Patent AU-2016275764-B2 (AU)
Title: Efflux-pump inhibitors and therapeutic uses thereof
Inventor: DREIER JÜRG
IPC: C07D403/12
Filed: 2016-06-13
Granted: 2021-02-18
Abstract: The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC is -N(R8)(R9)ASC-1 ASC-1 is Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom and wherein one CH2 moiety in ring A is optionally replaced by CH(R21) and wherein one carbon atom in ring A that is not adjacent to the nitrogen atom is optionally replaced by O, and wherein ring A is connected to X via a carbon atom; X represents a bond, -CH2- or -C(=O)-; ARl, AR2 represent independently phenyl or a 5- to 6- membered heteroaryl ring containing one to three heteroatoms selected from O, S and N, wherein AR1 is connected to LI via a carbon atom, and wherein AR2 is connected to L1 and L2 via a carbon atom; R1, R2, R3 represent independently hydrogen, halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C3- C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -C1-C6alkylene-N(R12)R13, -N(R12)R13, -C(O)OR11l, - C(O)N(R12)R13, -S(O)OR11 or phenyl; R4 represents hydroxyl, hydrogen, halogen, nitro, cyano, amino, C1-C6alkyl optionally substituted by 1 to 5 R14, C2-C6alkenyl optionally substituted by 1 to 5 R14, C2-C6alkynyl optionally substituted by 1 to 5 R14, C1-C6alkoxy optionally substituted by 1 to 5 R14, C2-C6alkenyloxy optionally substituted by 1 to 5 R14, C2-C6alkynyloxy optionally substituted by 1 to 5 R14, -C(O)OR15, -CHO, -C(O)N(R16)R17, -C1- C6alkylene-N(R9)(R16)R17, -O-Cycle-P or -O-Cycle-Q; R5, R6, R7 represent independently hydrogen, halogen, cyano, Cl-C6alkyl, C1-C6haloalkyl, Cl-C6alkoxy or C1-C6haloalkoxy; R8 represents hydrogen, methyl or ASC-1; R9 is methyl or absent, and wherein when R9 is present the respective nitrogen atom carries a positive charge; R10 represents hydrogen or methyl; Rl11 represents independently at each occurrence hydrogen or C1-C6alkyl; R12, R13 represent independently at each occurrence hydrogen or C1-C6alkyl; R14 represents independently at each occurrence halogen, cyano, hydroxyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C8cycloalkyl, -C(O)OR11, -CHO, -C(O)N(R12)R13, -C1-C6alkylene-N(R12)R13, Cycle-P, O-Cycle-P, Cycle-Q or O-Cycle-Q; Cycle-P represents independently at each occurrence a saturated or partially unsaturated C3-C8 carbocyclic ring optionally substituted by 1 to 3 R18, or a saturated or partially unsaturated C3-C8 heterocyclic ring optionally substituted by 1 to 3 Rl 8 containing carbon atoms as ring members and one or two ring members independently selected from N(R9)(R12), N(R9) and O; Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 R19 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 R19; R15 represents independently at each occurrence hydrogen or C1-C6alkyl optionally substituted by 1 to 5 R14; R16 and R17 represent independently at each occurrence hydrogen or C1-C6alkyl optionally substituted by 1 to 5 R14; R18 and R19 represent independently at each occurrence halogen, cyano, hydroxyl, oxo, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, Cl-C4haloalkoxy or -CO(O)R11; R20 represents independently at each occurrence hydrogen or methyl; R21 represents N(R20)2 or CH2-N(R20)2; LI represents -CH=CH-, -CH2-O-, -O-CH2-, -CH2-O-CH2-,-CH2-S-, -S-CH2-, -CH2-S(O)-, -CH2-S(O2)-, -S(O)-CH2-; -S(O2)-CH2-, -C(CH3)(CH3)-, -C(=O)-NH-, -NH-C(=O)-, -CH2-CH2-, -CH=CH-CH2-, - CH2-NH-C(=O)-, -C(=O)-NH-CH2, -C≡C-, -S(O2)-NH-CH2-, -S(02)-NH, -O-CH2-CH2-O-, -O-, -NH- CH2-, -CH2-NH-, -CH2-CH2-O-, or -NH-C(=O)-CH2-O-, or a bond; L2 represents Cl-C7alkylene, wherein one or more CH2 moieties in the alkylene are optionally replaced independently by -N(R9)(R20)-, -CH(N(R9)(R20)(R20))-, or -C(=0)-, wherein within L2 there are no adjacent C(=O) moieties or adjacent -N(R9)(R20)- moieties, and wherein the terminal moiety of L2 is not - N(R9)(R20)-, or L2 represents -O-C1-C6alkylene-, or L2 represents a bond, providing that X represents - CH2- when L2 is a bond; as well as methods of using the compounds of formula I for treating or preventing bacterial infections.