DK1781640T3 - 2,4-di(aminophenyl)pyrimidiner som plk-inhibitorer. - Google Patents

2,4-di(aminophenyl)pyrimidiner som plk-inhibitorer. Download PDF

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DK1781640T3
DK1781640T3 DK05777896T DK05777896T DK1781640T3 DK 1781640 T3 DK1781640 T3 DK 1781640T3 DK 05777896 T DK05777896 T DK 05777896T DK 05777896 T DK05777896 T DK 05777896T DK 1781640 T3 DK1781640 T3 DK 1781640T3
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mmol
nr4c
nr8c
aryl
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Jens Juergen Quant
Ulrich Reiser
Heinz Stadtmueller
Harald Engelhardt
Martin Steegmaier
Anke Baum
Ulrich Guertler
Andreas Schoop
Flavio Solca
Rudolf Hauptmann
Stephan Karl Zahn
Lars Herfurth
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Boehringer Ingelheim Int
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Claims (14)

1. Forbindelse ifølge den generelle formel (1),
hvor W betyder N eller C-R2, X betyder -NRla, O eller S, Y betyder CH eller N, Z betyder halogen-Ci-3alkyl-, -COH, -C(=0)-Ci-3alkyl, -C(=0)-C2-3alkenyl, -C(=0)-C2. 3alkynyl, -C(=0)Ci_3alkyl-halogen og pseudohalogen; A er valgt blandt formlerne (i), (ii) eller (iii)
Qi betyder mono- eller bicykliske arylforbindelser; B1, B2, B3 og B4 betyder hhv. uafhængigt af hinanden C-R9Rh, N-R1, O eller S, hvor tilstødende B1 - B4 hhv. ikke betyder -O-; R1 og Rla betyder hhv. uafhængigt af hinanden hydrogen eller methyl, R2 betyder en rest valgt fra gruppen bestående af hydrogen, halogen, -OR4, -C(=0)R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -nr4so2r5, -N=CR4R5, -C=NR', -SR4, -SOR4, -S02R4, -S02NR4R5 og pseudohalogen eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci_5alkyl, C2.5alkenyl, C2.5alkynyl, C3.5cycloalkyl, aryl, hete-rocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)R5, -NR4C(=0)0Rs, -NR4C(=0)NRsR5, -NR4S02Rs, -N=CR4R5, -SR4, -SOR4, -S02R4, -S02NR4Rs, -NR4S02NRsR5, -0S02NRsR5 og pseudohalogen; Ra, Rb, Rc, Rd, Re, Rf, R9 og Rh hhv. uafhængigt af hinanden betyder en rest valgt fra gruppen bestående af hydrogen, halogen, =0, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)R5, -NR4C(=0)0R5, -NR4C(=0)NR5R5, -NR4S02R5, -N=CR4R5, -C=NR', -SR4, -SOR4, -S02R4, -S02NR4R5, -NR4S02NR5R5, -0S02NR5R5 og pseu-dohalogen; eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci-5alkyl, C2.5alkenyl, C2.5alkynyl, C3.5cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af halo gen, R8, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)R5, -NR4C(=0)0R5, -NR4C(=0)NR5R5, -nr4so2r5, -N=CR4R5, -SR4, -SOR4, -so2r4, -S02NR4R5, -NR4S02NR5R5, -0S02NRsR5 og pseudohalogen; og eventuelt kan R9 og Rh, der er placeret på det samme eller tilstødende C-atomer, være forbundet i en hvilken som helst kombination med en fælles mættet eller delvist umættet 3-5-leddet alkylbro, som eventuelt kan indeholde én til to heteroatomer; R1 betyder en rest valgt fra gruppen bestående af hydrogen, =0, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0Rs, -NR4C(=0)NRsR5, -NR4S02R5, -N=CR4R5, -SR4, -SOR4, -S02R4, -S02NR4R5, -NR4S02NR5R5, -0S02NR5R5 og pseudohalogen; eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-5cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af halogen, R8,-N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)R5, -NR4C(=0)0R5, -NR4C(=0)NR5R5, -NR4S02Rs, -N=CR4R5, -SR4, -SOR4, -S02R4, -S02NR4R5, -NR4S02NR5R5, -0S02NRsR5 og pseudohalogen; og eventuelt kan R1, der er placeret på tilstødende N-atomer, være forbundet med hinanden eller R1 kan, sammen med R9 eller Rh, der er placeret på tilstødende C-atomer, være forbundet i en hvilken som helst kombination med en fælles mættet eller delvist umættet 3-5-leddet alkylbro, der eventuelt kan indeholde en til to heteroatomer; R3 er valgt blandt formlerne (iv) - (x),
-L-Q2-Q3-R7 (x) R4, R5 og R5 hhv. uafhængigt af hinanden betyder hydrogen eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci-5alkyl, C2.5alkenyl, C2. 5alkynyl, C3-i0cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af C3_i0cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -SR8, -SOR8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; L en binding eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci-i6alkyl, C2-i6alkenyl, C2-i6alkynyl, C3-i0cycloalkyl, aryl, heterocyclyl og hete- roaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -N02, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -SR8, -SOR8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; Q2 og Q3 hhv. uafhængigt af hinanden betyder en binding eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci_i5alkyl, C2_i5alkenyl, C2. i5alkynyl, C3.i0cycloalkyl, aryl, heterocyclyl og heteroaryl hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, - NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -sr8, -sor8, -so2r8, -so2nr8r9, -nr8so2nr9r10, -0S02NR8R9 og pseudohalogen; R7 betyder hydrogen eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci_i5alkyl, C2_i5alkenyl, C2_i5alkynyl, C3.i0cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen-, N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8COR9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NRC(=0)0NR9R1q, -nr8so2r9, -n=cr8r9, -sr8, -sor8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; R8, R9 og R10 betyder hhv. uafhængigt af hinanden hydrogen eller en rest valgt fra gruppen bestående af eventuelt substitueret Ci-8alkyl, C2.8alkenyl, C2.8alkynyl, C3. locycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen, methyl, ethyl, amino, methylamino, dimethylamino, -OH og pseudohalogen; hvor aryl er monocykliske eller bicykliske ringe med 6-12 kulstofatomer; heteroaryl er monocykliske eller bicykliske ringe, hvilke i stedet for et eller flere kulstofatomer indeholder en eller flere ens eller forskellige heteroatomer; heterocyclyl er mættede eller umættede, ikke aromatiske mono-, bicykliske, forbundne eller spirocykliske bicykliske ringe omfattende 5-12 kulstofatomer, hvilke i stedet for en eller flere kulstofatomer bærer heteroatomer som nitrogen, oxygen eller svovl; eventuelt i form af tautomerer, racemater, enantiomerer, diastereomerer og blandinger, såvel som eventuelt farmakologisk acceptable syreadditionssalte deraf.
2. Forbindelse ifølge krav 1 ifølge den generelle formel (1), hvor W betyder C-R2 og de øvrige rester er som defineret i ovenstående.
3. Forbindelse ifølge krav 1 eller 2, hvor X betyder -NRla eller oxygen, R1 og Rla betyder hydrogen; R3 betyder formel (iv) eller (x),
og de øvrige rester er som defineret i ovenstående.
4. Forbindelse ifølge krav 1-3, hvor Y betyder CH og Qi betyder monocykliske arylforbindelser og de øvrige rester er som defineret i ovenstående.
5. Forbindelse ifølge krav 1-4, hvor Rc betyder en rest valgt fra gruppen bestående af hydrogen, -F, -Cl, methyl og ethyl og de øvrige rester er som defineret i ovenstående.
6. Forbindelse ifølge krav 1-5, hvor Ra og Rb betyder hhv. uafhængigt af hinanden hydrogen eller fluor; eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci-2alkyl, C2alkenyl, C2alkynyl, C3-5cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substi-tuenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af hydrogen, halogen, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)R5, -NR4C(=0)0R5, -NR4C(=0)NRsR5, -NR4S02Rs, -N=CR4Rs, -SR4, -SOR5, -so2r4, -S02NR4Rs, -NR4, -S02NR4R5, -0S02NR4Rs og pseudohalogen og de øvrige rester er som defineret i ovenstående.
7. Forbindelse ifølge krav 1-6, hvor Ra og Rb betyder hhv. uafhængigt af hinanden hydrogen eller fluor og de øvrige rester er som defineret i ovenstående.
8. Forbindelse - eller farmaceutisk virksomme salte deraf - ifølge krav 1-7 som lægemiddel.
9. Forbindelse - eller farmaceutisk virksomme salte deraf - ifølge 1-7 til fremstilling af et lægemiddel med antiproliferativ virkning.
10. Forbindelse - eller farmaceutisk virksomme salte deraf - ifølge krav 1-7 til fremstilling af et lægemiddel med antiproliferativ virkning med en selektiv, kinaseinhiberende virkningsmekanisme.
11. Forbindelse - eller farmaceutisk virksomme salte deraf - ifølge krav 1-7 til fremstilling af et lægemiddel med antiproliferativ virkning med en PLK-inhiberende virkningsmekanisme.
12. Farmaceutisk præparat indeholdende som virkestof én eller flere forbindelser ifølge den generelle formel (1) ifølge et hvilket som helst af krav 1-7 eller fysiologisk acceptable salte deraf eventuelt i kombination med sædvanlige hjælpe- og/eller bærestoffer.
13. Anvendelse af en forbindelse ifølge krav 1 - 7 til fremstilling af et lægemiddel til behandling og/eller forbyggelse af kræft, infektioner, inflammatoriske- og autoimmune sygdomme.
14. Farmaceutisk fremstilling omfattende en forbindelse ifølge den generelle formel (1)
hvor W betyder N eller C-R2, X betyder -NRla, O eller S, Y betyder CH eller N, Z betyder halogen-Ci-3alkyl-, -COH, -C(=0)-Ci-3alkyl, -C(=0)-C2-3alkenyl, -C(=0)-C2. 3alkynyl, -C(=0)Ci_3alkyl-halogen og pseudohalogen; A er valgt blandt formlerne (i), (ii) eller (iii)
Qi betyder mono- eller bicykliske arylforbindelser; B1, B2, B3 og B4 hhv. uafhængigt af hinanden betyder C-R9Rh, N-R1, O eller S, hvor tilstødende B1 - B4 ikke alle betyder -O-; R1 og Rla hhv. uafhængigt af hinanden betyder hydrogen eller methyl, R2 betyder en rest valgt fra gruppen bestående af hydrogen, halogen, -OR4, -C(=0)R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -nr4so2r5, -N=CR4R5, -C=NR', -SR4, -SOR4, -S02R4, -S02NR4Rs og pseudohalogen eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci_5alkyl, C2.5alkenyl, C2.5alkynyl, C3.5cycloalkyl, aryl, hete-rocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og er valgt fra gruppen bestående af halogen, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0Rs, -NR4C(=0)NRsR5, -NR4S02Rs, -N=CR4R5, -SR4, -SOR4, -S02R4, -S02NR4Rs, -NR4S02NRsR5, -0S02NRsR5 og pseudohalogen; Ra, Rb, Rc, Rd, Re, Rf, R9 og Rh hhv. uafhængigt af hinanden betyder en rest valgt fra gruppen bestående af hydrogen, halogen, =0, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0Rs, -NR4C(=0)NRsR5, -NR4S02Rs, -N=CR4R5, -C=NR', -SR4, -SOR4, -S02R4, -S02NR4R5, -NR4S02NR5R5, -0S02NR5R5 og pseu-dohalogen; eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci_5alkyl, C2-6alkenyl, C2-6alkynyl, C3.5cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af halogen, R, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4Rs, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0R5, -NR4C(=0)NRsR5, -nr4so2r5, -n=cr4r5, -sr4, -sor4, -so2r4, -so2nr4r5, -NR4S02NR5R5, -0S02NR5Rs og pseudohalogen; og eventuelt kan R9 og Rb placeret ved det samme eller tilstødende C-atomer være forbundet i en hvilken som helst kombination med en fælles mættet eller delvist umættet 3-5-leddet alkylbro, der kan indeholde en til to he-teroatomer; R1 betyder en rest valgt fra gruppen bestående af hydrogen, =0, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0Rs, -NR4C(=0)NR5R5, -NR4S02R5, -N=CR4R5, -SR4, -SOR4, -S02R4, -S02NR4Rs, -NR4S02NRsR5, -0S02NR5R5 eller en eventuelt mono- eller polysubstitueret rest valgt fra gruppen bestående af Ci_5alkyl, C2. 5alkenyl, C2.5alkynyl, C3.5cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten kan være ens eller forskellig og valgt fra gruppen bestående af halogen, R8, -N02, -OR4, -C(=0)R4, -C(=0)0R4, -C(=0)NR4R5, -NR4R5, -NR4C(=0)Rs, -NR4C(=0)0Rs, - NR4C(=0)NR5R5, -nr4so2r5, -n=cr4r5, -sr4, -sor4, -so2r4, -so2nr4r5, -nr4so2nr5r5, - 0S02NR5R5 og pseudohalogen; og eventuelt kan R1, der er placeret på tilstødende N-atomer, være forbundet med hinanden eller R1 kan, sammen med R9 eller Rh, der er placeret på tilstødende C-atomer, være forbundet i en hvilken som helst kombination med en fælles mættet eller delvist umættet 3-5-leddet alkylbro, der eventuelt kan indeholde en til to heteroatomer; R3 er valgt blandt formlerne (iv) - (x),
R4, R5 og R5 hhv. uafhængigt af hinanden betyder hydrogen eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci_5alkyl, C2.5alkenyl, C2. 5alkynyl, C3_i0cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten/-erne kan være ens eller forskellig og valgt fra gruppen bestående af C3_i0cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -SR8, -SOR8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; L betyder en binding eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci-i6-alkyl, C2-i6-alkenyl, C2-i6-alkynyl, C3-i0-cykloalkyl, aryl, hetero-cyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -SR8, -SOR8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; Q2 og Q3 hhv. uafhængigt af hinanden betyder en binding eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci_i5-alkyl, C2_i5-alkenyl, C2. i6-alkynyl, C3-i0-cykloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8C(=0)R9, -NR8C(=0)0R9, -NR8C(=0)NR9R10, -NR8C(=0)ONR9R10, -nr8so2r9, -n=cr8r9, -sr8, -sor8, -so2r8, -so2nr8r9, -nr8so2nr9r10, -0S02NR8R9 og pseudohalogen; R7 betyder hydrogen eller en rest valgt fra gruppen bestående af eventuelt mono- eller polysubstitueret Ci_i5alkyl, C2_i5alkenyl, C2_i5alkynyl, C3.i0cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen-, N02, -OR8, -C(=0)R8, -C(=0)0R8, -C(=0)NR8R9, -NR8R9, -NR8COR9, -NR8C(=0)0R9, -NR8C(=0)NR9R1q, -NR8C(=0)0NR9R1q, -NR8S02R9, -N=CR8R9, -SR8, -SOR8, -S02R8, -S02NR8R9, -NR8S02NR9R10, -0S02NR8R9 og pseudohalogen; R8, R9 og R10 betyder hhv. uafhængigt af hinanden hydrogen eller en rest valgt fra gruppen bestående af eventuelt substitueret Ci_8alkyl, C2.8alkenyl, C2.8alkynyl, C3. 10cycloalkyl, aryl, heterocyclyl og heteroaryl, hvor substituenten(erne) kan være ens eller forskellig og valgt fra gruppen bestående af halogen, -NH2, -OH og pseudohalogen; hvor aryl er monocykliske eller bicykliske ringe med 6-12 kulstofatomer; heteroaryl er monocykliske eller bicykliske ringe, hvilke i stedet for en eller flere kulstofatomer indeholder en eller flere, ens eller forskellige heteroatomer; heterocyclyl er mættede eller umættede, ikke-aromatiske mono-, bicyckliske, forbundne eller spirocykliske bicykliske ringe omfattende 5-12 kulstofatomer, hvilke i stedet for en eller flere kulstofatomer bærer heteroatomer som nitrogen, oxygen eller svovl; eventuelt i form af tautomerer, racemater, enantiomerer, diastereomerer og blandinger deraf, såvel som eventuelt farmakologisk acceptable syreadditionssalte deraf og mindst et yderligere cytostatisk eller cytotoksisk aktivt stof, eventuelt i form af tautomerer, racemater, enantiomerer, diastereomerer og blandinger deraf, såvel som eventuelt farmakologisk acceptable syreadditionssalte deraf.
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US20090149438A1 (en) 2009-06-11
HUE025285T2 (en) 2016-03-29
TWI421248B (zh) 2014-01-01
RU2007109870A (ru) 2008-11-10
CN101044137A (zh) 2007-09-26
NZ553632A (en) 2010-12-24
US20060148800A1 (en) 2006-07-06
RU2404979C2 (ru) 2010-11-27
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US20090163465A1 (en) 2009-06-25
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