WO2010015585A1 - 6-benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds - Google Patents

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

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Publication number
WO2010015585A1
WO2010015585A1 PCT/EP2009/059998 EP2009059998W WO2010015585A1 WO 2010015585 A1 WO2010015585 A1 WO 2010015585A1 EP 2009059998 W EP2009059998 W EP 2009059998W WO 2010015585 A1 WO2010015585 A1 WO 2010015585A1
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Prior art keywords
fluoro
hydroxy
alkyl
optionally substituted
membered heterocyclyl
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PCT/EP2009/059998
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French (fr)
Inventor
Björn BARTELS
Steffen Weinbrenner
Degenhard Marx
Jörg DIEFENBACH
Torsten Dunkern
Wiro M.P.B. Menge
Johannes A. M. Christiaans
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Nycomed Gmbh
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Publication of WO2010015585A1 publication Critical patent/WO2010015585A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to 6-Benzyl-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.
  • a further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
  • 6-Benzyl-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)
  • dotted lines each represent a covalent bond which may be present or absent to give rise to a double bond or a single bond, respectively, with the proviso that at least one of the covalent bonds represented by the dotted line is absent so that the respective bond is a single bond;
  • R ⁇ 01 and R ⁇ 02 are eacn independently selected from the members of the groups (hi ) and (h2) as defined below:
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound to the C- ] _g- alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocy- clyl is bound via C, N is substituted by R ⁇ 03 and
  • R A01 anc j RA02 combine to form a hydroxylamino-group; wherein one of the substituents R ⁇ 01 and R ⁇ 02 J S absent in case the dotted line represents a double bond;
  • RA03 JS selected from the group consisting of hydrogen, C-
  • RA04 anc j RA05 are each independently selected from the group consisting of hydrogen, C-
  • Cg-14-aryl wherein the Cg.-
  • RA04 anc j RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • RA06 js selected from the group consisting of hydrogen, C-
  • RA07 anc j RA08 are eac
  • RA09 js selected from the group consisting of hydrogen, C-
  • RA010 JS selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • RA011 j selected from the group consisting of
  • C- j .g-alkyl wherein the C-
  • R A012 R A017 anc j R A018 are eacn independently selected from the group consisting of hydrogen, C-
  • R A013 anc j R A014 are eacn independently selected from the group consisting of hydrogen, C-
  • -C(O)-C 1 .6-alkyl wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C 3 . 6 -cyclyl, wherein the C3_ ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA013 anc j RA014 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ OI? O and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
  • RA015 anc j RA016 are eacn independently selected from the group consisting of hydrogen, C-
  • RA015 anc j RA016 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR A018 , O and S;
  • RA1 1 and RA12 are eacn independently selected from the members of the groups (M ) and (i2) as defined below:
  • R A1 1 and R A12 combine to form the group -0-CH 2 -CH 2 -O-; or
  • R A 11 and R A ⁇ combine to form an oxo-group; wherein one of the substituents R A ⁇ ⁇ and R A ⁇ j s absent in case the dotted line represents a double bond;
  • RA13 anc j RA14 are eacn independently selected from the group consisting of hydrogen, C- ] . ⁇ -alkyl, wherein the C-
  • C 6 . 14 -aryl wherein the Cg.-
  • cj RA16 are eacn independently selected from the group consisting of hydrogen, C-
  • R A1 13 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; or RA15 anc j RA16 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A1 14 , O and S;
  • R A 17, RA110 RA113 anc j RA114 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-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;
  • RA18 js selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-
  • R A19 j selected from the group consisting of
  • R A111 anc j R A112 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C 1 .6-alkyl, wherein the -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • C 3 . 6 -cyclyl wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R A123 ; or
  • RA111 anc j RA112 com bine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA124 Q and S;
  • RA115 RA118 RA123 anc j RA124 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RA116, RA117 RA119 anc j RA120 are eacn independently selected from the group consisting of hydrogen, C-
  • -C(O)-C 1 . g-alkyl wherein the -C(O)-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C 3 .g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA116 RA117 RA119 anc j RA120 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ I 25 Q anc j ⁇ , and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
  • RA121 anc j RA122 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RA125 anc j RA126 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • one of the substituents R ⁇ 01 and R ⁇ 02 anc j O ne of the substituents R ⁇ 11 and R ⁇ 12 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group;
  • R ⁇ 21 and R ⁇ 22 a re each independently selected from the members of the groups (j1 ) and (j2) as defined below: (j1 ) hydrogen and C-i. ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is not substituted,
  • R A21 and R A22 combine to form the group -0-CH 2 CH 2 -O-; or
  • R A2 ⁇ and R A22 combine to form an oxo-group; wherein one of the substituents R A2 ⁇ and R A22 is absent in case the dotted line represents a double bond;
  • R A2 3 and R A24 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • C 3 .g-cyclyl wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • -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; or RA23 anc
  • RA24 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A21 1 , O and S;
  • RA25 anc j RA26 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C- ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • the Cg ⁇ -aryl is optionally substituted, C 3 . 6 -cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-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 se- lected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R A212 , C 3 .
  • R A2 ⁇ , R A2 ⁇ 0, R A2 ⁇ 1 and RA212 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • RA28 anc j RA29 are eacn independently selected from the group consisting of hydrogen, C-
  • RA28 anc j RA29 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A21 1 , O and S;
  • RA213 js selected from the group consisting of C- j . ⁇ -alkyl, wherein the C-
  • RA214 JS selected from the group consisting of hydrogen, hydroxy, C-
  • C 3 . 6 -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 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-
  • C- j .g-alkoxy wherein the C-
  • RA215 anc j RA216 are eacn independently selected from the group consisting of hydrogen, C-
  • R A215 anc j RA216 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A21 1 , O and S;
  • RA217 anc j RA218 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • . ⁇ -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;
  • RA219 anc j RA220 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 se- lected from fluoro, hydroxy, C- j .g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 3 . 6 -cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more 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- j .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C- j .g-alkyl via C, N is substituted by RA221 C 3 .
  • RA219 anc j RA220 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A223 , O and S;
  • RA221 RA222 anc j RA223 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • R ⁇ 31 and R A32 are eacn independently selected from the members of the groups (k1 ) and (k2) as defined below:
  • .g-alkoxy wherein the C-
  • R A31 and R A32 combine to form the group -0-CH 2 CH 2 -O-; wherein one of the substituents R A3 ⁇ and R A32 is absent in case the dotted line represents a double bond;
  • R A 33 anc j RA34 are eacn independently selected from the group consisting of hydrogen, C- ] .g-alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .g-alkoxy, wherein the C- j .g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C 3 .
  • NR A38 R A39 C 3 .g-cyclyl wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA310 ; or
  • R A33 anc j RA34 com bine 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR ⁇ 311 1 o and S;
  • RA35 anc j RA36 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA310
  • A310 RA311 anc j RA312 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C 1 .6-alkyl, wherein the -C(O)-C 1 . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA38 anc j RA39 are eacn independently selected from the group consisting of hydrogen, C- ] . ⁇ -alkyl, wherein the C-
  • .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C 1 .6-alkyl, wherein the -C(O)-C 1 . g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; C 3 .
  • RA38 anc j RA39 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A316 , O and S;
  • RA313 js selected from the group consisting of C 1 . ⁇ -alkyl, wherein the C-
  • RA314 j selected from the group consisting of hydroxy, C- j .g-alkyl, wherein the C-
  • R A315 anc j R A316 are each independently selected from the group consisting of hydrogen, C-
  • RA317 anc j RA318 are each independently selected from the group consisting of hydrogen, C-
  • g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA317 anc j RA318 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR A324 , O and S;
  • RA319 anc j RA320 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -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 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-
  • ⁇ -alkyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy
  • RA321 anc j RA322 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • ⁇ -cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NR A328 , O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C, and -C(O)C 1 . 6 -alkyl, wherein the C-
  • RA323 js selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • RA324 RA325 RA326 RA327 anc j RA328 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; with the proviso that at least one of the substituents R A01 , R A02 , R A1 1 , R A12 , R A21 , R A22 , R A31 and R A ⁇ 2 is selected from a member of the groups (h2), (i2), (j2) and (k2);
  • RB41 js selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino;
  • RB51 JS selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C 1 .3- alkoxy, nitro, amino, -NH-C(O)- C-
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and -CH 2 -CH 2 -O-;
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B ⁇ 1 JS selected from the group consisting of hydrogen and halogen
  • RB81 JS selected from the group consisting of hydrogen and halogen; 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.
  • R ⁇ 01 and R ⁇ 02 are eacn independently selected from the members of the groups (h1a) and (h2a) as defined below:
  • Ci_ 3 -alkoxy wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, -NR A04 R A05 , wherein RA04 anc j RA05 nave t ne same meanings as defined above, or preferably below.
  • R ⁇ 01 an d RA02 are eacn j nc j e . pendently selected from the members of the groups (h1 b) and (h2b) as defined below:
  • RA04 anc j RA05 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, C ⁇ .g-cyclyl, wherein the C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-
  • RA08 are eacn independently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy;
  • RA010 J S selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • R A013 anc j R A014 com bine 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR ⁇ OI 7 Q and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups, wherein R A017 nas ⁇ 16 same meanings as defined above, or preferably below.
  • R A ⁇ 1 and R ⁇ 12 are eacn jndepend- ently selected from the members of the groups (Ma) and (i2a) as defined below:
  • R A1 1 and R A12 combine to form the group -0-CH 2 -CH 2 -O-; or
  • RA11 and R A ⁇ combine to form an oxo-group, wherein R A ⁇ anc j R A14 nave ⁇ 16 same meanings as defined above, or preferably below.
  • R A ⁇ 1 and R A ⁇ 2 are each independently selected from the members of the groups (j1a) and (j2a) as defined below:
  • R A21 and R A22 combine to form the group -0-CH 2 CH 2 -O-; or
  • R A2 ⁇ and R A22 combine to form an oxo-group, wherein R A23 , R A24 , R A2 5 and R A2 ⁇ have the same meanings as defined above, or preferably below.
  • R A2 ⁇ and R A22 are each independently selected from the members of the groups (ji b) and (j2b) as defined below:
  • R A3 ⁇ and R A32 are each independently selected from the members of the groups (k1a) and (k2a) as defined below:
  • ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NR A33 R A34 and -NR A3 5R A3 6 ; or RA31 anc j RA32 combine to form an oxo-group; or R A31 and R A32 combine to form the group -0-CH 2 CH 2 -O-, wherein R A33 , RA34 RA35 anc j RA36 nave t ne same meanings as defined above, or preferably below.
  • R A3 ⁇ and R A32 are each inde- pendently selected from the members of the groups (k1 b) and (k2b) as defined below:
  • RA35 anc j RA36 are eacn independently selected from the group consisting of hydrogen, C- j .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 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 RA310, and
  • k is 0 or 1.
  • R B ⁇ 1 j selected from the group consisting of hydrogen, halogen and C- j . ⁇ -alkoxy.
  • R B ⁇ 1 is selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkyl, hydroxy, C- j . ⁇ -alkoxy, nitro, amino and a methoxy group substi- tuted by 2 or 3 fluorine atoms, or
  • R B41 and R B51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH 2 -CH 2 -O-.
  • R B ⁇ 1 j s selected from the group con- sisting of hydrogen, halogen, C- j . ⁇ -alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
  • one of the substituents R ⁇ OI and RA02 j s hydrogen and the other substituent is selected from the members of the groups consisting Of
  • RA04 anc j R A05 nave t ne S ame meanings as defined above, or preferably below, or
  • R A ⁇ , R A ⁇ 2 , RA31 anc j RA32 are eacn hydrogen
  • R A21 and R A22 are both methyl.
  • one of the substituents R A 01 and R A02 is hydrogen and the other substituent is -NR A04 R A05 , wherein RA04 anc j R A05 nave t ne S ame meanings as defined above, or preferably below,
  • R A11 R A12 R A31 and R A32 are eacn hydrogen
  • R A2 1 and R A22 are both methyl.
  • one of the substituents R A 01 and R A02 j s hydrogen and the other substituent is selected from the members of the groups consisting of (hid) hydroxy,
  • one of the substituents R A ⁇ ⁇ and R A ⁇ 2 is hydrogen and the other substituent is selected from hydroxy, azido, halogen and -NR A ⁇ R A 14, w h ere j n RA13 anc j RA14 have the same meanings as defined above, or preferably below,
  • R A2 1 and R A22 are both methyl
  • R A31 anc j R A32 are eac h hydrogen.
  • RAOI 1 RA02 RA21 RA22 RA31 a nd RA32 are eacn hydrogen and one of the substituents R A ⁇ 1 and R A ⁇ 2 J S hydrogen and the other substituent is selected from hydroxy, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
  • C- j . ⁇ -alkoxy wherein the C- j . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, N R A13 R A14 or R A1 1 and R A12 combine to form the group -0-CH 2 -CH 2 -O-; or
  • R A ⁇ a nd RA14 combine to form an oxo-group, wherein R A ⁇ a nd RA14 have the same meanings as defined above, or preferably below.
  • R A 01 1 RA02 RA11 RA12 RA31 anc j R A32 are each hydrogen and one of the substituents R A2 ⁇ and R A22 j s hydrogen and the other substituent is selected from hydroxy and NR ⁇ 25RA26 or R 21 and R A22 combine to form the group -0-CH 2 -CH 2 -O-; or
  • R A2 ⁇ and R A22 combine to form an oxo-group, wherein R A2 ⁇ and R A2 ⁇ have the same meanings as defined above, or preferably below.
  • R A 01 1 RA02 RA11 RA12 RA21 anc j RA22 are each hydrogen and one of the substituents R ⁇ 31 and R ⁇ 32 j s hydrogen and the other substituent is selected from the group consisting of hydroxy and -NRA35RA36 or R A31 and R A32 combine to form the group -0-CH 2 -CH 2 -O-, or R A 31 an d R A ⁇ 2 combine to form an oxo-group, wherein RA35 anc j RA36 have the same meanings as defined above, or preferably below.
  • R A 01 and R A 02 a re each independently selected from the members of the groups (hie) and (h2e) as defined below:
  • R ⁇ 01 and R ⁇ 02 are each independently selected from the members of the groups (h1f) and (h2f) as defined below:
  • RA01 anc j RA02 combine to form a hydroxylamino-group; wherein one of the substituents R A 01 and R A ⁇ 2 j s absent in case the dotted line repre- sents a double bond; wherein RA04 anc j RA05 naV e the same meanings as defined above, or preferably below.
  • RA04 anc j RA05 are eac h independently selected from the group consisting of hydrogen, C-
  • RA04 anc j RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A012 , O and S; wherein R ⁇ 7 RA08 RA010 RA011 and RA012 nave ( ne same meanings as defined above, or preferably below.
  • RA04 anc j RA05 are each jnde- pendently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from C3_g-cyclyl, 3- to 7-membered heterocyclyl, 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-
  • R A04 anc j R A05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR A012 , O and S; wherein R A ⁇ , R A 08 RA010 RA011 an d RA012 nave the same meanings as defined above, or preferably below.
  • R A ⁇ and R A 08 are eacn independently selected from the group consisting of hydrogen and C-
  • R A ⁇ and R A 08 are eacn jnde- pendently selected from the group consisting of hydrogen and C- j . ⁇ -alkyl;
  • RA010 J S selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen or C-
  • RA010 J S selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents se- lected from hydroxy, C- j . ⁇ -alkoxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .
  • ⁇ -alkyl via C or N with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-
  • RA012 J S independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl or -C(O)-C- ] .g-alkyl,
  • RA012 J S independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl or -C(O)-C- ] .3-alkyl,
  • RA015 anc j RA016 are eacn independently selected from the group consisting of hydrogen or C- ] .g-alkyl,
  • RA015 anc j RA016 are eacn j nc
  • R A ⁇ 1 and RA12 are each inde- pendently selected from the members of the groups (M b) and (i2b) as defined below:
  • R A RA11 and R A ⁇ combine to form an oxo-group; wherein one of the substituents R A ⁇ ⁇ and R A ⁇ j s absent in case the dotted line represents a double bond; wherein R A ⁇ 3 and R A ⁇ 4 have the same meanings as defined above, or preferably below.
  • R A ⁇ ⁇ and R A ⁇ are each independently selected from the members of the groups (Mc) and (i2c) as defined below:
  • R A 11 and R A ⁇ combine to form an oxo-group; wherein one of the substituents R A ⁇ ⁇ and R A ⁇ j s absent in case the dotted line repre- sents a double bond; wherein RA13 anc j RA14 nave ( ne same meanings as defined above, or preferably below.
  • R A ⁇ 3 anc j RA14 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • RA13 anc j RA14 are eacn j nc
  • R A ⁇ 8 j s selected from the group consisting of hydrogen, C-
  • R A ⁇ 8 j s selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents se- lected from hydroxy or C- j .
  • one of the substituents RA01 and RA02 and one of the substituents R A ⁇ 1 and R A ⁇ 2 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group;
  • R A2 ⁇ and R A22 a re each independently selected from the members of the groups (j1c) and (j2c) as defined below:
  • R A21 and R A22 combine to form the group -0-CH 2 CH 2 -O-; or
  • R A2 ⁇ and R A22 combine to form an oxo-group; wherein one of the substituents R A2 ⁇ and R A22 is absent in case the dotted line represents a double bond; wherein R A2 ⁇ and R A2f ⁇ have the same meanings as defined above, or preferably below.
  • R A2 ⁇ and R A22 are each independently selected from the members of the groups (j1c) and (j2c) as defined below:
  • R A21 and R A22 combine to form the group -0-CH 2 CH 2 -O-; or
  • R A2 ⁇ and R A22 combine to form an oxo-group; wherein one of the substituents R A2 ⁇ and R A22 is absent in case the dotted line represents a double bond; wherein R ⁇ 25 anc j RA26 nave t ne same meanings as defined above, or preferably below.
  • R A ⁇ 5 anc j RA26 are each independently selected from the group consisting of hydrogen, C- j .g-alkyl, wherein the C-
  • R A ⁇ 5 anc j RA26 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by Cg.-
  • RA214 J S selected from the group con- sisting of hydrogen, hydroxy, C-
  • RA219 anc j R A220 have the same meanings as defined above, or preferably below.
  • RA214 J S se ected from the group consisting of hydrogen, hydroxy, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from hydroxy or C- j . ⁇ -alkoxy, C- j . ⁇ -alkoxy,
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen, C- j . ⁇ -alkyl or -C(O)-C- ] .3-alkyl, and _ NR A219 R A220. wherein RA219 a nd RA220 nave t ne same meanings as defined above, or preferably below.
  • RA219 anc j RA220 are eacn independently selected from the group consisting of hydrogen, C-
  • RA219 anc j RA220 are each jnde- pendently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from hydroxy or C- j . ⁇ -alkoxy,
  • R ⁇ 31 and R ⁇ 32 are eacn independently selected from the members of the groups (k1 c) and (k2c) as defined below:
  • RA31 and RA32 com bine to form an oxo-group
  • R A31 and R A32 combine to form the group -0-CH 2 CH 2 -O-; wherein one of the substituents R A 31 and R A 32 j s absent in case the dotted line represents a double bond; wherein RA35 an d RA36 na ve the same meanings as defined above, or preferably below.
  • R ⁇ 31 and R ⁇ 32 are eacn j nc
  • R A 31 and R ⁇ 32 combine to form an oxo-group
  • R A31 and R A32 combine to form the group -0-CH 2 CH 2 -O-; wherein one of the substituents R A3 ⁇ and R A32 is absent in case the dotted line repre- sents a double bond; wherein R A 35 anc j RA36 naV e the same meanings as defined above, or preferably below.
  • R A 35 anc j RA36 are eacn independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by - 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;
  • RA35 anc j RA36 are eacn j nc j e . pendently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C- j . ⁇ -alkyl is optionally substituted by one or more substituents selected from hydroxy, C- j . ⁇ -alkoxy, Cg.-14-aryl, C 3 .g-cyclyl,
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by - C(O)-C- ] .3-alkyl, wherein the -C(O)-C- ] .3-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; -(CH 2 ) k -C(O)-RA314 wherein k is 0, 1 and 2; wherein RA314 nas ⁇ g same meaning as defined above, or preferably below.
  • RA314 J S selected from the group consisting of hydroxy, C-
  • NR A321 R A322 3. to 7- me mbered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NR A323 , O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C; wherein R A3 ⁇ 9 , R A 320 R A321 R A322 anc j R A323 naV e the same meanings as defined above, or preferably below.
  • R A 314 J S selected from the group consisting of hydroxy, C- ] .3-alkyl, wherein the C-
  • RA319 anc j R A320 are each independently selected from the group consisting of hydrogen, C-
  • RA319 anc j RA320 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl or -C(O)O-C- ] .3-alkyl;
  • RA321 anc j RA322 are each independently selected from the group consisting of hydrogen, C- ] .g-alkyl;
  • RA321 anc j RA322 are eacn j nc j e . pendently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl;
  • RA323 J S selected from the group consisting of hydrogen, C-
  • RA323 J S selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, -C(O)-C 1.3-alkyl or -C(O)O-C 1 .3-alkyl,
  • R ⁇ 41 j selected from the group consisting of hydrogen, halogen, C- j . ⁇ -alkoxy, nitro and amino;
  • R ⁇ 51 J S selected from the group consisting of hydrogen, C- j . ⁇ -alkoxy, amino or
  • R ⁇ 41 an d R ⁇ 51 combine to form a group selected from -O-CH2-O-;
  • R ⁇ 61 is selected from the group consisting of hydrogen and halogen
  • R ⁇ 81 is hydrogen;
  • R ⁇ 01 and R ⁇ 02 are eacn j nc
  • RA01 anc j RA02 combine to form an oxo-group, (h2) Ci_ 6 -alkoxy,
  • RA01 anc j RA02 com bine to form a hydroxylamino-group; wherein one of the substituents R ⁇ 01 an d R ⁇ 02 j s a bsent in case the dotted line represents a double bond; RA04 anc j RA05 are each independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • RA04 anc j R A05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-
  • RA07 anc j RA08 are eac
  • RA09 js selected from the group consisting of hydrogen, C-
  • RA010 JS selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C- j .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C- j .g-alkyl via C, N is substituted by R A 09 anc j
  • 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 RA09, and N R A013 R A014.
  • R A015 anc j R A016 are each independently selected from the group consisting of hydrogen, C-
  • R A1 1 and R A12 combine to form the group -0-CH 2 -CH 2 -O-; or RA11 and R A ⁇ combine to form an oxo-group; wherein one of the substituents R ⁇ 11 and RA12 J S absent in case the dotted line represents a double bond; RA13 anc j RA14 are eacn independently selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • RA18 JS selected from the group consisting of hydrogen, C- j . ⁇ -alkyl, wherein the C-
  • . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C- j .
  • R A21 and R A22 combine to form the group -0-CH 2 CH 2 -O-; or R A 21 and R A 22 combine to form an oxo-group; wherein one of the substituents R A 21 and R A 22 j s absent in case the dotted line represents a double bond;
  • R A 25 anc j RA26 are eac h independently selected from the group consisting of hydrogen, C-
  • RA214 js selected from the group consisting of hydrogen, hydroxy, 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 RA218 and _ NR A219 R A220.
  • RA219 anc j RA220 are each independently selected from the group consisting of hydrogen, C-
  • R A31 anc j RA32 combine to form an oxo-group; or R A31 and R A32 combine to form the group -0-CH 2 CH 2 -O-; wherein one of the substituents R A 31 and R A 32 j s absent in case the dotted line represents a double bond;
  • RA35 anc j RA36 are each independently selected from the group consisting of hydrogen, C-
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA310 -(CH 2 ) k -C(O)-R A314 , wherein k is 0, 1 and 2;
  • RA37 RA310 RA311 anc j RA312 are eacn independently selected from the group consisting of hydrogen, C- j .g-alkyl, -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; RA314 js selected from the group consisting of hydroxy, C 1 . g-alkyl, wherein the C-
  • NR A321 R A322 c 3 .g-cyclyl wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NR A323 , O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C; RA319 anc j RA320 are each independently selected from the group consisting of hydrogen, C-
  • RA321 anc j RA322 are hydrogen; RA323 js selected from the group consisting of hydrogen, C-
  • R A01 , R A02 , R A1 1 , R A12 , R A21 , R A22 , R A31 and R A ⁇ 2 is selected from a member of the groups (h2), (i2), (j2) and (k2); R ⁇ 41 js selected from the group consisting of hydrogen, halogen and amino; RB51 JS selected from the group consisting of hydrogen, C- j . ⁇ -alkoxy, amino; or
  • R B41 and R B51 combine to form a group Of -O-CH 2 -O-;
  • RB61 JS selected from the group consisting of hydrogen and halogen
  • R B71 and R B81 are hydrogen
  • the compounds of Formula (I) are selected from the group consisting of
  • a compound with the chemical name 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
  • 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 at least one of the substituents R A01 , R A02 , R A1 1 , R A12 , RA 21 , R A22 , R A31 and R A32 is selected from a member of the groups (h2), (h2a), (h2b), (h2c), (h2d), (i2), (i2a), (j2), (J 2 a), (J 2 b), (k2) and (k2a).
  • halogen used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom and a bromine atom are preferred.
  • Ci_5-alkyl used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-
  • C ⁇ -alkyl are more preferred and alkyl groups having 1 to 2 carbon atoms (C- ] _2- alkyl) are still more preferred.
  • C ⁇ -alkyl used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms.
  • alkyl groups examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n- pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,2-di
  • 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 indicates cycloalkyl groups having 3 to 6 carbon atoms.
  • Examples of the C ⁇ . ⁇ -cyclyl group 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. More preferred examples are a pyrrolidinyl group, a piperidinyl group,
  • 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 morpholinyl 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-
  • the Cg ⁇ -aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • a phenyl group is more preferred.
  • 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-membered aromatic heterocyclic group which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In the present invention 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 op- tionally 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 pyridinyl group is more preferred.
  • the above-mentioned C- j .g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C- j .g-alkoxy, C ⁇ .g-cyclyl, 3- to 7-membered heterocy- clyl, Cg.-
  • .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 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
  • .g-alkyl group is substituted by at least one C-
  • .g-alkyl group can be any group as specified above with respect to C-
  • .g-alkoxy group can be any group as specified above for C-
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-
  • 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-alkyl group can be any group as specified above with respect to C-
  • the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-
  • .g-alkyl group is substituted by at least one C- ⁇ .-13-heteroaryl
  • .g-alkyl group can be any group as specified above with respect to C-
  • 3-heteroaryl group can be any group as specified above for C- ⁇ .-13-heteroaryl, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C- j .-i ⁇ - heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring se- lected from N, O or S. Further preferred is that the C-
  • .g-alkyl group can be any group as specified above with respect to C-
  • the amine or amide group can be any group as specified above for amine or amide, unless specified otherwise.
  • .g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
  • .g-alkoxy group may be substituted with one or more substituents se- lected from the group consisting of fluoro, hydroxy, C-
  • the C- j .g-alkoxy group can be any group as specified above with respect to C- j .g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C- j .g-alkoxy, wherein the mono-, tri- 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.
  • .g-alkoxy group can be any group as specified above with respect to C-
  • Examples of such C-1.3- alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
  • .g-alkoxy groups can be any group as specified above with respect to C-
  • .g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
  • .g-alkoxy is substituted by one other C-
  • Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the C3_g-cyclyl group can be any group as specified above for C3_g-cyclyl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ .g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-
  • .g-alkoxy group is substituted by at least one 3- to 7-membered heterocyclyl
  • . ⁇ -alkoxy group can be any group as specified above with respect to C-
  • the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more pref- erably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-
  • .g-alkoxy group is substituted by at least one C- ⁇ .-13-heteroaryl
  • .g-alkoxy group can be any group as specified above with respect to C-
  • the C- ⁇ .-13-heteroaryl group can be any group as specified above for C- j .-i ⁇ - heteroaryl, unless specified otherwise.
  • .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C- j .-i ⁇ -heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-
  • the above-mentioned 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 C3.5- cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C ⁇ .g-cyclyl, wherein the mono-, di- and perfluoro substituted C ⁇ .g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C ⁇ .g-cyclyl groups.
  • the C ⁇ .g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g- cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C3. g-cyclyl, wherein monohydroxy substituted C ⁇ .g-cyclyl groups are more preferred.
  • the above-mentioned 3- to 7-membered heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, hydrogen, C-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group 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 sub- stituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
  • the 3- to 7-membered heterocyclyl group is substituted by one or more substituents se- lected 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.
  • 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 and -C(O)-C 1 _g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C 1 _g-alkyl is -C(O)-CH 3 and - C(O)-CH 2 OH.
  • the above-mentioned 3- to 7-membered heterocycle may be substituted with one or more sub- stituents selected from the group consisting of fluoro, hydroxy, C-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • the 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • the 3- to 7-membered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
  • the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C-
  • the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise.
  • .g-alkyl moiety of the -C(O)-C 1 . g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C 1 . g-alkyl.
  • .g-alkyl and -C(O)-C 1 . g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C 1 . g-alkyl is -C(O)-CH 3 and -C(O)-CH 2 OH.
  • the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof. 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.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzo- ates, 2-(4-hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fu- marates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (
  • salts with bases include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine and guanidinium salts.
  • the salts include water-insoluble and, particularly, water-soluble salts.
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof may contain, e.g. when isolated in crystalline form, varying amounts of solvents. Included within the scope of the invention are, therefore, all solvates of the compounds of formula (I), the salts thereof, the N-oxides of the compounds and the salts thereof and the stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof. Hydrates are a preferred example of said solvates.
  • N-oxides of the compounds according to the invention, the salts thereof, the stereoisomers of the compounds and the salts thereof include compounds, wherein the nitrogen atom of the pyridine moiety is oxidized, as illustrated by formula (Ia) below:
  • the compounds according to the invention, the salts thereof, the N-oxides of the compounds and the salts thereof include stereoisomers.
  • Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog).
  • the invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
  • Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
  • derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention.
  • Said biological system is e.g. a mammalian organism, particularly a human subject.
  • the bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
  • the compounds according to the invention can be prepared as follows.
  • a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating.
  • the compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
  • a compound of formula (IV) can be reacted with a compound of formula (Vl), in which X is a suitable leaving group, e.g. halogen, such as chlorine, or a conjugate base of an acid, such as trifluoroacetate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable solvent, e.g.
  • halogen such as chlorine
  • an acid such as trifluoroacetate
  • acetic acid preferably at elevated temperature
  • a cyclization condensation reaction with ammonia in an appropriate solvent, e.g. methanol, preferably at elevated temperature, to give a corresponding compound of formula (I).
  • an appropriate solvent e.g. methanol, preferably at elevated temperature
  • a compound of formula (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 (IV) can be obtained as shown in reaction scheme 4.
  • indole (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)].
  • the resulting hydroxy- compound of formula (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroace- tic anhydride as activator [see e.g. J. Org. Chem.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 5.
  • indole (Xl) is reacted with a compound of formula (XII) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diiso- propylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper(ll)-2- ethylhexanoate.
  • a suitable base e.g. lithium diiso- propylamide or lithium hexamethyldisilazide
  • a suitable oxidation agent e.g. copper(ll)-2- ethylhexanoate.
  • the thus obtained compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
  • Indole (Xl) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 6.
  • indole (Xl) is reacted with a compound of formula (XIII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)].
  • a base e.g. pyrrolidine or potassium hydroxide
  • the thus obtained unsaturated compound of formula (XIV) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)].
  • the resulting hydroxy-com pound (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV).
  • the compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
  • a compound of formula (IV) can be obtained as illustrated in reaction scheme 7.
  • isatine (XV) 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 (XVI) can be transformed into compounds of formula (V) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)].
  • the resulting hydroxy-com pound of formula (V) can be oxidized in a manner known to the skilled person, e.g.
  • Isatine (XV) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
  • reaction scheme 8 An alternative synthetic route to compounds of formula (Ic) is depicted in reaction scheme 8.
  • X being a leaving group, such as halogen, preferably bromine or chlorine, can be reacted in a multi-component unsymmetric Hantzsch reaction in the presence of catalytic amounts of acid, e.g. acetic acid, and amine, e.g. benzylamine [see e.g. Tetrahedron Letters 42, 4507 (2001 ) or Tetrahedron 63, 1946 (2007)].
  • the resulting nitro- dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid.
  • the final ring closing reaction to obtain compounds of formula (Ic) can be achieved by reacting compounds of formula (XXI) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g.
  • compounds of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXII) with carbonyl diimidazole in the presence of nitromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
  • a suitable base e.g. potassium tertbutylate
  • acetal hydrolysis reaction e.g. using a suitable acid, such
  • a suitable reduction agent such as hydrazine (e.g. according to a Wolff-Kishner reduction)
  • reductive amidation reaction e.g. with the aid
  • 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 suitable solvent e.g. methanol
  • a suitable acid e.g. acetic acid or p- toluenesulfonic acid
  • a suitable Lewis acid e.g. titanium(IV) tetraisopropyl oxide
  • a suitable solvent e.g. methanol
  • a suitable solvent e
  • these two steps are conducted in one pot, without isolation of intermediate imine or imminium compounds; • a compound of formula (I), wherein one or more R 1 ⁇ 1 is carbonylamino-, e.g. -NH-C(O)-R A01 °
  • a base e.g. triethylamine, pyridine or potassium carbonate
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or
  • 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hydroxybenzotriazole;
  • a base e.g. triethylamine, pyridine or potassium carbonate
  • . 6 alkyl wherein C-
  • R Ax1 is alkoxycarbonyl, -C(O)-OC-
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride
  • a suitable base e.g. triethylamine or diis
  • a suitable solvent e.g. methanol
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g. triethylamine or di
  • Ci_ 6 -alkyl-X wherein X represents halide, preferably iodine or bromine or chlorine, or a conjugate base of an acid, such as methylsulfonate, and wherein said Ci_ 6 -alkyl may be optionally substituted as described above for each individual R ⁇ in the presence of a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran;
  • a suitable base e.g. sodium hydride
  • a suitable solvent e.g. dimethylformamide or tetrahydrofuran
  • a suitable reduction agent such as lithium aluminium hydride
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
  • a suitable reduction agent such as tin dichloride or hydrogen gas and a palladium on carbon catalyst
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represent(s) a group -NH-C(O)-Ci_ 2 -alkyl can be prepared e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
  • a base e.g. triethylamine, pyridine or potassium carbonate
  • a dehydrating agent e.g. dicyclohexylcarbodiimide
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents -NH-C(O)-NH 2 can be obtained e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
  • a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein R B41 and/or R B51 and/or R B61 and/or R B71 and/or R B81 is C-
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, 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. ammonia, trimethylamine or methylamine.
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceuti- cally 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 bo- ronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-80 0 C.
  • a dehydrating agent such as calcium hydride
  • Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure 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. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent.
  • chiral auxiliary agents for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts.
  • chiral acids such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid
  • chiral bases such as (+)- or (-)-brucine, (+)- or (-
  • diastereomeric derivatives such as diastereomeric esters can be formed from enanti- omeric 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 suit- able method for the isolation of enantiomers is the enzymatic separation.
  • 1 H nmr spectra are recorded on a Bruker DPX200 ( 1 H 200 MHz), a Bruker Avance ( 1 H 300 MHz) or a Bruker AV400 ( 1 H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1 H). Chemical shifts are given in ppm ( ⁇ ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multi- plet) and b (broadened). Coupling constants, J, are reported in Hz.
  • Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology.
  • Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode.
  • ESI electrospray ionization
  • Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O 0 C in a vacuum of 10 ⁇ 1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
  • Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments.
  • the temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments.
  • the reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
  • Step 1 2-(1-Acetyl-1 H-indol-1-yl)-3-hydroxy-5,5-dimethyl-cyclohex-2-enone.
  • 1-Acetyl-1 ,2-dihydro- indol-3-one (10.5 g) is suspended in acetic acid (50 ml) and a suspension of 5,5-dimethyl- cyclohexane-1 ,3-dione (8.4 g) in acetic acid (50 ml) is added.
  • the reaction mixture is stirred for 20 min and triethylamine (8.3 ml) is added slowly.
  • Step 2 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone.
  • 2-(1-Acetyl-1 H-indol-1-yl)-3- hydroxy-5,5-dimethyl-cyclohex-2-enone (5.95 g) is dissolved in aqueous 1 N NaOH solution (65 ml) and stirred for 2 h.
  • the reaction mixture is diluted with dichloromethane (50 ml) and acidified with aqueous 6N hydrogen chloride solution (pH 5).
  • the organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml).
  • the combined organic layers are dried (MgSO 4 ) and concentrated in vacuo to give 5.09 g of the title compound.
  • 6-(4- Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one 200 mg is suspended in acetonitrile (10 ml) and 25% (w/v) aqueous ammonia solution (10 ml) is added.
  • the reaction mixture is heated in a sealed vial using microwave radiation at 13O 0 C for 25 min.
  • the solvent is removed and the residue is dissolved in dichloromethane (50 ml) and water (50 ml).
  • Step 1 6-(1.S-Benzodioxol-S-ylnnethylene ⁇ S.S-dinnethyl-S ⁇ . ⁇ J-tetrahydrochronnenop ⁇ -blindol- 1(2H)-one.
  • 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone (example A1 ) (2.4 g) is dissolved in dry dichloromethane (75 ml), zinc dichloride (1 M in diethyl ether, 28 ml) is added and the solution is cooled to O 0 C (ice bath).
  • Step 2 ⁇ I .S-Benzodioxol-S-ylmethyO-S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i- one.
  • Indole (7.03 g) and 1 ,4-dioxaspiro[4.5]decan-8-one (4.69 g) are dissolved under nitrogen atmosphere in dry tetrahydrofuran (500 ml) and the solution is cooled to -75 0 C.
  • Lithium hexamethyldisi- lazide (1 M in THF, 90 ml) is added drop by drop.
  • the mixture is stirred for 30 min at -75 0 C, then copper(ll)-2-ethylhexanoate (15.75 g) is added.
  • the reaction is stirred at -75 0 C for 18 h.
  • Potassium hydroxide (36.0 g) is dissolved in methanol (350 ml), indole (18.5 g) and 1 ,4-cyclohexa- dione monoethylen acetal (50.0 g) are added and the mixture is refluxed for 3 h. Upon cooling (ice bath), the product precipitates. It is filtered, washed with cold methanol (50 ml) and dried in vacuo to give rise to 25.3 g (62%) of the title compound.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / heptane to obtain 11.65 g (54%) of the title compound.
  • the mixture is stirred for 2 h at O 0 C. After warming to room temperature, the mixture is poured in 1 M hydrochloric acid (200 ml). The aqueous phase is ex- tracted with dichloromethane (1 x 200 ml), the combined organic extracts are washed with saturated ammonium chloride solution (2 x 200 ml) and saturated sodium chloride solution (1 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :1 (v/v)) to yield 8.14 g (71 %) of the title compound.
  • N-t ⁇ -methoxybenzyO-S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i-yllformamide (example 1 , 2.9 g) is dissolved in a 2M solution of HCI in methanol (150 ml, prepared before by dropping acetyl chloride (24 ml) in methanol (150 ml)). The mixture is refluxed for 18 h, after that it is concentrated in vacuo. The residue is stirred in tetrahydrofuran (50 ml), the precipitate is filtered off to give rise to 3.0 g (93%) of the title compound.
  • Step 1 e ⁇ i .S-Benzodioxol-S-ylmethyO-S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i- one (example A5) (1.5 g) is suspended in formamide (11 ml) and ammoniumformiate (17.8 g), formic acid (85%, 11 ml) are added. The mixture is stirred for 16 h at 17O 0 C. After cooling, ethanol (10 ml) is added, the mixture is stirred for 15 min and cone, ammonia (25%, 20 ml) is added (pH > 10).
  • Step 2 N-[6-(1 ,3-benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1-yl]formamide (crude from preceeding step, 0.7 g) is dissolved in a 2M solution of HCI in methanol (50 ml, prepared before by dropping acetyl chloride (7 ml) in methanol (50 ml)). The mixture is re- fluxed for 3 h, after that it is concentrated in vacuo. The residue is dissolved in ethyl acetate
  • Step i N-p ⁇ -Dimethyl-e ⁇ S-nitrobenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i- yl]formamide. 3,3-Dimethyl-6-(3-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (ex- ample A7) (1.0 g) is suspended in formamide (7.5 ml) and ammoniumformiate (12.0 g), formic acid (85%, 7 ml) are added. The mixture is stirred for 16 h at 16O 0 C.
  • Step 2 N- ⁇ S-AminobenzyO-S ⁇ -dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i- yl]formamide.
  • Crude N-P.S-dimethyl- ⁇ S-nitrobenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin- 1-yl]formamide (1.6 g) is suspended in ethanol (20 ml) and tin dichloride dihydrate (4.0 g) is added. The mixture is stirred for 3 h at 7O 0 C. After cooling, it is filtered, the filtrate is concentrated in vacuo.
  • Step 3 ⁇ S-Amino-benzyO-S.S-dimethyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-i-ylamine.
  • N- [6-(3-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide (crude from preceeding step, 0.7 g) is dissolved in a 2M solution of HCI in methanol (10 ml, prepared before by dropping acetyl chloride (1.2 ml) in methanol (10 ml)). The mixture is stirred 3 h at 7O 0 C, after that it is concentrated in vacuo.
  • the reaction mixture is concentrated in vacuo, the residue is redissolved in ethyl acetate (20 ml), washed with cone, sodium hydrogencarbonate solution (1 x 20 ml), the organic layer is dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is dissolved methanol (10 ml), sodium cyanoborohydride (101 mg) is added and the suspension is stirred for 18 h at room temperature. After that, the mix- ture is concentrated in vacuo, the residue is redissolved in ethyl acetate (20 ml), washed with water (1 x 20 ml) and cone, sodium chloride solution (1 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)).
  • the resulting oil is dissolved in THF (5 ml), HCI (2M in ether, 1 ml) is added, the mixture is stirred for 2 h at room temperature.
  • the resulting precipitate is filtered off to yield 50 mg (13%) of the title compound.
  • 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine (example 2, amine set free by reaction with 2M aqueous sodium carbonate in dichloromethane, followed by extraction with dichloromethane) (422 mg) is dissolved in methanol (5 ml), acetone (0.32 ml) and acetic acid (63 ⁇ l) are added and the mixture is stirred at room temperature for 3 h.
  • 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (100 mg) is suspended in tetrahydrofuran (0.7 ml), pyrrolidine (28 ⁇ l) and titanium tetraisopropyl oxide (154 ⁇ l) are added and the mixture is stirred at room temperature for 18 h. After that time, additional pyrrolidine (22 ⁇ l) and titanium tetraisopropyl oxide (77 ⁇ l) are added and the mixture is stirred for additional 24 h, until complete consumption of starting material (ketone) is detected by tic.
  • 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (0.50 g) is suspended in dichloromethane (10 ml) and dimethylsulfamoyl chloride (0.34 g), triethylamine (1.0 ml) and 4-dimethylamino pyridine (10 mg) are added. The mixture is refluxed for 18 h.
  • the crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to give rise to 348 mg (87%) of the title compound as a single diastereoisomer.
  • 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-ol (example A22) (600 mg) is dissolved in dichloromethane (20 ml) and triethylamine (322 ⁇ l) followed by methane- sulfonyl chloride (133 ⁇ l) is added. The mixture is heated for 20 min at 14O 0 C in the microwave. Further triethylamine (215 ⁇ l) and methanesulfonyl chloride (60 ⁇ l) are added and the mixture heated again for 30 min at 14O 0 C.
  • Citric acid (104 mg) is dissolved in tert-butanol / water (2 ml, 1 :1 (v/v)), 6-(4-methoxybenzyl)-3,3- dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline (example 28) (100 mg), /V-methylmorpholine-A/- oxide (35 mg) and finally potassium osmate(VI) dihydrate (40 mg) are added and the mixture is stirred for 18 h at room temperature.
  • Step 1 6-(4-Methoxybenzylidene)-3,4,6,7-tetrahydro-1 H-spiro[chromeno[3,4-b]indole-2,2'- [1 ,3]dioxolane].
  • 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one (example A8) (990 mg) and (4- methoxyphenyl) acetic acid anhydride (9.96 g) are suspended in nitromethane (30 ml).
  • the resulting slurry is stirred for 10 min at room temperature and 70% (v/v) aqueous HCIO 4 solution (270 ⁇ l) is added in portions (6 portions, every 15 minutes). The mixture is stirred for one additional hour at room temperature. Thereafter, it is diluted with ethyl acetate (50 ml) and washed with a mixture of saturated aqueous NaHCO 3 solution and saturated aqueous Na 2 CO 3 solution (1 :1 (v/v), 4 x 30 ml). The combined aqueous phase is reextracted with ethyl acetate (1 x 80 ml). The combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo. The crude product (6.7 g) is used for the next step without further purification.
  • Step 2 6'-(4-Methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline].
  • 6- (4-Methoxybenzylidene)-3,4,6,7-tetrahydro-1 H-spiro[chromeno[3,4-b]indole-2,2'-[1 ,3]dioxolane] (crude product of step 1 , 6.7 g) is dissolved in acetonitrile (12 ml) and treated with 25% (w/v) aqueous NH 3 solution (12 ml).
  • the reaction mixture is heated in several portions in sealed vials in a microwave at 13O 0 C for 25 min.
  • the mixtures are recombined and diluted with ethyl acetate (100 ml) and water (40 ml).
  • the aqueous phase is extracted with ethyl acetate (2 x 40 ml), the combined organic extracts dried (MgSO 4 ) and concentrated in vacuo.
  • the residue is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane), followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to give rise to 23 mg (2%, 2 steps) of the title compound.
  • Step 1 3-Hydroxy-3-(8-oxo-1 ,4-dioxaspiro[4.5]dec-7-yl)-1 ,3-dihydro-2H-indol-2-one.
  • lsatine (5.88 g) is dissolved in ethyl acetate (120 ml), 1 ,4-dioxaspiro[4.5]decan-8-one (9.36 g) and diethyl amine (1 ml) are added and the reaction mixture is stirred for 18 h at room temperature.
  • Step 2 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-ol.
  • Lithium aluminium hydride (1.18 g) is suspended in dry tetrahydrofuran and 3-hydroxy-3-(8-oxo-1 ,4-dioxaspiro[4.5]dec-7-yl)-1 ,3-dihydro-2H- indol-2-one (3.00 g) is added in portions.
  • the suspension is stirred for 3 h at room temperature and 1 h at 8O 0 C. After cooling to room temperature, water (3 ml) is added drop by drop, followed by tetrahydrofuran (20 ml).
  • Step 3 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one.
  • Dimethylsulfoxide (0.84 ml) is dissolved in dry dichloromethane (10 ml) and the solution is cooled to -75 0 C.
  • Trifluroacetanhydride (1.21 ml) is added drop by drop and the mixture is stirred for 30 min at -75 0 C.
  • Step 4 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3- c]quinoline].
  • 3-Fluoro-4-methoxyphenylacetic acid (1.11 g) is dissolved in 1 ,2-dichloroethane (2 ml), trifluoroacetic anhydride (0.83 ml) is added and the solution is stirred for 15 min at room temperature.
  • the reaction mixture is diluted with ethyl acetate (20 ml) and water (10 ml), the aqueous phase is extracted with ethyl acetate (3 x 20 ml), the combined organic extracts are washed with 2N aque- ous ammonia (2 x 50 ml) and water (1 x 50 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 3:2 (v/v)) to give rise to 250 mg (15%) of the title compound.
  • 6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one (example 40) (1.5 g) is suspended in formamide (12.9 ml) and formic acid (85%, 12.1 ml) and ammonium formiate (20.0 g) are added. The mixture is stirred for 18 h at 16O 0 C. After cooling, it is diluted with water (50 ml), extracted thoroughly with ethyl acetate (8 x 50 ml), the combined organic extracts are washed with 2M sodium carbonate solution (1 x 200 ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 5:1 (v/v) to ethyl acetate / methanol / triethyl amine 5:1 :0.1 (v/v/v)) to yield 250 mg (25%) of the title compound.
  • 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine (example 49) (300 mg) is dissolved in dichloromethane (25 ml), triethyl amine (100 ⁇ l) and methoxy acetyl chlo- ride (90 ⁇ l) are added and the mixture is stirred for 1 h at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (20 ml) and added to the zinc chloride mixture, prepared above, within 20 min. The mixture is stirred for 90 min at O 0 C. After that, glacial acetic acid (140 ml) and ammonium acetate (34.0 g) are added and the mixture is stirred for 16 h at 100 0 C. After cooling, water (200 ml) is added and the mixture is basified with solid sodium hydrogencarbonate. Additional water (200 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 250 ml), the combined organic extracts are washed with water (1 x 400 ml), dried (MgSO 4 ) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) to yield 3.19 g (26%) of the title compound.
  • the crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 3:1 (v/v) to ethyl acetate / methanol / triethyl amine 1 :1 :0.1 (v/v/v)), followed by crystallization from ethyl acetate to yield 1.07 g (44%) of the title compound.
  • 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamine (example 57) (0.3 g) is suspended in tetrahydrofuran (15 ml), the suspension is cooled to O 0 C (ice bath) and triethyl amine (100 ⁇ l) and a solution of ethyl chloroformate (108 ⁇ l) in tetrahydrofuran (5 ml) are added. The mixture is stirred at room temperature for 4 h.
  • Morpholine-4-carboxylic acid [6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H- indolo[2,3-c]quinolin-3-yl]-amide
  • Step 1 [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamino]- acetic acid (example 62) (190 mg) is suspended in dry dichloromethane (5 ml) and dimethyl- formamide (1 ml), 2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethanamine (154 mg), 1-hydroxybenzotriazole (90 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (168 mg) and triethylamine (305 ⁇ l) are added.
  • the crude product is purified by column chromatography (amino-modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)) to obtain 170 mg (66%) of N-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-N-2-[6-(3- fluoro ⁇ -methoxybenzyl ⁇ .S ⁇ J-tetrahydro-I H-indolo ⁇ .S-clquinolin-S-yllglycinamide.
  • Step 2 N-(2- ⁇ [tert-Butyl(dimethyl)silyl]oxy ⁇ ethyl)-N-2-[6-(3-fluoro-4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]glycinamide (170 mg) is dissolved in tetrahydrofuran (3 ml) and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 576 ⁇ l) is added. The mixture is stirred for 18 h at room temperature.
  • the formed mixed anhydride is diluted with dichloroethane (15 ml) and added to the zinc chloride mixture, prepared above, within 30 min. The mixture is stirred for 3 h at room temperature. After that, ammonium acetate (5.0 g) and ammonia (7M in methanol, 40 ml) are added, the formed suspension is divided into microwave vials, the vials are capped and heated for 30 min at 8O 0 C in the microwave.
  • the precipitate is then filtered, washed (dichloromethane), the combined filtrate is diluted with water (100 ml), the aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts again filtered over Celite®, dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 9:1 (v/v)) followed by crystallization from diethyl ether / petroleum ether to give rise to 2.91 g (33%) of the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4-one (example 68) (150 mg) is suspended in methanol (2.5 ml) and glycinamide hydrochloride (180 mg), glacial acetic acid (23 ⁇ l) and sodium cyanoborohydride (1 M in tetrahydrofuran, 2 ml) are added. The mixture is stirred for 3 h at room temperature and for 3 h at 5O 0 C.
  • a white precipitate is formed, that is filtered, washed with water and dried over potassium hydroxide. It is the title compound as acetate salt (1.51 g).
  • the free amine is obtained by dissolution of the acetate salt in dichloromethane / methanol (9:1 (v/v), 20 ml) and addition of 2N sodium hydroxide solution until pH 9. After that, the mixture is diluted with dichloromethane (10 ml), the organic phase is washed with water (1 x 20 ml) and saturated sodium chloride solution (1 x 20 ml), dried (MgSO 4 ), concentrated and dried in vacuo to yield 1.21 g (75%) of the title compound as colorless crystals.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine (example 83) (150 mg) is suspended in dichloromethane (6 ml) and 1-methylpiperidine-4-carboxylic acid (144 mg), 1-hydroxybenzotriazole (81 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg) and triethylamine (260 ⁇ l) are added. The mixture is stirred for 18 h at room temperature.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-ol (example 72) (120 mg) is suspended in dichloromethane (5 ml), triethylamine (214 ⁇ l) and 4-(dimethylamino)- pyridine (10 mg) are added and the suspension is cooled to O 0 C (ice bath). Methanesulfonyl chlo- ride (50 ⁇ l) is added and the mixture is stirred for 1 h at O 0 C and 1 h at room temperature.
  • 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 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
  • 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 pulmo- nary 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), interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not
  • 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 treat- ment 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 invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
  • 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 manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
  • the invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • 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, 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 preeclamp
  • 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, idio- pathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • an acute or chronic airway disease for example, but not limited to, pulmonary hypertension, lung fibrosis, idio- pathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • the invention preferably relates to a method of treating or preventing portal hyperten- sion, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • 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.
  • 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 com- pounds, 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 fu- marate, 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 in- elude 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 pharmaceutical composition comprises: a compound of the invention and bisoprolol, a compound of the invention and nebivolol, a compound of the invention and metoprolol, a compound of the invention and carvedilol, a compound of the invention and atenolol, or a compound of the invention and nadolol.
  • 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 phar- maceutical 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 exam- pies.
  • the invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
  • the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • 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 inven- tion, 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.
  • a further embodiment of the invention is a pharmaceutically acceptable salt of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof for use in the treatment or prophylaxis of diseases.
  • a further embodiment of the invention is a pharmaceutical composition of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salts thereof, N-oxides of the compound and the salts thereof and N-oxides of the salts thereof with at least one pharmaceutically acceptable auxiliary.
  • a further embodiment of the invention is a pharmaceutical composition of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salts thereof, N-oxides of the compound and the salts thereof and N-oxides of the salts thereof with at least one pharmaceutically acceptable auxiliary 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.
  • a further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof in the manu- facture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
  • a further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
  • a further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
  • a further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof 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.
  • a further embodiment of the invention is the method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4- methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N- oxide of the compound or the salt thereof or the N-oxide of the salt thereof.
  • a further embodiment of the invention is the method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H- indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof.
  • a further embodiment of the invention is the method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H- indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof, 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.
  • a further embodiment of the invention is the 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 with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof.
  • 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
  • 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 administration 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, anticho- linergics, 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 therapeu- tic 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 aerosol-producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion.
  • the powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers.
  • the solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings.
  • the 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
  • solutions e.g., but not limited to, sterile solutions, isotonic solutions
  • 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. 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.
  • composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics
  • administration of the compound of the invention and administration of the therapeutic agent can be made simultaneously or sequentially.
  • the compound of the invention can be administered before or after administration of the therapeutic agent.

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Abstract

The present invention pertains to 6-benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds of formula (I), as well as the resulting pharmaceutical compositions, and their use in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases. Furthermore, the present invention pertains to the methods of manufacturing these 6-benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds.

Description

Description
6-Benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds
Field of application of the invention
The invention relates to 6-Benzyl-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 discloses nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO02/028859 and WO02/10166 discloses fused heterocyclic derivatives as phosphodiesterases. WO2008027182 discloses indoloquinoline compounds as calcium channel blockers.
It is an object of the present invention to provide novel compounds and pharmaceutical composi- tions 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 6-Benzyl-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
wherein the dotted lines each represent a covalent bond which may be present or absent to give rise to a double bond or a single bond, respectively, with the proviso that at least one of the covalent bonds represented by the dotted line is absent so that the respective bond is a single bond;
wherein R^01 and R^02 are eacn independently selected from the members of the groups (hi ) and (h2) as defined below:
(hi ) hydrogen and hydroxy, or
RA01 ancj RA02 combine to form an oxo-group,
(h2) C-j.β-alkoxy, wherein the C-|.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, and hydroxy, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound to the C-] _g- alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocy- clyl is bound via C, N is substituted by R^03 and
_NRA04RA05. or
RA01 ancj RA02 combine to form a hydroxylamino-group; wherein one of the substituents R^01 and R^02 JS absent in case the dotted line represents a double bond;
RA03 JS selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-Ci. g-alkyl, wherein the -C(O)-C-J _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA04 ancj RA05 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.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 RA06,
Cg-14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C"|_i3-heteroaryl, wherein the C-i.-13-heteroaryl has at least one heteroatom selected from N,
O and S, and wherein the C-i.-13-heteroaryl is optionally substituted, and
NRA07RA08 C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, 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 RA09, and -C(O)RA010 and -S(O)2RA01 1 ; or
RA04 ancj RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents se- lected from fluoro and hydroxy; and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA012, O and S;
RA06 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA07 ancj RA08 are eac|-| independently selected from the group consisting of hydrogen and C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA09 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA010 JS selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA09 ancj
NRA013RA014 C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the 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 RA09, and
NRA013RA014;
RA011 js selected from the group consisting of
C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA015RA016 C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy, and
NRA015RA016;
RA012 RA017 ancj RA018 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA013 ancj RA014 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.β-alkyl is optionally 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(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C3.6-cyclyl, wherein the C3_β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA013 ancj RA014 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^OI? O and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA015 ancj RA016 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
RA015 ancj RA016 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA018, O and S;
wherein RA1 1 and RA12 are eacn independently selected from the members of the groups (M ) and (i2) as defined below:
(M ) hydrogen, (i2) hydroxy, C-|.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, azido, halogen, -NRA13RA14, -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)NRA15RA16; or
RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^ combine to form an oxo-group; wherein one of the substituents RA^ ^ and RA^ js absent in case the dotted line represents a double bond;
RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen, C-] .β-alkyl, wherein the C-|_5-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg^-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.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 RA^, 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 RA17,
C6.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, -CORA18 and -S(O)2RA19; cj RA16 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by RA^ ^ and NRA111 RA112 C3.g-cyclyl, wherein the C3_g-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
RA1 13, 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; or RA15 ancj RA16 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA1 14, O and S;
RA17, RA110 RA113 ancj RA114 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA18 js selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 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.β-alkyl via C, N is substituted by R^115, and
NRA116RA117 C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the C3_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 RA1 18, and
NRA119RA120.
RA19 js selected from the group consisting of
C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA121 RA122.
RA111 ancj RA112 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -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;
C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA123; or
RA111 ancj RA112 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA124 Q and S;
RA115 RA118 RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents 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;
RA116, RA117 RA119 ancj RA120 are eacn independently selected from the group consisting of hydrogen, C-|. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
-C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA116 RA117 RA119 ancj RA120 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^I 25 Q ancj §, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA126 Q and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA125 ancj RA126 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)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
one of the substituents R^01 and R^02 ancj One of the substituents R^ 11 and R^12 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group;
wherein R^21 and R^22 are each independently selected from the members of the groups (j1 ) and (j2) as defined below: (j1 ) hydrogen and C-i.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2) hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is substituted by fluoro, chloro and hydroxy, C4.6-alkyl, wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)NRA23RA24, and -NRA25RA26; or RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group; wherein one of the substituents RA2^ and RA22 is absent in case the dotted line represents a double bond;
RA23 and RA24 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound 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^27 ancj NRA28RA29, 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 RA210, 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; or RA23 anc| RA24 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA25 ancj RA26 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy,
wherein the Cg^-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-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 se- lected 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 RA212, 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 RA210 -S(O)2RA213, and
-(CH2)|CORA214; wherein I is 0, 1 and 2; or RA25 ancj RA26 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA2^, RA2^0, RA2^ 1 and RA212 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA28 ancj RA29 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents 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, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA212. or
RA28 ancj RA29 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA213 js selected from the group consisting of C-j.β-alkyl, wherein the C-|_5-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA215RA216.
RA214 JS selected from the group consisting of hydrogen, hydroxy, C-|_5-alkyl, wherein the C-|_5-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more 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 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-j.g-alkyl via C, N is substituted by R^17
C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro or hydroxy, 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 proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA218 and _NRA219RA220.
RA215 ancj RA216 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 se- lected 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; or
RA215 ancj RA216 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA217 ancj RA218 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA219 ancj RA220 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 se- lected from fluoro, hydroxy, C-j.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more 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-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA221 C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA222. or
RA219 ancj RA220 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA223, O and S;
RA221 RA222 ancj RA223 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
wherein R^31 and RA32 are eacn independently selected from the members of the groups (k1 ) and (k2) as defined below:
(k1 ) hydrogen,
(k2) hydroxy, C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA33RA34 and -NRA35RA36; or RA31 and RA32 combine to form an oxo-group; or
RA31 and RA32 combine to form the group -0-CH2CH2-O-; wherein one of the substituents RA3^ and RA32 is absent in case the dotted line represents a double bond;
RA33 ancj RA34 are eacn independently selected from the group consisting of hydrogen, C-] .g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 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 R^37 ancj
NRA38RA39 C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA310; or
RA33 ancj RA34 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR^3111 o and S;
RA35 ancj RA36 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg^-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA312, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected 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 RA310
-S(O)2RA313, and -(CH2)k-C(O)-RA314, wherein k is 0, 1 and 2; A310 RA311 ancj RA312 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA38 ancj RA39 are eacn independently selected from the group consisting of hydrogen, C-] .β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -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; C3.6-cyclyl, wherein the C3_β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA315; or
RA38 ancj RA39 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA316, O and S;
RA313 js selected from the group consisting of C1. β-alkyl, wherein the C-|_5-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.β-cyclyl, wherein the C-j.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-cyclyl, wherein the C-|.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA317RA318;
RA314 js selected from the group consisting of hydroxy, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and NRA319RA320 C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, NRA321 RA322 c3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NRA323, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C;
RA315 ancj RA316 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 se- lected 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;
RA317 ancj RA318 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)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA317 ancj RA318 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-nnennbered heterocycle is optionally substituted by one or more sub- stituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA324, O and S;
RA319 ancj RA320 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.β-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-membered heterocyclyl is bound to the C-j.β-alkyl via C, N is substituted by RA325 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 NRA326, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C, and -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.β-alkyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, RA321 ancj RA322 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.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^327 C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected 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 NRA328, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C, and -C(O)C1.6-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy;
RA323 js selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)O-C1.6-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy;
RA324 RA325 RA326 RA327 ancj RA328 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)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; with the proviso that at least one of the substituents RA01 , RA02, RA1 1 , RA12, RA21 , RA22, RA31 and RA^2 is selected from a member of the groups (h2), (i2), (j2) and (k2);
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C1.3- alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(O)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB^1 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen; 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 and R^02 are eacn independently selected from the members of the groups (h1a) and (h2a) as defined below:
(h1a) hydrogen and hydroxy, or RA01 and RA02 combine to form an oxo-group,
(h2a) Ci_3-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, -NRA04RA05, wherein RA04 ancj RA05 nave tne same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R^01 and RA02 are eacn jncje. pendently selected from the members of the groups (h1 b) and (h2b) as defined below:
(h1 b) hydrogen and
(h2b) -NRA04RA05, wherein RA04 ancj RA05 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA04 ancj RA05 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents 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, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA06, wherein the Cg.-|4-aryl is optionally substituted, C"|_i3-heteroaryl, 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
NRA07RA08 C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)RAO1O, wherein R^06 RA07 RA08 ancj RA010 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention, R^07 anc| RA08 are eacn independently selected from the group consisting of hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy;
According to another embodiment of the present invention, RA010 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-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R^09 ancj NRA013RA014 and NRA013RA014 wherein R^09, RA013 ancj RA014 nave the same meanings as defined above, or preferably below.
Acccording to another embodiment of the present invention, RA013 ancj RA014 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^OI 7 Q and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups, wherein RA017 nas ^16 same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA^ 1 and R^12 are eacn jndepend- ently selected from the members of the groups (Ma) and (i2a) as defined below:
(Ma) hydrogen,
(i2a) hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, NRA13RA14, or
RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^ combine to form an oxo-group, wherein RA^ ancj RA14 nave ^16 same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA^1 and RA^2 are each independently selected from the members of the groups (j1a) and (j2a) as defined below:
(j1a) hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2a) hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is substituted by fluoro, chloro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA23RA24, and
-NRA25RA26; or
RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group, wherein RA23, RA24, RA25 and RA2^ have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA2^ and RA22 are each independently selected from the members of the groups (ji b) and (j2b) as defined below:
(ji b) hydrogen
(j2b) -C(O)NRA23RA24, and _NRA25RA26, wherein RA23, RA24, RA25 and RA2f^ have the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA3^ and RA32 are each independently selected from the members of the groups (k1a) and (k2a) as defined below:
(k1a) hydrogen,
(k2a) hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA33RA34 and -NRA35RA36; or RA31 ancj RA32 combine to form an oxo-group; or RA31 and RA32 combine to form the group -0-CH2CH2-O-, wherein RA33, RA34 RA35 ancj RA36 nave tne same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA3^ and RA32 are each inde- pendently selected from the members of the groups (k1 b) and (k2b) as defined below:
(k1 b) hydrogen,
(k2b) -C(O)NRA33RA34 and -NRA35RA36, wherein RA33, RA34, RA35 ancj RA36 naVe the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA35 ancj RA36 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg_i4-aryl, wherein the Cg.-14-aryl is optionally substituted, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA312, C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected 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 RA310, and
-(CH2)k-C(O)-RA314, wherein k is 0, 1 and 2, wherein R^312 RA310 ancj RA314 nave the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, k is 0 or 1.
According to an embodiment of the present invention, RB^1 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy.
Acccording to an embodiment of the present invention, RB^1 is selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β-alkoxy, nitro, amino and a methoxy group substi- tuted by 2 or 3 fluorine atoms, or
RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH2-CH2-O-.
According to another embodiment of the present invention, RB^1 js selected from the group con- sisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms.
According to yet another embodiment of the present invention, one of the substituents R^OI and RA02 js hydrogen and the other substituent is selected from the members of the groups consisting Of
(h1c) hydroxy,
(h2c) Ci_3-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
_NRA04RA05 wherein RA04 ancj RA05 nave tne Same meanings as defined above, or preferably below, or
(h1c) RA01 and RA02 combine to form an oxo-group,
RA^ , RA^ 2, RA31 ancj RA32 are eacn hydrogen, and
RA21 and RA22 are both methyl.
According to yet another embodiment of the present invention, one of the substituents RA01 and RA02 is hydrogen and the other substituent is -NRA04RA05, wherein RA04 ancj RA05 nave tne Same meanings as defined above, or preferably below,
RA11 RA12 RA31 and RA32 are eacn hydrogen, and
RA21 and RA22 are both methyl.
According to yet another embodiment of the present invention, one of the substituents RA01 and RA02 js hydrogen and the other substituent is selected from the members of the groups consisting of (hid) hydroxy,
(h2d) Ci_3-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
(hid) RA01 and RA 2 combine to form an oxo-group,
one of the substituents RA^ ^ and RA^2 is hydrogen and the other substituent is selected from hydroxy, azido, halogen and -NRA^RA14, wherejn RA13 ancj RA14 have the same meanings as defined above, or preferably below,
RA21 and RA22 are both methyl, and
RA31 ancj RA32 are each hydrogen. According to another embodiment of the present invention, RAOI 1 RA02 RA21 RA22 RA31 and RA32 are eacn hydrogen and one of the substituents RA^ 1 and RA^2 JS hydrogen and the other substituent is selected from hydroxy, 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-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, NRA13RA14 or RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^2 combine to form an oxo-group, wherein RA^ and RA14 have the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA011 RA02 RA11 RA12 RA31 ancj RA32 are each hydrogen and one of the substituents RA2^ and RA22 js hydrogen and the other substituent is selected from hydroxy and NR^25RA26 or R21 and RA22 combine to form the group -0-CH2-CH2-O-; or
RA2^ and RA22 combine to form an oxo-group, wherein RA2^ and RA2^ have the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA011 RA02 RA11 RA12 RA21 ancj RA22 are each hydrogen and one of the substituents R^31 and R^32 js hydrogen and the other substituent is selected from the group consisting of hydroxy and -NRA35RA36 or RA31 and RA32 combine to form the group -0-CH2-CH2-O-, or RA31 and RA^2 combine to form an oxo-group, wherein RA35 ancj RA36 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA01 and RA02 are each independently selected from the members of the groups (hie) and (h2e) as defined below:
(hie) hydrogen and hydroxy, or
RA01 and RA02 combine to form an oxo-group,
(h2e) C-i.e-alkoxy, -NRA04RA05; or RA01 ancj RA02 combine to form a hydroxylamino-group; wherein one of the substituents R^01 and R^02 js absent in case the dotted line represents a double bond; wherein RA04 ancj RA05 naVe the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R^01 and R^02 are each independently selected from the members of the groups (h1f) and (h2f) as defined below:
(h1f) hydrogen and hydroxy, or RA01 and R^02 combine to form an oxo-group,
(h2f) 0^3-alkoxy, -NRA04RA05; or
RA01 ancj RA02 combine to form a hydroxylamino-group; wherein one of the substituents RA01 and RA^2 js absent in case the dotted line repre- sents a double bond; wherein RA04 ancj RA05 naVe the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA04 ancj RA05 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 C3_g-cyclyl, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound 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 hydrogen, C-|.g-alkyl or -
CtCO-C-i.g-alkyl, Cg.14-aryl, NRA07RA08
C3.g-cyclyl,
-C(O)RA01° and -S(O)2RA01 1 ; or
RA04 ancj RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA012, O and S; wherein R^7 RA08 RA010 RA011 and RA012 nave (ne same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA04 ancj RA05 are each jnde- 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 selected from C3_g-cyclyl, 3- to 7-membered heterocyclyl, 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 hydrogen, C-|.g-alkyl or -
CtCO-C-i.g-alkyl, Cg.14-aryl,
NRA07RA08 C3.g-cyclyl,
-C(O)RA01° and -S(O)2RA01 1 ; or
RA04 ancj RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA012, O and S; wherein RA^^, RA08 RA010 RA011 and RA012 nave the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA^^ and RA08 are eacn independently selected from the group consisting of hydrogen and C-|.g-alkyl;
According to yet another embodiment of the present invention, RA^^ and RA08 are eacn jnde- pendently selected from the group consisting of hydrogen and C-j.β-alkyl;
According to yet another embodiment of the present invention RA010 JS selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-j.g-alkoxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by hydrogen or C-|.g-alkyl, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen or C-|.g-alkyl;
According to yet another embodiment of the present invention RA010 JS 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 hydroxy, C-j.β-alkoxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.β-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by hydrogen or C-j.β-alkyl, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen or C-j.β-alkyl;
According to another embodiment of the present invention RA01 1 JS NRA015RA016- wherein RA015 ancj RA016 naVe the same meanings as defined above, or preferably below. According to another embodiment of the present invention RA012 JS independently selected from the group consisting of hydrogen, C-j.β-alkyl or -C(O)-C-] .g-alkyl,
According to yet another embodiment of the present invention RA012 JS independently selected from the group consisting of hydrogen, C-j.β-alkyl or -C(O)-C-] .3-alkyl,
According to another embodiment of the present invention RA015 ancj RA016 are eacn independently selected from the group consisting of hydrogen or C-] .g-alkyl,
According to yet another embodiment of the present invention RA015 ancj RA016 are eacn jnc|e. pendently selected from the group consisting of hydrogen or C-j.β-alkyl,
According to yet another embodiment of the present invention, RA^ 1 and RA12 are each inde- pendently selected from the members of the groups (M b) and (i2b) as defined below:
(M b) hydrogen,
(i2b) hydroxy, C-|_6-alkyl, azido, halogen, -NRA13RA14, -C(O)O-C-|_6-alkyl; or RA11 and RA^ combine to form the group -O-CH2-CH2-O-; or
RA11 and RA^ combine to form an oxo-group; wherein one of the substituents RA^ ^ and RA^ js absent in case the dotted line represents a double bond; wherein RA^3 and RA^4 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA^ ^ and RA^ are each independently selected from the members of the groups (Mc) and (i2c) as defined below:
(M c) hydrogen,
(i2c) hydroxy, C-|_3-alkyl, azido, halogen, -NRA13RA14, -C(O)O-C-|_3-alkyl; or RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^ combine to form an oxo-group; wherein one of the substituents RA^ ^ and RA^ js absent in case the dotted line repre- sents a double bond; wherein RA13 ancj RA14 nave (ne same meanings as defined above, or preferably below.
According to another embodiment of the present invention RA^3 ancj RA14 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy, Cg.-14-aryl, C3.6-cyclyl, C6.14-aryl, wherein the Cg-^-aryl is optionally substituted with C-j.β-alkoxy,
-CORA18, wherein R^I 8 nas the same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention RA13 ancj RA14 are eacn jnc|epend- ently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-j.β-alkoxy, Cg-^-aryl, C3.6-cyclyl, Cβ.-|4-aryl, wherein the Cg.-14-aryl is optionally substituted with C-j.β-alkoxy,
-CORA18, wherein RA^8 nas the same meaning as defined above, or preferably below.
According to another embodiment of the present invention RA^8 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from hydroxy or C-j.g-alkoxy, or
According to yet another embodiment of the present invention RA^8 js 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 hydroxy or C-j.β-alkoxy, According to another embodiment of the present invention one of the substituents RA01 and RA02 and one of the substituents RA^ 1 and RA^2 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group;
According to yet another embodiment of the present invention, RA2^ and RA22 are each independently selected from the members of the groups (j1c) and (j2c) as defined below:
(j1 c) hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2c) hydroxy or C-j.β-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)NRA23RA24, and -NRA25RA26; or RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group; wherein one of the substituents RA2^ and RA22 is absent in case the dotted line represents a double bond; wherein RA2^ and RA2f^ have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA2^ and RA22 are each independently selected from the members of the groups (j1c) and (j2c) as defined below:
(j1d) hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2d) hydroxy or -NRA25RA26; or
RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group; wherein one of the substituents RA2^ and RA22 is absent in case the dotted line represents a double bond; wherein R^25 ancj RA26 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention RA^5 ancj RA26 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by Cg.-|4-aryl,
-(CH2)|CORA214; wherein I is 0, 1 and 2; wherein RA214 nas tne same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention RA^5 ancj RA26 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by Cg.-|4-aryl, -(CH2)|CORA214; wherein I is 0, 1 and 2; wherein RA214 nas fne same meaning as defined above, or preferably below.
According to another embodiment of the present invention RA214 JS selected from the group con- sisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy or C-|.g-alkoxy, C-|.g-alkoxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen, C-|.g-alkyl or -C(O)-C-] .g-alkyl, and
_NRA219RA220. wherein RA219 ancj RA220 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention RA214 JS se|ected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from hydroxy or C-j.β-alkoxy, C-j.β-alkoxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by hydrogen, C-j.β-alkyl or -C(O)-C-] .3-alkyl, and _NRA219RA220. wherein RA219 and RA220 nave tne same meanings as defined above, or preferably below.
According to another embodiment of the present invention RA219 ancj RA220 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from hydroxy or C-j.β-alkoxy,
According to yet another embodiment of the present invention RA219 ancj RA220 are each jnde- 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 selected from hydroxy or C-j.β-alkoxy,
According to yet another embodiment of the present invention, R^31 and R^32 are eacn independently selected from the members of the groups (k1 c) and (k2c) as defined below:
(k1c) hydrogen,
(k2c) hydroxy, C^-alkyl, -NRA35RA36; or
RA31 and RA32 combine to form an oxo-group; or
RA31 and RA32 combine to form the group -0-CH2CH2-O-; wherein one of the substituents RA31 and RA32 js absent in case the dotted line represents a double bond; wherein RA35 and RA36 nave the same meanings as defined above, or preferably below. According to yet another embodiment of the present invention, R^31 and R^32 are eacn jnc|e. pendently selected from the members of the groups (kid) and (k2d) as defined below:
(kid) hydrogen,
(k2d) hydroxy, C-|_3-alkyl, -NRA35RA36; or
RA31 and R^32 combine to form an oxo-group; or
RA31 and RA32 combine to form the group -0-CH2CH2-O-; wherein one of the substituents RA3^ and RA32 is absent in case the dotted line repre- sents a double bond; wherein RA35 ancj RA36 naVe the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA35 ancj RA36 are eacn independently selected from the group consisting of hydrogen, C-|_g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy, Cg.-14-aryl, C3.6-cyclyl,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by - 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;
-(CH2)k-C(O)-RA314 wherein k is 0, 1 and 2; wherein RA314 nas ^16 same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention, RA35 ancj RA36 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 selected from hydroxy, C-j.β-alkoxy, Cg.-14-aryl, C3.g-cyclyl,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-mennbered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by - C(O)-C-] .3-alkyl, wherein the -C(O)-C-] .3-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; -(CH2)k-C(O)-RA314 wherein k is 0, 1 and 2; wherein RA314 nas ^g same meaning as defined above, or preferably below.
According to another embodiment of the present invention, RA314 JS selected from the group consisting of hydroxy, C-|.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from hydroxy and NRA319RA32°,
NRA321 RA322 3. to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NRA323, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C; wherein RA3^9, RA320 RA321 RA322 ancj RA323 naVe the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA314 JS selected from the group consisting of hydroxy, C-] .3-alkyl, wherein the C-|_3-alkyl is optionally substituted by one or more substituents selected from hydroxy and NRA319RA32°, NRA321 RA322 3. to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NRA323, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C; wherein RA3^9, RA320 RA321 RA322 ancj RA323 nave the same meanings as defined above, or preferably below.
According to another embodiment of the present invention, RA319 ancj RA320 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl or -C(O)O-C-] .g-alkyl;
According to yet another embodiment of the present invention, RA319 ancj RA320 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl or -C(O)O-C-] .3-alkyl;
According to another embodiment of the present invention, RA321 ancj RA322 are each independently selected from the group consisting of hydrogen, C-] .g-alkyl;
According to yet another embodiment of the present invention, RA321 ancj RA322 are eacn jncje. pendently selected from the group consisting of hydrogen, C-j.β-alkyl;
According to another embodiment of the present invention, RA323 JS selected from the group consisting of hydrogen, C-|.6-alkyl, -C(O)-C1 _6-alkyl or -C(O)O-C -|.6-alkyl,
According to yet another embodiment of the present invention, RA323 JS selected from the group consisting of hydrogen, C-j.β-alkyl, -C(O)-C 1.3-alkyl or -C(O)O-C1.3-alkyl,
According to yet another embodiment of the present invention, R^41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
According to yet another embodiment of the present invention, R^51 JS selected from the group consisting of hydrogen, C-j.β-alkoxy, amino or
According to yet another embodiment of the present invention, R^41 and R^51 combine to form a group selected from -O-CH2-O-;
According to yet another embodiment of the present invention, R^61 is selected from the group consisting of hydrogen and halogen;
According to yet another embodiment of the present invention, R^71 js hydrogen;
According to yet another embodiment of the present invention, R^81 is hydrogen; According to yet another embodiment of the present invention, R^01 and R^02 are eacn jnc|e. pendently selected from the members of the groups (hi ) and (h2) as defined below: (hi ) hydrogen and hydroxy, or
RA01 ancj RA02 combine to form an oxo-group, (h2) Ci_6-alkoxy,
.NRA04RA05. or
RA01 ancj RA02 combine to form a hydroxylamino-group; wherein one of the substituents R^01 and R^02 js absent in case the dotted line represents a double bond; RA04 ancj RA05 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, C3.6-cyclyl, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA06,
C-|.-|3-heteroaryl, wherein the C-|.-|3-heteroaryl has at least one heteroatom selected from N,
O and S, and NRA07RA08
C3.6-cyclyl,
-C(O)RA01° and -S(O)2RA01 1 ; or RA04 ancj RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA012, O and S; RA07 ancj RA08 are eac|-| independently selected from the group consisting of hydrogen and C-j.g-alkyl,
RA09 js selected from the group consisting of hydrogen, C-|.g-alkyl, RA010 JS selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA09 ancj
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 RA09, and NRA013RA014.
RA011 JS NRA015RA016-
RA015 ancj RA016 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein RA1 1 and RA12 are each independently selected from the members of the groups (M ) and (i2) as defined below: (M ) hydrogen, (i2) hydroxy, C-|.g-alkyl, azido, halogen, -NRA13RA14, -C(O)O-C1. g-alkyl; or RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or RA11 and RA^ combine to form an oxo-group; wherein one of the substituents R^ 11 and RA12 JS absent in case the dotted line represents a double bond; RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, Cg.-14-aryl, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6_i4-aryl, wherein the Cβ.-|4-aryl is optionally substituted by one or more substituents selected from hydroxy, C-|.g-alkoxy,
-CORA18;
RA18 JS selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy; or one of the substituents R^01 and R^02 anc| one of the substituents R^ 11 and RA12 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group; wherein R^21 and R^22 are each independently selected from the members of the groups (j1 ) and (j2) as defined below: (j1 ) hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2) hydroxy,
-NRA25RA26; or
RA21 and RA22 combine to form the group -0-CH2CH2-O-; or RA21 and RA22 combine to form an oxo-group; wherein one of the substituents RA21 and RA22 js absent in case the dotted line represents a double bond;
RA25 ancj RA26 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, Cg-14-aryl, -(CH2)|CORA214; wherein I is 0, 1 and 2; or
RA214 js selected from the group consisting of hydrogen, hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, C-|.g-alkoxy,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA218 and _NRA219RA220. RA219 ancj RA220 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein R^31 and R^32 are each independently selected from the members of the groups (k1 ) and (k2) as defined below: (k1 ) hydrogen, (k2) hydroxy, C-|.g-alkyl,
-NRA35RA36; or
RA31 ancj RA32 combine to form an oxo-group; or RA31 and RA32 combine to form the group -0-CH2CH2-O-; wherein one of the substituents RA31 and RA32 js absent in case the dotted line represents a double bond;
RA35 ancj RA36 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, Cg--|4-aryl,
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 RA310 -(CH2)k-C(O)-RA314, wherein k is 0, 1 and 2;
RA37 RA310 RA311 ancj RA312 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, -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; RA314 js selected from the group consisting of hydroxy, C1. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy and NRA319RA32°,
NRA321 RA322 c3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NRA323, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C; RA319 ancj RA320 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, -C(O)O-C1.6-alkyl; RA321 ancj RA322 are hydrogen; RA323 js selected from the group consisting of hydrogen, C-|.g-alkyl, -C(O)-C1.6-alkyl,
-C(O)O-C1.6-alkyl; with the proviso that at least one of the substituents RA01 , RA02, RA1 1 , RA12, RA21 , RA22, RA31 and RA^2 is selected from a member of the groups (h2), (i2), (j2) and (k2); R^41 js selected from the group consisting of hydrogen, halogen and amino; RB51 JS selected from the group consisting of hydrogen, C-j.β-alkoxy, amino; or
RB41 and RB51 combine to form a group Of -O-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB71 and RB81 are hydrogen;
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide; 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydrochloride; 6-(1 ,3-Benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; 6-(3-Amino-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1- ylamine; 6-(4-Aminobenzyl)-3, 3-dimethyl-2, 3,4, 7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; Benzyl-tθ^-methoxy-benzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll-amine hydrochloride; [6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]- pyridin-2-ylmethyl-amine; lsopropyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-1-yl]-amine; 6-(4-Methoxybenzyl)-3,3-dimethyl-1 -pyrrolidin-1 -yl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; N-Cyclopentyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Ethyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Methyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-3,3- dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-amine; N'-[6-(4-Methoxybenzyl)-3,3- dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-N,N-dimethylpropane-1 ,3-diamine; 6-(4-Methoxybenzyl)-3,3-dimethyl-N-(tetrahydrofuran-2-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; θ^-MethoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i- one oxime; 2-Methoxy-N-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-yl]-acetamide; Morpholine-4-carboxylic acid [6-(4-methoxy-benzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-amide; N'-[6-(4-Methoxybenzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-N,N-dimethylsulfamide; N-[6-(4-Methoxybenzyl)- S^-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll^^-methylpiperazin-i-yOacetamide; (S^N-te^-MethoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll-i- methylprolinamide; 1-Methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinoline; 2-Bronno-6-(4-nnethoxybenzyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1-one; 2-Bronno-6-(4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 1 ,1- Dinnethoxy-6-(4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 2-Hydroxy-6-(4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one hydrochloride; 2-Bromo-6-(4- nnethoxybenzyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 6-(4-Methoxybenzyl)- 3,3-dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline; cis-6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-1 ,2-diol; 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 2-Amino-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 7-(4-Methoxybenzyl)-4,4-dimethyl-3,3a,4,5,8,12d- hexahydro-2H-indolo[2,3-c][1 ,3]oxazolo[5,4-f]quinolin-2-one; 6'-(4-Methoxybenzyl)-1',3',4',7'- tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; Ethyl 6-(4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-2-carboxylate; 6-(4-Methoxybenzyl)-2-methyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-4-nnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 6'-(3-Fluoro-4-methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; 6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; N-[6-(4-Methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-formamide; 6-(4-Methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; Cyclopropyl-[6-(3-fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-annine; Ethyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-2-yl]-(4-nnethoxy-phenyl)-annine; Benzyl-[6-(3-fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-(2-nnethoxy-ethyl)-annine; 6-(3-Fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; N-[6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-2-methoxy-acetamide; 6'-(3-Fluoro-4-methoxybenzyl)- 1',2',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,3'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolo^.S-clquinolin-S-one^-te^S-Fluoro^-methoxy-benzyl^.S^J- tetrahydro-I H-indolo^.S-clquinolin-S-ylanninol-acetannide; [6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylannino]-acetic acid methyl ester; Benzyl-[6-(3-fluoro-4- methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-annine; N-2-[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-N~2~-nnethylglycinannide; 6-(3- Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylannine; [6-(3-Fluoro-4- nnethoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-carbannic acid ethyl ester; N-tθ^S-Fluoro^-methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll^-methoxy- acetamide; N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]- acetamide; Morpholine-4-carboxylic acid [6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-amide; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- cjquinolin-S-ylanninol-acetic acid; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-N-methylglycinannide; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-N-isopropylglycinamide; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-N-^-hydroxypropyllglycinannide (mixture of diastereoisomers); N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-3-yl]-N-(2-hydroxyethyl)glycinamide; 6'-(3-Fluoro-4-methoxybenzyl)-1',2',3',7'- tetrahydrospiro[1 ,3-dioxolane-2,4'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)-1 , 2,3,7- tetrahydro-4H-indolo[2,3-c]quinolin-4-one; 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-2-ol; 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ol; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-ol; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinannide; N-Ethyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-annine; N-Cyclopropyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-annine; 2-{[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]annino}ethanol; N-(1- Acetylpiperidin^-y^-Θ^S-fluoro^-nnethoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^- amine; 2-(4-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]amino}- piperidin-1-yl)-2-oxoethanol; (4RS)-N-[(3S)-1-Acetylpiperidin-3-yl]-6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; (4RS)-N-[(3R)-1-Acetylpiperidin-3-yl]-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-(1-Acetylazetidin- 3-yl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-amine; N-Benzyl- 6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-1-methylpiperidine-4- carboxamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]acetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-2- hydroxyacetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]-N-2-,N-2-dimethylglycinamide; (2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-4-yl]amino}-2-oxoethyl)carbamate; 1-Acetyl-N-[6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]piperidine-4-carboxamide; 3-{[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllcarbamoylJazetidine-i-carboxylate; N-tθ^S-Fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinamide; 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline; 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
N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide; 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydrochloride; 6-(1 ,3-Benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; 6-(3-Amino-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1- ylamine; 6-(4-Aminobenzyl)-3, 3-dimethyl-2, 3,4, 7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; Benzyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-amine hydrochloride; [6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]- pyridin-2-ylmethyl-amine; lsopropyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-1-yl]-amine; 6-(4-Methoxybenzyl)-3,3-dimethyl-1 -pyrrolidin-1 -yl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; N-Cyclopentyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Ethyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Methyl-6-(4-methoxybenzyl)-3,3-dimethyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-3,3- dimethyl-2, 3,4, 7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N'-[6-(4-Methoxybenzyl)-3,3- dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-N,N-dimethylpropane-1 ,3-diamine; 6-(4-Methoxybenzyl)-3,3-dimethyl-N-(tetrahydrofuran-2-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; θ-^-Methoxybenzy^-S.S-dimethyl^S^J-tetrahydro-I H-indolo^S-clquinolin-i- one oxime; 2-Methoxy-N-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-yl]-acetamide; Morpholine-4-carboxylic acid [6-(4-methoxy-benzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-amide; N'-[6-(4-Methoxybenzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-N,N-dimethylsulfamide; N-[6-(4-Methoxybenzyl)- S^-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yl^^-methylpiperazin-i-y^acetamide; (S^N-tθ^-MethoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll-i- methylprolinamide; 1-Methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinoline; 2-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1-one; 2-Bromo-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 1 ,1- Dimethoxy-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 2-Hydroxy-6-(4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one hydrochloride; 2-Bromo-6-(4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 6-(4-Methoxybenzyl)- 3,3-dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline; cis-6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-1 ,2-diol; 2-Azido-6-(4-methoxybenzyl)-3, 3-dimethyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 2-Amino-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 7-(4-Methoxybenzyl)-4,4-dimethyl-3,3a,4,5,8,12d- hexahydro-2H-indolo[2,3-c][1 ,3]oxazolo[5,4-f]quinolin-2-one; 6'-(4-Methoxybenzyl)-1',3',4',7'- tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; Ethyl 6-(4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-2-carboxylate; 6-(4-Methoxybenzyl)-2-methyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-4-nnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 6'-(3-Fluoro-4-methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; 6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; N-[6-(4-Methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-formamide; 6-(4-Methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; Cyclopropyl-[6-(3-fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; Ethyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-2-yl]-(4-methoxy-phenyl)-amine; Benzyl-[6-(3-fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-(2-methoxy-ethyl)-annine; 6-(3-Fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; N-[6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-2-methoxy-acetannide; 6'-(3-Fluoro-4-methoxybenzyl)- 1',2',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,3'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)- I ^^J-tetrahydro-SH-indolop.S-clquinolin-S-one^-^S-Fluoro^-methoxy-benzyO^.S^J- tetrahydro-I H-indolo^S-clquinolin-S-ylaminol-acetamide; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7- tetrahydro-I H-indolo^.S-clquinolin-S-ylanninol-acetic acid methyl ester; Benzyl-[6-(3-fluoro-4- methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-annine; N-2-[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-N~2 — methylglycinamide; 6-(3- Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylannine; [6-(3-Fluoro-4- methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-carbannic acid ethyl ester; N-tθ^S-Fluoro^-methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll^-methoxy- acetamide; N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]- acetamide; Morpholine-4-carboxylic acid [6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-amide; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-3-ylamino]-acetic acid; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-N-methylglycinamide; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7- tetrahydro-I H-indolo^.S-clquinolin-S-yll-N-isopropylglycinamide; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-N-^-hydroxypropyllglycinamide (mixture of diastereoisomers); N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-3-yl]-N-(2-hydroxyethyl)glycinamide; 6'-(3-Fluoro-4-methoxybenzyl)-1',2',3',7'- tetrahydrospiro[1 ,3-dioxolane-2,4'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)-1 , 2,3,7- tetrahydro-4H-indolo[2,3-c]quinolin-4-one; 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-2-ol; 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ol; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-ol; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinamide; N-Ethyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-Cyclopropyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; 2-{[6-(3-Fluoro-4- methoxybenzyl^S^J-tetrahydro-I H-indolo^S-clquinolin^-yljaminoJethanol; N-(1- Acetylpiperidin-4-yl)-6-(3-fluoro-4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- amine; 2-(4-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]annino}- piperidin-1-yl)-2-oxoethanol; (4RS)-N-[(3S)-1-Acetylpiperidin-3-yl]-6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; (4RS)-N-[(3R)-1-Acetylpiperidin-3-yl]-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-annine; N-(1-Acetylazetidin- 3-yl)-6-(3-fluoro-4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-annine; N-Benzyl- 6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-annine; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-annine; N-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yll-i-nnethylpiperidine^- carboxamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]acetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-2- hydroxyacetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]-N-2-,N-2-dimethylglycinamide; (2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-4-yl]amino}-2-oxoethyl)carbannate; 1-Acetyl-N-[6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]piperidine-4-carboxannide; 3-{[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllcarbannoylJazetidine-i-carboxylate; N-^S-Fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinannide, 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, a compound with the chemical name 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
Wherever two substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen, one of the substituents may be hydrogen and the other may have a meaning as defined.
In addition to the compounds exemplified herein and the specific substituent combinations mentioned above, the present invention expressly pertains to all compounds that can be derived from each and every combination of the specific meanings of substituents and other variable groups characterized above as embodiments of the present invention, with the proviso that at least one of the substituents RA01 , RA02, RA1 1 , RA12, RA21 , RA22, RA31 and RA32 is selected from a member of the groups (h2), (h2a), (h2b), (h2c), (h2d), (i2), (i2a), (j2), (J2a), (J2b), (k2) and (k2a).
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 and a bromine atom are preferred. The term "Ci_5-alkyl" used in the specification of the present application indicates linear or branched alkyl groups having 1 to 6 carbon atoms. Among these, linear or branched alkyl groups having 1 to 4 carbon atoms (C-|_4-alkyl) are preferred, linear or branched alkyl groups having 1 to 3 carbon atoms (C-j.β-alkyl) are more preferred and alkyl groups having 1 to 2 carbon atoms (C-] _2- alkyl) are still more preferred. In the same way, the term "C^-alkyl" used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms. Examples of the above-defined alkyl groups include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n- pentyl group, a 1 ,1-dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1 ,3- dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group or a n-hexyl group. More 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 indicates cycloalkyl groups having 3 to 6 carbon atoms. Examples of the Cβ.β-cyclyl group 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. More preferred examples are a pyrrolidinyl group, a piperidinyl group, a tetrahydrofuranyl group and an acetidyl group.
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 morpholinyl 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-|.g-alkyl, preferably methyl; C-|.g-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo. The Cg^-aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. Among the above examples, a phenyl group is more preferred.
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-membered aromatic heterocyclic group which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In 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 op- tionally 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, pref- erably 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 pyridinyl group is more preferred.
The above-mentioned C-j.g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C-j.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocy- clyl, Cg.-|4-aryl, C-|.-|3-heteroaryl, an amine, such as defined, for instance, for NRA07RA08 wherein the C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg.-14-aryl and C-|_-| 3- 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 hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-isopropyl, 2- hydroxy-isopropyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl and 3-hydroxy-n-propyl, wherein a hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-isopropyl and 2-hydroxy-n-propyl are still more preferred, and hydroxymethyl is particularly preferred.
In case the C-|.g-alkyl group is substituted by at least one C-|.g-alkoxy, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the C-|.g-alkoxy group can be any group as specified above for C-|.g-alkoxy, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the C-|.g-alkyl is substituted one C-|.g-alkoxy.
Particlulary preferred are a methoxymethyl group and a 2-methoxyethyl group.
In case the C-|.g-alkyl group is substituted by at least one Cβ.g-cyclyl, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the Cβ.g-cyclyl group can be any group as specified above for Cβ.g-cyclyl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the 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.
In case the C-|.g-alkyl group is substituted by at least one Cg.-14-aryl, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-|.g-alkyl is substituted one Cg.-14-aryl. Particularly preferred is a benzyl group.
In case the C-|.g-alkyl group is substituted by at least one C-ι.-13-heteroaryl, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the C-|.-|3-heteroaryl group can be any group as specified above for C-ι.-13-heteroaryl, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-j.-iβ- heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring se- lected from N, O or S. Further preferred is that the C-|.g-alkyl is substituted by one C-j.-iβ- heteroaryl. Particularly preferred is a pyridylmethyl group.
In case the C-|.g-alkyl group is substituted by at least one amine or amide group, the C-|.g-alkyl group can be any group as specified above with respect to C-|.g-alkyl, unless specified otherwise. Similarly, the amine or amide group can be any group as specified above for amine or amide, unless specified otherwise. The C-|.g-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom.
The above-mentioned C-|.g-alkoxy group may be substituted with one or more substituents se- lected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-membered heterocyclyl, Cg.-14-aryl, C-ι.-13-heteroaryl and an amine, wherein the C-|.g-alkoxy, Cβ.g-cyclyl, 3- to 7-nnennbered heterocyclyl, Cg.-14-aryl and C-ι.-13-heteroaryl have the same meanings as defined above.
In case the C-j.g-alkoxy group is substituted by at least one fluorine atom, the C-j.g-alkoxy group can be any group as specified above with respect to C-j.g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C-j.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-1.3- alkoxy groups substituted with at least one hydroxy group include hy- droxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1- hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2- hydroxyethoxy, 2-hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
In case the C-|.g-alkoxy group is substituted by at least one another C-|.g-alkoxy, both C-|.g-alkoxy groups can be any group as specified above with respect to C-|.g-alkoxy. The first mentioned C-|.g- alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the other C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom. Further preferred is that the first mentioned C-|.g-alkoxy is substituted by one other C-|.g-alkoxy. Particulary preferred are a methoxymethoxy group, a ethoxymethoxy group, a 2-methoxyethoxy group and a 2-ethoxyethoxy group.
In case the C-|.g-alkoxy group is substituted by at least one C3_g-cyclyl, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. Similarly, the C3_g-cyclyl group can be any group as specified above for C3_g-cyclyl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cβ.g-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C-|_g-alkoxy is substituted by one Cβ.β-cyclyl. Particluarly preferred is a cyclopropylmethoxy group.
In case the C-|.g-alkoxy group is substituted by at least one 3- to 7-membered heterocyclyl, the C-|. ρ-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. Similarly, the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more pref- erably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5- membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C-|.g-alkoxy is substituted by one 3- to 7-membered heterocyclyl.
In case the C-|.g-alkoxy group is substituted by at least one Cg.-14-aryl, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified otherwise. Similarly, the Cg.-14-aryl group can be any group as specified above for Cg.-14-aryl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the Cg.-14-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C-|.g-alkoxy is substituted by one Cg.-14-aryl. Particularly preferred is a benzyloxy group.
In case the C-|.g-alkoxy group is substituted by at least one C-ι.-13-heteroaryl, the C-|.g-alkoxy group can be any group as specified above with respect to C-|.g-alkoxy, unless specified other- wise. Similarly, the C-ι.-13-heteroaryl group can be any group as specified above for C-j.-iβ- heteroaryl, unless specified otherwise. The C-|.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C-j.-iβ-heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C-|.g-alkoxy is substituted by one C-|. 13-heteroaryl. Particularly preferred is a pyridylmethoxy group.
The above-mentioned Cβ.g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy. In case the Cβ.g-cyclyl group is substituted by one or more fluoro, the Cβ.g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The C3.5- 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 selected from fluoro and hydroxy, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more fluoro, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocyclyl, wherein the mono-, di- and perfluoro substituted 3- to 7-membered heterocyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocyclyl groups.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more hydroxy, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7- membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group sub- stituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents se- lected 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)-C1 _g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C1 _g-alkyl is -C(O)-CH3 and - C(O)-CH2OH.
The above-mentioned 3- to 7-membered heterocycle may be substituted with one or more sub- stituents selected from the group consisting of fluoro, hydroxy, C-|.g-alkoxy, amide, hydrogen, C-].
6-alkyl and -C(O)-C1 _g-alkyl.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy and amide, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocycle is substituted by one or more fluoro, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
In case the 3- to 7-membered heterocycle is substituted by one or more hydroxy, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C-|_g-alkyl and -C(O)-C1.g-alkyl, the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. Similarly the C-|.g-alkyl group and the C-|.g-alkyl moiety of the -C(O)-C1. g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C1. g-alkyl. It is preferred that the substituent(s) hydrogen, C-|.g-alkyl and -C(O)-C1. g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C1. g-alkyl is -C(O)-CH3 and -C(O)-CH2OH.
It is to be understood that the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof. It is to be understood that the invention covers all combinations of substituent groups referred to hereinabove. In particular, the invention covers all combinations of preferred groups described herein.
Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
Examples of acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D- gluconates and L-gluconates, glucuronates including D-glucuronates and L-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 imgf000069_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^1 and RAy2, wherein x = y and x, y = 0, 1 , 2, or 3, are different from one another, the compounds according to the invention, the salts thereof, the N- oxides of the compounds and the salts thereof have one or more stereogenic centers. Each of said stereogenic centers may have the absolute configuration R or the absolute configuration S (according to the rules of Cahn, lngold and Prelog). Accordingly, the stereoisomers (1 R), (1S), (2R), (2S), (3R), (3S), (4R), (4S), (1 R,2R), (1 R,2S), (1S,2R), (1S,2S), (1 R,3R), (1 R,3S), (1S,3R), (1S,3S), (1 R,4R), (1 R,4S), (1S,4R), (1S,4S), (2R,3R), (2R,3S), (2S,3R), (2S,3S), (2R,4R), (2R,4S), (2S,4R), (2S,4S), (3R,4R), (3R,4S), (3S,4R) and (3S,4S), wherein the numbers refer to the atoms indicated in formula (Ib) below,
Figure imgf000069_0002
as well as all possible permutations for 3 and 4 stereogenic centers, the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
Furthermore, derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
The compounds according to the invention can be prepared as follows.
As shown in reaction scheme 1 , a compound of formula (I) can be obtained by reacting a compound of formula (II) or (Na) or (lib) or a mixture thereof with ammonia in an appropriate solvent, e.g. acetonitrile, preferably under microwave heating. The compound of formula (II) or (Ma) or (Mb) or a mixture thereof can be prepared by cyclization of a compound of formula (IV) with a compound of formula (III) in the presence of a strong inorganic acid, e.g. perchloric acid, in a suitable solvent, e.g. nitromethane.
Compounds of formula (III) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 1 :
Figure imgf000071_0001
Figure imgf000071_0002
In an alternative procedure, as illustrated in reaction scheme 2, a compound of formula (IV) can be reacted with a compound of formula (Vl), in which X is a suitable leaving group, e.g. halogen, such as chlorine, or a conjugate base of an acid, such as trifluoroacetate, in a Friedel-Crafts acylation reaction in the presence of an appropriate Lewis acid, e.g. zinc chloride, boron trifluoride etherate or orthophosphoric acid, in a suitable solvent, e.g. dichloromethane, dichloroethane, diethylether, toluene, nitromethane and/or chlorobenzene, to give the corresponding compound of formula (II) or (Na) or (Mb) or a mixture thereof. Said Friedel-Crafts acylation reaction can be based on, for example, work of Duval et al. [see e.g. Tetrahedron Letters 45, 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 imgf000072_0001
Figure imgf000072_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 imgf000072_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 (IV) can be obtained as shown in reaction scheme 4. In particular, indole (Xl) can be reacted with a compound of formula (X) in an art-known nucleophilic substitution reaction [see e.g. Heterocycles 31 (8), 1497-1504 (1990)]. The resulting hydroxy- compound of formula (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroace- tic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 4:
Figure imgf000073_0001
The compounds of formula (X) and indole (Xl) are known, commercially available or can be obtained according to known procedures.
Alternatively, a compound of formula (IV) can be obtained as illustrated in reaction scheme 5. In a first step, indole (Xl) is reacted with a compound of formula (XII) in an art-known oxidative coupling reaction [see e.g. JACS 129, 12857 (2007)], in the presence of a suitable base, e.g. lithium diiso- propylamide or lithium hexamethyldisilazide, and a suitable oxidation agent, e.g. copper(ll)-2- ethylhexanoate. The thus obtained compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 5:
Figure imgf000074_0001
(Xl) (XII) (IV)
Indole (Xl) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
Moreover, a compound of formula (IV) can be obtained as illustrated in reaction scheme 6. In a first step, indole (Xl) is reacted with a compound of formula (XIII) in an art-known condensation reaction in the presence of a base, e.g. pyrrolidine or potassium hydroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 3099 (2007)]. The thus obtained unsaturated compound of formula (XIV) can be hydroxylated in a hydroboration - oxidation reaction known to the person skilled in the art, e.g. by using borane and sodium hydroxide / hydrogen peroxide [see e.g. Bioorganic & Medicinal Chemistry Letters 16, 3524 (2006)]. The resulting hydroxy-com pound (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 6:
Figure imgf000074_0002
(Xl) (XIII) (XIV) (V)
Figure imgf000074_0003
(IV) Indole (Xl) is commercially available, compounds of formula (XIII) are known, commercially available or can be obtained according to known procedures.
As an alternative approach, a compound of formula (IV) can be obtained as illustrated in reaction scheme 7. In a first step, isatine (XV) is reacted with a compound of formula (XII) in an art-known aldol addition reaction [see e.g. Tetrahedron 58, 8399 (2002)]. The thus obtained hydroxy compound of formula (XVI) can be transformed into compounds of formula (V) by using reductive agents, such as, for example, borane tetrahydrofuran complex or lithium aluminium hydride [see e.g. Tetrahedron 58, 8399 (2002)]. The resulting hydroxy-com pound of formula (V) can be oxidized in a manner known to the skilled person, e.g. according to a Swern oxidation [see e.g. Tetrahedron 47, 8653 (1991 )] or a variant thereof using trifluoroacetic anhydride as activator [see e.g. J. Org. Chem. 41 , 957 (1976)] or by utilizing sulfur trioxide pyridine complex as oxidizing agent [see e.g. Organic Process Research & Development 10, 163 (2006)], to give the corresponding compound of formula (IV). The compound of formula (IV) can be reacted according to reaction scheme 1 or 2 to give a compound of formula (I).
Reaction scheme 7:
Figure imgf000075_0001
(XV) (XII) (XVI) (V)
Figure imgf000075_0002
(IV)
Isatine (XV) is commercially available, compounds of formula (XII) are known, commercially available or can be obtained according to known procedures.
An alternative synthetic route to compounds of formula (Ic) is depicted in reaction scheme 8. Com- pounds of formulae (XVII), (XVIII) and (XIX), with X being a leaving group, such as halogen, preferably bromine or chlorine, can be reacted in a multi-component unsymmetric Hantzsch reaction in the presence of catalytic amounts of acid, e.g. acetic acid, and amine, e.g. benzylamine [see e.g. Tetrahedron Letters 42, 4507 (2001 ) or Tetrahedron 63, 1946 (2007)]. The resulting nitro- dihydropyridine of formula (XX) can be converted to amino-pyridine of formula (XXI) either in two steps (oxidation of dihydropyridine and reduction of nitro group) or, preferably, in one step by using, e.g., elementary iron in the presence of concentrated hydrochloric acid or elementary zinc in the presence of acetic acid. The final ring closing reaction to obtain compounds of formula (Ic) can be achieved by reacting compounds of formula (XXI) under nitrogen atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or tetrakis(triphenylphosphine)palladium (0), and, if necessary, of a suitable phosphine ligand, in the presence of a suitable base, e.g. sodium tert-butoxide or sodium carbonate [see e.g. Bioorganic & Medicinal Chemistry Letters 17, 1043 (2007)].
Reaction scheme 8:
Figure imgf000076_0001
(XXI) (Ic)
Compounds of formulae (XVII), (XVIII) and (XIX) are known, commercially available or can be obtained according to known procedures.
As an example, compounds of formula (XIX) can be obtained, as shown in reaction scheme 9, by reacting the corresponding acids of formula (XXII) with carbonyl diimidazole in the presence of nitromethane and a suitable base, e.g. potassium tertbutylate [see e.g. J. Am. Chem. Soc. 125, 157 (2003)].
Reaction scheme 9:
Figure imgf000076_0002
(XXII) (XIX) Compounds of formula (XXII) are known, commercially available or can be obtained according to known procedures.
Compounds of formula (I) can be converted into different compounds of formula (I) by methods known in the art. For example,
• a compound of formula (I), wherein one or more R1^1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y, combine to form, together with the carbon atom, that they are attached to, a 1 ,3-dioxolane ring, wherein the single carbon atom in between the two oxygen atoms ("C2") is the carbon atom, that the substituents RAx1 and RAy2, wherein x = y, are attached to, by acetal hydrolysis reaction, e.g. using a suitable acid, such as hydrochloric acid, in the presence of water and a suitable solvent, such as tetrahydrofuran or dioxan;
• a compound of formula (I), wherein one or more R1^1 is hydroxy and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as sodium borohydride;
• a compound of formula (I), wherein one or more R^1 is hydrogen and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as hydrazine (e.g. according to a Wolff-Kishner reduction);
• a compound of formula (I), wherein one or more R^1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, by reductive amidation reaction, e.g. with the aid of a suitable amide, e.g. formamide, in combination with a suitable reduction agent, such as formic acid or ammonium formiate in a suitable solvent, e.g. formic acid, at elevated temperatures, preferably 14O0C - 18O0C, followed by amide hydrolysis reaction, e.g. with the aid of a strong acid, such as hydrogen chloride, in a suitable solvent, such as methanol;
• a compound of formula (I), wherein one or more R1^1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, by reductive amination reaction, e.g. with the aid of a suitable amine, e.g. benzylamine, in combination with a suitable reduction agent, such as sodium cyanoborohydride or sodium borohydride, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by hydrogenation, e.g. with the aid of a transition metal catalyst, such as palladium(O), in combination with a suitable hydrogen source, e.g. hydrogen gas or ammonium formiate, in a suitable solvent, such as methanol;
• a compound of formula (I), wherein one or more R1^1 is substituted amino, e.g. -NRA04RA05 (x =
0) and/or -NRA13RA14 (x = 1 ) and/or -NRA25RA26 (x = 2) and/or -NRA35RA36 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding R^1 and RAy2, wherein x = y and x, y = 0, 1 , 2 and / or 3, combine to form an oxo group, by imine (imminium) formation reaction, with the aid of the corresponding amine, i.e. HNRA04RA05 (x = 0) or HNRA13RA14 (x = 1 ) or HNRA25RA26 (x = 2) or HNRA35RA36 (x = 3), respectively, in the presence of a suitable acid, e.g. acetic acid or p- toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by reduction, e.g. with the aid of a suitable reduction agent, such as sodium cyanoborohydride, in a suitable solvent, e.g. methanol and/or ethanol. Preferably, these two steps are conducted in one pot, without isolation of intermediate imine or imminium compounds; • a compound of formula (I), wherein one or more R1^1 is carbonylamino-, e.g. -NH-C(O)-RA01°
(x = 0) and/or -NH-C(O)-RA18 (x = 1 ) and/or -NH-C(O)-RA214 (x = 2) and/or -NH-C(O)-RA314 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reaction with an appropriate carboxylic acid chloride, e.g. RA010C(O)CI (x = 0) and/or RA18C(O)CI (x = 1 ) and/or RA214C(O)CI (x = 2) and/or
RA314C(O)CI (x = 3), or carboxylic anhydride, e.g. (RA010C(O))2O (x = 0) and/or (RA18C(O))2O (x =
1 ) and/or (RA214C(O))2O (x = 2) and/or (RA314C(O))2O (x = 3), in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid, e.g. RA010C(O)OH (x = 0) and/or RA18C(O)OH (x = 1 ) and/or RA214C(O)OH (x = 2) and/or RA314C(O)OH (x = 3), 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 one or more R^1 is sulfonylamino, e.g. -NH-SO2-RA011 (x = 0) and/or -NH-SO2-RA19 (x = 1 ) and/or -NH-SO2-RA213 (x = 2) and/or -NH-SO2-RA313 (x = 3), and
RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reaction with an appropriate sulfonyl chloride, e.g. RA011SO2CI (x = 0) and/or RA19SO2CI (x = 1 ) and/or RA213SO2CI (x = 2) and/or RA313SO2CI (x = 3), in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate;
• a compound of formula (I), wherein one or more R^1 is sulfamoylamino, e.g. -NH-SO2- NR AOI5 R AOI6 (χ = 0) and/or _NH-SO2-NRA121RA122 (x = 1 ) and/or -N H-SO2-N RA215RA216 (x = 2) and/or -N H-SO2-N RA317RA318 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reaction with an appropriate sulfamoyl chloride, e.g. RA015RA016NSO2CI (x = 0) and/or RA121RA122NSO2CI (x = 1 ) and/or RA215RA216NSO2CI (x = 2) and/or RA317RA318NSO2CI (x = 3), in the presence of a base, e.g. triethylamine or pyridine, and a catalytic amount of an appropriate pyridine, e.g. A- dimethylamino pyridine;
• a compound of formula (I), wherein one or more R1^1 is carbamoylamino, e.g. -NH-C(O)- NR AOI3 R AOI4 (χ = 0) and/or _NH-C(O)-NRA119RA12° (X = 1 ) and/or -NH-C(O)-NRA219RA220 (x = 2) and/or -NH-C(O)-NRA321RA322 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding R^1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reaction with an appropriate amine carbonyl chloride, e.g. RA013RA014NC(O)CI (x = 0) and/or RA119RA120NC(O)CI (x = 1 ) and/or RA219RA220NC(O)CI (x = 2) and/or RA321RA322NC(O)CI (x = 3), in the presence of a base, e.g. triethylamine or pyridine, and, optionally, a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine; • a compound of formula (I), wherein one or more R1^1 represents -NH-C(O)-NH2 and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be obtained e.g. from a compound of formula (I), wherein the corresponding R^1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, 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 one or more R^1 is alkoxycarbonylamino, -NH-C(O)-
OC-|.6alkyl, wherein C-|.6alkyl may be optionally substituted as defined above for the individual RAx1, and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 is amino and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reaction with an appropriate formic acid ester chloride Ci_6alkylOC(O)CI, wherein d_6alkyl may be optionally substituted as defined above for the individual R^1, in the presence of a base, e.g. triethylamine or pyridine, and, optionally, a catalytic amount of an appropriate pyridine, e.g. 4-dimethylamino pyridine;
• a compound of formula (I), wherein one or more R^1 is carbamoyl, e.g. -C(O)N RA15RA16 (x = 1 ) or -C(O)NRA23RA24 (x = 2) or -C(O)N RA33RA34 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 1 , 2 or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding
RAx1 is alkoxycarbonyl, -C(O)-OC-|.3alkyl, and RAy2 is hydrogen, wherein x = y and x, y = 1 , 2 or 3, by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan and / or water, followed by amide formation reaction with an appropriate amine, e.g. HNRA15RA16 (x = 1 ) or HNRA23RA24 (x = 2) or HNRA33RA34 (x = 3), in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodi- imide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole; • a compound of formula (I), wherein one or more R1^1 is carbamoyl-C-i.-alkylamino, e.g. -NRA26- (CH2),C(O)NRA219RA22° (x = 2) or -NRA36-(CH2)kC(O)NRA321RA322 (x = 3), and RAy2 is hydrogen, wherein x = y and x, y = 2 or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 2 or 3, combine to form an oxo group, by imine (imminium) formation reaction, with the aid of the corresponding carbamoyl-Ci-2-alkyl- amine, i.e. HNRA26-(CH2),C(O)NRA219RA220 (x = 2) or HNRA36-(CH2)kC(O)NRA321RA322 (x = 3), e.g. H2NCH2C(O)NH2, in the presence of a suitable acid, e.g. acetic acid or p-toluenesulfonic acid, or a suitable Lewis acid, e.g. titanium(IV) tetraisopropyl oxide, in a suitable solvent, e.g. methanol, followed by reduction, e.g. with the aid of a suitable reduction agent, such as sodium cyanoborohydride, in a suitable solvent, e.g. methanol and/or ethanol; alternatively, such a compound can be obtained by reaction of a compound of formula (I), wherein the corresponding RAx1 and RAy2, wherein x = y and x, y = 2 or 3, combine to form an oxo group, with an appropiate amino-C-|.2-alkyl-C-|.3alkylester, i.e. HNRA26-(CH2)|C(O)OC-|.3-alkyl (x = 2) or HNRA36-(CH2)kC(O)OCi-3-alkyl (x = 3), e.g. H2NCH2CO2CH3, in a reductive amination reaction as described above, followed by ester hydrolysis, e.g. with the aid of an alkaline hydroxide, preferably lithium hydroxide, sodium hydroxide or potassium hydroxide, in an appropriate solvent, e.g. tetrahydrofuran, dioxan and / or water, followed by amide formation reaction with an appropriate amine, e.g. HNRA219RA220 (x = 2) or HNRA321RA322 (x = 3), in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1- hyd roxy be nzotriazo Ie ;
• a compound of formula (I), wherein one or more R^1 is alkoxy-, -OCi-6-alkyl, wherein said OC-ι-6-alkyl may be optionally substituted as described above for each individual R^\ and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, can be prepared e.g. from a compound of formula (I), wherein the corresponding R1^1 is hydroxy and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by alkylation reaction, with the aid of the corresponding electrophilic reagent C-|.6-alkyl-X, wherein X represents halide, preferably iodine or bromine or chlorine, or a conjugate base of an acid, such as methylsulfonate, and wherein said Ci_6-alkyl may be optionally substituted as described above for each individual R^\ in the presence of a suitable base, e.g. sodium hydride, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran;
• a compound of formula (I), wherein one or more R1^1 is hydroxyalkyl, -C-|.3-alkyl-OH, and RAy2 is hydrogen, wherein x = y and x, y = 1 , 2 and / or 3, can be prepared from a compound of formula (I), wherein the corresponding RAx1 is -C0-2-alkyl-C(O)OCi_3-alkyl, and RAy2 is hydrogen, wherein x = y and x, y = 0, 1 , 2 and / or 3, by reduction reaction, e.g. with the aid of a suitable reduction agent, such as lithium aluminium hydride, in a suitable solvent, such as tetrahydrofuran or diethyl ether;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a nitro group can be converted into the corresponding amino compound by reduction reaction, e.g. with the aid of a suitable reduction agent, such as tin dichloride or hydrogen gas and a palladium on carbon catalyst;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represent(s) a group -NH-C(O)-Ci_2-alkyl can be prepared e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents an amino group by reaction with an appropriate carboxylic acid chloride or carboxylic anhydride, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents -NH-C(O)-NH2 can be obtained e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 represents an amino group by reaction with potassium cyanate in the presence of a mineral acid, such as hydrochloric acid, or by condensation with urea;
• a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is hydroxy can be synthesized e.g. from a compound of formula (I), wherein RB41 and/or RB51 and/or RB61 and/or RB71 and/or RB81 is C-|.3-alkoxy by dealkylation with a Lewis acid, such as boron tribromide.
It is known to the person skilled in the art that, if there are a number of reactive centers on a starting or intermediate compound, it may be necessary to block one or more reactive centers temporarily by protective groups in order to allow a reaction to proceed specifically at the desired reaction center.
Starting materials or building blocks, that are necessary for the synthesis of compounds according to the invention are either commercially available, or are prior art, or can be synthesized by a person skilled in the art, or are described within this document as an example or as a general methodology.
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. ammonia, trimethylamine or methylamine. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceuti- cally 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 bo- ronic acid and L-tartaric acid in the presence of a dehydrating agent such as calcium hydride, preferably at temperatures of 60-800C.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure 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. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enanti- omeric 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 suit- able method for the isolation of enantiomers is the enzymatic separation.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.
The compounds which are mentioned in the examples, the salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof represent preferred embodiments of the invention.
Examples
1H nmr spectra are recorded on a Bruker DPX200 (1H 200 MHz), a Bruker Avance (1H 300 MHz) or a Bruker AV400 (1H 400 MHz) spectrometer. Spectra are calibrated on tetramethylsilane (TMS) as internal standard (0.00 ppm for 1H). Chemical shifts are given in ppm (δ) relative to TMS, multiplicities are indicated by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multi- plet) and b (broadened). Coupling constants, J, are reported in Hz. Data are reported in the form δ = chemical shift (multiplicity, (coupling constant(s) if appropriate), integral in fold of 1 H). If appropriate, reasons for multiple peaks (e.g. 2s) are given in square brackets behind the integral (e.g. [rotamers] or [diastereomers]).
Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology. Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode. Data are reported in the form MS (ionized particle found) = m/z. In that context, the molecule is abbreviated by M. For compounds containing bromine, both isotopic forms are reported, for compounds containing chlorine and all other elements, only the major isotopes are reported. Melting points, mp., are measured on a Bϋchi B-540 or a Bϋchi B-541 instrument and are uncor- rected.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE: di- chloroethane, THF: tetrahydrofuran, mp.: melting point, RT: room temperature (20 to 250C), tic: thin layer chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spec- troscopy.
Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 15O0C in a vacuum of 10~1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments. The temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments. The reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal tem- perature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
Purchased chemicals and solvents are used without further purification.
Column chromatography is performed using silica gel 60 (0.040 - 0.063 mm), pH 6.5 - 7.5, from Merck KGaA or amino modified silica gel Bulk Isolute® Sorbent Flash NH2 60 (0.040 - 0.070 mm) from International Sorbent Technology Ltd. If pressure (max. 0.3 bar) is applied to increase the flow of the mobile phase the chromatography is referred to as flash chromatography. Preparative HPLC purification is performed on a customary instrument from Gilson using a reversed phase column (C18, Phenomenex, Gemini, 75x30 mm, 5μm) as stationary phase and an acetonitrile / water gradient as mobile phase at a flow of 40 ml/min.
Starting Compounds
A1. 3-Hydroxy-2-(1H-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.: 23O0C
Step 2: 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone. 2-(1-Acetyl-1 H-indol-1-yl)-3- hydroxy-5,5-dimethyl-cyclohex-2-enone (5.95 g) is dissolved in aqueous 1 N NaOH solution (65 ml) and stirred for 2 h. The reaction mixture is diluted with dichloromethane (50 ml) and acidified with aqueous 6N hydrogen chloride solution (pH 5). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml). The combined organic layers are dried (MgSO4) and concentrated in vacuo to give 5.09 g of the title compound.
1H-NMR (200 MHz, CDCI3): δ = 1.22 (s, 6H), 2.50 (s, 4H), 7.00 (d, J = 2.5 Hz, 1 H), 7.06-7.21 (m, 2H), 7.25-7.32 (m, 2H), 8.73 (br, 1 H). mp.: 1780C
The following compound is obtained by using the procedure of example A1 analogously.
A2. 3-Hydroxy-2-(1 H-indol-3-yl)cyclohex-2-en-1 -one
Starting compounds: 1-Acetyl-1 ,2-dihydro-indol-3-one and cyclohexane-1 ,3-dione; 1H-NMR (200 MHz, CDCI3): δ = 2.06-2.20 (m, 2H), 2.59-2.65 (m, 4H), 7.07-7.43 (m, 5H), 8.61 (br, 1 H). mp.: 151-1530C A3. 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one Step 1 : 6-(4-Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]- fluoren-1-one. 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone (example A1 ) (5.08 g) and 4-methoxyphenyl acetic acid anhydride (62.55 g) are dissolved in nitromethane (150 ml). Perchloric acid (70% (v/v) in water, 0.2 ml) is added in 6 portions (every 10 minutes) and the mixture is stirred for one additional hour. The reaction mixture is diluted with dichloromethane (100 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic layer is separated and the aqueous layer is extracted again with dichloromethane (2 x 50 ml). The combined organic extracts are dried (MgSO4) and crystallized from nitromethane to give 4.65 g (58%) 6-(4-methoxy- benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one. 1H-NMR (200 MHz, CDCI3): δ = 1.17 (s, 6H), 2.46 (s, 2H), 2.63 (s, 2H), 3.85 (s, 3H), 6.0 (s, 1 H), 6.92-6.96 (m, 2H), 7.14-7.32 (m, 3H), 7.56-7.62 (m, 2H), 8.07 (br, 1 H), 8.81 (d, J = 7.5 Hz, 1 H). Step 2: e^-Methoxy-benzyO-S.S-dimethyl^.S^J-tetrahydro-indolo^.S-clquinolin-i-one. 6-(4- Methoxy-benzylidene)-3,3-dimethyl-3,4,6,7-tetrahydro-2H-5-oxa-7-aza-benzo[c]fluoren-1-one (200 mg) is suspended in acetonitrile (10 ml) and 25% (w/v) aqueous ammonia solution (10 ml) is added. The reaction mixture is heated in a sealed vial using microwave radiation at 13O0C for 25 min. The solvent is removed and the residue is dissolved in dichloromethane (50 ml) and water (50 ml). After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2 x 50 ml), the combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane 5:95 to 1 :1 (v/v)) to give 134 mg (67%) of the title compound.
1H-NMR (200 MHz, CDCI3): δ = 1.19 (s, 6H), 2.71 (s, 2H), 3.24 (s, 2H), 3.77 (s, 3H), 4.50 (s, 2H), 6.82-6.88 (m, 2H), 7.19-7.34 (m, 4H), 7.99 (br, 1 H), 9.34 (d, J = 8.3 Hz, 1 H). mp.: 1690C
The following compound is obtained by using the procedure of example A3 analogously.
A4. 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one Starting compounds: 3-Hydroxy-2-(1 H-indol-3-yl)-cyclohex-2-enone (example A2) and 4- methoxyphenyl acetic acid anhydride; yield: 29%.
1H-NMR (200 MHz, CDCI3): δ = 2.20-2.33 (m, 2H), 2.86 (t, J = QA Hz, 2H), 3.38 (t, J = 6.2 Hz, 2H),
3.74 (s, 3H), 4.57 (s, 2H), 6.77-6.83 (m, 2H), 7.23-7.32 (m, 3H), 7.38-7.42 (m, 1 H), 7.50-7.61 (m,
1 H), 8.52 (br, 1 H), 9.31 (d, J = 8.3 Hz, 1 H). mp.: 1770C A5. 6-(1 ,3-Benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-one
Step 1 : 6-(1.S-Benzodioxol-S-ylnnethylene^S.S-dinnethyl-S^.ΘJ-tetrahydrochronnenop^-blindol- 1(2H)-one. 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone (example A1 ) (2.4 g) is dissolved in dry dichloromethane (75 ml), zinc dichloride (1 M in diethyl ether, 28 ml) is added and the solution is cooled to O0C (ice bath). A solution of 1 ,3-benzodioxol-5-ylacetyl chloride (5.5 g) in dichloromethane (25 ml) is added drop by drop within 30 min and the mixture is stirred for 2 h at room temperature. After that, the reaction mixture is poured into ice-cold 1 M HCI solution (50 ml) and the aqueous phase is extracted with dichloromethane (2 x 50 ml). The combined organic extracts are washed with 1 M hydrochloric acid (2 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude Θ^I .S-benzodioxol-S-ylmethylene^S.S-dimethyl-S^.ΘJ-tetrahydrochromenop^-blindol- 1(2H)-one thus obtained is used immediately without further purification in the next step. Step 2: Θ^I .S-Benzodioxol-S-ylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i- one. The crude 6-(1 ,3-benzodioxol-5-ylmethylene)-3,3-dimethyl-3,4,6,7-tetrahydrochromeno[3,4- b]indol-1(2H)-one is dissolved in glacial acetic acid (50 ml) and ammonium acetate (27.8 g) is added. The mixture is stirred for 2 h at 9O0C. The acetic acid is evaporated. Ethyl acetate (100 ml) and sodium carbonate solution (1 M, 200 ml) are added. The organic layer is washed with sodium carbonate solution (1 M, 2 x 100 ml), dried (MgSO4) and concentrated in vacuo. The product is puri- fied by column chromatography (silica gel, eluting with gradient petroleum ether / ethyl acetate 4:1 to 3:2 (v/v)), followed by crystallization from ether to yield 2.18 g (58%) of the title compound. 1H-NMR (300 MHz, d6-DMSO): δ = 1.09 (s, 6H), 2.67 (s, 2H), 3.14 (s, 2H), 4.42 (s, 2H), 5.93 (s, 2H), 6.75-6.89 (m, 2H), 6.95-6.99 (m, 1 H), 7.18-7.27 (m, 1 H), 7.52-7.68 (m, 2H), 9.22 (d, J = 8.4 Hz, 1 H), 11.93 (s, 1 H).
The following compounds are obtained by using the procedure of example A5 analogously.
A6. 3,3-Dimethyl-6-(4-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one hydrochloride Starting compounds: 3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dimethyl-cyclohex-2-enone (example A1 ) and 4-nitrophenyl acetic acid chloride; final purification as hydrochloride salt by crystallization from tet- rahydrofuran / hydrochloride solution in ether; yield 15%.
1H-NMR (200 MHz, DMSO): δ = 1.14 (s, 6H), 2.79 (s, 2H), 3.39 (s, 2H), 5.05 (s, 2H), 7.31-7.49 (m, 1 H), 7.71-7.92 (m, 5H), 8.18 (d, J = 8.8 Hz, 2H), 9.26 (d, J = 8.4 Hz, 1 H), 13.24 (bs, 1 H). MS (MH+ found) = 400.3
A7. 3,3-Dimethyl-6-(3-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-dimethyl-cyclohex-2-enone (example A1 ) and 4-nitrophenyl acetic acid chloride; yield 34%; 1H-NMR (200 MHz, CDCI3): δ = 1.17 (s, 6H), 2.71 (s, 2H), 3.22 (s, 2H), 4.60 (s, 2H), 7.20-7.68 (m, 5H), 8.07 (d, J = 8.1 Hz, 1 H), 8.11-8.21 (m, 1 H), 8.28 (bs, 1 H), 9.34 (d, J = 8.4 Hz, 1 H). MS (MH+ found) =400.3
Aδ. 7-(1H-lndol-3-yl)-1,4-dioxaspiro[4.5]decan-8-one
Indole (7.03 g) and 1 ,4-dioxaspiro[4.5]decan-8-one (4.69 g) are dissolved under nitrogen atmosphere in dry tetrahydrofuran (500 ml) and the solution is cooled to -750C. Lithium hexamethyldisi- lazide (1 M in THF, 90 ml) is added drop by drop. The mixture is stirred for 30 min at -750C, then copper(ll)-2-ethylhexanoate (15.75 g) is added. The reaction is stirred at -750C for 18 h. After warming to room temperature, the mixture is poured in 1 M hydrochloric acid (300 ml) and ethyl acetate (300 ml) is added. The organic phase is washed subsequently with 1 M hydrochloric acid (1 x 300 ml), saturated sodium hydrogencarbonate solution (1 x 300 ml) and saturated sodium chloride solution (1 x 300 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 1.456 g (18%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.01-2.18 (m, 2H), 2.18-2.29 (m, 1 H), 2.29-2.45 (m, 2H), 3.90- 4.09 (m, 4H), 4.09-4.20 (m, 1 H), 6.86-6.97 (m, 1 H), 6.97-7.10 (m, 1 H), 7.12-7.24 (m, 1 H), 7.30-7.40 (m, 2H), 10.86 (bs, 1 H). MS (MH+ found) = 272.1
The following compounds are obtained by using the procedure of example A8 analogously.
A9. Ethyl 3-(1H-indol-3-yl)-4-oxocyclohexanecarboxylate
Starting compounds: Indole and ethyl 4-oxocyclohexanecarboxylate; yield: 33%. 1H-NMR (200 MHz, d6-DMSO); δ = 1.24 (t, J =7.1 Hz, 3H), 1.35-1.96 (m, 2H), 2.01-2.51 (m, 4H), 2.69-3.15 (2m, 1 H [diastereomers]), 3.91-4.27 (m, 3H), 6.81-7.15 (m, 2H), 7.21-7.50 (m, 3H), 10.94 (bs, 1 H). MS (MH+ found) = 286.1
A10. 2-(1H-lndol-3-yl)-4-methylcyclohexanone
Starting compounds: Indole and 4-methylcyclohexanone; yield: 24%.
1H-NMR (200 MHz, d6-DMSO); δ = 1.10 (d, J = 6.5 Hz, 3H), 1.32-1.72 (m, 1 H), 1.73-2.08 (m, 2H), 2.10-2.55 (m, 3H), 3.81-3.92 (m, 1 H), 6.85-7.14 (m, 2H), 7.22-7.50 (m, 3H), 10.96 (bs, 1 H). MS (MH+ found) = 228.1 A11. 2-(1H-lndol-3-yl)-5-methylcyclohexanone
Starting compounds: Indole and 3-methylcyclohexanone; yield: 11 %.
1H-NMR (400 MHz, d6-DMSO); δ = 0.97, 1.05 (2d, J = 6.4 Hz, 3H [syn-,anti-]), 1.52-1.76 (2m, 1 H [syn-,anti-]), 1.88-2.52 (m, 6H), 3.81-3.92 (m, 1 H), 6.88-6.98 (m, 1 H), 7.04 (dd, J = 7.1 Hz, 15.1 Hz, 1 H), 7.12, 7.26 (2d, J = 2.2 Hz, 1 H [syn-,anti-]), 7.30-7.40 (m, 2H), 10.84, 10.95 (2s, 1 H [syn-, anti-]). MS (MH+ found) = 228.2
A12. 2-(1H-lndol-3-yl)-6-methylcyclohexanone
Starting compounds: Indole and 2-methylcyclohexanone; yield: 19%.
1H-NMR (200 MHz, d6-DMSO); δ = 0.95 (d, J = 6.6 Hz, 3H), 1.36-1.57 (m, 1 H), 1.62-1.81 (m, 1 H), 1.89-2.20 (m, 3H), 2.25-2.69 (m, 2H), 3.81-3.93 (m, 1 H), 6.82-7.15 (m, 2H), 7.28-7.40 (m, 3H), 10.80, 10.99 (2s, 1 H [syn-,anti-]). MS (MH+ found) = 228.1
A13. e^-MethoxybenzyO-S.S-dimethyl-i-^trimethylsilyOoxyl^J-dihydro-SH-indolo^.S- cjquinoline
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (1000 mg) is dissolved in acetonitrile (7 ml) and sodium iodide (463 mg), dichloromethane (2 ml), triethylamine (435 μl) and trimethylsilyl chloride (399 μl) are added subsequently. The reaction mixture is stirred for 18 h at room temperature. After that, additional sodium iodide (386 mg), triethylamine (363 μl) and trimethylsilyl chloride (332 μl) are added and the mixture is stirred for further 24 h. The mixture is diluted with ice water (25 ml), the aqueous phase is extracted with di- chloromethane (3 x 25 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to give rise to 485 mg (41 %) of the title compound.
1H-NMR (400 MHz, CDCI3); δ = 0.15 (s, 9H), 1.13 (s, 6H), 3.03 (s, 2H), 3.78 (s, 3H), 4.47 (s, 2H), 5.28 (s, 1 H), 6.85 (d, J = 8.6 Hz, 2H), 7.10-7.30 (m, 4H), 7.42 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.66 (bs, 1 H), 8.74 (d, J = 8.2 Hz, 1 H). MS (MH+ found) = 457.3
A14. 3-(1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl)-1 H-indole
Potassium hydroxide (36.0 g) is dissolved in methanol (350 ml), indole (18.5 g) and 1 ,4-cyclohexa- dione monoethylen acetal (50.0 g) are added and the mixture is refluxed for 3 h. Upon cooling (ice bath), the product precipitates. It is filtered, washed with cold methanol (50 ml) and dried in vacuo to give rise to 25.3 g (62%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.75-1.88 (m, 2H), 2.32-2.46 (m, 2H), 2.52-2.65 (m, 2H), 3.92 (s, 4H), 5.98-6.08 (m, 1 H), 6.95-7.18 (m, 2H), 7.30-7.40 (m, 2H), 7.77 (d, J = 7.9 Hz, 1 H), 11.05 (bs, 1 H).
A15. δ-(1H-lndol-3-yl)-1,4-dioxaspiro[4.5]decan-7-ol
3-(1 ,4-Dioxaspiro[4.5]dec-7-en-8-yl)-1 H-indole (example A14) (20.0 g) is suspended in dry tetrahy- drofuran (80 ml) and the suspension is cooled to O0C (ice bath). Borane tetrahydrofuran adduct (1 M in tetrahydrofuran, 117.5 ml) is added drop by drop within 20 min. The mixture is stirred for 1 h at O0C and 1 h at room temperature. After that, hydrogen peroxide (30% in water, 14.6 g) and sodium hydroxide (30% in water, 44 ml) are added carefully simultaneously within 2 h via two dropping funnels. The reaction is exothermic, the internal temperature should not exceed 6O0C. The mixture is stirred at 6O0C for 1 h. After cooling, it is poured on water (300 ml), the aqueous phase is extracted with ethyl acetate (3 x 200 ml), the combined organic extracts are dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) followed by crystallization from ethyl acetate / heptane to obtain 11.65 g (54%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.48-1.85 (m, 5H), 1.95-2.10 (m, 1 H), 2.55-2.70 (m, 1 H), 3.70- 4.00 (m, 5H), 4.26 (d, J = 5.9 Hz, 1 H), 6.88-6.98 (m, 1 H), 6.98-7.12 (m, 2H), 7.31 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 10.72 (bs, 1 H). MS (MH+ found) = 274.0 mp.: 139-14O0C
A16. 8-(1H-lndol-3-yl)-1,4-dioxaspiro[4.5]decan-7-one
8-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-7-ol (example A15) (1 1.5 g) is dissolved in dimethyl- sulfoxide (90 ml) and dichloromethane (90 ml), diisopropylethyl amine (19.04 g) is added and the solution is cooled to O0C (ice bath). A solution of sulfurtrioxide pyridine complex (13.4 g) in di- methylsulfoxide (115 ml) and pyridine (6.8 ml) is added drop by drop within 45 min at a rate that the internal temperature is kept below 50C. The mixture is stirred for 2 h at O0C. After warming to room temperature, the mixture is poured in 1 M hydrochloric acid (200 ml). The aqueous phase is ex- tracted with dichloromethane (1 x 200 ml), the combined organic extracts are washed with saturated ammonium chloride solution (2 x 200 ml) and saturated sodium chloride solution (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / dichloromethane 1 :1 (v/v)) to yield 8.14 g (71 %) of the title compound. 1H-NMR (300 MHz, d6-DMSO); 5 = 2.00-2.15 (m, 4H), 2.47-2.60 (m, 1 H), 2.94 (d, J = 13.3 Hz, 1 H), 3.67-3.83 (m, 1 H), 3.85-4.01 (m, 5H), 6.86-6.99 (m, 1 H), 6.99-7.10 (m, 1 H), 7.11-7.19 (m, 1 H), 7.25-7.38 (m, 2H), 10.86 (bs, 1 H). A17. 7-(1H-lndol-3-yl)-1,4-dioxaspiro[4.5]decan-6-ol (mixture of diastereoisomers)
Indole (16.0 g) is dissolved under argon in tetrahydrofuran (300 ml) and the solution is cooled to O0C (ice bath). Methyl magnesium bromide (1.4M in tetrahydrofuran / toluene, 97.2 ml) is added drop by drop within 45 min. The mixture is stirred for 2 h at room temperature and a solution of spiro[1 ,3-dioxolane-2,2'-[7]oxabicyclo[4.1.0]heptane] (25.6 g) in tetrahydrofuran (75 ml) is added within 20 min. The mixture is stirred for 16 h at room temperature. After that, saturated ammonium chloride solution (250 ml) and water (100 ml) is added, the aqueous phase is extracted with ethyl acetate (2 x 200 ml), the combined organic extracts are washed with water (1 x 300 ml) and satu- rated sodium chloride solution (1 x 300 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate to yield 7.00 g (19%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.48-1.67 (m, 4H), 1.68-1.88 (m, 2H), 2.87-3.04 (m, 1 H), 3.61- 3.72 (m, 1 H), 3.82-4.19 (m, 5H), 6.92 (dd, J = 6.8 Hz, 6.9 Hz, 1 H), 7.01 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.05-7.12 (m, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 10.68 (bs, 1 H).
A18. 7-(1H-lndol-3-yl)-1,4-dioxaspiro[4.5]decan-6-one
7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-6-ol (example A17) (6.3 g) is dissolved in dimethyl- sulfoxide (70 ml) and dichloromethane (60 ml), diisopropylethyl amine (13.8 ml) is added and the solution is cooled to O0C (ice bath). A solution of sulfur trioxide pyridine complex (7.32 g) in di- methylsulfoxide (70 ml) and pyridine (3.71 ml) is added drop by drop within 45 min at a rate that the internal temperature is kept below 50C. The mixture is stirred for 1 h at O0C. After warming to room temperature, the mixture is poured into saturated ammonium chloride solution (200 ml). The aqueous phase is extracted with dichloromethane (1 x 200 ml), the combined organic extracts are washed with 0.1 M hydrochloric acid (2 x 75 ml) and saturated sodium chloride solution
(1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate to obtain 5.71 g (91%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.81-2.12 (m, 5H), 2.12-2.26 (m, 1 H), 3.79-3.91 (m, 2H), 3.91- 4.07 (m, 2H), 4.14-4.29 (m, 1 H), 6.93 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.05 (dd, J = 7.0 Hz, 7.1 Hz, 1 H), 7.12-7.21 (m, 1 H), 7.26 (d, J = 7.9 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 10.87 (bs, 1 H). mp.: 193-1940C
A19. 7-Allyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin- 1-one 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (1.112 g) is dissolved in acetone (45 ml) and potassium carbonate (998 mg), followed by allyl bromide (550 μl) are added. The mixture is stirred for 18 h at 6O0C. After that, solvent and excess allyl bromide is removed in vacuo, water (40 ml) and dichloromethane (30 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 40 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 1.080 g (88%) of the title compound. 1H-NMR (400 MHz, CDCI3); δ = 1.20 (s, 6H), 2.75 (s, 2H), 3.25 (s, 2H), 3.76 (s, 3H), 4.60 (s, 2H), 4.78 (d, J = 17.1 Hz, 1 H), 4.86-4.99 (m, 2H), 5.18 (d, J = 10.5 Hz, 1 H), 5.96-6.10 (m, 1 H), 6.80 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 7.37-7.88 (m, 2H), 7.53-7.65 (m, 1 H), 9.40 (d, J = 8.0 Hz, 1 H).
A20. 7-Allyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin- 1-ol 7-Allyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example A19) (1.08 g) is suspended in methanol (50 ml) and sodium borohydride (241 mg) is added in portions. The mixture is stirred for 30 min at room temperature. After that, the solvent is removed in vacuo, water (20 ml) and dichloromethane (20 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 941 mg (87%) of the title compound.
1H-NMR (400 MHz, CDCI3); δ = 1.09 (s, 3H), 1.29 (s, 3H), 1.89-2.09 (m, 2H), 2.17-2.35 (m, 1 H), 2.83 (d, AB, J = 6.6 Hz, 1 H), 3.04 (d, AB, J = 6.5 Hz, 1 H), 3.74 (s, 3H), 4.56 (s, 2H), 4.71-4.95 (m, 3H), 5.15 (d, J = 10.4 Hz, 1 H), 5.66 (dd, J = 6.1 Hz, 12.2 Hz, 1 H), 5.85-6.11 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 7.30 (bs, 1 H), 7.34 (bs, 1 H), 7.48-7.62 (m, 1 H), 8.53 (d, J = 7.9 Hz, 1 H).
A21. 7-AIIyM -methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- cjquinoline 7-Allyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol (example A20) (50 mg) is dissolved in dry tetrahydrofuran (1 ml) and sodium hydride (60% suspension in mineral oil, 6 mg) followed by methyl iodide (9 μl) is added. The mixture is stirred for 2 h at room temperature. After that, water (10 ml) and dichloromethane (10 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product (48 mg, 93%) has sufficient purity (measured by tic) and is used without further purification for the next step (see example 22).
A22. 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -ol
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (700 mg) is suspended in methanol (42 ml) and sodium borohydride (172 mg) is added in portions. The reaction mixture is stirred for 15 min at room temperature. After that, the mixture is concentrated in vacuo, water (20 ml) and dichloromethane (20 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 700 mg (99%) of the title compound. 1H-NMR (200 MHz, CDCI3): δ = 1.07 (s, 3H), 1.22 (s, 3H), 1.86-1.99 (m, 2H), 2.23 (dd, J = 13.7 Hz, J = 6.3 Hz, 1 H), 2.85 (d, J = 16.5 Hz, 1 H), 3.05 (d, J = 16.5 Hz, 1 H), 3.77 (s, 3H), 4.45 (s, 2H), 5.56-5.59 (m, 1 H), 6.82-6.86 (m, 2H), 7.20-7.34 (m, 4H), 7.42-7.50 (m, 1 H), 7.74 (br, 1 H), 8.46 (d, J = 8.0 Hz, 1 H). mp.: 1460C
Final Compounds
1. N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 - yljformamide
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (5.0 g) is suspended in formamide (39 ml) and formic acid (85%, 22 ml) followed by water (1.9 ml) are added. The mixture is stirred for 16 h at 16O0C. Ethanol (26 ml) is added, the mixture is stirred for 15 min and cone, ammonia (25%, 43 ml) is added (pH > 10). It is extracted with dichlorome- thane (3 x 50 ml), the combined organic extracts washed with water (1 x 100 ml), dried (MgSO4), the solvents removed in vacuo. The residue is stirred in ethyl acetate / ethyl ether (1 :1 , ca. 50 ml), the precipitate is filtered and dried in high vacuum to yield 2.9 g (54%) of the title compound. 1H-NMR (200 MHz, DMSO); δ = 1.10 (s, 3H), 1.17 (s, 3H), 1.88-2.02 (m, 1 H), 2.21-2.40 (m, 1 H), 2.86 (d, AB, J = 16.6 Hz, 1 H), 3.05 (d, AB, J = 16.6 Hz, 1 H), 3.77 (s, 3H), 4.44 (s, 2H), 5.68-5.81 (m, 1 H), 5.81-5.99 (m, 1 H), 6.84 (d, J = 8.1 Hz, 2H), 7.13-7.61 (m, 5H), 7.76-8.02 (m, 2H), 8.22 (s, 1 H).
2. 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine dihydrochloride
N-tθ^-methoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yllformamide (example 1 , 2.9 g) is dissolved in a 2M solution of HCI in methanol (150 ml, prepared before by dropping acetyl chloride (24 ml) in methanol (150 ml)). The mixture is refluxed for 18 h, after that it is concentrated in vacuo. The residue is stirred in tetrahydrofuran (50 ml), the precipitate is filtered off to give rise to 3.0 g (93%) of the title compound.
1H-NMR (200 MHz, d6-DMSO); δ = 0.81 (s, 3H), 1.17 (s, 3H), 1.71-1.90 (m, 1 H), 2.11-2.31 (m, 1 H), 2.59-2.77 (m, 1 H), 2.89-3.07 (m, 1 H), 3.67 (s, 3H), 4.29 (d, AB, J = 14.0 Hz, 1 H), 4.47 (d, AB, J = 14.0 Hz, 1 H), 5.22 (t, J = 7.4 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2H), 7.15-7.43 (m, 5H), 7.52-7.72 (m, 2H), 8.22 (d, J = 8.1 Hz, 1 H), 1 1.86 (br, 1 H). MS (MH+ found) = 386.3 3. 6-(1 ,3-Benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine
Step 1 : e^i .S-Benzodioxol-S-ylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i- one (example A5) (1.5 g) is suspended in formamide (11 ml) and ammoniumformiate (17.8 g), formic acid (85%, 11 ml) are added. The mixture is stirred for 16 h at 17O0C. After cooling, ethanol (10 ml) is added, the mixture is stirred for 15 min and cone, ammonia (25%, 20 ml) is added (pH > 10). It is extracted with dichloromethane (3 x 50 ml), the combined organic extracts washed with water (1 x 100 ml), dried (MgSO4), the solvents removed in vacuo. The residue, crude N-[6-(1 ,3- benzodioxol-S-ylmethyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yllformamide (0.7 g, 44%) is used in the next step without further purification.
Step 2: N-[6-(1 ,3-benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1-yl]formamide (crude from preceeding step, 0.7 g) is dissolved in a 2M solution of HCI in methanol (50 ml, prepared before by dropping acetyl chloride (7 ml) in methanol (50 ml)). The mixture is re- fluxed for 3 h, after that it is concentrated in vacuo. The residue is dissolved in ethyl acetate
(30 ml), washed with 1 M sodium carbonate solution (3 x 20 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 95:5 (v/v)), followed by crystallization from ethyl acetate / petroleum ether to yield 72 mg (11 %) of the title compound. 1H-NMR (200 MHz, CDCI3); δ = 0.97 (s, 3H), 1.19 (s, 3H), 1.49-1.70 (m, 1 H), 2.02 (br, 2H), 2.18- 2.38 (m, 1 H), 2.80 (d, AB, J = 16.4 Hz, 1 H), 3.01 (d, AB, J = 16.4 Hz, 1 H), 4.39 (s, 2H), 4.79 (t, J = 7.4 Hz, 1 H), 5.87 (s, 2H), 6.58-6.88 (m, 3H), 7.19-7.55 (m, 3H), 8.12 (br, 1 H), 8.26 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 400.3
4. 6-(3-Amino-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 - ylamine
Step i : N-p^-Dimethyl-e^S-nitrobenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i- yl]formamide. 3,3-Dimethyl-6-(3-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (ex- ample A7) (1.0 g) is suspended in formamide (7.5 ml) and ammoniumformiate (12.0 g), formic acid (85%, 7 ml) are added. The mixture is stirred for 16 h at 16O0C. After cooling, ethanol (10 ml) is added, the mixture is stirred for 15 min and cone, ammonia (25%, 15 ml) is added (pH > 10). It is extracted with ethyl acetate (3 x 30 ml), the combined organic extracts washed with 1 M sodium carbonate solution (2 x 50 ml), dried (MgSO4), the solvents removed in vacuo. The residue, crude N-[3,3-dimethyl-6-(3-nitrobenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide (1.6 g) is used in the next step without further purification.
Step 2: N-^S-AminobenzyO-S^-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i- yl]formamide. Crude N-P.S-dimethyl-Θ^S-nitrobenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin- 1-yl]formamide (1.6 g) is suspended in ethanol (20 ml) and tin dichloride dihydrate (4.0 g) is added. The mixture is stirred for 3 h at 7O0C. After cooling, it is filtered, the filtrate is concentrated in vacuo. The residue is redissolved in dichloromethane, 200 ml) and 1 M sodium hydroxide solution is added (100 ml). The organic phase is dried (MgSO4) and concentrated in vacuo. The crude product, N-[6- (3-aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide (0.7 g), is used in the next step without further purification. Step 3: Θ^S-Amino-benzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-ylamine. N- [6-(3-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]formamide (crude from preceeding step, 0.7 g) is dissolved in a 2M solution of HCI in methanol (10 ml, prepared before by dropping acetyl chloride (1.2 ml) in methanol (10 ml)). The mixture is stirred 3 h at 7O0C, after that it is concentrated in vacuo. The residue is dissolved in ethyl acetate (20 ml), washed with 1 M sodium carbonate solution (3 x 10 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) to ethyl acetate / methanol 6:1 (v/v)), followed by crystallization from ethyl acetate to yield 140 mg (15%, 3 steps) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 0.89 (s, 3H), 1.14 (s, 3H), 1.51-1.68 (m, 1 H), 1.84-2.02 (m, 2H), 2.02-2.14 (m, 1 H), 2.62 (d, J = 16.1 Hz, 1 H), 2.86 (d, J = 16.0 Hz, 1 H), 4.12-4.40 (m, 2H), 4.62 (dd, J = 7.0 Hz, 7.0 Hz, 1 H), 4.88 (s, 2H), 6.34 (d, J = 7.8 Hz, 1 H), 6.48-6.59 (m, 2H), 6.87 (dd, J = 7.7 Hz, 7.7 Hz, 1 H), 7.41-7.67 (m, 2H), 8.37 (d, J = 8.0 Hz, 1 H), 11.48 (s, 1 H). MS (MH+ found) = 371.3
The following compound is obtained by using the procedure of example 4 analogously.
5. 6-(4-Aminobenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine
Starting compound: S.S-Dimethyl-θ-^-nitrobenzyl^S^J-tetrahydro-I H-indolo^S-clquinolin-i- one hydrochloride (example A6); yield 7% (3 steps); 1H-NMR (200 MHz, d6-DMSO); δ = 0.89 (s, 3H), 1.13 (s, 3H), 1.48-1.68 (m, 1 H), 1.80-2.20 (m, 3H), 2.62 (d, AB, J = 16.2 Hz, 1 H), 2.87 (d, AB, J = 16.2 Hz, 1 H), 4.13 (d, AB, J = 14.0 Hz, 1 H), 4.27 (d, AB, J = 14.1 Hz, 1 H), 4.50-4.70 (m, 1 H), 4.81 (s, 2H), 6.44 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 7.19 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.40-7.65 (m, 2H), 8.36 (d, J = 8.1 Hz, 1 H), 11.45 (s, 1 H). MS (MH+ found) = 371.3
6. Benzyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1 -yl]-amine hydrochloride
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (0.33 g) is suspended in toluene (10 ml), benzylamine (0.17 g) and p-toluenesulfonic acid (20 mg) are added and the mixture is refluxed in a Dean Stark apparatus for 18 h. After that, the reaction mixture is concentrated in vacuo, the residue is redissolved in ethyl acetate (20 ml), washed with cone, sodium hydrogencarbonate solution (1 x 20 ml), the organic layer is dried (MgSO4) and concentrated in vacuo. The crude product is dissolved methanol (10 ml), sodium cyanoborohydride (101 mg) is added and the suspension is stirred for 18 h at room temperature. After that, the mix- ture is concentrated in vacuo, the residue is redissolved in ethyl acetate (20 ml), washed with water (1 x 20 ml) and cone, sodium chloride solution (1 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with petroleum ether / ethyl acetate 1 :1 (v/v)). The resulting oil is dissolved in THF (5 ml), HCI (2M in ether, 1 ml) is added, the mixture is stirred for 2 h at room temperature. The resulting precipitate is filtered off to yield 50 mg (13%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 0.98 (s, 3H), 1.25 (s, 3H), 1.72-2.07 (m, 1 H), 2.11-2.35 (m, 1 H), 2.71-2.92 (m, 1 H), 3.00-3.20 (m, 1 H), 3.74 (s, 3H), 3.85-4.20 (m, 2H), 4.41 (s, 2H), 6.80 (d, J = 8.6 Hz, 2H), 7.02-7.57 (m, 11 H), 8.03 (d, J = 8.0 Hz, 1 H). mp.: 209-210 0C
The following compound is obtained by using the procedure of example 6 analogously. Adaptations are necessary for the chromatography purification step.
7. [6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-yl]- pyridin-2-ylmethyl -amine
Starting compounds: θ-^-Methoxy-benzyO-S.S-dimethyl^S^J-tetrahydro-indolo^S-clquinolin-i- one (example A3) and pyridin-2-yl-methylamine; purification: chromatography (silica gel, eluting with ethyl acetate / methanol 20:1 (v/v)), followed by crystallization from ether; yield: 17%. 1H-NMR (200 MHz, CDCI3); δ = 0.96 (s, 3H), 1.23 (s, 3H), 1.85-2.01 (m, 1 H), 2.09-2.33 (m, 1 H), 2.83 (d, AB, J = 16.2 Hz, 1 H), 3.09 (d, AB, J = 16.2 Hz, 1 H), 3.74 (s, 3H), 4.08-4.29 (m, 2H), 4.43 (s, 2H), 4.76 (t, J = 7.0 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 2H), 6.98-7.59 (m, 9H), 7.91 (br, 1 H), 8.13 (d, J = 7.9 Hz, 1 H), 8.44 (d, J = 4.8 Hz, 1 H). mp.: 143-144 0C
8. lsopropyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1 -yl]-amine
6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine (example 2, amine set free by reaction with 2M aqueous sodium carbonate in dichloromethane, followed by extraction with dichloromethane) (422 mg) is dissolved in methanol (5 ml), acetone (0.32 ml) and acetic acid (63 μl) are added and the mixture is stirred at room temperature for 3 h. After that, sodium cyanoborohydride (140 mg) is added and the suspension is stirred for 18 h at room tempera- ture.The mixture is concentrated in vacuo, the residue is redissolved in dichloromethane (20 ml), washed with 2N sodium carbonate solution (1 x 20 ml). The aqueous phase is extracted with di- chloromethane (2 x 20 ml), the combined organic extracts washed with water (1 x 40 ml), dried (MgSO4) and concentrated in vacuo to yield 230 mg (49%) of the title compound. 1H-NMR (200 MHz, CDCI3); δ = 0.94 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H), 1.14-1.38 (m, 6H), 1.72-1.90 (m, 1 H), 2.02-2.21 (m, 1 H), 2.80 (d, AB, J = 16.4 Hz, 1 H), 3.08 (d, AB, J = 16.4 Hz, 1 H), 3.74 (s, 3H), 4.41 (s, 2H), 4.79 (t, J = 7.3 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 2H), 7.12-7.50 (m, 5H), 7.80 (s, 1 H), 8.38 (d, J = 8.0 Hz, 1 H). mp.: 128-129 0C
9. 6-(4-Methoxybenzyl)-3,3-dimethyl-1 -pyrrolidin-1 -yl-2,3,4,7-tetrahydro-1 H-indolo[2,3- cjquinoline
6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (100 mg) is suspended in tetrahydrofuran (0.7 ml), pyrrolidine (28 μl) and titanium tetraisopropyl oxide (154 μl) are added and the mixture is stirred at room temperature for 18 h. After that time, additional pyrrolidine (22 μl) and titanium tetraisopropyl oxide (77 μl) are added and the mixture is stirred for additional 24 h, until complete consumption of starting material (ketone) is detected by tic. Ethanol (0.65 ml) followed by sodium cyanoborohydride (33 mg) are added and the suspension is stirred for 2 h at room temperature. After that, water (1 ml) and ethanol (3 ml) are added, the precipitate is filtered, washed thoroughly with ethanol and the filtrate is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol gradient) to give rise to 96 mg (84%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.78 (s, 3H), 1.17 (s, 3H), 1.42-1.64 (m, 3H), 1.67-1.92 (m, 2H), 2.26-2.40 (m, 2H), 2.57-2.70 (m, 3H), 2.88 (d, J = 15.5 Hz, 1 H), 3.67 (s, 3H), 4.27 (d, AB, J = 14.2 Hz, 1 H), 4.36 (d, AB, J = 14.3 Hz, 1 H), 4.80 (t, J = 8.0 Hz, 1 H), 6.82 (d, J = 6.7 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1 H), 7.53 (d, J = 8.1 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 11.40 (s, 1 H). MS (MH+ found) = 440.2
The following compounds are obtained by using the procedure of example 9 analogously.
10. N-Cyclopentyl-e^-methoxybenzyO-S.S-dimethyl^.S^y-tetrahydro-IH-indolo^.S- c]quinolin-1 -amine
Starting compounds: θ-^-Methoxy-benzy^-S.S-dimethyl^S^J-tetrahydro-indolo^S-clquinolin-i- one (example A3) and cyclopropylamine; yield: 14%. 1H-NMR (200 MHz, CDCI3); δ = 0.95 (s, 3H), 1.23 (s, 3H), 1.41-2.25 (m, 11 H), 2.74-2.91 (m, 1 H), 3.02-3.18 (m, 1 H), 3.32-3.55 (m, 1 H), 3.77 (s, 3H), 4.44 (s, 2H), 4.72 (t, J = 7.2 Hz, 1 H), 6.77-6.91 (m, 2H), 7.12-7.55 (m, 5H), 7.77 (br, 1 H), 8.24 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 454.2
11. N-Ethyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine
Starting compounds: θ-^-Methoxy-benzy^-S.S-dimethyl^S^J-tetrahydro-indolo^S-cJquinolin-i- one (example A3) and ethylamine; yield: 41 %. 1H-NMR (400 MHz, d6-DMSO); δ = 0.86 (s, 3H), 0.99 (t, J = 7.0 Hz, 3H), 1.15 (s, 3H), 1.35-1.68 (m, 1H), 1.69-1.78 (m, 1H), 1.99-2.11 (m, 1H), 2.64 (d, AB, J = 16.2 Hz, 1H), 2.69-2.80 (m, 1H), 2.88 (d, AB, J= 16.2 Hz, 1H), 3.67 (s, 3H), 4.26 (d, AB, J= 14.2 Hz, 1H), 4.38 (d, AB, J= 14.1 Hz, 1H), 4.41-4.50 (m, 1H), 6.81 (d, J= 8.7 Hz, 2H), 7.20 (t, J= 7.3 Hz, 1H), 7.27 (d, J= 8.7Hz, 2H), 7.48 (t, J =7.4 Hz, 1H), 7.57 (d, J =8.1 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H), 11.48 (s, 1H). MS (MH+ found) = 414.2
12. N-Methyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1 -amine Starting compounds: 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1- one (example A3) and methylamine; yield: 49%.
1H-NMR (400 MHz, CDCI3); δ = 0.97 (s, 3H), 1.23 (s, 3H), 1.76-1.87 (m, 1H), 2.10-2.21 (m, 1H), 2.62 (s, 3H), 2.83 (d, J= 16.2 Hz, 1H), 3.07 (d, J= 16.1 Hz, 1H), 3.78 (s, 3H), 4.46 (s, 2H), 4.50 (t, J = 7.1 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 2H), 7.18-7.30 (m, 3H), 7.34 (d, J = 8.2 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1H), 7.71 (br, 1H), 8.03 (d, J= 8.1 Hz, 1H). MS (MH+ - MeNH2 found) = 369.2
13. N^CyclopropylmethyO-e^-methoxybenzyO-S.S-dimethyl^.S^.y-tetrahydro-IH- indolo[2,3-c]quinolin-1 -amine Starting compounds: θ-^-Methoxy-benzyO-S.S-dimethyl^S^J-tetrahydro-indolo^S-clquinolin-i- one (example A3) and cyclopropylmethylamine; yield: 42%.
1H-NMR (400 MHz, d6-DMSO); δ = 0.06-0.21 (m, 2H), 0.30-0.41 (m, 2H), 1.08 (s, 3H), 1.14 (s, 3H), 1.57-1.77 (m, 2H), 1.95-2.07 (m, 1H), 2.38 (d, J= 15.5Hz, 1H), 2.48-2.72 (m, 3H), 2.92 (d, J = 16.6Hz, 1H), 3.67 (s, 3H), 4.27 (d, AB, J= 14.2 Hz, 1H), 4.38 (d, AB, J= 14.3 Hz, 1H), 4.44 (bs, 1H), 6.81 (d, J =8.6 Hz, 2H), 7.16-7.32 (m, 3H), 7.46-7.53 (m, 1H), 7.56-7.68 (m, 1H), 8.13 (d, J = 8.0 Hz, 1H), 11.50(s, 1H). MS (MH+ found) = 440.2
14. N'-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1- yl]-N,N-dimethylpropane-1,3-diamine
Starting compounds: 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1- one (example A3) and N,N-dimethyl-1,3-propanediamine; yield: 23%.
1H-NMR (200 MHz, CDCI3); δ = 0.95 (s, 3H), 1.22 (s, 3H), 1.56-1.90 (m, 2H), 2.16 (s, 6H), 2.02- 2.40 (m, 5H), 2.73-3.15 (m, 4H), 3.77 (s, 3H), 4.44 (s, 2H), 4.61 (t, J= 7.0 Hz, 1H), 6.83 (d, J = 8.6Hz, 2H), 7.12-7.52 (m, 5H), 7.81 (bs, 1H), 8.04 (d, J= 8.1 Hz, 1H). MS (MH+ - Me2N(CH2)3NH2 found) = 369.2 15. 6-(4-Methoxybenzyl)-3,3-dimethyl-N-(tetrahydrofuran-2-ylmethyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-1 -amine
Starting compounds: θ-^-Methoxy-benzy^-S.S-dimethyl^S^J-tetrahydro-indolo^S-clquinolin-i- one (example A3) and tetrahydrofurfurylamine; yield: 58%; diastereoisomers can be separated via column chromatography (silica gel, eluting with gradient dichloromethane / methanol 99:1 to 95:5 (v/v)).
Diastereoisomer A (major): 1H-NMR (200MHz, CDCI3); δ = 0.96 (s, 3H), 1.23 (s, 3H), 1.41-2.02 (m, 6H), 2.02-2-21 (m, 1 H), 2.72-3.17 (m, 4H), 3.50-3.75 (m, 2H), 3.78 (s, 3H), 3.83-4.05 (m, 1 H), 4.45 (s, 2H), 4.61 (t, J = 7.1 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 2H), 7.13-7.37 (m, 4H), 7.44 (t, J = 7.2 Hz, 1 H), 7.71 (s, 1 H), 8.14 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 470.2
16. 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-one oxime 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (110 mg) is suspended in methanol (8 ml) and hydroxylamine hydrochloride (440 mg) and cone, sulfuric acid (50 μl) are added. The mixture is refluxed for 24 h. The solvent is removed in vacuo, the residue is redissolved in dichloromethane (20 ml), water (20 ml) is added. The precipitate (product) is filtered, after phase separation the aqueous phase is extracted with dichloromethane (2 x 20 ml), the organic phases are combined with the precipitate, the solvents removed in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 97:3 (v/v)) to yield 32 mg (28%) of the title compound.
1H-NMR (200 MHz, d6-DMSO); δ = 1.00 (s, 6H), 2.70 (s, 2H), 2.88 (s, 2H), 3.67 (s, 3H), 4.37 (s, 2H), 6.82 (d, J = 8.6 Hz, 2H), 7.05-7.21 (m, 1 H), 7.22-7.35 (m, 2H), 7.42-7.63 (m, 2H), 9.08 (d, J = 8.2 Hz, 1 H), 11.38 (s, 1 H), 11.65 (s, 1 H).
17. 2-Methoxy-N-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1 -yl]-acetamide
6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (example 2) (0.50 g) is suspended in dichloromethane (10 ml) and methoxyacetyl chloride (0.18 g) and triethylamine (1.0 ml) are added. The mixture is stirred for 18 h at room temperature. After that, 1 M hydrochloric acid (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are washed subsequently with 1 M hydrochloric acid (20 ml) and 1 M sodium carbonate solution (2 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product, a foam, solidifies upon treatment with diethyl ether (10 ml). The filtered solid is again washed by stirring over diethyl ether (10 ml) for 18 h. It is filtered off to yield 0.31 g (53%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 1.08 (s, 3H), 1.14 (s, 3H), 1.80-1.99 (m, 1 H), 2.18-2.38 (m, 1 H), 2.86 (d, AB, J = 16.6 Hz, 1 H), 3.05 (d, AB, J = 16.6 Hz, 1 H), 3.12 (s, 3H), 3.75 (s, 3H), 3.89 (s, 2H), 4.46 (s, 2H), 5.75-5.98 (m, 1 H), 6.70 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 2H), 7.10-7.49 (m, 5H), 7.87 (d, J = 8.1 Hz, 1 H), 8.05 (br, 1 H). mp.: 123-124 0C
18. Morpholine-4-carboxylic acid [6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-1 -yl] -amide
6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (example 2) (0.50 g) is suspended in dichloromethane (10 ml) and morpholine carbonyl chloride (0.21 g) and triethylamine (1.0 ml) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are washed with 1 M sodium carbonate solution (20 ml), dried (MgSO4) and concentrated in vacuo. The crude product, a foam, solidifies upon treatment with a diethyl ether / ethyl acetate mixture (10 ml, 1 :1 (v/v)). The precipitate is filtered off and gives rise to 0.41 g (66%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 1.05 (s, 3H), 1.13 (s, 3H), 1.78-1.92 (m, 1 H), 2.20-2.40 (m, 1 H), 2.83 (d, AB, J = 16.6 Hz, 1 H), 3.01 (d, AB, J = 16.6 Hz, 1 H), 3.04-3.39 (m, 4H), 3.40-3.64 (m, 4H), 3.74 (s, 3H), 4.42 (s, 2H), 4.63 (d, J = 6.9 Hz, 1 H), 5.60-5.78 (m, 1 H), 6.81 (d, J = 8.6 Hz, 2H), 7.11-7.50 (m, 5H), 7.92 (d, J = 8.1 Hz, 1 H), 8.05 (br, 1 H). mp.: 169-17O 0C
19. N'-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1- yl]-N,N-dimethylsulfamide
6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (example 2) (0.50 g) is suspended in dichloromethane (10 ml) and dimethylsulfamoyl chloride (0.34 g), triethylamine (1.0 ml) and 4-dimethylamino pyridine (10 mg) are added. The mixture is refluxed for 18 h. After that, 1 M hydrochloric acid (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are washed subsequently with 1 M hydrochloric acid (20 ml) and 1 M sodium carbonate solution (2 x 20 ml), dried (MgSO4) and concentrated in vacuo. The crude product, an oil, is crystallized by addition of diethyl ether (10 ml) and filtered off to yield 0.26 g (43%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 0.88 (s, 3H), 1.18 (s, 3H), 1.92-2.02 (m, 1 H), 2.12-2.22 (m, 1 H), 2.60 (s, 6H), 2.61-2.73 (m, 1 H), 2.88-3.01 (m, 1 H), 3.68 (s, 2H), 4.31 (d, AB, J = 13.8 Hz, 1 H), 4.47 (d, AB, J = 13.8 Hz, 1 H), 5.18-5.30 (m, 1 H), 6.83 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 2H), 7.47-7.57 (m, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.53 (d, J = 8.1 Hz, 1 H), 11.70 (br, 1 H). mp.: 130-131 0C 20. N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -yl]- 2-(4-methylpiperazin-1-yl)acetamide θ-^-Methoxybenzy^-S.S-dimethyl^S^J-tetrahydro-IH-indolo^S-clquinolin-i -amine dihydro- chloride (example 2) (160 mg) is suspended in dichloromethane (4 ml) and 4-methyl-piperazin-1- yl)-acetic acid (166 mg), diisopropylethylamine (371 μl) and 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (202 mg) are added. The mixture is stirred for 18 h at room temperature. After that, saturated sodium hydrogencarbonate solution (5 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol gradient) to yield 140 mg (76%) of the title compound. 1H-NMR (400MHz, CDCI3); δ = 1.13 (s, 3H), 1.16 (s, 3H), 1.50-1.86 (m, 3H), 1.90 (dd, J = 4.2 Hz, 13.8 Hz, 1 H), 2.12 (s, 3H), 2.21-2.32 (m, 3H), 2.34-2.50 (m, 2H), 2.90 (d, AB, J = 16.5 Hz, 1 H), 3.00 (s, 2H), 3.07 (d, AB, J = 16.6 Hz, 1 H), 3.79 (s, 3H), 4.49 (s, 2H), 5.30 (s, 2H), 5.81-5.90 (m, 1 H), 6.88 (d, J = 8.7 Hz, 2H), 7.18 (t, J = 7.2Hz, 1 H), 7.24-7.38 (m, 3H), 7.44 (dd, J = 7.3 Hz, 8.0 Hz, 1 H), 7.77 (s, 1 H), 7.89 (d, J = 8.1 Hz, 1 H). MS (MH+ found) = 526.2
21. (S)-N-[6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1 -yl]-1 -methylprolinamide 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydro- chloride (example 2) (69 mg) is suspended in dichloromethane (2 ml) and (2S)-1-methyl-pyrroli- dine-2-carboxylic acid (47 mg), diisopropylethylamine (108 μl) and 1-ethyl-3-(3-dimethylamino- propyl)-carbodiimide hydrochloride (69 mg) are added. The mixture is stirred for 18 h at room temperature. After that, saturated sodium hydrogencarbonate solution (2 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 3 ml), the combined organic extracts are dried
(MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC to yield 41 mg (55%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.01 (s, 3H), 1.09 (s, 3H), 1.39-1.50 (m, 1 H), 1.53-1.68 (m, 1 H), 1.85 (s, 1 H), 1.90-2.18 (m, 3H), 2.20 (s, 2H), 2.63-2.94 (m, 4H), 3.68 (s, 3H), 4.24-4.41 (m, 2H), 5.50-5.62 (m, 1 H), 6.83 (d, J = 8.7 Hz, 2H), 7.11 (dd, J = 7.2 Hz, 7.7 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 2H), 7.45-7.53 (m, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.78 (dd, J = 7.9 Hz, 7.9 Hz, 1 H), 8.16 (s, 1 H), 1 1.62 (s, 1 H). MS (MH+ found) = 497.4
22. 1 -Methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- cjquinoline
7-Allyl-1-methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline (crude product of example A21 ) (48 mg) is dissolved under argon in dry dichloromethane (0.9 ml) and glacial acetic acid (0.5 ml). After that, tetrakis(triphenylphosphine)palladium(0) (6 mg) and phenyl silane (134 μl) is added. The mixture is stirred for 6 h at 450C and 12 h at room temperature. Dichloromethane (3 ml) and saturated sodium hydrogencarbonate (3 ml) is added and after phase separation the aqueous phase extracted with dichloromethane (2 x 3 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient), followed by preparative HPLC to give rise to 12 mg (27%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 1.05 (s, 3H), 1.22 (s, 3H), 2.00-2.09 (m, 2H), 2.86 (d, AB, J = 16.4 Hz, 1 H), 3.07 (d, AB, J = 16.4 Hz, 1 H), 3.53 (s, 3H), 3.77 (s, 3H), 5.25 (t, J = 6.1 Hz, 1 H), 6.82 (d, J = 8.5 Hz, 2H), 7.11-7.37 (m, 4H), 7.45 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.79 (br, 1 H), 8.10 (d, J = 8.0 Hz, 1 H).
MS (MH+ found) = 401.3
23. 2-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1-one 6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A3) (1.0 g) is dissolved in hydrobromic acid (7 ml, 33% in glacial acetic acid) and the solution is stirred for 10 min at room temperature. A solution of bromine (147 μl) in hydrobromic acid (3.5 ml, 33% in glacial acetic acid) is added dropwise and the suspension is stirred for 2 h at 450C. After that, the reaction mixture is neutralized by addition of 5M sodium hydroxide solution, extracted with with dichloromethane (3 x 30 ml), the combined organic extracts washed with aqueous sodium hydro- gensulfite solution, dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 817 mg (68%) of the title compound. 1H-NMR (200 MHz, CDCI3); δ = 1.32 (s, 3H), 1.35 (s, 3H), 3.12-3.30 (m, 1 H), 3.45-3.60 (m, 1 H), 3.78 (s, 3H), 4.48-4.61 (m, 3H), 6.86 (d, J = 8.6 Hz, 2H), 7.19-7.42 (m, 4H), 7.55 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 8.13 (br, 1 H), 9.24 (d, J = 8.3 Hz, 1 H). MS (MH+ found) = 463.4, 465.2
The following compound is obtained by using the procedure of example 23 analogously.
24. 2-Bromo-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one
Starting compound: 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one (example A4); yield: 22%.
1H-NMR (400 MHz, d6-DMSO); δ = 2.42-2.52 (m, 1 H), 2.68-2.81 (m, 1 H), 3.20-3.48 (m, 2H), 3.68 (s, 3H), 4.48 (m, 2H), 5.19 (m, 1 H), 6.84 (d, J = 8.7 Hz, 2H), 7.27 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.32 (d, J = 8.7 Hz, 2H), 7.59-7.71 (m, 2H), 9.17 (d, J = 8.3 Hz, 1 H), 12.18 (s, 1 H). MS (MH+ found) = 435.1 , 437.2 25. 1 ,1 -Dimethoxy-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol
2-Bronno-6-(4-nnethoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 24) (315 mg) is suspended in methanol (25 ml) and solid, powdered sodium hydroxide (289 mg) is added. The mixture is stirred for 15 min at 5O0C and 1 h at room temperature. After that, the mixture is concentrated in vacuo, the residue is treated with water (30 ml) and extracted with ethyl acetate (3 x 150 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 140 mg (46%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.90-2.08 (m, 1 H), 2.10-2.25 (m, 1 H), 2.85-2.99 (m, 1 H), 3.04 (s, 3H), 3.10-3.25 (m, 1 H), 3.54 (s, 3H), 3.67 (s, 3H), 4.27 (s, 1 H), 4.30-4.42 (m, 2H), 4.71 (s, 1 H), 6.82 (d, J = 8.6 Hz, 2H), 7.12-7.25 (m, 1 H), 7.29 (d, J = 8.5 Hz, 2H), 7.47 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 7.57 (d, J = 8.1 Hz, 1 H), 8.60 (d, J = 8.4 Hz, 1 H), 11.55 (s, 1 H). MS (MH+ found) = 419.2
26. 2-Hydroxy-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one hydrochloride
1 ,1-Dimethoxy-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol (example 25) (37 mg) is dissolved in methanol (1 ml) and hydrochloric acid (2M in water, 500 μl) is added. The mixture is stirred for 1 h at room temperature. After that, it is concentrated in vacuo and the residue is co-evaporated with dichloromethane and ether to yield 32 mg (89%) of the title compound. 1H-NMR (200 MHz, d6-DMSO); δ = 1.11-1.30 (m, 1 H), 2.07-2.30 (m, 1 H), 2.33-2.60 (m, 1 H), 3.40- 3.60 (m, 1 H), 3.68 (s, 3H), 3.80-4.40 (m, 1 H), 4.45-4.65 (m, 1 H), 4.73 (s, 2H), 6.86 (d, J = 8.7 Hz, 2H), 7.30-7.54 (m, 3H), 7.70-7.85 (m, 2H), 9.19 (d, J = 8.5 Hz, 2H), 13.05 (s, 1 H). MS (MH+ found) = 373.2
27. 2-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-1-ol
2-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (ex- ample 24) (400 mg) is suspended in methanol (24 ml) and sodium borohydride (90 mg) is added in portions. The reaction mixture is stirred for 30 min at room temperature. After that, the mixture is concentrated in vacuo, saturated sodium chloride solution (30 ml) and dichloromethane (25 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to give rise to 348 mg (87%) of the title compound as a single diastereoisomer.
1H-NMR (400 MHz, CDCI3); δ = 1.29 (s, 3H), 1.33 (s, 3H), 2.95 (d, J = 5.0 Hz, 1 H), 3.03 (d, J = 17.0 Hz, 1 H), 3.37 (d, J = 17.0 Hz, 1 H), 3.79 (s, 3H), 4.46 (s, 2H), 4.74 (d, J = 1.0 Hz, 1 H), 5.59 (t, J = 4.6 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2H), 7.20-7.30 (m, 3H), 7.33 (d, J = 8.2 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.75 (s, 1 H), 8.43 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 465.4, 467.4
28. 6-(4-Methoxybenzyl)-3,3-dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline
6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1-ol (example A22) (600 mg) is dissolved in dichloromethane (20 ml) and triethylamine (322 μl) followed by methane- sulfonyl chloride (133 μl) is added. The mixture is heated for 20 min at 14O0C in the microwave. Further triethylamine (215 μl) and methanesulfonyl chloride (60 μl) are added and the mixture heated again for 30 min at 14O0C. After that, water (20 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 292 mg (51 %) of the title compound. 1H-NMR (200 MHz, CDCI3), δ =1.18 (s, 6H), 3.07 (s, 2H), 3.78 (s, 3H), 4.45 (s, 2H), 6.03 (d, J = 9.7 Hz, 1 H), 6.79-6.93 (m, 2H), 7.13-7.37 (m, 5H), 7.37-7.49 (m, 1 H), 7.58 (bs, 1 H), 8.19 (d, J = 8.0 Hz, 1 H). MS (MH+ found) =369.3
29. cis-6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinoline- 1,2-diol
Citric acid (104 mg) is dissolved in tert-butanol / water (2 ml, 1 :1 (v/v)), 6-(4-methoxybenzyl)-3,3- dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline (example 28) (100 mg), /V-methylmorpholine-A/- oxide (35 mg) and finally potassium osmate(VI) dihydrate (40 mg) are added and the mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 28 mg (26%) of the title compound. 1H-NMR (400 MHz, CDCI3); δ = 1.13 (s, 3H), 1.22 (s, 3H), 2.64 (d, J = 6.1 Hz, 1 H), 2.76 (d, J = 6.8 Hz, 1 H), 2.87 (d, J = 16.8 Hz, 1 H), 3.25 (d, J = 16.8 Hz, 1 H), 3.78 (s, 3H), 3.93 (t, J = 5.6 Hz, 1 H), 4.48 (s, 2H), 5.43-5.52 (m, 1 H), 6.85 (d, J = 8.7 Hz, 2H), 7.19-7.31 (m, 3H), 7.35 (d, J = 8.2 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.79 (br, 1 H), 8.50 (d, J = 8.1 Hz, 1 H). MS (MH+ found) = 403.4
30. 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-one θ^-Methoxybenzy^-S.S-dimethyl-i-^trimethylsily^oxyl^J-dihydro-SH-indolo^.S-clquinoline (example A13) (100 mg) is suspended in dry acetonitrile (0.6 ml) and the suspension is cooled to -2O0C. Sodium azide (71 mg) and a solution of eerie ammonium nitrate (637 mg) in dry acetonitrile (1.6 ml) are added, the latter drop by drop. The reaction mixture is stirred for 30 min at -2O0C. After that, water (25 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to give rise to 45 mg (48%) of the title compound.
1H-NMR (200 MHz, CDCI3); δ = 1.08 (s, 3H), 1.33 (s, 3H), 3.32 (s, 2H), 3.78 (s, 3H), 4.24 (s, 1 H), 4.52 (s, 2H), 6.79-6.93 (m, 2H), 7.15-7.42 (m, 4H), 7.46-7.61 (m, 1 H), 8.01 (br, 1 H), 9.34 (d, J = 8.4 Hz, 1 H).
MS (MH+ found) = 426.2
31. 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-ol
2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one (example 30) (50 mg) is dissolved in methanol (1.5 ml) and sodium borohydride (11 mg) is added in portions. The reaction mixture is stirred for 20 min at room temperature. After that, saturated sodium chloride solution (10 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 48 mg (94%) of the title compound. 1H-NMR (200 MHz, d6-DMSO); δ = 1.01 (s, 3H), 1.17 (s, 3H), 2.50-2.69 (m, 1 H), 2.85-3.02 (m, 1 H), 3.67 (s, 3H), 3.82 (d, J = 4.8 Hz, 1 H), 4.20-448 (m, 2H), 5.45-5.58 (m, 1 H), 5.73 (d, J = 7.1 Hz, 1 H), 6.72-6.89 (m, 2H), 7.10-7.45 (m, 3H), 7.41-7.62 (m, 2H), 8.49 (d, J = 8.1 Hz, 1 H), 11.52 (s, 1 H). MS (MH+ found) = 428.1
32. 2-Amino-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-ol
2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol (example 31 ) (45 mg) is dissolved in methanol / water (2 ml, 9:1 (v/v)) and palladium on charcoal (10% Pd, 10 mg) are added. The mixture is stirred under an atmosphere of hydrogen (1 atm) for 2 h at room temperature. After that, it is filtered through a plug of Celite®, the plug is washed with dichloromethane (25 ml) and the combined filtrate is dried (MgSO4), concentrated in vacuo and dried in high vacuum to yield 35 mg (87%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.01 (s, 3H), 1.02 (s, 3H), 1.83 (br, 1 H), 2.64 (d, J = 16.9 Hz, 1 H), 2.81-2.91 (m, 1 H), 2.96 (d, J = 16.7 Hz, 1 H), 3.67 (s, 3H), 4.27-4.41 (m, 2H), 5.07-5.28 (m, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.18 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 8.44 (d, J = 8.1 Hz, 1 H), 11.49 (br, 1 H). MS (MH+ found) = 402.3 33. 7-(4-Methoxybenzyl)-4,4-dimethyl-3,3a,4,5,δ,12d-hexahydro-2H-indolo[2,3- c][1,3]oxazolo[5,4-f]quinolin-2-one
2-Annino-6-(4-nnethoxybenzyl)-3,3-dinnethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol (example 32) (50 mg) is dissolved in dichloromethane (2 ml), potassium carbonate (138 mg) and triphos- gene (39 mg) are added and the mixture is stirred for 1 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (3 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with n-hexane / ethyl acetate gradient) to yield 17 mg (32%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 0.93 (s, 3H), 1.03 (s, 3H), 2.66 (d, J = 15.8 Hz, 1 H), 2.96 (d, J = 16.0 Hz, 1 H), 3.67 (s, 3H), 3.96-4.09 (m, 1 H), 4.30-4.42 (m, 2H), 6.30 (d, J = 7.6 Hz, 1 H), 6.82 (d, J = 8.5 Hz, 2H), 7.20-7.29 (m, 3H), 7.55 (dd, J = 7.9 Hz, 7.9 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 8.09 (s, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 11.69 (br, 1 H). MS (MH+ found) = 428.3
34. δ'^-MethoxybenzyO-r.S'^'J'-tetrahydrospiroti .S-dioxolane^^'-indolo^.S- cjquinoline]
Step 1 : 6-(4-Methoxybenzylidene)-3,4,6,7-tetrahydro-1 H-spiro[chromeno[3,4-b]indole-2,2'- [1 ,3]dioxolane]. 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one (example A8) (990 mg) and (4- methoxyphenyl) acetic acid anhydride (9.96 g) are suspended in nitromethane (30 ml). The resulting slurry is stirred for 10 min at room temperature and 70% (v/v) aqueous HCIO4 solution (270 μl) is added in portions (6 portions, every 15 minutes). The mixture is stirred for one additional hour at room temperature. Thereafter, it is diluted with ethyl acetate (50 ml) and washed with a mixture of saturated aqueous NaHCO3 solution and saturated aqueous Na2CO3 solution (1 :1 (v/v), 4 x 30 ml). The combined aqueous phase is reextracted with ethyl acetate (1 x 80 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product (6.7 g) is used for the next step without further purification.
Step 2: 6'-(4-Methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]. 6- (4-Methoxybenzylidene)-3,4,6,7-tetrahydro-1 H-spiro[chromeno[3,4-b]indole-2,2'-[1 ,3]dioxolane] (crude product of step 1 , 6.7 g) is dissolved in acetonitrile (12 ml) and treated with 25% (w/v) aqueous NH3 solution (12 ml). The reaction mixture is heated in several portions in sealed vials in a microwave at 13O0C for 25 min. The mixtures are recombined and diluted with ethyl acetate (100 ml) and water (40 ml). The aqueous phase is extracted with ethyl acetate (2 x 40 ml), the combined organic extracts dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / n-hexane), followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to give rise to 23 mg (2%, 2 steps) of the title compound. 1H-NMR (400 MHz, CDCI3); δ = 2.18 (t, J = 6.7 Hz, 2H), 3.32-3.44 (m, 2H), 3.57 (s, 2H), 3.71-8.81 (m, 3H), 4.07-4.19 (m, 4H), 4.48 (s, 2H), 6.82 (d, J = 8.5 Hz, 2H), 7.19-7.31 (m, 3H), 7.37 (d, J = 8.2 Hz, 1 H), 7.46 (dd, J = 7.8 Hz, 7.8 Hz, 1 H), 7.83 (br, 1 H), 8.11 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 401.2
The following compounds are obtained by using the procedure of example 34 analogously.
35. Ethyl 6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline-2-carboxylate
Starting compounds: Ethyl 3-(1 H-indol-3-yl)-4-oxocyclohexanecarboxylate (example A9) and (4- methoxyphenyl) acetic acid anhydride; yield: 2% (2 steps).
1H-NMR (400 MHz,CDCI3); δ = 1.34 (t, J = 7.2 Hz, 3H), 2.01-2.17 (m, 1 H), 2.38-2.48 (m, 1 H), 2.89- 3.00 (m, 1 H), 3.11-3.30 (m, 2H), 3.46-3.59 (m, 1 H), 3.60-3.70 (m, 1 H), 3.77 (s, 3H), 4.20-4.31 (m, 2H), 4.47 (s, 3H), 6.48 (d, J = 8.5 Hz, 2H), 7.20-7.30 (m, 3H), 7.37 (d, J = 8.1 Hz, 1 H), 7.45 (t, J =
8.4 Hz, 1 H), 7.81 (br, 1 H), 8.16 (d, J = 8.0 Hz, 1 H). MS (MH+ found) = 415.3
36. 6-(4-Methoxybenzyl)-2-methyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinoline
Starting compounds: 2-(1 H-lndol-3-yl)-4-methylcyclohexanone (example A10) and (4-methoxy- phenyl) acetic acid anhydride; yield: 10% (2 steps). 1H-NMR (400 MHz, d6-DMSO); δ = 1.19 (d, J = 6.4 Hz, 3H), 1.48-1.60 (m, 1 H), 1.90-2.09 (m, 2H), 2.71-2.86 (m, 1 H), 2.90-3.00 (m, 2H), 3.40-3.50 (m, 1 H), 3.67 (s, 3H), 4.30 (s, 2H), 6.81 (d, J =
8.5 Hz, 2H), 7.20 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 7.8 Hz, 7.8 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 11.55 (s, 1 H).
MS (MH+ found) = 357.3
37. 6-(4-Methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinoline
Starting compounds: 2-(1 H-lndol-3-yl)-5-methylcyclohexanone (example A11 ) and (4-methoxy- phenyl) acetic acid anhydride; yield: 9% (2 steps).
1H-NMR (400 MHz, d6-DMSO); δ = 1.11 (d, J = 6.1 Hz, 3H), 1.42-1.60 (m, 1 H), 1.90-2.10 (m, 2H), 2.48-2.65 (m, 1 H), 2.97-3.19 (m, 1 H), 3.15-3.45 (m, 2H), 3.67 (s, 3H), 4.35 (s, 2H), 6.81 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 11.65 (s, 1 H). MS (MH+ found) = 357.3
38. 6-(4-Methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline
Starting compounds: 2-(1 H-lndol-3-yl)-6-methylcyclohexanone (example A12) and (4-methoxy- phenyl) acetic acid anhydride; yield: 8% (2 steps).
1H-NMR (200 MHz, d6-DMSO); δ = 1.36 (d, J = 6.9 Hz, 3H), 1.56-1.75 (m, 1 H), 1.75-2.15 (m, 3H), 2.91-3.12 (m, 1 H), 3.18-3.39 (m, 2H), 3.67 (s, 3H), 4.31 (s, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.19 (dd, J = 6.9 Hz, 6.9 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 2H), 7.40-7.62 (m, 2H), 8.12 (d, J = 8.0 Hz, 1 H), 11.40
(s, 1 H).
MS (MH+ found) = 357.2
39. e'^S-Fluoro^-methoxybenzyO-i'.S'^'J'-tetrahydrospiroti .S-dioxolane^^'-indolo^.S- cjquinoline]
Step 1 : 3-Hydroxy-3-(8-oxo-1 ,4-dioxaspiro[4.5]dec-7-yl)-1 ,3-dihydro-2H-indol-2-one. lsatine (5.88 g) is dissolved in ethyl acetate (120 ml), 1 ,4-dioxaspiro[4.5]decan-8-one (9.36 g) and diethyl amine (1 ml) are added and the reaction mixture is stirred for 18 h at room temperature. After that, the mixture is concentrated in vacuo and the residue is crystallized from an ethyl acetate / petroleum ether mixture (2:1 (v/v)) to yield 8.42 g (69%) of 3-hydroxy-3-(8-oxo-1 ,4-dioxaspiro[4.5]dec-7- yl)-1 ,3-dihydro-2H-indol-2-one.
Step 2: 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-ol. Lithium aluminium hydride (1.18 g) is suspended in dry tetrahydrofuran and 3-hydroxy-3-(8-oxo-1 ,4-dioxaspiro[4.5]dec-7-yl)-1 ,3-dihydro-2H- indol-2-one (3.00 g) is added in portions. The suspension is stirred for 3 h at room temperature and 1 h at 8O0C. After cooling to room temperature, water (3 ml) is added drop by drop, followed by tetrahydrofuran (20 ml). The suspension is stirred for 30 min at room temperature, then filtered, the solid washed thoroughly with ethyl acetate, the combined filtrate is dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (silica gel, eluting with dichloro- methane / ethyl acetate 11 :9 (v/v)) to yield 1.44 g (53%) of 7-(1 H-indol-3-yl)-1 ,4- d ioxaspiro[4.5]d ecan-8-ol .
Step 3: 7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one. Dimethylsulfoxide (0.84 ml) is dissolved in dry dichloromethane (10 ml) and the solution is cooled to -750C. Trifluroacetanhydride (1.21 ml) is added drop by drop and the mixture is stirred for 30 min at -750C. A solution of 7-(1 H-indol-3-yl)- 1 ,4-dioxaspiro[4.5]decan-8-ol (1.40 g) in dry tetrahydrofuran (15 ml) is then added via syringe and the mixture is stirred for further 1 h at -750C. Triethyl amine (3.28 ml) is added and the reaction mixture is allowed to warm to room temperature. Water (50 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloromethane (1 x 50 ml), the combined organic extracts are washed with water (2 x 80 ml), dried (MgSO4) and concentrated in vacuo to give rise to 1.24 g (89%) of 7-(1 H-indol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one.
Step 4: 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3- c]quinoline]. 3-Fluoro-4-methoxyphenylacetic acid (1.11 g) is dissolved in 1 ,2-dichloroethane (2 ml), trifluoroacetic anhydride (0.83 ml) is added and the solution is stirred for 15 min at room temperature. Then, it is cooled (ice bath) and a solution of 7-(1 H-indol-3-yl)-1 ,4-dioxaspiro[4.5]decan-8-one (1.09 g) in 1 ,2-dichloroethane (2 ml) is added, followed by a catalytic amount (4 drops) of phosphorus acid (H3PO4). After stirring for 5 h at room temperature, ammonia (7N in methanol, 4 ml) is added and the mixture is heated for 30 min in a sealed vial at 15O0C using microwave radiation. The reaction mixture is diluted with ethyl acetate (20 ml) and water (10 ml), the aqueous phase is extracted with ethyl acetate (3 x 20 ml), the combined organic extracts are washed with 2N aque- ous ammonia (2 x 50 ml) and water (1 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 3:2 (v/v)) to give rise to 250 mg (15%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.05 (t, J = 6.7 Hz, 2H), 3.09 (t, J = 6.6 Hz, 2H), 3.43 (s, 2H), 3.75 (s, 3H), 3.95-4.10 (m, 4H), 4.32 (s, 2H), 7.03 (t, J = 8.8 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.15- 7.28 (m, 2H), 7.52 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 8.1 1 (d, J = 7.9 Hz, 1 H), 11.52 (s, 1 H).
40. 6-(4-Methoxybenzyl)-1,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one
6'-(4-Methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline] (example 34) (0.25 g) is dissolved in tetrahydrofuran (10 ml) and the solution is cooled (ice bath). Aqueous hydrochloric acid (5%, 3 ml) is added drop by drop, the mixture is allowed to warm to room temperature and stirred for 18 h. The mixture is basified with saturated sodium hydrogen carbonate solution (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from ethyl acetate / diethyl ether to yield 180 mg (82%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 2.67 (t, J = 7.2 Hz, 2H), 3.22-3.38 (m, 2H), 3.67 (s, 3H), 4.13 (s, 2H), 4.36 (s, 2H), 6.82 (d, J = 8.8 Hz, 2H), 7.22 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 2H), 7.53 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.62 (s, 1 H). MS (MH+ found) = 357.2
The following compounds are obtained by using the procedure of example 40 analogously.
41. 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one
Starting compound: 6'-(3-Fluoro-4-methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'- indolo[2,3-c]quinoline] (example 39); yield: 45%.
1H-NMR (400 MHz, d6-DMSO); δ = 2.74 (t, J = 7.2 Hz, 2H), 3.22-3.35 (m, 2H), 3.67 (s, 3H), 4.13 (s, 2H), 4.36 (s, 2H), 6.78-6.88 (m, 2H), 7.22 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.53 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 11.62 (s, 1 H).
42. N-[6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-formamide
6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one (example 40) (1.5 g) is suspended in formamide (12.9 ml) and formic acid (85%, 12.1 ml) and ammonium formiate (20.0 g) are added. The mixture is stirred for 18 h at 16O0C. After cooling, it is diluted with water (50 ml), extracted thoroughly with ethyl acetate (8 x 50 ml), the combined organic extracts are washed with 2M sodium carbonate solution (1 x 200 ml), dried (MgSO4) and concentrated in vacuo. The residue is crystallized from ethyl acetate to give rise to 700 mg (43%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.83-1.98 (m, 1 H), 2.02-2.15 (m, 1 H), 2.98-3.09 (m, 2H), 3.10- 3.20 (m, 1 H), 3.52-3.63 (m, 1 H), 3.67 (s, 3H), 4.20-4.30 (m, 1 H), 4.32 (s, 2H), 6.8 (d, J = 6.9 Hz, 2H), 7.22 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 2H), 7.51 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 8.10 (s, 1 H), 8.15 (s, 1 H), 8.28 (d, J = 6.9 Hz, 1 H), 11.52 (s, 1 H). MS (MH+ found) = 386.3
43. 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine
N-[6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-fornnannide (example 42) (0.6 g) is dissolved in a 2M solution of hydrogen chloride in methanol (15 ml, prepared before by dropping acetyl chloride (1.1 ml) in methanol (15 ml)). The mixture is stirred for 20 h at 750C, after that it is concentrated in vacuo. The residue is treated with water (20 ml), extracted with ethyl ace- tate (3 x 20 ml), the combined organic extracts washed with 2M sodium carbonate solution
(1 x 30 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / triethyl amine 10:1 (v/v) to ethyl acetate / methanol / triethyl amine 4:1 :0.1 (v/v/v)) to yield 70 mg (12%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.60-1.79 (m, 1 H), 2.00-2.10 (m, 1 H), 2.88-3.08 (m, 2H), 3.20- 3.42 (m, 4H), 3.50-3.61 (m, 1 H), 3.66 (s, 3H), 4.31 (s, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.22 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.27 (d, J = 8.7 Hz, 2H), 7.51 (dd, J = 7.3 Hz, 7.3 Hz 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.49 (s, 1 H). MS (MH+ found) = 358.3
44. Cyclopropyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3- c]quinolin-2-yl]-amine
6'-(3-Fluoro-4-methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline] (example 39) (1.0 g) is dissolved in tetrahydrofuran / acetone (1 :1 (v/v), 50 ml) and 2M hydrochloric acid (10 ml) is added. The mixture is refluxed for 16 h. After cooling, the mixture is basified by addition of saturated sodium carbonate solution, extracted with ethyl acetate (3 x 100 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo.
The residue is redissolved in dichloromethane (50 ml) and cyclopropylamine (0.18 ml), sodium borohydride (0.67 g) and acetic acid (0.14 ml) are added. The mixture is stirred at room tempera- ture for 18 h. After that, saturated sodium carbonate solution (50 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 50 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 5:1 (v/v) to ethyl acetate / methanol / triethyl amine 5:1 :0.1 (v/v/v)) to yield 250 mg (25%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 0.23-0.36 (m, 2H), 0.40-0.50 (m, 2H), 1.61-1.78 (m, 1 H), 2.11- 2.30 (m, 2H), 2.35-2.48 (m, 1 H), 2.89-3.08 (m, 3H), 3.08-3.22 (m, 1 H), 3.51-3.68 (m, 1 H), 3.75 (s, 3H), 4.31 (s, 2H), 7.03 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.15-7.27 (m, 2H), 7.51 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.49 (s, 1 H). MS (MH+ found) = 416.4 The following compounds are obtained by using the procedure of example 44 analogously.
45. Ethyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-yl]- amine
Starting compounds: 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'- indolo[2,3-c]quinoline] (example 39) and ethylamine; yield: 28%.
1H-NMR (400 MHz, d6-DMSO); δ = 1.09 (t, J = 7.1 Hz, 3H), 1.60-1.74 (m, 1 H), 2.05-2.18 (m, 1 H), 2.69-2.80 (m, 2H), 2.35-3.10 (m, 4H), 3.50-3.61 (m, 2H), 3.75 (s, 3H), 4.31 (s, 2H), 7.03 (dd, J = 8.7 Hz, 8.7 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.12-7.38 (m, 2H), 7.51 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.48 (s, 1 H). MS (MH+ found) = 404.3
46. [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-yl]-(4- methoxy-phenyl)-amine
Starting compounds: 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'- indolo[2,3-c]quinoline] (example 39) and 4-methoxyaniline; purification by column chromatography (silica gel, eluting with gradient dichloromethane to dichloromethane / ethyl acetate 3:2 (v/v)), followed by crystallization from ethyl acetate / ether; yield: 26%. 1H-NMR (400 MHz, d6-DMSO); δ = 2.08-2.25 (m, 1 H), 2.25-2.40 (m, 1 H), 3.15-3.31 (m, 1 H), 3.33- 3.72 (m, 2H), 3.76 (s, 3H), 3.78 (s, 3H), 3.85-4.00 (m, 1 H), 4.01-4.16 (m, 1 H), 4.77 (s, 2H), 6.99- 7.16 (m, 3H), 7.31-7.60 (m, 6H), 7.74-7.88 (m, 2H), 8.18 (d, J = 8.1 Hz, 1 H), 13.11 (s, 1 H). MS (MH+ found) = 482.3
47. Benzyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2- yl]-amine
Starting compounds: 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'- indolo[2,3-c]quinoline] (example 39) and benzylamine; purification by column chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 2:1 (v/v)), followed by crystal- lization from ethyl acetate; yield: 27%.
1H-NMR (400 MHz, d6-DMSO); δ = 1.62-1.81 (m, 1 H), 2.08-2.21 (m, 1 H), 2.31-2.48 (m, 1 H), 2.83- 3.12 (m, 4H), 3.49-3.61 (m, 1 H), 3.75 (s, 3H), 3.82-4.00 (m, 2H), 4.30 (s, 2H), 7.03 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 1 H), 7.13-7.28 (m, 3H), 7.33 (dd, J = 7.7 Hz, 7.7 Hz, 2H), 7.43 (d, J = 7.1 Hz, 2H), 7.50 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 1 1.47 (s, 1 H). 48. [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-yl]-(2- methoxy-ethyl)-amine
Starting compounds: 6'-(3-Fluoro-4-methoxybenzyl)-1 ',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'- indolo[2,3-c]quinoline] (example 39) and 2-methoxyethyl amine; purification by column chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 2:1 (v/v)), followed by crystallization from ethyl acetate; yield: 21 %.
1H-NMR (400 MHz, d6-DMSO); δ = 1.59-1.78 (m, 1 H), 2.05-2.18 (m, 1 H), 2.70-3.10 (m, 7H), 3.27 (s, 3H), 3.46 (t, J = 5.7 Hz, 2H), 3.50-3.61 (m, 1 H), 3.75 (s, 3H), 4.31 (s, 2H), 7.03 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.1 1 (d, J = 8.5 Hz, 1 H), 7.14-7.26 (m, 2H), 7.51 (dd, J = 7.5 Hz, 7.5 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 11.49 (s, 1 H).
49. 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-ylamine
Benzyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine (ex- ample 47) (500 mg) is dissolved in methanol (20 ml), and ammonium formiate (0.281 g) and palladium on charcoal (10%, 0.11 g) are added. The mixture is refluxed until complete conversion (by tic). After cooling, it is concentrated in vacuo, the residue is diluted with 2M sodium carbonate solution (40 ml), extracted with ethyl acetate / tetrahydrofuran (9:1 (v/v), 3 x 40 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / methanol 3:1 (v/v) to ethyl acetate / methanol / triethyl amine 2:1 :0.1 (v/v/v)) to yield 300 mg (73%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 2.05-2.20 (m, 1 H), 2.26-2.41 (m, 1 H), 3.19-3.56 (m, 4H), 3.76 (s, 3H), 3.84-3.99 (m, 1 H), 4.77 (s, 2H), 7.09 (dd, J = 8.7 Hz, 8.7 Hz, 1 H), 7.31-7.50 (m, 2H), 7.51- 7.64 (m, 1 H), 7.71-7.90 (m, 2H), 8.18-8.30 (m, 1 H), 8.51 (s, 2H), 13.18 (s, 1 H).
50. N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-yl]-2- methoxy-acetamide
6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine (example 49) (300 mg) is dissolved in dichloromethane (25 ml), triethyl amine (100 μl) and methoxy acetyl chlo- ride (90 μl) are added and the mixture is stirred for 1 h at room temperature. After that, 2M sodium carbonate solution (25 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 25 ml), the combined organic extracts are washed with 2M sodium carbonate solution, dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from ethyl acetate to give rise to 170 mg (48%) of the title compound. 1H-NMR (400 MHz, d6-DMSO); δ = 1.86-2.01 (m, 1 H), 2.02-2.13 (m, 1 H), 2.94-3.12 (m, 2H), 3.18- 3.32 (m, 1 H), 3.35 (s, 3H), 3.50-3.61 (m, 1 H), 3.76 (s, 3H), 3.87 (s, 2H), 4.18-4.30 (m, 1 H), 4.35 (s, 2H), 7.04 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 7.16-7.29 (m, 2H), 7.54 (dd, J = 7.8 Hz, 7.8 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H), 7.92 (d, J = 7.7 Hz, 1 H), 8.1 1 (d, J = 8.0 Hz, 1 H), 11.60 (bs, 1 H). 51. δ'^S-Fluoro^-methoxybenzylJ-i'^'^'J'-tetrahydrospiroti .S-dioxolane^.S'-indolo^.S- cjquinoline]
8-(1 H-indol-3-yl)-1 ,4-dioxaspiro[4.5]decan-7-one (example A16) (8.00 g) is dissolved in dichloro- ethane (50 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 45 ml) is added drop by drop and the mixture is stirred at O0C for 90 min. In parallel, 3-fluoro-4-methoxy- phenyl acetic acid (8.3 g) is dissolved in trifluoroacetic acid anhydride (6.3 ml) and the mixture is stirred for 30 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (20 ml) and added to the zinc chloride mixture, prepared above, within 20 min. The mixture is stirred for 90 min at O0C. After that, glacial acetic acid (140 ml) and ammonium acetate (34.0 g) are added and the mixture is stirred for 16 h at 1000C. After cooling, water (200 ml) is added and the mixture is basified with solid sodium hydrogencarbonate. Additional water (200 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 250 ml), the combined organic extracts are washed with water (1 x 400 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate) to yield 3.19 g (26%) of the title compound.
1H-NMR (400MHz, d6-DMSO); δ = 2.06 (t, J = 6.7 Hz, 2H), 3.11 (s, 2H), 3.37 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.98 (s, 4H), 4.32 (s, 2H), 6.99 (m, 2H), 7.16-7.28 (m, 2H), 7.52 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.52 (s, 1 H).
52. 6-(3-Fluoro-4-methoxybenzyl)-1,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3-one
6'-(3-Fluoro-4-methoxybenzyl)-1',2',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,3'-indolo[2,3-c]quinoline] (example 51 ) (3.00 g) is dissolved in tetrahydrofuran (110 ml) and 2M hydrochloric acid (45 ml) is added. The mixture is refluxed for 4 h, and stirred at room temperature for 12 h. After that, it is ba- sified with saturated sodium hydrogen carbonate solution (200 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is crystallized from ethyl acetate / n-heptane and dried in vacuo to yield 2.09 g (78%) of the title compound as orange crystals. 1H-NMR (300 MHz, d6-DMSO); δ = 2.72 (t, J = 6.9 Hz, 2H), 3.62 (t, J = 6.9 Hz, 2H), 3.75 (s, 3H), 3.82 (s, 2H), 4.36 (s, 2H), 6.98-7.30 (m, 4H), 7.54 (t, J = 7.4 Hz, 1 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 1 1.68 (s, 1 H).
53. 2-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3- ylaminoj-acetamide 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3-one (example 52) (100 mg) is suspended in methanol (3 ml) and glycinamide hydrochloride (30 mg), glacial acetic acid (15 μl) and sodium cyanoborohydride (1 M in tetrahydrofuran, 374 μl) are added. The mixture is stirred for 4 h at room temperature. After that, water (10 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are concentrated in vacuo. The crude product is purified by flash chromatography (amino- modified silica gel, eluting with ethyl acetate / methanol 9:1 (v/v)), followed by crystallization from ethyl acetate to obtain 45 mg (39%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.59-1.79 (m, 1 H), 2.05-2.21 (m, 1 H), 2.22-2.48 (m, 1 H), 2.64- 2.80 (m, 1 H), 2.91-3.05 (m, 1 H), 3.08-3.25 (m, 4H), 3.32-3.49 (m, 1 H), 3.75 (s, 3H), 4.31 (s, 2H), 6.93-7.13 (m, 3H), 7.13-7.25 (m, 2H), 7.30 (s, 1 H), 7.50 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.59 (d, J = 8.0 Hz, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 11.48 (s, 1 H). MS (MH+ found) = 433.1
The following compounds are obtained by using the procedure of example 53 analogously.
54. [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3- ylamino]-acetic acid methyl ester
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3- one (example 52) and glycin methylester; purification by column chromatography (amino-modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)); yield: 59%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.60-1.80 (m, 1 H), 2.05-2.21 (m, 2H), 2.61-2.79 (m, 1 H), 2.99- 3.26 (m, 3H), 3.32-3.48 (m, 1 H), 3.50 (s, 2H), 3.64 (s, 3H), 3.75 (s, 3H), 4.31 (s, 2H), 6.97-7.12 (m, 2H), 7.13-7.26 (m, 2H), 7.50 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.45 (s, 1 H). MS (MH+ found) = 448.0
55. Benzyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3- yl]-amine Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3- one (example 52) and benzylamine; purification by column chromatography (silica gel, eluting with ethyl acetate / methanol 5:1 (v/v)).
1H-NMR (400 MHz, d6-DMSO); δ = 2.11-2.28 (m, 1 H), 2.56-2.68 (m, 1 H), 3.25-3.48 (m, 1 H), 3.48- 3.61 (m, 1 H), 3.62-3.98 (m, 6H), 4.20-4.44 (m, 2H), 4.76 (s, 2H), 7.09 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.29-7.62 (m, 6H), 7.62-7.88 (m, 4H), 8.21-8.41 (m, 1 H), 9.77 (bs, 1 H), 9.97 (bs, 1 H).
56. N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]- N~2 — methylglycinamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3- one (example 52) and N-methylglycin amide; purification by column chromatography (amino modified silica gel, eluting with ethyl acetate / methanol 95:5 (v/v)), followed by preparative HPLC (C18, eluting with gradient acetonitrile / water); yield: 33%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.65-1.85 (m, 1 H), 2.12-2.28 (m, 1 H), 2.38 (s, 3H), 2.85-3.29 (m, 6H), 3.40-3.56 (m, 1 H), 3.75 (s, 3H), 4.32 (s, 2H), 6.98-7.29 (m, 6H), 7.51 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.8 Hz, 1 H), 11.50 (s, 1 H).
57. 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-ylamine
Benzyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-annine (example 55) (3.0 g) is dissolved in methanol (30 ml), palladium on charcoal (10%, 0.68 g) and ammonium formiate (0.95 g) are added and the mixture is refluxed for 18 h. After cooling, it is filtered through a short pad of Celite, washed (methanol) and the filtrate is concentrated in vacuo. The residue is redissolved in ethyl acetate (50 ml) and 2M sodium carbonate solution (50 ml), the aqueous phase is extracted with ethyl acetate (2 x 50 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient ethyl acetate to ethyl acetate / methanol 3:1 (v/v) to ethyl acetate / methanol / triethyl amine 1 :1 :0.1 (v/v/v)), followed by crystallization from ethyl acetate to yield 1.07 g (44%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.53-1.87 (m, 2H), 2.01-2.17 (m, 1 H), 2.59-2.75 (m, 1 H), 3.10- 3.48 (m, 5H), 3.75 (s, 3H), 4.31 (s, 2H), 6.96-7.24 (m, 4H), 7.50 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 1 1.46 (s, 1 H). MS (MH+ found) = 376.2
58. [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]- carbamic acid ethyl ester
6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamine (example 57) (0.3 g) is suspended in tetrahydrofuran (15 ml), the suspension is cooled to O0C (ice bath) and triethyl amine (100 μl) and a solution of ethyl chloroformate (108 μl) in tetrahydrofuran (5 ml) are added. The mixture is stirred at room temperature for 4 h. After that, water (20 ml) and ethyl acetate (20 ml) is added, the aqueous phase is extracted with ethyl acetate (2 x 20 ml), the combined organic extracts are washed with 2M sodium carbonate solution (1 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / methanol 5:1 (v/v)), followed by crystallization from ethyl acetate / ether to yield 210 mg (59%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.18 (t, J = 7.1 Hz, 3H), 1.90-2.06 (m, 1 H), 2.10-2.23 (m, 1 H), 3.05-3.19 (m, 1 H), 3.36-3.47 (m, 1 H), 3.48-3.59 (m, 1 H), 3.76 (s, 3H), 3.94-4.13 (m, 3H), 4.74 (s, 2H), 7.09 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 7.38-7.58 (m, 3H), 7.70-7.86 (m, 2H), 8.33 (d, J = 8.2 Hz, 1 H), 12.95 (s, 1 H), 15.65 (s, 1 H). 59. N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]-2- methoxy-acetamide θ-^-Fluoro^-methoxy-benzyl^S^J-tetrahydro-I H-indolo^S-clquinolin-S-ylamine (example 57) (0.3 g) is suspended in tetrahydrofuran (25 ml), the suspension is cooled to O0C (ice bath) and triethyl amine (100 μl) and a solution of methoxyacetyl chloride (84 μl) in tetrahydrofuran (10 ml) are added. The mixture is stirred at room temperature for 2 h. After that, water (20 ml) and ethyl acetate (20 ml) is added, the aqueous phase is extracted with ethyl acetate (2 x 20 ml), the combined organic extracts are washed with 2M sodium carbonate solution (1 x 40 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / methanol 5:1 (v/v)), followed by crystallization from ethyl acetate / etha- nol / ether to obtain 240 mg (84%) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.99-2.10 (m, 1 H), 2.10-2.20 (m, 1 H), 3.13-3.28 (m, 1 H), 3.29- 3.60 (m, 6H), 3.76 (s, 3H), 3.87 (s, 2H), 4.25-4.39 (m, 1 H), 4.75 (s, 2H), 7.09 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.41 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.52 (d, J = 12.5 Hz, 1 H), 7.70-7.86 (m, 2H), 8.08 (d, J = 7.7 Hz, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 12.99 (s, 1 H), 15.75 (s, 1 H).
The following compound is obtained by using the procedure of example 59 analogously.
60. N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]- acetamide
Starting compounds: θ-^-Fluoro^-methoxy-benzyl^S^J-tetrahydro-I H-indolo^S-clquinolin-S- ylamine (example 57) and acetyl chloride;
1H-NMR (400 MHz, d6-DMSO); δ = 1.85 (s, 3H), 1.90-2.05 (m, 1 H), 2.09-2.20 (m, 1 H), 3.02-3.14 (m, 1 H), 3.28-3.60 (m, 3H), 3.76 (s, 3H), 4.18-4.30 (m, 1 H), 4.75 (s, 2H), 7.10 (dd, J = 8.8 Hz,
8.8 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 7.41 (dd, J = 7.3 Hz, 7.3 Hz, 1 H), 7.52 (d, J = 11.1 Hz, 1 H), 7.71-7.88 (m, 2H), 8.12 (d, J = 7.0 Hz, 1 H), 8.35 (d, J = 8.2 Hz, 1 H), 12.99 (s, 1 H), 15.72 (s, 1 H).
61. Morpholine-4-carboxylic acid [6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H- indolo[2,3-c]quinolin-3-yl]-amide
6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamine (example 57) (0.25 g) is dissolved in dichloromethane (20 ml), the suspension is cooled to O0C (ice bath) and triethyl amine (102 μl) and morpholine carbonyl chloride (87 μl) in tetrahydrofuran (10 ml) are added. The mixture is stirred at room temperature for 18 h. After that, water (20 ml) is added, the aqueous phase is extracted with dichloromethane (3 x 20 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate / ether to obtain 180 mg (61 %) of the title compound.
1H-NMR (400 MHz, d6-DMSO); δ = 1.74-1.89 (m, 1 H), 2.11-2.22 (m, 1 H), 2.83-2.97 (m, 1 H), 3.10- 3.38 (m, 6H), 3.38-3.50 (m, 1 H), 3.52-3.61 (m, 4H), 3.75 (s, 3H), 3.92-4.08 (m, 1 H), 4.32 (s, 2H), 6.45 (d, J = 7.2 Hz, 1 H), 7.04 (dd, J = 8.8 Hz, 8.8 Hz, 1 H), 7.1 1 (d, J = 8.4 Hz, 1 H), 7.15-7.26 (m, 2H), 7.51 (dd, J = 7.4 Hz, 7.4 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 1 1.50 (s, 1 H).
62. [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3- ylamino]-acetic acid
^-(S-Fluoro^-methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-ylanninol-acetic acid methyl ester (example 54) (1.43 g) is dissolved in dioxane (3.2 ml) and lithium hydroxide (3M in water, 3.2 ml) is added. The mixture is stirred for 3 h at 8O0C. After cooling, it is poured into saturated ammonium chloride solution (10 ml), diluted with water (20 ml) and stirred for 1 h at room temperature. The precipitate is filtered, washed (water) and dried over P2O5 to give rise to 0.94 g (68%) of the title compound as colorless crystals.
1H-NMR (300 MHz, d6-DMSO); δ = 1.78-1.99 (m, 1 H), 2.30-2.48 (m, 1 H), 2.85-4.22 (m, 12H), 4.33 (s, 2H), 6.98-7.15 (m, 2H), 7.16-7.29 (m, 2H), 7.52 (dd, J = 8.0 Hz, 8.0 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.63 (s, 1 H).
63. N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]- N-methylglycinamide
[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamino]-acetic acid (example 62) (100 mg) is suspended in dry dichloromethane (4 ml) and dimethylformamide (1 ml), methylamine (2M in tetrahydrofuran, 240 μl), 1-hydroxybenzotriazole (47 mg), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (88 mg) and triethylamine (154 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (5 ml) and dichloromethane (10 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient water / acetonitrile) to yield 22 mg (22%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.61-1.81 (m, 1 H), 2.09-2.25 (m, 1 H), 2.62 (d, J = 4.8 Hz, 3H), 2.69-2.86 (m, 1 H), 2.97-3.10 (m, 1 H), 3.10-3.27 (m, 2H), 3.31 (s, 2H), 3.34-3.50 (m, 1 H), 3.75 (s, 3H), 4.31 (m, 2H), 6.99-7.14 (m, 2H), 7.14-7.25 (m, 2H), 7.45-7.55 (m, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.75-7.90 (m, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.17 (s, 1 H), 1 1.50 (s, 1 H). MS (MH+ found) = 447.1
The following compounds are obtained by using the procedure of example 63 analogously.
64. N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]- N-isopropylglycinamide
Starting compounds: [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3- ylamino]-acetic acid (example 62) and isopropylamine; yield: 33%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.03 (d, J = 3.5 Hz, 6H), 1.62-1.81 (m, 1 H), 2.06-2.20 (m, 1 H), 2.67-2.82 (m, 1 H), 2.91-3.09 (m, 1 H), 3.09-3.68 (m, 5H), 3.75 (s, 3H), 3.79-4.91 (m, 1 H), 4.31 (s, 2H), 6.98-7.13 (m, 2H), 7.15-7.27 (m, 2H), 7.49 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.56-7.69 (m, 2H), 8.13 (d, J = 8.0 Hz, 1 H), 8.18 (s, 1 H), 11.49 (s, 1 H).
65. N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]- N-[2-hydroxypropyl]glycinamide (mixture of diastereoisomers)
Starting compounds: [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3- ylamino]-acetic acid (example 62) and 2-hydroxypropylamine; yield: 15%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.00 (d, J = 6.2 Hz, 3H),1.51-1.78 (m, 1 H), 2.09-2.25 (m, 1 H), 2.67-2.80 (m, 1 H), 2.9-3.49 (m, 9H), 3.58-3.72 (m, 1 H), 3.75 (s, 3H), 4.31 (s, 2H), 4.68 (br, 1 H), 6.99-7.15 (m, 2H), 7.16-7.26 (m, 2H), 7.50 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.59 (d, J =8.0 Hz, 1 H), 7.78-7.89 (m, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.49 (s, 1 H). MS (MH+ found) = 491.1
66. N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-3-yl]- N-(2-hydroxyethyl)glycinamide
Step 1 : [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamino]- acetic acid (example 62) (190 mg) is suspended in dry dichloromethane (5 ml) and dimethyl- formamide (1 ml), 2-{[tert-butyl(dimethyl)silyl]oxy}ethanamine (154 mg), 1-hydroxybenzotriazole (90 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (168 mg) and triethylamine (305 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (amino-modified silica gel, eluting with ethyl acetate / methanol 98:2 (v/v)) to obtain 170 mg (66%) of N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-N-2-[6-(3- fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yllglycinamide. Step 2: N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-2-[6-(3-fluoro-4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]glycinamide (170 mg) is dissolved in tetrahydrofuran (3 ml) and tetra-n-butylammonium fluoride (1 M in tetrahydrofuran, 576 μl) is added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 15 ml), the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient water / acetonitrile) to yield 49 mg (36%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.60-1.79 (m, 1 H), 2.08-2.22 (m, 1 H), 2.68-2.80 (m, 1 H), 2.88- 3.02 (m, 1 H), 3.08-3.50 (m, 10H), 3.75 (s, 3H), 4.31 (s, 2H), 4.60-4.72 (m, 1 H), 6.98-7.12 (m, 2H), 7.13-7.25 (m, 2H), 7.50 (dd, J = 7.2Hz, 7.2 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.85 (dd, J = 5.7 Hz, 5.7 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.45 (s, 1 H). MS (MH+ found) = 477.1 67. δ'^S-Fluoro^-methoxybenzylJ-i'^'.S'J'-tetrahydrospiroti .S-dioxolane^^'-indolo^.S- cjquinoline]
7-(1 H-lndol-3-yl)-1 ,4-dioxaspiro[4.5]decan-6-one (example A18) (5.65 g) is dissolved in dichloro- ethane (70 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 42 ml) is added drop by drop and the mixture is stirred at O0C for 1 h. In parallel, 3-fluoro-4-methoxyphenyl acetic acid (7.67 g) is dissolved in trifluoroacetic acid anhydride (6.0 ml) and the mixture is stirred for 1 h at room temperature. The formed mixed anhydride is diluted with dichloroethane (15 ml) and added to the zinc chloride mixture, prepared above, within 30 min. The mixture is stirred for 3 h at room temperature. After that, ammonium acetate (5.0 g) and ammonia (7M in methanol, 40 ml) are added, the formed suspension is divided into microwave vials, the vials are capped and heated for 30 min at 8O0C in the microwave. The precipitate is then filtered, washed (dichloromethane), the combined filtrate is diluted with water (100 ml), the aqueous phase is extracted with dichloromethane (2 x 100 ml), the combined organic extracts again filtered over Celite®, dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane / ethyl acetate 9:1 (v/v)) followed by crystallization from diethyl ether / petroleum ether to give rise to 2.91 g (33%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.05 (s, 4H), 3.20-3.35 (m, 2H), 3.77 (s, 3H), 3.95-4.08 (m, 2H), 4.26-4.40 (m, 4H), 7.06 (dd, J = 8.7 Hz, 8.8 Hz, 1 H), 7.10-7.19 (m, 1 H), 7.19-7.30 (m, 2H), 7.48- 7.59 (m, 1 H), 7.64 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.68 (s, 1 H). mp.: 213-214°C
68. 6-(3-Fluoro-4-methoxybenzyl)-1,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4-one 6'-(3-Fluoro-4-methoxybenzyl)-1',2',3',7'-tetrahydrospiro[1 ,3-dioxolane-2,4'-indolo[2,3-c]quinoline] (example 67) (2.35 g) is dissolved in tetrahydrofuran (80 ml) and 2M hydrochloric acid (35 ml) is added. The mixture is stirred for 1 h at 6O0C. After cooling, it is basified with saturated sodium hydrogen carbonate solution (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts are washed with water (1 x 150 ml), dried (MgSO4) and concentrated in vacuo. The crude product is not purified further and gives rise to 2.1 g (99%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.16-2.32 (m, 2H), 2.68-2.80 (m, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.75 (s, 3H), 4.42 (s, 2H), 6.99-7.15 (m, 2H), 7.18-7.28 (m, 1 H), 7.33 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.60 (dd, J = 7.1 Hz, 7.1 Hz, 1 H), 7.71 (d, J = 8.2 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 12.16 (bs, 1 H).
The following compounds are obtained by using the procedure of example A22 analogously. 69. 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-ol
Starting compound: 6-(4-Methoxybenzyl)-1,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one (example 40); modifications: extraction with dichloromethane / methanol 9:1 (v/v), flash chromatography with ethyl acetate as eluent, then crystallization from ethyl acetate / petroleum ether; yield: 71%. 1H-NMR (200 MHz, CDCI3); δ = 1.90-2.30 (m, 2H), 2.57 (s, 1H), 3.00-3.39 (m, 3H), 3.58-3.80 (m, 4H), 4.25-4.50 (m, 3H), 6.74 (d, J = 6.6 Hz, 2H), 7.02-7.50 (m, 5H), 8.07 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H).
70. 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-2-ol
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2- one (example 41); flash chromatography with gradient dichloromethane / ethyl acetate to ethyl acetate as eluent; yield: 68%.
1H-NMR (400 MHz,d6-DMSO);δ= 1.79-1.95 (m, 1H), 1.98-2.10 (m, 1H), 2.88-3.00 (m, 1H), 3.00- 3.16 (m, 2H), 3.49-3.58 (m, 1H), 3.75 (s, 3H), 4.09-4.21 (m, 1H), 4.31 (s, 2H), 4.89 (d, J= 3.8 Hz, 1H), 7.03 (dd, J= 8.7 Hz, 8.7 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 7.18-7.29 (m, 2H), 7.51 (dd, J = 7.2 Hz, 7.2 Hz, 1H), 7.59 (d, J= 8.2 Hz, 1H), 8.11 (d, J= 8.9 Hz, 1H), 11.48 (s, 1H). MS (MH+ found) = 377.3
71. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ol
Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-3- one (example 52); flash chromatography with gradient dichloromethane / ethyl acetate to ethyl acetate as eluent;
1H-NMR (300 MHz, d6-DMSO);δ= 1.72-1.92 (m, 1H), 2.02-2.19 (m, 1H), 2.77-2.91 (m, 1H), 2.98- 3.68 (m, 3H), 3.75 (s, 3H), 4.02-4.18 (m, 1H), 4.31 (s, 2H), 4.82 (br, 1H), 6.97-7.15 (m, 2H), 7.16- 7.25 (m, 2H), 7.48-7.56 (m, 1H), 7.59 (d, J= 8.1 Hz, 1H), 8.13 (d, J= 6.5 Hz, 1H), 11.48 (s, 1H). MS (MH+ found) = 377.3
72. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-ol Starting compound: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68);
1H-NMR (300 MHz, d6-DMSO); 1.80-2.21 (m, 4H), 3.08-3.55 (m, 2H), 3.75 (s, 3H), 4.36 (s, 2H), 4.67-4.79 (m, 1H), 4.86 (bs, 1H), 7.03 (dd, J= 8.8 Hz, 8.8 Hz, 1H), 7.10-7.30 (m, 3H), 7.52 (dd, J = 7.1 Hz, 7.2 Hz, 1H), 7.61 (d, J= 8.1 Hz, 1H), 8.14 (d, J= 8.0 Hz, 1H), 11.56 (bs, 1H). MS (MH+ found) = 377.3 73. N^-fβ^S-Fluoro^-methoxybenzylJ^^^y-tetrahydro-IH-indolo^^-clquinolin^- yljglycinamide
6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4-one (example 68) (150 mg) is suspended in methanol (2.5 ml) and glycinamide hydrochloride (180 mg), glacial acetic acid (23 μl) and sodium cyanoborohydride (1 M in tetrahydrofuran, 2 ml) are added. The mixture is stirred for 3 h at room temperature and for 3 h at 5O0C. After cooling, the mixture is neutralized with saturated sodium hydrogencarbonate solution and dichloromethane (10 ml) is added, the aqueous phase is extracted with dichloromethane (2 x 10 ml), the combined organic extracts are concen- trated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 85:14:1 (v/v/v)), followed by preparative HPLC (C18, eluting with gradient water / acetonitrile) to yield 45 mg (26%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.71-1.92 (m, 2H), 1.99-2.20 (m, 2H), 3.19-3.38 (m, 4H), 3.75 (s, 3H), 3.80-3.90 (m, 1 H), 4.35 (s, 2H), 7.03 (dd, J = 8.8 Hz, 8.9 Hz, 1 H), 7.12 (bs, 1 H), 7.15-7.31 (m, 3H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.44 (bs, 1 H), 8.15 (d, J =
8.0 Hz, 1 H), 8.19 (s, 1 H), 11.61 (s, 1 H). MS (MH+ found) = 432.9
The following compounds are obtained by using the procedure of example 73 analogously.
74. N-Ethyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and ethylamine; yield: 67%. 1H-NMR (300 MHz, d6-DMSO); δ = 1.13 (t, J = 7.1 Hz, 3H), 1.76-1.93 (m, 2H), 2.05-2.20 (m, 2H), 2.73-2.91 (m, 2H), 3.20-3.36 (m, 2H), 3.76 (s, 3H), 3.98-4.10 (m, 1 H), 4.33 (d, AB, J = 14.3 Hz, 1 H), 4.42 (d, AB, J = 14.3 Hz, 1 H), 7.04 (dd, J = 8.7 Hz, 8.8 Hz, 1 H), 7.10-7.32 (m, 3H), 7.52 (dd, J = 7.2 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 11.75 (s, 1 H). MS (MH+ found) = 403.8
75. N-Cyclopropyl-6-(3-fluoro-4-methoxybenzyl)-2,3A7-tetrahydro-1H-indolo[2,3- c]quinolin-4 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and cyclopropylamine; yield: 79%. 1H-NMR (300 MHz, d6-DMSO); δ = 0.20-0.45 (m, 3H), 0.45-0.58 (m, 1 H), 1.73-1.94 (m, 2H), 2.00- 2.28 (m, 3H), 3.31-3.65 (m, 1 H), 3.76 (s, 3H), 3.90-4.01 (m, 1 H), 4.32 (d, AB, J = 14.4 Hz, 1 H), 4.38 (d, AB, J = 14.4 Hz, 1 H), 6.98-7.16 (m, 2H), 7.16-7.30 (m, 2H), 7.45-7.58 (m, 1 H), 7.61 (d, J =
8.1 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.56 (s, 1 H). MS (MH+ found) = 415.9 76. 2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- yl]amino}ethanol
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and 2-aminoethanol; yield: 67%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.68-1.90 (m, 2H), 1.96-2.19 (m, 2H), 2.58-2.82 (m, 3H), 3.19- 3.36 (m, 2H), 3.41-3.66 (m, 2H), 3.75 (s, 3H), 3.76-3.88 (m, 1 H), 4.34 (s, 2H), 4.52-4.62 (m, 1 H), 6.95-7.09 (m, 1 H), 7.09-7.30 (m, 2H), 7.52 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.53 (s, 1 H). MS (MH+ found) = 419.9
77. N-(1 -Acetylpiperidin-4-yl)-6-(3-fluoro-4-methoxybenzyl)-2,3 A7-tetrahydro-1 H- indolo[2,3-c]quinolin-4 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and 1-acetylpiperidin-4-amine; yield: 66%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.02-1.35 (m, 2H), 1.67-2.21 (m, 9H), 2.70-2.85 (m, 1 H), 2.85- 3.00 (m, 1 H), 3.00-3.15 (m, 1 H), 3.15-3.44 (m, 3H), 3.61-3.79 (m, 1 H), 3.76 (s, 3H), 3.92-4.02 (m, 1 H), 4.02-4.22 (m, 1 H), 4.29 (d, AB, J = 14.5 Hz, 1 H), 4.40 (d, AB, J = 14.6 Hz, 1 H), 7.04 (dd, J = 8.7 Hz, 8.8 Hz, 1 H), 7.09-7.15 (m, 1 H), 7.15-7.30 (m, 2H), 7.52 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 11.60 (s, 1 H). MS (MH+ found) = 501.0
78. 2-(4-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- yl]amino}piperidin-1-yl)-2-oxoethanol Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and 2-(4-aminopiperidin-1-yl)-2-oxoethanol; yield: 9%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.11-1.40 (m, 2H), 1.69-2.00 (m, 4H), 2.00-2.20 (m, 2H), 2.71- 2.90 (m, 1 H), 2.90-3.11 (m, 2H), 3.11-3.72 (m, 5H), 3.76 (s, 3H), 3.99-4.23 (m, 5H), 4.30 (d, AB, J = 14.5 Hz, 1 H), 4.41 (d, AB, J = 14.5 Hz, 1 H), 7.04 (dd, J = 8.6 Hz, 8.7 Hz, 1 H), 7.08-7.17 (m, 1 H), 7.17-7.29 (m, 2H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 7.9 Hz, 1 H), 8.21 (s, 1 H), 11.63 (bs, 1 H). MS (MH+ found) = 516.9
79. (4RS)-N-[(3S)-1-Acetylpiperidin-3-yl]-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-4-amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and (3S)-1-acetylpiperidin-3-amine; yield: 34%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.20-1.50 (m, 2H), 1.60-1.90 (m, 4H), 1.99, 2.02, 2.04 (3s, 3H [diastereomers & rotamers]), 1.99-2.19 (m, 2H), 2.53-2.89 (m, 2H), 2.90-3.12 (m, 1 H), 3.19-3.33 (m, 2H), 3.38-3.19 (m, 2H), 3.67, 3.68 (2s, 3H [diastereomers]), 3.88-4.01 (m, 1 H), 4.19-4.42 (m, 2H), 7.00-7.10 (m, 1 H), 7.10-7.30 (m, 3H), 7.35 (dd, J = 7.5 Hz, 7.6 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 11.56, 11.58, 11.60 (3s, 1 H [diastereomers & rotamers]). MS (MH+ found) = 501.1
80. (4RS)-N-[(3R)-1-Acetylpiperidin-3-yl]-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro- 1H-indolo[2,3-c]quinolin-4 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and (3R)-1-acetylpiperidin-3-amine; yield: 55%. 1H-NMR (300 MHz, d6-DMSO); δ =1.20-1.50 (m, 2H), 1.60-1.90 (m, 4H), 1.99, 2.02, 2.04 (3s, 3H [diastereomers & rotamers]), 1.99-2.19 (m, 2H), 2.53-2.89 (m, 2H), 2.90-3.12 (m, 1 H), 3.19-3.33 (m, 2H), 3.38-3.19 (m, 2H), 3.67, 3.68 (2s, 3H) [diastereomers]),3.88-4.01 (m, 1 H), 4.19-4.42 (m, 2H), 7.00-7.10 (m, 1 H), 7.10-7.30 (m, 3H), 7.35 (dd, J = 7.5 Hz, 7.6 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1 H), 11.56, 11.58, 11.60 (3s, 1 H [diastereomers & rotamers]). MS (MH+ found) = 501.1
81. N-(1 -Acetylazetidin-3-yl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-4 -amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and i-acetylazetidin-3-amine; yield: 58%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.63-1.91 (m, 5H), 1.91-2.21 (m, 2H), 3.10-3.70 (m, 3H), 3.70- 3.86 (m, 6H), 3.86-4.44 (m, 5H), 7.04 (dd, J = 8.7 Hz, 8.8 Hz, 1 H), 7.09-7.18 (m, 1 H), 7.18-7.29 (m, 2H), 7.49-7.54 (m, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 1 1.59 (bs, 1 H). MS (MH+ found) = 473.0
82. N-Benzyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- amine
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c]quinolin-4- one (example 68) and benzylamine; purification by crystallization from acetonitrile / water 4:1 (v/v); yield: 77%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.78-1.92 (m, 2H), 2.05-2.25 (m, 2H), 3.20-3.41 (m, 3H), 3.74 (s, 3H), 3.90-4.08 (m, 3H), 4.34 (d, AB, J = 14.4 Hz, 1 H), 4.42 (d, AB, J = 14.5 Hz, 1 H), 7.00 (dd, J = 8.8 Hz, 8.9 Hz, 1 H), 7.08-7.45 (m, 9H), 7.53 (dd, J = 7.1 Hz, 7.2 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 1 1.68 (bs, 1 H). MS (MH+ found) = 465.9
83. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-amine
N-Benzyl-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine (example 82) (2.00 g) is suspended in methanol (30 ml), glacial acetic acid (1.5 ml) and palladium on charcoal (10%, 300 mg) are added and the mixture is stirred under hydrogen atmosphere (1.1 atm) at room temperature for 36 h. After that, the mixture is filtered over Celite, the Celite plug is washed thoroughly with methanol, the combined filtrate is concentrated in vacuo. The residue is dissolved in water and the solution is neutralized with saturated sodium hydrogencarbonate solution. A white precipitate is formed, that is filtered, washed with water and dried over potassium hydroxide. It is the title compound as acetate salt (1.51 g). The free amine is obtained by dissolution of the acetate salt in dichloromethane / methanol (9:1 (v/v), 20 ml) and addition of 2N sodium hydroxide solution until pH 9. After that, the mixture is diluted with dichloromethane (10 ml), the organic phase is washed with water (1 x 20 ml) and saturated sodium chloride solution (1 x 20 ml), dried (MgSO4), concentrated and dried in vacuo to yield 1.21 g (75%) of the title compound as colorless crystals. 1H-NMR (300 MHz, d6-DMSO); δ = 1.58-1.90 (m, 2H), 1.90-2.19 (m, 4H), 3.17-3.39 (m, 2H), 3.75 (s, 3H), 3.94-4.08 (m, 1 H), 4.35 (s, 2H), 7.04 (dd, J = 8.7 Hz, 8.8 Hz, 1 H), 7.10-7.29 (m, 3H), 7.44- 7.55 (m, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 11.53 (bs, 1 H). MS (MH+ found) = 375.9
84. N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-1 - methylpiperidine-4-carboxamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine (example 83) (150 mg) is suspended in dichloromethane (6 ml) and 1-methylpiperidine-4-carboxylic acid (144 mg), 1-hydroxybenzotriazole (81 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg) and triethylamine (260 μl) are added. The mixture is stirred for 18 h at room temperature. After that, water (10 ml) and dichloromethane (15 ml) are added, the organic phase is separated and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with dichloromethane / methanol 4:1 (v/v)) and either crystallized from acetonitrile / water 4:1 (v/v) or further purified by preparative HPLC (C18, eluting with gradient acetonitrile / water). In this case it is crystallized to yield 173 mg (87%) of the title compound. 1H-NMR (300 MHz, d6-DMSO); δ = 1.57-1.77 (m, 4H), 1.82-2.16 (m, 7H), 2.22 (s, 3H), 2.79-2.92 (m, 2H), 3.12-3.50 (m, 2H), 3.75 (s, 3H), 4.26 (d, AB, J = 14.1 Hz, 1 H), 4.39 (d, AB, J = 14.2 Hz, 1 H), 4.98-5.10 (m, 1 H), 6.95-7.07 (m, 1 H), 7.12-7.30 (m, 3H), 7.48-7.58 (m, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 8.1 Hz, 1 H), 11.64 (bs, 1 H). MS (MH+ found) = 501.1
The following compounds are obtained by using the procedure of example 84 analogously.
85. N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yljacetamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- amine (example 83) and acetic acid; final purification by crystallization from acetonitrile / water 4:1 (v/v); yield 78% 1H-NMR (300 MHz, d6-DMSO);δ= 1.10-1.30 (m, 1H), 1.85 (s, 3H), 1.75-2.10 (m, 4H), 3.10-3.43 (m, 1H), 3.75 (s, 3H), 4.33 (s, 2H), 4.99-5.11 (m, 1H), 6.94-7.10 (m, 1H), 7.10-7.32 (m, 3H), 7.46- 7.58 (m, 1 H), 7.58-7.68 (m, 1 H), 8.05-8.22 (m, 2H), 11.58 (bs, 1 H). MS (MH+ found) = 529.2
86. N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-yl]-2- hyd roxyacetam i de
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- amine (example 83) and glycol acid; final purification by preparative HPLC; yield 80% 1H-NMR (300 MHz, d6-DMSO);δ= 1.74-2.11 (m, 3H), 2.19-2.31 (m, 1H), 3.19-3.41 (m, 2H), 3.75 (s, 3H), 3.82-3.94 (m, 2H), 4.30 (d, AB, J= 14.3 Hz, 1H), 4.36 (d, AB, J= 14.3 Hz, 1H), 4.92-5.03 (m, 1H), 5.45 (t, J= 5.8 Hz, 1H), 7.02 (dd, J= 8.7 Hz, 8.8 Hz, 1H), 7.11-7.30 (m, 3H), 7.48-7.59 (m, 1H), 7.62 (d, J= 8.1 Hz, 1H), 7.88 (d, J= 6.6 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 11.62 (s, 1H). MS (MH+ found) = 434.0
87. N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-yl]-N- 2-,N-2-dimethylglycinamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- amine (example 83) and N,N-dimethylglycine; final purification by crystallization from acetonitrile / water 4:1 (v/v); yield 71%
1H-NMR (300 MHz, d6-DMSO); δ = 1.72-2.12 (m, 3H), 2.12-2.30 (m, 1H), 2.23 (s, 6H), 2.82 (d, AB, J= 15.3 Hz, 1H), 2.98 (d, AB, J= 14.2 Hz, 1H), 3.75 (s, 3H), 4.27 (d, AB, J= 14.1 Hz, 1H), 4.38 (d, AB, J= 14.2 Hz, 1H), 4.91-5.05 (m, 1H), 7.02 (dd, J= 8.7 Hz, 8.7 Hz, 1H), 7.10-7.29 (m, 3H), 7.36 (dd, J =7.2 Hz, 7.3 Hz, 1H), 7.45 (d, J= 8.2 Hz, 1H), 7.73 (d, J= 6.9 Hz, 1H), 7.97 (d, J= 8.1 Hz, 1H), 11.36 (bs, 1H).
MS (MH+ found) = 461.1
88. (2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4- yl]amino}-2-oxoethyl)carbamate Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- amine (example 83) and N-(tert-butoxycarbonyl)glycine; final purification by crystallization from acetonitrile /water 4:1 (v/v); yield 68%
1H-NMR (300 MHz, d6-DMSO); δ = 1.38 (s, 9H), 1.87-2.11 (m, 4H), 3.11-3.45 (m, 2H), 3.51-3.15 (m, 2H), 3.75 (s, 3H), 4.33 (s, 2H), 4.96-5.09 (m, 1H), 6.80-6.90 (m, 1H), 6.95-7.10 (m, 1H), 7.10- 7.31 (m, 3H), 7.53 (dd, J= 7.2 Hz, 7.3 Hz, 1H), 7.62 (d, J= 8.1 Hz, 1H), 8.03 (d, J= 7.4 Hz, 1H), 8.16 (d, J= 8.1 Hz, 1H), 11.58 (bs, 1H). 89. 1 -Acetyl-N-[6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 4-yl]piperidine-4-carboxamide
Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- amine (example 83) and i-acetylpiperidine^-carboxylic acid; final purification by crystallization from acetonitrile / water 4:1 (v/v); yield 81 %
1H-NMR (300 MHz, d6-DMSO); δ =1.10-1.79 (m, 5H), 1.80-2.13 (m, 6H), 2.29-2.62 (m, 2H), 2.91- 3.10 (m, 1 H), 3.10-3.48 (m, 2H), 3.70-3.89 (m, 4H), 4.20-4.48 (m, 3H), 4.98-5.10 (m, 1 H), 6.96-7.11 (m, 1 H), 7.11-7.30 (m, 3H), 7.47-7.58 (m, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 1 1.60 (bs, 1 H). MS (MH+ found) = 529.2
90. 3-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-yl]- carbamoyl}azetidine-1-carboxylate Starting compounds: 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- amine (example 83) and 1-(methoxycarbonyl)azetidine-3-carboxylic acid; final purification by crystallization from acetonitrile / water 4:1 (v/v); yield 69%.
1H-NMR (300 MHz, d6-DMSO); δ = 1.83-2.08 (m, 4H), 3.11-3.41 (m, 3H), 3.56 (s, 3H), 3.76 (s, 3H), 3.90-4.09 (m, 4H), 4.28 (d, AB, J = 14.3 Hz, 1 H), 4.35 (d, AB, J = 14.3 Hz, 1 H), 5.03-5.18 (m, 1 H), 7.02 (dd, J = 8.6 Hz, 8.7 Hz, 1 H), 7.09-7.29 (m, 3H), 7.47-7.59 (m, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 8.29 (d, J = 8.0 Hz, 1 H), 11.60 (bs, 1 H). MS (MH+ found) = 517.1
91. N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yljglycinamide
(2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]amino}-2- oxoethyl)carbamate (example 88) (80 mg) is dissolved in dioxane (2.5 ml) and concentrated hydrochloric acid (2 drops) is added. The mixture is stirred for 18 h at room temperature. The formed precipitate is filtered, washed (dioxane) and dried in vacuo to yield 62 mg (82%) of the title com- pound.
1H-NMR (300 MHz, d6-DMSO); δ = 1.97-2.16 (m, 4H), 3.20-3.62 (m, 4H), 3.77 (s, 3H), 4.70-5.30 (m, 2H), 5.26-5.41 (m, 1 H), 7.00-7.16 (m, 1 H), 7.30-7.60 (m, 3H), 7.70-7.90 (m, 2H), 8.15-8.42 (m, 3H), 9.20 (bs, 1 H), 13.30 (bs, 1 H). MS (MH+ found) = 433.1
92. 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1H-indolo[2,3-c]quinoline
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-ol (example 72) (120 mg) is suspended in dichloromethane (5 ml), triethylamine (214 μl) and 4-(dimethylamino)- pyridine (10 mg) are added and the suspension is cooled to O0C (ice bath). Methanesulfonyl chlo- ride (50 μl) is added and the mixture is stirred for 1 h at O0C and 1 h at room temperature. After that, it is neutralized by addition of saturated sodium hydrogencarbonate solution (5 ml) and diluted with dichloromethane (3 ml). The organic phase is concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :1 (v/v)), followed by crystallization from ethyl acetate / n-heptane to yield 44 mg (39%) of the title compound.
1H-NMR (300 MHz, d6-DMSO); δ = 2.39-2.55 (m, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.75 (s, 3H), 4.32 (s, 2H), 6.05-6.19 (m, 1 H), 6.64 (d, J = 8.0 Hz, 1 H), 6.08-7.15 (m, 2H), 7.15-7.29 (m, 2H), 7.52 (dd, J = 7.6 Hz, 7.6 Hz, 1 H), 7.59 (d, J = 8.1 Hz, 1 H), 8.21 (d, J = 8.0 Hz, 1 H), 1 1.54 (bs, 1 H).
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, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea), disorders of the arthritis type (e.g., but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [e.g., but not limited to, AIDS (acquired immunodeficiency syndrome), multiple sclerosis], graft versus host reaction, allograft rejections, shock [e.g., but not limited to, septic shock, endotoxin shock, gram-negative sepsis shock, toxic shock syndrome and ARDS (adult respiratory distress syndrome)], gastrointestinal inflammations (e.g., but not limited to, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, im- munological false reactions (e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps); pain, such as, but not limited to, inflammatory pain; right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia; ischaemic diseases, such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlusion, congestive heart failure; diabetic gastroparesis and diseases with symptoms of gastroparesis; diseases or conditions in which it is desirable to suppress platelet function, for example, but not limited to, after stent implantations (e.g., but not limited to, coronary stenting), after bypass operations, in pulmonary hypertension, thrombotic diseases, post-angioplasty stenosis, coronary artery disease, infarction (e.g., but not limited to, myocardial infarction), instable angina pectoris, stroke, and arterial and venous occlusion diseases (e.g., but not limited to, claudicatio intermittens); diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, such as, but not limited to, arteriosclerotic dementia, multi-infarct dementia, cerebral senility; diseases which are based on neuronal damage or degradation, such as but not limited to, stroke, spinal cord injury, brain injury, morbus parkinson, amyotrophic lateral sclerosis, morbus alzheimer, amyloidosis, prion diseases and neuropathy; peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia (Alzheimer's disease), Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia; portal hypertension, liver cirrhosis, toxic liver damage (e.g., but not limited to, alcohol-induced liver damage), hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins (e.g., but without limitation, due to tumors), arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis (bilharziosis), sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders (e.g., but not limited to, chronic myeloid leukemia, osteomyelofibrosis), lymphatic systemic diseases, collagenosis (e.g., but not limited to, systemic lupus erythematodes, sclerodermia), morbus Osier (congenital arteriovenous malformations, inter alia in the liver), nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis; benign prostatic hyperplasia; overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction; insufficient brain skills, such as but not limited to, verbal attainment, attention, concentration, deductive thinking, central auditory processing, cognition, learning, vigilance, apprehension and reagibility.
In a further embodiment, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, peri- carditis 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 pulmo- nary hypertension of the newborn; pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central pulmonary veins (e.g. fibrosing mediastinitis, adenopathy in relation to tumors), pulmonary veno- occlusive disease; - pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia; pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH); pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomatosis.
Preferably, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepa- titis and liver fibrosis.
Furthermore, the invention further relates to the compounds of the invention for use in the treat- ment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis. The invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
In particular, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
The invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In particular, the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Especially, the invention relates to a method of treating or preventing a disease which is alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
The invention relates to a method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skillsPreferably, 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, idio- pathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing portal hyperten- sion, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds of the invention can be used. Preferably, one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
In a particularly preferred embodiment of the invention, the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
The invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary. The invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease. Preferably, the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention.
In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
In this respect, the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the com- pounds, 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 fu- marate, 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 in- elude without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin. Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab. Examples of diuretics include without limitation furosemide, bumetanide and torsemide. Examples of digitalis glycosides include without limitation digoxin and digitoxin.
In a preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and budesonide, a compound of the invention and fluticasone, a compound of the invention and beclometasone, a compound of the invention and triamcinolone, or a compound of the invention and ciclesonide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and indacaterol, a compound of the invention and tiotropium, or a compound of the invention and ipratropium. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and formoterol, or a compound of the invention and salmeterol. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and lusupultide, a compound of the invention and poractant alfa, a compound of the invention and sinapultide, a compound of the invention and beractant, a compound of the invention and bovactant, a compound of the invention and colfosceril, a compound of the invention and surfactant-TA, or a compound of the invention and calfactant.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bosentan, a compound of the invention and ambrisentan, or a compound of the invention and sitaxsentan.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and iloprost, a compound of the invention and epoprostenol, a compound of the invention and triprostinil.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and amlodipine, a compound of the invention and nifedipine, a compound of the invention and diltiazem, a compound of the invention and verapamil, or a compound of the invention and felodipine.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bisoprolol, a compound of the invention and nebivolol, a compound of the invention and metoprolol, a compound of the invention and carvedilol, a compound of the invention and atenolol, or a compound of the invention and nadolol. In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and roflumilast, a compound of the invention and roflumilast N-oxide, a compound of the invention and cilomilast, a compound of the invention and tetomilast, or a compound of the invention and oglemilast.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant. In a particularly preferred embodiment, the phar- maceutical 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 exam- pies.
The invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
The invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
Futhermore, the invention also encompasses pharmaceutical compositions according to the inven- tion, 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. A further embodiment of the invention is a pharmaceutically acceptable salt of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof for use in the treatment or prophylaxis of diseases.
A further embodiment of the invention is a pharmaceutical composition of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salts thereof, N-oxides of the compound and the salts thereof and N-oxides of the salts thereof with at least one pharmaceutically acceptable auxiliary.
A further embodiment of the invention is a pharmaceutical composition of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salts thereof, N-oxides of the compound and the salts thereof and N-oxides of the salts thereof with at least one pharmaceutically acceptable auxiliary 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.
A further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof in the manu- facture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
A further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
A further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
A further embodiment of the invention is the use of a compound with the chemical name of 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof 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.
A further embodiment of the invention is the method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4- methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N- oxide of the compound or the salt thereof or the N-oxide of the salt thereof.
A further embodiment of the invention is the method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H- indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof.
A further embodiment of the invention is the method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H- indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof, 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.
A further embodiment of the invention is the 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 with the chemical name of 6-(3-Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%. In case at least one therapeutic agent selected from the group consist- ing of corticosteroids, anticholinergics, beta-mi metics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics is present in the pharmaceutical compositions of the invention, the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is 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 administration is preferred.
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticho- linergics, 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 therapeu- tic agent can be administered by inhalation or instillation.
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer.
Administration by inhalation or instillation is preferably made by using an aerosol. The aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
The aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the compound of the invention, and optionally the therapeutic agent, to be administered, the aerosol-producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The 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-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, administration of the compound of the invention and administration of the therapeutic agent can be made simultaneously or sequentially. In case of sequential administration, the compound of the invention can be administered before or after administration of the therapeutic agent.
Biological investigations
Method for measuring inhibition of PDE5 activity:
As a source for human PDE5, platelets were used. For that purpose, 150 ml fresh blood from human donors anticoagulated with citrate [final concentration 0.3% (w/v)] was centrifuged at 200 g for 10 min to obtain the so-called platelet-rich-plasma (PRP) as a supernatant. 1/10 volume of ACD solution (85 mM Na3-citrate, 1 11 mM D-glucose, 71 mM citric acid, pH 4.4) was added to 9/10 volume of PRP. After centrifugation (1 ,400 g, 10 min) the cell pellet was resuspended in 3 ml 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 imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001

Claims

Claims:
1. Compound of Formula (I)
Figure imgf000149_0001
wherein the dotted lines each represent a covalent bond which may be present or absent to give rise to a double bond or a single bond, respectively, with the proviso that at least one of the covalent bonds represented by the dotted line is absent so that the respective bond is a single bond;
wherein R^01 and R^02 are eacn independently selected from the members of the groups (hi ) and (h2) as defined below:
(hi ) hydrogen and hydroxy, or RA01 and R^02 combine to form an oxo-group,
(h2) Ci_6-alkoxy, wherein the C-|.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, and hydroxy, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|_g- alkoxy via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA03 ancj _NRA04RA05. or
RA01 ancj RA02 combine to form a hydroxylamino-group; wherein one of the substituents R^01 and R^02 js absent in case the dotted line represents a double bond;
RA03 JS selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA04 ancj RA05 are each independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-mennbered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by R^6
C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted,
C 1 _ 13-heteroary I , 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, and NRA07RA08
C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substitu- ents 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
RA09, and -C(O)RA01° and -S(O)2RA01 1 ; or RA04 ancj RA05 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|_g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy; and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA012, O and S;
RA06 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA07 and RA08 are each independently selected from the group consisting of hydrogen and C1. β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA09 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA010 JS selected from the group consisting of hydrogen, C-] .g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C1. g-alkyl via C, N is substituted by RA09, and NRA013RA014
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents 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,
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
RA09, and NRA013RA014;
RA011 js selected from the group consisting of C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA015RA016,
C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA015RA016;
RA012 RA017 ancj RA018 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)-Ci. g-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA013 ancj RA014 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy; or
RA013 ancj RA014 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA017 Q, and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA015 ancj RA016 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro 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; or RA015 ancj RA016 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA018, O and S; wherein RA^ and RA12 are eacn independently selected from the members of the groups (M ) and (i2) as defined below:
(M ) hydrogen,
(i2) hydroxy, C-|.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-^g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, azido, halogen, -NRA13RA14, -C(O)O-C1.6-alkyl, wherein the -C(O)O-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)NRA15RA16; or
RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^ combine to form an oxo-group; wherein one of the substituents RA^ ^ and RA^ js absent in case the dotted line represents a double bond;
RA13 ancj RA14 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|_5-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-14-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-mennbered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by RA17, 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 RA17 Cβ.-|4-aryl, wherein the Cg.-14-aryl is optionally substituted,
-CORA18 and -S(O)2RA19; d RA^ are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound 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 RA^0, and NRA111 RA112 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
RA113, 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; or
RA15 ancj RA16 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA1 14, O and S;
RA17 RA110 RA113 ancj RA114 are eacn independently selected from the group consisting of hydrogen, C-|. g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents se- lected 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;
RA18 is 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-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R^115 and
NRA116RA117 C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the 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 RA1 18, and
NRA119RA120.
RA19 js selected from the group consisting of
C^g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA121 RA122.
RA111 ancj RA112 are each independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents 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, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RA123; or
RA111 ancj RA112 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^I 24 Q ancj g.
RA115 RA118 RA123 ancj RA124 are eacn independently selected from the group consisting of hydrogen, C-|. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA116 RA117 RA119 ancj RA120 are eacn independently selected from the group consisting of hydrogen, C-|. g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and Cβ.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA116 RA117 RA119 ancj RA120 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA125 Q and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA121 ancj RA122 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1. β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
RA121 ancj RA122 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NRA126 Q and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups;
RA125 ancj RA126 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|_5-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; or one of the substituents R^01 and R^02 and one of the substituents RA^ 1 and RA^2 combine to form a 5- to 7-membered ring, wherein the 5- to 7-membered ring may have one or more heteroatoms selected from N, O and S in its ring and, wherein the 5- to 7-membered ring may have an oxo-group;
wherein RA2^ and RA22 are each independently selected from the members of the groups (j1 ) and (j2) as defined below:
(j1 ) hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is not substituted,
(j2) hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is substituted by fluoro, chloro and hydroxy, C4_6-alkyl, wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
-C(O)NRA23RA24, and -NRA25RA26; or
RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group; wherein one of the substituents RA2^ and RA22 is absent in case the dotted line represents a double bond;
RA23 ancj RA24 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 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 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 RA^7 ancj NRA28RA29, 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 RA210, 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; or RA23 anc| RA24 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA25 ancj RA26 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, Cg.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C3.6-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 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 RA212, C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents se- lected 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 RA210
-S(O)2RA213, and -(CH2)|CORA214; wherein I is 0, 1 and 2; or RA25 ancj RA26 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA2^, RA2"O, RA21 "I and RA212 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA28 ancj RA29 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
C3.6-cyclyl, wherein the C3_β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the pro- viso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by
RA212. or
RA28 ancj RA29 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA213 js selected from the group consisting of
C-j.β-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA215RA216.
RA214 js selected from the group consisting of hydrogen, hydroxy, C-|_5-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by R^17
C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro or hydroxy, 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 proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA218 and _NRA219RA220. ncj RA216 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 se- lected from fluoro and hydroxy, and
-C(O)-C1. g-alkyl, wherein the -C(O)-C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA215 ancj RA216 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA21 1 , O and S;
RA217 ancj RA218 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-] .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA219 ancj RA220 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 se- lected from fluoro, hydroxy, C-|.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.g-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more 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 C1. g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by RA221 C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-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 RA222. or
RA219 ancj RA220 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NR^223 Q and S;
RA221 RA222 ancj RA223 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
wherein RA3^ and RA32 are eacn independently selected from the members of the groups (k1 ) and (k2) as defined below:
(k1 ) hydrogen,
(k2) hydroxy, C1. g-alkyl, wherein the C-^g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy,
C-j.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA33RA34 and -NRA35RA36; or RA31 and RA32 combine to form an oxo-group; or
RA31 and RA32 combine to form the group -0-CH2CH2-O-; wherein one of the substituents R^31 and R^32 JS absent in case the dotted line represents a double bond;
RA33 ancj RA34 are each independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound 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.β-alkyl via C, N is substituted by R^37 and
NRA38RA39 C3.6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA310; or
RA33 ancj RA34 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, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA31 1 , O and S; RA35 anc| RA36 are eacn independently selected from the group consisting of hydrogen, C-j.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy, C-|.g-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy, C6.14-aryl, wherein the Cg.-|4-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by RA312,
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
RA310
-S(O)2RA313, and -(CH2)k-C(O)-RA314, wherein k is 0, 1 and 2;
RA37 RA310 RA311 ancj RA312 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1.6-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA38 ancj RA39 are eacn independently selected from the group consisting of hydrogen, C-] .g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; C3.g-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-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 RA315; or
RA38 ancj RA39 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- tom(s) selected from NRA316, O and S;
RA313 js selected from the group consisting of C1. g-alkyl, wherein the C1. g-alkyl is optionally substituted by one or more substituents se- lected from fluoro, hydroxy and C-|.g-cyclyl, wherein the C-|.g-cyclyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, C-i-6-cyclyl, wherein the C-|.g-cyclyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy, and
NRA317RA318;
RA314 js selected from the group consisting of hydroxy, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and NRA319RA32°, C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, N RA321 RA322 c3.g-cyclyl , wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from NRA323, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C;
RA315 ancj RA316 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)-C1. g-alkyl, wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA317 ancj RA318 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)-C1.6-alkyl, wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
RA317 ancj RA318 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^324 Q ancj g.
RA319 ancj RA320 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein the C-j.g-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-j.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-j.g-alkyl via C, N is substituted by R^325 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 NRA326, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C, and
-C(O)O-C1.6-alkyl, wherein the -C(O)O-C-] .g-alkyl is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy,
RA321 ancj RA322 are eacn independently selected from the group consisting of hydrogen, C-|_g-alkyl, wherein the C-|_g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-|.g-alkoxy, wherein C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, C3.6-cyclyl, wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-] .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-| .g-alkyl via C, N is substituted by R^327
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 NRA328, O and S, and wherein the 3- to 7-membered heterocyclyl is be bound via C, and -C(O)Ci. g-alkyl, wherein the C-| .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy;
RA323 js selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1.6-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents se- lected from fluoro and hydroxy, and
-C(O)O-C1.6-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA324 RA325 RA326 RA327 ancj RA328 are eacn independently selected from the group consisting of hydrogen, C-|.g-alkyl, wherein the C-|.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C1. g-alkyl, wherein the -C(O)-C1. g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
with the proviso that at least one of the substituents RA01 , RA02, RA1 1 , RA12, RA21 , RA22, RA31 and RA^2 is selected from a member of the groups (h2), (i2), (j2) and (k2);
RB41 js selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy, nitro and amino;
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkyl, hydroxy, C-j.β- alkoxy, nitro, amino, -NH-C(O)- C-|.2-alkyl, -NH-C(O)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and -CH2-CH2-O-;
RB61 JS selected from the group consisting of hydrogen and halogen;
RB71 JS selected from the group consisting of hydrogen and halogen;
RB81 JS selected from the group consisting of hydrogen and halogen; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
2. Compound according to claim 1 , wherein R^01 and R^02 are eacn independently selected from the groups consisting of hydrogen, hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -NRA04RA05, or
RA01 ancj RA02 combine to form an oxo-group; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
3. Compound according to claim 1 or 2, wherein RA04 ancj RA05 are eacn independently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, Cβ.g-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound 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.β-alkyl via C, N is substituted by RA06 Cβ.-|4-aryl, wherein the Cβ.-|4-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, and
NRA07RA08 C3_6-cyclyl, wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-j.g-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substitu- ents selected from fluoro and hydroxy, and
-C(O)RA01°; and wherein
RA07 ancj RA08 are eacn independently selected from the group consisting of hydrogen and C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; and wherein
RA010 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-alkoxy, wherein the C-|.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C-|.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-|.g-alkyl via C, N is substituted by R^09, ancj NRA013RA014 and NRA013RA014; and wherein
RA013 and RA014 combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroa- toms selected from NR^OI 7 O and S, and wherein the 3- to 7-membered heterocycle may have one or more oxo-groups; 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 RA^ 1 and RA^2 are eacn jncje. pendently selected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA13RA14 or
RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-; or
RA11 and RA^2 combine to form an oxo-group; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
5. Compound according to any one of claims 1 to 4, wherein RA2^ and RA22 are each independently selected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by fluoro, chloro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA23RA24, and
_NRA25RA26. or
RA21 and RA22 combine to form the group -0-CH2CH2-O-; or
RA2^ and RA22 combine to form an oxo-group; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
6. Compound according to any one of claims 1 to 5, wherein RA^1 and RA32 are each independently selected from the group consisting of hydrogen, hydroxy, C-j.β-alkyl, wherein the C-j.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)NRA33RA34 and _NRA35RA36; or RA31 and R^32 combine to form an oxo-group; or
RA31 and RA32 combine to form the group -0-CH2CH2-O-; 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 RA35 ancj RA36 are eacn jncje. pendently selected from the group consisting of hydrogen, C-j.β-alkyl, wherein the C-|.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C-j.β-alkoxy, wherein the is optionally substituted by one or more substituents selected from fluoro and hydroxy,
wherein the Cg.-14-aryl is optionally substituted, C3.6-cyclyl, wherein the Cβ.β-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and 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 RA312, 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-mennbered heterocyclyl is bound via C, N is substituted by RA310, and
-(CH2)k-C(O)-RA314, wherein k is 0 to 2; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
8. Compound according to any one of claims 1 to 7, wherein RB41 js selected from the group consisting of hydrogen, halogen and C-j.β-alkoxy,
RB51 JS selected from the group consisting of hydrogen, halogen, C-j.β-alkoxy and a methoxy group substituted by 2 or 3 fluorine atoms, or
RB41 and RB51 combine to form a group selected from -O-CH2-O-, -O-CH2-CH2- and
-CH2-CH2-O-; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
9. Compound according to any one of claims 1 to 8, wherein
RA01 and RA02 js hydrogen and the other substituent is selected from the group consisting of hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-NRACMRAOS, or RA01 and RA02 combine to form an oxo-group, RA11 , RA12 RA31 ancj RA32 are eacn hydrogen, and RA21 and R^22 are both methyl; or wherein
RA01 ancj RA02 JS hydrogen and the other substituent is selected from the group consisting of hydroxy, C-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
RA01 anc| RA02 combine to form an oxo-group, one of the substituents RA11 and RA12 JS hydrogen and the other substituent is selected from hydroxy, azido, halogen and -NRA13RA14 RA21 and RA22 are both methyl, and R^31 and R^32 are each hydrogen; or wherein RA01 RA02 RA21 RA22 RA31 and RA32 are each hydrogen and one of the substituents RA1 1 and RA12 JS hydrogen and the other substituent is selected from hydroxy, 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-j.β-alkoxy, wherein the C-j.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and NRA13RA14 or RA1 1 and RA12 combine to form the group -0-CH2-CH2-O-, or RA11 and RA^2 combine to form an oxo-group; or wherein
RA01 RA02 RA11 RA12 RA31 and RA32 are each hydrogen and one of the substituents RA21 and RA22 is hydrogen and the other substituent is selected from hydroxy and NRA2^RA26, Or R21 and RA22 combine to form the group -0-CH2-CH2-O-, or
RA21 and RA22 combine to form an oxo-group; or wherein
RA01 RA02 RA11 RA12 RA21 and RA22 are each hydrogen and one of the substituents RA31 and RA32 is hydrogen and the other substituent is selected from the group consisting of hydroxy and -NRA35RA36, or
RA31 and RA32 combine to form the group -0-CH2-CH2-O-, or
RA31 and RA32 combine to form an oxo-group; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
10. Compound according to any one of claims 1 to 9 selected from the group consisting of N-tθ^-MethoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yllformamide; 6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-1 -amine dihydrochloride; 6-(1 ,3-Benzodioxol-5-ylmethyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; 6-(3-Amino-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1- ylamine; 6-(4-Aminobenzyl)-3, 3-dimethyl-2, 3,4, 7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; Benzyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-amine hydrochloride; [6-(4-Methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]- pyridin-2-ylmethyl-amine; lsopropyl-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-1-yl]-amine; 6-(4-Methoxybenzyl)-3,3-dimethyl-1 -pyrrolidin-1 -yl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; N-Cyclopentyl-6-(4-methoxybenzyl)-3, 3-dimethyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Ethyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-Methyl-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N-(Cyclopropylmethyl)-6-(4-methoxybenzyl)-3,3- dimethyl-2, 3,4, 7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -amine; N'-[6-(4-Methoxybenzyl)-3,3- dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll-N.N-dimethylpropane-I .S-diamine;
6-(4-Methoxybenzyl)-3,3-dimethyl-N-(tetrahydrofuran-2-ylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1 -amine; θ-^-Methoxybenzy^-S.S-dimethyl^S^J-tetrahydro-I H-indolo^S-clquinolin-i- one oxime; 2-Methoxy-N-[6-(4-methoxy-benzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-1-yl]-acetamide; Morpholine-4-carboxylic acid [6-(4-methoxy-benzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-amide; N'-[6-(4-Methoxybenzyl)-3,3-dimethyl- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-yl]-N,N-dimethylsulfamide; N-[6-(4-Methoxybenzyl)- S^-dimethyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-i-yll^^-methylpiperazin-i-yOacetamide; (S^N-tθ^-MethoxybenzyO-S.S-dimethyl^.S^J-tetrahydro-i l-l-indolo^.S-clquinolin-i-yll-i- methylprolinamide; 1-Methoxy-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinoline; 2-Bromo-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin- 1-one; 2-Bromo-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 1 ,1- Dimethoxy-6-(4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 2-Hydroxy-6-(4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-one hydrochloride; 2-Bromo-6-(4- methoxybenzyl)-3,3-dimethyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 6-(4-Methoxybenzyl)- 3,3-dimethyl-4,7-dihydro-3H-indolo[2,3-c]quinoline; cis-6-(4-Methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-1 ,2-diol; 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-one; 2-Azido-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 2-Amino-6-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-1-ol; 7-(4-Methoxybenzyl)-4,4-dimethyl-3,3a,4,5,8,12d- hexahydro-2H-indolo[2,3-c][1 ,3]oxazolo[5,4-f]quinolin-2-one; 6'-(4-Methoxybenzyl)-1',3',4',7'- tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; Ethyl 6-(4-methoxybenzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline-2-carboxylate; 6-(4-Methoxybenzyl)-2-methyl-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-3-methyl-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinoline; 6-(4-Methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinoline; 6'-(3-Fluoro-4-methoxybenzyl)-1',3',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,2'-indolo[2,3-c]quinoline]; 6-(4-Methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; 6-(3-Fluoro-4- methoxybenzyl)-1 ,3,4,7-tetrahydro-2H-indolo[2,3-c]quinolin-2-one; N-[6-(4-Methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-formamide; 6-(4-Methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; Cyclopropyl-[6-(3-fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; Ethyl-[6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro- 1 H-indolo[2,3-c]quinolin-2-yl]-(4-methoxy-phenyl)-amine; Benzyl-[6-(3-fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-amine; [6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-2-yl]-(2-methoxy-ethyl)-amine; 6-(3-Fluoro-4-methoxy-benzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ylamine; N-[6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-I H-indolo^S-clquinolin^-yll^-methoxy-acetamide; 6'-(3-Fluoro-4-methoxybenzyl)- 1',2',4',7'-tetrahydrospiro[1 ,3-dioxolane-2,3'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)- 1 ,2,4,7-tetrahydro-3H-indolo[2,3-c]quinolin-3-one; 2-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7- tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylamino]-acetannide; [6-(3-Fluoro-4-methoxy-benzyl)-2, 3,4,7- tetrahydro-I H-indolo^S-clquinolin-S-ylaminoJ-acetic acid methyl ester; Benzyl-[6-(3-fluoro-4- methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-annine; N-2-[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]-N~2 — methylglycinamide; 6-(3- Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ylannine; [6-(3-Fluoro-4- methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-carbannic acid ethyl ester; N-[6- (S-Fluoro^-methoxy-benzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll^-nnethoxy- acetamide; N-[6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-yl]- acetamide; Morpholine-4-carboxylic acid [6-(3-fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-annide; [6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-3-ylamino]-acetic acid; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-3-yl]-N-nnethylglycinannide; N-2-[6-(3-Fluoro-4-methoxybenzyl)-2, 3,4,7- tetrahydro-I H-indolo^.S-clquinolin-S-yll-N-isopropylglycinannide; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin-S-yll-N-^-hydroxypropyllglycinannide (mixture of diastereoisomers); N-2-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-3-yl]-N-(2-hydroxyethyl)glycinamide; 6'-(3-Fluoro-4-methoxybenzyl)-1',2',3',7'- tetrahydrospiro[1 ,3-dioxolane-2,4'-indolo[2,3-c]quinoline]; 6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7- tetrahydro-4H-indolo[2,3-c]quinolin-4-one; 6-(4-Methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c]quinolin-2-ol; 6-(3-Fluoro-4-methoxy-benzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-2-ol; 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-3-ol; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-ol; N-2-[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinamide; N-Ethyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-Cyclopropyl-6-(3-fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; 2-{[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]amino}ethanol; N-(1- Acetylpiperidin^-yO-Θ^S-fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^- amine; 2-(4-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]amino}- piperidin-1-yl)-2-oxoethanol; (4RS)-N-[(3S)-1-Acetylpiperidin-3-yl]-6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; (4RS)-N-[(3R)-1-Acetylpiperidin-3-yl]-6-(3- fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-(1-Acetylazetidin- 3-yl)-6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1H-indolo[2,3-c]quinolin-4-amine; N-Benzyl- 6-(3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; 6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-amine; N-[6-(3-Fluoro-4- methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-1-methylpiperidine-4- carboxamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]acetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]-2- hydroxyacetamide; N-[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4- yl]-N-2-,N-2-dimethylglycinamide; (2-{[6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H- indolo[2,3-c]quinolin-4-yl]amino}-2-oxoethyl)carbamate; 1-Acetyl-N-[6-(3-fluoro-4-methoxybenzyl)- 2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-4-yl]piperidine-4-carboxannide; 3-{[6-(3-Fluoro-4- methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllcarbannoylJazetidine-i-carboxylate; N-^S-Fluoro^-methoxybenzyl^.S^J-tetrahydro-I H-indolo^.S-clquinolin^-yllglycinannide; 6-(3- Fluoro-4-methoxybenzyl)-2,7-dihydro-1 H-indolo[2,3-c]quinoline 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.
11. Compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 for use in the treatment or prophylaxis of diseases.
12. Pharmaceutical composition comprising at least one of the compounds, pharmaceutically acceptable salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to any of claims 1 to 10 together with at least one pharmaceutically acceptable auxiliary.
13. Pharmaceutical composition according to claim 12 further comprising at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics.
14. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
15. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, peri- carditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
16. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
17. Use according to claim 16, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
18. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N- oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
19. Method of treating or preventing diseases alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10.
20. Method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, im- munological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and, insufficient brain skills comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof according to any of claims 1 to 10.
21. Method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceuti- cally acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10.
22. Method for treating or preventing an acute or chronic airway disease according to claim 21 , in which the acute or chronic airway disease is selected from the group consisting of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
23. Method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 10.
PCT/EP2009/059998 2008-08-05 2009-08-03 6-benzyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinoline compounds WO2010015585A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010166A1 (en) * 2000-08-02 2002-02-07 Lilly Icos Llc Fused heterocyclic derivatives as phosphodiesterase inhibitors
WO2002028859A2 (en) * 2000-10-02 2002-04-11 Lilly Icos Llc Condensed pyridoindole derivatives
WO2008027182A2 (en) * 2006-08-28 2008-03-06 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
WO2008095835A1 (en) * 2007-02-05 2008-08-14 Nycomed Gmbh 6-benzyl-2,3,4,7-tetrahydro-indolo [2, 3-c] quinoline compounds useful as pde5 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010166A1 (en) * 2000-08-02 2002-02-07 Lilly Icos Llc Fused heterocyclic derivatives as phosphodiesterase inhibitors
WO2002028859A2 (en) * 2000-10-02 2002-04-11 Lilly Icos Llc Condensed pyridoindole derivatives
WO2008027182A2 (en) * 2006-08-28 2008-03-06 Medipropharma, Inc. Indoloquinoline compounds as calcium channel blockers
WO2008095835A1 (en) * 2007-02-05 2008-08-14 Nycomed Gmbh 6-benzyl-2,3,4,7-tetrahydro-indolo [2, 3-c] quinoline compounds useful as pde5 inhibitors

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