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WO2010015588A1 - Benzyl-substituted tetracyclic heterocyclic compounds - Google Patents

Benzyl-substituted tetracyclic heterocyclic compounds Download PDF

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Publication number
WO2010015588A1
WO2010015588A1 PCT/EP2009/060001 EP2009060001W WO2010015588A1 WO 2010015588 A1 WO2010015588 A1 WO 2010015588A1 EP 2009060001 W EP2009060001 W EP 2009060001W WO 2010015588 A1 WO2010015588 A1 WO 2010015588A1
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Prior art keywords
fluoro
tetrahydro
indolo
hydroxy
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2009/060001
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French (fr)
Inventor
Björn BARTELS
Steffen Weinbrenner
Degenhard Marx
Jörg DIEFENBACH
Torsten Dunkern
Wiro M.P.B. Menge
Johannes A. M. Christiaans
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Takeda GmbH
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Nycomed GmbH
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Publication of WO2010015588A1 publication Critical patent/WO2010015588A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D515/14—Ortho-condensed systems

Definitions

  • the invention relates to 5-Benzyl-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole compounds, 5-Benzyl-1 ,2,3,6-tetrahydrofurano[3',4':5,6]pyrido[3,4-b]indole compounds, 5-Benzyl-1 ,2,3,6-tetrahydrothiopheno[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,6]naphthyridine compounds, 6-Benzyl-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-1 ,3,4,7-tetrahydrothiopyrano[3
  • a further object of the present invention is to provide methods of manufacture of the compounds and compositions of the present invention.
  • a ⁇ and A 2 are each independently selected from the group consisting of C, N, O and S, wherein one of A ⁇ and A 2 is N, O or S; n represents 0 or 1 ;
  • RA01 and RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-
  • .g-alkoxy wherein the C-
  • R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-; with the proviso that, if R A01 and R A 02 combine to form an oxo-group or R A ⁇ and R A 02 combine to form the group -O- CH 2 -CH 2 -O-, A 1 may not be N, O or S;
  • RA03 anc j RA04 are eacn independently selected from the group consisting of hydrogen, C-
  • RA03 anc j R A04 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-
  • RA05 anc j RA06 are eacn indpendently selected from the group consisting of hydrogen, C-
  • RA07 anc j RA08 are each independently selected from the group consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • RA09 js selected from the group consisting of hydrogen and C 1 . g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C-
  • RA010 anc j RA011 are eacn independently selected from the group consisting of hydrogen and C- j .g-alkyl, wherein the C-
  • _ 6 -alkyl wherein the C-
  • R A013 and R A014 nave the same meanings as R A05 and R A06 , and RA015 and R A016 nave tne same meanings as RA07 anc j RA08-
  • RA017 RA018 and RA019 are eacn independently selected from the group consisting of hydrogen, C-
  • RA11 and R ⁇ 12 are each independently selected from the group consisting of hydrogen, C-
  • heteroaryl is optionally substituted, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • N is substituted by RA125 -S(O) 2 -Ci.6-alkyl, wherein the -S(O) 2 -C- ] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO 2 NRA 1 SRAM 1 .(CH 2 ) m -RA15, _ (C RA16 R A17 )
  • R A111 and a lone pair or in case A 1 is S, it is optionally substituted by one or two oxo-groups; wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
  • RA13 anc j RA14 are eacn independently selected from the group consisting of hydrogen and C-
  • RA15 js selected from the group consisting of hydroxy, C- j .g-alkoxy, wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _ NR A112 R A113.
  • R A16 anc j RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C-
  • R A16 anc j RA17 combine to form a C ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA18 JS selected from the group consisting of hydroxy, C-
  • RA19 and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-
  • R A19 anc j R A110 combine to form a C ⁇ .s-cyclyl, wherein the C3_5-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA19 anc j R A110 combine to form an oxo-group;
  • R A111 j selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)R A120 , -NR A121 R A122 , -CONR A123 R A124 , C 1 -6 - alkyl, wherein the C-
  • 3-heteroaryl wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C 3 .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C- j .g-alkoxy via C, N is substituted by R A 125 anc
  • R A112 anc j R A113 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • g-alkyl wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)OR A127 , C 3 .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • N is substituted by R A128 ; or RA112 anc j RA113 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • RA114 anc j RA115 are eacn independently selected from the group consisting of hydrogen, C-
  • RA116 anc j RA117 are eacn independently selected from the group consisting of hydrogen, C-
  • Cg.-14-aryl wherein the Cg.-14-aryl is optionally substituted, C- j .g-heteroaryl, wherein the C- j .g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)O-C 1 . 6 -alkyl, wherein the -C(O)O-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 3 . 6 -cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 -CONRA132 R A133 ; or
  • R A116 anc j RA117 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
  • RA118 anc j RA119 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C 1 . 6 -alkyl, wherein the C(O)-C 1 .
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA120 J S se
  • RA121 anc j RA122 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .g-alkoxy, wherein the C-
  • .g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 6 . 14 -aryl, wherein the Cg.-14-aryl is optionally substituted,
  • C- j .g-heteroaryl wherein the C- j .g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C- j .g-heteroaryl is optionally substituted, C 3 .
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 anc j RA122 com bine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C- j . ⁇ -alkyl, wherein the C- j .
  • ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA 1 31 , O and S;
  • RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C-
  • the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA128 C 3 .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or R A123 and R A124 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
  • R A125 RA126 RA128 R A131 and R A142 are eacn independently selected from the group consisting of hydrogen, C-
  • R A129, R A130, R A134 R A135, R A138 R A139, R A140 and R A141 are each independently selected from the group consisting of hydrogen and C-
  • R A132 R A133 R A136 R A137 R A143 and R A144 are each independently selected from the group consisting of hydrogen, C-
  • RA21 and R ⁇ 2 have the same meanings as RA11 and R ⁇ ;
  • RA31 anc j RA32 are eac h independently selected from the group consisting of hydrogen, hydroxy, C-
  • RA31 anc j RA32 com bine to form an oxo-group, or RA31 and R ⁇ 32 combine to form the group -O-CH2-CH2-O-; with the proviso that, if R ⁇ 31 and RA32 combine to form an oxo-group or R ⁇ 31 and R ⁇ 32 combine to form the group -0-CH 2 -CH 2 - O-, A 2 may not be N, O or S;
  • RA33 and R ⁇ 34 a re each independently selected from the group consisting of hydrogen, C-
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino;
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C 1 .3- alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH 2 -CH 2 -O-;
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • R B 81 JS selected from the group consisting of hydrogen and halogen; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
  • one of the substituents A ⁇ and A ⁇ is selected from N and O, and the other substituent is a carbon atom.
  • one of the substituents A ⁇ and A ⁇ is a nitrogen atom and the other is a carbon atom.
  • one of the substituents A ⁇ and A ⁇ is selected from N and O, and the other substituent is a carbon atom, with the provisio if A ⁇ is N one of the substituents R ⁇ or R A ⁇ 2 J S absent and with the provisio if A ⁇ is N one of the substituents RA21 O r RA22 J S absent and with the provisio if A ⁇ is O or S both substituents R ⁇ and R A ⁇ 2 a re absent and with the proviso if A ⁇ is O or S both substituents R A 21 a nd R A 22 a re absent.
  • one of the substituents A ⁇ and A2 is a nitrogen atom and the other is a carbon atom, with the provisio if A ⁇ is N one of the substituents RA1 " Or RA12 J S absent and with the provisio if A ⁇ is N one of the substituents R ⁇ 21 O r R ⁇ 22 J S absent.
  • R ⁇ 01 and R ⁇ 02 a re each independently selected from the group consisting of hydrogen, hydroxy, C-
  • RA01 and R ⁇ 02 combine to form an oxo-group
  • R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-; with the proviso that, if R A01 and R A 02 combine to form an oxo-group or R A 01 and R A 02 combine to form the group -O- CH 2 -CH 2 -O-, A 1 may not be N or O; wherein the substituents R A03 and R A04 have the same meanings as defined above.
  • RA017 RA018 a nd RA019 are each independently selected from the group consisting of hydrogen and C-
  • R ⁇ 01 and R ⁇ 02 are eacn j nc
  • both substituents R ⁇ 01 and R ⁇ 02 represent hydrogen, or one of the substituents R ⁇ 01 and R ⁇ 02 represents hydroxy and the other substituent represents hydrogen, wherein the carbon atom to which the substituents R ⁇ 01 and R ⁇ 02 t>ind is in the R- config u ration, or R ⁇ 01 and R ⁇ 02 combine to form an oxo-group.
  • R ⁇ 11 and RA12 a re each independently selected from the group consisting of hydrogen, C-
  • R A19 R A110 anc j R A111 nave the same meanings as defined above, or the preferred or further preferred meanings of these substituents as defined below.
  • RA11 and RA12 are each independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • R A ⁇ and R A ⁇ 7 are each independently selected from the group consisting of hydrogen, hydroxy and C-
  • R A ⁇ j s selected from the group consisting of
  • R A ⁇ and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-
  • R A ⁇ 11 is selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , -CONR A123 R A124 , C ⁇ -alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C- j . ⁇ -alkoxy, wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-
  • heteroaryl is optionally substituted, C 3 . 6 -cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-
  • R A ⁇ ⁇ ⁇ is selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , -CONR A123 R A124 , and
  • .g-alkoxy wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-
  • RA112 anc j RA113 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • N is substituted by RA128- or RA112 anc j RA113 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • RA112 anc j RA113 are eacn independently selected from the group consisting of hydrogen, C-
  • RA116 anc j RA117 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)O-C 1 . g-alkyl, wherein the -C(O)O-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 3 .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 -CONRA132 R A133 ; or a nc j RA117 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q anc j s, wherein the substituents R ⁇ 128 RA131 RA132 anc j RA133 nave t ne same meanings as defined in the embodiments above, or preferably below.
  • RA116 anc j RA117 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R ⁇ 131 wherein the substituent RA131 nas t ne same meanings as defined in the embodiments above, or preferably below.
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen, C-
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .
  • ⁇ -alkyl via
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • R A121 anc j R A122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-
  • RA121 anc j R A122 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkyl via C or N, with the proviso that, if the 3- to 7-mennbered heterocyclyl is bound to the C-
  • C- j .g-alkoxy wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -CONR A14 3RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q anc j s, wherein the substituents RA131 RA142 RA143 anc j RA144 nave the same meanings as defined in the embodiments above, or preferably below.
  • RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkyl via
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA128
  • C 3 . 6 -cyclyl wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-Ci.6-alkyl, wherein the -C(O)-C- ] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O) 2 -C 1 . 6 -alkyl, wherein the -S(O) 2 -C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
  • RA123 anc j RA124 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA131 Q anc j s, wherein the substituents RA128 anc j RA131 nave t ne same meanings as defined in the embodiments above, or preferably below.
  • RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C-
  • RA129 anc j RA130 are eacn independently selected from the group consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • RA132 anc j RA133 are eacn independently selected from the group consisting of hydrogen, C-
  • RA21 and R ⁇ 22 have each independently the same meanings as the substituents R ⁇ 11 and R ⁇ 12 defined in the above embodiments.
  • the present invention may be that, if A ⁇ is N, one of the substituents R ⁇ 21 and R ⁇ 22 j s a lone pair and the other substituent has the same meanings as defined above, or that, if A ⁇ is C, both substituents R ⁇ 21 and R ⁇ 22 represent hydrogen.
  • R ⁇ 31 and R ⁇ 32 a re each independently selected from the group consisting of hydrogen, hydroxy and C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA33RA34. or
  • RA31 anc j RA32 combine to form the group -O-CH2-CH2-O-, with the proviso that, if R ⁇ 31 and
  • RA32 combine to form an oxo-group or R ⁇ 31 and R ⁇ 32 combine to form the group -O-CH2-CH2-
  • a ⁇ may not be N or O, wherein RA33 anc j RA34 nave ⁇ 16 sam e meanings as defined above.
  • R ⁇ 31 and R ⁇ 32 a re each independently selected from the group consisting of hydrogen, hydroxy and C-
  • RA31 anc j RA32 combine to form an oxo-group, with the proviso that, if R ⁇ 31 and R ⁇ 32 combine to form an oxo-group, A ⁇ may not be N or O.
  • R ⁇ 41 j selected from the group con- sisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R ⁇ is selected from the group consisting of hydrogen, halogen, C-i. ⁇ -alkyl, hydroxy, C-i. ⁇ -alkoxy, nitro, amino and a methoxy group substituted by 2 or 3 fluorine atoms, or R B41 and R B51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH 2 -CH 2 -O-.
  • R ⁇ 51 j s selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
  • one of the atoms A ⁇ and A ⁇ is N, and the other atom is a carbon atom.
  • one of the atoms A ⁇ and A ⁇ is N, and the other atom is a carbon atom, with the provisio if A ⁇ is N one of the substituents RA1 " Or RA12 JS absent and with the provisio if A ⁇ is N one of the substituents R ⁇ " Or R ⁇ 22 j s absent.
  • one of the atoms A ⁇ and A ⁇ is N, and the other is a carbon atom which is substituted by two hydrogen atoms.
  • n is 0, A ⁇ is N and R ⁇ 01 1 RA02 RA31 anc j RA32 are eacn hydrogen.
  • n is 1
  • a ⁇ is N and RA01 , RA02 RA21 and R ⁇ 22 are each hydrogen.
  • n 1
  • a ⁇ is N
  • RA11 and RA12 are each hydrogen and R ⁇ 31 and R ⁇ 32 are each hydrogen or combine to form an oxo-group.
  • n is 0 or 1
  • one of the atoms A ⁇ and A2 is N and the other is C or absent
  • the substituent bound to said N is selected from the group consisting of consisting of hydrogen, hydroxy, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • the substituent bound to said N is selected from the group consisting of consisting of hydrogen, hydroxy, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • n 1
  • a ⁇ is N
  • a ⁇ is C
  • R ⁇ OI , RA02 RA21 anc j RA22 are eacn hydrogen
  • one p a j r and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-
  • RA03 anc j RA04 nave the same meanings as defined above
  • RA31 and R ⁇ 32 are eacn independently selected from the group consisting of hydrogen, hydroxy and C-
  • n 0, A ⁇ is C, A ⁇ is N, R ⁇ OI 1 RA02 RA31 anc j RA32 are eacn hydrogen, and one of the substituents R ⁇ 21 and R ⁇ 22 j s a
  • n is 1
  • a ⁇ is C
  • a ⁇ is N
  • one p a j r anc j the other substituent is selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by R A ⁇ 5 -S(O) 2 -Ci.6-alkyl, wherein the -S(O) 2 -C-J _ ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA03RA04. or
  • RA01 anc j RA02 com bine to form an oxo-group; or R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-, wherein the substituents RA03 anc j RA04 have the same meanings as defined above, and RA31 and R A ⁇ 2 are b o t n hydrogen or combine to form an oxo-group.
  • n is 1 , A ⁇ is C, A ⁇ is N, R A ⁇ ⁇ , RA12 RA31 anc j RA32 are eacn hydrogen, R A 1 anc
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-
  • C 3 . 6 -cyclyl wherein the C ⁇ . ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl is bound via C, and wherein N is substituted by RA125 -S(O) 2 -C 1 .
  • n is 1 , A 1 is C, A ⁇ is N, RA11 , RA12 R A31 anc j R A32 are eacn hydrogen, RA01 and RA02 are both hydrogen, or one of the substituents RA01 and RA02 J S hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA02 t ⁇ iincd is in the R-configu ration, or RA01 and RA02 combine to form an oxo-group, and one of the substituents RA21 and RA22 J S a lone pair and the other is selected from the group con- sisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkyl via
  • n 1
  • a ⁇ is C
  • a 2 is N
  • R A ⁇ , R A02 R A11 R A12 R A31 and R A32 are eacn hydrogen
  • one of the substituents R A2 ⁇ and R A22 is a lone pair and the other is selected from the group con- sisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkyl via
  • N is substituted by R A125 , -S(O) 2 -C 1 . 6 -alkyl, wherein the -S(O) 2 -C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • n is 1 , A ⁇ is C, A 2 is N, R A ⁇ ⁇ , R A ⁇ 2 , R A 31 and R A32 are each hydrogen, one of the substituents R A ⁇ and R A ⁇ 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents R A ⁇ and RA02 t ⁇ j ⁇ d j s j n ( ne / ⁇ -configuration, and one of the substituents R A2 1 and R A22 j s a
  • one p a j r anc j the other is selected from the group consisting of hydrogen, C- j .
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C ⁇ . ⁇ -cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j . ⁇ -alkyl via
  • n is 1
  • a ⁇ is C
  • a 2 is N
  • R A ⁇ ⁇ , RA12 RA31 anc j RA32 are eacn hydrogen
  • R A ⁇ and R A 2 combine to form an oxo-group
  • one of the substituents R A2 ⁇ and R A22 is a lone pair and the other is selected from the group con- sisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j . ⁇ -alkyl via
  • N is substituted by R A125 , -S(O) 2 -C 1 . 6 -alkyl, wherein the -S(O) 2 -C 1 . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • a ⁇ and A 2 are each independently selected from the group consisting of C, N, O and S, wherein one of A ⁇ and A 2 is N, O or S; With the provisio if A ⁇ is N one of the substituents R A ⁇ or R A ⁇ 2 is absent and with the provisio if A 2 is N one of the substituents R A2 ⁇ or R A22 is absent and with the provisio if one of A ⁇ and A 2 are O or S both substituents bonded to are absent.
  • R A ⁇ and R A ⁇ 2 are each independently selected from the group consisting of hydrogen, hydroxy, C 1 . ⁇ -alkyl; or
  • RA01 anc j RA02 combine to form an oxo-group; with the proviso that, if R A ⁇ and R A ⁇ 2 combine to form an oxo-group A ⁇ may not be N or O;
  • R A ⁇ ⁇ and R A ⁇ 2 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • R A ⁇ ⁇ and R A ⁇ are hydrogen and R A ⁇ 1 and R A ⁇ 2 are each independently selected from the group consisting of hydrogen, C-
  • RA110 and R A ⁇ ⁇ ⁇ have the same meanings as defined in the embodiments above, or preferably below.
  • R A ⁇ , R A ⁇ t RA31 a nd R A ⁇ 2 are hydrogen and R A ⁇ 1 and R A ⁇ 2 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j .
  • ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O) 2 -Ci.6-alkyl, -SO 2 NR A1 3RA14, .(CH 2 ) m -R A1 5, -(CR A16 R A17 )
  • R A ⁇ and R A ⁇ 7 are each independently selected from the group consisting of hydrogen and C-
  • R A ⁇ 8 is selected of _ NR A116 R A117 wherein RA116 anc j RA117 nave ( ne same meanings as defined in the embodiments above, or preferably below.
  • RA19 and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-
  • RA111 is selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , -CONR A123 R A124 , C ⁇ g-alkyl, wherein the C-
  • RA111 is selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , -CONR A123 R A124 , and C ⁇ g-alkoxy, wherein the C-
  • RA112 anc j RA113 are eacn independently selected from the group consisting of hydrogen, C-
  • RA116 anc j RA117 are eacn independently selected from the group consisting of hydrogen, C-
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C 1 . 6 -alkyl wherein the -C(O)-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O) 2 -C 1 . 6 -alkyl, wherein the -S(O) 2 -C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • C 3 . 6 -cyclyl wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
  • the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 anc j RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or
  • RA121 anc j RA122 com bine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from hydroxy, oxo, C 1 .g-alkyl, -CONR ⁇ 3RA144 anc j wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S, wherein the substituents RA142 RA143 anc j RA144 nave ⁇ 16 same meanings as defined in the embodiments above, or preferably below.
  • RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C-
  • R ⁇ 31 and R ⁇ 32 are hydrogen.
  • R ⁇ 51 is selected from the group consisting of hydrogen, halogen, hydroxy, C- j . ⁇ -alkoxy, or
  • RB41 and R ⁇ 51 combine to form a group selected from -O-CH2-O-.
  • R ⁇ 51 J S selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy.
  • n is 0 or 1
  • one of the atoms A ⁇ and A ⁇ is N and the other is C or absent, wherein the substituent bound to said N is selected from the group consisting of consisting of hydrogen, hydroxy, C- j . ⁇ -alkyl.
  • n is 1
  • a ⁇ is N
  • a ⁇ is C
  • RA22 are eacn hydrogen
  • one p a j r and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-
  • n 0, A ⁇ is C, A ⁇ is N, R ⁇ 01 1
  • RA02 RA31 anc j RA32 are eac h hydrogen, and one of the substituents RA21 and R ⁇ 2 J S a lone pair and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-
  • n is 1
  • a ⁇ is C
  • a ⁇ is N
  • one p a j r anc j the other substituent is selected from the group consisting of hydrogen, C-
  • RA19 RA110 anc j RA111 nave the same meanings as defined in the embodiments above, or preferably below, and RA01 anc j RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C- j . ⁇ -alkyl, or
  • RA01 anc j RA02 combine to form an oxo-group; and RA31 anc j RA32 are both hydrogen, wherein m, I and k, and the substituents R A13 , R A14 , R A15 , R A16 , R A17 , R A18 , R A19 , R A1 1 ° and R A ⁇ ⁇ ⁇ have the same meanings as defined in the embodiments defined above, or preferably below.
  • n is 1
  • a ⁇ is C
  • a ⁇ is N
  • the carbon atom to which the substituents R A 01 and R A 2 bind is in the R-configu ration, or R A 01 and R A 2 combine to form an oxo-group
  • one of the substituents R A ⁇ 1 and R A ⁇ 2 is a lone pair and the other is selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from hydroxy -S(O) 2 -Ci.6-alky
  • n 1
  • a ⁇ is C
  • a ⁇ is N, RA1 ⁇ ,
  • RA12 RA31 anc j RA32 are eacn hydrogen, RA01 and RA02 are both hydrogen, or one of the substituents RA01 and RA02 j s hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA02 bind is in the R-configu ration, or RA01 and RA02 combine to form an oxo-group, and one of the substituents RA21 and RA22 j s a lone pair and the other is selected from the group consisting of hydrogen, C-
  • RA110 and RA111 have the same meanings as defined in the embodiments above, or preferably below.
  • n is 1
  • a ⁇ is C
  • a ⁇ is N
  • one of the substituents RA01 and RA02 J S hydrogen and the other substituent is hydroxy
  • the carbon atom to which the substituents RA01 and RA02 bjnd is in the R-configu ration
  • one of the substituents RA21 and RA22 J S a lone pair and the other is selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from hydroxy
  • n is 1
  • a ⁇ is C
  • a ⁇ is N
  • R A12 RA31 anc j RA32 are eacn hydrogen, RA01 anc
  • O ne pair and the other is selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from hydroxy, -S(O) 2 -C 1 . 6 -alkyl,
  • a 1 and A ⁇ are each independently selected from the group consisting of C, N, O and S, wherein one of A 1 and A ⁇ is N, O or S; n represents 0 or 1 ;
  • R A01 anc j R A02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-
  • R A01 anc j R A02 combine to form an oxo-group; with the proviso that, if RA01 and RA02 combine to form an oxo-group A 1 may not be N, O or S;
  • RA1 1 and RA12 are hydrogen
  • RA21 and RA22 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-
  • RA13 anc j RA14 are eacn independently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl,
  • RA15 js selected from the group consisting of hydroxy, C-
  • RA16 and RA17 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C- j . ⁇ -alkyl,
  • RA18 JS selected from the group consisting of C-
  • R A19 anc j R A110 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C-
  • R A19 anc j R A110 combine to form a C ⁇ ⁇ -cyclyl, wherein the C ⁇ .s-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA111 js selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)R A120 , -NR A121 R A122 , -CONR A123 R A124 , C 1 -6 - alkyl, wherein the C-
  • . 6 -alkoxy wherein the C-
  • RA112 anc j RA113 are eacn independently selected from the group consisting of hydrogen, C-
  • RA116 anc j RA117 are eacn independently selected from the group consisting of hydrogen, C-
  • RA118 anc j RA119 are each independently selected from the group consisting of hydrogen, C-
  • RA120 JS selected from the group consisting of hydrogen and C 1 .g-alkyl
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen, C-
  • -C(O)-C 1 . 6 -alkyl wherein the -C(O)-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O) 2 -C 1 .6-alkyl, wherein the -S(O) 2 -C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 3 .
  • the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 anc j RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C- j .g-alkyl,
  • RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • RA143 anc j RA144 are hydrogen
  • RA31 anc j RA32 are eacn hydrogen
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy;
  • RB51 JS selected from the group consisting of hydrogen, halogen, hydroxy, C- j . ⁇ -alkoxy; or
  • R B41 and R B51 combine to form a group Of -O-CH 2 -O-;
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B71 and R B81 are hydrogen
  • the compounds of Formula (I) are selected from the group consisting of
  • the compounds of Formula (I) are selected from the group consisting of
  • substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen
  • one of the substituents may be hydrogen and the other may have a meaning as defined.
  • the present invention expressly pertains to all compounds that can be derived from each and every combination of the specific meanings of substituents and other variable groups characterized above as embodiments of the present invention.
  • halogen used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is preferred.
  • Ci_5-alkyl used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-
  • C ⁇ -alkyl used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms.
  • Examples of the above-defined alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n- pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a
  • alkyl groups having 1 to 6 carbon atoms are a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group, and still more preferred examples are a methyl group, an ethyl group, a n-propyl group, an isopropyl group and an isobutyl group, wherein a methyl group is particularly preferred.
  • C- j _5-alkoxy used in the specification of the present invention indicates alkoxy groups having 1 to 6 carbon atoms, wherein alkoxy groups having 1 to 3 carbon atoms (C- j . ⁇ -alkoxy) are preferred.
  • .g-alkoxy group include a methoxy group, an ethoxy group, an n- propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, an isopentoxy group, a sec-pentoxy group, a 3- methylpentoxy group, an n-hexoxy group, a 1 ,1-dimethylpropoxy group, a 1 ,2-dimethylpropoxy group, a 2,2-dimethylpropyloxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-m ethyl propoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1
  • C3_5-cyclyl and “C3_5-cyclyl” used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms and 3 to 5 carbon atoms in their rings, respectively.
  • Examples of the C ⁇ .g-cyclyl and C3_5-cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
  • heterocyclyl includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated.
  • Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group, tet- rahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomor- pholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
  • a more preferred example is an oxetanyl group.
  • 3- to 7-membered heterocycle used in the specification of the present invention indi- cates a monocyclic 3- to 7-membered non-aromatic heterocyclic group which contains a nitrogen atom and optionally one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • the preferable example includes an aziridinyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a piperidinyl group, a piperazinyl group, a piperazine-2,3-dione group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group, a pyr- rolidine-2,5-dione group, a piperazine-2,3-dione group and the like. More preferred examples are a morpholinyl group, a pyrrolidine-2,5-dione group; a piperazine-2,3-dione group, a pyrrolidinyl group, an acetidyl group.
  • C ⁇ . ⁇ -aryl used in the specification of the present application means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, such as a monocyclic group, a bicyclic group and a tricyclic group.
  • a phenyl group an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group.
  • C ⁇ . ⁇ -aryl which is optionally substituted means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, wherein the aromatic hydrocarbon cyclic group has the same meaning as defined above and is optionally substituted by one or more sub- stituents.
  • substituents are hydroxy; C- j . ⁇ -alkyl, preferably methyl; C- j . ⁇ -alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo.
  • the Cg.-14-aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • a phenyl group, a phenyl group substituted with one fluoro and one methoxy, such as 3-fluoro-4-methoxyphenyl, me- thylen-3,4-dioxophenyl are more preferred.
  • the term "Ci_i3-heteroaryl" used in the specification of the present application refers to aromatic groups having 1 to 13 carbon atoms and one or more heteroatoms selected from N, O and S.
  • Preferred embodiments of such groups can be characterized as "5- to 14-membered heteroaryl" which indicates a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic heterocyclic group which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • C- j _g-heteroaryl used in the specification of the present invention refers to aromatic groups having 1 to 9 carbon atoms and one or more heteroatoms selected from N, O and S.
  • Preferred embodiments of such groups can be characterized as "5- to 10-membered heteroaryl" which indicates a monocyclic or bicyclic 5- to 10-membered heteroaryl which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • a 5- to 10-membered heteroaryl may preferably be used, and a 5 to 6 membered heteroaryl is more preferred.
  • aromatic heterocyclic group having include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imid
  • Ci_i3-heteroaryl which is optionally substituted means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, typically being a 5- to 14-membered aromatic heterocyclic group, which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, wherein the 5- to 14-membered aromatic heterocyclic group is substituted by one or more substituents.
  • substituents are hy- droxy; C-
  • the 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • .g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-
  • .g-alkyl group is substituted by at least one fluorine atom
  • .g-alkyl group can be any group as specified above with respect to the C-
  • .g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-
  • .g-alkyl groups are fluoromethyl, 1-fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3-fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro- n-propyl and perfluoroisobutyl.
  • .g-alkyl group can be any group as specified above with respect to the C-
  • .g-alkyl sub- stituted by at least one hydroxy is preferably a C-
  • ⁇ -alkyl groups substituted with at least one hydroxy group includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hy- droxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
  • .g-alkyl group is substituted by at least one C-
  • .g-alkyl group can be any group as specified above with respect to C-
  • .g-alkoxy group can be any group as specified above for C-
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-
  • the C- j .g-alkyl group is substituted by at least one C ⁇ .g-cyclyl
  • the C- j .g-alkyl group can be any group as specified above with respect to C-
  • the C ⁇ .g-cyclyl group can be any group as specified above for C ⁇ .g-cyclyl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ .g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-
  • .g-alkyl group is substituted by at least one 3- to 7-membered heterocyclyl
  • _g- alkyl group can be any group as specified above with respect to C-
  • the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-
  • .g-alkyl group can be any group as specified above with respect to C-
  • the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-
  • .g-alkyl group is substituted by at least one C- ⁇ .-13-heteroaryl
  • .g-alkyl group can be any group as specified above with respect to C-
  • 3-heteroaryl group can be any group as specified above for C- ⁇ .-13-heteroaryl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C- j .-i ⁇ - heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-
  • the C- j .g-alkyl group is substituted by at least one amine or amide group
  • the C- j .g-alkyl group can be any group as specified above with respect to C-
  • the amine or amide group can be any group as specified above for amine or amide, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
  • .g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-
  • .g-alkoxy group can be any group as specified above with respect to C-
  • .g-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobu- toxy.
  • .g-alkoxy group is substituted by at least one hydroxy
  • .g-alkoxy group can be any group as specified above with respect to C-
  • Examples of such C 1.3- alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
  • .g-alkoxy groups can be any group as specified above with respect to C-
  • .g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
  • _g-alkoxy is substituted by one other C-
  • Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the C ⁇ .g-cyclyl group can be any group as specified above for C ⁇ .g-cyclyl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ .g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-
  • .g-alkoxy group is substituted by at least one 3- to 7-membered heterocyclyl
  • . g-alkoxy group can be any group as specified above with respect to C-
  • the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-
  • .g-alkoxy group is substituted by at least one C- ⁇ .-13-heteroaryl
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the C- ⁇ .-13-heteroaryl group can be any group as specified above for C- j .-i ⁇ - heteroaryl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-
  • 3-heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-
  • C ⁇ .g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
  • the C ⁇ .g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g- cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C ⁇ .g-cyclyl, wherein the mono-, di- and perfluoro substituted C ⁇ .g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C ⁇ .g-cyclyl groups.
  • the C ⁇ .g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g- cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C3. g-cyclyl, wherein monohydroxy substituted C ⁇ .g-cyclyl groups are more preferred.
  • the above-mentioned 3- to 7-membered heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, hydrogen, C-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group sub- stituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocyclyl, wherein the mono-, di- and perfluoro substituted 3- to 7-membered heterocyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocyclyl groups.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group sub- stituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
  • the 3- to 7-membered heterocyclyl group is substituted by one or more substituents selected from hydrogen, C-
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise.
  • _g-alkyl moiety of the -C(O)-C 1 _g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C- ] _g- alkyl.
  • .g-alkyl and -C(O)-C- ] .g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C- ] .g-alkyl is -C(O)-Ch ⁇ and - C(O)-CH 2 OH.
  • the above-mentioned 3- to 7-membered heterocycle may be substituted with one or more sub- stituents selected from the group consisting of fluoro, hydroxy, C-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • the 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • the 3- to 7-membered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
  • the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C-
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • .g-alkyl moiety of the -C(O)-C 1 . g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C- j . ⁇ -alkyl.
  • .g-alkyl and -C(O)-C- ] .g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-Ci _ 6 -alkyl is - C (°)- CH 3 and -C(O)-CH 2 OH.
  • the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
  • Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof. Hydrates are a preferred example of said solvates.
  • N-oxides of the compounds according to the invention, the salts thereof, the stereoisomers of the compounds and the salts thereof include compounds, wherein the nitrogen atom of the pyridine moiety is oxidized, as illustrated by formula (Ia) below:
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers.
  • Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog).
  • the invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
  • Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
  • derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
  • a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating.
  • the compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
  • a compound of formula (IV) can be reacted with a compound of formula (Vl), in which X is a suitable leaving group, e.g. halogen, such as chlorine, or a conjugate base of an acid, such as trifluoroacetate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable solvent, e.g.
  • halogen such as chlorine
  • an acid such as trifluoroacetate
  • acetic acid preferably at elevated temperature
  • a cyclization condensation reaction with ammonia in an appropriate solvent, e.g. methanol, preferably at elevated temperature, to give a corresponding compound of formula (I).
  • an appropriate solvent e.g. methanol, preferably at elevated temperature
  • a compound of formula (Ic) is obtainable via an aldol-type condensation of a compound of formula (VIII), in which PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl, with a compound of formula (VII), and subsequent removal of PG.
  • PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl
  • the compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ic).
  • Reaction scheme 3 :
  • a compound of formula (IV) can be obtained as shown in reaction scheme 4.
  • indole (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic sub- stitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)].
  • the resulting hydroxy- compound of formula (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroace- tic anhydride as activator [see e.g. J. Org. Chem.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 5.
  • indole is reacted with a compound of formula (XII) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diiso- propylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper(ll)-2- ethylhexanoate.
  • a suitable base e.g. lithium diiso- propylamide or lithium hexamethyldisilazide
  • a suitable oxidation agent e.g. copper(ll)-2- ethylhexanoate.
  • the thus obtained compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
  • Indole (Xl) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 6.
  • indole (Xl) is reacted with a compound of formula (XIII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)].
  • a base e.g. pyrrolidine or potassium hydroxide
  • the thus obtained unsaturated compound of formula (XIV) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)].
  • the resulting hydroxy-compound of formula (V) can be oxi- dized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV).
  • the compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
  • Reaction scheme 6 :
  • Indole (Xl) is commercially available, compounds of formula (XIII) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 7.
  • isatine (XV) is reacted with a compound of formula (XIII) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)].
  • the thus obtained hydroxy compound of formula (XVI) can be transformed into a compound of formula (V) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)].
  • the resulting hydroxy-com pound (V) can be oxidized in a manner known to the skilled person, e.g.
  • lsatine (XV) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • nitro-dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid.
  • the final ring closing reaction to obtain a compound of formula (Ic) can be achieved by reacting a compound of formula (XXI) under inert atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or tetrakis(triphenylphosphine)palladium (0), and, if necessary, of a suitable phosphine ligand, in the presence of a suitable base, e.g. sodium tert-butoxide or sodium carbonate [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 1043 (2007)].
  • a suitable palladium source e.g. tris(dibenzylideneacetone)dipalladium (0) or tetrakis(triphenylphosphine)palladium (0)
  • a suitable phosphine ligand e.g. sodium tert-butoxide or sodium carbonate
  • a compound of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acid of formula (XXII) with carbonyl diimidazole in the presence of ni- tromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
  • a suitable base e.g. potassium tertbutylate
  • a compound of formula (I), wherein R A31 and R A32 combine to form an oxo group can be prepared from a compound of formula (I), wherein R A31 and R A32 combine to form, together with the carbon atom, that they are attached to, a 1 ,3-dioxolane ring, wherein the single carbon atom in between the two oxygen atoms (“C2") is the carbon atom, that the substituents R A31 and R A32 are attached to, by acetal hydrolysis reaction, e.g. using a suitable acid, such as hydrochloric acid, in the presence of water and a suitable solvent, such as tetrahydrofuran or dioxan;
  • a suitable acid e.g. acetic acid or p-toluenesulfonic acid
  • a suitable Lewis acid e.g.
  • titanium(IV) tetraisopropyl oxide in a suitable solvent, e.g. methanol, followed by hydrogenation, e.g. with the aid of a transition metal catalyst, such as palladium(O), in combination with a suitable hydrogen source, e.g. hydrogen gas or ammonium formiate, in a suitable solvent, such as methanol;
  • a suitable solvent e.g. methanol
  • hydrogenation e.g. with the aid of a transition metal catalyst, such as palladium(O)
  • a suitable hydrogen source e.g. hydrogen gas or ammonium formiate
  • acetic acid or p-toluenesulfonic acid or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by reduction, e.g. with the aid of a suitable reduction agent, such as sodium cyanoborohydride, in a suitable solvent, e.g. methanol and/or ethanol.
  • a suitable solvent e.g. methanol
  • a suitable solvent e.g. methanol
  • these two steps are conducted in one pot, without isolation of intermediate imine or imminium compounds;
  • dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hydroxybenzotriazole;
  • X represents halide, preferably iodine or bromine or chlorine, or a conjugate base of an acid, such as methylsulfonate, and that may be optionally substituted as defined above, in the presence of a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran; • a compound of formula (I), wherein R ⁇ 1 is "substituted alkyl", e.g.
  • dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
  • a base e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride
  • a suitable polar, aprotic solvent e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof;
  • an appropriate alkylating agent e.g. Hal-(CR A16 R A17 )i-C(O)OCi.
  • an alkaline hydroxide preferably lithium hydroxide, sodium hydroxide or potassium hydroxide
  • an appropriate solvent e.g. tetrahydrofuran, dioxan and / or water
  • amide formation reaction with an appropriate amine HNR A116 R A117 in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g. triethylamine or diis
  • an appropriate alkylating agent e.g. Hal-(CR A16 R A17 )i-C(O)OCi.
  • R Ax1 is hydrogen
  • R Ax2 is a free electron pair
  • a x is N
  • a catalytic amount of acid e.g. hydrochloric acid, or Lewis acid, e.g. copper (II) acetate
  • a suitable polar solvent e.g. acetonitrile or water or a mixture thereof.
  • x 1 or 2
  • a catalytic amount of acid e.g. hydrochloric acid, or Lewis acid, e.g. copper (II) acetate
  • a suitable polar solvent e.g. acetonitrile or water or a mixture thereof
  • ester hydrolysis e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan and / or water, followed by amide formation reaction with an appropriate amine HNR A116 R A117 in the presence of a dehydrating agent, e.g.
  • dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hyd roxy be nzotriazo Ie ;
  • a suitable base e.g. triethylamine or diisopropylethylamine
  • a suitable polar solvent e.g. dimethylformamide or acetonitrile
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
  • a suitable reduction agent such as tin dichloride or hydrogen gas and a palladium on carbon catalyst
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a group -NH-C(O)-C- ⁇ _ 2 -alkyl can be prepared e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
  • a base e.g. triethylamine, pyridine or potassium carbonate
  • a dehydrating agent e.g. dicyclohexylcarbodiimide
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents -NH-C(O)-NH 2 can be obtained e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is Ci_ 3 -alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
  • . 3 -alkyl can be prepared e.g. from a compound of formula (XXII), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents a hydroxy group by reaction with an excess (ca.
  • alkyl halide preferably alkyl iodide or alkyl bromide, e.g. methyl iodide or ethyl iodide or propyl iodide, in the presence of a suitable base, e.g. sodium hydride, in an appropriate polar solvent, e.g. dimethylformamide, at temperatures between -1O 0 C to 100 0 C, preferably O 0 C - 4O 0 C, followed by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan or water, or a mixture thereof.
  • a suitable base e.g. sodium hydride
  • polar solvent e.g. dimethylformamide
  • a suitable base e.g. sodium hydroxide, potassium carbonate, sodium carbonate or sodium hydrogencarbonate
  • a suitable solvent e.g. toluene, dichloromethane, hexane or water, or a mixture thereof, preferably at temperatures between O 0 C and 5O 0 C.
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, alu- minium oxide.
  • a suitable support material e.g. silica gel, reversed phase silica gel, amino modified silica gel, alu- minium oxide.
  • Salts of the compounds of formula (I), the N-oxides thereof and the stereoisomers of the compounds and the N-oxides thereof according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or me- thylis
  • acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid.
  • bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. ammonia, trimethylamine or methylamine.
  • the acid or base can be employed in salt preparation, de- pending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts.
  • pharmaceutically unacceptable salts which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid.
  • peracids such as m-chloroperbenzoic acid or peracetic acid.
  • the person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
  • Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • the pure diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
  • the (IS)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein R A01 and R A02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • a suitable aprotic solvent preferably tetrahydrofuran or dioxan
  • (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • the (I R)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, re- solving the diastereomers obtained and removing the chiral auxiliary agent.
  • chiral auxiliary agents for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts.
  • chiral acids such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid
  • chiral bases such as (+)- or (-)-brucine, (+)- or (-
  • diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1- phenylethanol, respectively, as chiral auxiliary agents.
  • diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
  • enanti- omeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • 1 H NMR spectra are recorded on a Bruker DPX200 ( 1 H 200 MHz), a Bruker Avance ( 1 H 300 MHz) or a Bruker AV400 ( 1 H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1 H). Chemical shifts are given in ppm ( ⁇ ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), ddd (doublet of doublet of doublet), t (triplet), q (quartet), m (multiplet) and b (broadened).
  • TMS tetramethylsilane
  • Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology.
  • Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode.
  • ESI electrospray ionization
  • Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O 0 C in a vacuum of 10 ⁇ 1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
  • Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments.
  • the temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments.
  • the reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
  • Benzyl-3-pyrroline-1-carboxylate (90%, 30.0 g) is dissolved in dichloromethane (900 ml), m-chloro- perbenzoic acid (46.0 g) is added and the solution is stirred for 18 h at room temperature. After that, the mixture is poured into 10% aqueous sodium hydrogencarbonate solution (200 ml), the aqueous phase is extracted with dichloromethane (2 x 200 ml), the combined organic extracts are washed with 10% aqueous sodium hydrogencarbonate solution (2 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :4 to 1 :1 (v/v)) to yield 28.6 g (98%) of the title compound as a colorless oil.
  • Benzyl S-hydroxy- ⁇ I H-indol-S-yOpyrrolidine-i-carboxylate (example A2) (28.7 g) is dissolved in dimethylsulfoxide (225 ml) and dichloromethane (225 ml), diisopropylethyl amine (51.2 ml) is added and the solution is cooled to O 0 C (ice bath).
  • a solution of sulfurtrioxide pyridine complex (27.2 g) in dimethylsulfoxide (290 ml) and pyridine (13.8 ml) is added drop by drop within 1 h at a rate that the internal temperature is kept below 5 0 C. The mixture is stirred for 1 h at O 0 C.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 6.19 g (22%) of the title compound as yellow crystals.
  • the crude product is purified by column chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 4:1 (v/v) to 1 :1 (v/v)) to yield 33.0 g (70%) of the title compound as a yellow viscous oil.
  • Ethyl 4-(1 H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (example A4) (32.9 g) is dissolved under argon in dry tetrahydrofuran (200 ml) und the solution is cooled to O 0 C (ice bath). Borane tetrahydrofuran complex (1 M in tetrahydrofuran, 180 ml) is added within 20 min. The ice bath is removed, the mixture is stirred for 2.5 h at room temperature.
  • the crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / heptane to obtain 19.1 g (54%) of the title compound.
  • Ethyl 4-(1H-indol-3-yl)-3-oxopiperidine-1-carboxylate Ethyl 3-hydroxy-4-(1 H-indol-3-yl)piperidine-1-carboxylate (example A5) (19.0 g) is dissolved in dimethylsulfoxide (120 ml) and dichloromethane (120 ml), diisopropylethyl amine (40.0 ml) is added and the solution is cooled to O 0 C (ice bath).
  • Step 1 Methyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate.
  • 3,5-Dimethoxypyridine (8.5 g) is dissolved under nitrogen in acetonitrile (230 ml), sodium borohydride (4.16 g) is added in portions within 10 min and the mixture is stirred for 10 min at -45 0 C.
  • Methyl chlorocarbonate (5.7 ml) is added drop by drop at a rate that the internal temperature does not exceed -4O 0 C (ca. 20 min), the mixture is stirred for 20 min at -4O 0 C - -45 0 C.
  • Step 2 Methyl 4-(1-acetyl-1 H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate.
  • Methyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (6.06 g) is dissolved in glacial acetic acid (15 ml), 1-acetyl-1 ,2-dihydro-3H-indol-3-one (5.26 g) and sodium acetate (2.46 g) is added and the mixture is refluxed under light exclusion for 3 h.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 3:7 (v/v) to petroleum ether / ethyl acetate / acetic acid 3:7:0.1 (v/v/v) to ethyl acetate / acetic acid 20:1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 2.80 g (28%) of the title compound.
  • the formed precipitate is filtered, washed with dichloromethane (5 ml) and water (3 x 20 ml) and dried over phosphorus pentoxide.
  • the aqueous phase of the combined filtrate is extracted with dichloromethane (3 x 50 ml), the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the residue is crystallized from ethyl acetate / n-heptane to give rise to a second crop of the title compound (total yield: 1.51 g (63%)).
  • Benzyl carbonochloridoate (37.8 ml) is added drop by drop at a rate that the internal temperature does not exceed -4O 0 C (ca. 20 min), the mixture is stirred for 40 min at -4O 0 C - -45 0 C. After that, 1 M hydrochloric acid (550 ml) is added, followed immediately by saturated sodium hydrogencarbonate solution (550 ml, pH 9). It is extracted with ethyl acetate (3 x 1000 ml), the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the combined aqueous phases are cooled to O 0 C (ice bath), acidified by addition of 6M hydrochloric acid, extracted with ethyl acetate (3 x 1500 ml), dried (MgSO 4 ) and concentrated in vacuo to give rise to crude benzyl 5-hydroxy-3-oxo- 3,6-dihydropyridine-1(2H)-carboxylate (35.4 g, 64%), that is used without further purification in the next step. It is stored with glacial acetic acid (6 ml) as stabilizer in the refrigerator.
  • Step 2 Benzyl 4-(1-acetyl-1 H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate.
  • Benzyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (34.01 g) is dissolved in glacial acetic acid (100 ml), 1-acetyl-1 ,2-dihydro-3H-indol-3-one (24.1 g) and sodium acetate (1 1.3 g) is added and the mixture is stirred for 24 h at room temperature under light exclusion and for further 24 h at 65 0 C.
  • the crude product contains a mixture of benzyl 4-(1-acetyl-1 H-indol-3- yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate and deacetylated benzyl 5-hydroxy-4- (1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate and is used without further purification is the next step.
  • Step 3 Benzyl 5-hydroxy-4-(1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate.
  • Crude product of step 2 is dissolved in 1 M aqueous lithium hydroxide solution (300 ml) and the mixture is stirred under light exclusion for 2 h at room temperature. After that, it is acidified by addition of hydrochloric acid (10% in water) to pH 5. The formed precipitate is filtered and washed thoroughly with water (3 x 50 ml).
  • Cyclopropylmethanamine (1.75 g) is dissolved in water (12 ml) and the mixture is cooled to O 0 C (ice bath).
  • a solution of bromoacetyl bromide (4.97 g) in dichloromethane (30 ml) and 2M aqueous sodium hydroxide solution (24.6 ml) are added in parallel drop by drop at a rate, that the internal temperature does not exceed 5 0 C.
  • the biphasic mixture is stirred for further 1 h at O 0 C.
  • Di-1 H-imidazol-1-ylmethanone (carbonyldiimidazole, 5.18 g) is suspended in dichloromethane (50 ml) and the suspension is cooled to O 0 C (ice bath).
  • Imidazole (1.81 g) and 2-(benzyloxy)ethan- amine hydrochloride (5.00 g) are added and the mixture is stirred for 18 h at room temperature. After that, saturated aqueous sodium hydrogencarbonate solution (50 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 50 ml).
  • Benzyl 3-(1 H-indol-3-yl)-4-oxopyrrolidine-1-carboxylate (example A3) (6.0 g) is suspended under nitrogen in dichloroethane (60 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 37.7 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C.
  • 3- fluoro-4-methoxyphenyl acetic acid (6.74 g) is dissolved in trifluoroacetic acid anhydride (5.2 ml) and the mixture is stirred for 60 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (20 ml) and added to the zinc chloride mixture, prepared above, within 15 min.
  • the mixture is stirred for 1 h at O 0 C and for 2.5 h at room temperature.
  • ammonia 7M in methanol, 25 ml
  • the mixture is refluxed for 16 h.
  • it is poured into water (100 ml), concentrated ammonia (25 ml) is added, the aqueous phase is extracted with dichloro- methane (2 x 100 ml), the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 20 ml) and water (1 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / ethanol 9:1 (v/v)) followed by crystallization from ethyl acetate / hydrogen chlo- ride (solution in diethyl ether) to yield 48 mg (39%) of the title compound.
  • the aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 30 ml) and water (1 x 30 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / petroleum ether to yield 26 mg (10%) of the title compound.
  • Step 1 tert-Butyl ⁇ 2-[5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol- 2(1 H)-yl]-2-oxoethyl ⁇ carbamate.
  • Step 2 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1 H)-yl]-2- oxoethanamine.
  • Step 2 1 ,5-Anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)pentitol.
  • the organic phase is washed with 0.3M hydrochloric acid (1 x 150 ml), the combined aqueous phases are extracted with ethyl acetate (2 x 200 ml), the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane / ethyl acetate 1 :1 to 1 :5 (v/v)) to obtain 1.08 g (25%) of 1 ,5-anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)pentitol.
  • Step 3 3-(1 H-lndol-3-yl)tetrahydro-4H-pyran-4-one.
  • Dimethylsulfoxide (0.81 ml) is dissolved in dry dichloromethane (15 ml) and the solution is cooled to -75 0 C.
  • Trifluoroacetanhydride (1.17 ml) is added drop by drop and the mixture is stirred for 30 min at -75 0 C.
  • 3-(1 H- lndol-3-yl)tetrahydro-4H-pyran-4-one 500 mg is dissolved in dry dichloroethane (2 ml), zinc di- chloride (1 M in diethyl ether, 6.9 ml) and 3-fluoro-4-methoxyphenylacetyl chloride (0.94 g) are added and the mixture is stirred for 8 min in a sealed vial at 8O 0 C using microwave radiation. After that, ammonia (7N in methanol, 8 ml) is added and the mixture is stirred for 30 min in a sealed vial at 15O 0 C using microwave radiation.
  • the reaction mixture is then filtered, the solids washed with dichloromethane, the combined filtrate is washed with 2M aqueous ammonia (2 x 50 ml) and water (1 x 50 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 1 :1 (v/v)) followed by crystallisation from ethyl acetate / petroleum ether to give rise to 140 mg (17%) of the title compound.
  • Step 2 1 ,5-Anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)-1-thiopentitol.
  • 3-Hydroxy-3-(4-oxotetrahydro-2H- thiopyran-3-yl)-1 ,3-dihydro-2H-indol-2-one (2.63 g) is suspended in dry tetrahydrofuran (30 ml), borane tetrahydrofuran complex (1 M in ether, 40 ml) is added in portions and the mixture is stirred for 20 h at room temperature.
  • Trifluoroacetanhydride (2.1 ml) is added drop by drop and the mixture is stirred for 30 min at -75 0 C.
  • a solution of 1 ,5-anhydro-2,4- dideoxy-2-(1 H-indol-3-yl)-1-thiopentitol (2.03 g) in dry tetrahydrofuran (30 ml) is then added via syringe and the mixture is stirred for further 1 h at -75 0 C.
  • Triethyl amine (5.58 ml) is added and the reaction mixture is allowed to warm to room temperature. Water (50 ml) and dichloromethane
  • Step 4 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole.
  • Zinc chloride (1 M in diethyl ether, 15.4 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C. After that, ammonia (7M in methanol, 18 ml) is added and the mixture is refluxed for 16 h. After cooling, it is diluted with ethyl acetate (100 ml). The organic layer is washed with 2M ammonia solution (1 x 100 ml), the aqueous phase is extracted with ethyl acetate (2 x 100 ml), the combined organic extracts are washed with water (1 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :9 (v/v)) to yield 0.80 g (19%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole (0.43 g) is dissolved under nitrogen in acetonitrile (5 ml), N-methylmorpholine-N-oxide (0.40 g) is added and the mixture is stirred for 5 min. Tetra-n-propylammonium perruthenate (20 mg) is added and the mixture is stirred for 3 h at 4O 0 C.
  • 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole (0.43 g) is dissolved under nitrogen in acetonitrile (5 ml), N-methylmorpholine-N-oxide (0.40 g) is added and the mixture is stirred for 5 min. Tetra-n-propylammonium perruthenate (20 mg) is added and the mixture is stirred for 3 h at 4O 0 C.
  • Step 1 3-(1-Methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-indole.
  • Indole (15.0 g) is suspended in methanol (250 ml), 1-methylpiperidin-4-one (14.4 g) and potassium hydroxide (14.3 g) are added and the reaction mixture is refluxed for 18 h. After that, the mixture is cooled, the crystalline precipi- tate is filtered, washed with methanol and dried to obtain 21.64 g (80%) of 3-(1-methyl-1 ,2,3,6- tetrahydropyridin-4-yl)-1 H-indole. mp. 227° - 228 0 C.
  • Step 2 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-ol.
  • Sodium borohydride (4.2 g) is dissolved in dry tetrahydrofuran (500 ml) and the solution is cooled to O 0 C (ice bath).
  • Boron trifluoride diethyl ether complex (15 ml) is added drop by drop at O 0 C and the mixture is stirred for 1 h at room temperature. It is cooled again to O 0 C (ice bath) and a suspension of 3-(1-methyl-1 ,2,3,6-tetrahydropyridin- 4-yl)-1 H-indole (12.5 g) in dry tetrahydrofuran (100 ml) is added in portions.
  • the mixture is stirred at room temperature for 2 h, then it is again cooled to O 0 C (ice bath) and water (60 ml), ethanol (60 ml), 3M sodium hydroxide solution (49 ml) are added, followed by hydrogen peroxide (30%, 30 ml, drop by drop).
  • the mixture is stirred at 55 0 C for 18 h. After cooling, the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane (150 ml) and washed with saturated sodium chloride solution (1 x 100 ml).
  • the aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 150 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chroma- tography (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) to yield 6.8 g (50%) of 4-(1 H- indol-3-yl)-1-methylpiperidin-3-ol.
  • Step 3 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-one.
  • Dimethylsulfoxide (3.55 ml) is dissolved in dry dichloromethane (100 ml) and the solution is cooled to -75 0 C.
  • Trifluoroacetanhydride (5.14 ml) is added drop by drop and the mixture is stirred for 30 min at -75 0 C.
  • a warm solution of 4-(1 H-indol- 3-yl)-1-methylpiperidin-3-ol (5.0 g) in dimethylsulfoxide (50 ml) is then added and the mixture is stirred for further 1 h at -75 0 C.
  • Triethyl amine (13.9 ml) is added and the reaction mixture is allowed to warm to room temperature. Water (100 ml) and dichloromethane (100 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts are washed with 2M sodium carbonate solution (2 x 200 ml) and water (1 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • Step 4 6-(3-Fluoro-4-methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine dihydrochloride.
  • 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-one (2.0 g) is dissolved under nitrogen in dichloroethane (12 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 13 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C.
  • 3-fluoro-4-methoxyphenyl acetic acid (3.23 g) is dissolved in trifluoroacetic acid anhydride (2.44 ml) and the mixture is stirred for 40 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (5.3 ml) and added to the zinc chloride mixture, prepared above, within 10 min.
  • the mixture is stirred for 5 min at O 0 C and for 1 h at room temperature.
  • ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 16 h.
  • Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) (17.2 g) is dissolved under ni- trogen in dichloroethane (120 ml) and the solution is cooled to O 0 C (ice bath). Zinc chloride (1 M in diethyl ether, 120 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C.
  • 3- fluoro-4-methoxyphenyl acetic acid (22.1 g) is dissolved in trifluoroacetic acid anhydride (16.7 ml) and the mixture is stirred for 40 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (50 ml) and added to the zinc chloride mixture, prepared above, within 20 min.
  • the mixture is stirred for 5 min at O 0 C and for 2.5 h at room temperature.
  • ammonia 7M in methanol, 53 ml
  • ammonium acetate (13.9 g) are added and the mixture is refluxed for 16 h. After cooling, it is filtered over a plug of Celite ® , the plug is washed thoroughly with methanol.
  • the formed mixed anhydride is diluted with dichloroethane (3 ml) and added to the zinc chloride mixture, prepared above, within 5 min.
  • the mixture is stirred for 3 h at room temperature.
  • Nitro- methane (30 ml) is added and the mixture is stirred for 18 h at room temperature.
  • am- monia (7M in methanol, 1.83 ml) and ammonium acetate (480 mg) are added and the mixture is heated in a sealed vial at 100 0 C for 45 min using microwave radiation. After cooling, it is filtered over a plug of Celite ® , the plug is washed thoroughly with dichloromethane. The combined filtrate is concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 6:10:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 257 mg (30%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (10 ml), triethylamine (330 ⁇ l) and methyl chloro- formate (92 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added.
  • the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with water (1 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :2 (v/v)) followed by crystallization from diethyl ether / petroleum ether to yield 200 mg (40%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (300 mg) is dissolved in methanol (10 ml), benzaldehyde (168 ⁇ l) and glacial acetic acid (20 ⁇ l) are added and the mixture is stirred for 30 min at room temperature. Sodium borohydride (188 mg) is added in portions and the mixture is stirred for 18 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (400 mg) is dissolved in dry dichloromethane (15 ml), triethylamine (222 mg) and morpholinecar- bonylchloride (172 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (361 mg) is dissolved in dry dichloromethane (10 ml), triethylamine (500 ⁇ l) and dimethylsulfamoyl chloride (145 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added.
  • the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with water (1 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by crystallization from ethyl acetate to give rise to 302 mg (64%) of the title compound.
  • Step 1 Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl](oxo)acetate.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (20 ml), triethyl- amine (310 ⁇ l) is added and the mixture is cooled to 1O 0 C.
  • Methyl chloro(oxo)acetate (130 ⁇ l) is added drop by drop at 1O 0 C and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (20 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are washed with water (1 x 40 ml), dried (MgSO 4 ) and concentrated in vacuo to yield 500 mg (99%) of methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate, that is used without further purifica- tion in the next step.
  • Step 2 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]- 2-oxoacetamide.
  • Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl](oxo)acetate 300 mg is dissolved in methanol (5 ml) and ammonia (7M in methanol, 7 ml) is added.
  • Step 1 Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl](oxo)acetate.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (20 ml), triethyl- amine (310 ⁇ l) is added and the mixture is cooled to 1O 0 C.
  • Methyl chloro(oxo)acetate (130 ⁇ l) is added drop by drop at 1O 0 C and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (20 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are washed with water (1 x 40 ml), dried (MgSO 4 ) and concentrated in vacuo to yield 500 mg (99%) of methyl [6-(3-fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate, that is used without further purification in the next step.
  • Step 2 N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoacetamide.
  • Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate 250 mg is dissolved in methanol (10 ml) and 1-(1 ,3-benzodioxol-5-yl)methanamine (250 ⁇ l) is added. The mixture is stirred for 18 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (180 mg) is dissolved in acetone (5 ml), potassium carbonate (0.28 g) and methansulfonyl chloride (63 mg) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is diluted with methanol (20 ml), filtered over Celite ® and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 119 mg (54%) of the title compound.
  • the crude product is purified by flash chromatography (amino modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)) followed by crystallization from ethyl acetate / n-heptane to give rise to 117 mg (40%) of the title compound.
  • the neutral form is obtained by the follow- ing procedure:
  • the triethylammonium salt (150 mg) is dissolved in dichloromethane / methanol (9:1 (v/v), 20 ml), 1 M citric acid (3 ml) and water (15 ml) are added.
  • the aqueous phase is extracted with dichloromethane / methanol (9:1 (v/v), 2 x 20 ml), the combined organic extracts are washed with saturated ammonium chloride solution (1 x 30 ml) and water (1 x 30 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is crystallized from ethyl acetate to obtain 55 mg (16%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (360 mg) is suspended in acetone (10 ml), potassium carbonate (0.55 g) and 2-bromopropanamide (182 mg) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is diluted with methanol (20 ml), filtered over Celite ® and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / triethylamine) followed by crystallization from ethyl acetate / n-heptane to yield 99 mg (23%) of the title com- pound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is dissolved in ethanol (10 ml), sodium carbonate (176 mg) and 1-bromo-2-methoxy- ethane (80 ⁇ l) are added and the mixture is refluxed for 18 h.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (240 mg) is suspended in acetone (5 ml), diisopropylethyl amine (282 ⁇ l) and N-acetyl-2-bromo- acetamide (140 mg) are added and the mixture is stirred for 7 h at room temperature. After that, the mixture is diluted with water (20 ml). The precipitate is filtered, washed (petroleum ether) and dried in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with dichloro- methane, followed by ethyl acetate / triethyl amine 9:1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to obtain 164 mg (54%) of the title compound.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 9:1 :1 (v/v/v)) followed by crystallization from ethyl acetate to yield 615 mg (69%) of the title compound.
  • the aqueous phase is extracted with ethyl acetate (3 x 20 ml), the combined organic extracts are washed with saturated ammonium chloride solution (1 x 40 ml) and saturated sodium chloride solution (1 x 40 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / triethylamine 5:1 (v/v)) to give rise to 117 mg (99%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is suspended in dichloromethane (4 ml) and N,N-dimethylglycine (89 mg), 1-hydroxy- benzotriazole (84 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg) and triethylamine (231 ⁇ l) are added. The mixture is stirred for 18 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is suspended in dichloromethane (3 ml), 4-(dimethylamino)pyridine (10 mg) and triethylamine (116 ⁇ l) are added and the mixture is cooled to O 0 C (ice bath). Acetanhydride (59 ⁇ l) is added drop by drop. The mixture is stirred for 20 min at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (1.08 g) is suspended in dichloromethane (25 ml) and 3-ethoxy-3-oxopropanoic acid (790 mg), 1- hydroxybenzotriazole (610 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g) and triethylamine (2.09 ml) are added. The mixture is stirred for 18 h at room temperature.
  • the mixture is stirred for 2 h at 8O 0 C. After cooling, it is diluted with water (20 ml) and pH is adjusted to 4.5 - 5 by addition of 6M hydrochloric acid. The formed precipitate is filtered and washed with water. It is redissolved in 3M sodium hydroxide solution (50 ml), extracted with ethyl acetate (2 x 50 ml). The aqueous phase is diluted with dioxane (10 ml) and acidified to pH 4.5 - 5 with 6M hydrochloric acid. The precipitate is filtered, washed with water and dried in vacuo to yield 179 mg (38%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (360 mg) is suspended in dichloromethane (12 ml) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (406 mg), 1-hydroxybenzotriazole (202 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (385 mg) and triethylamine (696 ⁇ l) are added. The mixture is stirred for 18 h at room temperature.
  • the crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :1 to 7:3 (v/v)) to give rise to 419 mg of tert-butyl ⁇ (1S)-2-[6-(3- fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-methyl-2- oxoethyl ⁇ methylcarbamate.
  • Step 2 (2S)-1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1-oxopropan-2-amine.
  • tert-Butyl ⁇ (IS ⁇ -te- ⁇ -fluoro ⁇ -methoxybenzyO-I ⁇ J-tetrahydro-SH- (419 mg) is dissolved in dioxane (7 ml) and concentrated hydrochloric acid (0.5 ml) is added. The mixture is stirred for 1 h at room temperature.
  • the precipitate is filtered, redissolved in dichloromethane / methanol (1 :1 (v/v), ca. 10 ml) and combined with the organic phase of the filtrate.
  • Addi- tional dichloromethane is added (20 ml), the organic phase is washed with saturated ammonium chloride solution (1 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo. The residue is crystallized from dichloromethane to yield 50 mg (75%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is dissolved in acetonitrile (1.5 ml) and water (1.5 ml), acrylamide (33 mg) and copper-(ll)- acetate (10 mg) are added and the mixture is stirred for 18 h at room temperature. After that, it is diluted with dichloromethane (10 ml), water (10 ml) is added and the mixture is vigorously stirred. The organic phase is concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 28 mg (15%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (3.24 g) is suspended in dichloromethane (45 ml), 4-(dimethylamino)pyridine (219 mg) and triethyl- amine (2.5 ml) is added and the mixture is cooled to O 0 C (ice bath). Bromoacetyl bromide (1.18 ml) is added drop by drop within 5 min, the mixture is stirred for 30 min at room temperature.
  • Step 1 3- ⁇ [2-(Benzyloxy)ethoxy]acetyl ⁇ -6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (200 mg) is suspended in dichloromethane (6 ml) and [2-
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (181 mg) is suspended in dichloromethane (5 ml) and 3-hydroxypropionic acid (30% in water, 300 ⁇ l), 1-hydroxybenzotriazole hydrate (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg), triethylamine (347 ⁇ l) and 4A molecular sieves (300 mg) are added. The mixture is stirred for 18 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (181 mg) is suspended in dichloromethane (5 ml) and rac-2,3-dihydroxypropanoic acid (5.2 M in water, 192 ⁇ l), 1-hydroxybenzotriazole hydrate (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbo- diimide hydrochloride (192 mg), triethylamine (347 ⁇ l) and 4A molecular sieves (250 mg) are added.
  • Zinc chloride (1 M in diethyl ether, 34.6 ml) is added drop by drop and the mixture is stirred for 10 min at O 0 C.
  • 3- fluoro-4-methoxyphenyl acetic acid (12.75 g) is dissolved in trifluoroacetic acid anhydride (9.87 ml) and the mixture is stirred for 1 h at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (50 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O 0 C. The mixture is stirred for 2 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one hydro- bromide (example 105) (149 mg) is suspended in dichloromethane (2.5 ml) and glacial acetic acid (38 ⁇ l), 1-hydroxybenzotriazole hydrate (76 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg) and triethylamine (229 ⁇ l) are added. The mixture is stirred for 18 h at room temperature.

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Abstract

The present invention pertains to Benzyl-substituted tetracyclic heterocyclic compounds of formula (I), as well as the resulting pharmaceutical compositions, and their use in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. Furthermore, the present invention pertains to the methods of manufacturing these Benzyl -substituted tetracyclic heterocyclic compounds.

Description

Description
Benzyl-substituted tetracyclic heterocyclic compounds
Field of application of the invention
The invention relates to 5-Benzyl-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole compounds, 5-Benzyl-1 ,2,3,6-tetrahydrofurano[3',4':5,6]pyrido[3,4-b]indole compounds, 5-Benzyl-1 ,2,3,6-tetrahydrothiopheno[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,6]naphthyridine compounds, 6-Benzyl-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine compounds, 6-Benzyl-1 ,3,4,7-tetrahydropyrano[4',5':5,6]pyrido[3,4-b]indole compounds and 6-Benzyl-1 ,3,4,7-tetrahydrothiopyrano[4',5':5,6]pyrido[3,4-b]indole compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
Background of the Invention
6-Benzyl-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one is described in Khimiya Get- erotsiklicheskikh Soedinenii (1985) 3, 363-6 without mentioning any pharmaceutical activity thereof. WO 02/064590 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO2008027182 discloses indoloquinoline compounds as calcium channel blockers.
It is an object of the present invention to provide novel compounds and pharmaceutical compositions which may be used in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
A further object of the present invention is to provide methods of manufacture of the compounds and compositions of the present invention.
It is a further object of the present invention to provide methods for treating diseases alleviated by inhibition of type 5 phosphodiesterases in a subject in need thereof. Description of the invention
It has now been found that the 5-Benzyl-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole compounds,
5-Benzyl-1 ,2,3,6-tetrahydrofurano[3',4':5,6]pyrido[3,4-b]indole compounds, 5-Benzyl-1 ,2,3,6-tetrahydrothiopheno[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,6]naphthyridine compounds, 6-Benzyl-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole compounds, 6-Benzyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine compounds, 6-Benzyl-1 ,3,4,7-tetrahydropyrano[4',5':5,6]pyrido[3,4-b]indole compounds and 6-Benzyl-1 ,3,4,7-tetrahydrothiopyrano[4',5':5,6]pyrido[3,4-b]indole compounds, which are described in detail below, have surprising and advantageous properties, making them especially useful in the treatment and prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
The compounds of the invention are specified in Formula (I) as depicted in the following.
The present invention thus pertains to compounds of the following Formula (I)
Figure imgf000004_0001
wherein A^ and A2 are each independently selected from the group consisting of C, N, O and S, wherein one of A^ and A2 is N, O or S; n represents 0 or 1 ;
RA01 and RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA03RA04. or
RA01 ancj RA02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-; with the proviso that, if RA01 and RA02 combine to form an oxo-group or RA^ and RA02 combine to form the group -O- CH2-CH2-O-, A1 may not be N, O or S;
RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, _NRA05RA06 and _C(O)-NRA07RA08
-C(O)-RA09, -C(O)-NRA010RA01 1 and -C(O)ORA012; or RA03 ancj RA04 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, _NRA013RA014 and _C(O)-NRA015RA016, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from N RA017 o and S;
RA05 ancj RA06 are eacn indpendently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA05 ancj RA06 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA018, O and S;
RA07 ancj RA08 are each independently selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA07 ancj RA08 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from N R^O 19 o and S;
RA09 js selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA010 ancj RA011 are eacn independently selected from the group consisting of hydrogen and C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA012 j3 c-|_6-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA013 and RA014 nave the same meanings as RA05 and RA06, and RA015 and RA016 nave tne same meanings as RA07 ancj RA08-
RA017 RA018 and RA019 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA11 and R^12 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and
S, and wherein the heteroaryl is optionally substituted, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by RA125 -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17)|.CORA18] -CO(CRA19RA110)k.RA111 and a lone pair; or in case A1 is S, it is optionally substituted by one or two oxo-groups; wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA15 js selected from the group consisting of hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA112RA113.
RA16 ancj RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
Cg-14-aryl, wherein the Cg.-14-aryl is optionally substituted, and _NRA114RA115; or
RA16 ancj RA17 combine to form a Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA18 JS selected from the group consisting of hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA116RA117.
RA19 and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA118RA119; or
RA19 ancj RA110 combine to form a Cβ.s-cyclyl, wherein the C3_5-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA19 ancj RA110 combine to form an oxo-group;
RA111 js selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)RA120, -NRA121 RA122, -CONRA123RA124, C1 -6- alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted,
C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkoxy via C, N is substituted by RA125 ancj
_NRA125RA126.
RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)ORA127, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or
N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g- alkyl via C, N is substituted by RA128; or RA112 ancj RA113 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR^128 Q, and S;
RA114 ancj RA115 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-Ci. g-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-j.g-heteroaryl, wherein the C-j.g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|_g-heteroaryl is optionally substituted,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by RA128, and _NRA129RA130 -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 -CONRA132RA133; or
RA116 ancj RA117 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
RA118 ancj RA119 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA120 JS se|ectec| from ^e group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA121 ancj RA122 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted,
C-j.g-heteroaryl, wherein the C-j.g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-j.g-heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA131 ,
-NRA134RA135 and .CONRA136RA137 -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl wherein the -C(O)-C1 _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -CONRA138RA139, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1 _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-S(O)2NRA140RA141 C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-| _-| 3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA1 31 , O and S;
RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg^-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-i.g-alkyl via C, N is substituted by RA128, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA128 C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O)2-C1. g-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or RA123 and RA124 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
RA125 RA126 RA128 RA131 and RA142 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA127 js represented by C-j.-jQ-alkyl, wherein the C-j.-ig-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA129, RA130, RA134 RA135, RA138 RA139, RA140 and RA141 are each independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA132 RA133 RA136 RA137 RA143 and RA144 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA21 and R^2 have the same meanings as RA11 and R^^; RA31 ancj RA32 are each independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA33RA34. or
RA31 ancj RA32 combine to form an oxo-group, or RA31 and R^32 combine to form the group -O-CH2-CH2-O-; with the proviso that, if R^31 and RA32 combine to form an oxo-group or R^31 and R^32 combine to form the group -0-CH2-CH2- O-, A2 may not be N, O or S;
RA33 and R^34 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)H and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C1.3- alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB^1 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
Special embodiments of the present application are described in the following.
According to one embodiment of the present invention, one of the substituents A^ and A^ is selected from N and O, and the other substituent is a carbon atom.
According to another embodiment of the present invention, one of the substituents A^ and A^ is a nitrogen atom and the other is a carbon atom.
According to yet another embodiment of the present invention, one of the substituents A^ and A^ is selected from N and O, and the other substituent is a carbon atom, with the provisio if A^ is N one of the substituents R^^or RA^2 JS absent and with the provisio if A^ is N one of the substituents RA21Or RA22 JS absent and with the provisio if A^ is O or S both substituents R^^and RA^2 are absent and with the proviso if A^ is O or S both substituents RA21and RA22 are absent.
According to yet another embodiment of the present invention, one of the substituents A^ and A2 is a nitrogen atom and the other is a carbon atom, with the provisio if A^ is N one of the substituents RA1 "Or RA12 JS absent and with the provisio if A^ is N one of the substituents R^21Or R^22 JS absent.
According to another embodiment of the present invention, R^01 and R^02 are each independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA03RA04. or
RA01 and R^02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-; with the proviso that, if RA01 and RA02 combine to form an oxo-group or RA01 and RA02 combine to form the group -O- CH2-CH2-O-, A1 may not be N or O; wherein the substituents RA03 and RA04 have the same meanings as defined above. According to another embodiment of the present invention, RA017 RA018 and RA019 are each independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to yet another embodiment of the present invention, R^01 and R^02 are eacn jnc|e. pendently selected from the group consisting of hydrogen and hydroxy, or R^01 and R^02 combine to form an oxo-group.
According to yet another embodiment, both substituents R^01 and R^02 represent hydrogen, or one of the substituents R^01 and R^02 represents hydroxy and the other substituent represents hydrogen, wherein the carbon atom to which the substituents R^01 and R^02 t>ind is in the R- config u ration, or R^01 and R^02 combine to form an oxo-group.
According to another embodiment of the present invention, R^ 11 and RA12 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by RA125 -S(O)2-Ci. β-alkyl, wherein the -S(O)2-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17)|.CORA18] -CO(CRA19RA110)k.RA111 and a lone pair; wherein m, I and k, and the substituents RA125 RA13 RA14 RA15 RA16 RA17 RA18
RA19 RA110 ancj RA111 nave the same meanings as defined above, or the preferred or further preferred meanings of these substituents as defined below.
According to yet another embodiment of the present invention, RA11 and RA12 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-| .g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C1.g-alkyl via C, N is substituted by RA125 -S(O)2-C1. g-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below.
According to the present invention, it may be that, if A^ is N, one of the substituents RA^ and RA^2 js a lone pair and the other substituent has the same meanings as defined above, or that, if A^ is C, both substituents RA^ and RA^ represent hydrogen.
According to another embodiment of the present invention, RA^ and RA^7 are each independently selected from the group consisting of hydrogen, hydroxy and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or RA^6 and RA^7 combine to form a Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to another embodiment of the present invention, RA^ js selected from the group consisting of
C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA116RA117, wherein RA116 ancj RA117 nave the same meanings as defined in the embodiments above, or preferably below.
According to another embodiment of the present invention, RA^ and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by fluoro and hydroxy, or RA^9 and RA110 combine to form an oxo-group. According to another embodiment of the present invention, RA^ 11 is selected from the group consisting of hydrogen, hydroxy, -NRA121RA122, -CONRA123RA124, C^-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg^-aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N,
O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkoxy via C, N is substituted by RA^2^, and _NRA125RA126 wherein the substituents RA121 , RA122, RA123, RA124, RA125 and RA126 have the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA^ ^ ^ is selected from the group consisting of hydrogen, hydroxy, -NRA121 RA122, -CONRA123RA124, and
C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkoxy via C, N is substituted by R^^5 wherein the substituents RA121 , RA122, RA123, RA124 and RA125 nave tne same meanings as defined in the embodiments above, or preferably below.
According to another embodiment of the present invention, RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|_g-alkyl via C or
N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_g- alkyl via C, N is substituted by RA128- or RA112 ancj RA113 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|_g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA128 Q, ancj §, wherein the substituent RA128 nas tne same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|_g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-Ci. g-alkyl, wherein the -C(O)-C-J _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the substituent RA128 nas tne same meanings as defined in the embodiments above, or preferably below.
According to another embodiment of the present invention, RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-|_g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA128, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1. g-alkyl, wherein the S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)O-C1. g-alkyl, wherein the -C(O)O-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 -CONRA132RA133; or ancj RA117 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q ancj s, wherein the substituents R^128 RA131 RA132 ancj RA133 nave tne same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-Ci.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.g-alkyl, wherein the S(O)2-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R^131 wherein the substituent RA131 nas tne same meanings as defined in the embodiments above, or preferably below. According to another embodiment of the present invention, RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA131 , -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl wherein the -C(O)-C1. β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-CONRA138RA139, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2NRA140RA141 C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or
RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q ancj s, wherein the substituents RA131 , RA138 RA139, RA140, RA141 RA142 RA143 and RA144 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-mennbered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA131 , -C(O)-C1.6-alkyl wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142 or ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q ancj s, wherein the substituents RA131 RA142 RA143 ancj RA144 nave the same meanings as defined in the embodiments above, or preferably below. According to another embodiment of the present invention, RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA128,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA128
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-Ci.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
RA123 ancj RA124 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA131 Q ancj s, wherein the substituents RA128 ancj RA131 nave tne same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to another embodiment of the present invention, RA129 ancj RA130 are eacn independently selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to another embodiment of the present invention, RA132 ancj RA133 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy.
RA21 and R^22 have each independently the same meanings as the substituents R^ 11 and R^12 defined in the above embodiments.
According to another embodiment the present invention, it may be that, if A^ is N, one of the substituents R^21 and R^22 js a lone pair and the other substituent has the same meanings as defined above, or that, if A^ is C, both substituents R^21 and R^22 represent hydrogen.
According to another embodiment of the present invention, R^31 and R^32 are each independently selected from the group consisting of hydrogen, hydroxy and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA33RA34. or
RA31 ancj RA32 combine to form an oxo-group, or
RA31 ancj RA32 combine to form the group -O-CH2-CH2-O-, with the proviso that, if R^31 and
RA32 combine to form an oxo-group or R^31 and R^32 combine to form the group -O-CH2-CH2-
O-, A^ may not be N or O, wherein RA33 ancj RA34 nave ^16 same meanings as defined above.
According to yet another embodiment of the present invention, R^31 and R^32 are each independently selected from the group consisting of hydrogen, hydroxy and C-|.g-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
RA31 ancj RA32 combine to form an oxo-group, with the proviso that, if R^31 and R^32 combine to form an oxo-group, A^ may not be N or O.
According to another embodiment of the present invention, R^41 js selected from the group con- sisting of hydrogen, halogen and C-j.β-alkoxy.
Acccording to another embodiment of the present invention, R^^^ is selected from the group consisting of hydrogen, halogen, C-i.β-alkyl, hydroxy, C-i.β-alkoxy, nitro, amino and a methoxy group substituted by 2 or 3 fluorine atoms, or RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH2-CH2-O-.
According to yet another embodiment of the present invention, R^51 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
According to yet another embodiment of the present invention, one of the atoms A^ and A^ is N, and the other atom is a carbon atom.
According to yet another embodiment of the present invention, one of the atoms A^ and A^ is N, and the other atom is a carbon atom, with the provisio if A^ is N one of the substituents RA1 "Or RA12 JS absent and with the provisio if A^ is N one of the substituents R^ "Or R^22 js absent.According to yet another embodiment of the present invention, one of the atoms A^ and A^ is N, and the other is a carbon atom which is substituted by two hydrogen atoms.
According to yet another embodiment of the present invention, n is 0, A^ is N and R^011 RA02 RA31 ancj RA32 are eacn hydrogen.
According to yet another embodiment of the present invention, n is 1 , A^ is N and RA01 , RA02 RA21 and R^22 are each hydrogen.
According to yet another embodiment of the present invention, n is 1 , A^ is N, RA11 and RA12 are each hydrogen and R^31 and R^32 are each hydrogen or combine to form an oxo-group.
According to yet another embodiment of the present invention, n is 0 or 1 , and one of the atoms A^ and A2 is N and the other is C or absent, wherein the substituent bound to said N is selected from the group consisting of consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA03RA04- wherein the substituents RA03 ancj RA04 haVe the same meanings as defined above. According to yet another embodiment of the present invention, n is 1 , A^ is N, A^ is C, R^OI , RA02 RA21 ancj RA22 are eacn hydrogen, one of the substituents R^ 11 and R^I 2 js a |one pajr and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA03RA04- wnerejn the substituents RA03 ancj RA04 nave the same meanings as defined above, and RA31 and R^32 are eacn independently selected from the group consisting of hydrogen, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA31 ancj RA32 combine to form an oxo-group, or RA31 and RA32 combine to form the group -0-CH2-CH2-O-.
According to yet another embodiment of the present invention, n is 0, A^ is C, A^ is N, R^OI 1 RA02 RA31 ancj RA32 are eacn hydrogen, and one of the substituents R^21 and R^22 js a |one pair and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-|_g- alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA03RA04- wherein the substituents RA03 ancj RA04 have the same meanings as defined above.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, one of the substituents RA21 and R^22 js a |one pajr ancj the other substituent is selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by RA^5 -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-J _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below, and ncj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA03RA04. or
RA01 ancj RA02 combine to form an oxo-group; or RA01 and RA02 combine to form the group -0-CH2-CH2-O-, wherein the substituents RA03 ancj RA04 have the same meanings as defined above, and RA31 and RA^2 are botn hydrogen or combine to form an oxo-group.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, RA^ ^ , RA12 RA31 ancj RA32 are eacn hydrogen, RA 1 anc| RA02 are ^o^ hydrogen, or one of the substituents RA01 and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA 1 anc| RA02 kjnc| js jn ^e R-configu ration, or RA 1 anc| RA02 combine to form an oxo-group, and one of the substituents RA^1 and RA^2 js a |One pair and the other is selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_β-alkyl via C, N is substituted by RA125,
C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl is bound via C, and wherein N is substituted by RA125 -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17^c0RAIe -CO(CRA19RA110)k.RA111 and a lone pair, wherein m, I and k, and the substituents RA125 RA13 RA14 RA15 RA16 RA17 RA18 RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments defined above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A1 is C, A^ is N, RA11 , RA12 RA31 ancj RA32 are eacn hydrogen, RA01 and RA02 are both hydrogen, or one of the substituents RA01 and RA02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA02 t^iincd is in the R-configu ration, or RA01 and RA02 combine to form an oxo-group, and one of the substituents RA21 and RA22 JS a lone pair and the other is selected from the group con- sisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125 -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A2 is N, RA^ , RA02 RA11 RA12 RA31 and RA32 are eacn hydrogen, and one of the substituents RA2^ and RA22 is a lone pair and the other is selected from the group con- sisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA125, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRA13RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA^9, RA110 ancj RA111 nave ^16 same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A2 is N, RA^ ^ , RA^2, RA31 and RA32 are each hydrogen, one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA^ and RA02 tøjηd js jn (ne /^-configuration, and one of the substituents RA21 and RA22 js a |one pajr ancj the other is selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.β-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1 _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A2 is N, RA^ ^ , RA12 RA31 ancj RA32 are eacn hydrogen, RA^ and RA 2 combine to form an oxo-group, and one of the substituents RA2^ and RA22 is a lone pair and the other is selected from the group con- sisting of hydrogen, C-|.g-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.β-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA125, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRAI 3RA14 -(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18, RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiment above, or preferably below.
According to another embodiment of the present invention, A^ and A2 are each independently selected from the group consisting of C, N, O and S, wherein one of A^ and A2 is N, O or S; With the provisio if A^ is N one of the substituents RA^or RA^2 is absent and with the provisio if A2 is N one of the substituents RA2^or RA22 is absent and with the provisio if one of A^ and A2 are O or S both substituents bonded to are absent.
According to yet another embodiment of the present invention, RA^ and RA^2 are each independently selected from the group consisting of hydrogen, hydroxy, C1.β-alkyl; or
RA01 ancj RA02 combine to form an oxo-group; with the proviso that, if RA^ and RA^2 combine to form an oxo-group A^ may not be N or O;
According to yet another embodiment of the present invention, RA^ ^ and RA^2 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, -SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA^ ^ and RA^ are hydrogen and RA^1 and RA^2 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl,
-SO2NRA13RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19,
RA110 and RA^ ^ ^ have the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA^ , RA^ t RA31 and RA^2 are hydrogen and RA^1 and RA^2 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-Ci.6-alkyl, -SO2NRA13RA14, .(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA110 and RA^ ^ ^ have the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA^ and RA^7 are each independently selected from the group consisting of hydrogen and C-|.g-alkyl,
According to another embodiment of the present invention, RA^8 is selected of _NRA116RA117 wherein RA116 ancj RA117 nave (ne same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA19 and RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected of hydroxy
According to yet another embodiment of the present invention, RA111 is selected from the group consisting of hydrogen, hydroxy, -NRA121RA122, -CONRA123RA124, C^g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy, Cg.-14-aryl, wherein the substituents RA121 , RA122 RA123 ancj RA124 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA111 is selected from the group consisting of hydrogen, hydroxy, -NRA121RA122, -CONRA123RA124, and C^g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from hydroxy, wherein the substituents RA121 , RA122 RA123 ancj RA124 nave the same meanings as defined in the embodiments above, or preferably below.
According to another embodiment of the present invention, RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, -C(O)-C1. g-alkyl, According to yet another embodiment of the present invention, RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy,
-C(O)-C1.6-alkyl,
-S(O)2-Ci.6-alkyl,
According to another embodiment of the present invention, RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkyl, -CONR^^3RA144 ancj wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR^I 31 , O and S, wherein the substituents R^142 RA143 ancj RA144 nave the same meanings as defined in the embodiments above, or preferably below.
According to another embodiment of the present invention, RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|_g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy, Cβ.g-cyclyl, -C(O)O-C1.6-alkyl, -C(O)-Ci. g-alkyl
-S(O)2-Ci. g-alkyl, C3.6-cyclyl,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or
RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from hydroxy, oxo, C1.g-alkyl, -CONR^^3RA144 ancj wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S, wherein the substituents RA142 RA143 ancj RA144 nave ^16 same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy, 3- to 7-nnennbered heterocyclyl, wherein the 3- to 7-nnennbered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA128, wherein the substituent RA128 nas tne same meaning as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, R^31 and R^32 are hydrogen.
Acccording to another embodiment of the present invention, R^51 is selected from the group consisting of hydrogen, halogen, hydroxy, C-j.β-alkoxy, or
RB41 and R^51 combine to form a group selected from -O-CH2-O-.
According to yet another embodiment of the present invention, R^51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy.
According to yet another embodiment of the present invention, n is 0 or 1 , and one of the atoms A^ and A^ is N and the other is C or absent, wherein the substituent bound to said N is selected from the group consisting of consisting of hydrogen, hydroxy, C-j.β-alkyl.
According to yet another embodiment of the present invention, n is 1 , A^ is N, A^ is C, R^ 11 RA02 RA21 anc| RA22 are eacn hydrogen, one of the substituents R^ 11 and RA12 JS a |one pajr and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, and RA31 ancj RA32 are hydrogen.
According to yet another embodiment of the present invention, n is 0, A^ is C, A^ is N, R^011
RA02 RA31 ancj RA32 are each hydrogen, and one of the substituents RA21 and R^2 JS a lone pair and the other substituent is selected from the group consisting of hydrogen, hydroxy, C-|.β- alkyl. According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, one of the substituents R^1 and RA^2 js a |one pajr ancj the other substituent is selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from hydroxy -S(O)2-Ci.6-alkyl,
-SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RA1 7)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein m, I and k, and the substituents RA125, RA13, RA14, RA15, RA16, RA17, RA18,
RA19 RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below, and RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, or
RA01 ancj RA02 combine to form an oxo-group; and RA31 ancj RA32 are both hydrogen, wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA1 1° and RA^ ^ ^ have the same meanings as defined in the embodiments defined above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, RA^ ^ , RA^2, RA31 and RA32 are each hydrogen, RA^ and RA^2 are both hydrogen, or one of the sub- stituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA 2 bind is in the R-configu ration, or RA01 and RA 2 combine to form an oxo-group, and one of the substituents RA^1 and RA^2 is a lone pair and the other is selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from hydroxy -S(O)2-Ci.6-alkyl,
-SO2NRA13RA14, .(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA1 10 and RA1 ^ ^ have the same meanings as defined in the embodiments defined above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, RA1 ^ ,
RA12 RA31 ancj RA32 are eacn hydrogen, RA01 and RA02 are both hydrogen, or one of the substituents RA01 and RA02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA02 bind is in the R-configu ration, or RA01 and RA02 combine to form an oxo-group, and one of the substituents RA21 and RA22 js a lone pair and the other is selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, -S(O)2-C1.6-alkyl,
-SO2NRAI 3RA14 .(CH2)m-RA15, -(CRA16RAI T^CORAI 8 -CO(CRA19RA110)k.RA111 and a lone pair; wherein m, I and k, and the substituents RA"I3 RA14 RA15 RA16 RA17 RA18 RA19
RA110 and RA111 have the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, RA11 , RA12 RA31 and RA32 are each hydrogen, one of the substituents RA01 and RA02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the substituents RA01 and RA02 bjnd is in the R-configu ration, and one of the substituents RA21 and RA22 JS a lone pair and the other is selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from hydroxy,
-S(O)2-Ci. g-alkyl,
-SO2NRAI 3RA14 .(CH2)m-RA15, _(CRA16RA17^c0RAIe, -CO(CRA19RA110)k.RA111 and a lone pair; wherein m, I and k, and the substituents RA13, RA14, RA15, RA16, RA17, RA18, RA19, RA110 ancj RA111 nave the same meanings as defined in the embodiments above, or preferably below.
According to yet another embodiment of the present invention, n is 1 , A^ is C, A^ is N, RA1 ^ , RA12 RA31 ancj RA32 are eacn hydrogen, RA01 anc| RA02 combine to form an oxo-group, and one of the substituents RA21 and RA22 js a |One pair and the other is selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, -S(O)2-C1.6-alkyl,
-SO2NRA1 SRAM1 .(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m, I and k, and the substituents RA"I3 RA14 RA15 RA16 RA17 RA18 RA19 RA1 10 and RA111 have the same meanings as defined in the embodiment above, or preferably below.
According to yet another embodiment of the present invention, A1 and A^ are each independently selected from the group consisting of C, N, O and S, wherein one of A1 and A^ is N, O or S; n represents 0 or 1 ;
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl; or
RA01 ancj RA02 combine to form an oxo-group; with the proviso that, if RA01 and RA02 combine to form an oxo-group A1 may not be N, O or S;
RA1 1 and RA12 are hydrogen;
RA21 and RA22 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted,
Cg.14-aryl, -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17^c0RAIe -CO(CRA19RA110)k.RA111 and a lone pair; or in case A1 is S, it is optionally substituted by one or two oxo-groups;
wherein m is 0, 1 , 2 and 3, I is 1 , 2 and 3 and k is 0, 1 and 2;
RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen and C-j.β-alkyl,
RA15 js selected from the group consisting of hydroxy, C-|.g-alkoxy, -NRA112RA113;
RA16 and RA17 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C-j.β-alkyl,
RA18 JS selected from the group consisting of C-|.g-alkoxy,
_NRA116RA117.
RA19 ancj RA110 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by fluoro and hydroxy, C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA118RA119; or
RA19 ancj RA110 combine to form a Cβ^-cyclyl, wherein the Cβ.s-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA111 js selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)RA120, -NRA121 RA122, -CONRA123RA124, C1 -6- alkyl, wherein the C-|.6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
C-|.6-alkoxy, wherein the C-|.6-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-|.6-alkyl, wherein the C-|.6-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)ORA127,
RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, -C(O)-C1. g-alkyl, -S(O)2-C1. g-alkyl;
RA118 ancj RA119 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, -C(O)-C1. g-alkyl;
RA120 JS selected from the group consisting of hydrogen and C1.g-alkyl;
RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, C3.6-cyclyl, -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)-C1.6-alkyl wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-j.g-alkyl,
-CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA128,
RA127 js represented by C-j.-iQ-alkyl;
RA143 ancj RA144 are hydrogen;
RA31 ancj RA32 are eacn hydrogen;
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy;
RB51 JS selected from the group consisting of hydrogen, halogen, hydroxy, C-j.β-alkoxy; or
RB41 and RB51 combine to form a group Of -O-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB71 and RB81 are hydrogen;
a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
Benzyl 5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indole-2(1 H)- carboxylate; 5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 5-(3-Fluoro-4-methoxybenzyl)-2-(methoxyacetyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4- b]indole hydrochloride; 2-Benzoyl-5-(3-fluoro-4-methoxybenzyl)-1 ,2,3,6- tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6- dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1 H)-yl]-2-oxoethanamine; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(4-Methoxybenzyl)-1 , 3,4,7- tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2-oxide; 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2,2-dioxide; 6-(3-Fluoro-4-methoxybenzyl)-3- methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine dihydrochloride; Ethyl 6-(3-fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,5- difluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridine-S-carboxylate; Ethyl 6-(1 ,3-benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3- carboxylate; Ethyl 6-(4-fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,4-difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3-chloro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo^.S-cKI Jlnaphthyridinei e^S.S-Difluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S- c][1 ,7]naphthyridine; 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; e^S-Chloro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-cKI Jlnaphthyridine; 6-(4-Ethoxy-3- fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(4-Methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; Methyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4-methoxybenzyl)- 1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridine-S-carboxylate; 3-Benzyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(3-Fluoro-4- methoxybenzy^-S^morpholin^-ylcarbonyl^.S^J-tetrahydro-I H-indolo^.S-clII Jlnaphthyridine; Θ^S-Fluoro^-methoxybenzyO-N.N-dimethyl-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine- 3-carboxamide; 1-Ethyl-4-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]carbonyl}piperazine-2,3-dione; 6-(3-Fluoro-4-methoxybenzyl)-N,N-dinnethyl- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-sulfonamide; 2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-oxoacetamide; 2-[6-(3- Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- methoxyethyl)-2-oxoacetannide; N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-nnethoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoacetamide; 6-(3-Fluoro-4- methoxybenzyl)-3-(methylsulfonyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c][1 ,7]naphthyridine; 2-[6-(3- Fluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N- oxetan-3-ylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-isopropylacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolop.S-cKI Jlnaphthyridin-S-yll-N^methylsulfonyOacetamide^-^S- Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllpropanannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- methylpropanamide; Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo^.S-cKI Jlnaphthyridin-S-yllethylJcarbamate^-^S-Fluoro^-methoxybenzyO-I ^^J- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methylethanamine; 2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 6-(3-Fluoro-4- nnethoxybenzyl)-3-(2-nnethoxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Acetyl- 2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-hydroxyethyl)acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxypropyl)acetamide; 2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^-hydroxy-i- methylethyl)acetannide; 2-(Dinnethylannino)-1-[6-(3-fluoro-4-nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-(nnorpholin-4- ylacetyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 3-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N.N-dinnethyl-S-oxopropan-i-annine; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}methanesulfonannide; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanol; 1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-ol; 1-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-i-oxobutan^-ol; tert- Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}carbamate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}methylcarbannate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-methyl-2-oxoethyl}carbamate; tert-Butyl (i-I^S-fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]carbonyl}propyl)carbaιmate; 1-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}pyrrolidine-2,5-dione; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dinnethyl-1-oxopropan-2-annine; 1-{[6-(3- Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]carbonyl}cyclopropanecarboxamide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c][1 ,7]naphthyridine; Ethyl 3-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoate; 3-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoic acid; 3-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-oxopropanannide; S-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- methyl-3-oxopropanannide; (2S)-1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-1-oxopropan-2-annine; (2R)-1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methyl-1-oxopropan-2-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethanamine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanannine; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-annine; 1-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-i-oxobutan^-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanamine; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dimethylethanannine; 3-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propanamide; 3-(Bromoacetyl)-6-(3-fluoro- 4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-oxoethanannine; 2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)ethanol; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- cKI JJnaphthyridin-S-yll^-oxoethylJcyclopropanannine; N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanamine; N-{2- [6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}propan-1 -amine; N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanamine; 2-[{2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}(methyl)annino]ethanol; rac-2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}amino)propan-1-ol; 1-{2-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-oxoethylJazetidin-S-ol; i^-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- oxoethyl}azetidine-3-carboxamide; 6-(3-Fluoro-4-methoxybenzyl)-3-(pyrrolidin-1-ylacetyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-methoxyethyl)-2-oxoethanamine; 2-({2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)acetannide; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac- 1-[6-(3-Fl uoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-S-hydroxybutan-i-one; rac-i-^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; Benzyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridin-1-one hydrobromide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; rac-1-[6-(3,4- DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^S.S-Difluoro^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^^- hyd roxyethoxy)ethanone ; 6-(3-Fl uoro-4-methoxybenzyl)-3-[(2-hyd roxyethoxy)acetyl]-2 ,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetamide^-te^-Ethoxy-S-fluorobenzyO-i , 2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1- oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetamide; rac-2-[6-(3-Fluoro-4- methoxybenzy^-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide;
2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4- Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3-Benzodioxol-5- ylmethyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^i .S-Benzodioxol-S-ylmethyO-I ^^J-tetrahydro-SH-indolop.S-cKI Jlnaphthyridin-S-yl]^- (dimethylannino)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylamino)-1-[6-(4-fluoro-3- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4-Ethoxy- 3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6- (4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylannino)-1-[6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3-Chloro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(3-Chloro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone; i-tθ^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin- 3-yl]-2-(dimethylannino)ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; 1-[6-(4-Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylamino)-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-[(2S)- 2-hydroxypropanoyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 3-Acetyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5- Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3- hydroxybutan-1-one; cis-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 Jlnaphthyridin-S-yip-hydroxycyclopentyllmethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(3,4- Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl][2- hydroxycyclopentyl]methanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; i-te^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S- hydroxybutan-1-one; cis-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- ^[I Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; 3-Hydroxy-1-[6-(4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]butan-1-one; 1-[6-(3,4-Difluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2- hydroxyethoxy)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 2-(2- Hydroxyethoxy^i-te^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yllethanone^-^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]acetamide; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(3,4-Difluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; Methyl [6-(1 ,3-benzodioxol-5-ylmethyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetate^-te^-Ethoxy-S-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Ethoxy-3-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3-Chloro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(3-Chloro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 2-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; 2-[6-(3-Chloro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; N-(2- Hydroxyethyl^-tθ^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yllacetamide^-^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- (2-hydroxyethyl)acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; i-^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 2-[(2-Hydroxyethyl)amino]-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1- hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2- hydroxyethyl)amino]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; rac-1-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxyethanone; rac-HΘ-^-Fluoro^-methoxybenzyO-i-hydroxy-I ^^J-tetrahydro-SH-indolo^S- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-2-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(3,4- DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac-i-tθ^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(4-Ethoxy-3- fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-i-te^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 3-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]propan-1-one; rac-2,3-Dihydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; cis-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone, a salt thereof, or a stereoisomer of the compound or the salt thereof.
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
Benzyl 5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indole-2(1 H)- carboxylate; 5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 5-(3-Fluoro-4-nnethoxybenzyl)-2-(nnethoxyacetyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4- b]indole hydrochloride; 2-Benzoyl-5-(3-fluoro-4-methoxybenzyl)-1 ,2,3,6- tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6- dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1 H)-yl]-2-oxoethanamine; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(4-Methoxybenzyl)-1 ,3,4,7- tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2-oxide; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2,2-dioxide; 6-(3-Fluoro-4-methoxybenzyl)-3- methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine dihydrochloride; Ethyl 6-(3-fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,5- difluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridine-S-carboxylate; Ethyl 6-(1 ,3-benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3- carboxylate; Ethyl 6-(4-fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,4-difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3-chloro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine; 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; e^S-Chloro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-cKI Jlnaphthyridine; 6-(4-Ethoxy-3- fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(4-Methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; Methyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4-methoxybenzyl)- 1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridine-S-carboxylate; 3-Benzyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(3-Fluoro-4- nnethoxybenzyl)-3-(nnorpholin-4-ylcarbonyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; Θ^S-Fluoro^-methoxybenzyO-N.N-dimethyl-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine- 3-carboxamide; 1-Ethyl-4-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]carbonyl}piperazine-2,3-dione; 6-(3-Fluoro-4-methoxybenzyl)-N,N-dimethyl- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-sulfonamide; 2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-oxoacetamide; 2-[6-(3- Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- methoxyethyl)-2-oxoacetannide; N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoacetamide; 6-(3-Fluoro-4- methoxybenzyO-S^methylsulfonyl^.S^J-tetrahydro-IH-indolo^.S-cKI Jlnaphthyridine^-te^S- Fluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N- oxetan-3-ylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-nnethylacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-isopropylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolop.S-cKI Jlnaphthyridin-S-yll-N^methylsulfonyOacetamide^-^S- Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllpropanannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- methylpropanamide; Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethyl}carbamate; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methylethanamine; 2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 6-(3-Fluoro-4- methoxybenzyl)-3-(2-nnethoxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Acetyl- 2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- S-yll-N^-hydroxyethyOacetamide^-te^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxypropyl)acetamide; 2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxy-1- methylethyl)acetannide; 2-(Dinnethylannino)-1-[6-(3-fluoro-4-nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-(nnorpholin-4- ylacetyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 3-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dimethyl-3-oxopropan-1-annine; N^-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- oxoethyl}methanesulfonannide; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanol; 1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-ol; 1-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxobutan-2-ol; tert- Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 , 2,4, 7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}carbamate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}methylcarbannate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-i-methyl^-oxoethylJcarbamate; tert-Butyl (1-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]carbonyl}propyl)carbamate; 1-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}pyrrolidine-2,5-dione; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dinnethyl-1-oxopropan-2-annine; 1-{[6-(3- Fluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S- yl]carbonyl}cyclopropanecarboxamide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c][1 ,7]naphthyridine; Ethyl 3-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoate; 3-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoic acid; 3-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanannide; S-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- methyl-3-oxopropanannide; (2S)-1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-1-oxopropan-2-amine; (2R)-1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-nnethyl-1-oxopropan-2-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethanamine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanannine; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-annine; 1-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-i-oxobutan^-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanamine; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dimethylethanannine; 3-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propanamide; 3-(Bromoacetyl)-6-(3-fluoro- 4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-oxoethanannine;
2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)ethanol; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- cKI JJnaphthyridin-S-yll^-oxoethylJcyclopropanannine; N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4- nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanannine; N-{2- [6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}propan-1 -amine; N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanamine; 2-[{2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}(methyl)annino]ethanol; rac-2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}amino)propan-1-ol; 1-{2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-oxoethylJazetidin-S-ol; i^-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- oxoethyl}azetidine-3-carboxamide; 6-(3-Fluoro-4-methoxybenzyl)-3-(pyrrolidin-1-ylacetyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-methoxyethyl)-2-oxoethanamine; 2-({2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)acetannide; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac- 1 -[6-(3-Fl uoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-hydroxybutan-i-one; rac-i-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; Benzyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridin-1-one hydrobromide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; rac-1-[6-(3,4- DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^S.S-Difluoro^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^^- hyd roxyethoxy)ethanone ; 6-(3-Fl uoro-4-methoxybenzyl)-3-[(2-hyd roxyethoxy)acetyl]-2 ,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4-Ethoxy-3-fluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1- oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetamide; rac-2-[6-(3-Fluoro-4- methoxybenzy^-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3-
Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4- Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3-Benzodioxol-5- ylmethy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^i .S-Benzodioxol-S-ylmethyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- (dimethylannino)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro- SH-indolo^.S-cKI Jlnaphthyridin-S-yllethanone^^Dimethylamino^i-te^-fluoro-S- nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4-Ethoxy- 3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6- (4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylannino)-1-[6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3-Chloro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(3-Chloro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone; i-tθ^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin- 3-yl]-2-(dimethylannino)ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; 1-[6-(4-Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylamino)-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-[(2S)- 2-hydroxypropanoyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 3-Acetyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5- Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3- hydroxybutan-1-one; cis-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl][2-hydroxycyclopentyl]methanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(3,4- Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl][2- hydroxycyclopentyl]methanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; i-te^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S- hydroxybutan-1-one; cis-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- ciπ Jlnaphthyridin-S-yip-hydroxycyclopentyllmethanone; 3-Hydroxy-1-[6-(4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]butan-1-one; 1-[6-(3,4-Difluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2- hydroxyethoxy)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 2-(2- Hydroxyethoxy^i-tθ^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone; 2-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(3,4-Difluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; Methyl [6-(1 ,3-benzodioxol-5-ylmethyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetate; 2-[6-(4-Ethoxy-3-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Ethoxy-3-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3-Chloro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(3-Chloro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 2-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; 2-[6-(3-Chloro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^-hydroxyethyOacetamide; N-(2- Hydroxyethyl^-te^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yllacetamide^-^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- (2-hydroxyethyl)acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; i-^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 2-[(2-Hydroxyethyl)amino]-1-[6-(4-nnethoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1- hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2- hydroxyethyl)amino]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; rac-1-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxyethanone; rac-i-tθ^S-Fluoro^-methoxybenzyO-i-hydroxy-I ^^J-tetrahydro-SH-indolop.S- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-2-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(3,4- Difluorobenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac-i-^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(4-Ethoxy-3- fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-i-tθ^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 3-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]propan-1-one; rac-2,3-Dihydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; cis-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; cis-(2- HydroxycyclopentyOtθ^-nnethoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]methanone; [6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetate; i-^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one; N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4-nnethoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetamide^-^S-Fluoro- 4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N- dimethylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methylacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 , 2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N-methylacetamide; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzy^-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; rac- 2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1-methyl-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide; N-(2,3-Dihydroxypropyl)-2-[6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3,4-Difluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2,3-dihydroxypropyl)acetamide; 1-[6- (3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxy-2- (hydroxymethyl)-2-nnethylpropan-1-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxy-2-(hydroxymethyl)-2-nnethylpropan-1-one; N-(2,3- Dihydroxypropyl)-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxamide; 6-(3-Fluoro-4-methoxybenzyl)-N-(2-hydroxyethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide; 2-[6-(3-Fluoro-4-hydroxybenzyl)-1- oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N-methylacetamide; rac-2-[6-(3- Fluoro^-hydroxybenzyO-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- methylacetamide; 2-[(1f?)-6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide, a salt thereof, or a stereoisomer of the compound or the salt thereof.
Wherever two substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen, one of the substituents may be hydrogen and the other may have a meaning as defined.
In addition to the compounds exemplified herein and the specific substituent combinations mentioned above, the present invention expressly pertains to all compounds that can be derived from each and every combination of the specific meanings of substituents and other variable groups characterized above as embodiments of the present invention.
These compounds are effective inhibitors of the type 5 phosphodiesterase.
The term "halogen" used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is preferred. The term "Ci_5-alkyl" used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-|_4-alkyl) are preferred, linear or branched alkyl groups having 1 to 3 carbon atoms (C-j.β-alkyl) are more preferred and alkyl groups having 1 to 2 carbon atoms (C-|_2- alkyl) are still more preferred. In the same way, the term "C^-alkyl" used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms. Examples of the above-defined alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n- pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1 ,3- dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group or a n-hexyl group. More pre- ferred examples of the alkyl groups having 1 to 6 carbon atoms are a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group, and still more preferred examples are a methyl group, an ethyl group, a n-propyl group, an isopropyl group and an isobutyl group, wherein a methyl group is particularly preferred.
The term "C-j_5-alkoxy" used in the specification of the present invention indicates alkoxy groups having 1 to 6 carbon atoms, wherein alkoxy groups having 1 to 3 carbon atoms (C-j.β-alkoxy) are preferred. Examples of the C-|.g-alkoxy group include a methoxy group, an ethoxy group, an n- propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, an isopentoxy group, a sec-pentoxy group, a 3- methylpentoxy group, an n-hexoxy group, a 1 ,1-dimethylpropoxy group, a 1 ,2-dimethylpropoxy group, a 2,2-dimethylpropyloxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-m ethyl propoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1-dimethylbutoxy group, a 1 ,2-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2,3- dimethylbutoxy group, a 1 ,3-dimethylbutyloxy group, a 2-ethylbutoxy group, a 1 ,3-dimethylbutoxy group, a 2-methylpentoxy group, a 3-methylpentyloxy group, a hexyloxy group, wherein a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group and a tert-butoxy group are preferred, and a methoxy group, ethoxy group, isopropoxy group and a isobutoxy group are more preferred.
The terms "C3_5-cyclyl" and "C3_5-cyclyl" used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms and 3 to 5 carbon atoms in their rings, respectively. Examples of the Cβ.g-cyclyl and C3_5-cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
The term "3- to 7-membered heterocyclyl" includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated. Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group, tet- rahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomor- pholinyl group, an imidazolinyl group, an oxazolinyl group and the like. A more preferred example is an oxetanyl group.
The term "3- to 7-membered heterocycle" used in the specification of the present invention indi- cates a monocyclic 3- to 7-membered non-aromatic heterocyclic group which contains a nitrogen atom and optionally one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. The preferable example includes an aziridinyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a piperidinyl group, a piperazinyl group, a piperazine-2,3-dione group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group, a pyr- rolidine-2,5-dione group, a piperazine-2,3-dione group and the like. More preferred examples are a morpholinyl group, a pyrrolidine-2,5-dione group; a piperazine-2,3-dione group, a pyrrolidinyl group, an acetidyl group.
The term "Cβ.^-aryl" used in the specification of the present application means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, such as a monocyclic group, a bicyclic group and a tricyclic group. Preferable examples are a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group. Further- more, the term "Cβ.^-aryl which is optionally substituted" means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, wherein the aromatic hydrocarbon cyclic group has the same meaning as defined above and is optionally substituted by one or more sub- stituents. Examples of such substituents are hydroxy; C-j.β-alkyl, preferably methyl; C-j.β-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo. The Cg.-14-aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. Among the above examples, a phenyl group, a phenyl group substituted with one fluoro and one methoxy, such as 3-fluoro-4-methoxyphenyl, me- thylen-3,4-dioxophenyl are more preferred. The term "Ci_i3-heteroaryl" used in the specification of the present application refers to aromatic groups having 1 to 13 carbon atoms and one or more heteroatoms selected from N, O and S. Preferred embodiments of such groups can be characterized as "5- to 14-membered heteroaryl" which indicates a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic heterocyclic group which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In a similar way, the term "C-j_g-heteroaryl" used in the specification of the present invention refers to aromatic groups having 1 to 9 carbon atoms and one or more heteroatoms selected from N, O and S. Preferred embodiments of such groups can be characterized as "5- to 10-membered heteroaryl" which indicates a monocyclic or bicyclic 5- to 10-membered heteroaryl which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In the present invention a 5- to 10-membered heteroaryl may preferably be used, and a 5 to 6 membered heteroaryl is more preferred.
Examples of the aromatic heterocyclic group having include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group, a phenanthridinyl group, a carbazolyl group, a carbolinyl group, a perimidinyl group, a phenanthrolinyl group, a phenazinyl group, an imida- zopyridinyl group, an imidazopyrimidinyl group, a pyrazolopyridinyl group, and the like; a thiophenyl group (thienyl group), a benzothiophenyl group (benzothienyl group) and the like; a furyl group, a pyranyl group, a cyclopentapyranyl group, a benzofuryl group, an isobenzofuryl group,a thiazolyl group, an isothiazolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, an oxazolyl group, an isooxa- zoyl group, a benzoxazolyl group, an oxadiazolyl group, a pyrazolooxazolyl group, an imidazothia- zolyl group, a thienofuranyl group, a furopyrrolyl group, a pyridoxazinyl group and the like. Fur- thermore, the term "Ci_i3-heteroaryl which is optionally substituted" means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, typically being a 5- to 14-membered aromatic heterocyclic group, which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, wherein the 5- to 14-membered aromatic heterocyclic group is substituted by one or more substituents. Examples of such substituents are hy- droxy; C-|.g-alkyl, preferably methyl; C-|.g-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylenedioxo. The 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. The above-mentioned C-|.g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocy- clyl, Cg.-|4-aryl, C-ι.-13-heteroaryl, an amine and an amide, such as defined, for instance, for NRA05RA06 and -C(O)-NRA07RA08, wherein the C^g-alkoxy, C3.g-cyclyl, 3- to 7-membered heterocyclyl, Cg.-14-aryl and C-ι.-13-heteroaryl have the same meanings as defined above.
In case the C-|.g-alkyl group is substituted by at least one fluorine atom, the C-|.g-alkyl group can be any group as specified above with respect to the C-|.g-alkyl, unless specified otherwise. The C-|.g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-|.g-alkyl, wherein the mono-, tri- and perfluoro substituted C-|.g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C-|.g-alkyl groups. Examples of these still more preferred mono- and perfluoro substituted C-|.g-alkyl groups are fluoromethyl, 1-fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3-fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro- n-propyl and perfluoroisobutyl.
In case the C-|.g-alkyl is substituted by at least one hydroxy, the C-|.g-alkyl group can be any group as specified above with respect to the C-|.g-alkyl, unless specified otherwise. The C-|.g-alkyl sub- stituted by at least one hydroxy is preferably a C-|.g-alkyl group which is substituted by one or two hydroxy groups, more preferably a C-j.β-alkyl group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C-j.β-alkyl groups substituted with at least one hydroxy group includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hy- droxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
In case the C-|.g-alkyl group is substituted by at least one C-|.g-alkoxy, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the C-|.g-alkoxy group can be any group as specified above for C-|.g-alkoxy, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-|.g-alkyl is substituted one C-|.g-alkoxy. Particlulary preferred are a methoxymethyl group and a 2-methoxyethyl group. In case the C-j.g-alkyl group is substituted by at least one Cβ.g-cyclyl, the C-j.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the Cβ.g-cyclyl group can be any group as specified above for Cβ.g-cyclyl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cβ.g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-|.g-alkyl is substituted one Cβ.g- cyclyl. Particluarly preferred is a cyclopropylmethyl group.
In case the C-|.g-alkyl group is substituted by at least one 3- to 7-membered heterocyclyl, the C-|_g- alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-|.g-alkyl is substituted by one 3- to 7-membered heterocyclyl.
In case the C-|.g-alkyl group is substituted by at least one Cg.-14-aryl, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-|.g-alkyl is substituted one Cg.-14-aryl. Par- ticularly preferred is a benzyl group.
In case the C-|.g-alkyl group is substituted by at least one C-ι.-13-heteroaryl, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the C-|.-|3-heteroaryl group can be any group as specified above for C-ι.-13-heteroaryl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-j.-iβ- heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-|.g-alkyl is substituted by one C-j.-iβ- heteroaryl. Particularly preferred is a pyridylmethyl group. In case the C-j.g-alkyl group is substituted by at least one amine or amide group, the C-j.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise.
Similarly, the amine or amide group can be any group as specified above for amine or amide, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
The above-mentioned C-|.g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg.-14-aryl, C-ι.-13-heteroaryl and an amine, wherein the C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg.-14-aryl and C-ι.-13-heteroaryl have the same meanings as defined above.
In case the C-|.g-alkoxy group is substituted by at least one fluorine atom, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-|.g-alkoxy, wherein the mono-, tri- and perfluoro substituted C-|.g-alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C-|.g-alkoxy groups. Examples of these more preferred mono- and perfluoro substituted C-|.g-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobu- toxy.
In case the C-|.g-alkoxy group is substituted by at least one hydroxy, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. It is prefera- bly a C-|.g-alkoxy group which is substituted by one or two hydroxy groups, more preferably a C-|. 3- alkoxy group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C 1.3- alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
In case the C-|.g-alkoxy group is substituted by at least one another C-|.g-alkoxy, both C-|.g-alkoxy groups can be any group as specified above with respect to C-|.g-alkoxy. The first mentioned C-|.g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the first mentioned C-|_g-alkoxy is substituted by one other C-|.g-alkoxy. Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
In case the C-|.g-alkoxy group is substituted by at least one Cβ.g-cyclyl, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. Similarly, the Cβ.g-cyclyl group can be any group as specified above for Cβ.g-cyclyl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cβ.g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-|.g-alkoxy is substituted by one Cβ.g-cyclyl. Particluarly preferred is a cyclopropylmethoxy group.
In case the C-|.g-alkoxy group is substituted by at least one 3- to 7-membered heterocyclyl, the C-|. g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. Similarly, the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise. The C-| .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-| .g-alkoxy is substituted by one 3- to 7-membered heterocyclyl.
In case the C-| .g-alkoxy group is substituted by at least one Cg.-14-aryl, the C-| .g-alkoxy group can be any group as specified above with respect to C-| .g-alkoxy, unless specified otherwise. Similarly, the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise. The C-| .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-| .g-alkoxy is substituted by one Cg.-14-aryl. Particularly preferred is a benzyloxy group.
In case the C-| .g-alkoxy group is substituted by at least one C-ι.-13-heteroaryl, the C-| .g-alkoxy group can be any group as specified above with respect to C-| .g-alkoxy, unless specified otherwise. Similarly, the C-ι.-13-heteroaryl group can be any group as specified above for C-j.-iβ- heteroaryl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-|.-|3-heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-|.g-alkoxy is substituted by one C-|. 13-heteroaryl. Particularly preferred is a pyridylmethoxy group.
The above-mentioned Cβ.g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
In case the Cβ.g-cyclyl group is substituted by one or more fluoro, the Cβ.g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The Cβ.g- cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted Cβ.g-cyclyl, wherein the mono-, di- and perfluoro substituted Cβ.g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted Cβ.g-cyclyl groups.
In case the Cβ.g-cyclyl group is substituted by one or more hydroxy, the Cβ.g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The Cβ.g- cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C3. g-cyclyl, wherein monohydroxy substituted Cβ.g-cyclyl groups are more preferred.
The above-mentioned 3- to 7-membered heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, hydrogen, C-|.g-alkyl and -C(O)-
C-|.g-alkyl.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents se- lected from fluoro and hydroxy, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more fluoro, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group sub- stituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocyclyl, wherein the mono-, di- and perfluoro substituted 3- to 7-membered heterocyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocyclyl groups.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more hydroxy, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group sub- stituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents selected from hydrogen, C-|_g-alkyl and -C(O)-C-] .g-alkyl, the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise. Similarly the C-|_g-alkyl group and the C-|_g-alkyl moiety of the -C(O)-C1 _g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C-] _g- alkyl. It is preferred that the substituent(s) hydrogen, C-|.g-alkyl and -C(O)-C-] .g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C-] .g-alkyl is -C(O)-Ch^ and - C(O)-CH2OH.
The above-mentioned 3- to 7-membered heterocycle may be substituted with one or more sub- stituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, amide, hydrogen, C-]. g-alkyl and -C(O)-C1.g-alkyl.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy and amide, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocycle is substituted by one or more fluoro, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
In case the 3- to 7-membered heterocycle is substituted by one or more hydroxy, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C-|.g-alkyl and -C(O)-C1.g-alkyl, the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. Similarly the C-|.g-alkyl group and the C-|.g-alkyl moiety of the -C(O)-C1. g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C-j.β-alkyl. It is preferred that the substituent(s) hydrogen, C-|.g-alkyl and -C(O)-C-] .g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-Ci _6-alkyl is -C(°)-CH3 and -C(O)-CH2OH.
It is to be understood that the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
It is to be understood that the invention covers all combinations of substituent groups referred to hereinabove. In particular, the invention covers all combinations of preferred groups described herein.
Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesi- lates), laurylsulfonates, 3-hydroxy-2-naphthoat.es, lactobionates (salts of 4-O-beta-D- galactopyranosyl-D-gluconic acid), galactarates, embonates and ascorbates.
Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
The salts include water-insoluble and, particularly, water-soluble salts.
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof. Hydrates are a preferred example of said solvates.
The N-oxides of the compounds according to the invention, the salts thereof, the stereoisomers of the compounds and the salts thereof include compounds, wherein the nitrogen atom of the pyridine moiety is oxidized, as illustrated by formula (Ia) below:
Figure imgf000077_0001
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers. In case R1^1 and RAy2, wherein x = y and x, y = 0, 1 , 2, or 3, are different from one another, the compounds according to the invention, the salts thereof, the N- oxides of the compounds and the salts thereof have one or more stereogenic centers. Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog). Accordingly, the stereoisomers (1 R), (1S), (2R), (2S), (3R), (3S), (4R), (4S), (1 R,2R), (1 R,2S), (1S,2R), (1S,2S), (1 R,3R), (1R,3S), (1S,3R), (1 S,3S), (1 R,4R), (1 R,4S), (1S,4R), (1S,4S), (2R,3R), (2R,3S), (2S,3R), (2S,3S), (2R,4R), (2R,4S), (2S,4R), (2S,4S), (3R,4R), (3R,4S), (3S,4R) and (3S,4S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
Figure imgf000078_0001
(Ib)
as well as all possible permutations for 3 stereogenic centers, the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
Furthermore, derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
The compounds according to the invention can be prepared as follows. As shown in reaction scheme 1 , a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating. The compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
Compounds of formula (III) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 1 :
Figure imgf000079_0001
Figure imgf000079_0003
Figure imgf000079_0002
In an alternative procedure, as illustrated in reaction scheme 2, a compound of formula (IV) can be reacted with a compound of formula (Vl), in which X is a suitable leaving group, e.g. halogen, such as chlorine, or a conjugate base of an acid, such as trifluoroacetate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable solvent, e.g. dichloromethane, dichloroethane, diethylether, toluene, nitromethane and/or chlorobenzene, to give the corresponding compound of formula (M) or (Na) or (Mb) or a mixture thereof. Said Friedel-Crafts acylation reaction can be based on, for example, work of Duval et al. [see e.g. Tetrahedron Letters 45, 5411 (2004)]. The compound of formula (II) or (Ma) or (lib) or a mixture thereof can be subjected to a cyclization condensation reaction with ammonium acetate in an appropriate solvent, e.g. acetic acid, preferably at elevated temperature, or a cyclization condensation reaction with ammonia in an appropriate solvent, e.g. methanol, preferably at elevated temperature, to give a corresponding compound of formula (I). In some cases it may be convenient to perform both the Friedel-Crafts acylation reaction and the cyclization condensation reaction in one pot.
Compounds of formula (Vl) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 2:
Figure imgf000080_0001
Figure imgf000080_0002
As shown in reaction scheme 3, a compound of formula (Ic) is obtainable via an aldol-type condensation of a compound of formula (VIII), in which PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl, with a compound of formula (VII), and subsequent removal of PG. The compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ic). Reaction scheme 3:
Figure imgf000081_0001
Compounds of formulae (VIII) and (VII) are commercially available or can be obtained according to procedures known in the art.
Furthermore, a compound of formula (IV) can be obtained as shown in reaction scheme 4. In particular, indole (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic sub- stitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)]. The resulting hydroxy- compound of formula (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroace- tic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 4:
Figure imgf000081_0002
The compounds of formulae (X) and (Xl) are known, commercially available or can be obtained according to known procedures.
Alternatively, a compound of formula (IV) can be obtained as illustrated in reaction scheme 5. In a first step, indole is reacted with a compound of formula (XII) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diiso- propylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper(ll)-2- ethylhexanoate. The thus obtained compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 5:
Figure imgf000082_0001
Indole (Xl) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (IV) can be obtained as illustrated in reaction scheme 6. In a first step, indole (Xl) is reacted with a compound of formula (XIII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)]. The thus obtained unsaturated compound of formula (XIV) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)]. The resulting hydroxy-compound of formula (V) can be oxi- dized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I). Reaction scheme 6:
Figure imgf000083_0001
(Xl) (XIII) (XIV) (V)
Figure imgf000083_0002
Indole (Xl) is commercially available, compounds of formula (XIII) are known, commercially available or can be obtained according to known procedures.
As an alternative approach, a compound of formula (IV) can be obtained as illustrated in reaction scheme 7. In a first step, isatine (XV) is reacted with a compound of formula (XIII) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)]. The thus obtained hydroxy compound of formula (XVI) can be transformed into a compound of formula (V) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)]. The resulting hydroxy-com pound (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I). Reaction scheme 7:
Figure imgf000084_0001
lsatine (XV) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
An alternative synthetic route to a compound of formula (Ic) is depicted in reaction scheme 8. Compounds of formulae (XVII), (XVIII) and (XIX), wherein X is a suitable leaving group, such as halogen, preferably bromine or chlorine, can be reacted in a multi-component unsymmetric
Hantzsch reaction in the presence of catalytic amounts of acid, e.g. acetic acid, and amine, e.g. benzylamine [see e.g. Tetrahedron Letters 42, 4507 (2001 ) or Tetrahedron 63, 1946 (2007)]. The resulting nitro-dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid. The final ring closing reaction to obtain a compound of formula (Ic) can be achieved by reacting a compound of formula (XXI) under inert atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or tetrakis(triphenylphosphine)palladium (0), and, if necessary, of a suitable phosphine ligand, in the presence of a suitable base, e.g. sodium tert-butoxide or sodium carbonate [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 1043 (2007)]. Reaction scheme 8:
Figure imgf000085_0001
(XXl) (Ic)
Compounds of formulae (XVII), (XVIII) and (XIX) are known, commercially available or can be obtained according to known procedures.
As an example, a compound of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acid of formula (XXII) with carbonyl diimidazole in the presence of ni- tromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
Reaction scheme 9:
Figure imgf000085_0002
(XXII) (XIX)
Compounds of formula (XXII) are known, commercially available or can be obtained according to known procedures.
Compounds of formula (I) can be converted into different compounds of formula (I) by methods known in the art. For example,
• a compound of formula (I), wherein RA31 and RA32 combine to form an oxo group, can be prepared from a compound of formula (I), wherein RA31 and RA32 combine to form, together with the carbon atom, that they are attached to, a 1 ,3-dioxolane ring, wherein the single carbon atom in between the two oxygen atoms ("C2") is the carbon atom, that the substituents RA31 and RA32 are attached to, by acetal hydrolysis reaction, e.g. using a suitable acid, such as hydrochloric acid, in the presence of water and a suitable solvent, such as tetrahydrofuran or dioxan;
• a compound of formula (I), wherein RA01 is hydroxy and RA02 is hydrogen, or wherein RA31 is hydroxy and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAx2, wherein x = 0 or 3, combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as sodium borohydride;
• a compound of formula (I), wherein RA01 is hydrogen and RA02 is hydrogen, or wherein RA31 is hydrogen and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAx2, wherein x = 0 or 3, combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as hydrazine (e.g. according to a Wolff-Kishner reduction);
• a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen, or wherein RA31 is amino and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAx2, wherein x = 0 or 3, combine to form an oxo group, by reductive amidation reaction, e.g. with the aid of a suitable amide, e.g. formamide, in combination with a suitable reduction agent, such as formic acid or ammonium formiate in a suitable solvent, e.g. formic acid, at elevated temperatures, preferably 14O0C - 18O0C, followed by amide hydrolysis reaction, e.g. with the aid of a strong acid, such as hydrogen chloride, in a suitable solvent, such as methanol or water or a mixture thereof;
• a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen, or wherein RA31 is amino and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAx2, wherein x = 0 or 3, combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. benzylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by hydrogenation, e.g. with the aid of a transition metal catalyst, such as palladium(O), in combination with a suitable hydrogen source, e.g. hydrogen gas or ammonium formiate, in a suitable solvent, such as methanol;
• a compound of formula (I), wherein RA01 is substituted amino, -NRA03RA04, and RA02 is hydrogen, or wherein RA31 is substituted amino, -NRA33RA34, and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAx2, wherein x = 0 or 3, combine to form an oxo group, by imine (imminium) formation reaction, with the aid of the corresponding amine, i.e. HNRA03RA04 or HNRA33RA34, respectively, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by reduction, e.g. with the aid of a suitable reduction agent, such as sodium cyanoborohydride, in a suitable solvent, e.g. methanol and/or ethanol. Preferably, these two steps are conducted in one pot, without isolation of intermediate imine or imminium compounds;
• a compound of formula (I), wherein RA01 is carbonylamino-, -NH-C(O)-RA09, and RA02 is hydrogen, or wherein RA31 is carbonylamino-, -N H-C(O)-C1.6-alkyl, that may be optionally substituted as defined above, and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding R1^1 is amino and R**2 is hydrogen, wherein x = 0 or 3, by reaction with an appropriate carboxylic acid chloride, e.g. RA09C(O)CI or C-|.6-alkyl-C(O)CI, that may be optionally substituted as defined above, or carboxylic anhydride, e.g. (RA09C(O))2O or (C"i-6-alkyl-C(O))2θ, that may be optionally substituted as defined above, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid, e.g. RA09C(O)OH or Ci-6-alkyl-C(O)OH, that may be optionally substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hydroxybenzotriazole;
• a compound of formula (I), wherein RA01 is alkoxy-, -OCi-6-alkyl, that may be optionally substituted as defined above, and RA02 is hydrogen, or wherein RA31 is alkoxy-, -OC-|.6-alkyl, that may be optionally substituted as defined above, and RA32 is hydrogen, can be prepared from a compound of formula (I), wherein the corresponding RAx1 is hydroxy and R**2 is hydrogen, wherein x = 0 or 3, by alkylation reaction with the corresponding electrophilic reagent
C-ι-6-alkyl-X, wherein X represents halide, preferably iodine or bromine or chlorine, or a conjugate base of an acid, such as methylsulfonate, and that may be optionally substituted as defined above, in the presence of a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran; • a compound of formula (I), wherein R^1 is "substituted alkyl", e.g. -Ci-6-alkyl, or -C3-6-CyCIyI, or -3- to 7-membered heterocyclyl, all that may be optionally substituted as defined above, or -(CH2)mRA15, or -(CRA16RA17)ι-CORA18, wherein m > 1 , I > 0, and x = 1 or 2, R^2 is a free electron pair and Ax is N, wherein m > 1 , I > 0, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, R**2 is a free electron pair and Ax is N, by alkylation reaction, e.g. by reacting with an appropriate alkylating agent, e.g.
C-ι-6-alkyl-Hal, or C3.6-cyclyl-Hal, or 3- to 7-membered heterocyclyl-Hal, all that may be optionally substituted as defined above, or Hal-(CH2)mRA15, or Hal-(CRA16RA17),-CORA18, wherein m > 1 , I > 0, and x = 1 or 2, preferred halogens (Hal) are bromine or chlorine, in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof.
• a compound of formula (I), wherein R^1 is carbonyl, e.g. -C(O)(CRA19RA110)k-RA111, R^2 is a free electron pair and Ax is N, wherein k is 0 or 1 or 2, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, R**2 is a free electron pair and Ax is N, by reaction with an appropriate carboxylic acid chloride
RA111-(CRA19RA110)kC(O)CI or carboxylic anhydride [RA111-(CRA19RA110)kC(O)]2O, wherein x = 1 or 2, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid RA111-(CRA19RA110)kC(O)OH, wherein x = 1 or 2, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
• a compound of formula (I), wherein R^1 is carbamoyl, e.g. -C(O)NRA121RA122, R^2 is a free electron pair and Ax is N, wherein x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, R**2 is a free electron pair and Ax is N, by reaction with an appropriate amine carbonyl chloride RA121RA122NC(O)CI, wherein x = 1 or 2, in the presence of a base, e.g. triethylamine or pyridine, and, optionally, a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine;
• a compound of formula (I), wherein R^1 is sulfonyl, e.g. -SO2-Ci.6-alkyl, that may be optionally substituted as defined above, R**2 is a free electron pair and Ax is N, wherein x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with an appropriate sulfonyl chloride C"i-6-alkyl-Sθ2CI, that may be optionally substituted as defined above, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate; • a compound of formula (I), wherein R1^1 is sulfamoylamino, e.g. -SO2-NRA13RA14, RA12 is a free electron pair and Ax is N, wherein x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, R**2 is a free electron pair and Ax is N, by reaction with an appropriate sulfamoyl chloride RA13RA14NSO2CI, wherein x = 1 or 2, in the presence of a base, e.g. triethylamine or pyridine, and a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine;
• a compound of formula (I), wherein R1^1 represents -C(O)-NH2, R**2 is a free electron pair and Ax is N, wherein x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
• a compound of formula (I), wherein R^1 is alkoxycarbonyl-, -C(O)-Ci.6-alkoxy, that may be optionally substituted as defined above, R^2 is a free electron pair and Ax is N, wherein x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding R1^1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with an appropriate formic acid ester chloride Ci_6-alkoxy-C(O)CI, that may be optionally substituted as defined above, in the presence of a base, e.g. triethylamine or pyridine, and, optionally, a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine;
• a compound of formula (I), wherein R^1 is carbamoyl-alkyl-, -(CRA16RA17),-CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, R^2 is a free electron pair and Ax is N, by alkylation reaction, e.g. by reacting with an appropriate alkylating agent, e.g. Hal-(CRA16RA17),-CONRA116RA117, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, preferably Ci-(CRA1βRA17),-CONRA11βRA117 or Br-(CRA16RA17),-CONRA116RA117, in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof;
• alternatively, a compound of formula (I), wherein R^1 is carbamoyl-alkyl-, -(CRA16RA17)r CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding R1^1 is hydrogen, RAx2 is a free electron pair and Ax is N, by alkylation reaction, e.g. by reacting with an appropriate alkylating agent, e.g. Hal-(CRA16RA17)i-C(O)OCi.3-alkyl, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, preferably CI-(CRA16RA17),-COOC1_2-alkyl or Br-(CRA16RA17),-COOC1_2-alkyl, in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof, followed by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan and / or water, followed by amide formation reaction with an appropriate amine HNRA116RA117 in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
• alternatively, a compound of formula (I), wherein R1^1 is carbamoyl-alkyl-, -(CRA16RA17)r CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding R^1 is hydrogen, RAx2 is a free electron pair and Ax is N, by alkylation reaction, e.g. by reacting with an appropriate alkylating agent, e.g. Hal-(CRA16RA17)i-C(O)OCi.3-alkyl, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, preferably CI-(CRA16RA17),-COOCH3 or Br-(CRA16RA17),-COOCH3, in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof, followed by amide formation reaction with an excess of the appropriate amine HNRA116RA117 at high concentrations, preferably neat, and at temperatures from O0C to 2000C, preferably 8O0C to 14O0C, optionally using microwave radiation as energy source; • a compound of formula (I), wherein R^1 is carbamoyl-alkyl-, -(CRA16RA17),-CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 2, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by addition reaction, e.g. by reacting with an appropriate acceptor agent, e.g. C(RA16RA17)=C(RA16RA17)-CONRA116RA117, wherein x = 1 or 2, optionally in the presence of a catalytic amount of acid, e.g. hydrochloric acid, or Lewis acid, e.g. copper (II) acetate, in a suitable polar solvent, e.g. acetonitrile or water or a mixture thereof.
• alternatively, a compound of formula (I), wherein R^1 is carbamoyl-alkyl-, -(CRA16RA17)r CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 2, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by addition reaction, e.g. by reacting with an appropriate acceptor agent, e.g. C(RA16RA17)=C(RA16RA17)-C(O)Od.3-alkyl, wherein x = 1 or 2, optionally in the presence of a catalytic amount of acid, e.g. hydrochloric acid, or Lewis acid, e.g. copper (II) acetate, in a suitable polar solvent, e.g. acetonitrile or water or a mixture thereof, followed by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan and / or water, followed by amide formation reaction with an appropriate amine HNRA116RA117 in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hyd roxy be nzotriazo Ie ;
• alternatively, a compound of formula (I), wherein R^1 is carbamoyl-alkyl-, -(CRA16RA17)r CONRA116RA117 and RAx2 is a free electron pair and Ax is N, wherein I = 2, and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by addition reaction, e.g. by reacting with an appropriate acceptor agent, e.g. C(RA16RA17)=C(RA16RA17)-C(O)OC1_3-alkyl, wherein x = 1 or 2, optionally in the presence of a catalytic amount of acid, e.g. hydrochloric acid, or Lewis acid, e.g. copper (II) acetate, in a suitable polar solvent, e.g. acetonitrile or water or a mixture thereof, followed by amide formation reaction with an excess of the appropriate amine HNRA116RA117 at high concentrations, preferably neat, and at temperatures from O0C to 2000C, preferably 8O0C to
14O0C, optionally using microwave radiation as energy source;
• a compound of formula (I), wherein R^1 is aminocarbonyl, e.g. -C(O)(CRA19RA110)k-NRA125RA126, RAx2 is a free electron pair and Ax is N, wherein k is 1 , and x = 1 or 2, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with an appropriate haloalkanoylhalide, i.e.
Hal(CRA19RA110)kC(O)Hal, wherein k is 1 , x = 1 or 2 and preferred halogens (Hal) are bromine or chlorine, e.g. bromoacetylbromide, BrCH2C(O)Br, or bromoacetylchloride, BrCH2C(O)CI, in the presence of a base, e.g. triethylamine or pyridine, and, optionally, a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine, followed by a substitution reaction, e.g. by reacting with an appropriate amine HNRA125RA126 in the presence of a suitable base, e.g. triethylamine or diisopropylethylamine, in a suitable polar solvent, e.g. dimethylformamide or acetonitrile;
• a compound of formula (I), wherein R^1 is aminocarbonyl, e.g. -C(O)(CRA19RA110)k-NRA125RA126, RAx2 is a free electron pair and Ax is N, wherein k is 1 , and x = 1 or 2, can be synthesized e.g. from a compound of formula (I), wherein the corresponding R^1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with an appropriate haloacetic acid carboxylic acid, i.e. Hal(CRA19RA110)kC(O)OH, wherein k is 1 , x = 1 or 2 and preferred halogens (Hal) are bromine or chlorine, e.g. bromoacetic acid, BrCH2C(O)OH, or chloroacetic acid, CICH2C(O)OH, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hyd roxybenzotriazole ;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a group -NH-C(O)-C-ι_2-alkyl can be prepared e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents -NH-C(O)-NH2 can be obtained e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is Ci_3-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center.
Starting materials or building blocks, that are necessary for the synthesis of compounds according to the invention are either commercially available, or are prior art, or can be synthesized by a person skilled in the art, or are described within this document as an example or as a general methodology. In particular, building blocks of formula (XXII), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) an alkoxy group, -O-C-|.3-alkyl, can be prepared e.g. from a compound of formula (XXII), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents a hydroxy group by reaction with an excess (ca. 2 equivalents) of an appropriate alkyl halide, preferably alkyl iodide or alkyl bromide, e.g. methyl iodide or ethyl iodide or propyl iodide, in the presence of a suitable base, e.g. sodium hydride, in an appropriate polar solvent, e.g. dimethylformamide, at temperatures between -1O0C to 1000C, preferably O0C - 4O0C, followed by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan or water, or a mixture thereof.
Moreover, alkylating agents of general formula Hal-(CRA16RA17),-CONRA116RA117, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, e.g. CI-(CRA16RA17),-CONRA116RA117 or Br-(CRA16RA17),-CONRA116RA117, can be synthesized by reaction of a haloalkanoylhalide, i.e. Hal-(CRA16RA17)rCOHal, wherein I = 1 , 2, 3 or 4, x = 1 or 2, and preferred halogens (Hal) are bromine or chlorine, e.g. Br-(CRA16RA17)rCOBr, with an appropriate amine, e.g. HNRA116RA117, wherein I = 1 , 2, 3 or 4 and x = 1 or 2, optionally as hydrochloride or hydrobromide salt, optionally in excess, optionally in the presence of a suitable base, e.g. sodium hydroxide, potassium carbonate, sodium carbonate or sodium hydrogencarbonate, in a suitable solvent, e.g. toluene, dichloromethane, hexane or water, or a mixture thereof, preferably at temperatures between O0C and 5O0C.
The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, alu- minium oxide.
Salts of the compounds of formula (I), the N-oxides thereof and the stereoisomers of the compounds and the N-oxides thereof according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added. Examples for acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid. Examples for bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. ammonia, trimethylamine or methylamine. The acid or base can be employed in salt preparation, de- pending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
The compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid. The person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Preferably, the pure diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
In particular, for example the (IS)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein RA01 and RA02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C. Likewise, for example the (I R)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, re- solving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts. Fur- thermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1- phenylethanol, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enanti- omeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.
All patents, patent applications, publications, test methods and other materials cited herein are incorporated by reference in their entireties.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.
The compounds which are mentioned in the examples, the salts thereof, N-oxides of the com- pounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof represent preferred embodiments of the invention.
Examples
1H NMR spectra are recorded on a Bruker DPX200 (1H 200 MHz), a Bruker Avance (1H 300 MHz) or a Bruker AV400 (1H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1H). Chemical shifts are given in ppm (δ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), ddd (doublet of doublet of doublet), t (triplet), q (quartet), m (multiplet) and b (broadened). Coupling constants, J, are reported in Hz. Data are reported in the form δ = chemical shift (multiplicity, (coupling constant(s) if appropriate), integral in fold of 1 H). If appropriate, reasons for multiple peaks (e.g. 2s) are given in square brackets behind the integral (e.g. [rotamers] or [diastereomers]).
Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology. Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode. Data are reported in the form MS (ionized particle found) = m/z. In that context, the molecule is abbreviated by M. For compounds containing bromine, both isotopic forms are reported, for compounds containing chlorine and all other elements, only the major isotopes are reported. Melting points, mp., are measured on a Bϋchi B-540 or a Bϋchi B-541 instrument and are uncor- rected.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE: di- chloroethane, THF: tetrahydrofuran, mp.: melting point, RT: room temperature (20 to 250C), tic: thin layer chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spec- troscopy.
Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O0C in a vacuum of 10~1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments. The temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments. The reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
Purchased chemicals and solvents are used without further purification.
Column chromatography is performed using silica gel 60 (0.040 - 0.063 mm), pH 6.5 - 7.5, from Merck KGaA or amino modified silica gel Bulk Isolute® Sorbent Flash NH2 60 (0.040 - 0.070 mm) from International Sorbent Technology Ltd. If pressure (max. 0.3 bar) is applied to increase the flow of the mobile phase the chromatography is referred to as flash chromatography. Preparative HPLC purification is performed on a customary instrument from Gilson using a reversed phase column (C18, Phenomenex, Gemini, 75x30 mm, 5μm) as stationary phase and an acetonitrile / water gradient as mobile phase at a flow of 40 ml/min.
Starting materials
A1. Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate
Benzyl-3-pyrroline-1-carboxylate (90%, 30.0 g) is dissolved in dichloromethane (900 ml), m-chloro- perbenzoic acid (46.0 g) is added and the solution is stirred for 18 h at room temperature. After that, the mixture is poured into 10% aqueous sodium hydrogencarbonate solution (200 ml), the aqueous phase is extracted with dichloromethane (2 x 200 ml), the combined organic extracts are washed with 10% aqueous sodium hydrogencarbonate solution (2 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :4 to 1 :1 (v/v)) to yield 28.6 g (98%) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCI3); δ = 3.30-3.41 (m, 2H), 3.61-3.71 (m, 2H), 3.84 (d, AB, J = 12.7 Hz, 1 H), 3.89 (d, AB, J = 12.9 Hz, 1 H), 5.09 (d, AB, J = 12.4 Hz, 1 H), 5.13 (d, AB, J = 12.4 Hz, 1 H), 7.26-7.39 (m, 4H).
A2. Benzyl 3-hydroxy-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate
Indole (15.4 g) is dissolved in tetrahydrofuran (270 ml) and the solution is cooled to O0C (ice bath). Methylmagnesium chloride (3M in tetrahydrofuran, 44 ml) is added drop by drop within 45 min. The mixture is stirred at room temperature for 2 h, then a solution of benzyl 6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate (example A1 ) (28.5 g) in tetrahydrofuran (100 ml) is added drop by drop within 20 min. The mixture is stirred for 18 h at room temperature. After that, it is poured into 10% aqueous sodium hydrogencarbonate solution (200 ml). The aqueous phase is extracted with ethyl acetate (3 x 200 ml), the combined organic extracts are washed with water (1 x 400 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :1 (v/v) to ethyl acetate) to obtain 28.8 g (66%) of the title compound as an orange oil. 1H-NMR (300 MHz, d6-DMSO); δ = 3.19-3.32 (m, 1 H), 3.40-3.52 (m, 1 H), 3.53-3.67 (m, 2H), 3.80- 3.93 (m, 1 H), 4.28-4.36 (m, 1 H), 5.09 (s, 2H), 5.29 (d, J = 4.2 Hz, 1 H), 6.98 (dd, J = 7.2 Hz, 7.6 Hz, 1 H), 7.02-7.13 (m, 2H), 7.26-7.41 (m, 6H), 7.58 (d, J = 7.9 Hz, 1 H). A3. Benzyl 3-(1H-indol-3-yl)-4-oxopyrrolidine-1-carboxylate
Benzyl S-hydroxy-^I H-indol-S-yOpyrrolidine-i-carboxylate (example A2) (28.7 g) is dissolved in dimethylsulfoxide (225 ml) and dichloromethane (225 ml), diisopropylethyl amine (51.2 ml) is added and the solution is cooled to O0C (ice bath). A solution of sulfurtrioxide pyridine complex (27.2 g) in dimethylsulfoxide (290 ml) and pyridine (13.8 ml) is added drop by drop within 1 h at a rate that the internal temperature is kept below 50C. The mixture is stirred for 1 h at O0C. After warming to room temperature 1 M hydrochloric acid (200 ml) is added. The aqueous phase is extracted with dichloromethane (3 x 200 ml), the combined organic extracts are washed subsequently with 1 M hy- drochloric acid (1 x 200 ml), saturated ammonium chloride solution (2 x 300 ml) and saturated sodium chloride solution (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 6.19 g (22%) of the title compound as yellow crystals. 1H-NMR (300 MHz, d6-DMSO): δ = 3.66-3.85 (m, 1 H), 3.90-4.12 (m, 2H), 4.13-4.37 (m, 2H), 5.17 (s, 2H), 5.29 (d, J = 4.2 Hz, 1 H), 6.97 (ddd, J = 1.0 Hz, 7.1 Hz, 7.9 Hz, 1 H), 7.09 (ddd, J = 1.1 Hz, 7.0 Hz, 8.2 Hz, 1 H), 7.24 (d, J = 2.5 Hz, 1 H), 7.24-7.48 (m, 7H), 11.02 (bs, 1 H).
A4. Ethyl 4-(1H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate Potassium hydroxide (20.2 g) is dissolved in ethanol (350 ml), N-carbethoxy-4-piperidone (62.5 g) and indole (20.4 g) are added and the mixture is refluxed for 18 h. After cooling, the suspension is poured into water (1000 ml), extracted with ethyl acetate (2 x 1000 ml), the combined organic extracts are washed with concentrated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 4:1 (v/v) to 1 :1 (v/v)) to yield 33.0 g (70%) of the title compound as a yellow viscous oil.
1H-NMR (300 MHz, CDCI3); δ = 1.30 (t, J = 7.1 Hz, 3H), 2.51-2.15 (m, 2H), 3.73 (t, J = 5.8 Hz, 2H), 4.13-4.28 (m, 4H), 6.10-6.22 (m, 1 H), 7.10-7.28 (m, 3H), 7.38 (d, J = 7.4 Hz, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 8.20 (bs, 1 H).
A5. Ethyl 3-hydroxy-4-(1H-indol-3-yl)piperidine-1-carboxylate
Ethyl 4-(1 H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (example A4) (32.9 g) is dissolved under argon in dry tetrahydrofuran (200 ml) und the solution is cooled to O0C (ice bath). Borane tetrahydrofuran complex (1 M in tetrahydrofuran, 180 ml) is added within 20 min. The ice bath is removed, the mixture is stirred for 2.5 h at room temperature. After that, it is again cooled to O0C (ice bath), water / ethanol (1 :1 (v/v), 240 ml) is added carefully, followed by 3M sodium hydroxide solution (90 ml) and hydrogen peroxide (30%, 60 ml). The mixture is stirred 15 min room temperature, then 3 h at 6O0C. After cooling, it is diluted with ethyl acetate (500 ml), the organic phase is washed with water (2 x 300 ml) and 10% aqueous sodium hydrogensulfite solution (1 x 300 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / heptane to obtain 19.1 g (54%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.18 (t, J = 7.0 Hz, 3H), 1.57-1.77 (m, 1 H), 1.80-1.95 (m, 1 H), 2.58-3.00 (m, 3H), 3.50-3.62 (m, 1 H), 3.91-4.20 (m, 4H), 4.74 (d, J = 5.4 Hz, 1 H), 6.93 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.03 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.10-7.18 (m, 1 H), 7.31 (d, J = 7.1 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 10.77 (bs, 1 H).
A6. Ethyl 4-(1H-indol-3-yl)-3-oxopiperidine-1-carboxylate Ethyl 3-hydroxy-4-(1 H-indol-3-yl)piperidine-1-carboxylate (example A5) (19.0 g) is dissolved in dimethylsulfoxide (120 ml) and dichloromethane (120 ml), diisopropylethyl amine (40.0 ml) is added and the solution is cooled to O0C (ice bath). A solution of sulfurtrioxide pyridine complex (21.0 g) in dimethylsulfoxide (150 ml) and pyridine (10.6 ml) is added drop by drop within 45 min at a rate that the internal temperature is kept below 50C. The mixture is stirred for 1 h at O0C. After warming to room temperature water (300 ml) is added, the mixture is acidified with 1 M hydrochloric acid
(pH 4). The aqueous phase is extracted with dichloromethane (3 x 200 ml), the combined organic extracts are washed with saturated ammonium chloride solution (2 x 300 ml) and saturated sodium chloride solution (1 x 300 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) to yield 18.15 g (96%) of the title compound as a viscous oil.
1H-NMR (300 MHz, CDCI3); δ = 1.29 (t, J = 7.1 Hz, 3H), 2.23-2.51 (m, 2H), 3.57-3.71 (m, 1 H), 3.92- 4.07 (m, 2H), 4.08-4.25 (m, 3H), 4.33 (d, AB, J = 17.8 Hz, 1 H), 7.02-7.23 (m, 3H), 7.36 (d, J = 8.1 Hz, 1 H), 7.46 (d, J = 7.4 Hz, 1 H), 8.15 (bs, 1 H).
A7. Methyl 4-(1-acetyl-1H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)- carboxylate
Step 1 : Methyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. 3,5-Dimethoxypyridine (8.5 g) is dissolved under nitrogen in acetonitrile (230 ml), sodium borohydride (4.16 g) is added in portions within 10 min and the mixture is stirred for 10 min at -450C. Methyl chlorocarbonate (5.7 ml) is added drop by drop at a rate that the internal temperature does not exceed -4O0C (ca. 20 min), the mixture is stirred for 20 min at -4O0C - -450C. After that, 1 M hydrochloric acid (150 ml) is added, followed immediately by saturated sodium hydrogencarbonate solution (150 ml, pH 9). It is extracted with ethyl acetate (3 x 300 ml), dried (MgSO4) and concentrated in vacuo. The residue is dissolved in tetrahydrofuran (200 ml) and 1 M hydrochloric acid (200 ml), the solution is cooled to O0C (ice bath) and stirred for 30 min. It is basified by addition of solid sodium hydroxide, ethyl acetate is added (150 ml) and the organic phase is extracted with 1 M aqueous sodium hydroxide solution (4 x 150 ml). The combined aqueous phases are cooled to O0C (ice bath), acidified by addition of 6M hydrochloric acid, extracted with ethyl acetate (3 x 400 ml), dried (MgSO4) and concentrated in vacuo to give rise to crude methyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (12.11 g), that is used without further purification in the next step. It is stored with acetic acid (1 ml) as stabilizer in the refrigerator.
Step 2: Methyl 4-(1-acetyl-1 H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. Methyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (6.06 g) is dissolved in glacial acetic acid (15 ml), 1-acetyl-1 ,2-dihydro-3H-indol-3-one (5.26 g) and sodium acetate (2.46 g) is added and the mixture is refluxed under light exclusion for 3 h. Additional methyl 5-hydroxy-3-oxo-3,6- dihydropyridine-1(2H)-carboxylate (6.06 g) is added and the mixture is refluxed for further 2 h. After cooling, it is diluted with ethyl acetate (150 ml) and water (150 ml) and the aqueous phase is extracted with ethyl acetate (2 x 150 ml). The combined organic extracts are washed with water (1 x 200 ml), dried (MgSO4), filtered through a plug of silica gel (eluting with ethyl acetate / acetic acid 10:1 (v/v)) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 3:7 (v/v) to petroleum ether / ethyl acetate / acetic acid 3:7:0.1 (v/v/v) to ethyl acetate / acetic acid 20:1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 2.80 g (28%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 2.62 (s, 3H), 3.70 (s, 3H), 4.31 (bs, 4H), 7.14-7.33 (m, 3H), 7.66 (s, 1 H), 8.32 (d, J = 8.2 Hz, 1 H), 1 1.60 (bs, 1 H). mp.: 184-185 0C
A8. Methyl 5-hydroxy-4-(1H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate Methyl 4-(1-acetyl-1 H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (example A7) (2.76 g) is dissolved in 1 M aqueous sodium hydroxide solution (27 ml) and the mixture is stirred under light exclusion for 5 h at room temperature. After that, it is diluted with dichloro- methane (20 ml) and acidified by addition of hydrochloric acid (10% in water) to pH 5. The formed precipitate is filtered, washed with dichloromethane (5 ml) and water (3 x 20 ml) and dried over phosphorus pentoxide. The aqueous phase of the combined filtrate is extracted with dichloromethane (3 x 50 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue is crystallized from ethyl acetate / n-heptane to give rise to a second crop of the title compound (total yield: 1.51 g (63%)). 1H-NMR (300 MHz, d6-DMSO); δ = 3.69 (s, 3H), 4.28 (bs, 4H), 6.92 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.04 (dd, J = 6.9 Hz, 7.0 Hz, 1 H), 7.16-7.26 (m, 2H), 7.35 (d, J = 8.0 Hz, 1 H), 1 1.03 (bs, 2H). mp.: 223-225 0C
A9. Methyl [2-(benzyloxy)ethoxy]acetate
Sodium hydride (60% suspension in mineral oil, 2.07 g) is suspended in dimethylformamide (30 ml) under nitrogen atmosphere and the suspension is cooled to O0C (ice bath). A solution of 2-
(benzyloxy)ethanol (7.5 g) in dimethylformamide (10 ml) is added drop by drop within 20 min. The mixture is stirred for 2 h at room temperature, until gas evolution ceases. A solution of methyl bro- moacetate (8.2 g) in dimethylformamide (10 ml) is added drop by drop. The mixture is stirred for 3 h at room temperature. After that, saturated ammonium chloride solution (10 ml), water (50 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 9:1 (v/v)) to yield 2.61 g (24%) of the title compound as a yellow oil.
1H-NMR (300 MHz, CDCI3); δ = 3.63-3.70 (m, 2H), 3.74 (s, 3H), 3.74-3.80 (m, 2H), 4.18 (s, 2H), 4.57 (s, 2H), 7.24-7.39 (m, 5H). MS (MH+ found) = 440.1
A10. [2-(Benzyloxy)ethoxy]acetic acid
Methyl [2-(benzyloxy)ethoxy]acetate (example A9) (2.50 g) is dissolved in dioxane (50 ml) and water (28 ml), lithium hydroxide (2.7 g) is added and the mixture is stirred for 1 h at 8O0C. After cooling, the mixture is acidified by addition of 6M hydrochloric acid, diluted with water (25 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic extracts are washed with water (1 x 100 ml) and saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo to give rise to 2.18 g (93%) of the title compound as a yellow oil. 1H-NMR (300 MHz, CDCI3); δ = 3.63-3.70 (m, 2H), 3.74-3.80 (m, 2H), 4.17 (s, 2H), 4.60 (s, 2H), 7.26-7.40 (m, 5H). MS (M+ found) = 210.2
A11. Benzyl 5-hydroxy-4-(1H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate Step 1 : Benzyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. 3,5-Dimethoxypyridine (31.18 g) is dissolved under nitrogen in acetonitrile (800 ml), sodium borohydride (15.3 g) is added in portions within 10 min and the mixture is stirred for 10 min at -450C. Benzyl carbonochloridoate (37.8 ml) is added drop by drop at a rate that the internal temperature does not exceed -4O0C (ca. 20 min), the mixture is stirred for 40 min at -4O0C - -450C. After that, 1 M hydrochloric acid (550 ml) is added, followed immediately by saturated sodium hydrogencarbonate solution (550 ml, pH 9). It is extracted with ethyl acetate (3 x 1000 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue is dissolved in tetrahydrofuran (700 ml) and 1 M hydrochloric acid (700 ml), the solution is cooled to O0C (ice bath) and stirred for 30 min. It is basified by addition of solid sodium hydroxide, ethyl acetate is added (500 ml) and the organic phase is extracted with 1 M aqueous sodium hydroxide solution (4 x 500 ml). The combined aqueous phases are cooled to O0C (ice bath), acidified by addition of 6M hydrochloric acid, extracted with ethyl acetate (3 x 1500 ml), dried (MgSO4) and concentrated in vacuo to give rise to crude benzyl 5-hydroxy-3-oxo- 3,6-dihydropyridine-1(2H)-carboxylate (35.4 g, 64%), that is used without further purification in the next step. It is stored with glacial acetic acid (6 ml) as stabilizer in the refrigerator. Step 2: Benzyl 4-(1-acetyl-1 H-indol-3-yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. Benzyl 5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (34.01 g) is dissolved in glacial acetic acid (100 ml), 1-acetyl-1 ,2-dihydro-3H-indol-3-one (24.1 g) and sodium acetate (1 1.3 g) is added and the mixture is stirred for 24 h at room temperature under light exclusion and for further 24 h at 650C. After cooling, it is diluted with ethyl acetate (300 ml) and water (1000 ml) and the aqueous phase is extracted with ethyl acetate (2 x 300 ml). The combined organic extracts are washed with water (2 x 500 ml), ice cold lithium hydroxide solution is added (ca. 10% in water, until pH 10), the organic phase is washed with ice cold lithium hydroxide solution (2 x 200 ml). The combined aqueous lithium hydroxide phases are washed with ethyl acetate (2 x 100 ml), acidified by addition of acetic acid (pH 5, ice bath) and extracted with ethyl acetate (4 x 200 ml). These last extraction fractions are combined, washed with saturated sodium chloride solution (2 x 300 ml), dried (MgSO4) and concentrated in vacuo. The crude product contains a mixture of benzyl 4-(1-acetyl-1 H-indol-3- yl)-5-hydroxy-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate and deacetylated benzyl 5-hydroxy-4- (1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate and is used without further purification is the next step.
Step 3: Benzyl 5-hydroxy-4-(1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. Crude product of step 2 is dissolved in 1 M aqueous lithium hydroxide solution (300 ml) and the mixture is stirred under light exclusion for 2 h at room temperature. After that, it is acidified by addition of hydrochloric acid (10% in water) to pH 5. The formed precipitate is filtered and washed thoroughly with water (3 x 50 ml). It is dissolved in dichloromethane (800 ml) and methanol (30 ml), washed with saturated sodium chloride solution (1 x 400 ml), dried (MgSO4) and concentrated in vacuo to yield 13.0 g of the title compound (26%, 2 steps). 1H-NMR (300 MHz, d6-DMSO); δ = 4.32 (bs, 4H), 5.17 (s, 2H), 6.91 (ddd, J = 1.0 Hz, 7.1 Hz,
8.0 Hz, 1 H), 7.04 (ddd, J = 1.2 Hz, 7.0 Hz, 7.1 Hz, 1 H), 7.18-7.24 (m, 2H), 7.29-7.44 (m, 6H), 11.03
(s, 1 H).
MS (M+ found) = 363.1
A12. 2-Bromo-N-(cyclopropylmethyl)acetamide
Cyclopropylmethanamine (1.75 g) is dissolved in water (12 ml) and the mixture is cooled to O0C (ice bath). A solution of bromoacetyl bromide (4.97 g) in dichloromethane (30 ml) and 2M aqueous sodium hydroxide solution (24.6 ml) are added in parallel drop by drop at a rate, that the internal temperature does not exceed 50C. After the addition is complete (ca. 1 h), the biphasic mixture is stirred for further 1 h at O0C. After that, it is diluted with dichloromethane (50 ml), the organic phase is separated, washed with saturated aqueous sodium chloride solution (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The product precipitates upon concentration. It is filtered and dried in vacuo to give rise to 3.8 g (81 %) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 0.11-0.20 (m, 2H), 0.37-0.45 (m, 2H), 0.83-0.97 (m, 1 H), 2.96 (dd, J = 5.7 Hz, 6.6 Hz, 2H), 3.84 (s, 2H), 8.31 (bs, 1 H). MS (M-Br+ found) = 112.1
A13. N-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl]-1H-imidazole-1-carboxamide Di-I H-imidazol-1-ylnnethanone (carbonyldiimidazole, 7.64 g) is suspended in dichloromethane (50 ml) and 1-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methanannine (5.00 g) is added drop by drop at room temperature. The mixture is stirred for 2 h at room temperature. After that, saturated aqueous sodium hydrogencarbonate solution (50 ml) is added and the aqueous phase is extracted with di- chloromethane (2 x 50 ml). The combined organic phases are dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from ethyl acetate / n-heptane to give rise to 8.5 g (99%) of the title compound as colorless crystals.
1H-NMR (300 MHz, d6-DMSO); δ = 1.27 (s, 3H), 1.34 (s, 3H), 3.35 (d, AB, J = 5.7 Hz, 1 H), 3.37 (d, AB, J = 5.8 Hz, 1 H), 3.70 (dd, J = 5.8 Hz, 8.4 Hz, 1 H), 4.02 (dd, J = 6.3 Hz, 8.5 Hz, 1 H), 4.18-4.28 (m, 1 H), 7.02-7.04 (m, 1 H), 7.68 (dd, J = 1.5 Hz, 1.5 Hz, 1 H), 8.24 (s, 1 H), 8.59-8.67 (m, 1 H). MS (MH+ found) = 225.8
A14. N-[2-(Benzyloxy)ethyl]-1H-imidazole-1-carboxamide
Di-1 H-imidazol-1-ylmethanone (carbonyldiimidazole, 5.18 g) is suspended in dichloromethane (50 ml) and the suspension is cooled to O0C (ice bath). Imidazole (1.81 g) and 2-(benzyloxy)ethan- amine hydrochloride (5.00 g) are added and the mixture is stirred for 18 h at room temperature. After that, saturated aqueous sodium hydrogencarbonate solution (50 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 50 ml). The combined organic phases are washed with saturated aqueous sodium hydrogencarbonate solution (1 x 100 ml) and saturated aqueous sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo to yield 6.42 g (97%) of the title compound as a colorless oil.
1H-NMR (300 MHz, d6-DMSO); δ = 3.41-3.50 (m, 2H), 3.55-3.61 (m, 2H), 4.51 (s, 2H), 7.02 (dd, J = 0.9 Hz, 1.5 Hz, 1 H), 7.22-7.37 (m, 5H), 7.67 (dd, J = 1.4 Hz, 1.4 Hz, 1 H), 8.23 (dd, J = 1.0 Hz, 1.1 Hz, 1 H), 8.57-8.65 (m, 1 H). MS (MH+ found) = 245.8
Final Compounds
1. Benzyl 5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indole-
2(1H)-carboxylate
Benzyl 3-(1 H-indol-3-yl)-4-oxopyrrolidine-1-carboxylate (example A3) (6.0 g) is suspended under nitrogen in dichloroethane (60 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 37.7 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3- fluoro-4-methoxyphenyl acetic acid (6.74 g) is dissolved in trifluoroacetic acid anhydride (5.2 ml) and the mixture is stirred for 60 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (20 ml) and added to the zinc chloride mixture, prepared above, within 15 min. The mixture is stirred for 1 h at O0C and for 2.5 h at room temperature. After that, ammonia (7M in methanol, 25 ml) is added and the mixture is refluxed for 16 h. After cooling, it is poured into water (100 ml), concentrated ammonia (25 ml) is added, the aqueous phase is extracted with dichloro- methane (2 x 100 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :9 (v/v)) to yield 0.86 g (10%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 3.76 (s, 3H), 4.40 (s, 2H), 4.72, 4.79 (2s, 2H [rotamers]), 5.14, 5.20 (2s, 2H [rotamers]), 5.22, 5.24 (2s, 2H [rotamers]), 6.98-7.16 (m, 2H), 7.16-7.51 (m, 7H), 7.51- 7.20 (m, 2H), 7.92-8.06 (m, 1 H), 11.76 (s,1 H).
2. 5-(3-Fluoro-4-methoxybenzyl)-1,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole Benzyl 5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indole-2(1 H)- carboxylate (example 1 ) (800 mg) is suspended in methanol (15 ml), ammonium formiate (0.42 g) and palladium (10% on charcoal, 0.2 g) are added and the mixture is refluxed for 1.5 h. Additional ammonium formiate (0.4 g) is then added and the mixture is refluxed for further 1.5 h. After that, the warm suspension is filtered over Celite®, washed with methanol / dichloromethane, the com- bined filtrate is concentrated in vacuo. The crude product is crystallized from ethyl acetate to yield 427 mg (74%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.90 (s, 3H), 3.97 (s, 2H), 4.57 (s, 2H), 4.67 (s, 2H), 6.79-7.44 (m, 6H), 7.45-7.58 (m, 1 H), 7.83 (d, J = 7.8 Hz, 1 H), 10.95 (s, 1 H).
3. 5-(3-Fluoro-4-methoxybenzyl)-2-(methoxyacetyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]- pyrido[3,4-b]indole hydrochloride
5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole (example 2) (100 mg) is suspended in dry dichloromethane (10 ml), triethylamine (80 μl) and a solution of methoxyacetyl chloride (26 μl) in dichloromethane (1 ml) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 20 ml) and water (1 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / ethanol 9:1 (v/v)) followed by crystallization from ethyl acetate / hydrogen chlo- ride (solution in diethyl ether) to yield 48 mg (39%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.39, 3.41 (2s, 2H [rotamers]), 3.76 (s, 3H), 4.12, 4.30 (2s, 2H [rotamers], 4.41 (s, 2H), 4.72, 4.86 (2s, 2H [rotamers]), 5.14, 5.28 (2s, 2H [rotamers]), 7.03 (dd, J = 8.7 Hz, 8.7 Hz, 1 H), 7.08-7.15 (m, 1 H), 7.15-7.22 (m, 1 H), 7.22-7.31 (m, 1 H), 7.52-7.70 (m, 2H), 8.01 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 1 1.77, 11.78 (2s, 1 H [rotamers]).
4. 2-Benzoyl-5-(3-fluoro-4-methoxybenzyl)-1,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4- bjindole
5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole (example 2) (200 mg) is suspended in dry dichloromethane (15 ml), triethylamine (160 μl) and benzoylchloride (70 μl) are added and the mixture is stirred at room temperature for 1 h. After that, 1 M sodium carbonate solution (20 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 30 ml) and water (1 x 30 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / petroleum ether to yield 26 mg (10%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.75, 3.76 (2s, 2H [rotamers]), 4.38, 4.42 (2s, 2H [rotamers]), 4.85, 4.49 (2s, 2H [rotamers]), 5.28, 5.35 (2s, 2H [rotamers]), 6.97-7.32 (m, 4H), 7.45-7.80 (m, 7H), 8.00-8.12 (m, 1 H), 1 1.76, 11.79 (2s, 1 H [rotamers]).
5. 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1H)- yl]-2-oxoethanamine
Step 1 : tert-Butyl {2-[5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol- 2(1 H)-yl]-2-oxoethyl}carbamate. 5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]- pyrido[3,4-b]indole (example 2) (100 mg) is suspended in dichloromethane (2 ml) and N-(tert- butoxycarbonyl)glycine (151 mg), 1-hydroxybenzotriazole (60 mg), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (110 mg) and triethylamine (185 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 5:1 (v/v)) to yield 67 mg (46%) of tert-butyl {2-[5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4- b]indol-2(1 H)-yl]-2-oxoethyl}carbamate. Step 2: 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1 H)-yl]-2- oxoethanamine. tert-Butyl {2-[5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4- b]indol-2(1 H)-yl]-2-oxoethyl}carbamate (67 mg) is dissolved in dioxane (2 ml) and concentrated hydrochloric acid (110 μl) is added. The mixture is stirred for 4 h at room temperature. After that, it is diluted with water (5 ml), neutralized by addition of saturated sodium hydrogencarbonate solution, extracted with dichloromethane (3 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 16 mg (29%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.54, 3.72 (2s, 2H [rotamers]), 3.91 (s, 3H), 3.45-4.40 (bs, 1 H), 4.47, 4.61 (2s, 2H [rotamers]), 4.85 (bs, 2H), 5.09, 5.21 (2s, 2H [rotamers]), 7.10-7.35 (m, 3H), 7.35-7.44 (m, 1 H), 7.87, 7.93 (2d, J787 = 7.9 Hz, J7 93 = 7.8 Hz, 1 H [rotamers]), 8.32 (s, 1 H), 11.19 (s, 1 H).
MS (MH+ found) = 405.0
6. 6-(3-Fluoro-4-methoxybenzyl)-1,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole Step 1 : 3-Hydroxy-3-(4-oxotetrahydro-2H-pyran-3-yl)-1 ,3-dihydro-2H-indol-2-one. lsatine (3.82 g) is dissolved in ethyl acetate (60 ml), tetrahydro-4H-pyran-4-one (3.92 g) and diethyl amine (1 ml) are added and the reaction mixture is stirred for 18 h at room temperature. After that, the mixture is concentrated in vacuo and the residue is crystallized from ethyl acetate / petroleum ether (5:1 (v/v)) to yield 5.45 g (85%) of 3-hydroxy-3-(4-oxotetrahydro-2H-pyran-3-yl)-1 ,3-dihydro-2H-indol-2-one. Step 2: 1 ,5-Anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)pentitol. 3-Hydroxy-3-(4-oxotetrahydro-2H-pyran- 3-yl)-1 ,3-dihydro-2H-indol-2-one (5.00 g) is suspended in dry tetrahydrofuran (20 ml), borane tetra- hydrofuran complex (1 M in ether, 80 ml) is added in portions and the mixture is stirred for 20 h at room temperature. After that, it is poured carefully into a mixture of 0.3M hydrochloric acid (150 ml) and ethyl acetate (100 ml). The organic phase is washed with 0.3M hydrochloric acid (1 x 150 ml), the combined aqueous phases are extracted with ethyl acetate (2 x 200 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane / ethyl acetate 1 :1 to 1 :5 (v/v)) to obtain 1.08 g (25%) of 1 ,5-anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)pentitol. Step 3: 3-(1 H-lndol-3-yl)tetrahydro-4H-pyran-4-one. Dimethylsulfoxide (0.81 ml) is dissolved in dry dichloromethane (15 ml) and the solution is cooled to -750C. Trifluoroacetanhydride (1.17 ml) is added drop by drop and the mixture is stirred for 30 min at -750C. A solution of 1 ,5-anhydro-2,4- dideoxy-2-(1 H-indol-3-yl)pentitol (1.08 g) in dry tetrahydrofuran (10 ml) is then added via syringe and the mixture is stirred for further 1 h at -750C. Triethyl amine (3.19 ml) is added and the reac- tion mixture is allowed to warm to room temperature. Water (50 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with water (2 x 80 ml), dried (MgSO4) and concentrated in vacuo to give rise to 0.95 g (89%) of 3-(1 H-indol-3-yl)tetrahydro-4H-pyran-4-one. Step 4: 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole. 3-(1 H- lndol-3-yl)tetrahydro-4H-pyran-4-one (500 mg) is dissolved in dry dichloroethane (2 ml), zinc di- chloride (1 M in diethyl ether, 6.9 ml) and 3-fluoro-4-methoxyphenylacetyl chloride (0.94 g) are added and the mixture is stirred for 8 min in a sealed vial at 8O0C using microwave radiation. After that, ammonia (7N in methanol, 8 ml) is added and the mixture is stirred for 30 min in a sealed vial at 15O0C using microwave radiation. The reaction mixture is then filtered, the solids washed with dichloromethane, the combined filtrate is washed with 2M aqueous ammonia (2 x 50 ml) and water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 1 :1 (v/v)) followed by crystallisation from ethyl acetate / petroleum ether to give rise to 140 mg (17%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 2.99 (t, J = 5.3 Hz, 2H), 3.75 (s, 3H), 4.06 (t, J = 5.5 Hz, 2H), 4.34 (s, 2H), 5.27 (s, 2H), 6.93-7.30 (m, 5H), 7.50-7.66 (m, 2H), 7.94 (d, J = 8.0 Hz, 1 H), 1 1.60 (s, 1 H).
The following compound is obtained by using the procedure of example 6 analogously.
7. 6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyriclo[3,4-b]inclole Starting compounds: Isatine, tetrahydro-4H-pyran-4-one and 3-fluoro-4-methoxyphenylacetyl chloride; Yield (step 4) 19%.
1H-NMR (400 MHz, d6-DMSO); δ = 2.99 (t, J = 5.4 Hz, 2H), 3.66 (s, 3H), 4.05 (t, J = 5.6 Hz, 2H), 4.34 (s, 2H), 5.26 (s, 2H), 6.77-6.88 (m, 2H), 7.20 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.26 (d, J = 8.7 Hz, 1 H), 7.51 (t, J = 7.2 Hz, 7.2 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 1 1.60 (s, 1 H).
8. 6-(3-Fluoro-4-methoxybenzyl)-1,3A7-tetrahydrothiopyrano^4^5,6]pyrido[3,4- bjindole Step 1 : 3-Hydroxy-3-(4-oxotetrahydro-2H-thiopyran-3-yl)-1 ,3-dihydro-2H-indol-2-one. Isatine (4.52 g) is suspended in ethyl acetate (90 ml), tetrahydro-4H-thiopyran-4-one (5.0 g) and diethyl amine (1 ml) are added and the reaction mixture is stirred for 18 h at room temperature. After that, the mixture is concentrated in vacuo and the residue is crystallized from ethyl acetate / petroleum ether (1 :2 (v/v)) to yield 7.69 g (95%) of 3-hydroxy-3-(4-oxotetrahydro-2H-thiopyran-3-yl)-1 ,3- dihydro-2H-indol-2-one.
Step 2: 1 ,5-Anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)-1-thiopentitol. 3-Hydroxy-3-(4-oxotetrahydro-2H- thiopyran-3-yl)-1 ,3-dihydro-2H-indol-2-one (2.63 g) is suspended in dry tetrahydrofuran (30 ml), borane tetrahydrofuran complex (1 M in ether, 40 ml) is added in portions and the mixture is stirred for 20 h at room temperature. After that, it is poured carefully into a mixture of 0.3M hydrochloric acid (150 ml) and ethyl acetate (100 ml). The organic phase is washed with 0.3M hydrochloric acid (1 x 150 ml), the combined aqueous phases are extracted with ethyl acetate (2 x 200 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 1 :1 (v/v)) to obtain 2.03 g (87%) of 1 ,5-anhydro-2,4-dideoxy-2-(1 H-indol-3-yl)-1-thiopentitol. Step 3: 3-(1 H-lndol-3-yl)tetrahydro-4H-thiopyran-4-one. Dimethylsulfoxide (1.42 ml) is dissolved in dry dichloromethane (45 ml) and the solution is cooled to -750C. Trifluoroacetanhydride (2.1 ml) is added drop by drop and the mixture is stirred for 30 min at -750C. A solution of 1 ,5-anhydro-2,4- dideoxy-2-(1 H-indol-3-yl)-1-thiopentitol (2.03 g) in dry tetrahydrofuran (30 ml) is then added via syringe and the mixture is stirred for further 1 h at -750C. Triethyl amine (5.58 ml) is added and the reaction mixture is allowed to warm to room temperature. Water (50 ml) and dichloromethane
(50 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with water (3 x 100 ml), dried (MgSO4) and concentrated in vacuo to give rise to 0.50 g (25%) of 3-(1 H-indol-3-yl)tetrahydro-4H-thiopyran-4-one. Step 4: 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole. 3- (1 H-lndol-3-yl)tetrahydro-4H-pyran-4-one (2.62 g) is dissolved under nitrogen in dichloroethane (8 ml) and the solution is cooled to O0C (ice bath). In parallel, 3-fluoro-4-methoxyphenyl acetic acid (4.27 g) is dissolved in trifluoroacetic acid anhydride (3.2 ml) and the mixture is stirred for 15 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (2 ml) and added to the solution of ketone prepared above. Zinc chloride (1 M in diethyl ether, 15.4 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. After that, ammonia (7M in methanol, 18 ml) is added and the mixture is refluxed for 16 h. After cooling, it is diluted with ethyl acetate (100 ml). The organic layer is washed with 2M ammonia solution (1 x 100 ml), the aqueous phase is extracted with ethyl acetate (2 x 100 ml), the combined organic extracts are washed with water (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :9 (v/v)) to yield 0.80 g (19%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.98-3.08 (m, 2H), 3.20-3.30 (m, 2H), 3.75 (s, 3H), 4.35 (s, 2H), 4.41 (s, 2H), 6.95-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.50-7.65 (m, 2H), 8.22 (d, J = 8.1 Hz, 1 H), 11.63 (s, 1 H).
9. 6-(3-Fluoro-4-methoxybenzyl)-1,3A7-tetrahydrothiopyrano^4':5,6]pyrido[3,4- bjindole 2 -oxide
6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole (example 8) (0.43 g) is dissolved under nitrogen in acetonitrile (5 ml), N-methylmorpholine-N-oxide (0.40 g) is added and the mixture is stirred for 5 min. Tetra-n-propylammonium perruthenate (20 mg) is added and the mixture is stirred for 3 h at 4O0C. After that, it is concentrated in vacuo and filtered through a short plug of silica gel (eluting with ethyl acetate / dichloromethane / methanol 3:1 :1 (v/v/v)). The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / dichloromethane / methanol 2.8:2:0.4 to 2:2:1 (v/v/v)) followed by crystallization from diethyl ether / methanol 2:1 (v/v) to give rise to 0.14 g (45%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ =3.10-3.38 (m, 3H), 3.41-3.59 (m, 1 H), 3.75 (s, 3H), 4.36 (s, 2H), 4.61 (s, 2H), 6.98-7.16 (m, 2H), 7.16-7.30 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 8.28 (d, J = 8.1 Hz, 1 H), 11.70 (s, 1 H).
10. 6-(3-Fluoro-4-methoxybenzyl)-1,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4- bjindole 2,2-dioxide
6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole (example 8) (0.43 g) is dissolved under nitrogen in acetonitrile (5 ml), N-methylmorpholine-N-oxide (0.40 g) is added and the mixture is stirred for 5 min. Tetra-n-propylammonium perruthenate (20 mg) is added and the mixture is stirred for 3 h at 4O0C. After that, it is concentrated in vacuo and filtered through a short plug of silica gel (eluting with ethyl acetate / dichloromethane / methanol 3:1 :1 (v/v/v)). The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / dichloromethane / methanol 2.8:2:0.4 to 2:2:1 (v/v/v)) to yield 10 mg (2%) of the title compound.
11. 6-(3-Fluoro-4-methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine dihydrochloride
Step 1 : 3-(1-Methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-1 H-indole. Indole (15.0 g) is suspended in methanol (250 ml), 1-methylpiperidin-4-one (14.4 g) and potassium hydroxide (14.3 g) are added and the reaction mixture is refluxed for 18 h. After that, the mixture is cooled, the crystalline precipi- tate is filtered, washed with methanol and dried to obtain 21.64 g (80%) of 3-(1-methyl-1 ,2,3,6- tetrahydropyridin-4-yl)-1 H-indole. mp. 227° - 2280C.
Step 2: 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-ol. Sodium borohydride (4.2 g) is dissolved in dry tetrahydrofuran (500 ml) and the solution is cooled to O0C (ice bath). Boron trifluoride diethyl ether complex (15 ml) is added drop by drop at O0C and the mixture is stirred for 1 h at room temperature. It is cooled again to O0C (ice bath) and a suspension of 3-(1-methyl-1 ,2,3,6-tetrahydropyridin- 4-yl)-1 H-indole (12.5 g) in dry tetrahydrofuran (100 ml) is added in portions. The mixture is stirred at room temperature for 2 h, then it is again cooled to O0C (ice bath) and water (60 ml), ethanol (60 ml), 3M sodium hydroxide solution (49 ml) are added, followed by hydrogen peroxide (30%, 30 ml, drop by drop). The mixture is stirred at 550C for 18 h. After cooling, the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane (150 ml) and washed with saturated sodium chloride solution (1 x 100 ml). The aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 150 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chroma- tography (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) to yield 6.8 g (50%) of 4-(1 H- indol-3-yl)-1-methylpiperidin-3-ol.
Step 3: 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-one. Dimethylsulfoxide (3.55 ml) is dissolved in dry dichloromethane (100 ml) and the solution is cooled to -750C. Trifluoroacetanhydride (5.14 ml) is added drop by drop and the mixture is stirred for 30 min at -750C. A warm solution of 4-(1 H-indol- 3-yl)-1-methylpiperidin-3-ol (5.0 g) in dimethylsulfoxide (50 ml) is then added and the mixture is stirred for further 1 h at -750C. Triethyl amine (13.9 ml) is added and the reaction mixture is allowed to warm to room temperature. Water (100 ml) and dichloromethane (100 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts are washed with 2M sodium carbonate solution (2 x 200 ml) and water (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / methanol 97:3 (v/v)) to yield 2.3 g (46%) of 4- (1 H-indol-3-yl)-1-methylpiperidin-3-one.
Step 4: 6-(3-Fluoro-4-methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine dihydrochloride. 4-(1 H-lndol-3-yl)-1-methylpiperidin-3-one (2.0 g) is dissolved under nitrogen in dichloroethane (12 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 13 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (3.23 g) is dissolved in trifluoroacetic acid anhydride (2.44 ml) and the mixture is stirred for 40 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (5.3 ml) and added to the zinc chloride mixture, prepared above, within 10 min. The mixture is stirred for 5 min at O0C and for 1 h at room temperature. After that, ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 16 h. After cooling, it is diluted with ethyl acetate (35 ml) and 2M ammonia solution (35 ml), the organic phase is washed with saturated sodium chloride solution (15 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane / methanol 95:5 to 3:1 (v/v)) followed by crystallization from ethyl acetate / hydrogen chloride (5M in diethyl ether) to yield 200 mg (6%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.04 (s, 3H), 3.41-4.02 (m, 6H), 3.76 (s, 3H), 4.61 (s, 2H), 7.07 (t, J = 8.9 Hz, 1 H), 7.26-7.52 (m, 3H), 7.65-7.74 (m, 1 H), 7.75-7.83 (m, 1 H), 8.26 (d, J = 8.2 Hz, 1 H), 1 1.41 (bs, 1 H), 12.73 (bs, 1 H).
12. Ethyl 6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) (17.2 g) is dissolved under ni- trogen in dichloroethane (120 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 120 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3- fluoro-4-methoxyphenyl acetic acid (22.1 g) is dissolved in trifluoroacetic acid anhydride (16.7 ml) and the mixture is stirred for 40 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (50 ml) and added to the zinc chloride mixture, prepared above, within 20 min. The mixture is stirred for 5 min at O0C and for 2.5 h at room temperature. After that, ammonia (7M in methanol, 53 ml) and ammonium acetate (13.9 g) are added and the mixture is refluxed for 16 h. After cooling, it is filtered over a plug of Celite®, the plug is washed thoroughly with methanol. Water (400 ml) is added to the filtrate, the aqueous phase is extracted with ethyl acetate (2 x 400 ml), the combined organic extracts are washed with water (1 x 500 ml), dried (MgSO4) and concen- trated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 5:5:1 (v/v/v)) to yield 13.8 g (53%) of the title compound as a red-brown foam.
1H-NMR (300 MHz, CDCI3); δ = 1.20-1.40 (m, 3H), 3.43 (t, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.94 (t, J = 5.9 Hz, 2H), 4.13-4.30 (m, 2H), 4.41 (s, 2H), 4.91 (s, 2H), 6.81-6.91 (m, 1 H), 6.92-7.07 (m, 2H), 7.15-7.31 (m, 1 H), 7.32-7.55 (m, 2H), 7.87 (bs, 1 H), 8.11 (d, J = 8.0 Hz, 1 H).
The following compounds are obtained by using the procedure of example 12 analogously.
13. Ethyl 6-(3,5-difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate
Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and 3,5- difluoro-4-methoxyphenyl acetic acid; yield: 22%.
1H-NMR (300 MHz, d6-DMSO); = 1.23 (t, J = 7.1 Hz, 3H), 3.24- 3,4 (m, 2H), 3.78-3.88 (m, 2H), 3.84 (s, 3H), 4.11 (q, J = 7.1 Hz, 2H), 4.37 (s, 2H), 4.7 (s, 2H), 7.03-7.18 (m, J = 7.1 Hz, 2H), 7.24 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.55 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 452.3
14. Ethyl 6-(1,3-benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and 1 ,3- benzodioxol-5-ylacetic acid; yield: 26%.
1H-NMR (300 MHz, d6-DMSO); = 1.23 (t, J = 7.1 Hz, 3H), 3.33 (t, J = 5.7 Hz, 2H), 3.82 (t, J = 5.7 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.32 (s, 2H), 4.69 (s, 2H), 5.92 (s, 2H), 6.76-6.86 (m, 2H), 6.95 (s, 1 H), 7.23 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 8.15 (d, J = 7.9 Hz, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 430.2
15. Ethyl 6-(4-fluoro-3-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and A- fluoro-3-methoxyphenyl acetic acid; yield: 28%.
1H-NMR (300 MHz, d6-DMSO); = 1.22 (t, J = 7.0 Hz, 3H), 3.34 (t, J= 5.7 Hz, 2H), 3.78-3.87 (m, 5H), 4.10 (q, J = 7.1 Hz, 2H), 4.39 (s, 2H), 4.70 (s, 2H), 6.80-6.87 (m, 1 H), 7.05 (dd, J = 8.3 Hz, 11.6 Hz, 1 H), 7.18-7.32 (m, 2H), 7.54 (dd, J = 7.2 Hz, 8.0 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 434.2
16. Ethyl 6-(3,4-difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridine-3- carboxylate
Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and 3,4- difluorophenyl acetic acid; yield: 23%.
1H-NMR (300 MHz, d6-DMSO); = 1.23 (t, J = 7.0 Hz, 3H), 3.34 (t, J = 5.9 Hz, 2H), 3.83 (t, J = 5.8 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.41 (s, 2H), 4.69 (s, 2H), 7.15-7.64 (m, 4H), 7.55 (ddd, J = 1.1 Hz, 8.0 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 422.2
17. Ethyl 6-(3-chloro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and 3- chloro-4-methoxyphenyl acetic acid; yield: 21 %.
1H-NMR (300MHz, d6-DMSO); δ = 1.23 (t, J = 7.1 Hz, 3H), 3.22-3.40 (m, 2H), 3.78 (s, 3H), 3.78- 3.89 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.35 (s, 2H), 4.69 (s, 2H), 7.04 (d, J = 8.5 Hz, 1 H), 7.19-7.31 (m, 2H), 7.43 (s, 1 H), 7.54 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 11.69 (s, 1 H). MS (MH+ found) = 450.1
18. Ethyl 6-(4-ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and A- ethoxy-3-fluorophenyl acetic acid; yield: 22%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.15-1.39 (m, 6H), 3.26-3.41 (m, 2H), 3.76-3.90 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 4.69 (s, 2H), 6.98-7.13 (m, 2H), 7.15-7.30 (m, 2H), 7.54 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 448.2
19. Ethyl 6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridine-3- carboxylate
Starting compounds: Ethyl 4-(1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A6) and A- methoxyphenyl acetic acid; yield: 25%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.23 (t, J = 7.0 Hz, 3H), 3.23-3.40 (m, 2H), 3.67 (s, 3H), 3.73- 3.88 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 4.69 (s, 2H), 6.82 (d, J = 6.7 Hz, 2H), 7.17-7.31 (m, 3H), 7.53 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.67 (bs, 1 H). MS (MH+ found) = 416.2
20. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine Ethyl 6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3- carboxylate (example 12) (14.21 g) is dissolved in ethylene glycol (260 ml), hydrazine hydrate (12.8 ml) and potassium hydroxide (34.8 g) are added and the mixture is stirred for 2 h at 14O0C. After cooling, it is poured into saturated ammonium chloride solution (1000 ml) and stirred for 30 min at room temperature. The precipitate is filtered off, washed thoroughly with water and petro- leum ether and dried in vacuo to give rise to 7.70 g (65%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.10-3.65 (m, 5H), 3.74 (s, 3H), 3.03 (s, 2H), 3.24 (s, 2H), 6.94- 7.12 (m, 2H), 7.12-7.29 (m, 2H), 7.44-7.65 (m, 2H), 8.10 (d, J = 8.0 Hz, 1 H), 8.65 (s, 1 H). MS (MH+ found) = 362.3
The following compounds are obtained by using the procedure of example 20 analogously.
21. 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine
Starting compound: Ethyl 6-(3,5-difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate (example 13); yield: 99%.
1H-NMR (300 MHz, d6-DMSO); δ = 3.39 (s, 2H), 3.53 (s, 4H), 3.83 (s, 3H), 4.36 (s, 2H), 4.42 (s, 1 H), 7.17 (d, J = 9.6 Hz, 2H), 7.22-7.32 (m, 1 H), 7.58 (dd, J = 8.1 Hz, 8.2 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 12.04 (s, 1 H). MS (MH+ found) = 380.3 22. θ-ti.S-Benzodioxol-δ-ylmethyO^^^y-tetrahydro-IH-indolo^^-cJtiyjnaphthyridine
Starting compound: Ethyl 6-(1,3-benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate (example 14); yield: 93%. 1H-NMR (300 MHz, d6-DMSO); δ = 3.06-3.17 (m, 2H), 3.17-3.24 (m, 2H), 3.40 (s, 2H), 4.29 (s, 2H), 4.41 (bs, 1H), 5.91 (s, 2H), 6.72-6.82 (m, 2H), 6.93 (s, 1H), 7.20 (dd, J = 7.3 Hz, 7.4 Hz, 1H), 7.51 (dd, J =7.4 Hz, 7.4 Hz, 1H), 7.59 (d, J= 8.2 Hz, 1H), 8.11 (d, J =8.0 Hz, 1H). MS (MH+ found) = 358.3
23. 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c][1,7]naphthyridine
Starting compound: Ethyl 6-(4-fluoro-3-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate (example 15); yield: 99%.
1H-NMR (300 MHz, d6-DMSO); δ = 3.49 (bs, 4H), 3.82 (s, 3H), 4.32 (s, 2H), 4.41 (s, 2H), 6.80-6.90 (m, 1H), 7.00-7.09 (m, 1H), 7.26 (dd, J= 7.0 Hz, 7.1 Hz, 1H), 7.34 (d, J= 5.5 Hz, 1H), 7.56 (dd, J = 7.1 Hz, 7.2 Hz, 1H), 7.67 (d, J= 8.2 Hz, 1H), 8.14 (d, J= 8.0 Hz, 1H), 11.97 (s, 1H). MS (MH+ found) = 362.3
24. 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine
Starting compound: Ethyl 6-(3,4-difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate (example 16); yield: 99%.
1H-NMR (300 MHz, d6-DMSO); δ = 3.11-3.30 (m, 4H), 4.04 (s, 2H), 4.39 (s, 2H), 7.11-7.45 (m, 4H), 7.48-7.57 (m, 1H), 7.61 (d, J= 8.1 Hz, 1H), 8.13 (d, J= 8.0 Hz, 1H), 11.61 (bs, 1H). MS (MH+ found) = 350.3
25. 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine
Starting compound: Ethyl 6-(3-chloro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate (example 17); yield: 99%.
1H-NMR (300 MHz, d6-DMSO); δ = 3.08-3.32 (m, 4H), 3.40 (s, 2H), 3.77 (s, 3H), 4.32 (s, 2H), 4.40 (bs, 1H), 7.03 (d, J= 8.5 Hz, 1H), 7.15-7.31 (m, 2H), 7.40 (s, 1H), 7.47-7.55 (m, 1H), 7.60 (d, J = 8.1 Hz, 1H), 8.12 (d, J= 8.0 Hz, 1H), 11.51 (bs, 1H). MS (MH+ found) = 378.2
26. 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine
Starting compound: Ethyl 6-(4-ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate (example 18); yield: 99%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J= 7.0 Hz, 3H), 3.08-3.18 (m, 2H), 3.18-3.28 (m, 2H), 3.39 (s, 2H), 3.92-4.05 (m, 2H), 4.31 (s, 2H), 4.46 (bs, 1H), 6.95-7.11 (m, 2H), 7.12-7.27 (m, 2H), 7.52 (dd, J= 7.1 Hz, 7.2 Hz, 1H), 7.60 (d, J= 8.1 Hz, 1H), 8.12 (d, J= 7.9 Hz, 1H), 11.54 (bs, 1H). MS (MH+ found) = 376.3 27. 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine
Starting compound: Ethyl 6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naph- thyridine-3-carboxylate (example 19); yield: 99%. 1H-NMR (300 MHz, d6-DMSO); δ = 3.54 (bs, 4H), 3.67 (s, 2H), 4.36 (s, 2H), 4.38 (s, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.20-7.32 (m, 3H), 7.57 (d, J = 7.1 Hz, 7.2 Hz, 1 H), 7.67 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 9.40 (bs, 1 H), 1 1.93 (s, 1 H). MS (MH+ found) = 344.3
28. Methyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
Methyl 5-hydroxy-4-(1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (example A8) (570 mg) is suspended under nitrogen in dichloroethane (4 ml) and the suspension is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 4 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (740 mg) is dissolved in trifluoroacetic acid anhydride (570 μl) and the mixture is stirred for 30 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (3 ml) and added to the zinc chloride mixture, prepared above, within 5 min. The mixture is stirred for 3 h at room temperature. Nitro- methane (30 ml) is added and the mixture is stirred for 18 h at room temperature. After that, am- monia (7M in methanol, 1.83 ml) and ammonium acetate (480 mg) are added and the mixture is heated in a sealed vial at 1000C for 45 min using microwave radiation. After cooling, it is filtered over a plug of Celite®, the plug is washed thoroughly with dichloromethane. The combined filtrate is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 6:10:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 257 mg (30%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ =3.66 (s, 3H), 3.77 (s, 3H), 4.42-4.55 (m, 4H), 4.95 (s, 2H), 7.01- 7.19 (m, 2H), 7.19-7.31 (m, 2H), 7.58-7.81 (m, 2H), 9.15 (d, J = 8.4 Hz, 1 H), 12.18 (s, 1 H). MS (MH+ found) = 434.1 mp.: 178-179 0C
29. Methyl 6-(3-fluoro-4-methoxybenzyl)-1 -hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
Methyl Θ^S-fluoro^-methoxybenzyO-i-oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine-S- carboxylate (example 28) (24 mg) is dissolved under nitrogen in methanol (1 ml) and sodium boro- hydride (21 mg) is added. The mixture is stirred for 15 min at room temperature. After that, water (2 ml) and dichloromethane (2 ml) are added and the aqueous phase is extracted with dichloromethane (2 x 2 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo to yield 257 mg (30%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 3.38-3.57 (m, 1 H), 3.67 (s, 3H), 3.75 (s, 3H), 4.12-4.30 (m, 1 H), 4.34-4.52 (m, 3H), 4.37-5.03 (m, 1 H), 5.25-5.38 (m, 1 H), 5.47-5.60 (m, 1 H), 7.00-7.18 (m, 2H), 7.18-7.29 (m, 2H), 7.53 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 436.2
30. Methyl 6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (10 ml), triethylamine (330 μl) and methyl chloro- formate (92 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with water (1 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :2 (v/v)) followed by crystallization from diethyl ether / petroleum ether to yield 200 mg (40%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.22-3.40 (m, 2H), 3.65 (s, 3H), 3.75 (s, 3H), 3.82 (t, J = 5.9 Hz, 2H), 4.33 (s, 2H), 4.68 (s, 2H), 7.00-7.15 (m, 2H), 7.15-7.29 (m, 2H), 7.52 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.61 (s, 1 H).
31. 3-Benzyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (300 mg) is dissolved in methanol (10 ml), benzaldehyde (168 μl) and glacial acetic acid (20 μl) are added and the mixture is stirred for 30 min at room temperature. Sodium borohydride (188 mg) is added in portions and the mixture is stirred for 18 h at room temperature. After that, it is diluted with dichloromethane (10 ml), saturated ammonium chloride solution (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. 1H-NMR (300 MHz, CDCI3); δ = 2.96 (t, J = 5.9 Hz, 2H), 3.45 (t, J = 5.9 Hz, 2H), 3.82 (s, 2H), 3.84 (s, 3H), 3.94 (s, 2H), 4.37 (s, 2H), 6.80-6.92 (m, 1 H), 6.92-7.05 (m, 2H), 7.18-7.53 (m, 8H), 7.73 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 452.3
32. 6-(3-Fluoro-4-methoxybenzyl)-3-(morpholin-4-ylcarbonyl)-2,3A7-tetrahydro-1H- indolo[2,3-c][1 ,7]naphthyridine
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (400 mg) is dissolved in dry dichloromethane (15 ml), triethylamine (222 mg) and morpholinecar- bonylchloride (172 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added. A precipitate is formed, which is filtered, washed (2 x 25 ml water and 2 x 25 ml ether) and dried in vacuo to yield 339 mg (65%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 3.18-3.28 (m, 4H), 3.34-3.43 (m, 2H), 3.56-3.71 (m, 6H), 3.75 (s, 3H), 4.33 (s, 2H), 4.51 (s, 2H), 7.02 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.08-7.14 (m, 1 H), 7.15-7.29 (m, 2H), 7.52 (dd, J = 7.9 Hz, 7.9 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.58 (s, 1 H). mp.: 264-266 0C
The following compounds are obtained by using the procedure of example 32 analogously.
33. 6-(3-Fluoro-4-methoxybenzyl)-N,N-dimethyl-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxamide Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and dimethylcarbamyl chloride; yield: 59%. 1H-NMR (400 MHz, d6-DMSO); δ = 2.81 (s, 6H), 3.33-3.42 (m, 2H), 3.54-3.64 (m, 2H), 3.74 (s, 3H), 4.33 (s, 2H), 4.46 (s, 2H), 7.02 (dd, J = 8.6 Hz, 8.6 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 7.16-7.29 (m, 2H), 7.51 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.60 (d, J = 7.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 1 1.60 (s, 1 H). mp.: 230-234 0C
34. 1 -Ethyl-4-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]carbonyl}piperazine-2,3-dione Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride; yield: 41 %. 1H-NMR (400 MHz, d6-DMSO); δ = 1.13 (t, J = 7.1 Hz, 3H), 3.35-3.92 (m, 13H), 4.34 (s, 2H), 4.60- 4.88 (m, 2H), 7.02 (dd, J = 8.6 Hz, 8.6 Hz, 1 H), 7.09-7.15 (m, 1 H), 7.15-7.30 (m, 2H), 7.53 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 8.07-8.21 (m, 1 H), 11.64 (s, 1 H). mp.: 160-162 0C
35. 6-(3-Fluoro-4-methoxybenzyl)-N,N-dimethyl-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-sulfonamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (361 mg) is dissolved in dry dichloromethane (10 ml), triethylamine (500 μl) and dimethylsulfamoyl chloride (145 mg) are added and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (15 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are washed with water (1 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate to give rise to 302 mg (64%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.80 (s, 6H), 3.40 (t, J = 5.8 Hz, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 4.34 (s, 2H), 4.50 (s, 2H), 7.03 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.16-7.30 (m, 2H), 7.53 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.64 (s, 1 H). mp.: 234-236 0C
36. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-oxoacetamide
Step 1 : Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl](oxo)acetate. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (20 ml), triethyl- amine (310 μl) is added and the mixture is cooled to 1O0C. Methyl chloro(oxo)acetate (130 μl) is added drop by drop at 1O0C and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (20 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are washed with water (1 x 40 ml), dried (MgSO4) and concentrated in vacuo to yield 500 mg (99%) of methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate, that is used without further purifica- tion in the next step.
Step 2: 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]- 2-oxoacetamide. Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl](oxo)acetate (300 mg) is dissolved in methanol (5 ml) and ammonia (7M in methanol, 7 ml) is added. The mixture is stirred for 3 h at room temperature. After that, the precipi- tate is filtered, washed with methanol (10 ml) and diethyl ether (10 ml) and dried in vacuo to yield 130 mg (45%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.21-3.48 (m, 2H), 3.75 (s, 3H), 3.77-4.00 (m, 2H), 4.30-4.40 (m, 2H), 4.74-4.86 (m, 2H), 6.99-7.18 (m, 2H), 7.18-7.30 (m, 2H), 7.50-7.59 (m, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.68-7.81 (m, 1 H), 8.04-8.21 (m, 2H), 11.61-11.71 (m, 1 H).
The following compounds are obtained by using the procedure of example 36 analogously.
37. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-methoxyethyl)-2-oxoacetamide Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20), methyl chloro(oxo)acetate and 2-methoxyethylamine (3 equivalents with respect to intermediate methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate). 1H-NMR (400 MHz, d6-DMSO); δ = 3.27-3.50 (m, 6H), 3.75 (s, 3H), 3.88-4.00 (m, 2H), 4.30-4.40 (m, 2H), 4.73-4.88 (m, 2H), 6.99-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.50-7.59 (m, 1 H), 7.59-7.68 (m, 1 H), 8.09-8.20 (m, 1 H), 8.67-8.82 (m, 1 H), 11.64 (s, 1 H).
38. N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-2-oxoacetamide
Step 1 : Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl](oxo)acetate. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (430 mg) is dissolved in dry dichloromethane (20 ml), triethyl- amine (310 μl) is added and the mixture is cooled to 1O0C. Methyl chloro(oxo)acetate (130 μl) is added drop by drop at 1O0C and the mixture is stirred at room temperature for 18 h. After that, 1 M sodium carbonate solution (20 ml) is added. The aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are washed with water (1 x 40 ml), dried (MgSO4) and concentrated in vacuo to yield 500 mg (99%) of methyl [6-(3-fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate, that is used without further purification in the next step.
Step 2: N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoacetamide. Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl](oxo)acetate (250 mg) is dissolved in methanol (10 ml) and 1-(1 ,3-benzodioxol-5-yl)methanamine (250 μl) is added. The mixture is stirred for 18 h at room temperature. After that, it is concentrated in vacuo, the residue is dissolved in dichloromethane (20 ml), washed with 0.1 M hydrochloric acid (20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from methanol to obtain 98 mg (31 %) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 3.34-3.42 (m, 2H), 3.75 (s, 3H), 3.85-4.00 (m, 2H), 4.19-4.40 (m, 4H), 4.75-4.88 (m, 2H), 5.93-6.05 (m, 2H), 6.70-6.92 (m, 3H), 6.98-7.17 (m, 2H), 7.18-7.29 (m, 2H), 7.53 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 8.09-8.20 (m, 1 H), 9.11-9.25 (m, 1 H), 11.64 (s, 1 H). mp.: 235-237 0C
39. 6-(3-Fluoro-4-methoxybenzyl)-3-(methylsulfonyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1 ,7]naphthyridine
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (180 mg) is dissolved in acetone (5 ml), potassium carbonate (0.28 g) and methansulfonyl chloride (63 mg) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is diluted with methanol (20 ml), filtered over Celite® and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 119 mg (54%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 2.93 (s, 3H), 3.48 (t, J = 5.9 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.85 (s, 3H), 4.39 (s, 2H), 4.72 (s, 2H), 6.89 (dd, J = 8.5 Hz, 8.5 Hz, 1 H), 7.01 (d, J = 10.0 Hz, 1 H), 7.21- 7.31 (m, 1 H), 7.40-7.58 (m, 2H), 7.92 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 440.1
40. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]acetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (250 mg), sodium hydride (60% suspension in mineral oil, 28 mg) and bromoacetamide (96 mg) are suspended in dimethylformamide (3 ml) and the mixture is stirred for 1 h at room temperature. After that, water (10 ml) and dichloromethane (10 ml) are added, the mixture is vigorously stirred and the organic phase is concentrated in vacuo. The crude product is purified by flash chromatography (amino modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)) followed by crystallization from ethyl acetate / n-heptane to give rise to 117 mg (40%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 2.81-3.00 (m, 2H), 3.13 (s, 2H), 3.21-3.46 (m, 2H), 3.75 (s, 3H), 3.80 (s, 2H), 4.32 (s, 2H), 6.98-7.40 (m, 6H), 7.52 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.55 (s, 1 H). mp.: 253-255 0C
The following compounds are obtained by using the procedure of example 40 analogously.
41. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl] -N -oxetan -3-y lacetamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-bromo-N-oxetan-3-ylacetamide; yield: 51 %.
1H-NMR (300 MHz, CDCI3); δ = 3.06 (t, J = 5.9 Hz, 2H), 3.32 (s, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.85 (s, 3H), 4.03 (s, 2H), 4.41 (s, 2H), 4.52 (t, J = 6.5 Hz, 2H), 4.93 (t, J = 7.1 Hz, 2H), 5.03-5.21 (m, 1 H), 6.89 (dd, J = 8.5 Hz, 8.5 Hz, 1 H), 7.01 (d, J = 9.9 Hz, 2H), 7.21-7.35 (m, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.48-7.58 (m, 1 H), 7.28-7.89 (m, 1 H), 7.92 (s, 1 H), 7.79 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 475.1 mp.: 200-201 0C
42. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-methylacetamide Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-bromo-N-methylpropanamide; purification by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 98:2:1 (v/v/v)) followed by crystallization from ethyl acetate; yield: 62%. 1H-NMR (300 MHz, d6-DMSO); δ = 2.64 (d, J = 4.6 Hz, 3H), 2.80-2.99 (m, 2H), 3.18 (s, 2H), 3.25- 3.49 (m, 2H), 3.69-3.89 (m, 5H), 4.33 (s, 2H), 6.99-7.16 (m, 2H), 7.16-7.30 (m, 2H), 7.48-7.69 (m, 2H), 7.81 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.56 (s, 1 H). MS (MH+ found) = 433.1 mp.: 224-226 0C
43. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-isopropylacetamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-bromo-N-isopropylacetamide; purification by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:5:1 (v/v/v)) followed by crystallization from ethyl acetate; yield: 45%.
1H-NMR (300 MHz, d6-DMSO); δ = 0.92-1.20 (m, 6H), 2.81-2.99 (m, 2H), 3.30 (s, 2H), 3.22-3.49 (m, 2H), 3.67-3.88 (m, 5H), 3.88-4.10 (m, 1 H), 4.33 (s, 2H), 6.96-7.15 (m, 2H), 7.15-7.35 (m, 2H), 7.47-7.69 (m, 3H), 8.14 (d, J = 8.0 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 461.1 mp.: 225-226 0C
44. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(methylsulfonyl)acetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (250 mg), sodium hydride (60% suspension in mineral oil, 55 mg) and 2-bromo-N-(methylsulfonyl)- acetamide hydrobromide (210 mg) are suspended in dimethylformamide (4 ml) and the mixture is stirred for 1 h at room temperature. After that, saturated ammonium chloride solution (2 ml) and water (20 ml) are added, the mixture is extracted with dichloromethane (3 x 30 ml), the combined organic extracts are washed with water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 10:10:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 176 mg of the title compound as triethylammonium salt. The neutral form is obtained by the follow- ing procedure: The triethylammonium salt (150 mg) is dissolved in dichloromethane / methanol (9:1 (v/v), 20 ml), 1 M citric acid (3 ml) and water (15 ml) are added. The aqueous phase is extracted with dichloromethane / methanol (9:1 (v/v), 2 x 20 ml), the combined organic extracts are washed with saturated ammonium chloride solution (1 x 30 ml) and water (1 x 30 ml), dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from ethyl acetate to obtain 55 mg (16%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.00 (s, 3H), 3.10-3.61 (m, 5H), 3.72 (s, 2H), 3.75 (s, 3H), 4.29- 4.47 (m, 4H), 7.04 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.10-7.32 (m, 3H), 7.58 (dd, J = 7.5 Hz, 7.5 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 8.1 Hz, 1 H), 11.92 (s, 1 H). mp.: >230 0C 45. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]propanamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (360 mg) is suspended in acetone (10 ml), potassium carbonate (0.55 g) and 2-bromopropanamide (182 mg) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is diluted with methanol (20 ml), filtered over Celite® and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / triethylamine) followed by crystallization from ethyl acetate / n-heptane to yield 99 mg (23%) of the title com- pound.
1H-NMR (300 MHz, CDCI3); δ = 1.45 (d, J = 7.0 Hz, 3H), 2.91-3.10 (m, 2H), 3.32-3.52 (m, 2H), 3.85 (s, 3H), 3.95 (d, AB, J = 4.8 Hz, 1 H), 4.16 (d, AB, J = 4.7 Hz, 1 H), 4.43 (s, 2H), 5.35-5.48 (m, 1 H), 6.88 (dd, J = 8.9 Hz, 8.9 Hz, 1 H), 6.98-7.09 (m, 2H), 7.10-7.21 (m, 1 H), 7.21-7.31 (m, 2H), 7.39- 7.58 (m, 2H), 7.96 (bs, 1 H), 8.11 (d, J = 8.0 Hz, 1 H). mp.: 236-237 0C
The following compounds are obtained by using the procedure of example 45 analogously.
46. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-methylpropanamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-bromo-2-methylpropanamide; reaction time: 14 days at room temperature; purification by flash chromatography (silica gel, eluting with ethyl acetate / triethylamine 9:1 (v/v)) followed by crystallization from acetonitrile / water; yield: 20%. 1H-NMR (300 MHz,CDCI3); δ = 1.24 (s, 6H), 2.69-2.81 (m, 2H), 3.02-3.61 (m, 4H), 3.75 (s, 3H),
3.85 (s, 2H), 4.32 (s, 2H), 7.00-7.31 (m, 4H), 7.52 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.54 (s, 1 H).
47. Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20), potassium carbonate (4.0 equivalents with respect to example 20) and methyl 2-bromoacetate (1.0 equivalents); purification by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / n-heptane; yield: 64%. 1H-NMR (300 MHz, CDCI3); δ = 3.10 (t, J = 6.0 Hz, 2H), 3.40-3.52 (m, 2H), 3.56 (s, 2H), 3.79 (s, 3H), 3.85 (s, 3H), 4.07 (s, 2H), 4.39 (s, 2H), 6.87 (dd, J = 8.5 Hz, 8.5 Hz, 1 H), 6.92-7.08 (m, 2H), 7.20-7.31 (m, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.46-7.52 (m, 1 H), 7.78 (s, 1 H), 8.09 (d, J = 7.7 Hz, 1 H). MS (MH+ found) = 434.3 48. tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethyl}carbamate
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20), potassium carbonate (4.0 equivalents with respect to example 20) and tert-butyl (2-bromoethyl)carbamate; purification by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether / triethylamine 6:3:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane; yield: 39%.
1H-NMR (300 MHz, CDCI3); δ = 1.44 (s, 9H), 2.77 (t, J = 6.0 Hz, 2H), 2.97 (t, J = 5.9 Hz, 2H), 3.32- 3.51 (m, 4H), 3.85 (s, 3H), 3.92 (s, 2H), 4.40 (s, 2H), 5.13 (bs, 1 H), 6.88 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 6.94-7.09 (m, 2H), 7.20-7.31 (m, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.49 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.81 (s, 1 H), 8.1 1 (d, J = 8.0 Hz, 1 H). mp.: 207-208 0C
49. 2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]-N-methylethanamine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20), potassium carbonate (6.0 equivalents with respect to example 20) and 2-chloro-N-methylethanamine hydrochloride (2.6 equivalents); purification by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether / triethylamine 6:3:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane; yield: 11 %.
1H-NMR (300 MHz, d4-MeOH); δ = 2.75 (bs, 3H), 2.94-3.01 (m, 2H), 3.05-3.12 (m, 2H), 3.50-3.60 (m, 2H), 3.79 (s, 3H), 3.98-4.03 (m, 2H), 4.48 (bs, 2H), 6.92-7.06 (m, 3H), 7.28-7.36 (m, 1 H), 7.57- 7.68 (m, 3H), 8.23 (bd, J = 8.1 Hz, 1 H).
50. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]ethanol
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is dissolved in ethanol (10 ml), sodium carbonate (176 mg) and 2-bromoethanol (59 μl) are added and the mixture is refluxed for 18 h. After that, the mixture is diluted with ethanol (10 ml), filtered over Celite® and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 50 mg (30%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 2.65 (t, J = 6.1 Hz, 2H), 2.81-2.95 (m, 2H), 3.20-3.39 (m, 2H), 3.58-3.70 (m, 2H), 3.70-3.84 (m, 5H), 4.32 (s, 2H), 4.46 (t, J = 5.3 Hz, 1 H), 6.95-7.29 (m, 4H), 7.45- 7.65 (m, 2H), 8.12 (d, J = 7.9 Hz, 1 H), 11.52 (s, 1 H). MS (MH+ found) = 406.2
51. 6-(3-Fluoro-4-methoxybenzyl)-3-(2-methoxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is dissolved in ethanol (10 ml), sodium carbonate (176 mg) and 1-bromo-2-methoxy- ethane (80 μl) are added and the mixture is refluxed for 18 h. After that, the mixture is diluted with ethanol (10 ml), filtered over Celite® and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 85 mg (49%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.74 (t, J = 5.8 Hz, 2H), 2.89 (t, J = 5.8 Hz, 2H), 3.20-3.40 (m, 5H), 3.58 (t, J = 5.8 Hz, 2H), 3.69-4.83 (m, 5H), 4.32 (s, 2H), 6.95-7.1 1 (m, 2H), 7.11-7.25 (m, 2H), 7.45-7.55 (m, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 11.53 (s, 1 H). MS (MH+ found) = 420.2
52. N-Acetyl-2-[6-(3-fluoro-4-methoxybenzyl)-1,2A7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (240 mg) is suspended in acetone (5 ml), diisopropylethyl amine (282 μl) and N-acetyl-2-bromo- acetamide (140 mg) are added and the mixture is stirred for 7 h at room temperature. After that, the mixture is diluted with water (20 ml). The precipitate is filtered, washed (petroleum ether) and dried in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloro- methane, followed by ethyl acetate / triethyl amine 9:1 (v/v)) followed by crystallization from ethyl acetate / n-heptane to obtain 164 mg (54%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.23 (s, 3H), 2.89-3.08 (m, 2H), 3.22-3.41 (m, 2H), 3.51 (s, 2H), 3.75 (s, 3H), 3.86 (s, 2H), 4.33 (s, 2H), 6.98-7.15 (m, 2H), 7.16-7.29 (m, 2H), 7.49-7.59 (m, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 10 42 (s, 1 H), 11.56 (s, 1 H). mp.: 199-200 0C
53. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-hydroxyethyl)acetamide
Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetate (example 47) (840 mg) is dissolved in 2-aminoethanol (15 ml) and the mixture is stirred for 18 h at 1000C. After cooling, the solution is poured into saturated ammonium chloride solution (100 ml). The formed precipitate is filtered and washed thoroughly with water. It is dissolved in methanol and dichloromethane and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 9:1 :1 (v/v/v)) followed by crystallization from ethyl acetate to yield 615 mg (69%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 3.00-3.17 (m, 2H), 3.35 (s, 2H), 3.42-3.59 (m, 5H), 3.70-3.81 (m, 2H), 3.85 (s, 2H), 4.03 (s, 2H), 4.41 (s, 2H), 6.81-6.98 (m, 1 H), 6.99-7.11 (m, 2H), 7.21-7.47 (m, 1 H), 7.38-7.58 (m, 2H), 7.60-7.78 (m, 1 H), 7.79-7.92 (m, 1 H), 8.07-8.19 (m, 1 H). mp.: 206-207 0C 54. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-hydroxypropyl)acetamide
Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetate (example 47) (108 mg) is dissolved in 1-amino-2-propanol (5 ml) and the mixture is stirred for 18 h at 1000C. After cooling, the solution is poured into saturated ammonium chloride solution (20 ml). The aqueous phase is extracted with dichloromethane (3 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate / n- heptane to yield 99 mg (83%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 0.93-1.11 (m, 3H), 2.82-2.98 (m, 2H), 2.98-3.25 (m, 4H), 3.25- 3.46 (m, 2H), 3.60-3.79 (m, 4H), 3.82 (s, 2H), 4.33 (s, 2H), 4.68 (d, J = 4.7 Hz, 1 H), 6.98-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.53 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.74 (dd, J = 5.9 Hz, 5.9 Hz, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 11.56 (s, 1 H). mp.: 166-167 0C
55. 2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]-N-(2-hydroxy-1-methylethyl)acetamide
Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetate (example 47) (108 mg) is dissolved in 2-amino-1-propanol (3.5 ml) and the mixture is stirred for 18 h at 1000C. After cooling, the solution is poured into saturated ammonium chloride solution (20 ml). The aqueous phase is extracted with ethyl acetate (3 x 20 ml), the combined organic extracts are washed with saturated ammonium chloride solution (1 x 40 ml) and saturated sodium chloride solution (1 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / triethylamine 5:1 (v/v)) to give rise to 117 mg (99%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 1.15-1.25 (m, 3H), 2.94-3.10 (m, 2H), 3.32 (s, 2H), 3.38-3.50 (m, 2H), 3.50-3.64 (m, 1 H), 3.65-3.78 (m, 1 H), 3.84 (s, 3H), 4.09 (s, 2H), 4.09-4.20 (m, 1 H), 4.42 (s, 2H), 5.59 (s, 1 H), 6.88 (dd, J = 8.4 Hz, 1 H), 6.98-7.12 (m, 2H), 7.20-7.31 (m, 1 H), 7.34-7.58 (m, 3H), 8.11 (d, J = 8.1 Hz, 1 H), 8.24 (s, 1 H).
56. 2-(Dimethylamino)-1 -[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is suspended in dichloromethane (4 ml) and N,N-dimethylglycine (89 mg), 1-hydroxy- benzotriazole (84 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg) and triethylamine (231 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (amino modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)) followed by crystallization from ethyl acetate / n-heptane to give rise to 132 mg (71 %) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.12-2.30 (m, 6H), 3.14-3.37 (m, 4H), 3.37-3.49 (m, 1 H), 3.76 (s, 3H), 3.72-4.06 (m, 2H), 4.35 (s, 2H), 4.75 (s, 1 H), 6.98-7.16 (m, 2H), 7.16-7.31 (m, 2H), 7.54 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 447.1
The following compounds are obtained by using the procedure of example 56 analogously, with adaptations in the purification step.
57. 6-(3-Fluoro-4-methoxybenzyl)-3-(morpholin-4-ylacetyl)-2,3A7-tetrahydro-1H- indolo[2,3-c][1 ,7]naphthyridine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and morpholin-4-ylacetic acid; purification by flash chromatogra- phy (amino modified silica gel, eluting with ethyl acetate / methanol 95:5 (v/v)) followed by crystallization from ethyl acetate / n-heptane; yield: 36%.
1H-NMR (300 MHz, d6-DMSO); δ = 2.30-2.60 (m, 4H), 3.19-3.50 (m, 6H), 3.51-3.68 (m, 3H), 3.75 (s, 3H), 3.82-4.10 (m, 2H), 4.27-4.43 (m, 2H), 4.75 (s, 1 H), 6.94-7.31 (m, 4H), 7.54 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 8.16 (d, J = 7.9 Hz, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 489.1
58. 3-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N,N-dimethyl-3-oxopropan-1 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N,N-dimethyl- -alanine hydrochloride; purification by flash chromatography (silica gel, eluting with gradient ethyl acetate / triethylamine 9:1 (v/v) to ethyl acetate / methanol / triethylamine 5:5:0.5 (v/v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 37%.
1H-NMR (300 MHz, d6-DMSO); δ = 2.17 (s, 3H), 2.21 (s, 3H), 2.46-2.70 (m, 4H), 3.20-3.49 (m, 2H), 3.76 (s, 3H), 3.85-3.96 (m, 2H), 4.30-4.40 (m, 2H), 4.76, 4.81 (2s, 2H [rotamers]), 6.95-7.13 (m, 2H), 7.13-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 461.2
59. N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}methanesulfonamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N-(methylsulfonyl)glycine; purification by filtration through plug (silica gel, eluting with dichloromethane / methanol 7:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 58%.
1H-NMR (300 MHz, d6-DMSO); δ = 2.96 (s, 3H), 3.10-3.50 (m, 2H), 3.76 (s, 3H), 3.80-4.00 (m, 2H), 4.01-4.19 (m, 2H), 4.35 (s, 2H), 4.79 (s, 2H), 6.99-7.18 (m, 3H), 7.18-7.30 (m, 2H), 7.54 (t, J = 7.6 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 8.08-8.22 (m, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 489.1
60. N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}acetamide Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N-acetylglycine; purification by filtration through plug (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 49%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.80-1.93 (m, 3H), 3.21-3.50 (m, 2H), 3.76 (s, 3H), 3.81-4.00 (m, 2H), 4.00-4.20 (m, 2H), 4.35 (s, 2H), 4.77 (s, 2H), 6.97-7.18 (m, 2H), 7.18-7.31 (m, 2H), 7.54
(dd, J = 7.7 Hz, 7.7 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 7.92-8.09 (m, 1 H), 8.09-8.22 (m, 1 H), 11.64
(s, 1 H).
MS (MH+ found) = 461.0
61. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-oxoethanol
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and glycol acid; purification by filtration through plug (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 51 %.
1H-NMR (300 MHz, d6-DMSO); δ = 3.17-3.50 (m, 2H), 3.68-4.00 (m, 5H), 4.16-4.41 (m, 4H), 4.52-
4.88 (m, 3H), 6.96-7.16 (m, 2H), 7.16-7.31 (m, 2H), 7.47-7.70 (m, 2H), 8.07-8.21 (m, 1 H), 11.65 (s,
1 H).
MS (MH+ found) = 420.1
62. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1 -oxopropan-2-ol
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-hydroxypropanoic acid; purification by filtration through plug (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 39%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.10-1.36 (m, 3H), 3.20-3.51 (m, 2H), 3.76 (s, 3H), 3.80-4.09 (m, 2H), 4.35 (s, 2H), 4.48-4.69 (m, 1 H), 4.69-5.10 (m, 3H), 6.96-7.18 (m, 2H), 7.18-7.31 (m, 2H), 7.54 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.06-8.22 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 434.1
63. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1 -oxobutan-2-ol Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 2-hydroxybutanoic acid; purification by column chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 4:1 (v/v) to ethyl acetate); yield: 79%.
1H-NMR (300 MHz, CDCI3); 5 = 0.79-0.92, 0.99-1.11 (2m, 3H [rotamers]), 1.49-1.68 (m, 1 H), 1.70- 1.91 (m, 1 H), 3.37-3.52 (m, 2H), 3.71-3.82 (m, 1 H), 3.85 (s, 3H), 3.88-4.01 (m, 1 H), 4.24-4.37 (m, 1 H), 4.41 (s, 2H), 4.47-4.58 (m, 1 H), 4.75-4.92, 5.01-5.10 (2m, 2H [rotamers]), 6.90 (dd, J = 8.4 Hz, 8.6 Hz, 1 H), 6.95-7.07 (m, 2H), 7.22-7.32 (m, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.52 (dd, J = 7.4 Hz, 7.6 Hz, 1 H), 7.87 (bs, 1 H), 8.03-8.13 (m, 1 H).
64. tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}carbamate
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N-(tert-butoxycarbonyl)glycine; purification as described in example XX; yield: 67%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.38 (s, 9H), 3.38-3.50 (m, 2H), 3.76 (s, 3H), 3.70-4.08 (m, 4H), 4.35 (s, 2H), 4.76 (s, 2H), 6.68-6.88 (m, 1 H), 6.96-7.33 (m, 4H), 7.48-7.69 (m, 2H), 8.08-8.22 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 518.9 mp.: 186-188 0C
65. tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}methylcarbamate
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N-(tert-butoxycarbonyl)-N-methylglycine; purification by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / n-heptane; yield: 66%.
1H-NMR (300 MHz, CDCI3 + CD3OD); δ = 1.39, 1.48 (2s, 9H [rotamers]), 2.96 (s, 3H), 3.20-3.52 (m, 2H), 3.83 (s, 3H), 3.83-4.1 1 (m, 2H), 4.12-4.32 (m, 2H), 4.39 (s, 2H), 4.80, 4.98 (2s, 2H [rotamers]), 6.87 (dd, J = 8.6 Hz, 1 H), 6.95-7.11 (m, 2H), 7.18-7.36 (m, 1 H), 7.47-7.59 (m, 2H), 7.92-8.19 (m, 1 H). mp.: 183-184 0C
66. tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-1 -methyl-2-oxoethyl}carbamate Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and rac-N-(tert-butoxycarbonyl)alanine; purification by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether 4:1 ) followed by crystallization from ethyl acetate / n-heptane; yield: 65%. 1H-NMR (300 MHz, CDCI3); δ = 1.37 (d, J = 6.9 Hz, 3H), 1.42, 1.44 (2s, 9H [rotamers]), 2.90-3.05, 3.16-3.30 (2m, 1 H [rotamers]), 3.33, 3.43 (m, 1 H), 3.58-3.73, 3.82-4.05 (2m, 1 H [rotamers]), 3.84 (s, 3H), 4.27-4.44 (m, 3H), 4.74-5.22 (m, 3H), 5.54-5.66 (m, 1 H), 6.88 (dd, J = 8.4 Hz, 8.6 Hz, 1 H), 7.00 (s, 1 H), 7.04 (bs, 1 H), 7.19-7.30 (m, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.43-7.56 (m, 1 H), 7.91- 8.00 (m, 1 H), 8.03, 8.34 (2s, 1 H [rotamers]). mp.: 216-217 0C
67. tert-Butyl (1 -{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1>7]naphthyridin-3-yl]carbonyl}propyl)carbamate
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and rac-2-[(tert-butoxycarbonyl)amino]butanoic acid; purification by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / n-heptane; yield: 68%.
1H-NMR (300 MHz, d6-DMSO); δ = 0.75-0.97 (m, 3H), 1.25, 1.34, 1.37 (3s, 9H [rotamers]), 1.41-
1.78 (m, 2H), 3.30-3.45 (m, 2H), 3.75 (s, 3H), 3.85-4.08 (m, 2H), 4.31-4.52 (m, 1 H), 4.35 (s, 2H), 4.59-4.92 (m, 2H), 6.95-7.12 (m, 2H), 7.15-7.30 (m, 2H), 7.54 (dd, J = 7.3 Hz, 7.5 Hz, 1 H), 7.62 (d,
J = 8.2 Hz, 1 H), 8.08-8.20 (m, 1 H), 11.64 (s, 1 H). mp.: 170-171 0C
68. 1 -{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}pyrrolidine-2,5-dione
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and (2,5-dioxopyrrolidin-1-yl)acetic acid; purification by flash chromatography (silica gel, eluting with ethyl acetate / methanol 10:1 (v/v)) followed by crystallization from diethyl ether; yield: 40%. 1H-NMR (400 MHz, d6-DMSO); δ = 2.72 (s, 4H), 3.20-3.39, 3.41-3.52 (2m, 2H [rotamers]), 3.74 (s, 3H), 3.75-3.97, 3.97-4.05 (2m, 2H [rotamers]), 4.31-4.40 (m, 2H), 4.42, 4.48 (2s, 2H [rotamers]), 4.77, 4.90 (2s, 2H [rotamers]), 6.98-7.18 (m, 2H), 7.18-7.31 (m, 2H), 7.49-7.61 (m, 1 H), 7.61-7.69 (m, 1 H), 8.11-8.20 (m, 1 H), 11.67 (bs, 1 H).
69. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N,N-dimethyl-1-oxopropan-2 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N,N-dimethylalanine; purification by flash chromatography (silica gel, eluting with ethyl acetate / triethylamine 9:1 (v/v)) followed by crystallization from ethyl acetate / n-heptane; yield: 62%.
1H-NMR (300 MHz, CDCI3); δ = 1.17-1.30 (m, 3H), 2.27, 2.32 (2s, 6H [rotamers]), 3.36-3.51 (m, 2H), 3.59-3.70 (m, 1 H), 3.85 (s, 3H), 3.91-4.28 (m, 2H), 4.42 (s, 2H), 4.85-5.25 (m, 2H), 6.89 (dd, J = 8.4 Hz, 8.5 Hz, 1 H), 6.95-7.09 (m, 2H), 7.20-7.31 (m, 1 H), 7.39-7.55 (m, 2H), 7.85-7.96 (m, 1 H), 8.06-8.17 (m, 1 H). mp.: 253-255 0C
70. 1 -{[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]carbonyl}cyclopropanecarboxamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and 1-carbamoylcyclopropanecarboxylic acid; purification by flash chromatography (silica gel, eluting with ethyl acetate / methanol 96:4 (v/v)) followed by crystallization from ethyl acetate; yield: 14%. 1H-NMR (400 MHz, d6-DMSO); δ = 0.98-1.30 (m, 4H), 3.25-3.50 (m, 2H), 3.74 (s, 3H), 3.88-3.99
(m, 2H), 4.34 (s, 2H), 4.77 (s, 2H), 7.00-7.29 (m, 6H), 7.52 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.60 (d, J =
8.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.60 (s, 1 H).
MS (MH+ found) = 473.1
71. 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is suspended in dichloromethane (3 ml), 4-(dimethylamino)pyridine (10 mg) and triethylamine (116 μl) are added and the mixture is cooled to O0C (ice bath). Acetanhydride (59 μl) is added drop by drop. The mixture is stirred for 20 min at room temperature. After that, it is diluted with dichloromethane (10 ml), saturated ammonium chloride solution (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / triethylamine 9:1 (v/v)) followed by crystallization from ethyl ace- tate / n-heptane to yield 93 mg (55%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.20-3.48 (m, 2H), 3.76 (s, 3H), 4.32-4.42 (m, 2H), 4.30-4.40 (m, 2H), 4.75, 4.78 (2s, 2H [rotamers]), 6.99-7.30 (m, 4H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H). mp.: 211-213 0C
72. Ethyl 3-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-3-oxopropanoate
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (1.08 g) is suspended in dichloromethane (25 ml) and 3-ethoxy-3-oxopropanoic acid (790 mg), 1- hydroxybenzotriazole (610 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g) and triethylamine (2.09 ml) are added. The mixture is stirred for 18 h at room temperature. After that, saturated sodium hydrogencarbonate solution (25 ml) is added, the mixture is filtered over Celite® and washed with dichloromethane (100 ml). The organic phase of the combined filtrate is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / triethylamine 9:1 (v/v)) followed by crystallization from ethyl acetate / n- heptane to obtain 587 mg (41 %) of the title compound.
1H-NMR (300 MHz, CDCI3); δ = 1.12-1.40 (m, 3H), 3.36-3.55 (m, 2H), 3.64, 3.65 (2s, 2H [rota- mers]), 3.85 (s, 3H), 3.92 (t, J = 6.0 Hz, 1 H [rotamer]), 4.02-4.32 (m, 2H + 1 H [rotamer]), 4.40 (s, 2H), 4.88, 5.06 (2s, 2H [rotamers]), 6.81-6.94 (m, 1 H), 6.94-7.09 (m, 2H), 7.20-7.33 (m, 1 H), 7.39- 7.59 (m, 2H), 7.85-8.00 (m, 1 H), 8.00-8.15 (m, 1 H).
73. 3-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-3-oxopropanoic acid Ethyl 3-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3- oxopropanoate (example 72) (500 mg) is suspended in dioxane (12 ml) and water (1 ml) and lithium hydroxide (500 mg) is added. The mixture is stirred for 2 h at 8O0C. After cooling, it is diluted with water (20 ml) and pH is adjusted to 4.5 - 5 by addition of 6M hydrochloric acid. The formed precipitate is filtered and washed with water. It is redissolved in 3M sodium hydroxide solution (50 ml), extracted with ethyl acetate (2 x 50 ml). The aqueous phase is diluted with dioxane (10 ml) and acidified to pH 4.5 - 5 with 6M hydrochloric acid. The precipitate is filtered, washed with water and dried in vacuo to yield 179 mg (38%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.10-2.22 (m, 2H), 3.35-3.55 (m, 2H), 3.76 (s, 3H), 3.74-4.00 (m, 2H), 4.38-4.59 (m, 2H), 4.79-5.00 (m, 2H), 6.99-7.40 (m, 4H), 7.55-7.79 (m, 2H), 8.14-8.30 (m, 1 H), 12.10 (bs, 1 H). mp.: >185 °C (dec.)
74. 3-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-3-oxopropanamide S-^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-ylj-S- oxopropanoic acid (example 73) (65 mg) is suspended in dichloromethane (2 ml) and ammonium chloride (16 mg), 1 -hydroxybenzotriazole (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg) and triethylamine (104 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (5 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane / triethylamine 9:1 (v/v) to dichloromethane / methanol / triethylamine 9:0.5:0.5 (v/v/v)) to yield 35 mg (52%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 3.02-3.15 (m, 2H), 3.35-3.47 (m, 2H), 3.75 (s, 3H), 3.86-3.97 (m, 2H), 4.35 (s, 2H), 4.77, 4.80 (2s, 2H [rotamers]), 6.91-7.14 (m, 3H), 7.17-7.29 (m, 2H), 7.44- 7.58 (m, 2H), 7.62 (d, J = 8.1 Hz, 1 H), 8.14 (dd, J = 7.9 Hz, 13.5 Hz, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 447.2
75. 3-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N -methyl -3-oxopropanamide
S-^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S- oxopropanoic acid (example 73) (65 mg) is suspended in dichloromethane (2 ml) and methylamine (2M in tetrahydrofuran, 150 μl), 1-hydroxybenzotriazole (30 mg), 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (58 mg) and triethylamine (104 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (5 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatogra- phy (silica gel, eluting with dichloromethane / triethylamine 9:1 (v/v)) to yield 20 mg (29%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.56, 2.60 (2d, J = 4.6 Hz, 3H [rotamers]), 3.01-3.14 (m, 2H), 3.32-3.46 (m, 2H), 3.75 (s, 3H), 3.87-3.98 (m, 2H), 4.36 (bs, 2H), 4.78, 4.81 (2bs, 2H [rotamers]), 7.00-7.30 (m, 4H), 7.49-7.60 (m, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 7.89-8.02 (m, 1 H), 8.10-8.20 (m, 1 H), 11.67 (bs, 1 H).
MS (MH+ found) = 461.2
76. (2S)-1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-1 -oxopropan-2-amine Step 1 : tert-Butyl {(1S)-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-1-methyl-2-oxoethyl}methylcarbamate. 6-(3-Fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (360 mg) is suspended in dichloromethane (12 ml) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (406 mg), 1-hydroxybenzotriazole (202 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (385 mg) and triethylamine (696 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (20 ml) and dichloromethane (20 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :1 to 7:3 (v/v)) to give rise to 419 mg of tert-butyl {(1S)-2-[6-(3- fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-methyl-2- oxoethyl}methylcarbamate.
Step 2: (2S)-1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1-oxopropan-2-amine. tert-Butyl {(IS^-te-^-fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-
Figure imgf000130_0001
(419 mg) is dissolved in dioxane (7 ml) and concentrated hydrochloric acid (0.5 ml) is added. The mixture is stirred for 1 h at room temperature. After that, it is neutralized by addition of saturated sodium hydrogencarbo- nate solution, extracted with dichloromethane (3 x 30 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (sil- ica gel, eluting with gradient ethyl acetate / methanol 1 :1 (v/v)) to yield 256 mg (57%, 2 steps) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 0.99-1.25 (m, 4H), 2.09-2.23 (m, 3H), 3.20-3.45 (m, 2H), 3.61- 3.77 (m, 1 H), 3.76 (s, 3H), 3.90-4.08 (m, 2H), 4.36 (s, 2H), 4.68-4.99 (m, 2H), 6.99-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.54 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.65 (s, 1 H).
Enantiomeric excess: 98.7% ee (determined by HPLC using Chiralpak AD-H, 250x4.6 mm, 5 μm column as stationary phase and n-heptane / ethanol 8:2 (v/v) + 0.1 % diethylamine as mobile phase at 3O0C)
The following compound is obtained by using the procedure of example 76 analogously.
77. (2R)-1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-1 -oxopropan-2-amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and N-(tert-butoxycarbonyl)-N-methyl-D-alanine; yield: 71 % (2 steps).
1H-NMR (300 MHz, CDCI3); δ = 1.20-1.40 (m, 4H), 2.30-2.40 (m, 3H), 3.37-3.52 (m, 2H), 3.62-3.72 (m, 1 H), 3.85 (s, 3H), 4.05-4.20 (m, 2H), 4.42 (s, 2H), 4.82-5.02, 5.14-5.27 (2m, 2H [rotamers]), 6.89 (dd, J = 8.3 Hz, 8.4 Hz, 1 H), 6.95-7.05 (m, 2H), 7.21-7.31 (m, 1 H), 7.49-7.56 (m, 2H), 7.90- 8.00 (m, 1 H), 8.10 (d, J = 7.9 Hz, 1 H).
Enantiomeric excess: 99.8% ee (determined by HPLC using Chiralpak AD-H, 250x4.6 mm, 5 μm column as stationary phase and n-heptane / ethanol 8:2 (v/v) + 0.1 % diethylamine as mobile phase at 3O0C)
78. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-oxoethanamine tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]-2-oxoethyl}carbamate (example 64) (100 mg) is suspended in dioxane (5 ml) and concentrated hydrochloric acid (160 μl) is added. The mixture is stirred for 5 h at 550C. After cooling, it is basified by addition saturated sodium hydrogencarbonate solution, extracted with dichloromethane (3 x
20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue is crystallized from ethyl acetate / n-heptane to yield 62 mg (77%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.64 (bs, 2H), 3.15-3.65 (m, 4H), 3.65-4.06 (m, 5H), 4.35 (s, 2H), 4.13-4.39 (m, 2H), 6.94-7.33 (m, 4H), 7.46-7.71 (m, 2H), 8.05-8.25 (m, 1 H), 11.64 (bs, 1 H). MS (MH+ found) = 419.1 mp.: 183-186 0C
The following compounds are obtained by using the procedure of example 78 analogously.
79. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-methyl-2-oxoethanamine
Starting compound: tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}methylcarbamate (example 65); yield: 76%. 1H-NMR (300 MHz, d6-DMSO); δ = 2.21-2.39 (m, 3H), 3.10-3.56 (m, 5H), 3.76 (s, 3H), 3.80-3.99 (m, 2H), 4.35 (s, 2H), 4.78 (s, 2H), 6.99-7.18 (m, 2H), 7.18-7.30 (m, 2H), 7.54 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.08-8.21 (m, 1 H), 11.64 (s, 1 H). mp.: >206 0C (dec.)
80. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1 -oxopropan-2-amine
Starting compound: tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-1-methyl-2-oxoethyl}carbamate (example 66); yield: 72%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.00-1.23 (m, 3H), 1.73 (bs, 2H), 3.20-3.52 (m, 2H), 3.76 (s, 3H), 3.81-4.07 (m, 3H), 4.35 (s, 2H), 4.62-4.96 (m, 2H), 6.97-7.16 (m, 2H), 7.16-7.30 (m, 2H), 7.54 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.07-8.20 (m, 1 H), 11.64 (s, 1 H).
81. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-1 -oxobutan-2-amine Starting compound: tert-Butyl (1-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- clli Jlnaphthyridin-S-yljcarbonylJpropy^carbamate (example 67); yield: 74%. 1H-NMR (300 MHz, CDCI3); δ = 0.90-1.14 (m, 3H), 1.48-1.83 (m, 2H), 3.28-3.47 (m, 2H), 3.85 (s, 3H), 3.77-3.89, 3.89-4.05 (2m, 2H [rotamers]), 4.15-4.30 (m, 1 H), 4.40 (s, 2H), 4.80-5.05 (m, 2H), 6.81-6.92 (m, 1 H), 6.92-7.08 (m, 2H), 7.20-7.31 (m, 1 H), 7.40-7.58 (m, 2H), 8.00-7.21 (m, 2H). MS (MH+ found) = 447.2 mp.: 1 18-12O 0C 82. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]ethanamine
Starting compound: tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethyl}carbamate (example 48); yield: 77%.
1H-NMR (300 MHz, CDCI3); δ = 1.56 (s, 2H), 2.74 (t, J = 6.1 Hz, 2H), 2.90-3.09 (m, 4H), 3.45 (t, J = 5.9 Hz, 2H), 3.85 (s, 3H), 3.93 (s, 2H), 4.40 (s, 2H), 6.81-6.93 (m, 1 H), 6.93-7.09 (m, 2H), 7.20- 7.31 (m, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.48 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.79 (s, 1 H), 8.11 (d, J = 8.0 Hz, 1 H). mp.: 145-146 0C
83. N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethyl}acetamide
2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanamine (example 82) (60 mg) is dissolved in dichloromethane (3 ml), A- dimethylaminopyridine (10 mg) and acetanhydride (16 μl) are added and the mixture is stirred at room temperature for 1 h. The suspension is diluted with dichloromethane (10 ml), then poured into saturated ammonium chloride solution (10 ml). The precipitate is filtered, redissolved in dichloromethane / methanol (1 :1 (v/v), ca. 10 ml) and combined with the organic phase of the filtrate. Addi- tional dichloromethane is added (20 ml), the organic phase is washed with saturated ammonium chloride solution (1 x 20 ml), dried (MgSO4) and concentrated in vacuo. The residue is crystallized from dichloromethane to yield 50 mg (75%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.80 (s, 3H), 2.61 (t, J = 6.6 Hz, 2H), 2.79-2.93 (m, 2H), 3.22- 3.40 (m, 4H), 3.69-3.81 (m, 5H), 4.32 (s, 2H), 6.95-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.52 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.75-7.81 (m, 1 H), 8.12 (d, J = 7.9 Hz, 1 H), 1 1.54 (s, 1 H). mp.: >239 0C (dec.)
84. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N,N-dimethylethanamine
2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanamine (example 82) (101 mg) is dissolved in methanol (4 ml) and formaldehyde (37% in water, 75 μl) is added. Sodium borohydride (95 mg) is added in portions. The mixture is stirred for 90 min at room temperature. After that, saturated ammonium chloride solution (10 ml) and di- chloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to give rise to 59 mg (55%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 2.42 (s, 6H), 2.70-2.81 (m, 2H), 2.81-2.93 (m, 2H), 3.01 (t, J = 6.0 Hz, 2H), 3.40-3.51 (m, 2H), 3.85 (s, 3H), 3.97 (s, 2H), 4.39 (s, 2H), 6.87 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 6.92-7.08 (m, 2H), 7.19-7.31 (m, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.48 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.44 (s, 1 H), 8.10 (d, J = 7.7 Hz, 1 H).
85. 3-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]propanamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is dissolved in acetonitrile (1.5 ml) and water (1.5 ml), acrylamide (33 mg) and copper-(ll)- acetate (10 mg) are added and the mixture is stirred for 18 h at room temperature. After that, it is diluted with dichloromethane (10 ml), water (10 ml) is added and the mixture is vigorously stirred. The organic phase is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 28 mg (15%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.37 (t, J = 7.0 Hz, 2H), 2.64-2.94 (m, 4H), 3.20-3.40 (m, 2H), 3.66-3.81 (m, 5H), 4.32 (s, 2H), 6.74 (bs, 1 H), 6.98-7.14 (m, 2H), 7.14-7.29 (m, 2H), 7.38 (s, 1 H), 7.48-7.69 (m, 2H), 8.11 (d, J = 7.9 Hz, 1 H), 11.54 (s, 1 H). MS (MH+ found) = 433.0
86. 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1 ,7]naphthyridine
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (3.24 g) is suspended in dichloromethane (45 ml), 4-(dimethylamino)pyridine (219 mg) and triethyl- amine (2.5 ml) is added and the mixture is cooled to O0C (ice bath). Bromoacetyl bromide (1.18 ml) is added drop by drop within 5 min, the mixture is stirred for 30 min at room temperature. After that, it is diluted with water (25 ml) and saturated sodium hydrogencarbonate solution (25 ml), the aqueous phase is extracted with dichloromethane (3 x 50 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 7:3 (v/v)) to yield 1.91 g (44%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 3.40-3.50, 3.50-3.60 (2m, 2H [rotamers]), 3.85 (s, 3H), 3.90-4.19 (m, 4H), 4.37-4.47 (m, 2H), 4.96, 5.03 (2s, 2H [rotamers]), 6.81-6.92 (m, 1 H), 6.92-7.08 (m, 2H), 7.21-7.82 (m, 1 H), 7.40-7.54 (m, 2H), 7.95 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 482.2, 484.3 87. N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethanamine
3-(Bronnoacetyl)-6-(3-fluoro-4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 86) (100 mg) is dissolved in dimethylformannide (0.5 ml), triethylamine (462 μl) and ethyl- amine (2M in tetrahydrofuran, 310 μl) are added and the mixture is stirred for 18 h at room temperature. After that, water (3 ml) and ethyl acetate (5 ml) are added, the aqueous phase is extracted with ethyl acetate (2 x 2 ml), the combined organic extracts are concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 65 mg (69%) of the title compound.
1H-NMR (300 MHz, CDCI3); δ = 1.08-1.20 (m, 3H), 2.62-2.78 (m, 2H), 3.37-3.48 (m, 2H), 3.58-3.66 (m, 2H), 3.85 (s, 3H), 3.80-3.91 , 4.01-4.14 (2m, 2H [rotamers]), 4.41 (s, 2H), 4.84, 5.04 (2s, 2H [rotamers]), 6.81-6.92 (m, 1 H), 6.92-7.05 (m, 2H), 7.20-7.30 (m, 1 H), 7.40-7.55 (m, 2H), 8.00-8.14 (m, 2H). MS (MH+ found) 447.3
The following compounds are obtained by using the procedure of example 87 analogously.
88. 2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}amino)ethanol
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and 2-aminoethanol; yield: 52%. 1H-NMR (300 MHz, d6-DMSO); δ = 2.65 (t, J = 5.7 Hz, 2H), 3.25-3.50 (m, 5H), 3.58-3.68 (m, 2H), 3.76 (s, 3H), 3.80-4.00 (m, 2H), 4.35 (s, 2H), 4.51 (bs, 1 H), 4.70-4.81 (m, 2H), 6.99-7.15 (m, 2H), 7.15-7.30 (m, 2H), 7.48-7.58 (m, 1 H), 7.58-7.67 (m, 1 H), 8.09-8.20 (m, 1 H), 11.65 (bs, 1 H). MS (MH+ found) 463.2
89. N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}cyclopropanamine Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and cyclopropanamine; yield: 45%. 1H-NMR (300 MHz, CDCI3); δ = 2.19-2.32 (m, 1 H), 3.38-3.51 (m, 2H), 3.68 (s, 2H), 3.86 (s, 3H), 3.81-3.95, 4.05-4.17 (2m, 2H [rotamers]), 4.42 (s, 2H), 4.86, 5.06 (2s, 2H [rotamers]), 6.83-6.95 (m, 1 H), 6.95-7.09 (m, 2H), 7.20-7.32 (m, 1 H), 7.40-7.59 (m, 2H), 7.89 (bs, 1 H), 8.11 (d, J = 8.1 Hz, 1 H). 90. N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1,2A7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]-2-oxoethanamine
Starting compounds: 3-(Bronnoacetyl)-6-(3-fluoro-4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and 1-cyclopropylmethanamine; yield: 45%.
1H-NMR (300 MHz, CDCI3); δ = 0.10-0.20 (m, 2H), 0.41-0.55 (m, 2H), 0.90-1.02 (m, 1 H), 2.44-2.60 (m, 2H), 3.35-3.48 (m, 2H), 3.59-3.70 (m, 2H), 3.85 (s, 3H), 3.80-3.90, 4.03-4.13 (2m, 2H [rotamers]), 4.41 (s, 2H), 4.84, 5.04 (2s, 2H [rotamers]), 6.82-6.94 (m, 1 H), 6.94-7.08 (m, 2H), 7.21- 7.32 (m, 1 H), 7.39-7.58 (m, 2H), 8.00 (bs, 1 H), 8.10 (d, J = 8.1 Hz, 1 H).
91. N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}propan-1 -amine
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and propan-1 -amine; yield: 50%.
1H-NMR (300 MHz, CDCI3); δ = 0.87-1.02 (m, 3H), 1.45-1.61 (m, 2H), 2.57-2.70 (m, 2H), 3.35-3.48 (m, 2H), 3.57-3.67 (m, 2H), 3.85 (s, 3H), 3.82-3.91 , 4.05-4.15 (2m, 2H [rotamers]), 4.41 (s, 2H), 4.84, 5.05 (2s, 2H [rotamers]), 6.82-6.95 (m, 1 H), 6.95-7.08 (m, 2H), 7.21-7.31 (m, 1 H), 7.40-7.55 (m, 2H), 7.95-8.13 (m, 2H).
92. N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-methyl-2-oxoethanamine
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and N-methylethanamine; yield: 20%. 1H-NMR (300 MHz, d6-DMSO); δ = 0.92, 1.02 (2t, J = 7.1 Hz, 3H [rotamers]), 2.14, 2.20 (2s, 2H [rotamers]), 2.32-2.55 (m, 2H), 3.20-3.50 (m, 4H), 3.75 (s, 3H), 3.85-3.94, 3.94-4.05 (2m, 2H [rotamers]), 4.35 (s, 2H), 4.75, 4.93 (2s, 2H [rotamers]), 6.99-7.30 (m, 4H), 7.48-7.58 (m, 1 H), 7.58- 7.66 (m, 1 H), 8.15 (d, J = 7.9 Hz, 1 H), 11.62 (s, 1 H). MS (MH+ found) 461.1
93. 2-[{2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}(methyl)amino]ethanol
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and 2-(methylamino)ethanol; yield: 17%. 1H-NMR (300 MHz, CDCI3); δ = 2.25, 2.47 (2s, 3H [rotamers]), 2.60-2.70, 2.70-2.80 (2m, 2H
[rotamers]), 3.39-3.72 (m, 6H), 3.85 (s, 3H), 3.90-4.02, 4.02-4.15 (2m, 2H [rotamers]), 4.41 (s, 2H), 4.96, 5.03 (2s, 2H [rotamers]), 6.83-6.95 (m, 1 H), 6.95-7.09 (m, 2H), 7.20-7.32 (m, 1 H), 7.38-7.57 (m, 2H), 7.91 (bs, 1 H), 8.10 (d, J = 7.9 Hz, 1 H). MS (MH+ found) = 477.1 94. rac-2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}amino)propan-1 -ol
Starting compounds: 3-(Bronnoacetyl)-6-(3-fluoro-4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and rac-2-aminopropan-i-ol; yield: 14%.
1H-NMR (300 MHz, CDCI3); δ = 1.08-1.20 (m, 3H), 2.77-2.91 (m, 1 H), 3.30-3.51 (m, 3H), 3.52-3.65 (m, 1 H), 3.65-3.78 (m, 2H), 3.86 (s, 3H), 3.82-3.90, 4.04-4.14 (2m, 2H [rotamers]), 4.41 (s, 2H), 4.84, 5.06 (2s, 2H [rotamers]), 6.84-6.96 (m, 1 H), 6.96-7.09 (m, 2H), 7.21-7.32 (m, 1 H), 7.40-7.48 (m, 1 H), 7.48-7.57 (m, 1 H), 7.85 (bs, 1 H), 8.02-8.17 (m, 1 H). MS (MH+ found) = 477.1
95. 1 -{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}azetidin-3-ol Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and azetidin-3-ol hydrochloride; yield: 3%. MS (MH+ found) = 475.1
96. 1 -{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}azetidine-3-carboxamide
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and azetidine-3-carboxamide hydrochloride; yield: 2%. MS (MH+ found) = 502.1
97. 6-(3-Fluoro-4-methoxybenzyl)-3-(pyrrolidin-1 -ylacetyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and pyrrolidine; yield: 12%. MS (MH+ found) 473.1
98. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-methoxyethyl)-2-oxoethanamine
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and 2-methoxyethanamine; yield: 12%. MS (MH+ found) 477.1
99. 2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-oxoethyl}amino)acetamide
Starting compounds: 3-(Bromoacetyl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 86) and glycinamide hydrochloride; yield: 4%. 1H-NMR (300 MHz, d6-DMSO); δ = 3.12 (s, 2H), 3.19-3.45 (m, 2H), 3.50-3.60 (m, 2H), 3.76 (s, 3H), 3.80-3.99 (m, 2H), 4.35 (s, 2H), 4.73, 4.78 (2s, 2H [rotamers]), 6.92-7.15 (m, 3H), 7.15-7.38 (m, 3H), 7.54 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.08-8.20 (m, 1 H), 11.64 (bs, 1 H). MS (MH+ found) 467.1
100. i-te^S-Fluoro^-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-
3-yl]-2-(2-hydroxyethoxy)ethanone
Step 1 : 3-{[2-(Benzyloxy)ethoxy]acetyl}-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) (200 mg) is suspended in dichloromethane (6 ml) and [2-
(benzyloxy)ethoxy]acetic acid (example A10) (231 mg), 1-hydroxybenzotriazole (111 mg), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (210 mg) and triethylamine (354 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether / triethylamine 5:5:1 (v/v/v)) to yield 260 mg (87%) of 3-{[2-(benzyloxy)ethoxy]acetyl}-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine as a colorless oil. 1H-NMR (300 MHz, d6-DMSO); δ = 3.30-3.41 , 3.49-3.60 (2m, 2H [rotamers]), 3.57-3.70 (m, 4H), 3.75 (s, 3H), 3.80-3.94 (m, 2H), 4.27-4.38 (m, 4H), 4.43, 4.50 (2s, 2H [rotamers]), 4.72-4.81 (m, 2H), 6.97-7.14 (m, 2H), 7.16-7.37 (m, 7H), 7.54 (dd, J = 7.8 Hz, 8.0 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.03, 8.16 (2d, J = 8.0 Hz, 1 H [rotamers]), 11.63 (s, 1 H). MS (MH+ found) = 554.3 Step 2: 2-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]-2-oxoethoxy}ethanol. 3-{[2-(Benzyloxy)ethoxy]acetyl}-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (250 mg) is dissolved in methanol (5 ml) under nitrogen atmosphere, ammonium formiate (117 mg) and palladium (10% on charcoal, 60 mg) are added and the mixture is stirred for 5 h at 8O0C. Ammonium formiate sublimes during heating, fresh portions (50 mg each) are added three times during the heating period. After cooling, the mixture is filtered through a short pad of Celite® , the pad is washed with methanol and dichloromethane. The combined filtrate is concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 31 mg (15%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 3.25-3.37, 3.40-3.49 (2m, 2H [rotamers]), 3.49-3.58 (m, 4H), 3.76 (s, 3H), 3.82-3.95 (m, 2H), 4.29-4.40 (m, 4H), 4.62-4.71 (m, 1 H), 4.76 (s, 2H), 7.00-7.15 (m, 2H), 7.17-7.39 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 464.2 101. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-3-hydroxypropan-1 -one
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (181 mg) is suspended in dichloromethane (5 ml) and 3-hydroxypropionic acid (30% in water, 300 μl), 1-hydroxybenzotriazole hydrate (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg), triethylamine (347 μl) and 4A molecular sieves (300 mg) are added. The mixture is stirred for 18 h at room temperature. After that, the mixture is filtered, the molecular sieves are washed with dichloromethane (15 ml). The combined filtrate is washed with water (15 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chro- matography (silica gel, eluting with dichloromethane / methanol 20:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 82 mg (38%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 2.68-2.78 (m, 2H), 3.39-3.50 (m, 2H), 3.85 (s, 3H), 3.88-4.00 (m, 2H + 2H [rotamers]), 4.09 (t, J = 6.0 Hz, 2H [rotamers]), 4.41 (s, 2H), 4.88, 5.06 (2s, 2H [rotamers]), 6.81-6.92 (m, 1 H), 6.97-7.05 (m, 2H), 7.21-7.31 (m, 1 H), 7.39-7.46 (m, 1 H), 7.46-7.55 (m, 1 H), 7.91-8.00 (m, 1 H), 8.02-8.12 (m, 1 H). MS (MH+ found) = 434.2
102. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1 -one 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (181 mg) is suspended in dichloromethane (5 ml) and rac-3-hydroxybutanoic acid (104 mg), 1- hydroxybenzotriazole hydrate (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg) and triethylamine (347 μl) are added. The mixture is stirred for 18 h at room temperature. After that, dichloromethane (15 ml) and water (15 ml) are added, the organic phase is dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 20:1 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 108 mg (48%) of the title compound. 1H-NMR (300 MHz, CDCI3); δ = 1.20-1.31 (m, 3H), 2.41-2.58 (m, 1 H), 2.61-2.69, 2.69-2.71 (2m, 1 H [rotamers]), 3.38-3.51 (m, 2H), 3.84, 3.85 (2s, 3H [rotamers]), 3.87-3.95, 4.02-4.18 (2m, 2H [rotamers]), 4.20-4.38 (m, 2H), 4.42 (s, 2H), 4.88, 5.05 (2s, 2H [rotamers]), 6.82-6.92 (m, 1 H), 6.92- 7.08 (m, 2H), 7.21-7.32 (m, 1 H), 7.40-7.58 (m, 2H), 7.98-8.15 (m, 2H). MS (MH+ found) = 448.2
103. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1 -one
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (181 mg) is suspended in dichloromethane (5 ml) and rac-2,3-dihydroxypropanoic acid (5.2 M in water, 192 μl), 1-hydroxybenzotriazole hydrate (230 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbo- diimide hydrochloride (192 mg), triethylamine (347 μl) and 4A molecular sieves (250 mg) are added. The mixture is stirred for 18 h at room temperature. After that, the mixture is filtered, the molecular sieves are washed with dichloromethane (15 ml). The combined filtrate is washed with water (15 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 56 mg (25%) of the title com- pound.
1H-NMR (300 MHz, CDCI3); δ = 3.40-3.52 (m, 2H), 3.71 (dd, J = 5.3 Hz, 11.6 Hz, 1 H), 3.77-4.00 (m, 3H), 3.85 (s, 3H), 4.30-4.42 (m, 1 H), 4.40 (s, 2H), 4.63-4.72 (m, 1 H), 4.87-4.94 (m, 1 H), 5.05- 5.10 (m, 1 H), 6.89 (dd, J = 8.4 Hz, 8.5 Hz, 1 H), 6.99 (s, 1 H), 7.00-7.06 (m, 1 H), 7.22-7.33 (m, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.52 (dd, J = 7.3 Hz, 7.9 Hz, 1 H), 7.94 (bs, 1 H), 8.08 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 450.2
104. Benzyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate Benzyl 5-hydroxy-4-(1 H-indol-3-yl)-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (example A11 ) (12.54 g) is suspended under nitrogen in dichloroethane (170 ml), dichloromethane (250 ml) and nitromethane (50 ml) and the suspension is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 34.6 ml) is added drop by drop and the mixture is stirred for 10 min at O0C. In parallel, 3- fluoro-4-methoxyphenyl acetic acid (12.75 g) is dissolved in trifluoroacetic acid anhydride (9.87 ml) and the mixture is stirred for 1 h at room temperature. The formed mixed anhydride is diluted with dichloroethane (50 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 2 h at room temperature. After that, ammonia (7M in methanol, 31.6 ml) and ammonium acetate (16.54 g) are added and the mixture is stirred at 7O0C for 18 h. After cooling, water (100 ml) is added, the mixture is filtered over a plug of Celite®, the plug is washed thor- oughly with dichloromethane. Saturated sodium chloride solution (100 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 300 ml), the combined organic extracts are dried (MgSO4), and the volume is reduced in vacuo to ca. 500 ml. Triethylamine (ca. 50 ml) is added and the mixture is filtered over a plug of silica gel (8 cm x 12 cm 0, eluting with dichloromethane / methanol 9:1 (v/v), 2500 ml). The filtrate is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate / triethylamine 5:5:1 to 6:10:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane / dichloromethane 4:4:1 (v/v/v) to yield 2.33 g (13%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ =3.76 (s, 3H), 4.48-4.60 (m, 2H), 4.50 (s, 2H), 4.92-5.05 (m, 2H), 5.14 (s, 2H), 7.06 (dd, J = 8.5 Hz, 8.7 Hz, 1 H), 7.14 (d, J = 9.5 Hz, 1 H), 7.20-7.48 (m, 7H), 7.60- 7.72 (m, 2H), 9.15 (d, J = 8.4 Hz, 1 H), 12.21 (s, 1 H). MS (MH+ found) = 510.1 105. e^S-Fluoro^-methoxybenzyO^.S^.y-tetrahydro-IH-indolo^.S-cltiyinaphthyridin-i- one hydrobromide
Benzyl Θ^S-fluoro^-nnethoxybenzyO-i-oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine-S- carboxylate (example 104) (2.17 g) is dissolved in glacial acetic acid (79 ml) and hydrogen bromide (5.7M in glacial acetic acid, 21 ml) is added. The mixture is stirred in a sealed vial at 14O0C for 15 min using microwave radiation (6 portions). The precipitate is filtered, washed thoroughly with cold glacial acetic acid (until filtrate is colorless) and ethyl acetate (3 x 20 ml) and dried in vacuo to give rise to 1.25 g (64%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 3.77 (s, 3H), 4.29 (s, 2H), 4.55 (s, 2H), 4.73 (s, 2H), 7.02-7.13 (m, 1 H), 7.14-7.40 (m, 3H), 7.63-7.80 (m, 2H), 9.16 (d, J = 8.2 Hz, 1 H), 9.82 (bs, 2H), 12.50 (s, 1 H). MS (MH+ found) = 376.2
106. 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1 ,7]naphthyridin-1 -one
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one hydro- bromide (example 105) (149 mg) is suspended in dichloromethane (2.5 ml) and glacial acetic acid (38 μl), 1-hydroxybenzotriazole hydrate (76 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (127 mg) and triethylamine (229 μl) are added. The mixture is stirred for 18 h at room temperature. After that, dichloromethane (5 ml) and water (5 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 5 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 56 mg (41 %) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.77 (s, 3H), 4.50, 4.51 (2s, 2H [rotamers]), 4.54, 4.58 (2s, 2H [rotamers]), 5.00, 5.05 (2s, 2H [rotamers]), 7.07 (dd, J = 8.5 Hz, 8.7 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.20-7.32 (m, 2H), 7.59-7.70 (m, 2H), 9.16 (d, J = 8.3 Hz, 1 H), 12.16 (s, 1 H). MS (MH+ found) = 418.2
The following compounds are obtained by using the procedure of example 56 analogously, with adaptations in the purification step.
107. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(dimethylamino)ethanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and N,N-dimethylglycine; yield: 30%. 1H-NMR (300 MHz, d6-DMSO); δ = 2.17, 2.22 (2s, 6H [rotamers]), 3.20, 3.23 (2s, 2H [rotamers]), 3.26-3.36, 3.37-3.47 (2m, 2H [rotamers]), 3.83 (s, 3H), 3.85-3.93, 3.95-4.03 (2m, 2H [rotamers]), 4.37, 4.38 (2s, 2H [rotamers]), 4.76, 4.92 (2s, 2H [rotamers]), 7.08-7.20 (m, 2H), 7.25 (dd, J = 7.3 Hz, 7.7 Hz, 1 H), 7.55 (dd, J = 7.2 Hz, 8.0 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.12-8.20 (m, 1 H), 11.70 (s, 1 H).
MS (MH+ found) = 465.1
108. rac-i-te^S^-DifluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyriclin-S- yl]-2-hydroxypropan-1 -one Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and rac-2-hydroxypropanoic acid; yield: 29%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.28 (2d, J1.19 = 7.1 Hz, JI.28 = 6.3 Hz, 3H [rotamers]), 3.23-3.35, 3.38-3.49 (2m, 2H [rotamers]), 3.81-4.08 (m, 2H), 4.42 (s, 2H), 4.50-4.66 (m, 1 H), 4.74- 5.09 (m, 3H), 7.13-7.48 (m, 4H), 7.55 (dd, J = 7.5 Hz, 7.6 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.11- 8.20 (m, 1 H), 11.68 (s, 1 H). MS (MH+ found) = 422.2
The following compounds are obtained by using the procedure of example 100 analogously, with adaptations in the purification step.
109. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and [2-(benzyloxy)ethoxy]acetic acid (example A10); yield: 16%. 1H-NMR (300 MHz, d6-DMSO); δ = 3.40-3.49 (m, 2H), 3.49 (s, 2H), 3.52 (s, 2H), 3.84 (s, 3H), 3.83- 3.94 (m, 2H), 4.32, 4.34 (2s, 2H [rotamers]), 4.38 (s, 2H), 4.67-4.78 (m, 1 H), 4.77 (s, 2H), 7.08-7.20 (m, 2H), 7.25 (dd, J = 7.3 Hz, 7.6 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.70 (s, 1 H). MS (MH+ found) = 482.3
110. 6-(3-Fluoro-4-methoxybenzyl)-3-[(2-hydroxyethoxy)acetyl]-2,3,4,7-tetrahydro-1H- indolo[2,3-c][1 ,7]naphthyridin-1 -one
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (example 105) and [2-(benzyloxy)ethoxy]acetic acid (ex- ample A10); yield: 10% (2 steps).
1H-NMR (300 MHz, d6-DMSO); δ = 3.39-3.53 (m, 4H), 3.76 (s, 3H), 4.31 (bs, 2H), 4.50 (s, 2H), 4.52-4.64 (m, 3H), 5.02 (bs, 2H), 7.06 (dd, J = 8.5 Hz, 8.8 Hz, 1 H), 7.15 (d, AB, J = 9.0 Hz, 1 H), 7.20-7.32 (m, 2H), 7.58-7.72 (m, 2H), 9.15 (d, J = 8.3 Hz, 1 H), 12.17 (s, 1 H). MS (MH+ found) = 478.1 The following compounds are obtained by using the procedure of example 45 analogously, with adaptations in the purification step.
111. 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and bromoacetamide; yield: 44%.
1H-NMR (300 MHz, d6-DMSO); δ = 2.83-2.96 (m, 2H), 3.14 (s, 2H), 3.32-3.43 (m, 2H), 3.81 (s, 2H), 3.83 (s, 3H), 4.35 (s, 2H), 7.06-7.37 (m, 5H), 7.54 (dd, J = 7.2 Hz, 7.4 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 437.2
112. 2-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljacetamide
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and bromoacetamide; yield: 70%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.90 (t, J = 5.6 Hz, 2H), 3.13 (s, 2H), 3.32-3.42 (m, 2H), 3.80 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.32 (s, 2H), 6.97-7.33 (m, 6H), 7.52 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 433.2
113. 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (example 105) and bromoacetamide; yield: 44%. 1H-NMR (300 MHz, d6-DMSO); δ = 3.22 (s, 2H), 3.59 (s, 2H), 3.76 (s, 3H), 4.08 (s, 2H), 4.78 (s, 2H), 7.00-7.19 (m, 3H), 7.20-7.31 (m, 2H) 7.37 (bs, 1 H) 7.56-7.70 (m, 2H), 9.23 (d, J = 8.3 Hz, 1 H), 12.09 (s, 1 H).
MS (MH+ found) = 433.1
The following compound is obtained by using the procedure of example 29 analogously, with adaptations in the purification step. 114. rac-2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
Starting compounds: 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide (example 113); purification by flash chromatography (silica gel, eluting with dichloromethane / methanol 95:5 (v/v)); yield: 24%.
1H-NMR (300 MHz, d6-DMSO); δ = 2.70-2.82 (m, 1 H), 3.01-3.22 (m, 3H), 3.56 (d, AB, J = 15.1 Hz, 1 H), 3.75 (s, 3H), 3.99 (d, AB, J = 14.9 Hz, 1 H), 4.30 (d, AB, J = 14.0 Hz, 1 H), 4.39 (d, AB, J = 14.1 Hz, 1 H), 5.13-5.22 (m, 1 H), 5.43 (d, J = 10.0 Hz, 1 H), 6.99-7.29 (m, 5H), 7.48-7.65 (m, 3H), 8.34 (d, J = 7.7 Hz, 1 H), 11.60 (s, 1 H). MS (MH+ found) = 435.1
The following compound is obtained by subsequently using the procedure of examples 47 and 53 analogously, with adaptations in the purification step.
115. 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ), methyl 2-bromoacetate and 2-aminoethanol; intermediate com- pound: methyl [6-(3,5-difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate; yield: 25% (2 steps). 1H-NMR (300 MHz, d6-DMSO); δ = 2.90 (t, J = 5.7 Hz, 2H), 3.16-3.25 (m, 4H), 3.33-3.48 (m, 4H),
3.83 (s, 2H), 3.83 (s, 3H), 4.35 (s, 2H), 4.65 (t, J = 5.3 Hz, 1 H), 7.03-7.16 (m, 2H), 7.23 (ddd, J = 1.0 Hz, 8.0 Hz, 8.0 Hz, 1 H), 7.54 (ddd, J = 1.0 Hz, 7.0 Hz, 8.0 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 7.81 (dd, J = 7.7 Hz, 7.8 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.58 (s, 1 H). MS (MH+ found) = 481.1
The following compounds were obtained by using the procedure of example 56 analogously, with adaptations in the purification step.
116. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-hydroxyethanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and hydroxyacetic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 3.26-3.46 (m, 2H), 3.78-3.88, 3.90-3.98 (2m, 2H [rotamers]),
3.84 (s, 3H), 4.19-4.31 (m, 2H), 4.38 (s, 2H), 4.58-4.71 (m, 1 H), 4.72, 4.79 (2s, 2H), 7.04-7.17 (m, 2H), 7.25 (dd, J = 7.0 Hz, 8.0 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 8.1 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 1 H), 8.10- 8.20 (m, 1 H), 11.67 (s, 1 H).
MS (MH+ found) = 438.2 117. 1 -[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yljethanone
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.24-3.34, 3.37-3.47 (2m, 2H [rotamers]), 3.83-3.92 (m, 2H), 4.41 , 4.42 (2s, 2H [rotamers]), 4.75, 4.78 (2s, 2H [rotamers]), 7.13- 7.48 (m, 4H), 7.55 (ddd, J = 1.1 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.12-8.20 (m, 1 H), 1 1.66, 11.68 (2s, 1 H [rotamers]). MS (MH+ found) = 392.3
118. 1 -[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- (dimethylamino)ethanone
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 2.18, 2.23 (2s, 6H [rotamers]), 3.21 , 3.24 (2s, 2H [rotamers]), 3.26-3.34, 3.38-3.46 (2m, 2H [rotamers]), 3.83-4.02 (m, 2H), 4.41 (s, 2H), 4.75, 4.91 (2s, 2H [rotamers]), 7.13-7.48 (m, 4H), 7.54 (dd, J = 7.1 Hz, 8.1 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.15 (bd, J = 8.0 Hz, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 435.0
119. 1 -[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-hydroxyethanone
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and hydroxyacetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.25-3.37, 3.37-3.44 (2m, 2H [rotamers]), 3.76-3.85, 3.89-3.98 (2m, 2H [rotamers]), 4.20-4.30 (m, 2H), 4.32 (s, 2H), 4.58-4.70 (m, 1 H), 4.71 , 4.78 (2s, 2H [rotamers]), 5.92 (s, 2H), 6.75-6.87 (m, 2H), 6.94 (d, J = 1.4 Hz, 1 H), 7.23 (ddd, J = 1.0 Hz, 7.5 Hz, 7.5 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.08- 8.20 (m, 1 H), 11.62 (s, 1 H).
MS (MH+ found) = 416.2
120. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.24-3.33, 3.37-3.44 (2m, 2H [rotamers]), 3.83-3.93 (m, 2H), 4.31 , 4.33 (2s, 2H [rotamers]), 4.75, 4.77 (2s, 2H [rotamers]), 5.91 (s, 2H), 6.74-6.86 (m, 2H), 6.95 (d, J = 1.4 Hz, 1 H), 7.23 (dd, J = 7.2 Hz, 7.8 Hz, 1 H), 7.54 (ddd, J = 1.0 Hz, 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10- 8.19 (m, 1 H), 1 1.60, 1 1.62 (2s, 1 H
[rotamers]).
MS (MH+ found) = 400.2
121. 1 -[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-hydroxypropan-1 -one
Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.27 (2d, J = 6.2 Hz, 3H [rotamers]), 3.24-3.36, 3.38-3.46 (2m, 2H [rotamers]), 3.81 (s, 3H), 3.92-4.06 (m, 1 H), 4.39 (s, 2H), 4.50-4.66 (m, 1 H), 4.74-5.08 (m, 3H), 6.79-6.90 (m, 1 H), 7.05 (dd, J = 8.3 Hz, 11.7 Hz, 1 H), 7.19-7.33 (m, 3H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 434.2
122. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1 -one
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.18, 1.27 (2d, J = 6.4 Hz, 3H [rotamers]), 3.25-3.38, 3.38-3.49 (2m, 2H [rotamers]), 3.83 (s, 3H), 3.84-4.08 (m, 2H), 4.38 (s, 2H), 4.50-4.67 (m, 1 H), 4.74-4.94 (m, 2H), 5.03, 5.09 (2d, J = 6.8 Hz, 1 H [rotamers]), 7.05-7.18 (m, 2H), 7.25 (dd, J = 7.2 Hz, 7.7 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.70 (s, 1 H). MS (MH+ found) = 452.2
123. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.14, 2.16 (2s, 3H [rotamers]), 3.25-3.36, 3.38-3.47 (2m, 2H [rotamers]), 3.80-3.93 (m, 2H), 3.83 (s, 3H), 4.37, 4.38 (2s, 2H [rotamers]), 4.76, 4.79 (2s, 2H
[rotamers]), 7.06-7.19 (m, 2H), 7.25 (dd, J = 6.8 Hz, 7.1 Hz, 1 H), 7.55 (dd, J = 7.2 Hz, 8.0 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 8.11- 8.21 (m, 1 H), 11.69, 11.70 (2s, 1 H [rotamers]). MS (MH+ found) = 422.2
124. 1-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-2- hydroxyethanone
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and hydroxyacetic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 3.28-3.47 (m, 2H), 3.77-3.85, 3.88-3.98 (2m, 2H [rotamers]), 4.19-4.31 (m, 2H), 4.42 (s, 2H), 4.62-4.71 (m, 1 H), 4.71 , 4.78 (2s, 2H [rotamers]), 7.12-7.48 (m, 4H), 7.55 (ddd, J = 1.0 Hz, 7.0 Hz, 8.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.21 (m, 1 H), 11.72 (s, 1 H). MS (MH+ found) = 408.2
125. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2A7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1 -one
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.27 (2d, J = 6.5 Hz, 3H [rotamers]), 3.25-3.44 (m, 2H), 3.80-3.92, 3.93-4.06 (2m, 2H [rotamers]), 4.32 (s, 2H), 4.52-4.64 (m, 1 H), 4.75-4.82 (m, 1 H), 4.84- 4.97 (m, 1 H), 5.02, 5.08 (2d, J = 6.9 Hz, 1 H [rotamers]), 5.92 (s, 2H), 6.76-6.88 (m, 2H), 6.95 (s, 1 H), 7.24 (dd, J = 7.0 Hz, 7.2 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.10-8.18 (m, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 430.3
126. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(dimethylamino)ethanone Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 2.22, 2.25 (2s, 6H [rotamers]), 3.24-3.45 (m, 4H), 3.86-3.93, 3.94-4.01 (2m, 2H [rotamers]), 4.32, 4.33 (2s, 2H [rotamers]), 4.76, 4.90 (2s, 2H [rotamers]), 5.92 (s, 2H), 6.76-6.88 (m, 2H), 6.93-6.98 (m, 1 H), 7.24 (dd, J = 7.1 Hz, 7.8 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.4 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.12-8.20 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 443.2
127. i-te^-Fluoro-S-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin- 3-yl]-2-hydroxyethanone Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and hydroxyacetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.26-3.37, 3.39-3.48 (2m, 2H [rotamers]), 3.75-3.87, 3.88-3.98 (2m, 2H [rotamers]), 3.82 (s, 3H), 4.22, 4.28 (2d, J = 5.4 Hz, 2H [rotamers]), 4.39 (s, 2H), 4.62-4.74 (m, 1 H), 4.71 , 4.79 (2s, 2H [rotamers]), 6.79-6.89 (m, 1 H), 7.06 (dd, J = 8.3 Hz, 11.7 Hz, 1 H), 7.20- 7.34 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.71 (s, 1 H). MS (MH+ found) = 420.3 128. i-tδ^-Fluoro-S-methoxybenzylJ-i^^.y-tetrahydro-SH-indolo^.S-cltiJlnaphthyridin- 3-yl]ethanone
Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and acetic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.25-3.36, 3.39-3.46 (2m, 2H [rotamers]), 3.82 (s, 3H), 3.83-3.93 (m, 2H), 4.38, 4.39 (2s, 2H [rotamers]), 4.76, 4.78 (2s, 2H [rotamers]), 6.79-6.86 (m, 1 H), 7.06 (ddd, J = 2.0 Hz, 8.3 Hz, 11.6 Hz, 1 H), 7.20-7.34 (m, 2H), 7.54 (ddd, J = 1.0 Hz, 7.0 Hz, 8.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.14, 8.16 (2d, J = 8.1 Hz, 1 H [rotamers]), 11.69, 11.71 (2s, 1 H [rotamers]). MS (MH+ found) = 404.2
129. 2-(Dimethylamino)-1-[6-(4-fluoro-3-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 2.20, 2.24 (2s, 6H [rotamers]), 3.19-3.48 (m, 4H), 3.82 (s, 3H), 3.86-4.02 (m, 2H), 4.39 (s, 2H), 4.76, 4.91 (2s, 2H [rotamers]), 6.80-6.90 (m, 1 H), 7.05 (dd, J = 8.3 Hz, 11.6 Hz, 1 H), 7.19-7.34 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.71 (s, 1 H). MS (MH+ found) = 447.2
130. i-te^-Ethoxy-S-fluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-S- yl]-2-hydroxyethanone
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and hydroxyacetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 3.22-3.35, 3.36-3.47 (2m, 2H [rotamers]), 3.76-3.86, 3.88-3.98 (2m, 2H [rotamers]), 4.01 (q, J = 7.0 Hz, 2H), 4.18-4.31 (m, 2H), 4.35 (s, 2H), 4.67-4.82 (m, 3H), 6.98-7.12 (m, 2H), 7.16-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 434.2
131. 1 -[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]-2-hydroxypropan-1 -one
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.19 & 1.22-1.32 (d, J = 6.3 Hz & m, 3H [rotamers]), 1.28 (t, J = 7.0 Hz, 3H), 3.23-3.35, 3.36-3.46 (2m, 2H [rotamers]), 3.82-4.08 (m, 4H), 4.35 (s, 2H), 4.50-4.66 (m, 1 H), 4.75-5.08 (m, 3H), 6.98-7.11 (m, 2H), 7.16-7.29 (m, 2H), 7.54 (dd, J = 7.3 Hz, 7.8 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 448.2
132. i-te^-Ethoxy-S-fluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyriclin-S- yljethanone Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.13, 2.16 (2s, 3H [rotamers]), 3.21- 3.45 (m, 2H), 3.82-3.93 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.34, 4.35 (2s, 2H [rotamers]), 4.75, 4.78 (2s, 2H [rotamers]), 6.99-7.12 (m, 2H), 7.16-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.63, 11.65 (2s, 1 H [rotamers]). MS (MH+ found) = 418.2
133. 2-(Dimethylamino)-1-[6-(4-ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.19, 2.23 (2s, 6H [rotamers]), 3.18- 3.45 (m, 4H), 3.85-4.02 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.34 (s, 2H), 4.76, 4.91 (2s, 2H [rotamers]), 6.98-7.10 (m, 2H), 7.13-7.28 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.11-8.20 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 461.2
134. i-te^S-Chloro^-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin- 3-yl]-2-hydroxyethanone Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25) and hydroxyacetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.26-3.46 (m, 2H), 3.73-3.87, 3.89-3.98 (2m, 2H [rotamers]), 3.77 (s, 3H), 4.19-4.32 (m, 2H), 4.35 (s, 2H), 4.58-4.82 (m, 3H), 7.04 (d, J = 8.5 Hz, 1 H), 7.20-7.33 (m, 2H), 7.30 (d, J = 2.0 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.10- 8.20 (m, 1 H), 11.66 (bs, 1 H). MS (MH+ found) = 436.2 135. i-te^S-Chloro^-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin- 3-yl]-2-hydroxypropan-1 -one
Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.27 (2d, J1 19 = 6.1 Hz, J1 27 = 6.4 Hz, 3H [rotamers]), 3.26-3.35, 3.37-3.45 (2m, 2H [rotamers]), 3.77 (s, 3H), 3.82-4.04 (m, 2H), 4.35 (s, 2H), 4.50-4.67 (m, 1 H), 4.74-5.08 (m, 3H), 7.04 (d, J = 8.5 Hz, 1 H), 7.20-7.33 (m, 2H), 7.42 (s, 1 H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.65 (bs, 1 H). MS (MH+ found) = 450.2
136. i-te^S-Chloro^-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin- 3-yl]ethanone
Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.25-3.33, 3.38-3.46 (2m, 2H [rotamers]), 3.77 (s, 3H), 3.82-3.93 (m, 2H), 4.34, 4.36 (2s, 2H [rotamers]), 4.75, 4.77 (2s, 2H [rotamers]), 7.04 (d, J = 8.5 Hz, 1 H), 7.20-7.32 (m, 2H), 7.42 (d, J = 2.0 Hz, 1 H), 7.54 (ddd, J = 1.0 Hz, 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 1 1.64, 11.66 (2s, 1 H [rotamers]).
MS (MH+ found) = 420.2
137. i-te^S-Chloro^-methoxybenzyO-i^^.y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin- 3-yl]-2-(dimethylamino)ethanone Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 2.20, 2.24 (2s, 6H [rotamers]), 3.19-3.50 (m, 4H), 3.77 (s, 3H), 3.84-4.01 (m, 2H), 4.35 (s, 2H), 4.75, 4.90 (2s, 2H [rotamers]), 7.04 (d, J = 8.6 Hz, 1 H), 7.20-7.32 (m, 2H), 7.43 (s, 1 H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 1 1.65 (s, 1 H).
MS (MH+ found) = 463.0
138. 2-Hydroxy-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and hydroxyacetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.25-3.46 (m, 2H), 3.67 (s, 3H), 3.76-3.85, 3.88-3.98 (2m, 2H [rotamers]), 4.19-4.30 (m, 2H), 4.35 (s, 2H), 4.58-4.81 (m, 3H), 6.82 (d, J = 8.7 Hz, 2H), 7.20-7.32 (m, 3H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.08-8.20 (m, 1 H), 11.63 (s,
1 H).
MS (MH+ found) = 402.2
139. 2-Hydroxy-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]propan-1 -one
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and 2-hydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.27 (2d, J1 19 = 6.4 Hz, J1 27 = 6.2 Hz, 3H [rotamers]), 3.22-3.46 (m, 2H), 3.67 (s, 3H), 3.80-4.05 (m, 2H), 4.35 (s, 2H), 4.50-4.66 (m, 1 H), 4.73-5.08 (m, 3H), 6.82 (d, J = 8.6 Hz, 2H), 7.20-7.32 (m, 3H), 7.53 (dd, J = 7.5 Hz, 7.7 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.09-8.19 (m, 1 H), 11.62 (s, 1H). MS (MH+ found) = 416.2
140. 1-[6-(4-Methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljethanone
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and acetic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.12, 2.16 (2s, 3H [rotamers]), 3.23-3.32, 3.36-3.45 (2m, 2H [rotamers]), 3.67 (s, 3H), 3.82-3.92 (m, 2H), 4.34, 4.35 (2s, 2H [rotamers]), 4.74, 4.77 (2s, 2H
[rotamers]), 6.82 (d, J = 8.6 Hz, 2H), 7.19-7.32 (m, 3H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.61 , 1 1.64 (2s, 1 H [rotamers]). MS (MH+ found) = 386.2
141. 2-(Dimethylamino)-1 -[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and N,N-dimethylglycine;
1H-NMR (300 MHz, d6-DMSO); δ = 2.23, 2.26 (2s, 6H [rotamers]), 3.12-3.47 (m, 4H), 3.67 (s, 3H), 3.84-4.00 (m, 2H), 4.34 (bs, 2H), 4.75, 4.88 (2s, 2H [rotamers]), 6.78-6.86 (m, 2H), 7.18-7.32 (m, 4H), 7.53 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 429.1
142. 6-(3-Fluoro-4-methoxybenzyl)-3-[(2S)-2-hydroxypropanoyl]-2,3,4,7-tetrahydro-1H- indolo[2,3-c][1 ,7]naphthyridin-1 -one
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (example 105) and 2-hydroxypropanoic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.12-1.24 (m, 3H), 3.76 (s, 3H), 4.50, 4.58 (2s, 2H [rotamers]), 4.43-4.81 (m, 3H), 4.90-5.28 (m, 3H), 7.06 (dd, J = 8.6 Hz, 8.6 Hz, 1 H), 7.15 (dd, J = 8.5 Hz, 1 H), 7.20-7.32 (m, 2H), 7.59-7.71 (m, 2H), 9.16 (d, J = 8.2 Hz, 1 H), 12.17 (s, 1 H). MS (MH+ found) = 448.2
143. 6-(3-Fluoro-4-methoxybenzyl)-3-(hydroxyacetyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1 ,7]naphthyridin-1 -one
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (example 105) and hydroxyacetic acid;
144. rac-1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1 -one
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and rac-3-hydroxybutanoic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.09, 1.14 (2d, J = 6.2 Hz, 3H [rotamers]), 2.41-2.54 (m, 1 H), 2.58-2.74 (m, 1 H), 3.25-3.35, 3.37-3.45 (2m, 2H [rotamers]), 3.84 (s, 3H), 3.88-3.98 (m, 2H), 4.00- 4.13 (m, 1 H), 4.37 (s, 2H), 4.59, 4.63 (2d, J = 4.4 Hz, 1 H [rotamers]), 4.79, 4.83 (2s, 2H [rotamers]), 7.06-7.18 (m, 2H), 7.25 (dd, J = 7.4 Hz, 7.5 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.11-8.20 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 466.2
145. cis-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 J]naphthyridin-3-yl][2-hydroxycyclopentyl]methanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and cis-2-hydroxycyclopentanecarboxylic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.39-2.12 (m, 6H), 3.04-3.12 (m, 1 H), 3.22-3.50 (m, 2H), 3.79- 4.10 (m, 2H), 3.83 (s, 3H), 4.27-4.46 (m, 3H), 4.71-4.93 (m, 3H), 7.06-7.17 (m, 2H), 7.25 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.08-8.20 (m, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 492.2
146. rac-i-te^S^-DifluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-S- yl]-3-hydroxybutan-1 -one
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and rac-3-hydroxybutanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.09, 1.14 (2d, J = 6.2 Hz, 3H [rotamers]), 2.40-2.53 (m, 1 H), 2.57-2.71 (m, 1 H), 3.24-3.35, 3.37-3.46 (2m, 2H [rotamers]), 3.87-3.97 (m, 2H), 3.99-4.12 (m, 1 H), 4.41 (s, 2H), 4.58, 4.63 (2d, J = 4.4 Hz, 1 H [rotamers]), 4.78, 4.82 (2s, 2H [rotamers]), 7.12-7.47 (m, 4H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.67 (s,
1 H).
MS (MH+ found) = 436.2
147. cis-[6-(3,4-Difluorobenzyl)-1,2A7-tetrahydro-3H-indolo[2,3-c][17]naphthyridin-3- yl][2-hydroxycyclopentyl]methanone
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and cis-2-hydroxycyclopentanecarboxylic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.39-2.12 (m, 6H), 3.03-3.16 (m, 1 H), 3.21-3.50 (m, 2H), 3.78- 4.10 (m, 2H), 4.28-4.45 (m, 3H), 4.75-4.93 (m, 3H), 7.12-7.48 (m, 4H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.06-8.20 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 462.2
148. rac-1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-3-hydroxybutan-1-one
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and rac-3-hydroxybutanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.10, 1.14 (2d, J = 6.2 Hz, 3H [rotamers]), 2.41-2.54 (m, 1 H),
2.57-2.71 (m, 1 H), 3.24-3.33, 3.36-3.44 (2m, 2H [rotamers]), 3.88-3.96 (m, 2H), 3.99-4.12 (m, 1 H), 4.32 (s, 2H), 4.59, 4.63 (2d, J = 4.5 Hz, 1 H [rotamers]), 4.78, 4.82 (2s, 2H [rotamers]), 5.91 (s, 2H),
6.76-6.87 (m, 2H), 6.95 (d, J = 1.2 Hz, 1 H), 7.23 (dd, J = 7.3 Hz, 7.7 Hz, 1 H), 7.53 (ddd, J = 1.0 Hz,
7.2 Hz, 8.0 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.60 (s, 1 H).
MS (MH+ found) = 444.2
149. cis-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 JJnaphthyridin^-ylJβ-hydroxycyclopentylJmethanone
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and cis-2-hydroxycyclopentanecarboxylic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.44-1.84 (m, 5H), 1.90-2.12 (m, 1 H), 3.05-3.16 (m, 1 H), 3.22- 3.48 (m, 2H), 3.76-4.11 (m, 2H), 4.28-4.43 (m, 1 H), 4.32 (s, 2H), 4.76-4.92 (m, 3H), 5.91 (s, 2H), 6.76-6.87 (m, 2H), 6.95 (s, 1 H), 7.23 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.53 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.18 (m, 1 H), 11.60 (s, 1 H). MS (MH+ found) = 470.2
150. rac-1-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1 -one
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and rac-3-hydroxybutanoic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.09, 1.14 (2d, J = 6.1 Hz, 3H [rotamers]), 1.28 (t, J = 7.0 Hz, 3H), 2.40-2.53 (m, 1 H), 2.57-2.70 (m, 1 H), 3.23-3.33, 3.37-3.46 (2m, 2H [rotamers]), 3.88-3.98 (m, 2H), 3.99-4.12 (m, 1 H), 4.01 (q, J = 7.0 Hz, 2H), 4.34 (s, 2H), 4.59, 4.63 (2d, J = 4.3 Hz, 1 H [rotamers]), 4.78, 4.82 (2s, 2H [rotamers]), 7.00-7.12 (m, 2H), 7.16-7.28 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 462.2
151. cis-te^-Ethoxy-S-fluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyriclin- 3-yl][2-hydroxycyclopentyl]methanone Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and cis-2-hydroxycyclopentanecarboxylic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 1.41-2.13 (m, 6H), 3.04-3.17 (m, 1 H), 3.21-3.51 (m, 2H), 3.78-4.10 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.28-4.43 (m, 1 H), 4.35 (s, 2H), 4.69-4.94 (m, 3H), 6.96-7.11 (m, 2H), 7.14-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.04-8.19 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 488.2
152. rac-3-Hydroxy-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]butan-1 -one Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and rac-3-hydroxybutanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.09, 1.14 (2d, J = 6.2 Hz, 3H [rotamers]), 2.40-2.53 (m, 1 H), 2.56-2.70 (m, 1 H), 3.24-3.33, 3.37-3.44 (2m, 2H [rotamers]), 3.67 (s, 3H), 3.87-3.96 (m, 2H), 3.99- 4.11 (m, 1 H), 4.34 (s, 2H), 4.59, 4.63 (2d, J = 4.4 Hz, 1 H [rotamers]), 4.77, 4.81 (2s, 2H [rotamers]), 6.82 (d, J = 8.7 Hz, 2H), 7.19-7.32 (m, 3H), 7.53 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.09-8.18 (m, 1 H), 11.61 , 1 1.63 (2s, 1 H [rotamers]). MS (MH+ found) = 430.2
The following compounds were obtained by using the procedure of example 100 analogously, with adaptations in the purification step.
153. 1-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-2- (2-hydroxyethoxy)ethanone
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and [2-(benzyloxy)ethoxy]acetic acid (example A10);
1H-NMR (300 MHz, d6-DMSO); δ = 3.26-3.38, 3.40-3.48 (2m, 2H [rotamers]), 3.49 (s, 2H), 3.52 (s, 2H), 3.82-3.96 (m, 2H), 4.31 , 4.33 (2s, 2H [rotamers]), 4.42 (s, 2H), 4.66-4.75 (m, 1 H), 4.76 (s, 2H), 7.12-7.49 (m, 4H), 7.55 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.71 (s, 1 H). MS (MH+ found) = 452.2
154. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2A7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and [2-(benzyloxy)ethoxy]acetic acid (example A10); 1H-NMR (300 MHz, d6-DMSO); δ = 3.25-3.34, 3.38-3.47 (2m, 2H [rotamers]), 3.49-3.57 (m, 4H), 3.82-3.94 (m, 2H), 4.32 (bs, 4H), 4.63-4.70 (m, 1 H), 4.76 (s, 2H), 5.91 (s, 2H), 6.75-6.87 (m, 1 H), 6.95 (d, J = 1.4 Hz, 1 H), 7.24 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 460.2
155. i-tδ^-Fluoro-S-methoxybenzylJ-i^^.y-tetrahydro-SH-indolo^.S-clti.yinaphthyridin- 3-yl]-2-(2-hydroxyethoxy)ethanone Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and [2-(benzyloxy)ethoxy]acetic acid (example A10); 1H-NMR (300 MHz, d6-DMSO); δ = 3.29-3.38, 3.39-3.48 (2m, 2H [rotamers]), 3.49 (s, 2H), 3.52 (s, 2H), 3.81-3.95 (m, 2H), 3.82 (s, 3H), 4.31 , 4.33 (2s, 2H [rotamers]), 4.39 (s, 2H), 4.66-4.76 (m, 1 H), 4.77 (s, 2H), 6.80-6.89 (m, 1 H), 7.05 (dd, J = 8.3 Hz, 11.6 Hz, 1 H), 7.20-7.35 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.70 (s, 1 H). MS (MH+ found) = 464.3
156. i-te^-Ethoxy-S-fluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-S- yl]-2-(2-hydroxyethoxy)ethanone Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and [2-(benzyloxy)ethoxy]acetic acid (example A10); 1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 3.23-2.36, 3.39-3.48 (2m, 2H [rotamers]), 3.48-3.59 (m, 4H), 3.82-3.95 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.28-4.39 (m, 4H), 4.62- 4.71 (m, 1 H), 4.76 (s, 2H), 6.98-7.12 (m, 2H), 7.16-7.29 (m, 2H), 7.54 (ddd, J = 1.1 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 478.3
157. 2-(2-Hydroxyethoxy)-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and [2-(benzyloxy)ethoxy]acetic acid (example A10);
1H-NMR (300 MHz, d6-DMSO); δ = 3.24-2.35, 3.38-3.47 (2m, 2H [rotamers]), 3.48-3.58 (m, 4H), 3.67 (s, 3H), 3.82-3.95 (m, 2H), 4.27-4.39 (m, 4H), 4.62-4.70 (m, 1 H), 4.75 (s, 2H), 6.82 (d, J = 8.8 Hz, 2H), 7.20-7.32 (m, 3H), 7.53 (ddd, J = 1.0 Hz, 7.2 Hz, 8.0 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.09-8.19 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 446.2
The following compounds were obtained by using the procedure of example 45 analogously, with adaptations in the purification step.
158. 2-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljacetamide Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine
(example 24) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 2.83-2.96 (m, 2H), 3.14 (s, 2H), 3.30-3.45 (m, 2H), 3.80 (s, 2H),
4.39 (s, 2H), 7.12-7.47 (m, 6H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.14 (d,
J = 7.9 Hz, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 407.1
159. 2-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 2.85-2.93 (m, 2H), 2.87 (s, 2H), 3.31-3.41 (m, 2H), 3.80 (s, 2H), 4.29 (s, 2H), 6.78 (d, J = 8.0 Hz, 1 H), 6.82 (dd, J = 1.5 Hz, 8.0 Hz, 1 H), 6.94 (d, J = 1.3 Hz, 1 H), 7.14-7.26 (m, 2H), 7.32 (bs, 1 H), 7.52 (ddd, J = 0.9 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 11.56 (s, 1 H). MS (MH+ found) = 415.1
160. 2-[6-(4-Fluoro-3-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]acetamide
Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 2.82-2.97 (m, 2H), 3.13 (s, 2H), 3.31-3.43 (m, 2H), 3.81 (s, 5H), 4.36 (s, 2H), 6.78-6.88 (m, 1 H), 7.05 (dd, J = 8.3 Hz, 11.6 Hz, 1 H), 7.12-7.39 (m, 4H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 1 1.62 (s, 1 H). MS (MH+ found) = 419.2
161. 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanol
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and 2-bromoethanol; 1H-NMR (300 MHz, d6-DMSO); δ = 2.66 (t, J = 6.1 Hz, 2H), 2.85-2.92 (m, 2H), 3.27-3.41 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.77 (s, 2H), 3.83 (s, 2H), 4.37 (s, 2H), 7.04-7.17 (m, 2H), 7.19-7.29 (m, 1 H), 7.49-7.67 (m, 2H), 8.09-8.18 (m, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 424.2
162. 2-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljethanol
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and 2-bromoethanol; 1H-NMR (300 MHz, d6-DMSO); δ = 2.65 (t, J = 6.1 Hz, 2H), 2.84-2.94 (m, 2H), 3.26-3.38 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.76 (s, 2H), 4.40 (s, 2H), 7.11-7.47 (m, 4H), 7.50-7.67 (m, 2H), 8.09-8.18 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 394.2
163. 2-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanol
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and 2-bromoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.63 (t, J = 6.1 Hz, 2H), 2.86-2.94 (m, 2H), 3.27-3.35 (m, 2H), 3.64 (t, J = 6.1 Hz, 2H), 3.76 (s, 2H), 4.29 (s, 2H), 5.91 (s, 2H), 6.76-6.85 (m, 2H), 6.93 (d, J =
1.2 Hz, 1 H), 7.21 (ddd, J = 1.0 Hz, 8.0 Hz, 8.0 Hz, 1 H), 7.52 (ddd, J = 1.0 Hz, 7.0 Hz, 8.1 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 11.54 (s, 1 H). MS (MH+ found) = 402.3
164. 2-[6-(4-Fluoro-3-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]ethanol
Starting compounds: 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 23) and 2-bromoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.66 (t, J = 6.1 Hz, 2H), 2.86-2.96 (m, 2H), 3.28-3.37 (m, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.78 (s, 2H), 3.81 (s, 3H), 4.36 (s, 2H), 6.78-6.86 (m, 1 H), 7.04 (dd, J =
8.3 Hz, 11.6 Hz, 1 H), 7.19-7.32 (m, 2H), 7.49-7.69 (m, 2H), 8.12 (d, J = 8.1 Hz, 1 H), 11.60 (s, 1 H). MS (MH+ found) = 406.2
165. Methyl [6-(1,3-benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and methyl 2-bromoacetate;
1H-NMR (300 MHz, d6-DMSO); δ = 2.95-3.02 (m, 2H), 3.27-3.37 (m, 2H), 3.52 (s, 2H), 3.67 (s, 3H), 3.84 (s, 2H), 4.29 (s, 2H), 5.91 (s, 2H), 6.77 (d, J = 8.0 Hz, 1 H), 6.82 (dd, J = 1.5 Hz, 8.0 Hz, 1 H), 6.93 (d, J = 1.3 Hz, 1H), 7.22 (ddd, J = 1.0 Hz, 7.0 Hz, 8.0 Hz, 1H), 7.52 (ddd, J= 1.0 Hz, 7.1 Hz, 8.2 Hz, 1H), 7.61 (d, J= 8.2 Hz, 1H), 8.12 (d, J= 7.9 Hz, 1H), 11.52 (s, 1H). MS (MH+ found) = 430.2
166. 2-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljethanol
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,7]naphthyridine (example 26) and 2-bromoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J= 7.0 Hz, 3H), 2.65 (t, J= 6.1 Hz, 2H), 2.83-2.92 (m, 2H), 3.23-3.40 (m, 2H), 3.60-3.69 (m, 2H), 3.75 (s, 2H), 3.94-4.06 (m, 2H), 4.32 (s, 2H), 4.47 (t, J = 5.3 Hz, 1H), 6.96-7.10 (m, 2H), 7.13-7.26 (m, 2H), 7.52 (dd, J= 7.0 Hz, 8.1 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 8.09-8.18 (m, 1H), 11.52(s, 1H). MS (MH+ found) = 420.2
167. 2-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljacetamide
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,7]naphthyridine (example 26) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J= 7.0 Hz, 3H), 2.90 (t, J= 5.6 Hz, 2H), 3.13 (s, 2H), 3.32-3.42 (m, 2H), 3.80 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.32 (s, 2H), 6.97-7.33 (m, 6H), 7.52 (dd, J = 7.1 Hz, 7.2Hz, 1H), 7.61 (d,J= 8.1 Hz, 1H), 8.13 (d, J= 8.0 Hz, 1H), 11.55(s, 1H). MS (MH+ found) = 433.2
168. 2-[6-(3-Chloro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]ethanol
Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,7]naphthyridine (example 25) and 2-bromoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.65 (t, J= 6.1 Hz, 2H), 2.83-2.93 (m, 2H), 3.22-3.40 (m, 2H), 3.59-3.69 (m, 2H), 3.72-3.80 (m, 5H), 4.32 (s, 2H), 4.43-4.50 (m, 1H), 7.03 (d, J= 8.5 Hz, 1H), 7.18-7.32 (m, 2H), 7.40 (d, J= 2.1 Hz, 1H), 7.52 (dd, J= 7.0 Hz, 8.1 Hz, 1H), 7.60 (d, J= 8.1 Hz, 1H), 8.08-8.17 (m, 1H), 11.54 (s, 1H). MS (MH+ found) = 422.2
169. 2-[6-(3-Chloro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]acetamide
Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,7]naphthyridine (example 25) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 2.85-2.94 (m, 2H), 3.13 (s, 2H), 3.32-3.41 (m, 2H), 3.77 (s, 3H), 3.80 (s, 2H), 4.32 (s, 2H), 7.03 (d, J= 8.5 Hz, 1H), 7.12 (bs, 1H), 7.19-7.32 (m, 3H), 7.41 (d, J = 2.1 Hz, 1 H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H),
11.56 (s, 1 H).
MS (MH+ found) = 435.1
170. 2-[6-(4-Methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljethanol
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and 2-bromoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.65 (t, J = 6.1 Hz, 2H), 2.98-3.07 (m, 2H), 3.26-3.40 (m, 4H), 3.65 (s, 3H), 3.74 (s, 2H), 4.31 (s, 2H), 4.46 (t, J = 5.3 Hz, 1 H), 6.81 (d, J = 8.8 Hz, 2H), 7.17-7.30 (m, 3H), 7.47-7.56 (m, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 8.08-8.18 (m, 1 H), 11.51 (s, 1 H). MS (MH+ found) = 388.3
171. 2-[6-(4-Methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yljacetamide
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and bromoacetamide;
1H-NMR (300 MHz, d6-DMSO); δ = 2.84-2.94 (m, 2H), 3.13 (s, 2H), 3.31-3.41 (m, 2H), 3.67 (s, 3H), 3.79 (s, 2H), 4.32 (s, 2H), 6.81 (d, J = 8.8 Hz, 1 H), 7.12 (bs, 1 H), 7.18-7.32 (m, 4H), 7.52 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.53 (s, 1 H). MS (MH+ found) = 401.2
The following compounds are obtained by subsequently using the procedure of examples 47 and 53 analogously, with adaptations in the purification step.
172. 2-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22), methyl 2-bromoacetate and 2-aminoethanol; 1H-NMR (300 MHz, d6-DMSO); δ = 2.84-2.93 (m, 2H), 3.14-3.25 (m, 4H), 3.32-3.49 (m, 4H), 3.81 (s, 2H), 4.30 (s, 2H), 4.65 (t, J = 5.3 Hz, 1 H), 5.91 (s, 2H), 6.74-6.85 (m, 2H), 6.93 (s, 1 H), 7.22 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.52 (dd, J = 7.2 Hz, 7.5 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.77-7.84 (m, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 11.53 (s, 1 H). MS (MH+ found) = 459.2
173. 2-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yl]-N-(2-hydroxyethyl)acetamide
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26), methyl 2-bromoacetate and 2-aminoethanol; 1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.85-2.93 (m, 2H), 3.14-3.25 (m, 4H), 3.33-3.48 (m, 4H), 3.81 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.32 (s, 2H), 4.61-4.70 (m, 1 H), 6.98-7.10 (m, 2H), 7.13-7.28 (m, 2H), 7.53 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.77-7.84 (m, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.56 (s, 1 H). MS (MH+ found) = 477.2
174. 2-[6-(3-Chloro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin- 3-yl]-N-(2-hydroxyethyl)acetamide
Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25), methyl 2-bromoacetate and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.82-2.93 (m, 2H), 3.14-3.25 (m, 4H), 3.33-3.48 (m, 4H), 3.77 (s, 3H), 3.81 (s, 2H), 4.33 (s, 2H), 4.65 (t, J = 5.3 Hz, 1 H), 7.03 (d, J = 8.6 Hz, 1 H), 7.19-7.31 (m, 2H), 7.41 (d, J = 2.1 Hz, 1 H), 7.53 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.77-7.85 (m, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.57 (s, 1 H). MS (MH+ found) = 479.2
175. N-(2-Hydroxyethyl)-2-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27), methyl 2-bromoacetate and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.82-2.93 (m, 2H), 3.13-3.25 (m, 4H), 3.32-3.48 (m, 4H), 3.67 (s, 3H), 3.80 (s, 2H), 4.32 (s, 2H), 4.66 (t, J = 5.4 Hz, 1 H), 6.81 (d, J = 8.7 Hz, 2H), 7.18-7.30 (m, 3H), 7.52 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.80 (t, J = 5.8 Hz, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 11.54 (s, 1 H). MS (MH+ found) = 445.2
176. 2-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-N- (2 -hyd roxy ethyl )acetam i de
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24), methyl 2-bromoacetate and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.82-2.95 (m, 2H), 3.12-3.25 (m, 4H), 3.33-3.49 (m, 4H), 3.82 (s, 2H), 4.39 (s, 2H), 4.66 (t, J = 5.4 Hz, 1 H), 4.40 (s, 2H), 7.12-7.46 (m, 4H), 7.54 (dd, J = 7.3 Hz, 7.7 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.76-7.85 (m, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 451.2
177. 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (example 105), methyl 2-bromoacetate and 2- aminoethanol;
The following compounds are obtained by subsequently using the procedure of examples 86 and 87 analogously, with adaptations in the purification step.
178. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ), bromoacetyl bromide and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.19 (bs, 1 H), 2.55-2.66 (m, 2H), 3.20-3.50 (m, 4H), 3.52, 3.57 (2s, 2H [rotamers]), 3.83-3.98 (m, 2H), 3.84 (s, 3H), 4.38 (s, 2H), 4.40-4.50 (m, 1 H), 4.78 (s, 2H), 7.06-7.18 (m, 2H), 7.25 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.55 (ddd, J = 0.9 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.11-8.21 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 481.1
179. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22), bromoacetyl bromide and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.10 (bs, 1 H), 2.55-2.64 (m, 2H), 3.33-3.50 (m, 4H), 3.52, 3.56 (2s, 2H [rotamers]), 3.82-3.97 (m, 2H), 4.32 (s, 2H), 4.42-4.49 (m, 1 H), 4.73-4.81 (m, 2H), 5.91 (s, 2H), 6.75-6.86 (m, 2H), 6.95 (d, J = 2.6 Hz, 1 H), 7.23 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.54 (ddd, J = 1.0 Hz, 7.0 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 459.2
180. 1-[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3- yl]-2-[(2-hydroxyethyl)amino]ethanone
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26), bromoacetyl bromide and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.13 (bs, 1 H), 2.55-2.65 (m, 2H), 3.34- 3.50 (m, 4H), 3.52, 3.57 (2s, 2H [rotamers]), 3.80-3.97 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.35 (s, 2H), 4.40-4.50 (m, 1 H), 4.76, 4.78 (2s, 2H [rotamers]), 6.98-7.12 (m, 2H), 7.15-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 477.2
181. 1 -[6-(3-Chloro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-2-[(2-hydroxyethyl)amino]ethanone Starting compounds: 6-(3-Chloro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 25), bromoacetyl bromide and 2-aminoethanol; 1H-NMR (300 MHz, d6-DMSO); δ = 2.08 (bs, 1 H), 2.54-2.65 (m, 2H), 3.33-3.50 (m, 4H), 3.51 , 3.56 (2s, 2H [rotamers]), 3.77 (s, 3H), 3.82-3.97 (m, 2H), 4.35 (s, 2H), 4.41-4.50 (m, 1 H), 4.76, 4.77 (2s, 2H [rotamers]), 7.04 (d, J = 8.5 Hz, 1 H), 7.20-7.32 (m, 2H), 7.42 (d, J = 2.1 Hz, 1 H), 7.54 (ddd, J = 1.1 Hz, 7.1 Hz, 8.1 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.65 (bs, 1 H). MS (MH+ found) = 479.2
182. 2-[(2-Hydroxyethyl)amino]-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27), bromoacetyl bromide and 2-aminoethanol;
1H-NMR (300 MHz, d6-DMSO); δ = 2.13 (bs, 1 H), 2.56-2.65 (m, 2H), 3.30-3.49 (m, 4H), 3.51 , 3.56 (2s, 2H [rotamers]), 3.67, 3.77 (2s, 3H [rotamers]), 3.82-3.97 (m, 2H), 4.35 (s, 2H), 4.41-4.51 (m, 1 H), 4.75, 4.77 (2s, 2H [rotamers]), 6.82 (d, J = 8.7 Hz, 2H), 7.20-7.32 (m, 3H), 7.50-7.58 (m, 2H), 7.62 (d, J = 8.1 Hz, 1 H), 8.08-8.20 (m, 1 H), 11.48-11.60 (m, 1 H). MS (MH+ found) = 445.2
The following compounds are obtained by using the procedure of example 29 analogously, with adaptations in the purification step.
183. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-3-[N-(2-hydroxyethyl)glycyl]-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one;
184. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-3-[(2-hydroxyethoxy)acetyl]-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c][1 ,7]naphthyridin-1 -one (example 110);
185. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-hydroxyethanone
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-3-(hydroxyacetyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridin-1 -one (example 143);
186. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2A7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1 -one
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-3-[2-hydroxypropanoyl]-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridin-1 -one (example 142);
187. rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
Starting compound: 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1 -one (example 106);
1H-NMR (300 MHz, d6-DMSO); δ = 2.15, 2.17 (2s, 3H [rotamers]), 3.26, 3.64 (2d, J = 12.4 Hz, 1 H [rotamers]), 4.08-4.23, 4.30-4.43, 4.52-4.69, 4.83-4.92 (4m, 4H [rotamers]), 5.33, 5.37 (2s, 2H [rotamers]), 5.43, 5.67 (2d, J543 = 6.9 Hz, J5 67 = 6.5 Hz, 1 H [rotamers]), 7.05 (dd, J = 8.6 Hz, 8.8 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 7.18-7.32 (m, 2H), 7.54 (dd, J = 7.4 Hz, 7.7 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.30 (d, J = 7.9 Hz, 1 H), 11.69, 11.71 (2s, 1 H [rotamers]). MS (MH+ found) = 420.2
188. rac-2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2A7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide Starting compound: 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide (example 177);
The following compounds were obtained by using the procedure of example 101 analogously, with adaptations in the purification step.
189. 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1 -one
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and 3-hydroxypropionic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 2.59-2.70 (m, 2H), 3.24-3.34, 3.37-3.45 (2m, 2H [rotamers]), 3.61-3.74 (m, 2H), 3.84 (s, 3H), 3.88-3.97 (m, 2H), 4.37 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.78, 4.82 (2s, 2H [rotamers]), 7.05-7.18 (m, 2H), 7.25 (dd, J = 7.5 Hz, 7.5 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.66 (s, 1 H). MS (MH+ found) = 452.2 190. rac-1-[6-(3,5-Difluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1 -one
Starting compounds: 6-(3,5-Difluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 21 ) and rac-2,3-dihydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.23-3.68 (m, 4H), 3.83 (s, 3H), 3.83-4.10 (m, 2H), 4.38 (s, 2H), 4.41-4.56 (m, 1 H), 4.61-4.77 (m, 1 H), 4.80, 4.92 (2s, 2H [rotamers]), 4.96-5.10 (m, 1 H), 7.07-7.18 (m, 2H), 7.25 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.55 (dd, J = 7.1 Hz, 8.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 468.2
191. 1 -[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3- hydroxypropan-1 -one
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and 3-hydroxypropionic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.58-2.70 (m, 2H), 3.25-3.35, 3.37-3.46 (2m, 2H [rotamers]), 3.60-3.74 (m, 2H), 3.86-3.97 (m, 2H), 4.41 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.78, 4.81 (2s, 2H [rotamers]), 7.13-7.48 (m, 4H), 7.55 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 422.2
192. rac-i-te^S^-DifluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-S- yl]-2,3-dihydroxypropan-1 -one
Starting compounds: 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) and rac-2,3-dihydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.23-3.68 (m, 4H), 3.80-4.10 (m, 2H), 4.37-4.55 (m, 1 H), 4.42 (s, 2H), 4.61-4.77 (m, 1 H), 4.79, 4.91 (2s, 2H [rotamers]), 4.94-5.10 (m, 1 H), 7.12-7.35 (m, 3H), 7.42 (ddd, J = 2.1 Hz, 8.0 Hz, 11.9 Hz, 1 H), 7.55 (dd, J = 7.0 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.67 (s, 1 H). MS (MH+ found) = 438.2
193. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1 -one
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and 3-hydroxypropionic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 2.58-2.69 (m, 2H), 3.25-3.33, 3.36-3.44 (2m, 2H [rotamers]), 3.62-3.73 (m, 2H), 3.87-3.96 (m, 2H), 4.32 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.77, 4.81 (2s, 2H [rotamers]), 5.91 (s, 2H), 6.76-6.87 (m, 2H), 6.95 (d, J = 1.2 Hz, 1 H), 7.23 (dd, J = 7.3 Hz, 7.5 Hz, 1 H), 7.54 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 430.2
194. rac-1 -[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1 -one
Starting compounds: 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 22) and rac-2,3-dihydroxypropanoic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 3.24-3.45 (m, 2H), 3.47-3.67 (m, 2H), 3.78-4.09 (m, 2H), 4.32 (s, 2H), 4.41-4.55 (m, 1 H), 4.62-4.77 (m, 1 H), 4.79, 4.91 (2s, 2H [rotamers]), 4.93-5.09 (m, 1 H), 5.91 (s, 2H), 6.75-6.87 (m, 2H), 6.95 (d, J = 1.4 Hz, 1 H), 7.23 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.54 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.18 (m, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 446.2
195. i-te^-Ethoxy-S-fluorobenzyO-i^^y-tetrahydro-SH-indolo^.S-cltiyinaphthyridin-S- yl]-3-hydroxypropan-1 -one
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and 3-hydroxypropionic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 2.58-2.69 (m, 2H), 3.24-3.33, 3.36-3.44 (2m, 2H [rotamers]), 3.63-3.73 (m, 2H), 3.88-3.96 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.34 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.77, 4.81 (2s, 2H [rotamers]), 6.99-7.11 (m, 2H), 7.16- 7.28 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.19 (m, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 448.3
196. rac-1 -[6-(4-Ethoxy-3-fluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1 -one
Starting compounds: 6-(4-Ethoxy-3-fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 26) and rac-2,3-dihydroxypropanoic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 1.28 (t, J = 7.0 Hz, 3H), 3.23-3.47 (m, 2H), 3.49-3.67 (m, 2H), 3.80-4.09 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 4.35 (s, 2H), 4.41-4.55 (m, 1 H), 4.62-4.77 (m, 1 H), 4.79, 4.91 (2s, 2H [rotamers]), 4.94-5.09 (m, 1 H), 6.98-7.12 (m, 2H), 7.17-7.29 (m, 2H), 7.54 (dd, J = 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.10-8.20 (m, 1 H), 11.64 (s, 1 H). MS (MH+ found) = 464.2
197. 3-Hydroxy-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]propan-1 -one
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and 3-hydroxypropionic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 2.58-2.70 (m, 2H), 3.24-3.34, 3.37-3.45 (2m, 2H [rotamers]), 3.61-3.75 (m, 2H), 3.67 (s, 3H), 3.86-3.97 (m, 2H), 4.34 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.77, 4.80 (2s, 2H [rotamers]), 6.82 (d, J = 8.6 Hz, 2H), 7.18-7.32 (m, 3H), 7.53 (ddd, J = 0.9 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.09-8.19 (m, 1 H), 11.61 , 11.63 (2s, 1 H [rotamers]).
MS (MH+ found) = 416.3198. rac-2,3-Dihydroxy-1-[6-(4-methoxybenzyl)-1,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1 -one
Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and rac-2,3-dihydroxypropanoic acid; 1H-NMR (300 MHz, d6-DMSO); δ = 3.26-3.35, 3.37-4.46 (2m, 2H [rotamers]), 3.50-3.67 (m, 2H), 3.67 (s, 3H), 3.79-4.08 (m, 2H), 4.35 (s, 2H), 4.40-4.55 (m, 1 H), 4.61-4.78 (m, 1 H), 4.78, 4.90 (2s, 2H [rotamers]), 4.93-5.08 (m, 1 H), 6.82 (d, J = 8.7 Hz, 2H), 7.20-7.32 (m, 3H), 7.53 (ddd, J = 1.0 Hz, 7.1 Hz, 8.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.09-8.19 (m, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 432.2
The following compounds are obtained by using the procedure of example 56 analogously, with adaptations in the purification step.
199. cis-[6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl][2-hydroxycyclopentyl]methanone
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 20) and cis-2-hydroxycyclopentanecarboxylic acid;
1H-NMR (300 MHz, d6-DMSO); δ = 1.45-1.84 (m, 5H), 1.92-2.11 (m, 1 H), 3.04-3.16 (m, 1 H), 3.23-
3.50 (m, 2H), 3.75 (s, 3H), 3.78-4.10 (m, 2H), 4.28-4.43 (m, 3H), 4.72-4.94 (m, 3H), 7.04 (dd, J = 8.6 Hz, 8.7 Hz, 1 H), 7.11 (d, J = 9.2 Hz, 1 H), 7.17-7.29 (m, 2H), 7.54 (dd, J = 7.2 Hz, 8.0 Hz, 1 H),
7.62 (d, J = 8.2 Hz, 1 H), 8.09-8.20 (m, 1 H), 11.62 (s, 1H).
200. cis-(2-Hydroxycyclopentyl)[6-(4-methoxybenzyl)-1,2A7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]methanone Starting compounds: 6-(4-Methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 27) and cis-2-hydroxycyclopentanecarboxylic acid; yield: 27%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.32-1.85 (m, 5H), 1.92-2.14 (m, 1 H), 3.03-3.15 (m, 1 H), 3.21-
3.51 (m, 2H), 3.67 (s, 3H), 3.77-4.10 (m, 2H), 4.27-4.44 (m, 1 H), 4.34 (s, 2H), 4.70-4.94 (m, 3H), 6.82 (d, J = 8.7 Hz, 2H), 7.18-7.32 (m, 3H), 7.53 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.05-8.19 (m, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 456.2
201. [6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yljacetate
Figure imgf000167_0001
jJnaphthyridine (example 24) (1.0 g) is suspended in acetone (5 ml), and dichloromethane (5 ml), triethylamine (400 μl) and methyl bro- moacetate (279 μl) are added and the mixture is stirred for 4 h at room temperature. After that, the mixture is diluted with water (20 ml), extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from acetonitrile / water 4:1 (v/v) to yield 0.78 g (65%) of the title compound. MS (MH+ found) = 422.2
202. i-te-tS^-DifluorobenzyO-i^^.y-tetrahydro-SH-indolop.S-cHiyinaphthyridin-S-yl]^- [(2-hydroxyethyl)amino]ethanone
Step i ^-Bromo-i-tθ^S^-difluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone. 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 24) (500 mg) is suspended in dichloromethane (15 ml), 4-(dimethylamino)pyridine (35 mg) and triethylamine (400 μl) is added and the mixture is cooled to O0C (ice bath). A solution of bromoace- tyl bromide (187 μl) in dichloromethane (5 ml) is added drop by drop within 45 min and the mixture is stirred for 1.5 h at room temperature. After that, it is diluted with water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml), the aqueous phase is extracted with dichloromethane (3 x 30 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 7:3 (v/v)) to yield 510 mg (76%) of 2-bromo-1-[6-(3,4-difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanone. Step 2: 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2- hydroxyethyl)amino]ethanone. 2-Bromo-1-[6-(3,4-difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone (500 mg) is dissolved in dimethylformamide (3 ml), triethylamine (2.37 ml) and 2-aminoethanol (200 mg) are added and the mixture is stirred for 18 h at room temperature. After that, water (10 ml) and saturated sodium hydrogencarbonate solution (10 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 30 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 122 mg (25%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.15 (bs, 1 H), 2.58-2.63 (m, 2H), 3.23-3.35, 3.39-3.49 (2m, 4H [rotamers]), 3.52, 3.57 (2s, 2H [rotamers]), 3.82-3.97 (m, 2H), 4.39-4.50 (m, 1 H), 4.42 (s, 2H), 4.76, 4.78 (2s, 2H [rotamers]), 7.13-7.36 (m, 3H), 7.39-7.47 (m, 1 H), 7.55 (dd, J = 7.3 Hz, 7.5 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.12-8.20 (m, 1 H), 11.67 (s, 1 H). MS (MH+ found) 451.2
203. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1 - one Benzyl Θ^S-fluoro^-nnethoxybenzyO-i-oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine-S- carboxylate (example 104) (0.44 g) is dissolved in glacial acetic acid (10 ml) and concentrated hydrochloric acid (4 ml) is added. The mixture is stirred in a sealed vial at 12O0C for 20 min using microwave radiation. After cooling, the mixture is diluted with water (20 ml) and neutralized by addi- tion of solid sodium carbonate. A yellow precipitate is formed. After 1 h stirring at room temperature, the precipitate is filtered, washed thoroughly with water and ethyl acetate and dried in vacuo to yield 300 mg (93%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 3.76 (s, 3H), 4.15 (s, 2H), 4.54 (s, 2H), 4.61 (s, 2H), 7.06 (dd, J = 8.7 Hz, 8.9 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.23-7.34 (m, 1 H), 7.66 (dd, J = 7.1 Hz, 8.0 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 9.17 (d, J = 8.3 Hz, 1 H), 12.49 (s, 1 H). MS (MH+ found) = 376.2
204. N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1,2A7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]acetamide 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (400 mg) is suspended in acetone (40 ml), potassium carbonate (0.61 g) and 2-bromo-N- (cyclopropylmethyl)acetamide (example A12) (220 mg) are added and the mixture is stirred for 20 h at room temperature. After that, the mixture is diluted with water (40 ml), extracted with di- chloromethane (2 x 70 ml), the combined organic extracts are washed with water (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 97:2:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 265 mg (51 %) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 0.13-0.20 (m, 2H), 0.34-0.42 (m, 2H), 0.90-1.01 (m, 1 H), 2.90 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 6.3 Hz, 2H), 3.19 (s, 2H), 3.32-3.42 (m, 2H), 3.75 (s, 3H), 3.81 (s, 2H), 4.32 (s, 2H), 7.03 (dd, J = 8.6 Hz, 8.8 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 7.14-7.26 (m, 2H), 7.53 (dd, J = 7.3 Hz, 7.9 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.83-7.92 (m, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 473.3
205. N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (400 mg) is suspended in acetone (40 ml), potassium carbonate (0.60 g) and 2-bromo-N- ethylacetamide (200 mg) are added and the mixture is stirred for 20 h at room temperature. After that, the mixture is diluted with water (40 ml), extracted with dichloromethane (2 x 70 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate to yield 410 mg (83%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.03 (t, J = 7.1 Hz, 3H), 2.83-2.92 (m, 2H), 3.08-3.20 (m, 4H), 3.33-3.42 (m, 2H), 3.75 (s, 3H), 3.80 (s, 2H), 4.32 (s, 2H), 6.99-7.13 (m, 2H), 7.15-7.27 (m, 2H), 7.52 (dd, J = 7.1 Hz, 8.1 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.81-7.89 (m, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 447.2
206. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N,N-dimethylacetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (400 mg) is suspended in acetone (40 ml), potassium carbonate (611 mg) and 2-chloro-N,N- dimethylacetamide (137 mg) are added and the mixture is stirred for 20 h at room temperature. After that, the mixture is diluted with water (40 ml), extracted with dichloromethane (2 x 70 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:5:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 185 mg (37%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.85 (s, 3H), 2.87-2.97 (m, 2H), 3.06 (s, 3H), 3.25-3.37 (m, 2H), 3.41 (s, 2H), 3.75 (s, 3H), 3.78 (s, 2H), 4.32 (s, 2H), 6.99-7.13 (m, 2H), 7.16-7.27 (m, 2H), 7.52 (dd, J = 7.4 Hz, 7.6 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.12 (d, J = 7.9 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 447.2
207. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 -oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-methylacetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one hydro- bromide (example 105) (500 mg) is suspended in acetone (15 ml), potassium carbonate (600 mg) and 2-bromo-N-methylacetamide (170 mg) are added and the mixture is stirred for 19 h at room temperature. After that, the mixture is diluted with water (20 ml), extracted with dichloromethane (2 x 40 ml), the combined organic extracts are washed with water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 149 mg (31 %) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.61 (d, J = 4.7 Hz, 3H), 3.25 (s, 2H), 3.57 (s, 2H), 3.76 (s, 3H), 4.07 (s, 2H), 4.48 (s, 2H), 7.01-7.30 (m, 4H), 7.58-7.70 (m, 2H), 7.83-7.92 (m, 1 H), 9.23 (d, J = 8.3 Hz, 1 H), 12.09 (s, 1 H). MS (MH+ found) = 447.2
208. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 -hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-methylacetamide 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-N- methylacetamide (example 207) (120 mg) is dissolved under nitrogen in methanol (3 ml) and sodium borohydride (102 mg) is added in portions. The mixture is stirred for 20 min at room temperature. After that, saturated aqueous ammonium chloride solution is added drop by drop until gas evolution ceases. The mixture is diluted with water (10 ml), the precipitate is filtered, washed with water and dried over P2O5 to give rise to 84 mg (70%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 2.64 (d, J = 4.7 Hz, 3H), 2.78-2.86 (m, 1 H), 3.02 (d, J = 11.2 Hz, 1H), 3.12-3.26 (m, 2H), 3.58 (d, J = 14.9 Hz, 1H), 3.75 (s, 3H), 3.96 (d, J = 15.0 Hz, 1H), 4.30 (d, AB, J= 14.2 Hz, 1H), 4.38 (d, AB, J= 14.3 Hz, 1H), 5.17 (bd, J= 10.2Hz, 1H), 5.43 (d, J = 10.2 Hz, 1H), 7.04 (dd, J =8.6 Hz, 8.8 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 7.15-7.27 (m, 2H), 7.53 (dd, J= 7.1 Hz, 8.1 Hz, 1H), 7.60 (d, J= 8.2 Hz, 1H), 8.03-8.11 (m, 1H), 8.35 (d, J= 8.0 Hz, 1H), 11.60(s, 1H). MS (MH+ found) = 449.1
209. N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
Step 1: N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide.6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1,7]naphthyridin-1-one (example 203) (100 mg) is suspended in acetone (3 ml), potassium car- bonate (147 mg) and 2-bromo-N-ethylacetamide (47 mg) are added and the mixture is stirred for 20 h at room temperature. After that, the mixture is diluted with water (5 ml), extracted with di- chloromethane (2x 10 ml), the combined organic extracts are washed with water (1 x 15 ml), dried (MgSO4) and concentrated in vacuo. The crude product, N-ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1- oxo-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]acetamide (140 mg), is used in the next step without further purification.
Step 2: N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide.2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]-N-methylacetamide (crude product from step 1) (120 mg) is dissolved under nitrogen in methanol (3 ml) and sodium borohydride (99 mg) is added in portions. The mixture is stirred for 20 min at room temperature. After that, saturated aqueous ammonium chloride solution is added drop by drop until gas evolution ceases. The mixture is diluted with water (10 ml), the precipitate is filtered, washed with water and dried over P2O5 to give rise to 68 mg (57%) of the title compound. 1H-NMR (400 MHz, d6-DMSO);δ= 1.03 (t, J= 7.1 Hz, 3H), 2.77 (dd, J = 2.6 Hz, 11.8Hz, 1H), 3.00-3.30 (m, 5H), 3.58 (d, J= 15.0Hz, 1H), 3.75 (s, 3H), 3.97 (d, J= 15.0 Hz, 1H), 4.31 (d, AB,
J= 14.3 Hz, 1H), 4.39 (d, AB, J= 14.3 Hz, 1H), 5.17 (d, J= 10.1 Hz, 1H), 5.49 (d, J= 10.0 Hz, 1H), 7.04 (dd, J= 8.6 Hz, 8.8 Hz, 1H), 7.12 (d, J= 8.6 Hz, 1H), 7.17-7.28 (m, 2H), 7.53 (dd, J= 7.1 Hz, 7.2 Hz, 1H), 7.60 (d, J= 8.2 Hz, 1H), 8.07-8.14 (m, 1H), 8.35 (d, J= 8.0 Hz, 1H), 11.60 (s, 1H). MS (MH+ found) = 463.1 210. rac-2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1-methyl-1,2,4,7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]acetamide
2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide (example 113) (200 mg) is suspended in dry tetrahydrofuran (5 ml) and methyl mag- nesiumiodide (3M in diethyl ether, 170 μl) is added drop by drop via syringe. The mixture is stirred for 4 h at room temperature; After that, saturated aqueous ammonium chloride solution is added drop by drop until gas evolution ceases. The mixture is diluted with water (20 ml), extracted with dichloromethane (2 x 40 ml), the combined organic extracts are washed with water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)), followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 21 mg (10%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.72 (s, 3H), 2.71 (d, AB, J = 10.8 Hz, 1 H), 2.86 (d, AB, J = 11.2 Hz, 1 H), 3.12 (s, 2H), 3.64 (d, AB, J = 14.6 Hz, 1 H), 3.75 (s, 3H), 3.93 (d, AB, J = 14.6 Hz,
1 H), 4.31 (Cl1 AB1 J = 14.4 Hz, 1 H), 4.35 (d, AB, J = 14.3 Hz, 1 H), 5.41 (s, 1 H), 7.04 (dd, J = 8.6 Hz, 8.8 Hz, 1 H), 7.09-7.23 (m, 4H), 7.49 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 8.86 (d, J = 8.2 Hz, 1 H), 11.59 (s, 1 H). MS (MH+ found) = 449.2
211. N-(2,3-Dihydroxypropyl)-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]acetamide
Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetate (example 47) (300 mg) is dissolved in 3-aminopropandiol (4 ml) and the mixture is stirred for 2 h at 12O0C. After cooling, the solution is poured into saturated ammonium chloride solution (15 ml). The formed precipitate is filtered and washed thoroughly with water. It is dissolved in methanol and dichloromethane and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 159 mg (47%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 2.86-2.94 (m, 2H), 3.03-3.12 (m, 1 H), 3.20 (s, 2H), 3.24-3.41 (m, 5H), 3.48-3.57 (m, 1 H), 3.75 (s, 3H), 3.83 (s, 2H), 4.33 (m, 2H), 4.54 (dd, J = 5.7 Hz, 5.9 Hz, 1 H), 4.76 (d, J = 5.0 Hz), 6.99-7.12 (m, 2H), 7.16-7.27 (m, 2H), 7.53 (dd, J = 7.2 Hz, 8.1 Hz, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.79 (t, J = 5.7 Hz, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 11.56 (s, 1 H). MS (MH+ found) = 493.4
212. 2-[6-(3,4-Difluorobenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c][1,7]naphthyridin-3-yl]-N- (2,3-dihydroxypropyl)acetamide
^-(S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yljacetate (example 201 ) (300 mg) is dissolved in 3-aminopropandiol (4 ml) and the mixture is stirred for 2 h at 12O0C. After cooling, the solution is poured into saturated ammonium chloride solution (15 ml) and water (20 ml). The formed suspension is stirred for 1 h, the precipitate is filtered, washed thoroughly with water and dried over P2O5 to yield 304 mg (89%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.83-2.98 (m, 2H), 3.02-3.14 (m, 1 H), 3.21 (s, 2H), 3.24-3.45 (m, 4H), 3.49-3.59 (m, 1 H), 3.84 (s, 2H), 4.40 (m, 2H), 4.50-4.60 (m, 1 H), 4.77 (d, J = 4.8 Hz), 7.12- 7.46 (m, 4H), 7.54 (dd, J = 7.3 Hz, 7.6 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.75-7.85 (m, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 481.2
213. 1 -[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (1.50 g) is suspended in dichloromethane (30 ml) and DMF (5 ml) and 3-hydroxy-2- (hydroxymethyl)-2-methylpropanoic acid (2.14 g), 1-hydroxybenzotriazole (1.69 g), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (3.20 g) and triethylamine (5.33 ml) are added. The mixture is stirred for 5 d at room temperature. After that, water (100 ml) and dichloromethane (150 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 150 ml), the combined organic extracts are washed with water (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl ace- tate / methanol / triethylamine 80:20:1 (v/v/v)) followed by crystallization from ethyl acetate to give rise to 450 mg (23%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.18 (s, 3H), 3.29-3.40 (m, 2H), 3.62 (d, J = 5.6 Hz, 4H), 3.75 (s, 3H), 3.96-4.09 (m, 2H), 4.35 (s, 2H), 4.54 (t, J = 5.6 Hz, 2H), 4.85 (s, 2H), 6.98-7.14 (m, 2H), 7.17-7.28 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 1 1.61 (s, 1 H).
MS (MH+ found) = 478.2
214. 1-[6-(1,3-Benzodioxol-5-ylmethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-3-hydroxy-2-(hydroxymethyl)-2-methylpropan-1-one 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 22) (143 mg) is suspended in dichloromethane (8 ml) and DMF (1 ml) and 3-hydroxy-2- (hydroxymethyl)-2-methylpropanoic acid (114 mg), 1-hydroxybenzotriazole (108 mg), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (191 mg) and triethylamine (133 μl) are added. The mixture is stirred for 5 d at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 98 mg (86%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.18 (s, 3H), 3.30-3.38 (m, 2H), 3.61 (d, J = 4.7 Hz, 4H), 3.98- 4.06 (m, 2H), 4.32 (s, 2H), 4.53 (t, J = 5.5 Hz, 2H), 4.85 (s, 2H), 5.91 (s, 2H), 6.77 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 6.95 (d, J = 1.4 Hz, 1 H), 7.23 (dd, J = 7.3 Hz, 7.7 Hz, 1 H), 7.53 (dd, J = 7.1 Hz, 7.4 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.59 (s, 1 H). MS (MH+ found) = 474.3
215. N-(2,3-Dihydroxypropyl)-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridine-3-carboxamide
Step 1 : N-[(2,2-Dimethyl-1 ,3-dioxolan-4-yl)methyl]-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (0.75 g) is suspended in toluene (25 ml) and N-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]-1 H-imidazole-1-carboxamide (example A13) (0.79 g) and imidazole (0.24 g) are added. The mixture is stirred for 3 h at 11O0C. After that, water (30 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloro- methane (2 x 50 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 70:30 (v/v)) to yield 870 mg (81 %) of N-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]-6-(3- fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide as a light brown oil. Step 2: N-(2,3-Dihydroxypropyl)-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxamide. N-[(2,2-Dimethyl-1 ,3-dioxolan-4-yl)methyl]-6-(3-fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine-S-carboxamide (750 mg) is dissolved in an acetic acid / water mixture (5:1 (v/v), 7.5 ml) and the mixture is stirred for 5 h at 4O0C. After cooling, it is neutralized by addition of 3N aqueous sodium hydroxide solution, ex- tracted with dichloromethane / methanol (9:1 (v/v), 3 x 20 ml), the combined organic extracts are washed with water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol / triethyl- amine 100:10:5 (v/v/v)) followed by crystallization from ethyl acetate / dichloromethane / n-heptane to yield 430 mg (62%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); 5 = 3.00-3.11 (m, 1 H), 3.15-3.37 (m, 5H), 3.47-3.58 (m, 1 H), 3.71- 3.85 (m, 5H), 4.35 (s, 2H), 4.49 (t, J = 5.9 Hz, 1 H), 4.66 (s, 2H), 4.77 (d, J = 4.7 Hz, 1 H), 6.70 (t, J = 5.4 Hz, 5.5 Hz, 1 H), 7.00-7.13 (m, 2H), 7.16-7.28 (m, 2H), 7.54 (dd, J = 7.1 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 479.3
216. 6-(3-Fluoro-4-methoxybenzyl)-N-(2-hydroxyethyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxamide
Step 1 : N-[2-(Benzyloxy)ethyl]-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxamide. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine (example 20) (750 mg) is suspended in toluene (25 ml) and N-[2- (benzyloxy)ethyl]-1 H-imidazole-1-carboxamide (example A14) (865 mg) and imidazole (240 mg) are added. The mixture is stirred for 3 h at 1 1O0C. After that, water (25 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with water (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate) to give rise to 1.1 g (99%) of N-[2-(benzyloxy)ethyl]-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide as a brown oil. MS (MH+ found) = 539.3 Step 2: 6-(3-Fluoro-4-methoxybenzyl)-N-(2-hydroxyethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxamide. N-[2-(Benzyloxy)ethyl]-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide (1.1 g) is dissolved in methanol (200 ml), ammoniumformiate (1.3 g) and palladium (10% on charcoal, 390 mg) are added and the mixture is refluxed for 2 h. After cooling, it is filtered through a short pad of silica gel and washed thoroughly with methanol. The filtrate is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / isopropanol / triethylamine 80:10:10 (v/v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 172 mg (19%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 3.10-3.18 (m, 2H), 3.23- 3.35 (m, 2H), 3.39-3.46 (m, 2H), 3.73- 3.82 (m, 2H), 3.75 (s, 3H), 4.35 (s, 2H), 4.60 (bs, 1 H), 4.64 (s, 2H), 6.68 (t, J = 5.4 Hz, 1 H), 7.04 (dd, J = 8.6 Hz, 8.7 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 1 H), 7.18-7.27 (m, 2H), 7.53 (dd, J = 7.2 Hz, 7.3 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.63 (s, 1 H). MS (MH+ found) = 449.2
217. 2-[6-(3-Fluoro-4-hydroxybenzyl)-1-oxo-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-methylacetamide
Step 1 : 6-(3-Fluoro-4-hydroxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one hydrobromide. Benzyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate (example 104) (2.3 g) is dissolved in glacial acetic acid (80 ml) and hydrogen bromide (5.7M in glacial acetic acid, 22 ml) is added. The mixture is stirred in a sealed vial at 15O0C for 30 min using microwave radiation (6 portions). The precipitate is filtered, washed thoroughly with cold glacial acetic acid (until filtrate is colorless) and ethyl acetate (3 x 20 ml) and dried in vacuo to give rise to 1.27 g (64%) of 6-(3-fluoro-4-hydroxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one hydrobromide. Step 2: 2-[6-(3-Fluoro-4-hydroxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-methylacetamide. 6-(3-Fluoro-4-hydroxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one hydrobromide (250 mg) is suspended in acetone (15 ml), potassium carbonate (300 mg) and 2-bromo-N-methylacetamide (85 mg) are added and the mixture is stirred for 19 h at room temperature. After that, the mixture is diluted with water (10 ml), extracted with di- chloromethane (2 x 30 ml), the combined organic extracts are washed with water (1 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 78 mg (32%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.61 (d, J = 4.7 Hz, 3H), 3.25 (s, 2H), 3.57 (s, 2H), 4.07 (s, 2H), 4.43 (s, 2H), 6.83 (dd, J = 8.5 Hz, 9.1 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 1 H), 7.15 (dd, J = 1.9 Hz,
12.4 Hz, 1 H), 7.26 (dd, J = 6.9 Hz, 7.0 Hz, 1 H), 7.59-7.69 (m, 2H), 7.83-7.91 (m, 1 H), 9.23 (d, J = 8.3 Hz, 1 H), 9.61 (s, 1 H), 12.07 (s, 1 H). MS (MH+ found) = 433.2
218. rac-2-[6-(3-Fluoro-4-hydroxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-N-methylacetamide
2-[6-(3-Fluoro-4-hydroxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N- methylacetamide (example 217) (50 mg) is dissolved under nitrogen in methanol (2 ml) and sodium borohydride (44 mg) is added in portions. The mixture is stirred for 20 min at room temperature. After that, saturated aqueous ammonium chloride solution is added drop by drop until gas evolution ceases. The mixture is diluted with water (10 ml), the precipitate is filtered, washed with water and dried over P2O5 to give rise to 40 mg (81 %) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.63 (d, J = 4.7 Hz, 3H), 2.78-2.86 (m, 1 H), 3.02 (d, J = 11.4 Hz, 1 H), 3.12-3.26 (m, 2H), 3.58 (d, AB, J = 14.9 Hz, 1 H), 3.96 (d, AB, J = 14.9 Hz, 1 H), 4.26 (d, AB, J = 14.2 Hz, 1 H), 4.34 (d, AB, J = 14.2 Hz, 1 H), 5.17 (bd, J = 10.3 Hz, 1 H), 5.43 (d, J = 10.2 Hz, 1 H), 6.81 (dd, J = 8.4 Hz, 9.1 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 7.11 (dd, J = 1.9 Hz, 12.4 Hz, 1 H), 7.23 (dd, J = 7.0 Hz, 7.2 Hz, 1 H), 7.53 (dd, J = 7.2 Hz, 8.0 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 8.02-8.11 (m, 1 H), 8.35 (d, J = 8.1 Hz, 1 H), 9.53 (s, 1 H), 11.59 (s, 1 H). MS (MH+ found) = 435.0
219. 2-[(1f?)-6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
3-Nitrophenylboronic acid (230 mg), D-(-)-tartaric acid (210 mg) and calcium hydride (127 mg) are suspended in THF (6 ml) and heated under reflux for 2 h. The suspension is filtered under nitrogen atmosphere. 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide (example 1 13) (200 g) is dissolved in the filtrate and sodium borohydride (53 mg) is added in 5 portions. The mixture is stirred for 1 h at room temperature. After that, methanol (1.5 ml) is added slowly (hydrogen evolution) and the mixture is stirred for 15 min at room temperature. Next, 1 M aqueous hydrochloric acid (19 ml) is added (pH = 1 ) and stirring is continued for 1 h. The mixture is basified with 2M aqueous sodium hydroxide solution (pH = 12), water (25 ml) is added and the mixture is extracted with dichloromethane (3 x 50 ml). The combined organic layers are washed with saturated aqueous sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane to ethyl acetate / dichloromethane / methanol / triethylamine 60:35:5:1 (v/v/v/v)) to yield 66 mg (33%) of the title compound. The 1H NMR and MS spectra are identical to those of example 114. enantiomeric excess: 30%ee (R) (determined using the following method: column: CHIRALPAK® AD-H 5 μm - 250 x 4.6 mm; mobile phase: n-heptane / isopropanol 75:25 (v/v); flow 1 ml/min; detection UV 240 nm; temperature 250C; tR (R-isomer) = 13.8 min, tR (S-isomer) = 17.8 min); assignment of absolute configuration by analogy (cf., e.g., Organic Process Research & Development 2006, 10, 949).
220. 1 -[6-(3-Fluoro-4-methoxy-benzyl)-1 ,2,4,7-tetrahydro-indolo[2,3-c][1 ,7]naphthyridin-3- yl]-2-methoxy-ethanone
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 20) (150 mg) is suspended in dry dichloromethane, triethylamine (80 mg) and methoxyacetyl chloride (45 mg) are added and the mixture is stirred at room temperature for 4 days. After that, sodium carbonate solution is added. The aqueous phase is extracted with dichloromethane, the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / methanol 9:1 (v/v)) followed by crystallization from diethyl ether to yield 110 mg (61 %) of the title compound. TLC: Rf silica (ethyl acetate / methanol, 9/1 (v/v)) = 0.55
Commercial utility
The compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable.
The compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable. In particular, as type 5 phosphodiesterase (PDE5) inhibitors, they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms. In particular, the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect. The compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
Accordingly, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie's disease; acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, extrinsic allergic alveolitis; inflammatory diseases, such as, but not limited to, vasculature inflammation, acute respiratory distress syndrome, mesangial glomerulonephritis, chronic inflammatory bowel disease, disseminated intravascular inflammation, allergic vasculitis, dermatoses (e.g., but not limited to, psoriasis, toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, fol- licular and widespread pyodermias, endogenous and exogenous acne, acne rosacea), disorders of the arthritis type (e.g., but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [e.g., but not limited to, AIDS (acquired immunodeficiency syndrome), multiple sclerosis], graft versus host reaction, allograft rejections, shock [e.g., but not limited to, septic shock, endotoxin shock, gram-negative sepsis shock, toxic shock syndrome and ARDS (adult respiratory distress syndrome)], gastrointestinal inflammations (e.g., but not limited to, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions (e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps); pain, such as, but not limited to, inflammatory pain; right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia; ischaemic diseases, such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlu- sion, congestive heart failure; diabetic gastroparesis and diseases with symptoms of gastroparesis; diseases or conditions in which it is desirable to suppress platelet function, for example, but not limited to, after stent implantations (e.g., but not limited to, coronary stenting), after bypass operations, in pulmonary hypertension, thrombotic diseases, post-angioplasty stenosis, coronary artery disease, infarction (e.g., but not limited to, myocardial infarction), instable angina pectoris, stroke, and arterial and venous occlusion diseases (e.g., but not limited to, claudicatio intermittens); diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, such as, but not limited to, arteriosclerotic dementia, multi-infarct dementia, cerebral senility; diseases which are based on neuronal damage or degradation, such as but not limited to, stroke, spinal cord injury, brain injury, morbus parkinson, amyotrophic lateral sclerosis, morbus alzheimer, amyloidosis, prion diseases and neuropathy; peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia (Alzheimer's disease), Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encepha- lopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia; portal hypertension, liver cirrhosis, toxic liver damage (e.g., but not limited to, alcohol-induced liver damage), hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins (e.g., but without limitation, due to tumors), arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis (bilharziosis), sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders (e.g., but not limited to, chronic myeloid leukemia, osteomyelofibrosis), lymphatic systemic diseases, collagenosis (e.g., but not limited to, systemic lupus erythematodes, sclerodermia), morbus Osier (congenital arteriovenous malformations, inter alia in the liver), nodular regenerative hyperplasia, tricuspid insuffi- ciency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis; benign prostatic hyperplasia; overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction; insufficient brain skills, such as but not limited to, verbal attainment, attention, concentration, deductive thinking, central auditory processing, cognition, learning, vigilance, apprehension and reagibility.
In a further embodiment, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pul- monale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fis- tula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
In this respect, the term "pulmonary hypertension" in particular embraces pulmonary arterial hypertension including primary pulmonary hypertension (e.g. sporadic or familial) and pulmonary arterial hypertension related, for example, but without limitation, to collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, human immunodeficiency virus infection, drugs or toxins (e.g., but not limited to, anorexigens), persistent pulmonary hypertension of the newborn; pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central pul- monary veins (e.g. fibrosing mediastinitis, adenopathy in relation to tumors), pulmonary veno- occlusive disease; pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), inter- stitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomatosis.
Preferably, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
Furthermore, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, em- physema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
In particular, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway dis- ease, such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
The invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In particular, the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Especially, the invention relates to a method of treating or preventing a disease which is alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
The invention relates to a method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neu- ronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic dis- eases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills Preferably, the invention relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds of the invention can be used. Preferably, one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
In a particularly preferred embodiment of the invention, the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
The invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention. In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
In this respect, the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
Examples of corticosteroids include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide. Examples of anticholinergics include without limitation in- dacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide. Examples of beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate. Examples of lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril auch as colfosceril palmi- tate, surfactant-TA, and calfactant. Examples of endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium. Examples of prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epopros- tenol sodium and treprostinil such as treprostinil sodium. Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine. Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, at- enolol and nadolol. Examples of type 4 phosphodiesterase inhibitors include without limitation ro- flumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast. Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride. Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin. Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab. Examples of diuretics include without limitation furosemide, bumetanide and torsemide. Examples of digitalis glycosides include without limitation digoxin and digitoxin.
In a preferred embodiment, the pharmaceutical composition comprises a compound of the inven- tion in combination with a corticosteroid. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and budesonide, a compound of the invention and fluticasone, a compound of the invention and beclometasone, a compound of the invention and triamcinolone, or a compound of the invention and ciclesonide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and indacaterol, a compound of the invention and tiotropium, or a compound of the invention and ipratropium.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic. In a particularly preferred embodiment, the pharma- ceutical composition comprises: a compound of the invention and formoterol, or a compound of the invention and salmeterol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant. In a particularly preferred embodiment, the phar- maceutical composition comprises: a compound of the invention and lusupultide, a compound of the invention and poractant alfa, a compound of the invention and sinapultide, a compound of the invention and beractant, a compound of the invention and bovactant, a compound of the invention and colfosceril, a compound of the invention and surfactant-TA, or a compound of the invention and calfactant.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bosentan, a compound of the invention and ambrisentan, or a compound of the invention and sitaxsentan. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and iloprost, a compound of the invention and epoprostenol, a compound of the invention and triprostinil.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and amlodipine, a compound of the invention and nifedipine, a compound of the invention and diltiazem, a compound of the invention and verapamil, or a compound of the invention and felodipine. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bisoprolol, a compound of the invention and nebivolol, a compound of the invention and metoprolol, a compound of the invention and carvedilol, a compound of the invention and atenolol, or a compound of the invention and nadolol. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and roflumilast, a compound of the invention and roflumilast N-oxide, a compound of the invention and cilomilast, a compound of the invention and tetomilast, or a compound of the invention and oglemilast.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bupropion.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and amoxicillin, a compound of the invention and ampicillin, a compound of the invention and levofloxacin, a compound of the invention and clarithromycin, a compound of the invention and ciprofloxacin, a compound of the invention and telithromycin, or a compound of the invention and azithromycin.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and clopidogrel, a compound of the invention and enoxaparin, a compound of the invention and cilostazol, a compound of the invention and nadroparin, a compound of the invention and warfarin, or a compound of the invention and abciximab. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a diuretic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and furosemide, a compound of the invention and bumetanide, or a compound of the invention and torsemide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and digoxin, or a compound of the invention and digitoxin.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention, budesonide and indacaterol, a compound of the invention, budesonide and formoterol, a compound of the invention, budesonide and salmeterol, a compound of the invention, fluticasone and indacaterol, a compound of the invention, fluticasone and formoterol, a compound of the invention, fluticasone and salmeterol, a compound of the invention, beclometasone and indacaterol, a compound of the invention, beclometasone and formoterol, a compound of the invention, beclometasone and salmeterol, a compound of the invention, triamcinolone and indacaterol, a compound of the invention, triamcinolone and formoterol, a compound of the invention, triamcinolone and salmeterol, a compound of the invention, ciclesonide and indacaterol, a compound of the invention, ciclesonide and formoterol, or a compound of the invention, ciclesonide and salmeterol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention, budesonide and tiotropium, a compound of the invention, budesonide and ipratropium, a compound of the invention, fluticasone and tiotropium, a compound of the invention, fluticasone and ipratropium, a compound of the invention, beclometasone and tiotropium, a compound of the invention, beclometasone and ipratropium, a compound of the invention, triamcinolone and tiotropium, a compound of the invention, triamcinolone and ipratropium, a compound of the invention, ciclesonide and tiotropium, or a compound of the invention, ciclesonide and ipratropium.
The above mentioned compound of the invention is preferably a compound according to the examples.
The invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
The invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
Futhermore, the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%. In case at least one therapeutic agent selected from the group consist- ing of corticosteroids, anticholinergics, beta-mi metics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics is present in the pharmaceutical compositions of the invention, the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is pref- erably in the range of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%, under the provision that the total amount of the compound or compounds of the invention and the therapeutic agent or therapeutic agents is less than 100 wt%. Preferably, the at least one compound of the invention and the at least one therapeutic agent are present in the pharmaceutical composition in a weight ratio of from 1000 : 1 to 1 : 1000, more preferably 500 : 1 to 1 : 500.
As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes. In particular, auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
The pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dra- gees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). Additionally, the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the com- pound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers).
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticho- linergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, the compound of the invention and the therapeutic agent may be formulated together into the same dosage form (e.g., but not limited to, tablets), separately into the same dosage form (e.g., but not limited to, tablets), or into different dosage forms (without limitation e.g. the compound of the inven- tion may be formulated as tablet and the therapeutic agent may be formulated as powder, solution or suspension).
The pharmaceutical compositions can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulat- ing, entrapping or lyophilizing processes. The selected formulation depends inter alia on the route of administering the pharmaceutical composition. The pharmaceutical compositions of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcu- taneous, intracutaneous, topical, transdermal, intranasal, intraocular, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administration is preferred.
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides, the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes, e.g., without limitation, the compound of the invention can be administered orally and the therapeutic agent can be administered by inhalation or instillation.
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer.
Administration by inhalation or instillation is preferably made by using an aerosol. The aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
The aerosol may be generated by means of aerosol-producing devices such as dry powder inhal- ers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the compound of the invention, and optionally the therapeutic agent, to be administered, the aerosol-producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the sol- vent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of carriers include, but are not limited to, saccharides, e.g. lactose and glucose. Examples of propellants in- dude, but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).
Specific aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, No- volizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers. The aerosol-producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
For parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration, preferably solu- tions (e.g., but not limited to, sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations.
For intraocular administration, solutions to be applied in drop form, gels and ointments are exemplified formulations.
Generally, the pharmaceutical compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for type 5 phosphodiesterase inhibitors. In particular, a dose in the range of from 0.01 to 4000 mg of the compound of the invention per day is preferred. In this respect, it is to be noted that the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, anticoagulants, diuretics and digitalis glycosides,the same dose ranges apply to the therapeutic agent.
The pharmaceutical compositions according to the invention can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the compound of the invention. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticoster- oids, anticholinergics, beta-mi metics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the therapeutic agent. Furthermore, the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the compound of the invention in form of a sparingly soluble salt or by using the compound of the invention coupled to a polymer. Administration of the pharmaceutical composition in a single dose per day is preferred.
In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, administration of the compound of the invention and administration of the therapeutic agent can be made simultaneously or sequentially. In case of sequential administration, the compound of the invention can be administered before or after administration of the therapeutic agent.
Biological investigations
Method for measuring inhibition of PDE5 activity:
As a source for human PDE5, platelets were used. For that purpose, 150 ml fresh blood from human donors anticoagulated with citrate [final concentration 0.3% (w/v)] was centrifuged at 200 g for 10 min to obtain the so-called platelet-rich-plasma (PRP) as a supernatant. 1/10 volume of ACD solution (85 mM Na3-citrate, 1 11 mM D-glucose, 71 mM citric acid, pH 4.4) was added to 9/10 volume of PRP. After centrifugation (1 ,400 g, 10 min) the cell pellet was resuspended in 3 ml homog- enization buffer (NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI2 1 mM, Tris-HCI 20 mM, beta- mercaptoethanol 1 mM, pH 8.2) plus protease-inhibitor mix giving rise to the final concentrations of 0.5 mM Pefablock (Roche), 10 μM Leupeptin, 5 μM Trypsininhibitor, 2 mM Benzamidin and 10 μM Pepstatin A. The suspension was sonified and thereafter centrifuged for 15 min at 10,000 g. The resulting supernatant (platelet lysate) was used for enzymatic testings.
PDE5A1 activity is inhibited by the compounds of the invention in a modified SPA (scintillation proximity assay) test, supplied by Amersham Biosciences (see procedural instructions "phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090"), carried out in 96-well microtitre plates (MTP's). The test volume is 100 μl and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg2+, 1 μM motapizone, 10 nM PDE2 inhibitor BAY-60-7550, 0.5 μM cGMP (including about 50,000 cpm of [3H]cGMP as a tracer), 1 μl of the respective compound dilution in dimethylsulfoxide (DMSO) and sufficient PDE5-containing platelet lysat (10,000xg supernatant, see above) to ensure that 10-20 wt% of the cGMP is converted under the said experimental conditions. The final concentration of DMSO in the assay (1 % v/v) does not substantially affect the activity of the PDE investigated. After a preincubation of 5 min at 370C, the reaction was started by adding the substrate (cGMP) and the assay was incubated for a further 15 min; after that, it was stopped by adding SPA beads (50 μl). In accordance with the manufacturer's instructions, the SPA beads had previously been resuspended in water, but were then diluted 1 :3 (v/v) in water; the diluted solution also contains 3 mM 8-methoxymethyl-3-isobutyl-1-methylxanthine (IBMX) to ensure a complete PDE activity stop. After the beads have been sedimented (> 30 min), the MTP's are analyzed in commercially available luminescence detection devices. The corre- sponding IC50 values of the compounds for the inhibition of PDE activity are determined from the concentration-effect curves by means of non-linear regression.
Representative inhibitory values determined for the compounds of the invention are given in the following Table:
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001

Claims

Claims:
1. Compound of Formula (I)
Figure imgf000202_0001
wherein A^ and A^ are each independently selected from the group consisting of C, N, O and S, wherein one of A^ and A^ is N, O or S; n represents 0 or 1 ;
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA03RA04. or
RA01 and RA02 combine to form an oxo-group; or RA01 and RA02 combine to form the group -0-CH2-CH2-O-; with the proviso that, if RA01 and RA02 combine to form an oxo-group or RA01 and RA02 combine to form the group -O- CH2-CH2-O-, A1 may not be N, O or S;
RA03 and RA04 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, _NRA05RA06 and -C(O)-NRA07RA08,
-C(0)-RA09, -C(O)-NRA010RA01 1 and _C(0)ORA012; or
RA03 ancj RA04 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -NRA013RA014 and _C(O)-NRA015RA016, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA017 O and S;
RA05 and RA06 are each indpendently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA05 and RA06 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|_g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA018 Q and S;
RA07 ancj RA08 are eacn independently selected from the group consisting of hydrogen and C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
RA07 ancj RA08 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from N R^O 19 o and S;
RA09 js selected from the group consisting of hydrogen and C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA010 ancj RA011 are each independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA012 is Ci_6_a|ky| wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA013 and RA014 nave the same meanings as RA05 and RA06, and RA015 and RA016 nave tne same meanings as RA07 anc| RA08-
RA017 RA018 and RA019 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA11 and R^12 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via C or N, with the proviso that, if the 3- to 7-mennbered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA125, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
wherein the Cg.-14-aryl is optionally substituted, C-| _-| 3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and
S, and wherein the heteroaryl is optionally substituted, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by RA125 -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17)|.CORA18] -CO(CRA19RA110)k.RA111 and a lone pair; or in case A1 is S, it is optionally substituted by one or two oxo-groups;
wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA15 js selected from the group consisting of hydroxy, C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA112RA113.
RA16 ancj RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg_i4-aryl, wherein the Cg.-14-aryl is optionally substituted, and _NRA114RA115; or RA16 ancj RA17 combine to form a Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA18 js selected from the group consisting of hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
_NRA116RA117.
RA19 ancj RA110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA118RA119; or RA19 ancj RA110 combine to form a Cβ^-cyclyl, wherein the Cβ.s-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA19 and RA110 combine to form an oxo-group;
RA111 js selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)RA120, -NRA121 RA122, -CONRA123RA124, C1 -6- alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-|.6-alkoxy, wherein the C-|.6-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.6-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-i.-13-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N,
O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkoxy via C, N is substituted by RA^2^, and _NRA125RA126.
RA112 ancj RA113 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)ORA127, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or
N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C1 _g- alkyl via C, N is substituted by RA128; or RA112 ancj RA113 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA128 O and S;
RA114 ancj RA115 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA116 ancj RA117 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted,
C-|_g-heteroaryl, wherein the C-j.g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-j.g-heteroaryl is optionally substituted, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA128, and _NRA129RA130 -C(O)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the S(O)2-C1. β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 -CONRA132RA133; or
RA116 anc| RA117 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA1311 o and S;
RA118 anc| RA119 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1.6-alkyl, wherein the C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA120 js selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA121 and RA122 are each independently selected from the group consisting of hydrogen, C-|. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C-|_g-heteroaryl, wherein the C-j.g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-j.g-heteroaryl is optionally substituted,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA131 , -NRA134RA135 and .CONRA136RA137 -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -CONRA138RA139, -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2NRA140RA141 Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-i.-13-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142- or
RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q ancj S;
RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted,
C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA128,
C6.14-aryl, wherein the Cβ.-|4-aryl is optionally substituted,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from
N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA128 C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O)2-C1.6-alkyl, wherein the -S(O)2-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or RA123 ancj RA124 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA131 Q and S;
RA125 RA126 RA128 RA131 and RA142 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1. g-alkyl, wherein the -C(O)-C-] .β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA127 js represented by C-j.-jQ-alkyl, wherein the C-|_-|rj-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA129, RA130, RA134 RA135, RA138 RA139, RA140 and RA141 are each independently selected from the group consisting of hydrogen and C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA132, RA133, RA136, RA137, RA143 and RA144 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA21 and RA22 have the same meanings as RA^ ^ and R^^-
RA31 and RA32 are each independently selected from the group consisting of hydrogen, hydroxy, C-j.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA33RA34. or
RA31 anc| RA32 combine to form an oxo-group, or RA31 ancj RA32 combine to form the group -O-CH2-CH2-O-; with the proviso that, if R^31 and RA32 combine to form an oxo-group or R^31 and R^32 combine to form the group -0-CH2-CH2- O-, A^ may not be N, O or S;
RA33 ancj RA34 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)H and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RB51 JS selected from the group consisting of hydrogen, halogen, C 1.β-alkyl, hydroxy, C-1.3- alkoxy, nitro, amino, -NH-C(O)- Ci_2-alkyl, -NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB71 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen;
a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
2. Compound according to claim 1 , wherein one of the substituents A^ and A^ is selected from N and O, and the other substituent is a carbon atom; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
3. Compound according to claim 1 or 2, wherein one of the substituents A^ and A^ is a nitrogen atom and the other is a carbon atom; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
4. Compound according to any one of claims 1 to 3, wherein R^01 and R^02 are each independently selected from the group consisting of hydrogen and hydroxy, wherein the carbon atom to which the substituents R^01 and R^02 t^iincd is in the R-configu ration, or R^01 and R^02 combine to form an oxo-group, with the proviso that, if R^01 and R^02 combine to form an oxo-group, A^ may not be N, O or S; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
5. Compound according to any one of claims 1 to 4, wherein R^31 and R^32 are each inde- pendently selected from the group consisting of hydrogen, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, or RA31 ancj RA32 combine to form an oxo-group, with the proviso that, if R^31 and R^32 combine to form an oxo-group, A2 may not be N, O or S; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
6. Compound according to any one of claims 1 to 5, wherein R^ 11 , RA12 RA21 and R^22 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA125, -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -SO2NRA1 SRAM1 .(CH2)m-RA15, _(CRA16RA17^c0RAIe -CO(CRA19RA110)k.RA111 and a lone pair; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
7. Compound according to any one of claims 1 to 6, wherein RA16 and RA17 are each inde- pendently selected from the group consisting of hydrogen, hydroxy and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or RA16 and RA17 combine to form a Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein RA18 js selected from the group consisting of C-j.β-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRA116RA117 and wherein
RA19 ancj RA110 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by fluoro and hydroxy, or RA19 ancj RA110 combine to form an oxo-group, and wherein RA111 js selected from the group consisting of hydrogen, hydroxy, -NRA121 RA122 _CONRA123RA124 and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.-|3-heteroaryl, wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the heteroaryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkoxy via C, N is substituted by RA125 ancj wherein RA112 ancj RA113 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein
RA116 ancj RA117 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|_g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1. g-alkyl, wherein the S(O)2-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA131 and wherein ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkyl via C, N is substituted by RA131 , -C(O)-C1.6-alkyl wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2-C1.6-alkyl, wherein the -S(O^-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA142 or
RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -CONRA143RA144 and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA131 Q and S, and wherein RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein
RA129 ancj RA130 are eacn independently selected from the group consisting of hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein RA132 ancj RA133 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxyl; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
8. Compound according to any one of claims 1 to 7, wherein
RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, and wherein RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
9. Compound according to any one of claims 1 to 8, wherein
n is 1 , A1 is N, A2 is C, RA01 , RA02, RA21 and RA22 are each hydrogen, and one of the substituents RA11 and RA^2 is a lone pair; or
n is 0, A1 is C, A2 is N, RA01 , RA02, RA31 and RA32 are each hydrogen, and one of the substitu- ents RA2^ and RA22 is a lone pair; or
n is 1 , A^ is C, A2 is N, one of the substituents RA2^ and RA22 is a lone pair and RA3^ and RA32 are both hydrogen or combine to form an oxo-group; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
10. Compound according to any one of claims 1 to 9 selected from the group consisting of Benzyl 5-(3-fluoro-4-methoxybenzyl)-3,6-dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indole-2(1 H)- carboxylate; 5-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 5-(3-Fluoro-4-methoxybenzyl)-2-(methoxyacetyl)-1 ,2,3,6-tetrahydropyrrolo[3',4':5,6]pyrido[3,4- b]indole hydrochloride; 2-Benzoyl-5-(3-fluoro-4-methoxybenzyl)-1 ,2,3,6- tetrahydropyrrolo[3',4':5,6]pyrido[3,4-b]indole; 2-[5-(3-Fluoro-4-methoxybenzyl)-3,6- dihydropyrrolo[3',4':5,6]pyrido[3,4-b]indol-2(1 H)-yl]-2-oxoethanamine; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(4-Methoxybenzyl)-1 , 3,4,7- tetrahydropyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole; 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2-oxide; 6-(3-Fluoro-4-methoxybenzyl)-1 , 3,4,7- tetrahydrothiopyrano[3',4':5,6]pyrido[3,4-b]indole 2,2-dioxide; 6-(3-Fluoro-4-methoxybenzyl)-3- methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine dihydrochloride; Ethyl 6-(3-fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,5- difluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-cJII Jlnaphthyridine-S-carboxylate; Ethyl 6-(1 ,3-benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3- carboxylate; Ethyl 6-(4-fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3,4-difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(3-chloro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Ethyl 6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo^.S-cKI Jlnaphthyridinei e^S.S-Difluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S- c][1 ,7]naphthyridine; 6-(1 ,3-Benzodioxol-5-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(4-Fluoro-3-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine; 6-(3,4-Difluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; Θ^S-Chloro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-cKI Jlnaphthyridine; 6-(4-Ethoxy-3- fluorobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(4-Methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; Methyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4-methoxybenzyl)- 1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; Methyl 6-(3-fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-cJII Jlnaphthyridine-S-carboxylate; 3-Benzyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 6-(3-Fluoro-4- methoxybenzy^-S^morpholin^-ylcarbonyl^.S^J-tetrahydro-I H-indolo^.S-clII Jlnaphthyridine; Θ^S-Fluoro^-methoxybenzyO-N.N-dimethyl-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine- 3-carboxamide; 1-Ethyl-4-{[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]carbonyl}piperazine-2,3-dione; 6-(3-Fluoro-4-methoxybenzyl)-N,N-dimethyl- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-sulfonamide; 2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-oxoacetamide; 2-[6-(3- Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- nnethoxyethyl)-2-oxoacetannide; N-(1 ,3-Benzodioxol-5-ylmethyl)-2-[6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoacetamide; 6-(3-Fluoro-4- methoxybenzyO-S^methylsulfonyl^.S^J-tetrahydro-IH-indolo^.S-cKI Jlnaphthyridine^-te^S- Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N- oxetan-3-ylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-isopropylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^methylsulfonyOacetamide; 2-[6-(3- Fluoro^-methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllpropanannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- methylpropanamide; Methyl [6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethyl}carbamate; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methylethanamine; 2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 6-(3-Fluoro-4- nnethoxybenzyl)-3-(2-nnethoxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Acetyl- 2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin- 3-yl]-N-(2-hydroxyethyl)acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxypropyl)acetamide; 2-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^-hydroxy-i- methylethyl)acetannide; 2-(Dinnethylannino)-1-[6-(3-fluoro-4-nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-(nnorpholin-4- ylacetyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 3-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dinnethyl-3-oxopropan-1-annine; N^-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- oxoethyl}methanesulfonannide; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanol; 1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-ol; 1-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-i-oxobutan^-ol; tert- Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}carbamate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}methylcarbannate; tert-Butyl {2-[6-(3-fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-i-methyl^-oxoethylJcarbamate; tert-Butyl (i-ltθ^S-fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yljcarbonyljpropy^carbannate; 1-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}pyrrolidine-2,5-dione; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dimethyl-1-oxopropan-2-amine; 1-{[6-(3- Fluoro^-nnethoxybenzyO-I ^^J-tetrahydro-SH-indolop.S-cKI Jlnaphthyridin-S- yl]carbonyl}cyclopropanecarboxamide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c][1 ,7]naphthyridine; Ethyl 3-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoate; 3-[6-(3-Fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-oxopropanoic acid; 3-[6-(3-Fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-oxopropanannide; S-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- methyl-3-oxopropanannide; (2S)-1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-1-oxopropan-2-annine; (2R)-1-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methyl-1-oxopropan-2-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethanamine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanannine; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-1-oxopropan-2-annine; 1-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-i-oxobutan^-annine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]ethanamine; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethyl}acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N-dimethylethanannine; 3-[6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propanamide; 3-(Bromoacetyl)-6-(3-fluoro- 4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; N-Ethyl-2-[6-(3-fluoro-4- nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethanannine; 2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)ethanol; N-{2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- ^[I Jlnaphthyridin-S-yll^-oxoethylJcyclopropanannine; N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-oxoethanannine; N-{2- [6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}propan-1 -amine; N-Ethyl-2-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methyl-2-oxoethanamine; 2-[{2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}(methyl)annino]ethanol; rac-2-({2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-oxoethyl}amino)propan-1-ol; 1-{2-[6-(3-Fluoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-oxoethylJazetidin-S-ol; i^-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^- oxoethyl}azetidine-3-carboxamide; 6-(3-Fluoro-4-methoxybenzyl)-3-(pyrrolidin-1-ylacetyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-methoxyethyl)-2-oxoethanamine; 2-({2-[6-(3-Fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- oxoethyl}amino)acetannide; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac- 1-[6-(3-Fl uoro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll-S-hydroxybutan-i-one; rac-i-tθ^S-Fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; Benzyl 6-(3-fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridine-3-carboxylate; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridin-1-one hydrobromide; 3-Acetyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; rac-1-[6-(3,4- Difluorobenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-tθ^S.S-Difluoro^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]^^- hyd roxyethoxy)ethanone ; 6-(3-Fl uoro-4-methoxybenzyl)-3-[(2-hyd roxyethoxy)acetyl]-2 ,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4-Ethoxy-3-fluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1- oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; rac-2-[6-(3-Fluoro-4- methoxybenzy^-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(dimethylannino)ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4- Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3,4-Difluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(1 ,3-Benzodioxol-5- ylmethy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- (dimethylannino)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylamino)-1-[6-(4-fluoro-3- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(4-Ethoxy- 3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 1-[6- (4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxypropan-1-one; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylannino)-1-[6-(4-ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 1-[6-(3-Chloro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxyethanone; 1-[6-(3-Chloro-4- methoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yll^-hydroxypropan-i-one; i-^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone; i-te^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin- 3-yl]-2-(dimethylamino)ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; 1-[6-(4-Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 2-(Dimethylamino)-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-3-[(2S)- 2-hydroxypropanoyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 3-Acetyl-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridin-1-one; 1-[6-(3,5- Difluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S- hydroxybutan-1-one; cis-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl][2-hydroxycyclopentyl]methanone; 1-[6-(3,4-Difluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(3,4- Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl][2- hydroxycyclopentyl]methanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; cis-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; i-te^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S- hydroxybutan-1-one; cis-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- cin Jlnaphthyridin-S-yip-hydroxycyclopentylJmethanone; 3-Hydroxy-1-[6-(4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]butan-1-one; 1-[6-(3,4-Difluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2- hydroxyethoxy)ethanone; 1-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 2-(2- Hydroxyethoxy^i-tθ^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]ethanone; 2-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3- yl]acetamide; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(3,4-Difluorobenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Fluoro-3-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; Methyl [6-(1 ,3-benzodioxol-5-ylmethyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetate; 2-[6-(4-Ethoxy-3-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4-Ethoxy-3-fluorobenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3-Chloro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllethanol^-te^S-Chloro^- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 2-[6-(4- Methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(1 ,3- Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 2-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- cKI Jlnaphthyridin-S-yll-N^-hydroxyethyOacetamide^-^S-Chloro^-methoxybenzyO-i , 2,4,7- tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^-hydroxyethyOacetamide; N-(2- Hydroxyethyl^-tθ^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]acetamide; 2-[6-(3,4-Difluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N- (2-hydroxyethyl)acetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2-hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; 1-[6-(4-Ethoxy-3-fluorobenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2-hydroxyethyl)amino]ethanone; i-^S-Chloro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 2-[(2-Hydroxyethyl)amino]-1-[6-(4-nnethoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1- hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-[(2- hydroxyethyl)amino]ethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1 -hydroxy-1 , 2,4, 7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; rac-1-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2- hydroxyethanone; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1 -hydroxy-1 , 2,4, 7-tetrahydro-3H-indolo[2, 3- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; rac-1-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-2-[6-(3-Fluoro-4- methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-(2- hydroxyethyl)acetamide; 1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(3,5-Difluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(3,4-
DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac-i-tθ^S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1-one; 1-[6-(4-Ethoxy-3- fluorobenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1-one; rac-i-tθ^-Ethoxy-S-fluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^.S- dihydroxypropan-1-one; 3-Hydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]propan-1-one; rac-2,3-Dihydroxy-1-[6-(4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]propan-1-one; cis-[6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-hydroxycyclopentyllnnethanone; cis-(2- Hydroxycyclopenty^IΘ^-nnethoxybenzy^-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S- yl]methanone; ^-(S^-DifluorobenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S- yl]acetate; i-te^S^-DifluorobenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll^-p- hydroxyethyl)amino]ethanone; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridin-1-one; N-(Cyclopropylmethyl)-2-[6-(3-fluoro-4-nnethoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yllacetamide; 2-[6-(3-Fluoro- 4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N,N- dimethylacetamide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-oxo-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-N-methylacetannide; 2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-N-methylacetamide; N-Ethyl-2-[6-(3-fluoro-4- methoxybenzy^-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-clII Jlnaphthyridin-S-yllacetannide; rac- 2-[6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1-methyl-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]acetamide; N-(2,3-Dihydroxypropyl)-2-[6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[6-(3,4-Difluorobenzyl)- I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N^.S-dihydroxypropyOacetamide; 1-[6- (3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxy-2- (hydroxymethyl)-2-nnethylpropan-1-one; 1-[6-(1 ,3-Benzodioxol-5-ylmethyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxy-2-(hydroxynnethyl)-2-nnethylpropan-1-one; N-(2,3- Dihydroxypropyl)-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxamide; 6-(3-Fluoro-4-methoxybenzyl)-N-(2-hydroxyethyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridine-3-carboxamide; 2-[6-(3-Fluoro-4-hydroxybenzyl)-1- oxo-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N-methylacetamide; rac-2-[6-(3- Fluoro^-hydroxybenzyO-i-hydroxy-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-N- methylacetamide; 2-[(1R)-6-(3-Fluoro-4-methoxybenzyl)-1-hydroxy-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide,a salt thereof, or a stereoisomer of the compound or the salt thereof.
11. Compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 for use in the treatment or prophylaxis of diseases.
12. Pharmaceutical composition comprising at least one of the compounds, pharmaceutically acceptable salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to any of claims 1 to 10 together with at least one pharmaceutically acceptable auxiliary.
13. Pharmaceutical composition according to claim 12 further comprising at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics.
14. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
15. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceuti- cal composition for the treatment or prophylaxis of male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic dis- eases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
16. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
17. Use according to claim 16, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
18. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N- oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
19. Method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodi- esterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10.
20. Method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Hunt- ington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno- occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and, insufficient brain skills comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10.
21. Method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10.
22. Method for treating or preventing an acute or chronic airway disease according to claim 21 , in which the acute or chronic airway disease is selected from the group consisting of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
23. Method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10.
PCT/EP2009/060001 2008-08-05 2009-08-03 Benzyl-substituted tetracyclic heterocyclic compounds Ceased WO2010015588A1 (en)

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Citations (3)

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WO2002064590A2 (en) * 2001-02-12 2002-08-22 Lilly Icos Llc Carboline derivatives
WO2008027182A2 (en) * 2006-08-28 2008-03-06 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
EP1953159A1 (en) * 2007-02-05 2008-08-06 Nycomed GmbH 6-Benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds useful as PDE5 inhibitors

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WO2002064590A2 (en) * 2001-02-12 2002-08-22 Lilly Icos Llc Carboline derivatives
WO2008027182A2 (en) * 2006-08-28 2008-03-06 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
EP1953159A1 (en) * 2007-02-05 2008-08-06 Nycomed GmbH 6-Benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds useful as PDE5 inhibitors

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