DK2790705T3 - Anvendelse af inhibitorer af aktiviteten eller funktionen af PI3K - Google Patents

Anvendelse af inhibitorer af aktiviteten eller funktionen af PI3K Download PDF

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DK2790705T3
DK2790705T3 DK12818825.7T DK12818825T DK2790705T3 DK 2790705 T3 DK2790705 T3 DK 2790705T3 DK 12818825 T DK12818825 T DK 12818825T DK 2790705 T3 DK2790705 T3 DK 2790705T3
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methoxy
pyrimidin
pyridin
yloxy
pyrrolidin
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Nigel Graham Cooke
Pascal Furet
Christina Hebach
Klemens Högenauer
Gregory HOLLINGWORTH
Christoph Kalis
Ian Lewis
Alexander Baxter Smith
Nicolas Soldermann
Frédéric Stauffer
Ross Strang
Frank Stowasser
Nicola Tufilli
Matt Anette Von
Romain Wolf
Gomes Dos Santos Paulo Antonio Fernandes
Frédéric Zecri
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Novartis Ag
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Claims (10)

1. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ved behandlingen af immunopathologi i et subjekt, som lider af en sygdom eller lidelse valgt blandt akut og cerebral malaria, via funktionl inhibering af TLR9 for det inficerede subjekt, hvor PI3K inhibitoren er valgt blandt tetrahydro-pyrido-pyri-midinforbindelser med formlen I og/eller tautomerer og/eller N-oxider og/eller farmaceutisk acceptable salte deraf,
(O hvor Y er valgt blandt O eller NR3; R1 er valgt blandt phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, eller
hvor R4 er valgt blandt CrCe-alkyl, halogen-Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, CrCe-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkyl-sulfonyl-Ci-Ce-alkyl, heterocyclyl, heterocyclyl-oxy, heterocyclyl-Ci-Ce-alkyl, C3-Ci2-cycloalkyl, C3-Ci2-cycloalkyl-Ci-C8-alkyl, hetero-aryl, heteroaryl-oxy, heteroaryl-Ci-Ce-alkyl, hydroxy, Ci-Ce-alkoxy, amino, N-Ci-Ce-alkylamino eller N.N-di-Ci-Ce-alkyl-amino, hvor "Ci-Ce-alkyl" i N-Ci-Ce-alkyl-amino og N.N-di-Ci-Ce-alkyl-amino kan være usubstitueret eller substitueret med halogen, hydroxy eller Ci-C4-alkoxy; hvor "C3-Ci2-cycloalkyl" i C3-Ci2-cycloalkyl og C3-Ci2-cycloalkyl-Ci-Ce-alkyl kan være usubstitueret eller substitueret med 1-5 substituenter uafhængigt valgt blandt oxo, halogen, Ci-Ce-alkyl.halogen-CrCe-alkyl, hydroxy-Ci-Ce-alkyl, hydroxyl, CrCe-alkoxy, CrCs-alkoxy-Ci-Ce-alkyl, amino, N-Ci-Ce-alkyl-amino, 1 N,N-di-Ci-C8-alkylamino, Ci-Ce-alkyl-carbonyl.halogen-Ci-Ce-alkyl-carbonyl, hydroxy-Ci-Ce-alkyl-carbonyl eller Ci-Ce-alkoxy-Ci-Ce-alkyl-carbonyl; hvor "heterocyclyl" er valgt blandt oxiranyl, aziridinyl, oxetanyl, thiethanyl, acetitinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, 2,3-dihydrothiophenyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, thiepanyl eller oxepanyl; som hver især er usubstitueret eller substitueret med 1-5 substituenter uafhængigt valgt blandt oxo, halogen, Cr Cs-alkyl, halogen-Ci-Ce-alkyl, hydroxy-Ci-Cs-alkyl, hydroxyl, Ci-Cs-alkoxy, Ci-Ce-alkoxy-C-i-Ce-alkyl, amino, N-C-i-Ce-alkyl-amino, N.N-di-Ci-Ce-alkyl-amino, C-i-Ce-alkylcarbonyl, halogen-Ci-Cs-alkyl-carbonyl, hydroxy-Ci-Cs-alkyl-carbonyl eller Cr Cs-alkoxy-Ci-Cs-alkyl-carbonyl; hvor "heterocyclyl" kan være forbundet ved et heteroatom eller carbonatom og hvor N og/eller S heteroatomerne også eventuelt kan være oxideret til forskellige oxidationstrin; hvor "heteroaryl" er valgt blandt furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,1,3,4-oxadiazo-lyl, 1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl eller 1,3,5-triazinyl; som hver isærer usubstitueret eller substitueret med 1-5 substituenter uafhængigt valgt blandt halogen, C-i-Ce-alkyl.halogen-Ci-Cs-alkyl, hydroxy-Ci-Cs-alkyl, hydroxyl, Ci-Cs-alkoxy, Ci-Cs-alkoxy-Ci-Ce-alkyl, amino, N-Ci-Ce-alkyl-amino, N.N-di-Ci-Ce-alkyl-amino, C-i-Ce-alkyl-carbonyl, halogen-Ci-Ce-alkyl-carbonyl, hydroxy-Ci-Ce-alkyl-carbonyl eller C-i-Ce-alkoxy-C-i-Ce-alkyl-carbonyl; hvor "heteroaryl" kan være forbundet ved et heteroatom eller carbonatom og hvor N og/eller S heteroatomerne også eventuelt kan være oxideret til forskellige oxidationstrin; R2 er valgt blandt phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl eller isoquinolinyl, som hver især er usubstitueret eller substitueret med 1-5 substituenter uafhængigt valgt blandt halogen, cyano, nitro, C-i-Ce-alkyl, halogen-Ci-Cs-alkyl, hydroxy-Ci-Cs-alkyl, hydroxyl, Ci-Cs-alkoxy, Ci-Cs-alkoxy-Ci-Ce-alkyl, amino, N-C-i-Ce-alkyl-amino, N.N-di-C-i-Ce-alkyl-amino, C-i-Ce-alkyl-carbonyl,halogen-Ci-Cs-alkyl-carbonyl, hydroxy-Ci-Cs-alkylcarbonyl eller Ci-Cs-alkoxy-Ci-Cs-alkyl-carbonyl; R3 er valgt blandt H, Ci-C4-alkyl eller halogen-Ci-C4-alkyl; og 9 m er valgt blandt O eller 1.
2. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge krav 1 med formlen Id'
(Id’), og/eller tautomerer og/eller N-oxider og/eller farmaceutisk acceptable salte deraf.
3. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge krav 1 med formlen le'
(le’), og/eller tautomerer og/eller N-oxider og/eller farmaceutisk acceptable salte deraf.
4. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse i overensstemmelse med ethvert af kravene 1 til 3, hvor R2 er valgt blandt naphthyl, pyridyl eller pyrimidinyl; som hver især er usubstitueret eller substitueret med 1-3 substituenter uafhængigt valgt blandt halogen, cyano, nitro, Ci-Ce-alkyl, halogen-Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, hydroxyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, amino, N-CrCe-alkyl-amino, N.N-di-Ci-Ce-alkyl-amino, Ci-Ce-alkyl-carbonyl, halogen-Ci-Ce-alkyl-carbonyl, hydroxy-Ci-Ce-alkyl-carbonyl eller Ci-Ce-alkoxy-Ci-Ce-alkyl-carbonyl.
5. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge ethvert af kravene 1 til 4, hvor R1, hvis den foreligger, er -C(0)-R4, hvor R4 er valgt blandt heterocyclyl, C4-C8-cycloalkyl eller heteroaryl; hvor "C3-Ci2-cycloalkyl" kan være usubstitueret eller substitueret med 1-3 substituenter uafhængigt valgt blandt fluor, Ci-C4-alkyl, hydroxyl, Ci-C4-alkoxy; hvor "heterocyclyl" er valgt blandt pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetra- hydrothiopyranyl, morpholinyl eller piperazinyl; som hver især er usubstitueret eller substitueret med 1-3 substituenter uafhængigt valgt blandt oxo, halogen, Ci-C4-alkyl, hydroxyl, Ci-C4-alkyl-carbonyl; hvor "heterocyclyl" kan være forbundet ved et heteroatom eller carbonatom og hvor N og/eller S heteroatomerne også eventuelt kan være oxideret til forskellige oxidationstrin; hvor "heteroaryl" er valgt blandt furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrazinyl; som hver især er usubstitueret eller substitueret med 1-3 substituenter uafhængigt valgt blandt CrC4-alkyl, hydroxyl; hvor "heteroaryl" kan være forbundet ved et heteroatom eller carbonatom og hvor N og/eller S heteroatomerne også eventuelt kan være oxideret til forskellige oxidationstrin.
6. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge ethvert af kravene 1 til 4, hvor R1, hvis den foreligger, er-C(0)-R4, og R4 er valgt blandt CrCe-alkyl, CrCe-alkoxy-CrCe-alkyl, CrCe-alkoxy eller N,N-di-Ci-C8-alkyl-amino, hvor "CrCe-alkyl" i N.N-di-CrCe-alkyl-amino kan være usubstitueret eller substitueret med halogen, hydroxy eller CrC4-alkoxy.
7. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge krav 1, hvor PI3K inhibitoren er valgt fra gruppen bestående af {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; {(S)-3-[6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; λ {3-[6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; 2-methoxy-5-{4-[(S)-1-(tetrahydropyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 1-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-propan-1-on; 1- {3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; 2- amino-5-{4-[(S)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-amino-5-{4-[1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; (S)-(3-(6-(5-fluor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(5-fluor-6-methoxypyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (S)-2-methoxy-5-(4-(1-(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]- pyrimidin-6(5H)-yl)nicotinnitril; 2-methoxy- 5-(4-(1 -(2-methoxyacetyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]-pyrimidin-6(5H)-yl)nicotinnitril; (S)-5-(4-(1-(cyclopentancarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin- 6(5H)-yl)-2-methoxynicotinnitril; 5-(4-(1-(cyclopentancarbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methoxynicotinnitril; (2,4-dimethyl-oxazol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; (2,4-dimethyl-oxazol-5-yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; furan-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; furan-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon; (3-methoxy-cyclobutyl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; (3-methoxy-cyclobutyl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; ({(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin- 4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon; ({3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyndo[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon; 1.(4-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon; 1.(4-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pynmidin- 4- yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyndin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(4-methyl-oxazol-5-yl)-methanon; 5- {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin- 4- yloxy]-pyrrolidin-1 -carbonyl}-1 H-pyridin-2-on; 5- {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -carbonyl}-1 H-pyridin-2-on; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1 H-imidazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-imidazol-4-yl)-methanon; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-4-yl-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-oxazol-4-yl-methanon; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-py rrol id i n-1 -yl}-oxazol-5-y l-m eth an on; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(2-methyl-oxazol-4-yl)-methanon; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-(2,2-dimethyl-tetrahydro-pyran-4-yl)-methanon; {(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanon; {3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pynmidin-4-yloxy]- pyrrolidin-1-yl}-(2,4-dimethyl-oxazol-5-yl)-methanon; (4,4-difluor-cyclohexyl)-{(S)-3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; (4,4-difluor-cyclohexyl)-{3-[6-(5,6-dimethoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyndo- [4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; 2-methoxy-5-{4-[(S)-1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy-5-{4-[1-(2-tetrahydro-pyran-4-yl-acetyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 5-{4-[(S)-1-(2,4-dimethyl-oxazol-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinnitnl; 5-{4-[1-(2,4-dimethyl-oxazol-5-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido-[4,3-d] py ri m id i n-6-yl}-2-m eth oxy-n icoti η n itri I; 5-{4-[(S)-1-(2,2-dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinnitril; 5-{4-[1-(2,2-dimethyl-tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-2-methoxy-nicotinnitnl; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(5-methyl-oxazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanon; {3-[6-(6-rnethoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrirriidin-4- yloxy]-pyrrolidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrirriidin-4- yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon; {3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(3-methyl-isoxazol-4-yl)-methanon; isoxazol-3-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido- [4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; isoxazol-3-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; isoxazol-5-yl-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido- [4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; isoxazol-5-yl-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; 2-methoxy-5-{4-[(S)-1-(thiazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy-5-{4-[1-(thiazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido-[4,3-d] py ri m id i n-6-yl}-n icoti η n itri I; 2-methoxy-5-{4-[(S)-1-(1-methyl-1H-pyrazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihyd ro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy-5-{4-[1-(1-methyl-1H-pyrazol-4-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy-5-{4-[(S )-1-(1-methyl-1 H-pyrazol-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; 2-methoxy- 5-{4-[1 -(1 -methyl-1 H-pyrazol-3-carbonyl)-pyrrolidin-3-yloxy]-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-nicotinnitril; (2,2-dimethyl-tetrahydro-pyran-4yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; (2,2-dimethyl-tetrahydro-pyran-4yl)-{3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanon; (1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[6-(6-methoxy-5-trifluormethyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyndo[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}- methanon; (1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{3-[6-(6-methoxy-5-trifluormethyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pynmidin-4-yloxy]-pyrrolidin-1-yl}- methanon; (S)-(2,4-dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; (2,4-dimethyloxazol-5-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyri- midin-4-yloxy)pyrrolidin-1-yl)(thiazol-5-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-pyrazol-5-yl)methanon; 4-((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on; 4-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-3-yl)methanon; (S)-(1H-imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; (1 H-imidazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetra- hydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; 5-((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on; 5-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)pyrrolidin-2-on; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydrc>pyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyridin-4-yl)methanon; (S)-(1,3-dimethyl-1 H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; (1,3-dimethyl-1H-pyrazol-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(1H-pyrazol-4-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(5-methyl-1,3,4-oxadiazol-2-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(pyrazin-2-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yloxy)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yloxy)pyrrolidin-1 -yl)(1 -methyl-1 H-imidazol-4-yl)methanon; {(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-4-yloxy]-pyrrolidin-1 -yl}-(1 -methyl-1 H-pyrazol-4-yl)-methanon; {3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1 -yl}-(1 -methyl-1 H-pyrazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanon; {3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-thiazol-4-yl-methanon; {(S)-3-[6-(5-chlor-6-methoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; {3-[6-(5-chlor-6-methoxy-pyridin-3-yl )-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; (S)-(3-(6-(6-amino-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(6-amino-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyndo[4,3-d]pynmidin-4- yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyri- midin-4-yloxy)azetidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; {(S)-3-[6-(2-methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; {3-[6-(2-methoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]- pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; [(S)-3-(6-quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]- (tetrahydro-pyran-4-yl)-methanon; [3-(6-quinolin-3-yl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]- (tetrahydro-pyran-4-yl)-methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (S)-1-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-on; 1 -(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethylbutan-1-on; 1-{(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on; 1- {3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyndo[4,3-d]-pyrimidin-4-yloxy]-pyrrolidin-1-yl}-propan-1-on; 2- methoxy-5-[4-((S)-1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]-pyrimidin-6-yl]-nicotinnitril; 2-methoxy-5-[4-(1-propionyl-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]pynmidin- 6-yl]-nicotinnitril; (S)-6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-4-(1 -(pyridin-2-yl)pyrrolidin-3-yloxy)- 5.6.7.8- tetrahydropyrido[4,3-d]pyrimidin; 6-(6-methoxy-5-(trifluormethyl)pyndin-3-yl)-4-(1-(pyndin-2-yl)pyrrolidin-3-yloxy)-5,6,7,8- tetrahydropyrido[4,3-d]pyrirriidin; (S )-6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-4-(1 -(py ri m id i n-2-yl )py rrol i d i n-3-y loxy )- 5.6.7.8- tetrahydropyrido[4,3-d]pyrimidin; 6-(6-methoxy-5-(tnfluormethyl)pyndin-3-yl)-4-(1-(pynmidin-2-yl)pyrrolidin-3-yloxy)- 5.6.7.8- tetrahydropyrido[4,3-d]pyrimidin; (S)-1-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on; 1- (3-(6-(6-methoxy-5-(trifluorrriethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-ylamino)pyrrolidin-1-yl)propan-1-on; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (S)-2-methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8- dihyd ropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinnitril; 2- methoxy-5-(4-(1-(tetrahydro-2H-pyran-4-carbonyl)pyrrolidin-3-ylamino)-7,8-di-hydropyrido[4,3-d]pyrimidin-6(5H)-yl)nicotinnitril; (S)-1-(4-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido- [4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-carbonyl)piperidin-1-yl)ethanon; 1-(4-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahyd ropyrido[4,3-d]- pyrimidin-4-ylamino)pyrrolidin-1-carbonyl)piperidin-1-yl)ethanon; (2,2-dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3- yl )-5,6,7,8-tetrahyd ropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; (2,2-dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)- 5.6.7.8- tetrahyd ropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyri-midin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon; ((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyri- midin-4-ylamino)pyrrolidin-1-yl)((1s,4R)-4-methoxycyclohexyl)methanon; ((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahyd ropyrido[4,3-d]-pyrimidin-4-ylamino)pyrrolidin-1-yl)((1r,4S)-4-methoxycyclohexyl)methanon; ((1s,4R)-4-hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)- 5.6.7.8- tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; ((1s,4R)-4-hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; ((1r,4S)-4-hydroxycyclohexyl)((S)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)- 5.6.7.8- tetrahyd ropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; ((1r,4S)-4-hydroxycyclohexyl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; (S)-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon; (3-(6-(6-methoxy-5-methylpyridin-3-yl )-5,6,7,8-tetrahyd ropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanon; (S)-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon; (3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- ylamino)pyrrolidin-1-yl)(oxazol-5-yl)methanon; (S)-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanon; (3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- ylamino)pyrrolidin-1-yl)(oxazol-4-yl)methanon; (2,2-dimethyltetrahydro-2H-pyran-4-yl)((S)-3-(6-(6-methoxy-5-methylpyridin-3-yl)- 5.6.7.8- tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; (2,2-dimethyltetrahydro-2H-pyran-4-yl)(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)methanon; (S)-1-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1 -yl)propan-1 -on; 1-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1 -yl)propan-1 -on; (S)-(3-(6-(5-chlor-6-methoxypyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(5-chlor-6-methoxypyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (S)-(3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (3-(6-(6-methoxy-5-methylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- ylamino)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanon; (tetrahydro-pyran-4-yl)-{(S)-3-{6-(5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanon; (tetrahyd ro-pyran-4-yl)-{3-{6-(5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-ylamino)pyrrolidin-1-yl}-methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(4-methylpiperazin-1-yl)methanon; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahyd ropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(morpholino)methanon; (S)-(4-hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8- tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl)methanon; 4-hydroxypiperidin-1-yl)(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetra- hydropyndo[4,3-d]pynmidin-4-yloxy)pyrrolidin-1-yl)methanon; (S)-N-(2-hydroxyethyl)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetra- hydropyndo[4,3-d]pynmidin-4-yloxy)-N-methylpyrrolidin-1-carboxamid; N-(2-hydroxyethyl)-3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-4-yloxy)-N-methylpyrrolidiri-1-carboxamid; (S)-1-(4-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido- [4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)piperazin-1-yl)ethanon; 1- (4-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl )-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yloxy)pyrrolidin-1-carbonyl)piperazin-1-yl)ethanon; (S)-2-methoxy-5-(4-(1-(morpholin-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido-[4,3-d]pyrimidin-6(5H)-yl)nicotinnitril; 2- methoxy-5-(4-(1-(morpholin-4-carbonyl)pyrrolidin-3-yloxy)-7,8-dihydropyrido[4,3-d]-pyrimidin-6(5H)-yl)nicotinnitril; (S)-(3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]- pyrimidin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanon; (3-(6-(6-methoxy-5-(trifluormethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyri- midin-4-yloxy)pyrrolidin-1-yl)(oxazol-4-yl)methanon; 1-(4-{(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido- [4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon; 1-(4-{3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-carbonyl}-piperidin-1-yl)-ethanon; {(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon; {3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin- 4-yloxy]-pyrrolidin-1-yl}-(3-methyl-3H-imidazol-4-yl)-methanon; {(S)-3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]- pyrimidin-4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon; {3-[6-(6-methoxy-5-trifluormethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin- 4-yloxy]-pyrrolidin-1-yl}-oxazol-5-yl-methanon; {(S)-3-[6-(6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon; og {3-[6-(6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanon.
8. PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, til anvendelse ifølge ethvert at kravene 1 til 7, i form af et salt valgt blandt a) citrat, fumarat eller napadisylat; eller b) phosphat, hydrochlorid eller hippurat.
9. Farmaceutisk sammensætning omfattende en PI3K inhibitor, hvor inhibitoren har en inhibitorisk virkning på PI3K isoformen delta, eller farmaceutisk acceptable salte eller solvater deraf, hvor PI3K inhibitoren er som angivet i ethvert af kravene 1 til 8, til anvendelse ved behandlingen af immunopathologi i et subjekt, som lider af en sygdom eller lidelse valgt blandt akut og cerebral malaria, via funktionel inhibering af TLR9 for det inficerede subjekt.
10. Kombination omfattende en PI3K inhibitor, hvor inhibitoren haren inhibitorisk virkning på PI3K isoformen delta, eller farmaceutisk acceptable salte eller solvater deraf, hvor PI3K inhibitoren er som angivet i ethvert af kravene 1 til 8, til anvendelse ved behandlingen af immunopathologi i et subjekt, som lider af en sygdom eller lidelse valgt blandt akut og cerebral malaria, via funktionel inhibering af TLR9 for det inficerede subjekt, og ét eller flere yderligere aktive ingredienser.
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