WO2011015523A1 - Benzyl-substituted tetracyclic heterocyclic compounds - Google Patents

Benzyl-substituted tetracyclic heterocyclic compounds Download PDF

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Publication number
WO2011015523A1
WO2011015523A1 PCT/EP2010/061081 EP2010061081W WO2011015523A1 WO 2011015523 A1 WO2011015523 A1 WO 2011015523A1 EP 2010061081 W EP2010061081 W EP 2010061081W WO 2011015523 A1 WO2011015523 A1 WO 2011015523A1
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Prior art keywords
alkyl
fluoro
hydroxy
group
optionally substituted
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PCT/EP2010/061081
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French (fr)
Inventor
Björn BARTELS
Ruslan Staver
Steffen Weinbrenner
Torsten Dunkern
Wiro M.P.B. Menge
Johannes A. M. Christiaans
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Nycomed Gmbh
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Publication of WO2011015523A1 publication Critical patent/WO2011015523A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the invention relates to Benzyl-substituted tetracyclic heterocyclic compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
  • WO 02/064590, WO2008095835 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds.
  • WO2008027182 discloses indoloquinoline compounds as calcium channel blockers.
  • a further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
  • the compounds of the present invention are characterized by Formula (I) as specified in the following.
  • the invention thus relates to compounds of Formula (I)
  • a 1 is each independently selected from the group consisting of N, O and S;
  • n 0 or 1 ; with the proviso that if A 1 is O or S the substituent R A31 is absent.
  • RA02 are eacn independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy,
  • C ⁇ _6-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .s-alkoxy, and
  • RA02 combine to form an oxo-group
  • R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-;
  • RA03 and RA04 are each independently selected from the group consisting of
  • C ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ _6-alkoxy,
  • RA04 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ .g-alkoxy,
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A01 7 , O and S;
  • RA05 and RA06 are eacn indpendently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, and
  • -C(O)-Ci -6 ⁇ al M is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy; or
  • RA05 and RA06 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy, and
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRAOI S 1 0 and S;
  • RA° 7 and RA08 are eacn independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy; or
  • RA07 and RA08 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy, and
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A 019 o and S;
  • C ⁇ .g-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy;
  • RA010 and RA011 are each independently selected from the group consisting of hydrogen and C ⁇ g-alkyl
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ g-alkoxy;
  • RA012 is Ci _ 6 _alkyl
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy;
  • R A01 3 and RA014 have the same mea nings as R A05 and R A06 , and R A01 5 and RA016 have the same meanings as R A ⁇ anc
  • RA019 are eacn independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R A1 1 and R A12 have the same meanings as R A01 and R A02 ;
  • R A 21 and R A22 are each independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA31 is selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C ⁇ -heteroaryl,
  • heteroaryl has at least one heteroatom which is selected from N, O and S,
  • 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
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • the 3- to 7-membered heterocyclyl may be bound to the G j .g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • heteroaryl has at least one heteroatom which is selected from N, O and S, 3- to 7-membered heterocyclyl,
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • N is substituted by R A325 ,
  • a 1 is S, it is optionally substituted by one or two oxo-groups; wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
  • RA34 are eacn independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; pA35 j s selected from the group consisting of
  • R A37 are each independently selected from the group consisting of
  • Ci. ⁇ -alkyI is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • Ci. ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • C ⁇ .g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • C ⁇ . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • C ⁇ . ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy, and
  • R A310 are eacn independently selected from the group consisting of
  • Ci. ⁇ -alkyI is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ . ⁇ -alkoxy,
  • R A310 combine to form a 03.5-CyCIyI 1
  • C3_5-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA39 anc
  • RA310 combine to form an oxo-group;
  • RA311 j selected from the group consisting of
  • C ⁇ g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ g-alkoxy,
  • heteroaryl has at least one heteroatom which is selected from N, O and S, and
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • RA312 and R A3 ⁇ 3 are each independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ .g-alkoxy,
  • C3_6-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
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 3- to 7-membered heterocyclyl may be bound to the G ⁇ -alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C ⁇ -alkyl via C, N is substituted by RA328 ; or
  • RA313 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ -alkoxy,
  • C ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A328 , O and S;
  • RA315 are eacn independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • -C(O)-C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA317 are eacn independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ g-alkoxy,
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • C ⁇ g-heteroaryl has at least one heteroatom selected from N, O and
  • 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
  • 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 ⁇ -alkyl via C, N is substituted by R A328 , and
  • -C(O)-C 1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ g-alkoxy,
  • C ⁇ -alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • S(O ⁇ -C 1 .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 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 F ⁇ 331 , -CONR A332 R A333 ; or
  • RA316 anc RA317 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A331 , O and S;
  • RA319 are eacn independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and -C(O)-C 1 . 6 -alkyl,
  • C(O)-C 1 _5-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R A320 j selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R A322 are each independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ g-alkoxy,
  • C ⁇ g-heteroaryl has at least one heteroatom selected from N, O and
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • 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 1 .6-alkyl via C, N is substituted by R A331 ,
  • heteroaryl has at least one heteroatom which is selected from N, O and S, C3_6-cyclyl,
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 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 F ⁇ 342 ; or RA321 anc
  • RA322 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C ⁇ _6-alkyl,
  • C ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A33 1 , O and S;
  • RA323 anc RA324 are each independently selected from the group consisting of
  • C ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C ⁇ _6-alkoxy,
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C ⁇ g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-i_e-alkyl via C, N is substituted by R A328 ,
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 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 ⁇ 328 , C 3 . 6 -cyclyl,
  • C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • -S(O) 2 -C 1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
  • RA324 com bine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NR A331 , O and S;
  • R A325 , R A326 , R A328 , RA331 and R A342 are each independently selected from the group consisting of
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • -C(O)-C 1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • _-i g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R A329 R A330 R A334 R A335 R A338 R A339 R A340 and R A341 are each independently selected from the group consisting of
  • C ⁇ _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R A332 R A333 ⁇ 3Se 1 R A337 R A343 and R A344 are each independently selected from the group consisting of
  • C ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C ⁇ _6-alkoxy,
  • C ⁇ .s-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • R B41 is selected from the group consisting of hydrogen, halogen, C ⁇ -alkoxy, nitro and amino;
  • R B51 is selected from the group consisting of hydrogen, halogen, C ⁇ -alkyl, hydroxy, C ⁇ -alkoxy, nitro, amino, -NH-C(O)- C ⁇ -alkyl, -NH-C(O)-NH 2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
  • R B41 and R B51 combine to form a group selected from -0-CH 2 -O-, -0-CH 2 -CH 2 - and
  • R B71 is selected from the group consisting of hydrogen and halogen;
  • Special embodiments of the present application are described in the following. According to another embodiment of the present invention, A ⁇ is N;
  • R A01 and R A02 are each independently selected from the group consisting of
  • RA02 combine to form an oxo-group
  • R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-;
  • R A01 and R A02 are each independently selected from the group consisting of
  • RA02 combine to form an oxo-group
  • R A01 and R A02 combine to form the group -0-CH 2 -CH 2 -O-;
  • R A ⁇ and R A ⁇ 2 are each independently selected from the group consisting of
  • R A ⁇ and R A ⁇ 2 are each independently selected from the group consisting of
  • R A ⁇ and R A ⁇ 2 are hydrogen;
  • R A01 and R A02 are each independently selected from the group consisting of hydrogen and hydroxy, wherein the carbon atom to which the substituents R A ⁇ ⁇ and R A ⁇ 2 bind is in the R-configu ration,
  • R A03 and R A04 are each independently selected from the group consisting of
  • RA04 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A01 7 , O and S;
  • R A05 , R A06 , R A07 , R A08 , R A09 , R A1 °, R A1 1 and R A12 have the same meanings as defined above, or preferably below.
  • R A03 and R A04 are each independently selected from the group consisting of
  • RA06 are each indpendently selected from the group consisting of
  • RA06 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A01 8 , O and S;
  • RA06 are eacn indpendently selected from the group consisting of
  • R A07 and R A08 are each independently selected from the group consisting of
  • RA08 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A01 9 , O and S;
  • R A ⁇ 7 and R A ⁇ 8 are each independently selected from the group consisting of
  • R A 09 j selected from the group consisting of hydrogen and C ⁇ . ⁇ -alkyl
  • RA011 are eacn independently selected from the group consisting of
  • pA019 are eacn independently selected from the group consisting of
  • pA019 are eacn independently selected from the group consisting of
  • R A1 1 and R A12 are each independently selected from the group consisting of hydrogen and hydroxy, wherein the carbon atom to which the substituents R A ⁇ ⁇ and R A ⁇ 2 bind is in the R-configu ration,
  • R A21 and R A22 are each independently selected from the group consisting of
  • R A2 ⁇ and R A22 are each independently selected from the group consisting of hydrogen and C ⁇ .g-alkyl, wherein the carbon atom to which the substituents R A21 and R A22 bind is in the R-configu ration;
  • R A31 and R A32 are each independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C ⁇ . ⁇ -heteroaryl,
  • heteroaryl has at least one heteroatom which is selected from N, O and S,
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • 3- to 7-membered heterocyclyl may be bound to the G ⁇ -alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the
  • heteroaryl has at least one heteroatom which is selected from N, O and S, 3- to 7-membered heterocyclyl,
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • N is substituted by R A325 ,
  • R A3 ⁇ and R A32 are each
  • C ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C 1 . ⁇ -heteroaryl,
  • heteroaryl has at least one heteroatom which is selected from N, O and S,
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • 3- to 7-membered heterocyclyl may be bound to the C ⁇ -alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C 1 .6-alkyl via C, N is substituted by R A325 ,
  • heteroaryl has at least one heteroatom which is selected from N, O and S, 3- to 7-membered heterocyclyl,
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • N is substituted by R A32 ⁇
  • R A3 ⁇ a nd R A32 are each
  • C ⁇ .g-alkyl is optionally substituted by one 3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • 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 ⁇ -alkyl via C, N is substituted by R A325 ,
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • N is substituted by R A32 ⁇
  • R A32 are each independently selected from the group consisting of
  • C ⁇ . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy and 4- to 6-membered heterocyclyl,
  • the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 4- to 6-membered heterocyclyl may be bound to the C ⁇ .g-alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C-i_e-alkyl via C, N is substituted by R A325 ,
  • R A33 and R A34 are each independently selected from the group consisting of
  • R A3 5 j selected from the group consisting of
  • R A3 5 j selected from the group consisting of
  • R A3 5 j s hydroxy
  • R A3 6 and R A37 are each independently selected from the group consisting of
  • R A36 and R A37 are each independently selected from the group consisting of
  • R A36 and R A37 are each independently selected from the group consisting of
  • R A3 6 and R A37 are hydrogen; According to yet another embodiment of the present invention, RA36 and R A37 are hydrogen, R A38 is _ Nh
  • RA38 J S selected from the group consisting of
  • R A310 are eacn independently selected from the group consisting of
  • RA39 and RA310 combine to form a C 3-5 -CyCIyI
  • R A310 are eacn independently selected from the group consisting of
  • R A310 are each independently selected from the group consisting of
  • RA311 JS selected from the group consisting of
  • R A324 nave me same meanings as defined above, or preferably below.
  • R A 311 j selected from the group consisting of hydrogen, hydroxy, halogen, C ⁇ -alkyl, C ⁇ -alkoxy;
  • RA31 ⁇ is selected from the group consisting of
  • pA313 are eacn independently selected from the group consisting of
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 3- to 7-membered heterocyclyl may be bound to the C ⁇ -alky! via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C ⁇ -alkyl via C, N is substituted by RA328 ; or
  • RA313 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A328 , O and S;
  • RA313 are each independently selected from the group consisting of
  • pA315 are eacn independently selected from the group consisting of
  • RA315 are eacn independently selected from the group consisting of
  • RA317 are eacn independently selected from the group consisting of
  • 3- to 7-membered heterocyclyl wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 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 ⁇ 33 ⁇ , -CONRA332 R A333. or
  • RA316 and RA317 combine to form a 3- to 7-membered heterocycle
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A331 , O and S;
  • R A316 and R A31 7 are each independently selected from the group consisting of
  • R A316 and R A31 7 are hydrogen
  • R A3 18 and R A3 19 are eacn independently selected from the group consisting of
  • R A31 8 and R A31 9 are each independently selected from the group consisting of
  • R A3 20 j selected from the group consisting of
  • R A3 21 and R A3 22 are each independently selected from the group consisting of
  • heteroaryl has at least one heteroatom which is selected from N, O and S, 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
  • 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 ⁇ 34Z or R A321 anc
  • C ⁇ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NR A331 , O and S;
  • substituents RA338, RASS Q 1 RA340, R A341 > R A342 j RA343, R A344 and R A331 have the same meanings as defined above, or preferably below.
  • R A322 are eacn independently selected from the group consisting of
  • R A324 are each independently selected from the group consisting of
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • 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 ⁇ 328 , C3_6-cyclyl,
  • 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NR A331 , O and S;
  • R A324 are each independently selected from the group consisting of
  • R A325 , R A326 , R A328 , R A331 and RA342 are each independently selected from the group consisting of
  • R A326 , R A328 , R A33 1 and R A3 42 are each independently selected from the group consisting of
  • R A32 ? is represented by
  • pA341 are eacn independently selected from the group consisting of hydrogen and Ci_6-alkyl,
  • RA344 are eacn independently selected from the group consisting of
  • R B41 is selected from the group consisting of hydrogen, halogen, Ci_3-alkoxy, nitro and amino;
  • R B41 is selected from the group consisting of hydrogen, halogen, Ci_3-alkoxy;
  • R B41 is halogen
  • R B ⁇ 1 is selected from the group consisting of hydrogen, halogen, Ci_3-alkyl, hydroxy, Ci_3-alkoxy, nitro, amino, -NH-C(O)- Ci_2-alkyl,
  • 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-;
  • R B ⁇ 1 js selected from the group consisting of hydrogen, halogen and C ⁇ -alkoxy
  • R B51 is selected from the group consisting of hydrogen, halogen, C ⁇ -alkoxy
  • R B61 is selected from the group consisting of hydrogen and halogen
  • R B61 is hydrogen
  • R B7 ⁇ JS selected from the group consisting of hydrogen and halogen
  • R B71 is hydrogen
  • R B81 is selected from the group consisting of hydrogen and halogen
  • R B8 ⁇ is hydrogen
  • n is 1 , A 1 is N, R A01 , R A02 , R A21 and RA22 are eacn hydrogen, and one of the substituents R A ⁇ and R A ⁇ 2 is hydroxy; or
  • n 0, A 1 is N, R A1 1 and R A12 are each hydrogen, and one of the substituents R A21 and R A22 is methyl;
  • n is 0 or 1
  • a ⁇ is N
  • R A ⁇ , R A ⁇ 2 are each hydrogen
  • R A1 1 , R A12 are hydroxy or hydrogen
  • R A21 , R A22 are C ⁇ -alkyl or hydrogen
  • R B81 , R B71 , R B61 are hydrogen, R B51 is C ⁇ -alkoxy, R B41 is halogen.
  • n is 0 or 1
  • a ⁇ is N
  • R A ⁇ , R A ⁇ 2 are each hydrogen
  • R A1 1 , R A12 are each independently selected from the group consisting of hydroxy or hydrogen
  • R A21 , R A22 are each independently selected from the group consisting of C- ] .5-alkyl or hydrogen
  • R B81 , R B71 , R B61 are hydrogen
  • R B51 is C ⁇ -alkoxy
  • R B41 is halogen
  • R A31 and R A32 are each independently selected from the group consisting of
  • C ⁇ . ⁇ -alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy and 4- to 6-membered heterocyclyl,
  • the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • the 4- to 6-membered heterocyclyl may be bound to the C ⁇ . ⁇ -alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C
  • n is 0 or 1
  • a 1 is N
  • R A01 , R A02 are each hydrogen
  • R A1 1 , R A12 are each independently selected from the group consisting of hydroxy or hydrogen
  • R A2 ⁇ , R A22 are each independently selected from the group consisting of C ⁇ _3-alkyl or hydrogen
  • R B81 , R B71 , R B61 are hydrogen
  • R B51 is C ⁇ -alkoxy
  • R B41 is halogen
  • R A31 and R A32 are each independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy and 4- to 6-membered heterocyclyl,
  • the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • the 4- to 6-membered heterocyclyl may be bound to the C ⁇ .g-alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C-
  • a 1 is N; n represents 0 or 1 ;
  • R A01 and R A02 are hydrogen
  • R A ⁇ 1 and R A ⁇ 2 are each independently selected from the group consisting of hydrogen and hydroxy;
  • R A21 and R A22 are each independently selected from the group consisting of
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C ⁇ . ⁇ -heteroaryl,
  • heteroaryl has at least one heteroatom which is selected from N, O and S,
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
  • 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
  • 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and
  • 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
  • N is substituted by R A ⁇ 25
  • a ⁇ is S, it is optionally substituted by one or two oxo-groups;
  • RA35 j selected from the group consisting of
  • C ⁇ .g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RA37 are eacn independently selected from the group consisting of
  • RA38 is . NR A316 R A317 ;
  • RA316 and R A317 are hydrogen; RA325 j s eacn independently selected from the group consisting of
  • -C(O)O-C 1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
  • RB41 j selected from the group consisting of hydrogen, halogen, C ⁇ -alkoxy;
  • R B51 is selected from the group consisting of hydrogen, C ⁇ -alkoxy
  • R B61 , R B71 and R B81 are hydrogen
  • the compounds of Formula (I) are selected from the group consisting of
  • substituents in the present invention bind to the same atom and the list of meanings of these substituents includes hydrogen
  • one of the substituents may be hydrogen and the other may have a meaning as defined.
  • halogen used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is more preferred.
  • C-i. ⁇ -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
  • Ci_3-alkyl are more preferred and alkyl groups having 1 to 2 carbon atoms (C ⁇ -alkyl) are still more preferred.
  • the term "C ⁇ -alkyl" used in the specification of the present invention indicates linear or branched alkyl groups having 4 to 6 carbon atoms.
  • alkyl groups examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, a 1 ,1 -dimethylpropyl group, a 1 ,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1 -ethylpropyl group, a 2-ethylpropyl group, a 1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a 1 ,1 ,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 1-ethylbutyl group, a 1 ,1-dimethylbutyl group, a 1 ,
  • alkyl groups having 1 to 6 carbon atoms are a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group and a sec-butyl group, and still more preferred examples are a methyl group, an ethyl group, a n-propyl group, an isopropyl group and an isobutyl group, wherein a methyl group is particularly preferred.
  • C ⁇ . ⁇ -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 ⁇ -alkoxy) are preferred.
  • Examples of the C ⁇ -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- methylpropoxy
  • C3_g-cyclyl and “C3_5-cyclyl” used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms and 3 to 5 carbon atoms in their rings, respectively.
  • Examples of the C3_6-cyclyl and C3_5-cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
  • heterocyclyl includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen.
  • Heterocyclic groups may be saturated or unsaturated.
  • Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group,
  • tetrahydrothiophenyl group a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a
  • 3- to 7-membered heterocycle used in the specification of the present invention indicates a monocyclic 3- to 7-membered non-aromatic heterocyclic group which contains a nitrogen atom and optionally one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • the preferable example includes an aziridinyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a piperidinyl group, a piperazinyl group, a piperazine-2,3-dione group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group, a pyrrolidine-2,5-dione group, a piperazine-2,3-dione group and the like.
  • Cg. ⁇ -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.
  • Cg. ⁇ -aryl which is optionally substituted means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, wherein the aromatic hydrocarbon cyclic group has the same meaning as defined above and is optionally substituted by one or more substituents.
  • substituents are hydroxy; C-
  • Cs. ⁇ -aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • C ⁇ . ⁇ -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.
  • the term "C ⁇ .g-heteroaryl” used in the specification of the present invention refers to aromatic groups having 1 to 9 carbon atoms and one or more heteroatoms selected from N, O and S.
  • Preferred embodiments of such groups can be characterized as "5- to 10-membered heteroaryl" which indicates a monocyclic or bicyclic 5- to 10-membered heteroaryl which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • a 5- to 10-membered heteroaryl may preferably be used, and a 5 to 6 membered heteroaryl is more preferred.
  • aromatic heterocyclic group examples include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imidazo
  • 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.
  • 3-heteroaryl which is optionally substituted means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, typically being a 5- to 14-membered aromatic heterocyclic group, which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, wherein the 5- to 14-membered aromatic heterocyclic group is substituted by one or more substituents.
  • substituents are hydroxy; C ⁇ .g-alkyl, preferably methyl; C ⁇ .g-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylenedioxo.
  • the 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other.
  • C ⁇ .g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C ⁇ .g-alkoxy, C3_6-cyclyl, 3- to 7-membered heterocyclyl, C ⁇ _i4-aryl, C ⁇ . ⁇ -heteroaryl, an amine and an amide, such as defined, for instance for
  • the C ⁇ .g-alkyl group can be any group as specified above with respect to the C ⁇ .g-alkyl, unless specified otherwise.
  • the C ⁇ _g- alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C ⁇ .g-alkyl, wherein the mono-, tri- and perfluoro substituted C ⁇ .g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C ⁇ .g-alkyl groups.
  • Examples of these still more preferred mono- and perfluoro substituted C ⁇ .g-alkyl groups are fluoromethyl, 1- fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3- fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro-n-propyl and perfluoroisobutyl.
  • 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 ⁇ _3-alkyl group which is substituted with one or two hydroxy groups, preferably one hydroxy group.
  • Examples of such 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.
  • the C ⁇ .g-alkyl group can be any group as specified above with respect to C ⁇ .g-alkyl, unless specified otherwise.
  • 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.
  • the C ⁇ .g-alkyl group can be any group as specified above with respect to C ⁇ .g-alkyl, unless specified otherwise.
  • the C3_g- cyclyl group can be any group as specified above for 03.5-CyCIyI 1 unless specified otherwise.
  • the C ⁇ _ 5-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 C3_6-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C ⁇ .g-alkyl is substituted one C3_6-cyclyl. Particluarly preferred is a cyclopropylmethyl group.
  • the C ⁇ _g- alkyl group can be any group as specified above with respect to C-
  • the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise.
  • the C ⁇ _ ⁇ -alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5-membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C ⁇ .g-alkyl is substituted by one 3- to 7- membered heterocyclyl.
  • the C ⁇ .g-alkyl group can be any group as specified above with respect to C ⁇ .5-alkyl, unless specified otherwise.
  • the Cg. ⁇ - aryl group can be any group as specified above for Cg. ⁇ -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. ⁇ -aryl is preferably phenyl or
  • Particularly preferred is a benzyl group.
  • the C ⁇ .g-alkyl group can be any group as specified above with respect to C ⁇ .g-alkyl, unless specified otherwise.
  • the Ci_i 3-heteroaryl group can be any group as specified above for C ⁇ . ⁇ -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 ⁇ . ⁇ -heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C ⁇ .g-alkyl is substituted by one C ⁇ . ⁇ -heteroaryl. Particularly preferred is a pyridylmethyl group.
  • the above-mentioned C ⁇ .g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C ⁇ .g-alkoxy, C3_g-cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C ⁇ . ⁇ -heteroaryl, wherein the C ⁇ .g-alkoxy, C3_g-cyclyl, 3- to 7-membered heterocyclyl, Cg. ⁇ -aryl and C ⁇ . ⁇ -heteroaryl have the same meanings as defined above.
  • the C ⁇ . ⁇ -alkoxy group is substituted by at least one fluorine atom, the C ⁇ .
  • ⁇ -alkoxy group can be any group as specified above with respect to C ⁇ .g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C ⁇ . ⁇ -alkoxy, wherein the mono-, tri- and perfluoro substituted C ⁇ .g-alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C ⁇ . ⁇ -alkoxy groups.
  • Ci_6-alkoxy groups examples include fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro-isopropoxy, 1-fluoro- n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobutoxy.
  • the C ⁇ . ⁇ -alkoxy group can be any group as specified above with respect to C ⁇ .g-alkoxy, unless specified otherwise. It is preferably a C ⁇ . ⁇ -alkoxy group which is substituted by one or two hydroxy groups, more preferably a O ⁇ _$- alkoxy group which is substituted with one or two hydroxy groups, preferably one hydroxy group.
  • C ⁇ _3" alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 1- hydroxyethoxy, 2-hydroxyethoxy, 1 -hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1-hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2-hydroxyethoxy, 2- hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
  • both C ⁇ . ⁇ -alkoxy groups can be any group as specified above with respect to C ⁇ . ⁇ -alkoxy.
  • the first mentioned C ⁇ .5- 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 ⁇ . ⁇ -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.
  • the C ⁇ .g-alkoxy group can be any group as specified above with respect to C ⁇ . ⁇ -alkoxy, unless specified otherwise.
  • the C3_6-cyclyl group can be any group as specified above for 03.5-CyCIyI 1 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 C3_6-cyclyl is preferably a ring having 3 to 5 carbon ring atoms.
  • the C ⁇ .g-alkoxy is substituted by one C3_6-cyclyl.
  • Particluarly preferred is a cyclopropylmethoxy group.
  • the C ⁇ _g- alkoxy group can be any group as specified above with respect to C ⁇ .g-alkoxy, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise.
  • the C ⁇ .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5-membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C ⁇ .g-alkoxy is substituted by one 3- to
  • the C ⁇ .g-alkoxy group can be any group as specified above with respect to C ⁇ .g-alkoxy, unless specified otherwise.
  • the Cg-14-aryl group can be any group as specified above for Cg. ⁇ -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. ⁇ -aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C ⁇ .g-alkoxy is substituted by one Cg. ⁇ -aryl. Particularly preferred is a benzyloxy group.
  • the C ⁇ .g-alkoxy group is substituted by at least one C ⁇ . ⁇ -heteroaryl
  • the C ⁇ .g-alkoxy group can be any group as specified above with respect to C ⁇ .g-alkoxy, unless specified otherwise.
  • the C ⁇ . ⁇ -heteroaryl group can be any group as specified above for C ⁇ . ⁇ -heteroaryl, unless specified otherwise.
  • the C ⁇ .g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C ⁇ . ⁇ 3- heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C ⁇ .g-alkoxy is substituted by one C ⁇ . ⁇ -heteroaryl.
  • Particularly preferred is a pyridylmethoxy group.
  • C ⁇ .g-cyclyl group may be substituted by one or more substituents selected from the group consisting of fluoro and hydroxy.
  • the C3_g-cyclyl group can be any group as specified above with respect to C ⁇ .g-cyclyl, unless specified otherwise.
  • the C ⁇ .g-cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C3_g-cyclyl, wherein the mono-, di- and perfluoro substituted C3_g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted G j .g-cyclyl groups.
  • the O j .g-cyclyl group can be any group as specified above with respect to C3_6-cyclyl, unless specified otherwise.
  • the C3_6-cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted C j .g-cyclyl, wherein monohydroxy substituted C3_6-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)-
  • this/these substituent(s) preferably bind to a ring carbon atom.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri— , polyfluoro or perfluoro substituted 3- to 7-membered heterocyclyl, wherein the mono-, di- and perfluoro substituted 3- to 7-membered heterocyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocyclyl groups.
  • the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise.
  • the 3- to 7-membered heterocyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
  • the 3- to 7-membered heterocyclyl group is substituted by one or more substituents selected from hydrogen, C ⁇ .g-alkyl and -C(O)-C 1 _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.
  • the C ⁇ .g-alkyl group and the C ⁇ .g-alkyl moiety of the -C(O)-C 1 _g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C ⁇ g-alkyl.
  • substituent(s) hydrogen, 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 _ 6 -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 substituents selected from the group consisting of fluoro, hydroxy, oxo, C ⁇ g-alkoxy, hydrogen, C ⁇ g-alkyl and
  • 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 ⁇ _6-alkyl and -C(O)-C ⁇ _6-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.
  • the Ci_6-alkyl group and the C ⁇ -alkyl moiety of the -C(O)-Ci _6-alkyl 9 rou P can be an Y group as specified above with respect to the substituted or unsubstituted C ⁇ _6-alkyl.
  • substituent(s) hydrogen, C ⁇ -alkyl and -C(O)-Ci -6 ⁇ al M bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C 1 _ 6 -alkyl is -C(O)-CH 3 and -C(O)-CH 2 OH.
  • the invention covers all tautomers of the compounds of formula (I), a salt thereof, an N-oxide of the tautomeric compound or the salt thereof, a stereoisomer of the tautomeric compound, the salt, the N-oxide of the stereoisomer of the tautomeric compound or the N-oxide of the salt thereof.
  • Salts of the compounds according to the invention, the N-oxides thereof, the stereoisomers of the salts and the N-oxides thereof include all inorganic and organic acid addition salts and salts with bases, especially all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases, particularly all pharmaceutically acceptable inorganic and organic acid addition salts and salts with bases customarily used in pharmacy.
  • acid addition salts include, but are not limited to, hydrochlorides, hydrobromides, phosphates, nitrates, sulfates, acetates, trifluoroacetates, citrates, gluconates including D-gluconates and L-gluconates, glucuronates including D-glucuronates and L-glucuronates, benzoates, 2-(4- hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fumarates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesil
  • 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 (2) wherein R 1 is a Ci_6-alkyl group and PG 1 is a suitable temporary protecting group, e.g. 2-(trimethylsilyl)ethoxymethyl or tert-butoxycarbonyl, is prepared by protection of a compound of formula (1), in a manner known to the skilled person, e.g. by utilizing 2-(trimethylsilyl)ethoxymethyl chloride or di-tert-butyl dicarbonate.
  • R 1 is a Ci -6 -alkyl group
  • PG 2 being a suitable temporary protecting group, e.g. benzyl
  • Ff 01 , R A02 , R A11 , R A12 , R A21 , R A22 and n have the above defined meaning
  • PG 2 is a suitable temporary protecting group, e.g. benzyl
  • X 1 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate, in an alkylation reaction in the presence of an appropriate base, e.g.
  • a suitable solvent e.g. dimethylformamide or tetrahydrofuran
  • removal of the protecting group PG 1 e.g. the cleavage of 2- (trimethylsilyl)ethoxymethyl protecting group with a suitable fluorine source, e.g. tetrabutylammonium fluoride, or the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid.
  • reaction scheme 2 a compound of formula (4), prepared according to above reaction scheme 1 , can be reacted with a compound of formula (5), wherein R 841 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning and X 2 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, in a suitable solvent, e.g.
  • halogen such as chlorine
  • an acid such as trifluoroacetate
  • dichloroethane, diethylether, or nitromethane preferably at temperatures of 0-40 0 C, followed by a cyclization condensation reaction with ammonium acetate and/or ammonia in an appropriate solvent, e.g.
  • hydroxy-compound (6) can be converted into compound (7), wherein Ff 01 , R A02 , R A11 , R A12 , R A21 , R A22 , n, PG 2 , R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning and X 3 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in a manner known to the skilled person.
  • X 3 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in a manner known to the skilled person.
  • a compound of formula (8) wherein ⁇ t° ⁇ R A02 , R A11 , R A12 , R A21 , R A22 , n, PG 2 , X 3 , R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning and PG 3 is a suitable temporary protecting group, e.g. tert-butoxycarbonyl can be prepared by protection of a compound of formula (7), prepared according to above reaction scheme 2 according to procedures known to the skilled person, e.g. by utilizing di-tert-butyl dicarbonate.
  • a compound of formula (10) is obtained by Buchwald-Hartwig reaction of the resulting compound of formula (8) with compound of formula (9), wherein R A31 , R A32 , and A 1 have the above mentioned meaning, under inert atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or palladium(ll) acetate, and, if necessary, of a suitable phosphine ligand, e.g. 2,2- bis(diphenylphosphino)-1 ,1-binaphthalene, in the presence of a suitable base, e.g. cesium carbonate, in a suitable solvent, e.g. dioxane, at elevated temperature, preferably at temperatures 50-120 0 C, optionally using microwave radiation as energy source [see e.g. Tetrahedron Letters, 1997, pp. 6363- 6366].
  • a suitable palladium source e.g.
  • reaction scheme 4 a compound of formula (10), prepared according to above reaction scheme 3 can be deprotected to afford compound of formula (11 ), wherein Ff 01 , R A02 , R A11 , R A12 , R A21 , R A22 , R A31 , R A32 , n, A 1 , R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning in a manner known to the skilled person, for example, by debenzylation utilizing a suitable hydrogen source, e.g. 1 ,4-cyclohexadiene, in the presence of a suitable hydrogenation catalyst, e.g. palladium on charcoal, in a suitable solvent, e.g.
  • a suitable hydrogen source e.g. 1 ,4-cyclohexadiene
  • a suitable hydrogenation catalyst e.g. palladium on charcoal
  • the compound of formula (I), wherein R A01 , R A02 , R A11 , R A12 , R A21 , R* 22 , R A31 , R A32 , n, A 1 , R B41 , R B51 , R B61 , R B71 and R B ⁇ 1 have the above mentioned meaning, can be prepared by cyclization of a compound of formula (11 ), either in one step, e.g. by using a intermediate formation of suitable leaving group, e.g.
  • a conjugate base of an acid such as trifluoromethanesulfonate
  • an appropriate base e.g. pyridine
  • a suitable solvent e.g. dichloromethane
  • a conversion of the alcohol into a suitable leaving group e.g. halogen, such as chloride
  • cyclization reaction in the presence of an appropriate base, e.g. triethylamine or pyridine, in a suitable solvent, e.g. dimethylformamide.
  • R ⁇ 01 , R A02 , R A11 , R A12 , R A21 , n, R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning
  • R 2 is hydrogen or a 1-5C-alkyl group
  • X 4 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate
  • PG 4 being a suitable temporary protecting group, e.g.
  • a suitable palladium source e.g. tris(dibenzylideneacetone)dipalladium (0) or palladium(ll) acetate
  • a suitable phosphine ligand e.g. 2,2-bis(diphenylphosphino)-1 ,1-binaphthalene
  • a suitable base e.g. cesium carbonate
  • a suitable solvent e.g.
  • dioxane, acetonitrile, or tetrahydrofuran at temperatures between 0 0 C to 180 0 C, preferably 80 0 C to 120 0 C, optionally using microwave radiation as energy source, followed by removal of the protecting group PG 4 , in a manner known to the skilled person, for example, by the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid, in a suitable solvent, e.g. dioxane, or in a mixture of suitable solvents, e.g. ethanol, dioxane, water, at temperatures between 0 0 C to 180 0 C, preferably 80 0 C to 140 0 C, optionally using microwave radiation as energy source, gives rise to the compound of formula (I).
  • a suitable acid e.g. hydrochloric acid
  • suitable solvent e.g. dioxane
  • suitable solvents e.g. ethanol, dioxane,
  • a compound of formula (12), used as starting compound in the above reaction scheme 5, can be prepared according to reaction scheme 6.
  • the hydroxy-compound of formula (13), wherein R A01 , R A02 , R A11 , R A12 , R A21 , n, R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning and R 2 being hydrogen or a 1 -5C-alkyl group can be converted into compound of formula (14), wherein R A01 , R A02 , R A11 , R A12 , R ⁇ 1 , n, R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning, R 2 is hydrogen or a C-i-s-alkyl group, and X 4 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in a manner known to the skilled person, for example, by treatment
  • a compound of formula (14) is protected with a suitable temporary protecting group PG 4 , e.g. tert-butoxycarbonyl, according to procedures known to the skilled person, e.g. by utilizing di-tert-butyl dicarbonate, to afford a compound of formula (12).
  • PG 4 e.g. tert-butoxycarbonyl
  • a compound of formula (16), wherein R* 01 , R A02 , R A11 , R A12 , R A21 have the above defined meaning, R 1 is a Ci_6-alkyl group, and R 2 being hydrogen or a Ci_5-alkyl group, can be prepared by reacting of a compound of formula (2) with a compound of formula (15), wherein ft 0 ⁇ , R A02 , R A11 , R A12 , R A21 and n have the above mentioned meaning, R 2 is hydrogen or a C-i-s-alkyl group, and X 5 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate, in an alkylation reactbn in the presence of an appropriate base, e.g.
  • halogen such as bromide
  • a conjugate base of an acid such as trifluoromethanesulfonate
  • a suitable solvent e.g. dimethylformamide or tetrahydrofuran
  • removal of the protecting group PG 1 e.g. the cleavage of 2- (trimethylsilyl)ethoxymethyl protecting group with a suitable fluorine source, e.g. tetrabutylammonium fluoride, or the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid.
  • the resulting compound of formula (16) can be reacted with a compound of formula (5), wherein R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning and X 2 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, in a suitable solvent, e.g.
  • halogen such as chlorine
  • an acid such as trifluoroacetate
  • dichloroethane, diethylether, or nitromethane preferably at temperatures of 0-40 0 C, followed by a cyclization condensation reaction with ammonium acetate and/or ammonia in an appropriate solvent, e.g. methanol or dichloroethane, preferably at elevated temperature, optionally using microwave radiation as energy source, to give a corresponding compound of formula (13).
  • an appropriate solvent e.g. methanol or dichloroethane, preferably at elevated temperature, optionally using microwave radiation as energy source, to give a corresponding compound of formula (13). It may be convenient to perform both the Friedel-Crafts acylation reaction and the cyclization condensation reaction in one pot.
  • epoxide (17) wherein Ff 01 , R A02 , R A11 , R A12 , R A21 , n, R B41 , R B51 , R B61 , R B71 and R B81 have the above mentioned meaning, R 2 is hydrogen or a 1-5C-alkyl group, X 4 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, and PG* being a suitable temporary protecting group, e.g. tert-butoxycarbonyl, can be reacted with a compound of formula (9) in an art-known epoxide ring-opening reaction in a suitable solvent, e.g.
  • a cyclization reaction e.g. an immediate intramolecular cyclization or a cyclization using an intramolecular Buchwald-Hartwig reaction under inert atmosphere with catalytic amounts of a suitable palladium source, e.g.
  • phosphine ligand e.g. 2,2-bis(diphenylphosphino)-1 ,1-binaphthalene
  • a suitable base e.g. caesium carbonate
  • a suitable solvent e.g. dioxane
  • a compound of formula (17), used as starting compound in the above reaction scheme 8, can be obtained as demonstrated in reaction scheme 9.
  • a compound of formula (12), which can be prepared as shown in reaction scheme 6, can be converted into epoxid of formula (17) in a manner known to the skilled person, for example, using a epoxidation reaction with a suitable oxidation reagent, e.g. a peroxycarboxylic acid, such as meta-chloroperoxybenzoic acid, in a suitable solvent, e.g.
  • a suitable oxidation reagent e.g. a peroxycarboxylic acid, such as meta-chloroperoxybenzoic acid
  • R A31 is "substituted alkyl", e.g. -C ⁇ . ⁇ -alkyl, or - C3_6-cyclyl, or -3- to 7-membered heterocyclyl, all that may be optionally substituted as defined above, or -(CH 2 ) m R A35 , or -(CR A36 R A37 ) r COR A38 , wherein m > 1 , I > 0, R* 32 is a free electron pair and A 1 is N, can be prepared e.g.
  • alkylation reaction e.g. by reacting with an appropriate alkylating agent, e.g. C ⁇ .g-alkyl-Hal, or C3_6-cyclyl-Hal, or 3- to 7-membered heterocyclyl-Hal, all that may be optionally substituted as defined above, or Hal-(CH 2 ) m R A35 , or HaI- (CR A36 R A37 )
  • potassium carbonate sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof;
  • a suitable polar, aprotic solvent e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof;
  • R A31 is 3- to 7-membered heterocyclyl, wherein it may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by R* 325 , consisting of -C(O)-C-
  • -C(O)-C ⁇ _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy
  • R A32 is a free electron pair and A 1 is N
  • R A325 can be prepared from a compound of formula (I), wherein R A31 is 3- to 7-membered heterocyclyl, wherein it may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by R A325 , consisting of hydrogen, R* 32 is a free electron pair and A 1 is N, by reaction with an appropriate carboxylic acid chloride Ci_g-alkyl-C(O)CI, that may be optionally substituted as defined above, or carboxylic anhydride, (Ci_g-alkyl-C(O)) 2 O, that may be optionally substituted as defined above, in the presence of a base, e.g.
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g. triethylamine or diisopropylethylamine
  • a suitable additive reagent such as 1-hydroxybenzotri
  • R A31 is C ⁇ .g-alkyl, wherein the C ⁇ .g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and 3- to 7- membered heterocyclyl, that may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl being bound to the C ⁇ .g-alkyl via C, and wherein the 3- to 7-membered heterocyclyl contains a N heteroatom, and wherein N is substituted by R* 325 , consisting of -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, R A32 is a free electron pair and A 1 is N, can be prepared from a compound of formula (I), wherein R* 31 is C ⁇ .g-alkyl, wherein the C ⁇ .g-alkyl is optionally substituted by one
  • a dehydrating agent e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • a suitable base e.g. triethylamine or diisopropylethylamine
  • a suitable additive reagent such as
  • the compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material, e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium oxide.
  • a suitable support material e.g. silica gel, reversed phase silica gel, amino modified silica gel, aluminium oxide.
  • Salts of the compounds of formula (I), the N-oxides thereof and the stereoisomers of the compounds and the N-oxides thereof according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or
  • methylisobutylketone an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added.
  • 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
  • acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid.
  • bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. ammonia, trimethylamine or methylamine.
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid.
  • peracids such as m-chloroperbenzoic acid or peracetic acid.
  • the person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
  • Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.
  • the pure diastereomeric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
  • Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography.
  • Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent.
  • chiral auxiliary agents for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts.
  • diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1 - phenylethanol, respectively, as chiral auxiliary agents.
  • diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures.
  • enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
  • reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 150 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 temperature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
  • Ethyl indole-3-acetate (107.6 g) is dissolved in dichloromethane (500 ml), di-tert-butyl dicarbonate (127.0 g), triethylamine (80.0 ml), and 4-dimethylaminopyridine (0.50 g) are added and the solution is stirred for 18 h at RT. After that, the solution is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :9 (v/v)) to yield the title compound as a light-yellow oil.
  • Step 1 tert-Butyl 3-[5-(benzyloxy)-1-ethoxy-1-oxopentan-2-yl]-1 H-indole-1-carboxylate.
  • tert-Butyl 3-(2- ethoxy-2-oxoethyl)-1 H-indole-1-carboxylate (example A1 ) (156.0 g) is dissolved in N, N- dimethylformamide (1600 ml) and the solution is cooled to 0 0 C (ice bath).
  • Sodium hydride (60% suspension in mineral oil, 61.7 g) is added in portions under nitrogen and the mixture is stirred for 15 min at 0 0 C.
  • Benzyl 3-bromopropyl ether (117.8 g) is added drop by drop at a rate that the internal temperature does not exceed 30 0 C (ca. 3 min) and the suspension is stirred for 90 min at RT. Ice and ethyl acetate are added in portions. The mixture is diluted with water (1000 ml) and saturated ammonium chloride solution (1500 ml), the aqueous phase is extracted with ethyl acetate (4 x 500 ml). The combined organic extracts are concentrated in vacuo.
  • the crude product contains a mixture of tert-butyl 3-[5-(benzyloxy)-1-ethoxy-1 -oxopentan-2-yl]-1 H-indole-1 -carboxylate and ethyl 5- (benzyloxy)-2-(1 H-indol-3-yl)pentanoate and is used without further purification in the next step.
  • Step 2 Ethyl 5-(benzyloxy)-2-(1 H-indol-3-yl)pentanoate.
  • the solution is cooled to 0 0 C, sodium hydroxide solution is added (ca. 10% in water, pH 5), the aqueous phase is extracted with ethyl acetate (4 x 500 ml).
  • the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is dissolved in ethyl acetate / petroleum ether 1 :9 (v/v), filtered through a filter pad of 11 cm silica, and the pad is washed with ethyl acetate / petroleum ether 1 :9 (v/v) followed by ethyl acetate / petroleum ether 1 :4 (v/v).
  • the combined filtrates are concentrated in vacuo.
  • ethyl 5-(benzyloxy)-2-(1 H-indol-3-yl)pentanoate (example A2) (9.5 g) is dissolved under argon in dichloroethane (100 ml) and the solution is cooled to 0 0 C (ice bath).
  • Zinc chloride (1 M in diethyl ether, 54 ml) is added drop by drop and the mixture is stirred for 5 min at 0 0 C.
  • the solution of a mixed anhydride, prepared above, is added drop by drop and the mixture is stirred for 10 min at 0 0 C and 90 min at room temperature.
  • ammonia (7M in methanol, 24.7 ml) and ammonium acetate (12.9 g) are added and the mixture is heated in sealed vials at 150 0 C for 30 min under microwave irradiation. After cooling, the content of the vials is filtered over a pad of Celite ® , the pad is washed with methanol. The combined filtrate is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :4 (v/v) to ethyl acetate) to yield the title compound as a yellow oil.
  • trifluoromethanesulphonic anhydride 53 ml is added and the solution is stirred for 90 min at 0 0 C.
  • An ice-cold mixture of saturated sodium chloride solution (1000 ml) and concentrated hydrochloric acid (100 ml) is added, the aqueous phase is acidified by addition of ice-cold concentrated hydrochloric acid to pH 5.5 and extracted with dichloromethane.
  • the combined organic extracts are filtered through a filter pad of 10 cm silica, and the pad is washed with dichloromethane (1000 ml).
  • the combined filtrates are concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / cyclohexane 1 :4 (v/v)) to yield the title compound as a yellow oil.
  • the mixture is stirred under argon for 18 h at 100 0 C.
  • the mixture is allowed to cool to room temperature, filtered over Celite ® , washed with methanol.
  • the combined filtrates are concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :9 (v/v)) to obtain the title compound as a yellow oil.
  • tert-Butyl 1-(3-fluoro ⁇ 4- methoxybenzyl ⁇ -Ioxiran ⁇ -ylmethyll-S-II ⁇ rifluoromethy ⁇ sulfonyljoxyJ- ⁇ H-beta-carboline- ⁇ -carboxylate (example A20) (600 mg) is dissolved in 2 N ammonia solution in ethanol (10 ml) and the solution is heated in a sealed vial at 80 0 C for 18 h. After cooling to room temperature, the content of the vial is concentrated in vacuo.
  • the crude product contains a mixture of tert-butyl 4-(3-amino-2-hydroxypropyl)- 1-(3-fluoro-4-methoxybenzyl)-3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -9H-beta-carboline-9-carboxylate and 4- (3-amino-2-hydroxypropyl)-1-(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-3-yl
  • Step 2 tert-Butyl 6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H-indolo[2,3- c][1 ,8]naphthyridine-7-carboxylate.
  • the crude product of step 1 is dissolved in dioxane (10 ml), then cesium carbonate (620 mg), tris(dibenzylideneacetone)dipalladium(0) (175 mg), and ( ⁇ )-2,2- bis(diphenylphosphino)-1 ,1-binaphthalene (180 mg) are added under argon. The mixture is stirred under argon for 18 h at 102 0 C.
  • the mixture is allowed to cool to room temperature, filtered over Celite ® , washed with methanol.
  • the combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with a mixture of dichloromethane and MeOH, then eluted with 7 N NH 3 solution in MeOH.
  • the filtrate is concentrated in vacuo.
  • the crude product contains a mixture of tert-butyl 6-(3-fluoro-4- methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H-indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate and 6- (3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol and is used without further purification in the next step.
  • Step 3 6-(3-Fuoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol.
  • the crude product of step 2 is dissolved in methanol, concentrated hydrochloric acid (1 ml) is added and the solution is heated under microwave irradiation in a sealed vial at 80 0 C for 15 min and at 90 0 C for 15 min. After cooling to room temperature, the content of the vial is concentrated in vacuo.
  • Step 2 6-(3-Fluoro ⁇ -methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine.
  • the crude product of step 1 is dissolved in a mixture of dimethylformamide (8 ml) and triethylamine (8 ml), potassium iodide (216 mg) is added, and the mixture is heated in a sealed vial at 100 0 C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is poured into 10% aqueous ammonium chloride solution and the aqueous phase is extracted with ethyl acetate.
  • the combined organic extracts are dried (MgSO 4 ) and concentrated in vacuo.
  • the crude product is loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with diluted NH 3 solution in MeOH.
  • the filtrate is concentrated in vacuo to obtain the title compound as a yellow foam.
  • the crude product is dissolved in dichloromethane, filtered through a filter pad of silica, and the pad is washed with ethyl acetate / petroleum ether / triethylamine 5:5:1 (v/v/v).
  • the combined filtrates are concentrated in vacuo.
  • the crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :4 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain the title compound.
  • 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine (example 1 ) (100 mg), potassium iodide (30 mg), and bromoacetamide (120 mg) are dissolved in a mixture of dimethylformamide (2 ml) and triethylamine (1 ml), and the mixture is heated in a sealed vial at 130 0 C for 20 min under microwave irradiation.
  • Step 1 tert-Butyl 5-(3-fluoro ⁇ -methoxybenzyl)-2,3-dimethyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4- b]indole-6(1 H)-carboxylate.
  • the mixture is heated in a sealed vial at 100 0 C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite ® , washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH 3 solution in MeOH.
  • Step 2 5-(3-Fluoro ⁇ -methoxybenzyl)-2,3-dimethyl-1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4- b]indole dihydrochloride.
  • the crude product of step 1 is dissolved in a mixture of dioxane (1 ml) and ethanol (1 ml), concentrated hydrochloric acid (154 ⁇ l) is added, and the mixture is heated in a sealed vial at 100 0 C for 30 min under microwave irradiation. After cooling to room temperature, the crystalline precipitate is filtered, washed with dioxane and dried to obtain the title compound.
  • Step 1 tert-Butyl 3- ⁇ [1-(tert-butoxycarbonyl)azetidin-3-yl]methyl ⁇ -5-(3-fluoro-4-methoxybenzyl)-2- methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate.
  • the mixture is heated in a sealed vial at 100 0 C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite ® , washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH 3 solution in MeOH.
  • Step 2 3-(Azetidin-3-ylmethyl)-5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,2,3,6- tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride.
  • the crude product of step 1 is dissolved in a mixture of dioxane (1 ml) and ethanol (1 ml), concentrated hydrochloric acid (350 ⁇ l) is added, and the mixture is heated in a sealed vial at 100 0 C for 15 min under microwave irradiation.
  • Step 3 1-(3- ⁇ [(5-(3-Fluoro ⁇ -methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol- 3(2H)-yl]methyl ⁇ azetidin-1 -yl)ethanone.
  • Step 1 tert-Butyl 3-benzyl-5-(3-fluoro-4-methoxybenzyl)-2-methyl-2,3- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate.
  • the mixture is heated in a sealed vial at 100 0 C for 45 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite ® , washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH 3 solution in MeOH.
  • Step 2 5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole.
  • the crude product of step 1 is dissolved in a 1-butanol (70 ml), under argon 1 ,4-cyclohexadiene (5.4 g) and palladium (10% on charcoal, 1.0 g) are added and the mixture is refluxed for 18 h. The suspension is cooled to room temperature, filtered over Celite ® , washed with 1-butanol.
  • Step 3 2-[5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)- yl]acetamide.
  • the combined organic extracts are dried and concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain the title compound.
  • Step 1 tert-Butyl 4- ⁇ 3-[(1-acetylpiperidin-4-yl)amino]-2-hydroxypropyl ⁇ -1-(3-fluoro-4-methoxybenzyl)-3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -9H-beta-carboline-9-carboxylate.
  • Step 2 tert-Butyl 4-(1 -acetylpiperidin ⁇ 4-yl)-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro- 7H-indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate.
  • tert-Butyl 4- ⁇ 3-[(1-acetylpiperidin-4-yl)amino]-2- hydroxypropyl ⁇ -1-(3-fluoro-4-methoxybenzyl)-3- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -9H-beta-carboline-9- carboxylate from step 1 (390 mg) is dissolved in dioxane (5 ml), then cesium carbonate (390 mg), ths(dibenzylideneacetone)dipalladium(0) (1 10 mg), and ( ⁇ )-2,2-bis(diphenylphosphino)-1 ,1- binaphthalene (110 mg) are added under argon.
  • the mixture is stirred under argon for 18 h at 80 0 C.
  • the mixture is allowed to cool to room temperature, filtered over Celite ® , washed with methanol.
  • the combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH 3 solution in MeOH.
  • the filtrate is concentrated in vacuo.
  • the crude product contains a mixture of tert-butyl 4-(1-acetylpiperidin-4-yl)-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H- indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate and 1 - ⁇ 4-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7- tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin-4-yl]piperidin-1-yl ⁇ ethanone and is used without further purification in the next step.
  • Step 3 1- ⁇ 4-6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3- c][1 ,8]naphthyridin-4-yl]piperidin-1 -yl ⁇ ethanone.
  • the crude product of step 2 is dissolved in ethanol (3 ml), concentrated hydrochloric acid (0.5 ml) is added and the solution is heated in a sealed vial at 100 0 C for 15 min under microwave irradiation. After cooling to room temperature, the content of the vial is concentrated in vacuo.
  • the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield the title compound.
  • Step 1 tert-Butyl 6-(3-fluoro ⁇ -methoxybenzyl)-2-hydroxy-4-methyl-1 ,2,3,4-tetrahydro-7H-indolo[2,3- c][1 ,8]naphthyridine-7-carboxylate.
  • Step 2 6-(3-fluoro-4-methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2- ol hydrochloride.
  • the crude product of step 1 is dissolved in ethanol (5 ml), concentrated hydrochloric acid (1.0 ml) is added, and the mixture is heated in a sealed vial at 100 0 C for 15 min under microwave irradiation. After cooling to room temperature, the crystalline precipitate is filtered, washed with methanol and dried to obtain the title compound.
  • the compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention.
  • the compounds of the invention are pharmaceutically acceptable.
  • the compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable.
  • PDE5 type 5 phosphodiesterase
  • they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms.
  • the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect.
  • the compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase.
  • the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie ' s disease;
  • acute and chronic airway diseases such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis in particular idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, extrinsic allergic alveolitis;
  • COPD chronic obstructive pulmonary disease
  • bronchitis emphysema
  • pulmonary vascular remodeling pulmonary hypertension
  • asthma cystic fibrosis
  • bronchiectasis bronchiolitis
  • 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
  • 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;
  • 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;
  • 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 hyperp
  • insufficient brain skills such as but not limited to, verbal attainment, attention, concentration, deductive thinking, central auditory processing, cognition, learning, vigilance, apprehension and reagibility.
  • 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
  • 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.
  • VOD veno-occlusive
  • 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
  • drugs or toxins e.g., but not limited to, anorexigens
  • persistent pulmonary hypertension of the newborn e.g., but not limited to, anorexigens
  • 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;
  • COPD chronic obstructive pulmonary disease
  • 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);
  • 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.
  • inflammatory disorders e.g., but not limited to, schistosomiasis, sarcoidosis
  • pulmonary capillary hemangiomatosis e.g., but not limited to, schistosomiasis, sarcoidosis
  • the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • 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 further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
  • 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 relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
  • an acute or chronic airway disease for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • the invention preferably relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive 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, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease
  • the invention preferably relates to a method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis 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.
  • 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
  • the invention additionally relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
  • the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
  • corticosteroids examples include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide.
  • anticholinergics include without limitation indacaterol, 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 palmitate, 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 epoprostenol sodium and treprostinil such as treprostinil sodium.
  • Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine.
  • Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, atenolol and nadolol.
  • Examples of type 4 phosphodiesterase inhibitors include without limitation roflumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast.
  • Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride.
  • Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin.
  • Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab.
  • diuretics include without limitation furosemide, bumetanide and torsemide.
  • 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:
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic.
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic.
  • composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant.
  • the pharmaceutical composition comprises: a compound of the invention and bupropion.
  • the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic.
  • the pharmaceutical composition comprises:
  • telithromycin a compound of the invention and telithromycin
  • the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a diuretic.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic.
  • the pharmaceutical composition comprises:

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Abstract

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

Description

Description
Benzyl-substituted tetracyclic heterocyclic compounds
Field of application of the invention
The invention relates to Benzyl-substituted tetracyclic heterocyclic compounds, and their use, as well as the resulting pharmaceutical compositions and uses thereof in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
Background of the Invention
6-Benzyl-3,3-dimethyl-2,3,4,7-tetrahydro-indolo[2,3-c]quinolin-1-one is described in Khimiya
Geterotsiklicheskikh Soedinenii (1985) 3, 363-6 without mentioning any pharmaceutical activity thereof. WO 02/064590, WO2008095835 and EP1953159 disclose nitrogen-containing heterocyclic PDE5 inhibiting compounds. WO2008027182 discloses indoloquinoline compounds as calcium channel blockers.
It is an object of the present invention to provide novel compounds and pharmaceutical compositions which may be used in the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterases.
A further object of the present invention is to provide a method of manufacture of the compounds and compositions of the present invention.
It is a further object of the present invention to provide a method for treating diseases alleviated by inhibition of type 5 phosphodiesterases in a subject in need thereof.
Description of the invention
It has now been found that the Benzyl-substituted tetracyclic heterocyclic compounds, which are described in detail below, have surprising and advantageous properties, and making them especially useful in the treatment and prophylaxis of diseases alleviated by inhibition of type 5
phosphodiesterases.
The compounds of the present invention are characterized by Formula (I) as specified in the following. The invention thus relates to compounds of Formula (I)
Figure imgf000003_0001
wherein A1 is each independently selected from the group consisting of N, O and S;
n represents 0 or 1 ; with the proviso that if A1 is O or S the substituent RA31 is absent.
RA01 anc| RA02 are eacn independently selected from the group consisting of
hydrogen, hydroxy, C-|_6-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy,
Ci_6-alkoxy,
wherein the C^_6-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.s-alkoxy, and
-NRA03RA04. or
RA01 anc| RA02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-;
RA03 and RA04 are each independently selected from the group consisting of
hydrogen, C^_6-alkyl,
wherein the C^^-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^_6-alkoxy,
-NRA05RA06 and -C(O)-NRAOZRAOS1 -C(0)-RA09 -C(O)-NRA010RA01 1 and -C(O)ORA012. or
RA03 anc| RA04 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^.g-alkoxy,
-NRA013RA014 and -C(O)-NRAOI SRAOIe1 and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA01 7, O and S;
RA05 and RA06 are eacn indpendently selected from the group consisting of
hydrogen, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, and
-C(O)-C1 _6-alkyl,
wherein the -C(O)-Ci -6~alM is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy; or
RA05 and RA06 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRAOI S1 0 and S;
RA°7 and RA08 are eacn independently selected from the group consisting of
hydrogen and C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy; or
RA07 and RA08 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA019 o and S;
RA09 js selected from the group consisting of
hydrogen and C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C^.g-alkoxy;
RA010 and RA011 are each independently selected from the group consisting of hydrogen and C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy;
RA012 is Ci _6_alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy;
RA01 3 and RA014 have the same meanings as RA05 and RA06, and RA01 5 and RA016 have the same meanings as RA^ anc| RA08-
RA01 7, RA018 anc| RA019 are eacn independently selected from the group consisting of
hydrogen, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1.6-alkyl,
wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA1 1 and RA12 have the same meanings as RA01 and RA02;
RA21 and RA22 are each independently selected from the group consisting of
Hydrogen or C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA31 is selected from the group consisting of
hydrogen, C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C^^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S,
C6-i4-aryl,
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 to the Gj.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 RA325,
C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6-i4-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, 3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl is bound via C, and
wherein N is substituted by RA325,
-S(O)2-C1.6-alkyl,
wherein the -S(O)2-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRA33RA34, -(CH2)m-RA35, -(CRA36RA37)|-CORA38, -CO(CRA39RA31 0)k-RA31 1 and a lone pair;
or in case A1 is S, it is optionally substituted by one or two oxo-groups; wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
RA33 anc| RA34 are eacn independently selected from the group consisting of
hydrogen and C^g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; pA35 js selected from the group consisting of
hydroxy, C^.g-alkoxy,
wherein the C^g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA312RA313-
RA36 anc| RA37 are each independently selected from the group consisting of
hydrogen, hydroxy, halogen, C^.β-alkyl,
wherein the Ci.β-alkyI is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C^.β-alkoxy,
wherein the Ci.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
_NRA314RA315; or
RA36 anc| RA37 combine to form a 03.5-CyCIyI1
wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA38 js selected from the group consisting of
hydroxy, C^.β-alkyl,
wherein the C^.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C^.β-alkoxy,
wherein the C^.β-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
_NRA316RA317;
RA39 anc| RA310 are eacn independently selected from the group consisting of
hydrogen, hydroxy, fluoro, C^.β-alkyl,
wherein the Ci.β-alkyI is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.β-alkoxy,
wherein the C^.s-alkoxy is optionally substituted by fluoro and hydroxy, C^.β-alkoxy,
wherein the C^.β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
_NRA318RA319. or
RA39 anc| RA310 combine to form a 03.5-CyCIyI1
wherein the C3_5-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or RA39 anc| RA310 combine to form an oxo-group;
RA311 js selected from the group consisting of
hydrogen, hydroxy, halogen, -CO(O)RA320, -NRA321 RA322, -CONRA323RA324, C^-alkyl, wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
Ci_6-alkoxy,
wherein the C^g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^g-alkoxy,
C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and
C3_6-cyclyl,
wherein the C3_6-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 Cj.g-alkoxy via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkoxy via C, N is substituted by RA325, and
_NRA325RA326-
RA312 and RA3^ 3 are each independently selected from the group consisting of
hydrogen, C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy,
-C(O)-C1.6-alkyl,
wherein the -C(O)-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)ORA327, C3.6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound to the G^-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C^-alkyl via C, N is substituted by RA328; or
RA312 anc| RA313 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^-alkoxy,
wherein the C^-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA328, O and S;
RA314 anc| RA315 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;
RA316 anc| RA317 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, hydroxy, C^g-alkoxy,
C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
C^g-heteroaryl,
wherein the C^g-heteroaryl has at least one heteroatom selected from N, O and
S, 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 Cj.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C^-alkyl via C, N is substituted by RA328, and
_NRA329RA330
-C(O)-C1.6-alkyl,
wherein the -C(O)-C1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy,
wherein the C^-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-S(O)2-C1.6-alkyl,
wherein the S(O^-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)O-C1.6-alkyl,
wherein the -C(O)O-C1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3_6-cyclyl,
wherein the C3_6-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 FΛ331 , -CONRA332RA333; or
RA316 anc| RA317 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S; pA318 anc| RA319 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 _5-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA320 js selected from the group consisting of
hydrogen and C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA321 anc| RA322 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,
C6.14-aryl,
C^g-heteroaryl,
wherein the C^g-heteroaryl has at least one heteroatom selected from N, O and
S,
C3_6-cyclyl,
wherein the C3_6-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 C1.6-alkyl via C, N is substituted by RA331 ,
_NRA334RA335 and _CON RA336RA337
-C(O)O-C1.6-alkyl,
wherein the -C(O)O-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)-C1.6-alkyl
wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-CONRA338RA339, -S(O)2-C1.6-alkyl, wherein the -S(O)2-Ci _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-S(O)2NRA340RA341 , C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by FΛ342; or RA321 anc| RA322 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C^_6-alkyl,
wherein the C^^-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
Ci_6-alkoxy,
-CONRA343RA344, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
RA323 anc| RA324 are each independently selected from the group consisting of
hydrogen, C^_6-alkyl,
wherein the C^^-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^_6-alkoxy,
C6.14-aryl,
C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 3- to 7-membered heterocyclyl may be bound to the C^g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C-i_e-alkyl via C, N is substituted by RA328,
C6.14-aryl,
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^328, C3.6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
and
-C(O)-C1 _6-alkyl,
wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-S(O)2-C1.6-alkyl,
wherein the -S(O)2-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
RA323 anc| RA324 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
RA325, RA326, RA328, RA331 and RA342 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 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
-C(O)O-C1 _6-alkyl,
wherein the -C(O)O-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA327 js represented by
C.|_1 0-alkyl,
wherein the C-|_-i g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA329 RA330 RA334 RA335 RA338 RA339 RA340 and RA341 are each independently selected from the group consisting of
hydrogen and C^^-alkyl,
wherein the C^_6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA332 RA333 ^3Se1 RA337 RA343 and RA344 are each independently selected from the group consisting of
hydrogen, C^-alkyl,
wherein the C^^-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^_6-alkoxy,
wherein the C^.s-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 is selected from the group consisting of hydrogen, halogen, C^-alkoxy, nitro and amino;
RB51 is selected from the group consisting of hydrogen, halogen, C^-alkyl, hydroxy, C^-alkoxy, nitro, amino, -NH-C(O)- C^-alkyl, -NH-C(O)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and
-CH2-CH2-O-;
RB61 js selected from the group consisting of hydrogen and halogen; RB71 is 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 another embodiment of the present invention, A^ is N;
According to another embodiment of the present invention, RA01 and RA02 are each independently selected from the group consisting of
hydrogen, hydroxy, C^-alkyl, C^-alkoxy, -NRA03RA04; or
RA01 anc| RA02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-;
wherein the substituents RA03 anc| RA04 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 group consisting of
hydrogen, hydroxy, C^_6-alkyl, C^_6-alkoxy, or
RA01 anc| RA02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-;
According to yet another embodiment of the present invention, RA^ and RA^2 are each independently selected from the group consisting of
hydrogen, hydroxy, C^-alkyl and C^-alkoxy;
According to yet another embodiment of the present invention, RA^ and RA^2 are each independently selected from the group consisting of
hydrogen and hydroxy;
According to yet another embodiment of the present invention, RA^ and RA^2 are hydrogen;
According to yet another embodiment of the present invention, RA01 and RA02 are each independently selected from the group consisting of hydrogen and hydroxy, wherein the carbon atom to which the substituents RA^ ^ and RA^2 bind is in the R-configu ration,
According to another embodiment of the present invention, RA03 and RA04 are each independently selected from the group consisting of
hydrogen, C^_6-alkyl,
_NRA05RA06 and -C(O)-N RA07RA08, -C(0)-RA09 -C(O)-NRA010RA01 1 and -C(O)ORA012. or
RA03 anc| RA04 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA01 7, O and S;
wherein the substituents RA05, RA06, RA07, RA08, RA09, RA1 °, RA1 1and RA12 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA03 and RA04 are each independently selected from the group consisting of
Hydrogen and C^.g-alkyl;
According to yet another embodiment of the present invention, RA05 anc| RA06 are each indpendently selected from the group consisting of
hydrogen, C^.g-alkyl, -C(O)-Ci .g-alkyl,
RA05 anc| RA06 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA01 8, O and S;
wherein the substituent RA018 nas j.ne same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention, RA05 anc| RA06 are eacn indpendently selected from the group consisting of
hydrogen and C-|_6-alkyl;
According to yet another embodiment of the present invention, RA07 and RA08 are each independently selected from the group consisting of
hydrogen and C^.g-alkyl,
RA07 anc| RA08 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA01 9, O and S;
wherein the substituent RA01 9 has the same meaning as defined above, or preferably below.
According to yet another embodiment of the present invention, RA^7 and RA^8 are each independently selected from the group consisting of
hydrogen and C^.g-alkyl;
According to yet another embodiment of the present invention, RA09 js selected from the group consisting of hydrogen and C^.β-alkyl;
According to yet another embodiment of the present invention, RA010 anc| RA011 are eacn independently selected from the group consisting of
hydrogen and C^.β-alkyl,
According to yet another embodiment of the present invention, RA012 JS c^.g-alkyl,
According to yet another embodiment of the present invention, R^O^ pA018 anc| pA019 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-C1 _6-alkyl,
According to yet another embodiment of the present invention, R^OI ^ pA018 anc| pA019 are eacn independently selected from the group consisting of
hydrogen and C^.g-alkyl;
According to yet another embodiment of the present invention, RA1 1 and RA12 are each independently selected from the group consisting of hydrogen and hydroxy, wherein the carbon atom to which the substituents RA^ ^ and RA^2 bind is in the R-configu ration,
According to yet another embodiment of the present invention, RA21 and RA22 are each independently selected from the group consisting of
Hydrogen and C^.g-alkyl;
According to yet another embodiment of the present invention, RA2^ and RA22 are each independently selected from the group consisting of hydrogen and C^.g-alkyl, wherein the carbon atom to which the substituents RA21 and RA22 bind is in the R-configu ration;
According to yet another embodiment of the present invention, RA31 and RA32 are each independently selected from the group consisting of
hydrogen, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C^.^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S,
C6.14-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 to the 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 RA325,
C3_6-cyclyl,
C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, 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 is bound via C, and
wherein N is substituted by RA325,
-S(O)2-C1.6-alkyl,
-SO2NRA33RA34, -(CH2)m-RA35, -(CRA36RA37)|-CORA38, -CO(CRA39RA31 0)k-RA31 1 and a lone pair;
wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2; and wherein the substituents RA325 RA33 RA34 RA35 RA36 RA37 RA38 RA39 RA310 and RA311 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA3^ and RA32 are each
independently selected from the group consisting of
hydrogen, C^-alkyl,
wherein the C^-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C1.^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S,
C6.14-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 to the C^-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C1.6-alkyl via C, N is substituted by RA325,
C3_6-cyclyl, C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, 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 is bound via C, and
wherein N is substituted by RA32^,
-(CH2)m-RA35, -(CRA36RA37)|.CORA38I _CO(CRA39RA310)k_RA311 and a bne pair;
wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2; and wherein the substituents RA325 RA35 RA36 RA37 RA38 RA39 RA310 and RA311 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA3^ and RA32 are each
independently selected from the group consisting of
hydrogen, C^.β-alkyl,
wherein the C^.g-alkyl is optionally substituted by one 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^-alkyl via C, N is substituted by RA325,
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 is bound via C, and
wherein N is substituted by RA32^,
-(CH2)m-RA35, -(CRA36RA37)|-CORA38 and a lone pair;
wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4; and wherein the substituents R^325, RA35, RA36, RA37 anc| RA38 nave the same meanings as defined above, or preferably below.
RA31 anc| RA32 are each independently selected from the group consisting of
hydrogen, C^.β-alkyl,
wherein the C^.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy and 4- to 6-membered heterocyclyl,
wherein the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and wherein the 4- to 6-membered heterocyclyl may be bound to the C^.g-alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C-i_e-alkyl via C, N is substituted by RA325,
-(CH2)m-RA35, -(CRA36RA37)|-CORA38 and a lone pair; wherein m is 2 and I is 1 ; and wherein the substituents RA325, RA35, RA36, RA37 and RA38 have the same meanings as defined above or below.
According to yet another embodiment of the present invention, RA33 and RA34 are each independently selected from the group consisting of
hydrogen and C-|_6-alkyl,
According to yet another embodiment of the present invention, RA35 js selected from the group consisting of
hydroxy, C^-alkoxy, -NRA312RA313;
wherein the substituents RA312 anc| RA313 have the same meanings as defined above or below.
According to yet another embodiment of the present invention, RA35 js selected from the group consisting of
hydroxy and C^.g-alkoxy,
According to yet another embodiment of the present invention, RA35 js hydroxy,
According to yet another embodiment of the present invention, RA36 and RA37 are each independently selected from the group consisting of
hydrogen, hydroxy, halogen, C-|_6-alkyl, C^.g-alkoxy, Cβ.^-aryl, -NRA314RA31 5; or RA36 and RA37 combine to form a C3_g-cyclyl,
wherein the substituents RA314 anc| RA315 have the same meanings as defined above or below.
According to yet another embodiment of the present invention, RA36 and RA37 are each independently selected from the group consisting of
hydrogen, hydroxy, halogen, C^.g-alkyl, C^.g-alkoxy,
According to yet another embodiment of the present invention, RA36 and RA37 are each independently selected from the group consisting of
hydrogen and C^.g-alkyl;
According to yet another embodiment of the present invention, RA36 and RA37 are hydrogen; According to yet another embodiment of the present invention, RA36 and RA37 are hydrogen, RA38 is _Nh|2 and RA325 is -C(O)-C1 _6-alkyl or -C(O)O-C1 _6-alkyl;
According to yet another embodiment of the present invention, RA38 JS selected from the group consisting of
hydroxy, C^-alkyl, C^-alkoxy, -NRA316RA317;
wherein the substituents RA316 anc| RA317 nave me same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA38 JS _NRA316RA317-
According to yet another embodiment of the present invention, RA39 anc| RA310 are eacn independently selected from the group consisting of
hydrogen, hydroxy, fluoro, C^-alkyl, C^-alkoxy, -NRA318RA319; or
RA39 and RA310 combine to form a C3-5-CyCIyI,
RA39 anc| RA310 combine to form an oxo-group;
wherein the substituents RA318 anc| RA319 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA39 anc| RA310 are eacn independently selected from the group consisting of
hydrogen, hydroxy, fluoro, C^-alkyl, C^-alkoxy;
According to yet another embodiment of the present invention, RA39 anc| RA310 are each independently selected from the group consisting of
hydrogen and C^-alkyl;
According to yet another embodiment of the present invention, RA311 JS selected from the group consisting of
hydrogen, hydroxy, halogen, -CO(O)RA320 _NRA321 RA322 _CONRA323RA324 c^-alkyl,
C^s-alkoxy,
wherein the substituents RA320 RA321 _ RA322_ RA323 anc| RA324 nave me same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA311 js selected from the group consisting of hydrogen, hydroxy, halogen, C^-alkyl, C^-alkoxy;
According to yet another embodiment of the present invention, RA31 ^ is selected from the group consisting of
hydrogen and C^-alkyl;
According to yet another embodiment of the present invention, RA312 anc| pA313 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-C1 _6-alkyl, -C(O)ORA327, 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 to the C^-alky! via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C^-alkyl via C, N is substituted by RA328; or
RA312 anc| RA313 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA328, O and S;
wherein the substituents RA327 anc| RA328 nave me same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA312 anc| RA313 are each independently selected from the group consisting of
hydrogen, C^-alkyl
According to yet another embodiment of the present invention, RA314 anc| pA315 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-C1 _6-alkyl,
According to yet another embodiment of the present invention, RA314 anc| RA315 are eacn independently selected from the group consisting of
hydrogen, C^-alky!,
According to yet another embodiment of the present invention, RA316 anc| RA317 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-C1 _6-alkyl, -S(O)2-C1.6-alkyl, -C(O)O-C1.6-alkyl, C3.6-cyclyl,
3- to 7-membered heterocyclyl, wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R^33^ , -CONRA332RA333. or
RA316 and RA317 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
wherein the substituents RA33^ , RA332 anc| RA333 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA316 and RA31 7 are each independently selected from the group consisting of
hydrogen, C^.g-alkyl,
According to yet another embodiment of the present invention, RA316 and RA31 7 are hydrogen
According to yet another embodiment of the present invention, RA318 and RA319 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-C1 _6-alkyl,
According to yet another embodiment of the present invention, RA31 8 and RA31 9 are each independently selected from the group consisting of
hydrogen, C^.g-alkyl,
According to yet another embodiment of the present invention, RA320 js selected from the group consisting of
hydrogen and C^g-alkyl,
According to yet another embodiment of the present invention, RA321 and RA322 are each independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)O-C1 _6-alkyl, -C(O)-C1.6-alkyl -CONRA338RA339, -S(O)2-C^6- alkyl, -S(O)2NRA340RA341 , C6.14-aryl, C^^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, 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 R^34Z or RA321 anc| RA322 combine to form a 3- to 7-membered heterocycle,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C^g-alkoxy,
-CONRA343RA344 and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
wherein the substituents RA338, RASSQ 1 RA340, RA341 > RA342j RA343, RA344 and RA331 have the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, R A321 anc| RA322 are eacn independently selected from the group consisting of
hydrogen, C^.g-alkyl,
According to yet another embodiment of the present invention, RA323 anc| RA324 are each independently selected from the group consisting of
hydrogen, C^.g-alkyl, Cβ.-^-aryl,
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 R^328, C3_6-cyclyl,
-C(O)-C1.6-alkyl,
-S(O)2-C1.6-alkyl, or
RA323 anc| RA324 COmbine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
wherein the substituents RA328 anc| RA331 nave the same meanings as defined above, or preferably below.
According to yet another embodiment of the present invention, RA323 anc| RA324 are each independently selected from the group consisting of
hydrogen, C^g-alkyl, According to yet another embodiment of the present invention, RA325, RA326, RA328, RA331 and RA342 are each independently selected from the group consisting of
hydrogen, C^-alkyl, -C(O)-Ci _6-alkyl, -C(O)O-Ci_6-alkyl
According to yet another embodiment of the present invention, RA325 js -C(O)-Ci _6-alkyl or -C(O)O-Ci.6-alkyl,
According to yet another embodiment of the present invention, RA326, RA328, RA331 and RA342 are each independently selected from the group consisting of
hydrogen and Ci_6-alkyl;
According to yet another embodiment of the present invention, RA32? is represented by
Ci_i O-alkyl,
According to yet another embodiment of the present invention, RA329, RA330, RA334, RA335 RA338 RA339 pA340 anc| pA341 are eacn independently selected from the group consisting of hydrogen and Ci_6-alkyl,
According to yet another embodiment of the present invention, RA332, RA333 RA336 RA337 RA343 anc| RA344 are eacn independently selected from the group consisting of
hydrogen, Ci_6-alkyl,
According to yet another embodiment of the present invention, RB41 is selected from the group consisting of hydrogen, halogen, Ci_3-alkoxy, nitro and amino;
According to yet another embodiment of the present invention, RB41 is selected from the group consisting of hydrogen, halogen, Ci_3-alkoxy;
According to yet another embodiment of the present invention, RB41 is halogen;
According to yet another embodiment of the present invention, RB^1 is selected from the group consisting of hydrogen, halogen, Ci_3-alkyl, hydroxy, Ci_3-alkoxy, nitro, amino, -NH-C(O)- Ci_2-alkyl,
-NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
According to yet another embodiment of the present invention, RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and -CH2-CH2-O-;
According to yet another embodiment of the present invention, RB*>1 js selected from the group consisting of hydrogen, halogen, C^_3-alkyl, hydroxy, C^_3-alkoxy;
According to yet another embodiment of the present invention, RB*>1 js C^_3-alkoxy;
According to yet another embodiment of the present invention, RB^1 js selected from the group consisting of hydrogen, halogen and C^-alkoxy, and RB51 is selected from the group consisting of hydrogen, halogen, C^-alkoxy;
According to yet another embodiment of the present invention, RB61 is selected from the group consisting of hydrogen and halogen;
According to yet another embodiment of the present invention, RB61 is hydrogen;
According to yet another embodiment of the present invention, RB7^ JS selected from the group consisting of hydrogen and halogen;
According to yet another embodiment of the present invention, RB71 is hydrogen;
According to yet another embodiment of the present invention, RB81 is selected from the group consisting of hydrogen and halogen;
According to yet another embodiment of the present invention, RB8^ is hydrogen;
According to yet another embodiment of the present invention, n is 1 , A1 is N, RA01 , RA02, RA21 and RA22 are eacn hydrogen, and one of the substituents RA^ and RA^2 is hydroxy; or
n is 0, A1 is N, RA1 1and RA12 are each hydrogen, and one of the substituents RA21 and RA22 is methyl;
According to yet another embodiment of the present invention, n is 0 or 1 , A^ is N, RA^ , RA^2 are each hydrogen, RA1 1 , RA12 are hydroxy or hydrogen, RA21 , RA22 are C^^-alkyl or hydrogen,
RB81 , RB71 , RB61 are hydrogen, RB51 is C^-alkoxy, RB41 is halogen.
According to yet another embodiment of the present invention, n is 0 or 1 , A^ is N, RA^ , RA^2 are each hydrogen, RA1 1 , RA12 are each independently selected from the group consisting of hydroxy or hydrogen, RA21 , RA22 are each independently selected from the group consisting of C-] .5-alkyl or hydrogen, RB81 , RB71 , RB61 are hydrogen, RB51 is C^-alkoxy, RB41 is halogen, RA31 and RA32 are each 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 and 4- to 6-membered heterocyclyl,
wherein the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
wherein the 4- to 6-membered heterocyclyl may be bound to the C^.β-alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C|_6-alkyl via C, N is substituted by RA325,
-(CH2)m-RA35, -(CRA36RA37)|-CORA38 and a lone pair; wherein m is 2 and I is 1 ; and wherein the substituents RA325, RA35, RA36, RA37 and RA38 have the same meanings as defined above or below.
According to yet another embodiment of the present invention, n is 0 or 1 , A1 is N, RA01 , RA02 are each hydrogen, RA1 1 , RA12 are each independently selected from the group consisting of hydroxy or hydrogen, RA2^ , RA22 are each independently selected from the group consisting of C^ _3-alkyl or hydrogen, RB81 , RB71 , RB61 are hydrogen, RB51 is C^-alkoxy, RB41 is halogen, RA31 and RA32 are each independently selected from the group consisting of
hydrogen, C^ .5-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy and 4- to 6-membered heterocyclyl,
wherein the 4- to 6-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
wherein the 4- to 6-membered heterocyclyl may be bound to the C^.g-alkyl via C or N, with the proviso that, if the 4- to 6-membered heterocyclyl is bound to the C-|_6-alkyl via C, N is substituted by RA325,
-(CH2)m-RA35, -(CRA36RA37)|-CORA38 and a lone pair; wherein m is 2 and I is 1 ; and wherein the substituents RA32^, RA3^, RA3^, RA37 and RA38 have the same meanings as defined above or below.
According to yet another embodiment of the present invention, A1 is N; n represents 0 or 1 ;
RA01 and RA02 are hydrogen;
RA^ 1 and RA^2 are each independently selected from the group consisting of hydrogen and hydroxy;
RA21 and RA22 are each independently selected from the group consisting of
Hydrogen or C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA31 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 and a C^.^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S,
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 RA325;
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl is bound via C, and
wherein N is substituted by RA^25
-(CH2)m-RA35, -(CRA36RA37)|.CoRA38.
or in case A^ is S, it is optionally substituted by one or two oxo-groups;
wherein m is 1 , 2 and 3, I is 1 , 2 and 3;
RA35 js selected from the group consisting of
hydroxy, C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA36 anc| RA37 are eacn independently selected from the group consisting of
hydrogen, hydroxy, halogen, C^.g-alkyl;
RA38 is .NRA316RA317;
RA316 and RA317 are hydrogen; RA325 js eacn independently selected from the group consisting of
-C(O)-C1.6-alkyl,
wherein the -C(O)-C1 -S-BIkYl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
-C(O)O-C1 _6-alkyl,
wherein the -C(O)O-C1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C^-alkoxy;
RB51 is selected from the group consisting of hydrogen, C^-alkoxy;
RB61 , RB71and RB81 are hydrogen;
a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
According to yet another embodiment of the present invention, the compounds of Formula (I) are selected from the group consisting of
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine; 6-(3-Fluoro^- methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indob[2,3-c][1 ,8]naphthyridine; 1-(4-[[6-(3-Fluoro-4- methoxybenzyO-I ^.SJ-tetrahydro^H-indolop.S-clIi .δlnaphthyridin^-yllmethylJpiperidin-i- yl)ethanone; i-^-IΘ-β-Fluoro^-methoxybenzyO-I ^SJ-tetrahydro^H-indoloβ.S-ciπ .Slnaphthyridin- 4-yl]piperidin-1 -yl}ethanone; Ethyl 4-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3- c][1 ,8]naphthyridin-4-yl]piperidine-1 -carboxylate; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro- 4H-indolo[2,3-c][1 ,8]naphthyridin-4-yl]acetamide; 5-(3-Fluoro-4-methoxybenzyl)-2,3-dimethyl-1 ,2,3,6- tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride; 2-[5-(3-Fluoro-4-methoxybenzyl)-2- methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]ethanol dihydrochloride; 1-(4-{[5-(3- Fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)- yl]methyl}piperidin-1-yl)ethanone; Ethyl 4-[5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,6- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]piperidine-1-carboxylate; 1-(3-{[(5-(3-Fluoro^- methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]methyl}azetidin-1- yl)ethanone; 1-{3-[5-(3-Fluoro^4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4- b]indol-3(2H)-yl]azetidin-1 -yl}ethanone; 2-[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,6- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]acetamide; 1-{4-6-(3-Fluoro^-methoxybenzyl)-2- hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin^-yl]piperidin-1-yl}ethanone; 1-{(3S)-3-[6- (3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin-4- yl]piperidin-1 -yl}ethanone; 1 -{(3R)-3-[6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H- indolo[2,3-c][1 ,8]naphthyridin-4-yl]piperidin-1-yl}ethanone; 6-(3-Fluoro-4-methoxybenzyl)-4-(2- hydroxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol; 6-(3-Fluoro-4-methoxybenzyl)- 4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol hydrochloride; 2-[6-(3-Fluoro-4- methoxybenzyl^-hydroxy-I ^.SJ-tetrahydro^H-indolop.S-clIi .δlnaphthyridin^-yllacetamide; 6-(3- Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol; a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
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.
The term "halogen" used in the specification of the present application means a fluorine atom, a chlorine atom and a bromine atom, wherein a fluorine atom is more preferred.
The term "C-i.β-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
(Ci_3-alkyl) are more preferred and alkyl groups having 1 to 2 carbon atoms (C^-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 "C^.β-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^-alkoxy) are preferred. Examples of the C^-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- methylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 ,2-trimethylpropoxy group, a 1 ,1 - dimethylbutoxy group, a 1 ,2-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2,3-dimethylbutoxy group, a 1 ,3-dimethylbutyloxy group, a 2-ethylbutoxy group, a 1 ,3-dimethylbutoxy group, a 2- methylpentoxy group, a 3-methylpentyloxy group, a hexyloxy group, wherein a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group and a tert-butoxy group are preferred, and a methoxy group, ethoxy group, isopropoxy group and a isobutoxy group are more preferred.
The terms "C3_g-cyclyl" and "C3_5-cyclyl" used in the specification of the present invention indicate cycloalkyl groups having 3 to 6 carbon atoms and 3 to 5 carbon atoms in their rings, respectively. Examples of the C3_6-cyclyl and C3_5-cyclyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, wherein a cyclopropyl group and a cyclopentyl group are preferred.
The term "3- to 7-membered heterocyclyl" includes ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is replaced by an atom other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated. Preferable examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolidonyl group, a tetrahydrofuranyl group,
tetrahydrothiophenyl group, a tetrahydropyranyl group, a piperidinyl group, a piperazinyl group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a
thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group and the like.
The term "3- to 7-membered heterocycle" used in the specification of the present invention indicates a monocyclic 3- to 7-membered non-aromatic heterocyclic group which contains a nitrogen atom and optionally one or more hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. The preferable example includes an aziridinyl group, an acetidyl group, a pyrrolidinyl group, a pyrrolinyl group, a piperidinyl group, a piperazinyl group, a piperazine-2,3-dione group, an imidazolinyl group, a pyrazolidinyl group, an imidazolidinyl group, a morpholinyl group, a thiomorpholinyl group, an imidazolinyl group, an oxazolinyl group, a pyrrolidine-2,5-dione group, a piperazine-2,3-dione group and the like.
The term "Cg.^-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 "Cg.^-aryl which is optionally substituted" means an aromatic hydrocarbon cyclic group which is constituted by 6 to 14 carbon atoms, wherein the aromatic hydrocarbon cyclic group has the same meaning as defined above and is optionally substituted by one or more substituents. Examples of such substituents are hydroxy; C-|_6-alkyl, preferably methyl; C^.s-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylendioxo. The Cs.^-aryl may be substituted by one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. The term "C^.^-heteroaryl" used in the specification of the present application refers to aromatic groups having 1 to 13 carbon atoms and one or more heteroatoms selected from N, O and S.
Preferred embodiments of such groups can be characterized as "5- to 14-membered heteroaryl" which indicates a monocyclic, bicyclic or tricyclic 5- to 14-membered aromatic heterocyclic group which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In a similar way, the term "C^.g-heteroaryl" used in the specification of the present invention refers to aromatic groups having 1 to 9 carbon atoms and one or more heteroatoms selected from N, O and S. Preferred embodiments of such groups can be characterized as "5- to 10-membered heteroaryl" which indicates a monocyclic or bicyclic 5- to 10-membered heteroaryl which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. In the present invention a 5- to 10-membered heteroaryl may preferably be used, and a 5 to 6 membered heteroaryl is more preferred.
Examples of the aromatic heterocyclic group include a pyrrolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indolyl group, an isoindolyl group, an indolizinyl group, a purinyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl group, a naphthylidinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an imidazotriazinyl group, a pyrazinopyridazinyl group, an acridinyl group, a phenanthridinyl group, a carbazolyl group, a carbolinyl group, a phenanthrolinyl group, a phenazinyl group, an imidazopyridinyl group, an imidazopyrimidinyl group, a pyrazolopyridinyl group, and the like; a thiophenyl group (thienyl group), a benzothiophenyl group (benzothienyl group) and the like; a furyl group, a pyranyl group, a cyclopentapyranyl group, a benzofuryl group, an isobenzofuryl group, a thiazolyl group, an isothiazolyl group, a benzothiazolyl group, a
benzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, an oxazolyl group, an isooxazoyl group, a benzoxazolyl group, an oxadiazolyl group, a pyrazolooxazolyl group, an imidazothiazolyl group, a thienofuranyl group, a furopyrrolyl group, a pyridoxazinyl group and the like. Furthermore, the term "C-|.-|3-heteroaryl which is optionally substituted" means a monocyclic, bicyclic or tricyclic aromatic heterocyclic group, typically being a 5- to 14-membered aromatic heterocyclic group, which contains one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, wherein the 5- to 14-membered aromatic heterocyclic group is substituted by one or more substituents. Examples of such substituents are hydroxy; C^.g-alkyl, preferably methyl; C^.g-alkoxy, preferably methoxy or ethoxy, more preferably methoxy; halogen, preferably fluoro and chloro, more preferably fluoro; nitro; and methylenedioxo. The 5- to 14-membered aromatic heterocyclic group may be substituted with only one of these substituents, but may also be substituted by two or more of these substituents which may be the same or may be different from each other. The above-mentioned C^.g-alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C^.g-alkoxy, C3_6-cyclyl, 3- to 7-membered heterocyclyl, Cβ_i4-aryl, C^.^-heteroaryl, an amine and an amide, such as defined, for instance for
NRA129RA130 and -C(O)-NRA1 36RA1 37, wherein the q.g-alkoxy, C3.6-cyclyl, 3- to 7-membered heterocyclyl, Cβ.^-aryl and C^.^-heteroaryl have the same meanings as defined above.
In case the C^.g-alkyl group is substituted by at least one fluorine atom, the C^.g-alkyl group can be any group as specified above with respect to the C^.g-alkyl, unless specified otherwise. The C^ _g- alkyl substituted by at least one fluorine atom is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C^.g-alkyl, wherein the mono-, tri- and perfluoro substituted C^.g-alkyl groups are more preferred. Still more preferred are mono- and perfluoro substituted C^.g-alkyl groups. Examples of these still more preferred mono- and perfluoro substituted C^.g-alkyl groups are fluoromethyl, 1- fluoroethyl, 2-fluoroyethyl, 1-fluoro-isopropyl, 1-fluoro-n-propyl, 2-fluoro-isopropyl, 2-fluoro-n-propyl, 3- fluoro-n-propyl, trifluoromethyl, pentafluoroethyl, perfluoroisopropyl, perfluoro-n-propyl and perfluoroisobutyl.
In case the C^.g-alkyl is substituted by at least one hydroxy, the C^.g-alkyl group can be any group as specified above with respect to the C^.g-alkyl, unless specified otherwise. The C^.g-alkyl 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^_3-alkyl group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such 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.
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 C3_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 C3_g- cyclyl group can be any group as specified above for 03.5-CyCIyI1 unless specified otherwise. The C^_ 5-alkyl is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C3_6-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C^.g-alkyl is substituted one C3_6-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-|_6-alkyl, unless specified otherwise. Similarly, the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise. The C^_ρ-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.^-aryl, the C^.g-alkyl group can be any group as specified above with respect to C^ .5-alkyl, unless specified otherwise. Similarly, the Cg.^- aryl group can be any group as specified above for Cg.^-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.^-aryl is preferably phenyl or
methylenedioxophenyl. Further preferred is that the C^.g-alkyl is substituted one Cg.^-aryl.
Particularly preferred is a benzyl group.
In case the C^.g-alkyl group is substituted by at least one C^.^-heteroaryl, the C^.g-alkyl group can be any group as specified above with respect to C^.g-alkyl, unless specified otherwise. Similarly, the Ci_i 3-heteroaryl group can be any group as specified above for C^.^-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^.^-heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C^.g-alkyl is substituted by one C^.^-heteroaryl. Particularly preferred is a pyridylmethyl group.
The above-mentioned C^.g-alkoxy group may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, C^.g-alkoxy, C3_g-cyclyl, 3- to 7-membered heterocyclyl, Cg_i4-aryl and C^.^-heteroaryl, wherein the C^.g-alkoxy, C3_g-cyclyl, 3- to 7-membered heterocyclyl, Cg.^-aryl and C^.^-heteroaryl have the same meanings as defined above. In case the C^.β-alkoxy group is substituted by at least one fluorine atom, the C^.β-alkoxy group can be any group as specified above with respect to C^.g-alkoxy, unless specified otherwise. It is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C^.β-alkoxy, wherein the mono-, tri- and perfluoro substituted C^.g-alkoxy groups are more preferred. More preferred are mono- and perfluoro substituted C^.β-alkoxy groups. Examples of these more preferred mono- and perfluoro substituted Ci_6-alkoxy groups are fluoromethoxy, 1-fluoroethoxy, 2-fluoroyethoxy, 1-fluoro-isopropoxy, 1-fluoro- n-propoxy, 2-fluoro-isopropoxy, 2-fluoro-n-propoxy, 3-fluoro-n-propoxy, trifluoromethoxy, pentafluoroethoxy, perfluoroisopropoxy, perfluoro-n-propoxy and perfluoroisobutoxy.
In case the C^.β-alkoxy group is substituted by at least one hydroxy, the C^.β-alkoxy group can be any group as specified above with respect to C^.g-alkoxy, unless specified otherwise. It is preferably a C^.β-alkoxy group which is substituted by one or two hydroxy groups, more preferably a O\_$- alkoxy group which is substituted with one or two hydroxy groups, preferably one hydroxy group. Examples of such C^_3" alkoxy groups substituted with at least one hydroxy group include hydroxymethoxy, 1- hydroxyethoxy, 2-hydroxyethoxy, 1 -hydroxy-isopropoxy, 2-hydroxy-isopropoxy, 1-hydroxy-n-propoxy, 2-hydroxy-n-propoxy and 3-hydroxy-n-propoxy, wherein a hydroxymethoxy, 2-hydroxyethoxy, 2- hydroxy-isopropoxy and 2-hydroxy-n-propoxy are still more preferred, and hydroxymethoxy is particularly preferred.
In case the C^.β-alkoxy group is substituted by at least one another C^.β-alkoxy, both C^.β-alkoxy groups can be any group as specified above with respect to C^.β-alkoxy. The first mentioned C^ .5- 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^.β-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_6-cyclyl, the C^.g-alkoxy group can be any group as specified above with respect to C^.β-alkoxy, unless specified otherwise. Similarly, the C3_6-cyclyl group can be any group as specified above for 03.5-CyCIyI1 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 C3_6-cyclyl is preferably a ring having 3 to 5 carbon ring atoms. Further preferred is that the C^.g-alkoxy is substituted by one C3_6-cyclyl. Particluarly preferred is a cyclopropylmethoxy group. In case the C^.g-alkoxy group is substituted by at least one 3- to 7-membered heterocyclyl, the C^ _g- alkoxy group can be any group as specified above with respect to C^.g-alkoxy, unless specified otherwise. Similarly, the 3- to 7-membered heterocyclyl group can be any group as specified above for 3- to 7-membered heterocyclyl, unless specified otherwise. The C^.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, more preferably 1 carbon atom, and the 3- to 7-membered heterocyclyl is preferably a 5 or 6-membered heterocyclyl having one heteroatom in its ring selected from N, O or S, more preferably a 5-membered heterocyclyl having an oxygen atom in its ring. Further preferred is that the C^.g-alkoxy is substituted by one 3- to
7-membered heterocyclyl.
In case the C^.g-alkoxy group is substituted by at least one Cg.^-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.^-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.^-aryl is preferably phenyl or methylenedioxophenyl. Further preferred is that the C^.g-alkoxy is substituted by one Cg.^-aryl. Particularly preferred is a benzyloxy group.
In case the C^.g-alkoxy group is substituted by at least one C^.^-heteroaryl, the C^.g-alkoxy group can be any group as specified above with respect to C^.g-alkoxy, unless specified otherwise.
Similarly, the C^.^-heteroaryl group can be any group as specified above for C^.^-heteroaryl, unless specified otherwise. The C^.g-alkoxy is preferably a group having 1 to 3 carbon atoms, more preferably a group having 1 or 2 carbon atoms, still more preferably 1 carbon atom, and the C^. ^ 3- heteroaryl is preferably a 5- to 6-membered aromatic ring having one heteroatom in its ring selected from N, O or S. Further preferred is that the C^.g-alkoxy is substituted by one C^.^-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 C3_g-cyclyl group is substituted by one or more fluoro, the C3_g-cyclyl group can be any group as specified above with respect to Cβ.g-cyclyl, unless specified otherwise. The Cβ.g-cyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted C3_g-cyclyl, wherein the mono-, di- and perfluoro substituted C3_g-cyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted Gj.g-cyclyl groups. In case the Cβ.g-cyclyl group is substituted by one or more hydroxy, the Oj.g-cyclyl group can be any group as specified above with respect to C3_6-cyclyl, unless specified otherwise. The C3_6-cyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted Cj.g-cyclyl, wherein monohydroxy substituted C3_6-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^e-alkyl.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents selected from fluoro and hydroxy, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more fluoro, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group substituted by one or more fluoro is preferably a mono-, di-, tri— , polyfluoro or perfluoro substituted 3- to 7-membered heterocyclyl, wherein the mono-, di- and perfluoro substituted 3- to 7-membered heterocyclyl groups are more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocyclyl groups.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more hydroxy, the 3- to 7- membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise. The 3- to 7-membered heterocyclyl group substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocyclyl, wherein monohydroxy substituted 3- to 7-membered heterocyclyl groups are more preferred.
In case the 3- to 7-membered heterocyclyl group is substituted by one or more substituents selected from hydrogen, C^.g-alkyl and -C(O)-C1 _g-alkyl, the 3- to 7-membered heterocyclyl group can be any group as specified above with respect to 3- to 7-membered heterocyclyl, unless specified otherwise. Similarly the C^.g-alkyl group and the C^.g-alkyl moiety of the -C(O)-C1 _g-alkyl group can be any group as specified above with respect to the substituted or unsubstituted C^g-alkyl. It is preferred that the substituent(s) hydrogen, C^g-alkyl and -C(O)-C1 _g-alkyl bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C1 _6-alkyl is -C(O)-CH3 and -C(O)-CH2OH.
The above-mentioned 3- to 7-membered heterocycle may be substituted with one or more substituents selected from the group consisting of fluoro, hydroxy, oxo, C^g-alkoxy, hydrogen, C^g-alkyl and
-C(O)-C1.6-alkyl. In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from fluoro, hydroxy, oxo, C^-alkoxy and C^-alkyl, this/these substituent(s) preferably bind to a ring carbon atom.
In case the 3- to 7-membered heterocycle is substituted by one or more fluoro, the 3- to 7-membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more fluoro is preferably a mono-, di-, tri-, polyfluoro or perfluoro substituted 3- to 7-membered heterocycle, wherein a mono-, di- and perfluoro substituted 3- to 7-membered heterocycle is more preferred. Still more preferred are mono- and perfluoro substituted 3- to 7-membered heterocycles.
In case the 3- to 7-membered heterocycle is substituted by one or more hydroxy, the 3- to 7- membered heterocycle can be any group as specified above with respect to 3- to 7-membered heterocycle, unless specified otherwise. The 3- to 7-membered heterocycle substituted by one or more hydroxy is preferably a mono- or dihydroxy substituted 3- to 7-membered heterocycle, wherein monohydroxy substituted 3- to 7-membered heterocycles are more preferred.
In case the 3- to 7-membered heterocycle is substituted by one or more substituents selected from hydrogen, C^_6-alkyl and -C(O)-C^ _6-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 Ci_6-alkyl group and the C^^-alkyl moiety of the -C(O)-Ci _6-alkyl 9rouP can be anY group as specified above with respect to the substituted or unsubstituted C^_6-alkyl. It is preferred that the substituent(s) hydrogen, C^^-alkyl and -C(O)-Ci -6~alM bind to a nitrogen ring atom. It is more preferred that the substituent -C(O)-C1 _6-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, benzoates, 2-(4- hydroxybenzoyl)benzoates, butyrates, salicylates, subsalicylates, maleates, laurates, malates including L-malates and D-malates, lactates including L-lactates and D-lactates, fumarates, succinates, oxalates, tartarates including L-tartarates, D-tartarates and meso-tartarates, stearates, benzenesulfonates (besilates), toluenesulfonates (tosilates), methanesulfonates (mesilates), laurylsulfonates, 3-hydroxy-2-naphthoates, 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 imgf000039_0001
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), (1 S), (2R), (2S), (3R), (3S), (4R), (4S), (1 R,2R), (1 R,2S), (1 S,2R), (1 S,2S), (1 R,3R), (1 R,3S), (1 S,3R), (1 S,3S), (1 R,4R), (1 R,4S), (1 S,4R), (1 S,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 imgf000040_0001
as well as all possible permutations for 3 stereogenic centers, the salts thereof, the N-oxides of the stereoisomers and the salts thereof are part of the invention.
The invention further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
Some of the compounds, salts thereof, N-oxides of the compounds and the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds and N-oxides of the salts thereof according to the invention may exist in different crystalline forms (polymorphs) which are within the scope of the invention.
Furthermore, derivatives of the compounds of formula (I), the salts thereof, the N-oxides of the compounds or the salts thereof, stereoisomers of the compounds, salts, N-oxides of the compounds or N-oxides of the salts thereof which are converted into compound (I) or a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof in a biological system (bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I), a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N- oxide of the compound or the N-oxide of the salt thereof by metabolic processes.
The compounds according to the invention can be prepared as follows.
Reaction scheme 1 :
Figure imgf000041_0001
(1 ) (2) (4)
As shown in reaction scheme 1 , a compound of formula (2), wherein R1 is a Ci_6-alkyl group and PG1 is a suitable temporary protecting group, e.g. 2-(trimethylsilyl)ethoxymethyl or tert-butoxycarbonyl, is prepared by protection of a compound of formula (1), in a manner known to the skilled person, e.g. by utilizing 2-(trimethylsilyl)ethoxymethyl chloride or di-tert-butyl dicarbonate. The compounds of formula (4), wherein RA01, RA02, RA11, RA12, RA21, RA22 and n have the above defined meaning, R1 is a Ci-6-alkyl group and PG2 being a suitable temporary protecting group, e.g. benzyl, can be obtained by reacting of a compound of formula (2) with a compound of formula (3), wherein Ff01, RA02, RA11, RA12, RA21, RA22 and n have the above defined meaning, PG2 is a suitable temporary protecting group, e.g. benzyl, and X1 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate, in an alkylation reaction in the presence of an appropriate base, e.g.
sodium hydride or lithium bis(trimethylsilyl)amide, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, followed by removal of the protecting group PG1, e.g. the cleavage of 2- (trimethylsilyl)ethoxymethyl protecting group with a suitable fluorine source, e.g. tetrabutylammonium fluoride, or the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid.
Compounds of formula (1 ) and (3) are commercially available or can be obtained according to procedures known in the art. Reaction scheme 2:
Figure imgf000042_0001
According to reaction scheme 2, a compound of formula (4), prepared according to above reaction scheme 1 , can be reacted with a compound of formula (5), wherein R841, RB51, RB61, RB71 and RB81 have the above mentioned meaning and X2 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, in a suitable solvent, e.g. dichloroethane, diethylether, or nitromethane, preferably at temperatures of 0-400C, followed by a cyclization condensation reaction with ammonium acetate and/or ammonia in an appropriate solvent, e.g.
methanol or dichloroethane, at elevated temperature, optionally using microwave radiation as energy source, to give a corresponding compound of formula (6). It may be convenient to perform both the Friedel-Crafts acylation reaction and the cyclization condensation reaction in one pot. The resulting hydroxy-compound (6) can be converted into compound (7), wherein Ff01 , RA02, RA11, RA12, RA21 , RA22, n, PG2, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning and X3 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in a manner known to the skilled person.
Compounds of formula (5) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 3:
As demonstrated in reaction scheme 3, a compound of formula (8), wherein ϊt°\ RA02, RA11, RA12, RA21, RA22, n, PG2, X3, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning and PG3 is a suitable temporary protecting group, e.g. tert-butoxycarbonyl can be prepared by protection of a compound of formula (7), prepared according to above reaction scheme 2 according to procedures known to the skilled person, e.g. by utilizing di-tert-butyl dicarbonate. A compound of formula (10) is obtained by Buchwald-Hartwig reaction of the resulting compound of formula (8) with compound of formula (9), wherein RA31, RA32, and A1 have the above mentioned meaning, under inert atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or palladium(ll) acetate, and, if necessary, of a suitable phosphine ligand, e.g. 2,2- bis(diphenylphosphino)-1 ,1-binaphthalene, in the presence of a suitable base, e.g. cesium carbonate, in a suitable solvent, e.g. dioxane, at elevated temperature, preferably at temperatures 50-1200C, optionally using microwave radiation as energy source [see e.g. Tetrahedron Letters, 1997, pp. 6363- 6366].
Compounds of formula (9) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 4:
Figure imgf000043_0001
According to reaction scheme 4, a compound of formula (10), prepared according to above reaction scheme 3 can be deprotected to afford compound of formula (11 ), wherein Ff01, RA02, RA11, RA12, RA21, RA22, RA31, RA32, n, A1, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning in a manner known to the skilled person, for example, by debenzylation utilizing a suitable hydrogen source, e.g. 1 ,4-cyclohexadiene, in the presence of a suitable hydrogenation catalyst, e.g. palladium on charcoal, in a suitable solvent, e.g. ethanol or 1 -butanol, at temperatures between 00C to 1800C, preferably 800C to 1600C, optionally using microwave radiation as energy source. The compound of formula (I), wherein RA01, RA02, RA11, RA12, RA21, R*22, RA31, RA32, n, A1, RB41, RB51, RB61, RB71 and RBβ1 have the above mentioned meaning, can be prepared by cyclization of a compound of formula (11 ), either in one step, e.g. by using a intermediate formation of suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in the presence of an appropriate base, e.g. pyridine, in a suitable solvent, e.g. dichloromethane, preferably at temperatures between -15°C and 400C, accompanied by the immediate intramolecular cyclization into compound of formula (I), or in two steps, e.g. by using a conversion of the alcohol into a suitable leaving group, e.g. halogen, such as chloride, followed by cyclization reaction in the presence of an appropriate base, e.g. triethylamine or pyridine, in a suitable solvent, e.g. dimethylformamide.
Reaction scheme 5:
Figure imgf000044_0001
Alternatively, a compound of formula (I), wherein R*01 , RAO2, RA11 , RA12, RA21, RA22, RA31, RA32, n, A1, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning, can be obtained as illustrated in reaction scheme 5. The cyclization reaction of compound of formula (12), wherein R^01, RA02, RA11, RA12, RA21, n, RB41 , RB51, RB61, RB71 and RB81 have the above mentioned meaning, R2 is hydrogen or a 1-5C-alkyl group, X4 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate, and PG4 being a suitable temporary protecting group, e.g. tert-butoxycarbonyl, with a compound of formula (9), wherein R*31, RA32, and A1 have the above mentioned meaning, under inert atmosphere with catalytic amounts of a suitable palladium source, e.g. tris(dibenzylideneacetone)dipalladium (0) or palladium(ll) acetate, and, if necessary, of a suitable phosphine ligand, e.g. 2,2-bis(diphenylphosphino)-1 ,1-binaphthalene, in the presence of a suitable base, e.g. cesium carbonate, in a suitable solvent, e.g. dioxane, acetonitrile, or tetrahydrofuran, at temperatures between 00C to 1800C, preferably 800C to 1200C, optionally using microwave radiation as energy source, followed by removal of the protecting group PG4, in a manner known to the skilled person, for example, by the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid, in a suitable solvent, e.g. dioxane, or in a mixture of suitable solvents, e.g. ethanol, dioxane, water, at temperatures between 00C to 1800C, preferably 800C to 1400C, optionally using microwave radiation as energy source, gives rise to the compound of formula (I).
Compounds of formula (9) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 6: protection
Figure imgf000045_0001
Figure imgf000045_0002
A compound of formula (12), used as starting compound in the above reaction scheme 5, can be prepared according to reaction scheme 6. In the first step, the hydroxy-compound of formula (13), wherein RA01, RA02, RA11, RA12, RA21, n, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning and R2 being hydrogen or a 1 -5C-alkyl group, can be converted into compound of formula (14), wherein RA01, RA02, RA11, RA12, R^1, n, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning, R2 is hydrogen or a C-i-s-alkyl group, and X4 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, in a manner known to the skilled person, for example, by treatment with trifluoromethanesulfonic anhydride in a suitable solvent, e.g.
dichloromethane, in the presence of a suitable base, e.g. pyridine. In the second step, a compound of formula (14) is protected with a suitable temporary protecting group PG4, e.g. tert-butoxycarbonyl, according to procedures known to the skilled person, e.g. by utilizing di-tert-butyl dicarbonate, to afford a compound of formula (12).
Reaction scheme 7:
Figure imgf000045_0003
A compound of formula (13), wherein R*01, RA02, RA11, RA12, RA21, n, RB41, RB51, RB61 , RB71 and RB81 have the above mentioned meaning and R2 being hydrogen or a 1 -5C-alkyl group, required as starting compound in the above reaction scheme 6, can be obtained as demonstrated in reaction scheme 7. A compound of formula (2), wherein R1 is a Ci_6-alkyl group and PG1 is a suitable temporary protecting group, e.g. 2-(trimethylsilyl)ethoxymethyl or tert-butoxycarbonyl, is prepared as shown in reaction scheme 1. A compound of formula (16), wherein R*01, RA02, RA11, RA12, RA21 have the above defined meaning, R1 is a Ci_6-alkyl group, and R2 being hydrogen or a Ci_5-alkyl group, can be prepared by reacting of a compound of formula (2) with a compound of formula (15), wherein ft0^, RA02, RA11, RA12, RA21 and n have the above mentioned meaning, R2 is hydrogen or a C-i-s-alkyl group, and X5 is a suitable leaving group, e.g. halogen, such as bromide, or a conjugate base of an acid, such as trifluoromethanesulfonate, in an alkylation reactbn in the presence of an appropriate base, e.g.
sodium hydride or lithium bis(trimethylsilyl)amide, in a suitable solvent, e.g. dimethylformamide or tetrahydrofuran, followed by removal of the protecting group PG1, e.g. the cleavage of 2- (trimethylsilyl)ethoxymethyl protecting group with a suitable fluorine source, e.g. tetrabutylammonium fluoride, or the cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid. The resulting compound of formula (16) can be reacted with a compound of formula (5), wherein RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning and X2 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, in a suitable solvent, e.g. dichloroethane, diethylether, or nitromethane, preferably at temperatures of 0-400C, followed by a cyclization condensation reaction with ammonium acetate and/or ammonia in an appropriate solvent, e.g. methanol or dichloroethane, preferably at elevated temperature, optionally using microwave radiation as energy source, to give a corresponding compound of formula (13). It may be convenient to perform both the Friedel-Crafts acylation reaction and the cyclization condensation reaction in one pot.
Compounds of formula (15) and (5) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 8:
Figure imgf000046_0001
Furthermore, a compound of formula (I), wherein R*01, RA02, RA11, RA12, R*21, R*22, RA31, RA32, n, A1, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning, can be obtained as shown in reaction scheme 8. In particular, epoxide (17), wherein Ff01, RA02, RA11, RA12, RA21, n, RB41, RB51, RB61, RB71 and RB81 have the above mentioned meaning, R2 is hydrogen or a 1-5C-alkyl group, X4 is a suitable leaving group, e.g. a conjugate base of an acid, such as trifluoromethanesulfonate, and PG* being a suitable temporary protecting group, e.g. tert-butoxycarbonyl, can be reacted with a compound of formula (9) in an art-known epoxide ring-opening reaction in a suitable solvent, e.g. methanol, at temperatures between 00C to 2000C, preferably 50°C to 1200C, followed by a cyclization reaction, e.g. an immediate intramolecular cyclization or a cyclization using an intramolecular Buchwald-Hartwig reaction under inert atmosphere with catalytic amounts of a suitable palladium source, e.g.
tris(dibenzylideneacetone)dipalladium (0) or palladium(ll) acetate, and, if necessary, of a suitable phosphine ligand, e.g. 2,2-bis(diphenylphosphino)-1 ,1-binaphthalene, in the presence of a suitable base, e.g. caesium carbonate, in a suitable solvent, e.g. dioxane, at elevated temperature, preferably at temperatures 50-1200C, optionally using microwave radiation as energy source [see e.g.
Tetrahedron Letters, 1997, pp. 6363-6366]. The subsequent removal of the protecting group PGf, e.g. by cleavage of tert-butoxycarbonyl protecting group with a suitable acid, e.g. hydrochloric acid, gives rise to a compound of formula (I). It may be convenient to perform the epoxide ring opening, the subsequent cyclization, and the deprotection reaction without the isolation of the individual intermediate compounds.
Compounds of formula (9) are commercially available or can be obtained according to procedures known in the art.
Reaction scheme 9:
Figure imgf000047_0001
A compound of formula (17), used as starting compound in the above reaction scheme 8, can be obtained as demonstrated in reaction scheme 9. A compound of formula (12), which can be prepared as shown in reaction scheme 6, can be converted into epoxid of formula (17) in a manner known to the skilled person, for example, using a epoxidation reaction with a suitable oxidation reagent, e.g. a peroxycarboxylic acid, such as meta-chloroperoxybenzoic acid, in a suitable solvent, e.g.
dichloromethane.
Compounds of formula (I) can be converted into different compounds of formula (I) by methods known in the art. For example,
a compound of formula (I), wherein RA31 is "substituted alkyl", e.g. -C^.β-alkyl, or - C3_6-cyclyl, or -3- to 7-membered heterocyclyl, all that may be optionally substituted as defined above, or -(CH2)mRA35, or -(CRA36RA37)rCORA38, wherein m > 1 , I > 0, R*32 is a free electron pair and A1 is N, can be prepared e.g. from a compound of formula (I), wherein the corresponding R^31 is hydrogen, RA32 is a free electron pair and A1 is N, by alkylation reaction, e.g. by reacting with an appropriate alkylating agent, e.g. C^.g-alkyl-Hal, or C3_6-cyclyl-Hal, or 3- to 7-membered heterocyclyl-Hal, all that may be optionally substituted as defined above, or Hal-(CH2)mRA35, or HaI- (CRA36RA37)|-CORA38, wherein m > 1 , I > 0, and preferred halogens (Hal) are bromine or chlorine, in the presence of a base, e.g. potassium carbonate, sodium carbonate, triethylamine or sodium hydride, in a suitable polar, aprotic solvent, e.g. dimethylformamide, acetone, tetrahydrofuran or dichloromethane, or a mixture thereof;
a compound of formula (I), wherein RA31 is 3- to 7-membered heterocyclyl, wherein it may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by R*325, consisting of -C(O)-C-|_6-alkyl, wherein the
-C(O)-C^ _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, RA32 is a free electron pair and A1 is N, can be prepared from a compound of formula (I), wherein RA31 is 3- to 7-membered heterocyclyl, wherein it may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl is bound via C, and wherein N is substituted by RA325, consisting of hydrogen, R*32 is a free electron pair and A1 is N, by reaction with an appropriate carboxylic acid chloride Ci_g-alkyl-C(O)CI, that may be optionally substituted as defined above, or carboxylic anhydride, (Ci_g-alkyl-C(O))2O, that may be optionally substituted as defined above, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid Ci_g-alkyl-C(O)OH, that may be optionally substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1-hydroxybenzotriazole;
a compound of formula (I), wherein RA31 is C^.g-alkyl, wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and 3- to 7- membered heterocyclyl, that may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl being bound to the C^.g-alkyl via C, and wherein the 3- to 7-membered heterocyclyl contains a N heteroatom, and wherein N is substituted by R*325, consisting of -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, RA32 is a free electron pair and A1 is N, can be prepared from a compound of formula (I), wherein R*31 is C^.g-alkyl, wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and 3- to 7-membered heterocyclyl, that may be optionally substituted as defined above, and wherein the 3- to 7-membered heterocyclyl being bound to the C^.g-alkyl via C, and wherein the 3- to 7-membered heterocyclyl contains a N heteroatom, and wherein N is substituted by R*325, consisting of hydrogen, R*32 is a free electron pair and A1 is N, by reaction with an appropriate carboxylic acid chloride C^_g-alkyl-C(O)CI, that may be optionally substituted as defined above, or carboxylic anhydride, (C-i_g-alkyl-C(O))2O, that may be optionally substituted as defined above, in the presence of a base, e.g. triethylamine, pyridine or potassium carbonate, or with an appropriate carboxylic acid C^_g-alkyl-C(O)OH, that may be optionally substituted as defined above, in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, a suitable base, e.g. triethylamine or diisopropylethylamine, and, optionally, a suitable additive reagent, such as 1 -hydroxybenzotriazole.
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
methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxan, a chlorinated hydrocarbon such as methylene chloride or chloroform, a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol, a low molecular weight aliphatic ester such as ethyl acetate or isopropyl acetate, or water) which contains the desired acid or base, or to which the desired acid or base is then added. Examples for acids include hydrochloric acid, hydrobromic acid, p-tolylsulfonic acid, methylsulfonic acid, trifluoromethylsulfonic acid, succinic acid, malic acid, citric acid, maleic acid, formic acid, acetic acid or pyroglutamic acid. Examples for bases include metal hydrides, such as sodium hydride or calcium hydride, metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, or amines, e.g. ammonia, trimethylamine or methylamine. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
The compounds of formula (I), the salts thereof and the stereoisomers of the compounds and the salts according to the invention can be converted into their N-oxides, for example, by reaction with peracids, such as m-chloroperbenzoic acid or peracetic acid. The person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.
Pure diastereomers and pure enantiomers of the compounds of formula (I), the salts thereof, the N- oxides of the compounds and the N-oxides of the salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and/or by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis. Preferably, the pure diastereomeric and pure enantiomeric compounds of the invention are obtainable by asymmetric synthesis and/or by using chiral starting compounds in synthesis.
Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography.
Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxiliary agent, resolving the diastereomers obtained and removing the chiral auxiliary agent. As chiral auxiliary agents, for example, chiral acids, such as (+)- or (-)-tartaric acid, (+)- or (-)-malic acid, (+)- or (-)- mandelic acid, (+)- or (-)-lactic acid or (+)- or (-)-camphersulfonic acid, can be used to separate enantiomeric bases and chiral bases, such as (+)- or (-)-brucine, (+)- or (-)-quinidine or (+)- or (-)- quinine, can be used to separate enantiomeric acids via formation of diastereomeric salts.
Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids, such as (+)- or (-)-lactic acid or (+)- or (-)-mandelic acid, or chiral alcohols, such as (+)- or (-)-1 - phenylethanol, respectively, as chiral auxiliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.
The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.
The compounds which are mentioned in the examples, the salts thereof, N-oxides of the compounds and the salts thereof and stereoisomers of the compounds, salts, N-oxides of the compounds and N- oxides of the salts thereof represent preferred embodiments of the invention. Examples
1H NMR spectra are recorded on a Bruker 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). Mass spectra are recorded on a LCQ classic or an LCQ advantage ion trap mass spectrometer from Thermofinnigan, using combined liquid chromatography / mass spectroscopy methodology, if not otherwise stated. Samples are dissolved in acetonitrile and chromatographed on a Survey HPLC from Thermofinnigan, using a reversed phase column (Merck LiChroCART 75-4, 60 RP-B) as stationary phase and a gradient of aqueous buffer (20 mM ammoniumacetate / formic acid, pH 4) and methanol as mobile phase at a flow of 0.8 ml/min, and ionized by electrospray ionization (ESI), positive mode, if not otherwise noted. Data are reported in the form MS (ionized particle found) = m/z. In that context, the molecule is abbreviated by M. For compounds containing bromine, both isotopic forms are reported, for compounds containing chlorine and all other elements, only the major isotopes are reported.
The following abbreviations are used: min: minutes, h: hour(s), DCM: dichloromethane, DCE:
dichloroethane, THF: tetrahydrofuran, RT: room temperature (20 to 25°C), tic: thin layer
chromatography, MS: mass spectrometry, 1H-NMR: 1H nuclear magnetic resonance spectroscopy. Reactions are performed in dry (water free) solvents and under air atmosphere unless otherwise noted. Glassware is heated to 1500C in a vacuum of 10~1 mbar for 5 min prior to use, unless otherwise noted. Furthermore, reactions and single processes, such as dissolutions, additions, filtering, extractions or chromatography, are performed at room temperature and under air atmosphere unless otherwise noted.
Reactions using microwave radiation are performed using Biotage Initiator Sixty (0 - 300 W) and Biotage Emry's Optimizer (0 - 300 W) instruments. The temperatures and times indicated for these reactions refer to the input data using the user interface of these instruments. The reaction mixtures are stirred in closed (sealed) reaction vials for the indicated time at the indicated internal temperature, the microwave radiation power is controlled by the internal temperature. Heating and cooling phase are not considered.
Purchased chemicals and solvents are used without further purification.
Column chromatography is performed using silica gel 60 (0.040 - 0.063 mm), pH 6.5 - 7.5, from Merck KgaA. 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. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-1 H-indole-1-carboxylate
Ethyl indole-3-acetate (107.6 g) is dissolved in dichloromethane (500 ml), di-tert-butyl dicarbonate (127.0 g), triethylamine (80.0 ml), and 4-dimethylaminopyridine (0.50 g) are added and the solution is stirred for 18 h at RT. After that, the solution is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :9 (v/v)) to yield the title compound as a light-yellow oil.
MS (IVlNH4 + found) = 320.8
A2. Ethyl 5-(benzyloxy)-2-(1 H-indol-3-yl)pentanoate
Step 1 : tert-Butyl 3-[5-(benzyloxy)-1-ethoxy-1-oxopentan-2-yl]-1 H-indole-1-carboxylate. tert-Butyl 3-(2- ethoxy-2-oxoethyl)-1 H-indole-1-carboxylate (example A1 ) (156.0 g) is dissolved in N, N- dimethylformamide (1600 ml) and the solution is cooled to 00C (ice bath). Sodium hydride (60% suspension in mineral oil, 61.7 g) is added in portions under nitrogen and the mixture is stirred for 15 min at 00C. Benzyl 3-bromopropyl ether (117.8 g) is added drop by drop at a rate that the internal temperature does not exceed 300C (ca. 3 min) and the suspension is stirred for 90 min at RT. Ice and ethyl acetate are added in portions. The mixture is diluted with water (1000 ml) and saturated ammonium chloride solution (1500 ml), the aqueous phase is extracted with ethyl acetate (4 x 500 ml). The combined organic extracts are concentrated in vacuo. The crude product contains a mixture of tert-butyl 3-[5-(benzyloxy)-1-ethoxy-1 -oxopentan-2-yl]-1 H-indole-1 -carboxylate and ethyl 5- (benzyloxy)-2-(1 H-indol-3-yl)pentanoate and is used without further purification in the next step. Step 2: Ethyl 5-(benzyloxy)-2-(1 H-indol-3-yl)pentanoate. To the crude product of step 1 concentrated hydrochloric acid (214 ml), water (200 ml) and ethanol (500 ml) are added and the solution is refluxed for 2 h. The solution is cooled to 00C, sodium hydroxide solution is added (ca. 10% in water, pH 5), the aqueous phase is extracted with ethyl acetate (4 x 500 ml). The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is dissolved in ethyl acetate / petroleum ether 1 :9 (v/v), filtered through a filter pad of 11 cm silica, and the pad is washed with ethyl acetate / petroleum ether 1 :9 (v/v) followed by ethyl acetate / petroleum ether 1 :4 (v/v). The combined filtrates are concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / cyclohexane 1 :9 to 1 :4 (v/v)) to yield the title compound as a yellow oil. MS (MH+ found) = 350.2
The following compound is obtained by using the procedure of example A2 analogously.
A3. Ethyl 2-(1 H-indol-3-yl)pent-4-enoate
Starting compounds: tert-Butyl 3-(2-ethoxy-2-oxoethyl)-1 H-indole-1-carboxylate (example A1 ) and allyl bromide;
MS (M+ found) = 243.4
A4. 4-[3-(Benzyloxy)propyl]-1 -(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-3-ol 3-Fluoro-4-methoxyphenyl acetic acid (12.4 g) is dissolved in trifluoroacetic acid anhydride (9.6 ml) and the mixture is stirred for 1 h at room temperature. The formed mixed anhydride is diluted with dichloroethane (20 ml). In parallel, ethyl 5-(benzyloxy)-2-(1 H-indol-3-yl)pentanoate (example A2) (9.5 g) is dissolved under argon in dichloroethane (100 ml) and the solution is cooled to 00C (ice bath). Zinc chloride (1 M in diethyl ether, 54 ml) is added drop by drop and the mixture is stirred for 5 min at 00C. The solution of a mixed anhydride, prepared above, is added drop by drop and the mixture is stirred for 10 min at 00C and 90 min at room temperature. After that, ammonia (7M in methanol, 24.7 ml) and ammonium acetate (12.9 g) are added and the mixture is heated in sealed vials at 1500C for 30 min under microwave irradiation. After cooling, the content of the vials is filtered over a pad of Celite®, the pad is washed with methanol. The combined filtrate is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :4 (v/v) to ethyl acetate) to yield the title compound as a yellow oil.
MS (MH+ found) = 471.2
The following compound is obtained by using the procedure of example A5 in a slightly modified manner.
A5. 1 -(3-Fluoro-4-methoxybenzyl)-4-(prop-2-en-1-yl)-9H-beta-carbolin-3-ol
Starting compound: Ethyl 2-(1 H-indol-3-yl)pent-4-enoate (example A3);
MS (MH+ found) = 363.3
A6. 4-[3-(Benzyloxy)propyl]-1 -(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-3-yl
trifluoromethanesulfonate
The mixture of 4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-9H-beta-carbolin-3-ol (example A4) (67.3 g) in dichloromethane (1400 ml) and pyridine (144 ml) is cooled to 00C,
trifluoromethanesulphonic anhydride (53 ml) is added and the solution is stirred for 90 min at 00C. An ice-cold mixture of saturated sodium chloride solution (1000 ml) and concentrated hydrochloric acid (100 ml) is added, the aqueous phase is acidified by addition of ice-cold concentrated hydrochloric acid to pH 5.5 and extracted with dichloromethane. The combined organic extracts are filtered through a filter pad of 10 cm silica, and the pad is washed with dichloromethane (1000 ml). The combined filtrates are concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / cyclohexane 1 :4 (v/v)) to yield the title compound as a yellow oil.
MS (MH+ found) = 603.1
The following compound is obtained by using the procedure of example A6 analogously.
A7. 1 -(3-Fluoro-4-methoxybenzyl)-4-(prop-2-en-1-yl)-9H-beta-carbolin-3-yl
trifluoromethanesulfonate
Starting compound: 1-(3-Fluoro-4-methoxybenzyl)-4-(prop-2-en-1-yl)-9H-beta-carbolin-3-ol (example
A5);
MS (MH+ found) = 495.0 A8. tert-Butyl 4-[3-(benzyloxy)propyl]-1-(3-fluoro-4-methoxybenzyl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate
4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-9H-beta-carbolin-3-yl trifluoromethanesulfonate (example A6) (37.6 g) is dissolved in dichloromethane (400 ml), di-tert-butyl dicarbonate (16.4 g), triethylamine (10.4 ml), and 4-dimethylaminopyridine (0.30 g) are added and the solution is stirred for 18 h at room temperature. After that, the solution is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with dichloromethane) to yield the title compound as a yellow oil.
MS (MH+ found) = 703.0
The following compound is obtained by using the procedure of example A8 analogously.
A9. tert-Butyl 1 -(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate
Starting compound: 1-(3-Fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-9H-beta-carbolin-3-yl trifluoromethanesulfonate (example A7);
MS (MH+ found) = 594.9
A10. tert-Butyl 3-(benzylamino)-4-[3-(benzyloxy)propyl]-1 -(3-fluoro-4-methoxybenzyl)-9H- beta-carboline-9-carboxylate
tert-Butyl 4-[3-(benzyloxy)propyl]-1-(3-fluoro-4-methoxybenzyl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H- beta-carboline-9-carboxylate (example A8) (8.6 g) is dissolved in dioxane (250 ml), then benzyl amine (2.7 ml), cesium carbonate (7.9 g), tris(dibenzylideneacetone)dipalladium(0) (2.2 g), and (±)-2,2- bis(diphenylphosphino)-1 ,1-binaphthalene (2.3 g) are added under argon. The mixture is stirred under argon for 18 h at 1000C. The mixture is allowed to cool to room temperature, filtered over Celite®, washed with methanol. The combined filtrates are concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :9 (v/v)) to obtain the title compound as a yellow oil.
MS (MH+ found) = 660.2
The following compounds are obtained by using the procedure of example A10 analogously or in a slightly modified manner.
A11. tert-Butyl 4-[3-(benzyloxy)propyl]-1 -(3-fluoro-4-methoxybenzyl)-3-(methylamino)-9H- beta-carboline-9-carboxylate
Starting compounds: tert-Butyl 4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A8) and methylamine; MS (MH+ found) = 584.2 A12. tert-Butyl 3-{[(1 -acetylpiperidin-4-yl)methyl]amino}-4-[3-(benzyloxy)propyl]-1-(3-fluoro-4- methoxybenzyl)-9H-beta-carboline-9-carboxylate
Starting compounds: tert-Butyl 4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-3-
{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A8) and 1 -(1 -acetylpiperid in-
4-yl)methanamine;
MS (MH+ found) = 709.3
A13. tert-Butyl 3-[(1 -acetylpiperidin-4-yl)amino]-4-[3-(benzyloxy)propyl]-1-(3-fluoro-4- methoxybenzyl)-9H-beta-carboline-9-carboxylate
Starting compounds: tert-Butyl 4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-3-
{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A8) and 1-acetylpiperidin-4- amine;
MS (MH+ found) = 695.3
A14. tert-Butyl 4-[3-(benzyloxy)propyl]-3-{[1-(ethoxycarbonyl)piperidin-4-yl]amino}-1-(3- fluoro-4-methoxybenzyl)-9H-beta-carboline-9-carboxylate
Starting compounds: tert-Butyl 4-[3-(benzyloxy)propyl]-1 -(3-fluoro^4-methoxybenzyl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A8) and ethyl 4-amino-1- piperidinecarboxylate;
MS (MH+ found) = 725.3
A15. 3-[3-Amino-1 -(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-4-yl]propan-1 -ol
tert-Butyl 3-(benzylamino)-4-[3-(benzyloxy)propyl]-1-(3-fluoro-4-methoxybenzyl)-9H-beta-carboline-9- carboxylate (example A10) (7.3 g) is dissolved in 1-butanol (600 ml), under argon 1 ,4-cyclohexadiene (20.8 ml) and palladium (10% on charcoal, 2.9 g) are added and the mixture is refluxed for 18 h. The suspension is cooled to room temperature, filtered over Celite®, washed with ethanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with diluted NH3 solution in MeOH. The filtrate is concentrated in vacuo to obtain the title compound as a yellow foam. MS (MH+ found) = 380.3
The following compounds are obtained by using the procedure of example A15 analogously or in a slightly modified manner.
A16. 3-[1 -(3-Fluoro-4-methoxybenzyl)-3-(methylamino)-9H-beta-carbolin-4-yl]propan-1-ol
Starting compound: tert-Butyl 4-[3-(benzyloxy)propyl]-1-(3-fluoro-4-methoxybenzyl)-3-(methylamino)- 9H-beta-carboline-9-carboxylate (example A11 );
MS (MH+ found) = 394.3
A17. 1 -[4-({[1 -(3-Fluoro-4-methoxybenzyl)-4-(3-hydroxypropyl)-9H-beta-carbolin-3- yl]amino}methyl)piperidin-1-yl]ethanone Starting compound: tert-Butyl 3-{[(1-acetylpiperidin-4-yl)methyl]amino}-4-[3-(benzyloxy)propyl]-1 -(3- fluoro^4-methoxybenzyl)-9H-beta-carboline-9-carboxylate (example A12);
MS (MH+ found) = 519.5
A18. 1 -(4-{[1 -(3-Fluoro-4-methoxybenzyl)-4-(3-hydroxypropyl)-9H-beta-carbolin-3- yl]amino}piperidin-1 -yl)ethanone
Starting compound: tert-Butyl 3-[(1-acetylpiperidin-4-yl)amino]-4-[3-(benzyloxy)propyl]-1-(3-fluoro-4- methoxybenzyl)-9H-beta-carboline-9-carboxylate (example A13);
MS (MH+ found) = 505.4
A19. Ethyl 4-{[1 -(3-fluoro-4-methoxybenzyl)-4-(3-hydroxypropyl)-9H-beta-carbolin-3- yl]amino}piperidine-1-carboxylate
Starting compound: tert-Butyl 4-[3-(benzyloxy)propyl]-3-{[1 -(ethoxycarbonyl)piperidin-4-yl]amino}-1-(3- fluoro^4-methoxybenzyl)-9H-beta-carboline-9-carboxylate (example A14);
MS (MH+ found) = 535.4
A20. tert-Butyl 1 -(3-fluoro-4-methoxybenzyl)-4-[oxiran-2-ylmethyl]-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate
tert-Butyl 1-(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H-beta- carboline-9-carboxylate (example A9) (6.3 g) is dissolved in dichloromethane (150 ml), 3- chloroperoxybenzoic acid (7.84 g) is added and the mixture is refluxed for 6 h. After cooling to room temperature, 3-chloroperoxybenzoic acid (1.0 g) is added and the mixture is refluxed for 6 h. After cooling to room temperature, 5% aqueous sodium hydrogen sulfite solution (250 ml) is added and the mixture is stirred for 30 min at room temperature. The aqueous phase is extracted with
dichloromethane, the combined organic extracts are washed twice with water, dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica, eluting with ethyl acetate / petroleum ether / triethylamine 2:8:1 (v/v/v)) to give rise to the title compound.
MS (MH+ found) = 611.0
A21. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol Step 1 : tert-Butyl 4-(3-amino-2-hydroxypropyl)-1 -(3-fluoro^4-methoxybenzyl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate. tert-Butyl 1-(3-fluoro^4- methoxybenzyl^-Ioxiran^-ylmethyll-S-II^rifluoromethy^sulfonyljoxyJ-ΘH-beta-carboline-θ-carboxylate (example A20) (600 mg) is dissolved in 2 N ammonia solution in ethanol (10 ml) and the solution is heated in a sealed vial at 800C for 18 h. After cooling to room temperature, the content of the vial is concentrated in vacuo. The crude product contains a mixture of tert-butyl 4-(3-amino-2-hydroxypropyl)- 1-(3-fluoro-4-methoxybenzyl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate and 4- (3-amino-2-hydroxypropyl)-1-(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-3-yl
trifluoromethanesulfonate and is used without further purification in the next step.
Step 2: tert-Butyl 6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H-indolo[2,3- c][1 ,8]naphthyridine-7-carboxylate. The crude product of step 1 is dissolved in dioxane (10 ml), then cesium carbonate (620 mg), tris(dibenzylideneacetone)dipalladium(0) (175 mg), and (±)-2,2- bis(diphenylphosphino)-1 ,1-binaphthalene (180 mg) are added under argon. The mixture is stirred under argon for 18 h at 1020C. The mixture is allowed to cool to room temperature, filtered over Celite®, washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with a mixture of dichloromethane and MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo. The crude product contains a mixture of tert-butyl 6-(3-fluoro-4- methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H-indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate and 6- (3-fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol and is used without further purification in the next step.
Step 3: 6-(3-Fuoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol. The crude product of step 2 is dissolved in methanol, concentrated hydrochloric acid (1 ml) is added and the solution is heated under microwave irradiation in a sealed vial at 800C for 15 min and at 900C for 15 min. After cooling to room temperature, the content of the vial is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 4:1 :1 (v/v/v)) followed by purification using Isolute® SCX-2 to yield the title compound. MS (MH+ found) = 378.2
Final Compounds
1. 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1,8]naphthyridine Step 1 : 4-(3-Chloropropyl)-1 -(3-fluoro-4-methoxybenzyl)-9H-beta-carbolin-3-amine. 3-[3-Amino-1-(3- fluoro^4-methoxybenzyl)-9H-beta-carbolin-4-yl]propan-1-ol (example A15) (0.5 g) is dissolved in dichloromethane (20 ml), thionyl chloride (961 μl) is added, and the mixture is shortly heated with a hot-air gun to reflux. The mixture is cooled to room temperature under stirring within 15 min and concentrated in vacuo to afford crude 4-(3-chloropropyl)-1-(3-fluoro-4-methoxybenzyl)-9H-beta- carbolin-3-amine, that is used without further purification in the next step.
Step 2: 6-(3-Fluoro^-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine. The crude product of step 1 is dissolved in a mixture of dimethylformamide (8 ml) and triethylamine (8 ml), potassium iodide (216 mg) is added, and the mixture is heated in a sealed vial at 1000C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is poured into 10% aqueous ammonium chloride solution and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with diluted NH3 solution in MeOH. The filtrate is concentrated in vacuo to obtain the title compound as a yellow foam.
1H-NMR (300 MHz,);
MS (MH+ found) = 362.4
The following compounds are obtained by using the procedure of example 1 analogously.
2. 6-(3-Fluoro-4-methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,8]naphthyridine Starting compound: 3-[1-(3-Fluoro-4-methoxybenzyl)-3-(methylamino)-9H-beta-carbolin-4-yl]propan-1- ol (example A16);
MS (MH+ found) = 376.4
3. 1 -(4-{[6-(3-Fluoro-4-methoxybenzyl)-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]methyl}piperidin-1 -yl)ethanone
Starting compound: 1-[4-({[1-(3-Fluoro-4-methoxybenzyl)-4-(3-hydroxypropyl)-9H-beta-carbolin-3- yl]amino}methyl)piperidin-1-yl]ethanone (example A17);
MS (MH+ found) = 501.4
4. 1 -{4-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin- 4-yl]piperidin-1-yl}ethanone
Starting compound: 1-(4-{[1-(3-Fluoro-4-methoxybenzyl)-4-(3-hydroxypropyl)-9H-beta-carbolin-3- yl]amino}piperidin-1 -yl)ethanone (example A18);
MS (MH+ found) = 487.3
5. Ethyl 4-[6-(3-fluoro-4-methoxybenzyl)-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]piperidine-1-carboxylate
Ethyl 4-{[1-(3-fluoro-4-methoxybenzyl)^4-(3-hydroxypropyl)-9H-beta-carbolin-3-yl]amino}piperidine-1 - carboxylate (example A19) (135 mg) is dissolved in dichloromethane (12 ml), pyridine (235 μl) and trifluoromethanesulfonic anhydride (162 μl) are added, and the solution is stirred at room temperature for 20 min. After that, water is added and the aqueous phase is extracted with dichloromethane. The dried extract is concentrated in vacuo. The crude product is dissolved in dichloromethane, filtered through a filter pad of silica, and the pad is washed with ethyl acetate / petroleum ether / triethylamine 5:5:1 (v/v/v). The combined filtrates are concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with ethyl acetate / petroleum ether 1 :4 (v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain the title compound.
MS (MH+ found) = 517.4
6. 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tEtrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin-4- yl]acetamide
6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine (example 1 ) (100 mg), potassium iodide (30 mg), and bromoacetamide (120 mg) are dissolved in a mixture of dimethylformamide (2 ml) and triethylamine (1 ml), and the mixture is heated in a sealed vial at 1300C for 20 min under microwave irradiation. Bromoacetamide (390 mg) is added, and the mixture is heated in a sealed vial for 40 min at 1400C and then for 60 min at 1500C under microwave irradiation. After cooling to room temperature, the content of the vial is poured into 10% aqueous ammonium chloride solution and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica, eluting with ethyl acetate / petroleum ether / triethylamine 5:5:1 (v/v/v)) to give rise to the title compound. MS (MH+ found) = 419.2
7. 5-(3-Fluoro-4-methoxybenzyl)-2,3-dimethyl-1,2,3,6-tetrahydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indole dihydrochloride
Step 1 : tert-Butyl 5-(3-fluoro^-methoxybenzyl)-2,3-dimethyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4- b]indole-6(1 H)-carboxylate. tert-Butyl 1-(3-fluoro-4-methoxybenzyl)^4-(prop-2-en-1 -yl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) (250 mg) is dissolved in acetonitrile (1 ml), then cesium carbonate (274 mg), palladium(ll) acetate (10 mg), (±)-2,2- bis(diphenylphosphino)-1 ,1-binaphthalene (39 mg), and 2 M methylamine solution in THF (1.5 ml) are added under argon. The mixture is heated in a sealed vial at 1000C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite®, washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo to afford crude tert-butyl 5-(3-fluoro-4-methoxybenzyl)-2,3-dimethyl-2,3- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate, that is used without further purification in the next step.
Step 2: 5-(3-Fluoro^-methoxybenzyl)-2,3-dimethyl-1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4- b]indole dihydrochloride. The crude product of step 1 is dissolved in a mixture of dioxane (1 ml) and ethanol (1 ml), concentrated hydrochloric acid (154 μl) is added, and the mixture is heated in a sealed vial at 1000C for 30 min under microwave irradiation. After cooling to room temperature, the crystalline precipitate is filtered, washed with dioxane and dried to obtain the title compound.
MS (MH+ found) = 376.3
The following compounds are obtained by using the procedure of example 7 analogously or in a slightly modified manner.
8. 2-[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]ethanol dihydrochloride
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) and 2-{[tert- butyl(dimethyl)silyl]oxy}ethanamine;
MS (MH+ found) = 406.3
9. 1 -(4-{[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]methyl}piperidin-1-yl)ethanone
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-3-
{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) and 1 -(1 -acetylpiperid in-
4-yl)methanamine;
MS (MH+ found) = 501.5 10. Ethyl 4-[5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]piperidine-1 -carboxylate
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) and ethyl 4-amino-1- piperidinecarboxylate;
MS (MH+ found) = 517.4
11. 1 -(3-{[(5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]methyl}azetidin-1 -yl)ethanone
Step 1 : tert-Butyl 3-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-5-(3-fluoro-4-methoxybenzyl)-2- methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate. tert-Butyl 1-(3-fluoro-4- methoxybenzyl)-4-(prop-2-en-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) (500 mg) is dissolved in acetonitrile (2 ml), then cesium carbonate (547 mg), palladium(ll) acetate (19 mg), (±)-2,2-bis(diphenylphosphino)-1 ,1 -binaphthalene (79 mg), and 3- aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (316 mg) are added under argon. The mixture is heated in a sealed vial at 1000C for 30 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite®, washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo to afford crude tert-butyl 3- {[1 -(tert-butoxycarbonyl)azetidin-3-yl]methyl}-5-(3-fluoro^4-methoxybenzyl)-2-methyl-2,3- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate, that is used without further purification in the next step.
Step 2: 3-(Azetidin-3-ylmethyl)-5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,2,3,6- tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride. The crude product of step 1 is dissolved in a mixture of dioxane (1 ml) and ethanol (1 ml), concentrated hydrochloric acid (350 μl) is added, and the mixture is heated in a sealed vial at 1000C for 15 min under microwave irradiation. After cooling to room temperature, the crystalline precipitate is filtered, washed with dioxane and dried to obtain 3- (azetidin-3-ylmethyl)-5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 , 2,3,6- tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride.
Step 3: 1-(3-{[(5-(3-Fluoro^-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol- 3(2H)-yl]methyl}azetidin-1 -yl)ethanone. 3-(Azetidin-3-ylmethyl)-5-(3-fluoro^4-methoxybenzyl)-2-methyl- 1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride from the step 2 (120 mg) is suspended in dichloromethane (2.5 ml), acetic acid (57 mg), 1-hydroxybenzotriazole (49 mg), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (92 mg), and triethylamine (200 μl) are added. The mixture is stirred for 20 h at room temperature. After that, water and dichloromethane are added, the aqueous phase is extracted with dichloromethane, the combined organic extracts are dried (MgSO4) and concentrated in vacuo. The crude product is purified by preparative HPLC (C18, eluting with gradient acetonitrile / water) to yield the title compound.
MS (MH+ found) = 473.4
The following compound is obtained by using the procedure of example 11 analogously. 12. 1 -{3-[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]azetidin-1-yl}ethanone
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)-4-(prop-2-en-1 -yl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) and tert-butyl 3- aminoazetidine-1-carboxylate;
MS (MH+ found) = 459.3
13. 2-[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3l,2l:5,6]pyrido[3,4- b]indol-3(2H)-yl]acetamide
Step 1 : tert-Butyl 3-benzyl-5-(3-fluoro-4-methoxybenzyl)-2-methyl-2,3- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indole-6(1 H)-carboxylate. tert-Butyl 1-(3-fluoro-4-methoxybenzyl)- 4-(prop-2-en-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A9) (1.0 g) is dissolved in acetonitrile (18 ml), then cesium carbonate (1.09 g), palladium(ll) acetate (38 mg), (±)-2,2-bis(diphenylphosphino)-1 ,1 -binaphthalene (157 mg), and benzyl amine (368 μl) are added under argon. The mixture is heated in a sealed vial at 1000C for 45 min under microwave irradiation. After cooling to room temperature, the content of the vial is diluted with methanol, filtered over Celite®, washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo to afford crude tert-butyl 3-benzyl-5-(3-fluoro-4-methoxybenzyl)-2-methyl-2,3-dihydropyrrolo[3',2':5,6]pyrido[3,4- b]indole-6(1 H)-carboxylate, that is used without further purification in the next step.
Step 2: 5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole. The crude product of step 1 is dissolved in a 1-butanol (70 ml), under argon 1 ,4-cyclohexadiene (5.4 g) and palladium (10% on charcoal, 1.0 g) are added and the mixture is refluxed for 18 h. The suspension is cooled to room temperature, filtered over Celite®, washed with 1-butanol. Concentrated hydrochloric acid (1.0 ml) is added to the combined filtrates and the solution is stirred for 18 h at room temperature. The solution is concentrated in vacuo, dichloromethane and saturated sodium hydrogencarbonate solution are added, and the aqueous phase is extracted with dichloromethane. The combined organic extracts are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with diluted NH3 solution in MeOH. The filtrate is concentrated in vacuo and the crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / triethylamine 10:1 to ethyl acetate / triethylamine / methanol 9:1 :1 (v/v/v)) to yield 5-(3-fluoro^4-methoxybenzyl)-2-methyl- 1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole.
Step 3: 2-[5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)- yl]acetamide. 5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,2,3,6-tetrahydropyrrolo[3',2':5,6]pyrido[3,4- b]indole from the step 2 (300 mg), bromoacetamide (234 mg) and catalytic amount of potassium iodide (30 mg) are dissolved in a mixture of dimethylformamide (2 ml) and triethylamine (2 ml), and the mixture is heated in a sealed vial at 1200C for 15 min under microwave irradiation. After cooling to room temperature, the content of the vial is poured into water and the aqueous phase is extracted with dichloromethane. The combined organic extracts are dried and concentrated in vacuo. The crude product is purified by flash chromatography (silica, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by preparative HPLC (C18, eluting with gradient acetonitrile / water) to obtain the title compound.
MS (MH+ found) = 419.3
14. 1 -{4-6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]piperidin-1-yl}ethanone
Step 1 : tert-Butyl 4-{3-[(1-acetylpiperidin-4-yl)amino]-2-hydroxypropyl}-1-(3-fluoro-4-methoxybenzyl)-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate. tert-Butyl 1-(3-fluoro^4- methoxybenzylH-Ioxiran^-ylmethyll-S-II^rifluoromethyOsulfonylloxyJ-ΘH-beta-carboline-g-carboxylate (example A20) (500 mg) and 1-acetylpiperidin^4-amine (580 mg) are dissolved in methanol (10 ml) and the solution is refluxed for 18 h. The solution is concentrated in vacuo and the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / triethylamine / methanol 9:1 :1 (v/v/v)) to yield 394 mg (74%) of tert-butyl 4-{3-[(1-acetylpiperidin^4-yl)amino]-2-hydroxypropyl}-1-(3- fluoro^-methoxybenzy^-S-^trifluoromethy^sulfonylJoxyJ-ΘH-beta-carboline-θ-carboxylate as a yellow oil.
Step 2: tert-Butyl 4-(1 -acetylpiperidin^4-yl)-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro- 7H-indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate. tert-Butyl 4-{3-[(1-acetylpiperidin-4-yl)amino]-2- hydroxypropyl}-1-(3-fluoro-4-methoxybenzyl)-3-{[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9- carboxylate from step 1 (390 mg) is dissolved in dioxane (5 ml), then cesium carbonate (390 mg), ths(dibenzylideneacetone)dipalladium(0) (1 10 mg), and (±)-2,2-bis(diphenylphosphino)-1 ,1- binaphthalene (110 mg) are added under argon. The mixture is stirred under argon for 18 h at 800C. The mixture is allowed to cool to room temperature, filtered over Celite®, washed with methanol. The combined filtrates are loaded onto Isolute® SCX-2 cartridge, washed with MeOH, then eluted with 7 N NH3 solution in MeOH. The filtrate is concentrated in vacuo. The crude product contains a mixture of tert-butyl 4-(1-acetylpiperidin-4-yl)-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,4-tetrahydro-7H- indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate and 1 -{4-6-(3-fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7- tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin-4-yl]piperidin-1-yl}ethanone and is used without further purification in the next step.
Step 3: 1-{4-6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3- c][1 ,8]naphthyridin-4-yl]piperidin-1 -yl}ethanone. The crude product of step 2 is dissolved in ethanol (3 ml), concentrated hydrochloric acid (0.5 ml) is added and the solution is heated in a sealed vial at 1000C for 15 min under microwave irradiation. After cooling to room temperature, the content of the vial is concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / methanol / triethylamine 95:4:1 (v/v/v)) followed by crystallization from ethyl acetate / n-heptane to yield the title compound.
MS (MH+ found) = 503.4
The following compounds are obtained by using the procedure of example 14 analogously or in a slightly modified manner. 15. 1 -{(3S)-3-[6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]piperidin-1-yl}ethanone
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)^4-[oxiran-2-ylmethyl]-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A20) and 1-[(3S)-3- aminopiperidin-1-yl]ethanone;
MS (MH+ found) = 503.2
16. 1 -{(3R)-3-[6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]piperidin-1-yl}ethanone
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)^4-[oxiran-2-ylmethyl]-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A20) and 1 -[(3R)-3- aminopiperidin-1-yl]ethanone;
MS (MH+ found) = 503.2
17. 6-(3-Fluoro-4-methoxybenzyl)-4-(2-hydroxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1,8]naphthyridin-2-ol
Starting compounds: tert-Butyl 1-(3-fluoro-4-methoxybenzyl)^4-[oxiran-2-ylmethyl]-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A20) and 2-{[tert- butyl(dimethyl)silyl]oxy}ethanamine;
MS (MH+ found) = 422.4
18. 6-(3-Fluoro-4-methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3- c][1 ,8]naphthyridin-2-ol hydrochloride
Step 1 : tert-Butyl 6-(3-fluoro^-methoxybenzyl)-2-hydroxy-4-methyl-1 ,2,3,4-tetrahydro-7H-indolo[2,3- c][1 ,8]naphthyridine-7-carboxylate. tert-Butyl 1-(3-fluoro-4-methoxybenzyl)^4-[oxiran-2-ylmethyl]-3- {[(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate (example A20) (500 mg) is dissolved in methanol (5 ml), 2 M methylamine solution in THF (5.0 ml) is added, and the solution is heated in a sealed vial at 800C for 5 h. After cooling to room temperature, the content of the vial is diluted with water and the aqueous phase is extracted with dichloromethane. The combined organic extracts are dried and concentrated in vacuo to afford crude tert-butyl 6-(3-fluoro^4-methoxybenzyl)-2-hydroxy^4- methyl-1 ,2,3,4-tetrahydro-7H-indolo[2,3-c][1 ,8]naphthyridine-7-carboxylate, that is used without further purification in the next step.
Step 2: 6-(3-fluoro-4-methoxybenzyl)-4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2- ol hydrochloride. The crude product of step 1 is dissolved in ethanol (5 ml), concentrated hydrochloric acid (1.0 ml) is added, and the mixture is heated in a sealed vial at 1000C for 15 min under microwave irradiation. After cooling to room temperature, the crystalline precipitate is filtered, washed with methanol and dried to obtain the title compound.
MS (MH+ found) = 392.3
19. 2-[6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]acetamide 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol (example A21 ) (50 mg), potassium carbonate (55 mg), and bromoacetamide (19 mg) are suspended in acetone (1.5 ml) and the mixture is stirred at room temperature for 18 h. Water is added to the mixture and the aqueous phase is extracted with dichloromethane. The combined organic extracts are dried and concentrated in vacuo. The crude product is purified by crystallization from ethyl acetate to yield the title compound.
MS (MH+ found) = 435.2
Commercial utility
The compounds, salts thereof, N-oxides of the compounds and the salts thereof, and the stereoisomers of the compounds, the salts, the N-oxides of the compounds and the N-oxides of the salts thereof according to the invention are hereinafter referred to as the compounds of the invention. In particular, the compounds of the invention are pharmaceutically acceptable.
The compounds of the invention have valuable pharmaceutical properties which make them commercially utilizable. In particular, as type 5 phosphodiesterase (PDE5) inhibitors, they are able to influence the physiological and pathophysiological function of various cells, e.g., but not limited to, smooth muscle cells, fibroblasts, myofibroblasts and platelets, which are involved in a great variety of physiological and pathophysiological mechanisms. In particular, the PDE5 inhibiting compounds of the invention can effect relaxation of the vasculature, thus increasing blood flow, improve the spatial balance between blood perfusion and ventilation within the lung ("re-matching" effect) thereby reducing the amount of so-called low V/Q-areas [areas within the lung with high perfusion (Q) but no or reduced ventilation (V)] and high V/Q-areas (areas within the lung with low perfusion but high ventilation), induce neurogenesis, inhibit platelet function, such as aggregation, adhesion and mediator release and, thus, have an anti-inflammatory effect. The compounds of the invention are distinguished by valuable and desirable properties, such as, for example, high efficacy, high selectivity, low toxicity, superior bioavailability in general (e.g. good enteral absorption), superior therapeutic window, superior pharmacokinetics (e.g. half-life), absence of significant side effects, and further beneficial effects related with their therapeutic and pharmaceutical suitability.
Accordingly, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, such as, but not limited to, male erectile dysfunction, premature ejaculation, Peyronie's disease;
acute and chronic airway diseases, such as, but not limited to, COPD (chronic obstructive pulmonary disease), bronchitis, emphysema, pulmonary vascular remodeling, pulmonary hypertension, lung fibrosis in particular idiopathic pulmonary lung fibrosis (IPF), asthma, cystic fibrosis, bronchiectasis, bronchiolitis obliterans, connective tissue diseases, sarcoidosis, kyphoscoliosis, pneumoconiosis, amyotrophic lateral sclerosis, thoracoplasty, extrinsic allergic alveolitis;
inflammatory diseases, such as, but not limited to, vasculature inflammation, acute respiratory distress syndrome, mesangial glomerulonephritis, chronic inflammatory bowel disease, disseminated intravascular inflammation, allergic vasculitis, dermatoses (e.g., but not limited to, psoriasis, toxic and allergic contact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex, sunburn, pruritus in the anogenital area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyodermias, endogenous and exogenous acne, acne rosacea), disorders of the arthritis type (e.g., but not limited to, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis), disorders of the immune system [e.g., but not limited to, AIDS (acquired immunodeficiency syndrome), multiple sclerosis], graft versus host reaction, allograft rejections, shock [e.g., but not limited to, septic shock, endotoxin shock, gram-negative sepsis shock, toxic shock syndrome and ARDS (adult respiratory distress syndrome)], gastrointestinal inflammations (e.g., but not limited to, Crohn's disease and ulcerative colitis); disorders which are based on allergic and/or chronic, immunological false reactions
(e.g., but not limited to, allergic rhinitis, allergic sinusitis, chronic rhinitis, chronic sinusitis, allergic conjunctivitis, nasal polyps);
pain, such as, but not limited to, inflammatory pain;
right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia;
ischaemic diseases, such as, but not limited to, diabetes mellitus, stroke, coronary artery disease, angina (including, but not limited to, vasospastic angina), myocardial infarction, peripheral artery disease, cerebrovascular obstruction, sleep apnea, macular ischaemia, arterial and venous occlusion, congestive heart failure;
diabetic gastroparesis and diseases with symptoms of gastroparesis;
diseases or conditions in which it is desirable to suppress platelet function, for example, but not limited to, after stent implantations (e.g., but not limited to, coronary stenting), after bypass operations, in pulmonary hypertension, thrombotic diseases, post-angioplasty stenosis, coronary artery disease, infarction (e.g., but not limited to, myocardial infarction), instable angina pectoris, stroke, and arterial and venous occlusion diseases (e.g., but not limited to, claudicatio intermittens);
diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, such as, but not limited to, arteriosclerotic dementia, multi-infarct dementia, cerebral senility;
diseases which are based on neuronal damage or degradation, such as but not limited to, stroke, spinal cord injury, brain injury, morbus parkinson, amyotrophic lateral sclerosis, morbus alzheimer, amyloidosis, prion diseases and neuropathy; peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia (Alzheimer's disease), Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic
encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia;
portal hypertension, liver cirrhosis, toxic liver damage (e.g., but not limited to, alcohol-induced liver damage), hepatitis, thrombosis of the portal vein, Budd-Chiari syndrome, malformation of liver veins, compression of liver veins (e.g., but without limitation, due to tumors), arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis (bilharziosis), sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders (e.g., but not limited to, chronic myeloid leukemia, osteomyelofibrosis), lymphatic systemic diseases, collagenosis (e.g., but not limited to, systemic lupus erythematodes, sclerodermia), morbus Osier (congenital arteriovenous malformations, inter alia in the liver), nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis;
benign prostatic hyperplasia; overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction;
insufficient brain skills, such as but not limited to, verbal attainment, attention, concentration, deductive thinking, central auditory processing, cognition, learning, vigilance, apprehension and reagibility.
In a further embodiment, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of diseases, especially diseases alleviated by inhibition of the type 5 phosphodiesterase. In particular, the invention relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia,
portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd- Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and insufficient brain skills.
In this respect, the term "pulmonary hypertension" in particular embraces
- pulmonary arterial hypertension including primary pulmonary hypertension (e.g. sporadic or familial) and pulmonary arterial hypertension related, for example, but without limitation, to collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, human
immunodeficiency virus infection, drugs or toxins (e.g., but not limited to, anorexigens), persistent pulmonary hypertension of the newborn;
- pulmonary venous hypertension due to, for example, but without limitation, left-sided atrial or ventricular heart disease, left-sided valvular heart disease, extrinsic compression of central pulmonary veins (e.g. fibrosing mediastinitis, adenopathy in relation to tumors), pulmonary veno-occlusive disease;
- pulmonary hypertension associated with disorders of the respiratory system or hypoxemia including, for example, but without limitation, chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia;
- pulmonary hypertension caused by chronic thrombotic or embolic diseases including thromboembolic obstruction of proximal pulmonary arteries and obstruction of distal pulmonary arteries, such as pulmonary embolism (due to thrombus, tumor, ova, parasites, or foreign material), in situ thrombosis and sickle-cell disease, in particular chronic thromboembolic pulmonary hypertension (CTEPH);
- pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature including inflammatory disorders (e.g., but not limited to, schistosomiasis, sarcoidosis) and pulmonary capillary hemangiomatosis.
Preferably, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
Furthermore, the invention further relates to the compounds of the invention for use in the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The invention also relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition inhibiting the type 5 phosphodiesterase, in particular a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase, preferably, a pharmaceutical composition for the treatment or prophylaxis of the diseases exemplified above.
In particular, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, such as, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Furthermore, the invention relates to the use of a compound of the invention in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis.
The invention further relates to a method of treating or preventing a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In particular, the invention relates to a method of treating or preventing one of the above mentioned diseases comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Especially, the invention relates to a method of treating or preventing a disease which is alleviated by inhibition of the type 5 phosphodiesterase comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
The invention relates to a method of treating or preventing male and female sexual dysfunction, acute and chronic airway diseases, inflammatory diseases, disorders which are based on allergic and/or chronic, immunological false reactions, pain, right-heart failure, right heart hypertrophy (cor pulmonale), hypertension, hypercholesterolemia, hypertriglyceridemia, ischaemic diseases, diabetic gastroparesis and diseases with symptoms of gastroparesis, diseases or conditions in which it is desirable to suppress platelet function, diseases or conditions with an impairment or dysfunction of cerebral vascular reactivity and/or neurovascular coupling, diseases which are based on neuronal damage or degradation, peripheral arterial diseases, chronic renal failure, chronic heart failure, sepsis, senile dementia, Creutzfeld-Jacob disease, septic encephalopathy, arteriosclerotic encephalopathy, diabetes associated encephalopathy, toxic encephalopathy, vascular and neuronal dementia, Huntington's disease, Parkinson's disease, multiple sclerosis and preeclampsia, portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, thrombosis of the portal vein, Budd- Chiari syndrome, malformation of liver veins, compression of liver veins, arteriovenous fistula, diseases associated with an enlarged spleen, schistosomiasis, sarcoidosis and other granulomatous diseases, primary biliary cirrhosis, myeloproliferative disorders, lymphatic systemic diseases, collagenosis, morbus Osier, nodular regenerative hyperplasia, tricuspid insufficiency, pericarditis constrictiva, veno-occlusive disease (VOD), non-alcoholic steatohepatitis (NASH), liver fibrosis, benign prostatic hyperplasia, overactive bladder, lower urinary tract disease, Raynaud's syndrome, insufficient uteroplacental blood flow in pregnancies with fetal growth restriction and
insufficient brain skills.
Preferably, the invention relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing an acute or chronic airway disease, for example, but not limited to, pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease, comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
Furthermore, the invention preferably relates to a method of treating or preventing portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis or liver fibrosis comprising administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds of the invention.
In the above methods, the patient is preferably a mammal, more preferably a human. Furthermore, in the above methods, at least one of the compounds of the invention can be used. Preferably, one or two of the compounds of the invention are used, more preferably, one of the compounds of the invention is used.
In a particularly preferred embodiment of the invention, the above methods of treating or preventing one of the above mentioned diseases comprise administering to a patient in need thereof a therapeutically effective amount of one compound of the examples according to the present invention.
The invention furthermore relates to a pharmaceutical composition which comprises at least one of the compounds of the invention together with at least one pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
The invention further relates to a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease, in particular for the treatment or prophylaxis of pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
Preferably, the pharmaceutical composition comprises one or two of the compounds of the invention. More preferably, the pharmaceutical composition comprises one of the compounds of the invention.
In a particularly preferred embodiment of the invention, the pharmaceutical composition comprises a compound of the examples according to the present invention together with at least one
pharmaceutically acceptable auxiliary.
The invention additionally relates to a pharmaceutical composition comprising at least one of the compounds of the invention, at least one pharmaceutically acceptable auxiliary and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta- mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides.
In this respect, the therapeutic agent includes the corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics in form of the free compounds, the pharmaceutically acceptable salts thereof, the pharmaceutically acceptable derivatives thereof (e.g., but not limited to, ester derivatives), the solvates thereof and the stereoisomers of the compounds, salts, derivatives and solvates.
Examples of corticosteroids include without limitation budesonide, fluticasone such as fluticasone propionate, beclometasone such as beclometasone dipropionate, triamcinolone such as triamcinolone acetonide, and ciclesonide. Examples of anticholinergics include without limitation indacaterol, tiotropium such as tiotropium bromide, and ipratropium such as ipratropium bromide. Examples of beta-mimetics include without limitation formoterol such as formoterol fumarate, and salmeterol such as salmeterol xinafoate. Examples of lung surfactants include without limitation lusupultide, poractant alfa, sinapultide, beractant, bovactant, colfosceril auch as colfosceril palmitate, surfactant-TA, and calfactant. Examples of endothelin antagonists include without limitation bosentan, ambrisentan and sitaxsentan such as sitaxsentan sodium. Examples of prostacyclins include without limitation iloprost such as iloprost tromethamine, epoprostenol such as epoprostenol sodium and treprostinil such as treprostinil sodium. Examples of calcium channel blockers include without limitation amlodipine such as amlodipine besylate and amlodipine maleate, nifedipine, diltiazem such as diltiazem hydrochloride, verapamil such as verapamil hydrochloride, and felodipine. Examples of beta-blockers include without limitation bisoprolol such as bisoprolol fumarate, nebivolol, metoprolol such as metoprolol succinate and metoprolol tartrate, carvedilol, atenolol and nadolol. Examples of type 4 phosphodiesterase inhibitors include without limitation roflumilast, roflumilast N-oxide, cilomilast, tetomilast and oglemilast. Examples of antidepressants include without limitation bupropion such as bupropion hydrochloride. Examples of antibiotics include without limitation amoxicillin, ampicillin, levofloxacin, clarithromycin, ciprofloxacin such as ciprofloxacin hydrochloride, telithromycin and azithromycin. Examples of anticoagulants include without limitation clopidogrel, enoxaparin, cilostazol, nadroparin, warfarin and abciximab.
Examples of diuretics include without limitation furosemide, bumetanide and torsemide. Examples of digitalis glycosides include without limitation digoxin and digitoxin.
In a preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and budesonide,
a compound of the invention and fluticasone,
a compound of the invention and beclometasone,
a compound of the invention and triamcinolone, or
a compound of the invention and ciclesonide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and indacaterol,
a compound of the invention and tiotropium, or
a compound of the invention and ipratropium.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-mimetic. In a particularly preferred embodiment, the
pharmaceutical composition comprises:
a compound of the invention and formoterol, or
a compound of the invention and salmeterol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a lung surfactant. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and lusupultide,
a compound of the invention and poractant alfa,
a compound of the invention and sinapultide,
a compound of the invention and beractant,
a compound of the invention and bovactant,
a compound of the invention and colfosceril,
a compound of the invention and surfactant-TA, or a compound of the invention and calfactant.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an endothelin antagonist. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and bosentan,
a compound of the invention and ambrisentan, or
a compound of the invention and sitaxsentan.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a prostacyclin. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and iloprost,
a compound of the invention and epoprostenol,
a compound of the invention and triprostinil.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a calcium channel blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and amlodipine,
a compound of the invention and nifedipine,
a compound of the invention and diltiazem,
a compound of the invention and verapamil, or
a compound of the invention and felodipine.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a beta-blocker. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and bisoprolol,
a compound of the invention and nebivolol,
a compound of the invention and metoprolol,
a compound of the invention and carvedilol,
a compound of the invention and atenolol, or
a compound of the invention and nadolol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a type 4 phosphodiesterase inhibitor. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and roflumilast,
a compound of the invention and roflumilast N-oxide,
a compound of the invention and cilomilast,
a compound of the invention and tetomilast, or
a compound of the invention and oglemilast.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antidepressant. In a particularly preferred embodiment, the pharmaceutical composition comprises: a compound of the invention and bupropion.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an antibiotic. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and amoxicillin,
a compound of the invention and ampicillin,
a compound of the invention and levofloxacin,
a compound of the invention and clarithromycin,
a compound of the invention and ciprofloxacin,
a compound of the invention and telithromycin, or
a compound of the invention and azithromycin.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with an anticoagulant. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and clopidogrel,
a compound of the invention and enoxaparin,
a compound of the invention and cilostazol,
a compound of the invention and nadroparin,
a compound of the invention and warfarin, or
a compound of the invention and abciximab.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a diuretic. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and furosemide,
a compound of the invention and bumetanide, or
a compound of the invention and torsemide.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a digitalis glycoside. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention and digoxin, or
a compound of the invention and digitoxin.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and a beta-mimetic. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention, budesonide and indacaterol,
a compound of the invention, budesonide and formoterol,
a compound of the invention, budesonide and salmeterol,
a compound of the invention, fluticasone and indacaterol,
a compound of the invention, fluticasone and formoterol,
a compound of the invention, fluticasone and salmeterol,
a compound of the invention, beclometasone and indacaterol, a compound of the invention, beclometasone and formoterol,
a compound of the invention, beclometasone and salmeterol,
a compound of the invention, triamcinolone and indacaterol,
a compound of the invention, triamcinolone and formoterol,
a compound of the invention, triamcinolone and salmeterol,
a compound of the invention, ciclesonide and indacaterol,
a compound of the invention, ciclesonide and formoterol, or
a compound of the invention, ciclesonide and salmeterol.
In a further preferred embodiment, the pharmaceutical composition comprises a compound of the invention in combination with a corticosteroid and an anticholinergic. In a particularly preferred embodiment, the pharmaceutical composition comprises:
a compound of the invention, budesonide and tiotropium,
a compound of the invention, budesonide and ipratropium,
a compound of the invention, fluticasone and tiotropium,
a compound of the invention, fluticasone and ipratropium,
a compound of the invention, beclometasone and tiotropium,
a compound of the invention, beclometasone and ipratropium,
a compound of the invention, triamcinolone and tiotropium,
a compound of the invention, triamcinolone and ipratropium,
a compound of the invention, ciclesonide and tiotropium, or
a compound of the invention, ciclesonide and ipratropium.
The above mentioned compound of the invention is preferably a compound according to the examples.
The invention furthermore relates to pharmaceutical compositions according to the invention, as defined above, inhibiting the type 5 phosphodiesterase, especially for the treatment or prophylaxis of diseases alleviated by inhibition of type 5 phosphodiesterase, in particular for the treatment or prophylaxis of the diseases exemplified above.
The invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, nonalcoholic steatohepatitis and liver fibrosis.
Furthermore, the invention also encompasses pharmaceutical compositions according to the invention, as defined above, for the treatment or prophylaxis of the following diseases: acute and chronic airway diseases, such as pulmonary hypertension, lung fibrosis, idiopathic pulmonary lung fibrosis (IPF), asthma, bronchitis, emphysema and chronic obstructive pulmonary disease; portal hypertension, liver cirrhosis, toxic liver damage, hepatitis, non-alcoholic steatohepatitis and liver fibrosis.
The pharmaceutical compositions according to the invention preferably contain the compound or compounds of the invention in a total amount of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%. In case at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics is present in the pharmaceutical compositions of the invention, the total amount of said therapeutic agent or therapeutic agents in the pharmaceutical compositions is preferably in the range of from 0.1 to 99.9 wt%, more preferably 5 to 95 wt%, in particular 20 to 80 wt%, under the provision that the total amount of the compound or compounds of the invention and the therapeutic agent or therapeutic agents is less than 100 wt%. Preferably, the at least one compound of the invention and the at least one therapeutic agent are present in the pharmaceutical composition in a weight ratio of from 1000 : 1 to 1 : 1000, more preferably 500 : 1 to 1 : 500.
As pharmaceutically acceptable auxiliaries, any auxiliaries known to be suitable for preparing pharmaceutical compositions can be used. Examples thereof include, but are not limited to, solvents, excipients, dispersants, emulsifiers, solubilizers, gel formers, ointment bases, antioxidants, preservatives, stabilizers, carriers, fillers, binders, thickeners, complexing agents, disintegrating agents, buffers, permeation promoters, polymers, lubricants, coating agents, propellants, tonicity adjusting agents, surfactants, colorants, flavorings, sweeteners and dyes. In particular, auxiliaries of a type appropriate to the desired formulation and the desired mode of administration are used.
The pharmaceutical compositions can be formulated, for example, into tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, powders, suppositories, solutions (e.g., but not limited to, sterile solutions), emulsions, suspensions, ointments, creams, lotions, pastes, oils, gels, sprays and patches (e.g., but not limited to, transdermal therapeutic systems). Additionally, the pharmaceutical compositions can be prepared as e.g. liposome delivery systems, systems in which the compound of the invention is coupled to monoclonal antibodies and systems in which the compound of the invention is coupled to polymers (e.g., but not limited to, soluble or biodegradable polymers).
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, the compound of the invention and the therapeutic agent may be formulated together into the same dosage form (e.g., but not limited to, tablets), separately into the same dosage form (e.g., but not limited to, tablets), or into different dosage forms (without limitation e.g. the compound of the invention may be formulated as tablet and the therapeutic agent may be formulated as powder, solution or suspension). The pharmaceutical compositions can be manufactured in a manner known to a person skilled in the art, e.g. by dissolving, mixing, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
The selected formulation depends inter alia on the route of administering the pharmaceutical composition. The pharmaceutical compositions of the invention can be administered by any suitable route, for example, by the oral, sublingual, buccal, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, topical, transdermal, intranasal, intraocular, intraperitoneal, intrasternal, intracoronary, transurethral, rectal or vaginal route, by inhalation or by insufflation. Oral administration is preferred.
In case of pharmaceutical compositions comprising at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta- blockers, type 4 phosphodiesterase inhibitors, antidepressants, antibiotics, anticoagulants, diuretics and digitalis glycosides, the compound of the invention and the therapeutic agent may be administered by the same route, e.g., without limitation, orally, or by different routes, e.g., without limitation, the compound of the invention can be administered orally and the therapeutic agent can be administered by inhalation or instillation.
Tablets, coated tablets (dragees), pills, cachets, capsules (caplets), granules, solutions, emulsions and suspensions are e.g. suitable for oral administration. In particular, said formulations can be adapted so as to represent, for example, an enteric form, an immediate release form, a delayed release form, a repeated dose release form, a prolonged release form or a sustained release form. Said forms can be obtained, for example, by coating tablets, by dividing tablets into several compartments separated by layers disintegrating under different conditions (e.g. pH conditions) or by coupling the compound of the invention to a biodegradable polymer.
Administration by inhalation or instillation is preferably made by using an aerosol. The aerosol is a liquid-gaseous dispersion, a solid-gaseous dispersion or a mixed liquid/solid-gaseous dispersion.
The aerosol may be generated by means of aerosol-producing devices such as dry powder inhalers (DPIs), pressurized metered dose inhalers (PMDIs) and nebulizers. Depending on the kind of the compound of the invention, and optionally the therapeutic agent, to be administered, the aerosol- producing device can contain the compound and, optionally, the therapeutic agent in form of a powder, a solution or a dispersion. The powder may contain, for example, one or more of the following auxiliaries: carriers, stabilizers and fillers. The solution may contain in addition to the solvent, for example, one or more of the following auxiliaries: propellants, solubilizers (co-solvents), surfactants, stabilizers, buffers, tonicity adjusting agents, preservatives and flavorings. The dispersion may contain in addition to the dispersant, for example, one or more of the following auxiliaries: propellants, surfactants, stabilizers, buffers, preservatives and flavorings. Examples of carriers include, but are not limited to, saccharides, e.g. lactose and glucose. Examples of propellants include, but are not limited to, fluorohydrocarbons, e.g. 1 ,1 ,1 ,2-tetrafluoroethane and 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
The particle size of the aerosol particles (solid, liquid or solid/liquid particles) is preferably less than 100 μm, more preferably it is in the range of from 0.5 to 10 μm, in particular in the range of from 2 to 6 μm (D50 value, measured by laser diffraction).
Specific aerosol-producing devices which may be used for inhaled administration include, but are not limited to, Cyclohaler®, Diskhaler®, Rotadisk®, Turbohaler®, Autohaler®, Turbohaler®, Novolizer®, Easyhaler®, Aerolizer®, Jethaler®, Diskus®, Ultrahaler® and Mystic® inhalers. The aerosol- producing devices may be combined with spacers or expanders, e.g. Aerochamber®, Nebulator®, Volumatic® and Rondo®, for improving inhalation efficiency.
In case of topical administration, suitable pharmaceutical formulations are, for example, ointments, creams, lotions, pastes, gels, powders, solutions, emulsions, suspensions, oils, sprays and patches (e.g., but not limited to, transdermal therapeutic systems).
For parenteral modes of administration such as, for example, intravenous, intraarterial, intramuscular, subcutaneous, intracutaneous, intraperitoneal and intrasternal administration, preferably solutions (e.g., but not limited to, sterile solutions, isotonic solutions) are used. They are preferably administered by injection or infusion techniques.
In case of intranasal administration, for example, sprays and solutions to be applied in drop form are preferred formulations.
For intraocular administration, solutions to be applied in drop form, gels and ointments are exemplified formulations.
Generally, the pharmaceutical compositions according to the invention can be administered such that the dose of the compound of the invention is in the range customary for type 5 phosphodiesterase inhibitors. In particular, a dose in the range of from 0.01 to 4000 mg of the compound of the invention per day is preferred. In this respect, it is to be noted that the dose is dependent, for example, on the specific compound used, the species treated, age, body weight, general health, sex and diet of the subject treated, mode and time of administration, rate of excretion, severity of the disease to be treated and drug combination. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, anticoagulants, diuretics and digitalis glycosides,the same dose ranges apply to the therapeutic agent. The pharmaceutical compositions according to the invention can be administered in a single dose per day or in multiple subdoses, for example, 2 to 4 doses per day. A single dose unit of the
pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the compound of the invention. In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-mimetics, lung surfactants, endothelin antagonists, prostacyclins, calcium channel blockers, beta-blockers, type 4 phosphodiesterase inhibitors, antidepressants and antibiotics, a single dose unit of the pharmaceutical composition can contain e.g. from 0.01 mg to 4000 mg, preferably 0.1 mg to 2000 mg, more preferably 0.5 to 1000 mg, most preferably 1 to 500 mg, of the therapeutic agent. Furthermore, the pharmaceutical composition can be adapted to weekly, monthly or even more infrequent administration, for example by using an implant, e.g. a subcutaneous or intramuscular implant, by using the compound of the invention in form of a sparingly soluble salt or by using the compound of the invention coupled to a polymer. Administration of the pharmaceutical composition in a single dose per day is preferred.
In case the pharmaceutical composition of the invention comprises at least one of the compounds of the invention and at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, beta-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, 11 1 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 1 mM, Tris-HCI 20 mM, beta-mercaptoethanol 1 mM, pH 8.2) plus protease-inhibitor mix giving rise to the final concentrations of 0.5 mM Pefablock (Roche), 10 μM Leupeptin, 5 μM Trypsininhibitor, 2 mM Benzamidin and 10 μM Pepstatin A. The suspension was sonified and thereafter centrifuged for 15 min at 10,000 g. The resulting supernatant (platelet lysate) was used for enzymatic testings. PDE5A1 activity is inhibited by the compounds of the invention in a modified SPA (scintillation proximity assay) test, supplied by Amersham Biosciences (see procedural instructions
"phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090"), carried out in 96-well microtitre plates (MTP's). The test volume is 100 μl and contains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serum albumin)/ml, 5 mM Mg2+, 1 μM motapizone, 10 nM PDE2 inhibitor BAY-60-7550, 0.5 μM cGMP (including about 50,000 cpm of [3H]cGMP as a tracer), 1 μl of the respective compound dilution in dimethylsulfoxide (DMSO) and sufficient PDE5-containing platelet lysat (10,000χg 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 37°C, 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 IQ0 values of the compounds for the inhibition of PDE activity are determined from the concentration-effect curves by means of non-linear regression.
For the following compounds inhibitory values [measured as -1OgIC50 (mol/l)] higher than 9.0 have been determined. The numbers of the compounds correspond to the numbers of the examples. Compounds: 1-8, 12-19.

Claims

Claims:
1 . Com pou n d of Form u la ( I )
Figure imgf000080_0001
wherein A^ is each independently selected from the group consisting of N, O and S;
n represents 0 or 1 ; with the proviso that if A1 is O or S the substituent RA31 is absent.
RA01 anc| RA02 are each independently selected from the group consisting of
hydrogen, hydroxy, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy,
C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
_N RA03RA04. or
RA01 anc| RA02 combine to form an oxo-group; or
RA01 and RA02 combine to form the group -0-CH2-CH2-O-;
RA03 anc| RA04 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,
-NRA05RA06 and -C(O)-NRAOZRAOS1
-C(O)-RA09, -C(O)-NRA01 0RA01 1 and -C(O)ORA012; or
RA°3 anc| RA04 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^g-alkoxy,
_NRA013RA014 and -C(O)-NRA01 SRAOIe1 and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA017, o and S;
RA°5 and RA06 are eacn indpendently selected from the group consisting of
hydrogen, C-|_6-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy, and
-C(O)-C1 _6-alkyl,
wherein the -C(O)-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy; or
RA°5 anc| RA06 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA0^1 o and S;
RA°7 and RA08 are each independently selected from the group consisting of
hydrogen and C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy; or
RA07 anc| RA08 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA019, O and S;
RA09 js selected from the group consisting of
hydrogen and C^g-alkyl, wherein the C^.β-alkyl is optionally substituted by one ore more substituents selected from fluoro, hydroxy and C^.s-alkoxy;
RA010 anc| RA011 are eacn independently selected from the group consisting of
hydrogen and C-|_6-alkyl,
wherein the C^.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.s-alkoxy;
RA012 is Ci _6_alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.β-alkoxy;
RA01 3 and RA014 have the same meanings as RA05 and RA06, and RA01 5 and RA016 have the same meanings as RA07 and RA08;
RAO^ RA018 anc| RA019 are eacn independently selected from the group consisting of
hydrogen, C^.β-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-C(O)-C1 _6-alkyl,
wherein the -C(O)-Ci .g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA1 1 and RA12 have the same meanings as RA01 and RA02;
RA2^ and RA22 are each independently selected from the group consisting of
Hydrogen or C^.β-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA31 is selected from the group consisting of
hydrogen, C^.β-alkyl,
wherein the C^.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and a C^.^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S,
C6.14-aryl, C3-6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound to the C^.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 RA325,
C3.6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, 3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxyl, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl is bound via C, and
wherein N is substituted by RA325,
-S(O)2-C1.6-alkyl,
wherein the -S(O)2-C1 _β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-SO2NRA33RA34 -(CH2)m-RA35i -(CRA36RA37)|.CORA38I _CO(CRA39RA310)k_RA311 and a lone pair;
or in case A^ is S, it is optionally substituted by one or two oxo-groups; wherein m is 0, 1 , 2, 3 and 4, I is 1 , 2, 3 and 4 and k is 0, 1 and 2;
RA33 anc| RA34 are eacn independently selected from the group consisting of
hydrogen and C^g-alkyl,
wherein the C^β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; RA35 js selected from the group consisting of
hydroxy, C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
_NRA312RA313.
RA36 anc| RA37 are eacn independently selected from the group consisting of
hydrogen, hydroxy, halogen, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
Ci_6-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
-NRA314RA315; or
pA36 and R^37 combine to form a Cβ.g-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA38 js selected from the group consisting of
hydroxy, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy, and
_NRA316RA317.
RA39 anc| RA310 are eacn independently selected from the group consisting of
hydrogen, hydroxy, fluoro, C^.g-alkyl,
wherein the C^.g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by fluoro and hydroxy, C^.g-alkoxy,
wherein the C^.g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy, and _NRA318RA319. or
RA39 anc| RA310 combine to form a 03.5-CyCIyI1
wherein the C3_5-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy; or
pA39 and RA310 COmbine to form an oxo-group;
RA311 js selected from the group consisting of
hydrogen, hydroxy, halogen, -CO(O)RA320, -NRA321 RA322, -CONRA323RA324, C^-alkyl, wherein the C^-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
Ci_6-alkoxy,
wherein the C^-alkoxy is optionally substituted by one or more substituents selected from fluoro, hydroxy, C^-alkoxy,
C6.14-aryl,
Ci_i 3-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, and
C3_6-cyclyl,
wherein the C3_6-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^-alkoxy via
C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the Ci_6-alkoxy via C, N is substituted by RA325, and
_NRA325RA326.
RA312 anc| RA313 are eacn independently selected from the group consisting of
hydrogen, C-|_6-alkyl,
wherein the C^-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C-|_6-alkoxy,
-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, -C(O)ORA327, C3.6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound to the C^-alky! via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C^-alky! via C, N is substituted by RA328; or
RA312 and RA313 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^-alkoxy,
wherein the C^-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA328, O and S;
RA314 and RA315 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl,
wherein the C^-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;
RA316 and RA317 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,
C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C6.14-aryl,
C^g-heteroaryl, wherein the C^ _g-heteroaryl has at least one heteroatom selected from N, O and
S, 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^.s-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the
C^-alkyl via C, N is substituted by RA328, and
_NRA329RA330
-C(O)-C1 _6-alkyl,
wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^.β-alkoxy,
wherein the C^β-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-S(O)2-Ci_6-alkyl,
wherein the S(O^-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-C(O)O-C1 _6-alkyl,
wherein the -C(O)O-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C3_6-cyclyl,
wherein the C3_6-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 FΛ331 , -CONRA332RA333; or
and RA3^ 7 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S; RA318 anc| RA319 are Q30I1 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;
RA320 js selected from the group consisting of
hydrogen and C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA321 and RA322 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,
C6.14-aryl,
C^g-heteroaryl,
wherein the C^g-heteroaryl has at least one heteroatom selected from N, O and
S,
C3_6-cyclyl,
wherein the C3_g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound to the Cj.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C1.6-alkyl via C, N is substituted by RA331 ,
_NRA334RA335 and _CONRA336RA337
-C(O)O-C1.6-alkyl,
wherein the -C(O)O-C1.g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, -C(O)-C1 _6-alkyl
wherein the -C(O)-Ci -6~alM is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-CONRA338RA339, -S(O)2-C1 _6-alkyl,
wherein the -S(O)2-C1 _g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
-S(O)2NRA340RA341 , C6.14-aryl,
C^^-heteroaryl,
wherein the heteroaryl has at least one heteroatom which is selected from N, O and S, C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N,
O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound via C, N is substituted by R^34^; or RA321 anc| RA322 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocycle is optionally substituted by one or more substituents selected from fluoro, hydroxy, oxo, C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
C^g-alkoxy,
-CONRA34SRA344 and
wherein the 3- to 7-membered heterocycle optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
RA323 anc| RA324 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,
C6.14-aryl,
C3.6-cyclyl,
wherein the Cβ.g-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and 3- to 7-membered heterocyclyl,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl has at least one heteroatom selected from N, O and S, and
wherein the 3- to 7-membered heterocyclyl may be bound to the C^.g-alkyl via C or N, with the proviso that, if the 3- to 7-membered heterocyclyl is bound to the C|_6-alkyl via C, N is substituted by RA328,
C6-i4-aryl,
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 RA328 C3_6-cyclyl,
wherein the C3_6-cyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy,
and
-C(O)-C1.6-alkyl,
wherein the -C(O)-C1.β-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
-S(O)2-C1.6-alkyl,
wherein the -S(O^-C1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, or
RA323 anc| RA324 combine to form a 3- to 7-membered heterocycle,
wherein the 3- to 7-membered heterocyclyl is optionally substituted by one or more substituents selected from fluoro and hydroxy, and
wherein the 3- to 7-membered heterocyclyl optionally has one or more additional heteroatom(s) selected from NRA331 , O and S;
RA325, RA326, RA328, RA331 and RA342 are eacn independently selected from the group consisting of
hydrogen, C^-alkyl,
wherein the C^-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 _5-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
-C(O)O-C1 _6-alkyl,
wherein the -C(O)O-C1 _6-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA327 is represented by
C1 -1 0-alkyl,
wherein the C^ g-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA329 RASSO1 RA334 RASSS1 RASSS1 RASSQ 1 RA340 and RA341 are each independently selected from the group consisting of
hydrogen and C-|_g-alkyl,
wherein the C^-alkyl is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RA332i RASSS1 RASSe1 RASST1 RA343 and RA344 are each independently selected from the group consisting of
hydrogen, C^g-alkyl,
wherein the C^g-alkyl is optionally substituted by one or more substituents selected from fluoro, hydroxy and C^g-alkoxy,
wherein the C^g-alkoxy is optionally substituted by one or more substituents selected from fluoro and hydroxy;
RB41 js selected from the group consisting of hydrogen, halogen, C^-alkoxy, nitro and amino;
RB51 js selected from the group consisting of hydrogen, halogen, C1_3-alkyl, hydroxy, C^-alkoxy, nitro, amino, -NH-C(O)- C^-alkyl, -NH-C(0)-NH2 and a methoxy group substituted by 2 or 3 fluorine atoms; or
RB41 and RB51 combine to form a group selected from -0-CH2-O-, -0-CH2-CH2- and
-CH2-CH2-O-;
RB61 is selected from the group consisting of hydrogen and halogen;
RB71 is selected from the group consisting of hydrogen and halogen; RB81 is 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 A1 is N;
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 any one of claims 1 to 2, wherein R^31 and RA32 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 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-i_e-alkyl via C, N is substituted by RA325,
-(CH2)m-RA35, -(CRA36RA37)|-CORA38 and a lone pair;
wherein m is 0, 1 , 2, 3 and I is 1 , 2, 3;
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 RA36 and RA37 are hydrogen, RA38 is _NH2I RA325 is -C(O)-C1 _6-alkyl or -C(O)O-C1 _6-alkyl
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
RB41 js selected from the group consisting of hydrogen, halogen and C^β-alkoxy, and wherein
RB51 is selected from the group consisting of hydrogen, halogen, C^-alkoxy;
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
n is 1 , A1 is N, RA01 , RA02, RA21 and RA22 are each hydrogen, and one of the substituents RA1 1 and RA^2 is hydroxy; or
n is 0, A1 is N, RA1 1and RA12 are each hydrogen, and one of the substituents RA21 and RA22 is methyl;
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 selected from the group consisting of 6-(3-Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine; 6-(3-Fluoro^- methoxybenzylH-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridine; 1 -(4-{[6-(3-Fluoro^- methoxybenzylj-I ^.SJ-tetrahydro^H-indolop.S-clIi .δlnaphthyridin^-ylJmethylJpiperidin-i- yl)ethanone; i-^-IΘ-β-Fluoro^-methoxybenzyO-I ^SJ-tetrahydro^H-indoloβ.S-ciπ .Slnaphthyridin- 4-yl]piperidin-1 -yl}ethanone; Ethyl 4-[6-(3-fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro-4H-indolo[2,3- c][1 ,8]naphthyridin-4-yl]piperidine-1 -carboxylate; 2-[6-(3-Fluoro-4-methoxybenzyl)-1 ,2,3,7-tetrahydro- 4H-indolo[2,3-c][1 ,8]naphthyridin-4-yl]acetamide; 5-(3-Fluoro-4-methoxybenzyl)-2,3-dimethyl-1 ,2,3,6- tetrahydropyrrolo[3',2':5,6]pyrido[3,4-b]indole dihydrochloride; 2-[5-(3-Fluoro-4-methoxybenzyl)-2- methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]ethanol dihydrochloride; 1-(4-{[5-(3- Fluoro-4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)- yl]methyl}piperidin-1-yl)ethanone; Ethyl 4-[5-(3-fluoro-4-methoxybenzyl)-2-methyl-1 ,6- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]piperidine-1-carboxylate; 1-(3-{[(5-(3-Fluoro^- methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]methyl}azetidin-1- yl)ethanone; 1-{3-[5-(3-Fluoro^4-methoxybenzyl)-2-methyl-1 ,6-dihydropyrrolo[3',2':5,6]pyrido[3,4- b]indol-3(2H)-yl]azetidin-1 -yl}ethanone; 2-[5-(3-Fluoro-4-methoxybenzyl)-2-methyl-1 ,6- dihydropyrrolo[3',2':5,6]pyrido[3,4-b]indol-3(2H)-yl]acetamide; 1 -{4-6-(3-Fluoro-4-methoxybenzyl)-2- hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin^-yl]piperidin-1-yl}ethanone; 1-{(3S)-3-[6- (3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H-indolo[2,3-c][1 ,8]naphthyridin-4- yl]piperidin-1 -yl}ethanone; 1 -{(3R)-3-[6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1 ,2,3,7-tetrahydro-4H- indolo[2,3-c][1 ,8]naphthyridin-4-yl]piperidin-1-yl}ethanone; 6-(3-Fluoro-4-methoxybenzyl)-4-(2- hydroxyethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol; 6-(3-Fluoro-4-methoxybenzyl)- 4-methyl-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol hydrochloride; 2-[6-(3-Fluoro-4- methoxybenzyO^-hydroxy-I ^.SJ-tetrahydro^H-indolop.S-clIi .δlnaphthyridin^-yllacetamide; 6-(3- Fluoro-4-methoxybenzyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c][1 ,8]naphthyridin-2-ol;
a salt thereof, an N-oxide of the compound or the salt thereof, or a stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof.
8. 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 7 for use in the treatment or prophylaxis of diseases.
9. 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 7 together with at least one pharmaceutically acceptable auxiliary.
10. Pharmaceutical composition according to claim 9 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.
1 1. 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 7 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of diseases alleviated by inhibition of the type 5 phosphodiesterase.
12. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 7 in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of an acute or chronic airway disease.
13. Use according to claim 12, wherein the acute or chronic airway disease is selected from pulmonary hypertension, lung fibrosis, asthma, bronchitis, emphysema and chronic obstructive pulmonary disease.
14. Use of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 7 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.
15. 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 7.
16. Method for treating or preventing an acute or chronic airway disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, N-oxide of the compound or the salt thereof or stereoisomer of the compound, the salt, the N-oxide of the compound or the N-oxide of the salt thereof or the pharmaceutically acceptable salt thereof according to any of claims 1 to 7.
17. Method for treating or preventing an acute or chronic airway disease according to claim 16, 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.
18. 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 7.
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WO2015009930A2 (en) 2013-07-17 2015-01-22 The Trustees Of Columbia University In The City Of New York Novel phosphodiesterase inhibitors and uses thereof
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