DK3344616T3 - Substituerede aminotriazoler til anvendelse som humane chitinase-hæmmere - Google Patents

Substituerede aminotriazoler til anvendelse som humane chitinase-hæmmere Download PDF

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DK3344616T3
DK3344616T3 DK16767368.0T DK16767368T DK3344616T3 DK 3344616 T3 DK3344616 T3 DK 3344616T3 DK 16767368 T DK16767368 T DK 16767368T DK 3344616 T3 DK3344616 T3 DK 3344616T3
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alkyl
aryl
heteroaryl
nhc
haloalkyl
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DK16767368.0T
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Marzena Mazur
Robert Koralewski
Sylwia Olejniczak
Wojciech J Czestkowski
Jacek P Olczak
Agnieszka Bartoszewicz
Michal L Kowalski
Bartlomiej Borek
Michal C Piotrowicz
Adam A Golebiowski
Elzbieta Pluta
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Oncoarendi Therapeutics Sa
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Claims (73)

1. Forbindelse repræsenteret ved formlen (I),
hvor: W er halo, (Ci-C3)alkyl, (Ci-C3)alkoxy- eller (Ci-C3)alkylthio-; X er en enkeltbinding, -CH2-, -CH2CH2-, -CH=CH-, -C((Ci-C3)alkyl)2- eller -C(O)-; Y er en enkeltbinding, -CH-, -CHCH2-, -CH2CH-, -C=CH-, -CH=C-, -N-, -O-, - OCH2-, -S(O)- eller - S(O)2-; hvis Y er en enkeltbinding, -O-, -OCH2-, -S(O)- eller -S(O)2-, så er R1 fraværende; R1 er H, OH, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, - C(O)aryl, -C(O)heteroaryl, -C(O)aryl(Ci-C6)alkyl, -C(O)heteroaryl(Ci-C6)alkyl, - S(O)2(Ci-C6)alkyl, -S(O)2aryl, -S(O)2heteroaryl, -S(O)2aryl(Ci-C6)alkyl, - S(O)2heteroaryl(Ci-C6)alkyl, -CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), - C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), - C(O)NH2, -C(O)NHOH, -C(O)NHCN, -C(O)NH((Ci-C6)alkyl), -C(O)N((Ci-C6)alkyl)2, - C(O)NH(aryl(Ci-C6)alkyl), -C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, -C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -C(O)NH((Ci-C6)haloalkyl), -C(O)N((Ci-C6)haloalkyl)2, -S(O)2NH2, -S(O)2NH((Ci-C6)alkyl), -S(O)2NH((Ci-C6)haloalkyl), -S(O)2NH(aryl), - S(O)2NH(heteroaryl(Ci-C6)alkyl), -S(O)2NH(heteroaryl), -S(O)2N((Ci-C6)alkyl)2, - S(O)2NHC(O)(Ci-C6)alkyl, -S(O)2NHC(O)(Ci-C6)haloalkyl, -S(O)2NHC(O)aryl, - S(O)2NHC(O)aryl(Ci-C6)alkyl, -S(O)2NHC(O)heteroaryl, -S(O)2NHC(O)heteroaryl(Ci-C6)alkyl, -NHS(O)2(Ci-C6)alkyl, -NHS(O)2aryl, -NHS(O)2(Ci-C6)haloalkyl, - NHS(O)2aryl(Ci-C6)alkyl, -NHS(O)2heteroaryl, -NHS(O)2heteroaryl(Ci-C6)alkyL - NHC(O)((Ci-C6)alkyl), -
NHC(O)((Ci-C6)haloalkyl), -NHC(O)(aryl), -NHC(O)(aryl(Ci-C6)alkyl), - NHC(O)(heteroaryl), -NHC(O)(heteroaryl(Ci-C6)alkyl), -NHC(O)NH(Ci-C6)alkyl, -NHC(O)NH(aryl), -NHC(O)NH(aryl(Ci-C6)alkyl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heteroaryl(Ci-C6)alkyl), -C(O)NHS(O)2(Ci-C6)alkyl, - C(O)NHS(O)2aryl, C(O)NHS(O)2((Ci-C6)haloalkyl), -C(O)NHS(O)2(aryl(Ci-C6)alkyl), - C(O)NHS(O)2heteroaryl, -C(O)NHS(O)2(heteroaryl(Ci-C6)alkyl), -P(O)(OH)2, -((Ci-Ce)alkylen)C(O)OH, -((Ci-C6)alkylen)C(O)O(Ci-C6)alkyl, -NH2, -NH(Ci-C6)alkyl, - N((Ci-C6)alkyl)2, -NC, -CN, -C(S)NH2, -NHC(O)NH2, -CeCH, (Ci-C6)alkylthio-, (Ci-C6)mercaptoalkyl- eller -C(O)heterocyclyl; Z er -CH-, -C(0)-, -C((Ci-C3)alkyl)- eller -C(=CH2)-; hvis Z er -C(0)-, så er R2 fraværende, R2 er H, OH, halo, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci- C6)alkoxy(Ci-C6)alkyl, -CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), -C(O)O(heteroaryl), - C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -C(O)NHOH, -C(O)NHCN, -C(O)NH2, -C(O)NH((Ci-C6)alkyl), -C(O)N((Ci-C6)alkyl)2, -C(O)NH(aryl(Ci-C6)alkyl), - C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, - C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -C(O)NH((Ci-C6)haloalkyl), -C(O)N((Ci-C6)haloalkyl)2, -S(O)2NH2, -S(O)2NH((Ci-C6)alkyl), - S(O)2NH((Ci-C6)haloalkyl), -S(O)2NH(aryl), -S(O)2NH(heteroaryl(Ci-C6)alkyl), - S(O)2NH(heteroaryl), -S(O)2NH(heteroaryl(Ci-C6) alkyl), -S(O)2N((Ci-C6)alkyl)2, - S(O)2NHC(O)(Ci-C6)alkyl, -S(O)2NHC(O)(Ci-C6)haloalkyl, -S(O)2NHC(O)aryl, -S(O)2NHC(O)aryl(Ci-C6)alkyl, -S(O)2NHC(O)heteroaryl, - S(O)2NHC(O)heteroaryl(Ci-C6)alkyl, -NHS(O)2(Ci-C6)alkyl, -NHS(O)2aryl, NHS(O)2(Ci-C6)haloalkyl, - NHS(O)2aryl(Ci-C6)alkyl, -NHS(O)2heteroaryl, -NHS(O)2heteroaryl(Ci-C6)alkyl, - NHC(O)((Ci-C6)alkyl), -NHC(O)((Ci- C6)haloalkyl), -NHC(O)(aryl), -NHC(O)(aryl(Ci-C6)alkyl), -NHC(O)(heteroaryl), -NHC(O)(heteroaryl(Ci-C6)alkyl), -NHC(O)NH(Ci-C6)alkyl, -NHC(O)NHaryl, -NHC(O)NH(aryl(Ci-C6)alkyl), -NHC(O)NH(heteroaryl), - NHC(O)NH(heteroaryl(Ci-C6)alkyl), -C(O)NHS(O)2(Ci-C6)alkyl, -C(O)NHS(O)2aryl, C(O)NHS(O)2((Ci-C6)haloalkyl), -C(O)NHS(O)2(aryl(Ci- C6)alkyl), - C(O)NHS(O)2heteroaryl, -C(O)NHS(O)2(heteroaryl(Ci-C6)alkyl), -P(O)(OH)2, aryl(Ci-C6)alkyl, (C3-C7)cycloalkyl(Ci-C6)alkyl-, -NC, -CN, -C(S)NH2, -NHC(O)NH2, -C=CH, (Ci-C6)alkylthio-, (Ci-C6)mercaptoalkyl- eller -C(O)heterocyclyl; eller R1 og R2, taget sammen med de intervenerende atomer, danner en carbocyklisk eller heterocyklisk ring; R3 erH, (Ci-C3)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, -NC, -CN, -C(S)NH2, -NHC(O)NH2 eller -C=CH; R4 is H, (Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, (Ci-C3)alkoxy(Ci-C3)alkyl- eller (Ci-C4)hydroxyalkyl; R5 is H, halo, -NO2, -CN, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -OH, (Ci-C6)alkoxy, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkoxy, -SH, (Ci-C3)alkylthio(Ci-C3)alkyl, -NC, -C(S)NH2, -NHC(O)NH2 eller-C^CH; og R6 er H, halo, -OH, -NH2 eller -SH; eller R6, taget sammen med det carbonatom, der bærer det, repræsenterer -C(O)-; hvor: en hvilken som helst forekomst af alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylen, heterocyclyl, cycloalkyl, alkoxy, alkylthio, haloalkyl eller hydroxyalkyl eventuelt er substitueret med en eller flere substituenter uafhængigt valgt fra gruppen bestående af-OH, halo, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -CN, -NO2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl, -C(O)OH, -C(O)O(Ci-C6)alkyl, - C(O)NH2, -C(O)NH(Ci-C6)alkyl og -C(O)N((Ci-C6)alkyl)2; eller et farmaceutisk acceptabelt salt, solvat, tautomer, stereoisomer eller polymorf deraf.
2. Forbindelse ifølge krav 1, hvor: W er halo, (Ci-C3)alkyl, (Ci-C3)alkoxy- eller (Ci-C3)alkylthio-; X er en enkeltbinding, -CH2-, -CH2CH2-, -CH=CH- eller -C(O)-; Y er en enkeltbinding, -CH-, -CHCH2-, -CH2CH-, -C=CH-, -CH=C-, -N-, -O-, -S(O)- eller -S(O)2-; hvis Y er en enkeltbinding, -O-, -S(O)- eller -S(O)2-, så er R1 fraværende; R1 erH, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -C(O)aryl, - C(O)heteroaryl, -C(O)aryl(Ci-C6)alkyl, -C(O)heteroaryl(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)2aryl, -S(O)2heteroaryl, -S(O)2aryl(Ci-C6)alkyl, -S(O)2heteroaryl(Ci-C6)alkyl, - CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -C(O)NH2, -C(O)NHOH, -C(O)NHCN, - C(O)NH((Ci-C6)alkyl), -C(O)N((Ci-C6)alkyl)2, -C(O)NH(aryl(Ci-C6)alkyl), - C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, - C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -C(O)NH((Ci-C6)haloalkyl), -C(O)N((Ci-C6)haloalkyl)2, -S(O)2NH2, -S(O)2NH((Ci-C6)alkyl), - S(O)2NH((Ci-C6)haloalkyl), -S(O)2NH(aryl), -S(O)2NH(heteroaryl(Ci-C6)alkyl), - S(O)2NH(heteroaryl), -S(O)2N((Ci-C6)alkyl)2, -S(O)2NHC(O)(Ci-C6)alkyl, - S(O)2NHC(O)(Ci-C6)haloalkyl, -S(O)2NHC(O)aryl, -S(O)2NHC(O)aryl(Ci-C6)alkyl, -S(O)2NHC(O)heteroaryl, -S(O)2NHC(O)heteroaryl(Ci-C6)alkyl, -NHS(O)2(Ci-C6)alkyl, - NHS(O)2aryl, -NHS(O)2(Ci-C6)haloalkyl, -NHS(O)2aryl(Ci-C6)alkyl, -NHS(O)2heteroaryl, -NHS(O)2heteroaryl(Ci-C6)alkyl± -NHC(O)((Ci-C6)alkyl), -NHC(O)((Ci-C6)haloalkyl), -NHC(O)(aryl), -NHC(O)(aryl(Ci-C6)alkyl), -NHC(O)(heteroaryl), -NHC(O)(heteroaryl(Ci-C6)alkyl), -NHC(O)NH(Ci-C6)alkyl, -NHC(O)NH(aryl), -NHC(O)NH(aryl(Ci-C6)alkyl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heteroaryl(Ci-C6)alkyl), -C(O)NHS(O)2(Ci-C6)alkyl, -C(O)NHS(O)2aryl, C(O)NHS(O)2((Ci-C6)haloalkyl), -C(O)NHS(O)2(aryl(Ci-C6)alkyl), - C(O)NHS(O)2heteroaryl, -C(O)NHS(O)2(heteroaryl(Ci-C6)alkyl), -P(O)(OH)2, -((Ci-C6)alkylen)C(O)OH, -((Ci-C6)alkylen)C(O)O(Ci-C6)alkyl, -NH2, -NH(Ci-C6)alkyl, - N((Ci-C6)alkyl)2, -NC, -CN, -C(S)NH2, -NHC(O)NH2, -CeCH, (Ci-C6)alkylthio-, (Ci-C6)mercaptoalkyl- eller -C(O)heterocyclyl; Z er -CH-, -C(O)- eller -C((Ci-C3)alkyl)-; hvis Z er -C(O)-, så er R2 fraværende, R2 er H, halo, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci- C6)alkyl, - CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -C(O)NHOH, -C(O)NHCN, -C(O)NH2, - C(O)NH((Ci-C6)alkyl), -C(O)N((Ci-C6)alkyl)2, -C(O)NH(aryl(Ci-C6)alkyl), - C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, - C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -C(O)NH((Ci-C6)haloalkyl), -C(O)N((Ci-C6)haloalkyl)2, -S(O)2NH2, -S(O)2NH((Ci-C6)alkyl), - S(O)2NH((Ci-C6)haloalkyl), - S(O)2NH(aryl), -S(O)2NH(heteroaryl(Ci-C6)alkyl), - S(O)2NH(heteroaryl), -S(O)2NH(heteroaryl(Ci-C6) alkyl), -S(O)2N((Ci-C6)alkyl)2, - S(O)2NHC(O)(Ci- C6)alkyl, -S(O)2NHC(O)(Ci-C6)haloalkyl, -S(O)2NHC(O)aryl, -S(O)2NHC(O)aryl(Ci-C6)alkyl, -S(O)2NHC(O)heteroaryl, -S(O)2NHC(O)heteroaryl(Ci-C6)alkyl, -NHS(O)2(Ci-C6)alkyl, -NHS(O)2aryl, NHS(O)2(Ci-C6)haloalkyl, - NHS(O)2aryl(Ci-C6)alkyl, -NHS(O)2heteroaryl, -NHS(O)2heteroaryl(Ci-C6)alkyl, - NHC(O)((Ci-C6)alkyl), -NHC(O)((Ci-C6)haloalkyl), -NHC(O)(aryl), -NHC(O)(aryl(Ci-C6)alkyl), -NHC(O)(heteroaryl), -NHC(O)(heteroaryl(Ci-C6)alkyl), -NHC(O)NH(Ci-C6)alkyl, -NHC(O)NH-aryl, -NHC(O)NH(aryl(Ci-C6)alkyl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heteroaryl(Ci-C6)alkyl), -C(O)NHS(O)2(Ci-C6)alkyl, - C(O)NHS(O)2aryl, C(O)NHS(O)2((Ci-C6)haloalkyl), -C(O)NHS(O)2(aryl(Ci-C6)alkyl), - C(O)NHS(O)2heteroaryl, -C(O)NHS(O)2(heteroaryl(Ci-C6)alkyl), - P(O)(OH)2, aryl(Ci-C6)alkyl, (C3-C7)cycloalkyl(Ci-C6)alkyl-, -NC, -CN, -C(S)NH2, -NHC(O)NH2, -C=CH, (Ci-C6)alkylthio-, (Ci-C6)mercaptoalkyl-eller - C(O)heterocyclyl; R3 erH, (Ci-C3)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, -NC, -CN, -C(S)NH2, -NHC(O)NH2 eller -C=CH; R4 is H, (Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, (Ci-C3)alkoxy(Ci-C3)alkyl- eller (Ci-C4)hydroxyalkyl; R5 er H, halo, -NO2, -CN, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -OH, (Ci-C6)alkoxy, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci- C6)alkyl, (Ci-C6)haloalkoxy, -SH, (Ci-C3)alkylthio(Ci-C3)alkyl, -NC, -C(S)NH2, -NHC(O)NH2 eller-C^CH; og R6 er H, halo, -OH, -NH2 eller -SH; eller R6, taget sammen med det carbonatom, der bærer det, repræsenterer -C(O)-; hvor: en hvilken som helst forekomst af alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylen, heterocyclyl, cycloalkyl, alkoxy, alkylthio, haloalkyl eller hydroxyalkyl eventuelt er substitueret med en eller flere substituenter uafhængigt valgt fra gruppen bestående af-OH, halo, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -CN, -NO2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl, -C(O)OH, -C(O)O(Ci-C6)alkyl, - C(O)NH2, -C(O)NH(Ci-C6)alkyl og -C(O)N((Ci-C6)alkyl)2.
3. Forbindelse ifølge krav 1 eller 2, hvor W er fluor, chlor, brom, methyl eller methoxy.
4. Forbindelse ifølge krav 3, hvor W er chlor eller brom.
5. Forbindelse ifølge krav 4, hvor W er chlor.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R6 er H eller -OH.
7. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R6 er H.
8. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor X er en enkeltbinding, - CH2- eller -C(O)-.
9. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor X er -CH2-,
10. Forbindelse ifølge et hvilket som helst af kravene 1 -9, hvor Y er en enkeltbinding, -CH-, -N-, -O- eller - S(O)2-,
11. Forbindelse ifølge et hvilket som helst af kravene 1 -9, hvor Y er en enkeltbinding, -O- eller -S(O)2-,
12. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvorY er en enkeltbinding.
13. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvorY er -O-.
14. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvorY er -CH- eller -N-.
15. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvorY er -CH-.
16. Forbindelse ifølge et hvilket som helst af kravene 1-9, hvorY er N.
17. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, -C(O)aryl, -C(O)heteroaryl, -C(O)aryl(Ci-C6)alkyl, -C(O)heteroaryl(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)2aryl, -S(O)2heteroaryl, -S(O)2aryl(Ci-C6)alkyl, -S(O)2heteroaryl(Ci-C6)alkyl, -CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -C(O)NH2, -C(O)NHOH, -C(O)NHCN, -C(O)NH((Cr C6)alkyl), -C(O)N((Ci-C6)alkyl)2, -C(O)NH(aryl(Ci-C6)alkyl), -C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, -C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -((Ci-C6)alkylen)C(O)OH, -((Ci-C6)alkylen)C(O)O(Ci-C6)alkyl, -NH2, -NH(Ci-C6)alkyl, -N((Ci-C6)alkyl)2 eller-C(O)heterocyclyl.
18. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er H, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, -C(O)(Ci-C6)alkyl, - C(O)aryl, - C(O)heteroaryl, -C(O)aryl(Ci-C6)alkyl, -C(O)heteroaryl(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)2aryl, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -((Ci-C6)alkylen)C(O)OH, -((Ci-C6)alkylen)C(O)O(Ci-C6)alkyl eller -C(O)heterocyclyl.
19. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er H, (Ci-C6)alkyl, (Ci-C6)alkoxy, -C(O)(Ci-C6)alkyl, -S(O)2(Ci-C6)alkyl, -S(O)2aryl, -C(O)O(Ci-C6)alkyl, -((Ci-C6)alkylen)C(O)OH eller -((Ci-C6)alkylen)C(O)O(Ci-C6)alkyl.
20. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er H eller (Ci-C6)alkyl.
21. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er -C(O)heterocyclyl valgt fra gruppen bestående af
22. Forbindelse ifølge et hvilket som helst af kravene 14-16, hvor R1 er -CH2CO2H eller -CH2C(O)O(Ci-C6)alkyl.
23. Forbindelse ifølge et hvilket som helst af kravene 1-22, hvor Z er -C(O)-.
24. Forbindelse ifølge et hvilket som helst af kravene 1-22, hvor Z er -C((Ci-C3)alkyl)-.
25. Forbindelse ifølge et hvilket som helst af kravene 1-22, hvor Z er -CH-.
26. Forbindelse ifølge krav 24 eller 25, hvor R2 er H, halo, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-C6)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, -CO2H, -C(O)O(Ci-C6)alkyl, -C(O)O(aryl), - C(O)O(heteroaryl), -C(O)O(aryl(Ci-C6)alkyl), -C(O)O(heteroaryl(Ci-C6)alkyl), -C(O)NH2, - C(O)NH((Ci-C6)alkyl), -C(O)N((Ci-C6)alkyl)2, -C(O)NH(aryl(Ci-C6)alkyl), -C(O)N(aryl(Ci-C6)alkyl)2, -C(O)NH(aryl), -C(O)N(aryl)((Ci-C6)alkyl), -C(O)N(aryl)2, -C(O)N(Ci-C6)alkyl)(aryl(Ci-C6)alkyl), -C(O)N(aryl)(aryl(Ci-C6)alkyl), -C(O)NH((Ci-C6)haloalkyl), - C(O)N((Ci-C6)haloalkyl)2, aryl(Ci-C6)alkyl, (C3-C7)cycloalkyl(Ci-C6)alkyl- eller - C(O)heterocyclyl.
27. Forbindelse ifølge krav 24 eller 25, hvor R2 er H, halo, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci-Ce)hydroxyalkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, -CO2H, -C(O)O(Ci-C6)alkyl, -C(O)NH2, -C(O)NH((Ci-C6)alkyl), aryl(Ci-C6)alkyl eller (C3-C7)cycloalkyl(Ci-C6)alkyl-.
28. Forbindelse ifølge krav 24 eller 25, hvor R2 er aryl(Ci-C6)alkyl eller (C3-C7)cycloalkyl(Ci-C6)alkyl-, eventuelt substitueret ved en hvilken som helst position af -OH, halo, -NH2, (Ci-C6)alkyl, (Ci-C6)haloalkyl eller (Ci-C6)alkoxy.
29. Forbindelse ifølge krav 24 eller 25, hvor R2 er H, (Ci-C6)alkyl eller (Ci-C6)alkoxy(Ci-C6)alkyl.
30. Forbindelse ifølge krav 24 eller 25, hvor R2 er -C(O)heterocyclyl valgt fra gruppen bestående af
31. Forbindelse ifølge krav 24 eller 25, hvor R2 er halo(1,4-phenylen)methyl.
32. Forbindelse ifølge et hvilket som helst af kravene 1-31, hvor R3 er H eller (Ci-C3)alkyl.
33. Forbindelse ifølge et hvilket som helst af kravene 1-31, hvor R3 er H.
34. Forbindelse ifølge et hvilket som helst af kravene 1-33, hvor R4 er H eller (Ci- C3)alkyl.
35. Forbindelse ifølge et hvilket som helst af kravene 1-33, hvor R4 er H.
36. Forbindelse ifølge et hvilket som helst af kravene 1-35, hvor R5 er H eller (Ci- C3)alkyl.
37. Forbindelse ifølge et hvilket som helst af kravene 1-35, hvor R5 er H.
38. Forbindelse ifølge et hvilket som helst af kravene 1-37 repræsenteret ved formlen (I'):
39. Forbindelse ifølge krav 1, hvor: W er brom eller chlor; X er en enkeltbinding, -CH2- eller -C(O)-; Y er en enkeltbinding, -CH-, -N-, -O- eller -S(O)2-; hvis Y er en enkeltbinding, -O- eller -S(O)2-, så er R1 fraværende,
R1 er H, methyl, isobutyl, methoxy, acetyl, methoxycarbonyl, methansulfonyl, p-toluensulfonyl, methoxycarbonylmethyl eller carboxymethyl; Z er -CH-, -C(O)- eller -C(CH3)-; hvis Z er -C(O)-, så er R2 fraværende, R2 er H, methyl, ethyl, isopropyl, isobutyl, -C(O)NH2, -C(O)NHMe, -CH2OH, -CH2OCH3, - CH2OCH2CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CO2H, -CO2CH2CH3, -OCH3, -F, -CH2-(p-chlorphenyl) eller -CH2-cyclohexyl; R3, R4 og R5 er hver H; og R6 er H eller OH.
40. Forbindelse repræsenteret ved formlen (II),
hvor: W er halo, (Ci-C3)alkyl, (Ci-C3)alkoxy- eller (Ci-C3)alkylthio-; X er en enkeltbinding, -CH2-, -CH2CH2-, -CH=CH-, -C((Ci-C3)alkyl)2-, -C(O)-, -CH2O-, -CH2NH- eller -CH2N((Ci-C3)alkyl)-, hvor når X er -CH2O-, -CH2NH- eller -CH2N((Ci-C3)alkyl)-, så er O- eller N-atomet kovalent bundet til Ring A; Ring A repræsenterer en eventuelt substitueret aryl- eller heteroarylring; R3 er H, (Ci-C3)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, -NC, -CN, -C(S)NH2, -NHC(O)NH2 eller -C=CH; R4 er H, (Ci-C3)alkyl, (Ci-C3)alkylthio(Ci-C3)alkyl, (Ci-C6)haloalkyl, (Ci- C3)alkoxy(Ci-C3)alkyl- eller (Ci-C4)hydroxyalkyl; R5 er H, halo, -NO2, -CN, (Ci-C6)alkyl, (Ci-C6)haloalkyl, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -OH, (Ci-C6)alkoxy, hydroxy(Ci-C6)alkyl, (Ci-C6)alkoxy(Ci-C6)alkyl, (Ci-C6)haloalkoxy, -SH, (Ci-C3)alkylthio(Ci-C3)alkyl, -NC, -C(S)NH2, -NHC(O)NH2 eller-C^CH; og R6 er H, halo, -OH, -NH2 eller -SH; eller
R6, taget sammen med det carbonatom, der bærer det, repræsenterer -C(O)-; hvor: en hvilken som helst forekomst af alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkylen, heterocyclyl, cycloalkyl, alkoxy, alkylthio, haloalkyl eller hydroxyalkyl eventuelt er substitueret med en eller flere substituenter uafhængigt valgt fra gruppen bestående af-OH, halo, -NH2, -NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -CN, -NO2, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)alkoxy, aryl, heteroaryl, aryl(Ci-C6)alkyl, heteroaryl(Ci-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl, -C(O)OH, -C(O)O(Ci-C6)alkyl, - C(O)NH2, -C(O)NH(Ci-C6)alkyl og -C(O)N((Ci-C6)alkyl)2; eller et/en farmaceutisk acceptabelt/acceptabel salt, solvat, tautomer, stereoisomer eller polymorf deraf.
41. Forbindelse ifølge krav 40, hvor W er fluor, chlor, brom, methyl eller methoxy.
42. Forbindelse ifølge krav 41, hvor W er chlor.
43. Forbindelse ifølge et hvilket som helst af kravene 40-42, hvor R6 er H.
44. Forbindelse ifølge et hvilket som helst af kravene 40-43, hvorX er -CH2O-, -CH2NH-eller - CH2N((Ci-C3)alkyl)-.
45. Forbindelse ifølge krav 44, hvor X er -CH2O- eller -CH2N(CH3)-.
46. Forbindelse ifølge et hvilket som helst af kravene 40-45, hvor R3 er H.
47. Forbindelse ifølge et hvilket som helst af kravene 40-46, hvor R4 er H.
48. Forbindelse ifølge et hvilket som helst af kravene 40-47, hvor R5 er H.
49. Forbindelse ifølge et hvilket som helst af kravene 40-48, hvor Ring A repræsenterer en heteroarylring.
50. Forbindelse ifølge krav 49, hvor Ring A repræsenterer en pyridylring.
51. Forbindelse ifølge et hvilket som helst af kravene 40-48, hvor Ring A repræsenterer en eventuelt substitueret phenylring.
52. Forbindelse ifølge krav 51, hvor Ring A repræsenterer en phenylring substitueret af en eller flere forekomster af halo.
53. Forbindelse ifølge krav 52, hvor Ring A repræsenterer en phenylring substitueret af en eller flere forekomster af chlor.
54. Forbindelse ifølge krav 1 eller krav 40 repræsenteret af en hvilken som helst af de følgende strukturformler:
55. Farmaceutisk sammensætning, der omfatter en terapeutisk virksom mængde af en forbindelse ifølge et hvilket som helst af kravene 1-54; og en farmaceutisk acceptabel bærer.
56. Farmaceutisk sammensætning ifølge krav 55, der endvidere omfatter en terapeutisk virksom mængde af et terapeutisk middel valgt fra gruppen bestående af steroider, membranstabilisatorer, 5L0-hæmmere, leukotriensyntese og receptorhæmmere, hæmmere af IgE-isotype-veksling eller IgE-syntese, IgG-isotype-veksling eller IgG-syntese, β-agonister, tryptase-hæmmere, acetylosalicylsyre, COX-hæmmere, methotrexat, anti-TNF-lægemidler, rituxin og andre B-celle-targeterede midler, THF-targeterede midler, PD4-hæmmere, p38-hæmmere, PDE4-hæmmere og antihistaminer.
57. Forbindelse ifølge et hvilket som helst af kravene 1-54 til anvendelse som hæmmer af sur pattedyr-chitinase i en celle eller et væv.
58. Forbindelse ifølge et hvilket som helst af kravene 1-54 til anvendelse som hæmmer af chitotriosidase i en celle eller et væv.
59. Forbindelse ifølge et hvilket som helst af kravene 1-54 eller en farmaceutisk sammensætning ifølge krav 55 til anvendelse i behandlingen eller forebyggelsen af en sygdom, lidelse eller tilstand forbundet med afvigende ekspression af eller aktivitet for sur pattedyr-chitinase.
60. Forbindelse ifølge et hvilket som helst af kravene 1-54 eller en farmaceutisk sammensætning ifølge krav 55 til anvendelse i behandlingen eller forebyggelsen af en sygdom, lidelse eller tilstand forbundet med afvigende ekspression af eller aktivitet for chitotriosidase.
61. Forbindelser til anvendelse ifølge krav 59 eller 60, hvor sygdommen, forstyrrelsen eller tilstanden er valgt fra gruppen bestående af allergiske sygdomme, akutte og kronisk inflammatoriske sygdomme, autoimmune sygdomme, tandsygdomme, neurologiske sygdomme, metaboliske sygdomme, leversygdomme, nyresygdomme, hudsygdomme, polycystisk ovariesyndrom, endometriose, fibrotiske forstyrrelser, ophobningssygdomme og cancer.
62. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er en allergisk sygdom valgt fra gruppen bestående af astma, allergisk rhinit, sæsonbetinget allergisk rhinit, kronisk rhinosinusitis med eller uden næsepolypper, conjunctivitis, keratoconjunctivitis, sæsonbetinget allergisk conjunctivitis, tørre øjnesyndrom, eosinofil øsofagitis, cøliaki, fødevareallergi, irritabel tarmsyndrom, irritabel tarmsygdom, atopisk eksem, atopisk dermatit, allergisk kontakeksem, eosinofil otitis media, eosinofil pneumoni og lgG4-medierede sygdomme.
63. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er en akut eller kronisk inflammatorisk sygdom valgt fra gruppen bestående af svampesygdomme, parasitinfektioner, cøliaki, mikroskopisk colitis, kronisk obstruktiv pulmonær sygdom (COPD), idiopatisk pulmonær fibrose, interstitielle lungesygdomme, cystisk fibrose, Hermansky-Pudlak syndrom og Alzheimers sygdom.
64. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er en autoimmun sygdom valgt fra gruppen bestående af inflammatorisk tarmsygdom, ulcerativ colitis, Crohns sygdom, rheumatoid arthritis, osteoarthritis, psoriasis, sklerodermi, multipel sklerose, Sjogrens syndrom, atherosklerose og sarkoidose.
65. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er periodontitis.
66. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er en metabolisk sygdom valgt fra gruppen bestående af insulin-afhængig diabetes mellitus og ikke-insulin-afhængig diabetes mellitus.
67. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen, forstyrrelsen eller tilstanden er en leversygdom valgt fra gruppen bestående af nonalkoholisk fedtleversygdom, nonalkoholisk steatohepatitis, hepatitis-C virus-induceret fibrose og cirrose og alkoholisk fibrose.
68. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen er cancer valgt fra gruppen bestående af glioblastom, brystcancer, coloncancer, primær og metastatisk lungecancer, mesotheliom, osteosarkom, malign melanom, ovariecancer, cervixcancer, prostatacancer, levercancer, mavecancer, metastatisk nyrecancer, leukæmi og lymfom.
69. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen er en nyresygdom valgt fra gruppen bestående af nefropati (f.eks. diabetisk nefropati), fokal segmental glomerulosklerose, tubulointerstitiel fibrose, postransplantationsfibrose og retroperitoneal fibrose (Ormonds sygdom).
70. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen er en fibrotisk sygdom.
71. Forbindelser til anvendelse ifølge krav 70, hvor den fibrotiske sygdom er idiopatisk pulmonær fibrose (IPF).
72. Forbindelser til anvendelse ifølge krav 61, hvor sygdommen er en ophobningssygdom valgt fra gruppen bestående af Gauchers sygdom, Fabrys sygdom, lysosomale ophobningssygdomme, Niemann-Picks sygdom, nefropatisk cysteinose og X-bundet globotiaosylceramidose.
73. Forbindelse ifølge et hvilket som helst af kravene 1-54 til anvendelse som hæmmer af chitotriosidase og sur pattedyr-chitinase i en celle eller et væv.
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