is substituted in position 4 with acetylamino, N-(acetyl)-methylamino, amino-methylcarbonylamino, methylaminomethylcarbonylamino, dimethyl-aminomethylcarbonylamino, morpholin-4-ylmethylcarbonylamino, methoxyacetylamino, N-(methoxyacetyl)-methylamino, tetrahydropyran-4- ylcarbonylamino, N-(tetrahydropyran-4-yl-carbonyl)-methylamino, tert-butyloxycarbonylamino, N-(tert-butyloxycarbonyl)-methylamino, aminocarbonylamino, methyl-aminocarbonylamino, N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl)-methylamino, N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino, N-(morpholin-4-ylcarbonyl)-methylamino or N-(4-methylpiperazin-1-ylcarbonyl)-methylamino group ,

cikloheksilna skupina, koja je u položaju 4 supstituirana s 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metilimidazolidin-1-il, 2-okso-heksahidropirimidin-1-il ili 2-okso-3-metil-heksahidropirimidin-1-ilnom skupinom, cyclohexyl group, which is substituted in position 4 with 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2- oxo-3-methylimidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s metilsulfonilamino, N-(metilsulfonil)-metilamino, etilsulfonilamino, N-(etilsulfonil)-metilamino, dimetilaminosulfonilamino, N-(dimetilaminosulfonil)metilamino, morfolin-4-ilsulfonilamino, N-(morfolin-4-il-sulfonil)-metilamino-3-klorpropilsulfonilamino, [2-(morfolin-4-il)-etil]sulfonilamino ili [3-(morfolin-4-il)-propil]sulfonilamino skupinom, cyclohexyl group, which is substituted in position 4 with methylsulfonylamino, N-(methylsulfonyl)-methylamino, ethylsulfonylamino, N-(ethylsulfonyl)-methylamino, dimethylaminosulfonylamino, N-(dimethylaminosulfonyl)methylamino, morpholin-4-ylsulfonylamino, N-(morpholin- 4-yl-sulfonyl)-methylamino-3-chloropropylsulfonylamino, [2-(morpholin-4-yl)-ethyl]sulfonylamino or [3-(morpholin-4-yl)-propyl]sulfonylamino group,

pirolidin-3-il skupina, pyrrolidin-3-yl group,

pirolidin-3-il skupina, koja je u položaju 1 supstituirana s metilnom, acetilnom, metoksiacetilnom, terc-butiloksikarbonilnom, morfolin-4-ilkarbonilnom ili metilsulfonilnom skupinom, pyrrolidin-3-yl group, which is substituted in position 1 with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group,

piperidin-3-il skupina, piperidin-3-yl group,

piperidin-3-il skupina, koja je u položaju 1 supstituirana s metilnom, acetilnom, metoksiacetilnom, terc-butiloksikarbonilnom, morfolin-4-ilkarbonilnom ili metilsulfonilnom skupinom, piperidin-3-yl group, which is substituted in position 1 with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group,

piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine metil, etil, propil, izopropil, 2-hidroksietil, 2-metoksietil, 3-metoksipropil, 2-(metilsulfonil)etil, 3-(metilsulfonil)-propil, 2-(terc-butiloksikarbonilamino)etil, 2-aminoetil, 2-(acetilamino)etil, 2-(etilkarbonilamino)etil, 2-propil-karbonilamino)etil, 2-(etilaminokarbonilamino)etil, 2-(di-metilaminokarbonilamino)etil, 2-(morfolin-4-ilkarbonil-amino)etil, 3-(acetilamino)propil, 3-(etil-karbonilamino)-propil, 3-(propilkarbonilamino)propil, 3-(etilamino-karbonilamino) propil, 3-(dimetilaminokarbonilamino)propil, 3-(morfolin-4-ilkarbonilamino)propil, 2-(metilsulfonil-amino)etil, 3-(metilsulfonilamino)propil, (aminokarbonil)-metil, (metilaminokarbonil)metil, (dimetilaminokarbonil)-metil, (pirolidin-1-ilkarbonil)metil, (morfolin-4-il-karbonil)metil, 2-(morfolin-4-ilkarbonil)etil ili 3-(morfolin-4-ilkarbonil)-propilna skupina, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl) )-propyl, 2-(tert-butyloxycarbonylamino)ethyl, 2-aminoethyl, 2-(acetylamino)ethyl, 2-(ethylcarbonylamino)ethyl, 2-propylcarbonylamino)ethyl, 2-(ethylaminocarbonylamino)ethyl, 2-(di -methylaminocarbonylamino)ethyl, 2-(morpholin-4-ylcarbonyl-amino)ethyl, 3-(acetylamino)propyl, 3-(ethyl-carbonylamino)-propyl, 3-(propylcarbonylamino)propyl, 3-(ethylamino-carbonylamino)propyl , 3-(dimethylaminocarbonylamino)propyl, 3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulfonylamino)ethyl, 3-(methylsulfonylamino)propyl, (aminocarbonyl)-methyl, (methylaminocarbonyl)methyl, (dimethylaminocarbonyl)- methyl, (pyrrolidin-1-ylcarbonyl)methyl, (morpholin-4-yl-carbonyl)methyl, 2-(morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)-propyl group,

piperidin-4-il skupina koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine 2-(2-okso-pirolidin-1-il)-etil, 2-(2-oksopiperidin-1-il)-etil, 2-(3-oksomorfolin-4-il)-etil, 2-(2-okso-imidazolidin-1-il)-etil, 2-(2-okso-3-metil-imidazolidin-1-il)-etil, 2-(2-okso-heksa-hidropirimidin-1-il)-etil ili 2-(2-okso-3-metil-heksahidro-pirimidin-1-il)-etilna skupina, piperidin-4-yl group which is substituted in position 1 with a substituent from the series consisting of 2-(2-oxo-pyrrolidin-1-yl)-ethyl, 2-(2-oxopiperidin-1-yl)-ethyl, 2- (3-oxomorpholin-4-yl)-ethyl, 2-(2-oxo-imidazolidin-1-yl)-ethyl, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl, 2- (2-oxo-hexa-hydropyrimidin-1-yl)-ethyl or 2-(2-oxo-3-methyl-hexahydro-pyrimidin-1-yl)-ethyl group,

piperidin-4-il skupina koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine 3-(2-okso-pirolidin-1-il)-propil, 3-(2-oksopiperidin-1-il)-propil, 3-(3-oksomorfolin-4-il)-propil, 3-(2-okso-imidazolidin-1-il)-propil, 3-(2-okso-3-metil-imidazolidin-1-il)-propil, 3-(2-okso-heksahidropirimidin-1-il)-propil ili 3-(2-okso-3-metil-heksahidropirimidin-1-il)-propilna skupina, piperidin-4-yl group which is substituted in position 1 with a substituent from the series consisting of 3-(2-oxo-pyrrolidin-1-yl)-propyl, 3-(2-oxopiperidin-1-yl)-propyl, 3- (3-oxomorpholin-4-yl)-propyl, 3-(2-oxo-imidazolidin-1-yl)-propyl, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl, 3- (2-oxo-hexahydropyrimidin-1-yl)-propyl or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group,

piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine formil, acetil, metoksiacetil, (2-metoksietil)karbonil, (3-metoksi-propil)karbonil, metilsulfonilacetil, aminoacetil, metil-aminoacetil, (dimetilamino)acetil, (morfolin-4-il)acetil, [2-(morfolin-4-il)-etil]karbonil, [3-(morfolin-4-il)-propil]karbonil, tetrahidrofuran-2-ilkarbonil ili tetra-hidropiran-4-ilkarbonilna skupina, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of formyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl, (3-methoxy-propyl)carbonyl, methylsulfonylacetyl, aminoacetyl, methylaminoacetyl, ( dimethylamino)acetyl, (morpholin-4-yl)acetyl, [2-(morpholin-4-yl)-ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl, tetrahydrofuran-2-ylcarbonyl or tetra -hydropyran-4-ylcarbonyl group,

piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine cijano, aminokarbonil, metilaminokarbonil, etilaminokarbonil, (2-metoksietil)aminokarbonil, N-metil-N-(2-metoksietil)-amino-karbonil, (3-metoksipropil)amino-karbonil, N-metil-N-(3-metoksipropil)aminokarbonil, izopropilaminokarbonil, fenil-aminokarbonil, dimetilamino-karbonil, dietilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, 2-metil-morfolin-4-ilkarbonil, 2,6-dimetil-morfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo-[3.2.1]okt-8-ilkarbonil, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarbonil, 4-metil-piperazin-1-il-karbonil, izopropiloksi-karbonil ili terc-butiloksikarbonilna skupina, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2-methoxyethyl)aminocarbonyl, N-methyl-N-(2-methoxyethyl)-amino-carbonyl, (3-Methoxypropyl)amino-carbonyl, N-methyl-N-(3-methoxypropyl)aminocarbonyl, isopropylaminocarbonyl, phenyl-aminocarbonyl, dimethylamino-carbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4- ylcarbonyl, 2-methyl-morpholin-4-ylcarbonyl, 2,6-dimethyl-morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo-[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, 4-methyl-piperazin-1-yl -carbonyl, isopropyloxy-carbonyl or tert-butyloxycarbonyl group,

piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine metil-sulfonil, etilsulfonil, [2-(morfolin-4-il)-etil]-sulfonil, [3-(morfolin-4-il)-propil]-sulfonil, amino-sulfoni1, metil-aminosulfonil, dimetilaminosulfonil ili morfolin-4-il-sulfonilna skupina, ili piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl-sulfonyl, ethylsulfonyl, [2-(morpholin-4-yl)-ethyl]-sulfonyl, [3-(morpholin-4-yl )-propyl]-sulfonyl, amino-sulfonyl, methyl-aminosulfonyl, dimethylaminosulfonyl or morpholin-4-yl-sulfonyl, or

tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd je vodikov atom, Rd is a hydrogen atom,

metoksi, difluormetoksi ili etiloksi skupina, 2-(morfolin-4-il)etiloksi, 3-(morfolin-4-il)propiloksi ili 4-(morfolin-4-il)butiloksi skupina, methoxy, difluoromethoxy or ethyloxy group, 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group,

3-(dimetilamino)propiloksi, 3-(dietilamino)-propiloksi, 3-[bis-(2-metoksietil)-amino]propiloksi, 3-(piperazin-e-il)propiloksi, 3-(4-metilpiperazin-e-il)-propiloksi ili 3-(4-etilpiperazin-e-il)-propiloksi skupina, 3-(homomorfolin-4-il)-propiloksi, 3-(2-oksa-5-aza-bi-ciklo[2.2.1]hept-5-il)-propiloksi, 3-(3-oksa-8-aza-biciklo-[3.2.1]okt-8-il)-propiloksi ili 3-(8-oksa-3-aza-biciklo-[3.2.1]okt-3-il)-propiloksi skupina, 3-(dimethylamino)propyloxy, 3-(diethylamino)-propyloxy, 3-[bis-(2-methoxyethyl)-amino]propyloxy, 3-(piperazin-e-yl)propyloxy, 3-(4-methylpiperazine-e- yl)-propyloxy or 3-(4-ethylpiperazin-e-yl)-propyloxy group, 3-(homomorpholin-4-yl)-propyloxy, 3-(2-oxa-5-aza-bi-cyclo[2.2.1 ]hept-5-yl)-propyloxy, 3-(3-oxa-8-aza-bicyclo-[3.2.1]oct-8-yl)-propyloxy or 3-(8-oxa-3-aza-bicyclo- [3.2.1]oct-3-yl)-propyloxy group,

2-(2-okso-pirolidin-1-il)-etiloksi, 2-(2-okso-piperidin-1-il)-etiloksi, 2-(3-oksomorfolin-4-il)-etiloksi, 2-(2-okso-imidazolidin-1-il)-etiloksi, 2-(2-okso-3-metil-imidazolidin-1-il)-etiloksi, 2-(2-okso-heksahidropirimidin-1-il)-etiloksi ili 2-(2-okso-3-metil-heksahidropirimidin-1-il)-etiloksi skupina, 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy, 2-(2-oxo-piperidin-1-yl)-ethyloxy, 2-(3-oxomorpholin-4-yl)-ethyloxy, 2-(2 -oxo-imidazolidin-1-yl)-ethyloxy, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyloxy, 2-(2-oxo-hexahydropyrimidin-1-yl)-ethyloxy or 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group,

3-(2-okso-pirolidin-1-il)-propiloksi, 3-(2-okso-piperidin-1-il)-propiloksi, 3-(3-oksomorfolin-4-il)-propiloksi, 3-(2-okso-imidazolidin-1-il)-propiloksi, 3-(2-okso-3-metil-imidazolidin-1-il)-propiloksi, 3-(2-okso-heksahidro-pirimidin-1-il)-propiloksi ili 3-(2-okso-3-metil-heksa-hidropirimidin-1-il)-propiloksi skupina, 3-(2-oxo-pyrrolidin-1-yl)-propyloxy, 3-(2-oxo-piperidin-1-yl)-propyloxy, 3-(3-oxomorpholin-4-yl)-propyloxy, 3-(2 -oxo-imidazolidin-1-yl)-propyloxy, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy, 3-(2-oxo-hexahydro-pyrimidin-1-yl)-propyloxy or 3-(2-oxo-3-methyl-hexa-hydropyrimidin-1-yl)-propyloxy group,

2-(metoksi)-etiloksi, 2-(terc-butiloksikarbonilamino)-etiloksi, 2-(amino)-etiloksi, 2-(acetilamino)-etiloksi, 2-(etilkarbonilamino)-etiloksi, 2-(propilkarbonilamino)-etiloksi, 2-(izobutilkarbonilarnino)-etiloksi, 2-(metoksi-acetilamino)-etiloksi, 2-(etilaminokarbonilamino)-etiloksi, 2-(dimetilaminokarbonilamino)-etiloksi, 2-(pirolidin-1-il-karbonilamino)-etiloksi, 2-(piperidin-1-ilkarbonilamino)-etiloksi, 2-(morfolin-4-ilkarbonilamino)-etiloksi, 2-(metilsulfonilamino)-etiloksi skupina, 2-(etilsulfonil-amino)etiloksi ili 2-(butilsulfonilamino)-etiloksi skupina, ili 2-(Methoxy)-ethyloxy, 2-(tert-butyloxycarbonylamino)-ethyloxy, 2-(amino)-ethyloxy, 2-(acetylamino)-ethyloxy, 2-(ethylcarbonylamino)-ethyloxy, 2-(propylcarbonylamino)-ethyloxy, 2-(isobutylcarbonylamino)-ethyloxy, 2-(methoxy-acetylamino)-ethyloxy, 2-(ethylaminocarbonylamino)-ethyloxy, 2-(dimethylaminocarbonylamino)-ethyloxy, 2-(pyrrolidin-1-yl-carbonylamino)-ethyloxy, 2- (piperidin-1-ylcarbonylamino)-ethyloxy, 2-(morpholin-4-ylcarbonylamino)-ethyloxy, 2-(methylsulfonylamino)-ethyloxy group, 2-(ethylsulfonylamino)ethyloxy or 2-(butylsulfonylamino)-ethyloxy group, or

3-(terc-butiloksikarbonilamino)-propiloksi, 3-(amino)-propiloksi, 3-(acetilamino)-propiloksi ili 3-(metil-sulfonilamino)-propiloksi skupina, i 3-(tert-butyloxycarbonylamino)-propyloxy, 3-(amino)-propyloxy, 3-(acetylamino)-propyloxy or 3-(methyl-sulfonylamino)-propyloxy group, and

X je dušikov atom, X is a nitrogen atom,

njihovim tautomerima, njihovim stereoizomerima, njihovim smjesama i njihovim solima. their tautomers, their stereoisomers, their mixtures and their salts.

Naročitu prednost imaju oni spojevi opće formule I u kojoj Those compounds of the general formula I in which

Ra predstavlja vodikov atom, Ra represents a hydrogen atom,

Rb ponajprije je 3-klor-4-fluor-fenilna skupina ili također 3-etinil-fenilna skupina, Rb is preferably a 3-chloro-4-fluoro-phenyl group or also a 3-ethynyl-phenyl group,

Rc je cikloheksilna skupina, koja je u položaju 3 supstituirana s amino, acetilamino, terc-butiloksi-karbonilamino ili metilsulfonilamino skupinom, Rc is a cyclohexyl group, which is substituted in position 3 with an amino, acetylamino, tert-butyloxy-carbonylamino or methylsulfonylamino group,

cikloheksilna skupina, koja je u položaju 4 supstituirana s amino, metilamino, dimetilamino, acetil-amino, N-(acetil)-metilamino, metoksiacetilamino, N-(metoksiacetil)-metilamino, tetrahidropiran-4-ilkarbonil-amino, N-(tetrahidropiran-4-ilkarbonil)-metilamino, terc-butiloksikarbonilamino, N-(terc-butiloksikarbonil)-metilamino, N-(etilaminokarbonil)-metilamino, dimetilamino-karbonilamino, N-(dimetilaminokarbonil)-metilamino, N-(piperidin-1-ilkarbonil)-metilamino, morfolin-4-il-karbonil-amino, N-(morfolin-4-ilkarbonil)-metilamino, N-(4-metil-piperazin-1-ilkarbonil)-metilamino, metilsulfonil-amino, N-(metilsulfonil)-metilamino, etilsulfonilamino, N-(etil-sulfonil)-metilamino, dimetilaminosulfonilamino, N-(dimetilaminosulfonil)metilamino, morfolin-4-ilsulfonil-amino, N-(morfolin-4-ilsulfonil)-metilamino, 3-klorpropil-sulfonil-amino ili [3-(morfolin-4-il)-propil]sulfonilamino skupina, cyclohexyl group, which is substituted in position 4 with amino, methylamino, dimethylamino, acetyl-amino, N-(acetyl)-methylamino, methoxyacetylamino, N-(methoxyacetyl)-methylamino, tetrahydropyran-4-ylcarbonyl-amino, N-(tetrahydropyran -4-ylcarbonyl)-methylamino, tert-butyloxycarbonylamino, N-(tert-butyloxycarbonyl)-methylamino, N-(ethylaminocarbonyl)-methylamino, dimethylamino-carbonylamino, N-(dimethylaminocarbonyl)-methylamino, N-(piperidin-1-ylcarbonyl) )-methylamino, morpholin-4-yl-carbonyl-amino, N-(morpholin-4-ylcarbonyl)-methylamino, N-(4-methyl-piperazin-1-ylcarbonyl)-methylamino, methylsulfonyl-amino, N-(methylsulfonyl )-methylamino, ethylsulfonylamino, N-(ethyl-sulfonyl)-methylamino, dimethylaminosulfonylamino, N-(dimethylaminosulfonyl)methylamino, morpholin-4-ylsulfonyl-amino, N-(morpholin-4-ylsulfonyl)-methylamino, 3-chloropropyl-sulfonyl -amino or [3-(morpholin-4-yl)-propyl]sulfonylamino group,

pirolidin-3-il skupina, pyrrolidin-3-yl group,

pirolidin-3-il skupina, koja je supstituirana u položaju 1 s terc-butiloksikarbonilnom ili metilsulfonilnom skupinom, a pyrrolidin-3-yl group, which is substituted in position 1 with a tert-butyloxycarbonyl or methylsulfonyl group,

piperidin-3-il skupina, piperidin-3-yl group,

piperidin-3-il skupina koja je supstituirana u položaju 1 s terc-butiloksikarbonilnom ili metilsulfonilnom skupinom, piperidin-3-yl group which is substituted in position 1 with tert-butyloxycarbonyl or methylsulfonyl group,

piperidin-4-il skupina, piperidin-4-yl group,

piperidin-4-il skupina, koja je supstituirana u položaju 1 sa supstituentom iz niza koji čine metil, (aminokarbonil)metil, (dimetilaminokarbonil) metil, (morfolin-4-ilkarbonil)metil, 2-(terc-butiloksikarbonil-amino)etil, 2-aminoetil, 2-(acetilamino)etil, 2-(metil-sulfonilamino)etil, cijano, acetil, metoksiacetil, (dimetilamino) acetil, (morfolin-4-il)acetil, tetrahidropiran-4-ilkarbonil, etilaminokarbonil, izopropilaminokarbonil, fenilaminokarbonil, dimetilaminokarbonil, dietilamino-karbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, 2-metilmorfolin-4-ilkarbonil, 2,6-dimetilmorfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 4-metilpiperazin-1-ilkarbonil, izopropiloksikarbonil, terc-butiloksikarbonil, metilsulfonil, dimetilaminosulfonil ili morfolin-4-ilsulfonilna skupina, ili piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl, (aminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (morpholin-4-ylcarbonyl)methyl, 2-(tert-butyloxycarbonyl-amino)ethyl , 2-aminoethyl, 2-(acetylamino)ethyl, 2-(methyl-sulfonylamino)ethyl, cyano, acetyl, methoxyacetyl, (dimethylamino)acetyl, (morpholin-4-yl)acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl , phenylaminocarbonyl, dimethylaminocarbonyl, diethylamino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl , 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, methylsulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or

tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group,

Rd je vodikov atom, metoksi ili etiloksi skupina, Rd is a hydrogen atom, methoxy or ethyloxy group,

2-(morfolin-4-il)etiloksi, 3-(morfolin-4-il)propiloksi ili 4-(morfolin-4-il)butiloksi skupina, 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group,

2-(3-metil-2-okso-heksahidropirimidin-1-il)-etiloksi skupina, 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group,

2-(metoksi)-etiloksi, 2-(terc-butiloksikarbonilamino)-etiloksi, 2-amino-etiloksi, 2-(acetilamino)-etiloksi ili 2-(metilsulfonilamino)-etiloksi skupina ili 2-(Methoxy)-ethyloxy, 2-(tert-butyloxycarbonylamino)-ethyloxy, 2-amino-ethyloxy, 2-(acetylamino)-ethyloxy or 2-(methylsulfonylamino)-ethyloxy group or

3-(terc-butiloksikarbonilamino)-propiloksi, 3-amino-propiloksi, 3-(acetilamino)-propiloksi ili 3-(metil-sulfoni1amino)-propiloksi skupina, i 3-(tert-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy, 3-(acetylamino)-propyloxy or 3-(methyl-sulfonylamino)-propyloxy group, and

X je dušikov atom, X is a nitrogen atom,

njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli. their tautomers, their stereoisomers, their mixtures and their salts.

Od gore opisanih bicikličkih heterocikla opće formule I kao i od u svakom slučaju spojeva kojima se daje prednost, posebnu prednost, posve posebnu prednost i naročitu prednost, treba posebno spomenuti u svakom slučaju one spojeve u kojima Of the bicyclic heterocycles of the general formula I described above, as well as of the compounds that are given preference, special preference, very special preference and special preference in each case, special mention should be made in each case of those compounds in which

(a) Rc predstavlja cikloheksilnu skupinu koja je supstituirana u položaju 4, (a) Rc represents a cyclohexyl group which is substituted in position 4,

(b) Rc predstavlja pirolidin-3-il skupina koja je prema potrebi supstituirana u položaju 1, (b) Rc represents a pyrrolidin-3-yl group which is optionally substituted in position 1,

(c) Rc predstavlja piperidin-3-il skupinu koja prema potrebi supstituirana u položaju 1, (c) Rc represents a piperidin-3-yl group which, if necessary, is substituted in position 1,

(d) Rc predstavlja piperidin-4-il skupinu koja je prema potrebi supstituirana u položaju 1, (d) Rc represents a piperidin-4-yl group which is optionally substituted in position 1,

(e) Rc predstavlja tetrahidrofuran-3-ilnu skupinu, (e) Rc represents a tetrahydrofuran-3-yl group,

(f) Rc predstavlja tetrahidropiran-3-ilnu skupinu, ili (f) Rc represents a tetrahydropyran-3-yl group, or

(g) Rc predstavlja tetrahidropiran-4-ilnu skupinu, (g) Rc represents a tetrahydropyran-4-yl group,

dok su Ra, Rb, Rd i X u svakom slučaju definirani kao što je gore spomenuto. while Ra, Rb, Rd and X are in each case defined as mentioned above.

Kao primjeri se mogu navesti slijedeći spojevi opće formule I kojima se daje posebnu prednost: As examples, the following compounds of the general formula I can be mentioned, which are particularly preferred:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin, (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-metoksi-kinazolin, (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxyquinazoline,

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-((R)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin, (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline,

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

(5) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-metan-sulfonilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methane-sulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,

(6) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-il-oksi)-7-metoksi-kinazolin, (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yl-oxy)-7-methoxy-quinazoline,

(7) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-7-metoksi-kinazolin, (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

(8) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{[3-(morfolin-4-il)-propil]sulfonil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1- yloxy)-7-methoxy-quinazoline,

(9) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-3-iloksi)-7-metoksi-kinazolin, (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline,

(10) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-{[3-(morfolin-4-il)-propil]sulfonil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1- yloxy)-7-methoxy-quinazoline,

(11) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metil-piperidin-4-iloksi)-7-metoksi-kinazolin, (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,

(12) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin, (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin-4-yl-oxy}-7-methoxy- quinazoline,

(13) 4-[(3-klor4-fluor-fenil)amino]-6-{1-[(metoksimetil)-karbonil]-piperidin4-il-oksi}-7-metoksi-kinazolin, (13) 4-[(3-chloro4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)-carbonyl]-piperidin4-yl-oxy}-7-methoxy-quinazoline,

(14) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-cijano-piperidin-4-iloksi)-7-metoksi-kinazolin, (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,

(15) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-sulfonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin, (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-sulfonyl]-piperidin-4-yl-oxy}-7-methoxy- quinazoline,

(16) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-acetilamino-etil)-piperidin-4-iloksi]-7-metoksi-kinazolin, (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,

(17) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(dimetil-amino)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethyl-amino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,

(18) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline ,

(19) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline ,

(20) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-acetilamino-etoksi)-kinazolin, (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,

(21) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metansulfonilamino-etoksi)-kinazolin i (21) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline and

(22) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metoksi-etoksi)-kinazolin, (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,

kao i njihove soli. as well as their salts.

Spojevi formule I mogu se dobiti, na primjer, slijedećim postupcima: Compounds of formula I can be obtained, for example, by the following procedures:

a) Reakcijom spoja opće formule a) By the reaction of a compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rd i X definirani kao ovdje ranije, reagira sa spojem opće formule wherein Ra, Rb, Rd and X are as defined hereinbefore, reacts with a compound of the general formula

Z1-Rc (III) Z1-Rc (III)

u kojoj je Rc definiran kao ovdje ranije, a Z je izlazna skupina kao halogeni atom, npr. klor ili atom broma, sulfoniloksi skupina kao metansulfoniloksi ili p-toluol-sulfoniloksi skupina ili hidroksi skupina. wherein Rc is defined as hereinbefore and Z is a leaving group such as a halogen atom, eg chlorine or bromine, a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy or a hydroxy group.

Sa spojem opće formule III, u Z predstavlja hidroksi skupinu, reakciju se provodi u prisutnosti sredstva za vezanje vode, ponajprije u prisutnosti fosfina i derivata azodikarboksilne kiselina kao što je npr. trifenilfosfin, dietil ester azodikarboksilne kiseline, uobičajeno u otapalu kao što je metilen klorid, acetonitril, tetrahidrofuran, dioksan, toluol ili etilenglikol dietil eter, pri temperaturi između -50 i 150° C, međutim ponajprije pri temperaturi između -20 i 80°C. With a compound of the general formula III, in Z represents a hydroxy group, the reaction is carried out in the presence of a water binding agent, preferably in the presence of phosphine and derivatives of azodicarboxylic acids such as, for example, triphenylphosphine, diethyl ester of azodicarboxylic acid, usually in a solvent such as methylene chloride , acetonitrile, tetrahydrofuran, dioxane, toluene or ethylene glycol diethyl ether, at a temperature between -50 and 150°C, however preferably at a temperature between -20 and 80°C.

b) Za pripravu spojeva opće formule I, u kojoj je Rd prema potrebi supstituirana alkiloksi skupina koja je gore spomenuta, spoj opće formule b) For the preparation of compounds of the general formula I, in which Rd is optionally substituted alkyloxy group mentioned above, a compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rc i X definirani kao ovdje gore, reagira sa spojem opće formule wherein Ra, Rb, Rc and X are as defined above, reacts with a compound of the general formula

Z2-Rd' (V) Z2-Rd' (V)

u kojoj Rd' predstavlja C1-4-alkilnu skupinu, metilnu skupinu supstituiranu s 1 do 3 atoma fluora, etilnu skupinu supstituiranu s 1 do 5 atoma fluora, C2-4-alkilnu skupinu supstituiranu s jednim ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao što je spomenuto ovdje gore, C1-4-alkilnu skupinu supstituiranu s pirolidinilnom, piperidinilnom ili homopiperidinilnom skupinom koja je u 1-položaju supstituirana s ostatkom R8, ili C1-4-alkilnu skupinu supstituiranu s morfolinilnom skupinom koja je u položaju 4 supstituirana s ostatkom R8, pri čemu je R8 u svakom slučaju definiran kao ovdje gore, i in which Rd' represents a C1-4-alkyl group, a methyl group substituted with 1 to 3 fluorine atoms, an ethyl group substituted with 1 to 5 fluorine atoms, a C2-4-alkyl group substituted with one residue R6 or R7, where R6 are and R7 defined as mentioned above, a C1-4-alkyl group substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group which is substituted in the 1-position with the R8 residue, or a C1-4-alkyl group substituted with a morpholinyl group which is in the position 4 substituted with the residue R 8 , wherein R 8 is in each case as defined hereinabove, i

Z2 je izlazna skupina, kao halogeni atom, alkil-oksisulfoniloksi, arilsulfoniloksi ili hidroksi skupina. Z 2 is a leaving group, such as a halogen atom, alkyloxysulfonyloxy, arylsulfonyloxy or a hydroxy group.

Ako je izlazna skupina halogeni atom, kao klor, brom ili atom joda, ili alkiloksisulfoniloksi ili arilsulfoniloksi skupina, kao metansulfoniloksi ili p-toluensulfonil-oksi skupina, reakciju se provodi ponajprije u prisutnosti organske ili anorganske baze, kao što je kalijev karbonat, natrijev hidrid ili N-etil-diizopropilamin. Ako je izlazna skupina hidroksi skupina, tada se reakciju provodi u prisutnosti sredstva za vezanje vode, ponajprije u prisutnosti fosfina i derivata azodikarboksilne kiselina kao što je npr. trifenilfosfin/dietil ester azodi-karboksilne kiseline. If the leaving group is a halogen atom, such as chlorine, bromine or an iodine atom, or an alkyloxysulfonyloxy or arylsulfonyloxy group, such as a methanesulfonyloxy or p-toluenesulfonyloxy group, the reaction is preferably carried out in the presence of an organic or inorganic base, such as potassium carbonate, sodium hydride or N-ethyl-diisopropylamine. If the leaving group is a hydroxy group, then the reaction is carried out in the presence of a water binding agent, preferably in the presence of phosphine and azodicarboxylic acid derivatives such as triphenylphosphine/azodicarboxylic acid diethyl ester.

c) Za pripravu spojeva opće formule I, u kojoj Rd predstavlja gore spomenutu alkiloksi skupinu, koja je prema potrebi supstituirana s amino, alkilamino ili dialkilamino skupinom ili s prema potrebi supstituiranom heterocikličkom skupinom povezanom preko imino dušikovog atoma, spoj opće formule c) For the preparation of compounds of the general formula I, in which Rd represents the above-mentioned alkyloxy group, which is optionally substituted with an amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group connected via an imino nitrogen atom, a compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rc i X definirani kao ovdje ranije, Z je izlazna skupina, kao što je halogeni atom, npr. klor ili atom broma ili sulfoniloksi skupina kao što je metan-sulfoniloksi ili p-toluensulfoniloksi skupina, reagira s amonijakom, s odgovarajućim, prema potrebi supstituiranim alkilaminom, dialkilaminom ili imino spojem ili njihovim prikladnim solima ili derivatima, kao što je na primjer morfolin. wherein Ra, Rb, Rc and X are as defined hereinbefore, Z is a leaving group, such as a halogen atom, eg chlorine or bromine atom or a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy, reacts with ammonia , with a corresponding optionally substituted alkylamine, dialkylamine or imino compound or suitable salts or derivatives thereof, such as for example morpholine.

d) Za pripravu spojeva opće formule I, u kojoj Rd predstavlja hidroksi skupinu: d) For the preparation of compounds of the general formula I, in which Rd represents a hydroxy group:

zaštitnu skupinu se odcijepi sa spoja opće formule the protective group is cleaved from the compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rc i X definirani kao ovdje ranije, a Rd'' je skupina koja se može prevesti u hidroksi skupinu, na primjer prema potrebi supstituirana benziloksi skupina, trimetilsililoksi, acetiloksi, benzoiloksi, metoksi, etoksi, terc-butoksi ili tritiloksi skupina. wherein Ra, Rb, Rc and X are as defined hereinbefore and Rd'' is a group which can be converted to a hydroxy group, for example optionally substituted benzyloxy, trimethylsilyloxy, acetyloxy, benzoyloxy, methoxy, ethoxy, tert-butoxy or a trityloxy group.

Odcjepljenje zaštitne skupine vrši, na primjer, hidrolizom u vodenom otapalu, npr. u vodi, izopropanol/vodi, octena kiselina/vodi, tetrahidrofuran/vodi ili u dioksan/vodu, u prisutnosti kiseline kao što je trifluor-octena kiselina, solna kiselina ili sumporna kiselina ili u prisutnosti alkalne baze kao što je natrijev hidroksid ili kalijev hidroksid, ili aprotonski, npr. u prisutnosti jod-trimetilsilana, pri temperaturi između 0 i 120°C, ponajprije pri temperaturi između 10 i 100°C. Removal of the protective group is carried out, for example, by hydrolysis in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or in dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkaline base such as sodium hydroxide or potassium hydroxide, or aprotic, for example in the presence of iodotrimethylsilane, at a temperature between 0 and 120°C, preferably at a temperature between 10 and 100°C.

Međutim, odcjepljenje benzilne ili metoksibenzilne skupine vrši se, na primjer, hidrogenolitički, npr. s vodikom u prisutnosti katalizatora kao što je paladij/ugljen, u prikladnom otapalu kao što je metanol, etanol, etil ester octene kiseline ili ledena octena kiselina, prema potrebi s dodatkom kiseline kao što je solna kiselina, pri temperaturi između 0 i 100°C, međutim ponajprije pri sobnoj temperaturi između 20 i 60°C, i pod tlakom vodika od 1 do 7 bara, a ponajprije od 3 do 5 bara. However, cleavage of the benzyl or methoxybenzyl group is carried out, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, as appropriate with the addition of an acid such as hydrochloric acid, at a temperature between 0 and 100°C, however preferably at room temperature between 20 and 60°C, and under a hydrogen pressure of 1 to 7 bar, and preferably of 3 to 5 bar.

Odcjepljenje 2,4-dimetoksibenzilne skupine vrši međutim ponajprije u trifluoroctenoj kiselini u prisutnosti anisola. However, the removal of the 2,4-dimethoxybenzyl group is preferably carried out in trifluoroacetic acid in the presence of anisole.

Odcjepljenje terc-butilne ili benzilne skupine vrši se, na primjer, obradom s kiselinom kao što je trifluor-octena kiselina, solna kiselina ili bromovodična kiselina, ili obradom s jodtrimetilsilanom prema potrebi uz upotrebu otapala kao što je metilen klorid, dioksan, metanol ili dietil eter. Cleavage of the tert-butyl or benzyl group is carried out, for example, by treatment with an acid such as trifluoroacetic acid, hydrochloric acid or hydrobromic acid, or by treatment with iodotrimethylsilane as appropriate using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

e) Za pripravu spojeva opće formule I, u kojoj Rc sadrži -NH skupinu, e) For the preparation of compounds of the general formula I, in which Rc contains an -NH group,

zaštitnu skupinu se odcijepi sa spoja opće formule the protective group is cleaved from the compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rd i X definirani kao ovdje ranije, i Rc' ima ranije dato značenje, pod uvjetom da Rc sadrži zaštićen dušikov atom. wherein Ra, Rb, Rd, and X are as defined hereinbefore, and Rc' has the meaning previously given, provided that Rc contains a protected nitrogen atom.

Uobičajene zaštitne skupine za amino, alkilamino ili imino skupinu jesu na primjer formil, acetil, trifluor-acetil, etoksikarbonil, terc-butoksikarbonil, benziloksi-karbonil, benzil, metoksibenzil ili 2,4-dimetoksibenzilna skupina, pri čemu za amino skupinu dodatno dolazi u obzir i ftalilna skupina. Common protecting groups for the amino, alkylamino or imino group are, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, whereby the amino group additionally occurs in also take into account the phthalyl group.

Odcjepljenje zaštitne skupine vrši, na primjer, hidrolizom u vodenom otapalu, npr. u vodi, izopropanol/vodi, octena kiselina/vodi, tetrahidrofuran/vodi ili u dioksan/vodi, u prisutnosti kiseline kao što je trifluor-octena kiselina, solna kiselina ili sumporna kiselina ili u prisutnosti baze alkalijskog metala kao što je natrijev hidroksid ili kalijev hidroksid ili aprotonski, npr. u prisutnost jodtrimetilsilana, pri temperaturi između 0 i 120°C, ponajprije pri temperaturi između 10 i 100°C. Removal of the protecting group is carried out, for example, by hydrolysis in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or in dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotic, eg in the presence of iodotrimethylsilane, at a temperature between 0 and 120°C, preferably at a temperature between 10 and 100°C.

Međutim, odcjepljenje benzilne ili metoksibenzilne skupine vrši se, na primjer, hidrogenolitički, npr. s vodikom u prisutnosti katalizatora kao što je paladij/ugljen u prikladnom otapalu kao što je metanol, etanol, etil ester octene kiseline ili ledena octena kiselina, prema potrebi s dodatkom kiseline kao što je solna kiselina, pri temperaturi između 0 i 100°C, međutim ponajprije pri sobnoj temperaturi između 20 i 60°C, i pod tlakom vodika od 1 do 7 bara, a ponajprije od 3 do 5 bara. However, cleavage of the benzyl or methoxybenzyl group is carried out, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with by the addition of an acid such as hydrochloric acid, at a temperature between 0 and 100°C, however preferably at a room temperature between 20 and 60°C, and under a hydrogen pressure of 1 to 7 bar, and preferably of 3 to 5 bar.

Odcjepljenje 2,4-dimetoksibenzilne skupine vrši međutim ponajprije u trifluoroctenoj kiselini u prisutnosti anisola. However, the removal of the 2,4-dimethoxybenzyl group is preferably carried out in trifluoroacetic acid in the presence of anisole.

Odcjepljenje terc-butilnog ili terc-butiloksi-karbonilnog ostatka vrši ponajprije obradom s kiselinom kao što je trifluoroctena kiselina ili solna kiselina ili obradom s jodtrimetilsilanom prema potrebi uz upotrebu otapala kao što je metilen klorid, dioksan, metanol ili dietil eter. Separation of the tert-butyl or tert-butyloxy-carbonyl residue is carried out primarily by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane as necessary with the use of solvents such as methylene chloride, dioxane, methanol or diethyl ether.

Odcjepljenje trifluoracetilnog ostatka vrši ponajprije obradom s kiselinom kao što je solna kiselina prema potrebi u prisutnosti otapala kao što je octena kiselina, pri temperaturi između 50 i 120°C ili obradom s natrijevom lužinom, prema potrebi u prisutnost otapala kao što je tetrahidrofuran, pri temperaturi između 0 i 50°C. The separation of the trifluoroacetyl residue is carried out primarily by treatment with an acid such as hydrochloric acid, if necessary in the presence of a solvent such as acetic acid, at a temperature between 50 and 120°C or by treatment with sodium alkali, if necessary in the presence of a solvent such as tetrahydrofuran, at a temperature between 0 and 50°C.

Odcjepljenje ftalilnog ostatka vrši ponajprije u prisutnosti hidrazina ili primarnog amina kao metilamina, etilamina ili n-butilamina, u otapalu kao što je metanol, etanol, izopropanol, toluol/voda ili dioksan, pri temperaturi između 20 i 50°C. Cleavage of the phthalyl residue is carried out primarily in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine, in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane, at a temperature between 20 and 50°C.

f) Za pripravu spojeva opće formule I, u kojoj Rc sadrži alkilnu skupinu supstituiranu s prema potrebi supstituiranom amino, alkilamino ili dialkilamino skupinom ili s prema potrebi supstituiranom heterocikličkom skupinom povezanom preko dušikovog atoma, spoj opće formule f) For the preparation of compounds of the general formula I, in which Rc contains an alkyl group substituted with an optionally substituted amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group connected via a nitrogen atom, a compound of the general formula

[image] [image]

u kojoj su Ra, Rb, Rd i X definirani kao ovdje ranije, a Z je izlazna skupina, na primjer halogeni atom kao klor ili atom broma, ili sulfoniloksi skupina, kao što je metan-sulfoniloksi ili p-toluolsulfoniloksi skupina, i Rc'' ima značenje dato gore za Rc, pod uvjetom da je jedan vodikov atom povezan na alifatski ugljikov atom zamijenjen sa skupinom Z3, wherein Ra, Rb, Rd and X are as defined hereinbefore and Z is a leaving group, for example a halogen atom such as chlorine or bromine, or a sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy, and Rc' ' has the meaning given above for Rc, provided that one hydrogen atom attached to an aliphatic carbon atom is replaced by a group Z3,

reagira s amonijakom, odgovarajućim i prema potrebi supstituiranim alkilaminom, dialkilaminom ili imino spojem ili s njihovim prikladnim solima ili derivatima, kao što je na primjer morfolin. reacts with ammonia, a suitable and optionally substituted alkylamine, dialkylamine or imino compound or with suitable salts or derivatives thereof, such as for example morpholine.

Ako se dobije spoj prema izumu opće formule I koji sadrži amino, alkilamino ili imino skupinu, on se prevede aciliranjem, cijaniranjem ili sulfoniliranjem u odgovarajući acilni, cijano ili sulfonilni spoj opće formule I, pri čemu se kao sredstvo za aciliranje može upotrijebiti, na primjer, izocijanat, karbamoil klorid, halogenid karboksilne kiseline, anhidrid karboksilne kiseline i karboksilna kiselina sa sredstvom za aktiviranje kao što je N,N"-karbonildiimidazol, N,N"-dicikloheksil-karbodiimid ili O-(benzotriazol-1-il)-N,N,N'N'-tetra-metiluronij-tetrafluorborat, kao sredstva za sulfoniliranje mogu se upotrijebiti sulfonil halogenidi i kao sredstva za cijaniranje mogu se upotrijebiti klorcijan ili bromcijan, i/ili If a compound according to the invention of the general formula I containing an amino, alkylamino or imino group is obtained, it is converted by acylation, cyanation or sulfonylation into the corresponding acyl, cyano or sulfonyl compound of the general formula I, whereby the acylating agent can be used, for example , isocyanate, carbamoyl chloride, carboxylic acid halide, carboxylic anhydride and carboxylic acid with an activating agent such as N,N"-carbonyldiimidazole, N,N"-dicyclohexylcarbodiimide or O-(benzotriazol-1-yl)-N ,N,N'N'-tetra-methyluronium-tetrafluoroborate, sulfonyl halides can be used as sulfonylating agents and cyanide or cyanide bromine can be used as cyanizing agents, and/or

ako tako dobiven spoj opće formule I sadrži amino, alkilamino ili imino skupinu, on se može prevesti alkiliranjem ili redukcijskim alkiliranjem u odgovarajući alkilni spoj opće formule I, i/ili if the thus obtained compound of the general formula I contains an amino, alkylamino or imino group, it can be converted by alkylation or reductive alkylation into the corresponding alkyl compound of the general formula I, and/or

ako se tako dobije spoj opće formule I, koji sadrži klor-C1-4-alkilsulfonilnu ili brom-C1-4-alkilsulfonilnu skupinu, on se može presti reakcijom s aminom u odgovarajući amino-C1-4-alkilsulfonilni spoj, i/ili if a compound of the general formula I containing a chloro-C1-4-alkylsulfonyl or bromo-C1-4-alkylsulfonyl group is thus obtained, it can be converted by reaction with an amine into the corresponding amino-C1-4-alkylsulfonyl compound, and/or

ako se tako dobije spoj opće formule I, koji sadrži terc-butiloksikarbonilamino, N-alkil-N-(terc-butiloksi-karbonil)-amino ili N-terc-butiloksikarbonilimino skupinu, on se može prevesti obradom s kiselinom, kao što je solna kiselina ili trifluoroctena kiselina, u odgovarajući amino, alkilamino ili imino spoj opće formule I. if a compound of the general formula I containing a tert-butyloxycarbonylamino, N-alkyl-N-(tert-butyloxycarbonyl)-amino or N-tert-butyloxycarbonylimino group is thus obtained, it can be converted by treatment with an acid, such as hydrochloric acid or trifluoroacetic acid, into the corresponding amino, alkylamino or imino compound of the general formula I.

U gore opisanim reakcijama sve upotrijebljene reaktivne skupine, kao hidroksi, amino, alkilamino ili imino skupine, mogu se zaštititi tijekom reakcije s uobičajenim zaštitnim skupinama koje se ponovno odcjepljuju nakon reakcije. In the reactions described above, all reactive groups used, such as hydroxy, amino, alkylamino or imino groups, can be protected during the reaction with the usual protecting groups that are cleaved off again after the reaction.

Na primjer, kao zaštitna skupina za hidroksi skupinu u obzir dolazi trimetilsilil, acetil, tritil, benzil ili tetrahidropiranilna skupina. For example, a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group is suitable as a protecting group for the hydroxy group.

Kao zaštitni ostatak za amino, alkilamino ili imino skupinu u obzir dolazi na primjer formil, acetil, trifluor-acetil, etoksikarbonil, terc-butoksikarbonil, benziloksi-karbonil, benzil, metoksibenzil ili 2,4-dimetoksibenzilna skupina. As a protective residue for an amino, alkylamino or imino group, for example a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group comes into consideration.

Prema potrebi slijedeće odcjepljenje upotrijebljenog zaštitnog ostatka vrši se, na primjer, hidrolizom u vodenom otapalu, npr. u vodi, izopropanol/vodi, octena kiselina/ vodi, tetrahidrofuran/vodi ili dioksan/vodi, u prisutnosti kiseline kao što je trifluor octena kiselina, solna kiselina ili sumporna kiselina ili u prisutnosti alkalijske baze, kao što je natrijev hidroksid ili kalijev hidroksid, ili aprotonski, npr. u prisutnosti jodtrimetil-silana, pri temperaturi između 0 i 120°C, ponajprije pri temperaturi između 10 i 100°C. If necessary, the subsequent cleavage of the protective residue used is carried out, for example, by hydrolysis in an aqueous solvent, for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkaline base, such as sodium hydroxide or potassium hydroxide, or aprotic, for example in the presence of iodotrimethylsilane, at a temperature between 0 and 120°C, preferably at a temperature between 10 and 100°C.

Međutim, odcjepljenje benzilne ili metoksibenzilne skupine vrši se, na primjer, hidrogenolitički, npr. s vodikom u prisutnosti katalizatora kao što je paladij/ugljen, u prikladnom otapalu kao što je metanol, etanol, etil ester octene kiseline ili ledena octena kiselina, prema potrebi s dodatkom kiseline kao što je solna kiselina, pri temperaturi između 0 i 100°C, međutim ponajprije pri sobnoj temperaturi između 20 i 60°C, i pod tlakom vodika od 1 do 7 bara, a ponajprije od 3 do 5 bara. Odcjepljenje 2,4-dimetoksi-benzilnog ostatka vrši se međutim ponajprije u trifluoroctenoj kiselini u prisutnosti anisola. However, cleavage of the benzyl or methoxybenzyl group is carried out, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, as appropriate with the addition of an acid such as hydrochloric acid, at a temperature between 0 and 100°C, however preferably at room temperature between 20 and 60°C, and under a hydrogen pressure of 1 to 7 bar, and preferably of 3 to 5 bar. However, the cleavage of the 2,4-dimethoxy-benzyl residue is primarily carried out in trifluoroacetic acid in the presence of anisole.

Odcjepljenje terc-butil ili terc-butiloksikarbonilnog ostatka vrši ponajprije obradom s kiselinom kao što je trifluoroctena kiselina ili solna kiselina ili obradom s jodtrimetilsilanom, prema potrebi uz upotrebu otapala kao što je metilen klorid, dioksan, metanol ili dietil eter. Separation of the tert-butyl or tert-butyloxycarbonyl residue is carried out primarily by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or treatment with iodotrimethylsilane, if necessary with the use of a solvent such as methylene chloride, dioxane, methanol or diethyl ether.

Odcjepljenje trifluoracetilnog ostatka vrši ponajprije obradom s kiselinom kao što je solna kiselina, prema potrebi u prisutnost otapala kao što je octena kiselina, pri temperaturi između 50 i 120°C, ili obradom s natrijevom lužinom prema potrebi u prisutnost otapala kao što je tetrahidrofuran, pri temperaturi između 0 i 50°C. Separation of the trifluoroacetyl residue is carried out primarily by treatment with an acid such as hydrochloric acid, if necessary in the presence of a solvent such as acetic acid, at a temperature between 50 and 120°C, or by treatment with sodium alkali as necessary in the presence of a solvent such as tetrahydrofuran, at temperature between 0 and 50°C.

Osim toga dobiveni spojevi opće formule I, kao što je već uvodno spomenuto, mogu se rastaviti na njihove enantiomere i/ili diastereomere. Tako se, na primjer, cis/trans smjese mogu rastaviti na njihove cis i trans izomere, a spojevi s najmanje jednim optički aktivnim ugljikovim atomom mogu se rastaviti na njihove enantiomere. In addition, the obtained compounds of the general formula I, as already mentioned in the introduction, can be separated into their enantiomers and/or diastereomers. Thus, for example, cis/trans mixtures can be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom can be resolved into their enantiomers.

Tako se, na primjer, dobivenu cis/trans smjesu može rastaviti kromatografijom na njezine cis i trans izomere, a dobiveni spojevi opće formule I koji se pobavljuju kao racemati mogu se poznatim metodama (vidi Allinger N. L. i Eliel E. L. u "Topics in Stereochemistry", sv. 6, Wiley Interscience, 1971)) rastaviti u njihove optičke antipode, i spojevi opće formule I s najmanje 2 asimetrična ugljikova atoma mogu se zbog njihovih fizičko-kemijskih razlika rastaviti poznatim metodama, npr. kromatografijom i/ili frakcijskom kristalizacijom, u njihove diastereomere, koji, ako se pojavljuju u racemičnom obliku, se zatim, kao što je gore spomenuto, mogu se rastaviti na enantiomere. Thus, for example, the resulting cis/trans mixture can be resolved by chromatography into its cis and trans isomers, and the resulting compounds of general formula I which are treated as racemates can be separated by known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971)) be resolved into their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can, due to their physical-chemical differences, be resolved by known methods, e.g. chromatography and/or fractional crystallization, into their diastereomers, which, if occurring in racemic form, can then, as mentioned above, be resolved into enantiomers.

Rastavljanje enantiomera vrši se ponajprije rastavljanjem na stupcu na kiralnim fazama ili prekristalizacijom iz optički aktivnog otapala ili reakcijom s optički aktivnom tvari koja tvori soli ili derivate racemičnog spoja kao što su npr. esteri ili amidi, naročito s kiselinama i s njihovim aktiviranim derivatima ili alkoholima, i rastavljanje tako dobivene diastereomerne smjese soli ili derivata, npr. na osnovi različite topivosti, pri čemu se iz čistih diastereomera soli ili derivata mogu osloboditi slobodni antipodi djelovanjem prikladnog sredstva. Optički aktivne kiseline koje se posebno upotrebljavaju jesu npr. D- i L oblici vinske kiseline ili dibenzoilvinske kiseline, di-o-tolilvinske kiseline, jabučne kiseline, bademove kiseline, kamfor-sulfonske kiseline, glutaminske kiseline, asparaginske kiseline ili kininske kiseline. Kao optički aktivan alkohol u obzir dolazi na primjer (+)- ili (-)-mentol, a kao optički aktivan acilni ostatak u amidima u obzir dolazi na primjer (+)- ili (-)-mentiloksikarbonil. Separation of enantiomers is primarily carried out by separation on a column on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance that forms salts or derivatives of a racemic compound such as, for example, esters or amides, especially with acids and their activated derivatives or alcohols, and separation of the thus obtained diastereomeric mixture of salts or derivatives, for example on the basis of different solubility, whereby the free antipodes can be released from the pure diastereomers of the salt or derivative by the action of a suitable agent. Optically active acids that are especially used are, for example, D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolylvic acid, malic acid, mandelic acid, camphor-sulfonic acid, glutamic acid, aspartic acid or quinic acid. Examples of optically active alcohols include (+)- or (-)-menthol, and examples of optically active acyl residues in amides include (+)- or (-)-menthyloxycarbonyl.

Nadalje, dobiveni spojevi formule I mogu se prevesti u njihove soli, naročito za farmaceutsku primjenu prevedu se u njihove fiziološki podnošljive soli s anorganskim ili organskim kiselinama. Kao kiseline ovdje u obzir dolaze na primjer solna kiselina, bromovodična kiselina, sumporna kiselina, metansulfonska kiselina, fosforna kiselina, fumarna kiselina, jantarna kiselina, mliječna kiselina, limunska kiselina, vinska kiselina ili maleinska kiselina. Furthermore, the obtained compounds of formula I can be translated into their salts, especially for pharmaceutical use they are translated into their physiologically tolerable salts with inorganic or organic acids. Examples of acids here are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Spojevi općih formula II do IX, koji se upotrebljavaju kao polazni materijali, su djelomično poznati iz literature ili se mogu dobiti postupcima poznatim iz literature (vidi primjere I do XXII) ili prethodno opisanim postupcima, prema potrebi uz dodatno uvođenje zaštitnih ostataka (npr. spojevi formule IV, odnosno VII i VIII). Compounds of the general formulas II to IX, which are used as starting materials, are partially known from the literature or can be obtained by procedures known from the literature (see examples I to XXII) or previously described procedures, if necessary with the additional introduction of protective residues (e.g. compounds formulas IV, or VII and VIII).

Kao što je već ranije spomenuto, spojevi opće formule I i njihove fiziološki podnošljive soli, prema izumu, imaju dragocjena farmakološka svojstva, naročito inhibicijski učinak na prijenos signala posredovan s receptorom epidermnog faktora rasta (EGF-R) , pri čemu se to može postići, na primjer, inhibicijom vezanja liganda, dimerizacijom receptora ili same tirozin kinaze. Osim toga, prijenos signala se može blokirati na komponentama koje se nalaze dalje silazno. As already mentioned earlier, compounds of the general formula I and their physiologically tolerable salts, according to the invention, have valuable pharmacological properties, in particular an inhibitory effect on signal transmission mediated by the epidermal growth factor receptor (EGF-R), whereby this can be achieved, for example, by inhibiting ligand binding, receptor dimerization or the tyrosine kinase itself. In addition, signal transmission can be blocked on downstream components.

Biološka svojstva novih spojeva ispitana su kako slijedi: The biological properties of the new compounds were tested as follows:

Inhibicija humanog EGF-receptor kinaze ispitana je pomoću domene citoplazmične tirozin kinaze (metionin 664 do alanin 1186 na temelju sekvence objavljene u Nature 309 (1984), 418). U tu svrhu protein je ekspresioniran u Sf9 stanicama insekata kao GST fuzijski protein uz upotrebu sistema ekspresije s bakulo virusom. Inhibition of human EGF-receptor kinase was tested using the cytoplasmic tyrosine kinase domain (methionine 664 to alanine 1186 based on the sequence published in Nature 309 (1984), 418). For this purpose, the protein was expressed in Sf9 insect cells as a GST fusion protein using a baculovirus expression system.

Mjerenje aktivnosti enzima provedeno je u prisutnosti ili u odsutnosti ispitnog spoja u nizu razrjeđenja. Kao podloga je upotrijebljen polimer pEY (4:1) tvrtke SIGMA. Biotinilirani pEY (bio-pEY) dodan je kao supstrat za ispitivanje. Svakih 100 μl reakcijske otopine sadržavalo je 10 μl inhibitore u 50% DMSO, 20 μl otopine supstrata (200 mM HEPES, pH 7,4, 50 mM magnezijevog acetata, 2,5 mg/ml poli(EY), 5 μl/ml bio-pEY) i 20 μl pripravka enzima. Enzimska reakcija započeta je dodatkom 50 μl otopine od 100 μM ATP-a u 10 mM magnezijevog klorida. Razrjeđenje enzimskog pripravka je bilo namješteno tako da je ugradnja fosfata u bio-pEY bila linearna s vremenom i količinom enzima. Enzimski pripravak je bio razrijeđen u 20 mM HEPES-a, pH 7,4, 1 mM EDTA, 130 mM NaCl, 0,05% tritona X-100, 1 mM DTT-a i 10% glicerina. Enzyme activity was measured in the presence or absence of the test compound in a series of dilutions. The polymer pEY (4:1) from SIGMA was used as a substrate. Biotinylated pEY (bio-pEY) was added as a substrate for the assay. Each 100 μl reaction solution contained 10 μl inhibitors in 50% DMSO, 20 μl substrate solution (200 mM HEPES, pH 7.4, 50 mM magnesium acetate, 2.5 mg/ml poly(EY), 5 μl/ml bio -pEY) and 20 μl of enzyme preparation. The enzyme reaction was started by the addition of 50 μl of a solution of 100 μM ATP in 10 mM magnesium chloride. The dilution of the enzyme preparation was adjusted so that the incorporation of phosphate into bio-pEY was linear with time and the amount of enzyme. The enzyme preparation was diluted in 20 mM HEPES, pH 7.4, 1 mM EDTA, 130 mM NaCl, 0.05% Triton X-100, 1 mM DTT, and 10% glycerin.

Enzimski pokus je proveden pri sobnoj temperaturi tijekom vremenskog perioda od 30 minuta i završen je s dodatkom 50 μl zaustavne otopine (250 mM EDTA u 20 mM HEPES-a, pH 7,4). 100 μl je stavljeno na mikrotitarsku pločicu prevučenu sa streptavidinom i inkubirano je 60 minuta pri sobnoj temperaturi. Nakon toga pločica je isprana s 200 μl otopine za ispiranje (50 mM tris, 0,05% Tween 20). Nakon dodatka 100 μl s HRPO obilježenog anti-PY antitijela (PY20H Anti-PTyr:HRP, dobivenog od tvrtke Transduction Laboratories, 250 ng/ml) inkubirano je 60 minuta. Nakon toga su mikrotitarske pločice isprane tri puta sa po 200 μl otopine za ispiranje. Uzorci su zatim pomiješani sa 100 μl otopine TMB-peroksidaze (A:B = 1:1, Kirkegaard Pery Laboratories). Reakcija je zaustavljena nakon 10 minuta. Ekstinkcija je izmjerenja pri OD450nm s ELISA čitačem. Svaka vrijednost je izmjerena puta. The enzyme experiment was carried out at room temperature for a period of 30 minutes and was terminated by the addition of 50 μl of stop solution (250 mM EDTA in 20 mM HEPES, pH 7.4). 100 μl was placed on a microtiter plate coated with streptavidin and incubated for 60 minutes at room temperature. After that, the plate was washed with 200 μl of washing solution (50 mM Tris, 0.05% Tween 20). After the addition of 100 μl of HRPO-labeled anti-PY antibody (PY20H Anti-PTyr:HRP, obtained from Transduction Laboratories, 250 ng/ml) it was incubated for 60 minutes. After that, the microtiter plates were washed three times with 200 μl of washing solution each. The samples were then mixed with 100 μl of TMB-peroxidase solution (A:B = 1:1, Kirkegaard Pery Laboratories). The reaction was stopped after 10 minutes. Extinction is measured at OD450nm with an ELISA reader. Each value was measured multiple times.

Podaci su prilagođeni pomoću iterativnog računa upotrebom analitičkog programa za sigmoidalne krivulje (Graph Pad Prism Version 3.0) s varijabilnim Hillovin nagibom. Svi dobiveni iterativni podaci imali su koeficijente korelacije iznad 0,9, a gornje i donje vrijednosti krivulja pokazivale su rasipanje najmanje za faktor 5. Iz tih krivulja utvrđena je koncentracija aktivne tvari koja inhibira aktivnost EGF-receptor kinaze za 50% (CC50). Data were fitted by an iterative calculation using a sigmoid curve analysis program (Graph Pad Prism Version 3.0) with a variable Hillovin slope. All obtained iterative data had correlation coefficients above 0.9, and the upper and lower values of the curves showed dispersion of at least a factor of 5. From these curves, the concentration of the active substance that inhibits EGF-receptor kinase activity by 50% (CC50) was determined.

Dobiveni su slijedeći rezultati: The following results were obtained:

[image] [image]

Stoga dakle, spojevi opće formule I prema izumu inhibiraju prijenos signala preko tirozin kinaze, kao što je, na primjer, pokazano s humanim EGF-rezeptorima, i oni se stoga mogu upotrijebiti za liječenje patofizioloških procesa koje uzrokuje hiperfunkcija tirozin kinaze. To su npr. benigni ili maligni tumori, naročito tumori epitelnog i neuroepitelnog porijekla, metastaziranje kao i nenormalna proliferacija vaskularnih endotelnih stanica (neo-angiogeneza). Therefore, the compounds of general formula I according to the invention inhibit signal transmission via tyrosine kinase, as, for example, has been demonstrated with human EGF-receptors, and they can therefore be used to treat pathophysiological processes caused by tyrosine kinase hyperfunction. These are, for example, benign or malignant tumors, especially tumors of epithelial and neuroepithelial origin, metastasis as well as abnormal proliferation of vascular endothelial cells (neo-angiogenesis).

Spojevi prema izumu mogu se također upotrijebiti za prevenciju i liječenje bolesti dišnih putova i pluća, koje su popraćene s povećanom ili promijenjenom proizvodnjom sluzi koju uzrokuje stimulacija tirozin kinase, kao npr. kod upalnih bolesti dišnih putova kao što je kronični bronhitis, kronični opstrukcijski bronhitis, astma, bronhijalne ektazije, alergijski ili nealergijski rinitis ili sinusitis, cistična fibroza, nedostatak α1-anti-tripsina, ili kod kašlja, plućnog emfizema, plućne fibroze i hiperreaktivnih dišnih putova. The compounds according to the invention can also be used for the prevention and treatment of diseases of the airways and lungs, which are accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinase, such as in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchial ectasia, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, α1-anti-trypsin deficiency, or in cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.

Ovi spojevi su također prikladni za liječenje bolesti gastrointestinalnog trakta i žučnog kanala i žučnog mjehura, koje su povezane s poremećenom aktivnosti tirozin kinaze, kao one koje se mogu pronaći npr. kod kroničnih upalnih promjena, kao holecistitis, Crohnova bolest, ulcerativni kolitis i čirevi u gastrointestinalnom traktu ili kao one koje se pojavljuju kod bolesti gastro-intestinalnog trakta koje su povezane s povećanom sekrecijom, kao Menetrierova bolest, sekrecijski adenomi i sindrom gubitka proteina. These compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile duct and gall bladder, which are associated with disturbed tyrosine kinase activity, such as those that can be found, for example, in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis and ulcers in gastrointestinal tract or as those occurring in diseases of the gastrointestinal tract that are associated with increased secretion, such as Menetrier's disease, secretory adenomas and protein loss syndrome.

Osim toga, spojevi opće formule I i njihove fiziološki podnošljive soli mogu se upotrijebiti za liječenje drugih bolesti uzrokovanih s nenormalnom funkcijom tirozin kinaze, kao što je npr. epidermalna hiperproliferacija (psorijaza), benigna hiperplazija prostate (BPH) , upalni procesi, bolesti imuno sistema, hiperproliferacija hematopoetskih stanica, liječenje nazalnih polipa, itd. In addition, the compounds of general formula I and their physiologically tolerable salts can be used for the treatment of other diseases caused by abnormal tyrosine kinase function, such as, for example, epidermal hyperproliferation (psoriasis), benign prostatic hyperplasia (BPH), inflammatory processes, diseases of the immune system , hyperproliferation of hematopoietic cells, treatment of nasal polyps, etc.

Zbog njihovih bioloških svojstava, spojevi prema izumu mogu se primijeniti sami ili u kombinaciji s drugim farmakološki učinkovitim spojevi, na primjer u terapiji tumora kao monoterapija ili u kombinaciji s drugim anti-tumorskim terapeuticima, na primjer u kombinaciji s inhibitorima topoizomeraze (npr. etoposid), s inhibitorima mitoze (npr. vinblastin), sa spojevima koji reagiraju zajedno s nukleinskim kiselinama (npr. cis-platin, ciklofosfamid, adriamicin), s antagonistima hormona (npr. tamoksifen), s inhibitorima metaboličkih procesa (npr. 5-FU itd.), sa citokinima (npr. interferoni), s antitijelima itd. Za liječenje bolesti dišnih putova ovi spojevi se mogu upotrijebiti sami ili u kombinaciji s drugim terapeuticima dišnih putova, kao što su npr. sekretolitici (npr. ambroksol, N-acetilcistein), bronholitici (npr. tiotropij ili ipratropij ili fenoterol, salmeterol, salbutamol) i/ili s aktivnim tvarima koje inhibiraju upalu (npr. teofilin ili glukokortikoidi). Za liječenje bolesti u području gastro-intestinalnog trakta ovi spojevi se također mogu upotrijebiti sami ili u kombinaciji s tvarima koje utječu na pokretljivost ili sekreciju. Ove kombinacije se mogu dati istovremeno ili uzastopno. Due to their biological properties, the compounds according to the invention can be administered alone or in combination with other pharmacologically effective compounds, for example in tumor therapy as monotherapy or in combination with other anti-tumor therapeutics, for example in combination with topoisomerase inhibitors (e.g. etoposide). , with mitosis inhibitors (e.g. vinblastine), with compounds that react together with nucleic acids (e.g. cis-platinum, cyclophosphamide, adriamycin), with hormone antagonists (e.g. tamoxifen), with inhibitors of metabolic processes (e.g. 5-FU etc. .), with cytokines (e.g. interferons), with antibodies, etc. For the treatment of respiratory diseases, these compounds can be used alone or in combination with other therapeutics of the respiratory tract, such as, for example, secretolytics (e.g. ambroxol, N-acetylcysteine) , broncholytics (eg tiotropium or ipratropium or fenoterol, salmeterol, salbutamol) and/or with active substances that inhibit inflammation (eg theophylline or glucocorticoids). For the treatment of diseases in the area of the gastro-intestinal tract, these compounds can also be used alone or in combination with substances that affect motility or secretion. These combinations can be given simultaneously or sequentially.

Ovi spojevi se mogu dati sami ili u kombinaciji s drugim aktivnim tvarima intravenski, supkutano, intra-muskularno, intraperitonealno, intranasalno, inhalacijom ili transdermalno ili oralno, pri čemu su za inhalaciju naročito prikladne formulacije aerosola. These compounds can be administered alone or in combination with other active substances intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation or transdermally or orally, with aerosol formulations particularly suitable for inhalation.

Za farmaceutsku primjenu spojevi prema izumu se daju u pravilu toplokrvnim kralježnjacima, naročito ljudima, u doziranjima od 0,01-100 mg/kg tjelesne težine, ponajprije od 0,1-15 mg/kg. Za aplikaciju oni se formuliraju s jednim ili više uobičajenih inertnih nosača i/ili sredstava za razrjeđivanje, kao što su npr. s kukuruzni škrob, laktoza, glukoza, mikrokristalinična celuloza, magnezijev stearat, polivinilpirolidon, limunska kiselina, vinska kiselina, voda, voda/etanol, voda/glicerin, voda/sorbit, voda/poli-etilenglikol, propilenglikol, stearilalkohol, karboksi-metilceluloza ili tvari koje sadrže masti kao što je tvrda mast ili njihove prikladne mješavine u uobičajenim galenskim pripravcima kao što su tablete, dražeje, kapsule, puderi, suspenzije, otopine, sprejevi ili čepići. For pharmaceutical use, the compounds according to the invention are usually administered to warm-blooded vertebrates, especially humans, in dosages of 0.01-100 mg/kg body weight, preferably 0.1-15 mg/kg. For application, they are formulated with one or more of the usual inert carriers and/or diluents, such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fat-containing substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as tablets, dragees, capsules, powders, suspensions, solutions, sprays or suppositories.

Slijedeći primjeri su predviđeni za pobliže objašnjenje predloženog izuma i oni ga ne ograničavaju. The following examples are provided for a more detailed explanation of the proposed invention and they do not limit it.

Priprava polaznih spojeva Preparation of initial connections

Primjer I Examples

4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-il-oksi)-7-benziloksi-kinazolin-hidroklorid 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yl-oxy)-7-benzyloxy-quinazoline-hydrochloride

Smjesu od 10,84 g 4-klor-6-(tetrahidropiran-4-iloksi)-7-benziloksi-kinazolina i 4,50 g 3-klor-4-fluoranilina u 300 ml izopropanola grije se četiri sata pod refluksom i zatim se pusti stajati preko noći pri sobnoj temperaturi. Nastali talog se odsisa, ispere s izopropanolom i pomiješa sa 150 ml metanola. Suspenziju se još miješa pola sata pri sobnoj temperaturi i se zatim odsisa. Kolač na filteru se više puta ispere s metanolom i osuši. Iskorištenje: 9,07 g (60% od teorijskog). A mixture of 10.84 g of 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline and 4.50 g of 3-chloro-4-fluoroaniline in 300 ml of isopropanol is heated for four hours under reflux and then let stand overnight at room temperature. The resulting precipitate is suctioned off, washed with isopropanol and mixed with 150 ml of methanol. The suspension is stirred for half an hour at room temperature and then suctioned off. The cake on the filter is washed several times with methanol and dried. Yield: 9.07 g (60% of theoretical).

Rf vrijednost: 0,27 (silika gel, cikloheksan/octeni ester = 1:1) Rf value: 0.27 (silica gel, cyclohexane/acetic ester = 1:1)

Maseni spektar (ESI-): m/z = 478, 480 [M-H]- Mass spectrum (ESI-): m/z = 478, 480 [M-H]-

Analogno primjeru I dobiveni su slijedeći spojevi: Analogous to example I, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino3-6-((S)-tetrahidrofuran-3-iloksi)-7-benziloksi-kinazolin-hidroklorid (1) 4-[(3-chloro-4-fluoro-phenyl)amino3-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline-hydrochloride

Rf vrijednost: 0,34 (silika gel, cikloheksan/octeni ester =1:1) Rf value: 0.34 (silica gel, cyclohexane/acetic ester = 1:1)

Maseni spektar (ESI+) : m/z = 466, 468 [M+H] + Mass spectrum (ESI+): m/z = 466, 468 [M+H] +

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-kinazolin-hidroklorid (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline hydrochloride

Rf vrijednost: 0,17 (TLC gotova pločica reverzne faze (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.17 (TLC ready reverse phase plate (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 469, 471 [M+H]+ Mass spectrum (ESI+): m/z = 469, 471 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-7-acetoksi-kinazolin-hidroklorid (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride

Rf vrijednost: 0,70 (silika gel, metilen klorid/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.70 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 527, 529 [M+H]+ Mass spectrum (ESI+): m/z = 527, 529 [M+H]+

(4) 4-[(3-etinil-fenil)amino]-6-acetoksi-7-metoksi-kinazolin (4) 4-[(3-ethynyl-phenyl)amino]-6-acetoxy-7-methoxy-quinazoline

Rf vrijednost: 0,59 (silika gel, octeni ester) Rf value: 0.59 (silica gel, acetic ester)

Maseni spektar (ESI+) : m/z = 334 [M+H]+ Mass spectrum (ESI+): m/z = 334 [M+H]+

Primjer II Example II

4-klor-6-(tetrahidropiran-4-iloksi)-7-benziloksi-kinazolin 4-chloro-6-(tetrahydropyran-4-yloxy)-7-benzyloxyquinazoline

Proizveden je reakcijom 6-(tetrahidropiran-4-iloksi)-7-benziloksi-3H-kinazolin-4-ona s tionil kloridom u prisutnosti N,N-dimetilformamida u acetonitrilu pod refluksom. It is produced by the reaction of 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazolin-4-one with thionyl chloride in the presence of N,N-dimethylformamide in refluxing acetonitrile.

Rf vrijednost: 0,90 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.90 (silica gel, acetic ester/methanol = 9:1)

Analogno primjeru II dobiveni su slijedeći spojevi: Analogous to example II, the following compounds were obtained:

(1) 4-klor-6-((S)-tetrahidrofuran-3-iloksi)-7-benziloksi-kinazolin (1) 4-chloro-6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-quinazoline

Rf vrijednost: 0,85 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.85 (silica gel, acetic ester/methanol = 9:1)

(2) 4-klor-6-(1-trifluoracetil-piperidin-4-iloksi)-kinazolin (2) 4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline

Rf vrijednost: 0,92 (silika gel, octeni ester) Rf value: 0.92 (silica gel, acetic ester)

(3) 4-klor-6-(1-trifluoracetil-piperidin-4-iloksi)-7-acetoksi-kinazolin (3) 4-chloro-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline

Primjer III Example III

6-(tetrahidropiran-4-iloksi)-7-benziloksi-3H-kinazolin-4-on 6-(tetrahydropyran-4-yloxy)-7-benzyloxy-3H-quinazolin-4-one

Smjesu od 15,08 g 2-amino-4-benziloksi-5-(tetrahidro-piran-4-iloksi)-benzojeve kiseline i 14,40 g formamidin acetata u 250 ml apsolutnog etanola grije se preko noći pod refluksom. Ohlađenu reakcijsku smjesu se pomiješa s 250 ml vode. Izlučeni talog se odsisa i osuši pri 70°C u komori za sušenje. A mixture of 15.08 g of 2-amino-4-benzyloxy-5-(tetrahydro-pyran-4-yloxy)-benzoic acid and 14.40 g of formamidine acetate in 250 ml of absolute ethanol is heated under reflux overnight. The cooled reaction mixture was mixed with 250 ml of water. The excreted sediment is sucked off and dried at 70°C in a drying chamber.

Iskorištenje: 10,00 g (65% od teorijskog). Yield: 10.00 g (65% of theoretical).

Rf vrijednost: 0,40 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.40 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 353 [M+H]+ Mass spectrum (ESI+): m/z = 353 [M+H]+

Analogno primjeru III dobiveni su slijedeći spojevi: Analogous to example III, the following compounds were obtained:

(1) 6-((S)-tetrahidrofuran-3-iloksi)-7-benziloksi-3H-kinazolin-4-on (1) 6-((S)-tetrahydrofuran-3-yloxy)-7-benzyloxy-3H-quinazolin-4-one

Rf vrijednost: 0,60 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluor octena kiselina 50:50:1) Rf value: 0.60 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid 50:50:1)

Maseni spektar (ESI+): m/z = 339 [M+H]+ Mass spectrum (ESI+): m/z = 339 [M+H]+

(2) 6-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-3H-kinazolin-4-on (2) 6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-3H-quinazolin-4-one

Rf vrijednost: 0,48 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.48 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 346[M+H]+ Mass spectrum (ESI+): m/z = 346[M+H]+

(3) 6-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-7-hidroksi-3H-kinazolin-4-on (3) 6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-hydroxy-3H-quinazolin-4-one

Rf vrijednost: 0,35 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 362 [M+H]+ Mass spectrum (ESI+): m/z = 362 [M+H]+

Primjer IV Example IV

2-amino-4-benziloksi-5-(tetrahidropiran-4-iloksi)-benzojeva kiselina 2-amino-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid

16,40 g 2-nitro-4-benziloksi-5-(tetrahidropiran-4-iloksi)-benzojeve kiseline hidrira se u prisutnosti 1,64 g Raney nikla u 800 ml metanola pri 55°C do utroška izračunate količine vodika. Katalizator se odfiltrira i filtrat se koncentrira, pri čemu izkristalizira željeni proizvod. 16.40 g of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid is hydrogenated in the presence of 1.64 g of Raney nickel in 800 ml of methanol at 55°C until the calculated amount of hydrogen is consumed. The catalyst is filtered off and the filtrate is concentrated to crystallize the desired product.

Iskorištenje: 15,08 g (100 % od teorijskog). Yield: 15.08 g (100% of theoretical).

Rf vrijednost: 0,60 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluor octena kiselina = 50:50:1) Rf value: 0.60 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Analogno primjeru IV dobiveni su slijedeći spojevi: Analogous to example IV, the following compounds were obtained:

(1) 2-amino-4-benziloksi-5-((S)-tetrahidrofuran-3-iloksi)-benzojeva kiselina benzil ester (1) 2-amino-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoic acid benzyl ester

Rf vrijednost: 0,70 (silika gel, cikloheksan/octeni ester = 1:1) Rf value: 0.70 (silica gel, cyclohexane/acetic ester = 1:1)

Maseni spektar (ESI+): m/z = 420 [M+H]+ Mass spectrum (ESI+): m/z = 420 [M+H]+

(2) 2-amino-5-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-benzojeva kiselina (2) 2-amino-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

Rf vrijednost: 0,43 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 337 [M+H]+ Mass spectrum (ESI+): m/z = 337 [M+H]+

(3) 2-amino-4-hidroksi-5-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-benzojeva kiselina (3) 2-amino-4-hydroxy-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

Rf vrijednost: 0,23 (silika gel, metilen klorid/metanol/ octena kiselina = 90:10:1) Rf value: 0.23 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1)

Primjer V Example V

2-nitro-4-benziloksi-5-(tetrahidropiran-4-iloksi)-benzojeva kiselina 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid

Proizvedena je saponifikacijom benzil estera 2-nitro-4-benziloksi-5-(tetrahidropiran-4-iloksi)-benzojeve kiseline s 1 N natrijevom lužinom u metanolu pri sobnoj temperaturi. It is produced by saponification of 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid benzyl ester with 1 N sodium hydroxide solution in methanol at room temperature.

Rf vrijednost: 0,20 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.20 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 374 [M+H]+ Mass spectrum (ESI+): m/z = 374 [M+H]+

Primjer VI Example VI

Benzil ester 2-nitro-4-benziloksi-5-(tetrahidro-piran-4-il-oksi)-benzojeve kiseline Benzyl ester of 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yl-oxy)-benzoic acid

K 38 ml tetrahidrofuran-4-ola u 228 ml N,N-dimetil-formamida uz hlađenje na ledenoj kupelji doda se 42,60 g kalijevog terc-butanolata. Smjesu se miješa jedan sat pri sobnoj temperaturi, zatim se doda 22,90 g 6-nitro-benzo-[1,3]dioksol-5-karboksilne kiseline. Nakon 1,5 sata reakcija je gotova prema tankoslojnom kromatogramu i tada se dokaplje 28,94 ml benzil bromida uz hlađenje na ledenoj kupelji. Reakcijsku smjesu se miješa preko noći pri sobnoj temperaturi, pomiješa se sa 100 ml 10%-tne limunske kiseline i miješa se još jedan dan pri sobnoj temperaturi. Zatim se reakcijsku smjesu koncentrira u vakuumu pri 60°C i prenese se na 800 ml ledene vode. Vodenu fazu se ekstrahira s octenim esterom i sjedinjeni ekstrakti se isperu s vodom i sa zasićenom otopinom natrijevog klorida, osuši se preko magnezijevog sulfata i koncentrira. 42.60 g of potassium tert-butanolate was added to 38 ml of tetrahydrofuran-4-ol in 228 ml of N,N-dimethylformamide while cooling in an ice bath. The mixture was stirred for one hour at room temperature, then 22.90 g of 6-nitro-benzo-[1,3]dioxole-5-carboxylic acid was added. After 1.5 hours, the reaction is complete according to the thin-layer chromatogram, and then 28.94 ml of benzyl bromide are added dropwise while cooling in an ice bath. The reaction mixture is stirred overnight at room temperature, mixed with 100 ml of 10% citric acid and stirred for another day at room temperature. The reaction mixture is then concentrated in a vacuum at 60°C and transferred to 800 ml of ice water. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated.

Ostatak se pomiješa s dietil eterom, pri čemu kao sporeni proizvod izkristalizira 2-nitro-4-benziloksi-5-(tetrahidropiran-4-iloksi)-benzojeva kiselina. Proizvod se odfiltrira i filtrat se koncentrira. Kao glavni proizvod zaostane benzil ester 2-nitro-4-benziloksi-5-(tetrahidro-piran-4-il-oksi)-benzojeve kiseline, koji se bez daljnjeg čišćenja saponificira u karboksilnu kiselinu (vidi primjer V). The residue is mixed with diethyl ether, whereby 2-nitro-4-benzyloxy-5-(tetrahydropyran-4-yloxy)-benzoic acid crystallizes as a secondary product. The product is filtered off and the filtrate is concentrated. As the main product, the benzyl ester of 2-nitro-4-benzyloxy-5-(tetrahydro-pyran-4-yl-oxy)-benzoic acid remains, which is saponified into a carboxylic acid without further purification (see example V).

Analog primjeru VI dobiveni su slijedeći spojevi: Analogous to example VI, the following compounds were obtained:

(1) benzil ester 2-nitro-4-benziloksi-5-((S)-tetrahidrofuran-3-iloksi)-benzojeve kiseline (1) 2-nitro-4-benzyloxy-5-((S)-tetrahydrofuran-3-yloxy)-benzoic acid benzyl ester

Rf vrijednost: 0,75 (silika gel, cikloheksan/octeni ester=1:1) Rf value: 0.75 (silica gel, cyclohexane/acetic ester=1:1)

Maseni spektar (ESI+): m/z = 450 [M+H]+ Mass spectrum (ESI+): m/z = 450 [M+H]+

(2) 2-nitro-4-hidroksi-5-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-benzojeva kiselina (2) 2-nitro-4-hydroxy-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

Izostavljena je reakcija s benzil bromidom. The reaction with benzyl bromide was omitted.

Rf vrijednost: 0,40 (silika gel, metilen klorid/metanol/octena kiselina = 90:10:1) Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1)

Maseni spektar (ESI-): m/z = 381 [M-H]- Mass spectrum (ESI-): m/z = 381 [M-H]-

Primjer VII Example VII

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[2-(terc-butiloksi-karbonilamino)-etil]-piperidin-4-iloksi}-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxy-carbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Smjesu od 410 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorida, 240 mg N-(terc-butiloksikarbonil)-2-brom-etilamina i 360 mg kalijevog karbonata u 5 ml N,N-dimetilformamida miješa se preko noći pri sobnoj temperaturi. Zatim se još jednom doda 80 mg N-(terc-butiloksikarbonil)-2-brom-etilamin i reakcijsku smjesu se miješa još četiri sata pri sobnoj temperaturi. Za obradu se razrijedi s vodom i ekstrahira s octenim esterom. Sjedinjene organske faze se isperu sa zasićenom otopinom natrijevog klorida, osuše se preko magnezijevog sulfata i koncentriraju. Ostatak se kromatografira preko stupca silika gela s octeni ester/ metanolom (95:5 na 90:1) kao protočnim sredstvom. Iskorištenje: 370 mg (79 % od teorijskog). A mixture of 410 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride, 240 mg of N-(tert-butyloxycarbonyl)-2 -bromoethylamine and 360 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at room temperature. Then 80 mg of N-(tert-butyloxycarbonyl)-2-bromo-ethylamine was added once more and the reaction mixture was stirred for another four hours at room temperature. For processing, it is diluted with water and extracted with acetic ester. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed over a column of silica gel with ethyl acetate/methanol (95:5 to 90:1) as eluant. Yield: 370 mg (79% of theoretical).

Rf vrijednost: 0,33 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.33 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI-): m/z = 544, 546 [M-H]- Mass spectrum (ESI-): m/z = 544, 546 [M-H]-

Analogno primjeru VII dobiven je slijedeći spoj: Analogous to example VII, the following compound was obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[2-(terc-butil-oksikarbonilamino)-etil]-piperidin-4-iloksi}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyl-oxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

Rf vrijednost: 0,38 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.38 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 516, 518[M+H]+ Mass spectrum (ESI+): m/z = 516, 518[M+H]+

Primjer VIII Example VIII

4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorid 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

Proizveden je obradom 4-[(3-klor-4-fluor-fenil)-amino]-6-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-7-metoksi-kinazolina s koncentriranom solnom kiselinom u dioksanu pri sobnoj temperaturi. It is produced by treating 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline with concentrated hydrochloric acid in dioxane at room temperature.

Rf vrijednost: 0,53 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.53 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 403, 405 [M+H]+ Mass spectrum (ESI+): m/z = 403, 405 [M+H]+

Analog primjeru VIII dobiveni su slijedeći spojevi: Analogous to example VIII, the following compounds were obtained:

(1) 6-(piperidin-4-iloksi)-3H-kinazolin-4-on x 2 trifluor-octena kiselina (1) 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x 2 trifluoroacetic acid

Provedba s trifluoroctenom kiselinom u metilen kloridu. Implementation with trifluoroacetic acid in methylene chloride.

Maseni spektar (ESI+): m/z = 246 [M+H]+ Mass spectrum (ESI+): m/z = 246 [M+H]+

(2) 6-(piperidin-4-iloksi)-7-hidroksi-3H-kinazolin-4-on (2) 6-(piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

Provedba s trifluoroctenom kiselinom u metilen kloridu. Implementation with trifluoroacetic acid in methylene chloride.

Rf vrijednost: 0,60 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.60 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 262 [M+H]+ Mass spectrum (ESI+): m/z = 262 [M+H]+

Primjer IX Example IX

4-[(3-klor-4-fluor-fenil)amino]-6-[1-(terc-butiloksi-karbonil)-piperidin-4-iloksi]-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxy-carbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

K smjesi iz 10,00 g 4-[(3-klor-4-fluor-fenil)amino]-6-hidroksi-7-metoksi-kinazolina i 9,40 g 1-(terc-butiloksi-karbonil)-4-hidroksi-piperidina i 12,40 g trifenilfosfina u 400 ml metilen klorida pri sobnoj temperaturi dokaplje se otopinu od 7,80 ml dietil estera azodikarboksilne kiseline u 100 ml metilen klorida. Suspenziju se miješa tri dana pri sobnoj temperaturi i zatim se odsisa. Filtrat se koncentrira i kromatografira preko stupca silika gela s metilen klorid/metanolom (98:2 na 95:5) kao protočnim sredstvom. Dobiveni sirov proizvod se pomiješa s diizopropil eterom, u tome se miješa preko noći, odsisa se i osuši. To a mixture of 10.00 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline and 9.40 g of 1-(tert-butyloxy-carbonyl)-4- hydroxy-piperidine and 12.40 g of triphenylphosphine in 400 ml of methylene chloride at room temperature are added dropwise to a solution of 7.80 ml of diethyl ester of azodicarboxylic acid in 100 ml of methylene chloride. The suspension is stirred for three days at room temperature and then suctioned off. The filtrate is concentrated and chromatographed over a column of silica gel with methylene chloride/methanol (98:2 to 95:5) as eluant. The resulting crude product is mixed with diisopropyl ether, stirred overnight, filtered off with suction and dried.

Iskorištenje: 5,34 g (34% od teorijskog). Yield: 5.34 g (34% of theoretical).

Rf vrijednost: 0,46 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.46 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 503, 505 [M+H]+ Mass spectrum (ESI+): m/z = 503, 505 [M+H]+

Primjer X Example X

4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(4-brom-butiloksi)-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(4-bromo-butyloxy)-quinazoline

Smjesu od 500 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-hidroksi-kinazolina, 165 μl 1-brom-4-klor-propana i 3 60 mg kalijevog karbonata u 5 ml N,N-dimetilforinamida miješa se preko noći pri 80°C. Za obradu, se reakcijsku smjesu razrijedi s vodom i ekstrahira s octenim esterom. Sjedinjene organske faze se isperu sa zasićenom otopinom natrijevog klorida, osuše se preko magnezijevog sulfata i koncentriraju. Sirov proizvod se dalje pretvara bez daljnjeg čišćenja. Iskorištenje: 650 mg (97% od teorijskog). A mixture of 500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline, 165 μl of 1-bromo-4-chloro-propane and 3 60 mg of potassium carbonate in 5 ml of N,N-dimethylforinamide is stirred overnight at 80°C. For processing, the reaction mixture is diluted with water and extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is further converted without further purification. Yield: 650 mg (97% of theoretical).

Analogno primjer X dobiveni su slijedeći spojevi: Analogous to example X, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-(4-brom-butiloksi)-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-(4-bromo-butyloxy)-quinazoline

Rf vrijednost: 0,84 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.84 (silica gel, acetic ester/methanol = 9:1)

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-7-etoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

Maseni spektar (ESI+): m/z = 513, 515[M+H]+ Mass spectrum (ESI+): m/z = 513, 515[M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-7-(2-metoksi-etoksi)-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf vrijednost: 0,38 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z - 543, 545 [M+H]+ Mass spectrum (ESI+): m/z - 543, 545 [M+H]+

Primjer XI Example XI

1-(2-hidroksi-etil)-3-metil-tetrahidropirimidin-2-on 1-(2-hydroxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one

Proizveden je hidrogenolitičkim cijepanjem 1-(2-benziloksi-etil)-3-metil-tetrahidropirimidin-2-ona u prisutnosti paladija na aktivnom ugljenu u metanolu pri sobnoj temperaturi. It is produced by hydrogenolytic cleavage of 1-(2-benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one in the presence of palladium on activated carbon in methanol at room temperature.

Rf vrijednost: 0,23(silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.23 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 159 [M+H]+ Mass spectrum (ESI+): m/z = 159 [M+H]+

Primjer XII Example XII

1-(2-benziloksi-etil)-3-metil-tetrahidropirimidin-2-on 1-(2-Benzyloxy-ethyl)-3-methyl-tetrahydropyrimidin-2-one

Proizveden je reakcijom 1-(2-benziloksi-etil)-tetra-hidropirimidin-2-ona s metil jodidom u prisutnosti kalijevog terc-butanolata u N,N-dimetilformamid pri sobnoj temperaturi. It is produced by the reaction of 1-(2-benzyloxy-ethyl)-tetra-hydropyrimidin-2-one with methyl iodide in the presence of potassium tert-butanolate in N,N-dimethylformamide at room temperature.

Rf vrijednost: 0,62 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.62 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 249 [M+H]+ Mass spectrum (ESI+): m/z = 249 [M+H]+

Primjer XIII Example XIII

1-(2-benziloksi-etil)-tetrahidropirimidin-2-on 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one

Proizveden je obradom 1-(2-benziloksi-etil)-3-(3-klor-propil)-uree s kalijevim-terc-butanolatom u N,N-dimetil-formamidu pri sobnoj temperaturi. It is produced by treating 1-(2-benzyloxy-ethyl)-3-(3-chloro-propyl)-urea with potassium tert-butanolate in N,N-dimethyl-formamide at room temperature.

Rf vrijednost: 0,42 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.42 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+) : m/z = 235 [M+H]+ Mass spectrum (ESI+): m/z = 235 [M+H]+

Primjer XIV Example XIV

1-(2-benziloksi-etil)-tetrahidropirimidin-2-on 1-(2-benzyloxy-ethyl)-tetrahydropyrimidin-2-one

Proizveden je reakcijom 2-benziloksi-etilamina s 3-klor-propil-izocijanatom u tetrahidrofuranu. It is produced by the reaction of 2-benzyloxy-ethylamine with 3-chloro-propyl-isocyanate in tetrahydrofuran.

Rf vrijednost: 0,73 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.73 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+) : m/z = 271, 273 [M+H]+ Mass spectrum (ESI+): m/z = 271, 273 [M+H]+

Primjer XV Example XV

3-(terc-butiloksikarbonilamino)-cikloheksanol 3-(tert-butyloxycarbonylamino)-cyclohexanol

Proizveden je reakcijom 3-amino-cikloheksanola s di-terc-butil pirokarbonatom u prisutnost trietilamina u mješavini dioksana i vode (2:1) pri 50°C. It is produced by the reaction of 3-amino-cyclohexanol with di-tert-butyl pyrocarbonate in the presence of triethylamine in a mixture of dioxane and water (2:1) at 50°C.

Rf vrijednost: 0,34 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.34 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+) : m/z = 214 [M-H]+ Mass spectrum (ESI+): m/z = 214 [M-H]+

Analogno primjeru XV dobiven je slijedeći spoj: Analogous to example XV, the following compound was obtained:

(1) cis-4-[N-(terc-butiloksikarbonil)-N-metil-amino]-cikloheksanol (1) cis-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexanol

Reakcija se odvija u metanolu. The reaction takes place in methanol.

Rf vrijednost: 0,70 (silika gel, octeni ester) Rf value: 0.70 (silica gel, acetic ester)

Maseni spektar (ESI+): m/z = 230 [M+H]+ Mass spectrum (ESI+): m/z = 230 [M+H]+

Primjer XVI Example XVI

6-(1-trifluoracetil-piperidin-4-iloksi)-3H-kinazolin-4-on 6-(1-Trifluoroacetyl-piperidin-4-yloxy)-3H-quinazolin-4-one

Proizveden je reakcijom 6-(piperidin-4-iloksi)-3H-kinazolin-4-ona x 2 trifluoroctena kiselina s anhidridom trifluoroctene kiseline u prisutnosti trietilamina u tetrahidrofuranu. It is produced by the reaction of 6-(piperidin-4-yloxy)-3H-quinazolin-4-one x 2 trifluoroacetic acid with trifluoroacetic anhydride in the presence of triethylamine in tetrahydrofuran.

Rf vrijednost: 0,48 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.48 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 342 [M+H]+ Mass spectrum (ESI+): m/z = 342 [M+H]+

Analogno primjeru XVI dobiven je slijedeći spoj: Analogous to example XVI, the following compound was obtained:

(1) 6-(1-trifluoracetil-piperidin-4-iloksi)-7-hidroksi-3H-kinazolin-4-on (1) 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one

Provedba s metil esterom trifluoroctene kiseline u prisutnost Hünigove baze u metanolu. Implementation with trifluoroacetic acid methyl ester in the presence of Hünig's base in methanol.

Rf vrijednost: 0,80(silika gel, metilen klorid/metanol = 4:1) Rf value: 0.80 (silica gel, methylene chloride/methanol = 4:1)

Maseni spektar (ESI+): m/z = 358 [M+H]+ Mass spectrum (ESI+): m/z = 358 [M+H]+

Primjer XVII Example XVII

2-nitro-5-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-benzojeva kiselina 2-nitro-5-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-benzoic acid

K 25,14 g 1-(terc-butiloksikarbonil)-piperidin-4-ola u 120 ml N,N-dimetilformamida uz hlađenje na ledenoj kupelji doda se u obrocima 21,00 g kalijevog terc-butanolata, pri čemu se temperaturu drži ispod 10°C. Smjesu se miješa još 30 minuta uz hlađenje na ledenoj kupelji i zatim se doda 11,60 g 5-fluor-2-nitro-benzojeve kiseline. Nakon daljnja tri sata, reakcijsku smjesu se prelije na vodu, s konc. solnom kiselinom se namjesti na pH 1 i ekstrahira se s octenim esterom. Sjedinjene organske faze se isperu s razrijeđenom otopinom limunske kiseline, osuše se preko magnezijevog sulfata i koncentriraju. Ostatak se protrlja s dietil eterom, odsisa i osuši. Nakon duljeg stajanja iz filtrata kristalizira daljnji proizvod, koji se također odsisa i osuši. To 25.14 g of 1-(tert-butyloxycarbonyl)-piperidin-4-ol in 120 ml of N,N-dimethylformamide, while cooling in an ice bath, 21.00 g of potassium tert-butanolate is added in portions, keeping the temperature below 10°C. The mixture is stirred for another 30 minutes while cooling in an ice bath and then 11.60 g of 5-fluoro-2-nitro-benzoic acid is added. After a further three hours, the reaction mixture is poured onto water, with conc. it is adjusted to pH 1 with hydrochloric acid and extracted with acetic ester. The combined organic phases are washed with dilute citric acid solution, dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, sucked off and dried. After standing longer, a further product crystallizes from the filtrate, which is also sucked off and dried.

Iskorištenje: 9,58 g (42% od teorijskog). Yield: 9.58 g (42% of theoretical).

Rf vrijednost: 0,43 (silika gel, metilen klorid/metanol/octena kiselina = 90:10:1) Rf value: 0.43 (silica gel, methylene chloride/methanol/acetic acid = 90:10:1)

Maseni spektar (ESI+): m/z = 367 [M+H]+ Mass spectrum (ESI+): m/z = 367 [M+H]+

Primjer XVIII Example XVIII

4-[(3-klor-4-fluor-fenil)amino]-6-(1-bromacetil-piperidin-4-iloksi)-kinazolin i 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-bromoacetyl-piperidin-4-yloxy)-quinazoline and

4-[(3-klor-4-fluor-fenil)amino]-6-(1-kloracetil-piperidin-4-iloksi)-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloroacetyl-piperidin-4-yloxy)-quinazoline

Proizvedeni su reakcijom 4-[(3-klor-4-fluor-fenil)-amino]-6-(piperidin-4-iloksi)-kinazolina s kloridom brom-octene kiseline u prisutnosti Hilnigove baze u tetrahidrofuranu pri sobnoj temperaturi. Dobije se smjesu spoja broma i spoja klora. They were produced by the reaction of 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(piperidin-4-yloxy)-quinazoline with bromoacetic acid chloride in the presence of Hilnig's base in tetrahydrofuran at room temperature. A mixture of bromine compound and chlorine compound is obtained.

Rf vrijednost: 0,43 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.43 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 493, 495, 497 [M1+H]+ i 449, 451, 453 [M2+H]+ Mass spectrum (ESI+): m/z = 493, 495, 497 [M1+H]+ and 449, 451, 453 [M2+H]+

Analogno primjeru XVIII dobiven je slijedeći spoj: Analogous to example XVIII, the following compound was obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-kloracetil-piperidin-4-iloksi)-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-chloroacetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s kloracetil kloridom. The conversion is done with chloroacetyl chloride.

Rf vrijednost: 0,59 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.59 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI-): m/z = 477, 479, 481 [M-H]- Mass spectrum (ESI-): m/z = 477, 479, 481 [M-H]-

Primjer XIX Example XIX

1-metil-3-[([1,4]oksazepan-4-il)karbonil]-3H-imidazol-1-ij-jodid 1-methyl-3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazol-1-yl-iodide

Proizveden je reakcijom 3-[([1,4]oksazepan-4-il)-karbonil]-3H-imidazola s metil jodidom u acetonitrilu pri sobnoj temperaturi. Sirov proizvod se dalje pretvara bez daljnjeg čišćenja. It is produced by the reaction of 3-[([1,4]oxazepan-4-yl)-carbonyl]-3H-imidazole with methyl iodide in acetonitrile at room temperature. The crude product is further converted without further purification.

Analogno primjeru XIX dobiveni su slijedeći spojevi: Analogous to example XIX, the following compounds were obtained:

(1) 1-metil-3-[(cis-2,6-dimetil-morfolin-4-il)karbonil]-3H-imidazol-1-ij-jodid (1) 1-methyl-3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-yl-iodide

Rf vrijednost: 0,12 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.12 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

(2) 1-metil-3-[(2-metil-morfolin-4-il)karbonil]-3H-imidazol-1-ij-jodid (2) 1-methyl-3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazol-1-yl-iodide

Rf vrijednost: 0,02 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.02 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Primjer XX Example XX

3-[([1,4]oksazepan-4-il)karbonil]-3H-imidazol 3-[([1,4]oxazepan-4-yl)carbonyl]-3H-imidazole

Proizveden je reakcijom [1,4]oksazepana s N,N'-karbonildiimidazolom u prisutnosti trietilamina u tetrahidrofuranu pri sobnoj temperaturi. It is produced by the reaction of [1,4]oxazepane with N,N'-carbonyldiimidazole in the presence of triethylamine in tetrahydrofuran at room temperature.

Rf vrijednost: 0,30 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.30 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 196 [M+H]+ Mass spectrum (ESI+): m/z = 196 [M+H]+

Analogno primjeru XX dobiveni su slijedeći spojevi: Analogous to example XX, the following compounds were obtained:

(1) 3-[(cis-2,6-dimetil-morfolin-4-il)karbonil]-3H-imidazol (1) 3-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-3H-imidazole

Rf vrijednost: 0,46 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.46 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

(2) 3-[(2-metil-morfolin-4-il) karbonil]-3H-imidazol (2) 3-[(2-methyl-morpholin-4-yl)carbonyl]-3H-imidazole

Rf vrijednost: 0,43 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.43 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Primjer XXI Example XXI

4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-7-hidroksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-quinazoline

Proizveden je obradom 4-[(3-klor-4-fluor-fenil)-amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-7-acetoksi-kinazolin-hidroklorida sa zasićenom otopinom natrijevog hidrogen-karbonata u metanolu pri sobnoj temperaturi. Pored željenog proizvoda kao sporedni proizvod je također izolirano i nešto 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-hidroksi-kinazolina. It was produced by treating 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-quinazoline-hydrochloride with a saturated solution of sodium hydrogen carbonate in methanol at room temperature. In addition to the desired product, some 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-hydroxyquinazoline was also isolated as a side product.

Rf vrijednost: 0,20 (silika gel, metilen klorid/metanol = 20:1) Rf value: 0.20 (silica gel, methylene chloride/methanol = 20:1)

Maseni spektar (ESI-): m/z = 483, 485 [M-H]- Mass spectrum (ESI-): m/z = 483, 485 [M-H]-

Analogno primjeru XXI dobiven je slijedeći spoj: Analogous to example XXI, the following compound was obtained:

(1) 4-[(3-etinil-fenil)amino]-6-hidroksi-7-metoksi-kinazolin (1) 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline

Provedba sa 40%-tnom natrijevom lužinom u etanolu. Implementation with 40% sodium lye in ethanol.

Rf vrijednost: 0,32 (silika gel, octeni ester) Rf value: 0.32 (silica gel, acetic ester)

Maseni spektar (ESI+): m/z = 292[M+H]+ Mass spectrum (ESI+): m/z = 292[M+H]+

Primjer XXII Example XXII

6-(1-trifluoracetil-piperidin-4-iloksi)-7-acetoksi-3H-kinazolin-4-on 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-acetoxy-3H-quinazolin-4-one

Proizveden je reakcijom 6-(1-trifluoracetil-piperidin-4-iloksi)-7-hidroksi-3H-kinazolin-4-ona s acetanhidridom u piridinu pri 80°C. It is produced by the reaction of 6-(1-trifluoroacetyl-piperidin-4-yloxy)-7-hydroxy-3H-quinazolin-4-one with acetic anhydride in pyridine at 80°C.

Rf vrijednost: 0,60 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.60 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 400 [M+H]+ Mass spectrum (ESI+): m/z = 400 [M+H]+

Priprava krajnjih spojeva Preparation of end joints

Primjer 1 Example 1

4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

[image] [image]

300 mg 4-[(3-klor-4-fluor-fenil)amino]-6-hidroksi-7-metoksi-kinazolina u 6 ml acetonitrila pomiješa se sa 114 μl (R)-3-hidroksi-tetrahidrofurana i 370 mg trifenil-fosfina. Zatim se doda 234 μl dietil estera azodi-karboksilne kiseline i rekcijsku smjesu se miješa preko noći pri sobnoj temperaturi. Za obradu se reakcijsku smjesu profiltrira i filtrat se koncentrira u vakuumu. Sirov proizvod se očisti kromatografijom preko stupca silika gela s octeni ester/metanolom (95:5) kao protočnim sredstvom. Iskorištenje: 53 mg (15 % od teorijskog). Talište: 178°C Maseni spektar (ESI+): m/z = 390, 392 [M+H]+ 300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline in 6 ml of acetonitrile is mixed with 114 μl of (R)-3-hydroxy-tetrahydrofuran and 370 mg of triphenyl -phosphine. Then 234 μl of diethyl ester of azodicarboxylic acid is added and the reaction mixture is stirred overnight at room temperature. For processing, the reaction mixture is filtered and the filtrate is concentrated in a vacuum. The crude product is purified by chromatography on a column of silica gel with ethyl acetate/methanol (95:5) as eluant. Yield: 53 mg (15% of theoretical). Melting point: 178°C Mass spectrum (ESI+): m/z = 390, 392 [M+H]+

Analogno primjeru 1 dobiveni su slijedeći spojevi: Analogous to example 1, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,54(silika gel, octeni ester/metanol =9:1) Rf value: 0.54 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 404, 406 [M+H]+ Mass spectrum (ESI+): m/z = 404, 406 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(terc-butil-oksikarbonilamino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(tert-butyl-oxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,70 (silika gel, octeni ester/metanol 9:1) Rf value: 0.70 (silica gel, acetic ester/methanol 9:1)

Maseni spektar (ESI+) : m/z = 517, 519 [M+H]+ Mass spectrum (ESI+): m/z = 517, 519 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-((R)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,64 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.64 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 390, 392 [M+H]+ Mass spectrum (ESI+): m/z = 390, 392 [M+H]+

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-[trans-4-(terc-butil-oksikarbonilamino)-ciklo-heksan-1-iloksi]-7-metoksi-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(tert-butyl-oxycarbonylamino)-cyclo-hexane-1-yloxy]-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,65 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.65 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 517, 519 [M+H]+ Mass spectrum (ESI+): m/z = 517, 519 [M+H]+

(5) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(terc-butil-oksi-karbonil)-piperidin-4-iloksi]-7-metoksi-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyl-oxy-carbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

[image] [image]

Talište: 184°C Melting point: 184°C

Maseni spektar (ESI+): m/z = 503, 505 [M+H]+ Mass spectrum (ESI+): m/z = 503, 505 [M+H]+

(6) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-3-iloksi)-7-metoksi-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,52 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.52 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 404, 406 [M+H]+ Mass spectrum (ESI+): m/z = 404, 406 [M+H]+

(7) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metil-piperidin-4-iloksi)-7-metoksi-kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[image] [image]

Talište: 218°C Melting point: 218°C

Maseni spektar (ESI+): m/z = 417, 419 [M+H]+ Mass spectrum (ESI+): m/z = 417, 419 [M+H]+

(8) 4-[(3-klor-4-fluor-fenil)amino]-6-[(S)-1-(terc-butil-oksikarbonil)-pirolidin-3-iloksi]-7-metoksi-kinazolin (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert-butyl-oxycarbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Rf vrijednost: 0,51 (silika gel, raetilen klorid/metanol = 9:1) Rf value: 0.51 (silica gel, ethylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(9) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(terc-butiloksi-karbonil)-piperidin-3-iloksi]-7-metoksi-kinazolin (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxy-carbonyl)-piperidin-3-yloxy]-7-methoxy-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Rf vrijednost: 0,56 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.56 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI-): m/z = 501, 503 [M-H]- Mass spectrum (ESI-): m/z = 501, 503 [M-H]-

(10) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-[2-(3-metil-2-okso-heksahidro-pirimidin-1-il)-etoksi]-kinazolin (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[2-(3-methyl-2-oxo-hexahydro- pyrimidine-1-yl)-ethoxy]-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Talište: 235°C Melting point: 235°C

Maseni spektar (ESI+): m/z = 516, 518 [M+H]+ Mass spectrum (ESI+): m/z = 516, 518 [M+H]+

(11) 4-[(3-klor-4-fluor-fenil)amino]-6-[3-(terc-butiloksi-karbonilamino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (11) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[3-(tert-butyloxy-carbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Rf vrijednost: 0,68 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.68 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI-) : m/z = 515, 517 [M-H]- Mass spectrum (ESI-): m/z = 515, 517 [M-H]-

(12) 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[N-(terc-butiloksikarbonil)-N-metil-amino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}- 7-methoxy-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Rf vrijednost: 0,37 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.37 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 531, 533 [M+H]+ Mass spectrum (ESI+): m/z = 531, 533 [M+H]+

(13) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[N-(terc-butiloksikarbonil)-N-metil-amino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[N-(tert-butyloxycarbonyl)-N-methyl-amino]-cyclohexan-1-yloxy}- 7-methoxy-quinazoline

Provedba s diizopropil azodikarboksilatom u metilen kloridu. Implementation with diisopropyl azodicarboxylate in methylene chloride.

Talište: 231°C Melting point: 231°C

Maseni spektar (ESI+): m/z = 531,533 [M+H] + Mass spectrum (ESI + ): m/z = 531.533 [M+H] +

Primjer 2 Example 2

4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-amino-cikloheksan-1-iloksi)-7-itietoksi-kinazolin x trifluoroctena kiselina 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-thiethoxy-quinazoline x trifluoroacetic acid

[image] [image]

Proizveden je obradom 4-[(3-klor-4-fluor-fenil; amino]-6-[cis-4-(terc-butiloksikarbonilamino)-cikloheksan-1-iloksi]-7-metoksi-kinazolina s trifluoroctenom kiselinom u metilen kloridu pri sobnoj temperaturi. It is produced by treating 4-[(3-chloro-4-fluoro-phenyl;amino]-6-[cis-4-(tert-butyloxycarbonylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline with trifluoroacetic acid to methylene chloride at room temperature.

Talište: 221°C Melting point: 221°C

Maseni spektar (ESI+): m/z = 417, 419 [M+H]+ Mass spectrum (ESI+): m/z = 417, 419 [M+H]+

Analogno primjeru 2 dobiveni su slijedeći spojevi: Analogous to example 2, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[image] [image]

Maseni spektar (ESI+): m/z = 417, 419 [M+H]+ Mass spectrum (ESI+): m/z = 417, 419 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-il-oksi)-7-metoksi-kinazolin x trifluoroctena kiselina (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yl-oxy)-7-methoxy-quinazoline x trifluoroacetic acid

[image] [image]

Talište: 232°C Melting point: 232°C

Maseni spektar (ESI+): m/z = 403, 405 [M+H]+ Mass spectrum (ESI+): m/z = 403, 405 [M+H]+

Primjer 3 Example 3

4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-metansulfonil-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methanesulfonyl-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[image] [image]

Proizveden je reakcijom 4-[(3-klor-4-fluor-fenil)-amino]-6-(cis-4-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin x trifluoroctene kiseline s kloridom metan-sulfonske kiseline u prisutnost Hünigove baze u tetrahidrofuranu pri sobnoj temperaturi. It is produced by the reaction of 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(cis-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline x trifluoroacetic acid with methanesulfonic chloride acid in the presence of Hünig's base in tetrahydrofuran at room temperature.

Rf vrijednost: 0,77 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 40:10:1) Rf value: 0.77 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 40:10:1)

Maseni spektar (ESI+): m/z = 495, 497 [M+H]+ Mass spectrum (ESI+): m/z = 495, 497 [M+H]+

Analogno primjeru 3 dobiveni su slijedeći spojevi: Analogous to example 3, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-metan-sulfonilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methane-sulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,20 (silika gel, octeni ester) Rf value: 0.20 (silica gel, acetic ester)

Maseni spektar (ESI+): m/z = 495, 497 [M+H]+ Mass spectrum (ESI+): m/z = 495, 497 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,59 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.59 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 481, 483 [M+H]+ Mass spectrum (ESI+): m/z = 481, 483 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[(3-klor-propil)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s 3-klorpropansulfonil kloridom. The conversion is done with 3-chloropropanesulfonyl chloride.

Rf vrijednost: 0,79 (silika gel, octeni ester/metanol : 9:1) Rf value: 0.79 (silica gel, acetic ester/methanol: 9:1)

Maseni spektar (ESI-): m/z = 555, 557, 559 [M-H]- Mass spectrum (ESI-): m/z = 555, 557, 559 [M-H]-

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(3-klor-propil)sulfoni1amino]-cikloneksan-1-iloksi}-7-metoksi-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(3-chloro-propyl)sulfonylamino]-cyclonexan-1-yloxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s 3-klorpropansulfonil kloridom. The conversion is done with 3-chloropropanesulfonyl chloride.

Rf vrijednost: 0,42 (silika gel, octeni ester) Rf value: 0.42 (silica gel, acetic ester)

Maseni spektar (ESI+) : m/z = 557, 559, 561 [M+H] + Mass spectrum (ESI+): m/z = 557, 559, 561 [M+H] +

(5) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metilkarbonil-piperidin-4-iloksi)-7-metoksi-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methylcarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s acetanhidridom. The conversion is done with acetic anhydride.

Talište:216 C Melting point: 216 C

Maseni spektar (ESI+): m/z = 445, 447 [M+H]+ Mass spectrum (ESI+): m/z = 445, 447 [M+H]+

(6) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino) karbonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s N,N-dimetilkarbamoil kloridom. The conversion is done with N,N-dimethylcarbamoyl chloride.

Rf vrijednost: 0,28 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.28 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 474, 476 [M+H]+ Mass spectrum (ESI+): m/z = 474, 476 [M+H]+

(7) 4-[(3-klor-4-fluor-fenil) amino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin-4-yl-oxy}-7-methoxy- quinazoline

[image] [image]

Pretvorba vrši s (morfolin-4-il)karbonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf vrijednost: 0,37 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.37 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 516, 518 [M+H]+ Mass spectrum (ESI+): m/z = 516, 518 [M+H]+

(8) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(metoksimetil)-karbonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin (8) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)-carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,80 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 475, 477 [M+H] + Mass spectrum (ESI + ): m/z = 475, 477 [M+H] +

(9) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-cijano-piperidin-4-iloksi)-7-metoksi-kinazolin (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s bromcijanom u metilen kloridu. The conversion is done with cyanogen bromide in methylene chloride.

Rf vrijednost: 0,40 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.40 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 428, 430 [M+H]+ Mass spectrum (ESI+): m/z = 428, 430 [M+H]+

(10) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino)-sulfonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (10) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)-sulfonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba vrši s N,N-dimetilsulfamoil kloridom u acetonitrilu. The conversion is carried out with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf vrijednost: 0,24 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.24 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 510, 512[M+H]+ Mass spectrum (ESI+): m/z = 510, 512[M+H]+

(11) 4-[(3-klor4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-sulfonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (11) 4-[(3-chloro4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-sulfonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

[image] [image]

Pretvorba se vrši s (morfolin-4-il)sulfonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf vrijednost: 0,29 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.29 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 552, 554 [M+H]+ Mass spectrum (ESI+): m/z = 552, 554 [M+H]+

(12) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-3-iloksi)-7-metoksi-kinazolin (12) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-3-yloxy)-7-methoxy-quinazoline

Rf vrijednost: 0,33 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.33 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 481, 483 [M+H]+ Mass spectrum (ESI+): m/z = 481, 483 [M+H]+

(13) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-1-metan-sulfonil-pirolidin-3-iloksi)-7-metoksi-kinazolin (13) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-1-methane-sulfonyl-pyrrolidin-3-yloxy)-7-methoxy-quinazoline

Talište: 249°C Melting point: 249°C

Maseni spektar (ESI+) : m/z = 467, 469 [M+H]+ Mass spectrum (ESI+): m/z = 467, 469 [M+H]+

(14) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-metan-sulfonilamino-etil)-piperidin-4-iloksi]-7-metoksi-kinazolin (14) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methane-sulfonylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Rf vrijednost: 0,49 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.49 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 524, 526 [M+H]+ Mass spectrum (ESI+): m/z = 524, 526 [M+H]+

(15) 4-[(3-klor-4-fluor-fenil)amino]-6-[l-(2-acetilamino-etil)-piperidin-4-iloksi]-7-metoksi-kinazolin (15) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Pretvorba se vrši s acetanhidridom. The conversion is done with acetic anhydride.

Rf vrijednost: 0,51 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.51 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 488, 490 [M+H]+ Mass spectrum (ESI+): m/z = 488, 490 [M+H]+

(16) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(dimetil-amino)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (16) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethyl-amino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s N,N-dimetilsulfamoil kloridom u acetonitrilu. The conversion is carried out with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf vrijednost: 0,69(silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.69 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 524, 526 [M+H] + Mass spectrum (ESI + ): m/z = 524, 526 [M+H] +

(17) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (17) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il) karbonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf vrijednost: 0,38 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.38 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

(18) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (18) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il) sulfonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Talište: 237°C Melting point: 237°C

Maseni spektar (ESI-): m/z = 564, 566 [M-H]- Mass spectrum (ESI-): m/z = 564, 566 [M-H]-

(19) 4-[(3-klor-4-fluor-fenil)amino]-6-(3-metansulfonil-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (19) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-methanesulfonyl-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Rf vrijednost: 0,66 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.66 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI-): m/z = 493, 495 [M-H]- Mass spectrum (ESI-): m/z = 493, 495 [M-H]-

(20) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-acetilamino-etoksi)-kinazolin (20) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline

Pretvorba se vrši s acetil kloridom u acetonitrilu. The conversion is carried out with acetyl chloride in acetonitrile.

Talište: 224°C Melting point: 224°C

Maseni spektar (ESI+): m/z = 475, 477 [M+H]+ Mass spectrum (ESI+): m/z = 475, 477 [M+H]+

(21) 4-t(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metansulfonilamino-etoksi)-kinazolin (21) 4-t(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline

Talište: 227° C Melting point: 227° C

Maseni spektar (ESI+): m/z = 511, 513 [M+H]+ Mass spectrum (ESI+): m/z = 511, 513 [M+H]+

(22) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-3-acetilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (22) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-3-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s acetil kloridom u acetonitrilu. The conversion is carried out with acetyl chloride in acetonitrile.

Cis- i trans-izomeri su rastavljeni kromatografski preko stupca silika gela. Cis- and trans-isomers were separated chromatographically over a silica gel column.

Rf vrijednost: 0,43 (silika gel, metilen klorid/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.43 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 459, 461 [M+H]+ Mass spectrum (ESI+): m/z = 459, 461 [M+H]+

(23) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-3-acetil-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (23) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-3-acetyl-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s acetil kloridom u acetonitrilu. The conversion is carried out with acetyl chloride in acetonitrile.

Cis- i trans-izomeri su rastavljeni kromatografski preko stupca silika gela. Cis- and trans-isomers were separated chromatographically over a silica gel column.

Rf vrijednost: 0,49 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.49 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 459, 461 [M+H]+ Mass spectrum (ESI+): m/z = 459, 461 [M+H]+

(24) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(3-acetilamino-propiloksi)-kinazolin (24) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-acetylamino-propyloxy)-quinazoline

Pretvorba se vrši s acetil kloridom. The conversion is done with acetyl chloride.

Talište: 225°C Melting point: 225°C

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(25) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(3-metansulfonilamino-propiloksi)-kinazolin (25) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-methanesulfonylamino-propyloxy)-quinazoline

Talište: 222°C Melting point: 222°C

Maseni spektar (ESI+): m/z =525, 527 [M+H]+ Mass spectrum (ESI+): m/z =525, 527 [M+H]+

(26) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-kinazolin (26) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-quinazoline

Rf vrijednost: 0,44 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.44 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 451, 453 [M+H]+ Mass spectrum (ESI+): m/z = 451, 453 [M+H]+

(27) 4-[(3-klor-4-fluor~fenil)arαino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin4-iloksi}-kinazolin (27) 4-[(3-chloro-4-fluoro~phenyl)arαino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin4-yloxy}-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)carbonyl chloride in acetonitrile.

Rf vrijednost: 0,40 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 486, 488 [M+H]+ Mass spectrum (ESI+): m/z = 486, 488 [M+H]+

(28) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-acetil-piperidin-4-iloksi)-kinazolin (28) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-quinazoline

Pretvorba se vrši s acetanhidridom. The conversion is done with acetic anhydride.

Rf vrijednost: 0,50 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 415, 417 [M+H]+ Mass spectrum (ESI+): m/z = 415, 417 [M+H]+

(29) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino)-karbonil]-piperidin-4-iloksi}-kinazolin (29) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)-carbonyl]-piperidin-4-yloxy}-quinazoline

Pretvorba se vrši s N,N-dimetilkarbamoil kloridom. The conversion is carried out with N,N-dimethylcarbamoyl chloride.

Rf vrijednost: 0,47 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.47 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 444, 446 [M+H]+ Mass spectrum (ESI+): m/z = 444, 446 [M+H]+

(30) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-acetil-amino-cikloheksan-1-iloksi}-7-metoksi-kinazolin (30) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-acetyl-amino-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s acetanhidridom. The conversion is done with acetic anhydride.

Rf vrijednost: 0,50 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 459, 461 [M+H]+ Mass spectrum (ESI+): m/z = 459, 461 [M+H]+

(31) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(dimetilamino)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (31) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s N,N-dimetilkarbamoil kloridom. The conversion is carried out with N,N-dimethylcarbamoyl chloride.

Rf vrijednost: 0,40 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 488, 490 [M+H]+ Mass spectrum (ESI+): m/z = 488, 490 [M+H]+

(32) 4-[(3-klor-4-fluor-fenil)amino]-6-[trans-4-(2-metoksi-acetilamino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (32) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,35 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(33) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-metoksi-acetil)-piperidin-4-iloksi]-kinazolin (33) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,41 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.41 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 445, 447 [M+H]+ Mass spectrum (ESI+): m/z = 445, 447 [M+H]+

(34) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-izopropiloksi-karbonil-piperidin-4-iloksi)-7-metoksi-kinazolin (34) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxy-carbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s izopropil esterom klormravlje kiseline. The conversion is done with isopropyl ester of chloroformic acid.

Rf vrijednost: 0,67 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 98:2:1) Rf value: 0.67 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 98:2:1)

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(35) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-cijano-piperidin-4-iloksi)-kinazolin (35) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-quinazoline

Pretvorba se vrši s bromcijanom u metilen kloridu. The conversion is done with cyanogen bromide in methylene chloride.

Rf vrijednost: 0,49 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.49 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI-): m/z = 396, 398 [M-H]- Mass spectrum (ESI-): m/z = 396, 398 [M-H]-

(36) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino)-sulfonil]-piperidin-4-iloksi}-kinazolin (36) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)-sulfonyl]-piperidin-4-yloxy}-quinazoline

Pretvorba se vrši s N,N-dimetilsulfamoil kloridom u acetonitrilu. The conversion is carried out with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf vrijednost: 0,34 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.34 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 480, 482 [M+H]+ Mass spectrum (ESI+): m/z = 480, 482 [M+H]+

(37) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-sulfonil]-piperidin-4-iloksi}-kinazolin (37) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-sulfonyl]-piperidin-4-yloxy}-quinazoline

Pretvorba se vrši s (morfolin-4-il)sulfonilkloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf vrijednost: 0,15 (silika gel, cikloheksan/octeni ester = 1:1) Rf value: 0.15 (silica gel, cyclohexane/acetic ester = 1:1)

Maseni spektar (ESI+): m/z = 522, 524 [M+H]+ Mass spectrum (ESI+): m/z = 522, 524 [M+H]+

(38) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-acetilamino-etil)-piperidin-4-iloksi]-kinazolin (38) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-quinazoline

Pretvorba se vrši s acetanhidridom u acetonitrilu. The conversion is carried out with acetic anhydride in acetonitrile.

Talište: 221°C Melting point: 221°C

Maseni spektar (ESI+): m/z = 458, 460 [M+H]+ Mass spectrum (ESI+): m/z = 458, 460 [M+H]+

(39) 4-[(3-klor-4-fluor-fenil) amino]-6-{1-[(dietilamino)-karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (39) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(diethylamino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s N,N-dietilkarbamoil kloridom. The conversion is carried out with N,N-diethylcarbamoyl chloride.

Rf vrijednost: 0,40 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 95:5:1) Rf value: 0.40 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 95:5:1)

Maseni spektar (ES1+) : m/z = 502, 504 [M+H]+ Mass spectrum (ES1+): m/z = 502, 504 [M+H]+

(40) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(piperidin-1-il)-karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (40) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (piperidin-1-il)karbonil kloridom. The conversion is carried out with (piperidin-1-yl)carbonyl chloride.

Rf vrijednost: 0,51 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 95:5:1) Rf value: 0.51 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 95:5:1)

Maseni spektar (ESI-): m/z - 512, 514 [M-H]- Mass spectrum (ESI-): m/z - 512, 514 [M-H]-

(41) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(pirolidin-1-il)-karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (41) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(pyrrolidin-1-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (pirolidin-1-il)karbonil kloridom. The conversion is carried out with (pyrrolidin-1-yl)carbonyl chloride.

Talište: 237°C Melting point: 237°C

Maseni spektar (ESI+): m/z = 500, 502 [M+H]+ Mass spectrum (ESI+): m/z = 500, 502 [M+H]+

(42) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(4-metil-piperazin-1-il)karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (42) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(4-methyl-piperazin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy - quinazoline

Pretvorba se vrši s (4-metil-piperazin-1-il)karbonil-klorid-hidrokloridom. The conversion is carried out with (4-methyl-piperazin-1-yl)carbonyl chloride hydrochloride.

Rf vrijednost: 0,28 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.28 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI-): m/z = 527, 529 [M-H]- Mass spectrum (ESI-): m/z = 527, 529 [M-H]-

(43) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(N-metan-sulfonil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (43) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methane-sulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline

Pretvorba se vrši u metilen kloridu. The conversion is carried out in methylene chloride.

Rf vrijednost: 0,71 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.71 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 509, 511 [M+H]+ Mass spectrum (ESI+): m/z = 509, 511 [M+H]+

(44) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(N-acetil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (44) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy- quinazoline

Pretvorba se vrši s acetanhidridom. The conversion is done with acetic anhydride.

Talište: 234°C Melting point: 234°C

Maseni spektar (ESI+): m/z = 473, 475 [M+H]+ Mass spectrum (ESI+): m/z = 473, 475 [M+H]+

(45) 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[N-(2-metoksi-acetil)-N-metil-amino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (45) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy }-7-methoxy-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost; 0,40 (silika gel, octeni ester/metanol = 9:1) Rf value; 0.40 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 503, 505 [M+H]+ Mass spectrum (ESI+): m/z = 503, 505 [M+H]+

(46) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(N-dimetil-aminokarbonil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (46) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethyl-aminocarbonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline

Pretvorba se vrši s N,N-dimetilkarbamoil kloridom. The conversion is carried out with N,N-dimethylcarbamoyl chloride.

Rf vrijednost: 0,51 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.51 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 502, 504 [M+H]+ Mass spectrum (ESI+): m/z = 502, 504 [M+H]+

(47) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(morfolin-4-il)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (47) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,50 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.50 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 544, 546 [M+H]+ Mass spectrum (ESI+): m/z = 544, 546 [M+H]+

(48) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(morfolin-4-il)sulfonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (48) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)sulfonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf vrijednost: 0,24 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.24 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 580, 582 [M+H]+ Mass spectrum (ESI+): m/z = 580, 582 [M+H]+

(49) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(N-dimetil-aminosulfonil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (49) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-dimethyl-aminosulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline

Pretvorba se vrši s N,N-dimetilsulfamoil kloridom u acetonitrilu. The conversion is carried out with N,N-dimethylsulfamoyl chloride in acetonitrile.

Rf vrijednost: 0,53 (silika gel, octeni ester) Rf value: 0.53 (silica gel, acetic ester)

Maseni spektar (ESI+): m/z = 538, 540 [M+H]+ Mass spectrum (ESI+): m/z = 538, 540 [M+H]+

(50) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-etan-sulfonilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (50) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethane-sulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s kloridom etansulfonske kiseline u metilen kloridu. The conversion is done with ethanesulfonic acid chloride in methylene chloride.

Rf vrijednost: 0,41 (silika gel, octeni ester) Rf value: 0.41 (silica gel, acetic ester)

Maseni spektar (ESI+): m/z = 509, 511 [M+H]+ Mass spectrum (ESI+): m/z = 509, 511 [M+H]+

(51) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin-4-iloksi}-7-etoksi-kinazolin (51) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin-4-yloxy}-7-ethoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,48 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

(52) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-7-etoksi-kinazolin (52) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

Rf vrijednost: 0,50 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 495, 497 [M+H]+ Mass spectrum (ESI+): m/z = 495, 497 [M+H]+

(53) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-metoksi-acetil)-piperidin-4-iloksi]-7-etoksi-kinazolin (53) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-ethoxy-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,40 (silika gel, metilen klorid/metanol 20:1) Rf value: 0.40 (silica gel, methylene chloride/methanol 20:1)

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(54) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-7-(2-metoksi-etoksi)-kinazolin (54) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf vrijednost: 0,47 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.47 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 525, 527 [M+H]+ Mass spectrum (ESI+): m/z = 525, 527 [M+H]+

(55) 4-[(3-klor4-fluor-fenil)amino]-6-{1-[(morfolin4-il)-karbonil]-piperidin4-iloksi}-7-(2-metoksi-etoksi)-kinazolin (55) 4-[(3-chloro4-fluoro-phenyl)amino]-6-{1-[(morpholin4-yl)-carbonyl]-piperidin4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,48 (silika gel, metilen klorid/metanol 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol 9:1)

Maseni spektar (ESI+): m/z = 560, 562 [M+H]+ Mass spectrum (ESI+): m/z = 560, 562 [M+H]+

(56) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-metoksi-acetil)-piperidin-4-iloksi]-7-(2-metoksi-etoksi)-kinazolin (56) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)- quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,48 (silika gel, metilen klorid/metanol 9:1) Rf value: 0.48 (silica gel, methylene chloride/methanol 9:1)

Maseni spektar (ESI+): m/z = 519, 521 [M+H]+ Mass spectrum (ESI+): m/z = 519, 521 [M+H]+

(57) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-acetilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (57) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s acetanhidridom. The conversion is done with acetic anhydride.

Talište: 281°C Melting point: 281°C

Maseni spektar (ESI+): m/z = 459, 461 [M+H]+ Mass spectrum (ESI+): m/z = 459, 461 [M+H]+

(58) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(2-metoksi-acetilamino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (58) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(2-methoxy-acetylamino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Talište: 264°C Melting point: 264°C

Maseni spektar (ESI+) : m/z =489, 491 [M+H]+ Mass spectrum (ESI+): m/z =489, 491 [M+H]+

(59) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(piperidin-1-il)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (59) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s (piperidin-1-il)karbonil kloridom. The conversion is carried out with (piperidin-1-yl)carbonyl chloride.

Talište: 253°C Melting point: 253°C

Maseni spektar (ESI+) : m/z = 542, 544 [M+H]+ Mass spectrum (ESI+): m/z = 542, 544 [M+H]+

(60) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(4-metil-piperazin-1-il)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (60) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino }-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s (4-metil-piperazin-1-il)karbonil-klorid-hidrokloridom. The conversion is carried out with (4-methyl-piperazin-1-yl)carbonyl chloride hydrochloride.

Talište: 262°C Melting point: 262°C

Maseni spektar (ESI+) : m/z = 557, 559 [M+H]+ Mass spectrum (ESI+): m/z = 557, 559 [M+H]+

(61) 4-[(3-klor-4-fluor-fenil)amino]-6-[cis-4-(N-etan-sulfonil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (61) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-ethane-sulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline

Pretvorba se vrši s kloridom etansulfonske kiseline u metilen kloridu. The conversion is done with ethanesulfonic acid chloride in methylene chloride.

Rf vrijednost: 0,19 (TLC gotova pločica reverzne faze) (E. Merck), acetonitrit/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.19 (TLC ready reverse phase plate) (E. Merck), acetonitrite/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 523, 525 [M+H]+ Mass spectrum (ESI+): m/z = 523, 525 [M+H]+

(62) 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[(morfolin-4-il)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (62) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,33 (TLC gotova pločica reverzne faze) (E. Merck), acetonitrit/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.33 (TLC ready reverse phase plate) (E. Merck), acetonitrite/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

(63) 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[(morfolin-4-il)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (63) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)sulfonil kloridom u acetonitrilu. The conversion is carried out with (morpholin-4-yl)sulfonyl chloride in acetonitrile.

Rf vrijednost: 0,81 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.81 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 566, 568 [M+H]+ Mass spectrum (ESI+): m/z = 566, 568 [M+H]+

(64) 4-[(3-etinil-fenil)amino]-6-(1-acetil-piperidin-4-il-oksi)-7-metoksi-kinazolin (64) 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yl-oxy)-7-methoxy-quinazoline

Pretvorba vrši s acetanhidridom. The conversion is done with acetic anhydride.

Rf vrijednost: 0,30 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.30 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z= 417 [M+H]+ Mass spectrum (ESI+): m/z= 417 [M+H]+

(65) 4-[(3-etinil-fenil)amino]-6-[1-(2-metoksi-acetil)-piperidin-4-iloksi]-7-metoksi-kinazolin (65) 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Pretvorba se vrši s kloridom metoksioctene kiseline. The conversion is carried out with methoxyacetic acid chloride.

Rf vrijednost: 0,37 (silika gel, metilen klorid/metanol/konc. vodeni amonijak 90:10:1) Rf value: 0.37 (silica gel, methylene chloride/methanol/conc. aqueous ammonia 90:10:1)

Maseni spektar (ESI+): m/z = 447 [M+H]+ Mass spectrum (ESI+): m/z = 447 [M+H]+

(66) 4-[(3-etinil-fenil)amino]-6-(1-metansulfonil-piperidin-4-iloksi)-7-metoksi-kinazolin (66) 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Rf vrijednost: 0,59 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.59 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 453 [M+H]+ Mass spectrum (ESI+): m/z = 453 [M+H]+

(67) 4-[(3-etinil-fenil)amino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (67) 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,43 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.43 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 488 [M+H]+ Mass spectrum (ESI+): m/z = 488 [M+H]+

(68) 4-[(3-klor-4-fluor-fenil)amino]-6-[trans-4-(N-metan-sulfonil-N-metil-amino)-cikloheksan-1-iloksi]-7-metoksi-kinazolin (68) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methane-sulfonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7- methoxy-quinazoline

Rf vrijednost: 0,50 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.50 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 509, 511 [M+H]+ Mass spectrum (ESI+): m/z = 509, 511 [M+H]+

(69) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-{N-[(morfolin-4-il)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (69) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexane- 1-yloxy)-7-methoxy-quinazoline

Pretvorba se vrši s (morfolin-4-il)karbonil kloridom. The conversion is carried out with (morpholin-4-yl)carbonyl chloride.

Rf vrijednost: 0,54 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.54 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 544, 546 [M+H]+ Mass spectrum (ESI+): m/z = 544, 546 [M+H]+

Primjer 4 Example 4

4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{[3-(morfolin-4-il)-propil]sulfonilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonylamino-cyclohexan-1-yloxy)-7-methoxy - quinazoline

[image] [image]

K 60 mg 4-[(3-klor-4-fluor-fenil)amino]-6-{cis-4-[(3-klor-propil)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolina u 2 ml acetonitrila doda se 23 μl morfolina i reakcijsku smjesu se grije preko noći pod refluksom. Za obradu se smjesu preuzme u octeni ester i ispere s vodom. Organsku faze se osuši preko magnezijevog sulfata i koncentrira. Sirov proizvod se očisti preko stupca silika gela s metilen klorid/metanolom (9:1) kao protočnim sredstvom. K 60 mg 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(3-chloro-propyl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline 23 μl of morpholine is added to 2 ml of acetonitrile and the reaction mixture is heated under reflux overnight. For processing, the mixture is taken up in acetic ester and washed with water. The organic phase is dried over magnesium sulfate and concentrated. The crude product is purified over a silica gel column with methylene chloride/methanol (9:1) as eluant.

Iskorištenje: 18 mg (27% od teorijskog) Yield: 18 mg (27% of theoretical)

Rf vrijednost: 0,36 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.36 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 608, 610 [M+H]+ Mass spectrum (ESI+): m/z = 608, 610 [M+H]+

Analogno primjeru 4 dobiveni su slijedeći spojevi: Analogous to example 4, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-{[3-(morfolin-4-il)-propil]sulfonil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1- yloxy)-7-methoxy-quinazoline

[image] [image]

Rf vrijednost: 0,16 (silika gel, octeni ester/metanol/konc. vodeni amonijak =90:10:1) Rf value: 0.16 (silica gel, acetic ester/methanol/conc. aqueous ammonia =90:10:1)

Maseni spektar (ESI+) : m/z - 608, 610 [M+H] + Mass spectrum (ESI+): m/z - 608, 610 [M+H] +

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-[4-(morfolin-4-il)-butiloksi]-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]-quinazoline

Provedba u prisutnosti natrijevog karbonata i natrijevog jodida u N-metil-pirolidonu pri 100°C. Conducted in the presence of sodium carbonate and sodium iodide in N-methyl-pyrrolidone at 100°C.

Rf vrijednost: 0,18 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 40:10:0,5) Rf value: 0.18 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 40:10:0.5)

Maseni spektar (ESI+): m/z = 531, 533 [M+H]+ Mass spectrum (ESI+): m/z = 531, 533 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-[4-(morfolin-4-il)-butiloksi]-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[4-(morpholin-4-yl)-butyloxy]- quinazoline

Provedba u prisutnosti natrijevog karbonata i natrijevog jodida u N-metil-pirolidonu pri 100°C. Conducted in the presence of sodium carbonate and sodium iodide in N-methyl-pyrrolidone at 100°C.

Rf vrijednost: 0,32 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 80:20:1) Rf value: 0.32 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 80:20:1)

Maseni spektar (ESI+) : m/z = 517, 519 [M+H]+ Mass spectrum (ESI+): m/z = 517, 519 [M+H]+

(4) 4-[(3-klor4-fluor-fenil)amino]-6-{1-[(morfolin4-il)-acetil]-piperidin4-iloksi}-kinazolin (4) 4-[(3-chloro4-fluoro-phenyl)amino]-6-{1-[(morpholin4-yl)-acetyl]-piperidin4-yloxy}-quinazoline

Provedba u prisutnosti Hünigove baze u tetrahidrofuranu pri sobnoj temperaturi. Conducted in the presence of Hünig's base in tetrahydrofuran at room temperature.

Rf vrijednost: 0,30 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.30 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI++): m/z = 500, 502 [M+H]+ Mass spectrum (ESI++): m/z = 500, 502 [M+H]+

(5) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-dimetilamino-acetil-piperidin-4-iloksi)-kinazolin (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylamino-acetyl-piperidin-4-yloxy)-quinazoline

Provedba u prisutnosti Hünigove baze u tetrahidrofuranu pri sobnoj temperaturi. Conducted in the presence of Hünig's base in tetrahydrofuran at room temperature.

Rf vrijednost: 0,11 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak 90:10:1) Rf value: 0.11 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia 90:10:1)

Maseni spektar (ESI+): m/z = 458, 460 [M+H]+ Mass spectrum (ESI+): m/z = 458, 460 [M+H]+

(6) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-dimetilamino-acetil-piperidin-4-iloksi)-7-metoksi-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-dimethylamino-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Provedba u prisutnosti Hünigove baze u tetrahidrofuranu pri sobnoj temperaturi. Conducted in the presence of Hünig's base in tetrahydrofuran at room temperature.

Rf vrijednost: 0,19 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.19 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 488, 490 [M+H]+ Mass spectrum (ESI+): m/z = 488, 490 [M+H]+

(7) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-acetil]-piperidin-4-iloksi}-7-metoksi-kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-acetyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Provedba u prisutnosti Hünigove baze u tetrahidrofuranu pri sobnoj temperaturi. Conducted in the presence of Hünig's base in tetrahydrofuran at room temperature.

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

Primjer 5 Example 5

4-[(3-klor4-fluor-fenil)amino]-6-((S)-pirolidin-3-iloksi)-7-metoksi-kinazolin-dihidroklorid 4-[(3-chloro4-fluoro-phenyl)amino]-6-((S)-pyrrolidin-3-yloxy)-7-methoxy-quinazoline-dihydrochloride

Otopinu od 370 mg 4-[(3-klor-4-fluor-fenil)amino]-6-[(S)-1-(terc-butiloksi-karbonil)-pirolidin-3-iloksi]-7-metoksi-kinazolina u 5 ml dioksana pomiješa se s 0,32 ml koncentrirane solne kiseline i miješa se preko noći pri sobnoj temperaturi. Izlučeni talog se odsisa i ispere oblilno s dioksanom. A solution of 370 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(S)-1-(tert-butyloxy-carbonyl)-pyrrolidin-3-yloxy]-7-methoxy-quinazoline in 5 ml of dioxane is mixed with 0.32 ml of concentrated hydrochloric acid and stirred overnight at room temperature. The secreted precipitate is suctioned off and washed thoroughly with dioxane.

Sirov proizvod se otopi u malo metanola i izluči dodatkom jednake količine octenog estera. Tako dobivenu bijelu krutu tvar se odsisa i osuši. Iskorištenje: 200 mg (57% od teorije). Talište: 281°C Maseni spektar (ESI+): m/z = 389, 391 [M+H]+ The crude product is dissolved in a little methanol and extracted by adding an equal amount of acetic ester. The white solid obtained in this way is sucked off and dried. Yield: 200 mg (57% of theory). Melting point: 281°C Mass spectrum (ESI+): m/z = 389, 391 [M+H]+

Analogno primjeru 5 dobiveni su slijedeći spojevi: Analogous to example 5, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-3-il-oksi)-7-metoksi-kinazolin-dihidroklorid (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yl-oxy)-7-methoxy-quinazoline-dihydrochloride

Talište: 263°C Melting point: 263°C

Maseni spektar (ESI+): m/z = 403, 505 [M+H]+ Mass spectrum (ESI+): m/z = 403, 505 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-amino-etil)-piperidin-4-iloksi]-7-metoksi-kinazolin-dihidroklorid (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-dihydrochloride

Talište: 277°C Melting point: 277°C

Maseni spektar (ESI+): m/z = 446, 448 [M+H]+ Mass spectrum (ESI+): m/z = 446, 448 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-(3-amino-ciklo-heksan-1-iloksi)-7-metoksi-kinazolin-dihidroklorid (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(3-amino-cyclo-hexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

Maseni spektar (ESI+): m/z = 417, 419 [M+H]+ Mass spectrum (ESI+): m/z = 417, 419 [M+H]+

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-amino-etoksi)-kinazolin-dihidroklorid (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-amino-ethoxy)-quinazoline-dihydrochloride

Provedba s izopropanolnom solnom kiselinom (5-6 M) u metilen kloridu. Implementation with isopropanol hydrochloric acid (5-6 M) in methylene chloride.

Rf vrijednost: 0,58 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.58 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 433, 435 [M+H]+ Mass spectrum (ESI+): m/z = 433, 435 [M+H]+

(5) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(3-amino-propiloksi)-kinazolin-dihidroklorid Provedba s izopropanolnom solnom kiselinom (5-6 M) u metilen kloridu. (5) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(3-amino-propyloxy)-quinazoline dihydrochloride Implementation with isopropanol hydrochloric acid (5 -6 M) in methylene chloride.

Rf vrijednost: 0,44 (TLC gotova pločica reverzne faze) (E. Merck), metanol/5%-tna vodena otopina natrijevog klorida = 7:3) Rf value: 0.44 (TLC ready reverse phase plate) (E. Merck), methanol/5% aqueous sodium chloride solution = 7:3)

Maseni spektar (ESI+) : m/z =447, 449 [M+H]+ Mass spectrum (ESI+): m/z =447, 449 [M+H]+

(6) 4-[(3-klor-4-fluor-fenil) amino]-6-[1-(2-amino-etil)-piperidin-4-iloksi]-kinazolin-dihidroklorid (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-amino-ethyl)-piperidin-4-yloxy]-quinazoline dihydrochloride

Rf vrijednost: 0,50 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.50 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 416, 418 [M+H]+ Mass spectrum (ESI+): m/z = 416, 418 [M+H]+

(7) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-metilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin-dihidroklorid (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

Provedba s izopropanolnom solnom kiselinom (5-6 M) u metilen kloridu. Implementation with isopropanol hydrochloric acid (5-6 M) in methylene chloride.

Rf vrijednost: 0,35 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.35 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 431, 433 [M+H]+ Mass spectrum (ESI+): m/z = 431, 433 [M+H]+

(8) 4-[(3-etinil-fenil) amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorid (8) 4-[(3-ethynyl-phenyl) amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride

Provedba s izopropanolnom solnom kiselinom (5-6 M) u metilen kloridu. Implementation with isopropanol hydrochloric acid (5-6 M) in methylene chloride.

Rf vrijednost: 0,50 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.50 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 375 [M+H]+ Mass spectrum (ESI+): m/z = 375 [M+H]+

(9) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-metilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin-dihidroklorid (9) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-dihydrochloride

Talište: 251°C Melting point: 251°C

Maseni spektar (ESI+): m/z = 431, 433 [M+H]+ Mass spectrum (ESI+): m/z = 431, 433 [M+H]+

Primjer 6 Example 6

4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-il-oksi)-7-hidroksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yl-oxy)-7-hydroxy-quinazoline

Smjesu od 9,00 g 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-benziloksi-kinazolin-hidro-klorida i 50 ml trifluoroctene kiseline grije se 1,5 sata pri 100°C. Zatim se reakcijsku smjesu koncentrira i ostatak se preuzme u 10 ml acetonitrila. Tu otopinu se dokaplje uz snažno miješanje u 100 ml zasićene otopine natrijevog hidrogen karbonata. Nakon 1,5 sata nastali talog se odsisa i više puta se ispere s vodom. Sirov proizvod se pomiješa s dietil eterom, odsisa i osuši. Iskorištenje: 5,90 g (87% od teorijskog). Rf vrijednost: 0,21 (silika gel, octeni ester) Maseni spektar (ESI+): m/z = 390, 392 [M+H]+ A mixture of 9.00 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-benzyloxy-quinazoline-hydrochloride and 50 ml of trifluoroacetic acid is heated for 1 ,5 hours at 100°C. Then the reaction mixture is concentrated and the residue is taken up in 10 ml of acetonitrile. This solution is added dropwise with vigorous stirring to 100 ml of saturated sodium hydrogen carbonate solution. After 1.5 hours, the formed precipitate is sucked off and washed several times with water. The crude product is mixed with diethyl ether, filtered under suction and dried. Yield: 5.90 g (87% of theoretical). Rf value: 0.21 (silica gel, acetic ester) Mass spectrum (ESI+): m/z = 390, 392 [M+H]+

Analogno primjeru 6 dobiven je slijedeći spoj: Analogous to example 6, the following compound was obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-hidroksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline

Rf vrijednost: 0,44 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.44 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+): m/z = 376, 378 [M+H]+ Mass spectrum (ESI+): m/z = 376, 378 [M+H]+

Primjer 7 Example 7

4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-il-oksi)-7-[3-(morfolin-4-il)-propiloksi]-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yl-oxy)-7-[3-(morpholin-4-yl)-propyloxy]-quinazoline

Smjesu od 300 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-hidroksi-kinazolina, 130 mg 3-(morfolin-4-il)-propilklorida i 530 mg kalijevog karbonata u 5 ml N,N-dimetilformamida miješa se preko noći pri 8 0°C. Za obradu, reakcijsku smjesu se razrijedi s 25 ml vode i ekstrahira s octenim esterom. Sjedinjene organske faze se isperu sa zasićenom otopinom natrijevog klorida, osuše se preko magnezijevog sulfata i koncentriraju. Ostatak se promiješa s dietil eterom, odsisa i osuši. Iskorištenje: 250 mg (63% od teorijskog). Talište: 205°C Maseni spektar (ESI+): m/z = 517, 519 [M+H]+ A mixture of 300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-hydroxy-quinazoline, 130 mg of 3-(morpholin-4-yl)-propyl chloride and 530 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at 80°C. For processing, the reaction mixture is diluted with 25 ml of water and extracted with acetic ester. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is mixed with diethyl ether, suction filtered and dried. Yield: 250 mg (63% of theoretical). Melting point: 205°C Mass spectrum (ESI+): m/z = 517, 519 [M+H]+

Analogno primjeru 7 dobiveni su slijedeći spojevi: Analogous to example 7, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-[2-(morfolin-4-il)-etoksi]-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(morpholin-4-yl)-ethoxy]-quinazoline

Rf vrijednost: 0,33 (silika gel, octeni ester/metanol/konc. vodeni amonijak - 40:10:0,5) Rf value: 0.33 (silica gel, acetic ester/methanol/conc. aqueous ammonia - 40:10:0.5)

Maseni spektar (ESI+): m/z = 503, 505 [M+H]+ Mass spectrum (ESI+): m/z = 503, 505 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-etoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxyquinazoline

Rf vrijednost: 0,76 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.76 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 418, 420 [M+H]+ Mass spectrum (ESI+): m/z = 418, 420 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-[3-(morfolin-4-il)-propiloksi]-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-[3-(morpholin-4-yl)-propyloxy]- quinazoline

Rf vrijednost: 0,20 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.20 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI-): m/z = 501, 503 [M-H]- Mass spectrum (ESI-): m/z = 501, 503 [M-H]-

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidro-furan-3-iloksi)-7-[2-(morfolin-4-il)-etoksi]-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydro-furan-3-yloxy)-7-[2-(morpholin-4-yl)-ethoxy ]-quinazoline

Rf vrijednost: 0,19 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.19 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 489, 491 [M+H]+ Mass spectrum (ESI+): m/z = 489, 491 [M+H]+

(5) -[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metoksi-etoksi)-kinazolin (5) -[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf vrijednost: 0,57 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.57 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 448, 450 [M+H]+ Mass spectrum (ESI+): m/z = 448, 450 [M+H]+

(6) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-[2-(terc-butiloksikarbonilamino)-etoksi]-kinazolin (6) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[2-(tert-butyloxycarbonylamino)-ethoxy]-quinazoline

Rf vrijednost: 0,64 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 95:5:0,1) Rf value: 0.64 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 95:5:0.1)

Maseni spektar (ESI+) : m/z = 533, 535 [M+H]+ Mass spectrum (ESI+): m/z = 533, 535 [M+H]+

(7) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-[3-(terc-butiloksikarbonilamino)-propiloksi]-kinazolin (7) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-[3-(tert-butyloxycarbonylamino)-propyloxy]-quinazoline

Rf vrijednost: 0,74(silika gel, octeni ester/metanol/konc. vodeni amonijak = 95:5:0,1) Rf value: 0.74 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 95:5:0.1)

Maseni spektar (ESI+): m/z = 547, 549 [M+H]+ Mass spectrum (ESI+): m/z = 547, 549 [M+H]+

Primjer 8 Example 8

4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-quinazoline

Otopinu od 4,55 g 4-[(3-klor-4-fluor-fenil)amino]-6-(1-trifluoracetil-piperidin-4-iloksi)-kinazolin-hidro-klorida u 35 ml metanola pomiješa se s 13 ml 3 N natrijeve lužine i miješa se otprilike pola sata pri sobnoj temperaturi. Za obradu, rekcijsku smjesu se razrijedi s vodom i ekstrahira se s octenim esterom. Sjedinjene organske faze se isperu sa zasićenom otopinom natrijevog klorida, osuše se preko magnezijevog sulfata i koncentriraju. Ostatak se razrijedi s dietil eterom, odsisa i osuši. A solution of 4.55 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-trifluoroacetyl-piperidin-4-yloxy)-quinazoline hydrochloride in 35 ml of methanol was mixed with 13 ml of 3 N sodium hydroxide solution and stirred for about half an hour at room temperature. For processing, the reaction mixture is diluted with water and extracted with acetic ester. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is diluted with diethyl ether, filtered off with suction and dried.

Iskorištenje: 3,00 g (89% od teorijskog) Yield: 3.00 g (89% of theoretical)

Rf vrijednost: 0,48 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.48 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+) : m/z = 373, 375 [M+H] + Mass spectrum (ESI+): m/z = 373, 375 [M+H] +

Analogno primjeru 8 dobiveni su slijedeći spojevi: Analogous to example 8, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-il-oksi)-7-etoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yl-oxy)-7-ethoxy-quinazoline

Rf vrijednost: 0,20 (silika gel, metilen klorid/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.20 (silica gel, methylene chloride/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 417, 419 [M+H]+ Mass spectrum (ESI+): m/z = 417, 419 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-il-oksi)-7-(2-metoksi-etoksi)-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yl-oxy)-7-(2-methoxy-ethoxy)-quinazoline

Rf vrijednost: 0,10 (silika gel, metilen klorid/metanol/konc. vodeni amonijak =90: 10: 1) Rf value: 0.10 (silica gel, methylene chloride/methanol/conc. aqueous ammonia =90: 10: 1)

Maseni spektar (ESI+): m/z = 447, 449 [M+H]+ Mass spectrum (ESI+): m/z = 447, 449 [M+H]+

Primjer 9 Example 9

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(etilamino)karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(ethylamino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Proizveden je reakcijom 4-[(3-klor-4-fluor-fenil)-amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin s etil-izocijanatom u tetrahidrofuranu pri sobnoj temperaturi. It is produced by reacting 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline with ethyl isocyanate in tetrahydrofuran at room temperature.

Rf vrijednost: 0,53 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.53 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 474, 476 [M+H]+ Mass spectrum (ESI+): m/z = 474, 476 [M+H]+

Analogno primjeru 9 dobiveni su slijedeći spojevi: Analogous to example 9, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(izopropil-amino)-karbonil]-piperidin4-iloksi}-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(isopropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Talište: 236°C Melting point: 236°C

Maseni spektar (ESI-) : m/z = 486, 488 [M-H]- Mass spectrum (ESI-): m/z = 486, 488 [M-H]-

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(fenilamino)-karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(phenylamino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Rf vrijednost: 0,70 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 95:5:0,1) Rf value: 0.70 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 95:5:0.1)

Maseni spektar (ESI+): m/z = 522, 524 [M+H]+ Mass spectrum (ESI+): m/z = 522, 524 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(etilamino)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(ethylamino)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy) -7-methoxy-quinazoline

Rf vrijednost: 0,38 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.38 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 502, 504 [M+H]+ Mass spectrum (ESI+): m/z = 502, 504 [M+H]+

Primjer 10 Example 10

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino)-karbonilmetil]-piperidin-4-iloksi}-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)-carbonylmethyl]-piperidin-4-yloxy}-quinazoline

Proizveden je reakcijom 4-[(3-klor-4-fluor-fenil)-amino]-6-(piperidin-4-iloksi)-kinazolina s 2-klor-N,N-di-metilacetamidom u prisutnosti kalijevog karbonata u N,N-dimetilformamida pri sobnoj temperaturi. It was produced by the reaction of 4-[(3-chloro-4-fluoro-phenyl)-amino]-6-(piperidin-4-yloxy)-quinazoline with 2-chloro-N,N-dimethylacetamide in the presence of potassium carbonate in N ,N-dimethylformamide at room temperature.

Rf vrijednost: 0,24 (silika gel, metilen klorid/metanol = 9:1) Rf value: 0.24 (silica gel, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 458, 460 [M+H] + Mass spectrum (ESI + ): m/z = 458, 460 [M+H] +

Analogno primjeru 10 dobiveni su slijedeći spojevi: Analogous to example 10, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-karbonilmetil]-piperidin-4-iloksi}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonylmethyl]-piperidin-4-yloxy}-quinazoline

Rf vrijednost: 0,42 {TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.42 {TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 500, 502 [M+H]+ Mass spectrum (ESI+): m/z = 500, 502 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-aminokarbonil-metil-piperidin-4-iloksi)-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonyl-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline

Talište: 251°C Melting point: 251°C

Maseni spektar (ESI+): m/z = 460, 462 [M+H]+ Mass spectrum (ESI+): m/z = 460, 462 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(dimetilamino)-karbonilmetil]-piperidin-4-iloksi}-7-metoksi-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(dimethylamino)-carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Talište: 233°C Melting point: 233°C

Maseni spektar (ESI+): m/z = 488, 490 [M+H]+ Mass spectrum (ESI+): m/z = 488, 490 [M+H]+

(4) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-karbonilmetil]-piperidin-4-iloksi}-7-metoksi-kinazolin (4) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonylmethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Talište: 245°C Melting point: 245°C

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

Primjer 11 Example 11

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(tetrahidropiran-4-il)karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(tetrahydropyran-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

K smjesi od 300 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorida, 82 mg tetrahidropiran-4-karboksilne kiseline i 0,54 ml Hünigove baze u 5 ml N,N-dimetilformamida doda se 90 mg 1-hidroksi-1H-benzotriazola i 250 mg 2-(1H-benzotriazol-1-il)-1,1,3,3-tetrametiluronijevog tetrafluorborata. Reakcijsku smjesa se miješa preko noći pri sobnoj temperaturi. Za obradu se pomiješa s 25 ml octenog estera i ispere se s vodom, 10%-tnom otopinom kalijevog karbonata i sa zasićenom otopinom natrijevog klorida. Organsku fazu se osuši preko magnezijevog sulfata i koncentrira. Ostatak se pomiješa s malo octenog estera, odsisa i osuši. Iskorištenje: 250 mg (77% od teorijskog). To a mixture of 300 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride, 82 mg of tetrahydropyran-4-carboxylic acid and 0 90 mg of 1-hydroxy-1H-benzotriazole and 250 mg of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate are added to 54 ml of Hünig's base in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred overnight at room temperature. For processing, it is mixed with 25 ml of acetic ester and washed with water, a 10% solution of potassium carbonate and with a saturated solution of sodium chloride. The organic phase is dried over magnesium sulfate and concentrated. The residue is mixed with a little acetic ester, sucked off and dried. Yield: 250 mg (77% of theoretical).

Rf vrijednost: 0,43 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.43 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 515, 517 [M+H]+ Mass spectrum (ESI+): m/z = 515, 517 [M+H]+

Analogno primjeru 11 dobiveni su slijedeći spojevi: Analogous to example 11, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(tetra-hidropiran-4-il)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(tetra-hydropyran-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy - quinazoline

Rf vrijednost: 0,44 {silika gel, octeni ester/metanol/konc. vodeni amonijak =90:10:1) Rf value: 0.44 {silica gel, acetic ester/methanol/conc. aqueous ammonia =90:10:1)

Maseni spektar (ESI+): m/z = 529, 531 [M+H]+ Mass spectrum (ESI+): m/z = 529, 531 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{N-[(tetra-hidropiran-4-il)karbonil]-N-metil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetra-hydropyran-4-yl)carbonyl]-N-methyl-amino}- cyclohexane-1-yloxy)-7-methoxy-quinazoline

Rf vrijednost: 0,31 (silika gel, octeni ester/metanol = 9:1) Rf value: 0.31 (silica gel, acetic ester/methanol = 9:1)

Maseni spektar (ESI+) : m/z = 543, 545 [M+H]+ Mass spectrum (ESI+): m/z = 543, 545 [M+H]+

Primjer 12 Example 12

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[([1,4]oksazepan-4-il)karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[([1,4]oxazepan-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

K 900 mg 1-metil-3-[([1,4]oksazepan-4-il)karbonil]-3H-imidazol-1-ij-jodida u 10 ml metilen klorida doda se 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorid i 1,05 ml trietilamina. Žutu suspenziju se miješa pribl. 24 sata pri sobnoj temperaturi. Za obradu se reakcijsku smjesu pomiješa 50 ml metilen klorida i s vodom i ekstrahira se s 10%-tnom limunskom kiselinom. Organsku fazu se ispere sa zasićenom otopinom natrijevog klorida, osuši se preko magnezijevog sulfata i koncentrira. Ostatak se kromatografira preko stupca silika gela s metilen klorid/metanol/konc. amonijakom kao protočnim sredstvom. Željeni proizvod se pomješa s dietil eterom, odsisa i osuši. 4-[(3-chloro-4 -fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride and 1.05 ml of triethylamine. The yellow suspension is mixed approx. 24 hours at room temperature. For processing, the reaction mixture is mixed with 50 ml of methylene chloride and water and extracted with 10% citric acid. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed over a silica gel column with methylene chloride/methanol/conc. with ammonia as a flow agent. The desired product is mixed with diethyl ether, filtered under suction and dried.

Iskorištenje: 800 mg (80 % od teorijskog) Utilization: 800 mg (80% of the theoretical)

Rf vrijednost: 0,30 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.30 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

Analogno primjeru 12 dobiveni su slijedeći spojevi: Analogous to example 12, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(cis-2,6-di-metil-morfolin-4-il)karbonil]-piperidin4-iloksi}-7-metoksi-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-di-methyl-morpholin-4-yl)carbonyl]-piperidin4-yloxy} -7-methoxy-quinazoline

Rf vrijednost: 0,41 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.41 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 544, 546 [M+H]+ Mass spectrum (ESI+): m/z = 544, 546 [M+H]+

(2) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(2-metil-morfolin-4-il)karbonil]-piperidin-4-iloksi}-7-metoksi-kinazolin (2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy - quinazoline

Rf vrijednost: 0,50 (silika gel, octeni ester/metanol/konc. vodeni amonijak = 90:10:1) Rf value: 0.50 (silica gel, acetic ester/methanol/conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 530, 532 [M+H]+ Mass spectrum (ESI+): m/z = 530, 532 [M+H]+

Primjer 13 Example 13

4-[(3-klor-4-fluor-fenil)amino]-6-(1-metil-piperidin-4-iloksi)-7-etoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-ethoxy-quinazoline

K 175 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-etoksi-kinazolina u 1 ml tetrahidrofurana doda se 35 μl 37%-tne vodene otopine formalina i 110 mg natrijevog triacetoksiborhidrida. Reakcijsku smjesa se miješa pribl. četiri sata pri sobnoj temperaturi. Za obradu se doda 5 ml zasićene otopine natrijevog hidrogen karbonata i smjesu se temeljito promiješa. Zatim se doda 20 ml octenog estera i vodenu fazu se odvoji. Organsku fazu se ispere s vodom i sa zasićenom otopinom natrijevog klorida, osuši se preko magnezijevog sulfata i koncentrira. Ostatak se promiješa s diizopropil eterom, odsisa i osuši. Iskorištenje: 144 mg (80 % od teorijskog). To 175 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-ethoxy-quinazoline in 1 ml of tetrahydrofuran, add 35 μl of a 37% aqueous formalin solution and 110 mg of sodium triacetoxyborohydride. The reaction mixture is stirred for approx. four hours at room temperature. For processing, 5 ml of saturated sodium hydrogen carbonate solution is added and the mixture is thoroughly mixed. Then 20 ml of acetic ester is added and the aqueous phase is separated. The organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is mixed with diisopropyl ether, suction filtered and dried. Yield: 144 mg (80% of theoretical).

Rf vrijednost: 0,80 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 60:10:1) Rf value: 0.80 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 60:10:1)

Maseni spektar (ESI+): m/z = 431, 433 [M+H]+ Mass spectrum (ESI+): m/z = 431, 433 [M+H]+

Analogno primjeru 13 su dobiveni slijedeći spojevi: Analogous to example 13, the following compounds were obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metil-piperidin-4-iloksi)-7 (2-metoksi-etoksi)-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7 (2-methoxy-ethoxy)-quinazoline

Rf vrijednost: 0,85 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 60:10:1) Rf value: 0.85 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 60:10:1)

Maseni spektar (ESI+): m/z = 461, 463 [M+H]+ Mass spectrum (ESI+): m/z = 461, 463 [M+H]+

(2) 4-[(3-etinil-fenil) amino]-6-(1-metil-piperidin-4-il-oksi)-7-metoksi-kinazolin-hidroklorid (2) 4-[(3-ethynyl-phenyl) amino]-6-(1-methyl-piperidin-4-yl-oxy)-7-methoxy-quinazoline-hydrochloride

Rf vrijednost: 0,26 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.26 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 389 [M+H]+ Mass spectrum (ESI+): m/z = 389 [M+H]+

(3) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-dimetil-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin (3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethyl-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline

Rf vrijednost: 0,80 (aluminijev oksid, metilen klorid/metanol = 9:1) Rf value: 0.80 (alumina, methylene chloride/methanol = 9:1)

Maseni spektar (ESI+): m/z = 445, 447 [M+H]+ Mass spectrum (ESI+): m/z = 445, 447 [M+H]+

Primjer 14 Example 14

4-[(3-etinil-fenil)amino]-6-[1-(terc-butiloksikarbonil)-piperidin-4-iloksi]-7-metoksi-kinazolin 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline

Smjesu od 3,00 g 4-[(3-etinil-fenil)amino]-6-hidroksi-7-metoksi-kinazolina, 4,50 g 1-(terc-butiloksikarbonil)-4-(p-toluolsulfoniloksi)-piperidina i 2,90 g kalijevog karbonata u 30 ml N,N-dimetilformamida miješa se dva dana pri 60°C. Za obradu se smjesu pomiješa s 200 ml octenog estera i ekstrahira s vodom. Organsku fazu se ispere sa zasićenom otopinom natrijevog klorida, osuši se preko magnezijevog sulfata i koncentrira. Sirov proizvod se očisti preko stupca silika gela s metilen klorid/ metanol/konc. amonijakom kao protočnim sredstvom. Iskorištenje: 3,25 g (67 % od teorijskog). A mixture of 3.00 g of 4-[(3-ethynyl-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline, 4.50 g of 1-(tert-butyloxycarbonyl)-4-(p-toluenesulfonyloxy)-piperidine and 2.90 g of potassium carbonate in 30 ml of N,N-dimethylformamide were mixed for two days at 60°C. For processing, the mixture is mixed with 200 ml of acetic ester and extracted with water. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product is purified over a silica gel column with methylene chloride/methanol/conc. with ammonia as a flow agent. Yield: 3.25 g (67% of theoretical).

Rf vrijednost: 0,25 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 95:5:1) Rf value: 0.25 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 95:5:1)

Maseni spektar (ESI+): m/z = 475 [M+H]+ Mass spectrum (ESI+): m/z = 475 [M+H]+

Analogno primjeru 14 dobiven je slijedeći spoj: Analogous to example 14, the following compound was obtained:

(1) 4-[(3-etinil-fenil)amino]-6-(tetrahidropiran-4-il-oksi]-7-raetoksi-kinazolin (1) 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yl-oxy]-7-raethoxy-quinazoline

Rf vrijednost: 0,40 (silika gel, metilen klorid/metanol/ konc. vodeni amonijak = 90:10:1) Rf value: 0.40 (silica gel, methylene chloride/methanol/ conc. aqueous ammonia = 90:10:1)

Maseni spektar (ESI+): m/z = 376 [M+H]+ Mass spectrum (ESI+): m/z = 376 [M+H]+

Primjer 15 Example 15

4-[(3-klor-4-fluor-fenil)amino]-6-{1-[2-(terc-butiloksi-karbonilamino)-etil]-piperidin-4-iloksi}-7-metoksi-kinazolin 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(tert-butyloxy-carbonylamino)-ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline

Smjesu od 410 mg 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-iloksi)-7-metoksi-kinazolin-dihidroklorida, 240 mg N-(terc-butiloksikarbonil)-2-brom-etilamina i 360 mg kalijevog karbonata u 5 ml N,N-dimetilformamida miješa se preko noći pri sobnoj temperaturi. Zatim se još jednom doda 80 mg N-(terc-butiloksikarbonil)-2-brom-etilamina i rekcijsku smjesa se miješa još četiri sata pri sobnoj temperaturi. Za obradu se razrijedi s vodom i ekstrahira s octenim esterom. Sjedinjene organske faze se isperu sa zasićenom otopinom natrijevog klorida, osuše se preko magnezijevog sulfata i koncentriraju. Ostatak se kromatografira preko stupca silika gela s octeni ester/ metanolom (95:5 na 90:1) kao protočnim sredstvom. Iskorištenje: 370 mg (79 % od teorijskog). A mixture of 410 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-dihydrochloride, 240 mg of N-(tert-butyloxycarbonyl)-2 -bromoethylamine and 360 mg of potassium carbonate in 5 ml of N,N-dimethylformamide are stirred overnight at room temperature. Then 80 mg of N-(tert-butyloxycarbonyl)-2-bromo-ethylamine was added once more and the reaction mixture was stirred for another four hours at room temperature. For processing, it is diluted with water and extracted with acetic ester. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed over a column of silica gel with ethyl acetate/methanol (95:5 to 90:1) as eluent. Yield: 370 mg (79% of theoretical).

Rf vrijednost: 0,33 (TLC gotova pločica reverzne faze) (E. Merck), acetonitrit/voda/trifluor octena kiselina 50:50:1) Rf value: 0.33 (TLC ready reverse phase plate) (E. Merck), acetonitrite/water/trifluoroacetic acid 50:50:1)

Maseni spektar (ESI-): m/z = 544, 546 [M-H]- Mass spectrum (ESI-): m/z = 544, 546 [M-H]-

Analogno primjeru 15 dobiven je slijedeći spoj: Analogous to example 15, the following compound was obtained:

(1) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[2-{terc-butil-oksikarbonilamino)-etil]-piperidin-4-iloksi}-kinazolin (1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-{tert-butyl-oxycarbonylamino)-ethyl]-piperidin-4-yloxy}-quinazoline

Rf vrijednost: 0,38 (TLC gotova pločica reverzne faze) (E. Merck), acetonitril/voda/trifluoroctena kiselina = 50:50:1) Rf value: 0.38 (TLC ready reverse phase plate) (E. Merck), acetonitrile/water/trifluoroacetic acid = 50:50:1)

Maseni spektar (ESI+): m/z = 516, 518 [M+H]+ Mass spectrum (ESI+): m/z = 516, 518 [M+H]+

Analogno prethodno navedenim primjerima i drugim postupcima koji su poznati iz literature, mogu se također proizvesti i slijedeći spojevi: Analogous to the previously mentioned examples and other procedures known from the literature, the following compounds can also be produced:

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Primjer 16 Example 16

Dražeje sa 75 mg aktivne tvari Dragees with 75 mg of active substance

Sastav Composition

1 dražeja sadrži: 1 dragee contains:

aktivna tvar 75,0 mg active substance 75.0 mg

kalcijev fosfat 93,0 mg calcium phosphate 93.0 mg

kukuruzni škrob 35,5 mg corn starch 35.5 mg

polivinilpirolidon 10,0 mg polyvinylpyrrolidone 10.0 mg

hidroksipropilmetilceluloza 15,0 mg hydroxypropylmethylcellulose 15.0 mg

magnezijev stearat 1,5 mg magnesium stearate 1.5 mg

230,0 mg 230.0 mg

Priprava Preparation

Aktivnu tvar se pomiješa s kalcijevim fosfatom, kukuruznim škrobom, polivinilpirolidonom, hidroksipropil-metilcelulozom i polovicom navedene količine magnezijevog stearata. Na stroju za izradu tableta izrade se otpresci promjera od pribl. 13 mm, koji se zatim prosiju kroz prikladno sito veličine oka od 1,5 mm i pomiješaju se s preostalom količinom magnezijevog stearata. Taj granulat se na struju za izradu tableta ispreša u tablete željenog oblika. The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose and half of the specified amount of magnesium stearate. On the machine for making tablets, blanks with a diameter of approx. 13 mm, which are then sieved through a suitable 1.5 mm mesh sieve and mixed with the remaining amount of magnesium stearate. This granulate is pressed into tablets of the desired shape using electricity to make tablets.

Masa jezgre: 230 mg Core weight: 230 mg

žig: 9 mm, konveksan. stamp: 9 mm, convex.

Tako proizvedene jezgre dražeja se prevuku s filmom koji se sastoji uglavnom od hidroksipropilmetilceluloze. Gotove, s filmom prevučene dražeje se poliraju s pčelinjim voskom. The dragee cores produced in this way are coated with a film consisting mainly of hydroxypropylmethylcellulose. Finished, film-coated dragees are polished with beeswax.

Masa dražeje: 245 mg. Dragee mass: 245 mg.

Primjer 17 Example 17

Tablete sa 100 mg aktivne tvari Tablets with 100 mg of active substance

Sastav: Composition:

1 tableta sadrži: 1 tablet contains:

aktivna tvar 100,0 mg active substance 100.0 mg

laktoza 80,0 mg lactose 80.0 mg

kukuruzni škrob 34,0 mg corn starch 34.0 mg

polivinilpirolidon 4,0 mg polyvinylpyrrolidone 4.0 mg

magnezijev stearat 2,0 mg magnesium stearate 2.0 mg

220,0 mg 220.0 mg

Postupak priprave Preparation process

Zajedno se pomiješaju aktivna tvar, laktoza i škrob i jednoliko se navlaže s vodenom otopinom polivinil-pirolidona. Nakon prosijavanja vlažne mase (veličina oka 2,0 mm) i sušenja u protočnoj komori za sušenje pri 50°C, ponovno se prosije (veličina oka 1,5 mm) i pomiješa s lubrikantom. Gotovu smjesu se ispreša u tablete. The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of polyvinyl-pyrrolidone. After sieving the wet mass (mesh size 2.0 mm) and drying in a flow drying chamber at 50°C, it is sieved again (mesh size 1.5 mm) and mixed with lubricant. The finished mixture is pressed into tablets.

Masa tablete: 220 mg Tablet mass: 220 mg

promjer: 10 mra, biplanarne, obostrano zarubljene i zarezane na jednoj strani. diameter: 10 mra, biplanar, beveled on both sides and notched on one side.

Primjer 18 Example 18

Tablete sa 150 mg aktivne tvari Tablets with 150 mg of active substance

Sastav: Composition:

1 tableta sadrži: 1 tablet contains:

aktivna tvar 150,0 mg active substance 150.0 mg

praškasta laktoza 89,0 mg powdered lactose 89.0 mg

kukuruzni škrob 40,0 mg corn starch 40.0 mg

koloidna silicijeva kiselina 10,0 mg colloidal silicic acid 10.0 mg

polivinilpirolidon 10,0 mg polyvinylpyrrolidone 10.0 mg

magnezijev stearat 1,0 mg magnesium stearate 1.0 mg

300,0 mg 300.0 mg

Priprava: Preparation:

Aktivnu tvar se pomiješa s laktozom, kukuruznim škrobom i silicijevom kiselinom i navlaži s 20%-tnom vodenom otopinom polivinilpirolidona i prosije se kroz sito veličine oka 1,5 mm. Granulat osušen pri 45°C se još jednom prosije kroz isto sito i pomiješa se s navedenom količinom magnezijevog stearata. Iz te smjese se prešaju tablete. The active substance is mixed with lactose, corn starch and silicic acid and moistened with a 20% aqueous solution of polyvinylpyrrolidone and sieved through a 1.5 mm sieve. The granulate dried at 45°C is sieved through the same sieve once more and mixed with the specified amount of magnesium stearate. Tablets are pressed from this mixture.

Masa tablete: 300 mg Tablet mass: 300 mg

žig: 10 mm, plosnate. stamp: 10 mm, flat.

Primjer 19 Example 19

Tvrde želatinske kapsule sa 150 mg aktivne tvari Hard gelatin capsules with 150 mg of active substance

Sastav: Composition:

1 kapsula sadrži: 1 capsule contains:

aktivna tvar 150,0 mg active substance 150.0 mg

suhi kukuruzni škrob pribl. 180,0 mg dry corn starch approx. 180.0 mg

praškasta laktoza pribl. 87,0 mg powdered lactose approx. 87.0 mg

magnezijev stearat 3,0 mg magnesium stearate 3.0 mg

pribl. 420,0 mg approx. 420.0 mg

Priprava Preparation

Aktivna tvar se pomiješa s pomoćnim tvarima, prosije se kroz sito veličine oka 0,75 mm i homogeno se pomiješa u prikladnom uređaju. Dobivenu mješavinu se puni u tvrde želatinske kapsule veličine 1. The active substance is mixed with excipients, sieved through a 0.75 mm sieve and homogeneously mixed in a suitable device. The resulting mixture is filled into hard gelatin capsules of size 1.

Punjenje kapsule: pribl. 320 mg Capsule filling: approx. 320 mg

ljuska kapsule: tvrde želatinske kapsule veličine 1. capsule shell: hard gelatin capsules size 1.

Primjer 20 Example 20

Čepići koji sadrže 150 mg aktivne tvari Suppositories containing 150 mg of active substance

Sastav: Composition:

1 čepić sadrži: 1 suppository contains:

aktivna tvar 150,0 mg active substance 150.0 mg

polietilenglikol 1500 550,0 mg polyethylene glycol 1500 550.0 mg

polietilenglikol 6000 460,0 mg polyethylene glycol 6000 460.0 mg

polioksietilen sorbitan monostearat 840,0 mg polyoxyethylene sorbitan monostearate 840.0 mg

2000,0 mg 2000.0 mg

Priprava Preparation

Kad se masa za čepiće otopi, aktivnu tvar se homogeno izmiješa u njoj i talinu se izlije u pothlađene kalupe. When the mass for suppositories melts, the active substance is homogeneously mixed in it and the melt is poured into cooled molds.

Primjer 21 Example 21

Suspenzija s 50 mg aktivne tvari Suspension with 50 mg of active substance

Sastav: Composition:

100 ml suspenzije sadrži: 100 ml of suspension contains:

aktivna tvar 1,00 g active substance 1.00 g

karboksimetilceluloza-Na-sol 0,10 g carboxymethylcellulose-Na-salt 0.10 g

metil p-hidroksibenzoat 0,05 g methyl p-hydroxybenzoate 0.05 g

propil p-hidroksibenzoat 0,01 g propyl p-hydroxybenzoate 0.01 g

glukoza 10,00 g glucose 10.00 g

glicerin 5,00 g glycerin 5.00 g

70%-tna otopina sorbitola 20,00 g 70% sorbitol solution 20.00 g

miris 0,30 g fragrance 0.30 g

dest. voda ad 100,00 ml dest. water ad 100.00 ml

Priprava Preparation

Destiliranu vodu se zagrije na 70°C. Uz miješanje dodaju se metil i propil p-hidroksibenzot, te glicerin i natrijeva sol karboksimetilceluloze. Ohladi se na sobnu temperaturu i uz miješanje se doda aktivnu tvari i homogeno se dispergira. Nakon dodatka i otapanja šećera, otopine sorbitola i mirisa, suspenziju se uz miješanje evakuira. Distilled water is heated to 70°C. Methyl and propyl p-hydroxybenzoate, as well as glycerin and sodium salt of carboxymethylcellulose are added with mixing. It is cooled to room temperature and the active substance is added with stirring and dispersed homogeneously. After adding and dissolving sugar, sorbitol solution and fragrance, the suspension is evacuated with stirring.

5 ml suspenzije sadrži 50 mg aktivne tvari. 5 ml of suspension contains 50 mg of active substance.

Primjer 22 Example 22

Ampule s 10 mg aktivne tvari Ampoules with 10 mg of active substance

Sastav: Composition:

aktivna tvar 10,0 mg active substance 10.0 mg

0,01 n solna kiselina s. q. 0.01 n hydrochloric acid s. q.

dva puta destilirana voda 2,0 ml twice distilled water 2.0 ml

Priprava Preparation

Aktivnu tvar se otopi u potrebnoj količini 0,01 N HCl, učini se izotoničnom s otopinom NaCl, sterilno se profiltrira i puni u ampule od 2 ml. The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with NaCl solution, sterile filtered and filled into ampoules of 2 ml.

Primjer 23 Example 23

Ampule s 50 mg aktivne tvari Ampoules with 50 mg of active substance

Sastav: Composition:

aktivna tvar 50,0 mg active substance 50.0 mg

0,01 n solna kiselina s. q. 0.01 n hydrochloric acid s. q.

dva puta destilirana voda 10,0 ml twice distilled water 10.0 ml

Priprava Preparation

Aktivnu tvar se otopi u potrebnoj količini 0,01 N HCl, učini se izotoničnom s otopinom NaCl, sterilno se profiltrira i puni u ampule od 10 ml. The active substance is dissolved in the required amount of 0.01 N HCl, made isotonic with NaCl solution, sterile filtered and filled into ampoules of 10 ml.

Primjer 24 Example 24

Kapsule za inhalaciju praha s 5 mg aktivne tvari Capsules for powder inhalation with 5 mg of active substance

1 kapsula sadrži 1 capsule contains

tvar 5,0 mg substance 5.0 mg

laktoza za inhalaciju 15,0 mg lactose for inhalation 15.0 mg

20,0 mg 20.0 mg

Priprava Preparation

Aktivnu tvar se pomiješa s laktozom za inhalaciju. Smjesu se pakira u kapsule na stroju za punjenje kapsula (masa prazne kapsule pribl. 50 mg). The active substance is mixed with lactose for inhalation. The mixture is packed into capsules on a capsule filling machine (weight of an empty capsule approx. 50 mg).

Masa kapsule: 70,0 mg Capsule mass: 70.0 mg

Veličina kapsule: 3 Capsule size: 3

Primjer 25 Example 25

Inhalacijska otopina za ručni atomizer koja sadrži 2,5 mg aktivne tvari Inhalation solution for manual atomizer containing 2.5 mg of active substance

1 sprej sadrži: 1 spray contains:

aktivna tvar 2,500 mg active substance 2,500 mg

benzalkonij klorid 0/001 mg benzalkonium chloride 0/001 mg

1 N solna kiselina q. s. 1 N hydrochloric acid q. with.

etanol/voda (50/50) ad 15,000 mg ethanol/water (50/50) ad 15,000 mg

Priprava Preparation

Aktivnu tvar i benzalkonij klorid se otope u etanol/vodi (50/50). pH vrijednost otopine namjesti se s 1N solnom kiselinom. Dobivenu otopinu se profiltrira i puni se u posude (kartuše) prikladne za ručne atomizere. Masa punjenja posude: 4,5 g The active substance and benzalkonium chloride are dissolved in ethanol/water (50/50). The pH value of the solution is adjusted with 1N hydrochloric acid. The resulting solution is filtered and filled into containers (cartridges) suitable for hand atomizers. Container filling weight: 4.5 g

Claims (11)

1. Biciklički heterocikli opće formule [image] naznačeni time, da u njima Ra predstavlja vodikov atom ili C1-4-alkilnu skupinu, Rbje fenilna ili 1-feniletilna skupina, u kojoj je fenilna jezgra supstituirana u svakom slučaju s radikalima R1 do R3, pri čemu R1 i R2, koji mogu biti jednaki ili različiti, u svakom slučaju predstavljaju vodik, fluor, klor, brom ili atom joda, C1-4-alkil, hidroksi, C1-4-alkoksi, C2-3-alkenil ili C2-3-alkinilnu skupinu, aril, ariloksi, arilmetil ili arilmetoksi skupinu, heteroaril, heteroariloksi, heteroarilmetil ili heteroarilmetoksi skupinu, metilnu ili metoksi skupinu supstituiranu s 1 do 3 atoma fluora, ili cijano, nitro ili amino skupinu, i R3je vodik, fluor, klor ili atom broma, ili metilna ili trifluormetilna skupina, Rc je ciklobutil, ciklopentil ili cikloheksilna skupina, koja je supstituirana u svakom slučaju sa skupinom R4-N-R5, pri čemu R4je vodikov atom ili C1-3-alkilna skupina i R5 je vodikov atom ili C1-3-alkilna skupina, aminokarbonil-C1-3-alkil, C1-3-alkil amino karbonil-C1-3-alkil, di(C1-3-alkil)aminokarbonil-C1-3-alkil, pirolidin-1-ilkarbonil-C1-3-alkil, piperidin-1-ilkarbonil-C1-3-alkil, homopiperidin-1-ilkarbonil-C1-3-alkil, morfolin-4-ilkarbonil-C1-3-alkil, homomorfolin-4-ilkarbonil-C1-3-alkil, piperazin-1-il-karbonil-C1-3-alkil, 4-C1-3-alkil-piperazin-1-ilkarbonil-C1-3-alkil, homopiperazin-1-ilkarbonil-C1-3-alkil ili 4-C1-3-alkil-homopiperazin-1-il-karbonil-C1-3-alkilna skupina, hidroksi-C2-4-alkil, C1-3-alkiloksi-C2-4-alkil, C1-4-alkiloksi-karbonilamino-C2-4-alkil, amino-C2-4-alkil, C1-3-alkilamino-C2-4-alkil, di-(C1-3-alkil) amino-C2-4-alkil, C1-3-alkilkarbonilamino-C2-4-alkil, aminokarbonilamino-C2-4-alkil, C1-3-alkilaminokarbonilamino-C2-4-alkil, di-(C1-3-alkil) amino-karbonilamino-C2-4-alkil, pirolidin-1-il-karbonilamino-C2-4-alkil, piperidin-1-ilkarbonilamino-C2-4-alkil, morfolion-4-ilkarbonilamino-C2-4-alkil, C1-3-alkilsulfonil-C2-4-alkil ili C1-3-alkilsulfonilamino-C2-4-alkilna skupina, (2-okso-pirolidin-1-il)-C2-4-alkil, (2-oksopiperidin-1-il)-C2-4-alkil, (3-okso-morfolin-4-il)-C2-4-alkil, 2-okso-imidazolidin-1-il)-C2-4-alkil, 2-okso-3-C1-3-alkil-imidazolidin-1-il)-C2-4-alkil, (2-okso-heksahidropirimidin-1-il)-C2-4-alkil ili (2-okso-3-C1-3-alkil-heksahidropirimidin-1-il)-C2-4-alkilna skupina, C1-4-alkilsulfonil, klor-C1-4-alkilsulfonil, brom-C1-4-alkilsulfonil, amino-C1-4-alkilsulfonil, C1-3-alkilamino-C1-4-alkilsulfonil, di-(C1-3-alkil)amino-C1-4-alkilsulfonil, (pirolidin-1-il)-C1-4-alkilsulfonil, (piperidin-1-il)-C1-4-alkilsulfonil, (homopiperidin-1-il)-C1-4-alkilsulfonil, (morfolin-4-il)-C1-4-alkilsulfonil, (homomorfolin-4-il)-C1-4-alkilsulfonil, (piperazin-1-il)-C1-4-alkilsulfonil, (4-C1-3-alkil-piperazin-1-il)-C1-4-alkilsulfonil, (homo-piperazin-1-il)-C1-4-alkilsulfonil ili (4-C1-3-alkil-homo-piperazin-1-il)-C1-4-alkilsulfonilna skupina, C1-4-alkiloksikarbonilna skupina, formil, C1-4-alkil-karbonil, C1-3-alkiloksi-C1-4-alkil-karbonil, tetrahidrofuranilkarbonil, tetrahidropiranil-karbonil, amino-C1-4-alkil-karbonil, C1-3-alkilamino-C1-4-alkil-karbonil, di-(C1-3-alkil)amino-C1-4-alkil-karbonil, pirolidin-1-il-C1-4-alkil-karbonil, piperidin-1-il-C1-4-alkil-karbonil, (homopiperidin-1-il)-C1-4-alkil-karbonil, morfolin-4-il-C1-4-alkil-karbonil, (homomorfolin-4-il)-C1-4-alkil-karbonil, (piperazin-1-il)-C1-4-alkil-karbonil, (4-C1-3-alkil-piperazin-1-il)-C1-4-alkil-karbonil, (homo-piperazin-1-il)-C1-4-alkil-karbonil, (4-C1-3-alkil-homo-piperazin-1-il)-C1-4-alkil-karbonil ili C1-3-alkilsulfonil-C1-4-alkil-karbonilna skupina, cijano, aminokarbonil, C1-3-alkil-aminokarbonil, di-(C1-3-alkil) amino-karbonil, (C1-3-alkiloksi-C2-4-alkil) aminokarbonil, N-(C1-3-alkil)-N-(C1-3-alkiloksi-C2-4-alkil)aminokarbonil, arilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, homopiperidin-1-ilkarbonil, morfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo-[3.2.1]okt-8-ilkarbonil, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarbonil, piperazin-1-ilkarbonil, 4-C1-3-alkil-piperazin-1-ilkarbonil, homopiperazin-1-ilkarbonil, 4-C1-3-alkil-homopiperazin-1-ilkarbonil, aminosulfonil, C1-3-alkil-aminosulfonil, di-(C1-3-alkil)amino-sulfoni1, pirolidin-1-il-sulfonil, piperidin-1-ilsulfonil, homopiperidin-1-il-sulfonil, morfolin-4-ilsulfonil, homomorfolin-4-ilsulfonil, piperazin-1-ilsulfonil, 4-C1-3-alkil-piperazin-1-il-sulfonil, homopiperazin-1-ilsulfonil ili 4-C1-3-alkil-homo-piperazin-1-ilsulfonilna skupina, ciklobutil, ciklopentil ili ciklohekslna skupina koja je supstituirana u svakom slučaju sa skupinom R6, gdje R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-C1-3-alkil-imidazolidin-1-il, 2-okso-heksahidro-pirimidin-1-il ili 2-okso-3-C1-3-alkil-heksahidro-pirimidin-1-il skupina, azetidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, pirolidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, piperidin-3-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, piperidin-4-il skupina, koja je u položaju 1 supstituirana s ostatkom R5, pri čemu je R5 definiran kao ovdje gore, ili tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, Rd je vodikov atom ili fluor, klor ili atom broma, hidroksi skupina, C1-4-alkiloksi skupina, metoksi skupina supstituirana s 1 do 3 atoma fluora, etiloksi skupina supstituirana s 1 do 5 atoma fluora, C2-4-alkiloksi skupina koja je supstituirana s radikalom R6 ili R7 , pri čemu R6 definiran kao ovdje gore, i R7 je hidroksi, C1-3-alkiloksi, C3-6-cikloalkiloksi, amino, C1-3-alkilamino, di-(C1-3-alkil)amino, bis-(2-metoksietil)amino, pirolidin-1-il, piperidin-1-il, homo-piperidin-1-il, morfolin-4-il, homomorfolin-4-il, 2-oksa-5-aza-biciklo[2.2.1]hept-5-il, 3-oksa-8-aza-biciklo[3.2.1]-okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il, 4-C1-3-alkil-piperazin-1-il, homopiperazin-1-il ili C1-3-alkil-homopiperazin-1-il skupina, ili formilamino, C1-4-alkilkarbonilamino, C1-3-alkiloksi-C1-3-alkil-karbonilamino, C1-4-alkiloksikarbonil amino, aminokarbonilamino, C1-3-alkilaminokarbonilamino, di-(C1-3-alkil)aminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarboni1amino, piperazin-1-i1karboni1amino, 4-C1-4-alkil-piperazin-1-ilkarbonilamino-morfolin-4-il-karbonilamino ili C1-4-alkilsulfonilarainoskupina, C3-7-cikloalkiloksi ili C3-7-cikloalkil-C1-4-alkiloksi skupina, tetrahidrofuran-3-iloksi, tetrahidropiran-3-iloksi ilitetrahidropiran-4-iloksi skupina, tetrahidrofuranil-C1-4-alkiloksi ili tetrahidro-piranil-C1-4-alkiloksi skupina, C1-4-alkoksi skupina, supstituirana s pirolidinilnom, piperidinilnom ili s homopiperidinilnom skupinom, koja je u položaju 1 supstituirana s radikalom R8, pri čemu R8 je vodikov atom ili C1-3-alkilna skupina, ili C1-4-alkoksi skupina supstituirana s morfolinilnom skupinom koja je u položaju 4 supstituirana s ostatkom R8, pri čemu je R8 definiran kao gore, i X je metinska skupina supstituirana sa cijano skupinom ili dušikov atom, pri čemu arilne skupine, koje su spomenute kod definicije gornjih radikala, znače u svakom slučaju fenilnu skupinu, koja je mono- ili disupstituirana s R9, pri čemu supstituenti mogu biti jednaki ili različiti i R9 je vodikov atom, fluor, klor, brom ili atom joda ili C1-3-alkil, hidroksi, C1-3-alkiloksi, difluormetil, trifluormetil, difluormetoksi, trifluormetoksi ili cijano skupina, heteroarilne skupine koje su spomenute kod definicije gornjih radikala znače piridil, piridazinil, pirimidinil ili pirazinilnu skupinu, pri čemu su gore spomenute heteroarilne skupine u svakom slučaju mono- ili disupstituirane s radikalom R i pri čemu supstituenti mogu biti jednaki ili različiti, a R9 je definiran kao gore, i gore spomenuta pirolidinilna, piperidinilna, piperazinilna i morfolinilna skupina mogu biti u svakom slučaju supstituirane s jednom ili dvije C1-3-alkilne skupine, i ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, pod uvjetom da je isključen spoj 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-hidroksi-kinazolin, njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli.1. Bicyclic heterocycles of the general formula [image] indicated by the fact that in them Ra represents a hydrogen atom or a C1-4-alkyl group, Rbje is a phenyl or 1-phenylethyl group, in which the phenyl nucleus is substituted in each case with radicals R1 to R3, wherein R1 and R2, which may be the same or different, in any case represent hydrogen, fluorine, chlorine, bromine or an iodine atom, C1-4-alkyl, hydroxy, C1-4-alkoxy, C2-3-alkenyl or C2-3-alkynyl group, an aryl, aryloxy, arylmethyl or arylmethoxy group, a heteroaryl, heteroaryloxy, heteroarylmethyl or heteroarylmethoxy group, a methyl or methoxy group substituted with 1 to 3 fluorine atoms, or cyano, nitro or amino group, i R 3 is hydrogen, fluorine, chlorine or a bromine atom, or methyl or trifluoromethyl group, Rc is a cyclobutyl, cyclopentyl or cyclohexyl group, which is substituted in each case with the group R4-N-R5, wherein R4 is a hydrogen atom or a C1-3-alkyl group and R5 is a hydrogen atom or a C1-3-alkyl group, aminocarbonyl-C1-3-alkyl, C1-3-alkyl aminocarbonyl-C1-3-alkyl, di(C1-3-alkyl)aminocarbonyl-C1-3-alkyl, pyrrolidin-1-ylcarbonyl-C1-3-alkyl, piperidin-1-ylcarbonyl-C1-3-alkyl, homopiperidin-1-ylcarbonyl-C1-3-alkyl, morpholin-4-ylcarbonyl-C1-3-alkyl, homomorpholin- 4-ylcarbonyl-C1-3-alkyl, piperazin-1-yl-carbonyl-C1-3-alkyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl-C1-3-alkyl, homopiperazin-1-ylcarbonyl- C1-3-alkyl or 4-C1-3-alkyl-homopiperazin-1-yl-carbonyl-C1-3-alkyl group, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C1-4-alkyloxy-carbonylamino-C2-4-alkyl, amino-C2-4-alkyl, C1-3-alkylamino-C2- 4-alkyl, di-(C1-3-alkyl) amino-C2-4-alkyl, C1-3-alkylcarbonylamino-C2-4-alkyl, aminocarbonylamino-C2-4-alkyl, C1-3-alkylaminocarbonylamino-C2-4 -alkyl, di-(C1-3-alkyl) amino-carbonylamino-C2-4-alkyl, pyrrolidin-1-yl-carbonylamino-C2-4-alkyl, piperidin-1-ylcarbonylamino-C2-4-alkyl, morpholion- 4-ylcarbonylamino-C2-4-alkyl, C1-3-alkylsulfonyl-C2-4-alkyl or C1-3-alkylsulfonylamino-C2-4-alkyl group, (2-oxo-pyrrolidin-1-yl)-C2-4-alkyl, (2-oxopiperidin-1-yl)-C2-4-alkyl, (3-oxo-morpholin-4-yl)-C2-4- alkyl, 2-oxo-imidazolidin-1-yl)-C2-4-alkyl, 2-oxo-3-C1-3-alkyl-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-hexahydropyrimidine -1-yl)-C2-4-alkyl or (2-oxo-3-C1-3-alkyl-hexahydropyrimidin-1-yl)-C2-4-alkyl group, C1-4-alkylsulfonyl, chloro-C1-4-alkylsulfonyl, bromo-C1-4-alkylsulfonyl, amino-C1-4-alkylsulfonyl, C1-3-alkylamino-C1-4-alkylsulfonyl, di-(C1-3-alkyl )amino-C1-4-alkylsulfonyl, (pyrrolidin-1-yl)-C1-4-alkylsulfonyl, (piperidin-1-yl)-C1-4-alkylsulfonyl, (homopiperidin-1-yl)-C1-4-alkylsulfonyl , (morpholin-4-yl)-C1-4-alkylsulfonyl, (homomorpholin-4-yl)-C1-4-alkylsulfonyl, (piperazin-1-yl)-C1-4-alkylsulfonyl, (4-C1-3- alkyl-piperazin-1-yl)-C1-4-alkylsulfonyl, (homo-piperazin-1-yl)-C1-4-alkylsulfonyl or (4-C1-3-alkyl-homo-piperazin-1-yl)-C1 -4-alkylsulfonyl group, C1-4-alkyloxycarbonyl group, formyl, C1-4-alkyl-carbonyl, C1-3-alkyloxy-C1-4-alkyl-carbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranyl-carbonyl, amino-C1-4-alkyl-carbonyl, C1-3-alkylamino-C1-4- alkyl-carbonyl, di-(C1-3-alkyl)amino-C1-4-alkyl-carbonyl, pyrrolidin-1-yl-C1-4-alkyl-carbonyl, piperidin-1-yl-C1-4-alkyl-carbonyl , (homopiperidin-1-yl)-C1-4-alkyl-carbonyl, morpholin-4-yl-C1-4-alkyl-carbonyl, (homomorpholin-4-yl)-C1-4-alkyl-carbonyl, (piperazine- 1-yl)-C1-4-alkyl-carbonyl, (4-C1-3-alkyl-piperazin-1-yl)-C1-4-alkyl-carbonyl, (homo-piperazin-1-yl)-C1-4 -alkyl-carbonyl, (4-C1-3-alkyl-homo-piperazin-1-yl)-C1-4-alkyl-carbonyl or C1-3-alkylsulfonyl-C1-4-alkyl-carbonyl group, cyano, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl) amino-carbonyl, (C1-3-alkyloxy-C2-4-alkyl) aminocarbonyl, N-(C1-3-alkyl)- N-(C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, arylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2 -oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[ 3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-C1-3-alkyl-piperazin-1-ylcarbonyl, homopiperazin-1-ylcarbonyl, 4-C1-3-alkyl-homopiperazin-1-ylcarbonyl, aminosulfonyl, C1-3-alkyl-aminosulfonyl, di-(C1-3-alkyl)amino-sulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl, homopiperidin-1-yl-sulfonyl, morpholin-4-ylsulfonyl , homomorpholin-4-ylsulfonyl, piperazin-1-ylsulfonyl, 4-C1-3-alkyl-piperazin-1-yl-sulfonyl, homopiperazin-1-ylsulfonyl or 4-C1-3-alkyl-homo-piperazin-1-ylsulfonyl group, cyclobutyl, cyclopentyl or cyclohexyl group which is substituted in each case with the group R6, where R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-C1-3- alkyl-imidazolidin-1-yl, 2-oxo-hexahydro-pyrimidin-1-yl or 2-oxo-3-C1-3-alkyl-hexahydro-pyrimidin-1-yl group, an azetidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above, a pyrrolidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above, a piperidin-3-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above, a piperidin-4-yl group, which is substituted in position 1 with the residue R5, where R5 is defined as above, or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd is a hydrogen atom or a fluorine, chlorine or bromine atom, hydroxy group, C1-4-alkyloxy group, methoxy group substituted with 1 to 3 fluorine atoms, ethyloxy group substituted with 1 to 5 fluorine atoms, C2-4-alkyloxy group which is substituted with the radical R6 or R7, wherein R6 defined as above, i R7 is hydroxy, C1-3-alkyloxy, C3-6-cycloalkyloxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-methoxyethyl)amino, pyrrolidin-1-yl, piperidin-1-yl, homo-piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa- 8-aza-bicyclo[3.2.1]-oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl, 4-C1-3-alkyl -piperazin-1-yl, homopiperazin-1-yl or C1-3-alkyl-homopiperazin-1-yl group, or formylamino, C1-4-alkylcarbonylamino, C1-3-alkyloxy-C1-3-alkylcarbonylamino, C1-4-alkyloxycarbonyl amino, aminocarbonylamino, C1-3-alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidine- 1-ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C1-4-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-yl-carbonylamino or C1-4-alkylsulfonylarino, C3-7-cycloalkyloxy or C3-7-cycloalkyl-C1-4-alkyloxy group, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy or tetrahydropyran-4-yloxy group, tetrahydrofuranyl-C1-4-alkyloxy or tetrahydro-pyranyl-C1-4-alkyloxy group, C1-4-Alkoxy group, substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group, which is substituted in position 1 with the radical R8, wherein R8 is a hydrogen atom or a C1-3-alkyl group, or a C1-4-alkoxy group substituted with a morpholinyl group which is substituted in position 4 with the residue R8, where R8 is defined as above, and X is a methine group substituted with a cyano group or a nitrogen atom, where the aryl groups, which are mentioned in the definition of the above radicals, mean in each case a phenyl group, which is mono- or disubstituted with R9, whereby the substituents can be the same or different and R9 is a hydrogen atom, fluorine, chlorine, bromine or iodine atom or a C1-3-alkyl, hydroxy, C1-3-alkyloxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano group, the heteroaryl groups mentioned in the definition of the above radicals mean a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group, wherein the above-mentioned heteroaryl groups are in each case mono- or disubstituted with the radical R and wherein the substituents may be the same or different, and R9 is defined as above, and the above-mentioned pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups may in each case be substituted with one or two C1-3-alkyl groups, and unless stated otherwise, the aforementioned alkyl groups may be straight or branched, provided that the compound 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline is excluded, their tautomers, their stereoisomers, their mixtures and their salts. 2. Biciklički heterocikli opće formule I prema zahtjevu 1, naznačeni time, da u njima Ra je vodikov atom, Rbje fenil skupina supstituirana s radikalima R1 do R3, pri čemu R1 je vodik, fluor, klor ili atom broma, metil, trifluormetil ili etinilna skupina, feniloksi ili fenilmetoksi skupina, pri čemu fenilni dio u gore spomenutim skupinama je prema potrebi supstituiran s jednim atomom fluora ili klora, ili piridiloksi ili piridinilmetoksi skupina, pri čemu piridinilni dio u gore spomenutim skupinama je prema potrebi supstituiran s metilnom ili trifluormetilnom skupinom, R2 je vodik, fluor ili atom klora ili metilna skupina i R3 je vodikov atom, Rc je ciklopentilna skupina, koja je u položaju 3 supstituirana sa skupinom R4-N-R5, pri čemu R4 je vodikov atom ili C1-3-alkilna skupina i R5 je vodikov atom ili C1-3-alkilna skupila, aminokarbonil-C1-3-alkil, C1-3-alkilaminokarbonil-C1-3-alkil, di-(C1-3-alkil)aminokarbonil-C1-3-alkil, pirolidin-1-ilkarbonil-C1-3-alkil, piperidin-1-il-karbonil-C1-3-alkil, piperazin-1-ilkarbonil-C1-3-alkil, 4-C1-3-alkil-piperazin-1-il-karbonil-C1-3-alkil ili morfolin-4-ilkarbonil-C1-3-alkilna skupina, hidroksi-C2-4-alkil, C1-3-alkiloksi-C2-4-alkil, C1-4-alkiloksi-karbonilamino-C2-4-alkil, amino-C2-4-alkil, C1-3-alkilamino-C2-4-alkil, di-(C1-3-alkil) amino-C2-4-alkil, C1-3-alkilkarbonilamino-C2-4-alkil, aminokarbonilamino-C2-4-alkil, C1-3-alkilaminokarbonilamino-C2-4-alkil, di-(C1-3-alkil)amino-karbonilamino-C2-4-alkil, morfolin-4-il-karbonilamino-C2-4-alkil, C1-3-alkilsulfonil-C2-4-alkil ili C1-3-alkilsulfonilamino-C2-4-alkilna skupina, (2-okso-pirolidin-1-il)-C2-4-alkil, (2-oksopiperidin-1-il)-C2-4-alkil, (3-okso-morfolin-4-il)-C2-4-alkil, (2-okso-imidazolidin-1-il)-C2-4-alkil, (2-okso-3-metil-imidazolidin-1-il)-C2-4-alkil, (2-okso-heksahidropirimidin-1-il)-C2-4-alkil ili (2-okso-3-metil-heksahidropirimidin-1-il)-C2-4-alkilna skupina, C1-3-alkilsulfonil, klor-C2-4-alkilsulfonil, brom-C2-4-alkilsulfonil, amino-C2-4-alkilsulfonil, C1-3-alkilamino-C2-4-alkilsulfonil, di-(C1-3-alkil)amino-C2-4-alkilsulfonil, (pirolidin-1-il)-C2-4-alkilsulfonil, (piperidin-1-il)-C2-4-alkilsulfonil ili (morfolin-4-il)-C2-4-alkilsulfonilna skupina, C1-4-alkiloksikarbonilna skupina, formil, C1-3-alkilkarbonil, C1-3-alkiloksi-C1-3-alkil-karbonil, tetrahidrofuranilkarbonil, tetrahidropiranil-karbonil, amino-C1-3-alkilkarbonil, C1-3-alkilamino-C1-3-alkilkarbonil, di-(C1-3-alkil) amino-C1-3-alkilkarbonil, pirolidin-1-il-C1-3-alkilkarbonil, piperidin-1-il-C1-3-alkilkarbonil, piperazin-1-il-C1-3-alkil-karbonil, 4-C1-3-alkilpiperazin-1-il-C1-3-alkilkarboni1, morfolin-4-il-C1-3-alkilkarbonil ili C1-3-alkilsulfonil-C1-3-alkilkarbonilna skupina, ili cijano, aminokarbonil, C1-3-alkilaminokarbonil, di-(C1-3-alkil)aminokarbonil, (C1-3-alkiloksi-C2-4-alkil)aminokarbonil, N-(C1-3-alkil)-N-(C1-3-alkiloksi-C2-4-alkil)aminokarbonil, fenilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, C1-3-alkil-morfolin-4-ilkarbonil, di-(C1-3-alkil)morfolin-4-il-karbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo-[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo[3.2.1]okt-8-ilkarboni1, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarboni1, piperazin-1-ilkarbonil, 4-(C1-3-alkil)-piperazin-1-il-karbonil, aminosulfonil, C1-3-alkil-aminosulfonil, di-(C1-3-alkil)aminosulfonil, pirolidin-1-il-sulfonil, piperidin-1-ilsulfonil ili morfolin-4-ilsulfonilna skupina, ili ciklopentilna skupina, koja je u položaju 3 supstituirana sa skupinom R6, pri čemu R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metil-imidazolidin-1-il, 2-okso-heksahidro-pirimidin-1-il-ili 2-okso-3-metil-heksahidropirimidin-1-il skupina, cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R4-N-R5, pri čemu su R4 i R5 definirani kao gore, cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R6, pri čemu je R6 definiran kao gore, pirolidin-3-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, piperidin-3-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, piperidin-4-il skupina, koja je u položaju 1 supstituirana sa skupinom R5, pri čemu je R5 definiran kao gore, ili tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, Rd je vodikov atom, C1-3-alkiloksi skupina, metoksi skupina, koja je supstituirana s jednim do tri atoma fluora, etiloksi skupina, koja je u položaju 2 supstituirana s radikalom R6 ili R7, pri čemu R6 je definiran kao gore i R7 je hidroksi, C1-3-alkil, amino, C1-3-alkilamino, di-(C1-3-alkil)amino, bis-(2-metoksietil)amino, pirolidin-1-il, piperidin-1-il, morfolin-4-il, 2-oksa-5-aza-biciklo-[2.2.1]hept-5-il, 3-oksa-8-aza[3.2.1]okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il ili 4-C1-3-alkil-piperazin-1-il skupina, ili formilamino, C1-4-alkilkarbonilamino, C1-3-alkiloksi-C1-3-alkil-karbonilamino, C1-4-alkiloksikarbonilamino, aminokarbonilamino, C1-3-alkilaminokarbonilamino, di-(C1-3-alkil)aminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarbonilamino, piperazin-1-ilkarbonilamino, 4-C1-3-alkil-piperazin-1-ilkarbonilamino-morfolin-4-il-karbonilamino ili C1-4-alkilsulfonilamino skupina, propiloksi skupina, koja je u položaju 3 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, ili butiloksi skupina, koja je u položaju 4 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, i X je dušikov atom, pri čemu, ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli.2. Bicyclic heterocycles of the general formula I according to claim 1, characterized in that in them Ra is a hydrogen atom, Rb is a phenyl group substituted with radicals R1 to R3, wherein R1 is hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl or ethynyl group, a phenyloxy or phenylmethoxy group, wherein the phenyl part in the aforementioned groups is optionally substituted with one fluorine or chlorine atom, or pyridyloxy or pyridinylmethoxy group, whereby the pyridinyl part in the above-mentioned groups is optionally substituted with a methyl or trifluoromethyl group, R2 is hydrogen, fluorine or chlorine atom or methyl group and R3 is a hydrogen atom, Rc is a cyclopentyl group, which is substituted in position 3 with the group R4-N-R5, whereby R4 is a hydrogen atom or a C1-3-alkyl group and R5 is a hydrogen atom or a C1-3-alkyl group, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, di-(C1-3-alkyl)aminocarbonyl-C1-3-alkyl, pyrrolidine -1-ylcarbonyl-C1-3-alkyl, piperidin-1-yl-carbonyl-C1-3-alkyl, piperazin-1-ylcarbonyl-C1-3-alkyl, 4-C1-3-alkyl-piperazin-1-yl -carbonyl-C1-3-alkyl or morpholin-4-ylcarbonyl-C1-3-alkyl group, hydroxy-C2-4-alkyl, C1-3-alkyloxy-C2-4-alkyl, C1-4-alkyloxy-carbonylamino-C2-4-alkyl, amino-C2-4-alkyl, C1-3-alkylamino-C2- 4-alkyl, di-(C1-3-alkyl) amino-C2-4-alkyl, C1-3-alkylcarbonylamino-C2-4-alkyl, aminocarbonylamino-C2-4-alkyl, C1-3-alkylaminocarbonylamino-C2-4 -alkyl, di-(C1-3-alkyl)amino-carbonylamino-C2-4-alkyl, morpholin-4-yl-carbonylamino-C2-4-alkyl, C1-3-alkylsulfonyl-C2-4-alkyl or C1- 3-alkylsulfonylamino-C2-4-alkyl group, (2-oxo-pyrrolidin-1-yl)-C2-4-alkyl, (2-oxopiperidin-1-yl)-C2-4-alkyl, (3-oxo-morpholin-4-yl)-C2-4- alkyl, (2-oxo-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-3-methyl-imidazolidin-1-yl)-C2-4-alkyl, (2-oxo-hexahydropyrimidin-1 -yl)-C2-4-alkyl or (2-oxo-3-methyl-hexahydropyrimidin-1-yl)-C2-4-alkyl group, C1-3-alkylsulfonyl, chloro-C2-4-alkylsulfonyl, bromo-C2-4-alkylsulfonyl, amino-C2-4-alkylsulfonyl, C1-3-alkylamino-C2-4-alkylsulfonyl, di-(C1-3-alkyl )amino-C2-4-alkylsulfonyl, (pyrrolidin-1-yl)-C2-4-alkylsulfonyl, (piperidin-1-yl)-C2-4-alkylsulfonyl or (morpholin-4-yl)-C2-4-alkylsulfonyl group, C1-4-alkyloxycarbonyl group, formyl, C1-3-alkylcarbonyl, C1-3-alkyloxy-C1-3-alkylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranyl-carbonyl, amino-C1-3-alkylcarbonyl, C1-3-alkylamino-C1-3-alkylcarbonyl, di- (C1-3-alkyl) amino-C1-3-alkylcarbonyl, pyrrolidin-1-yl-C1-3-alkylcarbonyl, piperidin-1-yl-C1-3-alkylcarbonyl, piperazin-1-yl-C1-3-alkyl -carbonyl, 4-C1-3-alkylpiperazin-1-yl-C1-3-alkylcarbonyl, morpholin-4-yl-C1-3-alkylcarbonyl or C1-3-alkylsulfonyl-C1-3-alkylcarbonyl group, or cyano, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)aminocarbonyl, (C1-3-alkyloxy-C2-4-alkyl)aminocarbonyl, N-(C1-3-alkyl)-N-(C1 -3-alkyloxy-C2-4-alkyl)aminocarbonyl, phenylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, C1-3-alkyl-morpholin-4-ylcarbonyl, di-(C1- 3-Alkyl)morpholin-4-yl-carbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo-[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2 .1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-3-alkyl)-piperazin-1-yl -carbonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, di-(C1-3-alkyl)aminosulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-1-ylsulfonyl or morpholin-4-ylsulfonyl group, or cyclopentyl group, which is substituted in position 3 with the group R6, wherein R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin- 1-yl, 2-oxo-hexahydro-pyrimidin-1-yl-or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, cyclohexyl group, which is substituted in position 3 or in position 4 with the group R4-N-R5, wherein R4 and R5 are defined as above, cyclohexyl group, which is substituted in the 3-position or in the 4-position with the group R6, wherein R6 is defined as above, pyrrolidin-3-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above, piperidin-3-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above, piperidin-4-yl group, which is substituted in position 1 with the group R5, wherein R5 is defined as above, or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd is a hydrogen atom, C1-3-alkyloxy group, methoxy group, which is substituted with one to three fluorine atoms, ethyloxy group, which is substituted in position 2 with the radical R6 or R7, whereby R6 is defined as above and R7 is hydroxy, C1-3-alkyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)amino, bis-(2-methoxyethyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 2-oxa-5-aza-bicyclo-[2.2.1]hept-5-yl, 3-oxa-8-aza[3.2.1]oct-8-yl, 8-oxa-3 -aza-bicyclo[3.2.1]oct-3-yl, piperazin-1-yl or 4-C1-3-alkyl-piperazin-1-yl group, or formylamino, C1-4-alkylcarbonylamino, C1-3-alkyloxy-C1-3-alkylcarbonylamino, C1-4-alkyloxycarbonylamino, aminocarbonylamino, C1-3-alkylaminocarbonylamino, di-(C1-3-alkyl)aminocarbonylamino, pyrrolidine-1 -ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, 4-C1-3-alkyl-piperazin-1-ylcarbonylamino-morpholin-4-yl-carbonylamino or C1-4-alkylsulfonylamino group, a propyloxy group, which is substituted in position 3 with the residue R6 or R7, wherein R6 and R7 are defined as above, or a butyloxy group, which is substituted in position 4 with the residue R6 or R7, wherein R6 and R7 are defined as above, and X is a nitrogen atom, wherein, unless otherwise stated, the aforementioned alkyl groups may be straight or branched, their tautomers, their stereoisomers, their mixtures and their salts. 3. Biciklički heterocikli opće formule 1 prema zahtjevu 1, naznačeni time, da u njima Ra je vodikov atom, Rbje 3-etinilfenil, 3-bromfenil, 3,4-difluorfenil ili 3-klor-4-fluor-fenilna skupina, 3-klor-4-benziloksi-fenil, 3-klor-4-[(3-fluor-benzil)-oksi]fenil, 4-(piridin-3-iloksi)-fenil, 4-[(6-metil-piridin-3-il)oksi]-fenil, 3-metil-4-(piridin-3-iloksi)-fenil, 3-metil-4-[(6-metil-piridin-3-il)oksi]-fenil, 3-klor-4-(piridin-3-iloksi)-fenil ili 3-klor-4-[(6-metil-piridin-3-il)oksi]-fenilna skupina, Rc je cikloheksilna skupina, koja je u položaju 3 ili u položaju 4 supstituirana sa skupinom R4-N-R5, pri čemu R4 je vodikov atom, metilna ili etilna skupina i R5 je vodikov atom, metil, aminokarbonilmetil, metilamino-karbonilmetil, dimetilaminokarbonilmetil, pirolidin-1-ilkarbonilmetil, piperidin-1-ilkarbonilmetil, piperazin-1-ilkarbonilmetil-, 4-metilpiperazin-1-il-karbonilmetil, morfolin-4-ilkarbonilmetil, 2-(morfolin-4-il-karbonil)etil ili 3-(morfolin-4-il-karbonil)propilna skupina, etil, propil, 2-hidroksietil, 3-hidroksipropil, 2-metoksietil, 3-metoksipropil, 2-(butiloksikarbonilamino)-etil, 2-aminoetil, 3-aminopropil, 2-(acetilamino)etil, 3-(acetilamino)propil, 2-(etilkarbonilamino)etil, 3-(etil-karbonilamino)propil, 2-(propilkarbonilamino)etil, 3-(propilkarbonilamino)propil, 2-(etilaminokarbonilamino)-etil, 3-(etilaminokarbonilamino)propil, 2-(dimetilamino-karbonilamino)etil, 3-(dimetilamino-karbonilamino)propil, 2-(morfolin-4-ilkarbonilamino)etil, 3-(morfolin-4-il-karbonilamino)propil, 2-(metilsulfonil)etil, 3-(metil-sulfonil)propil, 2-(metilsulfonilamino)etil ili 3-(metil-sulfonilamino)propilna skupina, 2-(2-okso-pirolidin-1-il)etil, 2-(2-okso-piperidin-1-il)etil, 2-(3-okso-morfolin-4-il)etil, 2-(2-okso-imidazolidin-1-il)etil, 2-(2-okso-3-metil-imidazolidin-1-il)-etil, 2-(2-okso-heksahidropiridin-1-il)etil ili 2-(2-okso-3-metil-heksahidropirimidin-1-il)etilna skupina, 3-(2-okso-pirolidin-1-il)propil, 3-(2-oksopiperidin-1-il)propil, 3-(3-okso-morfolin-4-il)propil, 3-(2-okso-imidazolidin-1-il)propil, 3-(2-okso-3-metil-imidazolidin-1-il)-propil, 3-(2-okso-heksahidropiridin-1-il)propil ili 3-(2-okso-3-metil-heksahidropirimidin-1-il)propilna skupina, metilsulfonil, etilsulfonil, 3-klorpropilsulfonil, 2-(morfolin-4-il)-etilsulfonil ili 3-(morfolin-4-il)-propil-sulfonilna skupina, propiloksikarbonilna ili butiloksikarbonilna skupina, formil, acetil, etilkarbonil, propilkarbonil, metoksi-acetil, (2-metoksietil)karbonil, (3-metoksipropil)-karbonil, tetrahidrofuran-2-ilkarbonil, tetrahidropiran-4-ilkarbonil, aminoacetil, metilaminoacetil, dimetilamino-acetil, morfolin-4-ilacetil, [2-(morfolin-4-il)etil]-karbonil, [3-(morfolin-4-il)propil]-karbonil ili metil-sulfonilacetilna skupina, cijano, aminokarbonil, metilaminokarbonil, dimetil-aminokarbonil, etilaminokarbonil, dietilaminokarbonil, propilaminokarbonil, (2-metoksietiljaminokarbonil, N-metil-N-(2-metoksietil)-aminokarbonil, (3-metoksipropil)-aminokarbonil, N-metil-N-(3-metoksipropil)-aminokarbonil, fenil-aminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-il-karbonil, morfolin-4-ilkarbonil, 2-metilmorfolin-4-il-karbonil, 2,6-dimetilmorfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo[3.2.1]okt-8-i1karbonil, 8-oksa-3-azabiciklo[3.2.1]okt-3-i1karbonil, 4-metilpiperazin-1-il-karbonil, aminosulfonil, metilaminosulfonil, dimetil-amino-sulfonil ili morfolin-4-ilsulfonilna skupina, cikloheksilna skupina koja je supstituirana u položaju 3 ili u položaju 4 sa skupinom R6, dok R6 je 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metil-imidazolidin-1-il, 2-okso-heksahidropirimidin-1-il ili 2-okso-3-metil-heksahidropirimidin-1-il skupina, pirolidin-3-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, piperidin-3-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, piperidin-4-il skupina koja je supstituirana u položaju 1 sa skupinom R5, dok je R5 definiran kao gore, tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, Rd je vodikov atom, metoksi, difluormetoksi ili etiloksi skupina, etiloksi skupina, koja je suptituirana u položaju 2 s ostatkom R6 ili R7, pri čemu je R6 definiran kao gore, i R7 je hidroksi, metoksi, etoksi, amino, dimetilamino, dietilamino, bis-(2-metoksietil)-amino, pirolidin-1-il, piperidin-1-il, morfolin-4-il, homomorfolin-4-il, 2-oksa-5-aza-biciklo[2.2.1]hept-5-il, 3-oksa-8-aza-biciklo[3.2.1]-okt-8-il, 8-oksa-3-aza-biciklo[3.2.1]okt-3-il, piperazin-1-il, 4-metil-piperazin-1-il ili 4-etilpiperazin-1-il skupina, ili acetilamino, etilkarbonilamino, propilkarbonilamino, butilkarbonilamino, metoksiacetilamino, butiloksikarbonil-amino, etilaminokarbonilamino, dimetilaminokarbonilamino, pirolidin-1-ilkarbonilamino, piperidin-1-ilkarboni1amino, morfolin-4-ilkarbonilamino, metilsulfonilamino, etil-sulfonilamino ili butilsulfonilamino skupina, propiloksi skupina, koja je u položaju 3 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, ili butiloksi skupina, koja je u položaju 4 supstituirana s ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao gore, i X je dušikov atom, pri čemu, ako nije navedeno drugačije, gore spomenute alkilne skupine mogu biti ravne ili razgranate, njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli.3. Bicyclic heterocycles of the general formula 1 according to claim 1, characterized in that in them Ra is a hydrogen atom, Rbje 3-ethynylphenyl, 3-bromophenyl, 3,4-difluorophenyl or 3-chloro-4-fluoro-phenyl group, 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluoro-benzyl) -oxy]phenyl, 4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-methyl-4-(pyridin-3-yloxy)- phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3-chloro-4-(pyridin-3-yloxy)-phenyl or 3-chloro-4-[(6 -methyl-pyridin-3-yl)oxy]-phenyl group, Rc is a cyclohexyl group, which is substituted in position 3 or in position 4 with the group R4-N-R5, whereby R4 is a hydrogen atom, methyl or ethyl group and R5 is a hydrogen atom, methyl, aminocarbonylmethyl, methylamino-carbonylmethyl, dimethylaminocarbonylmethyl, pyrrolidin-1-ylcarbonylmethyl, piperidin-1-ylcarbonylmethyl, piperazin-1-ylcarbonylmethyl-, 4-methylpiperazin-1-yl-carbonylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl-carbonyl)ethyl or 3-(morpholin-4-yl-carbonyl)propyl group, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-(butyloxycarbonylamino)-ethyl, 2-aminoethyl, 3-aminopropyl, 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 2-(ethylcarbonylamino)ethyl, 3-(ethyl-carbonylamino)propyl, 2-(propylcarbonylamino)ethyl, 3-(propylcarbonylamino)propyl, 2-(ethylaminocarbonylamino)-ethyl, 3-(ethylaminocarbonylamino)propyl, 2-(dimethylamino- carbonylamino)ethyl, 3-(dimethylamino-carbonylamino)propyl, 2-(morpholin-4-ylcarbonylamino)ethyl, 3-(morpholin-4-yl-carbonylamino)propyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl) )propyl, 2-(methylsulfonylamino)ethyl or 3-(methylsulfonylamino)propyl group, 2-(2-oxo-pyrrolidin-1-yl)ethyl, 2-(2-oxo-piperidin-1-yl)ethyl, 2-(3-oxo-morpholin-4-yl)ethyl, 2-(2- oxo-imidazolidin-1-yl)ethyl, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl, 2-(2-oxo-hexahydropyridin-1-yl)ethyl or 2-(2- oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl group, 3-(2-oxo-pyrrolidin-1-yl)propyl, 3-(2-oxopiperidin-1-yl)propyl, 3-(3-oxo-morpholin-4-yl)propyl, 3-(2-oxo- imidazolidin-1-yl)propyl, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl, 3-(2-oxo-hexahydropyridin-1-yl)propyl or 3-(2-oxo- 3-methyl-hexahydropyrimidin-1-yl)propyl group, methylsulfonyl, ethylsulfonyl, 3-chloropropylsulfonyl, 2-(morpholin-4-yl)-ethylsulfonyl or 3-(morpholin-4-yl)-propyl-sulfonyl group, propyloxycarbonyl or butyloxycarbonyl group, formyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxy-acetyl, (2-methoxyethyl)carbonyl, (3-methoxypropyl)-carbonyl, tetrahydrofuran-2-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, aminoacetyl, methylaminoacetyl, dimethylaminoacetyl, morpholine-4 -ylacetyl, [2-(morpholin-4-yl)ethyl]-carbonyl, [3-(morpholin-4-yl)propyl]-carbonyl or methyl-sulfonylacetyl group, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, (2-methoxyethylaminocarbonyl, N-methyl-N-(2-methoxyethyl)-aminocarbonyl, (3-methoxypropyl)-aminocarbonyl, N-methyl-N-( 3-methoxypropyl)-aminocarbonyl, phenyl-aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-yl-carbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-yl-carbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl , homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo[3.2.1]oct-8-ylcarbonyl, 8-oxa -3-azabicyclo[3.2.1]oct-3-ylcarbonyl, 4-methylpiperazin-1-yl-carbonyl, aminosulfonyl, methylaminosulfonyl, dimethyl-amino-sulfonyl or morpholin-4-ylsulfonyl group, cyclohexyl group which is substituted in position 3 or in position 4 with the group R6, doc R6 is 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2-oxo-3-methyl-imidazolidin- 1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, a pyrrolidin-3-yl group which is substituted in position 1 with the group R5, while R5 is defined as above, piperidin-3-yl group which is substituted in position 1 with the group R5, while R5 is defined as above, piperidin-4-yl group which is substituted in position 1 with the group R5, while R5 is defined as above, tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd is a hydrogen atom, methoxy, difluoromethoxy or ethyloxy group, an ethyloxy group, which is substituted in position 2 with a residue R6 or R7, where R6 is defined as above, and R7 is hydroxy, methoxy, ethoxy, amino, dimethylamino, diethylamino, bis-(2-methoxyethyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, homomorpholin-4-yl, 2- oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3.2.1]-oct-8-yl, 8-oxa-3-aza-bicyclo[3.2 .1]oct-3-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl or 4-ethylpiperazin-1-yl group, or acetylamino, ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, methoxyacetylamino, butyloxycarbonylamino, ethylaminocarbonylamino, dimethylaminocarbonylamino, pyrrolidin-1-ylcarbonylamino, piperidin-1-ylcarbonylamino, morpholin-4-ylcarbonylamino, methylsulfonylamino, ethylsulfonylamino or butylsulfonylamino, a propyloxy group, which is substituted in position 3 with the residue R6 or R7, wherein R6 and R7 are defined as above, or a butyloxy group, which is substituted in position 4 with the residue R6 or R7, wherein R6 and R7 are defined as above, and X is a nitrogen atom, wherein, unless otherwise stated, the aforementioned alkyl groups may be straight or branched, their tautomers, their stereoisomers, their mixtures and their salts. 4. Biciklički heterocikli opće formule I prema zahtjevu 1, naznačeni time, da u njima Ra je vodikov atom, Rb je 3-bromfenil, 3,4-difluorfenil, 3-klor-4-fluor-fenil ili 3-etinilfenilna skupina, ili 3-klor-4-benziloksi-fenil, 3-klor-4-[(3-fluorbenzil)-oksi]-fenil, 4-(piridin-3-iloksi)-fenil, 4-[(6-metil-piridin-3-il)oksi]-fenil, 3-metil-4-(piridin-3-iloksi)-fenil, 3-metil-4-[(6-metil-piridin-3-il)oksi]-fenil, 3-klor-4-(piridin-3-iloksi)-fenil ili 3-klor-4-[(6-metil-piridin-3-il)oksi]-fenilna skupina, Rc je cikloheksilna skupina, koja je u položaju 3 supstituirana s amino, acetilamino, terc-butiloksikarbonil-amino ili metilsulfonilamino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s amino, metilamino, etilamino, dimetilamino, aminokarbonilmetilamino, metilaminokarbonilmetilamino, dimetilaminokarbonilmetilamino, morfolin-4-ilkarbonil-metilamino, [3-(morfolin-4-ilkarbonil)propil]amino, [2-(metil-sulfonil)etil]amino, [3-(metilsulfonil)propil]amino ili [2-(metilsulfonilamino)etil]amino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s [2-(2-okso-pirolidin-1-il)etil]amino, [2-(2-oksopiperidin-1-il)etil]amino, [2-(2-okso-imidazolidin-1-il)etil]amino, [2-(2-okso-3-metil-imidazolidin-1-il)-etil]amino, [2-(2-okso-heksahidropirimidin-1-il)etil]amino ili [2-(2-okso-3-metil-heksahidropirimidin-1-il)etil]amino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s [3-(2-okso-pirolidin-1-il)propil]amino, [3-(2-oksopiperidin-1-il)propil]amino, [3-(2-okso-imidazolidin-1-il)propil]amino, [3-(2-okso-3-metil-imidazolidin-1-il)propil]amino, [3-(2-okso-heksahidropirimidin-1-il)propil]amino ili [3-(2-okso-3-metil-heksahidro-pirimidin-1-il)propil]amino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s acetilamino, N-(acetil)-metilamino, amino-metilkarbonilamino, metilaminometilkarbonilamino, dimetil-aminometilkarbonilamino, morfolin-4-ilmetilkarbonilamino, metoksiacetilamino, N-(metoksiacetil)-metilamino, tetrahidropiran-4-ilkarbonilamino, N-(tetrahidropiran-4-il-karbonil)-metilamino, terc-butiloksikarbonilamino, N-(terc-butiloksikarbonil)-metilamino, aminokarbonilamino, metil-aminokarbonilamino, N-(etilaminokarbonil)-metilamino, di-metilaminokarbonilamino, N-(dimetilaminokarbonil)-metilamino, N-(piperidin-1-ilkarbonil)-metilamino, morfolin-4-ilkarbonilamino, N-(morfolin-4-ilkarbonil)-metilamino ili N-(4-metilpiperazin-1-ilkarbonil)-metilamino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s 2-okso-pirolidin-1-il, 2-oksopiperidin-1-il, 3-okso-morfolin-4-il, 2-okso-imidazolidin-1-il, 2-okso-3-metilimidazolidin-1-il, 2-okso-heksahidropirimidin-1-il ili 2-okso-3-metil-heksahidropirimidin-1-ilnom skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s metilsulfonilamino, N-(metilsulfonil)-metilamino, etilsulfonilamino, N-(etilsulfonil)-metilamino, dimetilaminosulfonilamino, N-(dimetilaminosulfonil)metilamino, morfolin-4-ilsulfonilamino, N-(morfolin-4-il-sulfonil)-metilamino-3-klorpropilsulfonilamino, [2-(morfolin-4-il)-etil]sulfonilamino ili [3-(morfolin-4-il)-propil]sulfonilamino skupinom, pirolidin-3-il skupina, pirolidin-3-il skupina, koja je u položaju 1 supstituirana s metilnom, acetilnom, metoksiacetilnom, terc-butiloksikarbonilnom, morfolin-4-ilkarbonilnom ili metilsulfonilnom skupinom, piperidin-3-il skupina, piperidin-3-il skupina, koja je u položaju 1 supstituirana s metilnom, acetilnom, metoksiacetilnom, terc-butiloksikarbonilnom, morfolin-4-ilkarbonilnom ili metilsulfonilnom skupinom, piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine metil, etil, propil, izopropil, 2-hidroksietil, 2-metoksietil, 3-metoksipropil, 2-(metilsulfonil)etil, 3-(metilsulfonil)-propil, 2-(terc-butiloksikarbonilamino)etil, 2-aminoetil, 2-(acetilamino)etil, 2-(etilkarbonilamino)etil, 2-propil-karbonilamino)etil, 2-(etilaminokarbonilamino)etil, 2-(di-metilaminokarbonilamino)etil, 2-(morfolin-4-ilkarbonil-amino)etil, 3-(acetilamino)propil, 3-(etil-karbonilamino)-propil, 3-(propilkarbonilamino)propil, 3-(etilamino-karbonilamino) propil, 3-(dimetilaminokarbonilamino)propil, 3-(morfolin-4-ilkarbonilamino)propil, 2-(metilsulfonil-amino)etil, 3-(metilsulfonilamino)propil, (aminokarbonil)-metil, (metilaminokarbonil)metil, (dimetilaminokarbonil)-metil, (pirolidin-1-ilkarbonil)metil, (morfolin-4-il-karbonil)metil, 2-(morfolin-4-ilkarbonil)etil ili 3-(morfolin-4-ilkarbonil)-propilna skupina, piperidin-4-il skupina koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine 2-(2-okso-pirolidin-1-il)-etil, 2-(2-oksopiperidin-1-il)-etil, 2-(3-oksomorfolin-4-il)-etil, 2-(2-okso-imidazolidin-1-il)-etil, 2-(2-okso-3-metil-imidazolidin-1-il)-etil, 2-(2-okso-heksa-hidropirimidin-1-il)-etil ili 2-(2-okso-3-metil-heksahidro-pirimidin-1-il)-etilna skupina, piperidin-4-il skupina koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine 3-(2-okso-pirolidin-1-il)-propil, 3-(2-oksopiperidin-1-il)-propil, 3-(3-oksomorfolin-4-il)-propil, 3-(2-okso-imidazolidin-1-il)-propil, 3-(2-okso-3-metil-imidazolidin-1-il)-propil, 3-(2-okso-heksahidropirimidin-1-il)-propil ili 3-(2-okso-3-metil-heksahidropirimidin-1-il)-propilna skupina, piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine formil, acetil, metoksiacetil, (2-metoksietil)karbonil, (3-metoksi-propil)karbonil, metilsulfonilacetil, aminoacetil, metil-aminoacetil, (dimetilamino)acetil, (morfolin-4-il)acetil, [2-(morfolin-4-il)-etil]karbonil, [3-(morfolin-4-il)-propil]karbonil, tetrahidrofuran-2-ilkarbonil ili tetra-hidropiran-4-ilkarbonilna skupina, piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine cijano, aminokarbonil, metilaminokarbonil, etilaminokarbonil, (2-metoksietil)aminokarbonil, N-metil-N-(2-metoksietil)-amino-karbonil, (3-metoksipropil)amino-karbonil, N-metil-N-(3-metoksipropil)aminokarbonil, izopropilaminokarbonil, fenil-aminokarbonil, dimetilamino-karbonil, dietilaminokarbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, 2-metil-morfolin-4-ilkarbonil, 2,6-dimetil-morfolin-4-ilkarbonil, homomorfolin-4-ilkarbonil, 2-oksa-5-aza-biciklo[2.2.1]hept-5-ilkarbonil, 3-oksa-8-aza-biciklo-[3.2.1]okt-8-ilkarbonil, 8-oksa-3-aza-biciklo[3.2.1]okt-3-ilkarbonil, 4-metil-piperazin-1-il-karbonil, izopropiloksi-karbonil ili terc-butiloksikarbonilna skupina, piperidin-4-il skupina, koja je u položaju 1 supstituirana sa supstituentom iz niza koji čine metil-sulfonil, etilsulfonil, [2-(morfolin-4-il)-etil]-sulfonil, [3-(morfolin-4-il)-propil]-sulfonil, amino-sulfoni1, metil-aminosulfonil, dimetilaminosulfonil ili morfolin-4-il-sulfonilna skupina, ili tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetra-hidropiran-4-il skupina, Rd je vodikov atom, metoksi, difluormetoksi ili etiloksi skupina, 2-(morfolin-4-il)etiloksi, 3-(morfolin-4-il)propiloksi ili 4-(morfolin-4-il)butiloksi skupina, 3-(dimetilamino)propiloksi, 3-(dietilamino)-propiloksi, 3-[bis-(2-metoksietil)-amino]propiloksi, 3-(piperazin-e-il)propiloksi, 3-(4-metilpiperazin-e-il)-propiloksi ili 3-(4-etilpiperazin-e-il)-propiloksi skupina, 3-(homomorfolin-4-il)-propiloksi, 3-(2-oksa-5-aza-bi-ciklo[2.2.1]hept-5-il)-propiloksi, 3-(3-oksa-8-aza-biciklo-[3.2.1]okt-8-il)-propiloksi ili 3-(8-oksa-3-aza-biciklo-[3.2.1]okt-3-il)-propiloksi skupina, 2-(2-okso-pirolidin-1-il)-etiloksi, 2-(2-okso-piperidin-1-il)-etiloksi, 2-(3-oksomorfolin-4-il)-etiloksi, 2-(2-okso-imidazolidin-1-il)-etiloksi, 2-(2-okso-3-metil-imidazolidin-1-il)-etiloksi, 2-(2-okso-heksahidropirimidin-1-il)-etiloksi ili 2-(2-okso-3-metil-heksahidropirimidin-1-il)-etiloksi skupina, 3-(2-okso-pirolidin-1-il)-propiloksi, 3-(2-okso-piperidin-1-il)-propiloksi, 3-(3-oksomorfolin-4-il)-propiloksi, 3-(2-okso-imidazolidin-1-il)-propiloksi, 3-(2-okso-3-metil-imidazolidin-1-il)-propiloksi, 3-(2-okso-heksahidro-pirimidin-1-il)-propiloksi ili 3-(2-okso-3-metil-heksa-hidropirimidin-1-il)-propiloksi skupina, 2-(metoksi)-etiloksi, 2-(terc-butiloksikarbonilamino)-etiloksi, 2-(amino)-etiloksi, 2-(acetilamino)-etiloksi, 2-(etilkarbonilamino)-etiloksi, 2-(propilkarbonilamino)-etiloksi, 2-(izobutilkarbonilarnino)-etiloksi, 2-(metoksi-acetilamino)-etiloksi, 2-(etilaminokarbonilamino)-etiloksi, 2-(dimetilaminokarbonilamino)-etiloksi, 2-(pirolidin-1-il-karbonilamino)-etiloksi, 2-(piperidin-1-ilkarbonilamino)-etiloksi, 2-(morfolin-4-ilkarbonilamino)-etiloksi, 2-(metilsulfonilamino)-etiloksi skupina, 2-(etilsulfonil-amino)etiloksi ili 2-(butilsulfonilamino)-etiloksi skupina, ili 3-(terc-butiloksikarbonilamino)-propiloksi, 3-(amino)-propiloksi, 3-(acetilamino)-propiloksi ili 3-(metil-sulfonilamino)-propiloksi skupina, i X je dušikov atom, njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli.4. Bicyclic heterocycles of the general formula I according to claim 1, characterized in that in them Ra is a hydrogen atom, Rb is a 3-bromophenyl, 3,4-difluorophenyl, 3-chloro-4-fluoro-phenyl or 3-ethynylphenyl group, or 3-chloro-4-benzyloxy-phenyl, 3-chloro-4-[(3-fluorobenzyl)-oxy]-phenyl, 4-(pyridin-3-yloxy)-phenyl, 4-[(6-methyl-pyridine- 3-yl)oxy]-phenyl, 3-methyl-4-(pyridin-3-yloxy)-phenyl, 3-methyl-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl, 3- chloro-4-(pyridin-3-yloxy)-phenyl or 3-chloro-4-[(6-methyl-pyridin-3-yl)oxy]-phenyl group, Rc is a cyclohexyl group, which is substituted in position 3 with an amino, acetylamino, tert-butyloxycarbonyl-amino or methylsulfonylamino group, cyclohexyl group, which is substituted in position 4 with amino, methylamino, ethylamino, dimethylamino, aminocarbonylmethylamino, methylaminocarbonylmethylamino, dimethylaminocarbonylmethylamino, morpholin-4-ylcarbonyl-methylamino, [3-(morpholin-4-ylcarbonyl)propyl]amino, [2-( methylsulfonyl)ethyl]amino, [3-(methylsulfonyl)propyl]amino or [2-(methylsulfonylamino)ethyl]amino group, cyclohexyl group, which is substituted in position 4 with [2-(2-oxo-pyrrolidin-1-yl)ethyl]amino, [2-(2-oxopiperidin-1-yl)ethyl]amino, [2-(2- oxo-imidazolidin-1-yl)ethyl]amino, [2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl]amino, [2-(2-oxo-hexahydropyrimidin-1-yl)ethyl ]amino or [2-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)ethyl]amino group, cyclohexyl group, which is substituted in position 4 with [3-(2-oxo-pyrrolidin-1-yl)propyl]amino, [3-(2-oxopiperidin-1-yl)propyl]amino, [3-(2- oxo-imidazolidin-1-yl)propyl]amino, [3-(2-oxo-3-methyl-imidazolidin-1-yl)propyl]amino, [3-(2-oxo-hexahydropyrimidin-1-yl)propyl] amino or [3-(2-oxo-3-methyl-hexahydro-pyrimidin-1-yl)propyl]amino group, cyclohexyl group, which is substituted in position 4 with acetylamino, N-(acetyl)-methylamino, amino-methylcarbonylamino, methylaminomethylcarbonylamino, dimethyl-aminomethylcarbonylamino, morpholin-4-ylmethylcarbonylamino, methoxyacetylamino, N-(methoxyacetyl)-methylamino, tetrahydropyran-4- ylcarbonylamino, N-(tetrahydropyran-4-yl-carbonyl)-methylamino, tert-butyloxycarbonylamino, N-(tert-butyloxycarbonyl)-methylamino, aminocarbonylamino, methyl-aminocarbonylamino, N-(ethylaminocarbonyl)-methylamino, dimethylaminocarbonylamino, N- (dimethylaminocarbonyl)-methylamino, N-(piperidin-1-ylcarbonyl)-methylamino, morpholin-4-ylcarbonylamino, N-(morpholin-4-ylcarbonyl)-methylamino or N-(4-methylpiperazin-1-ylcarbonyl)-methylamino group , cyclohexyl group, which is substituted in position 4 with 2-oxo-pyrrolidin-1-yl, 2-oxopiperidin-1-yl, 3-oxo-morpholin-4-yl, 2-oxo-imidazolidin-1-yl, 2- oxo-3-methylimidazolidin-1-yl, 2-oxo-hexahydropyrimidin-1-yl or 2-oxo-3-methyl-hexahydropyrimidin-1-yl group, cyclohexyl group, which is substituted in position 4 with methylsulfonylamino, N-(methylsulfonyl)-methylamino, ethylsulfonylamino, N-(ethylsulfonyl)-methylamino, dimethylaminosulfonylamino, N-(dimethylaminosulfonyl)methylamino, morpholin-4-ylsulfonylamino, N-(morpholin- 4-yl-sulfonyl)-methylamino-3-chloropropylsulfonylamino, [2-(morpholin-4-yl)-ethyl]sulfonylamino or [3-(morpholin-4-yl)-propyl]sulfonylamino group, pyrrolidin-3-yl group, pyrrolidin-3-yl group, which is substituted in position 1 with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, piperidin-3-yl group, piperidin-3-yl group, which is substituted in position 1 with a methyl, acetyl, methoxyacetyl, tert-butyloxycarbonyl, morpholin-4-ylcarbonyl or methylsulfonyl group, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 3-methoxypropyl, 2-(methylsulfonyl)ethyl, 3-(methylsulfonyl) )-propyl, 2-(tert-butyloxycarbonylamino)ethyl, 2-aminoethyl, 2-(acetylamino)ethyl, 2-(ethylcarbonylamino)ethyl, 2-propylcarbonylamino)ethyl, 2-(ethylaminocarbonylamino)ethyl, 2-(di -methylaminocarbonylamino)ethyl, 2-(morpholin-4-ylcarbonyl-amino)ethyl, 3-(acetylamino)propyl, 3-(ethyl-carbonylamino)-propyl, 3-(propylcarbonylamino)propyl, 3-(ethylamino-carbonylamino)propyl , 3-(dimethylaminocarbonylamino)propyl, 3-(morpholin-4-ylcarbonylamino)propyl, 2-(methylsulfonylamino)ethyl, 3-(methylsulfonylamino)propyl, (aminocarbonyl)-methyl, (methylaminocarbonyl)methyl, (dimethylaminocarbonyl)- methyl, (pyrrolidin-1-ylcarbonyl)methyl, (morpholin-4-yl-carbonyl)methyl, 2-(morpholin-4-ylcarbonyl)ethyl or 3-(morpholin-4-ylcarbonyl)-propyl group, piperidin-4-yl group which is substituted in position 1 with a substituent from the series consisting of 2-(2-oxo-pyrrolidin-1-yl)-ethyl, 2-(2-oxopiperidin-1-yl)-ethyl, 2- (3-oxomorpholin-4-yl)-ethyl, 2-(2-oxo-imidazolidin-1-yl)-ethyl, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyl, 2- (2-oxo-hexa-hydropyrimidin-1-yl)-ethyl or 2-(2-oxo-3-methyl-hexahydro-pyrimidin-1-yl)-ethyl group, piperidin-4-yl group which is substituted in position 1 with a substituent from the series consisting of 3-(2-oxo-pyrrolidin-1-yl)-propyl, 3-(2-oxopiperidin-1-yl)-propyl, 3- (3-oxomorpholin-4-yl)-propyl, 3-(2-oxo-imidazolidin-1-yl)-propyl, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyl, 3- (2-oxo-hexahydropyrimidin-1-yl)-propyl or 3-(2-oxo-3-methyl-hexahydropyrimidin-1-yl)-propyl group, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of formyl, acetyl, methoxyacetyl, (2-methoxyethyl)carbonyl, (3-methoxy-propyl)carbonyl, methylsulfonylacetyl, aminoacetyl, methylaminoacetyl, ( dimethylamino)acetyl, (morpholin-4-yl)acetyl, [2-(morpholin-4-yl)-ethyl]carbonyl, [3-(morpholin-4-yl)-propyl]carbonyl, tetrahydrofuran-2-ylcarbonyl or tetra -hydropyran-4-ylcarbonyl group, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of cyano, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, (2-methoxyethyl)aminocarbonyl, N-methyl-N-(2-methoxyethyl)-amino-carbonyl, (3-Methoxypropyl)amino-carbonyl, N-methyl-N-(3-methoxypropyl)aminocarbonyl, isopropylaminocarbonyl, phenyl-aminocarbonyl, dimethylamino-carbonyl, diethylaminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4- ylcarbonyl, 2-methyl-morpholin-4-ylcarbonyl, 2,6-dimethyl-morpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylcarbonyl, 3-oxa-8-aza-bicyclo-[3.2.1]oct-8-ylcarbonyl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-ylcarbonyl, 4-methyl-piperazin-1-yl -carbonyl, isopropyloxy-carbonyl or tert-butyloxycarbonyl group, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl-sulfonyl, ethylsulfonyl, [2-(morpholin-4-yl)-ethyl]-sulfonyl, [3-(morpholin-4-yl )-propyl]-sulfonyl, amino-sulfonyl, methyl-aminosulfonyl, dimethylaminosulfonyl or morpholin-4-yl-sulfonyl, or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, Rd is a hydrogen atom, methoxy, difluoromethoxy or ethyloxy group, 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group, 3-(dimethylamino)propyloxy, 3-(diethylamino)-propyloxy, 3-[bis-(2-methoxyethyl)-amino]propyloxy, 3-(piperazin-e-yl)propyloxy, 3-(4-methylpiperazine-e- yl)-propyloxy or 3-(4-ethylpiperazin-e-yl)-propyloxy group, 3-(homomorpholin-4-yl)-propyloxy, 3-(2-oxa-5-aza-bi-cyclo[2.2.1 ]hept-5-yl)-propyloxy, 3-(3-oxa-8-aza-bicyclo-[3.2.1]oct-8-yl)-propyloxy or 3-(8-oxa-3-aza-bicyclo- [3.2.1]oct-3-yl)-propyloxy group, 2-(2-oxo-pyrrolidin-1-yl)-ethyloxy, 2-(2-oxo-piperidin-1-yl)-ethyloxy, 2-(3-oxomorpholin-4-yl)-ethyloxy, 2-(2 -oxo-imidazolidin-1-yl)-ethyloxy, 2-(2-oxo-3-methyl-imidazolidin-1-yl)-ethyloxy, 2-(2-oxo-hexahydropyrimidin-1-yl)-ethyloxy or 2- (2-oxo-3-methyl-hexahydropyrimidin-1-yl)-ethyloxy group, 3-(2-oxo-pyrrolidin-1-yl)-propyloxy, 3-(2-oxo-piperidin-1-yl)-propyloxy, 3-(3-oxomorpholin-4-yl)-propyloxy, 3-(2 -oxo-imidazolidin-1-yl)-propyloxy, 3-(2-oxo-3-methyl-imidazolidin-1-yl)-propyloxy, 3-(2-oxo-hexahydro-pyrimidin-1-yl)-propyloxy or 3-(2-oxo-3-methyl-hexa-hydropyrimidin-1-yl)-propyloxy group, 2-(Methoxy)-ethyloxy, 2-(tert-butyloxycarbonylamino)-ethyloxy, 2-(amino)-ethyloxy, 2-(acetylamino)-ethyloxy, 2-(ethylcarbonylamino)-ethyloxy, 2-(propylcarbonylamino)-ethyloxy, 2-(isobutylcarbonylamino)-ethyloxy, 2-(methoxy-acetylamino)-ethyloxy, 2-(ethylaminocarbonylamino)-ethyloxy, 2-(dimethylaminocarbonylamino)-ethyloxy, 2-(pyrrolidin-1-yl-carbonylamino)-ethyloxy, 2- (piperidin-1-ylcarbonylamino)-ethyloxy, 2-(morpholin-4-ylcarbonylamino)-ethyloxy, 2-(methylsulfonylamino)-ethyloxy group, 2-(ethylsulfonylamino)ethyloxy or 2-(butylsulfonylamino)-ethyloxy group, or 3-(tert-butyloxycarbonylamino)-propyloxy, 3-(amino)-propyloxy, 3-(acetylamino)-propyloxy or 3-(methyl-sulfonylamino)-propyloxy group, and X is a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. 5. Biciklički heterocikli opće formule I prema zahtjevu 1, naznačeni time, da u njima Ra predstavlja vodikov atom, Rb je 3-klor-4-fluor-fenilna skupina ili 3-etinil-fenilna skupina, Rc je cikloheksilna skupina, koja je u položaju 3 supstituirana s amino, acetilamino, terc-butiloksi-karbonilamino ili metilsulfonilamino skupinom, cikloheksilna skupina, koja je u položaju 4 supstituirana s amino, metilamino, dimetilamino, acetilamino, N-(acetil)-metilamino, metoksiacetilamino, N-(metoksiacetil)-metilamino, tetrahidropiran-4-ilkarbonil-amino, N-(tetrahidropiran-4-ilkarbonil)-metilamino, terc-butiloksikarbonilamino, N-(terc-butiloksikarbonil)-metilamino, N-(etilaminokarbonil)-metilamino, dimetilamino-karbonilamino, N-(dimetilaminokarbonil)-metilamino, N-(piperidin-1-ilkarbonil)-metilamino, morfolin-4-il-karbonil-amino, N-(morfolin-4-ilkarbonil)-metilamino, N-(4-metil-piperazin-1-ilkarbonil)-metilamino, metilsulfonilamino, N-(metilsulfonil)-metilamino, etilsulfonilamino, N-(etil-sulfonil)-metilamino, dimetilaminosulfonilamino, N-(dimetilaminosulfonil)metilamino, morfolin-4-ilsulfonil-amino, N-(morfolin-4-ilsulfonil)-metilamino, 3-klorpropil-sulfonilamino ili [3-(morfolin-4-il)-propil]sulfonilamino skupina, pirolidin-3-il skupina, pirolidin-3-il skupina, koja je supstituirana u položaju 1 s terc-butiloksikarbonilnom ili metilsulfonilnom skupinom, piperidin-3-il skupina, piperidin-3-il skupina koja je supstituirana u položaju 1 s terc-butiloksikarbonilnom ili metilsulfonilnom skupinom, piperidin-4-il skupina, piperidin-4-il skupina, koja je supstituirana u položaju 1 sa supstituentom iz niza koji čine metil, (aminokarbonil)metil, (dimetilaminokarbonil) metil, (morfolin-4-ilkarbonil)metil, 2-(terc-butiloksikarbonil-amino)etil, 2-aminoetil, 2-(acetilamino)etil, 2-(metil-sulfonilamino)etil, cijano, acetil, metoksiacetil, (di-metilamino)acetil, (morfolin-4-il)acetil, tetrahidropiran-4-ilkarbonil, etilaminokarbonil, izopropilaminokarbonil, fenilaminokarbonil, dimetilaminokarbonil, dietilamino-karbonil, pirolidin-1-ilkarbonil, piperidin-1-ilkarbonil, morfolin-4-ilkarbonil, 2-metilmorfolin-4-ilkarbonil, 2,6-dimetilmorfolin-4-ilkarbonil, homomorfolin-4-i1karboni1, 4-metilpiperazin-1-ilkarbonil, izopropiloksikarbonil, terc-butiloksikarbonil, metilsulfonil, dimetilaminosulfonil ili morfolin-4-ilsulfonilna skupina, ili tetrahidrofuran-3-il, tetrahidropiran-3-il ili tetrahidropiran-4-il skupina, Rdje vodikov atom, metoksi ili etiloksi skupina, 2-(morfolin-4-il)etiloksi, 3-(morfolin-4-il)propiloksi ili 4-(morfolin-4-il)butiloksi skupina, 2-(3-metil-2-okso-heksahidropirimidin-1-il)-etiloksi skupina, 2-(metoksi)-etiloksi, 2-(terc-butiloksikarbonilamino)-etiloksi, 2-amino-etiloksi, 2-(acetilamino)-etiloksi ili 2-(metilsulfonilamino)-etiloksi skupina ili 3-(terc-butiloksikarbonilamino)-propiloksi, 3-amino-propiloksi, 3-(acetilaminoj-propiloksi ili 3-(metil-sulfonilamino)-propiloksi skupina, i X je dušikov atom, njihovi tautomeri, njihovi stereoizomeri, njihove smjese i njihove soli.5. Bicyclic heterocycles of the general formula I according to claim 1, characterized in that in them Ra represents a hydrogen atom, Rb is a 3-chloro-4-fluoro-phenyl group or a 3-ethynyl-phenyl group, Rc is a cyclohexyl group, which is substituted in position 3 with an amino, acetylamino, tert-butyloxy-carbonylamino or methylsulfonylamino group, cyclohexyl group, which is substituted in position 4 with amino, methylamino, dimethylamino, acetylamino, N-(acetyl)-methylamino, methoxyacetylamino, N-(methoxyacetyl)-methylamino, tetrahydropyran-4-ylcarbonyl-amino, N-(tetrahydropyran-4 -ylcarbonyl)-methylamino, tert-butyloxycarbonylamino, N-(tert-butyloxycarbonyl)-methylamino, N-(ethylaminocarbonyl)-methylamino, dimethylamino-carbonylamino, N-(dimethylaminocarbonyl)-methylamino, N-(piperidin-1-ylcarbonyl)- methylamino, morpholin-4-yl-carbonyl-amino, N-(morpholin-4-ylcarbonyl)-methylamino, N-(4-methyl-piperazin-1-ylcarbonyl)-methylamino, methylsulfonylamino, N-(methylsulfonyl)-methylamino, ethylsulfonylamino, N-(ethyl-sulfonyl)-methylamino, dimethylaminosulfonylamino, N-(dimethylaminosulfonyl)methylamino, morpholin-4-ylsulfonyl-amino, N-(morpholin-4-ylsulfonyl)-methylamino, 3-chloropropyl-sulfonylamino or [3- (morpholin-4-yl)-propyl]sulfonylamino group, pyrrolidin-3-yl group, a pyrrolidin-3-yl group, which is substituted in position 1 with a tert-butyloxycarbonyl or methylsulfonyl group, piperidin-3-yl group, piperidin-3-yl group which is substituted in position 1 with tert-butyloxycarbonyl or methylsulfonyl group, piperidin-4-yl group, piperidin-4-yl group, which is substituted in position 1 with a substituent from the series consisting of methyl, (aminocarbonyl)methyl, (dimethylaminocarbonyl)methyl, (morpholin-4-ylcarbonyl)methyl, 2-(tert-butyloxycarbonyl-amino)ethyl , 2-aminoethyl, 2-(acetylamino)ethyl, 2-(methyl-sulfonylamino)ethyl, cyano, acetyl, methoxyacetyl, (di-methylamino)acetyl, (morpholin-4-yl)acetyl, tetrahydropyran-4-ylcarbonyl, ethylaminocarbonyl , isopropylaminocarbonyl, phenylaminocarbonyl, dimethylaminocarbonyl, diethylamino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, 2-methylmorpholin-4-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, homomorpholin-4-ylcarbonyl. -i1carbonyl, 4-methylpiperazin-1-ylcarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, methylsulfonyl, dimethylaminosulfonyl or morpholin-4-ylsulfonyl group, or tetrahydrofuran-3-yl, tetrahydropyran-3-yl or tetrahydropyran-4-yl group, The hydrogen atom rusts, methoxy or ethyloxy group, 2-(morpholin-4-yl)ethyloxy, 3-(morpholin-4-yl)propyloxy or 4-(morpholin-4-yl)butyloxy group, 2-(3-methyl-2-oxo-hexahydropyrimidin-1-yl)-ethyloxy group, 2-(Methoxy)-ethyloxy, 2-(tert-butyloxycarbonylamino)-ethyloxy, 2-amino-ethyloxy, 2-(acetylamino)-ethyloxy or 2-(methylsulfonylamino)-ethyloxy group or 3-(tert-butyloxycarbonylamino)-propyloxy, 3-amino-propyloxy, 3-(acetylaminoj-propyloxy or 3-(methyl-sulfonylamino)-propyloxy group, and X is a nitrogen atom, their tautomers, their stereoisomers, their mixtures and their salts. 6. Slijedeći spojevi opće formule 1 prema zahtjevu 1, naznačeni time, da su to (a) 4-[(3-klor-4-fluor-fenil)amino]-6-((S)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin, (b) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-metoksi-kinazolin, (c) 4-[(3-klor-4-fluor-fenil)amino]-6-R)-tetrahidrofuran-3-iloksi)-7-metoksi-kinazolin, (d) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-amino-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (e) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-metan-sulfonilamino-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (f) 4-[(3-klor-4-fluor-fenil)amino]-6-(piperidin-4-il-oksi)-7-metoksi-kinazolin, (g) 4-[(3-klor-4-fluor-fenil)amino)-6-(1-metansulfonil-piperidin-4-iloksi)-7-metoksi-kinazolin, (h) 4-[(3-klor-4-fluor-fenil)amino]-6-(cis-4-{[3-(morfolin-4-il)-propil]sulfonil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (i) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-3-iloksi)-7-metoksi-kinazolin, (k) 4-[(3-klor-4-fluor-fenil)amino]-6-(trans-4-{[3-{morfolin-4-il)-propil]sulfonil-amino}-cikloheksan-1-iloksi)-7-metoksi-kinazolin, (l) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-metil-piperidin-4-iloksi)-7-metoksi-kinazolin, (m) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin-4-il)-karbonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin, (n) 4-[(3-klor4-fluor-fenil)amino]-6-{1-[(metoksimetil)-karboni1]-piperidin4-il-oksi}-7-metoksi-kinazolin, (o) 4-[(3-klor-4-fluor-fenil)amino]-6-(1-cijano-piperidin-4-iloksi)-7-metoksi-kinazolin, (p) 4-[(3-klor-4-fluor-fenil)amino]-6-{1-[(morfolin4-il)-sulfonil]-piperidin-4-il-oksi}-7-metoksi-kinazolin, (q) 4-[(3-klor-4-fluor-fenil)amino]-6-[1-(2-acetilamino-etil)-piperidin-4-iloksi]-7-metoksi-kinazolin, (r) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(dimetil-amino)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (s) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)karbonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (t) 4-[(3-klor-4-fluor-fenil)amino]-6-{trans-4-[(morfolin-4-il)sulfonilamino]-cikloheksan-1-iloksi}-7-metoksi-kinazolin, (u) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-acetilamino-etoksi)-kinazolin, (v) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metansulfonilamino-etoksi)-kinazolin i (w) 4-[(3-klor-4-fluor-fenil)amino]-6-(tetrahidropiran-4-iloksi)-7-(2-metoksi-etoksi)-kinazolin, kao i njihove soli.6. The following compounds of general formula 1 according to claim 1, characterized in that they are (a) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline, (b) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-methoxy-quinazoline, (c) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-R)-tetrahydrofuran-3-yloxy)-7-methoxy-quinazoline, (d) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (e) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methane-sulfonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, (f) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-4-yl-oxy)-7-methoxy-quinazoline, (g) 4-[(3-chloro-4-fluoro-phenyl)amino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (h) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{[3-(morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1- yloxy)-7-methoxy-quinazoline, (i) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline, (k) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{[3-{morpholin-4-yl)-propyl]sulfonyl-amino}-cyclohexane-1- yloxy)-7-methoxy-quinazoline, (l) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, (m) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)-carbonyl]-piperidin-4-yl-oxy}-7-methoxy- quinazoline, (n) 4-[(3-chloro4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)-carbonyl]-piperidin4-yl-oxy}-7-methoxy-quinazoline, (o) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, (p) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin4-yl)-sulfonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline, (q) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, (r) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethyl-amino)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, (s) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline , (t) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline , (u) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, (v) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylamino-ethoxy)-quinazoline and (w) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, as well as their salts. 7. Fiziološki podnošljive soli spojeva prema barem jednom zahtjevu 1 do 6, naznačen time, da su to soli s anorganskim ili organskim kiselinama ili bazama.7. Physiologically tolerable salts of compounds according to at least one claim 1 to 6, characterized in that they are salts with inorganic or organic acids or bases. 8. Lijek, naznačen time, da on sadrži spoj prema barem jednom zahtjevu 1 do 6 ili fiziološki podnošljivu sol prema zahtjevu 7 pored, prema potrebi, jednog ili više inertnih nosača i/ili sredstava za razrjeđivanje.8. Medicine, characterized in that it contains a compound according to at least one claim 1 to 6 or a physiologically tolerable salt according to claim 7 in addition to, if necessary, one or more inert carriers and/or diluents. 9. Upotreba spoja prema barem jednom zahtjevu 1 do 7 za pripravu lijeka, naznačena time, da se on koristi za liječenje benignih ili malignih tumora, za prevenciju i liječenje bolesti dišnih putova i pluća, kao i za liječenje bolesti gastrointestinalnog trakta, žučnog kanala i žučnog mjehura.9. The use of a compound according to at least one of claims 1 to 7 for the preparation of a medicine, indicated by the fact that it is used for the treatment of benign or malignant tumors, for the prevention and treatment of diseases of the respiratory tract and lungs, as well as for the treatment of diseases of the gastrointestinal tract, bile duct and gall bladder. 10. Postupak za pripravu lijeka prema zahtjevu 8, naznačen time, da se na nekemijski način spoj prema barem jednom zahtjevu 1 do 7 ugradi u jedan ili više inertnih nosača i/ili sredstava za razrjeđivanje.10. Method for the preparation of a medicine according to claim 8, characterized in that the compound according to at least one of claims 1 to 7 is incorporated in one or more inert carriers and/or diluents in a non-chemical way. 11. Postupak za pripravu spojeva opće formule I prema zahtjevima 1 do 6, naznačen time, da a) spoj opće formule [image] u kojoj su Ra, Rb, Rd i X definirani kao zahtjevima 1 do 6, reagira sa spojem opće formule Z1-Rc (III) u kojoj je Rc definiran kao zahtjevima 1 do 6, a Z je izlazna skupina, ili b) za pripravu spojeva opće formule I, u kojoj je Rd prema potrebi supstituirana alkiloksi skupina koja je spomenuta u zahtjevima 1 do 6, spoj opće formule [image] u kojoj su Ra, Rb, Rc i X definirani kao zahtjevima 1 do 6, reagira sa spojem opće formule Z2-Rd' (V) u kojoj Rd' predstavlja C1-4-alkilnu skupinu, metilnu skupinu supstituiranu s 1 do 3 atoma fluora, etilnu skupinu supstituiranu s 1 do 5 atoma fluora, C2-4-alkilnu skupinu supstituiranu s jednim ostatkom R6 ili R7, pri čemu su R6 i R7 definirani kao što je spomenuto u zahtjevima 1 do 6, C1-4-alkilnu skupinu supstituiranu s pirolidinilnom, piperidinilnom ili homopiperidinilnom skupinom koja je u 1-položaju supstituirana s ostatkom R8, ili C1-4-alkilnu skupinu supstituiranu s morfolinilnom skupinom koja je u položaju 4 supstituirana s ostatkom R8, pri čemu je R8 u svakom slučaju definiran kao u zahtjevima 1 do 6, i Z je izlazna skupina, ili c) za pripravu spojeva opće formule I, u kojoj R2 predstavlja alkiloksi skupinu spomenutu u zahtjevima 1 do 6, koja je prema potrebi supstituirana s amino, alkilamino ili dialkilamino skupinom ili s prema potrebi supstituiranom heterocikličkom skupinom povezanom preko imino dušikovog atoma, spoj opće formule [image] u kojoj su Ra, Rb, Rc i X definirani kao u zahtjevima 1 do 6, a Z je izlazna skupina, reagira s amonijakom, s odgovarajućim i prema potrebi supstituiranim alkilaminom, dialkilaminom ili s imino spojem ili njihovim prikladnim solima ili derivatima, ili d) za pripravu spojeva opće formule I, u kojoj Rd predstavlja hidroksi skupinu, sa spoja opće formule VII se odcijepi zaštitnu skupinu [image] u kojoj su Ra, Rb, Rc i X definirani kao u zahtjevima 1 do 6, a Rd'' je skupina koja se može prevesti u hidroksi skupinu, ili e) za pripravu spojeva opće formule I, u kojoj Rc sadrži -NH skupinu, sa spoja opće formule VIII se odcijepi zaštitnu skupinu [image] u kojoj su Ra, Rb, Rd i X definirani kao u zahtjevima 1 do 6, a Rc' ima značenje dato u zahtjevima 1 do 6, pod uvjetom da Rc sadrži zaštićen dušikov atom, ili f) za pripravu spojeva opće formule I, u kojoj Rc sadrži alkilnu skupinu supstituiranu s prema potrebi supstituiranom amino, alkilamino ili dialkilamino skupinom ili s prema potrebi supstituiranom heterocikličkom skupinom povezanom preko dušikovog atoma, spoj opće formule [image] u kojoj su Ra, Rb, Rd i X definirani kao u zahtjevima 1 do 6, a Z je izlazna skupina, i Rc'' ima značenje dato u zahtjevima 1 do 6, pod uvjetom da je vodikov atom, povezan na alifatski ugljikov, atom zamijenjen sa skupinom Z3, reagira s amonijakom, s odgovarajućim, prema potrebi supstituiranim alkilaminom, dialkilaminom ili imino spojem ili njihovim prikladnim solima ili derivatima, i po želji, tako dobiven spoj opće formule I, koji sadrži amino, alkilamino ili imino skupinu, prevede se aciliranjem, cijaniranjem ili sulfoniliranjem u odgovarajući acilni, cijano ili sulfonilni spoj opće formule I, i/ili tako dobiven spoj opće formule I, koji sadrži amino, alkilamino ili imino skupinu prevede se alkiliranjem ili redukcijskim alkiliranjem u odgovarajući alkilni spoj opće formule I, i/ili tako dobiven spoj opće formule I, koji sadrži klor-C1-4-alkilsulfonilnu ili brom-C1-4-alkilsulfonilnu skupinu, prevede se reakcijom s aminom u odgovarajući amino-C1-4-alkilsulfonilni spoj, i/ili tako dobiven spoj opće formule I, koji sadrži terc-butiloksikarbonilamino, N-alkil-N-(terc-butiloksikarbonil)-amino ili N-terc-butiloksikarbonilimino skupinu, prevede se obradom s kiselinom u odgovarajući amino, alkilamino ili imino spoj opće formule I, i/ili prema potrebi, sve upotrijebljene zaštitne skupine u gore opisanim reakcijama se ponovno odcijepe, i/ili po želji, tako dobiven spoj opće formule I rastavi se na svoje stereoizomere, i/ili tako dobiven spoj opće formule I prevede se u njegovu sol, naročito za farmaceutsku primjenu prevede se njegovu fiziološki podnošljivu sol.11. Process for the preparation of compounds of general formula I according to claims 1 to 6, characterized in that a) a compound of the general formula [image] wherein Ra, Rb, Rd and X are defined as in claims 1 to 6, reacts with a compound of the general formula Z1-Rc (III) wherein Rc is defined as in claims 1 to 6 and Z is a leaving group, or b) for the preparation of compounds of the general formula I, in which Rd is optionally substituted by the alkyloxy group mentioned in claims 1 to 6, compound of the general formula [image] wherein Ra, Rb, Rc and X are defined as in claims 1 to 6, reacts with a compound of the general formula Z2-Rd' (V) in which Rd' represents a C1-4-alkyl group, a methyl group substituted with 1 to 3 fluorine atoms, an ethyl group substituted with 1 to 5 fluorine atoms, a C2-4-alkyl group substituted with one residue R6 or R7, where R6 are and R7 defined as mentioned in claims 1 to 6, a C1-4-alkyl group substituted with a pyrrolidinyl, piperidinyl or homopiperidinyl group which is substituted in the 1-position with the residue R8, or a C1-4-alkyl group substituted with a morpholinyl group which is substituted in the 4-position with the residue R8, wherein R8 is in each case defined as in claims 1 to 6, and Z is a leaving group, or c) for the preparation of compounds of the general formula I, in which R2 represents the alkyloxy group mentioned in claims 1 to 6, which is optionally substituted with an amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group connected via an imino nitrogen atom, a compound of the general formula [image] wherein Ra, Rb, Rc and X are defined as in claims 1 to 6 and Z is a leaving group, reacts with ammonia, with a suitable and optionally substituted alkylamine, dialkylamine or with an imino compound or their suitable salts or derivatives, or d) for the preparation of compounds of the general formula I, in which Rd represents a hydroxy group, the protecting group is cleaved from the compound of the general formula VII [image] wherein Ra, Rb, Rc and X are defined as in claims 1 to 6 and Rd'' is a group which can be converted to a hydroxy group, or e) for the preparation of compounds of the general formula I, in which Rc contains an -NH group, the protective group is cleaved from the compound of general formula VIII [image] wherein Ra, Rb, Rd and X are defined as in claims 1 to 6 and Rc' has the meaning given in claims 1 to 6, provided that Rc contains a protected nitrogen atom, or f) for the preparation of compounds of the general formula I, in which Rc contains an alkyl group substituted with an optionally substituted amino, alkylamino or dialkylamino group or with an optionally substituted heterocyclic group connected via a nitrogen atom, a compound of the general formula [image] wherein Ra, Rb, Rd and X are defined as in claims 1 to 6 and Z is a leaving group, and Rc'' has the meaning given in claims 1 to 6, provided that the hydrogen atom attached to the aliphatic carbon atom replaced with group Z3, reacts with ammonia, with a suitable, optionally substituted alkylamine, dialkylamine or imino compound or their suitable salts or derivatives, and optionally, the thus obtained compound of the general formula I, which contains an amino, alkylamino or imino group, is converted by acylation, cyanation or sulfonylation into the corresponding acyl, cyano or sulfonyl compound of the general formula I, and/or the thus obtained compound of the general formula I, which contains an amino, alkylamino or imino group, is converted by alkylation or reductive alkylation into the corresponding alkyl compound of the general formula I, and/or the thus obtained compound of the general formula I, which contains a chloro-C1-4-alkylsulfonyl or bromo-C1-4-alkylsulfonyl group, is converted by reaction with an amine into the corresponding amino-C1-4-alkylsulfonyl compound, and/or The thus obtained compound of the general formula I, which contains a tert-butyloxycarbonylamino, N-alkyl-N-(tert-butyloxycarbonyl)-amino or N-tert-butyloxycarbonylimino group, is converted by treatment with an acid into the corresponding amino, alkylamino or imino compound of the general formula I , and/or if necessary, all protective groups used in the reactions described above are cleaved off again, and/or if desired, the thus obtained compound of the general formula I is separated into its stereoisomers, and/or the thus obtained compound of the general formula I is translated into its salt, especially for pharmaceutical use, its physiologically tolerable salt is translated.
HR20040898A 2002-03-30 2004-09-29 4-(n-phenylamino)-quinazolines/quinolines as tyrosine kinase inhibitors HRP20040898A2 (en)

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DE10214412A DE10214412A1 (en) 2002-03-30 2002-03-30 Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and process for their preparation
DE2002131711 DE10231711A1 (en) 2002-07-13 2002-07-13 New 4-amino-quinazoline or quinoline derivatives, are tyrosine kinase-mediated signal transduction inhibitors useful e.g. for treating tumors or respiratory or gastrointestinal diseases
PCT/EP2003/003062 WO2003082290A1 (en) 2002-03-30 2003-03-25 4-(n-phenylamino)-quinazolines / quinolines as tyrosine kinase inhibitors

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