WO2010015589A1 - Benzyl-substituted tetracyclic heterocyclic compounds as pde5 inhibitors - Google Patents

Benzyl-substituted tetracyclic heterocyclic compounds as pde5 inhibitors Download PDF

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Publication number
WO2010015589A1
WO2010015589A1 PCT/EP2009/060002 EP2009060002W WO2010015589A1 WO 2010015589 A1 WO2010015589 A1 WO 2010015589A1 EP 2009060002 W EP2009060002 W EP 2009060002W WO 2010015589 A1 WO2010015589 A1 WO 2010015589A1
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Prior art keywords
fluoro
hydroxy
alkyl
optionally substituted
group
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PCT/EP2009/060002
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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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Nycomed Gmbh
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Publication of WO2010015589A1 publication Critical patent/WO2010015589A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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

Definitions

  • the invention relates to Benzyl-substituted tetracyclic heterocyclic 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.
  • a further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
  • the compounds of the present invention are characterized by Formula (I) as specified in the following.
  • the invention thus relates to compounds of Formula (I)
  • a ⁇ and A ⁇ are each independently selected from the group consisting of C, N, O and S; with the proviso that at least one of the radicals A ⁇ and A ⁇ is a carbon atom;
  • RA01 anc j RA02 are eacn independently selected from the group 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-
  • R A01 anc j RA02 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;
  • RA03 anc j RA04 are eacn independently selected from the group consisting of hydrogen, C-
  • RA12 are eacn independently selected from the group consisting of hydrogen, C-
  • Cg. 14 -aryl wherein the Cg.-14-aryl 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, 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 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 may be bound to the C-
  • C or N with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C 1 . g-alkyl via C, N is substituted by R A125 , C 3 .g-cyclyl, wherein the C ⁇ .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-i.-13-heteroaryl, wherein the C- ⁇ .-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C- ⁇ .-13-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 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 -R A1 5, .( C RA16 R A17 ⁇ c 0 RAIe -CO(CRA19 R A110 )k . R A111 and a lone pair; or in case A 1 is S, it is optionally substituted by one or two oxo-groups;
  • R A13 anc j RA14 are eacn independently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA15 js selected from the group consisting of hydroxy, C-
  • R A16 anc j RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C- j .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, C 6 .
  • R A19 anc j R A110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, 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; 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 ⁇ g-alkyl, wherein the C-
  • 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- j .g-alkoxy via C, N is substituted by RA125 anc j _ NR A125 R A126.
  • n c j RA113 are eacn independently selected from the group consisting of hydrogen, 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, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • RA114 anc j RA115 are eacn independently selected from the group consisting of hydrogen, C-
  • RA116 anc j RA117 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-
  • C- j .g-heteroaryl 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,
  • 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-
  • 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 heteroatoms selected from NR A131 , O and S;
  • R A118 anc j R A119 are eacn independently selected from the group consisting of hydrogen, C- ] . ⁇ -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 js selected from the group consisting of hydrogen and C-
  • 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-
  • 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-
  • 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-
  • g-alkyl wherein the -C(O)-C- ] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -CONRA 138 RA 139 , -S(O) 2 -C 1 . 6 -alkyl, wherein the -S(O)2-C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O) 2 NR A1 40 R A141 C 6 .
  • 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 RA " I 42 ; 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 1 .g-alkyl, wherein the C-
  • R A123 anc j R A124 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
  • 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 -C(O)-C 1 . g-alkyl, wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -S(O) 2 -C 1 .
  • g-alkyl wherein the -S(O)2-C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or n c 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 heteroatoms selected from NR A131 , O 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- 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-
  • RA21 and R ⁇ 22 have the same meanings as R ⁇ 11 and RA12;
  • R A31 and R A32 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-
  • RA31 anc j RA32 together represent the moiety -O-CH2-CH2-O-, and thus forms a cyclic acetal together with the adjacent C-atom to which they bind; with the proviso that, if R ⁇ 31 and R ⁇ 32 combine to form an oxo-group or R ⁇ 31 and R ⁇ 32 together represent the moiety -O-CH2-CH2-O-, A ⁇ may not be N, O or S;
  • RA33 anc j RA34 are eacn 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- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - 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
  • RB81 JS selected from the group consisting of hydrogen and halogen
  • D ⁇ , D ⁇ , D ⁇ and D ⁇ are each independently selected from the group consisting of C and N;
  • RD1 1 RD21 RD31 anc j RD41 are eacn independently selected from the group consisting of hydrogen, halogen, 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-
  • ⁇ -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(O)-C 1 .5- alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the -C(O)-C 1 . 6 -alkyl via C, N is substituted by R 017 ,
  • R 01 ⁇ , R 01 3 and R 017 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, and -C(O)-C 1 . 6 -alkyl, wherein the -C(O)-C- ] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RD14 RD15 anc j RD16 are each independently selected from the group consisting of hydrogen, C-
  • RD18 js selected from the group consisting of 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
  • RD19 anc j RD110 are each independently selected from the group consisting of hydrogen, C- ] .g-alkyl, wherein the C-
  • RD111 j selected from the group consisting of hydrogen, C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; with the proviso that, if each of D ⁇ , D ⁇ , D ⁇ and D ⁇ is a carbon atom, at least one of the substituents R D11 R D21 R D31 and R D41 is different from hydrogen and at least one of the substituents R B41 , R B51 R B61 R B71 and R B81 j s different from hydrogen.
  • a ⁇ and A ⁇ are each independently selected from the group consisting of C, N, O and S; with the proviso that at least one of the radicals
  • a ⁇ and A ⁇ is a carbon atom
  • 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 R ⁇ 01 and R ⁇ 02 combine to form an oxo group, A ⁇ may not be N, O or S;
  • R A03 anc j R A04 are eac h 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, C(O)H 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
  • d RA12 are eacn 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, hydroxy and a C-i.-13-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-i.-13-heteroaryl is optionally substituted,
  • C 6 . 14 -aryl wherein the Cg.-14-aryl 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, 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 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 may be bound to 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 is substituted by RA125 -S(O) 2 -C 1 . 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 -R A1 5, .( C RA16 R A17 ⁇ c 0 RAIe -CO(CRAI QRAI I O) ⁇ RAI 11 and a lone pair; or in case A 1 is S, it is optionally substituted by one or two oxo-groups;
  • RA13 anc j RA14 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 and hydroxy;
  • RA15 js selected from the group consisting of hydroxy, C- j .g-alkoxy, wherein the C-
  • RA16 anc j RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C- j .g-alkyl, wherein the C- j .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -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, and .
  • NR A114 R A115 ; or RA16 anc j RA17 combine to form a C3_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- j .g-alkyl, wherein the C-
  • R A19 anc j R A110 are eacn independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-
  • R A19 anc j R A110 combine to form a C ⁇ ⁇ -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 ⁇ g-alkyl, wherein the C-
  • Cg.-14-aryl wherein the Cg.-14-aryl is optionally substituted, C-
  • 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
  • the 3- to 7-membered heterocyclyl may be bound to the C 1 . g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the 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-
  • 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 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
  • 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 ⁇ 1 -CONR A132 R A133 ; or RA116 anc j RA117 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 and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatoms selected from NR A131 , O and S;
  • RA118 anc j RA119 are eacn independently selected from the group consisting of hydrogen, C- ] .g-alkyl, wherein the C-
  • RA120 js selected from the group consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • n c j RA122 are eacn independently selected from the group consisting of hydrogen, C-
  • Cg.-14-aryl wherein the Cg.-14-aryl is optionally substituted, C-
  • 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-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C0NR A138 RA 13 ⁇ -S(O) 2 -C 1 . g-alkyl, wherein the -S(0)2-C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O) 2 NR A14 °R A141 , Cg.
  • 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-
  • 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
  • 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 A 128 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)-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, and -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 heteroatoms selected from NR A131 , O and S;
  • R A125 RA126 RA128 R A131 and R A142 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RA127 js represented by C- j .- j Q-alkyl, wherein the C- j .- j Q-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • 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 1 . g-alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • 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 ⁇ 22 have the same meanings as R ⁇ 11 and R ⁇ 12;
  • R A31 and R A32 are eacn independently selected from the group consisting of hydrogen, hydroxy, C 1 . g-alkyl, wherein the C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-
  • R A31 and R A32 com bine to form an oxo-group
  • R A31 and R A32 together represent the moiety -O-CH2-CH2-O-, and thus forms a cyclic acetal together with the adjacent C-atom to which they bind; with the proviso that, if R ⁇ 31 and R ⁇ 32 combine to form an oxo-group or R ⁇ 31 and R ⁇ 32 together represent the moiety -O-CH2-CH2-O-, A ⁇ may not be N, O or S;
  • RA33 anc j RA34 are eacn 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- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and -CH 2 -CH 2 -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
  • D ⁇ , D ⁇ , D ⁇ and D ⁇ are each independently selected from the group consisting of C and N;
  • RD1 1 RD21 RD31 anc j RD41 are eacn independently selected from the group consisting of hydrogen, halogen, C-
  • RD12 RD13 anc j RD17 are eacn 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, 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;
  • RD14 RD15 anc j RD16 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the 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
  • R D19 anc j R D110 are eacn independently selected from the group consisting of hydrogen, C-
  • RD111 is selected from the group consisting of hydrogen, C-
  • R ⁇ 01 and R ⁇ 02 are eacn independently selected from the group consisting of hydrogen, hydroxy and C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
  • RA01 anc j RA02 com bine 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.
  • R ⁇ 01 and R ⁇ 02 a re each independently selected from the group consisting of hydrogen and hydroxy; or
  • RA01 anc j RA02 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.
  • R ⁇ 11 and R ⁇ 12 a re each independently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
  • R ⁇ 11 and RA12 eac h are hydrogen.
  • RA15 is selected from the group consisting of hydroxy
  • RA16 and RA17 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C- j . ⁇ -alkyl, C- j . ⁇ -alkoxy;
  • R ⁇ 16 and R ⁇ a re each independently selected from the group consisting of hydrogen;
  • RA19 a nd RA1 10 a re each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-
  • R A ⁇ 11 is selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)R A120 , -NR A121 R A122 , -CONR A123 R A124 , C ⁇ -alkyl, C- j . ⁇ -alkoxy, wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .g-alkoxy,
  • R A ⁇ ⁇ is selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , C ⁇ -alkyl, C- j . ⁇ -alkoxy, wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .g-alkoxy,
  • RA1 16 anc j RA1 17 are eacn independently selected from the group consisting of hydrogen and C-
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen and C-
  • R A2 ⁇ and R A22 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl,
  • R A2 ⁇ and R A22 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl,
  • R ⁇ 1 and R A ⁇ 2 are eacn 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, -(CR A16 R A17 )
  • RA16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 nave the same meaning as defined above.
  • R A ⁇ 1 and R A ⁇ 2 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl,
  • RA16 anc j RA17 each are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • R A ⁇ 1 and R A ⁇ 2 are each independently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
  • R A ⁇ 1 and R A ⁇ 2 each are methyl.
  • R A ⁇ 1 and R A ⁇ 2 each are hydrogen.
  • R ⁇ 41 j selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R ⁇ 41 j s selected from the group consisting of hydrogen and halogen.
  • R B ⁇ 1 j s selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -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
  • R B ⁇ 1 j s selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
  • R B ⁇ 1 j selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R B ⁇ 1 j selected from the group consisting of halogen and C- j . ⁇ -alkoxy.
  • R ⁇ I ⁇ , R ⁇ I t RD31 anc j RD41 are eacn independently selected from the group consisting of hydrogen, halogen, NH 2 , C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair.
  • R ⁇ I ⁇ , RD21 t RD31 anc j RD41 are eacn independently selected from the group consisting of
  • each of A ⁇ and A ⁇ is carbon
  • each of R A ⁇ 1 , R A 12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen, one of the substituents R A 21 and R A ⁇ 2 J S selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • RA16 anc j RA17 eac h are hydrogen and RA18 j s NR A1 16RA117 W herein RA111 RA116 anc j RA117 have the same meaning as defined above.
  • each of the atoms D ⁇ , D ⁇ , D ⁇ and D ⁇ is a carbon atom and at least one of the substituents R ⁇ ⁇ ⁇ , R ⁇ 1 1 RD31 anc j RD41 J S selected from the group consisting of halogen, NH2, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C- j . ⁇ -alkoxy, wherein the C- j .
  • ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen.
  • at least one of the atoms D ⁇ , D 2 and D 3 is
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair.
  • At least one of the atoms D ⁇ , D 2 and D 3 is N, D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which RD1 1 RD21 anc
  • At least one of the atoms D ⁇ , D 2 , D 3 and D 4 is N and the remaining atoms are C, A ⁇ is C and R ⁇ 11 , RA12 RA31 anc j RA32 eacn are hydrogen.
  • one, two or three of the atoms D ⁇ , D 2 , D 3 and D 4 represent N, and the remaining atoms represent C.
  • each of D ⁇ , D 2 , D 3 and D 4 is C, and A ⁇ is selected from C, N, O and S, with the proviso that at least one of the substituents R D1 1 , R D21 , R D31 and R ⁇ 4 1 is different from hydrogen.
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 2 is hydrogen and the other substituent is hydroxy
  • R ⁇ 2 1 and R ⁇ 22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ ⁇ , RD21 RD31 anc j RD41 J S selected from the group consisting of halogen, NH2, C- j .
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 02 J S hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R ⁇ 01 and R ⁇ O 2 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C- j .
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-
  • each of A ⁇ and A 2 is carbon
  • each of RA1 1 RA12 R31 anc j R32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 2 is hydrogen and the other substituent is hydroxy
  • R ⁇ 2 1 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ 1 ⁇ , R ⁇ 2" ! and R ⁇ 3" ! bind is N
  • the respective substituent(s) represent(s) a lone pair.
  • a ⁇ is C
  • a 2 is N
  • each of R ⁇ 11 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 2" ! and R ⁇ 22 is selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _ (CR A16 R A17J 1- CORAI 8 and .
  • R A18 is NR A1 16 R A1 17 , wherein
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ R A31 anc j RA32 are hydrogen, one of the substituents R A ⁇ 1 and R A ⁇ 2 j s selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • RA16 anc j RA17 eacn are hydrogen and RA18 is NR A116 R A117 wherein RA111 R A116 anc j RA117 nave 16 same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , RA12 R A31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ an d R A22 j s selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • RA16 anc j RA17 each are hydrogen and
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R A ⁇ and R A ⁇ 2 is hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R ⁇ 22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ I ⁇ , RD21 , RD31 anc j RD41 j s selected from the group consisting of halogen, NH2, C- j .
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino,
  • R B41 and R B51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and
  • 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
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t>ind is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH 2 , C- j .
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino, RE351 J S se
  • f rom tne group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - 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
  • RB81 JS selected from the group consisting of hydrogen and halogen.
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 02 J S hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R ⁇ 01 and R ⁇ O 2 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ 1 ⁇ , R ⁇ 2" ! and R ⁇ 31 bind is N, the respective substituent(s) represent(s) a lone pair
  • the respective substituent(s) represent(s) a lone pair
  • R B4 ⁇ is 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- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 is selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen.
  • a ⁇ is C
  • a 2 is N
  • each of R ⁇ 11 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 2" ! and R ⁇ 22 is selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _ (CR A16 R A17J 1- CORAI 8 and .
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino,
  • R B51 j selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • R B61 j selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • R B81 j selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • R A111 R A116 anc j RA117 nave the same meaning as defined above.
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ ⁇ , R A ⁇ R A31 anc j RA32 are hydrogen, one of the substituents R A ⁇ 1 and R A ⁇ 2 j s selected from hydrogen, C-i. ⁇ -alkyl, wherein the C-i. ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _ (CR A16 R A17J 1- CORAI 8 and .
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
  • RB 4 I is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino,
  • R B51 j selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • R B61 j selected from the group consisting of hydrogen and halogen
  • RB71 JS selected from the group consisting of hydrogen and halogen
  • R B81 j selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wh erein
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j R A32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl, wherein the C-i. ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _ (CR A16 R A17J 1- CORAI 8 and .
  • RB 4 I is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino,
  • R B51 j selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -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
  • R B61 j selected from the group consisting of hydrogen and halogen
  • RB71 JS selected from the group consisting of hydrogen and halogen
  • R B81 j selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wherein
  • R A111 R A116 anc j R A117 have the same meaning as defined above.
  • each of A ⁇ and A 2 is carbon
  • each of R A11 R A12 R A31 anc j R A32 are hydrogen
  • one of the substituents R A ⁇ and R A ⁇ 2 is hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R A 01 and R A 02 bind is in the S-configu ration, or R A01 anc j R A02 combine to form an oxo-group
  • R A2 ⁇ and R A22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ ⁇ , R D21 R D31 anc j R D41 j s selected from the group consisting of halogen, NH 2 , C-i.
  • RB41 js selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 02 J S hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R ⁇ 01 and R ⁇ O 2 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH 2 , C- j .
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
  • R B4 ⁇ is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 is selected from the group consisting of hydrogen and halogen
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R A ⁇ 2 t>i ind is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R A22 eac h are methyl
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ 1 ⁇ , R ⁇ 2" ! and R ⁇ 3" ! bind is N
  • the respective substituent(s) represent(s)
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • each of the substituents R A ⁇ and R A ⁇ 2 is hydrogen, or 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 R A 01 and R A 02 bind is in the R-configu ration, or RA01 anc j RA02 combine to form an oxo group, and each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ ⁇ , RD21 RD31 anc j RD41 J S selected from the group consisting of halogen, NH 2 , C- j .
  • RB41 js selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 each are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 nave ⁇ 16 same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • C- j . ⁇ -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C- j . ⁇ -alkoxy, wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
  • RB41 js selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 each are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 nave ⁇ 16 same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ and R A22 j s selected from hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • R B4 1 is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and -CH 2 -CH 2 -O-,
  • RB61 js selected from the group consisting of hydrogen and halogen
  • RB71 js selected from the group consisting of hydrogen and halogen
  • RA16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ ⁇ , R A ⁇ RA31 anc j RA32 are hydrogen, one of the substituents R A ⁇ 1 and R A ⁇ 2 j s selected from hydrogen, C- j . ⁇ -alkyl
  • RA111 RA116 anc j RA117 have the same meaning as defined above.
  • each of the atoms D ⁇ , D ⁇ , D ⁇ and D ⁇ is a carbon atom and at least one of the substituents R ⁇ ⁇ , R ⁇ 1 1 RD31 anc j RD41 J S selected from the group consisting of halogen, NH 2 , C- j . ⁇ -alkyl, C- j . ⁇ -alkoxy and the remaining substituent(s) is/are hydrogen.
  • At least one of the atoms D ⁇ , D ⁇ and D ⁇ is
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH 2 , C-i. ⁇ -alkyl, C-i. ⁇ -alkoxy and a lone pair.
  • at least one of the atoms D ⁇ , D 2 and D 3 is
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair.
  • At least one of the atoms D ⁇ , D 2 and D 3 is N
  • D 4 is C
  • R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which RD1 1 RD21 anc
  • At least one of the atoms D ⁇ , D 2 , D 3 , D 4 , A ⁇ and A 2 is N and the remaining atoms are C and R ⁇ 11 , RA12 RA31 anc j RA32 eacn are hydrogen.
  • At least one of the atoms D ⁇ , D 2 , D 3 , D 4 and A 2 is N and the remaining atoms are C, A ⁇ is C and R ⁇ 11 , RA12 RA31 anc j RA32 eacn are hydrogen.
  • At least one of the atoms D ⁇ , D 2 , D 3 and D 4 is N and the remaining atoms are C, A ⁇ is C and R ⁇ 11 , RA12 RA31 anc j RA32 eacn are hydrogen.
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ OI an d RA02 is hydrogen and the other substituent is hydroxy
  • R ⁇ 2 1 and R ⁇ 22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ I ⁇ , RD21 RD31 anc j RD41 J S selected from the group consisting of halogen, NH2, C- j . ⁇ -alkyl, C- j . ⁇ -alkoxy and the remaining substituent(s) is/are hydrogen.
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 an d R ⁇ O 2 is hydrogen and the other substituent is hydroxy
  • R ⁇ 2 1 and R ⁇ 22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C- j . ⁇ -alkyl, C- j . ⁇ -alkoxy and a lone pair.
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 02 J S hydrogen and the other substituent is hydroxy
  • R A2 ⁇ and R A22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , R A ⁇ 2 , RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • R ⁇ 2" ! , R ⁇ 3" ! and R ⁇ 4 ⁇ is selected from the group consisting of halogen, NH2, C- j . ⁇ -alkyl, C- j . ⁇ -alkoxy and the remaining substituent(s) is/are hydrogen, wherein I is 1 , k is O,
  • RA16 anc j RA17 eac h are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 have the same meaning as defined above ot below.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C-i. ⁇ -alkyl, _ (CR A16 R A17J 1- CORAI 8 and .
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • R A111 R A116 anc j RA117 have the same meaning as defined above ot below.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ an d R A22 j s selected from hydrogen, C- j . ⁇ -alkyl
  • R A16 anc j R A17 eac h are hydrogen and RA18 is NR A116 R A117 wh erein RA111 R A116 anc j R A117 h aV e the same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j R A32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A 01 and R A 02 is hydrogen, or one of the substituents R A ⁇ and R A ⁇ 2 j s hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R A 01 and R A 02 bind is in the R-configuration or R A01 anc j RA02 combine to form an oxo group, and at least one of the atoms D 1 , D 2 and D 3 is N, D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein Ms 1 , k is O, RA16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wh erein
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j R A32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • R A16 anc j R A17 each are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R A ⁇ 2 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R A22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ 1 ⁇ , RD21 , RD31 anc j RD41 j s selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy,
  • 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
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t>ind is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R A22 e ach are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
  • RB41 is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen.
  • a ⁇ is C
  • a 2 is N
  • each of RA11 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 2" ! and R ⁇ 22 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A 01 and R A 02 is hydrogen, or one of the substituents R ⁇ 01 and R ⁇ 02 J S hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R ⁇ 01 and R ⁇ 02 t>ind is in the R-configu ration, or RA01 anc j RA02 combine to form an oxo group, and each of the atoms D ⁇ , D ⁇ , D ⁇ and D ⁇ is a carbon atom and at least one of the substituents R ⁇ I ⁇ , RD21 , RD31 anc j RD41 j s selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-
  • RB51 JS selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 each are hydrogen and
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ 1 , RA12 R A31 anc j RA32 are hydrogen, one of the substituents R A ⁇ 1 an d R A 22 j s selected from hydrogen, C- j . ⁇ -alkyl
  • RB51 JS selected from the group consisting of hydrogen, halogen and C- j .
  • ⁇ -alkoxy RB61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein Ms 1 , k is O,
  • R A18 is NR A1 16 R A1 17 , wherein
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ and R A22 j s selected from hydrogen, C- j . ⁇ -alkyl
  • RB 4 I is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 eac h are hydrogen and
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • RB 4 I is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy,
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 each are hydrogen and
  • R A111 R A116 anc j RA117 nave 16 same meaning as defined above.
  • each of A ⁇ and A 2 is carbon
  • each of RA1 1 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 2 is hydrogen and the other substituent is hydroxy
  • R ⁇ 2 1 and R ⁇ 22 each are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ ⁇ , RD21 RD31 anc j RD41 J S selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen
  • R ⁇ 4" ! is selected from the group consisting of hydrogen, halogen and C- j .
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy 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,
  • each of A ⁇ and A 2 is carbon
  • each of RA11 RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R ⁇ 01 and R ⁇ 2 is hydrogen and the other substituent is hydroxy
  • the carbon atom to which the R ⁇ 01 and R A ⁇ 2 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R A22 each are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
  • RB 4 I is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy, RE351 J S se
  • each of A ⁇ and A 2 is carbon
  • RA32 are hydrogen
  • R A2 1 and R A22 each are methyl
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ 1 ⁇ , R ⁇ 2" ! and R ⁇ 3" ! bind is N
  • the respective substituent(s) represent(s) a lone pair
  • R ⁇ 4 1 is selected from the group consisting of hydrogen, halogen and C- j .
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • 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 ⁇ is C
  • a 2 is N
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A ⁇ and R A ⁇ 2 is hydrogen, or 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 R A ⁇ and R A ⁇ 2 bind is in the R-configu ration, or RA01 anc j RA02 com bine to form an oxo group, and each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ 1 ⁇ ,
  • 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, wherein
  • RA16 anc j RA17 each are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 nave the same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • RB41 is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • 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, wherein
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 have the same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , RA31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ an d R A22 j s selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A ⁇ and R A 2 is hydrogen, or 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 R A ⁇ and R A 2 bind is in the R-configuration or RA01 anc j RA02 combine to form an oxo group, and at least one of the atoms D 1 , D 2 and D 3 is N, D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ I ⁇ , R ⁇ 2" ! and R ⁇ 3" ! bind is N, the respective substituent(s) represent(s) a lone pair, and
  • RB41 is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • 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, wherein
  • RA16 anc j RA17 each are hydrogen and
  • RA111 RA116 anc j RA117 have the same meaning as defined above.
  • each of A ⁇ and A 2 is carbon, each of
  • RA11 RA12 RA31 anc j RA32 are 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 R A 01 and R A 2 bind is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group, and R A2 1 and R A22 each are methyl, and each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ ⁇ ,
  • R ⁇ 2 ⁇ , R ⁇ 3 ⁇ and R ⁇ 4 ⁇ is selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • RB71 js selected from the group consisting of hydrogen and halogen
  • each of A ⁇ and A 2 is carbon
  • RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t>ind is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R A22 each are methyl, and at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
  • RB41 is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • RB51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • 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 ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • R ⁇ 2 ⁇ , R ⁇ 3 ⁇ and R ⁇ 4 ⁇ is selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and
  • R ⁇ 4" ! is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, RB51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy, RE361 J S se
  • R B81 JS selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wherein
  • R A111 R A116 anc j RA117 have the same meaning as defined above.
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ 1 , RA12 R A31 anc j RA32 are hydrogen
  • one of the substituents R A ⁇ 1 an d R A 22 J S selected from hydrogen, C- j . ⁇ -alkyl
  • R B51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • R B61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • R B81 JS selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j R A17 eac h are hydrogen and
  • R A111 R A116 anc j R A117 have the same meaning as defined above.
  • a ⁇ is C
  • a ⁇ is N
  • each of R A ⁇ ⁇ , R A ⁇ R A31 anc j R A32 are hydrogen
  • one of the substituents R A ⁇ 1 and R A ⁇ 2 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A 01 and R A 02 is hydrogen, or one of the substituents R A ⁇ and R A ⁇ 2 j s hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R A 01 and R A 02 bind is in the R-configuration or R A01 anc j RA02 combine to form an oxo group, and at least one of the atoms D 1 , D 2 and D 3 is N, D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
  • RB 4 I is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy,
  • R B51 j selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • R B61 j selected from the group consisting of hydrogen and halogen
  • RB71 js selected from the group consisting of hydrogen and halogen
  • R B81 j selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • R A111 R A116 anc j RA117 have the same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents RA01 and R A 2 is hydrogen, or one of the substituents RA01 and R A ⁇ 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and R A 2 bind is in the R-configuration or R A01 anc j R A02 combine to form an oxo group, and at least one of the atoms D 1 , D 2 and D 3 is N, D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ ⁇ , R ⁇ 2 ⁇ and R ⁇ 3 ⁇ bind is N, the respective substituent(s) represent(s) a lone pair, and
  • R ⁇ 4" ! is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, RB51 j s selected from the group consisting of halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, RE361 J S se
  • RB81 JS selected from the group consisting of hydrogen and halogen, wherein
  • RA16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wherein
  • R A111 R A116 anc j RA117 have the same meaning as defined above.
  • each of A ⁇ and A 2 is carbon
  • each of R A11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 com bine to form an oxo-group
  • RA21 and R ⁇ 22 e ach are methyl
  • each of the atoms D ⁇ , D 2 , D 3 and D 4 is a carbon atom and at least one of the substituents R ⁇ 1 ⁇ , RD21 , RD31 anc j RD41 j s selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen
  • R B51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • R B61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • each of A ⁇ and A 2 is carbon
  • each of RA1 1 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t ⁇ iincd is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R ⁇ 2 e ach are methyl
  • at least one of the atoms D 1 , D 2 and D 3 is N
  • D 4 is C and R D 1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
  • RB 4 I is selected from the group consisting of hydrogen, halogen and C-j. ⁇ -alkoxy, RB51 JS selected from the group consisting of halogen and C-j. ⁇ -alkoxy, RE361 J S se
  • each of A ⁇ and A 2 is carbon
  • each of R A11 RA12 RA31 anc j RA32 are hydrogen
  • the carbon atom to which the R ⁇ 01 and R ⁇ 02 t>ind is in the S-configu ration, or RA01 anc j RA02 combine to form an oxo-group
  • RA21 and R A22 e ach are methyl
  • D 4 is C and R D1 1 , R D21 , R D31 and R D41 are each hydrogen, or, in case the atom to which R ⁇ I ⁇ , R ⁇ 2" ! and R ⁇ 3" ! bind is N
  • the respective substituent(s) represent(s) a lone pair
  • the respective substituent(s) represent(s) a lone pair
  • RB 4 I is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy, RE351 J S se
  • f rom (he group consisting of halogen and C- j . ⁇ -alkoxy, RE361 J S se
  • f rom (he group consisting of hydrogen and halogen, RB ⁇ I js selected from the group consisting of hydrogen and halogen, RB81 JS selected from the group consisting of hydrogen and halogen.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wherein
  • R A111 R A116 anc j RA117 nave 16 same meaning as defined above.
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ 1 , RA12 R A31 anc j RA32 are hydrogen, one of the substituents R A2 ⁇ an d R A22 j s selected from hydrogen, C- j . ⁇ -alkyl
  • RB41 is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • R B51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • R B61 JS selected from the group consisting of hydrogen and halogen
  • RB71 js selected from the group consisting of hydrogen and halogen
  • R B81 JS selected from the group consisting of hydrogen and halogen, wherein
  • R A16 anc j R A17 each are hydrogen and
  • a ⁇ is C
  • a 2 is N
  • each of R A ⁇ ⁇ , R A ⁇ 2 , R A31 anc j R A32 are hydrogen
  • one of the substituents R A2 ⁇ and R A22 is selected from hydrogen, C- j . ⁇ -alkyl
  • RB 4 I is selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy,
  • R B51 JS selected from the group consisting of halogen and C- j . ⁇ -alkoxy,
  • R B61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 wherein
  • At least one of the atoms D ⁇ , D 2 , D 3 , D 4 , A ⁇ and A 2 is N and the remaining atoms are C
  • each of R A ⁇ 1 , R A ⁇ 2 , RA31 a nd R A32 are hydrogen
  • one of the substituents R A2 ⁇ and R ⁇ 22 is selected from hydrogen, C- j . ⁇ -alkyl
  • R A16 anc j R A17 each are hydrogen and R A18 is NR A1 16 R A1 17 , wherein RA111 R A116 anc j R A117 nave 16 same meaning as defined above ot below.
  • at least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen, one of the substituents R ⁇ 21 and R A ⁇ 2 J S selected from hydrogen, C- j . ⁇ -alkyl,
  • R A18 is NR A1 16 R A1 17 , wherein
  • At least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C
  • each of R A ⁇ ⁇ , R A ⁇ R A 31 an d R A 32 are hydrogen
  • one of the substituents R A ⁇ 1 and R A ⁇ 2 is selected from hydrogen, C- j . ⁇ -alkyl
  • each of the substituents R A 01 and R A 2 is hydrogen, or one of the substituents R A ⁇ and R A ⁇ js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R A ⁇ and R A ⁇ bind is in the R-configuration or RA01 and RA02 com bine to form an oxo group, and RD1 1 RD21 RD31 and RD41 are eacn independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein Ms 1 , k is O, RA16 and RA17 eacn are hydrogen and
  • R A1 8 is NR A1 1 6R A1 1 7 , wherein R A111 R A116 anc j RA117 h ave 16 same meaning as defined above.
  • At least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen
  • one of the substituents R A2 1 and R A ⁇ 2 J S selected from hydrogen, C- j . ⁇ -alkyl
  • R D11 R D21 R D31 and R D41 are eacn hydrogen, or, in case the atom to which R D1 1 , R D21 and R D31 bj nc
  • R A18 is NR A116 R A117 wh erein
  • At least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C, each of R A ⁇ ⁇ , R A ⁇ R A31 and R A32 are hydrogen, one of the substituents R A ⁇ 1 an d R A 22 j s selected from hydrogen, C-i. ⁇ -alkyl,
  • At least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C
  • each of R A ⁇ 1 , RA12 RA31 anc j RA32 are hydrogen
  • R B51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy,
  • R B61 JS selected from the group consisting of hydrogen and halogen
  • RB ⁇ I js selected from the group consisting of hydrogen and halogen
  • R A16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A116 R A117 W herein
  • R A111 R A116 anc j RA117 have the same meaning as defined above.
  • At least one of the atoms D ⁇ , D ⁇ , D ⁇ , D ⁇ , A ⁇ and A ⁇ is N and the remaining atoms are C, each of R A ⁇ ⁇ , R A ⁇ R A ⁇ and R A ⁇ a re hydrogen, one of the substituents R A ⁇ 1 and R A ⁇ 2 is selected from hydrogen, C- j . ⁇ -alkyl,
  • R B51 j s selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, R B61 j s selected from the group consisting of hydrogen and halogen, RB71 js selected from the group consisting of hydrogen and halogen, RE381 J S se
  • RA16 anc j RA17 eacn are hydrogen and
  • R A18 is NR A1 16 R A1 17 , wherein
  • RA111 RA116 anc j RA117 nave 16 same meaning as defined above.
  • a ⁇ and A ⁇ are each independently selected from the group consisting of C and N; with the proviso that at least one of the radicals A ⁇ and A ⁇ is a carbon atom; and
  • RA01 anc j RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy; or
  • RA01 anc j RA02 combine to form an oxo group, with the proviso that, if R A ⁇ and R A 02 combine to form an oxo group, A ⁇ may not be N, O or S;
  • R A ⁇ and R A ⁇ are hydrogen
  • R A 21 and R A ⁇ 2 are eacn independently selected from the group consisting of hydrogen, C-
  • RA16 anc j RA17 are hydrogen
  • R A18 is . NR A116 R A117 ;
  • R A19 anc j R A110 are eac h independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-
  • R A111 j selected from the group consisting of hydrogen, hydroxy, -NR A121 R A122 , C ⁇ g-alkyl, wherein the C-
  • R A116 and RA117 are hydrogen
  • R A121 and RA122 are c ⁇ g-alkyl, wherein the C-
  • R A31 anc j RA32 are hydrogen
  • RB41 js selected from the group consisting of hydrogen and halogen
  • RB51 JS selected from the group consisting of hydrogen and C- j . ⁇ -alkoxy;
  • R B71 and R B81 are hydrogen
  • D ⁇ , D 2 , D ⁇ and D ⁇ are each independently selected from the group consisting of C and N;
  • RD1 1 RD21 RD31 anc j RD41 are eac h independently selected from the group consisting of hydrogen, halogen, with the proviso that, if each of D ⁇ , D ⁇ , D ⁇ and D 4 is a carbon atom, at least one of the substituents R D11 R D21 R D31 and R D41 is different from hydrogen and at least one of the substituents R B41 , R B51 R B61 R B71 and R B81 j s different from hydrogen.
  • a ⁇ is C
  • a ⁇ is C or N
  • each of R ⁇ 31 and R A32 are hydrogen
  • R ⁇ 1 a nd R ⁇ 02 are eacn independently selected from the group consisting of hydrogen, hydroxy, or R ⁇ 01 and R ⁇ 02 combine to form an oxo group
  • D ⁇ and D 4 are C
  • R ⁇ 4 1 j s selected from the group consisting of hydrogen or halogen
  • R B61 R B71 R B81 are eacn hydrogen
  • R D1 1 , R D21 , R D31 and R D41 are each independently selected from the group consisting of hydrogen or halogen.
  • the compounds of Formula (I) are selected from the group consisting of
  • 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, with the proviso that, if each of D ⁇ , D ⁇ , D ⁇ and D ⁇ is a carbon atom, at least one of the substituents R ⁇ 1 ⁇ , R ⁇ 21 1 RD31 anc j RD41 J S different from hydrogen.
  • 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 more 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- j . ⁇ -alkyl are more preferred and alkyl groups having 1 to 2 carbon atoms (C-
  • the term "C ⁇ ⁇ -alkyl" used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms.
  • alkyl groups examples 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- dimethylpropyl group
  • 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-di methyl propoxy 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- methylpropoxy group, a 1 ,1 ,2-tri methyl propoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1- dimethylbutoxy group, a 1 ,2-dimethyl
  • 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 C ⁇ .s-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, tetrahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
  • 3- to 7-membered heterocycle used in the specification of the present invention indicates 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 pyrrolidine-2,5-dione group, a piperazine-2,3-dione group and the like.
  • 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 substituents.
  • substituents are hydroxy; C- j .g-alkyl, preferably methyl; C- j .g-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.
  • C- ] .- ] 3-heteroaryl 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 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 examples 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 imidazo
  • 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 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 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- j .g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C- j .g-alkoxy, C ⁇ .g-cyclyl, 3- to 7-membered heterocyclyl, ⁇ 6-14' ar y'' Ci_i3-heteroaryl, an amine and an amide, such as defined, for instance for N R A129 R A130 and -C(O)-NR A136 R A137 , wherein the C ⁇ .g-alkoxy, C 3 . 6 -cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C-
  • 3-heteroaryl have the same meanings as defined above.
  • the C- j .g-alkyl group is substituted by at least one fluorine atom
  • the C- j .g-alkyl group can be any group as specified above with respect to the C- j .g-alkyl, unless specified otherwise.
  • _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 substituted 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 hydroxymethyl, 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-
  • .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 C3_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. ⁇ 4- 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- ⁇ .-13-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 group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C- j .g-alkoxy, C ⁇ .g-cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C-i.-13-heteroaryl, wherein the 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 perfluoroisobutoxy.
  • .g-alkoxy group can be any group as specified above with respect to C-
  • .3- alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 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. Further preferred is that the first mentioned 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 C3_g-cyclyl group can be any group as specified above for C3_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- ⁇ .-13-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-
  • Particularly preferred is a pyridylmethoxy group.
  • C3_g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
  • the C3_g-cyclyl group can be any group as specified above with respect to C3_g-cyclyl, unless specified otherwise.
  • the C3_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 C ⁇ .g-cyclyl, wherein monohydroxy substituted C3_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 substituted 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 substituted 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- ] .g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C- ] .g-alkyl.
  • 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 1 .g-alkyl is -C(O)-CH 3 and -C(O)-CH 2 OH.
  • the above-mentioned 3- to 7-nnennbered heterocycle may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, oxo, 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.
  • the C 1 . g-alkyl group and the C 1 . 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 1 . g-alkyl.
  • .g-alkyl and -C(O)-C 1 . g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C 1 . g-alkyl is -C(O)-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-g Iu euro nates, benzoates, 2-(4- hydroxybenzoyl)benzoates, butyrates, salicylates, sulfosalicylat.es, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fumarates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), me
  • 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 stereoisomers 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, stereoisomers 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.
  • the compounds according to the invention can be prepared as follows.
  • a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (Mb) 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).
  • a compound of formula (IV) can be obtained as shown in reaction scheme 4.
  • a compound of formula (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)].
  • the resulting hydroxy-com pound 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 trifluoroacetic anhydride as activator [see e.g. J. Org. Chem.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 5.
  • a compound of formula (Xl) 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 diisopropylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper(ll)-2-ethylhexanoate.
  • a suitable base e.g. lithium diisopropylamide 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).
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 6.
  • a compound of formula (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-com pound 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 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 :
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 7.
  • a compound of formula (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 compounds of formula (XVI) can be transformed into compounds 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 of formula (V) can be oxidized in a manner known to the skilled person, e.g.
  • reaction scheme 8 An alternative synthetic route to compounds of formula (Ic) is depicted in reaction scheme 8.
  • X being a 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 compounds of formula (XXI) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g.
  • compounds of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXII) with carbonyl diimidazole in the presence of nitromethane 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 (Id) in which R A01 , R A02 , R A11 , R A12 , R A21 , R A22 , R A21 and R A22 are hydrogen and A 1 and A 2 are carbon, can also be obtained by a condensation reaction as shown in reaction scheme 10.
  • a compound of formula (IX) is, for example, reacted with a compound of formula
  • a compound of formula (I) can be converted into different compounds of formula (I) by methods known in the art.
  • 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.
  • a suitable reduction agent such as sodium borohydride
  • 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.
  • a suitable reduction agent such as sodium cyanoborohydride or sodium borohydride
  • a suitable acid e.g. acetic acid or p-toluenesulfonic acid
  • a suitable Lewis acid e.g. titanium(IV) tetraisopropyl oxide
  • a suitable solvent e.g. methanol
  • hydrogenation e.g. with the aid of a transition
  • 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; a compound of formula (I), wherein R A01 is carbonylamino-, -NH-C(O)-R A09 , and R A02 is hydrogen, or wherein R A31 is carbonylamino-, -NH-C(O)-C-
  • 6 -alkyl-C(O)CI that may be optionally substituted as defined above, or carboxylic anhydride, e.g. (R A09 C(O)) 2 O or (C-
  • 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 compound of formula (I), wherein R A01 is alkoxy-, -OC-
  • 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 ⁇ 1 is "substituted alkyl", e.g. -C-
  • a base e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride
  • a compound of formula (I), wherein R ⁇ 1 is carbonyl, e.g. -C(O)(CR A19 R A110 ) k -R A111 , R ⁇ 2 is a free electron pair and A x is N, wherein k is 0 or 1 or 2, and x 1 or 2, can be prepared e.g.
  • R A12 is a free electron pair and A x is N
  • x 1 or 2
  • R A12 is a free electron pair and A x is N
  • a base e.g. triethylamine or pyridine
  • R ⁇ 2 is a free electron pair and A x is N
  • a base e.g. triethylamine or pyridine
  • a base e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride
  • a base e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride
  • a suitable polar, aprotic solvent e.g. dimethylformamide, acetone, tetrahydrofuran or dich
  • 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.
  • a base e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride
  • 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,
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g.
  • a compound of formula (I), wherein R ⁇ 1 is aminocarbonyl, e.g. -C(O)(CR A19 R A110 ) k -NR A125 R A126 , R Ax2 is a free electron pair and A x is N, wherein k is 1 , and x 1 or 2, can be prepared e.g.
  • R Ax1 is hydrogen
  • R** 2 is a free electron pair
  • a x is N
  • 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 HNR A125 R A126 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.
  • bromoacetic acid BrCH 2 C(O)OH, or chloroacetic acid, CICH 2 C(O)OH
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g.
  • 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.
  • 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 wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is C-
  • a compound of formula (I), wherein R D11 and/or R D21 and/or R D31 and/or R D41 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein R D11 and/or R D21 and/or R D31 and/or R D41 is d- 3 -alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
  • a compound of formula (I), wherein R D11 and/or R D21 and/or R D31 and/or R D41 is hydroxy can be synthesized e.g.
  • R D11 and/or R D21 and/or R D31 and/or R D41 is benzyloxy by debenzylation reaction with, e.g., hydrogen gas, or 1 ,4-cyclohexadiene, or ammonium formiate, in the presence of, e.g., catalytic amounts of palladium or an appropriate palladium salt, in a suitable solvent, e.g. methanol and/or acetic acid; a compound of formula (I), wherein R D11 and/or R D21 and/or R D31 and/or R D41 is alkoxy-, -OC-
  • a suitable solvent e.g. methanol and/or acetic acid
  • 6 - alkyl that may be optionally substituted as defined above, can be prepared from a compound of formula (I), wherein the corresponding R D11 and/or R D21 and/or R D31 and/or R D41 is hydroxy, by alkylation reaction with the corresponding electrophilic reagent Ci_ 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.
  • a suitable base e.g. sodium hydride
  • a compound of formula (I), wherein R D11 and/or R D21 and/or R D31 and/or R D41 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;
  • . 6 -alkyl, that may be optionally substituted as defined above, can be prepared e.g.
  • R D11 and/or R D21 and/or R D31 and/or R D41 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 wherein R D11 and/or R D21 and/or R D31 and/or R D41 represent(s) substituted amino, e.g. -NR 019 R 0110 , can be prepared e.g.
  • R 011 and/or R 021 and/or R 031 and/or R 041 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate amine, e.g. HNR 019 R 0110 , in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium or copper, e.g. tris(dibenzylideneacetone)dipalladium(0) or palladium(ll) acetate, a catalytic amount of an appropriate ligand, preferably phosphines or diamines, e.g.
  • a compound of formula (I), wherein R 011 and/or R 021 and/or R 031 and/or R 041 represent(s) C 6 -i 4 -aryl or C- ⁇ - 13 -heteroaryl can be prepared e.g. from a compound of formula (I), wherein the corresponding R 011 and/or R 021 and/or R 031 and/or R 041 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate boronic acid, e.g.
  • C 6 -i 4 -aryl-B(OH) 2 or C 1 .- ⁇ - heteroaryl-B(OH) 2 respectively, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium, e.g. dichlorobis (tricyclohexylphosphine) palladium (II), optionally a catalytic amount of an appropriate ligand, preferably phosphines, and a stoichiometric amount of base, e.g. cesium carbonate or sodium carbonate, in an appropriate solvent, e.g. dimethoxyethane and/or tetrahydrofuran and/or ethanol, at elevated temperature, preferably 80-11O 0 C, or using microwave radiation at 120-140 0 C, and under nitrogen or argon atmosphere;
  • a transition metal complex preferably incorporating palladium, e.g. dichlorobis (tricyclohexylphosphine) palladium (II), optional
  • building blocks of formula (XXII), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) an alkoxy group, -O-Ci -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. 2 equivalents) of an appropriate alkyl halide, preferably alkyl iodide or alkyl bromide, e.g.
  • an appropriate alkyl halide preferably alkyl iodide or alkyl bromide
  • 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 -10°C to 100°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
  • an appropriate 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.
  • building blocks of formula (XXIXa), or (XXIXb), or a mixture thereof can be synthesized according to the sequence outlined in reaction scheme 11.
  • Compounds of formula (XXV) can be reacted with a haloacetic acid, preferably chloroacetic acid or bromoacetic acid, in the presence of a suitable base, e.g. sodium hydroxide and / or sodium carbonate, in an appropriate protic solvent, e.g. water.
  • a suitable base e.g. sodium hydroxide and / or sodium carbonate
  • an appropriate protic solvent e.g. water.
  • the resulting aminoacetic acid of formula (XXVI) is then reacted with an acetylating agent, e.g. acetic anhydride or acetyl chloride, in the presence of a suitable base, e.g.
  • the resulting compound of formula (XXVII) can be cyclized to a compound of formula (XXVIII) by reaction in neat acetic anhydride in the presence of a suitable base, e.g. triethylamine or diisopropylethylamine, at temperatures between 2O 0 C and 200 0 C, preferably 120°C-150°C.
  • a suitable base e.g. triethylamine or diisopropylethylamine
  • a compound of formula (XXIXa), or (XXIXb), or a mixture thereof can be synthesized by reaction of a compound of formula (XXVIII) with an appropriate base, e.g., sodium sulfite, in a suitable protic solvent, e.g. water, preferably at elevated temperatures, e.g. 60-100 0 C.
  • a suitable protic solvent e.g. water
  • the compound of formula (XXIXa), or (XXIXb), or a mixture thereof can be reacted according to reaction scheme 3 [replacing compound (VIII)] to give a compound of formula (Ic).
  • 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, aluminium oxide.
  • a suitable support material e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium 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 methylisobutylketone, 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 methylisobutylketone, an
  • 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, depending 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.
  • 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 diastereomeric 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 (1 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.
  • a suitable aprotic solvent preferably tetrahydrofuran or dioxan
  • (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, resolving 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.
  • enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • 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
  • 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, if not otherwise noted.
  • MS ionized particle found
  • M is abbreviated by M.
  • 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 B ⁇ chi B-540 or a B ⁇ chi B-541 instrument and are uncorrected.
  • 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.
  • 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 temperature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
  • Step 1 2-(1-Acetyl-1 H-indol-1-yl)-3-hydroxy-5,5-dimethyl-cyclohex-2-enone.
  • 1-Acetyl-1 ,2-dihydro- indol-3-one (10.5 g) is suspended in acetic acid (50 ml) and a suspension of 5,5-dimethyl- cyclohexane-1 ,3-dione (8.4 g) in acetic acid (50 ml) is added.
  • the reaction mixture is stirred for 20 min and triethylamine (8.3 ml) is added slowly.
  • Step 2 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone.
  • 2-(1-Acetyl-1 H-indol-1-yl)-3- hydroxy-5,5-dimethyl-cyclohex-2-enone (5.95 g) is dissolved in aqueous 1 N NaOH solution (65 ml) and stirred for 2 h.
  • the reaction mixture is diluted with dichloromethane (50 ml) and acidified with aqueous HCI solution (pH 5).
  • the organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml).
  • the combined organic layers are dried (MgSO 4 ) and concentrated in vacuo to give 5.09 g of the title compound.
  • 6-(4- Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one (200 mg) is suspended in acetonitrile (10 ml) and 25% (w/v) aqueous ammonia solution (10 ml) is added.
  • the reaction mixture is heated in a sealed vial using microwave radiation at 13O 0 C for 25 min.
  • the solvent is removed in vacuo and the residue is dissolved in dichloromethane (50 ml) and water (50 ml).
  • Step 1 2-[(Carboxymethyl)amino]-4-chlorobenzoic acid.
  • Chloroacetic acid (15 g) is dissolved in water (15 ml) and sodium carbonate (16 g) is added in portions (carbon dioxide evolves) and the mixture is stirred at 45 0 C for 30 min.
  • 2-amino-4-chlorobenzoic acid is dissolved in water (15 ml)
  • 1 M aqueous sodium hydroxide solution (15 ml) is added, followed by the sodium chloroacetate solution prepared above.
  • the resulting mixture is stirred at 6O 0 C for 2 days.
  • 1 M aqueous sodium hydroxide solution is added, after that, it is acidified by addition of concentrated hydrochloric acid.
  • Step 2 i-Acetyl- ⁇ -chloro-I H-indol-S-yl acetate.
  • Crude 2-[(carboxymethyl)amino]-4-chlorobenzoic acid (20.0 g) is dissolved in acetic anhydride (250 ml), the solution is cooled to O 0 C (ice bath) and triethylamine (11.02 ml) is added slowly drop by drop. After the addition is complete, the mixture is stirred at 14O 0 C for 30 min. After cooling, the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane (100 ml) and washed with saturated sodium carbonate solution (3 x 100 ml).
  • 3-Fluoro-4-methoxyphenyl acetic acid (7.0 g) is dissolved in dry tetrahydrofuran (250 ml), carbonyl diimidazole (7.4 g) is added and the mixture is refluxed for 2 h.
  • potassium tert-butylate (5.5 g) is suspended in dry tetrahydrofuran (100 ml) and nitromethane is added drop by drop. The mixture is stirred for 2 h at room temperature. Then, the solution of imidazolide, prepared above and cooled down to room temperature, is added. The resulting mixture is refluxed for 16 h.
  • 2-Chloro-3-pyridinecarboxaldehyde (2.27 g) is dissolved in isopropanol (240 ml), 3-amino-5,5- dimethyl-2-cyclohexen-1-one (2.23 g), 1-(3-fluoro-4-methoxyphenyl)-3-nitroacetone (example A7) (3.65 g), benzylamine (88 ⁇ l) and glacial acetic acid (48 ⁇ l) are added subsequently and the mixture is stirred for 16 h at 8O 0 C.
  • the aqueous phase is extracted with ethyl acetate (2 x 50 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 5:5:1 (v/v/v)) to yield 321 mg (23%) of the title compound.
  • Step 1 Benzyl 5-amino-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate.
  • Benzyl 5-hydroxy-3-oxo-3,6- dihydropyridine-1(2H)-carboxylate (1.34 g, 77% in glacial acetic acid, prepared as described in Organic Letters 6, 4483-4485 (2004)) is dissolved in dry acetonitrile (20 ml), ammonium chloride (0.97 g) is added and the mixture in stirred in a sealed vial at 8O 0 C for 15 min using microwave radiation.
  • Step 2 Benzyl 4-(2-chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-3-nitro-5-oxo-4,5,6,8-tetrahydro- 1 ,7-naphthyridine-7(1 H)-carboxylate.
  • 2-Chloro-3-pyridinecarboxaldehyde (0.37 g) is dissolved in isopropanol (20 ml), crude benzyl 5-amino-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (0.64 g), 1-(3- fluoro-4-methoxyphenyl)-3-nitroacetone (example A7) (0.59 g), benzylamine (14 ⁇ l) and glacial acetic acid (8 ⁇ l) are added subsequently and the mixture is stirred for 16 h at 8O 0 C.
  • Step 2 Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-hydroxypiperidine-1-carboxylate.
  • Crude ethyl 4-(5-fluoro-1 H- indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (126.4 g) is dissolved under argon in dry tetrahydrofuran (575 ml) und the solution is cooled to O 0 C (ice bath).
  • Borane tetrahydrofuran complex (1 M in tetrahydrofuran, 515 ml) is added drop by drop within 40 min. The ice bath is removed, the mixture is stirred for 2.5 h at room temperature.
  • Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-hydroxypiperidine-1 -carboxylate (example A11 ) (40.16 g) is dissolved in dimethylsulfoxide (235 ml) and dichloromethane (235 ml), the solution is cooled to O 0 C (ice bath) and diisopropylethyl amine (78.0 ml) is added.
  • a solution of sulfurtrioxide pyridine complex (41.38 g) in dimethylsulfoxide (293 ml) and pyridine (21.0 ml) is added drop by drop within 40 min at a rate that the internal temperature is kept below 5 0 C.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 2:3 (v/v)) to yield 39.1 g (99%) of the title compound as a viscous oil.
  • 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A2) (200 mg) is suspended in chloroform (1 ml) and diethyl ether (1 ml) and the suspension is cooled to O 0 C (ice bath). A solution of bromine (40 ⁇ l) in diethyl ether (1 ml) is added drop by drop and the resulting orange suspension is stirred for 18 h at O 0 C.
  • Step 1 2-(4-Fluoro-1 H-indol-3-yl)cyclohexanone.
  • Phosphorus acid (2N, 7 ml) is dissolved in glacial acetic acid (30 ml) and the solution is refluxed.
  • 4-Fluoroindole (5.0 g) and 2-hydroxycyclohexanone dimer (5.0 g) are added and the mixture is refluxed for 18 h.
  • Step 2 1 i-Fluoro- ⁇ S-fluoro ⁇ -methoxybenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinoline.
  • 2-(4- Fluoro-1 H-indol-3-yl)cyclohexanone (800 mg) is dissolved under nitrogen in dichloroethane (3.5 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 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 (1.3 g) is dissolved in trifluoroacetic acid anhydride (1 ml) and the mixture is stirred for 20 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (3.5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O 0 C.
  • the mixture is stirred for 1 h at O 0 C and 3 h at room temperature.
  • ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 16 h.
  • Step 1 2-(4-Bromo-1 H-indol-3-yl)cyclohexanone.
  • Phosphorus acid (2N, 15 ml) is dissolved in glacial acetic acid (75 ml) and the solution is refluxed.
  • 4-Bromoindole (10.0 g) and 2-hydroxycyclohexanone dimer (8.7 g) are added and the mixture is refluxed for 18 h.
  • Step 2 1 i-Bromo- ⁇ S-fluoro ⁇ -methoxybenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinoline.
  • 2-(4- Bromo-1 H-indol-3-yl)cyclohexanone (1.7 g) is dissolved under nitrogen in dry dichloroethane (15 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 9 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C.
  • 3-fluoro-4-methoxyphenyl acetic acid (1.3 g) is dissolved in trifluoroacetic acid anhydride (1 ml) and the mixture is stirred for 15 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (3.5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O 0 C.
  • the mixture is stirred for 30 min at O 0 C and 3 h at room temperature.
  • ammonia (7M in methanol, 9 ml) and ammonium acetate (9.0 g) in glacial acetic acid (15 ml) are added and the mixture is heated for 120 min at 15O 0 C in a sealed vial using microwave radiation.
  • Step 1 2-(5-Fluoro-1 H-indol-3-yl)cyclohexanone.
  • Phosphorus acid (2N, 7 ml) is dissolved in glacial acetic acid (30 ml) and the solution is refluxed.
  • 5-Fluoroindole (5.0 g) and 2-hydroxycyclohexanone dimer (5.0 g) are added and the mixture is refluxed for 18 h.
  • Step 2 lO-Fluoro-e ⁇ S-fluoro ⁇ -methoxybenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinoline.
  • 2-(5- Fluoro-1 H-indol-3-yl)cyclohexanone (920 mg) is dissolved under nitrogen in dry dichloroethane (5 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 8 ml) is added drop by drop and the mixture is stirred for 1 h at O 0 C.
  • 3-fluoro-4-methoxyphenyl acetic acid (1.5 g) is dissolved in trifluoroacetic acid anhydride (1.1 ml) and the mixture is stirred for 15 min at room temperature.
  • the formed mixed anhydride is diluted with dry dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O 0 C.
  • the mixture is stirred for 1 h at O 0 C and 3 h at room temperature.
  • ammonia (7M in methanol, 8 ml) is added and the mixture is refluxed for 16 h.
  • the formed mixed anhydride is diluted with dichloromethane (10 ml) and added drop by drop to the zinc chloride mixture, prepared above, within 5 min at room temperature. Nitromethane (10 ml) is added and the mixture is stirred for 2 h at room temperature and for 18 h at 5O 0 C. After that, ammonium acetate (0.85 g) and ammonia (7M in methanol, 1.6 ml) are added and the mixture is refluxed for 2 h. After cooling, 2N aqueous ammonia (20 ml) is added, the aqueous phase is extracted with ethyl acetate (2 x 50 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 ethyl acetate / n-heptane 2:3 (v/v)) followed by crystallization from diethyl ether / n-heptane to give 0.7 g (72%) of the title compound.
  • 3-Nitrophenylboronic acid (229 mg), D-(-)-tartaric acid (206 mg) and calcium hydride (115 mg) are suspended in THF (5 ml) and heated under reflux for 3 h. The suspension is cooled and filtered under nitrogen atmosphere.
  • 9-Chloro-6-(3-fluoro-4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-1-one (example 5) (200 g) is dissolved in the filtrate, the solution is cooled to O 0 C (ice bath) and sodium borohydride (50.2 mg) is added in 5 portions at O 0 C.
  • the crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 5:5:1 (v/v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 41 mg (21 %) of the title compound.
  • Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A12) (39.1 g) is dissolved under nitrogen in dry dichloroethane (262 ml) and the solution is cooled to O 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 256 ml) is added drop by drop within 10 min and the mixture is stirred for 10 min at O 0 C.
  • 3-fluoro-4-methoxyphenyl acetic acid (47.2 g) is dissolved in trifluoroacetic acid anhydride (37 ml) and the mixture is stirred for 1.5 h at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (109 ml) and added drop by drop to the zinc chloride mixture, prepared above, within 20 min at O 0 C.
  • the mixture is stirred for 5 min at O 0 C and 3 h at room temperature.
  • ammonium acetate (30.6 g) and ammonia (7M in methanol, 117 ml) are added and the mixture is refluxed for 18 h. After cooling, it is filtered over a plug of Celite ® , the plug is washed thoroughly with methanol.

Abstract

The present invention pertains to Benzyl-substituted tetracyclic heterocyclic compounds, 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
AS PDE5 INHIBITORS
Field of application of the invention
The invention relates to Benzyl-substituted tetracyclic heterocyclic 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 Geterotsiklicheskikh Soedinenii (1985) 3, 363-6 without mentioning any pharmaceutical activity thereof. WO 02/064590 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO2008027182 (US2008051426) 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 a method of manufacture of the compounds and compositions of the present invention.
It is a further object of the present invention to provide a method 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 Benzyl-substituted tetracyclic heterocyclic compounds, which are described in detail below, have surprising and advantageous properties, and making them especially useful in the treatment and prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
The compounds of the present invention are characterized by Formula (I) as specified in the following. The invention thus relates to compounds of Formula (I)
Figure imgf000003_0001
wherein A^ and A^ are each independently selected from the group consisting of C, N, O and S; with the proviso that at least one of the radicals A^ and A^ is a carbon atom; and
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, and C-j.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 ancj RA02 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;
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(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; d RA12 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 and a C-i.-13-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-i.-13-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 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 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, 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-i.-13-heteroaryl, wherein the C-ι.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-ι.-13-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-mennbered 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^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, 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-|.g-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-j.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, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, and _NRA114RA115; or RA16 ancj RA17 combine to form a C3_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-j.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 _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 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, C^g-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.-|4-aryl is optionally substituted, C"|_i3-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-i.-13-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-j.g-alkoxy via C, N is substituted by RA125 ancj _NRA125RA126. ncj 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, -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-mennbered heterocyclyl is bound to the C-j.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-j.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 heteroatoms 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)-C1.6-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.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, 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-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-mennbered 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 Ci_6-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-|.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-C-|.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 R^131 -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 heteroatoms selected from NRA131 , O and S;
RA118 ancj RA119 are eacn independently selected from the group consisting of hydrogen, C-] .β-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 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-|.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-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,
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-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 RA131 , -NRA134RA135 and .CONRA136RA137 -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, -C(O)-C1. g-alkyl wherein the -C(O)-C-] .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-C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2NRA140RA141 C6.14-aryl, wherein the Cβ.-|4-aryl is optionally substituted, C i _ 13-heteroary I , 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 via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA"I 42; 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, C1.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 heteroatoms 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-|.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, 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-C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or ncj 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 heteroatoms selected from NRA131 , O 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.-jQ-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-|.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-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;
RA21 and R^22 have the same meanings as R^ 11 and RA12;
RA31 and RA32 are eacn 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, and C-|.g-alkoxy, wherein the C-|.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 ancj RA32 together represent the moiety -O-CH2-CH2-O-, and thus forms a cyclic acetal together with the adjacent C-atom to which they bind; with the proviso that, if R^31 and R^32 combine to form an oxo-group or R^31 and R^32 together represent the moiety -O-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 _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, C-j.β-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 -0-CH2-O-, -0-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;
wherein D^ , D^, D^ and D^ are each independently selected from the group consisting of C and N; and
RD1 1 RD21 RD31 ancj RD41 are eacn independently selected from the group consisting of hydrogen, halogen, 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.β-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-|.-|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 to the C-|.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 RD12, C-j.β-alkoxy, wherein the C-|.g-alkoxy 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, C6.14-aryl, wherein the Cβ.-|4-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 C3-6-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-|.g-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.β-alkoxy via C, N is substituted by R01^,
-C(O)OR014, and -C(O)NR015R016, -C(O)-C1.6-alkyl, wherein the -C(O)C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-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.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(O)-C1.5- alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the -C(O)-C1.6-alkyl via C, N is substituted by R017,
-C(O)-R018, NR01QR01 1O and a lone pair;
R01^, R013 and R017 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, and -C(O)-C1.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RD14 RD15 ancj RD16 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;
RD18 js selected from the group consisting of 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 R^I ^ ^ ;
RD19 ancj RD110 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, -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;
RD111 js 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; with the proviso that, if each of D^ , D^, D^ and D^ is a carbon atom, at least one of the substituents RD11 RD21 RD31 and RD41 is different from hydrogen and at least one of the substituents RB41 , RB51 RB61 RB71 and RB81 js different from 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.
Special embodiments of the present application are described in the following.
According to another embodiment of the present invention, A^ and A^ are each independently selected from the group consisting of C, N, O and S; with the proviso that at least one of the radicals
A^ and A^ is a carbon atom; and
RA01 ancj 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 C-j.β-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 NRA03RA04. or
RA01 ancj RA02 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;
RA03 ancj RA04 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, 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; d RA12 are eacn 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, hydroxy and a C-i.-13-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-i.-13-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 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 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.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-i.-13-heteroaryl, wherein the C-ι.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-ι.-13-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 is bound via C, and wherein N is substituted by RA125 -S(O)2-C1.6-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(CRAI QRAI I O)^RAI 11 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.g-alkyl, wherein the C-j.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-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA1 12RA1 13;
RA16 ancj RA17 are eacn independently selected from the group consisting of hydrogen, hydroxy, halogen, C-j.g-alkyl, wherein the C-j.g-alkyl is optionally substituted by one or more substituents selected from 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, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, and .NRA114RA115; or RA16 ancj RA17 combine to form a C3_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-j.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, hydroxy and C-j.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 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, C^g-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 C-ι.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-ι.-13-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-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 C1. 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 heteroatoms 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)-C1.6-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 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-|_g-heteroaryl, wherein the C-|_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-|.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, 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-|.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-C-|_6-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 R^^1 -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 heteroatoms selected from NRA131 , O and S;
RA118 ancj RA119 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;
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; ncj 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, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-|_g-heteroaryl, wherein the C-|_g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|_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-|.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 RA131 , -NRA134RA135 and .CONRA136RA137 -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, -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, -C0NRA138RA13^ -S(O)2-C1. g-alkyl, wherein the -S(0)2-C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -S(O)2NRA14°RA141 , Cg.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C"|_i3-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 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 heteroatoms 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-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, C6.14-aryl, wherein the Cg.-|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. β-alkyl, wherein the -S(O)2-C-|.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 heteroatoms selected from NRA131 , O and S;
RA125 RA126 RA128 RA131 and RA142 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 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.-jQ-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 C1. g-alkyl, wherein the C-|.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-|.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 the same meanings as R^ 11 and R^12;
RA31 and RA32 are eacn independently selected from the group consisting of hydrogen, hydroxy, C1. g-alkyl, wherein the C1. 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 and hydroxy, and NRA33RA34. or
RA31 and RA32 combine to form an oxo-group, or
RA31 and RA32 together represent the moiety -O-CH2-CH2-O-, and thus forms a cyclic acetal together with the adjacent C-atom to which they bind; with the proviso that, if R^31 and R^32 combine to form an oxo-group or R^31 and R^32 together represent the moiety -O-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-j.β-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, C-j.β-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 -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;
wherein D^ , D^, D^ and D^ are each independently selected from the group consisting of C and N; and
RD1 1 RD21 RD31 ancj RD41 are eacn independently selected from the group consisting of hydrogen, halogen, C-|.g-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-j.β-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-|_-| 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 Ci_6-alkyl via C, N is substituted by RD12, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-j.β-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-|.-|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 C3-6-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-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.β-alkoxy via C, N is substituted by R01^,
-C(O)OR014, and -C(O)NR015R016, -C(O)-C1.6-alkyl, wherein the -C(O)C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cβ.-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.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(O)-C1. β- alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the -C(O)-C1.6-alkyl via C, N is substituted by RD17,
-C(O)-R01S, NRD19RD110 and a lone pair;
RD12 RD13 ancj RD17 are eacn 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, 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;
RD14 RD15 ancj RD16 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 and hydroxy; RD18 js se|ectec| from tne group consisting of 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 R^1 ^ ^ ;
RD19 ancj RD110 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)-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;
RD111 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 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;
with the proviso that, if each of D^ , D^, D^ and D^ is a carbon atom, at least one of the substituents RD11 RD21 RD31 and RD41 js different from 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 one embodiment of the present invention, R^01 and R^02 are eacn independently 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
RA01 ancj RA02 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.
According to another embodiment of the present invention, R^01 and R^02 are each independently selected from the group consisting of hydrogen and hydroxy; or
RA01 ancj RA02 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.
According to another embodiment of the present invention, R^ 11 and R^12 are each 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.
According to yet another embodiment of the present invention, R^ 11 and RA12 each are hydrogen.
According to another embodiment of the present invention, RA15 is selected from the group consisting of hydroxy;
According to another embodiment of the present invention, RA16 and RA17 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, C-j.β-alkyl, C-j.β-alkoxy;
According to another embodiment of the present invention, R^16 and R^^ are each independently selected from the group consisting of hydrogen;
According to another embodiment of the present invention, RA19 and RA1 10 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.g-alkyl,
C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and According to another embodiment of the present invention, RA^ 11 is selected from the group consisting of hydrogen, hydroxy, halogen, -CO(O)RA120, -NRA121 RA122, -CONRA123RA124, C^-alkyl, C-j.β-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy,
According to another embodiment of the present invention, RA^ ^ is selected from the group consisting of hydrogen, hydroxy, -NRA121 RA122, C^-alkyl, C-j.β-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy,
According to another embodiment of the present invention, RA1 16 ancj RA1 17 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl,
According to another embodiment of the present invention, RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl,
According to another embodiment of the present invention, RA2^ and RA22 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl,
-(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair;
wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
According to another embodiment of the present invention, RA2^ and RA22 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl,
-(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair;
wherein m is 1 , 2 and 3, I is 1 and 2 and k is 0, 1 and 2; According to yet another embodiment of the present invention, R^1 and RA^2 are eacn 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, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave the same meaning as defined above.
According to yet another embodiment of the present invention, RA^1 and RA^2 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl,
-(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above or below.According to yet another embodiment of the present invention, RA^1 and RA^2 are each 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.
According to yet another embodiment of the present invention, RA^1 and RA^2 each are methyl.
According to another embodiment of the present invention, RA^1 and RA^2 each are hydrogen.
According to another embodiment of the present invention, R^41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy.
According to another embodiment of the present invention, R^41 js selected from the group consisting of hydrogen and halogen. Acccording to another embodiment of the present invention, RB^1 js selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.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, RB^1 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, RB^1 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy.
According to yet another embodiment of the present invention, RB^1 js selected from the group consisting of halogen and C-j.β-alkoxy.
According to another embodiment of the present invention, R^I ^ , R^I t RD31 ancj RD41 are eacn independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair.
According to yet another embodiment of the present invention, at least one of the substituents R^I ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and the remaining substituent(s) is/are hydrogen. According to another embodiment of the present invention, R^I ^ , RD21 t RD31 ancj RD41 are eacn independently selected from the group consisting of
Hydrogen, halogen, C-|_g-alkyl,According to another embodiment of the present invention, each of A^ and A^ is carbon, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA^2 each are methyl.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA21 and RA^2 JS selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17J1-CORAI 8 and _C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 t>iιnd is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, wherein I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and RA18 js NRA1 16RA117 Wherein RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^ ^ ^ , R^ 11 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen. According to another embodiment of the present invention, at least one of the atoms D^ , D2 and D3 is
N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair.
According to yet another embodiment of the present invention, at least one of the atoms D^ , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which RD1 1 RD21 anc|/or RD31 e^ js ^ tne respective substituent(s) represent(s) a lone pair.
According to another embodiment of the present invention, at least one of the atoms D^ , D2, D3 and D4 is N and the remaining atoms are C, A^ is C and R^ 11 , RA12 RA31 ancj RA32 eacn are hydrogen.
According to another embodiment, one, two or three of the atoms D^ , D2, D3 and D4 represent N, and the remaining atoms represent C.
According to another embodiment of the present invention, each of D^ , D2, D3 and D4 is C, and A^ is selected from C, N, O and S, with the proviso that at least one of the substituents RD1 1 , RD21 , RD31 and R^41 is different from hydrogen.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA02 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and 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 the remaining substituent(s) is/are hydrogen.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^O2 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|_3-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair.
According yet to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA1 1 RA12 R31 ancj R32 are hydrogen, one of the substituents R^01 and R^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^1 ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair.
According to another embodiment of the present invention, A^ is C, A2 is N, each of R^ 11 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^2"! and R^22 is selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, wherein I is 1 , k is O, RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave ^16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^ RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA^2 js selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17),_CORA18 and -C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^^ js hydrogen, or one of the substituents RA^ and RA^^ js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, wherein Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and RA18 is NRA116RA117 wherein RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17)rCoRA18 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^^ ^ , R^2^ and R^3^ bind is N, the respective substituent(s) represent(s) a lone pair, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 haVe the same meaning as defined above.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^I ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, and
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino,
RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|_2-alkyl, -NH-C(O)-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,
RB71 JS selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino, RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(O)-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, RB^1 JS selected from the group consisting of hydrogen and halogen, RB81 JS selected from the group consisting of hydrogen and halogen.
According yet to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^O2 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^1 ^ , R^2"! and R^31 bind is N, the respective substituent(s) represent(s) a lone pair, and
RB4^ is 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, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(O)-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,
RB^1 is selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen.
According to another embodiment of the present invention, A^ is C, A2 is N, each of R^ 11 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^2"! and R^22 is selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^1 ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, and
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, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(O)-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,
RB^1 JS selected from the group consisting of hydrogen and halogen,
RB81 js selected from the group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ ^ , RA^ RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA^2 js selected from hydrogen, C-i.β-alkyl, wherein the C-i.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
RB4I is 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, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|_2-alkyl, -NH-C(O)-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, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl, wherein the C-i.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, _(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^I ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and
RB4I is 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, C-j.β-alkoxy, nitro, amino, -NH-C(O)- C-|_2-alkyl, -NH-C(O)-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,
RB71 JS selected from the group consisting of hydrogen and halogen,
RB81 js selected from the group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA2^ and RA22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ , RD21 RD31 ancj RD41 js selected from the group consisting of halogen, NH2, C-i.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, and
RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
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, 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,
RB^1 JS selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^O2 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
RB4^ is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
RB^1 is selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen. According yet to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA^2 t>i ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^1 ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and RB4I is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
RB^1 JS selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17J1-CORAI 8 and _C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, and
RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
RB^1 JS selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave ^16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents RA01 and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, and
RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
RB^1 JS selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave ^16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA 2 is hydrogen, or one of the substituents RA^ and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^^ ^ , R^2^ and R^3^ bind is N, the respective substituent(s) represent(s) a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
RE381 JS se|ectec| from tne group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ ^ , RA^ RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA^2 js selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, wherein I is 1 , k is O, RA16 ancj RA17 each are hydrogen and
RA18 JS NRA1 16RA117 wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^^ ^ , R^^11 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, C-j.β-alkoxy and the remaining substituent(s) is/are hydrogen.
According to another embodiment of the present invention, at least one of the atoms D^ , D^ and D^ is
N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-i.β-alkyl, C-i.β-alkoxy and a lone pair. According to another embodiment of the present invention, at least one of the atoms D^ , D2 and D3 is
N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair.
According to yet another embodiment of the present invention, at least one of the atoms D^ , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which RD1 1 RD21 anc|/or RD31 bjnc| is N, the respective substituent(s) represent(s) a lone pair.
According to another embodiment of the present invention, at least one of the atoms D^ , D2, D3, D4, A^ and A2 is N and the remaining atoms are C and R^ 11 , RA12 RA31 ancj RA32 eacn are hydrogen.
According to another embodiment of the present invention, at least one of the atoms D^ , D2, D3, D4 and A2 is N and the remaining atoms are C, A^ is C and R^ 11 , RA12 RA31 ancj RA32 eacn are hydrogen.
According to another embodiment of the present invention, at least one of the atoms D^ , D2, D3 and D4 is N and the remaining atoms are C, A^ is C and R^ 11 , RA12 RA31 ancj RA32 eacn are hydrogen.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^OI and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^OI and RA02 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^I ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, C-j.β-alkoxy and the remaining substituent(s) is/are hydrogen.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^O2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^OI and R^O2 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, C-j.β-alkoxy and a lone pair.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA^2 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA2^ and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents R^01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ ,
R^2"! , R^3"! and R^4^ is selected from the group consisting of halogen, NH2, C-j.β-alkyl, C-j.β-alkoxy and the remaining substituent(s) is/are hydrogen, wherein I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above ot below.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-i.β-alkyl, _(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen, NH2, C-j.β-alkyl, C-j.β-alkoxy and the remaining substituent(s) is/are hydrogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above ot below.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and -C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^^ js hydrogen, or one of the substituents RA^ and RA^^ js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and RA18 is NRA116RA117 wherein RA111 RA116 ancj RA117 haVe the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and _C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein Ms 1 , k is O, RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rC0RA18 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA 2 is hydrogen, or one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA 2 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^^ ^ , R^2^ and R^3^ bind is N, the respective substituent(s) represent(s) a lone pair, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 haVe the same meaning as defined above. According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA^2 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy,
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,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen, RB^I js selected from the group consisting of hydrogen and halogen, RB81 JS selected from the group consisting of hydrogen and halogen.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA11 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^2"! and R^22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^I ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 JS NRA1 16RA1 17 wherein
RA111 RA116 ancj RA117 nave ^16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA22 js selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^^ ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RB61 JS selected from the group consisting of hydrogen and halogen, RB^I js selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein Ms 1 , k is O,
RA16 ancj RA17 eac|η are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave (ne same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rCoRA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA 2 is hydrogen, or one of the substituents RA^ and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA 2 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 js NRA1 16RA117 Wherein
RA111 RA116 ancj RA117 haVe the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rCoRA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^I I , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 JS NRA1 16RA1 17 wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA1 1 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and R^4"! is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy 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,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA^2 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkoxy, RE361 JS se|ectec| from tne group consisting of hydrogen and halogen, RB^I js selected from the group consisting of hydrogen and halogen, RB81 JS selected from the group consisting of hydrogen and halogen.
According yet to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 anc| RA32 are hydrogen, one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and RA^2 bind is in the S-configu ration, or RA01 anc| RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^1 ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and R^41 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
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.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 anc| RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and -CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ ,
RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RE351 JS se|ectec| from tne group consisting of hydrogen, halogen, C-j.β-alkoxy,
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, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^^ js hydrogen, or one of the substituents RA01 and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
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, wherein
I is 1 , k is O, RA16 ancj RA17 eac|η are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rCoRA18 and _C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA 2 is hydrogen, or one of the substituents RA^ and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA 2 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^I ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
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, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 JS NRA1 16RA117 Wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of
RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA 2 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ ,
R^2^ , R^3^ and R^4^ is selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RE351 JS se|ectec| from tne group consisting of halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB71 js selected from the group consisting of hydrogen and halogen,
RE381 JS se|ectec| from tne group consisting of hydrogen and halogen,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 anc| RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy,
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.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^1 and RA^2 is hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ ,
R^2^ , R^3^ and R^4^ is selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and
R^4"! is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy, RE361 JS se|ectec| from t|ηe 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, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA22 JS selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rCoRA18 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D^, D^ and D^ is a carbon atom and at least one of the substituents R^^ ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RB81 JS selected from the group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 JS NRA116RA117 Wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A^ is N, each of RA^ ^ , RA^ RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA^2 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and _C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents RA^ and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 js selected from the group consisting of halogen and C-j.β-alkoxy,
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, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and -C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents RA01 and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA 2 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^^ ^ , R^2^ and R^3^ bind is N, the respective substituent(s) represent(s) a lone pair, and
R^4"! is selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, RB51 js selected from the group consisting of halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, RE361 JS se|ectec| from t|ηe 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, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ , RD21 , RD31 ancj RD41 js selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RE381 JS se|ectec| from (he group consisting of hydrogen and halogen,
According to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA1 1 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t^iincd is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and R^2 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD 1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy, RE361 JS se|ectec| from t|ηe 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.
According yet to another embodiment of the present invention, each of A^ and A2 is carbon, each of RA11 RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and RA^2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^02 t>ind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 each are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^I ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RE351 JS se|ectec| from (he group consisting of halogen and C-j.β-alkoxy, RE361 JS se|ectec| from (he group consisting of hydrogen and halogen, RB^I js selected from the group consisting of hydrogen and halogen, RB81 JS selected from the group consisting of hydrogen and halogen.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^^ ^ , RD21 RD31 ancj RD41 JS selected from the group consisting of halogen and the remaining substituent(s) is/are hydrogen, and R^4"! is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy, RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy, RB61 JS selected from the group consisting of hydrogen and halogen, RB71 js selected from the group consisting of hydrogen and halogen, RE381 JS se|ectec| from t|ηe group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 js selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rCoRA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen and a lone pair, and
RB41 is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy,
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, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 JS NRA116RA117 Wherein
RA111 RA116 ancj RA117 haVe the same meaning as defined above.
According to another embodiment of the present invention, A^ is C, A2 is N, each of RA^ ^ , RA^2, RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rC0RA18 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents R^01 and R^02 JS hydrogen, or one of the substituents R^01 and R^02 JS hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 t^iincd is in the R-configu ration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each hydrogen, or, in case the atom to which R^1 ^ , R^2"! and R^3"! bind is N, the respective substituent(s) represent(s) a lone pair, and
RB4I is selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of halogen and C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RE381 JS se|ectec| from tne group consisting of hydrogen and halogen, wherein
Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 ancj RA117 nave ^16 same meaning as defined above.
According to another embodiment of the present invention, at least one of the atoms D^ , D2, D3, D4, A^ and A2 is N and the remaining atoms are C, each of RA^ 1 , RA^2, RA31 and RA32 are hydrogen, one of the substituents RA2^ and R^22 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rC0RA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA02 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and wherein I is 1 , k is O,
RA16 ancj RA17 each are hydrogen and RA18 is NRA1 16RA1 17, wherein RA111 RA116 ancj RA117 nave 16 same meaning as defined above ot below. According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^21 and RA^2 JS selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rCoRA18 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA02 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA02 t>iιnd is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and RD11 RD21 RD31 ancj RD41 are eacn independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein I is 1 , k is O, RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C, each of RA^ ^ , RA^ RA31 and RA32 are hydrogen, one of the substituents RA^1 and RA^2 is selected from hydrogen, C-j.β-alkyl,
_(CRA16RA17)rCoRA18 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents RA^ and RA^^ js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 and RA02 combine to form an oxo group, and RD1 1 RD21 RD31 and RD41 are eacn independently selected from the group consisting of hydrogen, halogen and a lone pair, wherein Ms 1 , k is O, RA16 and RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 1 7, wherein RA111 RA116 ancj RA117 have 16 same meaning as defined above.
According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA21 and RA^2 JS selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rCoRA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA02 is hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 t>iιnd is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and
RD11 RD21 RD31 and RD41 are eacn hydrogen, or, in case the atom to which RD1 1 , RD21 and RD31 bjnc| js N the respective substituent(s) represent(s) a lone pair, wherein Ms 1 , k is O, RA16 and RA17 each are hydrogen and
RA18 is NRA116RA117 wherein
RA111 RA116 and RA117 haVe the same meaning as defined above.
According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C, each of RA^ ^ , RA^ RA31 and RA32 are hydrogen, one of the substituents RA^1 and RA22 js selected from hydrogen, C-i.β-alkyl,
-(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m is 1 , 2 and 3, I is 1 and 2 and k is 0, 1 and 2; each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents RA01 and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configuration or RA01 and 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, and RA18 is NRA116RA117 wherein RA16 RA17 RA111 RA116 and RA117 haVe the same meaning as defined above. According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA^1 and RA^2 js selected from hydrogen, C-j.β-alkyl,
-(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; wherein m is 1 , 2 and 3, I is 1 and 2 and k is 0, 1 and 2; each of the substituents RA^ and RA^^ js hydrogen, or one of the substituents RA^ and RA 2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^^ bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, with the proviso that, if RA^ and RA^^ combine to form an oxo group, A^ may not be N, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy,
RB61 JS selected from the group consisting of hydrogen and halogen,
RB^I js selected from the group consisting of hydrogen and halogen,
RE381 JS se|ectec| from tne group consisting of hydrogen and halogen,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA116RA117 Wherein
RA111 RA116 ancj RA117 have the same meaning as defined above.
According to another embodiment of the present invention, at least one of the atoms D^ , D^, D^, D^, A^ and A^ is N and the remaining atoms are C, each of RA^ ^ , RA^ RA^^ and RA^^ are hydrogen, one of the substituents RA^1 and RA^2 is selected from hydrogen, C-j.β-alkyl,
.(CRA16RA17)rC0RA18 and .CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA01 and RA 2 is hydrogen, or one of the substituents RA^ and RA^^ js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA01 and RA 2 bind is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, with the proviso that, if RA^ and RA^^ combine to form an oxo group, A^ may not be N, and RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy,
RB51 js selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, RB61 js selected from the group consisting of hydrogen and halogen, RB71 js selected from the group consisting of hydrogen and halogen, RE381 JS se|ectec| from t|ηe group consisting of hydrogen and halogen, wherein
I is 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave 16 same meaning as defined above.
According to another embodiment of the present invention, A^ and A^ are each independently selected from the group consisting of C and N; with the proviso that at least one of the radicals A^ and A^ is a carbon atom; and
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy; or
RA01 ancj RA02 combine to form an oxo group, with the proviso that, if RA^ and RA02 combine to form an oxo group, A^ may not be N, O or S;
RA^ and RA^ are hydrogen;
RA21 and RA^2 are eacn independently 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 fluoro, hydroxy and a C-|.-|3-heteroaryl,
-(CH2)m-RA15, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair; or in case A^ 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, k is 0, 1 and 2;
RA15 JS hydroxy;
RA16 ancj RA17 are hydrogen;
RA18 is .NRA116RA117;
RA19 ancj RA110 are each independently selected from the group consisting of hydrogen, hydroxy, fluoro, C-|.β-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 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;
RA111 js selected from the group consisting of hydrogen, hydroxy, -NRA121 RA122, C^g-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,
RA116 and RA117 are hydrogen;
RA121 and RA122 are c^g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy;
RA31 ancj RA32 are hydrogen;
RB41 js selected from the group consisting of hydrogen and halogen;
RB51 JS selected from the group consisting of hydrogen and C-j.β-alkoxy;
RE361 JS se|ectec| from (he group consisting of hydrogen and halogen;
RB71 and RB81 are hydrogen;
wherein D^ , D2, D^ and D^ are each independently selected from the group consisting of C and N; and
RD1 1 RD21 RD31 ancj RD41 are each independently selected from the group consisting of hydrogen, halogen, with the proviso that, if each of D^ , D^, D^ and D4 is a carbon atom, at least one of the substituents RD11 RD21 RD31 and RD41 is different from hydrogen and at least one of the substituents RB41 , RB51 RB61 RB71 and RB81 js different from 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 another embodiment of the present invention, A^ is C, A^ is C or N, each of R^31 and RA32 are hydrogen, R^1and R^02 are eacn independently selected from the group consisting of hydrogen, hydroxy, or R^01 and R^02 combine to form an oxo group, D^ and D4 are C, R^41 js selected from the group consisting of hydrogen or halogen, R^51 JS C-j.β-alkoxy,
RB61 RB71 RB81 are eacn hydrogen, RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen or halogen.
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
10-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 11- Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 11-Bromo-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 10-Fluoro-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 9-Chloro-6-(3-fluoro-4-methoxybenzyl)- 3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; (1 S)-9-chloro-6-(3-fluoro-4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 6-(3-Fluoro-4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-pyrido[3',2':4,5]pyrrolo[2,3-c]quinolin-1-one; 6-(3- Fluoro^-methoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-pyrido^'.S'^.Slpyrrolo^.S-clquinolin-i- one; Ethyl 10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine; 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; 1-[10-Fluoro-6-(3-fluoro-4- methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 2- (Dimethylamino)-1-[10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; 1-[10-Fluoro-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- i-tiO-Fluoro-Θ^S-fluoro^-methoxybenzylJ-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yl]- 2,3-dihydroxypropan-1-one; 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone. 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, with the proviso that, if each of D^ , D^, D^ and D^ is a carbon atom, at least one of the substituents R^1 ^ , R^211 RD31 ancj RD41 JS different from hydrogen.
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 more 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^β-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 preferred 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-di methyl propoxy 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- methylpropoxy group, a 1 ,1 ,2-tri methyl propoxy 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 Cβ.s-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, tetrahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
The term "3- to 7-membered heterocycle" used in the specification of the present invention indicates 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 pyrrolidine-2,5-dione group, a piperazine-2,3-dione group and the like.
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. Furthermore, 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 substituents. Examples of such substituents are hydroxy; C-j.g-alkyl, preferably methyl; C-j.g-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.
The term "C-].-]3-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 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 phenanthrolinyl group, a phenazinyl group, an imidazopyridinyl 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 isooxazoyl group, a benzoxazolyl group, an oxadiazolyl group, a pyrazolooxazolyl group, an imidazothiazolyl group, a thienofuranyl group, a furopyrrolyl group, a pyridoxazinyl group and the like. Furthermore, 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 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 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-j.g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-j.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, ^6-14'ary'' Ci_i3-heteroaryl, an amine and an amide, such as defined, for instance for NRA129RA130 and -C(O)-NRA136RA137, wherein the C^.g-alkoxy, C3.6-cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C-|.-|3-heteroaryl have the same meanings as defined above.
In case the C-j.g-alkyl group is substituted by at least one fluorine atom, the C-j.g-alkyl group can be any group as specified above with respect to the C-j.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 substituted 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 hydroxymethyl, 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-|.g-alkyl group is substituted by at least one Cβ.g-cyclyl, the C-|.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 C3_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. \ 4- 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. Particularly 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-ι.-13-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-ι.-13-heteroaryl. Particularly preferred is a pyridylmethyl group. The above-mentioned C-|.g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-j.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C-i.-13-heteroaryl, 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 perfluoroisobutoxy.
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 preferably a C-|.g-alkoxy group which is substituted by one or two hydroxy groups, more preferably a C-1.3- alkoxy group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C-| .3- alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 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 C3_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 C3_g-cyclyl group can be any group as specified above for C3_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.β-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-ι.-13-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-ι.-13-heteroaryl.
Particularly preferred is a pyridylmethoxy group.
The above-mentioned C3_g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
In case the C3_g-cyclyl group is substituted by one or more fluoro, the C3_g-cyclyl group can be any group as specified above with respect to C3_g-cyclyl, unless specified otherwise. The C3_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 Cβ.g-cyclyl, wherein monohydroxy substituted C3_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 selected 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 substituted 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 substituted 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)-C-] .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)-C1.g-alkyl is -C(O)-CH3 and -C(O)-CH2OH. The above-mentioned 3- to 7-nnennbered heterocycle may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, oxo, C-|.g-alkoxy, hydrogen, C-|.g-alkyl and
-C(O)-C1 -6-BIlCyI.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from fluoro, hydroxy, oxo, C-|.g-alkoxy and C-|.g-alkyl, 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 C1. g-alkyl group and the C1. 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 C1. g-alkyl. It is preferred that the substituent(s) hydrogen, C-|.g-alkyl and -C(O)-C1. g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C1. g-alkyl is -C(O)-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-g Iu euro nates, benzoates, 2-(4- hydroxybenzoyl)benzoates, butyrates, salicylates, sulfosalicylat.es, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fumarates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesilates), 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 stereoisomers 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 imgf000086_0001
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers. In case RAx1 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), (1 R,3S), (1S,3R), (1S,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 imgf000086_0002
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, stereoisomers 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 (Mb) 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 imgf000088_0001
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 (II) 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, 541 1 (2004)]. The compound of formula (II) or (Na) 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, and / 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 imgf000089_0001
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: r-,A22
Figure imgf000090_0001
The 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, a compound of formula (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)]. The resulting hydroxy-com pound 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 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 4:
Figure imgf000090_0002
(IV) 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, a compound of formula (Xl) 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 diisopropylamide 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 imgf000091_0001
(Xl) (XII) (IV)
The compounds of formulae (Xl) and (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, a compound of formula (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-com pound 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 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 imgf000092_0001
Figure imgf000092_0002
(V) (IV)
The compounds of formulae (Xl) and (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, a compound of formula (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 compounds of formula (XVI) can be transformed into compounds 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 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 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 imgf000093_0001
(XV) (XII) (XVI)
Figure imgf000093_0002
The compounds of formulae (XV) and (XII) are known, commercially available or can be obtained according to known procedures.
An alternative synthetic route to compounds of formula (Ic) is depicted in reaction scheme 8. Compounds of formulae (XVII), (XVIII) and (XIX), with X being a 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 compounds of formula (XXI) under nitrogen 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 imgf000094_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, compounds of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXII) with carbonyl diimidazole in the presence of nitromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
Reaction scheme 9:
Figure imgf000094_0002
(XXII) (XlX)
Compounds of formula (XXII) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (Id), in which RA01, RA02, RA11, RA12, RA21, RA22, RA21 and RA22 are hydrogen and A1 and A2 are carbon, can also be obtained by a condensation reaction as shown in reaction scheme 10. A compound of formula (IX) is, for example, reacted with a compound of formula
(XXIII) in the presence of acetic acid and H3PO4, preferably at elevated temperature. Compound
(XXIV) thus obtained can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id). Reaction scheme 10:
Figure imgf000095_0001
The compounds of formula (IX) and 2-hydroxycyclohexanone dimer (XXIII) 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 R is amino and R is hydrogen, or wherein R 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-, -NH-C(O)-C-|.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 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-|.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)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 RA01 is alkoxy-, -OC-|.6-alkyl, that may be optionally substituted as defined above, and RA02 is hydrogen, or wherein RA31 is alkoxy-, -OCi-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-|.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 R1^1 is "substituted alkyl", e.g. -C-|.6-alkyl, or -Cs-β-cyclyl, or -3- to 7-membered heterocyclyl, all that may be optionally substituted as defined above, or -(CH2)mRA15, or -(CRA16RA17),-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 R1^1 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. d-e-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)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 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, RAx2 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 Ci_6-alkyl-SO2CI, 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 R^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, RAx2 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 R1^1 is alkoxycarbonyl-, -C(O)-C-|.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 R^1 is hydrogen, RAx2 is a free electron pair and Ax is N, by reaction with an appropriate formic acid ester chloride C-ι-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 R^2 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),-CONRA116RA117, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, preferably CI-(CRA16RA17),-CONRA116RA117 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 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)rC(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- hyd roxy be nzotriazo Ie ; 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)rC(O)OCi.3-alkyl, wherein I = 1 , 2, 3 or 4, and x = 1 or 2, preferably CI-(CRA16RA17)rCOOCH3 or Br-(CRA16RA17)rCOOCH3, 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)rCONRA116RA117 and R^2 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, R^2 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)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 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 R1^1 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 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, R**2 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 RAx1 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 wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is C-|.3-alkoxy by dealkylation with a Lewis acid, such as boron tribromide. a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 is d-3-alkoxy by dealkylation with a Lewis acid, such as boron tribromide. a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 is benzyloxy by debenzylation reaction with, e.g., hydrogen gas, or 1 ,4-cyclohexadiene, or ammonium formiate, in the presence of, e.g., catalytic amounts of palladium or an appropriate palladium salt, in a suitable solvent, e.g. methanol and/or acetic acid; a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 is alkoxy-, -OC-|.6- alkyl, that may be optionally substituted as defined above, can be prepared from a compound of formula (I), wherein the corresponding RD11 and/or RD21 and/or RD31 and/or RD41 is hydroxy, by alkylation reaction with the corresponding electrophilic reagent Ci_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 RD11 and/or RD21 and/or RD31 and/or RD41 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 RD11 and/or RD21 and/or RD31 and/or RD41 represent(s) carbonylamino-, e.g. -NH-C(O)-C-|.6-alkyl, that may be optionally substituted as defined above, can be prepared e.g. from a compound of formula (I), wherein RD11 and/or RD21 and/or RD31 and/or RD41 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 wherein RD11 and/or RD21 and/or RD31 and/or RD41 represent(s) substituted amino, e.g. -NR019R0110, can be prepared e.g. from a compound of formula (I), wherein the corresponding R011 and/or R021 and/or R031 and/or R041 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate amine, e.g. HNR019R0110, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium or copper, e.g. tris(dibenzylideneacetone)dipalladium(0) or palladium(ll) acetate, a catalytic amount of an appropriate ligand, preferably phosphines or diamines, e.g. dicyclohexyl-(2',4',6'- trisisopropyl-biphenyl-2-yl)-phosphane and a stoichiometric amount of base, e.g. cesium carbonate or sodium carbonate, in an appropriate solvent, e.g. toluene or tert-butanol, at elevated temperature, preferably 80-11O0C, and under nitrogen or argon atmosphere [see e.g. J. Am. Chem. Soc. 125, 6653-6655 (2003)]; a compound of formula (I), wherein R011 and/or R021 and/or R031 and/or R041 represent(s) C6-i4-aryl or C-ι-13-heteroaryl can be prepared e.g. from a compound of formula (I), wherein the corresponding R011 and/or R021 and/or R031 and/or R041 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate boronic acid, e.g. C6-i4-aryl-B(OH)2 or C1.-^- heteroaryl-B(OH)2, respectively, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium, e.g. dichlorobis (tricyclohexylphosphine) palladium (II), optionally a catalytic amount of an appropriate ligand, preferably phosphines, and a stoichiometric amount of base, e.g. cesium carbonate or sodium carbonate, in an appropriate solvent, e.g. dimethoxyethane and/or tetrahydrofuran and/or ethanol, at elevated temperature, preferably 80-11O0C, or using microwave radiation at 120-1400C, and under nitrogen or argon atmosphere;
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-Ci-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 -10°C to 100°C, 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.
Furthermore, building blocks of formula (XXIXa), or (XXIXb), or a mixture thereof, can be synthesized according to the sequence outlined in reaction scheme 11. Compounds of formula (XXV) can be reacted with a haloacetic acid, preferably chloroacetic acid or bromoacetic acid, in the presence of a suitable base, e.g. sodium hydroxide and / or sodium carbonate, in an appropriate protic solvent, e.g. water. The resulting aminoacetic acid of formula (XXVI) is then reacted with an acetylating agent, e.g. acetic anhydride or acetyl chloride, in the presence of a suitable base, e.g. sodium carbonate, in an appropriate polar or preferably protic solvent, e.g. water. The resulting compound of formula (XXVII) can be cyclized to a compound of formula (XXVIII) by reaction in neat acetic anhydride in the presence of a suitable base, e.g. triethylamine or diisopropylethylamine, at temperatures between 2O0C and 2000C, preferably 120°C-150°C. Finally, a compound of formula (XXIXa), or (XXIXb), or a mixture thereof, can be synthesized by reaction of a compound of formula (XXVIII) with an appropriate base, e.g., sodium sulfite, in a suitable protic solvent, e.g. water, preferably at elevated temperatures, e.g. 60-1000C. The compound of formula (XXIXa), or (XXIXb), or a mixture thereof, can be reacted according to reaction scheme 3 [replacing compound (VIII)] to give a compound of formula (Ic).
Reaction scheme 11 :
Figure imgf000103_0001
(XXV) (XXVI) (XXVII)
Figure imgf000103_0002
Compounds of formula (XXV) are known, commercially available or can be obtained according to known procedures.
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, aluminium 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 methylisobutylketone, 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, depending 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 diastereomeric 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 (1 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, resolving 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. Furthermore, 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, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
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 compounds 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, if not otherwise stated. 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, if not otherwise noted. 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 uncorrected.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE: dichloroethane, THF: tetrahydrofuran, mp.: melting point, RT: room temperature (20 to 250C), tic: thin layer chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spectroscopy.
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 temperature, 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 Compounds
A1. 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone
Step 1 : 2-(1-Acetyl-1 H-indol-1-yl)-3-hydroxy-5,5-dimethyl-cyclohex-2-enone. 1-Acetyl-1 ,2-dihydro- indol-3-one (10.5 g) is suspended in acetic acid (50 ml) and a suspension of 5,5-dimethyl- cyclohexane-1 ,3-dione (8.4 g) in acetic acid (50 ml) is added. The reaction mixture is stirred for 20 min and triethylamine (8.3 ml) is added slowly. The mixture is refluxed for 24 h, evaporated to dryness, treated with 2N methanolic HCI solution (30 ml) and evaporated to dryness again. The residue is purified by flash chromatography and crystallized from diethyl ether to give 11.5 g of 2-( 1 -acetyl- 1 H- indol-1-yl)-3-hydroxy-5,5-dimethyl-cyclohex-2-enone.
1H-NMR (200 MHz, d6-DMSO): δ = 1.13 (s, 6H), 2.42 (br, 4H), 2.61 (s, 3H), 7.17-7.19 (m, 2H), 7.23-
7.31 (m, 1 H), 8.31 (d, J = 7.8 Hz, 1 H). mp.: 230°C
Step 2: 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone. 2-(1-Acetyl-1 H-indol-1-yl)-3- hydroxy-5,5-dimethyl-cyclohex-2-enone (5.95 g) is dissolved in aqueous 1 N NaOH solution (65 ml) and stirred for 2 h. The reaction mixture is diluted with dichloromethane (50 ml) and acidified with aqueous HCI solution (pH 5). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml). The combined organic layers are dried (MgSO4) and concentrated in vacuo to give 5.09 g of the title compound.
1H-NMR (200 MHz, CDCI3): δ = 1.22 (s, 6H), 2.50 (s, 4H), 7.00 (d, J = 2.5 Hz, 1 H), 7.06-7.21 (m, 2H),
7.25-7.32 (m, 2H), 8.73 (br, 1 H). mp.: 1780C
A2. 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one Step 1 : 6-(4-Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1- one. 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone (example A1 ) (5.08 g) and 4- methoxyphenyl acetic acid anhydride (62.55 g) are dissolved in nitromethane (150 ml). Perchloric acid (70% (v/v) in water, 0.2 ml) is added in 6 portions (every 10 minutes) and the mixture is stirred for one additional hour. The reaction mixture is diluted with dichloromethane (100 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml). The combined organic extracts are dried (MgSO4) and crystallized from nitromethane to give 4.65 g (58%) of 6-(4-methoxy-benzylidene)-3, 3-dimethyl-3, 4,6,7- tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one.
1H-NMR (200 MHz, CDCI3): δ = 1.17 (s, 6H), 2.46 (s, 2H), 2.63 (s, 2H), 3.85 (s, 3H), 6.0 (s, 1 H), 6.92- 6.96 (m, 2H), 7.14-7.32 (m, 3H), 7.56-7.62 (m, 2H), 8.07 (br, 1 H), 8.81 (d, J = 7.5 Hz, 1 H). Step 2: θ^-Methoxy-benzyO-S.S-dimethyl^.S^J-tetrahydro-indolo^.S-clquinolin-i-one. 6-(4- Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one (200 mg) is suspended in acetonitrile (10 ml) and 25% (w/v) aqueous ammonia solution (10 ml) is added. The reaction mixture is heated in a sealed vial using microwave radiation at 13O0C for 25 min. The solvent is removed in vacuo and the residue is dissolved in dichloromethane (50 ml) and water (50 ml). After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2 x 50 ml), the combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane 5:95 to 1 :1 (v/v)) to give 134 mg (67%) of the title compound.
1H-NMR (200 MHz, CDCI3): δ = 1.19 (s, 6H), 2.71 (s, 2H), 3.24 (s, 2H), 3.77 (s, 3H), 4.50 (s, 2H), 6.82- 6.88 (m, 2H), 7.19-7.34 (m, 4H), 7.99 (br, 1 H), 9.34 (d, J = 8.3 Hz, 1 H). mp.: 1690C
A3. i-Acetyl-θ-chloro-IH-indol-S-yl acetate
Step 1 : 2-[(Carboxymethyl)amino]-4-chlorobenzoic acid. Chloroacetic acid (15 g) is dissolved in water (15 ml) and sodium carbonate (16 g) is added in portions (carbon dioxide evolves) and the mixture is stirred at 450C for 30 min. In parallel, 2-amino-4-chlorobenzoic acid is dissolved in water (15 ml), 1 M aqueous sodium hydroxide solution (15 ml) is added, followed by the sodium chloroacetate solution prepared above. The resulting mixture is stirred at 6O0C for 2 days. After cooling, 1 M aqueous sodium hydroxide solution is added, after that, it is acidified by addition of concentrated hydrochloric acid. The yellow precipitate, that is formed, is filtered off and washed with water (100 ml). It is redissolved in tetrahydrofuran / ethyl acetate (1 :1 (v/v), 150 ml), dried (Na2SO4) and concentrated in vacuo. The residue, 20.0 g of crude 2-[(carboxymethyl)amino]-4-chlorobenzoic acid as a yellow solid, is used without further purification in the next step.
Step 2: i-Acetyl-θ-chloro-I H-indol-S-yl acetate. Crude 2-[(carboxymethyl)amino]-4-chlorobenzoic acid (20.0 g) is dissolved in acetic anhydride (250 ml), the solution is cooled to O0C (ice bath) and triethylamine (11.02 ml) is added slowly drop by drop. After the addition is complete, the mixture is stirred at 14O0C for 30 min. After cooling, the mixture is concentrated in vacuo, the residue is dissolved in dichloromethane (100 ml) and washed with saturated sodium carbonate solution (3 x 100 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-heptane 1 :4 to 2:3 (v/v)) to give 4.8 g (16%, 2 steps) of the title compound.
1H-NMR (300 MHz, d6-DMSO+CD3OD): δ = 2.38 (s, 3H), 2.62 (s, 3H), 7.36 (dd, J = 1.9 Hz, 8.4 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.92 (s, 1 H), 8.40 (d, J = 1.6 Hz, 1 H). MS (M+ found) = 251.4 [GC/MS, El]
A4. 1 -Acetyl-θ-chloro-1 ,2-dihydro-3H-indol-3-one
Sodium sulfite (6.0 g) is dissolved in water (50 ml), the solution is stirred at 750C and a solution of 1- acetyl-6-chloro-1 H-indol-3-yl acetate (example A3) (3.4 g) in tetrahydrofuran (10 ml) is added drop by drop at that temperature. The mixture is stirred at 750C for 90 min. After that, it is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / n- heptane 1 :1 (v/v)) to give 1.8 g (60%) of the title compound.
1H-NMR (300 MHz, d6-DMSO+CD3OD): δ = 2.27 (s, 3H), 4.58 (s, 2H), 7.30 (dd, J = 1.8 Hz, 8.2 Hz,
1 H), 7.71 (d, J = 8.2 Hz, 1 H), 8.47 (bs, 1 H).
MS (M+ found) = 209.2 [GC/MS, El]
A5. 2-(1 -Acetyl-δ-chloro-1 H-indol-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1 -one i-Acetyl-θ-chloro-i ^-dihydro-SH-indol-S-one (example A4) (1.5 g) is dissolved in acetic acid (10 ml) and a suspension of 5,5-dimethyl-cyclohexane-1 ,3-dione (1.0 g) in acetic acid (10 ml) is added. The reaction mixture is stirred for 20 min and triethylamine (1.05 ml) is added slowly. The mixture is refluxed for 24 h. After that, it is concentrated in vacuo, redissolved in dichloromethane (50 ml) and washed with 1 M aqueous hydrochloric acid (50 ml). The organic layer is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / n-heptane 2:1 (v/v)) followed by crystallization from diethyl ether to give 2.2 g (92%) of the title compound as a slightly brown solid.
1H-NMR (300 MHz, d6-DMSO+CD3OD): δ = 1.13 (s, 6H), 2.43 (bs, 4H), 2.63 (s, 3H), 7.20 (d, J = 8.3 Hz, 1 H), 7.26 (dd, J = 1.8 Hz, 8.4 Hz, 1 H), 7.62 (s, 1 H), 8.36 (d, J = 1.7 Hz, 1 H). MS (MH+ found) = 332.0
A6. 2-(6-Chloro-1 H-indol-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1 -one
2-(1-Acetyl-6-chloro-1 H-indol-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one (example A5) (2.0 g) is dissolved in aqueous 1 N sodium hydroxide solution (30 ml) and stirred for 2 h at room temperature. The reaction mixture is diluted with dichloromethane (50 ml) and acidified with 6N aqueous HCI solution (pH 5). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 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 ethyl acetate / n-heptane 1 :1 to 4:1 (v/v)) to yield 1.14 g (65%) of the title compound. 1H-NMR (300 MHz, d6-DMSO+CD3OD): δ = 1.12 (s, 6H), 2.41 (bs, 4H), 6.93 (dd, J = 1.9 Hz, 8.5 Hz, 1 H), 7.15 (s, 1 H), 7.16 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 1.6 Hz, 1 H), 1 1.03 (bs, 1 H). MS (MH+ found) = 290.2
A7. 1 -(3-Fluoro-4-methoxyphenyl)-3-nitroacetone
3-Fluoro-4-methoxyphenyl acetic acid (7.0 g) is dissolved in dry tetrahydrofuran (250 ml), carbonyl diimidazole (7.4 g) is added and the mixture is refluxed for 2 h. In parallel, potassium tert-butylate (5.5 g) is suspended in dry tetrahydrofuran (100 ml) and nitromethane is added drop by drop. The mixture is stirred for 2 h at room temperature. Then, the solution of imidazolide, prepared above and cooled down to room temperature, is added. The resulting mixture is refluxed for 16 h. After cooling, the precipitate is filtered and washed with dichloromethane (2 x 20 ml). It is dissolved in water (100 ml), the solution is acidified with concentrated hydrochloric acid to pH 3, the resulting precipitate is filtered, washed with water (2 x 20 ml) and dried in vacuo to give rise to 4.6 g (53%) of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ = 3.82 (s, 3H), 3.87 (s, 2H), 6.99 (bd, J = 8.4 Hz, 1 H), 7.07-7.18 (m,
2H).
MS (M+ found) = 227.2
A8. 4-(2-Chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-7,7-dimethyl-3-nitro-4,6,7,8- tetrahydroquinolin-5(1 H)-one
2-Chloro-3-pyridinecarboxaldehyde (2.27 g) is dissolved in isopropanol (240 ml), 3-amino-5,5- dimethyl-2-cyclohexen-1-one (2.23 g), 1-(3-fluoro-4-methoxyphenyl)-3-nitroacetone (example A7) (3.65 g), benzylamine (88 μl) and glacial acetic acid (48 μl) are added subsequently and the mixture is stirred for 16 h at 8O0C. After cooling, it is concentrated in vacuo and the residue is purified by column chromatography (silica gel, eluting with dichloromethane / ethyl acetate 9:1 (v/v)) to yield 1.5 g (20%) of the title compound.
1H-NMR (300 MHz, d6-DMSO, major isomer): δ = 0.88 (s, 3H), 1.03 (s, 3H), 1.98 (d, AB, J = 15.9 Hz, 1 H), 2.21 (d, J = 16.4 Hz, 1 H), 2.42 (s, 1 H), 3.81 (s, 3H), 4.08 (d, AB, J = 14.4 Hz, 1 H), 4.18 (d, AB, J = 14.4 Hz. 1 H), 5.48 (s, 2H), 7.03-7.18 (m, 3H), 7.33 (dd, J = 4.6 Hz, 7.5 Hz, 1 H), 7.78 (dd, J = 1.9 Hz, 7.6 Hz, 1 H), 8.18 (dd, J = 1.8 Hz, 4.6 Hz, 1 H), 10.07 (s, 1 H). MS (MH+ found) = 472.0
A9. 3-Amino-4-(2-chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-7,7-dimethyl-7,8- dihydroquinolin-5(6H)-one
4-(2-Chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-7,7-dimethyl-3-nitro-4,6,7,8-tetrahydroquinolin- 5(1 H)-one (example A8) (1.49 g) is dissolved in ethanol (20 ml), iron powder (0.71 g) and a solution of concentrated hydrochloric acid (1.07 ml) in ethanol (20 ml) are added and the mixture is refluxed for 3 h. After cooling, water (50 ml) and ethyl acetate (50 ml) are added and the mixture is filtered over a plug of Celite®. The aqueous phase is extracted with ethyl acetate (2 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate / triethylamine 5:5:1 (v/v/v)) to yield 321 mg (23%) of the title compound.
1H-NMR (300 MHz, CDCI3): δ = 1.12 (s, 6H), 2.38 (d, AB, J = 16.1 Hz, 1 H), 2.48 (d, J = 16.0 Hz, 1 H), 3.05 (s, 2H), 3.31 (bs, 2H [exch.]), 3.86 (s, 3H), 4.16 (s, 2H), 6.86-7.00 (m, 3H), 7.32 (dd, J = 4.8 Hz, 7.6 Hz, 1 H), 7.47 (dd, J = 2.0 Hz, 7.6 Hz, 1 H), 8.44 (dd, J = 1.9 Hz, 4.8 Hz, 1 H). MS (MH+ found) = 440.1
A10. Benzyl 4-(2-chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-3-nitro-5-oxo-4,5,6,8- tetrahydro-1 ,7-naphthyridine-7(1 H)-carboxylate
Step 1 : Benzyl 5-amino-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate. Benzyl 5-hydroxy-3-oxo-3,6- dihydropyridine-1(2H)-carboxylate (1.34 g, 77% in glacial acetic acid, prepared as described in Organic Letters 6, 4483-4485 (2004)) is dissolved in dry acetonitrile (20 ml), ammonium chloride (0.97 g) is added and the mixture in stirred in a sealed vial at 8O0C for 15 min using microwave radiation. After cooling, it is diluted with water (20 ml) and ethyl acetate (20 ml), the aqueous phase is extracted with ethyl acetate (2 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The residue, 0.76 g of crude benzyl 5-amino-3-oxo-3,6-dihydropyridine-1(2H)- carboxylate (74%), is used without further purification in the next step.
Step 2: Benzyl 4-(2-chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-3-nitro-5-oxo-4,5,6,8-tetrahydro- 1 ,7-naphthyridine-7(1 H)-carboxylate. 2-Chloro-3-pyridinecarboxaldehyde (0.37 g) is dissolved in isopropanol (20 ml), crude benzyl 5-amino-3-oxo-3,6-dihydropyridine-1(2H)-carboxylate (0.64 g), 1-(3- fluoro-4-methoxyphenyl)-3-nitroacetone (example A7) (0.59 g), benzylamine (14 μl) and glacial acetic acid (8 μl) are added subsequently and the mixture is stirred for 16 h at 8O0C. After cooling, it is concentrated in vacuo and the residue is purified by column chromatography (silica gel, eluting with dichloromethane / ethyl acetate 4:1 (v/v)) to yield 282 mg (19%) of the title compound. 1H-NMR (300 MHz, d6-DMSO, major isomer): δ = 3.72-4.19 (m, 5H), 3.82 (s, 3H), 5.11 (bs, 2H), 5.15 (bs, 2H), 6.96-7.20 (m, 3H), 7.24-7.45 (m, 6H), 7.80 (dd, J = 1.9 Hz, 7.7 Hz, 1 H), 8.28 (dd, J = 1.9 Hz, 4.7 Hz, 1 H), 10.40 (s, 1 H). MS (MH+ found) = 578.9
A11. Ethyl 4-(5-fluoro-1H-indol-3-yl)-3-hydroxypiperidine-1-carboxylate Step 1 : Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate. N-Carbethoxy-4- piperidone (132 g) is dissolved in ethanol (1000 ml), potassium hydroxide (42.5 g) and 5-fluoroindole (47.9 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 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) to yield 126.4 g of ethyl 4-(5-fluoro-1 H-indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a yellow viscous oil, that is used without further purification in the next step.
Step 2: Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-hydroxypiperidine-1-carboxylate. Crude ethyl 4-(5-fluoro-1 H- indol-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (126.4 g) is dissolved under argon in dry tetrahydrofuran (575 ml) und the solution is cooled to O0C (ice bath). Borane tetrahydrofuran complex (1 M in tetrahydrofuran, 515 ml) is added drop by drop within 40 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), a water / ethanol mixture (1 :1 (v/v), 690 ml) is added carefully, followed by 3M sodium hydroxide solution (258 ml) and hydrogen peroxide (30% in water, 172 ml). The mixture is stirred 15 min room temperature, then 2 h at 6O0C. After cooling, it is poured into ice water (1000 ml), the mixture is extracted with ethyl acetate (3 x 800 ml), the combined organic extracts are washed with water (1 x 1000 ml), saturated aqueous sodium chloride solution (1 x 1000 ml) and 10% aqueous sodium hydrogensulfite solution (1 x 1000 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / heptane to obtain 40.16 g (37%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.20 (t, J = 7.0 Hz, 3H), 1.63 (ddd, J = 4.3 Hz, 12.3 Hz, 25.6 Hz, 1 H), 1.80-1.90 (m, 1 H), 2.56-2.97 (m, 3H), 3.41-3.55 (m, 1 H), 3.91-4.19 (m, 4H), 4.78 (d, J = 5.6 Hz, 1 H), 6.86 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.26-7.35 (m, 2H), 10.88 (s, 1 H). MS (MH+ found) = 306.9 mp.: 178-179 0C
A12. Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-oxopiperidine-1 -carboxylate
Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-hydroxypiperidine-1 -carboxylate (example A11 ) (40.16 g) is dissolved in dimethylsulfoxide (235 ml) and dichloromethane (235 ml), the solution is cooled to O0C (ice bath) and diisopropylethyl amine (78.0 ml) is added. A solution of sulfurtrioxide pyridine complex (41.38 g) in dimethylsulfoxide (293 ml) and pyridine (21.0 ml) is added drop by drop within 40 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 (1000 ml) is added, the mixture is acidified with 6M hydrochloric acid (pH 4). The aqueous phase is extracted with ethyl acetate (3 x 800 ml), the combined organic extracts are washed with 1 N aqueous hydrogen chloride solution (3 x 1000 ml) and saturated sodium chloride solution (2 x 1000 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 2:3 (v/v)) to yield 39.1 g (99%) of the title compound as a viscous oil.
1H-NMR (300 MHz, d6-DMSO); δ = 1.21 (t, J = 7.1 Hz, 3H), 2.20-2.31 (m, 2H), 3.48-3.63 (m, 1 H), 3.89 (ddd, J = 4.3 Hz, 4.3 Hz, 13.0 Hz, 1 H), 3.98-4.23 (m, 5H), 6.90 (ddd J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.16 (dd, J = 2.6 Hz, 10.3 Hz, 1 H), 7.25 (d, J = 2.5 Hz, 1 H), 7.33 (dd, J = 4.6 Hz, 8.9 Hz, 1 H), 1 1.02 (s, 1 H). MS (MH+ found) = 304.9
A13. 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 bromoacetate (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
A14. [2-(Benzyloxy)ethoxy]acetic acid
Methyl [2-(benzyloxy)ethoxy]acetate (example A13) (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
Final Compounds
1. 10-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin- 1-one
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A2) (200 mg) is suspended in chloroform (1 ml) and diethyl ether (1 ml) and the suspension is cooled to O0C (ice bath). A solution of bromine (40 μl) in diethyl ether (1 ml) is added drop by drop and the resulting orange suspension is stirred for 18 h at O0C. After that, dichloromethane (20 ml) and water (10 ml) are added, the organic phase is washed subsequently with 1 M sodium hydrogensulfite solution (10 ml), 1 M sodium hydrogencarbonate solution (10 ml) and again water (10 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane) to yield 210 mg (87%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 1.19 (s, 6H), 2.71 (s, 2H), 3.25 (s, 2H), 3.79 (s, 3H), 4.51 (s, 2H), 6.90 (d, J = 8.1 Hz, 2H), 7.15-7.31 (m, 3H), 7.54-7.67 (m, 1 H), 7.93 (s, 1 H), 9.56 (d, J = 2.0 Hz, 1 H). MS (MH+ found) = 463.4, 465.4
2. 11 -Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline Step 1 : 2-(4-Fluoro-1 H-indol-3-yl)cyclohexanone. Phosphorus acid (2N, 7 ml) is dissolved in glacial acetic acid (30 ml) and the solution is refluxed. 4-Fluoroindole (5.0 g) and 2-hydroxycyclohexanone dimer (5.0 g) are added and the mixture is refluxed for 18 h. After cooling to O0C (ice bath), concentrated ammonia (100 ml) is added drop by drop, the mixture is extracted with ethyl acetate (2 x 100 ml), the combined organic extracts are washed with 2M ammonia solution (2 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 9:1 (v/v)) followed by crystallization from ethanol to yield 800 mg (9%) of 2-(4-fluoro-1 H-indol-3-yl)cyclohexanone. mp.: 138-139 0C
Step 2: 1 i-Fluoro-Θ^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinoline. 2-(4- Fluoro-1 H-indol-3-yl)cyclohexanone (800 mg) is dissolved under nitrogen in dichloroethane (3.5 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 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 (1.3 g) is dissolved in trifluoroacetic acid anhydride (1 ml) and the mixture is stirred for 20 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (3.5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 1 h at O0C and 3 h at room temperature. After that, ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 16 h. After cooling, 2N aqueous ammonia (20 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 20 ml), the combined organic extracts are washed with 2N ammonia (3 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 3:1 (v/v)) followed by crystallization from diethyl ether to obtain 310 mg (24%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.80-1.94 (m, 4H), 2.78-3.01 (m, 2H), 3.22-3.38 (m, 2H), 3.76 (s, 3H), 4.47 (s, 2H), 6.89-7.00 (m, 1 H), 7.00-7.12 (m, 2H), 7.18 (d, J = 10.9 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.47-7.56 (m, 1 H), 11.80 (s, 1 H). MS (MH+ found) = 379.3 mp.: 172-173 0C
3. 11 -Bromo-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline
Step 1 : 2-(4-Bromo-1 H-indol-3-yl)cyclohexanone. Phosphorus acid (2N, 15 ml) is dissolved in glacial acetic acid (75 ml) and the solution is refluxed. 4-Bromoindole (10.0 g) and 2-hydroxycyclohexanone dimer (8.7 g) are added and the mixture is refluxed for 18 h. After cooling to O0C (ice bath), concentrated ammonia (150 ml) is added drop by drop, the mixture is extracted with ethyl acetate (2 x 150 ml), the combined organic extracts are washed with 2M ammonia solution (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethanol to yield 1.7 g (11 %) of 2-(4-bromo-1 H-indol-3-yl)cyclohexanone.
Step 2: 1 i-Bromo-Θ^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinoline. 2-(4- Bromo-1 H-indol-3-yl)cyclohexanone (1.7 g) is dissolved under nitrogen in dry dichloroethane (15 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 9 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (1.3 g) is dissolved in trifluoroacetic acid anhydride (1 ml) and the mixture is stirred for 15 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (3.5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 30 min at O0C and 3 h at room temperature. After that, ammonia (7M in methanol, 9 ml) and ammonium acetate (9.0 g) in glacial acetic acid (15 ml) are added and the mixture is heated for 120 min at 15O0C in a sealed vial using microwave radiation. After cooling, the mixture is concentrated in vacuo, ethyl acetate (100 ml) and 1 M aqueous sodium carbonate solution are added (100 ml), the aqueous phase is extracted with ethyl acetate (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 gradient dichloromethane to dichloromethane / ethyl acetate 1 :1 (v/v)) to yield 200 mg (8%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.74-1.92 (m, 4H), 2.91-3.03 (m, 2H), 3.60-3.70 (m, 2H), 3.75 (s, 3H), 4.33 (s, 2H), 6.99-7.10 (m, 2H), 7.17 (d, J = 11.1 Hz, 1 H), 7.37 (dd, J = 7.8 Hz, 7.9 Hz, 1 H), 7.48 (d, J = 6.6 Hz, 1 H), 7.62 (d, J = 3.1 Hz, 1 H), 11.90 (s, 1 H). MS (MH+ found) = 439.3, 441.3 4. lO-Fluoro-δ^S-fluoro^-methoxybenzylJ^.S^.y-tetrahydro-IH-indolo^.S-clquinoline Step 1 : 2-(5-Fluoro-1 H-indol-3-yl)cyclohexanone. Phosphorus acid (2N, 7 ml) is dissolved in glacial acetic acid (30 ml) and the solution is refluxed. 5-Fluoroindole (5.0 g) and 2-hydroxycyclohexanone dimer (5.0 g) are added and the mixture is refluxed for 18 h. After cooling to O0C (ice bath), concentrated ammonia (100 ml) is added drop by drop, the mixture is extracted with ethyl acetate (2 x 100 ml), the combined organic extracts are washed with 2M ammonia solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 8:2 (v/v)) followed by crystallization from ethanol to yield 1.9 g (22%) of 2-(5-fluoro-1 H-indol-3-yl)cyclohexanone.
Step 2: lO-Fluoro-e^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinoline. 2-(5- Fluoro-1 H-indol-3-yl)cyclohexanone (920 mg) is dissolved under nitrogen in dry dichloroethane (5 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 8 ml) is added drop by drop and the mixture is stirred for 1 h at O0C. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (1.5 g) is dissolved in trifluoroacetic acid anhydride (1.1 ml) and the mixture is stirred for 15 min at room temperature. The formed mixed anhydride is diluted with dry dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 1 h at O0C and 3 h at room temperature. After that, ammonia (7M in methanol, 8 ml) is added and the mixture is refluxed for 16 h. After cooling, 2N aqueous ammonia (25 ml) is added, the aqueous phase is extracted with ethyl acetate (3 x 25 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 gradient dichloromethane to dichloromethane / ethyl acetate 4:1 (v/v)) followed by crystallization from diethyl ether to obtain 0.5 g (33%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.80-1.99 (m, 4H), 2.89-2.99 (m, 2H), 3.19-3.29 (m, 2H), 3.75 (s, 3H), 4.30 (s, 2H), 6.98-7.12 (m, 2H), 7.18 (dd, J = 2.0 Hz, 12.7 Hz, 1 H), 7.38 (ddd, J = 2.4 Hz, 9.2 Hz, 9.2 Hz, 1 H), 7.59 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.87 (dd, J = 2.5 Hz, 9.7 Hz, 1 H), 11.53 (s, 1 H). MS (MH+ found) = 379.3 mp.: 1 16-121 0C
5. θ-Chloro-e^S-fluoro^-methoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S- c]quinolin-1-one
2-(6-Chloro-1 H-indol-3-yl)-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one (example A6) (640 mg) is dissolved under nitrogen in dry dichloromethane (20 ml). Zinc chloride (1 M in diethyl ether, 4.5 ml) is added drop by drop and the mixture is stirred for 20 min at room temperature. In parallel, 3-fluoro-4- methoxyphenyl acetic acid (814 mg) is dissolved in trifluoroacetic acid anhydride (0.61 ml) and the mixture is stirred for 20 min at room temperature. The formed mixed anhydride is diluted with dichloromethane (10 ml) and added drop by drop to the zinc chloride mixture, prepared above, within 5 min at room temperature. Nitromethane (10 ml) is added and the mixture is stirred for 2 h at room temperature and for 18 h at 5O0C. After that, ammonium acetate (0.85 g) and ammonia (7M in methanol, 1.6 ml) are added and the mixture is refluxed for 2 h. After cooling, 2N aqueous ammonia (20 ml) is added, the aqueous phase is extracted with ethyl acetate (2 x 50 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 / n-heptane 2:3 (v/v)) followed by crystallization from diethyl ether / n-heptane to give 0.7 g (72%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.08 (s, 6H), 2.67 (s, 2H), 3.13 (s, 2H), 3.77 (s, 3H), 4.45 (s, 2H), 7.03-7.16 (m, 2H), 7.20-7.30 (m, 2H), 7.64 (d, J = 1.8 Hz, 1 H), 9.23 (d, J = 8.9 Hz, 1 H), 12.17 (s, 1 H). MS (MH+ found) = 337.2
6. (ISJ-θ-Chloro-e^S-fluoro^-methoxybenzyO-S.S-dimethyl^.S^.y-tetrahydro-IH- indolo[2,3-c]quinolin-1 -ol
3-Nitrophenylboronic acid (229 mg), D-(-)-tartaric acid (206 mg) and calcium hydride (115 mg) are suspended in THF (5 ml) and heated under reflux for 3 h. The suspension is cooled and filtered under nitrogen atmosphere. 9-Chloro-6-(3-fluoro-4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-1-one (example 5) (200 g) is dissolved in the filtrate, the solution is cooled to O0C (ice bath) and sodium borohydride (50.2 mg) is added in 5 portions at O0C. The mixture is stirred for 18 h at room temperature. After that, methanol (1 ml) is added slowly (hydrogen evolution) and the mixture is stirred for 30 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 5:95 (v/v)) to yield 40 mg (20%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 0.92 (s, 3H), 1.12 (s, 3H), 1.75 (dd, J = 7.0 Hz, 13.3 Hz, 1 H), 2.04 (dd, J = 6.1 Hz, 13.5 Hz, 1 H), 2.65 (d, AB, J = 16.5 Hz, 1 H), 2.85 (d, AB, J = 16.2 Hz, 1 H), 3.75 (s, 3H), 4.28 (d, AB, J = 14.3 Hz, 1 H), 4.37 (d, AB, J = 14.3 Hz, 1 H), 5.12 (d, J = 7.0 Hz, 1 H), 5.21-5.31 (m, 1 H), 6.98-7.12 (m, 2H), 7.13-7.23 (m, 2H), 7.56 (d, J = 1.9 Hz, 1 H), 8.45 (d, J = 8.7 Hz, 1 H), 11.67 (s, 1 H).
MS (MH+ found) = 439.3 ee > 95% (S) (determined by chiral HPLC using Diacel Chiralcel OD-RH, 250x4.6 mm, 5μ as stationary phase and acetonitrile / water / triethylamine 49:49:2 (v/v/v), isocratic, as mobile phase, UV detection, flow 1 ml/min, T = 350C, tR (R-isomer) = 13.4 min, tR (S-isomer) = 15.0 min, absolute configuration by analogy)
7. 6-(3-Fluoro-4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H- pyrido[3',2':4,5]pyrrolo[2,3-c]quinolin-1-one
3-Amino-4-(2-chloropyridin-3-yl)-2-(3-fluoro-4-methoxybenzyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one (example A9) (210 mg) is dissolved under argon in dry, degased toluene (15 ml) in a microwave vial, tris(dibenzylideneacetone)dipalladium (0) (24 mg), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (16 mg) and potassium tert-butoxide (80 mg) are added under argon and the mixture is stirred in a sealed vial at 2000C for 30 min using microwave radiation. After cooling, the mixture is filtered over a plug of Celite® and washed with ethyl acetate (20 ml). The combined filtrate is concentrated in vacuo. The residue is redissolved in ethyl acetate and filtered over a plug of ion exchange resin (4 g, Isolute® Flash SCX-2, washed with ethyl acetate, compound is eluted with 7N ammonia in methanol (20 ml)). The filtrate is concentrated 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)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 41 mg (21 %) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.08 (s, 6H), 2.67 (s, 2H), 3.78 (s, 3H), 4.09 (s, 2H), 5.18 (bs, 1 H), 5.20 (s, 2H), 6.99-7.18 (m, 4H), 8.10 (dd, J = 1.7 Hz, 4.8 Hz, 1 H), 8.69 (dd, J = 1.7 Hz, 7.8 Hz, 1 H). MS (MH+ found) = 404.2
8. 6-(3-Fluoro-4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H- pyrido[4',3':4,5]pyrrolo[2,3-c]quinolin-1-one
3-Amino-4-(3-bromopyridin-4-yl)-2-(3-fluoro-4-methoxybenzyl)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)- one (prepared in analogy to example A9) (50 mg) is dissolved under argon in dry, degased toluene (2 ml) and dry, degased acetonitrile (0.2 ml) in a microwave vial, tris(dibenzylideneacetone)dipalladium (0) (4.7 mg), 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (3.2 mg) and potassium tert-butoxide (15 mg) are added under argon and the mixture is stirred in a sealed vial at 2000C for 30 min using microwave radiation. After cooling, 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 flash chromatography (silica gel, eluting with ethyl acetate) to yield 10 mg (24%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.09 (s, 6H), 2.69 (s, 2H), 3.16 (s, 2H), 3.77 (s, 3H), 4.50 (s, 2H), 7.02-7.18 (m, 2H), 7.26 (dd, J = 2.0 Hz, 12.6 Hz, 1 H), 8.42 (d, J = 5.6 Hz, 1 H), 9.03 (d, J = 5.7 Hz, 1 H), 9.12 (s, 1 H), 12.43 (s, 1 H). MS (MH+ found) = 404.2
9. Ethyl 10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridine-3-carboxylate
Ethyl 4-(5-fluoro-1 H-indol-3-yl)-3-oxopiperidine-1-carboxylate (example A12) (39.1 g) is dissolved under nitrogen in dry dichloroethane (262 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 256 ml) is added drop by drop within 10 min and the mixture is stirred for 10 min at O0C. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (47.2 g) is dissolved in trifluoroacetic acid anhydride (37 ml) and the mixture is stirred for 1.5 h at room temperature. The formed mixed anhydride is diluted with dichloroethane (109 ml) and added drop by drop to the zinc chloride mixture, prepared above, within 20 min at O0C. The mixture is stirred for 5 min at O0C and 3 h at room temperature. After that, ammonium acetate (30.6 g) and ammonia (7M in methanol, 117 ml) are added and the mixture is refluxed for 18 h. After cooling, it is filtered over a plug of Celite®, the plug is washed thoroughly with methanol. Water (1000 ml) is added to the filtrate, the aqueous phase is extracted with dichloromethane (2 x 1000 ml), the combined organic extracts are washed with water (1 x 1000 ml), dried (MgSO4) and 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 0:9:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield 12.5 g (22%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.23 (t, J = 7.1 Hz, 3H), 3.32 (t, J = 5.8 Hz, 2H), 3.76 (s, 3H), 3.81 (t, J = 5.8 Hz, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.34 (s, 2H), 4.68 (s, 2H), 7.00-7.13 (m, 2H), 7.20 (dd, J = 1.9 Hz, 12.6 Hz, 1 H), 7.42 (ddd, J = 2.6 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.62 (dd, J = 4.5 Hz, 8.9 Hz, 1 H), 7.92 (dd, J = 2.5 Hz, 9.6 Hz, 1 H), 1 1.71 (s, 1 H). MS (MH+ found) = 452.2 mp.: 212-213 0C
10. 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c][1 ,7]naphthyridine
Ethyl lO-fluoro-e^S-fluoro^-methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridine-S- carboxylate (example 9) (12 g) is dissolved in ethylene glycol (217 ml), hydrazine hydrate (10.5 ml) and potassium hydroxide (28.2 g) are added and the mixture is stirred for 2 h at 14O0C. After cooling, it is poured into ammonium chloride solution (1000 ml) and stirred for 30 min at room temperature. The precipitate is filtered off, washed thoroughly with water and petroleum ether and dried in vacuo to give rise to 10.3 g (99%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.17-3.33 (m, 4H), 3.39 (bs, 1 H), 3.75 (s, 3H), 4.08 (s, 2H), 4.32 (s, 2H), 6.99-7.13 (m, 2H), 7.18 (dd, J = 1.9 Hz, 12.6 Hz, 1 H), 7.41 (ddd, J = 2.6 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.62 (dd, J = 4.5 Hz, 8.9 Hz, 1 H), 7.88 (dd, J = 2.5 Hz, 9.6 Hz, 1 H), 11.68 (s, 1 H). MS (MH+ found) = 380.2
11. 1 -[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanone
10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 10) (151 mg) is suspended in dichloromethane (5 ml) and glacial acetic acid (46 μl), 1- hydroxybenzotriazole hydrate (92 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (153 mg) and triethylamine (148 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 preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 109 mg (64%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.13, 2.16 (2s, 3H [rotamers]), 3.22-3.33, 3.34-3.44 (2m, 2H [rotamers]), 3.76 (s, 3H), 3.81-3.92 (m, 2H), 4.34, 4.35 (2s, 2H [rotamers]), 4.74, 4.77 (2s, 2H [rotamers]), 6.99-7.14 (m, 2H), 7.19 (d, J = 12.7 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.5 Hz, 9.0 Hz, 1 H), 7.85-7.97 (m, 1 H), 1 1.70, 11.72 (2s, 1 H [rotamers]). MS (MH+ found) = 422.2
The following compounds are obtained by using the procedure of example 11 analogously.
12. rac-i-tiO-Fluoro-δ^S-fluoro^-methoxybenzylJ-i^^y-tetrahydro-SH-indolo^.S- c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1 -one Starting compounds: 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 10) and rac^-hydroxypropanoic acid.
1H-NMR (300 MHz, d6-DMSO); δ = 1.19, 1.27 (2d, J = 6.3 Hz, 3H [rotamers]), 3.22-3.34, 3.35-3.45
(2m, 2H [rotamers]), 3.76 (s, 3H), 3.81-4.06 (m, 2H), 4.34 (s, 2H), 4.51-4.66 (m, 1 H), 4.73-4.93 (m,
2H), 4.98, 5.04 (2d, J = 6.7 Hz, 1 H [rotamers]), 6.99-7.15 (m, 2H), 7.20 (dd, J = 1.8 Hz, 12.7 Hz, 1 H),
7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.85-7.97 (m, 1 H), 11.71
(s, 1 H).
MS (MH+ found) = 452.2
13. 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-hydroxyethanone
Starting compounds: 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 10) and hydroxyacetic acid.
1H-NMR (300 MHz, d6-DMSO); δ = 3.25-3.35, 3.35-3.46 (2m, 2H [rotamers]), 3.73-3.97 (m, 2H), 3.76
(s, 3H), 4.18-4.30 (m, 2H), 4.34 (s, 2H), 4.59-4.82 (m, 3H), 7.00-7.13 (m, 2H), 7.20 (dd, J = 1.9 Hz,
12.7 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.5 Hz, 9.0 Hz, 1 H), 7.83-7.98
(m, 1 H), 11.72 (s, 1 H).
MS (MH+ found) = 438.2
14. 2-(Dimethylamino)-1-[10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H- indolo[2,3-c][1,7]naphthyridin-3-yl]ethanone
Starting compounds: 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 10) and N,N-dimethylglycine.
1H-NMR (300 MHz, d6-DMSO); δ = 2.18, 2.22 (2s, 6H [rotamers]), 3.20, 3.22 (2s, 2H [rotamers]), 3.22-
3.34, 3.34-3.43 (2m, 2H [rotamers]), 3.76 (s, 3H), 3.83-3.92, 3.92-4.01 (2m, 2H [rotamers]), 4.34 (s,
2H), 4.74, 4.90 (2s, 2H [rotamers]), 7.00-7.13 (m, 2H), 7.20 (d, J = 12.6 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz,
9.1 Hz, 9.2 Hz, 1 H), 7.62 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.86-7.97 (m, 1 H), 11.70 (s, 1 H).
MS (MH+ found) = 465.1
15. rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1 -one
Starting compounds: 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 10) and rac-2-hydroxypropanoic acid.
1H-NMR (300 MHz, d6-DMSO); δ = 1.10, 1.14 (2d, J = 6.2 Hz, 3H [rotamers]), 2.40-2.53 (m, 1 H), 2.57- 2.70 (m, 1 H), 3.22-3.33, 3.34-3.43 (2m, 2H [rotamers]), 3.76 (s, 3H), 3.91 (t, J = 5.4 Hz, 2H), 3.98-4.12 (m, 1 H), 4.34 (s, 2H), 4.59, 4.63 (2d, J = 4.5 Hz, 1 H [rotamers]), 4.77, 4.81 (2s, 2H [rotamers]), 6.99- 7.12 (m, 2H), 7.20 (dd, J = 1.7 Hz, 12.6 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.82-7.97 (m, 1 H), 11.70 (s, 1 H). MS (MH+ found) = 466.2 16. 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-3-hydroxypropan-1 -one lO-Fluoro-Θ^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-cKI Jlnaphthyridine (example 10) (151 mg) is suspended in dichloromethane (5 ml) and 3-hydroxypropanoic acid (30% in water, 240 μl), 1-hydroxybenzotriazole hydrate (92 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride (153 mg), triethylamine (148 μl) and 4A molecular sieves (300 mg) are added. The mixture is stirred for 18 h at room temperature. After that, water (5 ml) is added, the mixture is filtered, the molecular sieves are washed with dichloromethane (10 ml). The aqueous phase of the combined filtrate 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 preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 65 mg (36%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.58-2.70 (m, 2H), 3.22-3.33, 3.35-3.44 (2m, 2H [rotamers]), 3.62- 3.75 (m, 2H), 3.76 (s, 3H), 3.90 (t, J = 5.6 Hz, 2H), 4.34 (s, 2H), 4.48, 4.54 (2t, J = 5.4 Hz, 1 H [rotamers]), 4.77, 4.80 (2s, 2H [rotamers]), 7.00-7.13 (m, 2H), 7.20 (d, J = 12.8 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.84-7.98 (m, 1 H), 11.70 (s, 1 H). MS (MH+ found) = 452.2
The following compound is obtained by using the procedure of example 16 analogously.
17. rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2A7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2,3-dihydroxypropan-1 -one
Starting compounds: 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,7]naphthyridine (example 10) and rac-2,3-dihydroxypropanoic acid.
1H-NMR (300 MHz, d6-DMSO); δ = 3.22-3.33, 3.35-3.44 (2m, 2H [rotamers]), 3.45-3.67 (m, 2H), 3.76 (s, 3H), 3.77-4.09 (m, 2H), 4.34 (s, 2H), 4.40-4.54, 4.50-4.76 (2m, 2H [rotamers]), 4.78, 4.90 (2bs, 2H [rotamers]), 4.92-5.09 (m, 1 H), 7.00-7.13 (m, 2H), 7.20 (dd, J = 1.9 Hz, 12.6 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.84-7.98 (m, 1 H), 11.71 (s, 1 H). MS (MH+ found) = 468.2
18. 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]acetamide
10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 10) (150 mg) is suspended in acetone (5 ml), potassium carbonate (218 mg) and 2- bromoacetamide (55 mg) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is diluted with water (4 ml), the formed precipitate is filtered, washed with water (2 ml) and dried in vacuo to yield 125 mg (72%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.89 (t, J = 5.6 Hz, 2H), 3.13 (s, 2H), 3.30-3.39 (m, 2H), 3.75 (s, 3H), 3.79 (s, 2H), 4.32 (s, 2H), 6.98-7.22 (m, 4H), 7.27 (bs, 1 H), 7.40 (ddd, J = 2.5 Hz, 9.2 Hz, 9.2 Hz, 1 H), 7.61 (dd, J = 4.5 Hz, 8.9 Hz, 1 H), 7.88 (dd, J = 2.5 Hz, 9.6 Hz, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 437.2 19. 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]ethanol lO-Fluoro-Θ^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-cKI Jlnaphthyridine
(example 10) (150 mg) is suspended in acetone (5 ml), potassium carbonate (218 mg) and 2- bromoethanol (28 μl) are added and the mixture is stirred for 18 h at room temperature. After that, the mixture is filtered over a plug of Celite® and the plug is washed thoroughly with dichloromethane. The combined filtrate is concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain 75 mg (63%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.06-3.14 (m, 2H), 3.15-3.22 (m, 2H), 3.26-3.35 (m, 2H), 3.75 (s,
3H), 3.97 (s, 2H), 4.31 (s, 2H), 6.99-7.11 (m, 2H), 7.17 (dd, J = 1.9 Hz, 12.8 Hz, 1 H), 7.39 (ddd, J =
2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.59 (dd, J = 4.5 Hz, 9.0 Hz, 1 H), 7.88 (dd, J = 2.5 Hz, 9.6 Hz, 1 H), 11.55
(s, 1 H).
MS (MH+ found) = 424.2
20. 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3- c][1,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone
Step 1 : 2-[2-(Benzyloxy)ethoxy]-1-[10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone. 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c][1 ,7]naphthyridine (example 10) (304 mg) is suspended in dichloromethane (10 ml) and [2-(benzyloxy)ethoxy]acetic acid (example A14) (336 mg), 1-hydroxybenzotriazole (184 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (306 mg) and triethylamine (296 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (15 ml) and dichloromethane (20 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product, 2-[2- (benzyloxy)ethoxy]-1-[10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone, is used in the next step without further purification. Step 2: 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone. Crude 2-[2-(benzyloxy)ethoxy]-1-[10-fluoro-6- (3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone (457 mg) is dissolved in methanol (10 ml) under nitrogen atmosphere, ammonium formiate (520 mg) and palladium (10% on charcoal, 150 mg) are added and the mixture is stirred for 3 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. The combined filtrate is concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield 128 mg (33%, 2 steps) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 3.22-3.34, 3.37-3.46 (2m, 2H [rotamers]), 3.48-3.59 (m, 4H), 3.76 (s, 3H), 3.81-3.94 (m, 2H), 4.27-4.38 (m, 2H), 4.34 (s, 2H), 4.61-4.72 (m, 1 H), 4.75 (s, 2H), 6.99-7.14 (m, 2H), 7.20 (dd, J = 1.9 Hz, 12.6 Hz, 1 H), 7.42 (ddd, J = 2.5 Hz, 9.1 Hz, 9.2 Hz, 1 H), 7.63 (dd, J = 4.6 Hz, 9.0 Hz, 1 H), 7.84-7.98 (m, 1 H), 11.71 (s, 1 H). MS (MH+ found) = 482.2 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 in particular 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, follicular 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 occlusion, 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 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 (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 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; 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 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 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 pulmonary 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), interstitial 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 steatohepatitis 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, emphysema 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 disease, 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 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 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.
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 indacaterol, 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 palmitate, 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 epoprostenol 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, atenolol and nadolol. Examples of type 4 phosphodiesterase inhibitors include without limitation roflumilast, 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 invention 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 pharmaceutical 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 pharmaceutical 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, nonalcoholic steatohepatitis and liver fibrosis.
Furthermore, 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 consisting 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 preferably 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 (dragees), 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 compound 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, anticholinergics, 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 invention 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, encapsulating, 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, subcutaneous, 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 inhalers (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 solvent, 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 include, 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®, Novolizer®, 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 solutions (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 corticosteroids, anticholinergics, beta-mimetics, 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-mi metics, 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 homogenization buffer (NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI2 1mM, 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 corresponding 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 imgf000137_0001

Claims

Claims:
1. Compound of Formula (I)
Figure imgf000138_0001
wherein A^ and A^ are each independently selected from the group consisting of C, N, O and S; with the proviso that at least one of the radicals A^ and A^ is a carbon atom; and
RA01 ancj RA02 are eacn independently selected from the group consisting of hydrogen, hydroxy, C-j.g-alkyl, wherein the C-j.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
C-j.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 NRA03RA04. or
RA01 ancj RA02 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;
RA03 ancj RA04 are each independently 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 fluoro, 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; d RA12 are eacn 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, hydroxy and a C-i.-13-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-i.-13-heteroaryl is optionally substituted,
C6.14-aryl, wherein the Cg^-aryl 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 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 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.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-i.-13-heteroaryl, wherein the C-ι.-13-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-ι.-13-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 is bound via C, and wherein N is substituted by RA125 -S(O)2-Ci.6-alkyl, wherein the -S(O)2-C-|_6-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 anc| 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-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cβ.-|4-aryl is optionally substituted, and _NRA114RA115; or RA16 ancj RA17 combine to form a C3_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.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, C^g-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, C6.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C-|_-| 3-heteroaryl, wherein the C-j_i 3-heteroaryl has at least one heteroatom which is selected from N, O and S, and wherein the C-j_i 3-heteroaryl is optionally substituted,
C3.6-cyclyl, wherein the C3_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. ncj 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 C3_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-|.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 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 heteroatoms selected from NRA128, O and S;
RA114 ancj RA115 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 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;
RA116 anc| RA117 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, 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-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-j.β-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-C-|.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.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 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 RA^1 -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 heteroatoms selected from NRA131 , O and S;
RA118 ancj RA119 are eacn independently selected from the group consisting of hydrogen, C-] .β-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;
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 ancj 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, Cg.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C-j.g-heteroaryl, wherein the C-|_g-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|_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-|.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 RA131 , -NRA134RA135 and .CONRA136RA137 -C(O)O-C1. g-alkyl, wherein the -C(O)O-C-] .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-C-|_6-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 1 _ 13-heteroary I , 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 RA"I 42; 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-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-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 heteroatoms 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-j.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-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-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-C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or ncj 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 heteroatoms selected from NRA131 , O and S;
RA125 RA126 RA128 RA131 and RA142 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 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.-jQ-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 C1. g-alkyl, wherein the C-|.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-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA21 and R^22 have the same meanings as R^ 11 and RA12;
RA31 anc| RA32 are eacn independently selected from the group consisting of hydrogen, hydroxy, C1. g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and 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 NRA33RA34. or
RA31 ancj RA32 combine to form an oxo-group, or
RA31 ancj RA32 together represent the moiety -O-CH2-CH2-O-, and thus forms a cyclic acetal together with the adjacent C-atom to which they bind; with the proviso that, if R^31 and R^32 combine to form an oxo-group or R^31 and R^32 together represent the moiety -O-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-j.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. g-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, C-j.β-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;
RB71 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen;
wherein D^ , D^, D^ and D^ are each independently selected from the group consisting of C and N; and
RD1 1 RD21 RD31 ancj RD41 are eacn independently selected from the group consisting of hydrogen, halogen, C-|.g-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cβ.-|4-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, 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 RD12, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6_i4-aryl, wherein the Cβ.-|4-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 C3-6-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-alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.β-alkoxy via C, N is substituted by R013,
-C(O)OR014, and -C(O)NR015R016, -C(O)-C1.6-alkyl, wherein the -C(O)C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the C-j.β-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-|_-| 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 to the -C(O)-C1.5- alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the -C(O)-C1.6-alkyl via C, N is substituted by R017,
-C(O)-R01S, NR01 QR01 1 O and a lone pair; D13 ancj RD17 are eacn 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, and -C(O)-C1.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RD14 RD15 ancj RD16 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;
RD18 js selected from the group consisting of 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 R^I ^ ^ ;
RD19 ancj RD110 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, -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;
RD111 js 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; with the proviso that, if each of D^ , D^, D^ and D^ is a carbon atom, at least one of the substituents RD11 RD21 RD31 and RD41 is different from hydrogen and at least one of the substituents RB41 , RB51 RB61 RB71 and RB81 js different from 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.
2. Compound according to claim 1 , wherein R^01 and R^02 are eacn independently selected from the group consisting of hydrogen and hydroxy; or RA01 ancj RA02 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.
3. Compound according to claim 1 or 2, wherein RA^ 1 and RA12 eacn are hydrogen and/or RA31 ancj RA32 eacn 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.
4. Compound according to any one of claims 1 to 3, wherein R^1 and R^22 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, -(CRA16RA17)|-CORA18, -CO(CRA19RA1 10)k-RA1 1 1 and a lone pair, wherein
Ms 1 , k is O,
RA16 ancj RA17 each are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 have the same meanings as defined in claim 1 ; 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^1 ^ , R^211 RD31 ancj RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-i.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, 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.
6. Compound according to any one of claims 1 to 5, wherein
at least one of the atoms D^ , D2, D^ and D4 is N and the remaining atoms are C, A^ is C and R^ 11 , RA12 RA31 and RA32 eacn are hydrogen; or wherein
each of D1 , D2, D3 and D4 is C, and A1 is selected from C, N, O and 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.
7. Compound according to any one of claims 1 to 6, wherein
A^ and A2 is carbon, each of R^ 11 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA01 ancj RA02 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^O2 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and R^21 and R^22 each are methyl, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^1 ^ , R^2"! , R^31 and R^41 is selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen; or wherein
each of A^ and A2 is carbon, each of R^ 11 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents R^01 and R^O2 js hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the R^01 and R^2 bind is in the S-configu ration, or RA01 ancj RA02 combine to form an oxo-group, and RA21 and RA22 eacn are methyl, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair; or wherein
A1 is C, A2 is N, each of RA1 1 , RA12, RA31 and RA32 are hydrogen, one of the substituents RA21 and RA22 is selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17)rCoRA18 and _CO(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 is hydrogen, or one of the substituents RA^ and RA^2 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 bind is in the R-configu ration, or RA01 ancj RA02 combine to form an oxo group, and each of the atoms D^ , D2, D3 and D4 is a carbon atom and at least one of the substituents R^I ^ , R^2"! , R^3"! and R^41 is selected from the group consisting of halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and the remaining substituent(s) is/are hydrogen, wherein I is 1 , k is O, RA16 ancj RA17 eacn are hydrogen and
RA18 is NRA1 16RA1 17, wherein
RA111 RA116 ancj RA117 nave the same meanings as defined in claim 1 ; or wherein A^ is C, A2 is N, each of RA^ 1 , RA12 RA31 ancj RA32 are hydrogen, one of the substituents RA2^ and RA22 JS selected from hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
_(CRA16RA17J1-CORAI 8 and .C0(CRA19RA1 10)k-RA1 1 1 , and the other represents a lone pair, and each of the substituents RA^ and RA^2 js hydrogen, or one of the substituents RA01 and RA02 is hydrogen and the other substituent is hydroxy, wherein the carbon atom to which the RA^ and RA^2 t>iιnd is in the R-configuration or RA01 ancj RA02 combine to form an oxo group, and at least one of the atoms D1 , D2 and D3 is N, D4 is C and RD1 1 , RD21 , RD31 and RD41 are each independently selected from the group consisting of hydrogen, halogen, NH2, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, and a lone pair, wherein Ms 1 , k is O,
RA16 ancj RA17 eacn are hydrogen and RA18 is NRA1 16RA117 Wherein
RA111 RA116 ancj RA117 haVe the same meanings as defined in claim 1 ; 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 selected from the group consisting of
10-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 11- Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 11-Bromo-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 10-Fluoro-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 9-Chloro-6-(3-fluoro-4-methoxybenzyl)- 3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; (1 S)-9-chloro-6-(3-fluoro-4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 6-(3-Fluoro-4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-pyrido[3',2':4,5]pyrrolo[2,3-c]quinolin-1-one; 6-(3- Fluoro-4-nnethoxybenzyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1 H-pyrido[4',3':4,5]pyrrolo[2,3-c]quinolin-1- one; Ethyl 10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridine-3-carboxylate; 10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c][1 ,7]naphthyridine; 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxypropan-1-one; 1-[10-Fluoro-6-(3-fluoro-4- nnethoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-hydroxyethanone; 2- (Dimethylamino)-1-[10-fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3- c][1 ,7]naphthyridin-3-yl]ethanone; rac-1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro- 3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-3-hydroxybutan-1-one; 1-[10-Fluoro-6-(3-fluoro-4- methoxybenzyO-I ^^J-tetrahydro-SH-indolo^.S-cKI Jlnaphthyridin-S-yll-S-hydroxypropan-i-one; rac- 1-[10-Fluoro-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; 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H- indolo[2,3-c][1 ,7]naphthyridin-3-yl]acetamide; 2-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)-1 , 2,4,7- tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]ethanol; 1-[10-Fluoro-6-(3-fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c][1 ,7]naphthyridin-3-yl]-2-(2-hydroxyethoxy)ethanone; 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, 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 8 for use in the treatment or prophylaxis of diseases.
10. 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 8 together with at least one pharmaceutically acceptable auxiliary.
11. Pharmaceutical composition according to claim 10 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.
12. 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 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
13. 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 8 in the manufacture of a pharmaceutical 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 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.
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 or the pharmaceutically acceptable salt thereof according to any of claims 1 to 8 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
15. Use according to claim 14, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
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 8 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.
17. Method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodiesterase 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 8.
18. 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, 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 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 8.
19. 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 8.
20. Method for treating or preventing an acute or chronic airway disease according to claim 19, 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.
21. 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 8.
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US9440976B2 (en) 2009-12-16 2016-09-13 Genentech, Inc. 1,7-diazacarbazoles and methods of use
US10626113B2 (en) 2012-01-17 2020-04-21 The Trustees Of Columbia University In The City Of New York Phosphodiesterase inhibitors and uses thereof
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