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WO2018086703A1 - Dihydropyridazinones substituées par des phénylurées - Google Patents

Dihydropyridazinones substituées par des phénylurées Download PDF

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Publication number
WO2018086703A1
WO2018086703A1 PCT/EP2016/077449 EP2016077449W WO2018086703A1 WO 2018086703 A1 WO2018086703 A1 WO 2018086703A1 EP 2016077449 W EP2016077449 W EP 2016077449W WO 2018086703 A1 WO2018086703 A1 WO 2018086703A1
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Prior art keywords
alkyl
phenyl
oxo
group
dihydro
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Inventor
Anja Giese
Maria QUANZ-SCHOEFFEL
Thomas Müller
Judith GÜNTHER
Niels Böhnke
Nils Griebenow
Naomi BARAK
Ulf Bömer
Roland Neuhaus
Maren OSMERS
Charlotte Christine Kopitz
Stefan KAULFUSS
Hartmut Rehwinkel
Jörg WEISKE
Benjamin Bader
Sven Christian
Roman Hillig
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Bayer Pharma AG
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Bayer Pharma AG
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Priority to PCT/EP2016/077449 priority Critical patent/WO2018086703A1/fr
Publication of WO2018086703A1 publication Critical patent/WO2018086703A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to dihydropyridazinone substituted cyclic urea derivatives, a process for their production and the use thereof. Background of the invention
  • Nicotinamide adenine dinucleotide is a biologically important coenzyme that plays a critical role in many cell metabolism-related transformations and in cell signaling [Lin, S-J.; Guarente L. Current Opinion Cell Biol. 2003, 15, 241-146; Ziegler M. Eur. J. Biochem. 2000, 267, 1550-1564].
  • NAMPT (nicotinamide phosphoribosyltransferase also known as pre-B-cell-colony-enhancing factor (PBEF) and visfatin, NMPRT, NMPETase or NAmPRTase, International nomenclature E.C.2.4.2.12) catalyzes the first step of this process, the phosphoribosylation of NAM to NMN (nicotineamide mononucleotide) which is further converted to NAD + by NMNATs (nicotinemaide mononucleotide adenylyltransferase).
  • NMN nicotineamide mononucleotide
  • NMNATs nicotinemaide mononucleotide adenylyltransferase
  • NAD + is used as electron carrier in glycolysis, which is up regulated in cancer cells due to the Warburg effect as well as in mitochondrial oxidative phosphorylation.
  • NAD + serves as a substrate for several enzymes, for example poly-ADP-ribose polymerases (PARPs) and sirtuins which are involved in DNA repair and gene expression, processes often aberrantly regulated in cancer cells [Berger F et al. 2004 Trends Biochem. Sci. 29, 1 1 1-1 18].
  • Phosphorylated forms of NAD7NADH also exist and are often employed for biosynthetic and/or cell protection purposes in addition to energy generation. They are also involved in the cellular response to oxidative stress [Massudi H. Redox Rep. 2012, 17, 28-46].
  • NAMPT is implicated in the regulation of cell viability during genotoxic or oxidative stress and that NAMPT inhibitors are potentially useful for the treatment of e.g. inflammation, metabolic disorders and cancer [Tong L. et al. Expert Opin. Ther. Targets 2007, 11, 695-705; Galli, M. et al. Cancer Res. 2010, 70, 8-1 1 , J. Med. Chem 2013, 56, 6279- 6296].
  • Daporinad also known as APO-866, FK866, WK175 or WK22 ((E)-N-[4-(l-benzoylpiperidin-4- yl)butyl]-3-(pyrldine-3-yl)-acrylamide is a highly potent and selective inhibitor of NAMPT which interferes with NAD biosynthesis, ATP generation and induces cell death.
  • An in vivo effect of daporinad was shown in murine renal cell carcinoma model [Anticancer Res 2003; 23:4853- 4858, PubMed:14981935].
  • CHS-828 also known as GMX 1778 (N-[6-(4-chlorophenoxy)hexyl]-N'-cyano-N"-4-pyridinyl-guanidine), an inhibitor of NAMPT as well as an inhibitor of NF- ⁇ pathway activity [Anticancer Res 2006, 26, 4431-4436], showed in vitro and in vivo highly cytotoxic effects in human breast and lung cancer [Cancer Res. 1999, 59, 5751-5757]. A Phase I study for this compound in patients with solid tumor malignancy was published in the year 2002 [ClinCancerRes 2002, 9, 2843-2850].
  • the present invention relates to chemical compounds that inhibit NAMPT.
  • WO9206087 and WO2006064189 disclose 1 -alkyl-6-oxo-1 ,4,5,6- tetrahydropyridazin-3-yl derivatives which may be useful for the treatment of anemia, cardiovascular and DGAT mediated disorders (e.g. diabetes), respectively.
  • WO2012067965 discloses 4-oxo-3,4-dihydrophthalazine phenyl cyclic urea derivatives which may be useful as NAMPT and ROCK inhibitors.
  • inhibitors of NAMPT represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs, particularly those NAMPT inhibitors with increased selectivity over other biological targets.
  • the invention relates to compounds of formula (I),
  • R represents a group selected from : methyl, C 2 -C 6 -alkyl, (1 ,3-dioxolan-2-yl)-(Ci-C 6 -alkyl)-, (1 ,3-dioxan-2-yl)-(Ci -C 6 -alkyl)-, azetidin-3-yl, (azetidin-3-yl)-(Ci-C6-alkyl)-, oxetan-3-yl, (oxetan-3-yl)-(Ci-C6-alkyl)-, C 3 -Ce- cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, a 5- to 7-membered heterocycloalkyl group, (5- to 7-membered heterocycloalkyl)-(Ci-C6-alkyl)-, phenyl, phenyl
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C 3 -alkoxy)-(Ci-C 4 -alkyl)-, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, -N(R 5 )R 6 , -C( 0)OH, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 9 represents H, Ci-C3-alkyl or Ci-C3-haloalkyl
  • R 0 represents Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl or phenyl;
  • C3-C6-cycloalkyl, azetidin-3-yl, oxetan-3-yl, and 5- to 7-membered heterocycloalkyi are optionally substituted with one or more substituents independently selected from the group consisting of:
  • hydroxy, halogen, cyano, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, and oxo ( 0); one or two of A, B, C and D is N and the others are CH or CR 4 , with the proviso that at least one of A, B, C and D is CH; n is 1 , 2 or 3,
  • n 0, 1 , 2 or 3
  • R 3 , R 4 represent, independently of each other, Ci-C3-alkyl, C 3 -C6-cycloalkyl or
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • R 4 represents, independently of each other, halogen, Ci-C3-alkyl, Ci-C3-alkoxy, C1-C3- haloalkoxy, -N(H)R 3 , -N(R 3 )R 4 or -NH 2 ;
  • the invention relates to compounds of formula (I) as described supra, wherein :
  • R represents a group selected from :
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C 3 -alkoxy)-(Ci-C 4 -alkyl)-, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, -N(R 5 )R 6 , -C( 0)OH, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 2 represents H, Ci-C4-alkyl-, C 3 -C6-cycloalkyl-, Ci-C 3 -haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy- and -N(H)R 3 , -N(R 3 )R 4 ;
  • R 9 represents H, Ci-C 3 -alkyl or Ci-C 3 -haloalkyl
  • R 2 and R 9 together with the carbon to which they are attached form a C 3 -C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, NR 2 , and S; wherein said C 3 -C6-cycloalkyl and 5- to 6-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 0 represents Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl or phenyl;
  • R represents H, Ci-C3-alkyl or Ci-C3-haloalkyl
  • R 0 and R together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 7-membered heterocycloalkyl group containing one heteroatom containing group selected from O, N R 2 , S,
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • n 1 , 2 or 3 ;
  • n 0, 1 , 2 or 3 ;
  • n + m is 2, 3 or 4 ;
  • Ci-C3-alkyl Ci-C3-alkoxy- and Ci-C3-haloalkoxy- ;
  • R 3 , R 4 represent, independently of each other Ci-C3-alkyl, Cs-Ce-cycloalkyl or
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • R 4 represents, independently of each other, halogen, Ci-alkyl, Ci-alkoxy, Ci-haloalkoxy, -
  • the invention relates to compounds of formula (I) as described supra, wherein :
  • * represents the point of attachment of said group with the rest of the compound of formula (I), represents a group selected from :
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C3-alkoxy)-(CrC 4 -alkyl)- ,C3-C6-cycloalkyl, and oxo ( 0) ; wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C3-alkyl Ci-C3-alkoxy- and Ci-C3-haloalkoxy- ;
  • R 2 and R 9 together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, and NR 12 ;
  • R 0 represents Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl or phenyl;
  • R represents H, or Ci-C3-alkyl; or R 0 and R together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, NR 12 ,
  • one or two of A, B, C and D is N and the others are CH or CR 4 , with the proviso that at least one of A, B, C and D is CH; n is 1 or 2 ;
  • n 0, 1 or 2 ;
  • n + m 2, 3 or 4; re resents a group which is selected from :
  • R 3 , R 4 represent, independently of each other, Ci-C2-alkyl,
  • R 5 , R 6 represent, independently of each other hydrogen, Ci-C3-alkyl, C3-cycloalkyl,
  • R 5 , R 6 together with the nitrogen to which they are attached form an azetidinyl group or a 5- to
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C3-alkoxy)-(0-C4-alkyl)- , oxo ( 0), and Cs-Ce-cycloalkyl ;
  • R 2 represents hydrogen, or Ci-alkyl
  • R 4 represents, independently of each other, halogen, Ci-alkyl, Ci-alkoxy, Ci-haloalkoxy, - N(H)R 3 , -N(R 3 )R 4 or -NH 2 ; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • the invention relates to compounds of formula (I) as described supra, wherein :
  • R represents a group selected from :
  • C2-C4-alkyl Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C4-alkyl)-, a 5- to 7- membered heterocycloalkyi group, (5- to 7-membered heterocycloalkyl)-(Ci-C4-alkyl)-, phenyl, phenyl-(Ci-C4-alkyl)- and a 5- to 6-membered heteroaryl group, in which 5- to 7-membered heterocycloalkyi and 5- to 6-membered heteroaryl are connected to the rest of the molecule via a carbon atom of the 5- to 7-membered heterocycloalkyi ring or via a carbon atom of the 5- to 6-membered heteroaryl ring, respectively; wherein C2-C4-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyi are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-alkyl, and oxo ( 0); wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 9 represents H, or Ci-C3-alkyl
  • R 10 represents Ci-C4-alkyl, C3-C4-cycloalkyl
  • R 11 represents H, or Ci-C3-alkyl
  • R 3 , R 4 represent, independently of each other, Ci-alkyl
  • R 2 represents hydrogen, or Ci-alkyl;
  • R 4 represents, independently of each other, N(H)R 3 , -N(R 3 )R 4 or -NH 2 ; or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • the invention relates to compounds of formula (I) as described supra, wherein represents:
  • * represents the point of attachment of said group with the rest of the compound of formula (I), represents a group selected from :
  • the invention relates to compounds of formula (I) as described supra, which have formula (lc) below:
  • R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 2 represents H-, d-Ce-alkyl-, C 3 -C6-cycloalkyl-, Ci-C4-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy- and -N(H)R 3 , -N(R 3 )R 4 ; one or two of A, B, C and D is N and the others are CH,
  • n 1 , 2 or 3
  • n 1 , 2 or 3
  • n + m is 2, 3 or 4 ;
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy-, R 3 (H)N- and -N(R 3 )R 4 ;
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • the invention relates to compounds of formula (Ic) as described supra, wherein :
  • R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy- and -N(H) R 3 , -N(R 3 )R 4 ;
  • R 2 represents H-, Ci-C4-alkyl-, C 3 -C6-cycloalkyl-, Ci-C 3 -haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy- and -N(H)R 3 , -N(R 3 )R 4 ;
  • one or two of A, B, C and D is N and the others are CH ;
  • n 1 , 2 or 3 ;
  • m 1 , 2 or 3 ;
  • n + m is 2, 3 or 4 ;
  • R 3 , R 4 represent, independently of each other Ci-C3-alkyl, C 3 -C6-cycloalkyl or alkyl) ;
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy Ci-C4-haloalkoxy
  • the invention relates to compounds of formula (lc) as described supra, wherein :
  • R represents a group selected from :
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C3-alkyl Ci-C3-alkoxy and Ci-C3-haloalkoxy ;
  • R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, Ci-C3-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C3-alkyl Ci-C3-alkoxy- and Ci-C3-haloalkoxy- ;
  • one or two of A, B, C and D is N and the others are CH ;
  • n 1 or 2 ;
  • n 1 or 2 ;
  • n + m 2, 3 or 4; re resents a group which is selected from
  • R 7 represents, independently of each other hydrogen, Ci-C3-alkyl or C3-C6-cycloalkyl ;
  • the invention relates to compounds of formula (Ic) as described supra, wherein
  • R represents a group selected from :
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, or phenyl,
  • R 5 , R 6 represent, independently of each other Ci-C3-alkyl
  • R 5 , R 6 together with the nitrogen to which they are attached form a 6-membered nitrogen containing heterocycloalkyi group, optionally containing one additional heteroatom containing group selected from O and NR 7 ,
  • R 7 represents, independently of each other hydrogen, Ci-C3-alkyl
  • the invention relates to compounds of formula (Ic) as described supra, wherein
  • R represents a group selected from methyl, ethyl, -CH 2 CF 3 , cyclopropyl, cyclopentyl, -CH 2 CH 2 OH, isopropyl, -CH 2 CH 2 N(R 5 )R 6 , phenyl, tetrahydro-2H-pyran-4-yl 4-(difluoromethoxy)benzyl-, 2,2-difluoroethyl-, 3- methoxypropyl-, 3-hydroxypropyl-, 2-methoxyethyl-, 3-methoxyphenyl-, (tetrahydro-2H-pyran-4- yl)CH 2 -, cyclobutyl and 1 -methoxypropan-2-yl ;
  • R 2 rep , propan-2-yl or phenyl
  • R 5 , R 6 represent methyl
  • One aspect of the invention are compounds of formula (I) as described in the examples, as characterized by their names in the title, as claimed in claim 6, and/or their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples.
  • Another aspect of the present invention is the intermediates as used for their synthesis.
  • One special aspect of the invention is intermediate (1-10),
  • R , R 2 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and L represents a leaving group such as, for example, Ci-C3-haloalkyl such as, for example, trichloromethyl or a imid such as, for example, pyrrolidine-2,5-dione.
  • One special aspect of the invention is intermediate (1 -28),
  • R , R 2 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and L 2 represents a group such as, for example, a H, CI or Br atom or an nitro group.
  • One special aspect of the invention is intermediate (1-8),
  • R , R 2 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein.
  • One special aspect of the invention is intermediate (1 -14),
  • R , R 2 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and PG represents an amine protecting group such as, for example, an acetyl group or a tert- butyloxycarbonyl (BOC group).
  • One special aspect of the invention is intermediate (1 -19),
  • R , R 2 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and X 2 represents a leaving group such as for example a CI, Br or I atom.
  • One special aspect of the invention is intermediate (1-61 ),
  • R , R 2 , R 9 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and L represents a leaving group such as, for example, a haloalkyl such as, for example, trichloromethyl, or an imide such as, for example, pyrrolidine-2,5-dione or 4-nitrophenyl.
  • One special aspect of the invention is intermediate (1 -60),
  • R ⁇ R 2 , R 9 , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and L represents a leaving group such as, for example, a haloalkyl such as, for example, trichloromethyl, or an imide such as, for example, pyrrolidine-2,5-dione or 4-nitrophenyl.
  • One special aspect of the invention is intermediate (1 -67),
  • R , R 0 , R , V, W, Y and Z are as defined for the compound of formula (I) in any one of claims 1 to 6 or as defined in any of the aspects or embodiments described herein, and L a leaving group such as, for example, a Ci-C3-haloalkyl such as, for example, trichloromethyl, or an imid such as, for example, pyrrolidine-2,5-dione, or a 4-nitrophenyl.
  • L a leaving group such as, for example, a Ci-C3-haloalkyl such as, for example, trichloromethyl, or an imid such as, for example, pyrrolidine-2,5-dione, or a 4-nitrophenyl.
  • One special aspect of the invention is intermediate (1 -66),
  • Another aspect of the invention relates to the use of an intermediate (1-10), intermediate (1-28), intermediate (1-8), intermediate (1-14), intermediate (1-19), intermediate (1-61 ), intermediate (1- 60), intermediate (1-67), or intermediate (1-66) as defined supra or in the general procedures below, for the preparation of a compound of formula (I), (la), (lb) or(lc) according to any one of claims 1 to 6 or according to the aspects and embodiments described herein, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound of formula (I), or a salt of said N-oxide, tautomer or stereoisomer.
  • Another aspect of the invention relates to the use of any of the intermediates described herein for preparing a compound of formula (I) as defined herein or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • the invention relates to compounds of formula (II),
  • R 2 , R 9 , R 0 , R , n, m, A, B, C, D, V, W, Y and Z have the meaning as given in the aspects and embodiments defined herein for the compound of formula (I), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.
  • compounds of formula (II) as described herein may also be used as an intermediates for the preparation of compounds of general formula(l).
  • Another aspect of the invention relates to the use of a compound of formula (II) or a salt thereof as described herein, as an intermediate for the preparation of a compound of formula (I), (la), (lb) or (lc) according to any one of claims 1 to 6 or according to the aspects and embodiments described herein, or an N-oxide, a salt, a tautomer or a stereoisomer of said compound of formula (I), (la), (lb) or (lc), or a salt of said N-oxide, tautomer or stereoisomer.
  • the invention relates to compounds of formula (I), wherein, R represents a group selected from :
  • phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 2 represents H-, d-Ce-alkyl-, Cs-Ce-cycloalkyl- or phenyl, ;
  • one or two of A, B, C and D is N and the others are CH,
  • n 1 or 2
  • n 1 or 2
  • n + m is 2, 3 or 4 ; v-w — Y
  • roup which is selected from :
  • R 5 , R 6 represent, independently of each other, Ci-C3-alkyl
  • R 5 , R 6 together with the nitrogen to which they are attached form a 5- to 7-membered nitrogen containing heterocycloalkyi group containing one additional heteroatom containing group selected from O;
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C2-C6-alkyl C3-C6-cycloalkyl, a 5- to 7-membered heterocycloalkyi group, phenyl and phenyl-(CrC6-alkyl)-, in which 5- to 7-membered heterocycloalkyi is connected to the rest of the molecule via a carbon atom of the 5- to 7-membered heterocycloalkyi ring, wherein C2-C6-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • R 2 represents H-, Ci-C6-alkyl- or phenyl ;
  • one of A, B, C and D is N and the others are CH,
  • n 1 ,
  • n 1 or 2
  • n + m is 2 or 3 ;
  • R 5 , R 6 represent, independently of each other, Ci-C3-alkyl
  • R 5 , R 6 together with the nitrogen to which they are attached form a 5- to 7-membered nitrogen containing heterocycloalkyi group containing one additional heteroatom containing group selected from O;
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • R 2 represents H-, methyl, ethyl or phenyl
  • R 5 , R 6 represent methyl
  • the invention relates to compounds of formula (I), wherein
  • the invention relates to compounds of formula (I), wherein
  • the invention relates to compounds of formula (I), wherein R represents a group selected from methyl, C 2 -C 6 -alkyl, (1 ,3-dioxolan-2-yl)-(Ci-C 6 -alkyl)-, (1 ,3-dioxan-2-yl)-(Ci-C 6 -alkyl)-, azetidin-3-yl, (azetidin-3-yl)-(Ci-C6-alkyl)-, oxetan-3-yl, (oxetan-3-yl)-(Ci-C6-alkyl)-, C 3 -Ce- cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, a 5- to 7-membered heterocycloalkyl group, (5- to 7-membered heterocycloalkyl
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C 3 -alkoxy)-(Ci-C 4 -alkyl)-, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, -N(R 5 )R 6 , -C( 0)OH, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C3-alkoxy)-(CrC 4 -alkyl)- ,C3-C6-cycloalkyl, and oxo ( 0) ; wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C2-C4-alkyl Cs-Ce-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C4-alkyl)-, a 5- to 7- membered heterocycloalkyl group, (5- to 7-membered heterocycloalkyl)-(Ci-C4-alkyl)-, phenyl, phenyl-(Ci-C4-alkyl)- and a 5- to 6-membered heteroaryl group, in which 5- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl are connected to the rest of the molecule via a carbon atom of the 5- to 7-membered heterocycloalkyl ring or via a carbon atom of the 5- to 6-membered heteroaryl ring, respectively; wherein C2-C4-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-alkyl, and oxo ( 0); wherein said phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkoxy,Ci-C 3 -haloalkoxy- , -C( 0)OH and
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy-, -N(H)R 3 and -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I), wherein R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, (Ci-C 3 -alkoxy)-(Ci-C 4 -alkyl)-, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, -N(R 5 )R 6 , -C( 0)OH wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy- and -N(H) R 3 , -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C 3 -C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C3-alkyl Ci-C3-alkoxy and Ci-C3-haloalkoxy.
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C2-C4-alkyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • the invention relates to compounds of formula (I), wherein R represents a group selected from :
  • azetidin-3-yl and oxetan-3-yl are optionally substituted with one or two substituents independently selected from the group consisting of:
  • Ci-C 3 -alkyl Ci-C 3 -alkoxy-, Ci-C 3 -haloalkoxy-, -N(H)R 3 and -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy Ci-C4-haloalkoxy
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • phenyl, and 5- to 6-membered heteroaryl group in which 5- to 6-membered heteroaryl is connected to the rest of the molecule via a carbon atom of the 5- to 6-membered heteroaryl ring, respectively, wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • halogen 0-C 3 -alkyl, CrC 3 -alkoxy-, CrC 3 -haloalkoxy-, -N(H)R 3 and -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C 3 -C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • C3-C6-cycloalkyl and 5- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I), wherein
  • R represents a group selected from :
  • phenyl, and a 5- to 6-membered heteroaryl group in which 5- to 6-membered heteroaryl is connected to the rest of the molecule via a carbon atom of the 5- to 6-membered heteroaryl ring; wherein phenyl and 5- to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • Ci-C3-alkyl Ci-C3-alkoxy and Ci-C3-haloalkoxy.
  • the invention relates to compounds of formula (I), wherein the 5- to 7-membered heterocycloalkyl in R is a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms, and one or two, preferably one, heteroatom-containing group selected from O, NR 7 , in which R 7 is as defined herein, said heterocycloalkyl group being attached to the rest of the molecule via a carbon atom of the heterocycloalkyl ring.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H, d-Ce-alkyl-, Cs-Ce-cycloalkyl-, Ci-C4-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • halogen 0-C 3 -alkyl, CrC 3 -alkoxy-, CrC 3 -haloalkoxy- and -N(H)R 3 , -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, Ci-C3-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, methyl, ethyl, propan-2-yl or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, d-Ce-alkyl-, Cs-Ce-cycloalkyl-, Ci-C4-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, Ci-C3-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • halogen 0-C 3 -alkyl, CrC 3 -alkoxy-, CrC 3 -haloalkoxy- and -N(H)R 3 , -N(R 3 )R 4 .
  • the invention relates to compounds of formula (I) or (II), wherein R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, Ci-C3-haloalkyl- or phenyl,
  • phenyl is optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, Ci-C4-alkyl-, Cs-Ce-cycloalkyl-, or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents H-, methyl, ethyl, propan-2-yl or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein R 2 represents H-, methyl, ethyl or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 9 represents H, Ci-C3-alkyl or Ci-C3-haloalkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 9 represents H, Ci-C3-alkyl or Ci-C3-haloalkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 and R 9 together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, NR 12 , and S; wherein said C3-C6-cycloalkyl and 5- to 6-membered heterocycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 9 represents H, or Ci-C3-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 and R 9 together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, and NR 12 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 9 represents H, or Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 0 represents Ci-Ce-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl or phenyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R represents H, Ci-C3-alkyl or Ci-C3-haloalkyl
  • the invention relates to compounds of formula (I) or (II), wherein
  • C3-C6-cycloalkyl, azetidin-3-yl, oxetan-3-yl, and 5- to 7-membered heterocycloalkyi are optionally substituted with one or more substituents independently selected from the group consisting of:
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 0 and R together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 7-membered heterocycloalkyi group containing one heteroatom containing group selected from O, NR 12 , S,
  • the invention relates to compounds of formula (I) or (II), wherein
  • R represents H, or Ci-C3-alkyl
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 0 and R together with the carbon to which they are attached form a C3-C6-cycloalkyl group or a 5- to 6-membered heterocycloalkyl group containing one heteroatom containing group selected from O, NR 2 ,
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 0 represents Ci-C4-alkyl, C3-C4-cycloalkyl
  • the invention relates to compounds of formula (I) or (II), wherein
  • R represents H, or Ci-C3-alkyl
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 0 represents Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R represents H, or Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein one or two of A, B, C and D is N and the others are CH or CR 4 , with the proviso that at least one of A, B, C and D is CH.
  • the invention relates to compounds of formula (I) or (II), wherein one of A, B, C and D is N and the others are CH or CR 14 , with the proviso that at least one of A, B, C and D is CH.
  • the invention relates to compounds of formula (I) or (II), wherein two of A, B, C and D is N and the others are CH or CR 14 , with the proviso that at least one of A, B, C and D is CH.
  • the invention relates to compounds of formula (I) or (II), wherein one of A, B, C and D is N and the others are CH or CR 14 , with the proviso that two of A, B, C and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein one or two of A, B, C and D is N and the others are CH.
  • the invention relates to compounds of formula (I) or (II), wherein one of A, B, C and D is N and the others are CH.
  • the invention relates to compounds of formula (I), wherein two of A, B, C and D is N and the others are CH.
  • the invention relates to compounds of formula (I) or (II), wherein A is N and B, C and D are CH,
  • B is N and A, C and D are CH,
  • C is N and B, A and D are CH, or
  • D is N and B, C and A are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • A is N and B, C and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • B is N and A, C and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • C is N and B, A and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein D is N and B, C and A are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • a and B are N and C and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • a and C are N and B and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • a and D are N and C and B are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • B and C are N and A and D are CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • B and D are N and A and C are CH.
  • the invention relates to compounds of formula (I) or (II), wherein C and D are N and A and B are CH.
  • the invention relates to compounds of formula (I) or (II), wherein n is 1 , 2 or 3,
  • n 0, 1 , 2 or 3
  • n + m 2, 3 or 4.
  • the invention relates to compounds of formula (I) or (II), wherein n is 1 or 2 ;
  • n 1 or 2 ;
  • n + m 2, 3 or 4.
  • the invention relates to compounds of formula (I) or (II), wherein m is 0, 1 , 2 or 3.
  • the invention relates to compounds of formula (I) or (II), wherein m is 0, 1 or 2.
  • the invention relates to compounds of formula (I) or (II), wherein n is 1 , 2 or 3,
  • the invention relates to compounds of formula (I) or (II), wherein n is 1 or 2.
  • the invention relates to compounds of formula (I) or (II), wherein n is 1.
  • the invention relates to compounds of formula (I) or (II), wherein n is 2.
  • the invention relates to compounds of formula (I) or (II), wherein n is 3.
  • the invention relates to compounds of formula (I) or (II), wherein m is 1 , 2 or 3, In a further embodiment of the above-mentioned aspects, the invention relates to compounds of formula (I) or (II), wherein m is 1 or 2.
  • the invention relates to compounds of formula (I) or (II), wherein m is 1.
  • the invention relates to compounds of formula (I) or (II), wherein m is 2.
  • the invention relates to compounds of formula (I) or (II), wherein m is 3.
  • the invention relates to compounds of formula (I) or (II), with the proviso that n + m is 2, 3 or 4.
  • the invention relates to compounds of formula (I) or (II), with the proviso that n + m is 2 or 3.
  • the invention relates to compounds of formula (I) or (II), with the proviso that n + m is 2.
  • the invention relates to compounds of formula (I) or (II), with the proviso that n + m is 3.
  • the invention relates to compounds of formula (I) or (II), with the proviso that n + m is 4.
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein represents a group which is selected from
  • Ci-C3-alkyl Ci-C3-alkoxy- and Ci-C3-haloalkoxy-.
  • the invention relates to compounds of formula (I) or (II), wherein presents a group which is selected from in which * and # represent the points of attachment of said group with the rest of the compound of formula (I) or (II).
  • the invention relates to compounds of formula (I) or (II), wherein re resents a group which is selected from
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein v-w
  • the invention relates to compounds of formula (I) or (II), wherein v-w — Y
  • the invention relates to compounds of formula (I) or (II), wherein
  • V, W, Y and Z represent CH.
  • the invention relates to compounds of formula (I) or (II), wherein
  • Z represents N, and V, W, and Y represent CH.
  • the invention relates to compounds of formula (I) or (II), wherein Y represents N, and V, W, and Z represent CH.
  • the invention relates to compounds of formula (I) or (II), wherein Y, V represent N, and
  • W, Z represent CH.
  • the invention relates to compounds of formula (I) or (II), wherein Y, Z represent N, and
  • W, V represent CH.
  • the invention relates to compounds of formula (I) or (II), wherein R 3 , R 4 represent, independently of each other, Ci-C3-alkyl, Cs-Ce-cycloalkyl or
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein R 3 , R 4 represent, independently of each other, Ci-C2-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein R 3 , R 4 represent, independently of each other, Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy Ci-C4-haloalkoxy
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy Ci-C4-haloalkoxy
  • the invention relates to compounds of formula (I) or (II), wherein R 5 , R 6 represent, independently of each other hydrogen, Ci-C 3 -alkyl,r C 3 -cycloalkyl,
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy C1-C4- haloalkoxy, (Ci-C3-alkoxy)-(Ci-C4-alkyl)-, Cs-Ce-cycloalkyl, Cs-Ce-cycloalkyloxy, -
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 5 , R 6 represent, independently of each other hydrogen, Ci-C3-alkyl or C3-cycloalkyl.
  • the invention relates to compounds of formula (I) or (II), wherein R 5 , R 6 represent, independently of each other Ci-C3-alkyl, preferably methyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • Ci-C4-alkyl Ci-C4-haloalkyl
  • Ci-C4-alkoxy Ci-C4-haloalkoxy
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein R 5 , R 6 together with the nitrogen to which they are attached form a 6-membered nitrogen containing heterocycloalkyi group, optionally containing one additional heteroatom containing group selected from O and NR 7 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 7 represents, independently of each other hydrogen, Ci-C3-alkyl or Cs-Ce-cycloalkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 7 represents, independently of each other hydrogen, Ci-C3-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents hydrogen, or Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 2 represents hydrogen, or Ci-alkyl.
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 4 represents, independently of each other, halogen, Ci-C3-alkyl, Ci-C3-alkoxy, C1-C3- haloalkoxy, -N(H)R 3 , -N(R 3 )R 4 or -NH 2 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 4 represents, independently of each other, halogen, Ci-alkyl, Ci-alkoxy, Ci-haloalkoxy, - N(H)R 3 , -N(R 3 )R 4 or -NH 2 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 4 represents, independently of each other, halogen, Ci-alkyl, Ci-alkoxy, Ci-haloalkoxy, - N(H)R 3 , -N(R 3 )R 4 or -NH 2 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 4 represents, independently of each other, N(H)R 3 , -N(R 3 )R 4 or -NH 2 .
  • the invention relates to compounds of formula (I) or (II), wherein
  • R 4 represents -NH 2 .
  • a further aspect of the invention are compounds of formula (I), which are present as their salts.
  • Yet another aspect of the invention are compounds of formula (I) in which the salt is a pharmaceutically acceptable salt.
  • the present invention covers compounds of formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • Another embodiment of the invention are compounds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the exemplified compounds and subcombinations thereof.
  • Constituents which are optionally substituted as stated herein may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position.
  • each definition is independent.
  • each definition of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 0 , R , R 2 , R 3 , and/or R 4 occur more than one time, each definition of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 0 , R 11 , R 2 , R 3 , and R 4 is independent.
  • a constituent be composed of more than one part, e.g. (Ci-C3-alkoxy)-(C 2 -C6-alkyl)-
  • the position of a possible substituent can be at any of these parts at any suitable position.
  • a hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule.
  • the substitutent(s) could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
  • aspects and embodiments described herein for the compound of formula (I), are also aspects and embodiments of the compounds of formula (la), 1(b) and (lc).
  • the present invention covers all such aspects and embodiments of compound of formula (I), (la), (lb) and (lc).
  • certain aspects and embodiments of the present invention cover a compound of formula (I) in which R represents methyl.
  • the present invention also covers aspects and embodiments of the compounds of formula (la), (lb) and (lc) in which R represents hydrogen.
  • aspects and embodiments described herein for the compound of formula (II), are also aspects and embodiments of the compounds of formula (lla), ll(b).
  • the present invention covers all such aspects and embodiments of compound of formula (II), (lla) and (lb).
  • certain aspects and embodiments of the present invention cover a compound of formula (II) in which R 2 represents methyl.
  • the present invention also covers aspects and embodiments of the compounds of formula (lla), and (lib) in which R 2 represents hydrogen.
  • halogen atom halo- or Hal-
  • fluorine chlorine, bromine or iodine atom.
  • CrC6-alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 - methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1 , 1 -d
  • said group has 1 , 2, 3 or 4 carbon atoms (“CrC 4 -alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • CrC 4 -alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms
  • Si-C3-alkyl e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • C2-C6-alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms e.g. a ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1 , 1 -dimethylbutyl, 2,3
  • said group has 2, 3 or 4 carbon atoms ("C 2 -C 4 -alkyl”), e.g. a ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group or an isomer thereof.
  • R represents a group, which is connected to the rest of the molecule via a carbon atom of said group.
  • said group has 2, 3 or 4 carbon atoms ("C 2 -C 4 - alkyl").
  • C2-C6-alkyl substituted with one or more halogen includes, for example, -CH 2 CF 3 , - CH2CH2F, -CH2CHF2, -CH 2 CH 2 CF 3 , -CH(CH 2 F) 2 , -CH2CF2CI, -CH(CH 2 CI)(CHF 2 ), or -CH 2 CF 2 CI.
  • said halogen atom is F.
  • C2-C6-alkyl substituted with one or more hydroxy include, for example, 2- hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, or 2-hydroxy-2-methyl-propyl group.
  • C2-C6-alkyl substituted with one or more Ci-C 3 -alkoxy includes, for example, - CH 2 CH 2 OCH 3 , -CH(CH 2 OCH 3 ) 2 , or -CH 2 CH 2 CH 2 OCH 3 .
  • C2-C6-alkyl substituted with one or more -N(R 5 )R 6 includes, for example, - CH 2 CH 2 N(R 5 )R 6 , -CH(CH 2 N(R 5 )R 6 ) 2 , or -CH 2 CH 2 CH 2 N(R 5 )R 6 wherein R 5 and R 6 are as defined herein.
  • C2-C6-alkyl substituted with one or more substituents independently selected from halogen and N(R 5 )R 6 includes, for example, -CH(CH 2 N(R 5 )R 6 )(CH 2 F), or -CH 2 CH(F)CH 2 N(R 5 )R 6 wherein R 5 and R 6 are as defined herein.
  • 5- to 7-membered heterocycloalkyl is connected to the rest of the molecule via a carbon atom of the 5- to 7-membered heterocycloalkyl ring.
  • R ⁇ 5- to 6-membered heteroaryl is connected to the rest of the molecule via a carbon atom of the 5- to 6-membered heteroaryl ring.
  • R represents a 5- to 6- membered heteroaryl which is directly connected to the nitrogen of the 1 ,4,5,6- tetrahydropyridazinone ring to which R connects and also when R represents a 5- to 7- membered heterocycloalkyi which is connected to an alkyl group, such as, for example, in (5- to 6-membered heteroaryl)-(Ci -C6-alkyl)- or in (5- to 6-membered heteroaryl)-(Ci-C4-alkyl)-.
  • R ⁇ azetidin-3-yl, oxetan-3-yl, C3-C6-cycloalkyl, 5- to 7-membered heterocycloalkyi, phenyl and 5- to 6-membered heteroaryl may be optionally substituted as defined supra or as defined in any of the claims 1 to 6.
  • the substituents may be present both when said azetidin-3-yl, oxetan-3-yl, C3-C6-cycloalkyl, 5- to 7-membered heterocycloalkyi, phenyl and 5- to 6-membered heteroaryl exist as a (unitary) constituent or as part of a constituent composed of more than one part, such as for example, (azetidin-3-yl)-(Ci -C6-alkyl)-, (oxetan-3- yl)-(Ci-Ce-alkyl)-, (C3-C6-cycloalkyl)-(Ci-C6-alkyl)-, (5- to 7-membered heterocycloalkylHd-Ce- alkyl)-, phenyl-(Ci-Ce-alkyl)- or (5- to 6-membered heteroaryl)-(Ci-C6-alkyl)-, for example.
  • Ci-C4-haloalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "CrC 4 -alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said C1-C4- haloalkyl group is, for example, -CF 3 , -CHF 2 , -CH 2 F, -CF2CF3, -CH 2 CH 2 F, -CH 2 CH F 2 , -CH 2 CF 3 , - CH 2 CH 2 CF 3 , or -CH(CH 2 F) 2 .
  • said group has 1 , 2 or 3 carbon atoms ("C1-C3- haloalkyl").
  • Ci-C4-alkoxy is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -0-(Ci-C4-alkyl), in which the term “CrC 4 -alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, orsec-butoxy group, or an isomer thereof. Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci-C 3 -alkoxy").
  • Ci-C4-haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom.
  • said halogen atom is F.
  • Said Ci-Ce-haloalkoxy group is, for example, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCF 2 CF 3 , or - OCH2CF3.
  • said group has 1 , 2 or 3 carbon atoms ("CrC3-haloalkoxy").
  • C3-C6-cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl").
  • Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • said group has 3 carbon atoms (“C3- cycloalkyl”), i.e. a cyclopropyl group.
  • C3-C6-cycloalkyloxy is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon group of formula -O-cycloalkyl, in which the term “cycloalkyl” is defined supra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
  • said heterocycloalkyi can be a 5-membered ring, such as, but not limited to, tetrahydrofuranyl, pyrrolidinyl or pyrrolinyl, or a 6-membered ring, such as, but not limited to, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl, or a 7-membered ring, such as, but not limited to, an azepanyl ring, for example.
  • said heterocycloalkyi can be benzo fused.
  • said 5- to 7-membered heterocycloalkyi can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1 H- pyrrolyl, for example, or, it may be benzofused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • the term "5- to 6-membered heteroaryl group” is understood as meaning a monovalent, monocyclic aromatic ring system having 5 or 6 ring atoms and which contains at least one heteroatom, which may be identical or different, said heteroatom(s) being selected from oxygen, nitrogen and sulfur, and in addition in each case can be benzocondensed. It is understood that any heteroaryl group is attached to the rest of the molecule via a carbon atom of the heteroarylic ring.
  • said 5- to 6-membered heteroaryl group can be a 5- membered ring, such as, but not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thia-4H-pyrazolyl, furyl, triazolyl (1 ,2,4-triazolyl, 1 ,3,4-triazolyl or 1 ,2,3-triazolyl), thiadiazolyl (1 ,3,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,2,3- thiadiazolyl or 1 ,2,4-thiadiazolyl) and oxadiazolyl (1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,2,3- oxadiazolyl or 1 ,2,4-o
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences.
  • Non-limiting examples of 5- to 7- membered nitrogen containing heterocycloalkyi groups are, for example, piperidinyl, morpholinyl, thiomorpholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl or 2,2- dioxido-2-thia-6-azaspiro[3.3]hept-6-yl, for example.
  • piperidinyl and morpholinyl is especially preferred.
  • ⁇ - ⁇ as used throughout this text, e.g. in the context of the definition of "C1-C6- alkyl", “Ci-C6-haloalkyl", “CrC6-hydroxyalkyl”, “Ci-C6-alkoxy”, or “Ci-C6-haloalkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “d-Ce” is to be interpreted as any sub-range comprised therein, e.g.
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C 4 -C 6 , C 5 -C 6 ; particularly C 3 -C 6 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • substituents of the compounds of the general formulae of the present invention is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two”.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 3 C, 4 C, 5 N, 17 0, 8 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 8 F, 36 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 3 l, respectively.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 4 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure:
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention may exist as tautomers.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6- hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl- aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the salts include water-insoluble and, particularly, water-soluble salts. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition. Furthermore, derivatives of the compounds of formula (I) or (II) and the salts thereof which are converted into a compound of formula (I) or (II) or a 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) or (II) or a salt thereof by metabolic processes.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N- alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the term "pharmacokinetic profile" means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
  • Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered. Any such combination of a compound of formula (I) or (II) of the present invention with an anti-cancer agent as defined below is an embodiment of the invention.
  • the term "(chemotherapeutic) anti-cancer agents” includes but is not limited to :
  • said compounds of the present invention have surprisingly been found to effectively inhibit NAMPT and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by NAMPT, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • the compounds of the invention are selective inhibitors against NAMPT in the sense that their inhibitory activity over ROCK2 kinase is lower or inexistent compared to compounds of WO2012067965, as demonstrated in the Experimental part below.
  • the compounds of the invention may thus advantageously be used for the treatment of the herein described NAMPT mediated disorders where (significant) ROCK2 inhibition is not necessary or not desirable (e.g. should significant ROCK2 inhibition produce undesired (side) effects) for the therapeutic effect/benefit to be achieved.
  • the intermediates used for the synthesis of the compounds of claims 1 to 6 as described below, as well as their use for the synthesis of the compounds of claims 1 to 6, are one further aspect of the present invention. Preferred intermediates are the Intermediate Examples as disclosed below.
  • the compounds according to the invention can be prepared according to the following schemes 1 through 12.
  • Scheme 1 Route for the preparation of compounds of formula (I), wherein R , R 2 , A, B, C, D, n, m, V, W, Y and Z have the meaning as given for general formula (I), supra.
  • X represents a leaving group such as for example a CI or Br atom
  • X 1 represents a leaving group such as for example a CI, Br or I, or an aryl sulfonate such as for example p-toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • U represents a leaving group such as, for example, a haloalkyl such as, for example, trichloromethyl or a imid such as, for example, pyrrolidine-2,5-dione.
  • PG represents an amine protecting group as for example an acetyl group.
  • any of the substituents R ⁇ R 2 , L , A, B, C, D, V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted aromatic amine of general formula (1 -1 ), such as, for example, N- phenylacetamide, can be reacted with a suitable substituted acid chloride (1-2), such as, for example, 2-chloropropanoyl chloride, in the presence of a Lewis acid, such as, for example, aluminium trichloride, in a suitable solvent system, such as, for example, dichloromethane, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at 0°C, to furnish intermediates of general formula (1 -3).
  • a suitable substituted acid chloride such as, for example, 2-chloropropanoyl chloride
  • a Lewis acid such as, for example, aluminium trichloride
  • solvent system such as, for example, dichloromethane
  • Intermediates of general formula (1-3) can be converted to intermediates of general formula (1- 5) by reaction with a suitably alkyl malonate of the general formula (1-4), such as, for example, dimethyl malonate, in the presence of a suitable base, such as, for example sodium hydride, in a suitable solvent system, such as, for example, DMF, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 0°C.
  • a suitably alkyl malonate of the general formula (1-4) such as, for example, dimethyl malonate
  • a suitable base such as, for example sodium hydride
  • a suitable solvent system such as, for example, DMF
  • Intermediates of general formula (1-5) can be reacted with a suitable Broensted acid, such as, for example, hydrochloric acid or sulphuric acid, at temperatures ranging from 0°C to boiling point of the respective Broensted acid, preferably the reaction is carried out at 100°C, to furnish intermediates of general formula (1-6).
  • a suitable Broensted acid such as, for example, hydrochloric acid or sulphuric acid
  • Intermediates of general formula (1-6) can be converted to intermediates of general formula (1- 8) by reaction with a suitably hydrazine of the general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 80°C.
  • a suitably hydrazine of the general formula (1 -7) such as, for example, methylhydrazine
  • a suitable solvent system such as, for example, propan-1-ol
  • Intermediates of general formula (1 -10) can be converted to compounds of formula (I) by reaction with a suitably substituted amine of the general formula (1 -1 1 ), such as, for example, 1- (pyridin-3-yl)piperazine, in the presence of a suitable base, such as, for example triethylamine, in a suitable solvent system, such as, for example, DMF, in a temperature range from 0°C to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitably substituted amine of the general formula (1 -1 1 ) such as, for example, 1- (pyridin-3-yl)piperazine
  • a suitable base such as, for example triethylamine
  • a suitable solvent system such as, for example, DMF
  • Scheme 2 Route for the preparation of compounds of formula (I), wherein R ⁇ R 2 , A, B, C, D, n, m, V, W, Y and Z have the meaning as given for general formula (I), supra.
  • L represents a leaving group such as for example a halo alkyl such for example trichloromethyl or a imid such as, for example pyrrolidine-2,5-dione.
  • PG represents an amine protecting group such as, for example, an acetyl group.
  • any of the substituents R ⁇ R 2 , A, B, C, D, V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted aromatic amine of general formula (1 -1 ), such as, for example, N- phenylacetamide, can be reacted with a suitable substituted dihydrofuran-2,5-dione (1 -12), such as, for example, 3-methyldihydrofuran-2,5-dione, in the presence of a Lewis acid, such as, for example, aluminium trichloride, in a suitable solvent system, such as, for example, DMF, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at 0°C, to furnish intermediates of general formula (1 -13).
  • a Lewis acid such as, for example, aluminium trichloride
  • a suitable solvent system such as, for example, DMF
  • Intermediates of general formula (1 -13) can be converted to intermediates of general formula (1- 14) by reaction with a suitably substituted hydrazine of the general formula (1-7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 0°C.
  • a suitably substituted hydrazine of the general formula (1-7) such as, for example, methylhydrazine
  • a suitable solvent system such as, for example, propan-1-ol
  • Intermediates of general formula (1 -10) can be converted to compounds of formula (I) by reaction with a suitably substituted amine of the general formula (1 -1 1 ), such as, for example, 1- (pyridin-3-yl)piperazine, in the presence of a suitable base, such as, for example triethylamine, in a suitable solvent system, such as, for example, DMF, in a temperature range from 0°C to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitably substituted amine of the general formula (1 -1 1 ) such as, for example, 1- (pyridin-3-yl)piperazine
  • a suitable base such as, for example triethylamine
  • a suitable solvent system such as, for example, DMF
  • X 2 represents a leaving group such as for example a CI, Br or I atom.
  • interconversion of any of the substituents R ⁇ R 2 , V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Compounds 1-1 , 1-2, 1-4, 1 -7, and 1 -20 are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • a suitably substituted aromatic halide of general formula (1 -15), such as, for example, N- bromobenzene, can be reacted with a suitable substituted acid chloride (1 -2), such as, for example, 2-chloropropanoyl chloride, in the presence of a Lewis acid, such as, for example, aluminium trichloride, in a suitable solvent system, such as, for example, dichloromethane, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at 0°C, to furnish intermediates of general formula (1 -16).
  • a suitable substituted acid chloride (1 -2) such as, for example, 2-chloropropanoyl chloride
  • a Lewis acid such as, for example, aluminium trichloride
  • solvent system such as, for example, dichloromethane
  • Intermediates of general formula (1 -16) can be converted to intermediates of general formula (1 - 17) by reaction with a suitably alkyl malonate of the general formula (1 -4), such as, for example, dimethyl malonate, in the presence of a suitable base, such as, for example sodium hydride, in a suitable solvent system, such as, for example, DMF, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 0°C.
  • a suitably alkyl malonate of the general formula (1 -4) such as, for example, dimethyl malonate
  • a suitable base such as, for example sodium hydride
  • a suitable solvent system such as, for example, DMF
  • Intermediates of general formula (1-17) can be reacted with a suitable Broensted acid, such as, for example, hydrochloric acid or sulphuric acid, at temperatures ranging from 0°C to boiling point of the respective Broensted acid, preferably the reaction is carried out at 100°C, to furnish intermediates of general formula (1-18).
  • Intermediates of general formula (1 -18) can be converted to intermediates of general formula (1 - 19) by reaction with a suitably hydrazine of the general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 80°C.
  • Intermediates of general formula (1 -19) can be reacted with a suitable substituted carbamate, such as, for example tert-butyl carbamate (1-20), in the presence of a suitable base, such as, for example caesium carbonate, and a suitable palladium catalyst, such as for example bis(dibenzylideneacetone)-palladium(0), in the presence of a suitable ligand, such as for example 9(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), in a suitable solvent system, such as, for example, 1 ,4-dioxane, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at at 1 10°C to furnish compounds of formula (1 -21 ).
  • a suitable substituted carbamate such as, for example tert-butyl carbamate (1-20)
  • a suitable base such as, for example caesium carbonate
  • palladium catalysts can be used: allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2-yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di ⁇ -acetato)bis[o-(di-o- tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6- trimethylphenyl)imi
  • Intermediates of general formula (1 -21 ) can be converted to intermediates of general formula (1 - 8) by reaction with suitable Broensted acid, such as, for example trifluoroactic acid, in a suitable solvent system, such as, for example, dichloromethane, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • suitable Broensted acid such as, for example trifluoroactic acid
  • a suitable solvent system such as, for example, dichloromethane
  • X 2 represents a leaving group such as for example a CI or Br atom or an aryl sulfonate such as for example p-toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • PG represents an amine protecting group, such as, for example, an acetyl group.
  • interconversion of any of the substituents R ⁇ R 2 , V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted aromatic ketone of general formula (1 -22), such as, for example, N-(4- propionylphenyl)acetamide, can be reacted with a suitable substituted intermediate of general formula (1 -23), such as, for example, ethyl bromoacetate, in the presence of a suitable base, such as, for example, lithium 1 , 1 ,1 ,3,3,3-hexamethyldisilazan-2-ide, in a suitable solvent system, such as, for example, THF, at temperatures ranging from - 100°C to boiling point of the respective solvent, preferably the reaction is carried out at - 78°C, to furnish intermediates of general formula (1-24).
  • a suitable base such as, for example, lithium 1 , 1 ,1 ,3,3,3-hexamethyldisilazan-2-ide
  • a suitable solvent system such as, for example, THF
  • Intermediates of general formula (1 -24) can be converted to intermediates of general formula (1 - 14) by reaction with a suitably hydrazine of the general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 0°C.
  • a suitable Broensted acid such as, for example, hydrochloric acid or sulphuric acid, at temperatures ranging from 0°C to boiling point of the respective Broensted acid, preferably the reaction is carried out at 100°C, to furnish intermediates of general formula (1-8).
  • a suitable Broensted acid such as, for example, hydrochloric acid or sulphuric acid
  • any of the substituents A, B, C and D can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Compounds 1-1 1 and 1-25 are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • Intermediates of general formula (1-1 1 ) can be converted to intermediates of general formula (1 - 26) by reaction with a suitable substituted carbamate of the general formula (1-25), such as, for example, 4-nitrophenyl carbamate, in a suitable solvent system, such as, for example, ethanol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 79°C.
  • a suitable substituted carbamate of the general formula (1-25) such as, for example, 4-nitrophenyl carbamate
  • a suitable solvent system such as, for example, ethanol
  • Scheme 6 Route for the preparation of compounds of formula (I), wherein R ⁇ R 2 , A, B, C, D, n , m, V, W, Y and Z have the meaning as given for general formula (I), supra.
  • X 2 represents a leaving group such as for example a CI, Br or I atom or an aryl sulfonate such as for example p-toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • any of the substituents R ⁇ R 2 , A, B, C, D, V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • palladium catalysts can be used: allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2-yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di ⁇ -acetato)bis[o-(di-o- tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6- trimethylphenyl)imi
  • L 2 represents a group such as, for example, a H, CI or Br atom or an nitro group.
  • interconversion of any of the substituents R ⁇ R 2 , A, B, C, D, V, W, Y and Z can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • R 5 represents a leaving group such as for example an aryl sulfonate such as for example p- toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • aryl sulfonate such as for example p- toluene sulfonate
  • alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • L 3 and L 4 represent a H atom or an substituted alkyl group. L 3 and L 4 can form a ring system.
  • PG represents an amine protecting group as for example an acetyl group or a tert- butyloxycarbonyl group.
  • interconversion of any of the substituents R ⁇ R 2 , V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted dihydrofuran-2,5-dione of general formula (1 -12), such as, for example, 3- methyldihydrofuran-2,5-dione (1 -22), can be reacted with a suitable substituted hydrazine of general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, acetonitrile, at temperatures ranging from 0°C to boiling point of the respective solvent, preferably the reaction is carried out at 90°C, to furnish intermediates of general formula (1 -30) and side product (1 -29).
  • a suitable solvent system such as, for example, acetonitrile
  • Intermediates of general formula (1 -30) can be converted to intermediates of general formula (1 - 31 ) by reaction with a suitably acid anhydride, such as, for example, trifluoromethane sulfonic anhydride, in the presence of a suitable base, such as, for example, triethylamine, in a suitable solvent system, such as, for example, acetonitrile, in a temperature range from - 78°C to the boiling point of the respective solvent, preferably the reaction is carried out at -20°C.
  • a suitably acid anhydride such as, for example, trifluoromethane sulfonic anhydride
  • a suitable base such as, for example, triethylamine
  • a suitable solvent system such as, for example, acetonitrile
  • Intermediates of general formula (1-31 ) can be reacted with a suitable boronic acid derivative of the general formula (1-32), such as, for example, ⁇ 4-[(tert-butoxycarbonyl)amino]phenyl ⁇ boronic acid, in the presence of a suitable base, such as, for example sodium carbonate, and a suitable palladium catalyst, such as for example tetrakis(triphenylphosphine)palladium (0), in a suitable solvent system, such as, for example, 1 ,4-dioxane and water, in a temperature range from room temperature to the boiling point of the respective solvent, preferably the reaction is carried out at at 80°C to furnish compounds of formula (1-8).
  • a suitable boronic acid derivative of the general formula (1-32) such as, for example, ⁇ 4-[(tert-butoxycarbonyl)amino]phenyl ⁇ boronic acid
  • a suitable base such as, for example sodium carbonate
  • a suitable palladium catalyst
  • palladium catalysts can be used: allylpalladium chloride dimmer, dichlorobis(benzonitrile)palladium (II), palladium (II) acetate, palladium (II) chloride, bis(dibenzylideneacetone)-palladium(0), tris(dibenzylideneacetone)dipalladium (0), chloro(2'-amino-1 ,1 '-biphenyl-2-yl)palladium(ll) dimer, (2'-amino-1 ,1 '-biphenyl-2-yl)methanesulfonatopalladium(ll) dimer, trans-di ⁇ -acetato)bis[o-(di-o- tolylphosphino)benzyl]dipalladium(ll) [cataCXium® C], allylchloro[1 ,3-bis(2,4,6- trimethylphenyl)imidazol-2
  • phosphine dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'- diisopropoxybiphenyl-2-yl)phosphine, 2'-(dicyclohexylphosphino)-N,N-dimethyl-biphenyl-2- amine, 2'-(di-tert-butylphosphino)-N,N-dimethylbiphenyl-2-amine, 2'-(di-phenylphosphino)- N,N,N',N'-tetramethylbiphenyl-2,6-diamine, di-tert-butyl(2',4',6'-tricyclohexyl-3,6- dimethoxybiphenyl-2-yl)phosphine, bis[3,5-bis(trifluoromethyl)phe-nyl] (2
  • X 1 represents a leaving group such as for example a CI, Br or I, or an aryl sulfonate such as for example p-toluene sulfonate, or a alkyl sulfonate such as for example methane sulfonate or trifluoromethane sulfonate (triflate group).
  • interconversion of any of the substituents R ⁇ R 2 , V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Compounds 1-33 and 1-35 are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • Intermediates of general formula (1-6) can be converted to intermediates of general formula (1- 34) by reaction with a suitably substituted hydrazine of the general formula (1-33), such as, for example, hydrazine hydrate (1 :1 ), in a suitable solvent system, such as, for example, propan-1- ol, in a temperature range from 0°C to the boiling point of the respective solvent, preferably the reaction is carried out at 100°C.
  • a suitably substituted hydrazine of the general formula (1-33) such as, for example, hydrazine hydrate (1 :1 )
  • a suitable solvent system such as, for example, propan-1- ol
  • Intermediates of general formula (1 -34) are treated with an intermediate of general formula (1- 35), such as, for example, ethyl trifluoromethanesulfonate, in the presence of a suitable base, such as for example, sodium hydride, in the presence of a suitable phase transfere catalyst, such as for example, N,N,N-tributylbutan-1-aminium iodide in a suitable solvent system, such as, for example, DMF, at a temperature between 0°C and the boiling point of the respective solvent, preferably the reaction is carried out at room temperature to form the desired intermediate of general formula(1 -8).
  • a suitable base such as for example, sodium hydride
  • a suitable phase transfere catalyst such as for example, N,N,N-tributylbutan-1-aminium iodide
  • a suitable solvent system such as, for example, DMF
  • PG represents an amine protecting group as for example an acetyl group.
  • interconversion of any of the substituents V, W, Y and Z can be achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • a suitably substituted aromatic amine of general formula (1-1 ), such as, for example, N- phenylacetamide, can be reacted with a suitable substituted acid chloride (1 -36), such as, for example, propanoyl chloride, in the presence of a Lewis acid, such as, for example, aluminium trichloride, in a suitable solvent system, such as, for example, dichloromethane, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at 0°C, to furnish intermediates of general formula (1 -37).
  • a suitable substituted acid chloride (1 -36 such as, for example, propanoyl chloride
  • a Lewis acid such as, for example, aluminium trichloride
  • solvent system such as, for example, dichloromethane
  • Intermediates of general formula (1 -37) can be converted to intermediates of general formula (1 - 39) by reaction with a suitably glyoxylic acid derivative of the general formula (1 -38), such as, for example, glyoxylic acid monohydrate, in the presence of a suitable base, such as, for example sodium hydroxide, in the presence of a suitable phase transfer catalyst, such as, for example benzyltriethylammonium chloride, in a suitable solvent system, such as, for example, methanol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitably glyoxylic acid derivative of the general formula (1 -38) such as, for example, glyoxylic acid monohydrate
  • a suitable base such as, for example sodium hydroxide
  • a suitable phase transfer catalyst such as, for example benzyltriethylammonium chloride
  • solvent system such as, for example, methanol
  • Intermediates of general formula (1-39) can be reacted with a suitable Broensted acid, such as, for example, hydrochloric acid, in a suitable solvent system, such as, for example, methanol, at temperatures ranging from - 20°C to boiling point of the respective Broensted acid, preferably the reaction is carried out at 0°C, to furnish intermediates of general formula (1 -40).
  • a suitable Broensted acid such as, for example, hydrochloric acid
  • a suitable solvent system such as, for example, methanol
  • Intermediates of general formula (1-40) can be converted to intermediates of general formula (1 - 42) by reaction with a suitably sulfonyl chloride of the general formula (1-41 ), such as, for example, methanesulfonyl chloride, in the presence of a suitable base, such as, for example triethylamine, in a suitable solvent system, such as, for example, trichloromethane, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 0°C.
  • a suitably sulfonyl chloride of the general formula (1-41 ) such as, for example, methanesulfonyl chloride
  • a suitable base such as, for example triethylamine
  • a suitable solvent system such as, for example, trichloromethane
  • Intermediates of general formula (1 -43) can be converted to intermediates of general formula (1 - 44) by reaction with a suitable base, such as, for example sodium hydroxide, in a suitable solvent system, such as, for example, ethanol, in a temperature range from 0°C to the boiling point of the respective solvent, preferably the reaction is carried out at room temperature.
  • a suitable base such as, for example sodium hydroxide
  • a suitable solvent system such as, for example, ethanol
  • PG represents an amine protecting group as for example an acetyl group.
  • interconversion of any of the substituents R ⁇ V, W, Y and Z can be achieved before and/or after the exemplified transformations.
  • modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art.
  • transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999). Specific examples are described in the subsequent paragraphs.
  • Compounds 1-7 is either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the subsequent paragraphs.
  • Intermediates of general formula (1 -44) can be hydrogenated at a suitable hydrogen pressure, such as, for example, 80 atmospheres, in the presence of a chiral catalyst, such as, for example, Ru(OAc)2(S-BINAP), in a suitable solvent system, such as, for example, methanol, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at room temperature, to furnish intermediates of general formula (1-45).
  • a suitable hydrogen pressure such as, for example, 80 atmospheres
  • a chiral catalyst such as, for example, Ru(OAc)2(S-BINAP
  • solvent system such as, for example, methanol
  • Intermediates of general formula (1 -45) can be converted to intermediates of general formula (1 - 46) by reaction with a suitably hydrazine of the general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 80°C.
  • a suitably hydrazine of the general formula (1 -7) such as, for example, methylhydrazine
  • a suitable solvent system such as, for example, propan-1-ol
  • Intermediates of general formula (1-44) can be hydrogenated at a suitable hydrogen pressure, such as, for example, 80 atmospheres, in the presence of a chiral catalyst, such as, for example, Ru(OAc)2(S-BINAP), in a suitable solvent system, such as, for example, methanol, at temperatures ranging from - 20°C to boiling point of the respective solvent, preferably the reaction is carried out at room temperature, to furnish intermediates of general formula (1 -47).
  • a suitable hydrogen pressure such as, for example, 80 atmospheres
  • a chiral catalyst such as, for example, Ru(OAc)2(S-BINAP
  • solvent system such as, for example, methanol
  • Intermediates of general formula (1 -47) can be converted to intermediates of general formula (1 - 48) by reaction with a suitably hydrazine of the general formula (1 -7), such as, for example, methylhydrazine, in a suitable solvent system, such as, for example, propan-1-ol, in a temperature range from - 20°C to the boiling point of the respective solvent, preferably the reaction is carried out at 80°C.
  • a suitably hydrazine of the general formula (1 -7) such as, for example, methylhydrazine
  • a suitable solvent system such as, for example, propan-1-ol
  • Scheme 12 Route for the preparation of compounds of formula (1-8), wherein R ⁇ R 2 , V, W, Y and Z have the meaning as given for general formula (I), supra.
  • X 3 represents a halogen atom such as for example a CI or Br atom.

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Abstract

L'invention concerne des composés de formule (I) qui sont des inhibiteurs de nicotinamide phosphoribosyltransférase (NAMPT) et leur utilisation pour le traitement de maladies et/ou de troubles hyperprolifératifs sensibles à l'induction de la mort cellulaire.
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WO2019149637A1 (fr) * 2018-01-31 2019-08-08 Bayer Aktiengesellschaft Conjugués anticorps-médicament (adc) avec des inhibiteurs de nampt
WO2021013693A1 (fr) * 2019-07-23 2021-01-28 Bayer Pharma Aktiengesellschaft Conjugués anticorps-médicament (adc) avec des inhibiteurs de nampt
WO2022216961A1 (fr) * 2021-04-07 2022-10-13 The Board Of Trustees Of The University Of Illinois Activateurs de la nampt pour le traitement de troubles métaboliques et neurologiques
CN119431250A (zh) * 2024-11-06 2025-02-14 辽宁孚音生物科技有限公司 一种匹莫苯丹中间体及其合成方法
CN119431326A (zh) * 2024-11-06 2025-02-14 辽宁孚音生物科技有限公司 一种匹莫苯丹的合成方法

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WO2021013693A1 (fr) * 2019-07-23 2021-01-28 Bayer Pharma Aktiengesellschaft Conjugués anticorps-médicament (adc) avec des inhibiteurs de nampt
WO2022216961A1 (fr) * 2021-04-07 2022-10-13 The Board Of Trustees Of The University Of Illinois Activateurs de la nampt pour le traitement de troubles métaboliques et neurologiques
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