Aza (Indole)-, Benzothiophene-, And Benzofuran-3-Sulfonamides

Abstract

Disclosed are sulfonamide compounds with GPR17 modulating properties, which are useful for treating or preventing a variety of CNS and other diseases, in particular for preventing and treating myelinating diseases or disorders.

1 .- 30 . (canceled) 
     
     
         31 . A compound corresponding in structure to Formula VIa; 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable sale, solvate, isotope or co-crystal thereof, 
         wherein; 
         R2 is hydrogen or fluoro, 
         R4 is hydrogen or fluoro, 
         R5 is selected from hydrogen, halogen, cyano, C 1-2  alkyl, and C 1-2  alkyloxy, 
         R6 is selected from halogen, cyano, nitro, azido, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3  alkyloxy, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, C 1-3  alkylcarbonylamino, C-3 alkylaminocarbonyl, di(C 1-3 )alkylaminocarbonyl, (C 1-3 )alkylsulfinyl, (C 1-3 )alkylsulfonyl, C 3-6  cycloalkyl, C 3-6  cycloalkyloxy, C 3-6  cycloalkyl(C 1-2 )alkyl, C 3-6  cycloalkyl(C 1-3 )alkoxy, C 3-6  heterocycloalkyl, C 3-6  heterocycloalkyloxy, C 3-6  heterocycloalkyl(C 1-2 )alkyl, heterocycloalkyl(C 1-2 )alkyloxy, phenyl, phenyloxy, phenyl(C 1-2 )alkyl, phenyl(C 1-2 )alkoxy, phenylsulfonyl, phenylsulfinyl, phenyl(C 1-2 )alkylsulfonyl, phenyl(C 1-2 )alkylsulfinyl, C 3-6  heteroaryl, C 3-6  heteroaryloxy, C 3-6  heteroaryl(C 1-2 )alkyl, and C 3-6  heteroaryl(C 1-2 )alkoxy and wherein each group in R6 can be unsubstituted or substituted with one or more groups selected from fluoro, chloro, bromo, fluorinated or unsubstituted C 1-3 alkyl, fluorinated or unsubstituted C 1-3 alkyloxy, hydroxy, and cyano, 
         or 
         (i) R6 may form together with R7 and the carbon atoms to which R6 and R7 are attached, an unsubstituted or substituted phenyl, an unsubstituted or substituted pyridyl, an unsubstituted or substituted cyclopentyl or an unsubstituted or substituted cyclohexyl, 
         wherein each substitution, if present, is selected from hydroxy, halogen, methyl or methoxy, wherein each methyl or methoxy can be unsubstituted or substituted with one or more substituents selected from halogen, preferably fluoro, and methoxy, 
         or 
         (ii) R6 forms together with R5 and the carbon atoms to which R6 and R5 are attached, a 1,3-dioxolane which may be unsubstituted or substituted with one or two substituents selected from fluoro and methyl, 
         R7 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, azido, nitro, amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyloxy, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, C 1-3  alkylcarbonylamino, C 1-3  alkylaminocarbonyl, di(C 1-3 )alkylaminocarbonyl, C 1-3 alkylsulfinyl, C 1-3  alkylsulfonyl, C 1-3 alkylthio, C 3-6  cycloalkyl, C 3-6  cycloalkyloxy, C 3-6  cycloalkyl(C 1-2 )alkyl, C 3-6  cycloalkyl(C 1-3 )alkoxy, C 3-6  heterocycloalkyl, C 3-6  heterocycloalkyloxy, C 3-6  heterocycloalkyl(C 1-2 )alkyl, heterocycloalkyl(C 1-2 )alkyloxy, phenyl, phenyloxy, phenyl(C 1-2 )alkyl, phenyl(C 1-2 )alkoxy, phenylsulfonyl, phenylsulfinyl, C 3-6  heteroaryl, C 3-6  heteroaryloxy, C 5-6  heteroaryl(C 1-2 )alkyl, and C 5-6  heteroaryl(C 1-2 )alkoxy and wherein each group in R7 can be unsubstituted or substituted with one or more groups selected from fluoro, chloro, bromo, fluorinated or unsubstituted C 1-3 alkyl, fluorinated or unsubstituted C 1-3 alkyloxy, hydroxy, and cyano, 
         R8 is selected from hydrogen, halogen, cyano, optionally halogenated C 1-3  alkyloxy, optionally halogenated C 1-3  alkyl, optionally halogenated (C 1-3 )alkylsulfinyl, optionally halogenated (C 1-3 )alkylsulfonyl and optionally halogenated (C 1-3 )alkylthio, 
         R9 is selected from hydrogen, fluoro, chloro, bromo, iodo, C 1-3  alkyloxy, fluoro(C 1-3 )alkoxy, C 1-3  alkyl, and fluoro(C 1-3 )alkyl, and is preferably hydrogen, 
         R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, azido, pentafluorosulfanyl, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyloxy, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, C 1-3  alkylaminocarbonyl, di(C 1-3 )alkylaminocarbonyl, (C 1-3 )alkylsulfinyl, (C 1-3 )alkylsulfonyl, (C 1-3 )alkylthio, C 3-6  cycloalkyl, C 3-6  cycloalkyloxy, C 3-6  cycloalkyl(C 1-2 )alkyl, C 3-6  cycloalkyl(C 1-3 )alkoxy, C 3-6  heterocycloalkyl, C 3-6  heterocycloalkyloxy, C 3-6  heterocycloalkyl(C 1-2 )alkyl, C 3-6  heterocycloalkyl(C 1-2 )alkyloxy, and wherein each group in R10 can be unsubstituted or substituted with one or more groups selected from fluoro, chloro, bromo, fluorinated or unsubstituted C 1-3 alkyl, fluorinated or unsubstituted C 1-3  alkyloxy, fluorinated or unsubstituted C 1-3 alkoxycarbonyl, fluorinated or unsubstituted C 1-3 alkylcarbonyl, C 1-3  alkylaminocarbonyl, di(C 1-3 )alkylaminocarbonyl, hydroxy, and cyano, and 
         R11 is selected from hydrogen, fluoro, chloro, bromo, iodo, C 1-3  alkyl, fluoro(C 1-3 )alkyl, C 1-3  alkyloxy, fluoro(C 1-3 )alkoxy, unsubstituted or fluorinated C 1-3  alkylcarbonyl, unsubstituted or fluorinated C 1-3  alkoxycarbonyl, and cyano. 
       
     
     
         32 . The compound or pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein R2 and R4 are both hydrogen and R5 is selected from hydrogen, fluoro, chloro and bromo. 
     
     
         33 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 32 , wherein R6 is selected from chloro, bromo azido, cyano, cyclopropyl, methylsulfinyl, methylsulfonyl, mono-, di- and trifluoromethyl, methoxy, mono-, di- and trifluoromethoxy, and mono-, di- and trifluoroethoxy. 
     
     
         34 . The compound or the pharmaceutically acceptable salt, solvate isotope or co-crystal thereof according to  claim 33 , wherein R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, fluoromethyl, methoxy, fluoromethoxy and methylsulfonyl. 
     
     
         35 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 34 , wherein R8 is selected from fluoro, methoxy and fluoromethoxy. 
     
     
         36 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 35 , wherein R9 is hydrogen or fluoro and R11 is selected from hydrogen, fluoro, floromethyl, methoxy and fluoromethoxy. 
     
     
         37 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 36 , wherein R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, amino, azido, pentafluorosulfanyl, C 1-3 alkyl, C 2-3  alkenyl, C 2-3 alkynyl, C 1-3 alkyloxy, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, (C 1-3 )alkylsulfinyl, (C 1-3 )alkylsulfonyl, (C 1-3 )alkylthio, C 1-3 alkyloxycyclopropyl and C 1-3  alkyloxycarbonylcyclopropyl, wherein each alkyl, alkoxy, alkenyl and alkynyl group in R10 can be unsubstituted or substituted with one or more groups selected from fluoro, chloro, bromo, fluorinated or unsubstituted C 1-3 alkyl, fluorinated or unsubstituted C 1-3 alkyloxy, fluorinated or unsubstituted C 1-3 alkyloxycarbonyl, C 3-6  cycloalkyl and cyano. 
     
     
         38 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 36 , wherein R10 is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, pentafluorosulfanyl, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, methoxymethyl, fluoromethoxymethyl, methoxyethyl, fluoromethoxyethyl, methoxypropyl, fluoromethoxypropyl, ethoxymethyl, fluoroethoxymethyl, ethoxyethyl, fluoroethoxyethyl, methoxy, ethoxy, propoxy, butyloxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, methoxymethoxy, fluoromethoxymethoxy, methoxyethoxy, fluoromethoxyethoxy, methoxypropoxy, fluoromethoxypropoxy, ethoxymethoxy, fluoroethoxymethoxy, ethoxyethoxy, fluoroethoxyethoxy, ethenyl, propenyl, fluoroethenyl, fluoropropenyl, methoxyethenyl, fluoromethoxyethenyl, methoxypropenyl, fluoromethoxypropenyl, ethoxyethenyl, fluoroethoxyethenyl, ethynyl, propynyl, ethoxycyclopropyl, ethoxycarbonylcyclopropyl and cyclopropylmethoxy. 
     
     
         39 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 36 , wherein R10 is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, unsubstituted or fluorinated C 1-3 alkyl, unsubstituted or fluorinated C 1-3 alkoxy, unsubstituted or fluorinated C 1-2 alkoxy(C 1-3 )alkyl, unsubstituted or fluorinated C 1-2 alkoxy(C 1-3 )alkoxy, and unsubstituted or fluorinated C 1-2 aloxy(C 2-3 )alkenyl. 
     
     
         40 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein;
 R2 is hydrogen,   R4 is hydrogen or fluoro,   R5 is selected from hydrogen, fluoro, chloro and bromo;   R6 is selected from fluoro, chloro, bromo, azido, cyclopropyl, cyclopropyloxy, cycopropylmethoxy, unsubstituted or fluorinated C 1-3 alkyl, unsubstituted or fluorinated C 1-3  alkyloxy, methylsulfinyl, methylsulfonyl, pyridyl, optionally halogenated thienyl and benzyloxy;   R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, fluoromethyl, methoxy, fluoromethoxy, fluoroethoxy, methylsulfinyl, and methylsulfonyl;   R8 is selected from hydrogen, fluoro, chloro, bromo, methyl, fluoromethyl, methoxy and fluoromethoxy;   R9 is selected from hydrogen, fluoro, chloro, methyl, fluromethyl, methoxy and fluoromethoxy,   R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, azido, pentafluorosulfanyl, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkyloxy, C 1-3 alkylcarbonyl, C 1-3  alkoxycarbonyl and cyclopropyl, wherein the cyclopropyl is optionally substituted with a residue selected from cyano, C 1-2 alkoxy, fluoro(C 1-2 )alkoxy, C 1-2 alkoxycarbonyl and fluoro(C 1-2 )alkoxycarbonyl, and wherein each alkyl, alkoxy, alkenyl and alkynyl group in R10 can be unsubstituted or substituted with one or more groups selected from fluoro, chloro, bromo, fluorinated or unsubstituted C 1-2 alkyloxy, cyano, cyclopropyl and hydroxy, wherein such substitution is preferably selected from fluoro, fluorinated or unsubstituted C 1-2  alkyloxy and cyano;   and R11 is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl, methoxy, fluoromethoxy and cyano.   
     
     
         41 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein,
 R2, R4 and R5 are all hydrogen,   R6 is selected from fluoro, chloro, bromo, azido, methylsulfinyl, methylsulfonyl, methyl, mono-, di- and trifluoromethyl, methoxy, mono-, di- and trifluoromethoxy, and mono-, di- and trifluoroethoxy;   R7 is selected from hydrogen, fluoro, chloro, bromo, methyl, fluoromethyl, methoxy, fluoromethoxy, fluoroethoxy, methylsulfinyl and methylsulfonyl,   R8 is selected from fluoro and methoxy;   R9 is selected from hydrogen, fluoro, methoxy and fluoromethoxy,   R10 is selected from hydrogen, fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, cyanomethoxy, cyanoethoxy, unsubstituted or fluorinated C 1-3 alkyl, unsubstituted or fluorinated C 1-3 alkyloxy, unsubstituted or fluorinated C 1-2  alkyloxy(C 1-3 )alkyl, unsubstituted or fluorinated C 1-2 alkyloxy(C 1-3 )alkyloxy, unsubstituted or fluorinated C 1-2 alkyloxy(C 2-3 )alkenyl, cyclopropyl, cyclopropyloxy and cyclopropylmethoxy, wherein any cyclopropyl moiety is optionally substituted with a residue selected from fluoro, cyano, C 1-2 alkoxy, fluoro(C 1-2 )alkoxy, C 1-2 alkoxycarbonyl, fluoro(C 1-2 )alkoxycarbonyl; and   R11 is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl, methoxy and fluoromethoxy, and   wherein at least two substituents in R8, R10 and R11 are different from hydrogen.   
     
     
         42 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein;
 R2, R4 and R5 are all hydrogen,   R6 is selected from fluoro, chloro, bromo, methylsulfinyl, fluoromethyl, methoxy and fluoromethoxy,   R7 is selected from hydrogen, fluoro, chloro, bromo, unsubstituted or fluorinated C 1-2  alkyl, unsubstituted or fluorinated C 1-2  alkoxy, methylsulfinyl, and methylsulfonyl,   R8 is selected from hydrogen, fluoro, chloro methoxy and fluoromethoxy,   R9 is hydrogen, methoxy or fluoro, preferably hydrogen,   R10 is selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, unsubstituted or fluorinated and/or hydroxylated C 1-3 alkyl, unsubstituted or fluorinated and/or hydroxylated C 1-3 alkoxy, unsubstituted or fluorinated and/or hydroxylated C 1-2  alkoxy(C 1-3 )alkyl, unsubstituted or fluorinated and/or hydroxylated C 1-2 alkoxy(C 1-3 )alkoxy, unsubstituted or fluorinated and/or hydroxylated C 1-2  alkoxy(C 2-3 )alkenyl and unsubstituted or fluorinated C 1-2 alkoxycarbonylcyclopropyl, and is preferably selected from fluoro, chloro, bromo, iodo, cyano, cyanomethyl, cyanoethyl, unsubstituted or fluorinated C 1-3  alkyl, unsubstituted or fluorinated C 1-3  alkoxy, unsubstituted or fluorinated C 1-2  alkoxy(C 1-3 )alkyl, unsubstituted or fluorinated C 1-2 alkoxy(C 1-3 )alkoxy, unsubstituted or fluorinated C 1-2  alkoxy(C 2-3 )alkenyl, unsubstituted or fluorinated C 1-2 alkoxycarbonylcyclopropyl and unsubstituted or fluorinated C 1-3  alkoxycyclopropyl, and R11 is selected from hydrogen, fluoro, chloro, fluoromethyl, methoxy, and fluoromethoxy.   
     
     
         43 .- 46 . (canceled) 
     
     
         47 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein the compound is 6-chloro-N-(3,6-difluoropyridin-2-yl)-1H-indole-3-sulfonamide. 
     
     
         48 . The compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 , wherein the compound is 6-chloro-N-(3,5-difluoro-6-methoxypyridin-2-yl)-1H-indole-3-sulfonamide. 
     
     
         49 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 ; and a pharmaceutical acceptable carrier. 
     
     
         50 . A method for the prevention and/or treatment of multiple sclerosis, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 . 
     
     
         51 . A method for the prevention and/or treatment of a syndrome or disorder selected from a myelination disorder and a disorder or syndrome associated with a brain tissue damage, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or the pharmaceutically acceptable salt, solvate, isotope or co-crystal thereof according to  claim 31 . 
     
     
         52 . The compound according to  claim 31  comprising at least one isotope selected from (a) 11 C,  13 N,  15 O,  18 F,  76 Br and  124 I and/or (b) 99m Tc,  111 IN,  82 Rb,  137 Cs,  123 I,  125 I,  131 I,  67 Ga,  192 IR and  201 TI in an amount suitable for (a) PET and/or (b) SPECT imaging, respectively.