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DK2712358T3 - Pyrrolidinylurea-, pyrrolidinylthiourea- og pyrrolidinylguanidinforbindelser som trka-kinaseinhibitorer - Google Patents

Pyrrolidinylurea-, pyrrolidinylthiourea- og pyrrolidinylguanidinforbindelser som trka-kinaseinhibitorer Download PDF

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DK2712358T3
DK2712358T3 DK12743553.5T DK12743553T DK2712358T3 DK 2712358 T3 DK2712358 T3 DK 2712358T3 DK 12743553 T DK12743553 T DK 12743553T DK 2712358 T3 DK2712358 T3 DK 2712358T3
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alkyl
alkoxy
independently selected
compound
formula
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DK12743553.5T
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Kevin R Condroski
Shelley Allen
Steven W Andrews
James F Blake
Julia Haas
Lily Huang
Yutong Jiang
Timothy Kercher
Gabrielle R Kolakowski
Jeongbeob Seo
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Array Biopharma Inc
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Claims (40)

1. Forbindelse med formlen I:
I eller stereoisomerer, tautomere eller farmaceutisk acceptable salte eller solvater deraf, hvor: Y-B-delen og NH-C(=X)-NH-delen er i frans-konfigurationen; Ra, Rb, Rc og Rd er uafhængigt udvalgt fra H og (1-3C)alkyl; Xer O, S eller NH; R1 er (1-3C alkoxy)(1-6C)alkyl, (trifluormethoxy)(1-6C)alkyl, (1-3C sulfanyl)(1-6C)alkyl, monofluor(1-6C)alkyl, difluor(1-6C)alkyl, trifluor(1-6C)alkyl, tetrafluor(2-6C)alkyl, pentafluor(2-6C)alkyl, cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3C alkylamino)(1-3C)alkyl, (1-4C alkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3C alkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3C alkoxy)trifluor (1-6C)alkyl, hydroxytrifluor(1-6C)alkyl, (1-4C alkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3C alkoxy)(1-6C)alkyl, hetAr5(CH2)o-i eller Ar5(CH2)0o-i; R2 erH, F, eller OH; Y er en binding, -O- eller -OCH2-; B er Ar1, hetAr1, 1-6C alkyl eller (1-6C)alkoxy; Ar1 er phenyl eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra halogen, CF3, CF30-, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl og CN; hetAr1 er et 5-6-leddet heteroaryl med 1-3 ringheteroatomer uafhængigt udvalgt fra N, S og O, og eventuelt substitueret med 1-2 grupper uafhængigt udvalgt fra (1 -6C)alkyl, halogen, OH, CF3, NH2 og hydroxy(1-2C)alkyl; ring C er formel C-1, C-2 eller C-3
C-l C-2 C-3 R3 er H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar2, hetCyc1, (3-7C)cycloalkyl eller hetAr2; Ar2 er phenyl eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra halogen, (1-6C)alkyl og hydroxymethyl; hetCyc1 er en 5-6-leddet mættet eller delvist umættet heterocyklisk ring med 1-2 ringheteroatomer uafhængigt udvalgt fra N og O; hetAr2 er en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, O og S og eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl og halogen; R4 er H, OH, (1-6C)alkyl, monofluor(1-6C)alkyl, difluor(1-6C)alkyl, trifluor(1-6C)alkyl, tetrafluor(2-6C)alkyl, pentafluor(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, amino -carbonyl(1-6C) alkyl, (1-3C)alkylsulfonamid (1-6C)alkyl, sulfamid (1-6C)alkyl, hydroxyl-carbonyl(1-6C) alkyl, hetAr3(1-6C)alkyl, Ar3(1-6C)alkyl, (1-6C)alkoxy, monofluor(1-6C)alkoxy, difluor(1-6C)alkoxy trifluor(1-6C)alkoxy, tetrafluor(2-6C)alkoxy, pentafluor(2-6C)alkoxycyan(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2(1-6C)alkoxy, hetAr3 (1-6C)alkoxy, Ar3(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [eventuelt substitueret med F, OH, (1-6C alkyl), (1-6C) alkoxy, eller (1-3C alkoxy)(1-6C)alkyl], hetAr4, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy, hetCyc2C(=0)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy, hydroxytrifluor (1-6C)alkoxy, (1-3)alkylsulfonamido(1- 6C)alkoxy, (1-3C)alkylamido (1-6C)alkoxy, di(1-3C alkyl)aminocarboxy, hetCyc2C(=0)0-, hydroxydifluor(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, (1-3C alkoxy)amino-carbonyl, hetCyc3, halogen, CN, trifluormethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3C trifluoralkyl)pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy, isoindolinl ,3-dionyl(1 -6C)alkoxy eller N-(1-3C alkyl)oxadiazolonyl; hetCyc2 er en 4-6-leddet heterocyklisk ring med 1-2 ringheteroatomer uafhængigt udvalgt fra N og O og eventuelt substitueret med 1-2 grupper uafhængigt udvalgt fra (1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl og (1-6C)acyl; hetCyc3 er en 4-7-leddet heterocyklus med 1-2 ringheteroatomer uafhængigt udvalgt fra N og O og eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra F, CN, CF3, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl, trifluormethylsulfonyl og (1-4C alkoxy)carbonyl; hetAr3 er en 5-leddet heteroarylring med 1-3 ringatomer uafhængigt udvalgt fra N, O og S og eventuelt substitueret med (1-6C)alkyl; Ar3 er phenyl eventuelt substitueret med (1-4C)alkoxy; hetAr4 er en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, S og O og eventuelt substitueret med 1-2 substituenter uafhængigt udvalgt fra (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluor(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2-(3-6Ccycloalkyl)C(=0)-, (1-3Calkoxy) (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoralkoxy), (1-3C)trifluoralkyl, og methoxybenzyl; eller en 9-1 O-leddet bicyklisk heteroaryl med 1-3 ringnitrogenatomer; Ar4 er phenyl eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl, halogen, CN, CF3, CF30-, (1-6C)alkoxy, (1-6Calkyl)0C(=0)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)S02-, H0C(=0)- og (1-3C alkoxy)(1-3C alkyl)0C(=0)-; R5 er H, (1-6C)alkyl, monofluor(1-6C)alkyl, difluor(1-6C)alkyl, trifluor(1-6C)alkyl, tetrafluor(2-6C)alkyl, pentafluor(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)0C(=0)-, (1-6C)alkylthio, phenyl [eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra halogen, (1-6C)alkyl og (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl eller trifluor(1-3C alky)amido; eller R4 og R5 sammen med de atomer, hvortil de er bundet, danner en 5-6-leddet mættet, delvist umættet eller umættet carbocyklisk ring eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra (1-6C)alkyl, eller R4 og R5 sammen med de atomer, hvortil de er bundet, danner 5-6-leddet mættet, delvist umættet eller umættet heterocyklisk ring med et ringheteroatom udvalgt fra N, O eller S, hvor den heterocykliske ring eventuelt er substitueret med én eller to substituenter uafhængigt udvalgt fra (1-6C alkyl)C(=0)0-(1-6)acyl, (1-6C)alkyl og oxo, og svovlringatomet eventuelt er oxideret til S(=0) eller SO2; hetAr5 er en 5-6-leddet heteroa ryl ring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, O eller S, hvor ringen eventuelt et substitueret med én eller flere substituenter uafhængigt udvalgt fra halogen, (1-6C)alkyl, (1-6C)alkoxy og CF3; Ar5 er phenyl eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra halo gen, (1-6C)alkyl, (1-6C)alkoxy, CF30-, (1-4C)alkoxycarbonyl og aminocarbonyl; R3a er hydrogen, halogen, (1-6C)alkyl, trifluor(1-6C)alkyl, (3-6C)cycloalkyl, phenyl eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra halogen, (1-6C)alkyl og hydroxymethyl, eller en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, O og S og eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl og halogen; R3b er hydrogen, (1-6C)alkyl, trifluor(1-6C)alkyl, (3-6C)cycloalkyl, phenyl eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra halogen, (1-6C)alkyl og hydroxymethyl, eller en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, O og S og eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl og halogen; R4a er hydrogen, (1-6C)alkyl, trifluor(1-6C)alkyl, phenyl [eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl, halogen, CN, CF3, CF30-, (1-6C)alkoxy, (1-6Calkyl)0C(=0)-, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)S02-, H0C(=0)- og (1-3C alkoxy)(1-3C alkyl)0C(=0)-], eller en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, S og O og eventuelt substitueret med 1-2 substituenter uafhængigt udvalgt fra (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluor(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2-(3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3C trifluoralkoxy)(1-3C)trifluoralkyl og methoxybenzyl; og R5a er hydrogen, halogen, (1-6C)alkyl, trifluor(1-6C)alkyl, (3-6C)cycloalkyl, phenyl eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra halogen, (1-6C)alkyl og hydroxymethyl, eller en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, O og S og eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra (1-6C)alkyl og halogen.
2. Forbindelse ifølge krav 1, hvor X er O.
3. Forbindelse ifølge et hvilket som helst af kravene 1-2, hvor R1 er udvalgt fra (1-3C alkoxy)(1-6C)alkyl, difluor(1-6C)alkyl og trifluor(1-6C)alkyl, fortrinsvis R1 er (1-3C alkoxy)(1-6C)alkyl.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor B er Ar1, hvor Ar1 fortrinsvis er phenyl eventuelt substitueret med ét eller flere halogener.
5. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor B er hetAr1, hvor B fortrinsvis er pyridyl eventuelt substitueret med 1-2 grupper uafhængigt udvalgt fra (1-6C)alkyl eller halogen.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor Ring C er formel C-1.
7. Forbindelse ifølge krav 6, hvor: R4 er H, OH, (1-6C)alkyl, monofluor(1-6C)alkyl, difluor(1-6C)alkyl, trifluor(1-6C) alkyl, tetrafluor(2-6C)alkyl, pentafluor(2-6C)alkyl, cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, amino (1-6C)alkyl, amino-carbonyl(1-6C)alkyl, (1-3 C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl, hydroxyl- carbonyl(1-6C)alkyl, hetAr3(1-6C)alkyl, Ar3(1-6C) alkyl, (1-6C)alkoxy, monofluor(1-6C)alkoxy, difluor (1-6C)alkoxy, trifluor (1-6C)alkoxy, tetrafluor(2-6C)alkoxy, pentafluor(2-6C) alkoxy, cyano (1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C) alkoxy, aminocarbonyl(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy, hetCyc2(1-6C)alkoxy, hetAr3(1-6C)alkoxy, Ar3(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl, hetAr4 eller Ar4; og R5 er Η, (1 -6C)alkyl, monofluor(1-6C)alkyl, difluor( 1 -6C)alkyl, trifluor(1-6C)alkyl, tetrafluor(2-6C)alkyl, pentafluor(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C) alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4Calkyl)0C(=0)-, (1- 6C)alkylthio, eller phenyl eventuelt substitueret med én eller flere grupper uafhængigt udvalgt fra halogen, (1-6C)alkyl og (1-6C)alkoxy.
8. Forbindelse ifølge krav 7, hvor R4 er udvalgt fra (1-6C)alkyl, trifluor(1-6C)alkyl, cyano(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl og (3-6C)cycloalkyl, eller R4 er udvalgt fra (1-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy og (1-4C alkoxy)(1-6C)alkoxy.
9. Forbindelse ifølge krav 7, hvor R4 er udvalgt fra hetAr4 og Ar4.
10. Forbindelse ifølge krav 7, hvor R5 er (1-6C)alkyl.
11. Forbindelse ifølge et hvilket som helst af kravene 1-10, hvor: R4 og R5 sammen med de atomer, hvortil de er bundet, danner en 5-6-leddet mættet carbocyklisk ring eventuelt substitueret med én eller flere substituenter uafhængigt udvalgt fra (1-6C)alkyl, eller R4 og R5 sammen med de atomer, hvortil de er bundet, danner en 5-6-leddet mættet heterocyklisk ring med et ringheteroatom udvalgt fra N, O eller S, hvor ringnitrogenatomet eventuelt er substitueret med (1-6C alkyl)C(=0)0-, eller (1-6)acyl, og svovlringatomet eventuelt er oxideret til S(=0) eller S02.
12. Forbindelse ifølge et hvilket som helst af kravene 1-11, hvor R3 er Ar2.
13. Forbindelse ifølge et hvilket som helst af kravene 1-12, hvor R2 er H.
14. Forbindelse ifølge et hvilket som helst af kravene 1-13, hvor Ra, Rb, Rc og Rd er H.
15. Forbindelse ifølge et hvilket som helst af kravene 1-14, hvor Y-B-delen og -NH- C(=X)-NH-delen med formlen I er trans i den absolutte konfiguration, der vises i formel C:
16. Forbindelse ifølge et hvilket som helst af kravene 1-15, hvor Y-B-delen og -NH-C(=X)-NH-delen med formlen I er trans i den absolutte konfiguration, der vises i formlen D:
17. Forbindelse ifølge et hvilket som helst af kravene 1-16, hvor Y er en binding.
18. Forbindelse ifølge krav 1, udvalgt fra følgende forbindelser:
19. Forbindelse ifølge et hvilket som helst af kravene 1-18, hvor R4er hetAr4.
20. Forbindelse ifølge et hvilket som helst af kravene 1-19, hvor hetAr4 er en 5-6-leddet heteroarylring med 1-3 ringheteroatomer uafhængigt udvalgt fra N, S og O og eventuelt substitueret med 1-2 substituenter uafhængigt udvalgt fra (1-6C)alkyl.
21. Forbindelse ifølge krav 20, hvilken forbindelse er udvalgt fra
eller et farmaceutisk acceptabelt salt deraf
22. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf £3. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
24. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
25. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
26. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
27. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf.
28. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf.
29. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf.
30. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
31. Forbindelse ifølge krav 21, hvilken forbindelse er
eller et farmaceutisk acceptabelt salt deraf
32. Farmaceutisk sammensætning, der omfatter en forbindelse med formlen I som defineret i et hvilket som helst af kravene 1 til 31, eller et farmaceutisk acceptabelt salt deraf, og farmaceutisk acceptabelt fortyndingsmiddel eller bærer.
33. Forbindelse med formlen I som defineret i et hvilket som helst af kravene 1 til 31, eller et farmaceutisk acceptabelt salt deraf, til anvendelse i behandlingen af smerte, cancer, inflammation, neurodegenerativ sygdom eller Trypanosoma cruzi-infektion.
34. Forbindelse ifølge krav 33, til anvendelse i behandlingen af smerte.
35. Forbindelse til anvendelse som defineret i krav 34, hvor smerten er kronisk smerte.
36. Forbindelse til anvendelse som defineret i krav 34, hvor smerten er akut smerte.
37. Forbindelse til anvendelse som defineret i krav 34, hvor smerten er inflammatorisk smerte, neuropatisk smerte, smerte forbundet med cancer, smerte forbundet med kirurgi eller smerte forbundet med knoglefraktur.
38. Forbindelse ifølge krav 33 til anvendelse i behandlingen af cancer.
39. Forbindelse til anvendelse som defineret i krav 38, hvor canceren er neuroblastom, ovariecancer, pancreascancer, kolorektal cancer eller prostatacancer.
40. Anvendelse af en forbindelse med formlen I som defineret i et hvilket som helst af kravene 1 til 31, eller et farmaceutisk acceptabelt salt deraf, i fremstillingen af et medikament til behandling af cancer, inflammation, neurodegenerativ sygdom eller Trypanosoma cruzi-infektion.
41. Fremgangsmåde til fremstilling af forbindelse ifølge krav 1, der omfatter: (a) for en forbindelse med formlen I, hvor X er O, kobling af en tilsvarende forbindelse med formlen II
Π med en tilsvarende forbindelse med formlen III
01 i nærvær af carbonyldiimidazol og en base; eller (b) for en forbindelse med formlen I, hvor X er S, kobling af en tilsvarende forbindelse med formlen II
II med en tilsvarende forbindelse med formlen III
m i nærvær af di(1 H-imidazol-2-yl)methanethion og en base; eller (c) for en forbindelse med formlen I, hvor X er O, kobling af en tilsvarende forbindelse med formlen II
ΪΙ med en tilsvarende forbindelse med formlen IV
:tv hvor L1 er en fraspaltelig gruppe, i nærvær af en base; eller (d) for en forbindelse med formlen I, hvor X er O, kobling af en tilsvarende forbindelse med formlen V
V hvor L2 er en fraspaltelig gruppe, med en tilsvarende forbindelse med formlen III
m i nærvær af en base; eller (e) for en forbindelse med formlen I, hvor X er O, aktivering af en tilsvarende forbindelse med formlen VI
vt: med diphenylphosphorylazid efterfulgt af kobling af det aktiverede mellemprodukt med en tilsvarende forbindelse med formlen III
Ilt i nærvær af en base; eller (f) for en forbindelse med formlen I, hvor X er O, kobling af en tilsvarende forbindelse med formlen II
II med en tilsvarende forbindelse med formlen VII
Vil i nærvær af en base; eller (g) for en forbindelse med formlen I, hvor R1 er (trifluormethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluor(1-6C)alkyl, difluor(1-6C)alkyl, trifluor(1-6C)alkyl, tetrafluor(2-6C)alkyl eller pentafluor(2-6C)alkyl, omsætning af en tilsvarende forbindelse med formlen VIII
vm med en tilsvarende forbindelse med (trifluormethoxy)(1-6C)alkyl-L3, (1-3C sulfanyl)(1-6C)alkyl-L3, monofluor(1-6C)alkyl-L3, difluor(1-6C)alkyl-L3, trifluor(1-6C)alkyl-L3, tetrafluor(2-6C)alkyl-L3 eller pentafluor(2-6C)alkyl-L3, hvor L3 er et fraspalteligt atom eller en fraspaltelig gruppe, i nærvær af en base; eller (h) for en forbindelse med formlen I, hvor X er O, R4 er CH3OCH2- og R5 er OHCH2-, behandling af en tilsvarende forbindelse med den almene formel IX
IX med en uorganisk syre; og eventuel fjernelse af beskyttede grupper og eventuel fremstilling af et farmaceutisk acceptabelt salt deraf.
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