DK2227467T3 - Isoxazolo-pyridinderivater - Google Patents

Isoxazolo-pyridinderivater Download PDF

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DK2227467T3
DK2227467T3 DK08857137.7T DK08857137T DK2227467T3 DK 2227467 T3 DK2227467 T3 DK 2227467T3 DK 08857137 T DK08857137 T DK 08857137T DK 2227467 T3 DK2227467 T3 DK 2227467T3
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methyl
isoxazol
ylmethoxy
phenyl
nicotinamide
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Bernd Buettelmann
Roland Jakob-Roetne
Henner Knust
Andrew Thomas
Matthew C Lucas
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Hoffmann La Roche
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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    • 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
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    • 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
    • C07D491/10—Spiro-condensed systems

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Claims (22)

1. Forbindelse med formel I
I hvor X er 0 eller NH; R1 er phenyl, pyridinyl, eller pyrimidinyl, hver eventuelt substueret med 1, 2 eller 3 halo, R2 er H eller CH3 eller CF3; R3, R4, R5, og R5 hver uafhængigt er H, Ci-7alkyl, eventuelt substitueret med én eller flere halo, cyano, eller hydroxy, Ci-7alkoxy, eventuelt substitueret med én eller flere halo, CN, halo, N02, S-Ci-7alkyl, S(0)-Ci-7alkyl benzyloxy, eventuelt substitueret med én eller flere E, -C(0)-Ra, hvor Ra er hydroxy, Ci-7alkoxy, Ci-7alkyl, phenoxy eller phenyl, 3- til 7-leddet heterocyclyl, eventuelt substitueret med én eller flere A, -C(0)-NRbRc, hvor Rb og Rc er hver uafhængigt H, Ci-7alkyl, eventuelt substitueret med én eller flere halo, methyl, -(CH2)t-hydroxy, eller cyano, -(CH2) t-C3-7cycloalkyl, eventuelt substitueret med én eller flere B, og t er 0,1, 2, 3, 4, 5 eller 6, -(CH2)u-0-Ci-7alkyl, hvor u er 2, 3, 4, 5 eller 6, -CHR'-CfOJOR", hvor R er H, benzyl eller Ci-4alkyl, og R" er H eller Ci-7alkyl, -S(0)2-Ci-7alkyl eller -S(0)2-C3-7cycloalkyl -(CH2CH20)vRri, hvor v er fra 1 til 3, og Rni er H eller Ci-7alkyl, -(CH2)w-heteroaryl eller -(CH2)„-aryl, hver eventuelt substitueret med én eller flere E, og hvor w er 0, 1, 2, 3, eller 4, -(CH2)x-heterocyclyl, hvor x er 0, 1, 2, 3 eller 4, og hvor heterocyclyl eventuelt er substitueret med én eller flere oxo, Ci-7alkyl, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, CN, benzyl, eventuelt substitueret med én eller flere E, -(CH2)y-C(0)Riv, hvor y er 0, 1, 2, 3 eller 4, og Riv er hydroxy, Ci-7alkyl, eller Ci-7alkoxy, -(CH2)z-C(0)NRvRvi, hvor z er 0, 1, 2, 3 eller 4, og Rv og Rvi er uafhængigt hydrogen, Ci-7alkyl, eventuelt substitueret med én eller flere halo, OH eller CN, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, 5- eller 6-leddet heterocyclyl, eventuelt substitueret med én eller flere A, eller Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en heterocyclyl-eller heteroarylgruppe, eventuelt substitueret med én eller flere A, eller Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en 7- til 12-leddet spirocyklisk heterocykel, eventuelt substitueret med én eller flere A; med det forbehold at Rb og Rc ikke samtidigt er H, A er hydroxy, oxo, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, halo, eller CN; B er halo, hydroxy, CN, Ci-4alkyl, benzyloxy, eller Ci-4haloalkyl; E er halo, CN, NO2, hydroxy, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, Ci-7cyanoalkyl, Ci-7haloalkoxy, eller C3-7cycloalkyl; hvor udtrykket "heteroaryl" betegner en monovalent aromatisk 5- eller 6-leddet monocyclisk ring indeholdende en, to, eller tre ring heteroatomer valgt fra N, O, eller S; og hvor udtrykket "heterocyclyl" betegner et monovalent mættet eller delvist mættet 3- til 7-leddet monocyclisk eller 9- til 10-leddet bicyclisk ring system hvor en, to, tre eller fire ring carbon atomer er erstattet med N, O eller S, og med bindingspunktet på den mættede eller delvis mættede ring af ringsystemet; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelsen ifølge krav 1, hvor R3 og R5 er H, halo, CN eller Ci-7alkyl.
3. Forbindelsen ifølge krav 1 eller 2, hvor R4 is H, Ci-7alkyl, eventuelt substitueret med én eller flere halo, cyano, eller hydroxy, Ci-7alkoxy, eventuelt substitueret med én eller flere halo, CN, halo, N02, S-Ci-7alkyl, S(0)-Ci-7alkyl benzyloxy, eventuelt substitueret med én eller flere E, -C(0)-Ra, hvor Ra er hydroxy, Ci-7alkoxy, Ci-7alkyl, phenoxy eller phenyl, 3- til 7-leddet heterocyclyl, eventuelt substitueret med én eller flere A, -C(0)-NRbRc, hvor Rb og Rc er hver uafhængigt Η, Ci-7alkyl, eventuelt substitueret med én eller flere halo, methyl, -(CH2)t-hydroxy, eller cyano, -(CH2)rC3-7cycloalkyl, eventuelt substitueret med én eller flere B, og t er 0, 1, 2, 3, 4, 5 eller 6, -(CH2)u-0-Ci-7alkyl, hvor u er 2, 3, 4, 5 eller 6, -CHR'-C(0)0R'', hvor R' er H, benzyl eller Ci-4alkyl, og R" er H eller Ci-7alkyl, -S(0)2-Ci-7alkyl eller -S(0)2-C3-7cycloalkyl -(CH2CH20)vRni, hvor v er fra 1 til 3, og Rni er H eller Cwalkyl, -(CH2)„-heteroaryl eller -(CH2)w-aryl, hver eventuelt substitueret med én eller flere E, og hvor w er 0, 1, 2, 3, eller 4, -(CH2)x-heterocyclyl, hvor x er 0, 1, 2, 3 eller 4, og hvor heterocyclyl eventuelt er substitueret med én eller flere oxo, Ci-7alkyl, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, CN, benzyl, eventuelt substitueret med én eller flere E, -(CH2)y-C(0)Riv, hvor y er 0, 1, 2, 3 eller 4, og Riv er hydroxy, Ci-7alkyl, eller Ci-7alkoxy, -(CH2)z-C(0)NRvRvi, hvor z er 0, 1, 2, 3 eller 4, og Rv og Rvi er uafhængigt hydrogen, Ci-7alkyl, eventuelt substitueret med én eller flere halo, OH eller CN, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, 5- eller 6-leddet heterocyclyl, eventuelt substitueret med én eller flere A, eller Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en heterocyclyl-eller heteroarylgruppe, eventuelt substitueret med én eller flere A, eller Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en 7- til 12-leddet spirocyklisk heterocykel, eventuelt substitueret med én eller flere A; med det forbehold at Rb og Rc ikke samtidigt er H, A er hydroxy, oxo, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, halo, eller CN; B er halo, hydroxy, CN, Ci-4alkyl, benzyloxy, eller Ci-4haloalkyl; E er halo, CN, N02, hydroxy, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, Ci-7cyanoalkyl, Ci-7haloalkoxy, eller C3 7cycloalkyl; eller et farmaceutisk acceptabelt salt deraf.
4. Forbindelsen ifølge krav 1, 2 eller 3, hvor R4 er -C(0)-NRbRc, hvor Rb og Rc hver uafhængigt er H, Ci-7alkyl, eventuelt substitueret med én eller flere halo, methyl, -(CH2)t-hydroxy, eller cyano, -(CH2)t-C3-7cycloalkyl, eventuelt substitueret med én eller flere B, og t er 0, 1, 2, 3, 4, 5 eller 6, -(CH2)u-0-Ci-7alkyl, hvor u er 2, 3, 4, 5 eller 6, -CHR'-C(0)0R", hvor R' er H, benzyl eller Ci-4alkyl, og R" er H eller Ci-7alkyl, -S(0)2-Ci-7alkyl eller -S(0)2-C3-7cycloalkyl -(CH2CH20)vR'", hvor v er fra 1 til 3, og R'" er H eller Ci-7alkyl, -(CH2)w-heteroaryl eller -(CH2)w-aryl, hver eventuelt substitueret med én eller flere E, og hvor w er 0, 1, 2, 3, eller 4, -(CH2)x-heterocyclyl, hvor x er 0, 1, 2, 3 eller 4, og hvor heterocyclyl eventuelt er substitueret med én eller flere oxo, Cwalkyl, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, CN, benzyl, eventuelt substitueret med én eller flere E, -(CH2)y-C(0)Riv, hvor y er 0, 1, 2, 3 eller 4, og Riv er hydroxy, Ci-7alkyl, eller Ci-7alkoxy, -(CH2)z-C(0)NRvRvi, hvor z er 0, 1, 2, 3 eller 4, og Rv og Rvi er uafhængigt hydrogen, Ci-7alkyl, eventuelt substitueret med én eller flere halo, OH eller CN, C3-7cycloalkyl, eventuelt substitueret med én eller flere B, 5- eller 6-leddet heterocyclyl, eventuelt substitueret med én eller flere A, or Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en heterocyclyl-eller heteroarylgruppe, eventuelt substitueret med én eller flere A, eller Rb og Rc sammen med det nitrogen til hvilket de er bundet danner en 7- til 12-leddet spirocyklisk heterocykel, eventuelt substitueret med én eller flere A; med det forbehold at Rb og Rc ikke samtidigt er H, A er hydroxy, oxo, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, halo, eller CN; B er halo, hydroxy, CN, Ci-4alkyl, benzyloxy, eller Ci-4haloalkyl; E er halo, CN, N02, hydroxy, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, Ci-7cyanoalkyl, Ci-7haloalkoxy, eller C3-7cycloalkyl; eller et farmaceutisk acceptabelt salt deraf.
5. Forbindelsen ifølge krav 1, 2 eller 3, hvor R4 er H, Cwalkyl, eventuelt substitueret med én eller flere halo, cyano, eller hydroxy, Ci-7alkoxy, eventuelt substitueret med én eller flere halo, CN, halo, N02,
5- Ci-7alkyl, S(0)-Ci-7alkyl benzyloxy, eventuelt substitueret med én eller flere E, E er halo, CN, N02, hydroxy, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, Ci-7cyanoalkyl, Ci-7haloalkoxy, eller C3-7cycloalkyl; eller et farmaceutisk acceptabelt salt deraf.
6. Forbindelsen ifølge krav 1, 2 eller 3, hvor R4 er -C(0)-Ra, hvor Ra er hydroxy, Ci-7alkoxy, Ci 7alkyl, phenoxy eller phenyl.
7. Forbindelsen ifølge krav 1, 2 eller 3, hvor R4 er 3- til 7-leddet heterocyclyl, eventuelt substitueret med én eller flere A, A er hydroxy, oxo, Ci-7alkyl, Ci-7alkoxy, Ci-7haloalkyl, Ci-7hydroxyalkyl, halo, eller CN; eller et farmaceutisk acceptabelt salt deraf.
8. Forbindelsen ifølge et hvilket som helst af kravene 1 til 7, hvor R5 er H, Ci-7alkyl, eventuelt substitueret med én eller flere halo, hydroxy eller CN, benzyloxy, eventuelt substitueret med én eller flere E, 3- til 7-leddet heterocyclyl, eventuelt substitueret med én eller flere A, -C(0)-NRbRc, hvor Rb og Rc er hver uafhængigt H, A er hydroxy, oxo, Ci-7alkyl, Ci-7alkoxy, Cwhaloalkyl, Ci-7hydroxyalkyl, halo, eller CN; E er halo, CN, NO2, hydroxy, Ci-7alkyl, Ci-7alkoxy, Cwhaloalkyl, Ci-7hydroxyalkyl, Ci-7cyanoalkyl, Cwhaloalkoxy, eller C3-7cycloalkyl.
9. Forbindelsen ifølge et hvilket som helst af kravene 1 til 8, hvor forbindelsen er 2-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin, N-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-ethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2-fluor-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2,2-difluor-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6- (5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-ethyl)-nicotinamid, N-(2-hydroxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, (R,S)-N-(2-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(3-methoxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropylmethyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2-ethyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(4-cyano-thiazol-2-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-pyridin-2-ylmethyl-nicotinamid, N-(6-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4- ylmethoxy)-nicotinamid, N-isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclobutyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopentyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid, (R,S)-N-(2,2-dimethyl-tetrahydro-pyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4- ylmethoxy)-nicotinamid, N-(l,l-dioxo-hexahydro-l,6-thiopyran-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(l-methyl-piperidin-4-yl)-nicotinamid, N-(l-ethyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(l-isopropyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(l-benzyl-piperidin-4-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(l-ethyl-piperidin-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amino>-piperidin-l- yl)-eddikesyre, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-{l-[(2,2,2-trifluor-ethylcarbamoyl)- methyl]-piperidin-3-yl}-nicotinamid, N-{l-[(2-hydroxy-ethylcarbamoyl)-methyl]-piperidin-3-yl>-6-(5-methyl-3-phenyl- isoxazol-4-ylmethoxy)-nicotinamid, N-(4-fluor-phenyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 4-benzyloxy-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin, 1- methyl-2'-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-l,2,3,6-tetrahydro-[4,4']bipyridinyl, 2- (5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-ethyl)-isonicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-4-trifluormethyl-nicotinamid, 5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)- nicotinamid, N-isopropyl-5-methyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-furan-3-ylmethyl)-nicotinamid, [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-oxa-6-aza-spiro[3.3]hept- 6-yl)-methanon, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nikotinsyre isopropyl ester, 6-[3-(2-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)-nicotinamid, 6-[3-(2-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,3,3,3-pentafluor-propyl)-nicotinamid, 6-[3-(2-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(2-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(3-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)-nicotinamid, N-cyclopropylmethyl-6-[3-(3-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(3-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(3-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(3-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)- nicotinamid, 6-[3-(3-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamid, 6-[3-(3-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamid, 6-[3-(3-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)-nicotinamid, N-cyclopropylmethyl-6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, N-cyclopropyl-6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, (l,l-dioxo-lA5-thiomorpholin-4-yl)-{6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4- ylmethoxy]-pyridin-3-yl>-methanon, 3-{6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-oxetan-3-ol, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nikotinsyre-methylester, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropylmethyl-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, {6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-(l,l-dioxo-lA6- thiomorpholin-4-yl)-methanon, {6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyndin-3-yl}-morpholin-4-yl- methanon, {6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyndin-3-yl>-thiomorpholin-4-yl- methanon, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)- nicotinamid, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(4-fluor-phenyl)-5-trifluormethyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-ethyl)-nicotinamid, N-cyclopropylmethyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-isopropyl-6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid, N-isopropyl-6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinamid, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-{[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino>-N-(2,2,2-trifluor-ethyl)- nicotinamid, N-cyclopropylmethyl-6-{[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino>- nicotinamid, 6-{[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino>-N-isopropyl-nicotinamid, N-cyclopropyl-6-{[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethyl]-annino>-nicotinannid, 6-{[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino>-N-(tetrahydro-pyran-4-yl)- nicotinamid, N-(2-hydroxy-l,l-dimethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-(2-methoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-(l,l-dioxo-tetrahydro-thiophen-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(3,3,3-trifluor-2-hydroxy-propyl)- nicotinamid, (4-hydroxy-piperidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]- methanon, N-(3-hydroxy-2,2-dimethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-(2-isopropoxy-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-(2-hydroxy-l-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, (3-hydroxy-azetidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]- methanon, N-(2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-(2-hydroxy-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-(l-hydroxy-cyclopropylmethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((R)-2-hydroxy-l-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((S)-2-hydroxy-l-methyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((lR,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((lS,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((1S,2R) og (lR,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2-hydroxy-l-hydroxymethyl-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(S)-tetrahydro-furan-3-yl-nicotinamid, N-((lR,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid eller N-((lS,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-((lS,2R)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid eller N-((lR,2S)-2-hydroxy-cyclohexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-((S)-l-hydroxymethyl-2-methyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((S)-l-hydroxymethyl-3-methyl-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid, N-((S)-l-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-((R)-i-hydroxymethyl-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, N-((lR,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid eller N-((lS,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-((lS,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinamid eller N-((lR,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-((lS,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid eller N-((lR,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-((lR,2R)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid eller N-((lS,2S)-2-hydroxy-cyclopentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-[2-(2-oxo-imidazolidin-l-yl)-ethyl]- nicotinamid, N-(3-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amino>-azetidin-l- carboxylsyre-tert.butylester, N-(2,3-dihydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(3-hydroxy-propyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(4-hydroxy-butyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(5-hydroxy-pentyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, N-(6-hydroxy-hexyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, (3-hydroxy-pyrrolidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]- methanon, ((S)-2-hydroxymethyl-pyrrolidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- pyridin-3-yl]-methanon, ((R)-2-hydroxymethyl-pyrrolidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- pyridin-3-yl]-methanon, N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-(2-methyl-pyrrolidin-l-yl)- methanon, [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-pyrrolidin-l-yl-methanon, (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amino>-3-phenylpropionsyre methyl ester, (cis eller trans)-N-(3-benzyloxy-cyclobutyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amino>-3- phenylpropionsyre, N-(3-methyl-oxetan-3-yl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, butan-l-sulfonsyre [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-l-methyl-ethyl)- nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-((S)-2,2,2-trifluor-l-methyl-ethyl)- nicotinamid, cyclopropansulfonsyre-methyl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3- carbonyl]-amid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(l-methyl-lH-pyrazol-4-yl)-nicotinannid, 1- [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyndin-3-carbonyl]-l,2-dihydro-pyrazol- 3-on, N-(l-methyl-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, azetidin-l-yl-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyndin-3-yl]-methanon, (3-methoxy-azetidin-l-yl)-[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyndin-3-yl]- methanon, [6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyndin-3-yl]-thiazolidin-3-yl-methanon, N-(l-cyano-cyclopropyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(l-methyl-lH-pyrazol-3-yl)-nicotinannid, 2- (5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-methylsulfanyl-pyndin, 5- methanesulfinyl-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin, 6- [3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l,l-dimethyl-ethyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(l-methyl-lH-pyrazol-4-yl)- nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((R)-2-hydroxy-l-methyl-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((S)-2-hydroxy-l-methyl-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((S)-2,2,2-trifluor-l-methyl- ethyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((lR,2R)-2-hydroxy-cyclopentyl)-nicotinamid eller 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxycyclopentyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxy-cyclopentyl)-nicotinamid eller 6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-((lR,2R)-2-hydroxy-cyclopentyl)-nicotinamid, 6-[3-(2,3-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(2,3-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(2,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinannid, 6-[3-(2,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(2,5-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinannid, 6-[3-(2,5-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l,l-dimethyl- ethyl)-nicotinamid, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2- dimethylpropyl)-nicotinamid, 6-[3-(3,4-difluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-(2-hydroxy-2-methyl-propyl)- nicotinamid, 6-[3-(4-chlor-2-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nikotinsyre-methylester, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid, N-isopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl- methanon, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-ethyl)-nicotinamid, (l,l-dioxo-l,6-thiomorpholin-4-yl)-[6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)- pyridin-3-yl]-methanon, N-cyclopropylmethyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropyl-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, methyl-6-(5-methyl-3-pyndin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, ethyl-6-(5-methyl-3-pyndin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, (2-hydroxy-l,l-dimethyl-ethyl)-6-(5-methyl-3-pyndin-2-yl-isoxazol-4-ylmethoxy)- nicotinamid, [6-(5-methyl-3-pyndin-2-yl-isoxazol-4-ylmethoxy)-pyndin-3-yl]-thiomorpholin-4-yl- methanon, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nikotinsyre, (2-hydroxy-ethyl)-6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinannid, (2-methoxy-ethyl)-6-(5-methyl-3-pyndin-2-yl-isoxazol-4-ylmethoxy)-nicotinannid, 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nikotinsyre-methylester, 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy] -nikotinsyre, 6-[3-(5-fluor-pyridin-2-yl)-5-nnethyl-isoxazol-4-ylnnethoxy]-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-5-nnethyl-isoxazol-4-ylnnethoxy]-isopropyl-nicotinannid, cyclopropyl-6-[3-(5-fluor-pyridin-2-yl)-5-nnethyl-isoxazol-4-ylnnethoxy]-nicotinannid, 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylnnethoxy](2-hydroxy-l,l-dinnethyl- ethyl)-nicotinamid, cyclopropylmethyl-6-[3-(5-fluor-pyridin-2-yl)-5-nnethyl-isoxazol-4-ylnnethoxy]-nicotinannid, (l,l-dioxo-l,6-thiomorpholin-4-yl)-{6-[3-(5-fluor-pyridin-2-yl)-5-nnethyl-isoxazol-4- ylmethoxy]-pyridin-3-yl>-methanon, 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2,2,2-trifluor-ethyl)- nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinannid, {6-[3-(5-fluor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyndin-3-yl}-morpholin-4-yl- methanon, ethyl-6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(5-fluor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-methyl-nicotinamid, 6-[3-(5-fluor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-N-((S)-2,2,2-tnfluor-l-methylethyl)-nicotinamid, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nikotinsyre-methylester, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)- nicotinamid, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamid, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropyl-nicotinamid, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-nikotinsyre, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-l,l-dimethyl- ethyl)-nicotinamid, 6-[3-(5-chlor-pyndin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-cyclopropylmethyl- nicotinamid, {6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(l,l-dioxo-l,6- thiomorpholin-4-yl)-methanon, 6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2,2,2-trifluor-ethyl)- nicotinamid, {6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-morpholin-4-yl- methanon, {6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-thiomorpholin- 4-yl-methanon, 6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)- nicotinamid, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nikotinsyre-methylester, N-isopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-(2-hydroxy-l,l-dimethyl-ethyl)-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)- nicotinamid, [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl- methanon, N-ethyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-methyl-6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinamid, [6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-thiomorpholin-4-yl- methanon, N-(2-hydroxy-ethyl)-6-(5-methyl-3-pynmidin-4-yl-isoxazol-4-ylmethoxy)-nicotinannid, N-isopropyl-6-(3-phenyl-isoxazol-4-ylmethoxy)-nicotinannid, 6-(3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinannid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l-methyl-ethyl)-nicotinannid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((R)-2-hydroxy-l-methyl-ethyl)- nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((S)-2-hydroxy-l-methyl-ethyl)- nicotinamid, N-cyclopropylmethyl-6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-nicotinamid, N-cyclopropyl-6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)-nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxy-cyclopentyl)- nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((lR,2R)-2-hydroxy-cyclopentyl)-nicotinamid eller 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxy-cyclopentyl)-nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l-hydroxymethyl-ethyl)- nicotinamid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-methoxy-ethyl)-nicotinannid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((R)-2-hydroxy-propyl)-nicotinannid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinannid, 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-(l-hydroxy-cyclopropylmethyl)- nicotinamid, N-(l,l-dioxo-tetrahydro-l,6-thiophen-3-yl)-6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]- nicotinamid, 6- [3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((lR,2R)-2-hydroxy-cyclopentyl)-nicotinamid eller 6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxy-cyclopentyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(2,2,2-trifluor-ethyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-cyclopropyl-nicotinannid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(tetrahydro-pyran-4-yl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-ethyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy] -N-(2-hydroxy-propyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-propyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l,l-dimethyl-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(3-hydroxy-2,2-dinnethyl-propyl)- nicotinamid, 3-({6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-pyridin-3-carbonyl}-annino)-azetidine-l- carboxylsyre-tert.butylester, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-((lS,2S)-2-hydroxy-cydopentyl)-nicotinamid og 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-((lR,2R)-2-hydroxy-cyclopentyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-(2-hydroxy-l-hydroxymethyl-ethyl)-nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-((R)-2-hydroxy-l-methyl-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-((S)-2-hydroxy-l-methyl-ethyl)- nicotinamid, 6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-N-((S)-2,2,2-trifluor-l-methyl-ethyl)- nicotinamid, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid, N-isopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-cyclopropylmethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-N-(2,2,2-trifluor-ethyl)-nicotinamid, N-(2-hydroxy-ethyl)-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, N-ethyl-6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(tetrahydro-pyran-4-yl)-nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-isopropyl-nicotinamid, cyclopropyl-6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-l,l-dimethyl-ethyl)- nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2,2,2-trifluor-ethyl)-nicotinamid, 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-(2-hydroxy-ethyl)-nicotinamid, ethyl-6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-nicotinamid, eller 6-[3-(5-fluor-pyridin-2-yl)-isoxazol-4-ylmethoxy]-methyl-nicotinamid.
10. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er N-Isopropyl-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid eller et farmaceutisk acceptabelt salt deraf.
11. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er (1,1-dioxo-lA6-thiomorpholin-4-yl)-{6-[3-(4-fluor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]- pyridin-3-yl}-methanon eller et farmaceutisk acceptabelt salt deraf.
12. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er {6-[3-(4-chlor-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-morpholin-4-yl-methanon eller et farmaceutisk acceptabelt salt deraf.
13. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er [6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridin-3-yl]-morpholin-4-yl-methanon eller et farmaceutisk acceptabelt salt deraf.
14. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er 6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isopropyl-nicotinamid eller et farmaceutisk acceptabelt salt deraf.
15. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er (1,1-dioxo-lA6-thiomorpholin-4-yl)-{6-[3-(5-fluor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanon eller et farmaceutisk acceptabelt salt deraf.
16. Forbindelsen ifølge et hvilket som helst af kravene 1 til 9, hvor forbindelsen er {6-[3-(5-chlor-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl>-thiomorpholin-4-yl-methanon eller et farmaceutisk acceptabelt salt deraf.
17. Forbindelsen valgt fra: N-(2-acetylamino-ethyl)-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinamid, (2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-carbonyl]-amino>-ethyl)-carbaminsyre-tert-butyl ester, 6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid N-isopropyl-6-(5-methyl-3-m-tolyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamid N-isopropyl-6-(5-methyl-3-p-tolyl-isoxazol-4-ylmethoxy)-nicotinamid, 6-[3-(2-fluor-4-methyl-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-N-isopropyl-nicotinamid, N-(2-acetylamino-ethyl)-6-[3-(4-fluor-phenyl)-isoxazol-4-ylmethoxy]-nicotinamid, N-(2-acetylamino-ethyl)-6-[3-(4-chlor-phenyl)-isoxazol-4-ylmethoxy]-nicotinamid, 5-(3-methyl-[l,2,4]oxadiazol-5-yl)-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin, og 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-5-(5-methyl-4H-[l,2,4]triazol-3-yl)-pyridin.
18. Fremgangsmåde til fremstilling af en forbindelse med formel I
I hvor X er O og R1UI R6 er som defineret i krav 1, omfattende trinnene at a) omsætte en forbindelse med formel XIV
XIV med en forbindelse med formel XV
XV i tilstedeværelse af en base, i et opløsningsmiddel, eller alternativt b) omsætte forbindelsen med formel XIV med en forbindelse med formel XVI
XVI i tilstedeværelse af triphenylphosphin og diethylazodicarboxylat, i et opløsningsmiddel.
19. Fremgangsmåde til fremstilling af en forbindelse med formel Ic
Ic hvor R4 er -C(0)0H, eller -C(0)0Me, eller hvor R4 er -C(0)NRbRc er som defineret i krav 1, omfattende trinnene at a) omsætte forbindelse med formel XIX
XIX med methyl 6-chlornicotinat, i tilstedeværelse af en base, i et egnet opløsningsmiddel, til tilvejebringelse af enforbindelse med formel I-c';
I-c b) eventuelt efterfulgt af ester hydrolyse til tilvejebringelse af en forbindelse med formel I-c"
I 5Ϊ -c c) herefter eventuelt amidation omsætning af forbindelsen med formel I-c" med en amin med formel RbRcNH i opløsningsmiddel, til tilvejebringelse afen forbindelse med formel Ic, hvor R4 er -C(0)NRbRc som defineret i krav 1, eller alternativt d) omsætte en forbindelse med formel I-c' med MesAI, med en amin med formel RbRcNH i opløsningsmiddel til tilvejebringelse af en forbindelse med formel Ic hvor R4 er -C(0)NRbRc som defineret i krav 1.
20. Medikament indeholdende mindst én forbindelse med formel I ifølge et hvilket som helst af kravene 1 til 17.
21. Anvendelsen af en forbindelse med formel I ifølge et hvilket som helst af kravene 1 til 17 til fremstillingen af et medikament anvendelig som kognitiv forstærker eller til fremstillingen af et medikament til behandlingen af kognitive forstyrrelser.
22. Anvendelsen af forbindelse med formel I ifølge krav 21 til fremstillingen af et medikament til behandlingen af Alzheimer's sygdom.
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