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US 2026/0308172 A1Published application
Tricyclic compounds for treatment of bacterial infections
AssigneeHoffmann-La Roche Inc.
InventorsFabian DEY, Xiao DING, Christian LERNER, Houguang SHI, Xuefei TAN, Jun WU, Jiamin ZHENG
Life of this patent
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Abstract
The present invention relates to compounds of formula (I), wherein R1 to R3, X, Y, A and W are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.
Claims26
A compound of formula (I),
- wherein
- X is C1-6alkylene, O, S or NH;
- Y is C1-6alkylene, O, S, SO, SO2 or NH;
- A is CH or N;
- W is C1-6alkylene, haloC1-6alkylene, O, S, SO, SO2 or NH;
- R1 is H, (aminoheterocyclyl)C1-6alkyl, [(aminoC1-6alkyl)heterocyclyl]C1-6alkyl, amino, aminoC1-6alkyl, hydroxyC1-6alkyl or heterocyclylamino;
- R2 is amino, C1-6alkyl, halogen, haloC1-6alkyl, C1-6alkoxy or haloC1-6alkoxy;
- R3 is (aminoC1-6alkylamino)carbonylC2-6alkynyl,
- C3-7cycloalkyl substituted by (aminoC1-6alkyl)2aminocarbonyl, [(aminoC1-6alkyl)pyrrolidiniumyl]C1-6alkylamino, [(aminocarbonylC1-6alkyl)pyrrolidiniumylC1-6alkyl]amino, [aminocarbonylC1-6alkyl(C1-6alkyl)pyrrolidiniumylcarbonyl]amino, amino, aminoC1-6alkylaminocarbonyl or aminoC1-6alkylcarbonylamino,
- halogen,
- heterocyclyl unsubstituted or substituted by amino, C1-6alkyl, aminoC1-6alkylcarbonyl, (aminoC1-6alkylcarbonyl)aminoC1-6alkylcarbonyl, aminoC1-6alkyl or aminocarbonylC1-6alkyl, or
- aryl or heteroaryl unsubstituted or substituted by amino, C1-6alkyl, halogen, haloC1-6alkyl, C1-6alkoxy or haloC1-6alkoxy,
- or a pharmaceutically acceptable salt thereof.
10 more elements
A compound selected from:
- trans-3-(aminomethyl)-7-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-(6-chloro-4-cyclopropylsulfonyl-2-pyridyl) piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[4-(4-aminophenyl)sulfonyl-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-3-(aminomethyl)-7-[4-(6-chloro-4-cyclopropylsulfonyl-2-pyridyl) piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-3-(aminomethyl)-7-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-3-(aminomethyl)-7-[4-[6-chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 3-Amino-7-[4-[6-chloro-4-[1,4-dioxan-2-yl(difluoro)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro(3-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro-(1-methyl-4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 7-[4-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- 7-[4-[6-Chloro-4-(trifluoromethyl)-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- 7-[4-[4-(4-Aminophenyl)sulfonyl-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- 7-[4-[4-(4-Aminophenyl)sulfonyl-6-bromo-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- (3R,3aR)-3-(hydroxymethyl)-7-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 7-[4-[6-Chloro-4-[difluoro-(1-methyl-4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[6-chloro-4-[1,4-dioxan-2-yl(difluoro)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro(3-oxabicyclo[3.1.0]hexan-6-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- trans-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro-(2-methyl-4-pyridyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aS)-3-(Aminomethyl)-7-[4-[6-chloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3S,3aR)-3-(aminomethyl)-7-[4-[6-chloro-4-[[(2S)-1,4-dioxan-2-yl]-difluoro-methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3S,3aS)-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-3-(aminomethyl)-7-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aS)-3-[(3-aminoazetidin-1-yl)methyl]-7-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aS)-3-[[3-(aminomethyl)azetidin-1-yl]methyl]-7-[4-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]sulfonyl-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 7-[4-[6-Chloro-4-[difluoro-[rac-(2S)-1,4-dioxan-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(4-piperidylamino)-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[6-chloro-4-[difluoro(4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3S,3aS)-7-[4-[6-chloro-4-[difluoro(4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 7-[4-[6-Chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- 3-Amino-7-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- cis-7-[4-[6-chloro-4-[difluoro-[(2R)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- cis-7-[4-[6-Chloro-4-[difluoro(3-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[3-azabicyclo[3.1.0]hexan-6-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[azetidin-3-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[3-azabicyclo[3.1.0]hexan-1-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3S,3aR)-7-[4-[6-chloro-4-[difluoro(4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aS)-7-[4-[6-chloro-4-[difluoro(4-piperidyl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[2-azaspiro[3.3]heptan-6-yl(difluoro)methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aS)-7-[4-[6-chloro-4-[difluoro-(5-methylmorpholin-2-yl)methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[[1-(2-aminopropanoyl)azetidin-3-yl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-(4-aminocyclohexoxy)-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 3-Amino-7-[4-[4-(4-aminocyclohexoxy)-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-1-one;
- (E)-4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-N-(3-aminopropyl)-4,4-difluoro-but-2-enamide;
- 4-[[2-[4-[(3-Amino-1-oxo-2,3,3a,4-tetrahydropyrrolo[2,1-c][1,4]benzoxazin-7-yl)sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)cyclohexanecarboxamide;
- 4-[[2-[4-[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)cyclohexanecarboxamide;
- 4-[[2-[4-[[cis-3-(aminomethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)cyclohexanecarboxamide;
- 4-[[2-[4-[[(3R,3aS)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N,N-bis(3-aminopropyl)cyclohexanecarboxamide;
- 4-[[2-[4-[[(3R,3aS)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-(3-aminopropyl)cyclohexanecarboxamide;
- trans-7-[4-[6-chloro-4-[difluoro-[(2S)-morpholin-2-yl]methyl]-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- N-[4-[[2-[4-[[(3R,3aS)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]oxy]cyclohexyl]-3-amino-propanamide;
- (3R,3aR)-7-[4-[4-[[1-[2-[bis(2-aminoethyl)amino]acetyl]-4-piperidyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[[1-(2-aminoacetyl)-4-piperidyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[[1-(3-aminopropanoyl)-4-piperidyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- (3R,3aR)-7-[4-[4-[[1-(2-aminoethyl)-4-piperidyl]-difluoro-methyl]-6-chloro-2-pyridyl]piperazin-1-yl]sulfonyl-3-(hydroxymethyl)-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-1-one;
- 2-[4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-1-piperidyl]acetamide;
- N-[2-[4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-1-piperidyl]-2-oxo-ethyl]-2-amino-acetamide;
- (1S,2S)—N-[4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexyl]-1-(2-amino-2-oxo-ethyl)-1-methyl-pyrrolidin-1-ium-2-carboxamide;chloride;
- (1R,2S)—N-[4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexyl]-1-(2-amino-2-oxo-ethyl)-1-methyl-pyrrolidin-1-ium-2-carboxamide;chloride;
- (1S,2S)—N-[4-[[2-[4-[[(3S,3aR)-3-(aminomethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexyl]-1-(2-amino-2-oxo-ethyl)-1-methyl-pyrrolidin-1-ium-2-carboxamide;chloride;
- (1R,2S)—N-[4-[[2-[4-[[(3S,3aR)-3-(aminomethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]cyclohexyl]-1-(2-amino-2-oxo-ethyl)-1-methyl-pyrrolidin-1-ium-2-carboxamide;chloride;
- (2S)-1-(2-aminoethyl)-N-[4-[[2-chloro-6-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-4-pyridyl]-difluoro-methyl]cyclohexyl]-1-methyl-pyrrolidin-1-ium-2-carboxamide;chloride;
- 4-[[2-[4-[[(3R,3aR)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[2-[1-(2-amino-2-oxo-ethyl)pyrrolidin-1-ium-1-yl]ethyl]cyclohexanecarboxamide;chloride;
- and
- 4-[[2-[4-[[(3R,3aS)-3-(hydroxymethyl)-1-oxo-3a,4-dihydro-3H-oxazolo[4,3-c][1,4]benzoxazin-7-yl]sulfonyl]piperazin-1-yl]-6-chloro-4-pyridyl]-difluoro-methyl]-N-[2-[1-(2-aminoethyl)pyrrolidin-1-ium-1-yl]ethyl]cyclohexanecarboxamide;chloride;
- or a pharmaceutically acceptable salt thereof.
63 more elements
Dependencies are inferred from the claim text.