Indole Amide Derivatives and Related Compounds for Use in the Treatment of Neurodegenerative Diseases

Abstract

This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds.

1 .- 17 . (canceled) 
     
     
         18 . A compound of formula (BB1) or a stereoisomer, enantiomer or tautomer thereof, 
       
         
           
           
               
               
           
         
       
       wherein,
 each dotted line individually represents an optional double bond, wherein maximally two dotted lines selected from the five dotted lines are a double bond; 
 E 1  is independently selected from CR 1 ; and N; 
 E 2  is independently selected from NR 2 ; and O; 
 E 3  is independently selected from CR 3 ; and N; 
 R a  is hydrogen or can be taken together with R b  to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom, preferably a piperidine ring; 
 R b  is hydrogen or can be taken together with R a  to form a substituted or unsubstituted 4, 5, 6, 7 or 8 membered ring containing one N atom, preferably a piperidine ring; 
 Q is independently selected from NR b —C(O); C(O); and C(O)NH; 
 each R 1 , R 3 , R 4 , and R 6  is independently selected from hydrogen; halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 R 5  is selected from halogen; —OH; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ;- 
 R 2  is selected from hydrogen; alkyl; alkenyl; and alkynyl; 
 n is selected from 0; 1 or 2; 
 each of X, Y, T, W and V is independently selected from —CZ 1 H—; —CZ 1 —; —C—; —N—; NR 101 ; —O—; —S—; or —CO—; wherein at least one of X, Y, T; W or V is selected from —CZ 1 H— or —CZ 1 — or —Cl—; 
 L is independently selected from being not present; —O—; —NH—; —NR 10 —; C 1-6 alkylene; C 1-6 alkenylene; C 1-6 alkynylene; 
 wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene optionally includes one or more heteroatoms, said heteroatoms being selected from the heteroatoms consisting of O, S and N, and wherein each of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, can be unsubstituted or substituted; 
 and wherein a carbon atom or heteroatom of said C 1-6 alkylene, C 1-6 alkenylene or C 1-6 alkynylene, can be oxidized to form a C═S, N═O, N═S, S═O or S(O) 2 ; 
 B represents a cyclic structure selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle; 
 m is selected from 0; 1; 2; 3; 4 and 5; 
 R 8  is independently selected from hydrogen; halogen; alkyl; alkenyl; alkynyl; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; 
 wherein said alkyl, alkenyl and alkynyl optionally includes one or more heteroatoms, said heteroatoms being selected from the atoms O, S and N; 
 and wherein said alkyl, alkenyl and alkynyl can be unsubstituted or substituted with Z; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl and alkynyl, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 each Z is independently selected from halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 13 ; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; 
 each Z 1  is independently selected from hydrogen; alkyl; and Z; 
 each R 10  is independently selected from alkyl; alkenyl; alkynyl; aryl; heterocycle; 
 arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 each R 101  is independently selected from hydrogen and R 10 ; 
 each R 11  is independently selected from hydroxyl; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 each R 12  and R 13  is independently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 and wherein R 12  and R 13  can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted; 
 
       and stereoisomers, enantiomers or tautomers, solvates, hydrates, or salts (in particular pharmaceutically acceptable salts) thereof. 
     
     
         19 . The compound according to  claim 18 , having structural formula (BB2), (BB3), (BB4), (BB5), (BB6), or (BB7), 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       whereby all variables have the same meaning as defined in  claim 18 . 
     
     
         20 . The compound according to any one of  claim 18  or  19 , wherein each of X, Y, T, W and V is independently selected from —CZ 1 H—; —CZ 1 —; —C—; —N—; NR 101 ; —O—; —S—; or —CO—; and form with the dotted lines one of the cycles having one of the structural formula (Ib), (IIb), (IIIb), (IVb), or (Vb) 
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound of formula (CC 1) or a stereoisomer, enantiomer or tautomer thereof, 
       
         
           
           
               
               
           
         
       
       wherein,
 each dotted line individually represents an optional double bond, wherein maximally two dotted lines selected from the five dotted lines are a double bond; 
 each of G 1 , G 2 , G 3  and G 4  is independently selected from N; NR c3 ; O; CHR c3 ; and CR c3 ; wherein two of G 1 , G 2 , G 3  and G 4  are selected from N; NR c3 ; and O; while the other two of G 1 , G 2 , G 3  and G 4  are selected from CHR c3 ; and CR c3 ; 
 each R 3  is selected from hydrogen; and alkyl; 
 R 5  is independently selected from halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; heterocycle-alkynylene;
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 
 q is selected from 0; 1; 2; or 3; preferably q is 0 or 1; 
 E is selected from hydrogen; halogen; —OH; —OR 10 ; —SH; —SR 10 ; trifluoromethoxy; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; 
 each R 10  is independently selected from alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 each R 12  and R 13  is independently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 and wherein R 12  and R 13  can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted; 
 each of R 1c  and R 2c  is independently selected from hydrogen; halogen; alkyl; alkenyl or alkynyl; 
 
       and stereoisomers, enantiomers or tautomers, solvates, hydrates, or salts (in particular pharmaceutically acceptable salts) thereof. 
     
     
         22 . The compound according to  claim 21 , wherein each of G 1 , G 2 , G 3  and G 4  is independently selected from N; NR c3 ; O; CHR c3 ; and CR c3 ; and form with the dotted lines one of the cycles having one of the structural formula (Ic), (IIc), (IIIc), (IVc), or (Vc): 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound according to any one of  claim 21  or  22 , having structural formula (CC2), 
       
         
           
           
               
               
           
         
         wherein, 
         R 5  is independently selected from halogen; —OH; —OR 10 ; —SH; —SR 10 ; —S(O)R 11 ; —S(O) 2 R 11 ; —SO 2 NR 12 R 13 ; trifluoromethyl; trifluoromethoxy; nitro; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; -cyano; —COOH; —COOR 10 ; —C(O)NR 12 R 13 ; —C(O)R 11 ; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene; heterocycle-alkynylene;
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, optionally includes one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatoms being selected from the atoms O, S and N; 
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene can be unsubstituted or substituted with Z; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 
         q is selected from 0; 1; 2; or 3; preferably q is 0 or 1; 
         E is selected from hydrogen; halogen; —OH; —OR 10 ; —SH; —SR 10 ; trifluoromethoxy; —NHC(O)R 10 ; —NHS(O) 2 R 10 ; —NHC(O)NR 12 R 13 ; —NR 10 C(O)R 10 ; —NR 10 S(O) 2 R 10 ; —NR 10 C(O)NR 12 R 13 ; —NR 12 R 13 ; 
         each R 10  is independently selected from alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene;
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 
         each R 12  and R 13  is independently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkylene; arylalkenylene; arylalkynylene; heterocycle-alkylene; heterocycle-alkenylene or heterocycle-alkynylene;
 and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene optionally include one or more heteroatoms in the alkyl(ene), alkenyl(ene) or alkynyl(ene) moiety, said heteroatom selected from O, S and N; 
 and wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkylene, arylalkenylene, arylalkynylene, heterocycle-alkylene, heterocycle-alkenylene or heterocycle-alkynylene, can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O) 2 ; 
 and wherein R 12  and R 13  can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted; 
 
         each of R 1c  and R 2c  is independently selected from hydrogen; halogen; alkyl; alkenyl or alkynyl; 
       
       and isomers (in particular stereoisomers, enantiomers or tautomers), solvates, hydrates, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof. 
     
     
         24 . The compound according to  claim 21 , wherein E is selected from hydrogen; —OH; —NR 12 R 13  (preferably NH 2 , NHMe, N(Me) 2 , NHethyl or N(ethyl) 2 ); —O-alkyl; NHC(O)O-alkyl. 
     
     
         25 . The compound according to  claim 21 , wherein each of R 1c  and R 2c  is independently selected from hydrogen; halogen; or alkyl; yet more particularly is hydrogen. 
     
     
         26 . The compound according to  claim 21 , wherein R 5  is selected from halogen and alkyl, more preferably C 1-6  alkyl, yet more preferably methyl. 
     
     
         27 . A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to any one of  claim 18  or  21 . 
     
     
         28 . A method for the prevention or treatment of neurodegenerative disorders in a subject, the method comprising administering to the subject an effective amount of a compound according to  claim 18  or  21  or a stereoisomer, enantiomer or tautomer thereof; or of a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the compound according to  claim 18  or  21 . 
     
     
         29 . The method according to  claim 28 , wherein the neurodegenerative disorder is selected from Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, parkinsonism (linked to chromosome 17, FTDP-17), Parkinson's disease, diffuse Lewy body disease, traumatic brain injury, amyotrophic lateral sclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Down syndrome, neuroaxonal dystrophy, and multiple system atrophy.