Efflux-pump inhibitors and therapeutic uses thereof

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)—; AR1, 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)OR111, —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, C1-C6alkyl, C1-C6haloalkyl, C1-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; R111 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 R18 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, C1-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(O2)-NH, —O—CH2-CH2-O—, —O—, —NH—CH2-, —CH2-NH—, —CH2-CH2-O—, or —NH—C(═O)—CH2-O—, or a bond; L2 represents C1-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(═O)—, 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.

1 . A compound 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)—; 
         AR1, AR2 represent independently phenyl or a 5- to 6-membered heteroaryl ring containing one to three heteroatoms selected from O, S and N, wherein AR is connected to L1 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)OR11, —C(O)N(R12)R13, —S(O)OR11 or phenyl; 
         R4 represents hydrogen, hydroxyl, 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, C1-C6alkyl, C1-C6haloalkyl, C1-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; 
         R11 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 R18 containing carbon atoms as ring members and one or two ring members independently selected from N(R9)(R12) 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 R4; 
         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, C1-C4haloalkoxy or —CO(O)R11; 
         R20 represents independently at each occurrence hydrogen or methyl; 
         R21 represents N(R20)2 or CH2-N(R20)2; 
         L1 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(O2)-NH—, —O—CH2-CH2-O—, —O—, —NH—CH2-, —CH2-NH—, —CH2-CH2-O—, —NH—C(═O)—CH2-O— or a bond; 
         L2 represents C1-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(═O)—, 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; 
         wherein
 when L2 is C(═O), then R8 is ASC-1; 
 when L1 is a bond, then R1 is Br or C2-C6alkyl, and/or R4 is O—C2-C6alkenyl, O—C1-C6alkylene-Cycle-P or O—C1-C6alkylene-Cycle-Q1, wherein Cycle-P1 represents a saturated or partially unsaturated C3-C8 heterocyclic ring optionally substituted by 1 to 3 R18 containing carbon atoms as ring members and one or two ring members independently selected from N(R9)(R12) and O and Cycle-Q1 represents 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; 
 when L1 is —CH2-O— or —NH—C(═O)—CH2-O—, L2 is C1-C7alkylene as defined above, AR1 and AR2 are phenyl, ring A is a 6-membered ring, and R8 is hydrogen or methyl, then R1 is Br or C2-C6alkyl, and/or R4 is O—C2-C6alkenyl, O—C1-C6alkylene-Cycle-P or O—C1-C6alkylene-Cycle-Q1; 
 when L1 is —CH2-O— or —NH—C(═O)—CH2-O—, L2 is —CH2- or CH2-CH2-, AR1 and AR2 are phenyl, ring A is a 4- or 5-membered ring, X is C(═O) and R8 is hydrogen or methyl, then R1 is Br or C2-C6alkyl, and/or R4 is O—C2-C6alkenyl, O—C1-C6alkylene-Cycle-P1 or O—C1-C6alkylene-Cycle-Q1; 
 when L1 is —O—CH2-, —CH2-O—CH2-, —C(═O)—NH—, —NH—C(═O)—, —CH2-NH—C(═O)—, —C≡C—, —O—CH2-CH2-O— or —O—, L2 is —CH2-, AR1 and AR2 are phenyl, X is C(═O) and R8 is hydrogen or methyl, then R1 is Br or C2-C6alkyl, and/or R4 is O—C2-C6alkenyl, O—C1-C6alkylene-Cycle-P1 or O—C1-C6alkylene-Cycle-Q1; 
 when L1 is —O—, and AR1 and AR2 are phenyl, then ring A is a 4- or 5-membered ring; 
 
         wherein the compound of formula I is not 
         2-Pyrrolidinemethanamine, N-[[4-[(4-bromophenyl)methoxy]-3-methoxyphenyl]methyl]-1-methyl-; 
         2-Pyrrolidinemethanamine, N-[[3-bromo-4-(phenylmethoxy)phenyl]methyl]-1-methyl-; 
         2-Pyrrolidinemethanamine, N-[[3-[(2-chlorophenyl)methoxy]phenyl]methyl]-1-methyl-; 
         2-Pyrrolidinemethanamine,N-[[3-methoxy-4-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]methyl]-1-methyl-; 
         2-Pyrrolidinemethanamine, N-[[4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl]methyl]-1-methyl-; 
         Benzamide, N-(2,4-difluorophenyl)-3-[[methyl(3-piperidinylmethyl)amino]methyl]-; 
         Benzamide, N-(4-hydroxy[1,1′-biphenyl]-3-yl)-4-[[methyl[(1-methyl-4-piperidinyl) methyl]amino]methyl]-; 
         Benzamide, N-(4-hydroxy[1,1′-biphenyl]-3-yl)-4-[[[1-methyl-3-pyrrolidinyl)methyl]amino]methyl]-; 
         2-Furancarboxylic acid, 5-[[4-[[methyl[(1-methyl-2-piperidinyl)methyl]amino]methyl]phenoxy]methyl]-; 
         3-Pyrrolidinemethanamine, N,1-dimethyl-N-[[2-(2-pyridinylmethoxy)phenyl]methyl]-; 
         2-Pyrrolidinemethanamine, 1-methyl-N-[(3-phenoxyphenyl)methyl]-; 
         2-Pyrrolidinemethanamine, N-[[4-(4-chloro-2-nitrophenoxy)phenyl]methyl]-1-methyl-; 
         3-Azetidinamine, N-methyl-N-[(3-phenoxyphenyl)methyl]-; 
         3-Pyrrolidinamine, N-methyl-N-[(3-phenoxyphenyl)methyl]-; 
         3-Pyrrolidinamine, 1-methyl-N-[(3-phenoxyphenyl)methyl]-; 
         2-Pyrrolidinemethanamine, N-[[4-(4-bromophenoxy)phenyl]methyl]-N-methyl-; 
         3-Pyrrolidinecarboxamide, N-[[2-(3-methoxyphenoxy)-3-pyridinyl]methyl]-; 
         4-Piperidinecarboxamide, N-[[6-(2,5-dimethylphenoxy)-3-pyridinyl]methyl]-; 
         2-Pyrrolidinecarboxamide, N-[[2-(3,4-dimethylphenoxy)-4-pyridinyl]methyl]-; 
         4-Piperidinamine, N-[[5-bromo-2-(2-pyridinylmethoxy)phenyl]methyl]-1-methyl-. 
       
     
     
         2 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein AR1 represents phenyl, pyridinyl or thiazolyl and AR2 represents phenyl, pyridinyl or furanyl. 
     
     
         3 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein AR1 and AR2 represent phenyl. 
     
     
         4 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein AR1 represents pyridinyl and AR2 represents phenyl. 
     
     
         5 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein AR1 represents pyridinyl and AR2 represents pyridinyl. 
     
     
         6 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein AR1 and AR2 represent pyridinyl. 
     
     
         7 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L1 represents —CH═CH—. 
     
     
         8 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L1 represents —CH2-O—. 
     
     
         9 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L1 represents —C(CH3)(CH3)-. 
     
     
         10 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents C1-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(═O)—, 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-. 
     
     
         11 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ring A is a 4- to 6-membered saturated ring containing only CH2 moieties as ring members in addition to the nitrogen atom. 
     
     
         12 . The compound according to  claim 1 , or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
 X is CH2;   L2 represents C1-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(═O)—, 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)- and wherein the terminal moiety of L2 connected to ASC is —CH2-, or L2 represents —O—C1-C6alkylene-.   
     
     
         13 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents C1-C7alkylene, wherein one or two CH2 moieties in the alkylene are optionally replaced independently by —N(R9)(R20)- or —C(═O)—, and wherein the terminal moiety of L2 connected to ASC is —CH2-. 
     
     
         14 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents —CH2-, —CH2-CH2-, —CH2-CH2-CH2-, —CH(CH3)-, —CH2-NH—CH2-CH2-, —C(═O)—, —C(═O)—CH2, —C(═O)—NH—CH2-C(═O)—, —C(═O)—NH—CH2-CH2-, —CH2-N+(CH3)2-CH2-C(═O)—, —CH2-NH—C(═O)—CH2-, —CH2-NH—CH2-C(═O)—, —O—CH2-CH2-, —O—CH2-CH2-CH2- or —O—CH2-CH2-CH2-CH2-. 
     
     
         15 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents —CH2-, —CH2-CH2-, —CH(CH3)-, —CH2-CH2-CH2-, —CH2-NH—CH2-CH2-, —C(═O)—, —C(═O)—NH—CH2-CH2-, —O—CH2-CH2-, —O—CH2-CH2-CH2- or —O—CH2-CH2-CH2-CH2-. 
     
     
         16 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents —O—CH2-, —O—CH2-CH2-, —O—CH2-CH2-CH2-, —O—CH2-CH2-CH2-CH2-, —O—CH2-CH2-CH2-CH2-CH2- or —O—CH2-CH2-CH2-CH2-CH2-CH2-. 
     
     
         17 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R8 represents ASC-1, and preferably wherein ASC is ASC-o 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound according to  claim 17  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents —C(═O)—. 
     
     
         19 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is ASC-1a or ASC-1b 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound according to  claim 19  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom. 
     
     
         21 . The compound according to  claim 20  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is ASC-1a wherein ring A represents a 4- to 5-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom and X represents CH2, and preferably wherein ASC is ASC-a or ASC-g 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound according to  claim 21  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents —CH2-, —CH2-CH2-, CH(CH 3 )—, —CH2-CH2-CH2-, —CH2-NH—CH2-CH2-, —C(═O)—NH—CH2-CH2-, —O—CH2-CH2- —O—CH2-CH2-CH2- or —O—CH2-CH2-CH2-CH2-. 
     
     
         23 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
 ASC is —N(R8a)ASC-1 or —N(R8b)(R9)ASC-1; 
 Ring A represents a 4- to 5-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom; 
 X represents CH2; 
 L1 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(O2)-NH—, —O—CH2-CH2-O—, —O—, —NH—CH2-, —CH2-NH—, —CH2 CH2-O—, or —NH—C(═O)—CH2-O—; 
 R8a represents hydrogen or ASC-1; 
 R8b represents methyl or ASC-1; 
 R9 represents methyl; and 
 R10 represents hydrogen. 
 
     
     
         24 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R4 represents O—R22 and wherein R22 is C3-C6alkyl, C2-C6alkenyl, C1-C6alkyl-Cycle-P1, C1-C6alkyl-Cycle-Q1. 
     
     
         25 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R4 represents O—R22 and wherein R22 is C2-C6alkenyl. 
     
     
         26 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is ASC1a 
       
         
           
           
               
               
           
         
         Ring A represents a 4- to 5-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom; 
         X represents CH2; 
         AR1 represents phenyl or pyridinyl; 
         AR2 represents phenyl or pyridinyl; 
         R1 and R2 represent independently hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, —C(O)OR11 or —C(O)N(R12)R13; 
         R3 is hydrogen; 
         R4 represents hydrogen, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl or O—R22; 
         R5, R6, R7 are hydrogen or halogen; 
         R8 represents hydrogen, methyl or ASC-1; 
         R9 is methyl or absent; 
         R10 represents hydrogen; 
         R11 represents independently at each occurrence hydrogen or C1-C6alkyl; 
         R12 and R13 represent independently at each occurrence hydrogen or C1-C6alkyl; 
         R18 and R19 represent independently at each occurrence halogen, cyano, methyl, halomethyl, methoxy or halomethoxy; 
         R22 represents C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, C2-C6haloalkenyl, C1-C6alkyl-Cycle-P, C1-C6alkyl-Cycle-Q, C12C6alkenyl-Cycle-P or C2-C6alkenyl-Cycle-Q; 
         Cycle-P represents independently at each occurrence tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, or morpholinyl, each optionally substituted by 1 to 3 R18; 
         Cycle-Q represents independently at each occurrence phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, tetrazolyl, furanyl, or thiophenyl, each optionally substituted by 1 to 3 R19; 
         L1 represents —CH═CH—, —CH2-O— or —C(CH3)(CH3)-; 
         L2 represents —CH2-, —CH2-CH2-, —CH(CH3)-, —CH2-CH2-CH2-, —CH2-NH—CH2-CH2-, —C(═O)—, —C(═O)—NH—CH2-CH2, —O—CH2-, —O—CH2-CH2-, —O—CH2-CH2-CH2- or —O—CH2-CH2-CH2-CH2-. 
       
     
     
         27 . The compound according to  claim 26  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R8 represents ASC-1 and L2 represents —C(═O)—. 
     
     
         28 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-20 
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-21 
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-22 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-23 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-24 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-25 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-26 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-27 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-28 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-29 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-30 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-31 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-32 
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-33 
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-34 
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-35 
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-36 
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-37 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound according to  claim 1  or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula I-38 
       
         
           
           
               
               
           
         
       
     
     
         47 . (canceled) 
     
     
         48 . A pharmaceutical composition comprising (i) a compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof according to  claim 1 , and (ii) an antimicrobial agent. 
     
     
         49 . A method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising the step of administering the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof according to  claim 1  to said subject, and wherein said subject is receiving the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof in combination with an antimicrobial agent. 
     
     
         50 . The pharmaceutical composition according to  claim 48 , wherein the antimicrobial agent is a tetracycline antibiotic. 
     
     
         51 . The pharmaceutical composition according to  claim 48 , wherein the antimicrobial agent is an oxazolidinone antibiotic. 
     
     
         52 . The pharmaceutical composition according to  claim 50 , wherein said tetracycline antibiotic is minocycline. 
     
     
         53 . The pharmaceutical composition according to  claim 51 , wherein said oxazolidinone antibiotic is linezolid. 
     
     
         54 . The method according to  claim 49 , wherein the antimicrobial agent is a tetracycline antibiotic. 
     
     
         55 . The method according to  claim 54 , wherein the tetracycline antibiotic is minocycline. 
     
     
         56 . The method according to  claim 49 , wherein the antimicrobial agent is an oxazolidinone antibiotic. 
     
     
         57 . The method according to  claim 56 , wherein the oxazolidinone antibiotic is linezolid. 
     
     
         58 . A method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising the step of administering the compound 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)—; 
         AR1, 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 L1 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)OR11, —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, C1-C6alkyl, C1-C6haloalkyl, C1-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; 
         R11 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 R18 containing carbon atoms as ring members and one or two ring members independently selected from N(R9)(R12)- 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, C1-C4haloalkoxy or —CO(O)R11; 
         R20 represents independently at each occurrence hydrogen or methyl; 
         R21 represents N(R20)2 or CH2-N(R20)2; 
         L1 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(O2)-NH—, —O—CH2-CH2-O—, —O—, —NH—CH2-, —CH2-NH—, —CH2-CH2-O—, or —NH—C(═O)—CH2-O—, or a bond; 
         L2 represents C1-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(═O)—, 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, 
         to said subject, and wherein said subject is receiving the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof in combination with an antimicrobial agent. 
       
     
     
         59 . The method according to  claim 58 , wherein the antimicrobial agent is a tetracycline antibiotic. 
     
     
         60 . The method according to  claim 59 , wherein the tetracycline antibiotic is minocycline. 
     
     
         61 . The method according to  claim 58 , wherein the antimicrobial agent is an oxazolidinone antibiotic. 
     
     
         62 . The method according to  claim 61 , wherein the oxazolidinone antibiotic is linezolid.