DK2721016T3 - TRPV4-antagonister - Google Patents

TRPV4-antagonister Download PDF

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DK2721016T3
DK2721016T3 DK12814591.9T DK12814591T DK2721016T3 DK 2721016 T3 DK2721016 T3 DK 2721016T3 DK 12814591 T DK12814591 T DK 12814591T DK 2721016 T3 DK2721016 T3 DK 2721016T3
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methyl
oxa
carbonitrile
oxo
azaspiro
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Carl Brooks
Mui Cheung
Hilary Schenck Eidam
Krista B Goodman
Marlys Hammond
Mark A Hilfiker
Tram H Hoang
Jaclyn R Patterson
Patrick Stoy
Guosen Ye
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Glaxosmithkline Intellectual Property (No 2) Ltd
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Claims (17)

1. Forbindelse med formlen (I):
(i) hvor: Ri er hydrogen, Ci-3alkyl, CH2OH, CH2-0-CH3, CH2OCH2Ph, CH2CN, CN, halogen eller C(0)0CH3; R2 uafhaangigt er hydrogen, CN, CF3, halogen, S02Ci.3alkyl, Ci-3alkyl eller CECH; R3 er hydrogen, Ci.2alkyl, CF3 eller OH; R4 er hydrogen, halogen eller C-i-3alkyl; X er CR4 eller N; A er (CH2)n - Het; eller A er (CH2)n-(CRaRb)-(CH2)m-Het; Ra er hydrogen eller Ci-3alkyl, hvor Ci-3alkylet kan vaare yderligere substitue-ret med et eller fiere halogener; Rb er Ci-3alkyl; eller Ra og Rb sammen med det carbonatom, til hvilket de er bundet, danner en C3.6cycloalkylgruppe; eller et af carbonatomerne i C3-6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaare erstattet med oxygen til dannelse af en oxetan-, tetrahydrofuryl-eller tetrahydropyranylgroup; eller et af carbonatomerne i C3-6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med nitrogen til dannelse af en pyrrolidinyl- eller piperidi-nylgruppe; Het er:
hvor Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, Cr5alkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)„-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)„-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci-3alkyl, CH(OH)-C-i-5alkyl, C(CH3)2 - R5, C(0)N(CH3)p, N(C1.3alkyl)p, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl, tetrahydropyranyl, morpholinyl eller pyrazolyl; hvor phenyl-, pyrazolyl- og pyridyl-substituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, Ci-3alkyl eller CF3; og Ci-5alkyl- og C3.6cycloalkyl-substituenten pa Het kan vaere yderligere substitueret med CN eller OH; R5 er CN, 0-C1.4alkyl, (CH2)m - OH, (CH2)P - O - C(O) - O - C^alkyl eller O-(CH2)p-0 -R6; R6 er Ci-4alkyl eller P(0)2(CH3)2; n uafhaengigt er 0,1 eller 2; m uafhaengigt er 0, 1 eller 2; p uafhaengigt er 1 eller 2; og y er 1,2 eller 3; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifolge krav 1, hvor: Ri er hydrogen, Ci-3alkyl, CH2OH, CH2-0-CH3, CH2OCH2Ph, CH2CN, CN, halogen eller C(0)0CH3; R2 uafhaengigt er hydrogen, CN, CF3, halogen, S02Ci-3alkyl, Ci-3alkyl eller CECH; R3 er hydrogen, Ci_2alkyl, CF3 eller OH; R4 er hydrogen, halogen eller Ci-3alkyl; X er CR4 eller N; A er (CH2)n - Het; eller A er (CH2)n-(CRaRb)-(CH2)m-Het; Ra er hydrogen eller Ci-3alkyl, hvor Ci-3alkylet kan vaere yderligere substitue-ret med et eller fiere halogener; Rb er Ci-3alkyl; eller Ra og Rb sammen med det carbonatom, til hvilket de er bundet, danner en C3-6cycloalkylgruppe; eller et af carbonatomerne i C3-6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med oxygen til dannelse af en oxetan-, tetrahydrofuryl-eller tetrahydropyranylgruppe; eller et af carbonatomerne i C3-6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med nitrogen til dannelse af en pyrrolidinyl- eller piperidi-nylgruppe; Het er
hvor Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, Cr5alkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci-3alkyl, C(CH3)2-OH, C(CH3)2-0-CH3, C(CH3)2-CN, C(CH3)2-CH2OH, C(CH3)2-CHz-O-CiOJ-O-C^alkyl, C(0)N(CH3)p, NiC^alkylJp, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl eller tetrahydropyranyl; hvor phenyl- og pyridyl-substituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, C-i-3alkyl eller CF3; og Ci-5alkyl- og C3.6cycloalkylsubstituenten pa Het kan vaere yderligere substitueret med CN eller OH; n uafhaengigt er 0,1 eller 2; m uafhaengigt er 0, 1 eller 2; p uafhaengigt er 1 eller 2; y er 1,2 eller 3; eller et farmaceutisk acceptabelt salt deraf.
3. Forbindelse ifolge krav 1 eller 2, hvor: Ri er hydrogen, Ci-3alkyl eller CH2OH; R2 er CN; R3 er hydrogen; Xer N; A er (CH2)n - Het; eller A er (CH2)n-(CRaRb)-(CH2)m-Het; Ra er hydrogen eller C-i-3alkyl, hvor Ci-3alkyl kan vaere yderligere substitueret med et eller fiere halogener; Rb er Ci-3alkyl; eller Ra og Rb sammen med det carbonatom, til hvilket de er bundet, danner en C3.6cycloalkylgruppe; eller et af carbonatomerne i C3-6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med oxygen til dannelse af en oxetan-, tetrahydrofuryl-eller tetrahydropyranylgruppe; eller et af carbonatomerne i C3.6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med nitrogen til dannelse af en pyrrolidinyl- eller piperidi-nylgruppe; Het er
hvor Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, Ci-5alkyl, CN, CH2F, CHF2, CF3, C3.6cycloalkyl, (CH2)„-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0·^- 3alkyl, C(CH3)2-OH, C(CH3)2-0-CH3, C(CH3)2-CN, C(CH3)2-CH2OH, C(CH3)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH3)p, N(Ci-3alkyl)p, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl eller tetrahydropyranyl; hvor phenyl- og pyridylsubstituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, Ci-3alkyl eller CF3; og Ci-5alkyl- og C3.6cycloalkylsubstituenten pa Het kan vaere yderligere substitueret med CN eller OH; n uafhaengigt er 0 eller 1; m uafhaengigt er 0 eller 1; p uafhaengigt er 1 eller 2; og y er 1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
4. Forbindelse ifolge et af kravene 1-3, hvor: Ri er hydrogen, Ci_3alkyl eller CH2OH; R2 er CN; R3 er hydrogen; XerN; A er (CH2)n - Het; eller A er (CH2)n-(CRaRb)-(CH2)m-Het; Ra er hydrogen eller Ci_3alkyl, hvor C-|.3alkyl kan vaare yderligere substitueret med et eller fiere halogener; Rb er Ci_3alkyl; eller Ra og Rb sammen med det carbonatom, til hvilket de er bundet, danner en C3.6cycloalkylgruppe; eller et af carbonatomerne i C3.6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaare erstattet med oxygen til dannelse af en oxetan-, tetrahydrofuryl-eller tetrahydropyranylgruppe; eller et af carbonatomerne i C3.6cycloalkylgruppen, der er dannet af Ra og Rb, kan vaere erstattet med nitrogen til dannelse af en pyrrolidinyl- eller piperidi-nylgruppe; Het er
hvor Het Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, Ci-5alkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-
0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci.3alkyl, C(CH3)2-OH, C(CH3)2-0-CH3, C(CH3)2-CN, C(CH3)2-CH2OH, C(CH3)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH3)p, N(Ci-3alkyl)p, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl eller tetrahydropyranyl; hvor phenyl- og pyridylsubstituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, Ci-3alkyl eller CF3; og Ci.5alkyl- og C3.6cycloalkylsubstituenten pa Het kan vaere yderligere substitueret med CN eller OH; n uafhaengigt er 0 eller 1; m uafhaengigt er 0 eller 1; p uafhaengigt er 1 eller 2; og y er 1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
5. Forbindelse ifolge et af kravene 1-4, hvor: Ri er hydrogen, C-|.3alkyl eller CH2OH; R2 er CN; R3 er hydrogen; Xer N; A er (CH2)n - Het; Het er
hvor Het Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, C1.5alkyl, CN, CH2F, CHF2, CF3, C3.6cycloalkyl, (CH2)n-
0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci-3alkyl, C(CH3)2-OH, C(CH3)2-0-CH3, C(CH3)2-CN, C(CH3)2-CH2OH, C(CH3)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH3)p, N(Ci-3alkyl)p, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl eller tetrahydropyranyl; hvor phenyl- og pyridylsubstituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, Ci-3alkyl eller CF3; og Ci-salkyl- og C3.6cycloalkylsubstituenten pa Het kan vaere yderligere substitueret med CN eller OH; n uafhaengigt er 0 eller 1; p uafhaengigt er 1 eller 2; og y er 1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
6. Forbindelse ifolge et af kravene 1-5, hvor: Ri er hydrogen, C^alkyl eller CH2OH; R2 er CN; R3 er hydrogen; XerN; A er (CH2)n - Het; Het er
hvor Het kan vaere substitueret med en, to eller tre substituenter, der er valgt blandt: halogen, Ci-5alkyl, CN, CH2F, CHF2, CF3, C3.6cycloalkyl, (CH2)n-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci. 3alkyl, C(CH3)2-OH, C(CH3)2-0-CH3, C(CH3)2-CN, C(CH3)2-CH2OH, C(CH3)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH3)p, N(Ci-3alkyl)p, NH2, C(0)NH2, oxetan, oxetan-CH3, tetrahydrofuryl eller tetrahydropyranyl; hvor phenyl- og pyridylsubstituenten pa Het kan vaere yderligere substitueret med en eller to substituenter, der er valgt blandt: halogen, CN, OCH3, Ci-3alkyl eller CF3; og Ci-5alkyl- og C3-6cycloalkylsubstituenten pa Het kan vasre yderligere substitueret med CN eller OH; n er 0; p uafhasngigt er 1 eller 2; og y er 1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
7. Forbindelse ifolge krav 1, der er valgt blandt: 1 -({(5S,7S)-3-[3-(1,1 -dimethylethyl)-5-isoxazolyl]-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(2-cyanopropan-2-yl)isoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -({(5S,7S)-3-[5-(1,1 -dimethylethyl)-3-isoxazolyl]-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-7-methyl-2-oxo-3-(2-pyridinylmethyl)-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[2-methyl-2-(5-phenyl-1,3,4-oxadiazol-2-yl)propyl]-2-oxo- 1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[2-(3-ethyl-1,2,4-oxadiazol-5-yl)-2-methylpropyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{[3-methyl-1-(2-pyrimidinyl)-3-pyrrolidinyl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-7-methyl-2-oxo-3-[(1 -phenyl-1 H-1,2,3-triazol-4-yl)methyl]-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-2-oxo-3-({1 -[5-(trifluormethyl)-3-pyridinyl]-1 H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[4-chlor-3-(1,1 -dimethylethyl)-5-isoxazolyl]-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-2-oxo-3-[5-(trifluormethyl)-2-pyridinyl]-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[6-(ethyloxy)-3-pyridinyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-methoxypyridin-3-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-methoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(1 -ethyl-5-methyl-1 H-pyrazol-4-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((7S)-3-(5-methoxypyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-chlorpyridin-3-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-(dimethylamino)pyridin-3-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; tert-butyl (2-(5-((5S,7S)-7-((6-cyano-1 H-benzo[d]imidazol-1 -yl)methyl)- 7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)isoxazol-3-yl)-2- methylpropyl)-carbonat; 1 -(((5S, 7S)-3-(3-(1 -hydroxy-2-methylpropan-2-yl)isoxazol-5-yl)-7 - methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(4,6-dimethoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-ethoxy-4-methylpyridin-3-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-ethoxy-4-methylpyridazin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-7-methyl-2-oxo-3-(2-(trifluormethyl)pyrimidin-5-yl)-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-7-methyl-2-oxo-3-(3-(trifluormethyl)pyridin-2-yl)-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -({(5S,7S)-3-[(5-chlor-1 -benzothien-3-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-(2-{3-[1 -(ethyloxy)ethyl]-1,2,4-oxadiazol-5-yl}-2-methylpropyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-7-methyl-3-(5-methyl-2-pyridinyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-7-methyl-3-[3-(1 -methylethyl)-5-isoxazolyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-3-[3-(2-methylpropyl)-5-isoxazolyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-(1 -tert-butyl-1 H-pyrazol-4-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-(3-ethyl-5-isoxazolyl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-{[(5S,7S)-3-(3-cyclopropyl-5-isoxazolyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-7-methyl-2-oxo-3-(3-phenyl-5-isoxazolyl)-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[3-(1,1 -dimethylethyl)-1 -methyl-1 H-pyrazol-5-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-2-oxo-3-[3-(trifluormethyl)-5-isoxazolyl]-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[3-(1 -cyanocyclopropyl)-5-isoxazolyl]-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(2-fluorpropan-2-yl)isoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-cyclobutylisoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(tert-butyl)-4-methylisoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(4-(tert-butyl)oxazol-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(1 -(tert-butyl)-l H-pyrazol-4-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(tert-butyl)-4-fluorisoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(3-(1,1 -difluorethyl)isoxazol-5-yl)-7-methyl-2-oxo-1 -oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(tert-butyl)-4-methylisoxazol-5-yl)-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-(tert-butyl)-4-fluorisoxazol-5-yl)-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-(tert-butyl)pyridazin-3-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(tert-butyl)pyrimidin-2-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(2-(tert-butyl)-2H-1,2,3-triazol-4-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6- carbonitril; 1 -(((5S,7S)-7-methyl-3-(3-(1 -methyl-1 H-pyrazol-3-yl)isoxazol-5-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(1 -(tert-butyl)-l H-1,2,3-triazol-4-yl)-7-methyl-2-oxo-1 - oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6- carbonitril; 1-(((5S,7S)-3-(5-(tert-butyl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-7-methyl-2-oxo-3-(5-(trifluormethyl)pyrimidin-2-yl)-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-(2-methoxypropan-2-yl)pyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-2-oxo-3-(3-(prop-1 -en-2-yl)isoxazol-5-yl)-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3,4-dimethylisoxazol-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(3,4-dimethylisoxazol-5-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -({3-[(5-chlor-1 -benzothien-3-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-ylmethyl)-1 H-indol-6-carbonitril; 1 -({3-[(5-chlor-1 -benzothien-3-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-2-(trifluormethyl)-1 H-benzimidazol-6-carbonitril; 1 -({3-[(5-chlor-1 -benzothien-3-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -{[3-(1 -benzothien-3-ylmethyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(6-phenyl-2-pyridinyl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{2-methyl-2-[3-(tetrahydro-2H-pyran-4-yl)-1,2,4-oxadiazol-5-yl]propyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(4-phenyl-1,3-thiazol-2-yl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{[3-(4-chlorphenyl)-5-isoxazolyl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(3-phenyl-5-isoxazolyl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[(1 -methyl-5-phenyl-1 H-pyrazol-3-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-{[(5S,7S)-3-({4-[3-methyl-4-(methyloxy)phenyl]-1,3-thiazol-2-yl}methyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(3-phenyl-1 H-1,2,4-triazol-5-yl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(5-phenyl-3-pyridinyl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril-trifluoracetat; 4-chlor-1-({(5S,7S)-3-[2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[2-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{2-methyl-2-[3-(1 -methylethyl)-1,2,4-oxadiazol-5-yl]propyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1- ({(5S,7S)-3-[2-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)-2-methylpropyl]- 2- oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{2-methyl-2-[3-(5-pyrimidinyl)-1 ;2,4-oxadiazol-5- yl]propyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{2-[3-(1,1 -dimethylethyl)-1,2,4-oxadiazol-5-yl]-2-methylpropyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{2-methyl-2-[3-(trifluormethyl)-1,2,4-oxadiazol-5-yl]propyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1-{[(5S,7S)-3-(2-methyl-2-{3-[(methyloxy)methyl]-1,2,4-oxadiazol-5-yl}propyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-[((5S,7S)-3-{2-methyl-2-[3-(2-methylpropyl)-1,2,4-oxadiazol-5-yl]propyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[2-methyl-2-(3-{[(1 -methylethyl)oxy]methyl}-1,2,4-oxadiazol-5-yl)propyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 4-chlor-1 -[((5S,7S)-2-oxo-3-{[4-(3-phenyl-1,2,4-oxadiazol-5-yl)tetrahydro-2H-pyran-4-yl]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 4-chlor-1 -[((5S,7S)-3-{[4-(3-cyclopentyl-1,2,4-oxadiazol-5-yl)tetrahydro-2H-pyran-4-yl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-2-oxo-3-{[1 -(2-pyridinyl)-3-pyrrolidinyl]methyl}-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-2-oxo-3-[(1 -phenyl-1 H-1,2,3-triazol-4-yl)methyl]-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(4-cyanophenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(4-chlorphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3-chlorphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(4-methylphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3-cyanophenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-2-oxo-3-({1 -[3-(trifluormethyl)phenyl]-1 H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3-fluorphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-({1 -[3-(methyloxy)phenyl]-1 H-1,2,3-triazol-4-yl}methyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3-methylphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo- 1- oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[(1 -cyclohexaneyl-1 H-1,2,3-triazol-4-yl)methyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-({1 -[4-cyano-3-(trifluormethyl)phenyl]-1 H-1,2,3-triazol-4-yl}methyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3-chlor-5-cyanophenyl)-1 H-1,2,3-triazol-4-yl]methyl}- 2- oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-2-oxo-3-({1 -[2-(trifluormethyl)-4-pyridinyl]-1 H-1,2,3-triazol-4-yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(3,5-difluorphenyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-2-oxo-3-({1 -[4-(trifluormethyl)phenyl]-1 H-1,2,3-triazol-4- yl}methyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazol-6- carbonitril; 1 -[((5S,7S)-3-{[1 -(3-cyano-5-fluorphenyl)-1 H-1,2,3-triazol-4-yl]methyl}- 2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1H-benzimidazol-6- carbonitril; 1 -[((5S,7S)-7-methyl-3-{[1 -(1 -methylethyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1 -({(5R,7S)-7-methyl-2-oxo-3-[(1 -phenyl-1 H-1,2,3-triazol-4-yl)methyl]-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -[((5S,7S)-3-{[1 -(5-chlor-3-pyridinyl)-1 H-1,2,3-triazol-4-yl]methyl}-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl)methyl]-1 H-benzimidazol-6-carbonitril; 1- (((5S,7S)-3-(4-chlor-3-(2-cyanopropan-2-yl)isoxazol-5-yl)-7-methyl- 2- oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -({(5S,7S)-3-[4-bromo-3-(1,1 -dimethylethyl)-5-isoxazolyl]-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-3-[2-(methyloxy)-3-pyridinyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[2,6-bis(methyloxy)-3-pyridinyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[4-methyl-6-(methyloxy)-3-pyridinyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; 1 -(((7S)-3-(3,5-dichlorpyridin-2-yl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(2-ethoxypyrimidin-5-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-chlor-3-fluorpyridin-2-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-7-methyl-2-oxo-3-(5-(trifluormethyl)pyrazin-2-yl)-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(2-(tert-butyl)pyrimidin-5-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-3-(5-methylpyrazin-2-yl)-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-ethoxy-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-chlor-4-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-chlor-4-methylpyridin-3-yl)-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-chlor-3-methylpyridin-2-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-chlor-4-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-chlor-4-methoxypyridin-3-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(4-methyl-2-(trifluormethyl)pyrimidin-5-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(6-ethoxy-4-methylpyridin-3-yl)-2-oxo-1 -oxa-3- azaspiro[4.5]decan-7-yl)methyl)-5-fluor-1H-benzo[d]imidazol-6- carbonitril; 1-(((5S,7S)-3-(2-methoxy-6-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-methoxy-5-methylpyridin-2-yl)-7-methyl-2-oxo-1-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-chlor-5-methylpyridin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-(3-ethylpyridin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3,5-dimethylpyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(3-methyl-5-(trifluormethyl)pyrazin-2-yl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-methoxy-5-methylpyridin-3-yl)-7-methyl-2-oxo-1-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-(2-cyanopropan-2-yl)pyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(2-(tert-butyl)pyrimidin-5-yl)-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-3-[5-(methyloxy)-2-pyridinyl]-2-oxo-1-oxa-3- azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[6-(ethyloxy)-3-pyridazinyl]-7-methyl-2-oxo-1-oxa-3- azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -{[(5S,7S)-3-(3-chlor-2-pyridinyl)-7-methyl-2-oxo-1 -oxa-3- azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-3-[3-(methyloxy)-2-pyridinyl]-2-oxo-1-oxa-3- azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-({(5S,7S)-7-methyl-2-oxo-3-[6-(trifluormethyl)-3-pyridinyl]-1-oxa-3- azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -(((7S)-7-methyl-3-(6-methylpyridin-3-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1 -({(5S,7S)-3-[4,6-bis(methyloxy)-3-pyridinyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1 -({(5S,7S)-3-[6-(11 -methylethyl)-3-pyridinyl]-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazol-6-carbonitril; 1-((7-(hydroxymethyl)-3-(6-methoxy-4-methylpyridin-3-yl)-2-oxo-1-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-7-methyl-2-oxo-3-(4-(trifluormethyl)pyridin-3-yl)-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(2-(dimethylamino)pyrimidin-5-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-3-(4-methylpyridin-3-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-7-methyl-2-oxo- 1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazol-6- carbonitril; 1 -(((5S,7S)-3-(4-methoxypyridin-3-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(dimethylamino)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-{[(5S,7S)-2-oxo-3-(thieno[2,3-b]pyridin-3-ylmethyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-{[(trans)-7-methyl-2-oxo-3-(thieno[2,3-b]pyridin-3-ylmethyl)-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-({(5S,7S)-3-[(3-bromothieno[2,3-b]pyridin-2-yl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1 H-benzimidazol-6-carbonitril; og 1 -{[(5S,7S)-3-(2-methyl-2-{3-[1 -(methyloxy)ethyl]-1,2,4-oxadiazol-5-yl}propyl)-2-oxo-1 -oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1 H-benzimidazol-6-carbonitril; 1-(((5S,7S)-3-((5-ethoxypyrazin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-((4-ethoxypyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-((5-ethoxypyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-3-((4-fluorpyrid in-2-yl)methyl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-((5-fluorpyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-3-((4-(1 -methyl-1 H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H- benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-3-((6-(1 -methyl-1 H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(2-methoxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1- (((5S,7S)-3-(5-(2-(2-methoxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 2- ((2-(5-((5S,7S)-7-((6-cyano-1 H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinat; 1 -(((5S,7S)-3-(5,-fluor-4-methyl-[2,2'-bipyrid in]-5-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1 -(((5S,7S)-7-methyl-3-(4-methyl-6-morpholinopyrid in-3-yl)-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(5-(1-hydroxy-2-methylpropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1 -oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; 1-(((5S,7S)-3-(6-cyclopropyl-4-methoxypyridin-3-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril; eller et farmaceutisk acceptabelt salt deraf.
8. Forbindelse ifolge krav 1, der er 1-(((5S,7S)-3-(5-ethoxypyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril
eller et farmaceutisk acceptabelt salt deraf.
9. Forbindelse ifolge krav 1, der er 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1 H-benzo[d]imidazol-6-carbonitril
eller et farmaceutisk acceptabelt salt deraf.
10. Farmaceutisk sammensaetning omfattende en forbindelse ifolge et af kravene 1 -9 og en farmaceutisk acceptabel baerer eller excipiens.
11. Forbindelse til anvendelse ved terapi, hvor forbindelsen er en forbindelse ifolge et af kravene 1 -9.
12. Forbindelse til anvendelse ved behandling eller forebyggelse af en til-stand, hvor tilstanden er valgt fra gruppen bestaende af aterosklerose, lidel-ser, der er relateret til tarmodem, post-kirurgisk abdominalt odem, lokalt og systemisk odem, vasskeansamling, sepsis, forhojet blodtryk, inflammation, knoglerelaterede dysfunktioner og kongestiv hjerteinsufficiens, lungelidelser, kronisk obstruktiv lungesygdom, andedrastsinduceret lungeskade, hojdeindu-ceret lungeodem, akut respiratorisk distress syndrom, akut lungeskade, lun-gefibrose, sinusitis/rhinitis, astma, overaktiv blasrer, smerte, motorneuronli-delser, genetisk gain-of-function-lidelser, kardiovaskulasr sygdom, nyredys-funktion, osteoarthritis, Crohns sygdom, colitis, diarré, tarmuregelmasssighed (hyperreaktivitet/hyporeaktivitet), afforingsinkontinens, irritabel tyktarm (IBS), forstoppelse, tarmsmerter og -kramper, coliaki, laktoseintolerans og flatulens, hvor forbindelsen er en forbindelse ifolge et af kravene 1 -9.
13. Forbindelse til anvendelse ifolge krav 12, hvor forbindelsen administreres oralt.
14. Forbindelse til anvendelse ifolge krav 12, hvor forbindelsen administreres intravenost.
15. Forbindelse til anvendelse ifolge krav 12, hvor forbindelsen administreres ved inhalering.
16. Forbindelse til anvendelse ifolge krav 12, hvor sygdommen er kongestiv hjerteinsufficiens.
17. Forbindelse til anvendelse ifolge krav 12, hvor sygdommen er akut lun-geskade.
DK12814591.9T 2011-06-17 2012-06-15 TRPV4-antagonister DK2721016T3 (da)

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JPWO2015046193A1 (ja) 2013-09-25 2017-03-09 塩野義製薬株式会社 Ｔｒｐｖ４阻害活性を有する芳香族複素環式アミン誘導体
WO2017199199A1 (en) 2016-05-19 2017-11-23 Glaxosmithkline Intellectual Property (No.2) Limited Trpv4 antagonist
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CO6821953A2 (es) 2013-12-31
HUE029594T2 (en) 2017-03-28
MX337440B (es) 2016-03-03
HK1195068A1 (zh) 2014-10-31
CY1117792T1 (el) 2017-05-17
EP3121177A1 (en) 2017-01-25
ZA201308816B (en) 2015-02-25
BR112013032391B1 (pt) 2020-11-24
PE20141943A1 (es) 2014-12-28
PT2721016E (pt) 2016-06-06
KR101870003B1 (ko) 2018-06-22
SG195106A1 (en) 2013-12-30
CN103732583B (zh) 2015-12-23
SI2721016T1 (sl) 2016-06-30
MY173521A (en) 2020-01-30
EA201490037A1 (ru) 2015-12-30
ES2569193T3 (es) 2016-05-09
MX2013014898A (es) 2014-03-21
ME02416B (me) 2016-09-20
RS54858B1 (sr) 2016-10-31
MA35184B1 (fr) 2014-06-02
CA2839743A1 (en) 2013-01-24
KR20140041733A (ko) 2014-04-04
JO3154B1 (ar) 2017-09-20
TW201313705A (zh) 2013-04-01
US9187464B2 (en) 2015-11-17
AR086958A1 (es) 2014-02-05
AU2012284540B2 (en) 2014-08-28
EA023616B1 (ru) 2016-06-30
DOP2013000307A (es) 2014-06-01
CL2013003602A1 (es) 2014-07-04
UY34138A (es) 2013-01-03
SMT201600150B (it) 2016-07-01
CR20130671A (es) 2014-02-04
BR112013032391A2 (pt) 2016-08-16
HRP20160539T1 (hr) 2016-06-17
PL2721016T3 (pl) 2017-01-31
AU2012284540A1 (en) 2013-04-04
WO2013012500A1 (en) 2013-01-24
EP2721016A4 (en) 2014-10-08
CN103732583A (zh) 2014-04-16
CA2839743C (en) 2017-03-28
JP5969017B2 (ja) 2016-08-10
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