WO2010015586A2 - 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds - Google Patents

2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds Download PDF

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Publication number
WO2010015586A2
WO2010015586A2 PCT/EP2009/059999 EP2009059999W WO2010015586A2 WO 2010015586 A2 WO2010015586 A2 WO 2010015586A2 EP 2009059999 W EP2009059999 W EP 2009059999W WO 2010015586 A2 WO2010015586 A2 WO 2010015586A2
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optionally substituted
alkyl
hydroxy
fluoro
compound
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WO2010015586A3 (en
Inventor
Björn BARTELS
Steffen Weinbrenner
Degenhard Marx
Jörg DIEFENBACH
Torsten Dunkern
Wiro M.P.B. Menge
Johannes A. M. Christiaans
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Takeda GmbH
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Nycomed GmbH
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    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline 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.
  • SU753093 discloses 1-Methyl- 3,4-(delta-2,2-dimethyl- A- oxotetrahydro-benzo)indolo(2,3-c)-pyridine hydrochloride with tranquillising activity.
  • a further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
  • the invention thus relates to compounds of Formula (I)
  • RA01 js selected from the group consisting of hydrogen, hydroxy and NRA03RA04-
  • RA03 anc j RA04 are eacn independently selected from the group consisting of hydrogen, C-
  • RA21 js selected from the group consisting of hydrogen and C- j . ⁇ -alkyl
  • RA22 j s selected from the group consisting of hydrogen and C- j . ⁇ -alkyl;
  • m is 0 or 1 ;
  • the dotted lines signify 0, 1 , 2 or 3 covalent ⁇ -bonds that may or may not be conjugated and which may each be located between any two adjacent ring atoms, with the proviso that each ring atom participates in no more than one covalent ⁇ -bond;
  • B ⁇ , B ⁇ , B ⁇ , B ⁇ and B ⁇ are each independently selected from the group consisting of C, N, O and S; with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted;
  • R ⁇ 41 and R ⁇ 42 are each independently selected from the members of the groups (g1 ) and (g2) as defined below:
  • ⁇ -alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C4_ ⁇ -alkoxy, wherein the C ⁇ g-alkoxy is optionally substituted by one or more substitutents se- lected from fluoro and hydroxy,
  • C 3 . 6 -cyclyl wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C 3 _ 6 -cyclyl, wherein the -O-C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RB43, C 6 _i 4 -aryl, wherein the aryl is optionally substituted, C 3
  • -C(O)-C 1 . 6 -alkyl wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-
  • RB41 and R ⁇ 42 combine to form an oxo-group; wherein one of the substituents R ⁇ 41 and R ⁇ 42 j s absent in case the dotted lines signify a cova- lent ⁇ -bond between B 4 and one of the adjacent ring atoms;
  • RB44 and R ⁇ 45 are ea ch independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RB44 and R ⁇ 45 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ 47 O and S, and wherein, in case the atoms adjacent to the N which binds to B 4 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
  • RB46 JS selected from the group consisting of hydrogen, C-
  • C 3 . 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 via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
  • RB47 js selected from the groups 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)-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;
  • R B48 anc j RB49 are eacn independently selected from the group consisting of hydrogen and C-
  • ⁇ -alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl 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 substitutents selected from fluoro and hydroxy, C 3 . 6 -cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C 3 . 6 -cyclyl, wherein the -O-C ⁇ .
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-nnennbered heterocyclyl, wherein the 3- to 7-nnennbered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl 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 RB53
  • RB55 are eac h independently selected from the group consisting of hydrogen, C-
  • RB54 anc j RB55 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 65 7 O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
  • C 3 .g-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 via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
  • RB58 anc j RB59 are eacn independently selected from the group consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • R ⁇ 61 and R ⁇ 62 a re each independently selected from the members of the groups (M ) and (i2) as defined below:
  • .g-alkoxy wherein the C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RB63
  • RB63 JS selected from the groups consisting of hydrogen, C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • RB64 anc j RB65 are eac
  • RB64 anc j RB65 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 66 ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 6 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
  • RB66 js 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 ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxyl, and
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • RB68 are eacn independently selected from the group consisting of hydrogen and C-
  • R ⁇ 71 and R ⁇ 72 are eacn independently selected from the members of the groups (j1 ) and (j2) as defined below:
  • 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 RB73, C 6 . 14 -aryl, wherein the aryl is optionally substituted,
  • 3-heteroaryl is optionally substituted, -C(O)-Ci. ⁇ -alkyl, wherein the -C(O)-C- ] .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-
  • R B7 1 and R B7 ⁇ combine to form an oxo-group
  • R B7 ⁇ and R B7 ⁇ j s absent in case the dotted lines signify a cova- lent ⁇ -bond between B 7 and one of the adjacent ring atoms;
  • RB75 are each independently selected from the group consisting of hydrogen, C- ] .g-alkyl, wherein the C-
  • RB75 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 677 , O and S, and wherein, in case the atoms adjacent to the N which binds to B 7 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
  • RB76 JS selected from the group consisting of hydrogen, C- ] .g-alkyl, wherein the C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro 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 RB73,
  • C 6 . 14 -aryl wherein the aryl is optionally substituted
  • C i _ 13-heteroaryl wherein the C-
  • RB77 js selected from the groups consisting of hydrogen, C-
  • RB78 anc j RB79 are eacn independently selected from the groups consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • R ⁇ 81 and R ⁇ 82 are each independently selected from the members of the groups (k1 ) and (k2) as defined below:
  • -O-C 3 _g-cyclyl wherein the -O-C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
  • -C(O)-C 1 . g-alkyl wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-
  • RB83 JS selected from the groups consisting of hydrogen, C-
  • RB84 anc j RB85 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RB84 anc j RB85 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 68 ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 8 are carbon atoms, said carbon atoms independently are optionally substituted by an oxo-group;
  • RB86 JS 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 ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substitu- ents 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, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • RB87 j selected from the groups consisting of hydrogen, C-
  • RB88 anc j RB89 are each independently selected from the groups consisting of hydrogen and C 1 . g-alkyl, wherein the C-
  • R B51 and R B52 , R B61 and R B62 , R B71 and R B72 , R B81 and R B82 is absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (h2), (i2), (j2) and (k2) as defined above;
  • R ⁇ 01 is NRA03RA04 wherein RA03 anc j RA04 nas t
  • RA03 anc j RA04 are eacn independently selected from the group consisting of hydrogen, -C(O)H and -C(O)-Ci _ 6 -alkyl, wherein the -C(O)-C- ] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
  • m is 0.
  • m is 1.
  • m is 0 or 1.
  • the dotted lines signify 0 covalent ⁇ - bonds.
  • the dotted lines signify 2 covalent ⁇ - bonds.
  • the dotted lines signify 3 covalent ⁇ - bonds.
  • B ⁇ is a sulfur atom.
  • B 7 is a sulfur atom.
  • R ⁇ 41 and R ⁇ 42 are eacn independently selected from the members of the groups (g1a) and (g2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each independ- ently selected from the members of the groups (h1a) and (h2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each independ- ently selected from the members of the groups (h1a) and (h2a) as defined below: (h1a) hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is not substituted,
  • Ci_ 3 -alkyl wherein the C- j . ⁇ -alkyl is substituted by one or more substituents selected from fluoro and hydroxy, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and S, N R B54 R B55 and a lone pair, wherein one of the substituents R ⁇ 51 and R ⁇ 52 j s absent in case the dotted lines signify a cova- lent ⁇ -bond between B ⁇ and one of the adjacent ring atoms, and wherein R ⁇ 54 anc j R B55 nave t ne same meanings as defined above, or preferably below.
  • R ⁇ 51 and R ⁇ 52 are eacn j nc j e . pendently selected from the members of the groups (hi b) and (h2b) as defined below:
  • (h2b) 0 ⁇ 3-alkyl wherein the C- j . ⁇ -alkyl is substituted by one or more substituents selected from fluoro and hydroxy, C-
  • R ⁇ 54 anc j R B55 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ 57 O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
  • R ⁇ 54 anc j RB55 are eacn independently selected from the group consisting of hydrogen and -C(O)-R 656 , wherein R 6 56 nas t ne same meaning as defined above, or preferably below.
  • RB56 J S C ⁇ .g-cyclyl wherein the C3_ ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
  • RB56 J S cyclopropenyl
  • R ⁇ 61 an d R ⁇ 62 are each independently selected from the members of the groups (Ma) and (i2a) as defined below:
  • Ci_ 3 -alkyl wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, wherein one of the substituents R ⁇ 61 an d R ⁇ 62 is absent in case the dotted lines signify a cova- lent ⁇ -bond between B 6 and one of the adjacent ring atoms.
  • R ⁇ 61 an d R ⁇ 62 are hydrogen wherein one of the substituents R ⁇ 61 an d R ⁇ 62 is absent in case the dotted lines signify a covalent ⁇ -bond between B 6 and one of the adjacent ring atoms.
  • R ⁇ 71 an d R ⁇ 72 are eacn independently selected from the members of the groups (j1a) and (j2a) as defined below:
  • R ⁇ 71 and R ⁇ 72 a re each independently selected from the members of the groups (j1a) and (j2a) as defined below:
  • R ⁇ 81 and R ⁇ 82 a re each independently selected from the members of the groups (k1a) and (k2a) as defined below:
  • m is 1 and the dotted lines signify 0 covalent ⁇ -bonds.
  • R ⁇ 81 and R ⁇ 82 a re hydrogen wherein one of the substituents R ⁇ 1 and R ⁇ 82 j s absent in case the dotted lines signify a covalent ⁇ -bond between B ⁇ and one of the adjacent ring atoms.
  • m is 1 , each of B ⁇ , B ⁇ , B ⁇ , B ⁇ and B ⁇ are a carbon atom and the dotted lines signify 0 covalent ⁇ -bonds.
  • m is 1 , each of B 4 , B ⁇ , B ⁇ , B 7 and B 8 is a carbon atom, the dotted lines signify 0 covalent ⁇ -bonds and each of R B4 ⁇ 1 R B42 , RB51 R B52 R B61 R B62 R B71 R B72 R B81 and R B82 is hydrogen.
  • m is 1 and the dotted lines signify 0 covalent ⁇ -bonds.
  • m is 0 or 1 and the dotted lines signify 0 covalent ⁇ -bonds.
  • m is 0 or 1
  • each of B 4 , B ⁇ , B ⁇ , B 7 and B 8 is a carbon atom and the dotted lines signify 0 covalent ⁇ -bonds or at least one of B 4 , B ⁇ , B ⁇ ,
  • B 7 and B 8 are each independently selected from the group constisting of N, O, S and the the dotted lines signify 0, 1 , 2, 3 covalent ⁇ -bonds with the proviso that each ring atom participates in no more than one covalent ⁇ -bond and with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted wherein one of the substituents R B41 , R B42 , R B51 , R B52 , R B61 , R B62 , R B71 R B72 R B81 R B82 j s absent in case the dotted lines signify a covalent ⁇ -bond between B 4 , B 5 , B 6 , B 7 and B 8 one of the adjacent ring atoms and wherein R B41 , R B42 , R B51 , R B52 , R B61 , R B62 , R B71
  • m is 0 or 1
  • each of B 4 , B ⁇ , B ⁇ , B 7 and B 8 is a carbon atom and the dotted lines signify 0 covalent ⁇ -bonds or at least one of B 4 , B ⁇ , B ⁇ ,
  • B 7 and B 8 are each independently selected from the group constisting of N, O, S and the the dotted lines signify 0, 1 , 2, 3 covalent ⁇ -bonds.
  • m is 0, each of B 4 , B ⁇ , B 7 and B 8 are a carbon atom and the dotted lines signify 0 covalent ⁇ -bonds.
  • m is 0, each of B 4 , B ⁇ , B 7 and B 8 is a carbon atom, the dotted lines signify 0 covalent ⁇ -bonds and each of R B4 ⁇ , R B42 , R B ⁇ 1 , R B 52 R B71 R B72 R B81 and R B82 is hydroge n.
  • m is 0 or 1
  • each of B 4 , B ⁇ , B 7 and B 8 are a carbon atom and the dotted lines signify 0 covalent ⁇ -bonds.
  • m is 0 or 1
  • each of B 4 , B ⁇ , B ⁇ and B 8 is a carbon atom
  • the dotted lines signify 0 covalent ⁇ -bonds and each of R B4 ⁇ 1 RB42 RB51 R B52 R B71 R B72 R B81 and R B82 is hydrogen.
  • m is 0, at least one of B 4 , B ⁇ , B ⁇ , B ⁇ and B 8 are each independently selected from the group consisting of N, O, S.
  • m is 0 or 1
  • at least one of B 4 , B ⁇ , B ⁇ , B ⁇ and B 8 are each independently selected from the group constisting of N, O, S.
  • m is 0,
  • B ⁇ is a sulfur atom, each of B 4 , B ⁇ and B 8 are a carbon atom and the dotted lines signify 2 covalent ⁇ -bonds that are conjugated.
  • m is 0,
  • B ⁇ is a sulfur atom, each of B 4 , B ⁇ and B 8 are a carbon atom, the dotted lines signify 2 covalent ⁇ -bonds that are conjugated, each of R B41 , R B51 , R B81 and is hydrogen, R B42 , R B52 and R B82 are absent and R B71 and R B72 each represent a lone pair.
  • R ⁇ 01 is selected from the group consisting of hydrogen, hydroxy and NR ⁇ 3 R A04-
  • R A02 j hydrogen
  • R A03 and R A04 are hydrogen
  • R A2 1 is selected from the group consisting of hydrogen and C- j . ⁇ -alkyl;
  • R A22 is selected from the group consisting of hydrogen and C- j . ⁇ -alkyl
  • R B4 ⁇ and R B42 are each independently selected from the members of the groups (g1a) and (g2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each independently selected from the members of the groups (h1a) and (h2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each inde- pendently selected from the members of the groups (hi b) and (h2b) as defined below:
  • R ⁇ 54 a nd RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
  • R 65 ⁇ anc j RB55 are eacn independ- ently selected from the group consisting of
  • -C(O)-R 656 and RB54 anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 65 ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R 656 anc j RB57 nave 16 same meaning as defined above or below.
  • R 65 ⁇ anc j RB55 are eacn j nc
  • -C(O)-R 656 and RB54 anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R 656 has the same meaning as defined above or below.
  • R 656 is C ⁇ .g-cyclyl
  • R 656 is cyclopropenyl.
  • R ⁇ 01 is selected from the group consisting of hydrogen, hydroxy and NR ⁇ 3RA04-
  • R A03 and R A04 are hydrogen
  • RA21 js selected from the group consisting of hydrogen and C- j . ⁇ -alkyl
  • R ⁇ 41 and R ⁇ 42 are each independently selected from the members of the groups (g1a) and (g2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each independently selected from the members of the groups (h1a) and (h2a) as defined below:
  • R ⁇ 51 and R ⁇ 52 a re each independently selected from the members of the groups (hi b) and (h2b) as defined below:
  • Ci_i 3 -heteroaryl wherein the C-
  • R 65 ⁇ anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 65 ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
  • R 65 ⁇ anc j RB55 are eacn independently selected from the group consisting of
  • -C(O)-R 656 and RB54 anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR 65 ⁇ , O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R 656 anc j RB57 nave the same meaning as defined above or below.
  • R 65 ⁇ anc j RB55 are eac h independently selected from the group consisting of
  • -C(O)-R 656 and RB54 anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R 656 has the same meaning as defined above or below.
  • R 656 is C ⁇ .g-cyclyl
  • R 656 is cyclopropenyl.
  • R ⁇ 01 j s selected from the group consisting of hydrogen, hydroxy and NRA03RA04-
  • RA03 and R A04 are hydrogen
  • R A21 and R A22 are C 1 -3 -BIlCyI;
  • n 0 or 1 ;
  • the dotted lines signify 0, 1 , 2 or 3 covalent ⁇ -bonds that may or may not be conjugated and which may each be located between any two adjacent ring atoms, with the proviso that each ring atom participates in no more than one covalent ⁇ -bond;
  • B ⁇ , B ⁇ , B ⁇ , B ⁇ and B ⁇ are each independently selected from the group consisting of C, N, O and S; with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted;
  • R ⁇ 41 and R ⁇ 42 are each independently selected from the members of the groups (g1 ) and (g2) as defined below:
  • R ⁇ 51 and R ⁇ 52 are each independently selected from the members of the groups (hi ) and (h2) as defined below:
  • NR B54 R B55 and a lone pair signify a covalent ⁇ -bond between B ⁇ and one of the adjacent ring atoms;
  • RB54 anc j RB55 are eac
  • RB54 anc j RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR B5 7 O and S, and wherein, in case the atoms adjacent to the N which binds to B 5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
  • R B56 is C 3 . 6 -cyclyl
  • R 66" ! and R B ⁇ 2 are each hydrogen; wherein one of the substituents R 66" ! and R B ⁇ 2 j s absent in case the dotted lines signify a covalent ⁇ -bond between B 6 and one of the adjacent ring atoms;
  • R B7 ⁇ and R B72 a re each independently selected from the members of the groups (j1 ) and (j2) as defined below:
  • R B8 ⁇ and R B82 a re hydrogen, wherein one of the substituents R B8 ⁇ and R B82 j s absent in case the dotted lines signify a covalent ⁇ -bond between B 8 and one of the adjacent ring atoms;
  • R B51 and R B52 , R B61 and R B62 , R B71 and R B72 , R B81 and R B82 is absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (h2), and (j2) as defined above; 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.
  • the compounds of Formula (I) are selected from the group consisting of
  • substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen
  • one of the substituents may be hydrogen and the other may have a meaning as defined.
  • the present invention expressly pertains to all compounds that can be derived from each and every combination of the specific meanings of substituents and other variable groups characterized above as embodiments of the present invention, with the proviso that, in case m is 1 , B ⁇ , B ⁇ , B ⁇ , B ⁇ and B ⁇ is a carbon atom and the dotted lines signify 3 conjugated covalent ⁇ -bonds, one of each of the pairs of substituents R B41 and R B42 , R B51 and R B52 , R B61 and R B62 , R B71 and R B72 , RB81 anc j RB82 J S absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (g2a), (h2), (h2a), (h2b), (i2), (i2a), (j2), (J2a), (k2) and (k2a) as defined
  • 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-
  • Exam- pies 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
  • 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.
  • Ci_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. Examples of the C- j .
  • ⁇ -alkoxy group include a methoxy group, an ethoxy group, an n- propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, an isopentoxy group, a sec-pentoxy group, a 3- methylpentoxy group, an n-hexoxy group, a 1 ,1-dimethylpropoxy group, a 1 ,2-dimethylpropoxy group, a 2,2-dimethylpropyloxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-m ethyl propoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1-dimethylbutoxy group, a 1 ,2-dimethylbut
  • C3_5-cyclyl used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms.
  • Examples of the C ⁇ . ⁇ -cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
  • heterocyclyl includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated.
  • Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group, tet- rahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomor- pholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
  • 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 pyr- rolidine-2,5-dione group, a piperazine-2,3-dione group and the like. More preferred is a pyrrolidine- 2,5-dione group.
  • C ⁇ . ⁇ -aryl used in the specification of the present application means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, such as a monocyclic group, a bicyclic group and a tricyclic group.
  • a phenyl group an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group.
  • C ⁇ . ⁇ -aryl which is optionally substituted means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, wherein the aromatic hydrocarbon cyclic group has the same meaning as defined above and is optionally substituted by one or more sub- stituents.
  • substituents are hydroxy; C- j . ⁇ -alkyl, preferably methyl; C- j . ⁇ -alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo.
  • 4-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- j . ⁇ -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-nnennbered 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.
  • 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 isoindo- IyI group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imid
  • Ci_i3-heteroaryl which is optionally substituted means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, typically being a 5- to 14-membered aromatic heterocyclic group, which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, wherein the 5- to 14-membered aromatic heterocyclic group is substituted by one or more substitu- ents.
  • substituents are hydroxy; C-
  • the 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • a thiophenyl group is more preferred.
  • .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 and 3- to 7-membered het- erocyclyl, wherein the C- j .g-alkoxy, C ⁇ .g-cyclyl, 3- to 7-membered heterocyclyl, Cg- ⁇ -aryl and C-
  • .g-alkyl group is substituted by at least one fluorine atom
  • .g-alkyl group can be any group as specified above with respect to the C-
  • .g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C- j .g-alkyl, wherein the mono-, tri- and perfluoro substituted C- j .g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C- j .g-alkyl groups.
  • .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 hydroxy methyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hy- droxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
  • .g-alkyl group is substituted by at least one C-
  • .g-alkyl group can be any group as specified above with respect to C-
  • .g-alkoxy group can be any group as specified above for C-
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-
  • Particlulary preferred are a methoxymethyl group and a 2-methoxyethyl group.
  • .g-alkyl group is substituted by at least one C ⁇ .g-cyclyl
  • .g-alkyl group can be any group as specified above with respect to C-
  • the C ⁇ .g-cyclyl group can be any group as specified above for C ⁇ .g-cyclyl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ .g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms.
  • .g-alkyl is substituted one C ⁇ .g- cyclyl.
  • Particluarly preferred is a cyclopropylmethyl group.
  • .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- j .g-alkyl, unless specified otherwise.
  • the 3- to 7-mennbered heterocyclyl group can be any group as specified above for 3- to 7-mennbered heterocyclyl, unless specified otherwise.
  • the C- j .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-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-
  • .g-alkoxy group can be any group as specified above with respect to C-
  • .g-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobu- toxy.
  • .g-alkoxy group can be any group as specified above with respect to C-
  • ⁇ - alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
  • .g-alkoxy groups can be any group as specified above with respect to C-
  • .g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-
  • the first mentioned C- j .g-alkoxy is substituted by one other C- j .g-alkoxy.
  • Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
  • the C- j .g-alkoxy group can be any group as specified above with respect to C- j .g-alkoxy, unless specified otherwise.
  • the C ⁇ .g-cyclyl group can be any group as specified above for C ⁇ .g-cyclyl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ .g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C- j .g-alkoxy is substituted by one C ⁇ .g-cyclyl. Particluarly preferred is a cyclopropylmethoxy group.
  • C ⁇ .g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
  • the C ⁇ .g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g- cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C ⁇ .g-cyclyl, wherein the mono-, di- and perfluoro substituted C ⁇ .g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C ⁇ .g-cyclyl groups.
  • the C ⁇ .g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g- cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C3. g-cyclyl, wherein monohydroxy substituted C ⁇ .g-cyclyl groups are more preferred.
  • the above-mentioned 3- to 7-membered heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, hydrogen, C-
  • the 3- to 7-membered heterocyclyl group is substituted by one or more substituents se- lected from fluoro and hydroxy, this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-nnennbered 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-mennbered 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- ] .g-alkyl is -C(O)-Ch ⁇ and - C(O)-CH 2 OH.
  • the above-mentioned 3- to 7-membered heterocycle may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • the 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-mennbered heterocycle, unless specified otherwise.
  • the 3- to 7-mennbered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
  • the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C-
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • .g-alkyl moiety of the -C(O)-C- ] .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 invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
  • Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (
  • 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.
  • R being a hydroxy group
  • R being hydrogen and R A21 and R A22 representing identical groups
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center.
  • R A01 and R A02 being hydrogen or R A01 and R A02 combining to form an oxo group and R A21 and R A22 representing different groups
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center.
  • 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), (3R), (3S), (4R), (4S), (5R), (5S), (6R), (6S), (7R), (7S), (8R), (8S), (9R), (9S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
  • the invention relates to stereoisomers of formula (Ib) having the configuration (1 R) or (1 S), with the carbon atom at position number 3 not being an asymmetric carbon atom.
  • the invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
  • Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
  • derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
  • 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 (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating.
  • the compound of formula (II) or (Na) or (lib) 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 (IVa) or (IVb) or (IVc) or a mixture thereof are 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 (Id), in which R A01 and R A02 are hydrogen, can be obtained as shown in reaction scheme 4.
  • indole (IX) 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 thus obtained hydroxy-com pound 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.
  • Indole (IX) is commercially available, the compounds of formula (X) are known, commercially available or can be obtained according to known procedures.
  • reaction scheme 5 a compound of formula (Id), in which R A01 and R A02 are hydrogen, can be obtained as illustrated in reaction scheme 5.
  • indole (IX) 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 (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound
  • Indole (IX) is commercially available, the compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (Id) can be obtained as illustrated in reaction scheme 6.
  • indole (IX) is reacted with a compound of formula (XIII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)].
  • a base e.g. pyrrolidine or potassium hydroxide
  • the thus obtained unsaturated compound of formula (XVI) 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 (XV) 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 (Xl).
  • the compound of formula (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
  • Indole (IX) is commercially available, compounds of formula (XIII) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (Id) can be obtained as illustrated in reaction scheme 7.
  • isatine (XVI) is reacted with a compound of formula (XII) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)].
  • the thus obtained hydroxy compound of formula (XVII) can be transformed into a compound of formula (XV) 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-compound of formula (XV) 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 (Xl).
  • the compound of formula (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
  • Isatine (XVI) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • the resulting nitro- dihydropyridine of formula (XXI) can be converted to amino-pyridine of formula (XXII) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid.
  • the final ring closing reaction to obtain a compound of formula (Ic) can be achieved by reacting a compound of formula (XXII) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g.
  • a compound of formula (XX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXIII) 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 (Ie), in which R A01 , R A02 , R A21 and R A22 are hydrogen, 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 (XXIV) in the presence of acetic acid and H 3 PO 4 , preferably at elevated temperature.
  • the compound of formula (XXV) thus obtained can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ie).
  • a compound of formula (I), wherein R A01 is hydroxy and R A02 is hydrogen can be prepared from a compound of formula (I), wherein R A01 and R A02 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 R A01 is hydrogen and R A02 is hydrogen can be prepared from a compound of formula (I), wherein R A01 and R A02 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 R A01 is amino and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 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 14O 0 C - 18O 0 C, followed by amide hydrolysis reaction, e.g.
  • a compound of formula (I), wherein R A01 is amino and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 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.
  • a suitable acid e.g. acetic acid or p-toluenesulfonic acid
  • a suitable Lewis acid e.g.
  • a suitable solvent e.g. methanol
  • hydrogenation e.g. with the aid of a transition metal catalyst, such as palladium(O)
  • a suitable hydrogen source e.g. hydrogen gas or ammonium formiate
  • a suitable solvent such as methanol
  • . 6 -alkylamino, and R A02 is hydrogen can be prepared from a compound of formula (I), wherein the R A01 and R A02 combine to form an oxo group, by reductive amination reaction, e.g.
  • a suitable amine e.g. methylamine or diethylamine
  • a suitable reduction agent such as sodium cyanoborohydride or sodium borohydride
  • 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;
  • a compound of formula (I), wherein R A01 is carbonylamino-, e.g. -NH-C(O)-Ci_ 6 -alkyl, wherein said d- 6 -alkyl may be substituted as defined above, and R A02 is hydrogen, can be prepared e.g. from a compound of formula (I), wherein R A01 is amino and R A02 is hydrogen, by reaction with an appropriate carboxylic acid chloride, e.g. Ci_ 6 -alkylC(O)CI, wherein said Ci_ 6 -alkyl may be substituted as defined above, or carboxylic anhydride, e.g. (Ci.
  • Ci_ 6 -alkyl-C(O)OH an appropriate carboxylic acid, e.g. Ci. 6 -alkylC(O)OH, wherein said Ci_ 6 -alkyl may be substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g.
  • a suitable additive reagent such as 1-hydroxybenzotriazole
  • a compound of formula (I) wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
  • R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) carbonylamino-, e.g. -NH-C(O)-R 646 , -NH-C(O)-R 656 , -NH-C(O)-R 666 , -NH-C(O)-
  • R 676 or -NH-C(O)-R 686 can be prepared e.g. from a compound of formula (I), wherein R 641 and/or R 651 and/or R 661 and/or R 671 and/or R 681 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
  • a base e.g. triethylamine, pyridine or potassium carbonate
  • a dehydrating agent e.g. dicyclohexylcarbodiimide
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents -NH-C(O)-NH 2 can be obtained e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is 1-3C-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
  • R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) substituted amino, e.g. -NR B44 R B45 , -NR B54 R B55 , -NR B64 R B65 , -NR B74 R B75 or -NR B84 R B85 , can be prepared e.g. from a compound of formula (I), wherein the corresponding R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate amine, e.g.
  • a halogen preferably bromine or chlorine
  • HNR B44 R B45 , HNR B54 R B55 , HNR B64 R B65 , HNR B74 R B75 or HNR B84 R B85 respectively, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium or copper, e.g. tris(dibenzylideneacetone)- dipalladium(O) or palladium(ll) acetate, a catalytic amount of an appropriate ligand, preferably phosphines or diamines, e.g.
  • base e.g. cesium carbonate or sodium carbonate
  • an appropriate solvent e.g. toluene or tert-butanol
  • R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) C 6 -i 4 -aryl or C- ⁇ .- 13 -heteroaryl
  • R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) C 6 -i 4 -aryl or C- ⁇ .- 13 -heteroaryl
  • R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate boronic acid, e.g.
  • a catalytic amount of a transition metal complex preferably incorporating palladium, e.g. dichlorobis (tricyclohexyl- phosphine) 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 80-110 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 (tricyclohexyl- phosphine) palladium (II)
  • an appropriate ligand preferably phosphines
  • a stoichiometric amount of base e.g. cesium carbon
  • 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 me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or me- thylis
  • acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid.
  • bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. am- monia, 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 diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
  • the (IS)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein R A01 and R A02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • a suitable aprotic solvent preferably tetrahydrofuran or dioxan
  • (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • the (I R)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature.
  • (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, pref- erably 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 di- astereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enanti- omeric 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.
  • the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.
  • Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology.
  • Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode.
  • ESI electrospray ionization
  • Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments.
  • the temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments.
  • the reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
  • 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.
  • 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 hydrogen chloride 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.
  • the crude product is dissolved in glacial acetic acid (500 ml), ammonium acetate (125 g) is added and the mixture is stirred for 18 h at 8O 0 C. After that the volume is reduced in vacuo to 200 ml, solid sodium carbonate is added until pH 7 and ethyl acetate (300 ml) and water (200 ml) are added. The aqueous phase is extracted with ethyl acetate (1 x 200 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 200 ml) and water (1 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • cyclo- hexylacetic acid (1.00 ml) is dissolved in trifluoroacetic acid anhydride (1.0 ml) and the mixture is stirred for 15 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (2 ml) and added to the zinc chloride mixture, prepared above, within 5 min.
  • the mixture is stirred for 2 h at room temperature.
  • ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 18 h.
  • 2M ammonia solution 25 ml is added and the aqueous phase is extracted with dichloromethane (2 x 25 ml).
  • 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dinnethylcyclohex-2-en-1-one (example A1 ) (1.0 g) is dissolved in dry dichloroethane (15 ml) and the solution is cooled to O 0 C (ice bath). Zinc chloride (1 M in diethyl ether, 8.2 ml) is added drop by drop and the mixture is stirred at O 0 C for 30 min. In parallel, 3- thiopheneacetic acid (1.17 g) is dissolved in trifluoroacetic acid anhydride (1.17 ml) and the mixture is stirred for 20 min at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O 0 C. The mixture is stirred for 5 h at room temperature. After that, ammonia (7M in methanol, 5.6 ml) and ammonium acetate (3.02 g) are added and the mixture is refluxed for 18 h. After cooling, 2M am- monia solution (30 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 30 ml). The combined organic extracts are washed with 2M ammonia solution (2 x 50 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • a Schlenk tube is charged with tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2- thiopheneboronic acid (150 mg) and potassium fluoride (0.20 g), the mixture is degased and set under nitrogen atmosphere.
  • Step 1 4-( ⁇ 4-[(3,3-Dimethyl-1-oxo-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-6-yl)methyl]phenyl ⁇ - amino)-4-oxobutanoic acid.
  • 6-(4-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-one (example A3) (0.5 g) is suspended in toluene (50 ml) and dioxane (1 ml) and succinic anhydride (0.15 g) is added. The mixture is refluxed for 4 h.
  • Step 2 i ⁇ - ⁇ S ⁇ -Dimethyl-i-oxo ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-e-yOmethyllphenyl ⁇ - pyrrolidine-2,5-dione.
  • Step 2 ⁇ CyclopentylmethyO-S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i-amine.
  • N- ⁇ -(Cyclopentylmethy ⁇ -S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i-yljformamide (crude from preceeding step, 2.0 g) is dissolved in a 2M solution of HCI in methanol (250 ml, prepared before by dropping acetyl chloride (35 ml) in methanol (250 ml)). The mixture is refluxed for 3 h, after that it is concentrated in vacuo.
  • 3-Nitrophenylboronic acid (0.50 g), D-tartaric acid (0.45 g) and calcium hydride (0.25 g) are suspended in dry tetrahydrofuran (10 ml) and the mixture is refluxed for 1 h. The suspension is cooled, filtered under nitrogen atmosphere and washed with dry tetrahydrofuran (10 ml).
  • the mixture is basified with 1 M aqueous sodium carbonate solution (10 ml) and extracted with di- chloromethane (3 x 20 ml).
  • the combined organic extracts are washed with 1 M aqueous sodium carbonate solution (2 x 40 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane to ethyl ace- tate / dichloromethane 1 :4 (v/v)), followed by crystallization from diethyl ether to yield 140 mg (39%) of the title compound.
  • 3-Nitrophenylboronic acid 208 mg
  • D-tartaric acid 187 mg
  • calcium hydride 105 mg
  • the suspension is cooled, filtered under nitrogen atmosphere and washed with dry tetrahydrofuran (5 ml).
  • 3,3- Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 5) (150 mg) is suspended in the combined filtrate, the suspension is cooled to O 0 C (ice bath) and sodium borohydride (31 mg) is added in portions.
  • the crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :4 (v/v)), followed by crystallization from diethyl ether to yield 54 mg (36%) of the title compound.
  • 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.
  • the compounds of the invention are pharmaceutically acceptable.
  • the compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable.
  • PDE5 type 5 phosphodiesterase
  • 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.
  • 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.
  • 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.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie ' s disease; acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral
  • 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.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pul- monale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob
  • 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.
  • pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), inter- stitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, em- physema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • acute and chronic airway diseases such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, em- physema and chronic obstructive pulmonary disease
  • portal hypertension liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • the invention also relates to the use of a compound of the invention in the manufacture of a phar- maceutical 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.
  • 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.
  • an acute or chronic airway disease such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • 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.
  • 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.
  • the invention relates to the use of a compound of the invention in the manufac- ture 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.
  • 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.
  • 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, dia- betic 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-Jaco
  • 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.
  • an acute or chronic airway disease for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • 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 pul- monary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • 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 pul- monary disease
  • 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 com- prising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • the patient is preferably a mammal, more preferably a human.
  • at least one of the compounds of the invention can be used.
  • one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
  • 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.
  • pulmonary hypertension lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • 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.
  • 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
  • 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.
  • 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.
  • corticosteroids examples include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide.
  • anticholinergics include without limitation in- dacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide.
  • beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate.
  • lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril such as colfosceril palmi- tate, surfactant-TA, and calfactant.
  • endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium.
  • prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epopros- tenol sodium and treprostinil such as treprostinil sodium.
  • Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine.
  • Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, atenolol and nadolol.
  • Examples of type 4 phosphodiesterase inhibitors include without limitation ro- flumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast.
  • Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride.
  • Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin.
  • Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab.
  • Examples of diuretics include without limitation furosemide, bumetanide and torsemide.
  • Examples of digitalis glycosides include without limitation digoxin and digitoxin.
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic.
  • the pharmaceutical composition comprises: a compound of the invention and formoterol, or a compound of the invention and salmeterol.
  • the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker.
  • the pharma- ceutical 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant.
  • the pharmaceutical composition comprises: a compound of the invention and bupropion.
  • the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a diuretic.
  • 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.
  • the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside.
  • the pharmaceutical composition comprises: a compound of the invention and digoxin, or a compound of the invention and digitoxin.
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic.
  • 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, a compound of the invention, triam
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and an anticholinergic.
  • 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 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 de- fined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • 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.
  • 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.
  • 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%.
  • 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%.
  • the at least one compound of the invention and the at least one therapeutic agent are present in
  • 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.
  • auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
  • the pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dra- gees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
  • 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).
  • 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).
  • 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 administra- tion is preferred.
  • 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.
  • 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.
  • aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers.
  • the aero- sol-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 disper- sion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings.
  • carriers include, but are not limited to, saccharides, e.g. lactose and glucose.
  • 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 is preferably less than 100 ⁇ m, more preferably it is in the range of from 0.5 to 10 ⁇ m, in particular in the range of from 2 to 6 ⁇ m (D50 value, measured by laser diffraction).
  • Aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, No- volizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers.
  • the aerosol-producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
  • 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).
  • 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.
  • sprays and solutions to be applied in drop form are preferred formulations.
  • solutions to be applied in drop form, gels and ointments are exempli- fied formulations.
  • 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.
  • a dose in the range of from 0.01 to 4000 mg of the compound of the invention per day is preferred.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g.
  • 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.
  • the compound of the invention can be administered before or after administration of the therapeutic agent.
  • platelets were used as a source for human PDE5.
  • 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.
  • PRP platelet-rich-plasma
  • 1/10 volume of ACD solution 85 mM Na 3 -citrate, 1 11 mM D-glucose, 71 mM citric acid, pH 4.4 was added to 9/10 volume of PRP.
  • the cell pellet was resuspended in 3 ml homogenization buffer (NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI 2 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 ⁇ M Leupeptin, 5 ⁇ M Trypsininhibitor, 2 mM Benzamidin and 10 ⁇ M 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.
  • 3 ml homogenization buffer NaCI 140 mM, KCI 3.8 mM, EGTA 1 mM, MgCI 2 1mM, Tris-HCI 20 mM, beta-mercaptoethanol 1 mM,
  • 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).
  • modified SPA sintillation proximity assay
  • the test volume is 100 ⁇ l and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg 2+ , 1 ⁇ M motapizone, 10 nM PDE2 inhibitor BAY-60-7550, 0.5 ⁇ M cGMP (including about 50,000 cpm of [3H]cGMP as a tracer), 1 ⁇ l 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.
  • DMSO dimethylsulfoxide
  • the final concentration of DMSO in the assay does not substantially affect the activity of the PDE investigated.
  • 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 ⁇ l).
  • 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.
  • IBMX 3 mM 8-methoxymethyl-3-isobutyl- 1-methylxanthine
  • the MTP's are analyzed in commercially available luminescence detection devices.
  • the corresponding IC 50 values of the compounds for the inhibition of PDE activity are determined from the concentration-effect curves by means of non-linear regression.

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Abstract

The present invention pertains to 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline 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 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds.

Description

Description
2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds
Field of application of the invention
The invention relates to 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
Background of the Invention
6-Benzyl-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one is described in Khimiya Get- erotsiklicheskikh Soedinenii (1985) 3, 363-6 without mentioning any pharmaceutical activity thereof. WO02/064590 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO2008027182 discloses indoloquinoline compounds as calcium channel blockers. US4014883 discloses derivatives of 7H-indolo[2,3-c]quinolin-6(5H)-one and 7H-indolo[2,3- c]quinoline useful as anti-tumor agents. SU753093 discloses 1-Methyl- 3,4-(delta-2,2-dimethyl- A- oxotetrahydro-benzo)indolo(2,3-c)-pyridine hydrochloride with tranquillising activity.
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 the type 5 phosphodiesterase in a subject in need thereof.
Description of the invention
It has now been found that the 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds, which are described in detail below, have surprising and advantageous properties, making them especially useful in the treatment and prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. The compounds of the present invention are characterized by Formula (I) as specified in the following.
The invention thus relates to compounds of Formula (I)
Figure imgf000003_0001
(I) wherein
RA01 js selected from the group consisting of hydrogen, hydroxy and NRA03RA04-
RA02 JS hydrogen; or
RA01 ancj RA02 combine to form an oxo group;
RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|_6-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;
RA21 js selected from the group consisting of hydrogen and C-j.β-alkyl; RA22 js selected from the group consisting of hydrogen and C-j.β-alkyl;
B is
Figure imgf000004_0001
wherein m is 0 or 1 ;
the dotted lines signify 0, 1 , 2 or 3 covalent π-bonds that may or may not be conjugated and which may each be located between any two adjacent ring atoms, with the proviso that each ring atom participates in no more than one covalent π-bond;
B^, B^, B^, B^ and B^ are each independently selected from the group consisting of C, N, O and S; with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted;
wherein R^41 and R^42 are each independently selected from the members of the groups (g1 ) and (g2) as defined below:
(g1 ) hydrogen, halogen, C-j.β-alkoxy, wherein the C-j.β-alkoxy is not substituted, NO2 and NH2;
(g2) hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C4_β-alkoxy, wherein the C^g-alkoxy is optionally substituted by one or more substitutents se- lected from fluoro and hydroxy,
C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3_6-cyclyl, wherein the -O-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 RB43, C6_i4-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroaryl , wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-| 3-heteroaryl is optionally substituted,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substi- tutents selected from fluoro and hydroxy,
NRB44RB45, and a lone pair; or
RB41 and R^42 combine to form an oxo-group; wherein one of the substituents R^41 and R^42 js absent in case the dotted lines signify a cova- lent π-bond between B4 and one of the adjacent ring atoms;
RE343 JS se|ectec| from tne groUpS 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)-Ci_6-alkyl, wherein the -C(O)-C-] .β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB44 and R^45 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-R646; or
RB44 and R^45 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^47 O and S, and wherein, in case the atoms adjacent to the N which binds to B4 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB46 JS selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 R^43
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 via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB43, C6.14-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-i.-13-heteroaryl is optionally substituted, and
NRB48RB49.
RB47 js selected from the groups 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;
RB48 ancj RB49 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; wherein R^51 and R^52 are eacn independently selected from the members of the groups (hi ) and (h2) as defined below:
(hi ) hydrogen, halogen, hydroxy, C-| .3-alkyl, wherein the C-j.β-alkyl is not substituted, C-j.β-alkoxy, wherein the C-j.β-alkoxy is not substituted,
NO2, NH2, -NH-C(O)-C1.2-alkyl, -NH-C(O)-NH2 and a methoxy group, wherein the methoxy group is substituted by 2 or 3 fluorine atoms; or one of RB41 and R^42 anc| one of RB51 ancj RB52 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
(h2) C1.3-alkyl, wherein the C-j.β-alkyl is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C^g-alkyl, wherein the C^β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl 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 substitutents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3.6-cyclyl, wherein the -O-Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-nnennbered heterocyclyl, wherein the 3- to 7-nnennbered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl 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 RB53
C6.14-aryl, wherein the aryl is optionally substituted,
C i _ 13-heteroaryl , wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-| 3-heteroaryl is optionally substituted, -C(O)-Ci.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB54RB55 and a lone pair; or RB51 ancj RB52 combine to form an oxo-group;
wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms;
RE353 JS se|ectec| from tne groUpS consisting of hydrogen, C-|_g-alkyl, wherein the C-] .g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy, and
-C(O)-C-|_g-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB54 anc| RB55 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, and -C(O)-R656; or
RB54 ancj RB55 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR657 O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB56 js selected from the group consisting of C^β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R653
C3.g-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 via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB53
Cg.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-ι.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-ι.-13-heteroaryl is optionally substituted,
NRB58RB59-
RE357 JS se|ectecj from tne groUpS 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;
RB58 ancj RB59 are eacn independently selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
wherein R^61 and R^62 are each independently selected from the members of the groups (M ) and (i2) as defined below:
(M ) hydrogen and halogen;
(i2) hydroxy, NO2, C1. g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3_6-cyclyl, wherein the -O-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 RB63
C6.14-aryl, wherein the aryl is optionally substituted,
C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB64RB65 and a lone pair; wherein one of the substituents R^61 and R^62 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms;
RB63 JS selected from the groups 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^-C-i.g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RB64 ancj RB65 are eac|-| 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 se- lected from fluoro and hydroxy, and
-C(O)-R666; or RB64 ancj RB65 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR66^, O and S, and wherein, in case the atoms adjacent to the N which binds to B6 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB66 js 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, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxyl, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R66^, C3.g-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, chloro 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-mennbered heterocyclyl is bound via C, N is substituted by RB63
C6.14-aryl, wherein the aryl is optionally substituted,
C-|_i3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatoms selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted, and NRB68RB69;
RE367 JS se|ectecj from tne groUpS consisting of hydrogen, C-|.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents se- lected 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;
RB67 anc| RB68 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl;
wherein R^71 and R^72 are eacn independently selected from the members of the groups (j1 ) and (j2) as defined below:
(j1 ) hydrogen and halogen;
(j2) hydroxy, NO2, C-^g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl 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 substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3_6-cyclyl, wherein the -O-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 RB73, C6.14-aryl, wherein the aryl is optionally substituted,
C-|_-| 3-heteroaryl, wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C -|.-| 3-heteroaryl is optionally substituted, -C(O)-Ci. β-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB74RB75 and a lone pair; or
RB71 and RB7^ combine to form an oxo-group;
wherein one of the substituents RB7^ and RB7^ js absent in case the dotted lines signify a cova- lent π-bond between B7 and one of the adjacent ring atoms; RE373 JS se|ectec| from ^g groups 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)-C.i_6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
R^74 anc| RB75 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, and -C(O)-R676; or
R^74 anc| RB75 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR677, O and S, and wherein, in case the atoms adjacent to the N which binds to B7 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB76 JS selected from the group consisting of hydrogen, C-] .g-alkyl, wherein the C-| .g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-] .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-| .g-alkyl via C, N is substituted by R^73
C3.g-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, chloro 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 RB73,
C6.14-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroaryl , wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|.-| 3-heteroaryl is optionally substituted, and
NRB78NB79.
RB77 js selected from the groups 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;
RB78 ancj RB79 are eacn independently selected from the groups consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy;
wherein R^81 and R^82 are each independently selected from the members of the groups (k1 ) and (k2) as defined below:
(k1 ) hydrogen and halogen;
(k2) hydroxy, NO2, C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
-O-C3_g-cyclyl, wherein the -O-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 pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB83
Cg.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted,
-C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB84RB85 and a lone pair; or RB81 and R^82 combine to form an oxo-group; wherein one of the substituents R68^ and R68^ js absent in case the dotted lines signify a cova- lent π-bond between B8 and one of the adjacent ring atoms;
RB83 JS selected from the groups 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;
RB84 ancj RB85 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 se- lected from fluoro and hydroxy, and
-C(O)-R686; or RB84 ancj RB85 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR68^, O and S, and wherein, in case the atoms adjacent to the N which binds to B8 are carbon atoms, said carbon atoms independently are optionally substituted by an oxo-group;
RB86 JS 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, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents 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, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected 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 R^83 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, chloro 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 RB83 Cβ.-|4-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-i.-13-heteroaryl is optionally substituted, and
NRB88RB89-
RB87 js selected from the groups 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;
RB88 ancj RB89 are each independently selected from the groups 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; with the proviso that, in case m is 1 , B^, B^, B^, B7 and B8 is a carbon atom and the dotted lines signify 3 conjugated covalent π-bonds, one of each of the pairs of substituents RB^1 and RB^2
RB51 and RB52, RB61 and RB62, RB71 and RB72, RB81 and RB82 is absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (h2), (i2), (j2) and (k2) as defined above;
a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
Special embodiments of the present application are described in the following.
According to one embodiment of the present invention, R^01 is NRA03RA04 wherein RA03 ancj RA04 nas t|ηe same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, -C(O)H and -C(O)-Ci _6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to another embodiment of the present invention, m is 0.
According to another embodiment of the present invention, m is 1.
According to another embodiment of the present invention, m is 0 or 1.
According to another embodiment of the present invention, the dotted lines signify 0 covalent π- bonds.
According to another embodiment of the present invention, the dotted lines signify 2 covalent π- bonds.
According to another embodiment of the present invention, the dotted lines signify 3 covalent π- bonds.
According to another embodiment of the present invention, B^ is a sulfur atom.
According to another embodiment of the present invention, B7 is a sulfur atom. According to another embodiment of the present invention, R^41 and R^42 are eacn independently selected from the members of the groups (g1a) and (g2a) as defined below:
(g1a) hydrogen,
(g2a) C^β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, and a lone pair, wherein one of the substituents R^41 and R^42 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^51 and R^52 are each independ- ently selected from the members of the groups (h1a) and (h2a) as defined below:
(h1a) hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(h2a) C-|_3-alkyl, wherein the C-j.β-alkyl is substituted by one or more substituents selected from fluoro and hydroxy, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|.-|3-heteroaryl is optionally substituted,
NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 and RB55 naVe the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, R^51 and R^52 are each independ- ently selected from the members of the groups (h1a) and (h2a) as defined below: (h1a) hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(h2a) Ci_3-alkyl, wherein the C-j.β-alkyl is substituted by one or more substituents selected from fluoro and hydroxy, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and S, NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 ancj RB55 nave tne same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R^51 and R^52 are eacn jncje. pendently selected from the members of the groups (hi b) and (h2b) as defined below:
(h1 b) hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(h2b) 0^3-alkyl, wherein the C-j.β-alkyl is substituted by one or more substituents selected from fluoro and hydroxy, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has a sulfur atom in its ring, NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 ancj RB55 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention, R^54 ancj RB55 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^57 O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
According to another embodiment of the present invention, R^54 ancj RB55 are eacn independently selected from the group consisting of hydrogen and -C(O)-R656, wherein R656 nas tne same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention, RB56 JS Cβ.g-cyclyl, wherein the C3_β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy.
According to yet another embodiment of the present invention, RB56 JS cyclopropenyl.
According to another embodiment of the present invention, R^61 and R^62 are each independently selected from the members of the groups (Ma) and (i2a) as defined below:
(Ma) hydrogen,
(i2a) Ci_3-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, wherein one of the substituents R^61 and R^62 is absent in case the dotted lines signify a cova- lent π-bond between B6 and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^61 and R^62 are hydrogen wherein one of the substituents R^61 and R^62 is absent in case the dotted lines signify a covalent π-bond between B6 and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^71 and R^72 are eacn independently selected from the members of the groups (j1a) and (j2a) as defined below:
(j1a) hydrogen, (j2a) NO2 and C-|_3-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, wherein one of the substituents R^71 and R^72 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^71 and R^72 are each independently selected from the members of the groups (j1a) and (j2a) as defined below:
(j1a) hydrogen,
(j2a) NO2 wherein one of the substituents R^71 and R^72 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^81 and R^82 are each independently selected from the members of the groups (k1a) and (k2a) as defined below:
(k1a) hydrogen,
(k2a) NO2 and C-|_3-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy, wherein one of the substituents R^81 and R^82 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, m is 1 and the dotted lines signify 0 covalent π-bonds.
According to another embodiment of the present invention, R^81 and R^82 are hydrogen wherein one of the substituents R^^1 and R^82 js absent in case the dotted lines signify a covalent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, m is 1 , each of B^, B^, B^, B^ and B^ are a carbon atom and the dotted lines signify 0 covalent π-bonds. According to another embodiment of the present invention, m is 1 , each of B4, B^, B^, B7 and B8 is a carbon atom, the dotted lines signify 0 covalent π-bonds and each of RB4^ 1 RB42, RB51 RB52 RB61 RB62 RB71 RB72 RB81 and RB82 is hydrogen.
According to another embodiment of the present invention, m is 1 and the dotted lines signify 0 covalent π-bonds.
According to another embodiment of the present invention, m is 0 or 1 and the dotted lines signify 0 covalent π-bonds.
According to another embodiment of the present invention, m is 0 or 1 , each of B4, B^, B^, B7 and B8 is a carbon atom and the dotted lines signify 0 covalent π-bonds or at least one of B4, B^, B^,
B7 and B8 are each independently selected from the group constisting of N, O, S and the the dotted lines signify 0, 1 , 2, 3 covalent π-bonds with the proviso that each ring atom participates in no more than one covalent π-bond and with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted wherein one of the substituents RB41 , RB42, RB51 , RB52, RB61 , RB62, RB71 RB72 RB81 RB82 js absent in case the dotted lines signify a covalent π-bond between B4 , B5, B6, B7 and B8 one of the adjacent ring atoms and wherein RB41 , RB42, RB51 , RB52, RB61 , RB62, RB71 , RB72, RB81and RB82 have the meaning mentioned above or below.
According to another embodiment of the present invention, m is 0 or 1 , each of B4, B^, B^, B7 and B8 is a carbon atom and the dotted lines signify 0 covalent π-bonds or at least one of B4, B^, B^,
B7 and B8 are each independently selected from the group constisting of N, O, S and the the dotted lines signify 0, 1 , 2, 3 covalent π-bonds.
According to another embodiment of the present invention, m is 0, each of B4, B^, B7 and B8 are a carbon atom and the dotted lines signify 0 covalent π-bonds.
According to another embodiment of the present invention, m is 0, each of B4, B^, B7 and B8 is a carbon atom, the dotted lines signify 0 covalent π-bonds and each of RB4^ , RB42, RB^1 , RB52 RB71 RB72 RB81 and RB82 is hydrogen.
According to another embodiment of the present invention, m is 0 or 1 , each of B4, B^, B7 and B8 are a carbon atom and the dotted lines signify 0 covalent π-bonds. According to another embodiment of the present invention, m is 0 or 1 , each of B4, B^, B^ and B8 is a carbon atom, the dotted lines signify 0 covalent π-bonds and each of RB4^ 1 RB42 RB51 RB52 RB71 RB72 RB81 and RB82 is hydrogen.
According to another embodiment of the present invention, m is 0, at least one of B4, B^, B^, B^ and B8 are each independently selected from the group consisting of N, O, S.
According to another embodiment of the present invention, m is 0 or 1 , at least one of B4, B^, B^, B^ and B8 are each independently selected from the group constisting of N, O, S.
According to another embodiment of the present invention, m is 0, B^ is a sulfur atom, each of B4, B^ and B8 are a carbon atom and the dotted lines signify 2 covalent π-bonds that are conjugated.
According to yet another embodiment of the present invention, m is 0, B^ is a sulfur atom, each of B4, B^ and B8 are a carbon atom, the dotted lines signify 2 covalent π-bonds that are conjugated, each of RB41 , RB51 , RB81 and is hydrogen, RB42, RB52and RB82 are absent and RB71 and RB72 each represent a lone pair.
According to yet another embodiment of the present invention, R^01 is selected from the group consisting of hydrogen, hydroxy and NR^3RA04-
RA02 js hydrogen; or
RA01 ancj RA02 combine to form an oxo group;
RA03 and RA04 are hydrogen;
RA21 is selected from the group consisting of hydrogen and C-j.β-alkyl;
RA22 is selected from the group consisting of hydrogen and C-j.β-alkyl;
According to yet another embodiment of the present invention, RB4^ and RB42 are each independently selected from the members of the groups (g1a) and (g2a) as defined below:
(g1a) hydrogen, (g2a) C^β-alkyl, a lone pair, wherein one of the substituents R^41 and R^42 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^51 and R^52 are each independently selected from the members of the groups (h1a) and (h2a) as defined below:
(h1a) hydrogen,
(h2a) C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and S, NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 and RB55 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R^51 and R^52 are each inde- pendently selected from the members of the groups (hi b) and (h2b) as defined below:
(h1 b) hydrogen,
(h2b) Ci_i3-heteroaryl, wherein the C-|.-|3-heteroaryl has a sulfur atom in its ring,
NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 and RB55 naVe the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, R^54 and RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^^^, O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
According to another embodiment of the present invention, R65^ ancj RB55 are eacn independ- ently selected from the group consisting of
-C(O)-R656 and RB54 ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR65^, O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R656 ancj RB57 nave 16 same meaning as defined above or below.
According to another embodiment of the present invention, R65^ ancj RB55 are eacn jnc|epend- ently selected from the group consisting of
-C(O)-R656 and RB54 ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R656 has the same meaning as defined above or below.
According to yet another embodiment of the present invention, R656 is Cβ.g-cyclyl,
According to yet another embodiment of the present invention, R656 is cyclopropenyl.
According to yet another embodiment of the present invention, R^01 is selected from the group consisting of hydrogen, hydroxy and NR^3RA04-
RA02 js hydrogen; or
RA01 ancj RA02 combine to form an oxo group;
RA03 and RA04 are hydrogen;
RA21 js selected from the group consisting of hydrogen and C-j.β-alkyl; RA22 js selected from the group consisting of hydrogen and C-j.β-alkyl;
According to yet another embodiment of the present invention, R^41 and R^42 are each independently selected from the members of the groups (g1a) and (g2a) as defined below:
(g1a) hydrogen,
(g2a) C-i.e-alkyl, a lone pair, wherein one of the substituents R^41 and R^42 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms.
According to another embodiment of the present invention, R^51 and R^52 are each independently selected from the members of the groups (h1a) and (h2a) as defined below:
(h1a) hydrogen,
(h2a) C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and S, NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R^54 and RB55 naVe the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R^51 and R^52 are each independently selected from the members of the groups (hi b) and (h2b) as defined below:
(h1 b) hydrogen,
(h2b) Ci_i3-heteroaryl, wherein the C-|.-|3-heteroaryl has a sulfur atom in its ring, NRB54RB55 and a lone pair, wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms, and wherein R65^ ancj RB55 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention, R65^ ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR65^, O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group.
According to another embodiment of the present invention, R65^ ancj RB55 are eacn independently selected from the group consisting of
-C(O)-R656 and RB54 ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR65^, O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R656 ancj RB57 nave the same meaning as defined above or below.
According to another embodiment of the present invention, R65^ ancj RB55 are each independently selected from the group consisting of
-C(O)-R656 and RB54 ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group and wherein R656 has the same meaning as defined above or below.
According to yet another embodiment of the present invention, R656 is Cβ.g-cyclyl,
According to yet another embodiment of the present invention, R656 is cyclopropenyl.
According to yet another embodiment of the present invention, R^01 js selected from the group consisting of hydrogen, hydroxy and NRA03RA04-
RA02 JS hydrogen; or RA01 ancj RA02 combine to form an oxo group;
RA03 and RA04 are hydrogen;
RA21 and RA22 are C1 -3-BIlCyI;
m is 0 or 1 ;
the dotted lines signify 0, 1 , 2 or 3 covalent π-bonds that may or may not be conjugated and which may each be located between any two adjacent ring atoms, with the proviso that each ring atom participates in no more than one covalent π-bond;
B^, B^, B^, B^ and B^ are each independently selected from the group consisting of C, N, O and S; with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted;
wherein R^41 and R^42 are each independently selected from the members of the groups (g1 ) and (g2) as defined below:
(g1 ) hydrogen;
(g2) C^β-alkyl,
wherein R^51 and R^52 are each independently selected from the members of the groups (hi ) and (h2) as defined below:
(hi ) hydrogen;
(h2) C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and
NRB54RB55 and a lone pair; or wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a covalent π-bond between B^ and one of the adjacent ring atoms; RB54 ancj RB55 are eac|-| independently selected from the group consisting of hydrogen, C-j.β-alkyl,
-C(O)-R656; or
RB54 ancj RB55 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRB57 O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB56 is C3.6-cyclyl,
wherein R66"! and RB^2 are each hydrogen; wherein one of the substituents R66"! and RB^2 js absent in case the dotted lines signify a covalent π-bond between B6 and one of the adjacent ring atoms;
wherein RB7^ and RB72 are each independently selected from the members of the groups (j1 ) and (j2) as defined below:
(j1 ) hydrogen;
(J2) NO2, wherein one of the substituents RB7^ and RB72 js absent in case the dotted lines signify a covalent π-bond between B7 and one of the adjacent ring atoms;
wherein RB8^ and RB82 are hydrogen, wherein one of the substituents RB8^ and RB82 js absent in case the dotted lines signify a covalent π-bond between B8 and one of the adjacent ring atoms;
with the proviso that, in case m is 1 , B^, B5, B6, B7 and B8 is a carbon atom and the dotted lines signify 3 conjugated covalent π-bonds, one of each of the pairs of substituents RB^1 and RB^2
RB51 and RB52, RB61 and RB62, RB71 and RB72, RB81 and RB82 is absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (h2), and (j2) as defined above; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
Θ^CyclohexylmethyO-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i-one;
3,3-Dimethyl-6-(3-methylbenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
Θ^Cyclopentylmethy^-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i-one;
3,3-Dimethyl-6-(2-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
3,3-Dimethyl-6-[4-(2-thienyl)benzyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; i^-^S.S-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolo^.S-clquinolin-θ-yOmethyllphenylJpyrroli- dine-2,5-dione; N^-^S.S-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolo^.S-clquinolin-θ-yOmethyllphenylJcyclo- propanecarboxamide;
Θ^Cyclopentylmethy^-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i -amine;
Θ^CyclopentylmethyO-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i-ol;
3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; N^-^i-Hydroxy-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-θ-yOmethyllphenylJcydo- propanecarboxamide;
(IS^Θ^CyclohexylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-ol;
(1S)-3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol;
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 men- tioned 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, in case m is 1 , B^, B^, B^, B^ and B^ is a carbon atom and the dotted lines signify 3 conjugated covalent π-bonds, one of each of the pairs of substituents RB41 and RB42, RB51 and RB52, RB61 and RB62, RB71 and RB72, RB81 ancj RB82 JS absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (g2a), (h2), (h2a), (h2b), (i2), (i2a), (j2), (J2a), (k2) and (k2a) as defined above. 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. Exam- pies 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 "Ci_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-j.β-alkoxy group include a methoxy group, an ethoxy group, an n- propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a n-pentoxy group, an isopentoxy group, a sec-pentoxy group, a 3- methylpentoxy group, an n-hexoxy group, a 1 ,1-dimethylpropoxy group, a 1 ,2-dimethylpropoxy group, a 2,2-dimethylpropyloxy group, a 2-ethylpropoxy group, a 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-m ethyl propoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1-dimethylbutoxy group, a 1 ,2-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2,3- dimethylbutoxy group, a 1 ,3-dimethylbutyloxy group, a 2-ethylbutoxy group, a 1 ,3-dimethylbutoxy group, a 2-methylpentoxy group, a 3-methylpentyloxy group, a hexyloxy group, wherein a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group and a tert-butoxy group are preferred, and a methoxy group, ethoxy group, isopropoxy group and a isobutoxy group are more preferred.
The term "C3_5-cyclyl" used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms. Examples of the Cβ.β-cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
The term "3- to 7-membered heterocyclyl" includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated. Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group, tet- rahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomor- pholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
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 pyr- rolidine-2,5-dione group, a piperazine-2,3-dione group and the like. More preferred is a pyrrolidine- 2,5-dione group.
The term "Cβ.^-aryl" used in the specification of the present application means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, such as a monocyclic group, a bicyclic group and a tricyclic group. Preferable examples are a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, a heptalenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group. 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 sub- stituents. Examples of such substituents are hydroxy; C-j.β-alkyl, preferably methyl; C-j.β-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo. The Cβ.-|4-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-j.^-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-nnennbered 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 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 isoindo- IyI 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 pyrazinopyri- dazinyl 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 ben- zofuryl 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 substitu- ents. Examples of such substituents are hydroxy; C-|.g-alkyl, preferably methyl; C-|.g-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylenedioxo. The 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. Among the above examples, a thiophenyl group is more preferred.
The above-mentioned C-|.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 and 3- to 7-membered het- erocyclyl, wherein the C-j.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg-^-aryl and C-|. 13-heteroaryl have the same meanings as defined above.
In case the C-|.g-alkyl group is substituted by at least one fluorine atom, the C-|.g-alkyl group can be any group as specified above with respect to the C-|.g-alkyl, unless specified otherwise. The C-|.g-alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-j.g-alkyl, wherein the mono-, tri- and perfluoro substituted C-j.g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C-j.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 hydroxy methyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hy- droxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
In case the C-|.g-alkyl group is substituted by at least one C-|.g-alkoxy, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the C-|.g-alkoxy group can be any group as specified above for C-|.g-alkoxy, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-|.g-alkyl is substituted one C-|.g-alkoxy.
Particlulary preferred are a methoxymethyl group and a 2-methoxyethyl group.
In case the C-|.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 Cβ.g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-|.g-alkyl is substituted one Cβ.g- cyclyl. Particluarly preferred is a cyclopropylmethyl group. In case the C-|.g-alkyl group is substituted by at least one 3- to 7-membered heterocyclyl, the C-|_g- alkyl group can be any group as specified above with respect to C-j.g-alkyl, unless specified otherwise. Similarly, the 3- to 7-mennbered heterocyclyl group can be any group as specified above for 3- to 7-mennbered heterocyclyl, unless specified otherwise. The C-j.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.
The above-mentioned C-|.g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy and Cβ.g-cyclyl, wherein the C-|.g- alkoxy and Cβ.g-cyclyl have the same meanings as defined above.
In case the C-|.g-alkoxy group is substituted by at least one fluorine atom, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-|.g-alkoxy, wherein the mono-, tri- and perfluoro substituted C-|.g-alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C-|.g-alkoxy groups. Examples of these more preferred mono- and perfluoro substituted C-|.g-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro- isopropoxy, 1-fluoro-n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobu- toxy.
In case the C-|.g-alkoxy group is substituted by at least one hydroxy, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. It is preferably a C-|.g-alkoxy group which is substituted by one or two hydroxy groups, more preferably a C-|. 3- alkoxy group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C-j.β- alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
In case the C-|.g-alkoxy group is substituted by at least one another C-|.g-alkoxy, both C-|.g-alkoxy groups can be any group as specified above with respect to C-|.g-alkoxy. The first mentioned C-|.g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-|_g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the first mentioned C-j.g-alkoxy is substituted by one other C-j.g-alkoxy. Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
In case the C-j.g-alkoxy group is substituted by at least one Cβ.g-cyclyl, the C-j.g-alkoxy group can be any group as specified above with respect to C-j.g-alkoxy, unless specified otherwise. Similarly, the Cβ.g-cyclyl group can be any group as specified above for Cβ.g-cyclyl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cβ.g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-j.g-alkoxy is substituted by one Cβ.g-cyclyl. Particluarly preferred is a cyclopropylmethoxy group.
The above-mentioned Cβ.g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
In case the Cβ.g-cyclyl group is substituted by one or more fluoro, the Cβ.g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The Cβ.g- cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted Cβ.g-cyclyl, wherein the mono-, di- and perfluoro substituted Cβ.g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted Cβ.g-cyclyl groups.
In case the Cβ.g-cyclyl group is substituted by one or more hydroxy, the Cβ.g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The Cβ.g- cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C3. g-cyclyl, wherein monohydroxy substituted Cβ.g-cyclyl groups are more preferred.
The above-mentioned 3- to 7-membered heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, hydrogen, C-|.g-alkyl and -C(O)-
C-|.g-alkyl.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents se- lected from fluoro and hydroxy, this/these substituent(s) preferably bind to a ring carbon atom. In case the 3- to 7-nnennbered 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-mennbered 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)-C-] .g-alkyl is -C(O)-Ch^ and - C(O)-CH2OH.
The above-mentioned 3- to 7-membered heterocycle may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, amide, hydrogen, C-]. g-alkyl and -C(O)-C1.g-alkyl.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy and amide, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocycle is substituted by one or more fluoro, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles. In case the 3- to 7-nnennbered 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-mennbered heterocycle, unless specified otherwise. The 3- to 7-mennbered 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)-C-] .g-alkyl, the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. Similarly the C-] .g-alkyl group and the C-|.g-alkyl moiety of the -C(O)-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.
It is to be understood that the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
It is to be understood that the invention covers all combinations of substituent groups referred to hereinabove. In particular, the invention covers all combinations of preferred groups described herein.
Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesi- lates), laurylsulfonates, 3-hydroxy-2-naphthoat.es, lactobionates (salts of 4-O-beta-D- galactopyranosyl-D-gluconic acid), galactarates, embonates and ascorbates. Examples of salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
The salts include water-insoluble and, particularly, water-soluble salts.
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the 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 imgf000043_0001
(Ia)
The compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers. In case R being a hydroxy group, R being hydrogen and RA21 and RA22 representing identical groups, the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center. In case RA01 and RA02 being hydrogen or RA01 and RA02 combining to form an oxo group and RA21 and RA22 representing different groups, the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have one stereogenic center. In case RA01 being a hydroxy group, RA02 being hydrogen and RA21 and RA22 representing different groups, the com- pounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof have two stereogenic centers. Likewise, in case of both substituents RBx1 and RBy2, wherein x = y and x, y = 4, 5, 6, 7 or 8, exist and are different from one another, the corresponding atoms Bx may be stereogenic centers. Moreover, C9 (number refers to the atoms indicated in formula (Ib)) may be a stereogenic center. 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), (3R), (3S), (4R), (4S), (5R), (5S), (6R), (6S), (7R), (7S), (8R), (8S), (9R), (9S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
Figure imgf000044_0001
the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention. Accordingly, in the case of the presence of two stereocenters, all of the possible 20160 stereoisomers, e.g. (1 R,3R), (1 R,3S), (1S,3R), (1S,3S) or (1 R,9R), (1 R,9S), (1S,9R), (1 S,9S), wherein the numbers refer to the atoms indicated in formula (Ib), the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
Accordingly, in the case of the presence of three or more stereocenters, all of the possible stereoisomers, the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
In a preferred embodiment, the invention relates to stereoisomers of formula (Ib) having the configuration (1 R) or (1 S), with the carbon atom at position number 3 not being an asymmetric carbon atom. The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoi- somers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
Furthermore, derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
The compounds according to the invention can be prepared as follows.
As shown in reaction scheme 1 , a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating. The compound of formula (II) or (Na) or (lib) 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.
Reaction scheme 1 :
Figure imgf000046_0001
Figure imgf000046_0002
Compounds of formula (III) are commercially available or can be obtained according to procedures known in the art.
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 (lib) or a mixture thereof. Said Friedel-Crafts acylation reaction can be based on, for example, work of Duval et al. [see e.g. Tetrahedron Letters 45, 5411 (2004)]. The compound of formula (II) or (Na) or (Mb) 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 imgf000047_0001
Figure imgf000047_0002
As shown in reaction scheme 3, a compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof are obtainable via an aldol-type condensation of a compound of formula (VIII), in which PG stands for a suitable temporary protecting group, e.g. acetyl, formyl, allyl or methoxycarbonyl, with a compound of formula (VII), and subsequent removal of PG. The compound of formula (IVa) or (IVb) or (IVc) or a mixture thereof can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ic).
Reaction scheme 3:
Figure imgf000047_0003
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 (Id), in which RA01 and RA02 are hydrogen, can be obtained as shown in reaction scheme 4. In particular, indole (IX) 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 thus obtained hydroxy-com pound 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 (Xl). The compound of formula (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 4:
Figure imgf000048_0001
Indole (IX) is commercially available, the compounds of formula (X) are known, commercially available or can be obtained according to known procedures.
Alternatively, a compound of formula (Id), in which RA01 and RA02 are hydrogen, can be obtained as illustrated in reaction scheme 5. In a first step, indole (IX) 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 (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 5:
Figure imgf000049_0001
(IX) (XII) (Xl) (Id)
Indole (IX) is commercially available, the compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (Id) can be obtained as illustrated in reaction scheme 6. In a first step, indole (IX) 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 (XVI) 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 (XV) 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 (Xl). The compound of formula (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 6:
Figure imgf000049_0002
(IX) (XlIl) (XIV) (XV)
Figure imgf000049_0003
Indole (IX) is commercially available, compounds of formula (XIII) are known, commercially available or can be obtained according to known procedures.
As an alternative approach, a compound of formula (Id) can be obtained as illustrated in reaction scheme 7. In a first step, isatine (XVI) is reacted with a compound of formula (XII) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)]. The thus obtained hydroxy compound of formula (XVII) can be transformed into a compound of formula (XV) 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-compound of formula (XV) 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 (Xl). The compound of formula (Xl) can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Id).
Reaction scheme 7:
Figure imgf000050_0001
(XVI) (XII) (XVII) (XV)
Figure imgf000050_0002
(Xl) (Id)
Isatine (XVI) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
An alternative synthetic route to a compound of formula (Ic) is depicted in reaction scheme 8. Compounds of formulae (XVIII), (XIX) and (XX), 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 (XXI) can be converted to amino-pyridine of formula (XXII) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid. The final ring closing reaction to obtain a compound of formula (Ic) can be achieved by reacting a compound of formula (XXII) 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 imgf000051_0001
(XVIII) (XIX) (XX) (XXI)
Figure imgf000051_0002
(XXII) (Ic)
Compounds of formulae (XVIII), (XIX) and (XX) are known, commercially available or can be obtained according to known procedures.
As an example, a compound of formula (XX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXIII) 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 imgf000051_0003
(XXIII) (XX) Compounds of formula (XXIII) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (Ie), in which RA01, RA02, RA21 and RA22 are hydrogen, 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 (XXIV) in the presence of acetic acid and H3PO4, preferably at elevated temperature. The compound of formula (XXV) thus obtained can be reacted according to reaction scheme 1 or 2 [replacing compound (IV)] to give a compound of formula (Ie).
Reaction scheme 10:
Figure imgf000052_0001
Indole (IX) and 2-hydroxycyclohexanone dimer (XXIV) 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 RA01 is hydroxy and RA02 is hydrogen, can be prepared from a compound of formula (I), wherein RA01 and RA02 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, can be prepared from a compound of formula (I), wherein RA01 and RA02 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 can be prepared from a compound of formula (I), wherein the RA01 and RA02 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; a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen can be prepared from a compound of formula (I), wherein the RA01 and RA02 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 mono- or di-C-|.6-alkylamino, and RA02 is hydrogen can be prepared from a compound of formula (I), wherein the RA01 and RA02 combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. methylamine or diethylamine, 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;
• a compound of formula (I), wherein RA01 is carbonylamino-, e.g. -NH-C(O)-Ci_6-alkyl, wherein said d-6-alkyl may be substituted as defined above, and RA02 is hydrogen, can be prepared e.g. from a compound of formula (I), wherein RA01 is amino and RA02 is hydrogen, by reaction with an appropriate carboxylic acid chloride, e.g. Ci_6-alkylC(O)CI, wherein said Ci_6-alkyl may be substituted as defined above, or carboxylic anhydride, e.g. (Ci.6-alkyl-C(O))2O, wherein said d-6-alkyl may be 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. Ci.6-alkylC(O)OH, wherein said Ci_6-alkyl may be substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole; • a compound of formula (I), wherein 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) carbonylamino-, e.g. -NH-C(O)-R646, -NH-C(O)-R656, -NH-C(O)-R666, -NH-C(O)-
R676 or -NH-C(O)-R686, can be prepared e.g. from a compound of formula (I), wherein R641 and/or R651 and/or R661 and/or R671 and/or R681 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents -NH-C(O)-NH2 can be obtained e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is 1-3C-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) substituted amino, e.g. -NRB44RB45, -NRB54RB55, -NRB64RB65, -NRB74RB75 or -NRB84RB85, can be prepared e.g. from a compound of formula (I), wherein the corresponding RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate amine, e.g. HNRB44RB45, HNRB54RB55, HNRB64RB65, HNRB74RB75 or HNRB84RB85, respectively, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium or copper, e.g. tris(dibenzylideneacetone)- dipalladium(O) 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 RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) C6-i4-aryl or C-ι.-13-heteroaryl can be prepared e.g. from a compound of formula (I), wherein the corresponding RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a halogen, preferably bromine or chlorine, by reaction with an appropriate boronic acid, e.g. C6-M- aryl-B(OH)2 or C-|.-i3-heteroaryl-B(OH)2, respectively, in the presence of a catalytic amount of a transition metal complex, preferably incorporating palladium, e.g. dichlorobis (tricyclohexyl- phosphine) 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 80-1100C, 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 method- ology.
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 me- thylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added. Examples for acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid. Examples for bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. am- monia, 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 diastereo- meric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
In particular, for example the (IS)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained by reduction of the corresponding ketone precursors (wherein RA01 and RA02 combine to form an oxo group) with sodium borohydride in the presence of (4S,5S)-2-(3-nitro-phenyl)-[1 ,3,2]dioxaborolane- 4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4S,5S)-2-(3-Nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and D-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C. Likewise, for example the (I R)-enantiomers of the compounds of formula (Ib), the salts thereof, the N-oxides of the compounds and the salts thereof according to the invention can be obtained using (4R,5R)-2- (3-nitro-phenyl)-[1 ,3,2]dioxaborolane-4,5-dicarboxylic acid in a suitable aprotic solvent, preferably tetrahydrofuran or dioxan, preferably at room temperature. (4R,5R)-2-(3-Nitro-phenyl)- [1 ,3,2]dioxaborolane-4,5-dicarboxylic acid can be prepared by esterification of 3-nitrophenyl boronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, pref- erably at temperatures of 60-800C.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure di- astereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enanti- omeric 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. As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said embodiments that are within the spirit and scope of the invention as defined by the appended claims.
All patents, patent applications, publications, test methods and other materials cited herein are incorporated by reference in their entireties.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be pre- pared 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 appro- priate), integral in fold of 1 H).
Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology. Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode. Data are reported in the form MS (ionized particle found) = m/z. In that context, the molecule is abbreviated by M. For compounds containing bromine, both isotopic forms are reported, for compounds containing chlorine and all other elements, only the major isotopes are reported. Melting points, mp., are measured on a Bϋchi B-540 or a Bϋchi B-541 instrument and are uncor- rected.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE: di- chloroethane, THF: tetrahydrofuran, mp.: melting point, RT: room temperature (20 to 250C), tic: thin layer chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spec- troscopy. Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O0C in a vacuum of 10~1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments. The temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments. The reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
Purchased chemicals and solvents are used without further purification.
Column chromatography is performed using silica gel 60 (0.040 - 0.063 mm), pH 6.5 - 7.5, from Merck KGaA or amino modified silica gel Bulk Isolute® Sorbent Flash NH2 60 (0.040 - 0.070 mm) from International Sorbent Technology Ltd. If pressure (max. 0.3 bar) is applied to increase the flow of the mobile phase the chromatography is referred to as flash chromatography. Preparative HPLC purification is performed on a customary instrument from Gilson using a reversed phase column (C18, Phenomenex, Gemini, 75x30 mm, 5μm) as stationary phase and an acetonitrile / water gradient as mobile phase at a flow of 40 ml/min.
Starting 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 hydrogen chloride 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 sodium hydroxide solution (65 ml) and stirred for 2 h. The reaction mixture is diluted with dichloromethane and acidified with aqueous 6N hydrogen chloride solution (pH 5). The organic layer is separated and the aqueous layer is extracted again with dichloromethane. 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-Bromobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-one hydrochloride
3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) (1.0 g) is suspended in dichloromethane (30 ml) and the suspension is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 34 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. A solution of (4- bromophenyl)acetyl chloride (5.0 g) in dichloromethane (75 ml) is added drop by drop within
15 min. The mixture is stirred 2 h at room temperature. After that, it is poured into ice water (50 ml), the organic phase is washed with 1 M aqueous hydrochloric acid (50 ml) and 1 M aqueous sodium carbonate solution (50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is dissolved in glacial acetic acid (30 ml), ammonium acetate (1.5 g) is added and the mixture is stirred for 2 h at 6O0C. After that it is concentrated in vacuo. The residue is dissolved in ethyl acetate (50 ml), water (50 ml) is added, the organic phase is washed with 1 M sodium carbonate solution (50 ml), dried (MgSO4) and concentrated in vacuo. The residue is dissolved in tetrahydrofuran (10 ml), hydrogen chloride (4M in diethyl ether, 5 ml) is added, the precipitate is filtered and dried in vacuo to give rise to 0.70 g (39%) of the title compound. 1H-NMR (200 MHz, CDCI3): δ = 1.16 (s, 6H), 2.71 (s, 2H), 3.51 (s, 2H), 5.16 (s, 2H), 6.97 (d, J = 8.2 Hz, 2H), 7.36 (dd, J = 7.6 Hz, 7.7 Hz, 1 H), 7.52-7.80 (m, 3H), 7.99 (d, J = 8.3 Hz, 1 H), 9.26 (d, J = 8.5 Hz, 1 H), 13.27 (s, 1 H), 15.33 (s, 1 H). MS (MH+ found) = 433.3, 435.3 mp.: 244 0C (dec.)
A3. 6-(4-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-one Step 1 : S.S-Dimethyl-θ^-nitrobenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-one. (4- Nitrophenyl)acetyl chloride (22.7 g) is dissolved in dichloromethane (500 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 118 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. A suspension of 3-hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclo- hex-2-en-1-one (example A1 ) (10.0 g) in dichloromethane (40 ml) and ether (40 ml) is added drop by drop within 30 min. The mixture is stirred for 2 h at room temperature. After that, it is poured into cold 1 M aqueous hydrochloric acid (250 ml), the organic phase is washed with 1 M aqueous hydrochloric acid (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is dissolved in glacial acetic acid (500 ml), ammonium acetate (125 g) is added and the mixture is stirred for 18 h at 8O0C. After that the volume is reduced in vacuo to 200 ml, solid sodium carbonate is added until pH 7 and ethyl acetate (300 ml) and water (200 ml) are added. The aqueous phase is extracted with ethyl acetate (1 x 200 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (1 x 200 ml) and water (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 3:5 (v/v)), followed by crystallization from ethyl acetate / petroleum ether to obtain 3.05 g (20%) of S.S-dimethyl-θ^-nitrobenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-one. Step 2: e^-AminobenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-one. 3,3- Dimethyl-6-(4-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (3.0 g) is dissolved in ethanol (100 ml), tin(ll)dichloride dihydrate (8.8 g) is added and the mixture is stirred for 2 h at 7O0C. After that, it is poured into ice water (100 ml) and basified by addition of 1 M aqueous sodium hydroxide solution. The product is extracted with ethyl acetate (2 x 200 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystalliza- tion from diethyl ether to yield 2.1 g (76%) of the title compound.
1H-NMR (200 MHz, CDCI3): δ = 1.09 (s, 6H), 2.61 (s, 2H), 3.14 (s, 2H), 3,66 (bs, 2H), 4.37 (bs, 2H), 6.48-6.52 (m, 2H), 6.98-7.02 (m, 2H), 7.12-7.20 (m, 1 H), 7.33-7.47 (m, 2H), 9.25 (d, J = 8.3 Hz, 1 H), 9.59 (bs, 1 H). mp.: 123-1240C
Final Compounds
1. 6-(Cyclohexylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) (1.2 g) is dissolved in dichloroethane (10 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 at O0C for 30 min. In parallel, cyclo- hexylacetic acid (1.00 ml) is dissolved in trifluoroacetic acid anhydride (1.0 ml) and the mixture is stirred for 15 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (2 ml) and added to the zinc chloride mixture, prepared above, within 5 min. The mixture is stirred for 2 h at room temperature. After that, ammonia (7M in methanol, 7 ml) is added and the mixture is refluxed for 18 h. After cooling, 2M ammonia solution (25 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 25 ml). The combined organic extracts are washed with 2M ammonia solution (3 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is puri- fied by crystallization from methanol to yield 0.82 g (48%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.01-1.27 (m, 11 H), 1.54-1.71 (m, 5H), 1.90-2.05 (m, 1 H), 2.66 (s, 2H), 3.14 (d, J = 7.2 Hz, 2H), 3.13 (s, 2H), 7.21 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.52-7.68 (m, 2H), 9.22 (d, J = 8.3 Hz, 1 H), 11.76 (s, 1 H). mp.: 235-237 0C
The following compound is obtained by using the procedure of example 1 analogously.
2. 3,3-Dimethyl-6-(3-methylbenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one Starting compounds: 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) and (3-methylphenyl)acetic acid; yield 13%;
1H-NMR (400 MHz, d6-DMSO); δ = 1.08 (s, 6H), 2.24 (s, 3H), 2.67 (s, 2H), 3.13 (s, 2H), 4.48 (s, 2H), 6.92-7.02 (m, 1 H), 7.10-7.26 (m, 4H), 7.52-7.68 (m, 2H), 9.23 (d, J = 8.3 Hz, 1 H), 1 1.97 (s, 1 H).
MS (MH+ found) = 369.3 mp.: 181-183 0C
3. 6-(Cyclopentylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) (2.9 g) is suspended in dichloromethane (100 ml) and the suspension is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 34 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. A solution of cyclopentylacetic acid chloride (5.0 g) in dichloromethane (75 ml) is added drop by drop within 15 min. The mixture is stirred for 30 min at O0C, then 2 h at room temperature. After that, it is poured into 1 M aqueous hydrochloric acid (125 ml), the organic phase is washed with 1 M aqueous hydrochloric acid (3 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is dissolved in glacial acetic acid (75 ml), ammonium acetate (17.5 g) is added and the mixture is stirred for 3 h at 6O0C. After that it is concentrated in vacuo. The residue is dissolved in ethyl acetate (150 ml), poured into 1 M sodium carbonate solution (150 ml) and the aqueous phase is ex- tracted with ethyl acetate (2 x 150 ml). The combined organic extracts are washed with 1 M sodium carbonate solution (2 x 200 ml), dried (MgSO4) and concentrated in vacuo. The residue is crystallized from ethyl acetate / petroleum (1st crop) and diethyl ether (2nd crop) to yield 2.16 g (55%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.09 (s, 6H), 1.24-1.40 (m, 2H), 1.41-1.59 (m, 2H), 1.59-1.76 (m, 4H), 2.66 (s, 2H), 3.10-3.21 (m, 4H), 7.14-7.28 (m, 1 H), 7.51-7.68 (m, 2H), 9.22 (d, J = 8.3 Hz, 1 H), 11.80 (s, 1 H). MS (MH+ found) = 347.3
The following compound is obtained by using the procedure of example 3 analogously, with adap- tation of the purification step.
4. 3,3-Dimethyl-6-(2-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one
Starting compounds: 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) and (2-nitrophenyl)acetic acid chloride; purification by column chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 8:2 to 7:3 (v/v)); yield 15%;
1H-NMR (400 MHz, d6-DMSO); δ = 1.03 (s, 6H), 2.64 (s, 2H), 2.93 (s, 2H), 4.94 (s, 2H), 7.24 (dd, J = 6.8 Hz, 6.9 Hz, 1 H), 7.50 (d, J = 6.6 Hz, 1 H), 7.52-7.73 (m, 4H), 8.06 (d, J = 8.1 Hz, 1 H), 9.23 (d, J = 8.3 Hz, 1 H), 12.06 (s, 1 H). 5. 3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one
3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dinnethylcyclohex-2-en-1-one (example A1 ) (1.0 g) is dissolved in dry dichloroethane (15 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 8.2 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. In parallel, 3- thiopheneacetic acid (1.17 g) is dissolved in trifluoroacetic acid anhydride (1.17 ml) and the mixture is stirred for 20 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 5 h at room temperature. After that, ammonia (7M in methanol, 5.6 ml) and ammonium acetate (3.02 g) are added and the mixture is refluxed for 18 h. After cooling, 2M am- monia solution (30 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 30 ml). The combined organic extracts are washed with 2M ammonia solution (2 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane / ethyl acetate 98:2 to 90:10 (v/v)) to yield 57 mg (4%) of the title compound. 1H-NMR (300 MHz, d6-DMSO + CD3OD); δ = 1.10 (s, 6H), 2.68 (s, 2H), 3.16 (s, 2H), 4.52 (s, 2H), 7.10 (dd, J = 1.5 Hz, 4.9 Hz, 1 H), 7.23 (ddd, J = 1.5 Hz, 6.4 Hz, 8.1 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.39-7.44 (m, 1 H), 7.55-7.66 (m, 1 H), 9.24 (d, J = 8.1 Hz, 1 H). MS (MH+ found) = 361.3
6. 3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one
3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethylcyclohex-2-en-1-one (example A1 ) (520 mg) is dissolved in dichloroethane (10 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 6 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. 2-Thienylacetyl chloride (0.30 ml) is added drop by drop and the mixture is stirred for 3 h at room temperature. After that, ammonia (7M in methanol, 20 ml) is added and the mixture is refluxed for 18 h. After cooling, it is filtered and the precipitate is washed with dichloromethane. The combined filtrate is washed with 1 M aqueous sodium carbonate solution (20 ml), the organic phase is dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 95:5 (v/v)) to obtain 220 mg (31 %) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.09 (s, 6H), 2.68 (s, 2H), 3.15 (s, 2H), 4.72 (s, 2H), 6.89-6.98 (m, 1 H), 7.00-7.06 (m, 1 H), 7.23 (dd, J = 6.9 Hz, 7.0 Hz, 1 H), 7.29-7.35 (m, 1 H), 7.53-7.69 (m, 2H), 9.23 (d, J = 8.4 Hz, 1 H), 12.02 (s, 1 H). MS (MH+ found) = 361.3
7. 3,3-Dimethyl-6-[4-(2-thienyl)benzyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one
A Schlenk tube is charged with tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2- thiopheneboronic acid (150 mg) and potassium fluoride (0.20 g), the mixture is degased and set under nitrogen atmosphere. 6-(4-Bromobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-one hydrochloride (example A2) (0.5 g), dioxane (3 ml) and a solution of di-t- butylmethylphosphonium tetrafluoroborate (3.2 mg) in dioxane (1 ml) are added, the mixture is again degased, set under nitrogen atmosphere and stirred for 18 h at 7O0C. After cooling, it is concentrated in vacuo, ethyl acetate (10 ml) and water (10 ml) are added, the organic phase is washed with 1 M aqueous sodium carbonate solution (10 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :3 (v/v)), followed by crystallization from diethyl ether to yield 150 mg (33%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.09 (s, 6H), 2.67 (s, 2H), 3.14 (s, 2H), 4.54 (s, 2H), 7.04-7.14 (m, 1 H), 7.19-7.29 (m, 1 H), 7.38-7.47 (m, 3H), 7.48-7.52 (m, 1 H), 7.51-7.69 (m, 4H), 9.23 (d, J = 8.4 Hz, 1 H), 12.01 (s, 1 H). mp.: 178-1790C
8. 1 -{4-[(3,3-Dimethyl-1 -oxo-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-6- yl)methyl]phenyl}pyrrolidine-2,5-dione
Step 1 : 4-({4-[(3,3-Dimethyl-1-oxo-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-6-yl)methyl]phenyl}- amino)-4-oxobutanoic acid. 6-(4-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-one (example A3) (0.5 g) is suspended in toluene (50 ml) and dioxane (1 ml) and succinic anhydride (0.15 g) is added. The mixture is refluxed for 4 h. After cooling, the precipitate is filtered, washed with toluene, stirred in refluxing diethyl ether, filtered again and dried in vacuo to give rise to 500 mg (82%) of 4-({4-[(3,3-Dimethyl-1-oxo-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 6-yl)methyl]phenyl}amino)-4-oxobutanoic acid.
Step 2: i^-^S^-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolo^.S-clquinolin-e-yOmethyllphenyl}- pyrrolidine-2,5-dione. 4-({4-[(3,3-Dimethyl-1-oxo-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-6- yl)methyl]phenyl}amino)-4-oxobutanoic acid (400 mg) is suspended in dioxane (20 ml), 1-ethyl-3- (3-dimethylaminopropyl)-carbodiimide hydrochloride (0.37 g) and triethylamine (712 μl) are added and the mixture is refluxed for 18 h. After cooling, it is concentrated in vacuo, dichloromethane (20 ml) and 1 M aqueous sodium carbonate solution (20 ml) are added and the aqueous phase is extracted with dichloromethane (2 x 20 ml). The combined organic extracts are washed with 1 M aqueous sodium carbonate solution (1 x 30 ml) and water (1 x 30 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :1 to 3:1 (v/v)), followed by crystallization from ethyl acetate to yield 100 mg (21 %) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.08 (s, 6H), 2.66 (s, 2H), 2.75 (s, 4H), 3.15 (s, 2H), 4.57 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.46 (d, J = 8.4 Hz, 2H), 7.55-7.69 (m, 2H), 9.24 (d, J = 8.4 Hz, 1 H), 12.04 (s, 1 H). MS (MH+ found) = 452.4 9. N-{4-[(3,3-Dimethyl-1 -oxo-2,3 ,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-6- yl)methyl]phenyl}cyclopropanecarboxamide
6-(4-Anninobenzyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example A3) (0.5 g) is suspended in dichloromethane (10 ml), cyclopropanecarbonyl chloride (0.14 g) and triethylamine (174 μl) are added and the mixture is stirred for 1 h at room temperature. After that, water (10 ml) is added, the volume is reduced in vacuo, the precipitate is filtered, washed with water and diethyl ether to yield 0.51 g (96%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); 5 = 0.69-0.81 (m, 4H), 1.08 (s, 6H), 1.67-1.79 (m, 1 H), 2.66 (s, 2H), 3.13 (s, 2H), 4.46 (s, 2H), 7.17-7.31 (m, 3H), 7.47 (d, J = 8.5 Hz, 2H), 7.51-7.69 (m, 2H), 9.22 (d, J = 8.4 Hz, 1 H), 10.06 (s, 1 H), 11.95 (s, 1 H). MS (MH+ found) = 438.4
10. θ-tCyclopentylmethyO^^-dimethyl^^^y-tetrahydro-IH-indolo^^-cJquinolin-i- amine Step 1 : N-^CyclopentylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-cjquinolin-i- yl]formamide. Θ^CyclopentylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-one (example 3) (1.5 g) is suspended in formamide (13 ml) and ammoniumformiate (20.5 g), formic acid (85%, 12 ml) are added. The mixture is stirred for 40 h at 18O0C. After cooling, ethanol (10 ml) is added, the mixture is stirred for 15 min and concentrated ammonia (25%, 20 ml) is added (pH > 10). It is extracted with dichloromethane (3 x 50 ml), the combined organic extracts are washed with water (1 x 100 ml), dried (MgSO4), the solvents are removed in vacuo. The residue, crude N- ^-(cyclopentylmethy^-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yljformamide (2.0 g) is used in the next step without further purification. Step 2: Θ^CyclopentylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-amine. N- ^-(Cyclopentylmethy^-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yljformamide (crude from preceeding step, 2.0 g) is dissolved in a 2M solution of HCI in methanol (250 ml, prepared before by dropping acetyl chloride (35 ml) in methanol (250 ml)). The mixture is refluxed for 3 h, after that it is concentrated in vacuo. The residue is dissolved in ethyl acetate (100 ml), washed with 1 M sodium carbonate solution (3 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 8:1 (v/v)), followed by crystallization from diethyl ether to yield 230 mg (15%, 2 steps) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.88 (s, 3H), 1.14 (s, 3H), 1.24-1.40 (m, 2H), 1.40-1.57 (m, 2H), 1.57-1.74 (m, 5H), 1.88 (s, 2H), 2.02-2.12 (m, 1 H), 2.48-2.56 (m, 1 H), 2.62 (d, AB, J = 16.0 Hz, 1 H), 2.86 (d, AB, J = 16.0 Hz, 1 H), 2.96-3.12 (m, 2H), 4.61 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 7.18 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.47 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.56 (d, J = 7.1 Hz, 1 H), 8.36 (d, J = 8.0 Hz, 1 H), 11.35 (s, 1 H). MS (MH+ found) = 348.5 11. 6-(Cyclopentylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -ol
6-(Cyclopentylnnethyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-one (example 3) (350 mg) is dissolved in methanol (25 ml) and sodium borohydride (110 mg) is added in portions. The reaction mixture is stirred for 1 h at room temperature. After that, water (20 ml) is added, the formed precipitate is filtered, washed with water and dried in vacuo to give rise to 270 mg (77%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.93 (s, 3H), 1.13 (s, 3H), 1.26-1.40 (m, 2H), 1.41-1.58 (m, 2H), 1.58-1.72 (m, 4H), 1.72-1.84 (m, 1 H), 1.99-2.10 (m, 1 H), 2.38-2.55 (m, 1 H), 2.65 (d, AB, J = 16.2 Hz, 1 H), 2.85 (d, AB, J = 16.1 Hz, 1 H), 2.95-3.12 (m, 2H), 4.94-5.08 (m, 1 H), 5.24 (m, 1 H), 7.15 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.46 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 8.45 (d, J = 8.0 Hz, 1 H), 11.31 (s, 1 H). MS (MH+ found) = 349.4
12. 3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-ol 3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 6) (120 mg) is dissolved in methanol (10 ml) and sodium borohydride (28 mg) is added in portions. The reaction mixture is stirred for 1 h at room temperature. After that, water (50 ml) and ethyl acetate (25 ml) are added and the aqueous phase is extracted with ethyl acetate (2 x 25 ml). The combined organic extracts are washed with concentrated sodium chloride solution (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :9 (v/v)), followed by crystallization from diethyl ether / petroleum ether to yield 90 mg (30%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 0.94 (s, 3H), 1.13 (s, 3H), 1.72-1.84 (m, 1 H), 2.00-2.11 (m, 1 H), 2.67 (d, AB, J = 16.2 Hz, 1 H), 2.87 (d, AB, J = 16.3 Hz, 1 H), 4.55 (d, AB, J = 15.1 Hz, 1 H), 4.64 (d, AB, J = 15.0 Hz, 1 H), 5.05 (d, J = 6.8 Hz, 1 H), 5.28-5.39 (m, 1 H), 6.87-6.95 (m, 1 H), 6.97-7.02 (m, 1 H), 7.15 (dd, J = 7.0 Hz, 7.1 Hz, 1 H),7.35 (d, J = 5.0 Hz, 1 H), 7.48 (dd, J = 8.2 Hz, 8.3 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 8.47 (d, J = 8.1 Hz, 1 H), 11.50 (s, 1 H). MS (MH+ found) = 363.3
13. N-{4-[(1-Hydroxy-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-6- yl)methyl]phenyl}cyclopropanecarboxamide
N^-^S^-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolo^.S-clquinolin-e-yOmethyllphenylJcyclo- propanecarboxamide (example 9) (400 mg) is suspended in methanol (50 ml) and ethanol (10 ml) and sodium borohydride (107 mg) is added in portions. The reaction mixture is stirred for 1 h at room temperature. After that, the formed precipitate is filtered and washed with methanol. The combined filtrate is treated with water (50 ml), the precipitate is filtered and dried in vacuo to yield 150 mg (38%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.69-0.81 (m, 4H), 0.93 (s, 3H), 1.12 (s, 3H), 1.68-1.72 (m, 2H), 1.98-2.10 (m, 1 H), 2.65 (d, AB, J = 16.0 Hz, 1 H), 2.85 (d, AB, J = 16.1 Hz, 1 H), 4.29 (d, AB, J = 14.2 Hz, 1 H), 4.39 (d, AB, J = 14.3 Hz, 1 H), 4.97-5.09 (m, 1 H), 5.25-5.49 (m, 1 H), 7.16 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 2H), 7.39-7.51 (m, 3H), 7.56 (d, J = 8.1 Hz, 1 H), 8.46 (d, J = 8.1 Hz, 1 H), 10.03 (s, 1 H), 11.44 (s, 1 H). MS (MH+ found) = 440.4
14. (ISJ-e^CyclohexylmethylVS.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i- ol
3-Nitrophenylboronic acid (0.50 g), D-tartaric acid (0.45 g) and calcium hydride (0.25 g) are suspended in dry tetrahydrofuran (10 ml) and the mixture is refluxed for 1 h. The suspension is cooled, filtered under nitrogen atmosphere and washed with dry tetrahydrofuran (10 ml). 6-(Cyclohexyl- methyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 1 ) (360 mg) is suspended in the combined filtrate, the suspension is cooled to O0C (ice bath) and sodium boro- hydride (110 mg) is added in portions. The mixture is stirred for 30 min at O0C, then 2 h at room temperature. After that, methanol (5 ml) is added slowly (hydrogen evolution) and the mixture is stirred for 30 min. Next, 1 M hydrochloric acid (5 ml) is added and stirring is continued for 1 h. The mixture is basified with 1 M aqueous sodium carbonate solution (10 ml) and extracted with di- chloromethane (3 x 20 ml). The combined organic extracts are washed with 1 M aqueous sodium carbonate solution (2 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane to ethyl ace- tate / dichloromethane 1 :4 (v/v)), followed by crystallization from diethyl ether to yield 140 mg (39%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.93 (s, 3H), 1.00-1.27 (m, 8H), 1.53-1.71 (m, 5H), 1.74-1.81 (m, 1 H), 1.81-1.98 (m, 1 H), 1.99-2.10 (m, 1 H), 2.58-2.70 (m, 1 H), 2.78-2.91 (m, 2H), 2.91-3.02 (m, 1 H), 4.99 (d, J = 6.8 Hz, 1 H), 5.28 (d, AB, J = 6.6 Hz, 1 H), 5.32 (d, AB, J = 6.6 Hz, 1 H), 7.15 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.46 (dd, J = 6.9 Hz, 7.0 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 8.45 (d, J = 8.0 Hz, 1 H), 11.26 (s, 1 H). mp.: 210-211 0C ee > 95% (S) (absolute configuration by analogy)
15. (1S)-3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-ol
3-Nitrophenylboronic acid (208 mg), D-tartaric acid (187 mg) and calcium hydride (105 mg) are suspended in dry tetrahydrofuran (5 ml) and the mixture is refluxed for 3 h. The suspension is cooled, filtered under nitrogen atmosphere and washed with dry tetrahydrofuran (5 ml). 3,3- Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 5) (150 mg) is suspended in the combined filtrate, the suspension is cooled to O0C (ice bath) and sodium borohydride (31 mg) is added in portions. The mixture is stirred for 1 h at room temperature. After that, methanol (3 ml) is added slowly (hydrogen evolution) and the mixture is stirred for 30 min. Next, 1 M hydrochloric acid (5 ml) is added and stirring is continued for 1 h. The mixture is basified with 2M aqueous sodium hydroxide solution (5 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts are washed with 1 M aqueous sodium carbonate solu- tion (2 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :4 (v/v)), followed by crystallization from diethyl ether to yield 54 mg (36%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 0.93 (s, 3H), 1.13 (s, 3H), 1.77 (dd, J = 6.7 Hz, 13.3 Hz, 1 H), 2.04 (dd, J = 6.1 Hz, 13.3 Hz, 1 H), 2.66 (d, AB, J = 16.3 Hz, 1 H), 2.85 (d, AB, J = 16.2 Hz, 1 H), 4.34 (d, AB, J = 14.4 Hz, 1 H), 4.44 (d, AB, J = 14.5 Hz, 1 H), 5.06 (d, J = 6.8 Hz, 1 H), 5.26-5.37 (m, 1 H), 7.06 (dd, J = 1.2 Hz, 4.9 Hz, 1 H), 7.17 (ddd, J = 1.2 Hz, 8.1 Hz, 8.1 Hz, 1 H), 7.21-7.28 (m, 1 H), 7.40 (dd, J = 2.9 Hz, 4.9 Hz, 1 H), 7.43-7.52 (m, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 8.45 (d, J = 8.1 Hz, 1 H), 11.51 (s, 1 H). MS (MH+ found) = 363.3 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) = 8.2 min, tR (S-isomer) = 9.1 min, absolute configuration by analogy)
Commercial utility
The compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable.
The compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable. In particular, as type 5 phosphodiesterase (PDE5) inhibitors, they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms. In particular, the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect. The compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
Accordingly, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie's disease; acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, extrinsic allergic alveolitis; inflammatory diseases, such as, but not limited to, vasculature inflammation, acute respiratory distress syndrome, mesangial glomerulonephritis, chronic inflammatory bowel disease, disseminated intravascular inflammation, allergic vasculitis, dermatoses (e.g., but not limited to, psoriasis, toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, fol- licular and widespread pyodermias, endogenous and exogenous acne, acne rosacea), disorders of the arthritis type (e.g., but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [e.g., but not limited to, AIDS (acquired immunodeficiency syndrome), multiple sclerosis], graft versus host reaction, allograft rejections, shock [e.g., but not limited to, septic shock, endotoxin shock, gram-negative sepsis shock, toxic shock syndrome and ARDS (adult respiratory distress syndrome)], gastrointestinal inflammations (e.g., but not limited to, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions (e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps); pain, such as, but not limited to, inflammatory pain; right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia; ischaemic diseases, such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlu- sion, congestive heart failure; diabetic gastroparesis and diseases with symptoms of gastroparesis; diseases or conditions in which it is desirable to suppress platelet function, for example, but not limited to, after stent implantations (e.g., but not limited to, coronary stenting), after bypass operations, in pulmonary hypertension, thrombotic diseases, post-angioplasty stenosis, coronary artery disease, infarction (e.g., but not limited to, myocardial infarction), instable angina pectoris, stroke, and arterial and venous occlusion diseases (e.g., but not limited to, claudicatio intermittens); diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, such as, but not limited to, arteriosclerotic dementia, multi-infarct demen- tia, 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 arterio- venous 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 pul- monale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic en- cephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fis- tula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
In this respect, the term "pulmonary hypertension" in particular embraces pulmonary arterial hypertension including primary pulmonary hypertension (e.g. sporadic or familial) and pulmonary arterial hypertension related, for example, but without limitation, to collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, human immunodeficiency virus infection, drugs or toxins (e.g., but not limited to, anorexigens), persistent pulmonary hypertension of the newborn; pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central 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), inter- stitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomatosis.
Preferably, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis. Furthermore, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, em- physema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The invention also relates to the use of a compound of the invention in the manufacture of a phar- maceutical 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 manufac- ture 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, dia- betic 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 granu- lomatous 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 pul- monary 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 com- prising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds of the invention can be used. Preferably, one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
In a particularly preferred embodiment of the invention, the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
The invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention.
In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
In this respect, the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
Examples of corticosteroids include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide. Examples of anticholinergics include without limitation in- dacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide. Examples of beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate. Examples of lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril auch as colfosceril palmi- tate, surfactant-TA, and calfactant. Examples of endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium. Examples of prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epopros- tenol sodium and treprostinil such as treprostinil sodium. Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine. Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, atenolol and nadolol. Examples of type 4 phosphodiesterase inhibitors include without limitation ro- flumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast. Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride. Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin. Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab. Examples of diuretics include without limitation furosemide, bumetanide and torsemide. Examples of digitalis glycosides include without limitation digoxin and digitoxin.
In a preferred embodiment, the pharmaceutical composition comprises a compound of the 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 pharma- ceutical 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 de- fined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
Futhermore, the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%. In case at least one therapeutic agent selected from the group 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 (dra- gees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). Additionally, the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the 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 administra- tion 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 aero- sol-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 disper- sion 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®, No- volizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers. The aerosol-producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). For parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration, preferably 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 exempli- fied 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 imgf000083_0001

Claims

Claims:
1. Compound of Formula (I)
Figure imgf000084_0001
(I) wherein
RA01 js selected from the group consisting of hydrogen, hydroxy and NRA03RA04-
RA02 JS hydrogen; or
RA01 ancj RA02 combine to form an oxo group;
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 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;
RA21 js selected from the group consisting of hydrogen and C-j.β-alkyl;
RA22 JS selected from the group consisting of hydrogen and C-j.β-alkyl; B is
Figure imgf000085_0001
wherein m is 0 or 1 ;
the dotted lines signify 0, 1 , 2 or 3 covalent π-bonds that may or may not be conjugated and which may each be located between any two adjacent ring atoms, with the proviso that each ring atom participates in no more than one covalent π-bond;
B^, B^, B^, B^ and B^ are each independently selected from the group consisting of C, N, O and S; with the proviso that the fragment B does not represent a group selected from pyridine, pyrimidine, pyrrole, pyrazine and imidazole, each of which may optionally be substituted;
wherein R^41 and R^42 are each independently selected from the members of the groups (g1 ) and (g2) as defined below:
(g1 ) hydrogen, halogen, C-|_3-alkoxy, wherein the C-i.β-alkoxy is not substituted, NO2 and NH2;
(g2) hydroxy, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl 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 substitutents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
-O-C3_6-cyclyl, wherein the -O-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 pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB43, C6.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB44RB45, and a lone pair; or RB41 and R^42 combine to form an oxo-group; wherein one of the substituents R^41 and R^42 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms;
RB43 JS se|ected from (he groups 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;
RB44 and R^45 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 se- lected from fluoro and hydroxy, and
-C(O)-R646; or RB44 and R^45 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^47 O and S, and wherein, in case the atoms adjacent to the N which binds to B4 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB46 JS 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, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents 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 se- lected 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 R^43 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 via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RB43, Cβ.-|4-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-i.-13-heteroaryl is optionally substituted, and
NRB48RB49.
RB47 js selected from the groups 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 -CtCO-C-i.e-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB48 ancj RB49 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; wherein R^51 and R^52 are eacn independently selected from the members of the groups (hi ) and (h2) as defined below:
(hi ) hydrogen, halogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
C-j.β-alkoxy, wherein the C-j.β-alkoxy is not substituted, NO2, NH2, -NH-C(O)-C1.2-alkyl, -NH-C(O)-NH2 and a methoxy group, wherein the methoxy group is substituted by 2 or 3 fluorine atoms; or one of R^41 and R^42 anc| one of RB51 ancj RB52 combine to form a group selected from
-0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
(h2) C-^-alkyl, wherein the C-j.β-alkyl is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C^g-alkyl, wherein the C^β-alkyl is optionally substituted by one or more substitutents se- lected from fluoro and hydroxy,
C-j.β-alkoxy, wherein the C-j.β-alkoxy is substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C^g-alkoxy, wherein the C^g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3.6-cyclyl, wherein the -O-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 RB53 C6.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB54RB55 and a lone pair; or
RB51 ancj RB52 combine to form an oxo-group;
wherein one of the substituents R^51 and R^52 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms;
RE353 JS se|ectec| from tne groUpS 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;
RB54 ancj RB55 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, and -C(O)-R656; or
RB54 ancj RB55 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR657 O and S, and wherein, in case the atoms adjacent to the N which binds to B5 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB56 js selected from the group consisting of C^β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R653
C3.g-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 via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB53
Cg.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-ι.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-ι.-13-heteroaryl is optionally substituted,
NRB58RB59-
RE357 JS se|ectecj from tne groUpS 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;
RB58 ancj RB59 are eacn independently selected from the group consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
wherein R^61 and R^62 are each independently selected from the members of the groups (M ) and (i2) as defined below:
(M ) hydrogen and halogen;
(i2) hydroxy, NO2, C1. g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3_6-cyclyl, wherein the -O-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 RB63
C6.14-aryl, wherein the aryl is optionally substituted,
C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB64RB65 and a lone pair; wherein one of the substituents R^61 and R^62 js absent in case the dotted lines signify a cova- lent π-bond between B^ and one of the adjacent ring atoms;
RB63 JS selected from the groups 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^-C-i.g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RB64 ancj RB65 are eac|-| 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 se- lected from fluoro and hydroxy, and
-C(O)-R666; or RB64 ancj RB65 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, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR66^, O and S, and wherein, in case the atoms adjacent to the N which binds to B6 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB66 js 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, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxyl, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R66^, C3.g-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, chloro 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-mennbered heterocyclyl is bound via C, N is substituted by RB63
C6.14-aryl, wherein the aryl is optionally substituted,
C-|_i3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatoms selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted, and NRB68RB69;
RE367 JS se|ectecj from tne groUpS consisting of hydrogen, C-|.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents se- lected 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;
RB67 anc| RB68 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl;
wherein R^71 and R^72 are eacn independently selected from the members of the groups (j1 ) and (j2) as defined below:
(j1 ) hydrogen and halogen;
(j2) hydroxy, NO2, C-^g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl 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 substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -O-C3_6-cyclyl, wherein the -O-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 RB73, C6.14-aryl, wherein the aryl is optionally substituted,
C-|_-| 3-heteroaryl, wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C -|.-| 3-heteroaryl is optionally substituted, -C(O)-Ci. β-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB74RB75 and a lone pair; or
RB71 and RB7^ combine to form an oxo-group;
wherein one of the substituents RB7^ and RB7^ js absent in case the dotted lines signify a cova- lent π-bond between B7 and one of the adjacent ring atoms; RE373 JS se|ectec| from ^g groups 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)-C.i_6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
R^74 anc| RB75 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, and -C(O)-R676; or
R^74 anc| RB75 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR677, O and S, and wherein, in case the atoms adjacent to the N which binds to B7 are carbon atoms, said carbon atoms are each independently optionally substituted by an oxo-group;
RB76 JS selected from the group consisting of hydrogen, C-] .g-alkyl, wherein the C-| .g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-] .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-| .g-alkyl via C, N is substituted by R^73
C3.g-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, chloro 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 RB73,
C6.14-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroaryl , wherein the C-|.-| 3-heteroaryl has at least one heteroatom selected from N, O and S, and wherein the C-|.-| 3-heteroaryl is optionally substituted, and
NRB78NB79.
RB77 js selected from the groups 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;
RB78 ancj RB79 are eacn independently selected from the groups consisting of hydrogen and C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy;
wherein R^81 and R^82 are each independently selected from the members of the groups (k1 ) and (k2) as defined below:
(k1 ) hydrogen and halogen;
(k2) hydroxy, NO2, C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
-O-C3_g-cyclyl, wherein the -O-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 pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RB83
Cg.14-aryl, wherein the aryl is optionally substituted, C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted,
-C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substitutents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitutents selected from fluoro and hydroxy, NRB84RB85 and a lone pair; or RB81 and R^82 combine to form an oxo-group; wherein one of the substituents R68^ and R68^ js absent in case the dotted lines signify a cova- lent π-bond between B8 and one of the adjacent ring atoms;
RB83 JS selected from the groups 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;
RB84 ancj RB85 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 se- lected from fluoro and hydroxy, and
-C(O)-R686; or RB84 ancj RB85 combine to form a 3- to 7-membered heterocycle, wherein 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR68^, O and S, and wherein, in case the atoms adjacent to the N which binds to B8 are carbon atoms, said carbon atoms independently are optionally substituted by an oxo-group;
RB86 JS 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, Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents 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, chloro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom se- lected 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 R^83 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, chloro 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 RB83 Cβ.-|4-aryl, wherein the aryl is optionally substituted, C i _ 13-heteroary I , wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-i.-13-heteroaryl is optionally substituted, and
NRB88RB89-
RB87 js selected from the groups 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;
RB88 ancj RB89 are each independently selected from the groups 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; with the proviso that, in case m is 1 , B4, B^, B^, B7 and B8 is a carbon atom and the dotted lines signify 3 conjugated covalent π-bonds, one of each of the pairs of substituents RB4^ and RB42,
RB51 and RB52, RB61 and RB62, RB71 and RB72, RB81 and RB82 is absent, respectively, and at least one of the remaining substituents is selected from the members of the groups (g2), (h2), (i2), (j2) and (k2) as defined above;
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 is NRA03RA04- 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 RA03 ancj RA04 are eacn independently selected from the group consisting of hydrogen, -C(O)H and -C(O)-Ci _6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; 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 B^ is a sulfur atom and B4, B7 and B8 each are a carbon atom; or B7 is a sulfur atom and B4, B^ and B8 each are a carbon atom; or B4, B5, B6, B7 and B8 each are a carbon atom; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
5. Compound according to any one of claims 1 to 4, wherein RB4^ , RB42, RB^1 and RB^2 are each independently selected the group consisting of hydrogen, C-j.g-alkyl, wherein the C-] .g-alkyl is optionally substituted by one or more substitutents 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 RB^1 and RB^2 are eacn jncje. pendently 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 se- lected from fluoro and hydroxy,
C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N, O and
S, and wherein the C-|.-|3-heteroaryl is optionally substituted, NRB54RB55 and a lone pair; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
7. Compound according to any one of claims 1 to 6, wherein RB7^ t RB72 RB81 ancj RB82 are each independently selected from the group consisting of hydrogen, NO2 and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substitutents selected from fluoro and hydroxy; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
8. Compound according to any one of claims 1 to 7, wherein m is 0, B7 is a sulfur atom, each of B4, B^ and B8 are a carbon atom, the dotted lines signify 2 covalent π-bonds that are conjugated, each of RB^11 RB51 RB81 ancj js hydrogen, RB^2 RB52ancj RB82 are absent and RB7^ and RB72 each represent a lone pair; or
m is 1 , each of B4, B^, B^, B7 and B8 is a carbon atom, the dotted lines signify 0 covalent π-bonds and each of RB41 , RB42, RB51 , RB52, RB61 , RB62, RB71 , RB72, RB81 and RB82 is hydrogen; or
m is 0, each of B4, B^, B7 and B8 is a carbon atom, the dotted lines signify 0 covalent π-bonds and each of RB41 , RB42 RB51 , RB52 RB71 RB72 RB81 and RB82 is 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.
9. Compound according to any one of claims 1 to 9, selected from the group consisting of 6-(Cyclohexylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-one;
3,3-Dimethyl-6-(3-methylbenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
Θ^Cyclopentylnnethy^-S.S-dinnethyl^.S^J-tetrahydro-IH-indolop.S-clquinolin-i-one;
3,3-Dimethyl-6-(2-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one;
3,3-Dimethyl-6-[4-(2-thienyl)benzyl]-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; i^-^S.S-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolop.S-clquinolin-θ-yOmethyllphenylJpyrroli- dine-2,5-dione; N^-^S.S-Dimethyl-i-oxo^.S^J-tetrahydro-I H-indolop.S-clquinolin-θ-yOmethyllphenylJcycIo- propanecarboxamide;
Θ^CyclopentylnnethyO-S.S-dinnethyl^.S^J-tetrahydro-IH-indolop.S-clquinolin-i -amine;
G^CyclopentylmethyO-S.S-dimethyl^.S^J-tetrahydro-IH-indolo^.S-clquinolin-i-ol;
3,3-Dimethyl-6-(2-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; N^-^i-Hydroxy-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-θ-yOmethyllphenylJcycIo- propanecarboxamide;
(IS^Θ^CyclohexylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-ol;
(1S)-3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
10. Compound, 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 9 for use in the treatment or prophylaxis of diseases.
11. 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 9 together with at least one pharmaceutically acceptable auxiliary.
12. Pharmaceutical composition according to claim 11 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.
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 9 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phos- phodiesterase.
14. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 9 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, colla- genosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis con- strictiva, 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.
15. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 9 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
16. Use according to claim 15, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
17. 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 9 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.
18. Method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodi- esterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 9.
19. Method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Hunt- ington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno- occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and, insufficient brain skills comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 9.
20. Method for treating or preventing an acute or chronic airway disease comprising adminis- tering 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 9.
21. Method for treating or preventing an acute or chronic airway disease according to claim 20, 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.
22. 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 9.
PCT/EP2009/059999 2008-08-05 2009-08-03 2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds Ceased WO2010015586A2 (en)

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US4014883A (en) * 1973-09-10 1977-03-29 Hoffmann-La Roche Inc. Indoloquinolines, intermediates and processes
SU753093A1 (en) * 1979-03-05 1982-11-30 Институт физико-органической химии и углехимии АН УССР 1-methyl-3,4-(delta 2,2-dimethyl-4-oxotetrahydrobenzo)-tranquilizing activity
ES2248412T3 (en) * 2001-02-12 2006-03-16 Lilly Icos Llc CARBOLINE DERIVATIVES.
US7820691B2 (en) * 2006-08-28 2010-10-26 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
EP1953159A1 (en) * 2007-02-05 2008-08-06 Nycomed GmbH 6-Benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds useful as PDE5 inhibitors

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