WO2013072882A1 - 2 -amino- 1, 8 -naphthyridine-3 -carboxamide derivatives as antimicrobial agents - Google Patents

2 -amino- 1, 8 -naphthyridine-3 -carboxamide derivatives as antimicrobial agents Download PDF

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WO2013072882A1
WO2013072882A1 PCT/IB2012/056487 IB2012056487W WO2013072882A1 WO 2013072882 A1 WO2013072882 A1 WO 2013072882A1 IB 2012056487 W IB2012056487 W IB 2012056487W WO 2013072882 A1 WO2013072882 A1 WO 2013072882A1
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amino
yield
formula
mmol
naphthyridine
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PCT/IB2012/056487
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French (fr)
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Daniel Bur
Christian Hubschwerlen
Roland Lange
Christine Sigwalt
Jean-Luc Specklin
Jean-Philippe Surivet
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Actelion Pharmaceuticals Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14Ortho-condensed systems

Definitions

  • the present invention concerns novel 2-amino-l,8-naphthyridine-3-carboxamide derivatives, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections).
  • infections e.g. bacterial infections
  • These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram-positive and Gram-negative aerobic and anaerobic bacteria.
  • Enter obacteriacea are cephalosporin and quinolone resistant and strains resistant to carbapenems have been recently reported;
  • - P. aeruginosa are ⁇ -lactam and quinolone resistant.
  • Pyridochromanones (A) have been reported to be DNA ligase inhibitors and to display antibacterial activity (Broetz-Oesterhelt et al, J. Biol. Chem. (2003), 278(41), 39435-39442).
  • R 1 represents (C r C 4 )alkyl, (C r C 3 )haloalkyl, -CH(Me)NHS0 2 R a or halogen;
  • R represents H, halogen, (CrC 4 )alkyl, cyclopropyl, (C 2 -C 4 )alkenyl, arylmethyl or heteorarylmethyl; or
  • R 3 represents hydrogen, halogen, hydroxy, -NHR b , 2-(hydroxy)ethoxy, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, co-hydroxy(CrC 3 )alkyl, methoxymethyl or 2-carboxy-azetidin-l-yl; or R 2 and R 3 together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R represents hydrogen or hydroxy
  • B represents CH 2 CH 2 , CH 2 , CH(OH), O, S or a bond;
  • D represents CH(CH 2 OH);
  • R a represents (Ci-C 4 )alkyl, aryl or heteroaryl;
  • R b represents hydrogen, (CrC 4 )alkyl, (C2-C 4 )alkenyl, ⁇ »-hydroxy(C 2 -C 3 )alkyl or -CH 2 CH 2 CH(NH 2 )COOH;
  • R c represents hydrogen or methyl
  • R d represents hydrogen or methyl
  • R e represents hydrogen, methyl, hydroxymethyl or hydroxy
  • R d and R e together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R f represents hydrogen, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, (C3-C 4 )alkynyl or -CH 2 R X ;
  • R g represents hydrogen, (CrC 4 )alkyl, aryl, heteroaryl or -CH 2 R y ;
  • R h represents tert-butoxy or furan-2-yl
  • R 1 represents hydroxy or 2-(hydroxy)ethyl
  • R J represents heteroarylmethyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2- (hydroxy)ethyl;
  • R y represents -CH 2 OH, (CrC 4 )alkoxycarbonyl
  • the compounds of formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • alkyl refers to a saturated straight or branched chain alkyl group containing from one to four carbon atoms.
  • Representative examples of alkyl groups include methyl, ethyl, propyl, z ' so-propyl, ft-butyl, z ' so-butyl, sec-butyl and tert-butyl.
  • (C x -C y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms. Preferred are methyl, ethyl, /so-propyl and tert-butyl.
  • alkenyl refers to a straight or branched hydrocarbon chain of 2 to 6 (and preferably 2 to 4) carbon atoms with at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, ethenyl, prop-2-enyl and but-3-enyl.
  • (C 2 -C x )alkenyl (x being an integer) refers to a straight or branched chain alkenyl group containing 2 to x carbon atoms. Most preferred is ethenyl (i.e. vinyl), prop-2-en-l-yl (i.e. allyl) and prop-2-en-2-yl (i.e. /so-propenyl).
  • alkynyl refers to a straight or branched hydrocarbon chain of 2 to 6 (and preferably 3 to 4) carbon atoms with at least one carbon-carbon triple bond.
  • Representative examples of alkynyl groups include, but are not limited to, prop-2-ynyl and but-3-ynyl.
  • (C 2 -C x )alkynyl (x being an integer) refers to a straight or branched chain alkynyl group containing 2 to x carbon atoms. Most preferred is propargyl (i.e. prop-2-yn-l-yl).
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably to fluorine, chlorine or bromine. More preferred is bromine and chlorine.
  • alkoxy refers to a straight or branched chain alkoxy group containing from one to four carbon atoms.
  • (C x -C y )alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (CrC 3 )alkoxy group contains from one to three carbon atoms.
  • Representative examples of alkoxy groups include methoxy, ethoxy, ⁇ -propoxy and /so-propoxy as well as tert-butoxy. Preferred are methoxy, ethoxy and tert-butoxy.
  • haloalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with halogen.
  • (C x -C y )haloalkyl (x and y each being an integer) refers to a haloalkyl group as defined before containing x to y carbon atoms.
  • a (Ci-C3)haloalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with halogen and in particular fluorine.
  • Representative examples of haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.
  • aryl refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring atoms and preferably from five or six to ten carbon ring atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, alkoxy, carboxy, trifluoromethyl and trifluoromethoxy.
  • aryl examples include phenyl, naphthyl, 4-fluoro-phenyl, 4-chloro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-methoxy- phenyl, 4-methyl-phenyl, 4-carboxy-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4-dimethoxy- phenyl, 2,4-dimethyl-phenyl, 2,5-difluoro-phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl.
  • Preferred are those aryl residues exemplified herein.
  • heteroaryl refers to an aryl group as defined herein where one, two or more (preferably one to four, and notably one or two) ring carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl (i.e.
  • heteroaryl also covers bicyclic structures selected from the group consisting of quinolinyl, isoquinolinyl, quinazolinyl, quinoxazinyl, phthalazyl, naphthyridinyl, indolyl, indazolyl benzothiazol-2-yl and benzoxazol-2-yl.
  • heteroaryl group as defined herein may be substituted with one, two or more substituents on its aromatic ring(s), said substituents being from the group consisting of halogen, alkyl, dialkylamino and alkoxy.
  • substituents being from the group consisting of halogen, alkyl, dialkylamino and alkoxy.
  • heteroaryl groups include, but are not limited to pyridinyl, such as pyridin-4-yl, 4-chloropyridin-3-yl or 2-chloropyridin-3-yl, 4-methylthiazol-2- yl, 5-phenylthiazol-2-yl, furan-2-yl, 5-fluorobenzothiazol-2-yl, 6-fluorobenzothiazol-2- yl, phthalazin-l-yl and 5-NN-dimethylaminobenzothiazol-2-yl.
  • arylmethyl refers particularly to benzyl, 3-chlorobenzyl, 2,4-dimethoxybenzyl;
  • heteroarylmethyl refers particularly to thiophen-2-yl-methyl, (6-fluorobenzothiazol- 2-yl)methyl, (4-methylthiazol-2yl)methyl, (pyridin-4-yl)methyl;
  • ro-hydroxy(C 1 -C3)alkyl refers to hydroxymethyl, (2 -hydroxy) ethyl or (3 -hydroxy)propyl.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • room temperature refers to a temperature of 20 to 30°C, and preferably 25°C.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10%) of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • R 1 represents (C r C 4 )alkyl, (C r C 3 )haloalkyl, -CH(Me)NHS0 2 R a or halogen;
  • R 2 represents H, halogen, (CrC 4 )alkyl, cyclopropyl, (C 2 -C 4 )alkenyl, arylmethyl or heteorarylmethyl; or
  • R 3 represents hydrogen, halogen, hydroxy, -NHR b , 2-(hydroxy)ethoxy, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, ro-hydroxy(Ci-C 3 )alkyl, methoxymethyl or 2-carboxy-azetidin-l-yl; or R 2 and R 3 together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R 4 represents hydrogen or hydroxy
  • B represents CH 2 CH 2, CH 2 , CH(OH), O, S or a bond;
  • D represents CH(CH 2 OH);
  • R a represents (Ci-C 4 )alkyl, aryl or heteroaryl
  • R b represents hydrogen, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, ⁇ »-hydroxy(C 2 -C 3 )alkyl or -CH 2 CH 2 CH(NH 2 )COOH;
  • R c represents hydrogen or methyl
  • R d represents hydrogen or methyl
  • R e represents hydrogen, methyl, hydroxymethyl or hydroxy
  • R d and R e together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R f represents hydrogen, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, (C 3 -C 4 )alkynyl or -CH 2 R X ;
  • R g represents hydrogen, (CrC 4 )alkyl, aryl, heteroaryl or -CH 2 R y ;
  • R h represents tert-butoxy or furan-2-yl
  • R 1 represents hydroxy or 2-(hydroxy)ethyl
  • R J represents heteroarylmethyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2- (hydroxy)ethyl;
  • R y represents -CH 2 OH, (Ci-C 4 )alkoxycarbonyl
  • aryl represents phenyl unsubstituted or substituted with one or two residues selected from halogen, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, carboxy, trifluoromethyl or trifluoromethoxy; and
  • heteroaryl represents pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl (i.e.
  • any heteroaryl group may be unsubstituted or substituted with one or two substituents selected from halogen, (Ci-C 4 )alkyl, (Ci-C 4 )dialkylamino or (Ci-C 4 )alkoxy; and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I.
  • residue R 1 represents (CrC 4 )alkyl, (C r C 3 )haloalkyl, halogen, or -CH(Me)NHS0 2 R a ; and R a represents methyl, 2-chloro- pyridin-3-yl, 4-chloro-pyridin-3-yl, 4-methoxy-phenyl, or thiophen-2-yl.
  • residue R 1 represents (CrC 4 )alkyl, (Cp C 3 )haloalkyl, or halogen.
  • R 1 represents halogen, particularly CI, trifluoromethyl, t-butyl, methyl, /so-propyl.
  • R 1 represents CI, trifluoromethyl and t-butyl.
  • R 1 represents CI and trifluoromethyl.
  • residue R represents H, halogen, -C 4 )alkyl, cyclopropyl, enzyl or pyridin-4-yl-methyl, or R 2 and R 3
  • residue R represents H, halogen, particularly Br, methyl, ethyl, cyclopropyl, vinyl, allyl, /so-propenyl, benzyl, pyridin-4-yl- methyl, or R 2 and R 3 together represent -CH 2 CH 2 CH 2 CH 2 -.
  • residue R represents Br, methyl, cyclopropyl, vinyl, ethyl or benzyl.
  • residue R is Br.
  • R 1 and R 2 together represent #-CR c (Me)-A-CH 2 -CH 2 -*; "#" representing the point of attachment of R 1 and "*” representing the point of attachment of R 2 ;
  • R c represents methyl
  • R f represents hydrogen, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, (C3-C 4 )alkynyl or -CH 2 R X ;
  • R ⁇ represents hydrogen, (CrC 4 )alkyl, -CH 2 R y , phthalazin-l-yl or 4-carboxy-phen-l-yl;
  • R h represents tert-butoxy or furan-2-yl;
  • R 1 represents hydroxy or 2-(hydroxy)ethyl
  • R J represents (6-fluorobenzo[d]thiazol-2-yl)methyl, (4-methylthiazol-2-yl)methyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2-(hydroxy)ethyl;
  • R y represents -CH 2 OH or -COOEt.
  • the residues R 1 and R 2 together represent #-CR d R e -CH 2 -B-CH 2 -*; "#" representing the point of
  • B represents CH 2 CH 2 , CH 2 , CH(OH), O, S or a bond
  • R d represents hydrogen or methyl
  • R e represents hydrogen, methyl, hydroxymethyl or hydroxy
  • R d and R e together represent -CH 2 CH 2 CH 2 CH 2 -. xv) According to one embodiment of xii), the residues
  • R is H, allyl, cyclopropylmethyl, propargyl, 5-phenyl-thiazol-2-yl-methyl, thiazol-2-yl-methyl.
  • xviii) According to another preferred embodiment of xvi) or xvii) R is H, allyl and propargyl, particularly allyl.
  • residues R and R together represent #-CR d R e -CH 2 -B-CH 2 -*, B is CH(OH), CH 2 , CH 2 CH 2 , O or S.
  • B preferably is CH 2 .
  • R represents hydrogen, CI, hydroxy, -NHR b , 2-(hydroxy)ethoxy, methyl, ethyl, vinyl, hydroxymethyl, (2-hydroxy)ethyl, (3-hydroxy)propyl, methoxymethyl or 2-carboxy-azetidin-l-yl; wherein R b represents hydrogen, methyl, allyl, (2-hydroxy)ethyl, (3-hydroxy)propyl or -CH 2 CH 2 CH(NH 2 )COOH.
  • R 3 represents hydrogen, methyl, vinyl, ethyl or CI.
  • residue R 4 is H or OH.
  • R 4 preferably is H and when R 4 is OH, R 3 must be H.
  • R 1 represents methyl, /so-propyl, t-butyl, trifluoromethyl, CI, or -CH(Me)NHS0 2 R a ;
  • R represents H, Br, methyl, ethyl, cyclopropyl, (C 2 -C 4 )alkenyl vinyl, allyl, isopropenyl, benzyl, or pyridin-4-yl-methyl; or
  • R 3 represents hydrogen, CI, hydroxy, -NHR b , 2-(hydroxy)ethoxy, methyl, ethyl, vinyl, hydroxymethyl, (2-hydroxy)ethyl, (3-hydroxy)propyl, methoxymethyl or 2-carboxy- azetidin-l-yl; or
  • R 2 and R 3 together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R 4 represents hydrogen or hydroxy
  • B represents CH 2 CH 2, CH 2 , CH(OH), O, S or a bond;
  • D represents CH(CH 2 OH);
  • R a represents methyl, 2-chloro-pyridin-3-yl, 4-chloro-pyridin-3-yl, 4-methoxy-phenyl, or thiophen-2-yl;
  • R b represents hydrogen, methyl, allyl, (2-hydroxy)ethyl, (3-hydroxy)propyl or
  • R c represents methyl
  • R d represents hydrogen or methyl
  • R e represents hydrogen, methyl, hydroxymethyl or hydroxy
  • R d and R e together represent -CH 2 CH 2 CH 2 CH 2 -;
  • R f represents hydrogen, methyl, allyl, prop-2-ynyl, or -CH 2 R X ;
  • R ⁇ represents hydrogen, methyl, -C3 ⁇ 4R y , phthalazin-l-yl or 4-carboxy-phen-l-yl;
  • R h represents tert-butoxy or furan-2-yl
  • R 1 represents hydroxy or 2-(hydroxy)ethyl
  • R J represents (6-fluorobenzo[d]thiazol-2-yl)methyl, (4-methylthiazol-2-yl)methyl,
  • R y represents -CH 2 OH or -COOEt
  • the invention moreover relates to any individual compound of formula I selected from the compounds listed in ix), x), xi) and the examples, as well as to the salt (in particular pharmaceutically acceptable salt) thereof.
  • the compounds of formula I according to the invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections. They can be used in the treatment of Gram positive infections (notably those caused by Staphylococcus aureus including MRSA, Streptococcus pneumonia, enterococci and streptococci) and Gram negative infections (notably those caused by Haemophilus influenzae, Moraxella catarrhalis).
  • Gram positive infections notably those caused by Staphylococcus aureus including MRSA, Streptococcus pneumonia, enterococci and streptococci
  • Gram negative infections notably those caused by Haemophilus influenzae, Moraxella catarrhalis.
  • the compounds are suitable for the treatment of community acquired pneumonias (including hospital acquired pneumonia), skin and skin structure infections (whether complicated or uncomplicated), blood and tissue infections, including bacteremia, endocarditis and osteomyelitis, foreign body infections, meningitis, gastrointestinal infections including those caused by Clostridium difficile or Helicobacter pylory infections, topical infections, acne vulgaris, infected atopic dermatitis and opthalmological infections.
  • community acquired pneumonias including hospital acquired pneumonia
  • skin and skin structure infections whether complicated or uncomplicated
  • blood and tissue infections including bacteremia, endocarditis and osteomyelitis, foreign body infections, meningitis, gastrointestinal infections including those caused by Clostridium difficile or Helicobacter pylory infections, topical infections, acne vulgaris, infected atopic dermatitis and opthalmological infections.
  • the compounds of formula I according to one of embodiments i) to xxvii), or the pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection.
  • bacterial infections can also be treated using compounds of formula I according to one of embodiments 1) to xxvii) (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • the present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I according to one of embodiments i) to xxvii).
  • a pharmaceutical composition according to the present invention contains at least one compound of formula I according to one of embodiments i) to xxvii) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics especially those known to address DNA topology such as quinolones (e.g. ciprofloxacin or moxifloxacin) and inhibitor of RNA polymerase such as rifampicin.
  • additional known antibiotics especially those known to address DNA topology such as quinolones (e.g. ciprofloxacin or moxifloxacin) and inhibitor of RNA polymerase such as rifampicin.
  • the compounds of formula I according to one of embodiments i) to xxvii) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the compounds of formula I according to one of embodiments i) to xxvii) may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments or to make a room or an area aseptic.
  • the compounds of formula I could be contained in a solution or in a spray formulation.
  • IPr l 3-bis(2,6-diisopropylphenyl)-l,3-dihydro-2H-imidazol-2-ylidene
  • JosiPhos ligands (R)-l-[(SP)-2-(di-ierf- butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine or (R)-l-[(SP)-2-(di-ierf- butylphosphino)ferrocenyl] ethyl diphenylphosphine or
  • PEPPSITM-IPr [l,3-bis(2,6-diisopropylphenyl)imidazol-
  • a ring closure reaction is performed starting from the required 2-amino-3-formylpyridine derivatives (compounds of formula II) using a slight excess of cyanoacetamide in presence of an organic base such as TMG, in a protic solvent such as EtOH at a temperature ranging between rt and reflux, preferentially at reflux.
  • the benzyl carbamates are deprotected by hydrogenolysis over a noble metal catalyst (e.g. Pd/C or Pd(OH)2/C).
  • the Boc group is removed under acidic conditions such as HC1 in an organic solvent such as MeOH or dioxane, or TFA neat or diluted in a solvent such DCM.
  • the Alloc group is removed by the action of tetrakis(triphenylphosphine)palladium(0) in presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF.
  • the FMOC group is removed under mild basic conditions such as piperidine in DMF.
  • the N-acetyl protecting group is removed under basic conditions such as Na 2 C0 3 , LiOH or NaOH in aq. MeOH or THF, or under acidic conditions such as aq. HC1 in THF.
  • the N-benzyl protected amines are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd(OH) 2 ).
  • the 2,4-dimethoxybenzyl protecting group can be removed by reaction with TFA. Further general methods to remove amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3 rd Ed 1999, 494-653; T.W. Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York).
  • the silyl ether groups are removed either using fluoride anion sources such as TBAF in THF between 0°C and 40°C or HF in MeCN or water between 0°C and 40°C or using acidic conditions such as AcOH in aq. THF or HC1 in MeOH.
  • fluoride anion sources such as TBAF in THF between 0°C and 40°C or HF in MeCN or water between 0°C and 40°C or using acidic conditions such as AcOH in aq. THF or HC1 in MeOH.
  • Further methods to remove the TBDMS and TBDPS groups are given in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3 Ed 1999, 133-139 and 142-143 respectively (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Further general methods to remove alcohol protecting groups are described in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic
  • amino acids protected as NHBoc and tBu ester are sequentially treated with 4M HC1 in dioxane at rt and, after removal of the dioxane, with TF A/water (1 : 1) at 60°C for 2h.
  • a carboxylic acid is reacted with the required amine in presence of an activating agent such as DCC, EDC, HOBT, HOAT, T3P, HATU or di-(N-succinimidyl)-carbonate, in a dry aprotic solvent such as DCM, MeCN or DMF between -20°C and +60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York 1991, vol. 6, p. 381).
  • the carboxylic acid can first be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent such as DCM between -20°C and +60°C. Further activating agents can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2 nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999; Section nitriles, carboxylic acids and derivatives, p. 1941-1949.
  • a ketone or an aldehyde is reduced with a boron or aluminium hydride reducing agent such as LiBH 4 , NaBH 4 or LAH in a solvent such as THF between -20°C and +40°C.
  • a boron or aluminium hydride reducing agent such as LiBH 4 , NaBH 4 or LAH
  • a solvent such as THF between -20°C and +40°C.
  • a primary allylic or benzylic alcohol dissolved in an organic solvent such as DCM or THF is oxidized into the corresponding aldehyde with Mn0 2 . Further methods can be found in
  • carboxy protecting groups are alkyl, e.g. methyl, ethyl or tBu, haloalkyl, e.g. trichloroethyl, arylmethyl, e.g. benzyl or para nitrobenzyl, alkenyl, e.g. allyl, trialkylsilyl, e.g. trimethylsilyl, TBDMS or di-tBumethylsilyl, alkylthioalkyl, e.g. methylthiomethyl (MTM), alkoxyalkoxyalkyl, e.g. methoxyethoxymethyl (MEM), arylalkoxyalkyl, e.g.
  • alkyl e.g. methyl, ethyl or tBu
  • haloalkyl e.g. trichloroethyl
  • arylmethyl e.g. benzyl or para nitrobenzyl
  • alkenyl e
  • methyl and ethyl esters are deprotected either by saponification with an alkali hydroxide such as NaOH, LiOH or KOH or by hydrolysis in con. aq, HC1 ⁇ e.g. 6N), benzyl ester by hydrogeno lysis over a noble metal catalyst such as Pd/C, and tBu ester by treatment with TFA (neat or diluted in an organic solvent such as DCM) or a solution of HC1 in an organic solvent such as dioxane.
  • an alkali hydroxide such as NaOH, LiOH or KOH
  • benzyl ester by hydrogeno lysis over a noble metal catalyst such as Pd/C
  • tBu ester by treatment with TFA (neat or diluted in an organic solvent such as DCM) or a solution of HC1 in an organic solvent such as dioxane.
  • a palladium catalyst between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • a palladium catalyst between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh 3 ) 4 .
  • These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc) 2 or Pd 2 (dba) 3 and a ligand such as trialkylphosphines (e.g. PCy 3 or P(tBu) 3 ), dialkylphosphinobiphenyls (e.g.
  • reaction technique . 10 . (reductive . animation): .
  • the reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgS0 4 or Na 2 S0 4 ).
  • solvent is typically toluene, Hex, THF, NMP, DCM or DCE or a mixture of solvents such as DCE/MeOH.
  • the reaction can be catalyzed by traces or a stoichiometric amount of acid (usually AcOH or TsOH).
  • the intermediate imine is reduced with a suitable reducing agent (e.g.
  • reaction is carried out between -10° and +110°C, preferably between 0°C and 60°C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in the presence of a picoline-borane complex ⁇ Tetrahedron (2004), 60, 7899-7906).
  • Amines are usually protected as carbamates such as Alloc, Cbz, Boc or FMOC. They are obtained by reaction of the amine with allyl or benzyl chloro formate, di tert-butyl dicarbonate or FMOC-C1 in presence of a base such as NaOH, TEA, DMAP or imidazole. Amines can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as Na 2 C0 3 or TEA. Alternatively, N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde (see reaction technique 10).
  • Amines can furthermore be protected as sulphonamides by their reaction with 2-nitro- or 4-nitro-phenylsulphonyl chloride in a solvent such as DCM or THF in presence of a base such as TEA or aq. NaOH between -10°C and +40°C.
  • a base such as TEA or aq. NaOH between -10°C and +40°C.
  • Ketol-enol derivatives are prepared from the corresponding cyclic ketone by reaction with an alkyl formate (e.g. ethyl formate) in presence of a base such as NaH or sodium alcoholate in a solvent such as THF or ether.
  • alkyl formate e.g. ethyl formate
  • keto-enol derivatives can be prepared using N,N-dimethylformamide dimethyl acetal followed by acidic hydrolysis of the intermediate enamine.
  • the ketol-ester derivatives are prepared from the corresponding cyclic ketones by reaction with an alkyl chloroformate using the same conditions as when using an alkyl formate.
  • a ketal/acetonide is converted into its corresponding diol and ketone under acidic conditions using either aq. HC1 in MeOH, AcOH in aq. THF at a temperature ranging between rt and reflux, or by using an acidic resin such as Amberlite IR120H or DOWEX 50W8 in a water-solvent mixture such as MeOH/water, dioxane/water or THF/water.
  • the aromatic halide (typically a bromide) is reacted with the required organozinc reagent in the presence of a palladium catalyst between 20 °C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • a palladium catalyst between 20 °C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • a palladium catalyst are triarylphosphine palladium complexes such as Pd(PPh 3 ) 4 .
  • These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc) 2 or Pd 2 (dba) 3 and a ligand such as trialkylphosphines (e.g.
  • the aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K 2 C0 3 , Cs 2 C0 3 , K 3 P0 4 , tBuONa or tBuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%).
  • a palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh ) 4 .
  • catalysts can also be prepared in situ from a common palladium source such as Pd(OAc) 2 or Pd 2 (dba) 3 and a ligand such as trialkylphosphines (e.g. PCy 3 or P(tBu) 3 ), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos).
  • a commercially available precatalyst based on palladacycle e.g. SK-CC01-A
  • N-heterocyclic carbene complexes e.g. PEPPSITM-IPr
  • reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Chem. Rev. (1995), 95, 2457-2483, Synthesis (2004), 2419-2440, Aldrichimica Acta (2006), 39, 17-24 and 97-111, Acc. Chem. Res. (2008), 41, 1555-1564, and references cited therein.
  • the phenol is reacted with a sulfonyl chloride derivative such as MsCl, TfCl or TsCl in presence of a base such as TEA in a dry aprotic solvent such as Pyr, THF or DCM between -30°C and +50°C.
  • a base such as TEA
  • a dry aprotic solvent such as Pyr, THF or DCM between -30°C and +50°C.
  • Tf 2 0 or Ms 2 0 can also be used.
  • the aromatic halide is reacted with the required amine in the presence of a palladium catalyst and a base such as K 2 C0 3; Cs 2 C0 3 , K 3 P0 4; tBuONa or tBuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • a palladium catalyst and a base such as K 2 C0 3; Cs 2 C0 3 , K 3 P0 4; tBuONa or tBuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF.
  • a palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh ) 4 .
  • These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc) 2 or Pd 2 (dba) 3 and a ligand such
  • PCy 3 or P(tBu) 3 dialkylphosphinobiphenyls (e.g. X-Phos or BrettPhos), chelating diphosphines (e.g. ⁇ , XantPhos) or ferrocenylphosphines (e.g. Q-phos).
  • dialkylphosphinobiphenyls e.g. X-Phos or BrettPhos
  • chelating diphosphines e.g. ⁇ , XantPhos
  • ferrocenylphosphines e.g. Q-phos
  • a commercially available precatalyst based on palladacycle e.g. SK-CC02-A
  • N-heterocyclic carbene complexes e.g. PEPPSITM-IPr
  • the reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in J. Org. Chem.
  • the chloride derivative is reacted with an amine in a solvent such as THF, MeCN, DMF or NMP between 0° and 120°C.
  • a solvent such as THF, MeCN, DMF or NMP between 0° and 120°C.
  • the alcohols are protected as silyl ether (usually TBDMS or TBDPS).
  • the alcohol is reacted with the required silyl chloride reagent (TBDMSCl or TBDPSCl) in presence of a base such as imidazole or TEA in a solvent such as DCM or DMF between 10°C and 40°C.
  • a base such as imidazole or TEA
  • a solvent such as DCM or DMF between 10°C and 40°C.
  • the phenol derivative is reacted with POCl 3 either neat or in a solvent such as DCM, MeCN or toluene between 20°C and 120°C, or by reaction of the corresponding alcohol derivatives with PBr 3 in a solvent such as DCM, THF or toluene between 20°C and 120°C. Further variations of this transformation can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2 nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999; Section halides, p. 703.
  • Oximes and hydrazones are prepared by reaction of the corresponding ketones with respectively hydroxylamine or hydrazine derivatives in a solvent such as pyridine, NMP or aq. EtOH at a temperature ranging between rt and reflux.
  • a solvent such as pyridine, NMP or aq. EtOH at a temperature ranging between rt and reflux.
  • a base such as DIPEA or NaOAc can be added.
  • Molecular sieves can also be added to top the water that is formed.
  • the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
  • the compounds of formula I can be manufactured in accordance with the present invention by a) reacting the compounds of formula II
  • R 1 and R 2 are as defined in formula I
  • R 3a represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (Ci-C 4 )alkyl, (C 2 -C 4 )alkenyl, ⁇ »-hydroxy(C 2 -C3)alkyl, methoxymethyl or acetoxymethyl, with cyanoacetamide following general reaction technique 1 followed if required by a deprotection step using one of the general reaction techniques 2-4; or b) hydrolyzing the compounds of formula III
  • R 1 and R 2 are as defined in formula I and R 4a represents OH or halogen such a chlorine or bromine in presence of aq. TFA between 80°C and 200°C under microwave irradiation: or c) reacting the compounds of formula IV
  • R 1 and R2 are as defined in formula I, with the provisio that R 1 does not represent halogen, and X represents halogen such as chlorine or bromine, either with the compounds of formula V
  • R b is as defined in formula I or with 2-carboxy-azetidine, followed if required by a deprotection step using general reaction technique 3; or d) deprotecting the compounds of formula VI
  • R is as defined in formula I using general reaction technique 21; or reacting the compounds of formula VII with the compounds of formula IX
  • R g is as defined in formula I using general reaction technique 21; or reacting the compound of formula X
  • R a represents hydrogen or halogen with the compounds of formula XI
  • R and R are as defined in formula I and W represents (CrC 4 )alkyl with HBr in AcOH.
  • the compounds of formula I thus obtained may be, if desired, converted into their salts, and notably into their pharmaceutically acceptable salts.
  • the diastereomers can be separated using methods known to one skilled in the art, e.g. by HPLC over a chiral stationary phase such as a Regis Whelk-01(R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ) or AD-H (5 ⁇ ) column.
  • a chiral stationary phase such as a Regis Whelk-01(R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ) or AD-H (5 ⁇ ) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as TEA or diethylamine) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min.
  • EtOH eluent A
  • Hex eluent B
  • the mixtures of diasteromers may also be separated by an appropriate combination of silica gel chromatography, HPLC and crystallization techniques.
  • R 1 and R 2 are as defined in formula I
  • R 3a represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, ⁇ »-hydroxy(C 2 -C3)alkyl, methoxymethyl or acetoxymethyl
  • R 3b represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (Ci-C 4 )alkyl, (C 2 -C 4 )alkenyl, ⁇ »-hydroxy(C 2 -C3)alkyl, methoxymethyl or alkoxycarbonyl
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the esters of formula 1-1 are reduced with a hydride reagent such as LAH (Scheme 1) using general reaction technique 6 and the resulting alcohol derivatives are oxidized into the corresponding aldehydes using general reaction technique 7.
  • a hydride reagent such as LAH (Scheme 1)
  • the compounds of formula 1-1 are transformed into the corresponding derivatives of formula 1-2 wherein R 3a is acetoxymethyl upon reduction and workup.
  • the acetoxymethyl group is transformed into the corresponding hydroxymethyl group during the final cyclization step leading to the formation of the naphthyridine ring.
  • R u and R represent independently from each other benzyl or alkyl such as methyl or ethyl.
  • the ketone derivatives of formula II- 1 are reacted with the derivatives of formula II-2 affording the pyridine derivatives of formula II-3.
  • the latter are reduced using general technique 6 affording the corresponding diol derivative of formula II-4 which is transformed into the aldehyde of formula II using Mn0 2 as described in general reaction technique 7.
  • R 1 and R 2 are as defined in formula I and R 4a represents OH or halogen such as chlorine or bromine.
  • esters of formula I- 1 are hydro lyzed into the corresponding carboxylic acid derivatives of formula III-l using general reaction technique 8.
  • the resulting carboxylic acid derivatives are further reacted with triphosgene affording the isatoic acid anhydride derivatives of formula III-2 which are reacted with the sodium anion of malodinitrile affording the derivatives of formula III wherein R 4a represents OH.
  • R 4a represents OH.
  • the compounds of formula IV are prepared as described in a) starting from the compounds of formula II wherein R is halogen.
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the ester derivatives of formula IV- 1 are reduced into the corresponding alcohol derivative of formula IV-2 and oxidized into the aldehyde derivative of formula IV-3 using general reaction techniques 6 and 7 respectively.
  • the aldehyde of formula IV-3 is further transformed into the derivative of formula VI using the method described in a).
  • the compounds of formula VII are prepared by deprotecting the compounds of formula VI using general reaction technique 13.
  • R 2a represents H or halogen
  • R represents benzyl or alkyl such as methyl or ethyl
  • PG 1 represents an amino protecting group such as Boc or Cbz.
  • the compounds of formula XII can be prepared as described in f) by reaction of the compounds of formula VII with 2-(aminooxy)ethanamine.
  • R represents benzyl or alkyl such as methyl or ethyl and PG represents an amino protecting group such as Boc or Cbz.
  • the derivatives of formula IV- 1 are transformed into the ketone derivatives of formula VI- 1 using general reaction technique 13 and reacted with ammonium acetate under reductive amination conditions using general reaction technique 10 affording after protection of the amine group using general reaction technique 11, the derivatives of formula VI-2. These derivatives are transformed into the corresponding aldehydes of formula VI-3 using general reaction techniques 5 and 6. The aldehydes are further reacted with cyanoacetamide as described in a) and the amino protecting group in the compounds of formula VI-4 is removed using general reaction technique 2 affording the compound of formula XIII.
  • the compounds of formula XV are prepared as described in a) starting from the compounds of formula II wherein R is alkoxymethyl.
  • R represents hydrogen, (CrC 4 )alkyl, methoxymethyl or 2-(benzyloxy)ethyl and R represents benzyl or alkyl such as methyl or ethyl.
  • the compounds of formula 1-1 are obtained by reacting the compounds of formula II-2 with a derivative of formula VII- 1 in a solvent such as EtOH at a temperature ranging between rt and reflux.
  • a solvent such as EtOH
  • the compounds of formula 1-1 can also be prepared as summarised in Scheme 8 hereafter.
  • R 1 represents (CrC 4 )alkyl
  • R 2 represents hydrogen or (CrC 4 )alkyl, and especially the cyclic version wherein R 1 and R 2 together with the atoms which bear them form a 5, 6 or 7 membered ring and R represents hydrogen, (CrC 4 )alkyl, heteroalkyl or alkoxycarbonyl, R represent benzyl or alkyl such as methyl or ethyl.
  • R 1 represents OH or halogen
  • R 2 represents (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, arylmethyl or heteroarylmethyl
  • R 3 represents (CrC 4 )alkyl or R 2 and R 3 together represent CH 2 CH 2 CH 2 CH 2 , hereafter referred to respectively as the compounds of formula I- l 9a when R 1 is OH and as the compounds of formula 1-1 % when R 1 is halogen, can also be prepared as summarised in Scheme 9 hereafter.
  • R represents (CrC 4 )alkyl, (C 2 -C 4 )alkenyl, arylmethyl and heteroarylmethyl
  • R 3 represents (C r C 4 )alkyl or R 2 and R 3 together represent CH 2 CH 2 CH 2 CH 2
  • R and R v independently from each other represents benzyl or alkyl such as methyl or ethyl
  • X b represents a halogen such as chlorine or bromine.
  • the compounds of formula I-l 9a are obtained by reacting the derivatives of formula II-2 with the ester derivatives of formula IX- 1 (Scheme 9).
  • the derivatives can be further transformed into the derivatives of formula 1-1% by reaction with POCI3 or PBr 3 using general reaction technique 20.
  • R 1 represents haloalkyl, (CrC 4 )alkyl or halogen such as chlorine
  • X c represents chlorine or bromine
  • R represents hydrogen, (CrC 4 )alkyl, halogen, hydroxy or methoxymethyl
  • R represents benzyl or alkyl such as methyl or ethyl.
  • R represents (Ci-C 4 )alkyl or (C2-C 4 )alkenyl
  • R represents hydrogen, (Ci-C 4 )alkyl or methoxymethyl
  • R represents benzyl or alkyl such as methyl or ethyl.
  • R represents hydrogen, halogen, (Ci-C 4 )alkyl and R represents benzyl or alkyl such as methyl or ethyl.
  • R represents vinyl can be obtained from the corresponding compounds of formula I-l wherein R represents CI using general reaction technique 9 or 15.
  • the compounds wherein R represents (C 3 -C 4 )alkenyl can be obtained by using the same methods.
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the ketone derivative of formula XIII- 1 is reacted with derivatives of formula II-2 affording the pyridine derivatives of formual XIII-2.
  • the latter are treated under aq. acidic conditions, using general reaction technique 13, affording the ketone derivatives of formula XIII-3 which are further reduced into the corresponding alcohol derivatives of formula I-l 12 using a hydride reagent such as NaBH 4 using general reaction technique 6.
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the ketone derivative of formula XIV- 1 is reacted with the derivative of formula II-2 affording the pyridine derivatives of formula IV- 1.
  • the latter are treated under aq. acidic conditions using general reaction technique 13 to afford the ketone derivatives of formula VI-2 which are further reduced into the corresponding alcohol derivatives of formula I- 1 using a hydride reagent such as NaBH 4 using general reaction technique 6.
  • R and R represent (CrC 4 )alkyl
  • PG represents an amine protecting group such as ?ara-methoxybenzyl
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the derivatives of formula XV-1 are reacted with the diketone derivatives of formula XV- 2 and an amine of formula XV-3 in the presence of a base such as KOH in a solvent such as EtOH between 50°C and 100°C.
  • a base such as KOH
  • EtOH a solvent
  • the resulting pyridine derivatives of formula XV-4 are reacted with TFA affording the compounds of formula I-l 15 .
  • R z represents H or (C C 2 )alkyl and R represents benzyl or alkyl such as methyl or ethyl.
  • PG represents a phenol protecting group such as benzyl or?ara-methoxybenzyl
  • PG 5 represents 2,4-dimethoxybenzyl
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the compounds of formula XVII- 1 are sequentially reacted with a benzyl alcohol derivative such as ?ara-methoxybenzylalcohol in presence of a base such as NaH and then with a benzylamine derivative such as 2,4-dimethoxybenzylamine at a temperature ranging between 80°C and reflux affording the derivatives of formula XVII-3.
  • Protecting groups are cleaved using TFA affording the derivatives of formula I-l 1 wherein R represents H and R represents OH.
  • R 2 represents H and R 3 represents CI by reaction with POCl 3 using general reaction technique 20.
  • R represents benzyl or alkyl such as methyl or ethyl.
  • the ketone derivatives of formula XVIII- 1 are reacted with cyanamide affording the dihydroxy-pyridine derivatives of formula XVIII-2 which are further transformed into the dichloro derivatives of formula I-l 18 using general reaction technique 20.
  • the compounds of formula VIII-1 are prepared from compounds of formula XIX-1 according to general reaction technique 12.
  • the compounds of formula XIX-1 represent the following structures XIX- la to XIX- Id wherein R c represents H or methyl, R d represents H or methyl, R e represents H, methyl, OH, COOR w or R d and R e together represent -(CH 2 ) 4 -, A represents l,3-dioxolan-2-yl, NR J wherein R J represents benzyl or CHR 1 wherein R 1 represents 2-hydroxyethyl or OH, B represents CH 2 CH 2 , CH 2 , O, S or a bond and PG 6 represents an alcohol protecting group such as TBDMS or TBDMS and R w represents benzyl, alkyl such as methyl or ethyl:
  • A represents l,3-dioxolan-2-yl
  • B represents CH 2 CH 2 , CH 2; O, S, l,3-dioxolan-2-yl or a bond
  • R e represents methyl or alkoxycarbonyl
  • R c and R d represent methyl or H
  • PG 6 represents a alcohol protecting group such as TBDPS or TBDMS.
  • the lithio anion of derivatives of formula XX-3 can also be reacted with a formate source such as ethyl cyanoformate affording the derivatives of formula XX-4 wherein R d represents alkoxycarbonyl.
  • a formate source such as ethyl cyanoformate affording the derivatives of formula XX-4 wherein R d represents alkoxycarbonyl.
  • the compound of formula XIX- lb wherein B represents CH 2 , R e represents H or methyl and R e represents OH is prepared according to Synlett (2004), 2111-2114.
  • the aldehyde of formula XX-5 (prepared according to J. Org. Chem. (1993), 58, 2931-2932) is reduced using general reaction technique 6 affording the alcohol derivative of formula XX-6 which is protected using general reaction technique 19 affording the compounds of formula XIX- lc.
  • the compound of formula XIX- Id is commercially available (or prepared according to J. Org. Chem. (1997), 62, 6888-6896).
  • Q represents OH or OPG 7
  • PG 7 represents an alcohol protecting group such as TBDPS.
  • the ketone of formula XXI- 1 prepared according to Tetrahedron Asymmetry (1996), 2497- 2450 is reacted with (methoxycarbonylmethylene)triphenylphosphorane and the resulting compound of formula XXI-2 is hydrogenated over a noble metal catalyst such as Pd on charcoal or platinum oxide affording the compound of formula XXI-3.
  • the resulting ester function is reduced using general reaction technique 6 and the resulting alcohol derivative of formula XXI-4 is protected using general reaction technique 19.
  • the ketone protecting group is removed using general reaction technique 13 affording the compounds of formula XXI-6 wherein R c represents methyl and A represents CHR 1 and R 1 represents CH 2 CH 2 OPG .
  • the latter can be transformed into the derivative of formula XIX- la wherein A represents CHR 1 and R 1 represents 2-hydroxyethyl using general reaction technique 3.
  • the compounds of formulae II- 1 , XIII- 1 and XIV- 1 are prepared as described in Scheme 19.
  • the required starting ketones are either commercially available (1 -methyl- 2-oxo-cyclohexanecarboxylic acid ethyl ester) or prepared J. Org. Chem. (2010), 75, 7146-7158 (6,6-dimethyl-l ,4-dioxaspiro[4.5]decan-7-one) and WO 01/064685 (7,7-dimethyl-l ,4-dioxaspiro[4.5]decan-8-one).
  • R w and R represent independently from each other benzyl or alkyl such as methyl or ethyl.
  • the malonyl chlorides of formula XXII- 1 are reacted with the trifluorocrotonate derivatives of formula XXII-2 affording the dihydroxy-pyridine derivatives of formula XXII-3 which are further transformed into the dichloro derivatives of formula XVII- 1 using general reaction technique 20.
  • the compounds of formula II-2 are commercially available or prepared in analogy to Chem. Pharm. Bull. (1995), 43, 797-817.
  • Analytical TLC characterisations are performed with 0.2 mm plates: Merck, Silica gel 60 F 254 . Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection is done with UV or with a solution of KMnO 4 (3 g), K 2 CO 3 (20 g), 5% NaOH (3mL) and H 2 O (300mL) with subsequent heating. Prep-TLCs are performed with 2.0 mm plates: Merck, Silica gel 60 F 254 . Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection is done with UV.
  • CCs are performed using Brunschwig 60A silica gel (0.032-0.63mm), Redisep Rf ® cartridges from Teledyne ISCO; elution is performed with EA, Hept, DCM, MeOH or mixtures thereof.
  • a basic function e.g. amine
  • 1% of NH 4 OH (25% aq.) is added to the eluent(s).
  • Prep-HP LCs are performed on XBridge Prep C18 columns from Waters. The following conditions are used:
  • UV/Vis and/or MS and/or ELSD UV/Vis and/or MS and/or ELSD.
  • LC-MSs are performed on Sciex API 2000 with Agilent 1100 Binary Pump with DAD and ELSD; or Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD; or Thermo Finnigan MSQ Surveyor MS with Agilent 1100 Binary Pump, DAD and ELSD; or Thermo MSQ Plus with Dionex GHP 3200 Binary Pump, DAD and ELSD.
  • the number of decimals given for the [M+H + ] peak of each tested compound depends upon the accuracy of the LC-MS device actually used.
  • Methyl 6-acetyl-2-aminonicotinate Methyl 2-amino-6-chloronicotinate (1.0 g, 5.359 mmol), bis(triphenyl)palladium dichloride (0.20 g, 0.287 mmol) and toluene (lOmL) were introduced in reaction vessel. Once the vessel flushed with nitrogen, tributyl(l-ethoxyvinyl)tin (2.35 mL, 6.953 mmol) was added and the reaction mixture was heated at +100°C for 2 days with vigorous stirring. After cooling to rt, EA (50 mL) was added and the resulting slurry was filtered through Celite.
  • Ethyl 3,3-diaminoacrylate (15.36 g, 118 mmol, 1.0 eq.) and AcOH (8 mL, 140 mmol, 1.187 eq.) were added. The resulting mixture was heated to +60°C for 3 h. The reaction mixture was cooled to rt, and diluted with sat. NaHC0 3 (500 mL) and EA (600 mL). The aq. layer was extracted once with EA (600 mL). The combined org. layers were washed with brine (150 mL), dried over MgS0 4 , filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 9: 1), affording the title compound as a light yellow solid (30 g, 73% yield).
  • Ethyl 2-amino-5-bromo-6-(trifluoromethyl)nicotinate A solution of ethyl 2-amino-6-(trifluoromethyl)nicotinate (prepared as described in WO 2006/059103, 1.86 g, 7.9 mmol) and NBS (1.56 g, 8.7 mmol) in MeCN (15 mL) was stirred at +70°C overnight. The solvent was evaporated. The residue was partitioned between EA (100 mL) and water (50 mL). The org. layer was washed with water (20 mL), brine (20 mL), dried over MgSO 4 , filtered and the filtrate was evaporated. The residue was purified by CC (Hex/EA 9:1), affording the title bromide as a white solid (2.28 g, 92% yield).
  • Example 10 8- [(E)-2-acetylamino-ethoxyimino] -2-amino-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
  • Example 16 (Z)-2-amino-8-((cyclopropylmethoxy)imino)-9,9-dimethyl- 6,7,8,9-tetrahydrobenzo[6] [l,8]naphthyridine-3-carboxamide: Starting from intermediate l.v (92 mg, 0.32 mmol) and O-(cyclopropylmethyl)hydroxylamine (90 mg 1.04 mmol), the title compound was obtained as a yellow solid (104 mg) using the typical procedure described in Example 6, step 6.i (oxime formation: 91%> yield).
  • Example 18 2-amino-8-hy drazono-9,9-dimethyl-6,7,8,9-tetrahy dro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
  • Example 20 4- ⁇ N'-[2-amino-3-carbamoyl-9,9-dimethyl-6,9-dihydro- 7H-benzo[6][l,8]naphthyridin-(5E)-ylidene]-hydrazino ⁇ -benzoic acid:
  • Example 21 2-amino-9,9-dimethyl-8-(methyl-hy drazono)-6,7,8,9-tetr ahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
  • Example 28 2-amino-9,9-dimethyl-8-((4-methylthiazol-2-yl)methyl)- 6,7,8,9-tetrahydropyrido[2,3-6][l,7]naphthyridine-3-carboxamide: 28. i. Ethyl 2-amino-8,8-dimethyl-7-((4-methylthiazol-2-yl)methyl)-5,6, 7,8-tetrahydro-l, 7- naphthyridine-3-carboxylate:
  • Example 35 r c-2-amino-6-bromo-7-[l-(4-methoxy-benzenesulfonylamino)-ethyl]- [l,8]naphthyridine-3-carboxylic acid amide:
  • the title compound (7mg, 29%> yield) was obtained as a yellow powder, starting from the intermediate A.vi (15 mg, 0.048 mmol) and 4-methoxybenzene-l-sulfonyl chloride (1.2eq.) and using the procedure described in Example 32.
  • Example 40 (R)-2-amino-9-methyl-6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine- 3-carboxylic acid amide and (S -2-amino-9-methyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
  • the racemic material (0.28 g) was separated by chiral prep-HPLC using a Chiralcel OJ-H 250x4.6mm ID, 5 ⁇ column and Hept/EtOH 49: 1 (containing 0.1% DEA) isocratic gradient at a flow rate of 34 niL/min.
  • the first eluting compound came after 7.6 min and the second one after 8.5 min.
  • One the same analytical column and elution conditions at a flow rate of 0.8 mL/min., the respective retention times were 7.7 and 8.7 min.
  • the first eluting enantiomer A (0.108 g) was obtained as a white solid.
  • the second eluting enantiomer B (0.1 12 g) was obtained as a white solid. Both compounds showed same NMR than the racemic material. The absolute stereochemistry of each enantiomer has not been assigned.
  • Both enantiomers display similar analytical data. Only the data of the compound made from the first eluting intermediate A in step 40. ii were described. The absolute stereochemistry of each enantiomer has not been assigned.
  • Example 42 2-amino-10,10-dimethyl-7,8,9,10-tetrahydro- 6H-cyclohepta[6] [l,8]naphthyridine-3-carboxylic acid amide:
  • Example 54 2-amino-7-chloro-5-methyl-6-pyridin-4-ylmethyl- [1,8] naphthyridine-3- carbox lic acid amide: Starting from ethyl 3-oxo-2-(pyridin-4-ylmethyl)butanoate (prepared as described in J. Med. Chem. (1997), 40(15), 2347-2362; 10.2 g, 46 mmol) the title compound was obtained as a white solid (55 mg) using the procedures described in Example 53, steps 53. i and 53.
  • Example 55 6-allyl-2-amino-7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide: Starting from ethyl 2-acetylpent-4-enoate (13 g, 76 mmol) the title compound was obtained as a yellow solid (45 mg) using the procedures described in Example 53, steps 53. i and 53. ii (cyclization: 10%> yield, chlorination: 83%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 100%> yield, Mn0 2 oxidation: 71%> yield, cyclization: 69%> yield).

Abstract

The present invention concerns novel 2-amino-1,8-naphthyridine-3-carboxamide derivatives of formula I, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections). These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram-positive and Gram-negative aerobic and anaerobic bacteria.

Description

2 -AMINO- 1 , 8 -NAPHTHYRIDINE-3 -CARBOXAMIDE DERIVATIVES AS ANTIMICROBIAL AGENTS
The present invention concerns novel 2-amino-l,8-naphthyridine-3-carboxamide derivatives, a pharmaceutical antibacterial composition containing them and the use of these compounds in the manufacture of a medicament for the treatment of infections (e.g. bacterial infections). These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram-positive and Gram-negative aerobic and anaerobic bacteria.
The intensive use of antibiotics has exerted a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modern medicine and socio-economic behaviour exacerbates the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immuno-compromised patients.
An increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., and Pseudomonas aeruginosa, major sources of infections, are becoming multi-drug resistant and therefore difficult if not impossible to treat:
- S. aureus is resistant to β-lactams, quinolones and now even to vancomycin;
- S. pneumoniae is becoming resistant to penicillin or quinolone antibiotics and even to new macrolides;
- Enteroccocci are quinolone and vancomycin resistant and β-lactam antibiotics are inefficacious against these strains;
- Enter obacteriacea are cephalosporin and quinolone resistant and strains resistant to carbapenems have been recently reported;
- Acinetobacter baumanii is resistant to almost all classes of antibiotics;
- P. aeruginosa are β-lactam and quinolone resistant.
There is also an increasing number of cases of resistance in upper respiratory tract infections caused by fastidious Gram negative pathogens such as H. influenzae and M. catarrhalis. Further resistant strains of S. aureus have spread out of the clinical settings into the community. In addition, microorganisms that are causing persistent infections are increasingly being recognized as causative agents or cofactors of severe chronic diseases like peptic ulcers or heart diseases.
Pyridochromanones (A) have been reported to be DNA ligase inhibitors and to display antibacterial activity (Broetz-Oesterhelt et al, J. Biol. Chem. (2003), 278(41), 39435-39442).
Figure imgf000003_0001
(A)
Pyrido[2,3-<i]pyrimidines (B) have been reported to be DNA ligase
(US 2007/0082920 and Meier et al, FEBS Journal (2008), 275(21), 5258-5271).
Figure imgf000003_0002
(B)
Q = C(CH2Ph); Rla = 3,5-dimethoxybenzyl; Rlb = Me; R3 =Me
Q = N; Rla = Rlb = Me; R3 = H 5,7-dimethyl derivatives of 2,3-disubstituted 1,8-naphthyridines are known in literature as potential diuretic agents (Hawes et al, J. Med. Chem. (1977), 20(6) 838-41). This document particularly discloses 2-amino-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide, but doed not suggest or encompass any antibiotic activity. 2-amino- 5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide shall not be encompassed by the present invention. In other words, a compound of formula I as defined hereafter with R1 and R 3 simultaneaously being methyl and R 2 and R 4 at the same time being H, as defined below, shall be disclaimed from the present invention.
Therefore, there is a high medical need for new antibacterial agents harbouring a novel mechanism of action and/or containing new pharmacophoric groups and covering these pathogenic strains. The Applicants have now found particular 2-amino-l,8-naphthyridine- 3-carboxamide antibiotic derivatives corresponding to the formula I described hereafter.
Various embodiments of the invention are presented hereafter: i) The invention firstly relates to compounds of formula I
Figure imgf000004_0001
I wherein
R1 represents (CrC4)alkyl, (CrC3)haloalkyl, -CH(Me)NHS02Ra or halogen;
R represents H, halogen, (CrC4)alkyl, cyclopropyl, (C2-C4)alkenyl, arylmethyl or heteorarylmethyl; or
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*, #-CRdRe-CH2-B-CH2-*, #-C(Me)2-D=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*, "#" representing the point of attachment of R1 and "*" representing the point of attachment of R2;
R3 represents hydrogen, halogen, hydroxy, -NHRb, 2-(hydroxy)ethoxy, (CrC4)alkyl, (C2-C4)alkenyl, co-hydroxy(CrC3)alkyl, methoxymethyl or 2-carboxy-azetidin-l-yl; or R2 and R3 together represent -CH2CH2CH2CH2-;
R represents hydrogen or hydroxy;
A represents C=NORf, C=N-NHRg, CO, CHNHCORh, CHR\ NRj or l,3-dioxolan-2-yl; B represents CH2CH2, CH2, CH(OH), O, S or a bond;
D represents CH(CH2OH); Ra represents (Ci-C4)alkyl, aryl or heteroaryl;
Rb represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl or -CH2CH2CH(NH2)COOH;
Rc represents hydrogen or methyl;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-;
Rf represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, (C3-C4)alkynyl or -CH2RX;
Rg represents hydrogen, (CrC4)alkyl, aryl, heteroaryl or -CH2Ry;
Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl;
RJ represents heteroarylmethyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2- (hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, aryl, heteroaryl or 5-phenyl-thiazol-2-yl;
Ry represents -CH2OH, (CrC4)alkoxycarbonyl;
with the proviso that 2-amino-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide is disclaimed,
and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I.
The compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, for instance in case of A = CHR1. Substituents at a double bond may be present in the (Z)- or (E)-configuration unless indicated otherwise. The compounds of formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition: The term "alkyl", used alone or in combination, refers to a saturated straight or branched chain alkyl group containing from one to four carbon atoms. Representative examples of alkyl groups include methyl, ethyl, propyl, z'so-propyl, ft-butyl, z'so-butyl, sec-butyl and tert-butyl. The term "(Cx-Cy)alkyl" (x and y each being an integer) refers to an alkyl group as defined before containing x to y carbon atoms. Preferred are methyl, ethyl, /so-propyl and tert-butyl.
The term "alkenyl", used alone or in combination, refers to a straight or branched hydrocarbon chain of 2 to 6 (and preferably 2 to 4) carbon atoms with at least one carbon-carbon double bond. Representative examples of alkenyl groups include, but are not limited to, ethenyl, prop-2-enyl and but-3-enyl. The term "(C2-Cx)alkenyl" (x being an integer) refers to a straight or branched chain alkenyl group containing 2 to x carbon atoms. Most preferred is ethenyl (i.e. vinyl), prop-2-en-l-yl (i.e. allyl) and prop-2-en-2-yl (i.e. /so-propenyl).
The term "alkynyl", used alone or in combination, refers to a straight or branched hydrocarbon chain of 2 to 6 (and preferably 3 to 4) carbon atoms with at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, prop-2-ynyl and but-3-ynyl. The term "(C2-Cx)alkynyl" (x being an integer) refers to a straight or branched chain alkynyl group containing 2 to x carbon atoms. Most preferred is propargyl (i.e. prop-2-yn-l-yl).
The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably to fluorine, chlorine or bromine. More preferred is bromine and chlorine.
The term "alkoxy", used alone or in combination, refers to a straight or branched chain alkoxy group containing from one to four carbon atoms. The term "(Cx-Cy)alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example, a (CrC3)alkoxy group contains from one to three carbon atoms. Representative examples of alkoxy groups include methoxy, ethoxy, ^-propoxy and /so-propoxy as well as tert-butoxy. Preferred are methoxy, ethoxy and tert-butoxy.
The term "haloalkyl" refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with halogen. The term "(Cx-Cy)haloalkyl" (x and y each being an integer) refers to a haloalkyl group as defined before containing x to y carbon atoms. For example a (Ci-C3)haloalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with halogen and in particular fluorine. Representative examples of haloalkyl groups include trifluoromethyl and 2,2,2-trifluoroethyl. Preferred is trifluoromethyl.
The term "aryl", used alone or in combination, refers to an aromatic cyclic group with one, two or three rings, having five to 14 carbon ring atoms and preferably from five or six to ten carbon ring atoms, for example phenyl or naphthyl groups. Any aryl group as defined herein may be substituted with one, two or more substituents, each of which is independently selected from the group consisting of halogen, alkyl, alkoxy, carboxy, trifluoromethyl and trifluoromethoxy. Specific examples of aryl are phenyl, naphthyl, 4-fluoro-phenyl, 4-chloro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-methoxy- phenyl, 4-methyl-phenyl, 4-carboxy-phenyl, 4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dichloro-phenyl, 2,4-dimethoxy- phenyl, 2,4-dimethyl-phenyl, 2,5-difluoro-phenyl, 2,4-ditrifluoromethyl-phenyl and 2,4-ditrifluoromethoxy-phenyl. Preferred are those aryl residues exemplified herein.
The term "heteroaryl", used alone or in combination, refers to an aryl group as defined herein where one, two or more (preferably one to four, and notably one or two) ring carbon atoms are replaced by an oxygen, nitrogen or sulphur atom, for example pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl (i.e. thiophenyl), furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or tetrazolyl groups. The term "heteroaryl" also covers bicyclic structures selected from the group consisting of quinolinyl, isoquinolinyl, quinazolinyl, quinoxazinyl, phthalazyl, naphthyridinyl, indolyl, indazolyl benzothiazol-2-yl and benzoxazol-2-yl. Any heteroaryl group as defined herein may be substituted with one, two or more substituents on its aromatic ring(s), said substituents being from the group consisting of halogen, alkyl, dialkylamino and alkoxy.; Hence, examples of heteroaryl groups include, but are not limited to pyridinyl, such as pyridin-4-yl, 4-chloropyridin-3-yl or 2-chloropyridin-3-yl, 4-methylthiazol-2- yl, 5-phenylthiazol-2-yl, furan-2-yl, 5-fluorobenzothiazol-2-yl, 6-fluorobenzothiazol-2- yl, phthalazin-l-yl and 5-NN-dimethylaminobenzothiazol-2-yl. ❖ The aforegoing groups "methyl", "aryl" and "heteroaryl" when combined to form the groups "arylmethyl" or "heteroarylmethyl" have the same exemplary meaning as their constituents discussed above. As brief examples only, the combinations can mean:
❖ "arylmethyl": refers particularly to benzyl, 3-chlorobenzyl, 2,4-dimethoxybenzyl;
❖ "heteroarylmethyl": refers particularly to thiophen-2-yl-methyl, (6-fluorobenzothiazol- 2-yl)methyl, (4-methylthiazol-2yl)methyl, (pyridin-4-yl)methyl;
❖ The term "ro-hydroxy(C1-C3)alkyl" refers to hydroxymethyl, (2 -hydroxy) ethyl or (3 -hydroxy)propyl.
The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
The term "room temperature" as used herein refers to a temperature of 20 to 30°C, and preferably 25°C.
Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10%) of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
In the following, the above-mentioned invention is described in further embodiments, which may be combined with each other as indicated below.
ii) The invention notably relates to compounds of formula I
Figure imgf000009_0001
I wherein
R1 represents (CrC4)alkyl, (CrC3)haloalkyl, -CH(Me)NHS02Ra or halogen;
R2 represents H, halogen, (CrC4)alkyl, cyclopropyl, (C2-C4)alkenyl, arylmethyl or heteorarylmethyl; or
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*, #-CRdRe-CH2-B-CH2-*, #-C(Me)2-D=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*; "#" representing the point of attachment of R1 and "*" representing the point of attachment of R2;
R3 represents hydrogen, halogen, hydroxy, -NHRb, 2-(hydroxy)ethoxy, (CrC4)alkyl, (C2-C4)alkenyl, ro-hydroxy(Ci-C3)alkyl, methoxymethyl or 2-carboxy-azetidin-l-yl; or R2 and R3 together represent -CH2CH2CH2CH2-;
R4 represents hydrogen or hydroxy;
A represents C=NORf, C=N-NHRg, C=0, CHNHCORh, CHR\ NRj or l,3-dioxolan-2-yl; B represents CH2CH2, CH2, CH(OH), O, S or a bond;
D represents CH(CH2OH);
Ra represents (Ci-C4)alkyl, aryl or heteroaryl;
Rb represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl or -CH2CH2CH(NH2)COOH;
Rc represents hydrogen or methyl;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-;
Rf represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, (C3-C4)alkynyl or -CH2RX;
Rg represents hydrogen, (CrC4)alkyl, aryl, heteroaryl or -CH2Ry;
Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl; RJ represents heteroarylmethyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2- (hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, aryl, heteroaryl or 5-phenyl-thiazol-2-yl;
Ry represents -CH2OH, (Ci-C4)alkoxycarbonyl;
with the proviso that 2-amino-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide is disclaimed; and
wherein aryl represents phenyl unsubstituted or substituted with one or two residues selected from halogen, (Ci-C4)alkyl, (Ci-C4)alkoxy, carboxy, trifluoromethyl or trifluoromethoxy; and
wherein heteroaryl represents pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl (i.e. thiophenyl), furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxazinyl, phthalazyl, naphthyridinyl, indolyl, indazolyl benzothiazol-2-yl or benzoxazol-2-yl and any heteroaryl group may be unsubstituted or substituted with one or two substituents selected from halogen, (Ci-C4)alkyl, (Ci-C4)dialkylamino or (Ci-C4)alkoxy; and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I. iii) According to one embodiment of this invention, residue R1 represents (CrC4)alkyl, (CrC3)haloalkyl, halogen, or -CH(Me)NHS02Ra; and Ra represents methyl, 2-chloro- pyridin-3-yl, 4-chloro-pyridin-3-yl, 4-methoxy-phenyl, or thiophen-2-yl. iv) According to one embodiment of the invention, residue R1 represents (CrC4)alkyl, (Cp C3)haloalkyl, or halogen. v) According to one preferred embodiment of iv), R1 represents halogen, particularly CI, trifluoromethyl, t-butyl, methyl, /so-propyl. vi) According to another preferred embodiment of iv) and v), R1 represents CI, trifluoromethyl and t-butyl. vii) According to another preferred embodiment of iv) to vi), R1 represents CI and trifluoromethyl. viii) According to one embodiment of this invention, residue R represents H, halogen, -C4)alkyl, cyclopropyl, enzyl or pyridin-4-yl-methyl, or R 2 and R 3
(Ci (C2-C4)alkenyl, b
together represent -CH2CH2CH2CH2-. ix) According to one preferred embodiment of viii), residue R represents H, halogen, particularly Br, methyl, ethyl, cyclopropyl, vinyl, allyl, /so-propenyl, benzyl, pyridin-4-yl- methyl, or R2 and R3 together represent -CH2CH2CH2CH2-. x) According to another preferred embodiment of viii) or ix), residue R represents Br, methyl, cyclopropyl, vinyl, ethyl or benzyl. xi) According to another preferred embodiment of viii) to x), residue R is Br. xii) According to one embodiment of this invention, the residues R 1 and R 2 together represent #-CRc(Me)-A-CH2-CH2-*, #-CRdRe-CH2-B-CH2-*, #-C(Me)2-D=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*, "#" representing the point of attachment of R1 and "*" representing the point of attachment of R . xiii) According to one embodiment of xii), the residues
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*; "#" representing the point of attachment of R 1 and "*" representing the point of attachment of R 2 ;
A represents C=NORf, C=N-NHRg, CO, CHNHCORh, CHR\ NRj or l,3-dioxolan-2-yl;
Rc represents methyl;
Rf represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, (C3-C4)alkynyl or -CH2RX;
R§represents hydrogen, (CrC4)alkyl, -CH2Ry, phthalazin-l-yl or 4-carboxy-phen-l-yl; Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl;
RJ represents (6-fluorobenzo[d]thiazol-2-yl)methyl, (4-methylthiazol-2-yl)methyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2-(hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, 5-phenyl-thiazol-2-yl, benzothiazol-2-yl, thiazol-2-yl, 2-chlorophen-l-yl, or 3-chlorophen-l-yl;
Ry represents -CH2OH or -COOEt. xiv) According to one embodiment of xii), the residues R1 and R2 together represent #-CRdRe-CH2-B-CH2-*; "#" representing the point of
1 2
attachment of R and "*" representing the point of attachment of R ;
B represents CH2CH2, CH2, CH(OH), O, S or a bond;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-. xv) According to one embodiment of xii), the residues
R1 and R2 together represent #-C(Me)2-CH(OH)=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*; "#" representing the point of attachment of R1 and "*" representing the point of attachment of R2. R1 and R2 representing together #-C(Me)=CH-CH2-CH2-* is preferred.
1 2
xvi) According to another embodiment of xii), the residues R and R together represent #- CRc(Me)-A-CH2-CH2-*; Rc is methyl; A is C=NORf; and Rf is H, methyl, allyl, prop- 2-ynyl (propargyl), or -CH2RX; and Rx is cyclopropyl, thiazol-2-yl, 2,2-dimethyl- l,3-dioxolan-4-yl, 2-chlorophen-l-yl, 3-chlorophen-l-yl, 5-phenyl-thiazol-2-yl, benzothiazol-2-yl, -CH(OH)CH2OH, -CH=CHCH2OH, -CH2CH(NH2)COOH, -CH2NHCOCH3, or -COOH. xvii) According to a preferred embodiment of xvi), R is H, allyl, cyclopropylmethyl, propargyl, 5-phenyl-thiazol-2-yl-methyl, thiazol-2-yl-methyl. xviii) According to another preferred embodiment of xvi) or xvii) R is H, allyl and propargyl, particularly allyl.
1 2
xix) According to one embodiment of xii), the residues R and R together represent #-CRdRe-CH2-B-CH2-*, B is CH(OH), CH2, CH2CH2, O or S. xx) According to one embodiment of xix), B preferably is CH2. xxi) According to one embodiment of xix) or xx), residues Rd, Re are represented as follows: Rd = Re = methyl; or Rd = Re = H; or Rd = methyl and Re = H; or Rd = methyl and
Re = OH; or Rd = methyl and Re = CH2OH. xxii) According to another embodiment of xx), B is representing CH2 and Rd = Re = methyl or Rd = Re = H. xxiii) According to one embodiment of present invention, R represents hydrogen, CI, hydroxy, -NHRb, 2-(hydroxy)ethoxy, methyl, ethyl, vinyl, hydroxymethyl, (2-hydroxy)ethyl, (3-hydroxy)propyl, methoxymethyl or 2-carboxy-azetidin-l-yl; wherein Rb represents hydrogen, methyl, allyl, (2-hydroxy)ethyl, (3-hydroxy)propyl or -CH2CH2CH(NH2)COOH. xxiv) According to one embodiment of xxiii), preferably, R3 represents hydrogen, methyl, vinyl, ethyl or CI. xxv) According to one embodiment of this invention, residue R4 is H or OH. xxvi) According to one embodiment of xxii), R4 preferably is H and when R4 is OH, R3 must be H.
It is to be understood that each embodiment described under iii)-vii) may be combined with each embodiment described under viii)-xi), under xii)-xxii), under xxiii)-xxiv), under xxv)-xxvi) and vice versa. These embodiments relating to specific residues R may also be combined with or substitute the resepective residues R in embodiments i), ii) or xxvii). xxvii) According to another embodiment, present invention relates to compounds of formula I
Figure imgf000013_0001
wherein
R1 represents methyl, /so-propyl, t-butyl, trifluoromethyl, CI, or -CH(Me)NHS02Ra;
R represents H, Br, methyl, ethyl, cyclopropyl, (C2-C4)alkenyl vinyl, allyl, isopropenyl, benzyl, or pyridin-4-yl-methyl; or
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*, #-CRdRe-CH2-B-CH2-*, #-C(Me)2-D=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*; "#" representing the point of
1 2
attachment of R and "*" representing the point of attachment of R ; R3 represents hydrogen, CI, hydroxy, -NHRb, 2-(hydroxy)ethoxy, methyl, ethyl, vinyl, hydroxymethyl, (2-hydroxy)ethyl, (3-hydroxy)propyl, methoxymethyl or 2-carboxy- azetidin-l-yl; or
R2 and R3 together represent -CH2CH2CH2CH2-;
R4 represents hydrogen or hydroxy;
A represents C=NORf, C=N-NHRg, C=0, CHNHCORh, CHR\ NRj or l,3-dioxolan-2-yl; B represents CH2CH2, CH2, CH(OH), O, S or a bond;
D represents CH(CH2OH);
Ra represents methyl, 2-chloro-pyridin-3-yl, 4-chloro-pyridin-3-yl, 4-methoxy-phenyl, or thiophen-2-yl;
Rb represents hydrogen, methyl, allyl, (2-hydroxy)ethyl, (3-hydroxy)propyl or
-CH2CH2CH(NH2)COOH;
Rc represents methyl;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-;
Rf represents hydrogen, methyl, allyl, prop-2-ynyl, or -CH2RX;
R§ represents hydrogen, methyl, -C¾Ry, phthalazin-l-yl or 4-carboxy-phen-l-yl;
Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl;
RJ represents (6-fluorobenzo[d]thiazol-2-yl)methyl, (4-methylthiazol-2-yl)methyl,
2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2-(hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, 5-phenyl-thiazol-2-yl, benzothiazol-2-yl, thiazol-2-yl, 2-chlorophen-l-yl, or 3-chlorophen-l-yl;
Ry represents -CH2OH or -COOEt;
with the proviso that 2-amino-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide is disclaimed;
and to salts (in particular pharmaceutically acceptable salts) of compounds of formula I. xxv) Particularly preferred are the following compounds of formula I as defined in the above embodiments:
- 2-amino-6-bromo-7-(trifluoromethyl)-l,8-naphthyridine-3-carboxamide; - 2-amino-6-bromo-5,7-dichloro-[l,8]naphthyridine-3-carboxylic acid amide; or a salt of such a compound. xxvi) Further preferred are the following compounds of formula I as defined in the above embodiments:
- 2-amino-6-benzyl-7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-methyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide; or a salt of such a compound. xxvii) Further preferred are the following compounds of formula I as defined in the above embodiments:
- 2-amino-9,9-dimethyl-6,7,8,9-tetrahydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-chloro-5-ethyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-cyclopropyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-7-trifluoromethyl-6-vinyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-ethyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6,7,8,9-tetrahydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-9-methyl-6,7-dihydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-tert-butyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 8-[(E)-allyloxyimino]-2-amino-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-trifluoromethyl-5-vinyl-[l,8]naphthyridine-3-carboxylic acid amide; or a salt of such a compound.
The invention moreover relates to any individual compound of formula I selected from the compounds listed in ix), x), xi) and the examples, as well as to the salt (in particular pharmaceutically acceptable salt) thereof.
The compounds of formula I according to the invention are particularly active against bacteria and bacteria-like organisms. They are therefore particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections. They can be used in the treatment of Gram positive infections (notably those caused by Staphylococcus aureus including MRSA, Streptococcus pneumonia, enterococci and streptococci) and Gram negative infections (notably those caused by Haemophilus influenzae, Moraxella catarrhalis). The compounds are suitable for the treatment of community acquired pneumonias (including hospital acquired pneumonia), skin and skin structure infections (whether complicated or uncomplicated), blood and tissue infections, including bacteremia, endocarditis and osteomyelitis, foreign body infections, meningitis, gastrointestinal infections including those caused by Clostridium difficile or Helicobacter pylory infections, topical infections, acne vulgaris, infected atopic dermatitis and opthalmological infections.
The present list of pathogens is to be interpreted merely as examples and in no way as limiting.
The compounds of formula I according to one of embodiments i) to xxvii), or the pharmaceutically acceptable salts thereof, may be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection.
As well as in humans, bacterial infections can also be treated using compounds of formula I according to one of embodiments 1) to xxvii) (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.
The present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I according to one of embodiments i) to xxvii).
Any reference to a compound of formula I in this text (and notably in the embodiments presented above) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. A pharmaceutical composition according to the present invention contains at least one compound of formula I according to one of embodiments i) to xxvii) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics especially those known to address DNA topology such as quinolones (e.g. ciprofloxacin or moxifloxacin) and inhibitor of RNA polymerase such as rifampicin.
The compounds of formula I according to one of embodiments i) to xxvii) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Moreover, the compounds of formula I according to one of embodiments i) to xxvii) may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments or to make a room or an area aseptic. For such purposes, the compounds of formula I could be contained in a solution or in a spray formulation.
The compounds of formula I can be manufactured in accordance with the present invention using the procedures described hereafter.
PREPARATION OF COMPOUNDS OF FORMULA I
Abbreviations:
The following abbreviations are used throughout the specification and the examples:
Ac acetyl
AcOH acetic acid
AIBN azobisisobutyronitrile
anhydr. anhydrous
aq. aqueous
ΒΓΝΑΡ (±)-(!> 1 '-binaphthalene-2,2'-diyl)bis(diphenylphosphine) Boc tert-butoxycarbonyl
BrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-
1 , 1 '-biphenyl
Bu n -butyl
Cbz benzyloxycarbonyl
CC column chromatography over silica gel
cone. Concentrated
DBU l,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N'-dicyclohexylcarbodiimide
DCE 1,2-dichloroethane
DCM dichloromethane
DEA diethylamine
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIPEA N,N-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DME 1,2-dimethoxyethane
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
EA ethyl acetate
EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
ESI Electron Spray Ionisation
eq. equivalent
ether diethyl ether
Et ethyl
EtOH ethanol
HATU O-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
Hex hexane
Hept heptane
HO AT 1 -hydroxy-7-aza-benzotriazole
HOBT 1-hydroxybenzotriazole
HPLC high pressure liquid chromatography HV high vacuum conditions
IPr l,3-bis(2,6-diisopropylphenyl)-l,3-dihydro-2H-imidazol-2-ylidene
JosiPhos ligands (R)-l-[(SP)-2-(di-ierf- butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine or (R)-l-[(SP)-2-(di-ierf- butylphosphino)ferrocenyl] ethyl diphenylphosphine or
(R)-l-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine
LAH LiAlH4
LC liquid chromatography
LDA lithium diisopropylamide
Me methyl
MeCN acetonitrile
MeOH methanol
min minutes
MS Mass Spectroscopy
Ms methanesulfonyl (mesyl)
org. organic
ft-BuLi n -butyl lithium
NBS N-bromrosuccinimide
NCS N-chlorosuccinimide
NMM N-methyl-morpholine
NMP N-methyl-2-pyrrolidone
PCy3 tricyclohexylphosphine
Pd/C palladium on carbon
Pd2(dba)3 tris [dibenzylideneacetone] dipalladium(O)
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)
PEPPSI™-IPr [l,3-bis(2,6-diisopropylphenyl)imidazol-
2-ylidene](3-chloropyridyl)palladium(II) di chloride
Ph phenyl
Prep. preparative
prep-HPLC preparative HPLC
prep-TLC preparative TLC Pyr pyridine
quant. quantitative
Q-phos 1, 2,3,4, 5-pentaphenyl- -(di-tert-butylphosphino)ferrocene
RaNi Raney-nickel
rac racemic
rt room temperature
sat. saturated
S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
SK-CCO 1 -A 2'-(dimethylamino)-2-biphenylyl-palladium(II) chloride
dinorbornylphosphine complex
SK-CC02-A 2-(dimethylaminomethyl)ferrocen- 1 -yl-palladium(II) chloride dinorbornylphosphine complex
T3P propylphosphonic anhydride
TBAF tetrabutylammonium fluoride
TBDMS tert-butyldimethylsilyl
TBDPS tert-butyldiphenylsilyl
tBu tert-butyl
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
TMEDA tetramethylethylenediamine
TMG Ν,Ν,Ν ',Ν '-tetramethylguanidine
TsOH 7-toluenesulfonic acid monohydrate
tR retention time
v/v proportion by volume
wt% percent in weight
X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene General reaction techniques:
General reaction technique .1 _(r ing closure with cyano acetamide).:.
A ring closure reaction is performed starting from the required 2-amino-3-formylpyridine derivatives (compounds of formula II) using a slight excess of cyanoacetamide in presence of an organic base such as TMG, in a protic solvent such as EtOH at a temperature ranging between rt and reflux, preferentially at reflux.
General re ac ti on _t_e chni que 2 (r emo al of amine pr o te c ting group s) :
The benzyl carbamates are deprotected by hydrogenolysis over a noble metal catalyst (e.g. Pd/C or Pd(OH)2/C). The Boc group is removed under acidic conditions such as HC1 in an organic solvent such as MeOH or dioxane, or TFA neat or diluted in a solvent such DCM. The Alloc group is removed by the action of tetrakis(triphenylphosphine)palladium(0) in presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF. The FMOC group is removed under mild basic conditions such as piperidine in DMF. The N-acetyl protecting group is removed under basic conditions such as Na2C03, LiOH or NaOH in aq. MeOH or THF, or under acidic conditions such as aq. HC1 in THF. The N-benzyl protected amines are deprotected by hydrogenolysis over a noble catalyst (e.g. Pd(OH)2). The 2,4-dimethoxybenzyl protecting group can be removed by reaction with TFA. Further general methods to remove amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3rd Ed 1999, 494-653; T.W. Greene, P.G.M. Wuts (Publisher: John Wiley and Sons, Inc., New York).
.General reaction technique 3..(removal .of hydroxy. protecting. groups) :
The silyl ether groups are removed either using fluoride anion sources such as TBAF in THF between 0°C and 40°C or HF in MeCN or water between 0°C and 40°C or using acidic conditions such as AcOH in aq. THF or HC1 in MeOH. Further methods to remove the TBDMS and TBDPS groups are given in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3 Ed 1999, 133-139 and 142-143 respectively (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Further general methods to remove alcohol protecting groups are described in T.W. Greene, P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd Ed 1999, 23-147 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).
General .reaction technique 4.(de r ptectmg of amino .acids):
The amino acids protected as NHBoc and tBu ester are sequentially treated with 4M HC1 in dioxane at rt and, after removal of the dioxane, with TF A/water (1 : 1) at 60°C for 2h.
General reaction technique 5. amide.fo
A carboxylic acid is reacted with the required amine in presence of an activating agent such as DCC, EDC, HOBT, HOAT, T3P, HATU or di-(N-succinimidyl)-carbonate, in a dry aprotic solvent such as DCM, MeCN or DMF between -20°C and +60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York 1991, vol. 6, p. 381). Alternatively, the carboxylic acid can first be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent such as DCM between -20°C and +60°C. Further activating agents can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999; Section nitriles, carboxylic acids and derivatives, p. 1941-1949.
General reaction technique 6. ester.an^
A ketone or an aldehyde is reduced with a boron or aluminium hydride reducing agent such as LiBH4, NaBH4 or LAH in a solvent such as THF between -20°C and +40°C. Further general methods to reduce carbonyl groups as well as asymmetric reduction methods have been described in Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2nd Edition, R. C. Larock, Wiley-VC, New York, Chichester, Weinheim, Brisbane, Singapore, Toronto 1999, Section alcohols and phenols, p. 1075-1087 and p. 1097-1110.
Genera^
A primary allylic or benzylic alcohol dissolved in an organic solvent such as DCM or THF is oxidized into the corresponding aldehyde with Mn02. Further methods can be found in
Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999; Section aldehydes and ketones, p. 1234-1236.
General .reaction technique 8..(ester hydrolysis).:.
Representative carboxy protecting groups are alkyl, e.g. methyl, ethyl or tBu, haloalkyl, e.g. trichloroethyl, arylmethyl, e.g. benzyl or para nitrobenzyl, alkenyl, e.g. allyl, trialkylsilyl, e.g. trimethylsilyl, TBDMS or di-tBumethylsilyl, alkylthioalkyl, e.g. methylthiomethyl (MTM), alkoxyalkoxyalkyl, e.g. methoxyethoxymethyl (MEM), arylalkoxyalkyl, e.g. benzyloxymethyl (BOM), trialkylsilylalkoxyalkyl, e.g. 2-(trimethylsilyl)ethoxymethyl (SEM), trialkylsilylalkyl, e.g. 2-(trimethylsilyl)ethyl (TMSE). Further examples of protecting groups to mask carboxylic acids and the conditions to regenerate them are well known to those skilled in the art, and are listed in reference book such as P.J. Kocienski 'Protecting Groups ', Georg Thieme Verlag Stuttgart, New- York, 1994 pp. 118-143. In particular, methyl and ethyl esters are deprotected either by saponification with an alkali hydroxide such as NaOH, LiOH or KOH or by hydrolysis in con. aq, HC1 {e.g. 6N), benzyl ester by hydrogeno lysis over a noble metal catalyst such as Pd/C, and tBu ester by treatment with TFA (neat or diluted in an organic solvent such as DCM) or a solution of HC1 in an organic solvent such as dioxane.
General reaction technique ^ An aromatic halide is reacted with the required organostannane reagent in the presence of a palladium catalyst between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF. Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh3)4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(tBu)3), dialkylphosphinobiphenyls (e.g. X-Phos), ferrocenylphosphines (e.g. Josiphos) or N-heterocyclic carbenes (e.g. IPr). The reaction can also be run in presence of copper and fluoride additives (e.g. Cul and CsF) when less reactive organostannanes are used. The reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Angew. Chem. Int. Ed. Engl. (2004), 43, 4704-4734, Acc. Chem. Res. (2008), 41, 1555-1564, Aldrichimica Acta (2006), 39, 97-111, and references cited therein. General reaction technique .10.(reductive .animation):.
The reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgS04 or Na2S04). Such solvent is typically toluene, Hex, THF, NMP, DCM or DCE or a mixture of solvents such as DCE/MeOH. The reaction can be catalyzed by traces or a stoichiometric amount of acid (usually AcOH or TsOH). The intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBH3CN, or NaBH(OAc)3) or by hydrogenation over a noble metal catalyst such as Pd/C. The reaction is carried out between -10° and +110°C, preferably between 0°C and 60°C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in the presence of a picoline-borane complex {Tetrahedron (2004), 60, 7899-7906).
General reaction
Amines are usually protected as carbamates such as Alloc, Cbz, Boc or FMOC. They are obtained by reaction of the amine with allyl or benzyl chloro formate, di tert-butyl dicarbonate or FMOC-C1 in presence of a base such as NaOH, TEA, DMAP or imidazole. Amines can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as Na2C03 or TEA. Alternatively, N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde (see reaction technique 10). Amines can furthermore be protected as sulphonamides by their reaction with 2-nitro- or 4-nitro-phenylsulphonyl chloride in a solvent such as DCM or THF in presence of a base such as TEA or aq. NaOH between -10°C and +40°C. Further strategies to introduce other amine protecting groups have been described in Protecting Groups in Organic Synthesis, 3rd Ed 1999, 494-653; T.W. Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.).
General reaction technique .! 2^
Ketol-enol derivatives are prepared from the corresponding cyclic ketone by reaction with an alkyl formate (e.g. ethyl formate) in presence of a base such as NaH or sodium alcoholate in a solvent such as THF or ether. Alternatively, keto-enol derivatives can be prepared using N,N-dimethylformamide dimethyl acetal followed by acidic hydrolysis of the intermediate enamine. The ketol-ester derivatives are prepared from the corresponding cyclic ketones by reaction with an alkyl chloroformate using the same conditions as when using an alkyl formate.
General .reaction technique .13.(ketal. and acetoni.de depr otection).:.
A ketal/acetonide is converted into its corresponding diol and ketone under acidic conditions using either aq. HC1 in MeOH, AcOH in aq. THF at a temperature ranging between rt and reflux, or by using an acidic resin such as Amberlite IR120H or DOWEX 50W8 in a water-solvent mixture such as MeOH/water, dioxane/water or THF/water.
General reaction technique .14. (Negishj.cou
The aromatic halide (typically a bromide) is reacted with the required organozinc reagent in the presence of a palladium catalyst between 20 °C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF. Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh3)4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(tBu)3), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Josiphos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01-A) or N-heterocyclic carbene complexes (e.g. PEPPSI™-IPr). The reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Chem. Rev. (1993), 93, 2117-2188, Aldrichimica Acta (2006), 39, 17-24 and 97-111, Acc. Chem. Res. (2008), 41, 1555-1564, Chem. Soc. Rev. (2009), 38, 1598- 1607, and references cited therein. In the particular case wherein the methyl organozinc derivative is requested, the reaction is performed starting from dimethyl zinc.
General reaction technique
The aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2C03, Cs2C03, K3P04, tBuONa or tBuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%). Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh )4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(tBu)3), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01-A) or N-heterocyclic carbene complexes (e.g. PEPPSI™-IPr). The reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Chem. Rev. (1995), 95, 2457-2483, Synthesis (2004), 2419-2440, Aldrichimica Acta (2006), 39, 17-24 and 97-111, Acc. Chem. Res. (2008), 41, 1555-1564, and references cited therein.
General .reaction technique l^
The phenol is reacted with a sulfonyl chloride derivative such as MsCl, TfCl or TsCl in presence of a base such as TEA in a dry aprotic solvent such as Pyr, THF or DCM between -30°C and +50°C. In the case of the triflate or mesylate, Tf20 or Ms20 can also be used.
General . reaction technique 17^^
The aromatic halide is reacted with the required amine in the presence of a palladium catalyst and a base such as K2C03; Cs2C03, K3P04; tBuONa or tBuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF. Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh )4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(tBu)3), dialkylphosphinobiphenyls (e.g. X-Phos or BrettPhos), chelating diphosphines (e.g. ΒΓΝΑΡ, XantPhos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC02-A) or N-heterocyclic carbene complexes (e.g. PEPPSI™-IPr). The reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in J. Org. Chem. (2000), 65, 1144-1157, Angew. Chem. Int. Ed. (2005), 44, 1371-1375, Aldrichimica Acta (2006), 39, 17-24 and 97-111, Angew. Chem. Int. Ed. (2008), 47, 6338-6361, and references cited therein.
Generalxeaction
The chloride derivative is reacted with an amine in a solvent such as THF, MeCN, DMF or NMP between 0° and 120°C. General . reaction technique .^
The alcohols are protected as silyl ether (usually TBDMS or TBDPS). The alcohol is reacted with the required silyl chloride reagent (TBDMSCl or TBDPSCl) in presence of a base such as imidazole or TEA in a solvent such as DCM or DMF between 10°C and 40°C. Further strategies to introduce other alcohol protecting groups have been described in Protecting Groups in Organic Synthesis 3rd Ed; 1999, 23-147; T.W.Greene, P.G.M. Wuts; (Publisher: John Wiley and Sons, Inc., New York, N.Y.)
General .reaction technique.20 to
derivatives):. The phenol derivative is reacted with POCl3 either neat or in a solvent such as DCM, MeCN or toluene between 20°C and 120°C, or by reaction of the corresponding alcohol derivatives with PBr3 in a solvent such as DCM, THF or toluene between 20°C and 120°C. Further variations of this transformation can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999; Section halides, p. 703.
General .reaction technique 2 l__(oxm
Oximes and hydrazones are prepared by reaction of the corresponding ketones with respectively hydroxylamine or hydrazine derivatives in a solvent such as pyridine, NMP or aq. EtOH at a temperature ranging between rt and reflux. In case the reagents are used as their hydrochloride salts, a base such as DIPEA or NaOAc can be added. Molecular sieves can also be added to top the water that is formed.
General preparation methods:
Prep ar ation of the c mppunds .of formula I : The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. The compounds of formula I can be manufactured in accordance with the present invention by a) reacting the compounds of formula II
Figure imgf000028_0001
II
wherein R1 and R2 are as defined in formula I, R3a represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (Ci-C4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl, methoxymethyl or acetoxymethyl, with cyanoacetamide following general reaction technique 1 followed if required by a deprotection step using one of the general reaction techniques 2-4; or b) hydrolyzing the compounds of formula III
Figure imgf000028_0002
III
wherein R1 and R2 are as defined in formula I and R4a represents OH or halogen such a chlorine or bromine in presence of aq. TFA between 80°C and 200°C under microwave irradiation: or c) reacting the compounds of formula IV
Figure imgf000029_0001
IV wherein R 1 and R2 are as defined in formula I, with the provisio that R 1 does not represent halogen, and X represents halogen such as chlorine or bromine, either with the compounds of formula V
Rb-NH2
wherein Rb is as defined in formula I or with 2-carboxy-azetidine, followed if required by a deprotection step using general reaction technique 3; or d) deprotecting the compounds of formula VI
Figure imgf000029_0002
VI with an acid using general reaction technique 13; or e) reacting the compound of formula VII
Figure imgf000030_0001
VII
with the compounds of formula VIII
RfONH2
VIII
wherein R is as defined in formula I using general reaction technique 21; or reacting the compounds of formula VII with the compounds of formula IX
RgNHNH2
IX
wherein Rg is as defined in formula I using general reaction technique 21; or reacting the compound of formula X
Figure imgf000030_0002
X wherein, R a represents hydrogen or halogen with the compounds of formula XI
Ra-S02Xa
XI wherein Ra is as defined in formula I and Xa represents a halogen such as chlorine; or h) reacting the compound of formula XII
Figure imgf000031_0001
XII with acetic acid using general reaction technique 5; or reacting the compound of formula XIII
Figure imgf000031_0002
XIII with the compounds of formula XIV
R -COOH
XIV wherein R is as defined in formula I, or an activated form thereof, using general reaction technique 5. reacting the compounds of formula XV
Figure imgf000032_0001
1 2
wherein R and R are as defined in formula I and W represents (CrC4)alkyl with HBr in AcOH. The compounds of formula I thus obtained may be, if desired, converted into their salts, and notably into their pharmaceutically acceptable salts.
Besides, whenever the compounds of formula I are obtained in the form of mixtures of diastereomers, the diastereomers can be separated using methods known to one skilled in the art, e.g. by HPLC over a chiral stationary phase such as a Regis Whelk-01(R,R) (10 μιτι) column, a Daicel ChiralCel OD-H (5-10 μιτι) column, or a Daicel ChiralPak IA (10 μιτι) or AD-H (5 μιη) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as TEA or diethylamine) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min. The mixtures of diasteromers may also be separated by an appropriate combination of silica gel chromatography, HPLC and crystallization techniques.
Preparation of the intermediates used in the .preparation the compounds of formula I:
The compounds of formulae V, VIII, IX, XI or XIV are commercially available or can be obtained by methods known to someone skilled in the art. The other intermediates can be prepared (for example) as described hereafter. Compounds of formula II:
The compounds of formula II can be prepared as summarised in Scheme 1 hereafter.
Figure imgf000033_0001
Figure imgf000033_0002
Scheme 1
In Scheme 1, R1 and R2 are as defined in formula I, R3a represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (CrC4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl, methoxymethyl or acetoxymethyl, R3b represents hydrogen, halogen, hydroxy, 2-(hydroxy)ethoxy, (Ci-C4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl, methoxymethyl or alkoxycarbonyl and R represents benzyl or alkyl such as methyl or ethyl.
The esters of formula 1-1 are reduced with a hydride reagent such as LAH (Scheme 1) using general reaction technique 6 and the resulting alcohol derivatives are oxidized into the corresponding aldehydes using general reaction technique 7. In the particular case wherein R3b is alkoxycarbonyl, the compounds of formula 1-1 are transformed into the corresponding derivatives of formula 1-2 wherein R3a is acetoxymethyl upon reduction and workup. The acetoxymethyl group is transformed into the corresponding hydroxymethyl group during the final cyclization step leading to the formation of the naphthyridine ring.
The compounds of formula II wherein R1 and R2 together represents #-CRdRe-CH2-B-CH2- * wherein Rd represents methyl, Re represents hydroxymethyl, R3 represents H and B represents CH2 can be obtained as summarised in Scheme 2 hereafter.
Figure imgf000034_0001
Figure imgf000034_0002
!i-4 it
Scheme 2
In Scheme 2, Ru and R represent independently from each other benzyl or alkyl such as methyl or ethyl.
The ketone derivatives of formula II- 1 are reacted with the derivatives of formula II-2 affording the pyridine derivatives of formula II-3. The latter are reduced using general technique 6 affording the corresponding diol derivative of formula II-4 which is transformed into the aldehyde of formula II using Mn02 as described in general reaction technique 7.
Compounds of formula III:
The compounds of formula III can be prepared as summarised in Scheme 3 hereafter.
Figure imgf000035_0001
Figure imgf000035_0002
EM (R a = OH) i)E (R a = CL Br}
Scheme 3
In Scheme 3, R1 and R2 are as defined in formula I and R4a represents OH or halogen such as chlorine or bromine.
The esters of formula I- 1 are hydro lyzed into the corresponding carboxylic acid derivatives of formula III-l using general reaction technique 8. The resulting carboxylic acid derivatives are further reacted with triphosgene affording the isatoic acid anhydride derivatives of formula III-2 which are reacted with the sodium anion of malodinitrile affording the derivatives of formula III wherein R4a represents OH. These derivatives can be further transformed into the derivatives of formula III wherein R4a represents halogen using general reaction technique 20.
Compounds of formula IV:
The compounds of formula IV are prepared as described in a) starting from the compounds of formula II wherein R is halogen.
Compound of formula VI:
The compound of formula VI is prepared as described in Scheme 4 hereafter.
Figure imgf000036_0001
Figure imgf000036_0002
VI (V-3
Scheme 4
In Scheme 4, R represents benzyl or alkyl such as methyl or ethyl.
Using the same procedure as used for the preparation of compounds of formula II, the ester derivatives of formula IV- 1 are reduced into the corresponding alcohol derivative of formula IV-2 and oxidized into the aldehyde derivative of formula IV-3 using general reaction techniques 6 and 7 respectively. The aldehyde of formula IV-3 is further transformed into the derivative of formula VI using the method described in a).
Compounds of formula VII:
The compounds of formula VII are prepared by deprotecting the compounds of formula VI using general reaction technique 13.
Compounds of formula X:
The compounds of formula X can be prepared as summarised in Scheme 5 hereafter.
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000037_0003
V-5 X
Scheme 5
In Scheme 5, R2a represents H or halogen, R represents benzyl or alkyl such as methyl or ethyl and PG1 represents an amino protecting group such as Boc or Cbz.
1 2 3
The ester derivatives of formula 1-1 (wherein R represents CI and R and R represent H) are reacted with tributyl(l-ethoxyethenyl)stannane using general reaction technique 9 affording after work-up the acetyl derivatives of formula V-l wherein R2a=H. If required, these compounds can be further transformed into the corresponding derivatives of formula V-2 wherein R2a is bromine by reaction with NBS. Both compounds of formulae V-l and V-2 are reacted with ammonium acetate under reductive amination conditions using general reaction technique 10 affording the amine derivatives of formula V-3 which where sequentially protected using general reaction technique 11 and transformed into the corresponding aldehydes of formula V-4 using general reaction techniques 5 and 6. The aldehydes are further reacted with cyanoacetamide as described in a) and the amino protecting group in the compounds of formula V-5 is removed using general reaction technique 2 affording the compounds of formula X.
Compounds of formula XII:
The compounds of formula XII can be prepared as described in f) by reaction of the compounds of formula VII with 2-(aminooxy)ethanamine.
Compounds of formula XIII:
The compounds of formula XIII can be prepared as summarised in Scheme 6 hereafter.
Figure imgf000038_0001
VI -4 Xll!
Scheme 6 In Scheme 6, R represents benzyl or alkyl such as methyl or ethyl and PG represents an amino protecting group such as Boc or Cbz.
The derivatives of formula IV- 1 are transformed into the ketone derivatives of formula VI- 1 using general reaction technique 13 and reacted with ammonium acetate under reductive amination conditions using general reaction technique 10 affording after protection of the amine group using general reaction technique 11, the derivatives of formula VI-2. These derivatives are transformed into the corresponding aldehydes of formula VI-3 using general reaction techniques 5 and 6. The aldehydes are further reacted with cyanoacetamide as described in a) and the amino protecting group in the compounds of formula VI-4 is removed using general reaction technique 2 affording the compound of formula XIII.
Compounds of formula XV:
The compounds of formula XV are prepared as described in a) starting from the compounds of formula II wherein R is alkoxymethyl.
Compounds of formula 1-1:
The compounds of formula 1-1 wherein R1 is CF3 and R2 is H can be prepared as summarised in Scheme 7 hereafter.
Figure imgf000039_0001
VIM 1-1 (R = CF3; R^ =H)
Scheme 7
In Scheme 7, R represents hydrogen, (CrC4)alkyl, methoxymethyl or 2-(benzyloxy)ethyl and R represents benzyl or alkyl such as methyl or ethyl.
The compounds of formula 1-1 are obtained by reacting the compounds of formula II-2 with a derivative of formula VII- 1 in a solvent such as EtOH at a temperature ranging between rt and reflux. The compounds of formula 1-1 can also be prepared as summarised in Scheme 8 hereafter.
Figure imgf000040_0001
Scheme 8
In Scheme 8, R1 represents (CrC4)alkyl, R2 represents hydrogen or (CrC4)alkyl, and especially the cyclic version wherein R1 and R2 together with the atoms which bear them form a 5, 6 or 7 membered ring and R represents hydrogen, (CrC4)alkyl, heteroalkyl or alkoxycarbonyl, R represent benzyl or alkyl such as methyl or ethyl.
The compounds of formula 1-1 are prepared in analogy to Yakugaku Zasshi (1979), 4, 342-348, by reacting 3-amino-3-imino-propanoic acid alkyl ester (II-2; R = Me or Et) with a derivative of formula VIII- 1.
The compounds of formula 1-1 wherein R 1 represents OH or halogen, R 2 represents (CrC4)alkyl, (C2-C4)alkenyl, arylmethyl or heteroarylmethyl and R3 represents (CrC4)alkyl or R2 and R3 together represent CH2CH2CH2CH2, hereafter referred to respectively as the compounds of formula I- l9a when R1 is OH and as the compounds of formula 1-1% when R1 is halogen, can also be prepared as summarised in Scheme 9 hereafter.
Figure imgf000041_0001
Figure imgf000041_0002
Scheme 9
In Scheme 9, R represents (CrC4)alkyl, (C2-C4)alkenyl, arylmethyl and heteroarylmethyl, R3 represents (CrC4)alkyl or R2 and R3 together represent CH2CH2CH2CH2, R and Rv independently from each other represents benzyl or alkyl such as methyl or ethyl, Xb represents a halogen such as chlorine or bromine.
The compounds of formula I-l9a are obtained by reacting the derivatives of formula II-2 with the ester derivatives of formula IX- 1 (Scheme 9). The derivatives can be further transformed into the derivatives of formula 1-1% by reaction with POCI3 or PBr3 using general reaction technique 20.
The compounds of formula I-l wherein R1 is haloalkyl, (CrC4)alkyl or halogen such as chlorine, R 3 is hydrogen, (CrC4)alkyl, halogen, hydroxy, methoxymethyl and R 2 is halogen such as bromine or chlorine can be obtained as summarised in Scheme 10 hereafter.
Figure imgf000042_0001
i-1 (R2 ~ Η)
Scheme 10
In Scheme 10, R1 represents haloalkyl, (CrC4)alkyl or halogen such as chlorine, Xc represents chlorine or bromine, R represents hydrogen, (CrC4)alkyl, halogen, hydroxy or methoxymethyl and R represents benzyl or alkyl such as methyl or ethyl.
The compounds of formula I-l wherein R2 is H are reacted with NBS, bromine or NCS affording the compounds of formula I-l wherein R2 is halogen such as chlorine or bromine.
1 2
The compounds of formula I-l wherein R represents CF3 and R represents (Ci-C4)alkyl or (C2-C4)alkenyl can be obtained as summarised in Scheme 1 1 hereafter.
Figure imgf000042_0002
(R7 = -CH=C¾)
Figure imgf000042_0003
1-1 (R 1 = CF3, R2 = Ei)
Scheme 11 2 3
In Scheme 11, R represents (Ci-C4)alkyl or (C2-C4)alkenyl, R represents hydrogen, (Ci-C4)alkyl or methoxymethyl and R represents benzyl or alkyl such as methyl or ethyl.
Compounds of formula XI- 1 are alternatively reacted with an organozinc compound such as dimethylzinc using general reaction technique 14, with an organoboron derivative such as 2,4,6-trivinylcyclotriboroxane complex using general reaction technique 75 or in the case wherein R2 is cyclopropyl with potassium cyclopropyltrifluoroborate (commercial) in using general reaction technique 15. Compounds of formula I-l wherein R represents ethyl are obtained by hydrogenation of the corresponding compounds wherein R is vinyl over a noble metal catalyst such as Pd on charcoal or platinum oxide.
The compounds of formula I-l wherein R1 is CF3 and R3 is vinyl or halogen can be obtained as summarised in Scheme 12 hereafter.
Figure imgf000043_0001
Figure imgf000043_0002
1-1 (R1 = CF3, R3 = C!) 1-1 (R = CF3, Ra = -CH=CH2)
Scheme 12
In Scheme 12, R represents hydrogen, halogen, (Ci-C4)alkyl and R represents benzyl or alkyl such as methyl or ethyl.
1 3
The compounds of formula I-l wherein R represents CF and R represents OH are transformed into the corresponding triflate derivatives of formula XII- 1 using general reaction technique 16 and reacted with a tn'-butylalkenyl tin reagent such as tn'-butylethenyl-stannane using general reaction technique 9. The compounds of formula
I-l wherein R represents CI are obtained by treating the compounds of formula I-l wherein R 1 represents CF3 and R 3 represents OH with POCl3 using general reaction technique 20. Alternatively the compounds of formula I-l wherein R1 represents CF3 and
R represents vinyl can be obtained from the corresponding compounds of formula I-l wherein R represents CI using general reaction technique 9 or 15. The compounds wherein R represents (C3-C4)alkenyl can be obtained by using the same methods.
The compounds of formula I-l wherein R 1 and R 2 together represents #-CRcRd-CH2-B-CH2-* and B represents CHOH, hereafter referred to as the compounds of formula I-l13, can be obtained as summarised in Scheme 13 hereafter.
Figure imgf000044_0001
XM-1 ΧΙΪΙ-2
Figure imgf000044_0002
Xifl-3 1-1 13
Scheme 13
In Scheme 13, R represents benzyl or alkyl such as methyl or ethyl.
The ketone derivative of formula XIII- 1 is reacted with derivatives of formula II-2 affording the pyridine derivatives of formual XIII-2. The latter are treated under aq. acidic conditions, using general reaction technique 13, affording the ketone derivatives of formula XIII-3 which are further reduced into the corresponding alcohol derivatives of formula I-l12 using a hydride reagent such as NaBH4 using general reaction technique 6.
The compounds of formula 1-1 wherein R 1 and R 2 together represent #-CRc(Me)-A-CH2-CH2-*, R3 represents H, A represents CHR1, Rc represents methyl and R1 represents OH, hereafter referred to as the compounds of formula I-l14, can be obtained as summarised in Scheme 14.
Figure imgf000045_0001
Scheme 14
In Scheme 14, R represents benzyl or alkyl such as methyl or ethyl.
The ketone derivative of formula XIV- 1 is reacted with the derivative of formula II-2 affording the pyridine derivatives of formula IV- 1. The latter are treated under aq. acidic conditions using general reaction technique 13 to afford the ketone derivatives of formula VI-2 which are further reduced into the corresponding alcohol derivatives of formula I- 1 using a hydride reagent such as NaBH4 using general reaction technique 6.
The compounds of formula 1-1 wherein R 1 and R 3 each independently represent (CrC4)alkyl and R represents H, hereafter referred to as the compounds of formula I-l15, can be obtained as summarised in Scheme 15 hereafter.
Figure imgf000046_0001
XV-1 XV-2 XV-4
Figure imgf000046_0002
1-1 15
Scheme 15
1 3 3
In Scheme 15, R and R represent (CrC4)alkyl, PG represents an amine protecting group such as ?ara-methoxybenzyl and R represents benzyl or alkyl such as methyl or ethyl.
The derivatives of formula XV-1 are reacted with the diketone derivatives of formula XV- 2 and an amine of formula XV-3 in the presence of a base such as KOH in a solvent such as EtOH between 50°C and 100°C. The resulting pyridine derivatives of formula XV-4 are reacted with TFA affording the compounds of formula I-l 15.
1 2
The compounds of formula 1-1 wherein R represents (Ci-C4)alkyl or (C2-C4)alkenyl, R represents H and R represents halogen such as chlorine or bromine, hereafter referred to
1 2 3 respectively as the compounds of formula I-l 16a when R is (C2-C4)alkenyl, R is H and R
1 2 3 is Cl and as the compounds of formula I- l i 6b when R is (CrC4)alkyl, R is H and R is CI, can be obtained as summarised in Scheme 16 hereafter.
Figure imgf000047_0001
Scheme 16
In Scheme 16, Rz represents H or (C C2)alkyl and R represents benzyl or alkyl such as methyl or ethyl.
The amino derivatives of formula I-l wherein R 1 and R3 represent chlorine, R 2 represents H are reacted with the required boron derivatives (2,4,6-trivinylcyclotriboroxane-pyridine complex when RZ = H; 2,4,6-tri(l-methyl-ethenyl)cyclotriboroxane-pyridine complex when Rz = Me) using general reaction technique 15. The resulting derivatives of formula I-l16a are hydro genated over a noble metal catalyst such as Pd on charcoal or the Lindlar catalyst affording the compounds of formula I-l 16b- The compounds of formula I-l wherein R 1 represents CF3, R 2 represents H or bromine and R represents OH, benzyloxy or chlorine, hereafter referred to as the compounds of formula I-l1 , can be obtained as summarised in Scheme 17 hereafter.
Figure imgf000048_0001
XV1I-2
Figure imgf000048_0002
l-117 (R2= H , R3^OH) XVl!-3
Figure imgf000048_0003
Figure imgf000048_0004
-11?(R2= R3=Ci) M17(R2=hf R3=QBn} M^iR^Br. R3 = CS)
Scheme 17
In Scheme 17, PG represents a phenol protecting group such as benzyl or?ara-methoxybenzyl, PG5 represents 2,4-dimethoxybenzyl and R represents benzyl or alkyl such as methyl or ethyl.
The compounds of formula XVII- 1 are sequentially reacted with a benzyl alcohol derivative such as ?ara-methoxybenzylalcohol in presence of a base such as NaH and then with a benzylamine derivative such as 2,4-dimethoxybenzylamine at a temperature ranging between 80°C and reflux affording the derivatives of formula XVII-3. Protecting groups are cleaved using TFA affording the derivatives of formula I-l1 wherein R represents H and R represents OH. These derivatives are further transformed into the chloro derivatives of formula I-l17 wherein R 2 represents H and R 3 represents CI by reaction with POCl3 using general reaction technique 20. The compounds of formula XVII-3 can also be reacted with NBS, affording the corresponding bromo derivatives which are further transformed into the derivatives of formula I-l17 wherein R 2 represents Br and R 3 = CI using the same procedures as for the conversion of compounds of formula I-l17 wherein R represents H and R 3 represents OH into the compounds of formula I-l1 wherein R 2 represents H and R 3 represents CI. The derivatives of formula I-l1 wherein R 1 represents CF3 and R represents OH can be reacted with benzyl alcohol under Mitsunobu conditions (using PPh3 and either DEAD or DIAD), affording the compounds of formula I-l17 wherein R1 = CF3, R2 = H and R3 = OBn.
The compounds of formula 1-1 wherein R 1 represents CI, R2 represents H and R 3 represents CI, hereafter referred to as the compounds of formula 1-118, can be obtained as summarised in Scheme 18 hereafter.
Figure imgf000049_0001
XVfit-1 XVIf i-2
Scheme 18
In Scheme 18, R represents benzyl or alkyl such as methyl or ethyl.
The ketone derivatives of formula XVIII- 1 are reacted with cyanamide affording the dihydroxy-pyridine derivatives of formula XVIII-2 which are further transformed into the dichloro derivatives of formula I-l18 using general reaction technique 20.
The required compounds of formula 1-1 used as starting material in the schemes 1, 3, 5, 10-12 and 16 can be made according to one of the general methods described in schemes 7-18. Compounds of formula VIII- 1:
The compounds of formula VIII- 1 wherein R3 represents H and R1 and R2 together form a cyclic ring are obtained as summarised in Scheme 19 hereafter.
Figure imgf000050_0001
XIX-1 VIII-1 (R3
Scheme 19
1 2
In Scheme 19, the dotted line indicates that R and R together with the two carbon atoms which bear them are part of a cycle.
The compounds of formula VIII-1 are prepared from compounds of formula XIX-1 according to general reaction technique 12. The compounds of formula XIX-1 represent the following structures XIX- la to XIX- Id wherein Rc represents H or methyl, Rd represents H or methyl, Re represents H, methyl, OH, COORw or Rd and Re together represent -(CH2)4-, A represents l,3-dioxolan-2-yl, NRJ wherein RJ represents benzyl or CHR1 wherein R1 represents 2-hydroxyethyl or OH, B represents CH2CH2, CH2, O, S or a bond and PG6 represents an alcohol protecting group such as TBDMS or TBDMS and Rw represents benzyl, alkyl such as methyl or ethyl:
Figure imgf000050_0002
XIX-1 a XIX-1 b XIX-1 c XIX-1 d
These compounds are commercially available or can be obtained as described in Scheme 20 hereafter.
Figure imgf000051_0001
Figure imgf000051_0002
xx-s XX-6 XiX-1c
Scheme 20
In Scheme 20, A represents l,3-dioxolan-2-yl, B represents CH2CH2, CH2; O, S, l,3-dioxolan-2-yl or a bond, Re represents methyl or alkoxycarbonyl, Rc and Rd represent methyl or H and PG6 represents a alcohol protecting group such as TBDPS or TBDMS.
The compounds of formula XX-1 wherein A represents l,3-dioxolan-2-yl are reacted with methyl iodide affording the derivatives of formula XX-2. The latter derivatives can be further alkylated with methyl iodide or dimethyl sulphate affording the derivatives of formula XIX- la wherein Rc represents methyl. The compound of formula XIX- la wherein A represents N-benzyl and Rc represents methyl is prepared as described in Tetrahedron (2006), 62, 6361. The compounds of formula XX-3 wherein B represents CH2CH2, CH2, O, S, 1,3-dioxolan- 2-yl or a bond are reacted with methyl iodide or dimethyl sulphate after deprotonation with a base such as LDA in THF at -78°C or tBuOK in THF between -20°C and rt, affording the derivatives of formula XX-4 wherein Re represents methyl. The latter derivatives can be further alkylated with methyl iodide affording the derivatives of formula XIX- lb wherein Rd and Re represent methyl. The lithio anion of derivatives of formula XX-3 can also be reacted with a formate source such as ethyl cyanoformate affording the derivatives of formula XX-4 wherein Rd represents alkoxycarbonyl. The compound of formula XIX- lb wherein B represents CH2, Re represents H or methyl and Re represents OH is prepared according to Synlett (2004), 2111-2114.
The aldehyde of formula XX-5 (prepared according to J. Org. Chem. (1993), 58, 2931-2932) is reduced using general reaction technique 6 affording the alcohol derivative of formula XX-6 which is protected using general reaction technique 19 affording the compounds of formula XIX- lc. The compound of formula XIX- Id is commercially available (or prepared according to J. Org. Chem. (1997), 62, 6888-6896). The compounds of formulae XX-1 and XX-3 are commercially available (B = O or S) or prepared according to known procedures (A = 1,3- dioxolan-2-yl; Synth. Commun. (1984), 38, 851-854)
The compound of formula XIX- la wherein Rc represents methyl and A represents CHR1 and R1 represents 2-hydroxyethyl is prepared as described in Scheme 21 hereafter.
Figure imgf000053_0001
Figure imgf000053_0002
XXJ- XXf-5 XXf-6 (G » OPG7}
XIX-1a (Q = OH)
Scheme 21
In Scheme 21, Q represents OH or OPG7, PG7 represents an alcohol protecting group such as TBDPS.
The ketone of formula XXI- 1 prepared according to Tetrahedron Asymmetry (1996), 2497- 2450 is reacted with (methoxycarbonylmethylene)triphenylphosphorane and the resulting compound of formula XXI-2 is hydrogenated over a noble metal catalyst such as Pd on charcoal or platinum oxide affording the compound of formula XXI-3. The resulting ester function is reduced using general reaction technique 6 and the resulting alcohol derivative of formula XXI-4 is protected using general reaction technique 19. Finally, the ketone protecting group is removed using general reaction technique 13 affording the compounds of formula XXI-6 wherein Rc represents methyl and A represents CHR1 and R1 represents CH2CH2OPG . The latter can be transformed into the derivative of formula XIX- la wherein A represents CHR1 and R1 represents 2-hydroxyethyl using general reaction technique 3.
Compounds of formulae II- 1, XIII- 1 and XIV- 1:
The compounds of formulae II- 1 , XIII- 1 and XIV- 1 are prepared as described in Scheme 19. The required starting ketones are either commercially available (1 -methyl- 2-oxo-cyclohexanecarboxylic acid ethyl ester) or prepared J. Org. Chem. (2010), 75, 7146-7158 (6,6-dimethyl-l ,4-dioxaspiro[4.5]decan-7-one) and WO 01/064685 (7,7-dimethyl-l ,4-dioxaspiro[4.5]decan-8-one).
Compounds of formula XVII- 1:
The compounds of formula XVII- 1 can be obtained as summarised in Scheme 22 hereafter.
Figure imgf000054_0001
XX!l-1 XXIt-2 XXII-3
Figure imgf000054_0002
XVIi-1
Scheme 22
In Scheme 22, Rw and R represent independently from each other benzyl or alkyl such as methyl or ethyl. The malonyl chlorides of formula XXII- 1 are reacted with the trifluorocrotonate derivatives of formula XXII-2 affording the dihydroxy-pyridine derivatives of formula XXII-3 which are further transformed into the dichloro derivatives of formula XVII- 1 using general reaction technique 20. The compounds of formula II-2 are commercially available or prepared in analogy to Chem. Pharm. Bull. (1995), 43, 797-817.
The compounds of formula VII-1 are prepared in analogy to WO 2007/045868.
The compounds of formula VIII- 1 wherein R 1 and R 2 represent together #-CRdRe-CH2-B-CH2-*, wherein Rd and Re represent methyl and B represents CH2 and R3 represents alkoxycarbonyl are prepared in analogy to Bull. Soc. Chim. Fr. (1957), 1499. Other analogues of VIII- 1 wherein R3 represents alkoxycarbonyl are prepared by reacting the compounds of formula XIX- 1 with diethyl oxalate in presence of a base such as NaOEt or NaH.
The compounds of formula XV- 1 are prepared in analogy to J. Med. Chem. (1991), 34, 2468-2473.
The compounds of formula XVIII-2 are prepared in analogy to Tetrahedron (2005), 61, 2779-2794.
The compounds of formulae VIII- 1, IX- 1, XV-2, XVIII- 1 or XIX- 1, if not specifically described, are either commercially available or prepared according to one skill in the art methods.
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.
EXAMPLES
All temperatures are stated in °C. Unless otherwise indicated, the reactions take place at rt. Analytical TLC characterisations are performed with 0.2 mm plates: Merck, Silica gel 60 F254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection is done with UV or with a solution of KMnO4 (3 g), K2CO3 (20 g), 5% NaOH (3mL) and H2O (300mL) with subsequent heating. Prep-TLCs are performed with 2.0 mm plates: Merck, Silica gel 60 F254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection is done with UV.
CCs are performed using Brunschwig 60A silica gel (0.032-0.63mm), Redisep Rf® cartridges from Teledyne ISCO; elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. In the cases of compounds containing a basic function (e.g. amine), 1% of NH4OH (25% aq.) is added to the eluent(s).
Prep-HP LCs are performed on XBridge Prep C18 columns from Waters. The following conditions are used:
Eluents: A: H20 + 0.1% acidic or basic additive; B: MeCN + 0.1%> acidic or basic additive;
- Gradient: 5% B→ 95% B over 5 min.
- Detection: UV/Vis and/or MS and/or ELSD.
- Method A: Prep-HPLC (basic conditions): additive in A and B is 0.1% NH4OH.
- Method B: Prep-HPLC (acidic conditions): additive in A and B is 0.1% HC02H. LC-MSs are performed on Sciex API 2000 with Agilent 1100 Binary Pump with DAD and ELSD; or Agilent quadrupole MS 6140 with Agilent 1200 Binary Pump, DAD and ELSD; or Thermo Finnigan MSQ Surveyor MS with Agilent 1100 Binary Pump, DAD and ELSD; or Thermo MSQ Plus with Dionex GHP 3200 Binary Pump, DAD and ELSD. The number of decimals given for the [M+H+] peak of each tested compound depends upon the accuracy of the LC-MS device actually used.
NMR spectra are recorded on a Varian Mercury 300 (300 MHz) spectrometer unless indicated otherwise ("400 MHz" being used to mean a Bruker Avance 400 (400 MHz) spectrometer). Chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quadruplet, p = pentuplet, hex = hexuplet, hept = heptuplet, m = multiplet; br. = broad; app. = apparent; coupling constants are given in Hz. PREPARATIONS:
Preparation A: r c-2-amino-7-(l-aminoethyl)-6-bromo-l,8-naphthyridine- 3-carboxamide:
A.i. Methyl 6-acetyl-2-aminonicotinate: Methyl 2-amino-6-chloronicotinate (1.0 g, 5.359 mmol), bis(triphenyl)palladium dichloride (0.20 g, 0.287 mmol) and toluene (lOmL) were introduced in reaction vessel. Once the vessel flushed with nitrogen, tributyl(l-ethoxyvinyl)tin (2.35 mL, 6.953 mmol) was added and the reaction mixture was heated at +100°C for 2 days with vigorous stirring. After cooling to rt, EA (50 mL) was added and the resulting slurry was filtered through Celite. After concentration to dryness, the residue was taken up in THF (70 mL) and 6N HC1 (10 mL) was added. The reaction proceeded for 2 h at rt and then at +40°C for 30 min. The volatiles were removed under reduced pressure and the pH of the resulting aq. layer was adjusted to 7 by adding NaHCO3. The aq. layer was then extracted with EA (2 x 50 mL). The combined org. layers were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 5: 1) affording the title ketone as a yellow powder (6.53 g, 90% yield).
1H NMR (ί 6-DMSO) δ: 8.20 (d, J = 8.0 Hz, 1H); 7.32 (br. s, 2H); 7.13 (d, J = 8.0 Hz, 1H);
3.81 (s, 3H); 2.54 (s, 3H).
MS (ESI, m/z): 195.2 [M+H+] for C9Hi0N2O3. A.ii. Methyl 6-acetyl-2-amino-5-bromonicotinate:
To a solution of intermediate A.i (3.25 g, 16.7 mmol) in MeCN (100 mL) was added NBS (3.27 g, 18.4 mmol). The reaction proceeded for 7 h at rt. The reaction mixture was concentrated to dryness and directly subjected to CC (Hept/EA 4: 1) affording the title bromide as a yellow powder (4.03 g, 88% yield).
1H NMR (ί 6-DMSO) δ: 8.21 (s, 1H); 7.44 (br. s, 2H); 3.82 (s, 3H); 2.50 (s, 3H).
A.iii. Rac-methyl 2-amino-5-bromo-6-(l-((tert-butoxycarbonyl)amino)ethyl)nicotinate:
To a solution of intermediate A.ii (1 g, 3.66 mmol) and NH4OAc (4.5 g, 58.59 mmol) in MeOH (40 mL) was added NaBH3CN (1.15 g, 18.309 mmol). The solution was heated at +90°C for 2 h. The reaction mixture was cooled to rt, and partitioned between EA (100 mL) and sat. NaHC03 (30 mL). The combined org. layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was taken up in DCM (10 mL). TEA (0.43 mL, 3.1 mmol) and Boc20 (0.74 g, 3.4 mmol) were added. The reaction was stirred at rt for 2 h. Water (30 mL) was added and the two layers were separated. The aq. layer was extracted once with DCM (50 mL). The combined org. layers were washed with brine (30 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (Hex/EA 4:1) affording the title compound as a white foam (0.83 g, 72% yield).
1H NMR (ί 6-DMSO) δ: 8.08 (s, 1H); 7.25 (br. s, 2H); 6.71 (m, 1H); 4.84 (m, 1H); 3.79 (s, 3H); 1.35 (s, 9H); 1.24 (d, J = 6.7 Hz, 3H).
MS (ESI, m/z): 377.2 [M+H+] for Ci4H2oN304Br.
A.iv. Rac-tert-butyl (l-(6-amino-3-bromo-5-(hydroxymethyl)pyridin-2-yl)ethyl)carbamate:
To an ice-chilled solution of the intermediate A.iii (0.83 g, 2.2 mmol) in THF (7 mL) was added dropwise a LAH solution (IM in THF, 1.77 mL, 1.77 mmol). The reaction proceeded for 30 min at the same temperature and water (0.17 mL), 4N NaOH (0.3 mL) and water (0.3 mL) were successively added. After stirring 15 min, the resulting suspension was filtered and the solids were washed with EA (30 mL). The filtrate was concentrated to dryness affording the title alcohol as a yellowish foam (0.776 g, quant, yield).
MS (ESI, m/z): 348.0 [M+H+] for Ci3H20N3O3Br.
A.v. Rac-tert-butyl (l-(6-amino-3-bromo-5-formylpyridin-2-yl)ethyl)carbamate:
To a solution of intermediate A.iv (0.766 g, 0.22 mmol) in DCM (5 mL) was added Mn02 (2.92g, 33.6 mmol). The reaction mixture was heated to reflux for 30 min. After cooling, the reaction mixture was filtered through a pad of Celite and the filter cake was washed with DCM (10 mL). The filtrate was concentrated to dryness affording the title aldehyde (0.624g, 81% yield) as a yellowish foam.
MS (ESI, m/z): 344.0 [M+H+] for Ci3Hi8N303Br. A.vi. Rac-tert-butyl (l-(7-amino-3-bromo-6-carbamoyl-l,8-naphthyridin-2-yl)ethyl) carbamate:
TMG (0.228 mL, 1.81 mmol) was added to a mixture of intermediate A.v (0.624 g, 1.81 mmol) and cyanoacetamide (0.381 g, 4.52 mmol) in EtOH (5 mL). The reaction mixture was refluxed for 30 min. After cooling, the solid was filtered off, taken up in water and slurried for 1 h. After filtration, the solid was dried to constant weight affording the title carboxamide as a yellow powder (0.309 g, 42% yield). The mother liquor was concentrated to dryness and purified as before to afford in a 58% combined yield the title compound (0.440 g).
1H NMR (ί 6-DMSO) δ: 8.40 (s, 1H); 8.31 (s, 1H); 8.23 (br. s, 1H); 7.67 (br. s, 1H); 7.53 (br. s, 2H); 7.09 (br. s, 2H); 5.08 (m, 1H); 1.32-1.38 (m, 12H).
MS (ESI, m/z): 409.0 [M+H+] for C16H2oN503Br.
A. vii. Rac-2-amino-7-(l-aminoethyl)-6-bromo-l,8-naphthyridine-3-carboxamide:
Intermediate A.v (0.440 g, 1.075 mmol) was taken up in a HC1 solution (1.25 in EtOH, 15 mL). After stirring for 4 h, the solvent was removed in vacuo and the residue was dissolved in sat. NaHCO3 until pH 9 was reached. The mixture was concentrated to dryness and the residue was stirred in EA (10 mL) with water (3 mL). The resulting solid was filtered off and dried to constant weight affording the title amine as a yellow powder (0.19 g, 90% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.30 (s, 1H); 8.23 (br. s, 1H); 7.67 (br. s, 1H); 7.55 (br. s, 2H); 4.42 (q, J = 6.6 Hz, 1H); 1.30 (d, J = 6.6 Hz, 3H).
Preparation B: rac-tert-butyl 4-(aminooxy)- 2-((terf-butoxycarbonyl)amino)butanoate:
B. i. Rac-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-((l,3-dioxoisoindolin- 2-yl)oxy)butanoate
Typical procedure for a Mitsunobu-type reaction.
To a solution of rac-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-((l,3-dioxoisoindolin-2- yl)oxy)butanoate (2.09 g, 7.6 mmol, 1 eq.) in DCM (35 mL) were added N-hydroxyphthalimide (1.5 g, 9.24 mmol, 1.2 eq.) and PPh (3.081 g, 411.7 mmol, 1.5 eq.). The reaction mixture was cooled to 0°C and DIAD (2.4 mL, 11.4 mmol, 1.5 eq.) was added at this temperature. After 30min, the reaction mixture was allowed to warm up to rt and stirred overnight. The solvent was removed under reduced pressure and the residue was purified by CC (Hept/EA 3:2) affording a colourless residue. The residue was sonicated and stirred in EtOH (10 mL) for 30 min. The solid was collected by filtration, washed and dried in vacuo to constant weight, affording the title phthalimide derivative as a white solid (1.33 g, 55% yield).
MS (ESI, m/z): 443.0 [M+Na+] for C2iH28N207.
B. ii. Rac-tert-butyl 4-(aminooxy)-2-((tert-butoxycarbonyl)amino)butanoate :
Typical procedure for the deprotection of a phthalimido protecting group.
To an ice-chilled solution of intermediate B.ii (1.32 g, 3.15 mmol, 1 eq.) in DCM (30 mL) was added hydrazine monohydrate (0.814 mL, 15.7 mmol, 5 eq.). The cooling bath was removed and the reaction proceeded during 1 h at rt. The resulting precipitate was filtered and washed with DCM. The filtrate was dried over MgS04, filtered, evaporated to dryness to give an oil (0.938 g, quantitative yield) which crystallized on standing.
MS (ESI, m/z): 291.2 [M+H+] for Ci3H26N205.
Preparation C: ethyl 2-amino-4-hydroxy-6-(trifluoromethyl)nicotinate:
C. i. Ethyl 2, 4-dichloro-6-(trifluoromethyl)nicotinate:
A mixture of ethyl 2,4-dihydroxy-6-(trifluoromethyl)nicotinate (prepared according to WO 2007/093901, 19 g, 75.6 mmol), POCl3 (27.7 mL, 300 mmol, 4 eq.) and DMF (23.4 mL, 0.3 mol, 4 eq.) was heated at +90°C for 30 h. More POCl3 (2 mL) was added and the reaction mixture was further refluxed for 2 days. The volatiles were removed in vacuo. The residue was dissolved in DCM (160 mL) and slowly poured into water (1 L). The pH was adjusted to 5 by adding K2CO3. The aq. solution was extracted with DCM (2 x 500 mL). The combined org. layers were dried, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 9: 1), affording the title ester as a colourless oil (15.44 g, 71% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H), 4.46 (q, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 2H). C.ii. Ethyl 2-chloro-4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)nicotinate:
To an ice-chilled solution of intermediate C.i (15.47 g, 53.7 mmol) and 4-methoxybenzylalcohol (6.7 mL, 53.7 mmol) in DMF (120 mL) was added portionwise NaH (60% dispersion in oil, 2.06 g, 53.7 mmol, 1 eq.) at 0°C. The reaction proceeded for 90 min at 0°C. Water (100 mL) was carefully added. The mixture was extracted with EA (2 x 150 mL) and the combined org. layers were washed with brine (30 mL), dried over MgS04 and concentrated to dryness. The residue was purified by CC (Hept/EA 4:1) affording the title ether as a white solid (16.31 g, 78%> yield).
1H NMR (ί 6-DMSO) δ: 7.88 (s, 1H); 7.34 (d, J = 8.7 Hz, 2H); 6.95 (d, J = 8.7 Hz, 2H); 5.37 (s, 2H); 4.32 (q, J = 7.1 Hz, 2H); 3.74 (s, 3H); 1.19 (t, J = 7.1 Hz, 3H).
C. in. Ethyl 2-((3, 4-dimethoxybenzyl)amino)-4-((4-methoxybenzyl)oxy)- 6-(trifluoromethyl)nicotinate:
A mixture of intermediate C.ii (16.3 g, 41.8 mmol) and 3,4-dimethoxybenzylamine (25.4 mL, 167 mmol), was heated at +100°C for 45 min. The reaction mixture was then diluted with EA/MeOH (9:1, 100 mL). The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by CC (Hept/EA 7:3) affording the title compound as a white solid (14.4 g, 67%> yield).
1H NMR (ί 6-DMSO) δ: 7.61 (t, J = 5.8 Hz, 1H); 7.34 (d, J = 8.8 Hz, 2H); 6.89-6.94 (m , 5H); 5.19 (s, 2H); 4.45 (d, J = 5.8 Hz, 2H); 4.32 (q, J = 7.1 Hz, 2H); 3.73 (s, 3H); 3.68 (s, 3H); 3.67 (s, 3H); 1.19 (t, J = 7.1 Hz, 3H).
Civ. Ethyl 2-amino-4-hydroxy-6-(trifluoromethyl)nicotinate :
A mixture of intermediate C.iii (10.57 g, 20.3 mmol) in TFA (50 mL) was heated at +60°C for 2 h. The volatiles were removed in vacuo and the residue was diluted with water (200 mL). The pH was adjusted to 7 by adding solid NaHC03. The resulting mixture was extracted with EA (2 x 200 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was recrystallized from EA/Hex mixture. The desired product was obtained as a white powder (3.44 g).
1H NMR (ί 6-DMSO) δ: 11.70 (s, 1H); 7.17 (br. s, 2H); 6.50 (s, 1H); 4.34 (m, 2H); 1.29 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 251.0 [M+H+] for C9H9N203F3 Preparation D: ethyl 2-amino-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridine- 3-carboxylate:
D.i. Sodium (Z)-(l-benzyl-2,2-dimethyl-3-oxopiperidin-4-ylidene)methanolate:
In ether (15 mL), small chunks of Na (0.2 g, 9.295 mmol). HC02Et (1.1 mL, 13.6 mmol) and a solution of l-benzyl-2,2-dimethylpiperidin-3-one (prepared according to Tetrahedron (2006), 62(26), 6361-6369; 2.02 g, 9.3 mmol) in ether (5 mL) were introduced successively. The mixture was cooled to 0°C and EtOH (0.05 mL) was added. The mixture was stirred at rt overnight. EtOH (0.1 mL) was added and stirring was maintained for 2 h. The solid was collected by filtration under nitrogen, washed scarcely with ether, dried under vacuum affording the title compound as a beige solid (1.30 g, 52% yield).
1H NMR (ί 6-DMSO) hydrolyzed enolate δ: 9.16 (s, 1H); 8.50 (s, 1H); 7.08-7.36 (m, 5H); 3.48 (s, 2H); 2.30 (t, J = 5.7 Hz, 2H); 1.94 (t, J = 5.7 Hz, 2H); 1.12 (s, 6H).
D. ii. Ethyl 2-amino- 7-benzyl-8, 8-dimethyl-5, 6, 7,8-tetrahydro-l, 7 -naphthyridine- 3-carboxylate:
Typical cylization reaction involving a sodio enolate.
To a mixture of intermediate D.i. (prepared according to J. Heterocyclic Chem. (1989), 26(3), 705-708; 1.29 g, 4.85 mmol) in THF (20 mL) and AcOH (0.31 mL, 5.34 mmol) was added ethyl 3,3-diaminoacrylate (0.63 g, 4.853 mmol). The mixture was stirred at rt overnight. The reaction mixture was quenched by adding sat. NaHCO3 (15 mL). The two layers were separated and the aq. layer was extracted twice with EA (2 x 50 mL). The combined org. layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by CC (EA/Hept 1:7) affording the title compound as a yellowish solid (1.15 g, 70% yield).
1H NMR (ί 6-DMSO) δ: 7.73 (s, 1H); 7.16-7.40 (m, 5H); 6.83 (br. s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 3.66 (s, 2H); 2.52-2.56 (m, 2H); 2.48-2.50 (overlapped m, 2H); 1.42 (s, 6H); 1.27 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 340.2 [M+H+] for C20H25N3O D. in. Ethyl 2-amino-8, 8-dimethyl-5, 6, 7,8-tetrahydro-l, 7-naphthyridine-3-carboxylate:
To a solution of intermediate D.ii (1.15 g, 3.4 mmol) in EtOH (20 mL) and MeOH (25 mL) was added 10% Pd/C (0.64 g). The reaction vessel was flushed with nitrogen and let under hydrogen atmosphere overnight. The reaction mixture was diluted with EA (160 mL) and the catalyst was removed by filtration over Celite. The filtrate was concentrated to dryness affording the title amine as a yellow solid (0.86 g).
1H NMR (ί 6-DMSO) δ: 7.70 (s, 1H); 6.77 (br. s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 2.83-2.91 (m, 2H); 2.66 (br. s, 1H); 2.52-2.58 (m, 2H); 1.28 (s, 6H); 1.27 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 240.2 [M+H+] for C13H19N3O2
Preparation E: (2-amino-8,8-dimethyl-5,6,7,8-tetrahydro-l,7-naphthyridin- 3-yl)methanol:
Starting from intermediate D.ii (8.61 g, 25.4 mmol), the title alcohol was obtained as a yellow solid (5.1 g) using the procedures described in Example 1, step l.ii (ester reduction: 100%) yield) and Preparation D, step D.iii (benzyl cleavage: 99% yield).
1H NMR (ί 6-DMSO) δ: 6.99 (s, 1H); 5.28 (br. s, 2H); 5.00 (t, J = 5.4 Hz, 1H); 4.27 (d, J = 5.1 Hz, 2H); 2.85 (t, J = 5.8 Hz, 2H); 2.50 (overlapped t, J = 5.8 Hz, 2H); 1.92 (br. s, 1H); 1.26 (s, 6H).
Preparation F: 2-aniino-3-(hydroxymethyl)-8,8-dimethyl-5,6-dihydroquinolin- 7(8H)-one
F. i. Ethyl 2 '-amino- 5, 5, 8 ',8 '-tetramethyl-6 ', 8 '-dihydro-5 'H-spiro[[l, 3]dioxane- 2, 7'-quinolineJ-3'-carboxylate :
Typical procedure for sodium etiolate formation followed by a cyclization reaction.
Small chunks of Na (2.7 g, 118 mmol) were introduced in ether (250 mL). HC02Et (14.2 mL, 176 mmol, 1.5 eq.), a solution of 3,3,7,7-tetramethyl- l,5-dioxaspiro[5.5]undecan-8-one (26.67 g, 118 mmol, 1 eq.) in ether (120 mL) and EtOH (0.5 mL) were successively added. The mixture was stirred at rt overnight. The reaction mixture was diluted with THF (650 mL). Ethyl 3,3-diaminoacrylate (15.36 g, 118 mmol, 1.0 eq.) and AcOH (8 mL, 140 mmol, 1.187 eq.) were added. The resulting mixture was heated to +60°C for 3 h. The reaction mixture was cooled to rt, and diluted with sat. NaHC03 (500 mL) and EA (600 mL). The aq. layer was extracted once with EA (600 mL). The combined org. layers were washed with brine (150 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 9: 1), affording the title compound as a light yellow solid (30 g, 73% yield).
MS (ESI, m/z): 349.2 [M+H+] for C19H28N204.
F. ii. (2 '-amino-5, 5,8',8 '-tetramethyl-6 ', 8 '-dihydro-5 'H-spiro[[l, 3]dioxane-2, 7'-quinolin] - 3 '-yl)methanol :
To a solution of intermediate F.i (10 g, 28.8 mmol, 1 eq.) in THF (250 mL), cooled at 0°C was added portion wise solid LAH (1.18 g, 30.9 mmol, 1.077 eq.). The mixture was stirred at 0°C for 10 min. Water (1.2 mL), 15% NaOH (1.2 mL) and water (3 x 1.2 mL) were added. The mixture was diluted with EA (175 mL), dried over MgS04, filtered and concentrated to dryness. The residue (9.2 g, quant.) was carried on without further purification.
1H NMR (ί 6-DMSO) δ: 7.00 (s, 1H); 5.24 (s, 2H); 4.96 (t, J = 5.4 Hz, 1H); 4.27 (d, J = 5.4 Hz, 2H); 3.71 (d, J = 11.2 Hz, 2H); 3.26 (d, J = 11.2 Hz, 2H); 2.45 (t, J = 6.5 Hz, 2H); 2.18 (t, J = 6.5 Hz, 2H); 1.22 (s, 6H); 1.10 (s, 3H); 0.70 (s, 3H).
MS (ESI, m/z): 307.2 [M+H+] for Ci7H26N203.
F. in. 2-amino-3-(hydroxymethyl)-8, 8-dimethyl-5, 6-dihydroquinolin-7(8H)-one: Typical procedure for deprotection using aqueous TFA solution.
A solution of intermediate F.ii (2.83 g, 9.2 mmol) in water (5 mL) and TFA (10 mL) was stirred at rt for 30 min. The reaction mixture was concentrated to dryness and the residue was taken up in sat. NaHC03 (50 mL). The aq. layer was extracted twice with EA (2 x 50 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 1:2 then 0:1) affording the title compound as a yellow oil (2.39 g).
1H NMR (ί 6-DMSO) δ: 7.19 (s, 1H); 5.49 (s, 2H); 5.07 (t, J = 5.4 Hz, 1H); 4.31 (d, J = 5.4 Hz, 2H); 2.79 (t, J = 6.5 Hz, 2H); 2.58 (t, J = 6.5 Hz, 2H); 1.27 (s, 6H).
MS (ESI, m/z): 221.0 [M+H+] for Ci2Hi6N202. Preparation G: 0-((5-phenylthiazol-2-yl)methyl)hydroxylamine:
G. i. 2-(bromomethyl)-5-phenylthiazole:
To a solution of 2-methyl-5-phenylthiazole (0.476 g, 2.72 mmol) in CC14 (4 mL) were added NBS (0.585 g, 3.29 mmol) and AIBN (0.023 g, 0.142 mmol). The reaction mixture was refluxed for 6 h under irradiation. The reaction mixture was cooled to rt and the filtered through a pad of Celite. The filtrate was evaporated and the residue was purified by CC (Hept/EA 9: 1) affording the title bromide as a beige solid (0.285 g, 41% yield). 1H NMR (ί 6-DMSO) δ: 8.16 (s, 1H); 7.62-7.69 (m, 2H); 7.34-7.49 (m, 3H); 5.02 (br. s, 2H). G. ii. 2-((5-phenylthiazol-2-yl)methoxy)isoindoline-l, 3-dione:
To a solution of N-hydroxyphthalimide (0.070 g, 0.429 mmol) and sodium acetate (0.112 g, 1.37 mmol) in DMSO (1.5 mL) was added 2-(bromomethyl)-5-phenylthiazole (0.119 g, 0.468 mmol). The reaction was heated to +70°C for 3 h. The solution was cooled to rt and water (10 mL) was added. The mixture was extracted with DCM/MeOH (9:1, 3 x 15 mL). The combined org. layers were washed with water (2 x 10 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 3:1), affording the title product as a light brown solid (0.109 g, 76% yield).
MS (ESI, m/z): 337.0 [M+H+] for C18Hi2N203S.
G. in. 0-((5-phenylthiazol-2-yl)methyl)hydroxylamine: To a mixture of intermediate G.ii (0.104 g, 0.309 mmol) and DCM (0.6 mL) was added methylhydrazine (0.025 mL, 0.47 mmol). The reaction mixture was stirred for 10 min and the solids were filtered off and the filtrate was evaporated to dryness affording the title compound, contaminated with the by-product of the reaction.
MS (ESI, m/z): 207.0 [M+H+] for Ci0Hi0N2OS. Preparation H: ethyl 2-amino-4-chloro-6-isopropylnicotinate:
H. i. Ethyl 2-amino-4,6-dichloronicotinate:
The title compound was prepared as described in WO 2010/123945, using diethyl acetone-
I.3-dicarboxylate as a starting material. 1H NMR (ί 6-DMSO) δ: 7.10 (br. s, 2H); 6.80 (s, 1H); 4.30 (q, J = 7.1 Hz, 2H); 1.27 (t, J = 7.1 Hz, 3H).
H.ii. Ethyl 2-amino-4-chloro-6-(prop-l-en-2-yl)nicotinate:
A mixture of intermediate H.i (6.1 g, 25.95 mmol), 2,4,6-tri(prop-l-en-2-yl)- 1,3,5,2,4,6-trioxatriborinane in complex with pyridine (1:1, prepared according to WO 2008/128962; 3.72 g, 13.2 mmol) and K2CO3 (4.7 g, 34 mmol) in dioxane/water (4: 1, 150 mL) was degassed. Pd(PPh3)4 (1.58 g, 1.37 mmol) was added and the reaction was refluxed at +100°C for 4 h under nitrogen. After cooling to rt, the reaction mixture was partitioned between EA (100 mL) and water (50 mL). The two layers were separated and the aq. layer was extracted once more with EA (100 mL). The combined org. layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hex/EA 9:1 to 7:3), affording the title alkene (5.43 g, 87% yield) as a colourless oil. The compound contained around 15%> of the b/s-alkene.
1H NMR (ί 6-DMSO) δ: 6.87 (s, 1H); 6.61 (br. s, 2H); 5.91 (m, 1H); 5.31 (m, 1H); 4.31 (q, J = 7.1 Hz, 2H); 2.03 (s, 3H); 1.28 (t, J = 7.1 Hz, 3H).
H.iii. Ethyl 2-amino-4-chloro-6-isopropylnicotinate:
To a solution of intermediate H.ii (2.4 g, 10 mmol) in EA (100 mL) was added Lindlar catalyst (2 g). The reaction was stirred under hydrogen atmosphere until the starting material was entirely consumed. The catalyst was removed by filtration and the filtrate was concentrated to dryness affording the title alkane as a yellowish oil (2.44 g, 100%> yield). 1H NMR (ί 6-DMSO) δ: 6.58 (br. s, 2H); 6.57 (br. s, 1H); 4.29 (q, J = 7.1 Hz, 2H); 2.76 (heptuplet, J = 7.0 Hz, 1H); 1.28 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 7.0 Hz, 6H).
Preparation I: 2-amino-5-bromo-6-(trifluoromethyl)nicotinaldehyde:
Li. Ethyl 2-amino-5-bromo-6-(trifluoromethyl)nicotinate: A solution of ethyl 2-amino-6-(trifluoromethyl)nicotinate (prepared as described in WO 2006/059103, 1.86 g, 7.9 mmol) and NBS (1.56 g, 8.7 mmol) in MeCN (15 mL) was stirred at +70°C overnight. The solvent was evaporated. The residue was partitioned between EA (100 mL) and water (50 mL). The org. layer was washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and the filtrate was evaporated. The residue was purified by CC (Hex/EA 9:1), affording the title bromide as a white solid (2.28 g, 92% yield).
1H NMR (ί 6-DMSO) δ: 8.32 (s, 1H), 7.65 (br. s, 2H), 4.31 (q, J = 7.1 Hz, 2H); 1.31 (t, J = 7.1 Hz, 3H). I. ii. 2-amino-5-bromo-6-(trifluoromethyl)nicotinaldehyde:
Starting from intermediate Li (1.8 g, 5.75 mmol), the title aldehyde (1.21 g) was obtained as a yellow solid using the procedures described in Example 1, steps l.ii and l.iii (ester reduction: 98%> yield, Mn02 oxidation: 82% yield).
1H NMR (ί 6-DMSO) δ: 9.91 (s, 1H); 8.52 (s, 1H); 7.95 (br. s, 2H).
MS (ESI, m/z): 269.0 [M+H+] for C7H4N2OBrF3.
Preparation J: ethyl 2-amino-5-bromo-6-(trifluoromethyl)-4-vinylnicotinate:
J.i. Ethyl 2-amino-5-bromo-4-hydroxy-6-(trifluoromethyl)nicotinate\
Starting from the compound of Preparation C (0.6 g, 2.4 mmol), the title bromide was obtained as a yellow solid (0.672 g) using the procedure described in Example 50, step 50. ii (bromination: 85% yield).
1H NMR (ί 6-DMSO) δ: 12.50 (s, 1H); 7.36 (br. s, 2H); 4.43 (q, J = 7.1 Hz, 2H); 1.33 (t, J = 7.1 Hz, 3H).
J.ii. Ethyl 2-amino-5-bromo-6-(trifluoromethyl)-4-(((trifluoromethyl)sulfonyl)oxy) nicotinate: To an ice-chilled solution of intermediate J.i (672 mg, 2.04 mmol) in DCM (6 mL) and TEA (0.569 mL, 4.09 mmol) was added dropwise trifluoromethanesulfonic anhydride (0.687 mL, 4.09 mmol). The reaction was stirred 10 min at the same temperature and the crude mixture was directly subjected to CC (EA/Hept 9: 1), affording the title triflate as a white solid (0.607 g, 64% yield).
1H NMR (ί 6-DMSO) δ: 7.36 (br. s, 2H); 4.33 (q, J = 7.1 Hz, 2H); 1.29 (t, J = 7.1 Hz, 3H).
J. Hi. Ethyl 2-amino-5-bromo-6-(trifluoromethyl)-4-vinylnicotinate\
To a mixture of intermediate J.ii (0.559 g, 1.21 mmol) and bis(triphenylphosphine)palladium dichloride (0.085 g, 0.121 mmol) in toluene (5 mL) was added tri-ft-butylvinylstannane (0.357 mL, 1.22 mmol). The reaction mixture was heated to +92°C for 4 h. After cooling to rt, the reaction mixture was concentrated to dryness and the residue was directly subject to CC (Hept/EA 9: 1), affording the vinyl compound as a white powder (0.346 g, 84% yield).
1H NMR (ί 6-DMSO) δ: 6.86 (br. s, 2H); 6.71 (dd, J = 11.6, 17.4 Hz, 1H); 5.36 (d, J = 11.6 Hz, 1H); 5.33 (d, J = 17.5 Hz, 1H); 4.24 (q, J = 7.2 Hz, 2H); 1.21 (t, J = 7.1 Hz, 3H).
Preparation K: (Z)-0-(4-((teri-butyldimethylsilyl)oxy)but-2-en-l-yl)hydroxylainine:
To a solution of N-hydroxyphthalimide (0.422 g, 2.59 mmol) and NaOAc (0.643 g, 7.84 mmol, 3.028 eq.) in DMSO (6 mL) was added
(Z)-4-((tert-butyldimethylsilyl)oxy)but-2-en-l-yl methanesulfonate (prepared as described in J. Org. Chem. (1996), 61, 7681 ; 0.763 g, 2.72 mmol). The reaction was heated to +70°C for 3 h. The solution was cooled to rt and water (20 mL) was added. The resulting mixture was extracted with EA (3 x 30 mL). The combined org. layers were washed with water (2 x 20 mL), dried over MgS04, filtered and concentrated. The residue was purified by CC (Hept/EA 3:2) to give the intermediate phthalimide derivative (0.58 g, 64%> yield) as a colourless oil. The latter oil was taken up in DCM (3 mL) and methyl hydrazine (0.135 mL, 2.54 mmol) was added. The reaction mixture was stirred for 10 min. The reaction mixture was filtered and washed with DCM. The filtrate was evaporated to dryness to afford the title compound as a white solid (0.302 g).
1H NMR (ί 6-DMSO) δ: 6.04 (br. s, 2H); 5.47-5.61 (m, 2H); 4.16-4.19 (m, 2H); 4.05-4.09 (m, 2H); 0.84 (s, 9H), 0.02 (s, 6H).
Preparation L: 0-(thiazol-2-ylmethyl)hydroxylamine:
Starting from thiazol-2-ylmethanol (1.05 g, 9.1 mmol), the title compound was obtained as a yellowish tick oil (1.05 g), using the typical procedures described in Preparation B, step B.i (Mitsunobu reaction: 90%> yield) and Preparation G, step G.ii (deprotection: 98%> yield).
1H NMR (ί 6-DMSO) δ: 7.75 (m, 1H); 7.68 (m, 1H); 6.34 (br. s, 2H); 4.81 (s, 2H). EXAMPLES:
Example 1: 2-amino-9,9-dimethyl-8-oxo-6,7,8,9-tetrahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
1. i. Ethyl 2 '-amino-5, 5,8',8 '-tetramethyl-6 ', 8 '-dihydro-5 'H-spiro[[l ,3] dioxane- 2, 7'-quinoline] -3 '-carboxylate:
Typical procedure for the formation of a sodium etiolate followed by a cyclization reaction.
Small chunks of Na (2.7 g, 118 mmol) were introduced in ether (250 mL). HC02Et (14.2 mL, 176 mmol), a solution of 3,3,7, 7-tetramethyl-l,5-dioxaspiro[5.5]undecan-8-one (26.67 g, 118 mmol, 1 eq.) in ether (120 mL) and EtOH (0.5 mL) were successively added. The mixture was stirred at rt overnight. The reaction mixture was diluted with THF (650 mL). Ethyl 3,3-diaminoacrylate (15.36 g, 118 mmol, 1.0 eq.) and AcOH (8 mL, 140 mmol, 1.2 eq.) were added. The resulting mixture was heated to +60°C for 3 h. The reaction mixture was cooled to rt, and diluted with sat. NaHC03 (500 mL) and EA (600 mL). The aq. layer was extracted once with EA (600 mL). The combined org. layers were washed with brine (150 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (Hept/EA 9: 1) affording the title compound as a light yellow solid (30 g, 73% yield).
MS (ESI, m/z): 349.2 [M+H+] for Ci9H28N204. 1. ίί. (2 '-amino-5, 5, 8 ',8 '-tetramethyl-6 ', 8 '-dihydro-5 'H-spiroffl, 3] dioxane-2, 7'-quinolin] - 3 '-yl)methanol:
Typical procedure for an ester reduction using LAH.
To a solution of intermediate l.i (10.04 g, 28.8 mmol, 1 eq.) in THF (250 mL), cooled at 0°C was added portionwise solid LAH (1.178 g, 30.9 mmol, 1.1 eq.). The mixture was stirred at 0°C for 10 min. Water (1.2 mL), 15% NaOH (1.2 mL) and water (3 x 1.2 mL) were added. The mixture was diluted with EA (175 mL), dried over MgS04, filtered and concentrated to dryness. The residue (9.2 g, quant, yield) was carried on without further purification. 1H NMR (ί 6-DMSO) δ: 6.99 (s, 1H); 5.24 (br. s, 2H); 4.96 (t, J = 5.4 Hz, 1H); 4.27 (d, J = 5.4 Hz, 2H), 3.71 (d, J = 11.2 Hz, 2H); 3.26 (d, J = 11.2 Hz, 2H); 2.45 (t, J = 6.5 Hz, 2H); 2.18 (t, J = 6.5 Hz, 2H); 1.21 (s, 6H); 1.11 (s, 3H); 0.70 (s, 3H).
MS (ESI, m/z): 307.2 [M+H+] for Ci7H26N203. I. Hi. 2 '-amino-5, 5,8',8 '-tetramethyl-6 ', 8 '-dihydro-5 'H-spiroffl, 3]dioxane-2, 7'-quinoline] - 3 '-carbaldehyde
Typical procedure for the oxidation of a benzylic alcohol to the corresponding aldehyde. To a solution of intermediate l.ii (9.21 g, 30.1 mmol, 1 eq.) in DCM (300 mL) was added in one portion Mn02 (3.96 g, 456 mmol, 15 eq.). The mixture was stirred at +50°C for 30 min. After cooling to rt, the reaction mixture was filtered over Celite and the solids were washed with DCM. The filtrate was concentrated to dryness affording the crude aldehyde as a yellowish foam (7.51 g, 81% yield).
MS (ESI, m/z): 305.0 [M+H+] for Ci7H24N203.
1. iv. 2-amino-5 ', 5 ', 9, 9-tetramethyl- 7, 9-dihydro-6H-spiro[benzo[b] [1 ,8] naphthyridine- 8,2'-[l ,3] dioxane] -3-carboxamide:
Typical procedure for the introduction of the 2-amino-3 carboxamide unit.
To a mixture of intermediate l.iii (7.5 g, 24.6 mmol, 1 eq.) and EtOH (60 mL) was added cyanoacetamide (2.07 g, 24.7 mmol, 1 eq.) and TMG (3.1 mL, 24.6 mmol, 1 eq.). The reaction proceeded for 30 min at +100°C. After cooling to rt, the solvent was evaporated. EA was added, and the residue was stirred until precipitation occurred. The resulting solid was filtered, washed scarcely with EA and dried in vacuo to constant weight affording the title naphthyridine as a yellow solid (6.63 g, 73% yield).
1H NMR (ί 6-DMSO) δ: 8.36 (s, 1H); 8.17 (br. s, 1H); 7.68 (s, 1H); 7.55 (br. s, 1H); 7.32 (br. s, 2H); 3.76 (d, J = 11.0 Hz, 2H); 3.31 (d, J = 11.0 Hz, 2H); 2.77 (t, J = 6.6 Hz, 2H); 2.33 (t, J = 6.6 Hz, 2H); 1.34 (s, 6H); 1.13 (s, 3H); 0.72 (s, 3H).
MS (ESI, m/z): 371.2 [M+H+] for C20H26N4O3. 1. v. 2-amino-9, 9-dimethyl-8-oxo-6, 7, 8, 9-tetrahydro-benzofb] [1 ,8] naphthyridine- 3-carboxylic acid amide :
Typical procedure for an acidic deprotection using HCl in dioxane.
A solution of intermediate l.iv (6.61 g, 17 mmol) in a HCl solution (4M in dioxane, 100 mL, 400 mmol) and water (40 mL) was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure and the pH of the remaining layer was adjusted to 7 adding 2M NaOH. The precipitate was collected by filtration, washed scarcely with water and dried in vacuo to constant weight affording the title ketone as a yellow solid (4.04 g, 80% yield).
1H NMR (ί 6-DMSO) δ: 8.44 (s, 1H); 8.23 (br. s, 1H); 7.88 (s, 1H); 7.62 (br. s, 1H); 7.43 (br. s, 2H); 3.11 (dd, J = 5.6, 7.4 Hz, 2H); 2.69 (dd, J = 5.6, 7.4 Hz, 2H); 1.40 (s, 6H). MS (ESI, m/z): 371.2 [M+H+] for C15Hi6N4O2.
Example 2: 2-amino-9,9-dimethyl-7,9-dihydro-
6H-spiro[benzo[6][l,8]naphthyridine-8,2'-[l,3]dioxolane]-3-carboxamide: 2. i. 8-(hydroxymethylene)-6, 6-dimethyl-l, 4-dioxaspiro[4.5]decan- 7 -one:
NaH (60% in oil dispersion, 4.16 g, 104 mmol) was suspended in THF (150 mL). A solution of 6,6-dimethyl-l,4-dioxaspiro[4.5]decan-7-one (prepared according to Tetrahedron (2003), 59(27), 5115-5121; 7.7 g, 41.8 mmol) in dry THF (40 mL) was added dropwise. After cooling to 0°C, HCO2Et (12.5 mL, 162 mmol) and EtOH (1 mL) were added at 0°C. After 3h, the reaction mixture was cooled to 0°C. EtOH (5 mL) and water (5 mL) were slowly added. The org. layer was separated and the aq. layer was washed with ether (3 x 25 mL). The aq. layer was then acidified with IN HCl to pH = 4 and extracted with ether (3 x 25 mL). The combined org. layers were washed with brine, dried over MgSO4 and evaporated to give the keto-enol as a colourless oil (3.31 g, 37%> yield). The stereochemistry of the enol was not assigned.
1H NMR (CDC13) δ: 8.56 (d, J = 3.9Hz, 1H); 3.99 (s, 4H); 2.44 (t, J = 6.7 Hz, 2H); 1.83 (t, J = 6.7 Hz, 2H); 1.23 (s, 6H).
2. ii. Ethyl 2 '-amino-8 ',8'-dimethyl-6', 8 '-dihydro-5 'H-spiro[[l,3]dioxolane-2, 7'-quinoline] - 3 '-carboxylate: To a solution of intermediate 2.i (3.3 g, 15.6mmol) in THF (60 mL) was added ethyl 3,3-diaminoacrylate (2.0 g, 1 eq.). The reaction was stirred at rt overnight. The solvent was evaporated and the residue was purified by CC (Hept/EA 4: 1) to give the title product as a yellowish solid (4.41 g, 92% yield).
1H NMR (CDCls) δ: 7.82 (s, 1H); 6.09 (s, 2H); 4.02 (s, 4H); 2.77 (t, J = 6.8 Hz, 2H); 1.95 (t, J = 6.8 Hz, 2H); 1.30 (s, 6H).
MS (ESI, m/z): 307.5 [M+H+] for Ci6H22N204.
2. Hi. 2-amino-9,9-dimethyl-7,9-dihydro-6H-spiro[benzo[b][l,8]naphthy
8,2'-[l ,3] dioxolane] -3-carboxamide:
Starting from intermediate 7.ii (0.3 g, 0.98 mmol), the title compound was obtained as a yellowish solid (0.127 g) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 83% yield, Mn02 oxidation: 78%> yield, cyclization: 61%> yield). 1H NMR (CDCI3) δ: 8.38 (s, 1H), 8.18 (s, 1H); 7.72 (s, 1H); 7.57 (s, 1H); 7.34 (br. s, 2H); 3.90-4.03 (m, 4H); 2.91 (t, J = 6.7 Hz, 2H); 1.96 (t, J = 6.7 Hz, 2H); 1.30 (s, 6H).
MS (ESI, m/z): 329.4 [M+H+] for Ci7H2oN403. Example 3: r c-2-amino-8-hydroxy-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
3. i. Ethyl 2-amino-8, 8-dimethyl- 7-oxo-5, 6, 7, 8-tetrahydroquinoline-3-carboxylate: Typical procedure for an acidic deprotection using aq. AcOH.
A solution of intermediate 2.ii (3.75 g, 12.2 mmol) in a mixture of AcOH (40 mL), water (10 mL) and THF (5 mL) was refluxed overnight. After concentration to dryness, the residue was partitioned between EA (100 mL) and water (50 mL). The pH was adjusted to 7 by adding \M NaOH. The org. layer was dried over Na2S04, filtered and concentrated. The residue was purified by CC (Hept/EA 4:1), affording the title ketone as a yellow oil (2.6 g, 81% yield).
1H NMR (ί 6-DMSO) δ : 7.88 (s, 1H); 6.99 (br. s, 2H); 4.26 (q, J = 7.1 Hz, 2H); 2.86 (t, J = 6.6 Hz, 2H); 2.60 (t, J = 6.6 Hz, 2H); 2 H), 1.30 (t, J = 7.1 Hz, 3H); 1.30 (overlapped s, 6H).
MS (ESI, m/z): 263.3 [M+H+] for Ci4Hi8N203. 3. ίί. Ethyl 2-amino- 7-hydroxy-8, 8-dimethyl-5, 6, 7, 8-tetrahydroquinoline-3-carboxylate:
Typical procedure for a carbonyl reduction using sodium borohydride.
To a solution of intermediate 3.i (200 mg, 0.76 mmol) in MeOH (4 mL), cooled to 0°C, was added NaBH4 (44 mg, 1.15 mmol). The reaction proceeded for 15 min and water (1 mL) was added. After concentration to dryness, the residue was partitioned between EA (50 mL) and water (25 mL). The org. layer was dried over Na2S04, filtered and concentrated affording the title alcohol as a yellow oil (0.19 g, 95% yield).
1H NMR (ί 6-DMSO) δ : 7.69 (s, 1H); 6.99 (br. s, 2H); 4.71 (d, J = 4.5 Hz, 1H); 4.23 (q, J = 7.1 Hz, 2H); 3.56 (m, 1H); 2.69 (m, 1H); 2.56 (m, 1H); 1.65-1.86 (m, 2H); 1.26 (t, J = 7.1 Hz, 3H); 1.20 (s, 3H); 1.11 (s, 3H).
3. in. rac-2-amino-8-hydroxy-9, 9-dimethyl-6, 7, 8, 9-tetrahydro- benzofbj [1 ,8] naphthyridine-3-carboxylic acid amide:
Starting from intermediate 3.ii (0.19 g, 0.72 mmol), the title compound was obtained as a yellowish solid (44 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 80% yield, Mn02 oxidation: 57%> yield, cyclization: 47%> yield).
1H NMR (CDC13) δ: 8.36 (s, 1H); 8.16 (s, 1H); 7.66 (s, 1H); 7.55 (s, 1H); 7.34 (br. s, 2H); 4.80 (d, J = 4.3 Hz, 1H); 3.70 (m, 1H); 2.97 (m, 1H); 2.79 (m, 1H); 1.94 (m, 1H); 1.80 (m, 1H); 1.30 (s, 3H); 1.23 (s, 3H).
MS (ESI, m/z): [M+H+] for Ci5Hi8N402. Example 4: r c-2-amino-7-hydroxy-6,7,8,9-tetrahydro-benzo[6][l,8]naphthyridine- 3-carboxylic acid amide:
4. i. Ethyl 2-amino-6-oxo-5, 6, 7, 8-tetrahydroquinoline-3-carboxylate :
To a solution of 1,4-cyclohexanedione monoethylene acetal (2.04 g, 13 mmol) in DMF (21 mL) was added N,N-dimethylformamide dimethyl acetal (1.88 mL, 14 mmol). The reaction was refluxed 3.5 h. After cooling to rt and the solvent was evaporated to dryness. The residue was taken up in DCM (24 mL) and 2M HC1 (40 mL) was added. The mixture was stirred overnight. The two layers were separated and the aq. layer was extracted once with DCM (20 mL). The combined org. layers were dried over MgS04, filtered and evaporated. The residue was taken up in THF (40 mL) and ethyl 3,3-diaminoacrylate (1.24 g, 9.6 mmol) was added. The reaction was stirred at rt for 2 h. The solvent was evaporated and the residue was purified by CC (Hex-EA 1:1), affording the title ester as a yellow solid (0.26 g, 12% yield).
1H NMR (ί 6-DMSO) δ: 7.81 (s, 1H); 7.05 (br. s, 2H); 4.25 (q, J = 7.1 Hz, 2H); 3.46 (s, 2H); 2.97 (t, J = 6.7 Hz, 2H); 2.51 (overlapped t, J = 6.7 Hz, 2H); 1.28 (t, J = 7.1 Hz, 3H). MS (ESI, m/z): 235.2 [M+H+] for C12H14N2O3.
4. ii. rac-2-amino- 7-hydroxy-6, 7, 8, 9-tetrahydro-benzofb] [1 ,8] naphthyridine-3-carboxylic acid amide :
Starting from the intermediate 4.i (0.19 g, 0.72 mmol), the title compound (0.061 g) was obtained as a brown solid using the typical procedures described in Example 1, steps l.ii to l.iv (ester + ketone reduction: 96% yield, Mn02 oxidation: 67%> yield, cyclization: 39%> yield).
1H NMR (CDCI3) δ: 8.37 (s, 1H); 8.17 (s, 1H); 7.69 (s, 1H); 7.56 (s, 1H); 7.32 (br. s, 2H); 4.84 (m, 1H); 4.02 (m, 1H); 3.41 (m, 1H); 2.65-3.08 (m, 3H); 1.99 (m, 1H); 1.81 (m, 1H). MS (ESI, m/z): 259.1 [M+H+] for C13H14N4O2. Example 5: r c-2-amino-7-hydroxy-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
5. i. Ethyl 2 '-amino-8 ', 8 '-dimethyl-7', 8 '-dihydro-5 'H-spiro[[l,3]dioxolane-2,6'-quinoline]- 3 '-carboxylate:
Starting from 7,7-dimethyl-l,4-dioxaspiro[4.5]decan-8-one (1.85 g, 10 mmol), the title ester was obtained as a white solid (2.12 g) using the procedures described in Example 2, steps 2.i and 2.ii (enol formation: 88%> yield, cyclization: 64%> yield).
1H NMR (CDCI3) δ: 7.70 (s, 1H); 6.83 (s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 3.89 (s, 4H); 2.80 (s, 2H); 1.86 (s, 2H); 1.27 (t, J = 7.1 Hz, 3H); 1.26 (s, 6H).
MS (ESI, m/z): 307.2 [M+H+] for C16H22N204. 5.ii. Ethyl 2-amino-8,8-dimethyl-6-oxo-5,6, 7,8-tetrahydroquinoline-3-carboxylate\
A solution of intermediate 5.i (1.0 g, 3.3 mmol) in THF (22 mL) and 6N HC1 (3 mL) was refluxed for 6 days. The reaction was then cooled to rt, and the pH was adjusted to 7 adding 4M NaOH. EA (50 mL) was added and the two layers were separated. The org. layer was dried over MgS04, filtered and concentrated to dryness, affording the title ketone as a yellow oil (0.61 g, 70% yield).
MS (ESI, m/z): 263.2 [M+H+] for Ci4Hi8N203.
5.iii. Rac-ethyl 2-amino-6-hydroxy-8,8-dimethyl-5,6, 7 ,8-tetrahydroquinoline- 3-carboxylate:
Starting from intermediate 5.ii (0.610 g), the title alcohol was obtained as a brownish oil (0.207 g, 34% yield) using the procedure described in Example 3, step 3.ii. The crude material was purified by CC (Hex/EA 7:3).
MS (ESI, m/z): 265.2 [M+H+] for Ci4H20N2O3. 5.iv. Rac-2-amino-7-hydroxy-9,9-dimethyl-6, 7,8,9-tetrahydro- benzofbj [1 ,8] naphthyridine-3-carboxylic acid amide:
Starting from intermediate 5.iii (0.184 g, 0.7 mmol), the title compound was obtained as a yellow solid (0.016 g) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 89%> yield, Mn02 oxidation: 81%> yield, cyclization: 11%> yield). 1H NMR (ί 6-DMSO) δ: 8.51 (br. s, 1H); 8.46 (s, 1H); 8.24 (br. s, 1H); 7.76 (s, 1H); 7.48-7.65 (m, 2H); 4.86 (m, 1H); 4.00 (m, 1H); 3.10 (m, 1H); 2.67 (m, 1H); 1.95 (m, 1H); 1.70 (m, 1H); 1.39 (s, 3H); 1.26 (s, 3H).
MS (ESI, m/z): 287.2 [M+H+] for C15i½N402.
Example 6: (S,E)-2-amino-4-(((2-amino-3-carbamoyl-9,9-dimethyl- 6,7-dihydrobenzo[6] [l,8]naphthyridin-8(9H)-ylidene)amino)oxy)butanoic acid dihydrochloride:
6.i. (S.E)-tert-butyl 4-(((2-amino-3-carbamoyl-9,9-dimethyl- 6 -dihydrobenzo[b] [l,8]naphthyridin-8(9H)-ylidene)amino)oxy)- 2-((tert-butoxycarbonyl)amino)butanoate: To a solution of the intermediate l.v (0.113 g, 0.397 mmol) in Pyr (2.26 mL, 28.1 mmol) and NMP (2 mL) was added (S)-tert-butyl 4-(aminooxy)- 2-((tert-butoxycarbonyl)amino)butanoate (0.460 g, 1.59 mmol). The reaction mixture was stirred at +80°C for 72 h. The volatiles were removed in vacuo and the crude material was purified by prep-HPLC (Method A) affording the title compound as a yellow solid (0.11 g).
MS (ESI, m/z): 557.5 [M+H+] for C28H4oN606.
6.U. (S,E)-2-amino-4-(((2-amino-3-carbamoyl-9,9-dimethyl- 6, 7-dihydrobenzofbJ [1 ,8] naphthyridin-8(9H)-ylidene)amino)oxy)butanoic acid
dihydro ch loride :
Starting from intermediate 6.i (55 mg, 0.1 mmol), the title carboxamide was obtained as a yellow solid (10 mg, 21% yield). The crude product was purified by prep-HPLC (Method A).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.21 (s, 1H); 8.17 (s, 2H); 7.80 (s, 1H); 7.60 (s, 1H); 7.41 (br. s, 2H); 4.07-4.17 (m, 2H); 3.33 (br. s, 3H); 3.21 (m, 1H); 2.91-2.99 (m, 2H); 2.74-2.80 (m,2H); 2.09 (m, 1H); 1.95 (m, 1H), 1.46 (s, 6H).
MS (ESI, m/z): 401.2 [M+H+] for Ci9H24N604.
Example 7: [2-amino-3-carbamoyl-9,9-dimethyl-6,9-dihydro- 7H-benzo[6] [l,8]naphthyridin-(#E)-ylideneaminooxy]-acetic acid:
To a solution of intermediate l.v (0.098 g, 0.344 mmol) in DIPEA (0.1 mL) and NMP (1.7 mL) were added carboxymethylhydroxylamine hemihydrochloride (45 mg, 0.413 mmol) and 3 A molecular sieves (3 beads). The reaction mixture was heated to +100°C for 72 h. The solvent was evaporated and the residue was purified by prep-HPLC (Method B) affording the title compound as a yellow solid (9 mg, 7% yield).
MS (ESI, m/z): 358.0 [M+H+] for Ci7Hi9N504.
Example 8: r c-2-amino-8-[(E)-2,2-dimethyl-[l,3]dioxolan-4-ylmethoxyimino]- 9,9-dimethyl-6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate l.v (0.150 g, 0.53 mmol) and rac-O-((2,2-dimethyl- l,3-dioxolan-4-yl)methyl)hydroxylamine (0.246 g, 1.67 mmol), the title compound was obtained as a yellow solid (0.203 g) using the typical procedure described in Example 6, step 6.i (oxime formation: 93% yield). 1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H); 7.59 (br. s, 1H); 7.40 (br. s, 2H); 4.25 (m, 1H); 3.98-4.08 (m, 2H); 3.70 (dd, J = 6.4, 8.3 Hz, 1H); 2.95 (app. t, J = 6.8 Hz, 2H); 2.77 (app. t, J = 6.8 Hz, 2H); 1.49 (s, 6H); 1.30 (s, 3H); 1.25 (s, 3H). MS (ESI, m/z): 414.2 [M+H+] for C2iH27N504. Example 9: r c-2-amino-8-[(E)-2,3-dihydroxy-propoxyimino]-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
A solution of the compound of Example 8 (0.190 g, 0.459 mmol) in 4 HC1 (in dioxane, 2 mL) and water (1 mL) was stirred at rt for 30 min. The volatiles were removed in vacuo and the pH of the aq. layer was adjusted to 7 by adding \M NaOH. The mixture was directly purified by prep-HP LC (Method A), affording the title compound as a yellow solid (25 mg, 15% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.21 (br. s, 1H); 7.80 (s, 1H); 7.59 (br. s, 1H); 7.40 (br. s, 2H); 4.01 (dd, J = 5.0, 10.5 Hz, 1H); 3.89 (dd, J = 6.1 , 10.5 Hz, 1H); 3.68 (m, 1H); 3.28-3.40 (m, 2H); 2.95 (app. t, J = 6.8 Hz, 2H); 2.77 (app. t, J = 6.8 Hz, 2H); 1.71 (br. s, 2H); 1.49 (s, 6H).
MS (ESI, m/z): 374.0 [M+H+] for Ci8H23N504.
Example 10: 8- [(E)-2-acetylamino-ethoxyimino] -2-amino-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
10. i. (E)-tert-butyl (2-(((2-amino-3-carbamoyl-9,9-dimethyl- 6, 7-dihydrobenzofb] [1 ,8]naphthyridin-8(9H)-ylidene)amino)oxy)ethyl)carbamate\
Starting from intermediate l .v (0.1 g, 0.352 mmol) and tert-butyl (2-(aminooxy)ethyl)carbamate (0.248 g 1.41 mmol), the title compound was obtained as a yellow solid (87 mg) using the typical procedure described in Example 6, step 6.i (oxime formation: 56% yield).
MS (ESI, m/z): 443.3 [M+H+] for C22H3oN604.
10. ii (E)-2-amino-8-((2-aminoethoxy)imino)-9,9-dimethyl-
6, 7, 8,9-tetrahydrobenzofbJ [1 , 8] naphthyridine-3-carboxamide dihydrochloride
A mixture of intermediate 10. i (80 mg, 0.745 mmol) and a HCl solution (5N in 2-propanol, 1 mL) was stirred at rt for 2 h. The reaction mixture was diluted with ether (10 mL) and the resulting slurry was filtered. The solid was collected and dried to constant weight affording the title compound as a yellow solid (45 mg).
MS (ESI, m/z): 343.3 [M+H+] for Ci7H22N602.
10. in. 8-[(E)-2-acetylamino-ethoxyimino]-2-amino-9, 9-dimethyl-6, 7, 8, 9-tetrahydro- benzofb] [1 ,8] naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate lO.ii (34 mg, 0.099 mmol), DIPEA (0.082 mL, 0.496 mmol) and AcOH (0.008 mL, 0.149 mmol) in DMF (0.4 mL) was added dropwise at rt T3P (50% in EA, 0.085 mL, 0.139 mmol). The mixture was stirred at rt during 3 h. The solvent was evaporated and the residue was purified by prep-HPLC (Method A) affording the title compound as a yellow solid (21 mg, 55% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.86 (m, 1H); 7.80 (s, 1H); 7.60 (br. s, 1H); 7.40 (br. s, 2H); 3.99 (t, J = 5.8 Hz, 2H); 3.25 (overlapped q, J = 5.8 Hz, 2H); 2.95 (app. t, J = 6.8 Hz, 2H); 2.77 (app. t, J = 6.8 Hz, 2H); 1.77 (s, 3H); 1.49 (s, 6H).
MS (ESI, m/z): 385.0 [M+H+] for C20H25N5O3. Example 11 : 2-amino-8-[(Z)-3-chloro-benzyloxyimino]-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
77./. (Z)-2-amino-3-(hydroxymethyl)-8,8-dimethyl-5,6-dihydroquinolin-7(8H)-one
0- (3-chlorobenzyl) oxime:
To a solution of intermediate F.iii (64 mg, 0.291 mmol) in EtOH (1 mL) and water (0.5 mL) were added O-(3-chlorobenzyl)hydroxylamine hydrochloride (69 mg, 0.43 mmol) and NaOAc (49 mg, 0.603 mmol). The reaction mixture was stirred at +60°C for 1 h. After concentration to dryness, the residue was directly subjected to CC (Hept-EA
1- 2) affording the oxime compound as an oil (50 mg, 49%> yield).
MS (ESI, m/z): 360.0 [M+H+] for Ci9H22N302Cl. 77.// 2-amino-8-[(Z)-3-chloro-benzyloxyimino] -9,9-dimethyl-6, 7,8,9-tetrahydro- benzofbj [1 ,8] naphthyridine-3-carboxylic acid amide:
Starting from intermediate l l.i (47 mg, 0.13 mmol), the title compound was obtained as a yellow solid (30 mg) using the typical procedures described in Example 1, steps l.iii and l.iv (Mn02 oxidation: 92%> yield, cyclization: 76%> yield). 1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H); 7.59 (br. s, 1H); 7.40 (br. s, 2H); 7.29-7.39 (m, 4H); 5.09 (s, 2H); 2.96 (app. t, J = 6.8 Hz, 2H); 2.81 (app. t, J = 6.8 Hz, 2H); 1.48 (s, 6H).
MS (ESI, m/z): 424.1 [M+H+] for C22H22N5O2CI. Example 12: 2-amino-8-[(Z)-2-chloro-benzyloxyimino]-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (69 mg, 0.31 mmol) and
O-(2-chlorobenzyl)hydroxylamine hydrochloride (76 mg, 0.48 mmol), the title compound was obtained as a yellow solid (30 mg) using the procedures described in Example 11, step l l.i (oxime formation: 70% yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 75% yield, cyclization: 50%> yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H); 7.59 (br. s, 1H); 7.38-7.49 (m, 4H); 7.29-7.35 (m, 2H); 5.16 (s, 2H); 2.92-3.00 (m, 2H); 2.81-2.86 (m, 2H); 1.48 (s, 6H).
MS (ESI, m/z): 424.1 [M+H+] for C22H22N502C1.
Example 13: 2-amino-8-[(E)-hydroxyimino]-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (60 mg, 0.27 mmol) and hydroxylamine hydrochloride (28 mg, 0.40 mmol), the title compound was obtained as a yellow solid (0.020 g) using the typical procedures described in Example 11, step l l.i (oxime formation) and Example 1 , steps l.iii and l.iv (Mn02 oxidation: 90%> yield (over 2 steps), cyclization: 27%> yield). 1H NMR (ί 6-DMSO) δ: 10.6 (s, 1H); 8.41 (s, 1H); 8.19 (br. s, 1H); 7.80 (s, 1H); 7.58 (br. s, 1H); 7.38 (br. s, 2H); 2.92-2.97 (m, 2H); 2.72-2.78 (m, 2H); 1.49 (s, 6H).
MS (ESI, m/z): 300.2 [M+H+] for Ci5Hi7N502. Example 14: 2-amino-8-[(E)-methoxyimino]-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (60 mg, 0.27 mmol) and O-methylhydroxylamine hydrochloride (34 mg, 0.40 mmol), the title compound was obtained as a yellow solid (30 mg) using the typical procedures described in Example 11, step l l.i (oxime formation) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 59% yield (over 2 steps), cyclization: 56% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.19 (br. s, 1H); 7.80 (s, 1H); 7.58 (br. s, 1H); 7.38 (br. s, 2H); 3.78 (s, 3H); 2.91-2.98 (m, 2H); 2.72-2.78 (m, 2H); 1.49 (s, 6H).
MS (ESI, m/z): 313.8 [M+H+] for C16H19N5O2.
Example 15 : 2-amino-8- [(Z)-benzothiazol-2-ylmethoxyimino] -9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (82 mg, 0.37 mmol) and O-(benzo[<i]thiazol- 2-ylmethyl)hydroxylamine hydrochloride (34 mg, 0.40 mmol), the title compound was obtained as a yellow solid (7 mg) using the typical procedures described in Example 11, step l l.i (oxime formation: 35%> yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 68%> yield, cyclization: 17%> yield).
1H NMR (ί 6-DMSO) δ: 8.43 (s, 1H); 8.20 (br. s, 1H); 8.07 (dd, J = 1.3, 7.9 Hz, 1H); 7.96 (d, J = 7.9 Hz, 1H); 7.83 (s, 1H); 7.59 (br. s, 1H);7.49 (td, J = 1.3, 7.9 Hz, 1H); 7.37-7.44 (m, 3H); 5.49 (s, 2H); 2.99-3.06 (m, 2H); 2.87-2.94 (m, 2H); 1.49 (s, 6H).
MS (ESI, m/z): 447.0 [M+H+] for C23H22N602S.
Example 16: (Z)-2-amino-8-((cyclopropylmethoxy)imino)-9,9-dimethyl- 6,7,8,9-tetrahydrobenzo[6] [l,8]naphthyridine-3-carboxamide: Starting from intermediate l.v (92 mg, 0.32 mmol) and O-(cyclopropylmethyl)hydroxylamine (90 mg 1.04 mmol), the title compound was obtained as a yellow solid (104 mg) using the typical procedure described in Example 6, step 6.i (oxime formation: 91%> yield).
1H NMR (ί 6-DMSO) δ: 8.48 (s, 1H); 8.27 (br. s, 1H); 7.84 (s, 1H); 7.66 (br. s, 1H); 7.60 (br. s, 2H);3.83 (d, J = 7.0 Hz, 2H); 2.97 (t, J = 6.7 Hz, 2H); 2.78 (t, J = 6.7 Hz, 2H); 1.49 (s, 6H); 1.07 (m, 1H); 0.47 (m, 2H); 0.24 (m, 2H).
MS (ESI, m/z): 354.0 [M+H+] for Ci9H23N502. Example 17: (Z)-2-amino-9,9-dimethyl-8-(((5-phenylthiazol-2-yl)methoxy)imino)- 6,7,8,9-tetrahydrobenzo[6] [l,8]naphthyridine-3-carboxamide:
Starting from intermediate F.iii (85 mg, 0.38 mmol) and intermediate G.iii (80 mg,
0.38 mmol), the title compound was obtained as a yellow solid (50 mg) using the typical procedures described in Example 11, step l l.i (oxime formation: 80% yield) and Example
1, steps l.iii and l.iv (Mn02 oxidation: 87%> yield, cyclization: 40%>yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.20 (br. s, 1H); 8.13 (s, 1H); 7.81 (s, 1H); 7.55-7.67 (m, 3H); 7.30-7.44 (m, 5H); 5.34 (s, 2H); 2.82-2.90 (m, 2H); 2.82-2.90 (m, 2H); 1.54 (s, 6H).
MS (ESI, m/z): 473.0 [M+H+] for C25H24N602S.
Example 18 : 2-amino-8-hy drazono-9,9-dimethyl-6,7,8,9-tetrahy dro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate l.v (15 mg, 0.053 mmol) and EtOH (0.05 mL) were added hydrazine hydrate (53 mg, 1.06 mmol) and TEA (0.015 mL). The mixture was stirred at +100°C for 4 h. The reaction mixture was cooled to rt and the solid that formed was filtered, washed with water and dried to constant weight, affording the title carboxamide as a yellowish solid (10 mg, 62%> yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.19 (br. s, 1H); 7.78 (s, 1H); 7.57 (br. s, 1H); 7.36 (br. s, 2H); 5.76 (br. s, 2H); 3.00 (t, J = 6.8 Hz, 2H); 2.50 (t, J = 6.8 Hz, 2H); 1.43 (s, 6H).
MS (ESI, m/z): 299.2 [M+H+] for Ci5Hi8N60.
Example 19: {N'-[2-amino-3-carbamoyl-9,9-dimethyl-6,9-dihydro- 7H-benzo[6] [l,8]naphthyridin-(5E)-ylidene]-hydrazino}-acetic acid ethyl ester:
To a mixture of intermediate l.v (106 mg, 0.347 mmol) and NMP (1 mL) were added ethyl hydrazinoacetate hydrochloride (88 mg, 0.57 mmol), TEA (0.3 mL) and 3A molecular sieves (few beads). The mixture was stirred at 100°C overnight. The reaction mixture was cooled to rt and the solvent was evaporated. The residue was poured into water. The solid that formed was filtered, washed with water and dried to constant weight, affording the title carboxamide as a yellowish solid (67 mg, 47%> yield). 1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.20 (br. s, 1H); 7.79 (s, 1H); 7.59 (br. s, 1H); 7.38 (br. s, 2H); 6.03 (t, J = 5.2 Hz, 1H); 4.05 (q, J = 7.0 Hz, 2H); 3.78 (d, J = 5.2 Hz, 2H); 3.02 (t, J = 6.7 Hz, 2H); 2.55 (t, J = 6.7 Hz, 2H); 1.40 (s, 6H); 1.13 (t, J = 7.1 Hz, 3H). MS (ESI, m/z): 385.0 [M+H+] for ^Η24Ν603. Example 20: 4-{N'-[2-amino-3-carbamoyl-9,9-dimethyl-6,9-dihydro- 7H-benzo[6][l,8]naphthyridin-(5E)-ylidene]-hydrazino}-benzoic acid:
To a mixture of intermediate l.v (109 mg, 0.38 mmol) and NMP (1 mL) were added 4-hydrazinobenzoic acid (95 mg, 0.62 mmol), TEA (0.2 mL) and 3A molecular sieves (few beads). The mixture was stirred at +100°C during 2 h. The reaction mixture was cooled to rt and the solvent was evaporated. The residue was poured into water. The solid that formed was filtered, washed with water and dried to constant weight, affording the title carboxamide as a yellowish solid (140 mg, 87% yield).
1H NMR (ί 6-DMSO) δ: 12.1 (br. s, 1H); 9.44 (br. s, 1H); 8.43 (s, 1H); 8.20 (br. s, 1H); 7.82 (s, 1H); 7.76 (d, J = 8.8 Hz, 2H); 7.59 (br. s, 1H); 7.39 (br. s, 2H); 7.14 (d, J = 8.8 Hz, 2H); 3.08 (t, J = 6.8 Hz, 2H); 2.78 (t, J = 6.8 Hz, 2H); 1.57 (s, 6H).
MS (ESI, m/z): 419.0 [M+H+] for C22H22N603.
Example 21 : 2-amino-9,9-dimethyl-8-(methyl-hy drazono)-6,7,8,9-tetr ahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate l.v (99 mg, 0.347 mmol) and EtOH (0.3 mL) were added methyl hydrazine (0.3 mL, 5.64 mmol), TEA (0.6 mL) and 3A molecular sieves (few beads). The mixture was stirred at +100°C overnight. The reaction mixture was cooled to rt and the solvent was evaporated. The residue was poured into water. The solid that formed was filtered, washed with water and dried to constant weight, affording the title carboxamide as a yellowish solid (85 mg, 78% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.18 (br. s, 1H); 7.78 (s, 1H); 7.57 (br. s, 1H);
7.36 (br. s, 2H); 5.54 (q, J = 5.0 Hz, 1H); 3.0 (t, J = 6.7 Hz, 2H); 2.75 (d, J = 5.0 Hz, 3H);
2.50 (overlapped m, 2H); 1.43 (s, 6H).
MS (ESI, m/z): 313.0 [M+H+] for C16H2oN60. Example 22 : 2-amino-8- [(2-hy droxy-ethyl)-hy drazono] -9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate l.v (100 mg, 0.35 mmol) and NMP (1 mL) were added 2-hydroxyethylhydrazine (0.168 mL, 2 mmol), TEA (0.3 mL) and 3 A molecular sieves (few beads). The mixture was stirred at +100°C for 3 days. The reaction mixture was cooled to rt and the solvent was evaporated. The residue was purified by CC (DCM/MeOH 9:1 containing 1% aq. NH4OH) affording the title carboxamide as an orange gum (0.020 g, 17% yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.18 (br. s, 1H); 7.78 (s, 1H); 7.57 (br. s, 1H); 7.36 (br. s, 2H); 5.61 (m, 1H); 4.43 (t, J = 5.4 Hz, 1H); 3.43-3.53 (m, 2H); .3.05-3.12 (m, 2H); 2.98-3.03 (m, 2H); 2.50 (overlapped m, 2H); 1.43 (s, 6H).
MS (ESI, m/z): 343.2 [M+H+] for C17H22N602.
Example 23: 2-amino-9,9-dimethyl-8-(phthalazin-l-yl-hydrazono)- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate l.v (92 mg, 0.325 mmol) and NMP (1 mL) were added 1-hydrazinophthalazine (100 mg, 0.50 mmol), TEA (0.25 mL) and 3 A molecular sieves (few beads). The mixture was stirred at +100°C for 2 h. The reaction mixture was cooled to rt and the solvent was evaporated. The residue was poured into water. The solid that formed was filtered, washed with DCM/MeOH 9:1 mixture and dried to constant weight affording the title carboxamide as a yellowish solid (78 mg, 57% yield).
1H NMR (ί 6-DMSO) δ: 11.2 (br. s, 1H); 8.43 (s, 1H); 8.27 (m, 1H); 8.20 (br. s, 1H); 7.98 (s, 1H); 7.80 (s, 1H); 7.64-7.73 (m, 3H); 7.60 (br. s, 1H); 7.40 (br. s, 2H); 3.08-3.15 (m, 2H); 2.93-3.00 (m, 2H); 1.64 (s, 6H).
MS (ESI, m/z): 426.2 [M+H+] for C23H22N8O. Example 24 : r c-(2-amino-3-carbamoyl-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6][l,8]naphthyridin-8-yl)-carbamic acid tert-butyl ester:
24. i. Rac-ethyl 2-amino- 7- ( (tert-butoxycarbonyl)amino)-8, 8-dimethyl- 5, 6, 7,8-tetrahydroquinoline-3-carboxylate: To a solution of intermediate 3.i (2 g, 7.6 mmol) in MeOH (100 mL) were added ammonium acetate (9.4 g, 122 mmol) and NaBH3CN (2.39 g, 38.123 mmol). The mixture was heated to +76°C (oil bath temperature) for 60 min. The reaction mixture was cooled to rt, and partitioned between DCM (250 mL) and sat. NaHC03 (300 mL). The aq. layer was extracted with DCM/MeOH (9-1, 2 x 250 mL) and the combined org. layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was taken up in DCM (70 mL) and Boc2O (3.61 g, 16.569 mmol) was added. The mixture was stirred at rt for 2 h 30. After evaporation to dryness, the residue was directly subjected to CC (Hept/EA 4:1) affording the title compound as a colourless foam (2.39 g, 80% yield).
1H NMR (ί 6-DMSO) δ: 7.70 (s, 1H); 6.77 (br. s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 3.63 (m, 1H); 2.59-2.70 (m, 2H); 1.67-1.79 (m, 2H); 1.38 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); 1.19 (s, 3H); 1.05 (s, 3H).
24. ii Rac- (2-amino-3-carbamoyl-9, 9-dimethyl-6, 7, 8, 9-tetrahydro- benzofb] [1 ,8] naphthyridin-8-yl)-carbamic acid tert-butyl ester.
Starting from intermediate 24. i (55 mg, 0.15 mmol), the title carboxamide was obtained as a yellow solid (19 mg) using the procedures described in Example 1, steps l.ii to l.iv (ester reduction: 80%, MnO2 oxidation: 93% yield, cyclization: 44% yield).
1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 8.17 (s, 1H); 7.68 (s, 1H); 7.56 (s, 1H); 7.33 (br. s, 2H); 6.86 (m, 1H); 3.78 (m, 1H); 2.82-2.97 (m, 2H); 1.77-1.89 (m, 2H); 1.39 (s, 9H); 1.31 (s, 3H); 1.16 (s, 3H).
MS (ESI, m/z): 386.2 [M+H+] for C2oH27N5O3. Example 25: r c-2-amino-8-[(furan-2-carbonyl)-amino]-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[b] [l,8]naphthyridine-3-carboxylic acid amide:
25. i. Rac-2,8-diamino-9, 9-dimethyl-6, 7, 8, 9-tetrahydrobenzofb] [1 ,8] naphthyridine- 3-carboxam ide dihydroch loride :
A solution of intermediate 24. i (1.17 g, 3.1 mmol) in a HC1 solution (4M in dioxane,
18 mL) and dioxane (40 mL) was stirred at rt for 3 h. The reaction mixture was filtered and the solid was scarcely washed with dioxane, dried under vacuum at +50°C overnight affording the title dihydrochloride as a yellow solid (0.95 g, 93% yield).
1H NMR (ί 6-DMSO) δ: 8.91 (s, 1H); 8.63 (br. s, 1H); 8.29-8.43 (br. s, 4H); 8.07 (s, 1H);
8.04 (br. s, 1H); 3.49 (m, 1H); 2.97-3.05 (m, 2H); 1.96-2.19 (m, 2H); 1.48 (s, 3H); 1.33 (s,
3H).
25. ii. Rac-2-amino-8-[(furan-2-carbonyl)-amino]-9,9-dimethyl-6 ,8,9-tetrahydro- benzofbj [1 ,8] naphthyridine-3-carboxylic acid amide:
To a mixture of intermediate 25. i (52 mg, 0.145 mmol), DIPEA (0.12 mL, 0.72 mmol) and 2-furoic acid (21 mg, 0.19 mmol) in DMF (0.5 mL) was added dropwise at rt, T3P (50% in EA; 0.120 mL, 0.20 mmol). The mixture was stirred 2 h at rt. The solvent was evaporated and the residue was purified by CC (DCM/MeOH 9: 1 containing 1% aq. NH4OH). The relevant fractions were pooled and concentrated to dryness. The solid residue was triturated in ether, filtered and dried to constant weight, affording the title carboxamide as a yellow solid (0.015 g, 29% yield).
1H NMR (ί 6-DMSO) δ: 8.39 (s, 1H); 8.18 (br. s, 1H); 8.09 (m, 1H); 7.80 (s, 1H); 7.73 (s, 1H); 7.58 (s, 1H); 7.35 (br. s, 2H); 7.20 (m, 1H); 6.60 (m, 1H); 4.33 (m, 1H); 2.92-3.00 (m, 2H); 2.01 (m, 1H); 1.87 (m, 1H); 1.35 (s, 3H); 1.26 (s, 3H).
MS (ESI, m/z): 379.2 [M+H+] for C2oH2iN503. Example 26 : 2-amino-8-(2-hydroxyethyl)-9,9-dimethyl-6,7,8,9-tetrahydropyrido [2,3- 6][l,7]naphthyridine-3-carboxamide:
26. i. Ethyl 2-amino- 7-(2-( (tert-butyldimethylsilyl)oxy)ethyl)-8, 8-dimethyl-
5.6.7.8- tetrahydro-l, 7-naphthyridine-3-carboxylate: To a solution of intermediate D.iii (0.129 g, 0.519 mmol) in DMF (5 mL) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.147 g, 0.618 mmol) and K2CO3 (0.116 g, 0.840 mmol). The reaction was stirred at +80°C for 72 h. Sat. aq. NaHC03 (10 mL) and DCM (5 mL) were added. The two layers were decanted and the org. layer was dried over Na2S04, filtered and concentrated to dryness. The residue was purified by CC (Hex-EA 7:3), affording the title product as an orange oil (60 mg, 28% yield).
MS (ESI, m/z): 408.2 [M+H+] for C2iH37N303Si.
26. ii. 2-amino-8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-9,9-dimethyl-
6.7.8.9- tetrahydropyrido[2, 3-bJfl, 7] naphthyridineS-carboxamide:
Starting from intermediate 26. i (56 mg, 0.138 mmol), the title compound was obtained as a yellow solid (19 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 86% yield; Mn02 oxidation: 98%> yield; cyclization: 51% yield).
MS (ESI, m/z): 430.3 [M+H+] for C22H35N502Si.
26. in. 2-amino-8-(2-hydroxyethyl)-9, 9-dimethyl-
6, 7, 8,9-tetrahydropyrido[2, 3-bJfl, 7] naphthyridineS-carboxamide: A solution of intermediate 26.ii (14 mg, 0.033 mol) in TFA (0.4 mL) and water (0.1 mL) was stirred at rt for 1 h. The solvent was evaporated to dryness and the residue was treated with sat. NaHC03 until pH = 9 was reached. After concentration to dryness, the residue was purified by CC (DCM/MeOH 9:1 containing 1% aq. NH4OH) affording the title product as an orange solid (3 mg, 29% yield).
MS (ESI, m/z): 316.3 [M+H+] for Ci6H2iN502. Example 27: 2-amino-8-(4-hydroxybut-2-yn-l-yl)-9,9-dimethyl- 6,7,8,9-tetrahydropyrido[2,3-6][l,7]naphthyridine-3-carboxamide:
27. i. (2-amino- 7-(4-((tert-butyldimethylsilyl)oxy)but-2-yn-l-yl)-8,8-dimethyl-
5.6.7.8- tetrahydro-l, 7-naphthyridin-3-yl)methanol: To a solution of the compound of Preparation E (0.105 g, 0.5 mmol) and ((4-bromobut-2- yn-l-yl)oxy)(tert-butyl)dimethylsilane (prepared according to EP 157729; 0.147 g, 1.1 eq.) in DMF (2 mL) was CS2CO3 (0.222 g, 0.683 mmol, 1.344 eq.). The reaction was stirred at rt for 1 h. The mixture was concentrated to the dryness. The residue was poured into water and the mixture was extracted with EA (2 x 25 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness, affording the title compound as a yellowish oil (0.156 g, 79% yield).
MS (ESI, m/z): 390.2 [M+H+] for C21H35N3O2SL
27. ii. 2-amino-8-(4-hydroxybut-2-yn-l-yl)-9,9-dimethyl-
6.7.8.9- tetrahydropyrido[2, 3-bJfl, 7] naphthyridine-3-carboxamide: Starting from intermediate 27. i (145 mg, 0.37 mmol), the title compound was obtained as a yellow solid (32 mg) using the procedures described in Example 1, steps l.iii and 6.iv (Mn02 oxidation: 87% yield, cyclization: 79% yield) and Example 26, step 26.iii (deprotection: 40% yield)
1H NMR (ί 6-DMSO) δ: 8.38 (s, 1H); 8.18 (br. s, 1H), 7.72 (s, 1H); 7.57 (s, 1H); 7.35 (br. s, 2H); 5.08 (t, J = 5.9 Hz, 1H); 4.07 (d, J = 5.9 Hz, 2H); 3.50 (br. s, 2H); 2.85-2.99 (m, 4H); 1.43 (s, 6H).
MS (ESI, m/z): 340.3 [M+H+] for C18H21N502.
Example 28 : 2-amino-9,9-dimethyl-8-((4-methylthiazol-2-yl)methyl)- 6,7,8,9-tetrahydropyrido[2,3-6][l,7]naphthyridine-3-carboxamide: 28. i. Ethyl 2-amino-8,8-dimethyl-7-((4-methylthiazol-2-yl)methyl)-5,6, 7,8-tetrahydro-l, 7- naphthyridine-3-carboxylate:
Typical procedure for a reductive amination using NaBH(OAc)3.
A solution of intermediate D.iii (0.212 g, 0.854 mmol) and 4-methyl- 2-thiazolecarboxaldehyde (0.225 g, 1.95 mmol) in DCE (5 mL) was stirred for 15 min at rt. NaBH(OAc)3 (0.405 g, 2.22 mmol) was added and the reaction mixture was stirred at +60°C overnight. The reaction mixture was diluted with sat. NaHC03 (20 mL) and DCM (20 mL). The org. layer was dried over MgS04, filtered and concentrated to dryness under reduced pressure and the residue was purified by CC (EA), affording the title compound as a yellowish oil (0.12 g, 39% yield).
MS (ESI, m/z): 361.2 [M+H+] for C18H24N402S.
28. ii. 2-amino-9, 9-dimethyl-8-((4-methylthiazol-2-yl)methyl)-
6, 7, 8,9-tetrahydropyrido[2, 3-bJfl, 7] naphthyridineS-carboxamide:
Starting from intermediate 28. i (0.118 g, 0.328 mmol), the title compound was obtained as a yellow solid (13 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 81%> yield, Mn02 oxidation: 75%> yield, cyclization: 17%> yield).
1H NMR (ί 6-DMSO) δ: 8.40 (s, 1H); 8.20 (br. s, 1H); 7.76 (s, 1H); 7.59 (s, 1H); 7.38 (br. s, 2H); 7.09 (s, 1H); 4.00 (s, 2H); 2.79-2.91 (m, 4H); 2.31 (s, 3H); 1.40 (s, 6H). MS (ESI, m/z): 383.2 [M+H+] for C19H22N6OS. Example 29: 2-amino-8-(2-(benzyloxy)ethyl)-9,9-dimethyl-
6,7,8,9-tetrahydropyrido[2,3-6][l,7]naphthyridine-3-carboxamide:
Starting from intermediate D.iii (0.334 g, 1.34 mmol) and 2-(benzyloxy)acetaldehyde (0.201 g, 1.34 mmol), the title compound (0.132 g) was obtained as a yellow solid using the typical procedures described in Example 28, step 28. i (reductive animation: 61%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 98%> yield, Mn02 oxidation: 90%> yield, cyclization: 53%> yield).
1H NMR (ί 6-DMSO) δ: 8.38 (s, 1H); 8.18 (br. s, 1H); 7.71 (s, 1H); 7.57 (br. s, 1H); 7.22-7.40 (m, 7H); 4.51 (s, 2H); 3.51-3.58 (m, 2H); 2.79-2.91 (m, 4H); 2.69-2.78 (m, 2H); 1.40 (s, 6H).
MS (ESI, m/z): 406.2 [M+H+] for C23H27N502.
Example 30: 2-amino-8-((6-fluorobenzo[d]thiazol-2-yl)methyl)-9,9-dimethyl-6,7,8,9- tetrahydropyrido[2,3-6][l,7]naphthyridine-3-carboxamide:
Starting from the compound of Preparation E (0.103 g, 0.5 mmol) and 2-(bromomethyl)-6- fluorobenzo[(i]thiazole (0.127 g, 0.51 mmol), the title compound was obtained as a yellow solid (0.115 g) using the typical procedures described in Example 27, step 27. i (alkylation: 95% yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 99% yield, cyclization: 55% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.21 (br. s, 1H); 7.87-7.96 (m, 2H); 7.79 (s, 1H); 7.60 (br. s, 1H); 7.40 (br. s, 2H); 7.32 (m, 1H); 4.18 (s, 2H); 2.91 (br. s, 4H); 1.55 (s, 6H). MS (ESI, m/z): 436.2 [M+H+] for C22H2iN6OFS.
Example 31 : 2-amino-9,9-dimethyl-8-(prop-2-yn-l-yl)-6,7,8,9-tetrahydropyrido [2,3- 6][l,7]naphthyridine-3-carboxamide:
Starting from the compound of Preparation E (0.098 g, 0.47 mmol) and propargyl bromide (80 wt%> in toluene, 0.076 mL, 0.705 mmol), the title compound was obtained as a yellow solid (0.066 g) using the typical procedures described in Example 27, step 27. i (alkylation: 82%o yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 99%> yield, cyclization: 56% yield).
1H NMR (ί 6-DMSO) δ: 8.38 (s, 1H); 8.17 (br. s, 1H); 7.72 (s, 1H); 7.58 (s, 1H); 7.36 (br. s, 2H); 3.49 (br. s, 2H); 3.05 (m, 1H); 2.85-2.99 (m, 4H); 1.43 (s, 6H).
MS (ESI, m/z): 310.3 [M+H+] for C17Hi9N50.
Example 32: r c-2-amino-6-bromo-7-[l-(thiophene-2-sulfonylamino)-ethyl]- [l,8]naphthyridine-3-carboxylic acid amide:
To a solution of intermediate A.vi (15 mg, 0.048 mmol) in dioxane (0.6 mL) were added NaHC03 (14 mg, 0.17 mmol), water (0.02 mL) and thiophene-2-sulfonyl chloride (6 mg, 0.058 mmol). The reaction was heated to +70°C for 4 h. The reaction mixture was diluted with EA (1 mL) and water (0.5 mL). The solid that formed was filtered off and dried to constant weight affording the title sulfonamide as a yellow powder (21 mg, 97%> yield). MS (ESI, m/z): 456.0 [M+H+] for C15Hi4N503BrS2. Example 33: r c-2-amino-6-bromo-7-[l-(4-chloro-pyridine-3-sulfonylamino)-ethyl]- [l,8]naphthyridine-3-carboxylic acid amide:
The title compound was obtained as a yellow powder (0.009 g, 38% yield), starting from intermediate A.vi (15 mg, 0.048 mmol) and 4-chloropyridine-3-sulfonyl chloride (1.2 eq.) and using the procedure described in Example 32.
MS (ESI, m/z): 485.0 [M+H+] for Ci6Hi4N603BrClS.
Example 34: r c-2-amino-6-bromo-7-[l-(2-chloro-pyridine-3-sulfonylamino)-ethyl]- [l,8]naphthyridine-3-carboxylic acid amide:
The title compound was obtained as a yellow powder (9 mg, 38% yield), starting from intermediate A.vi (15 mg, 0.048 mmol) and 2-chloropyridine-3-sulfonyl chloride (1.2 eq.) and using the procedure described in Example 32.
MS (ESI, m/z): 485.0 [M+H+] for Ci6Hi4N603BrClS.
Example 35: r c-2-amino-6-bromo-7-[l-(4-methoxy-benzenesulfonylamino)-ethyl]- [l,8]naphthyridine-3-carboxylic acid amide: The title compound (7mg, 29%> yield) was obtained as a yellow powder, starting from the intermediate A.vi (15 mg, 0.048 mmol) and 4-methoxybenzene-l-sulfonyl chloride (1.2eq.) and using the procedure described in Example 32.
1H NMR (ί 6-DMSO) δ: 8.34 (s, 1H); 8.21 (br. s, 1H); 8.16 (s, 1H); 8.01 (s, 1H); 7.68 (s, 1H); 7.48-7.58 (m (br. s 2H + overlapped d, J = 8.6 Hz, 2H), 4H); 6.75 (d, J = 8.6 Hz, 2H); 4.90 (q, J = 6.7 Hz, 1H); 3.65 (s, 3H); 1.26 (d, J = 6.7 Hz, 3H).
MS (ESI, m/z): 485.0 [M+H+] for Ci8Hi8N504BrS.
Example 36: r c-2-amino-6-bromo-7-(l-methanesulfonylamino-ethyl)- [l,8]naphthyridine-3-carboxylic acid amide:
The title compound was obtained as a yellow powder (8 mg, 43%> yield), starting from intermediate A.vi (15 mg, 0.048 mmol) and MsCl (1.5 eq.) and using the procedure described in Example 32.
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.35 (br. s, 1H); 8.24 (br. s, 1H); 7.51-7.74 (m, 4H); 5.05 (m, 1H); 2.72 (s, 3H); 1.42 (d, J= 6.8Hz, 3H). MS (ESI, m/z): 388.0 [M+H+] for C12Hi4N503BrS.
Example 37: 2-amino-7,8-dihydro-5H-6-oxa-l,9-diaza-anthracene-3-carboxylic acid amide:
Starting from (Z)-3-(hydroxymethylene)dihydro-2H-pyran-4(3H)-one (prepared according to J. Heterocyclic Chem. (1984), 21, 1441-1444; 0.504 g, 3.93 mmol), the title compound was obtained as a yellow solid (6 mg) using the procedures described in Example 2, step 2.H (cyclization: 17% yield) and Example 1, steps l.ii to l.iv (ester reduction: 84% yield, Mn02 oxidation: 93% yield, cyclization: 60% yield).
1H NMR (ί 6-DMSO) δ: 8.40 (s, 1H); 8.20 (br. s, 1H); 7.70 (s, 1H); 7.59 (br. s, 1H); 7.41 (br. s, 2H); 4.78 (s, 2H); 4.01 (t, J = 5.9 Hz, 2H); 2.96 (t, J = 5.9 Hz, 2H).
MS (ESI, m/z): 245.0 [M+H+] for Ci2Hi2N402.
Example 38: 2-amino-7,8-dihydro-5H-6-thia-l,9-diaza-anthracene-3-carboxylic acid amide:
Starting from (E)-3-(hydroxymethylene)dihydro-2H-thiopyran-4(3H)-one (commercially available; 1.85 g, 12.8 mmol), the title compound was obtained as a yellow solid (54 mg) using the procedures described in Example 2, step 2.Π (cyclization: 36% yield) and Example 1, steps l.ii to l.iv (ester reduction: 71% yield, Mn02 oxidation: 54% yield, cyclization: 54% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.20 (br. s, 1H); 7.79 (s, 1H); 7.59 (br. s, 1H); 7.41 (br. s, 2H); 3.89 (s, 2H); 3.16 (t, J = 6.4 Hz, 2H); 2.99 (t, J = 6.4 Hz, 2H).
MS (ESI, m/z): 261.0 [M+H+] for Ci2Hi2N4OS.
Example 39 : 2-amino-9,9-dimethyl-6,7,8,9-tetrahydro-benzo [b] [1,8] naphthyridine-3- carbox lic acid amide:
Starting from 2,2-dimethylcyclohexanone (1 g, 7.92 mmol), the title carboxamide was obtained as a yellow solid (0.081 g) using the procedure described in Example 4, step 4.i (cyclization: 57% yield) and Example 1, steps l.ii to l.iv (ester reduction: quant., Mn02 oxidation: 77% yield, cyclization: 60% yield). 1H NMR (ί 6-DMSO) δ: 8.36 (s, 1H); 8.16 (br. s, 1H); 7.66 (s, 1H); 7.55 (br. s, 1H); 7.32 (br. s, 2H); 2.80-2.87 (m, 2H); 1.72-1.80 (m, 4H); 1.30 (s, 6H).
MS (ESI, m/z): 271.2 [M+H+] for Ci5Hi8N4O.
Example 40: (R)-2-amino-9-methyl-6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine- 3-carboxylic acid amide and (S -2-amino-9-methyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
40. i. (R)-ethyl 2-amino-8-methyl-5 , 6, 7,8-tetrahydroquinoline-3-carboxylate and (S)-ethyl 2-amino-8-methyl-5 , 6, 7, 8-tetrahydroquinoline-3-carboxylate
Starting from (Z)-2-(hydroxymethylene)-6-methylcyclohexanone (prepared from 2-methylcyclohexanone as described in Example 2, step 2.i; 0.54 g, 4.15 mmol), rac-ethyl 2-amino-8-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate was obtained as a yellow solid (0.464 g), using the procedure described in Example 2, step 2.Π (cyclization: 48% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.16 (br. s, 1H); 7.77 (s, 1H); 7.54 (br. s, 1H); 7.31 (br. s, 2H); 3.13 (m, 1H); 2.78-3.00 (m, 2H); 2.34 (m, 1H); 1.61 (m, 1H); 1.30 (d, J = 6.9 Hz, 3H).
MS (ESI, m/z): 243.2 [M+H+] for Ci3Hi4N4O.
The racemic material (0.28 g) was separated by chiral prep-HPLC using a Chiralcel OJ-H 250x4.6mm ID, 5μιτι column and Hept/EtOH 49: 1 (containing 0.1% DEA) isocratic gradient at a flow rate of 34 niL/min. The first eluting compound came after 7.6 min and the second one after 8.5 min. One the same analytical column and elution conditions at a flow rate of 0.8 mL/min., the respective retention times were 7.7 and 8.7 min. After evaporation of the fractions, the first eluting enantiomer A (0.108 g) was obtained as a white solid. The second eluting enantiomer B (0.1 12 g) was obtained as a white solid. Both compounds showed same NMR than the racemic material. The absolute stereochemistry of each enantiomer has not been assigned.
40. ii. (R)-2-amino-9-methyl-6, 7,8,9-tetrahydro-benzo[b] [1 ,8] naphthyridine-3-carboxylic acid amide and (S)-2-amino-9-methyl-6, 7,8,9-tetrahydro-benzofbJ [1 ,8] naphthyridine-3- carboxylic acid amide: Starting from the first and second eluting intermediates A and B from 40. i, the title (R) and (S) carboxamides (respectively 49 and 55 mg) were obtained as yellow solids using the procedures described in Example 1 , steps l .ii to l .iv (ester reduction: 96% yield, Mn02 oxidation: 90% yield, cyclization: 40%> yield).
Both enantiomers (first eluting A and second eluting B) display similar analytical data. Only the data of the compound made from the first eluting intermediate A in step 40. ii were described. The absolute stereochemistry of each enantiomer has not been assigned. 1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 8.16 (br. s, 1H); 7.67 (s, 1H); 7.55 (br. s, 1H); 7.31 (br. s, 2H); 2.93 (m, 1H); 2.83 (t, J = 6.3 Hz, 2H); 2.03 (m, 1H); 1.84 (m, 1H); 1.71 (m, 1H), 1.57 (m, 1H); 1.35 (d, J = 7.0 Hz, 3H).
MS (ESI, m/z): 257.2 [M+H+] for Ci4Hi6N4O.
Example 41 : 2-amino-9,9-dimethyl-8- [(Z)-thiazol-2-ylmethoxyimino] - 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (82 mg, 0.37 mmol) and O-(thiazol- 2-ylmethyl)hydroxylamine (105 mg, 0.8 mmol), the title compound was obtained as a yellow solid (63 mg) using the typical procedures described in Example 1 1 , step l l .i (oxime formation: 78%> yield) and Example 1 , steps l .iii and l .iv (MnO2 oxidation: 89%> yield, cyclization: 72%>yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H), 7.76 (d, J = 3.2 Hz, 1H); 7.67 (d, J = 3.2Hz, 1H); 7.40 (br. s, 1H); 5.34 (s, 2H); 2.97-3.00 (m, 2H); 2.80-2.86 (m, 2H); 1.51 (s, 6H).
MS (ESI, m/z): 397.0 [M+H+] for Ci9H2oN6O2S.
Example 42: 2-amino-10,10-dimethyl-7,8,9,10-tetrahydro- 6H-cyclohepta[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from 2,2-dimethylcycloheptanone (prepared as described in US US 2009/0253678; 500 mg, 3.55 mmol), the title compound was obtained as a yellow solid (0.060 g) using the procedures described in Example 2, steps 2.i and step 2.ii (enol formation: 50%> yield, cyclization: 35%> yield) and Example 1 , steps l .ii to l .iv (ester reduction: 100%> yield, MnO2 oxidation: 73%> yield, cyclization: 53%> yield).
1H NMR (ί 6-DMSO) δ: 8.36 (s, 1H); 8.15 (br. s, 1H); 7.68 (s, 1H); 7.54 (br. s, 1H); 7.37 (br. s, 2H); 2.90-2.97 (m, 2H), 1.75- 1.87 (m, 2H); 1.58-1.71 (M, 4H), 1.37 (s, 6H). MS (ESI, m/z): 285.2 [M+H+] for C16H20N4O.
Example 43: r c-2-amino-8-methyl-7,8-dihydro- 6H-cyclopenta[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from 3-methyl-2-oxocyclopentanecarbaldehyde (prepared from 2-methylcyclopentanone as described in Example 2, step 2.i; 0.83 g, 6.64 mmol), the title compound was obtained as a yellow solid (0.116 g) using the procedures described in Example 2, step 2.ii (cyclization: 83% yield) and Example 1, steps l.ii to l.iv (ester reduction: 100%> yield, Mn02 oxidation: 70%> yield, cyclization: 74% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.16 (br. s, 1H); 7.77 (s, 1H); 7.54 (br. s, 1H); 7.31 (br. s, 2H); 3.13 (m, 1H); 2.78-3.00 (m, 2H); 2.34 (m, 1H); 1.61 (m, 1H); 1.30 (d, J = 6.9 Hz, 3H).
MS (ESI, m/z): 243.2 [M+H+] for C13H14N4O.
Example 44 : r c-2-amino-9-hydroxy-6,7,8,9-tetrahydro-benzo [b] [1,8] naphthyridine- 3-carboxylic acid amide:
44. i. Rac-ethyl 2-amino-8-hydroxy-5 , 6, 7, 8-tetrahydroquinoline-3-carboxylate:
Starting from 2-((tert-butyldimethylsilyl)oxy)cyclohexanone (1 g, 4.38 mmol), the title ester enolate was obtained as a white powder (0.108 g) using the protocol described in Example 2, steps 2.i and 2.ii (enolate formation: 57%> yield, cyclization: 18%> yield) 1H NMR (ί 6-DMSO) δ: 7.78 (s, 1H); 6.86 (br. s, 2H); 4.84 (m, 1H); 4.33 (m, 1H); 4.25 (q, J = 7.1 Hz, 2H); 2.50-2.65 (m, 2H); 1.55-1.90 (m, 4H); 1.28 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 237.2 [M+H+] for C12Hi6N203.
44. ii. Rac-ethyl 2-amino-8-((tert-butyldimethylsilyl)oxy)-5,6 ,8-tetrahydroquinoline-3- carboxylate:
To a solution of intermediate 44. i (0.108 g, 0.45 mmol) in DMF (2 mL) were added imidazole (0.065 g, 0.96 mmol) and TBDMSC1 (0.15 g, 1 mmol). The reaction proceeded overnight at rt. The solvent was evaporated in vacuo and the residue was partitioned between EA (50 mL) and water (25 mL). The two layers were separated and the org. layer was washed with brine, dried over MgS04, filtered and concentrated to dryness affording the title silyl ether as a colourless oil (0.153 g, 95% yield). MS (ESI, m/z): 351.2 [M+H+] for C18H30N2O3SL
44. in. Rac-2-amino-9-hydroxy-6, 7, 8, 9-tetrahydrobenzofbJ [1 , 8] naphthyridine- 3-carboxamide:
Starting from intermediate 44. ii (0.153 g, 0.43 mmol), the title compound (14 mg) was obtained as a using the procedures described in Example 1, steps l.ii to l.iv (ester reduction: 97% yield, Mn02 oxidation: 81%> yield, cyclization: 82%> yield) and Preparation F, step F.iii (deprotection: 94 %> yield).
1H NMR (ί 6-DMSO) δ: 8.40 (s, 1H); 8.20 (br. s, 1H); 7.76 (s, 1H); 7.61 (br. s, 1H); 7.34 (br. s, 2H); 5.13 (d, J = 3.4 Hz, 1H); 4.59 (m, 1H); 2.70-2.93 (m, 2H); 1.66-2.06 (m, 4H).
MS (ESI, m/z): 259.2 [M+H+] for C13H14N4O2.
Example 45: 2-amino-8-hydroxymethyl-9,9-dimethyl-6,9-dihydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
45. i. (E)-4-methyl-N'-(3 , 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5] undecan-8-ylidene) benzenesulfonohydrazide
A mixture of 3, 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5]undecan-8-one (2.26 g, 10 mmol) and toluene-4-sulfonohydrazide (1.95 g, 10.5 mmol) in EtOH (12 mL) was gently heated at +40°C until complete dissolution. The solution was stirred at rt overnight. The solvent was evaporated and the solid residue stirred in MeOH/water (4:1, 8 mL). The solid was collected by filtration, washed with a MeOH/water mixture (4:1, 5 mL) and dried, affording the title hydrazone as a white solid (3.48 g, 88%> yield).
1H NMR (ί 6-DMSO) δ: 9.85 (s, 1H); 7.70 (d, J = 8.3 Hz, 2H); 7.36 (d, J = 8.3 Hz, 2H); 3.57 (d, J = 11.3 Hz, 2H); 3.20 (d, J = 11.3 Hz, 2H); 2.36 (s, 3H); 2.24 (t, J = 6.7 Hz, 2H); 1.98-2.07 (m, 2H); 1.31-1.42 (m, 2H); 1.04 (s, 3H); 0.98 (s, 6H); 0.65 (s, 3H). 45. ii. 3, 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5] undec-8-ene-8-carbaldehyde:
A solution of intermediate 45. i (3.48 g, 8.82 mmol) in TMEDA (67 mL) was cooled to -78°C. ft-BuLi (1.8 in Hex, 22 mL) was added dropwise. The reaction was immediately warmed to rt and further stirred for 5 min. The reaction mixture was cooled to 0°C and dry DMF (8.2 mL) was added dropwise. After stirring for 5 min, the reaction mixture was quenched with sat. NH4C1 (250 mL). The reaction was diluted with EA/Hex mixture (1: 1, 200 mL) and water (100 mL). The org. layer was washed with water (50 mL) and brine (50 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9), affording the title aldehyde as a white solid (1.65 g, 78% yield). 1H NMR (CDC13) δ: 9.36 (s, 1H); 6.61 (t, J = 3.7 Hz, 1H); 3.69 (d, J = 11.3 Hz, 2H); 3.39 (d, J = 11.3 Hz, 2H); 2.30-2.38 (m, 2H); 2.11 (t, J = 6.2 Hz, 2H); 1.33 (s, 6H); 1.20 (s, 6H); 0.74 (s, 3H).
45. in. (3, 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5] undec-8-en-8-yl)methanol:
Starting from intermediate 45. ii (0.477 g, 2 mmol), the title alcohol was obtained as a colourless solid (0.435 g, 91% yield) using the procedure described in Example 3, step 3.ii (reduction with NaBH4).
1H NMR (CDC13) δ: 5.65 (m, 1H); 4.17 (s, 1H); 4.13 (br. s, 2H); 3.70 (d, J = 11.3 Hz, 2H); 3.38 (d, J = 11.3 Hz, 2H); 2.08 (br. s, 4H); 1.51 (s, 3H); 1.18 (s, 6H); 0.73 (s, 3H).
45.iv. 3-(hydroxymethyl)-2,2-dimethylcyclohex-3-enone:
A solution of intermediate 45.iii (0.425 g, 1.81 mmol) in acetone (10 mL) was treated with IN HC1 (1 mL). The mixture was stirred at +40°C for 1 h. After cooling, sat. NaHC03 (2 mL) was added and the volatiles were removed in vacuo. The residue was dissolved in DCM, the two layers were separated and the org. layer was dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 2:3), affording the title ketone as a colourless oil (0.275 g, 99%> yield).
1H NMR (CDC13) δ: 5.92 (m, 1H); 4.17 (br. s, 2H); 2.40-2.58 (m, 4H); 1.25 (s, 6H).
45. v. 3-( ((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethylcyclohex-3-enone:
Starting from intermediate 45. iv (0.275 g, 1.78 mmol), the title silyl ether was obtained as a colourless oil (0.481 g, 100%> yield) using the procedure described in Example 44, step 44.ii.
1H NMR (CDC13) δ: 5.87 (m, 1H); 4.15 (br. s, 2H); 2.40-2.57 (m, 4H); 1.22 (s, 6H); 0.92 (s, 9H), 0.08 (s, 6H). 45. vi. 2-amino-8-hydroxymethyl-9,9-dimethyl-6,9-dihydro-benzo[b] [ 1 ,8] naphthyridine-3- carboxylic acid amide:
Starting from intermediate 45.v (0.481 g, 1.79 mmol), the title carboxamide was obtained as a yellow solid (0.017 g) using the procedures described in Preparation D, steps D.i and D.ii (enolate formation: 95% yield, cyclization: 76% yield), Example 1, steps l.ii to 6.iv (ester reduction and Mn02 oxidation: 80% yield, cyclization: 67% yield) and Preparation F, step F.iii (deprotection: 27% yield).
1H NMR (ί 6-DMSO) δ: 8.45 (s, 1H); 8.22 (br. s, 1H); 7.82 (s, 1H); 7.61 (br. s, 1H); 7.47 (br. s, 2H); 5.91 (m, 1H); 4.77 (m, 1H); 4.11 (br. s, 2H); 3.50 (br. s, 2H); 1.42 (s, 6H). MS (ESI, m/z): 299.2 [M+H+] for Ci6Hi8N402.
Example 46 : r c-2-amino-8-(2-h droxy-ethyl)-9,9-dimethyl-6,7,8,9-tetrah dro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
46. i. (E)-ethyl 2-(3, 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5] undecan-8-ylidene)acetate:
To a mixture of NaH (0.353 g, 8.8 mmol) and THF (5 mL), cooled at 0°C, was added dropwise triethyl phosphonoacetate (1.81 mL, 8.8 mmol). After 15 min, 3,3,7,7-tetramethyl-l,5-dioxaspiro[5.5]undecan-8-one (1 g, 4.4 mmol) was added and the mixture was refluxed overnight. The reaction mixture was partitioned between water (50 mL) and EA (50 mL). The org. layer was dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hept 1:7), affording the α,β-unsaturated ester (1.17 g, 89% yield).
1H NMR (ί 6-DMSO) δ: 5.58 (s, 1H); 4.03 (q, J = 7.1 Hz, 2H); 3.60 (d, J = 11.3 Hz, 2H); 3.22 (d, J = 11.3 Hz, 2H); 2.83-2.90 (m, 2H); 2.00-2.08 (m, 2H); 1.32-1.45 (m, 2H); 1.17 (t, J = 7.1 Hz, 3H); 1.11 (s, 6H); 1.06 (s, 3H); 0.66 (s, 3H).
46. ii. Ethyl 2-(3, 3, 7, 7-tetramethyl-l, 5-dioxaspiro[5.5] undecan-8-yl)acetate: To a solution of intermediate 46. i (1.58 g, 5.325 mmol) in EA (25 mL) under nitrogen was added Pt02 (monohydrate, 0.4 g). The reaction mixture was stirred at rt under a hydrogen atmosphere overnight. The catalyst was removed by filtration and the filtrate was concentrated to dryness affording the title ester as a colourless oil (1.42 g, 90% yield). 1H NMR (ί 6-DMSO) δ : 4.02 (q, J = 7.1 Hz, 2H); 3.66 (d, J = 11.5 Hz, 1H); 3.55 (d, J = 11.5 Hz, 1H); 3.18-3.27 (m, 2H); 2.35 (m, 1H); 1.99 (m, 1H); 1.87 (m, 1H); 1.32-1.49 (m, 2H); 1.08-1.25 (overlapped m, 4H); 1.15 (t, J = 7.1 Hz, 3H); 1.07 (s, 3H); 0.97 (s, 3H); 0.76 (s, 3H); 0.66 (s, 3H).
46.iii. Rac-tert-butyldiphenyl(2-(3 ,3 , 7, 7-tetramethyl-l,5-dioxaspiro[5.5]undecan- 8-yl)ethoxy)silane Starting from intermediate 46. ii (1.42 g, 4.78 mmol), the title silyl ether was obtained as a colourless oil (2.13 g, 88% yield) using the procedures described in Example 1, step l.ii (ester reduction: 100%) and Example 44, step 44.ii (replacing TBDMC1 with TBDPSC1, silyl ether formation: 88% yield).
1H NMR (ί 6-DMSO) δ : 7.55-7.62 (m, 4H); 7.35-7.45 (m, 6H); 3.49-3.69 (m, 4H); 3.15-3.22 (m, 2H); 1.53-1.71 (m, 2H); 1.02-1.42 (overlapped m, 7H); 1.07 (s, 3H); 0.97 (s, 9H); 0.93 (s, 3H); 0.72 (s, 3H); 0.65 (s, 3H).
46. iv. Rac-ethyl 2-amino- 7-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-8, 8-dimethyl-
5.6.7.8- tetrahydroquinoline-3-carboxylate
Starting from intermediate 46.iii (2.13g, 4.31mmol), the title ester was obtained as a thick oil (0.53 g) using the procedures described in Example 3, step 3.i (deprotection: 55% yield), and Example 1, step l.i (enolate formation followed by cyclization: 50% yield). MS (ESI, m/z): 531.4 [M+H+] for C32H42N2O3SL
46.v. Rac-ethyl 2-amino-7-(2-hydroxyethyl)-8,8-dimethyl-5,6, 7 ,8-tetrahydroquinoline-3- carboxylate: To a solution of intermediate 46. iv (0.53 g) in THF (5 mL) was added TBAF (\M in THF, 2 mL, 2 mmol). The mixture was stirred at +50°C for 2 h. The solvent was removed in vacuo. The residue was purified by CC (Hept/EA 1: 1), affording the title compound as a colourless oil (0.18 g, 62% yield).
MS (ESI, m/z): 293.2 [M+H+] for C16H24N203. 46.vi. Rac-2-amino-8-(2-hydroxyethyl)-9,9-dimethyl-
6.7.8.9- tetrahydrobenzofb] [ 1 ,8] naphthyridine-3-carboxamide
Starting from intermediate 46.v (0.18 g, 0.61 mmol), the title carboxamide was obtained as a beige solid (0.097 g) using the procedures described in Example 1, steps l.ii to l.iv (ester reduction: 84% yield, Mn02 oxidation: 93% yield, cyclization: 60% yield). 1H NMR (ί 6-DMSO) δ: 8.36 (s, 1H); 8.16 (br. s, 1H); 7.67 (s, 1H); 7.55 (br. s, 1H); 7.32 (br. s, 2H); 4.40 (t, J = 5.1 Hz, 1H); 3.41-3.62 (m, 2H); 2.75-2.88 (m, 2H); 1.44-1.96 (several m, 4H); 1.37 (s, 3H); 1.21 (m, 1H); 1.13 (s, 3H).
MS (ESI, m/z): 315.2 [M+H+] for Ci7H22N402. Example 47: 2-amino-5-hydroxymethyl-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[6][l,8]naphthyridine-3-carboxylic acid amide:
47. i. Diethyl 2-amino-8, 8-dimethyl-5, 6, 7, 8-tetrahydroquinoline-3 , 4-dicarboxylate:
Starting from (E)-ethyl 2-(3,3-dimethyl-2-oxocyclohexylidene)-2-hydroxyacetate (prepared according to Bull. Soc. Chim. Fr. (1957), 1499; 5.3 g, 23.4 mmol), the title diester was obtained as a white solid (4.57 g, 61% yield) using the procedure described in Example 2, step 2.H.
1H NMR (ί 6-DMSO) δ: 6.83 (br. s, 2H); 4.16-4.28 (two overlapped q, J = 7.2 Hz, 4H); 2.40 (m, 2H); 1.59-1.73 (m, 2H); 1.18-1.28 (two overlapped t, J = 7.2 Hz, 6H); 1.20 (s, 6H). 47. ii. (2-amino-3-(hydroxymethyl)-8, 8-dimethyl-5, 6, 7, 8-tetrahydroquinolin-4-yl)methyl acetate:
To an ice-chilled solution of intermediate 47. i (1 g, 3.4 mmol) in THF (20 mL) was added a LAH solution (I in THF, 11 mL). The mixture was stirred at the same temperature for 1 h at 0°C and then for 2.5 h at rt. EA (5 mL), water (0.417 mL), 2NNaOH (2 x 0.417 mL) and water (0.417 mL) were carefully added. After dilution with EA (100 mL), the mixture was stirred overnight. The resulting mixture was filtered off and the solids were washed with EA. The filtrate was concentrated to dryness. The residue was purified by CC (EA) affording the title acetate as a white solid (92 mg, 10% yield).
MS (ESI, m/z): 279.2 [M+H+] for C15H22N203. 47. in. 2-amino-5-(hydroxymethyl)-9,9-dimethyl-
6, 7, 8,9-tetrahydrobenzofb] [ 1 ,8] naphthyridineS-carboxamide:
Starting from intermediate 47. ii, the title carboxamide was obtained as a white solid (5 mg, 7%) yield) using the procedures described in Example 1, steps l.iii and l.iv (Mn02 oxidation: 68% yield, cyclization: 7% yield. 1H NMR (ί 6-DMSO) δ: 8.69 (s, 1H); 8.26 (br. s, 1H); 7.55 (s, 1H); 7.29 (br. s, 2H); 5.07 (m, 1H); 4.81 (m, 2H); 2.93 (m, 2H); 1.69-1.86 (m, 4H); 1.31 (s, 6H).
MS (ESI, m/z): 301.2 [M+H+] for Ci6H2oN402.
Example 48 : r c-2-amino-9-hy droxy methyl-9-methyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from ethyl l-methyl-2-oxocyclohexanecarboxylate (2.83 g, 15.4 mmol), the title carboxamide was obtained as a yellowish solid (0.155 g) using the procedures described in Example 4, step 4.i (enol formation and cyclization: 50% yield) and Example 1, steps l.ii to l.iv (ester reduction: 22% yield, Mn02 oxidation: 75% yield, cyclization: 67% yield). 1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 8.17 (br. s, 1H); 7.68 (s, 1H); 7.56 (br. s, 1H); 7.36 (br. s, 2H); 4.91 (m, 1H); 3.69 (dd, J = 6.6, 10.1 Hz, 1H); 3.50 (dd, J = 4.5, 10.1 Hz, 1H); 2.74-2.88 (m, 2H); 1.99 (m, 1H); 1.69-1.89 (m, 2H); 1.56 (m, 1H); 1.22 (s, 3H).
MS (ESI, m/z): 287.2 [M+H+] for Ci5Hi8N402.
Example 49: r c-2-amino-9-hydroxy-9-methyl-6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from 2-hydroxy-2-methylcyclohexanone (0.21 g, 1.64 mmol), the title carboxamide was obtained as a white solid (69 mg) using the procedures described in Example 2, steps 2.i and 2.ii (enol formation: 51% yield, cyclization: 71% yield) and Example 1, steps l.ii to l.iv (ester reduction: 100% yield, Mn02 oxidation: 68% yield, cyclization: 59% yield).
1H NMR (ί 6-DMSO) δ: 8.39 (s, 1H); 8.19 (br. s, 1H); 7.74 (s, 1H); 7.59 (br. s, 1H); 7.33 (br. s, 2H); 4.83 (s, 1H); 2.79-2.88 (m, 2H); 1.65-2.00 (m, 4H); 1.51 (s, 3H).
MS (ESI, m/z): 273.2 [M+H+] for Ci4Hi6N402.
Example 50: 2-amino-6-bromo-5-hydroxy-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
50. i. Ethyl 2-amino-4-(benzyloxy)-6-(trifluoromethyl)nicotinate:
Starting from the compound of Preparation C (0.122 g, 0.488 mmol) and benzyl alcohol (0.051 mL), the title compound was obtained as a white solid (0.122 g, 74% yield) using the typical procedure described in Preparation B, step B.i. The crude mixture was purified by purified by CC (Hept-EA 9-1).
1H NMR (ί 6-DMSO) δ: 7.29-745 (m, 5H); 6.90 (br. s, 2H); 6.87 (s, 1H); 5.27 (s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 1.16 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 341.2 [M+H+] for Ci6Hi5N203F3
50. ii. Ethyl 2-amino-4-(benzyloxy)-5-bromo-6-(trifluoromethyl)nicotinate: Typical procedure for a bromination reaction.
A solution of intermediate 50. i (0.122 g, 0.359 mmol) in MeCN (2 mL) was treated with NBS (88 mg, 0.494 mmol). After stirring at rt for 7 h, the reaction mixture was concentrated to dryness and the residue was purified by CC (Hept-EA 9-1), affording the title compound as a white powder (0.128g, 86% yield).
1H NMR (ί 6-DMSO) δ: 7.33-7.48 (m, 5H); 7.10 (br. s, 2H); 5.05 (s, 2H); 4.28 (q,
J = 7.1 Hz, 2H); 1.19 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 419.0 [M+H+] for C16Hi4N203BrF3 50. in. 2-amino-5-(benzyloxy)-6-bromo- 7-(trifluoromethyl)-l , 8-naphthyridine- 3-carboxamide:
Starting from intermediate 50. ii (0.128 g, 0.3 mmol), the title compound was obtained as a yellow solid (91 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 99% yield, Mn02 oxidation: 83%> yield, cyclization: 82%> yield).
1H NMR (ί 6-DMSO) δ: 8.46-8.52 (m, 2H); 7.77-7.88 (m, 3H); 7.57-7.62 (m, 2H); 7.36-7.45 (m, 3H); 5.29 (br. s, 2H).
MS (ESI, m/z): 441.0 [M+H+] for C17Hi2N402BrF3
50. iv. 2-amino-6-bromo-5-hydroxy-7-(trifluoromethyl)-l,8-naphtyridine-3-carboxamide:
A solution of intermediate 50.iii (20 mg, 0.045 mmol) in TFA (0.2 mL) was stirred at +70°C for 5 min. After the solvent was evaporated, the residue was diluted in water and the pH was adjusted to 7 adding NaHC03. The resulting solid was filtered and dried to constant weight. The title compound was obtained as a yellow solid (0.016 g, 100%> yield). MS (ESI, m/z): 351.0 [M+H+] for C10H6N4O2BrF3 Example 51: 2-amino-6-bromo-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide:
57./. Ethyl 2-amino-5-bromo-4,6-dimethylnicotinate:
Ethyl 2-amino-4,6-dimethylnicotinate (4.23 g, 21.7 mmol) was dissolved in a solution of bromine in AcOH (IM, 24 mL, 24 mmol). The reaction was stirred at rt for 10 min. The mixture was taken into water (10 mL) and the pH was adjusted to 7 by adding sat. NaHCO3. The solid that precipitated was filtered off and dried under vacuum at +50°C overnight, affording the title bromide as a white solid (5.78 g, 97% yield).
1H NMR (ί 6-DMSO) δ: 6.18 (br. s, 2H); 4.29 8(q, J = 7.1 Hz, 2H); 2.40 (s, 3H); 2.32 (s, 3H); 1.27 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 273.0 [M+H+] for Ci0Hi3N2O2Br.
51. ii. 2-amino-6-bromo-5, 7 -dimethyl- [1, 8] naphthyridine-3-carboxylic acid amide:
Starting from intermediate 51.i (0.116 g, 0.424 mmol), the title carboxamide was obtained as a yellow solid (34 mg) using the procedures described in Example 1, steps l.ii to l.iv (ester reduction: 100% yield, MnO2 oxidation: 73%> yield, cyclization: 67%> yield).
1H NMR (ί 6-DMSO) δ: 8.64 (s, 1H); 8.37 (br. s, 1H); 7.63 (br. s, 1H); 7.56 (br. s, 2H);
2.68 (s, 3H); 2.66 (s, 3H).
MS (ESI, m/z): 295.0 [M+H+] for CnHnN4OBr.
Example 52: 2-amino-6-bromo-5-chloro-7-isopropyl-[l,8]naphthyridine- 3-carboxylic acid amide
Starting from intermediate H.iii (2.5 g, 10.3 mmol), the title carboxamide (1.4 g) was obtained as a yellowish solid using the procedures described in Example 50, step 50. ii (bromination: 72%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 50%> yield, MnO2 oxidation: 99% yield, cyclization: 94% yield).
1H NMR (ί 6-DMSO) δ: 8.60 (s, 1H); 8.49 (br. s, 1H); 7.68-7.90 (m, 3H); 3.62 (hept, J = 6.6 Hz, 1H); 1.25 (d, J = 6.6 Hz, 6H).
MS (ESI, m/z): 343.0 [M+H+] for Ci2Hi2N4OBrCl. Example 53: 2-amino-6-benzyl-7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide:
53.L Ethyl 2-amino-5-benzyl-6-hydroxy-4-methylnicotinate:
Ethyl 3,3-diaminoacrylate (31.9 g, 245.34 mmol) was dissolved in EtOH (245 mL) under nitrogen. Pyr (1.775 mL, 22.06 mmol) followed by ethyl 2-benzylacetoacetate (48 mL, 241 mmol) were added and the reaction mixture was stirred at +100°C for 18 h. The reaction mixture was cooled to rt, filtered and washed with EtOH. The filtrate was evaporated and the residue was purified by CC (DCM/MeOH, 49: 1) to afford the impure title product. A portion of the latter product (5.65 g, 19.7 mmol) in MeCN (50 mL) was treated with BnEt3NCl (12.82 g, 56.28 mmol) and POCl3 (5.5 mL, 59 mmol). The reaction mixture was stirred at +80°C for 4 h. The reaction mixture was cooled and sat. NaHCO3 was slowly added until pH = 8-9 was reached. The volatiles were evaporated and the residue was extracted with EA (2 x 100 mL). The org. layer was separated, dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by CC (DCM/MeOH 49: 1 affording the title compound as a yellow solid (0.424 g).
1H NMR (ί 6-DMSO) δ: 10.8 (s, 1H); 7.17-7.24 (m, 2H); 7.07-7.13 (m, 3H); 6.95 (br. s, 2H); 4.15 (q, J = 7.1 Hz, 2H); 3.75 (s, 2H); 2.17 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 287.2 [M+H+] for Ci6Hi8N2O3
53. ii. Ethyl 2-amino-5-benzyl-6-chloro-4-methylnicotinate:
Intermediate 53. i (0.415 g, 1.45 mmol) was suspended in POCl3 (2 mL, 21.4 mmol) in a sealed tube. The mixture was stirred at +80°C overnight. The mixture was cooled to rt and evaporated. The residue was poured onto ice. EA (20 mL) was added to the pH was adjusted to 8 with sat. NaHCO3. The aq. layer was further extracted with EA (2 x 20 mL). The combined org. layers were dried over MgSO4, filtered and evaporated. The residue was purified by CC (EA) affording the title compound as a yellow solid (0.304 g, 69% yield).
1H NMR (ί 6-DMSO) δ: 10.8 (s, 1H); 7.17-7.24 (m, 2H); 7.07-7.13 (m, 3H); 6.95 (br. s, 2H); 4.15 (q, J = 7.1 Hz, 2H); 3.75 (s, 2H); 2.17 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 305.2.2 [M+H+] for Ci6Hi7N2O2Cl 53. Hi. 2-amino-6-benzyl- 7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 53. ii (0.151 g, 0.495 mmol), the title carboxamide was obtained as a yellow solid (0.110 g) using the procedures described in Example 1, steps l.ii to l.iv (ester reduction: 91% yield, Mn02 oxidation: 88%> yield, cyclization: 85%> yield).
H NMR (ί 6-DMSO) δ: 8.67 (s, 1H); 8.37 (br. s, 1H); 7.66 (br. s, 1H); 7.04-7.30 (m, 5H); 4.26 (s, 2H); 2.56 (s, 3H).
MS (ESI, m/z): 327.2 [M+H+] for C17Hi5N4OCl.
Example 54 : 2-amino-7-chloro-5-methyl-6-pyridin-4-ylmethyl- [1,8] naphthyridine-3- carbox lic acid amide: Starting from ethyl 3-oxo-2-(pyridin-4-ylmethyl)butanoate (prepared as described in J. Med. Chem. (1997), 40(15), 2347-2362; 10.2 g, 46 mmol) the title compound was obtained as a white solid (55 mg) using the procedures described in Example 53, steps 53. i and 53. ii (cyclization: 3%> yield, chlorination: 16%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 72%> yield, Mn02 oxidation: 90%> yield, cyclization: 85%> yield).
1H NMR (ί 6-DMSO) δ: 8.68 (s, 1H); 8.43 (d, J = 5.9 Hz, 2H); 8.37 (br. s, 1H); 7.69 (br. s, 3H); 7.09 (d, J = 5.9 Hz, 2H); 4.29 (s, 2H); 2.55 (s, 3H).
MS (ESI, m/z): 328.2 [M+H+] for Ci6Hi4N5OCl.
Example 55: 6-allyl-2-amino-7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide: Starting from ethyl 2-acetylpent-4-enoate (13 g, 76 mmol) the title compound was obtained as a yellow solid (45 mg) using the procedures described in Example 53, steps 53. i and 53. ii (cyclization: 10%> yield, chlorination: 83%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 100%> yield, Mn02 oxidation: 71%> yield, cyclization: 69%> yield).
1H NMR (ί 6-DMSO) δ: 8.65 (s, 1H); 8.37 (br. s, 1H); 7.55-7.74 (br. s, 3H); 5.93 (m, 1H); 5.05 (dd, J = 1.7, 10.2 Hz, 1H); 4.89 (dd, J = 1.7, 17.1 Hz, 1H); 3.57-3.63 (m, 2H); 2.58 (s, 3H).
MS (ESI, m/z): 276.0 [M+H+] for C13Hi3N4OCl. Example 56: 2-amino-6-bromo-7-(trifluoromethyl)-l,8-naphthyridine- 3-carboxamide:
Starting from intermediate I.ii (70 mg, 0.26 mmol), the title carboxamide was obtained as a yellow solid (81 mg, 93% yield) using the procedure described in Example 1, step l.iv. 1H NMR (ί 6-DMSO) δ: 8.64 (s, 1H); 8.47 (br. s, 1H); 8.35 (s, 1H); 7.83 (br. s, 1H); 7.79 (br. s, 2H).
MS (ESI, m/z): 335.1 [M+H+] for C10H6N4OBrF3.
Example 57: 3-amino-6-chloro-7,8,9,10-tetrahydro-benzo[c] [l,8] naphthyridine- 2-carboxylic acid amide: Starting from ethyl 2-oxocyclohexanecarboxylate (6.64 g, 39 mmol), the title compound was obtained as a yellow solid (0.040 g) using the procedures described in Example 53, steps 53. i and 53. ii (cyclization: 9% yield, chlorination: 87% yield) and Example 1, steps I.ii to l.iv (ester reduction: 98%> yield, Mn02 oxidation: 75%> yield, cyclization: 42%> yield).
H NMR (ί 6-DMSO) δ: 8.58 (s, 1H); 8.36 (br. s, 1H); 7.65 (br. s, 1H); 7.57 (br. s, 2H); 3.03-3.11 (m, 2H); 2.67-2.75 (m, 2H); 1.75-1.85 (m, 4H).
MS (ESI, m/z): 277.3 [M+H+] for d3Hi3N4OCl.
Example 58 : 2-amino-6-bromo-5-(2-hydroxy-ethoxy)-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide: 58. i. Ethyl 2-amino-4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)- 6-(trifluoromethyl)nicotinate:
Starting from the compound of Preparation C (0.152 g, 0.608 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethanol (0.118 g, 0.67 mmol), the title compound was obtained as a yellow powder (0.143 g, 58%> yield) using the typical procedure described in Preparation B, step B.i. The crude mixture was purified by purified by CC (Hept-EA 9-1). 1H NMR (ί 6-DMSO) δ: 6.79 (s, 1H); 6.73 (br. s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 4.18-4.23 (m, 2H); 3.82-3.88 (m, 2H); 1.25 (t, J = 7.1 Hz, 3H); 0.84 (s, 9H); 0.01 (s, 6H). MS (ESI, m/z): 409.2 [M+H+] for Ci7H27N204F3Si 58. ii. 2-amino-6-bromo-5-(2-hydroxyethoxy)-7-(trifluoromethyl)-l,8-naphthyridine- 3-carboxamide:
Starting from intermediate 58. i (0.139 g, 0.34 mmol), the title compound was obtained as a yellow solid (17 mg) using the typical procedures described in Example 50, step 50. ii (bromination: 55% yield), Example 1, steps l.ii to l.iv (ester reduction: 77% yield, Mn02 oxidation: 96%> yield, cyclization: 64%> yield) and Example 50, step 50. iv (deprotection: 94% yield)
1H NMR (ί 6-DMSO) δ: 8.70 (m, 1 H); 8.34 (m, 1 H); 7.83 (m, 3 H); 4.30 (m, 2 H); 4.29 (m); 3.82 (m, 2 H).
MS (ESI, m/z): 398.0 [M+H+] for Ci2HioN403BrF3
Example 59 : 2-amino-6-bromo-5-chloro-7-(trifluoromethyl)-l,8-naphthyridine- 3-carboxamide:
59. i. Ethyl 2-amino-4-chloro-6-(trifluoromethyl)nicotinate:
A mixture of the compound of Preparation C (2.04 g, 8.1 mmol) and POCI3 (11.95 mL, 130.4 mmol) was stirred at +80°C for 2 h. After cooling, the excess of reagent was evaporated and the residue was taken up in water. The pH was adjusted to 7 by adding solid NaHC03. The resulting mixture was extracted with EA (100 mL). The org. phase was dried over MgS04, filtered and evaporated to dryness. The residue was purified by CC (Hex/EA 1:9), affording the title compound as a white powder (1.92 g, 89%> yield).
1H NMR (ί 6-DMSO) δ: 7.14 (br. s, 2H); 7.12 (s, 1H); 4.35 (q, J = 7.1 Hz, 2H); 1.28 (t, J = 7.1 Hz, 3H).
59. ii. 2-amino-6-bromo-5-chloro-7-(trifluoromethyl)-l,8-naphthyridine-3-carboxamide:
Starting from intermediate 59. i (72 mg, 0.27 mmol), the title compound was obtained as a yellow solid (24 mg) using the typical procedures described in Example 50, step 50.ii (bromination: 63%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 51%> yield, Mn02 oxidation: 84%> yield, cyclization: 85%> yield).
1H NMR (ί 6-DMSO) δ: 8.70 (m, 1 H); 8.63 (s, 1 H); 8.02 (br. s, 2H); 7.88 (s, 1H).
MS (ESI, m/z): 369.0 [M+H+] for C10H5N4OBrClF3 Example 60: 5-allylamino-2-amino-6-bromo-7-trifluoromethyl-[l,8] naphthyridine- 3-carboxylic acid amide:
A mixture of intermediate 59.ii (30 mg, 0.081 mmol), TEA (0.04 mL, 1 eq.) and allylamine (0.028 mL, 0.141 mmol) in NMP (0.5 mL) was heated to +100°C for 2 h. The reaction mixture was directly subjected to prep-HPLC (Method A), affording the title compound as a yellow powder (18 mg, 57% yield).
1H NMR (ί 6-DMSO) δ: 8.62 (s, 1H); 8.13 (br. s, 1H); 7.66 (br. s, 1H); 7.52 (br. s, 2H); 6.74 (m, 1H); 5.98 (m, 1H); 5.14-5.30 (m, 2H); 4.38 (m, 2H).
MS (ESI, m/z): 390.0 [M+H+] for CisHnNjOBrFs. Example 61: sodium salt of (S -2-amino-4-(7-amino-3-bromo-6-carbamoyl- 2-trifluoromethyl-[l,8]naphthyridin-4-ylamino)-butanoic acid:
61. i. (S)-tert-butyl 4-((7-amino-3-bromo-6-carbamoyl-2-(trifluoromethyl)- l,8-naphthyridin-4-yl)amino)-2-((tert-butoxycarbonyl)amino)butanoate:
Starting from intermediate 59. ii (30 mg, 0.081 mmol) and (SHert-butyl 4-amino-2-((tert- butoxycarbonyl)amino)butanoate hydrochloride (38 mg, 1.5 eq.), the title compound was obtained as a yellow powder (20 mg, 40% yield) using the protocol described in Example 14. The purity of the material was around 75%>.
MS (ESI, m/z): 390.0 [M+H+] for C23H3oN605BrF3.
61. ii. Sodium salt of (S)-2-amino-4-(7-amino-3-bromo-6-carbamoyl-2-trifluoromethyl- [1, 8] naphthyridin-4-ylamino) -butyric acid:
A solution of intermediate 61.i (20 mg, 0.03 mmol) in TFA (2 mL) and water (0.3 mL) was heated to +60°C for 3 h. The solvent was evaporated and the residue was diluted in water (5 mL). Solid NaHC03 was added until pH 9 was reached. The solid that formed was filtered off and dried to constant weight, yielding the title compound as a yellow powder (11 mg, 74%> yield).
MS (ESI, m/z): 451.2 [M+H+] for Ci4Hi4N603BrF3. Example 62 : 2-amino-6-bromo-5-(2-hydroxy-ethylamino)-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 59. ii (30 mg, 0.08 mmol) and 3-aminoethanol (9 mg, 1.7 eq.), the title compound was obtained as a yellow powder (23 mg, 72% yield) using the protocol described in Example 60.
1H NMR (ί 6-DMSO) δ: 8.73 (s, 1H); 8.20 (br. s, 1H), 7.67 (br. s, 1H); 7.59 (br. s, 2H); 6.47 (t, J = 5.2 Hz, 1H); 5.09 (t, J = 4.9 Hz, 1H); 3.81 (q, J = 5.2 Hz, 2H); 3.66 (q, J = 5.0 Hz, 2H).
MS (ESI, m/z): 396.0 [M+H+] for Ci2HiiN502BrF3. Example 63: 2-amino-6-bromo-5-(3-hydroxy-propylamino)-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 59.ii (30 mg, 0.081 mmol) and 3-aminopropan-l-ol (11 mg, 1.7 eq.), the title compound was obtained as a yellow powder (27 mg, 81% yield) using the protocol described in Example 60.
1H NMR (ί 6-DMSO) δ: 8.68 (s, 1H); 8.20 (br. s, 1H); 7.65 (br. s, 1H); 7.58 (br. s, 1H); 6.77 (m, 1H); 4.81 (m, 1H); 3.84 (m, 2H); 3.55 (m, 2H); 1.81 (m, 2H).
MS (ESI, m/z): 406.0 [M-H+] for Ci2HiiN502BrF3.
Example 64: (S -l-(7-amino-3-bromo-6-carbamoyl-2-trifluoromethyl- [l,8]naphthyridin-4-yl)-azetidine-2-carboxylic acid: Starting from intermediate 59.ii (30 mg, 0.081 mmol) and (L^-azetidine-2-carboxylic acid (16 mg, 2 eq.), the title compound was obtained as a yellow powder (8 mg, 23% yield) using the protocol described in Example 60.
MS (ESI, m/z): 436.0 [M+H+] for Ci4HnN503BrF3.
Example 65: 2,5-diamino-6-bromo-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
Starting from intermediate 59. ii (0.1 g, 0.27 mmol) and (3,4-dimethoxyphenyl)methanamine (0.1 g, 1.16 mmol), the title compound was obtained as a yellow powder (0.05 g, 40% yield) using the protocol described in Example 60 (alkylation: 74% yield) and Preparation C, step Civ (deprotection with TFA: 71% yield). MS (ESI, m/z): 348.0 [M-H+] for Ci0H7N5OBrF3.
Example 66 : 2-amino-6-bromo-5-(2-hydroxy-ethyl)-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide:
66. i. ((3, 3-dimethoxybutoxy)methyl)benzene:
A solution of 4-benzyloxy-2-butanone (10 mL, 57.6 mmol), trimethylorthoformate (6.7 mL, 61.5 mmol) and 96% sulfuric acid (0.004 mL, 0.037 mmol) in MeOH (35 mL) was stirred at rt for 24 h. 30% NaOH (5 mL) was added and the volume was reduced in vacuo to one third. Water (50 mL) was added and the mixture was extracted twice with ether (2 x 100 mL). The mixture was dried over Na2SO4, filtered and evaporation at 50 mbar affording the title compound as a colourless oil (12.31 g, crude).
1H NMR (ί 6-DMSO) δ: 7.20-7.35 (m, 5H); 4.42 (br. s, 2H); 3.44 (t, J = 7.1 Hz, 2H); 3.03 (s, 6H); 1.85 (t, J = 7.1 Hz, 2H); 1.18 (s, 3H).. 66. ii (E)-6-(benzyloxy)-4-ethoxy-l ,1 , 1 -trifluorohex-3-en-2-one:
Typical synthesis of a l,l,l-trifluoro-4-methoxy-4-substituted but-3-en-2-one.
To an ice-chilled solution of intermediate 66. i (12.31 g, 54.8 mmol) and Pyr (8.8 mL, 109.7 mmol) in DCM (60 mL) was added trifluoroacetic acid anhydride (15.5 mL, 109.7 mmol). The reaction mixture was allowed to reach rt and stirred at +45°C overnight. The mixture was quenched by adding 0.1 HC1 (90 mL) and water (30 mL). The two phases were separated and the org. layer was dried over MgSO4, filtered and evaporated. The residue was purified by CC (EA/Hex 1:9), affording the title compound as a colourless oil (7.0 g, 44% yield).
1H NMR (ί 6-DMSO) δ: 7.22-7.35 (m, 5H); 5.84 (s, 1H); 4.44 (br. s, 2H); 3.83 (s, 3H); 3.62 (t, J = 6.6 Hz, 2H); 3.08 (t, J = 6.6 Hz, 2H). 66. Hi. Ethyl 2-amino-4-(2-(benzyloxy)ethyl)-6-(trifluoromethyl)nicotinate:
Typical cyclization of a 1 , 1 , 1 -trifluoro-4-methoxy-4-substituted but-3-en-2-one with ethyl 3, 3-diaminoacrylate.
A solution of intermediate 66.ii (4 g, 13.2 mmol) and ethyl 3, 3-diaminoacrylate (1.72 g, 13.2 mmol) in EtOH (5 mL) was stirred at rt for 24 h. After evaporation to dryness, the residue was directly subjected to CC (EA/Hex 1:9), affording the title compound as a yellowish oil (0.61 g, 13% yield).
1H NMR (ί 6-DMSO) δ: 7.20-7.34 (m, 5H); 6.95 (s, 1H); 6.79 (br. s, 2H); 4.43 (s, 2H); 4.28 (q, J = 7.1 Hz, 2H); 3.61 (t, J = 6.6 Hz, 2H); 2.93 (t, J = 6.6 Hz, 2H); 1.24 (t, J = 7.1 Hz, 3H).
66.1V. 2-amino-5-(2-^enzyloxy)ethyl)-6-bromo-7-(trifluoromethyl)-l,8-naphthyridine-3- carboxamide:
Starting from intermediate 19.iii (0.364 g, 0.99 mmol), the title compound (0.120 g) was obtained as a yellow solid using the typical procedures described in Example 11, step 1 l.ii (bromination: 63% yield) and Example 1, steps l.ii to l.iv (ester reduction: 91% yield, Mn02 oxidation: 66% yield, cyclization: 77% yield).
1H NMR (ί 6-DMSO) δ: 8.82 (s, 1H); 8.53 (s, 1 H); 7.79-7.95 (m, 3H); 7.13-7.29 m, 5H), 4.46 (s, 2H); 3.70-3.78 (m, 2H); 3.60-3.68 (m, 2H).
MS (ESI, m/z): 470.4.0 [M+H+] for Ci9Hi6N402BrF3. 66.v. 2-amino-6-bromo-5-(2-hydroxyethyl)-7-(trifluoromethyl)-l,8-naphthyridine- 3-carboxamide:
A solution of intermediate 66. iv (30 mg, 0.064 mmol) in 62% HBr in water (0.3 mL) was stirred at rt for 30 min. The reaction mixture was then diluted with water (2 mL) and NaHC03 was added until pH 7 was reached. The resulting solid was filtered off and dried to constant weight, affording the title compound as a yellow powder (16 mg, 68% yield). 1H NMR (ί 6-DMSO) δ: 8.74 (s, 1H); 8.48 (br. s, 1H); 7.73-7.90 (m, 3H); 4.84 (m, 1H); 3.63-3.73 (m, 2H); 3.43-3.53 (m, 2H).
MS (ESI, m/z): 381.0 [M+H+] for Ci2Hi0N4O2BrF3. Example 67: 2-amino-5-methyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from l,l,l-trifluoro-4-methoxypent-3-en-2-one (1.03 g, 6.15 mmol), the title compound was obtained as a yellow solid (0.053 g) using the typical procedures described in Example 66, step 66.iii (cyclization: 27% yield) and Example 1, steps l .ii to l.iv (ester reduction: 95% yield, MnO2 oxidation: 73 %> yield, cyclization: 93 %> yield)
1H NMR (ί 6-DMSO) δ: 8.70 (s, 1H); 8.45 (br. s, 1H); 7.64-7.84 (m, 3H); 7.48 (s, 1H); 2.70 (s, 3H).
MS (ESI, m/z): 271.2 [M+H+] for C11H9N4OF3. Example 68: 2-amino-6-bromo-5-hydroxymethyl-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide:
Starting from ((2,2-dimethoxypropoxy)methyl)benzene (prepared as described in Bull. Chem. Soc. Jap. (1999), 72, 2307-2313; 1 g, 4.76 mmol), the title compound was obtained as a yellow solid (13 mg) using the typical procedures described in Example 66, steps 66. ii and 66.iii (enone synthesis: 91%> yield, cyclization: 40%> yield), Example 50, step 50. ii (bromination: 55%> yield), Example 1, steps l.ii to l.iv (ester reduction: 30%> yield, MnO2 oxidation: 99%> yield, cyclization: 93%> yield) and Example 66, step 66.v (deprotection: 68% yield).
1H NMR (ί 6-DMSO) δ: 8.83 (s, 1H); 8.44 (br. s, 1H); 7.78-7.90 (br. s, 3H); 5.60 (t, J = 5.8 Hz, 1H); 5.06 (d, J = 5.8 Hz, 2H).
MS (ESI, m/z): 363.8 [M-H+] for CiiH8N4O2BrF3.
Example 69: 2-amino-6-bromo-7-chloro-5-ethyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from ethyl 2-amino-4-ethyl-6-oxo-l,6-dihydropyridine-3-carboxylate (prepared as described in WO 2006/124490 (p. 109); 9 g, 42.8 mmol), the title compound was obtained as a yellow solid (74 mg) using the typical procedures described in Example 59, step 59. i (chlorination, 90%> yield), Example 50, step 50. ii (bromination: 64%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 72%> yield, MnO2 oxidation and cyclization: 50%> yield). 1H NMR (ί 6-DMSO) δ: 8.63 (s, 1H); 8.47 (br. s, 1H); 7.69-7.97 (m, 3H); 3.21 (q, J=
7.5Hz, 1H); 1.18 (t, J= 7.5Hz, 3H).
MS (ESI, m/z): 329.0 [M+H+] for CnHi0N4OBrCl.
Example 70: 6-allyl-2-amino-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide:
70. i. Ethyl 5-allyl-2-amino-6-(trifluoromethyl)nicotinate:
A flask, charged with intermediate Li (0.3 g, 0.96 mmol), allyltributyltin (0.368 mL, 1.2 mmol) and DMF (3 mL) was degassed with nitrogen. LiCl (0.152 g, 3.6 mmol) and Pd(PPh3)4 (0.03 g, 0.024 mmol) were added and the mixture was heated to +100°C for 2 h. After evaporation to dryness, the residue was partitioned between EA (25 mL) and brine (20 mL). The aq. layer was extracted once with EA (25 mL). The combined org. layers were washed with brine (10 mL), dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9) to afford the title alkene as a white powder (0.241 g, 92% yield).
1H NMR (ί 6-DMSO) δ: 8.07 (s, 1H); 7.36 (br. s, 1H); 5.89 (m, 1H); 4.94-5.09 (m, 2H); 4.31 (q, J = 7.1 Hz, 1H); 3.35-3.40 (m, 2H); 1.30 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 275.2 [M+H+] for Ci2Hi3N202F3.
10. ii. 6-allyl-2 -amino- 7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 70. i (240 mg, 0.88 mmol), the title compound was obtained as a yellow solid (125 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 96% yield, Mn02 oxidation: 78% yield, cyclization: 64% yield).
1H NMR (ί 6-DMSO) δ: 8.52 (s, 1H); 8.28 (br. s, 1H); 8.15 (s, 1H); 7.76 (s, 1H); 7.64 (br. s, 2H); 6.00 (m, 1H); 5.02-5.16 (m, 2H); 3.55-3.62 (m, 2H).
MS (ESI, m/z): 297.2 [M+H+] for Ci3HnN4OF3. Example 71: 2-amino-6-isopropenyl-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
77./. Ethyl 2-amino-5-(prop-l-en-2-yl)-6-(trifluoromethyl)nicotinate:
A mixture of intermediate Li (0.3 g, 0.96 mmol), 2,4,6-tri(prop-l-en-2-yl)- 1,3,5,2,4,6-trioxatriborinane in complex with Pyr (1: 1, 0.162 g, 0.58 mmol) in a dioxane/water solution (4: 1, 5 mL) was degassed with argon. Pd(PPh3)4 (0.07 g,
0.06 mmol) was added. The mixture was degassed again and refluxed at +100°C for 14 h. After cooling to rt, the reaction mixture was partitioned between EA (10 mL) and water (5 mL). The two layers were separated and the aq. layer was extracted once more with EA (10 mL). The combined org. layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9) to afford the alkene as a white powder (0.229 g, 87% yield).
1H NMR (ί 6-DMSO) δ: 7.97 (s, 1H); 7.45 (br. s, 2H); 5.21 (s, 1H); 4.84 (br. s, 1H); 4.30 (q, J = 7.1 Hz, 2H); 1.97 (s, 3H); 1.30 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 275.0 [M+H+] for Ci2Hi3N202F3.
7 l.ii. 2-amino-6-isopropenyl-7-trifluoromethyl-fl,8Jnaphthyridine-3-carboxylic acid amide:
Starting from intermediate 71. i (229 mg, 0.84 mmol), the title compound was obtained as a yellow solid (33 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 93% yield, Mn02 oxidation: 91%> yield, cyclization: 57%> yield).
1H NMR (ί 6-DMSO) δ: 8.51 (s, 1H); 8.30 (br. s, 1H); 8.12 (s, 1H); 7.78 (s, 1H); 7.66 (br. s, 2H); 5.33 (br. s, 1H); 4.93 (br. s, 1H); 2.08 (s, 3H).
MS (ESI, m/z): 297.4 [M+H+] for Ci3HnN4OF3. Example 72: 2-amino-6-cyclopropyl-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
72. i. Ethyl 2-amino-5-cyclopropyl-6-(trifluoromethyl)nicotinate:
A mixture of intermediate I.i (0.5 g, 1.6 mmol), potassium cyclopropyltrifluoroborate (0.249 g, 1.68 mmol), Cs2C03 (1.46 g, 4.5 mmol) in THF -water (10-1, 9 mL) was degassed with argon. Dichloro-
1, r-bis(diphenlyphosphino)ferrocene]dichloropalladium(II).CH2Cl2 complex (0.122 g, 0.150 mmol) was added. The reaction mixture was heated at +85°C for 1 day. After cooling to rt, the reaction mixture was partitioned between EA (50 mL) and water (40 mL). The two layers were separated and the aq. layer was extracted once more with EA (50 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9) affording the title ester as a white powder (0.376 g, 86% yield).
1H NMR (ί 6-DMSO) δ: 7.83 (s, 1H); 7.31 (br. s, 2H); 4.30 (q, J = 7.1 Hz, 2H); 1.94 (m, 1H); 1.30 (t, J = 7.1 Hz, 3H); 0.88-0.95 (m, 2H); 0.57-0.64 (m, 2H).
MS (ESI, m/z): 275.2 [M+H+] for C12H13N2O2F3.
72. ii. 2-amino-6-cyclopropyl-7-trifluoromethyl-fl,8Jnaphthyridine-3-carboxylic acid amide:
Starting from intermediate 72. i (375 mg, 1.37 mmol), the title compound was obtained as a yellow solid (62 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 79% yield, Mn02 oxidation: 81% yield, cyclization: 87% yield).
1H NMR (ί 6-DMSO) δ: 8.45 (s, 1H); 8.26 (br. s, 1H); 7.95 (s, 1H); 7.74 (s, 1H); 7.54 (br. s, 2H); 2.14 (m, 1H); 1.00-1.07 (m, 2H); 0.76-0.83 (m, 2H).
MS (ESI, m/z): 297.5 [M+H+] for C13H11N4OF3.
Example 73: 2-amino-6-methyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide:
73. i. Ethyl 2-amino-5-methyl-6-(trifluoromethyl)nicotinate:
A solution of intermediate I.i (0.5 g, 1.6 mmol) in dioxane (5 mL) was treated methylzinc bromide (2M, 1.6 mL, 3.2 mmol). Pd(PPh3)4 (0.073 g, 0.064 mmol) was added and the mixture was heated to +80°C for 5 h. After cooling to rt, the reaction mixture was partitioned between EA (50 mL) and water (40 mL). The two layers were separated and the aq. layer was extracted once more with EA (50 mL). The combined org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (EA/Hex 1:9) affording the title ester as a white powder (0.1 g, 25% yield). The product was contaminated with traces of 2-amino-6-(trifluoromethyl)nicotinate.
1H NMR (ί 6-DMSO) δ: 8.10 (s, 1H); 7.28 (br. s, 1H); 4.30 (q, J = 7.1 Hz, 2H); 2.26 (q, J = 2.2 Hz, 3H); 1.30 (t, J = 7.1 Hz, 3H).
MS (ESI, m/z): 249.0 [M+H+] for C10H11N2O2F3.
73. ii. 2-amino-6-methyl- 7-trifluoromethyl- [ 1 ,8] naphthyridine-3-carboxylic acid amide: Starting from intermediate 73. i (100 mg, 1.37 mmol), the title compound was obtained as a yellow solid (19 mg) using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 37% yield, Mn02 oxidation: 98% yield, cyclization: 49%> yield).
MS (ESI, m/z): 271.2 [M+H+] for CnH9N4OF3.
Example 74: 2-amino-6-bromo-5-methyl-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
Starting from l,l,l-trifluoro-4-methoxypent-3-en-2-one (1.03 g, 6.15 mmol), the title compound was obtained as a yellow solid (0.033 g) using the typical procedures described in Example 66, step 66.iii (cyclization: 27%> yield), Example 50, step 50. ii (bromination: 85%o yield) and Example 1, steps l.ii to l.iv (ester reduction: 46%> yield, Mn02 oxidation: 53%o yield, cyclization: 61%> yield)
1H NMR (ί 6-DMSO) δ: 8.76 (s, 1H); 8.51 (br. s, 1H); 7.79-7.92 (m, 3H); 2.79 (s, 3H). MS (ESI, m/z): 350.0 [M+H+] for CnH8N4OBrF3.
Example 75: 2-amino-6-bromo-5-methoxymethyl-7-trifluoromethyl- [l,8]naphthyridine-3-carboxylic acid amide: Starting from 1 , 1 ,2-trimethoxyethane (4.3 g, 32 mmol), the title compound was obtained as a yellow solid (0.041 g) using the typical procedures described in Example 66, steps 66. ii and 66.iii (enone synthesis: 30%> yield, cyclization: 29%> yield), Example 50, step 50. ii (bromination: 53%> yield) and Example 1, steps l.ii to l.iv (ester reduction: 66%> yield, Mn02 oxidation: 82%. yield, cyclization: 73%> yield).
1H NMR (ί 6-DMSO) δ: 8.74 (s, 1H); 8.52 (br. s, 1H); 7.81-7.99 (m, 3H); 5.00 (s, 2H); 3.38 (s, 3H).
MS (ESI, m/z): 381.2 [M+H+] for C12Hi0N4O2BrF3.
Example 76: 2-amino-7-trifluoromethyl-6-vinyl-[l,8]naphthyridine-3-carboxylic acid amide: 76. i. Ethyl 2-amino-6-(trifluoromethyl)-5-vinylnicotinate:
Starting from intermediate I.i (381 mg, 1.22 mmol) and 2,4,6-trivinylcyclotriboroxane- pyridine (293 mg, 1.22 mmol), the title vinyl compound was obtained as a yellow powder (255 mg, 84%) yield) using the procedure described in Example 71, step 71.i. 1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 7.56 (br. s, 2H); 6.80 (m, 1H); 5.70 (d, J = 17.2 Hz, 1H); 5.33 (dd, J = 1.2, 10.5 Hz, 1H); 4.33 (q, J = 7.1 Hz, 2H); 1.32 (t, J = 7.1 Hz, 3H).
76. ii. (2-amino-6-(trifluoromethyl)-5-vinylpyridin-3-yl)methanoh
Starting from intermediate 76. i (100 mg, 0.38 mmol), the title alcohol was obtained as a yellow powder (81 mg) using the procedure described in Example 1, step l.ii (ester reduction 97% yield).
1H NMR (ί 6-DMSO) δ: 7.83 (s, 1H); 6.85 (br. s, 2H); 6.34 (d, J = 17.2 Hz, 1H); 5.34 (t, J = 5.5 Hz, 1H); 5.25 (dd, J = 1.2, 10.5 Hz, 1H); 4.38 (d, J = 5.5 Hz, 2H).
MS (ESI, m/z): 219.0 [M+H+] for C9H9N2OF3. 76. Hi. 2-amino-7-trifluoromethyl-6-vinyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 76. ii (81 mg, 0.37 mmol), the title compound was obtained as a yellow solid (59 mg) using the typical procedures described in Example 1, steps l.iii and l.iv (Mn02 oxidation: 74% yield, cyclization: 76%> yield).
1H NMR (ί 6-DMSO) δ: 8.54 (br. s, 2H); 8.33 (br. s, 1H); 7.79 (s, 1H); 7.72 (s, 2H); 6.99 (m, 2H); 5.92 (d, J = 17.2 Hz, 1H); 5.52 (dd, J = 1.2, 10.5 Hz, 1H).
MS (ESI, m/z): 283.2 [M+H+] for C12H9N4OF3.
Example 77: 2-amino-6-ethyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate 76. ii (50 mg, 0.19 mmol), the title compound was obtained as a yellow solid (28 mg) using the typical procedures described in Example 46, step 46. ii (hydrogenation: 100%> yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 72%> yield, cyclization: 60%> yield).
1H NMR (ί 6-DMSO) δ: 8.50 (s, 1H); 8.30 (br. s, 1H); 8.21 (s, 1H); 7.75 (br. s, 1H); 7.59 (br. s, 2H); 2.83 (q, J = 7.4 Hz, 2H); 1.23 (t, J = 7.4 Hz, 3H).
MS (ESI, m/z): 285.2 [M+H+] for C12HiiN4OF3. Example 78 : 2-amino-6-bromo-7-chloro-5-methoxymethyl- [1,8] naphthyridine- 3-carboxylic acid amide:
78. i. Ethyl 2-amino-5-bromo-4-(methoxymethyl)-6-oxo-l,6-dihydropyridine- 3-carboxylate: To a solution of 4-methoxyacetoacetic acid (1.85 mL, 12.7 mmol) in EtOH (15 mL) were added ethyl 3,3-diaminoacrylate (1.65 g, 12.7 mmol) and Pyr (0.092 mL). The reaction mixture was stirred at +100°C for 24 h. The mixture was cooled at rt. The solid was filtered, scarcely washed with EtOH and dried under reduced pressure to afford the title ester as a violet powder (1.39 g, 48% yield).
1H NMR (ί 6-DMSO) δ: 10.7 (s, 1H); 7.26 (br. s, 2H); 5.71 (s, 1H); 4.44 (s, 2H); 4.15 (q, J = 6.9 Hz, 2H); 3.31 (s, 3H); 1.25 (t, J = 6.9 Hz, 3H).
MS (ESI, m/z): 227.1 [M+H+] for C10H14N2O4.
78. ii. 2-amino-6-bromo- 7-chloro-5-methoxymethyl-[l,8]naphthyridine-3-carboxylic acid amide: Starting from intermediate 78. i (1.02 g, 4.3 mmol), the title compound was obtained as a yellow solid (165 mg) using the typical procedures described in Example 59, step 59. i (chlorination, 96% yield), Example 50, step 50. ii (bromination: 78% yield) and Example 1, steps l.ii to l.iv (ester reduction: 90% yield, MnO2 oxidation: 76% yield and cyclization: 73% yield).
1H NMR (ί 6-DMSO) δ: 8.68 (s, 1H); 8.44 (br. s, 1H); 7.72-7.94 (m, 3H); 4.95 (s, 2H); 3.35 (s, 3H).
MS (ESI, m/z): 347.0 [M+H+] for
Figure imgf000117_0001
Example 79: 2-amino-6-bromo-7-isopropyl-5-methylamino-[l,8]naphthyridine- 3-carboxylic acid amide: A mixture of compound of Example 52 (70 mg, 0.2 mmol), methylamine (2M in THF, 0.407 mL, 0.814 mmol), TEA (0.031 mL, 0.224 mmol) was stirred at 100°C for 4 h. The reaction mixture was directly subjected to prep-HPLC (Method A), affording the title compound as a yellow powder (35 mg, 51% yield). 1H NMR (ί 6-DMSO) δ: 8.71 (s, 1H); 8.07 (br. s, 1H); 7.47 (br. s, 1H); 7.31 (br. s, 2H); 6.35 (q, J = 5.2 Hz, 1H); 3.49 (hept, J = 6.6 Hz, 1H); 3.29 (d, J = 5.2 Hz, 3H); 1.18 (d, J = 6.6 Hz, 6H).
MS (ESI, m/z): 340.1 [M+H+] for Ci3Hi6N5OBr. Example 80: 2-amino-6,7,8,9-tetrahydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide:
Starting from cyclohexanone (2 mL, 19.3 mmol), the title carboxamide was obtained as a yellow solid (0.081 g) using the procedures described in Example 4, step 4.i (cyclization: 58% yield) and Example 1, steps l.ii to l.iv (ester reduction: 87% yield, Mn02 oxidation: 75% yield, cyclization: 69% yield).
1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 8.16 (br. s, 1H); 7.68 (s, 1H); 7.55 (br. s, 1H); 7.30 (br. s, 2H); 2.89 (t, J = 6.3 Hz, 2H); 2.82 (t, J = 6.3 Hz, 2H); 1.72-1.90 (m, 4H).
MS (ESI, m/z): 243.2 [M+H+] for Ci3Hi4N40.
Example 81: 2-amino-6-bromo-5,7-dichloro-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate H.i (0.5 g, 2.1 mmol), the title carboxamide was obtained as a yellowish solid (36 mg) using the procedures described in Example 50, step 50. ii (bromination: 43%> yield) and Example 1, steps l.ii to l.iv (ester reduction: quant, yield, Mn02 oxidation: 60%> yield, cyclization: 71 > yield).
1H NMR (ί 6-DMSO) δ: 8.60 (s, 1H); 8.55 (br. s, 1H); 7.99 (br. s, 2H); 7.79 (br. s, 1H). MS (ESI, m/z): 336.8 [M+H+] for C9H5N4OBrCl2.
Example 82: 2-amino-6-bromo-4-hydroxy-7-trifluoromethyl-[l,8]naphthyridine- 3-carboxylic acid amide:
82. i. 2-amino-5-bromo-6-(trifluoromethyl)nicotinic acid: A solution of intermediate Li (4 g, 12.7 mmol) in dioxane (64 mL) was treated with LiOH.H20 (2.2 g, 51 mmol) and water (3.2 mL). The reaction was stirred at +50°C overnight. The solvent was evaporated and the residue was dissolved in water and acidified to pH = 5 using \M HC1. The solid was collected by filtration and dried to constant weight, affording the title acid as a white solid (3.45 g, 95% yield).
MS (ESI, m/z): 285.0 [M+H+] for C7H4N202BrF3.
82. ii. 6-bromo- 7-(trifluoromethyl)-lH-pyrido[2,3-d] [1 , 3]oxazine-2, 4-dione:
A solution of intermediate 82. i (6.34 g, 22.2 mmol) in dioxane (70 mL) was treated with triphosgene (3.96 g, 13.3 mmol). The reaction was heated to +100°C for 4 h. The solvent was evaporated and the residue was partitioned between EA (170 mL) and water (170 mL). The org. layer was washed with brine (140 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was triturated in Hex, filtered, washed with Hex and dried to afford the title compound as a beige solid (5.88 g, 85% yield).
MS (ESI, m/z): 308.8 [M+H+] for C8H2N2O3BrF3.
82. in. 2-amino-6-bromo-4-hydroxy- 7-(trifluoromethyl)-l , 8-naphthyridine-3-carbonitrile:
A ice chilled mixture of NaH (60%> dispersion in oil, 1.51 g, 37.8 mmol) in THF (5 mL), was treated dropwise with a solution of malodinitrile (2.5 g, 37.856 mmol) in DMF (35 mL) The mixture was stirred at rt for 30 min. Intermediate 82. ii (5.8 g, 18.9 mmol) was added and the reaction was heated to +80°C overnight. The solvent was evaporated and the residue taken up in water (100 mL). The pH was adjusted to 7 by addition ofAcOH. The aq. layer was extracted with EA (4 x 150 mL). The org. layers were dried over MgS04, filtered and concentrated to dryness. The residue was purified by CC (DCM/MeOH 6: 1 containing 1%> aq. NH OH). The relevant fractions were collected and evaporated. The brown solid residue was further triturated with Hex and collected by filtration to afford, after drying, the title compound as a brown solid (2.18 g, 35%> yield). MS (ESI, m/z): 333.0 [M+H+] for Ci0H4N4OBrF3.
82.1V. 2-amino-6-bromo-4-chloro-7-(trifluoromethyl)-l,8-naphthyridi
Intermediate 82.iii (1 g, 3 mmol) was suspended in POCl3 (5 mL) in a sealed tube. The mixture was stirred at +80°C for 2 h. After cooling, the mixture was poured carefully in water (100 mL) and the resulting slurry was cooled to 0°C. 3 NaOH was added until the pH of the aq. layer was set to 7. The mixture was extracted with DCM/MeOH (9: 1, 3 x 200 mL) and the combined org. layers were dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in EA (150 mL) and filtered through a plug of silica gel to afford after evaporation the title compound as a beige solid (0.52 g, 49% yield).
1H NMR (ί 6-DMSO) δ: 8.76 (s, 1H); 8.01 (br. s, 1H).
82. v. 2-amino-6-bromo-4-hydroxy-7-trifluoromethyl-[ 1 ,8] ' naphthyridine-3-carboxylic acid amide: A solution of intermediate 82. iv (0.252 g, 0.719 mmol) in TFA/water (4: 1, 5 mL) was heated in under microwave irradiation for 3 h at +150°C. The reaction mixture was concentrated to dryness and the residue was treated with 32% NaOH (0.5 mL) and suspended in DCM/MeOH (9: 1). The mixture was directly subjected to CC (DCM/MeOH 19: 1) to afford the product as beige solid (80%> pure, 0.146 g). The latter solid was triturated in MeOH, filtered and dried to a constant weight to afford the title compound as a white solid (31 mg, 12% yield).
1H NMR (ί 6-DMSO) δ: 12.1 (s, 1H); 10.3 (br. s, 1H); 9.83 (br. s, 1H);.8.65 (s, 1H);
7.32 (br. s, 1H); 7.04 (br. s, 1H).
MS (ESI, m/z): 349.0 [M-H+] for CioH6N4O2BrF3. Example 83: 2-amino-9-methyl-6,7-dihydro-benzo[6] [l,8]naphthyridine- 3-carboxylic acid amide:
Starting from 2-methylcyclohex-2-enone (1.61 g, 14.7 mmol), the title carboxamide was obtained as a white solid (18 mg) using the procedures described in Example 2, steps 2.i and 2.ii (enol formation: 89% yield, cyclization: 50% yield) and Example 1, steps l.ii to l.iv (ester reduction: 89% yield, MnO2 oxidation: 42% yield, cyclization: 17%> yield).
1H NMR (ί 6-DMSO) δ: 8.37 (s, 1H); 8.16 (br. s, 1H); 7.69 (s, 1H); 7.54 (br. s, 1H); 7.32 (br. s, 2H); 6.38 (m, 1H); 2.86 (t, J = 7.5 Hz, 2H); 2.27-2.36 (m, 2H); 2.09 (br. d, J = 1.4 Hz, 3H).
MS (ESI, m/z): 255.2 [M+H+] for Ci4Hi4N4O.
Example 84: 2-amino-6-bromo-7-tert-butyl-[l,8]naphthyridine-3-carboxylic acid amide:
Starting from pinacolone (5 g, 6.2 mmol), the title carboxamide was obtained as a white solid (100 mg) using the procedures described in Preparation D, steps D.i and D.ii (sodio enolate formation: 16%> yield, cyclization: 36%> yield), Example 50, step 50. ii (bromination: quant, yield) and Example 1, steps l.ii to l.iv (ester reduction: 92% yield, Mn02 oxidation: 89%> yield, cyclization: 60% yield).
1H NMR (ί 6-DMSO) δ: 8.38 (s, 1H); 8.28 (s, 1H); 8.20 (br. s, 1H); 7.65 (br. s, 1H); 7.58 (br. s, 2H); 1.51 (s, 9H). Example 85: 2-amino-7,8-dihydro-6H-spiro[benzo[6] [l,8]naphthyridine- 9,l'-cyclopentane]-3-carboxamide:
Starting from spiro[4.5]decan-6-one (2 g, 13.4 mmol) , the title carboxamide was obtained as a yellow solid (450 mg) using the procedure described in Example 1, step l.i (sodio enolate formation and cyclization: 42%> yield) and Example 1, steps l.ii to l.iv (ester reduction: quant, yield, Mn02 oxidation: quant, yield, cyclization: 38%> yield).
1H NMR (ί 6-DMSO) δ: 8.36 (s, 1H); 8.16 (br. s, 1H); 7.65 (s, 1H); 7.54 (br. s, 1H); 7.33 (br. s, 2H); 2.80-2.86 (m, 2H); 2.20-2.25 (m, 2H); 1.58-1.92 (m, 10H).
MS (ESI, m/z): 297.5 [M+H+] for Ci7H20N4O.
Example 86: (R)-l-(7-amino-3-bromo-6-carbamoyl-2-trifluoromethyl- [l,8]naphthyridin-4-yl)-azetidine-2-carboxylic acid:
Starting from intermediate 59. ii (30 mg, 0.081 mmol) and (Z) -azetidine-2-carboxylic (16 mg, 2 eq.), the title compound was obtained as a yellow powder (8 mg, 23%> yield) using the protocol described in Example 60.
MS (ESI, m/z): 436.0 [M+H+] for Ci4HiiN503BrF3. Example 87: 8-[(E)-allyloxyimino]-2-amino-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[b] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate l.v (304 mg, 1.07 mmol) and O-allylhydroxylamine hydrochloride (176 mg 1.6 mmol), the title compound was obtained as a yellow solid (252 mg) using the typical procedure described in Example 6, step 6.i (oxime formation: 70% yield).
1H NMR (ί 6-DMSO) δ: 8.42 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H); 7.59 (br. s, 1H); 7.42 (br. s, 2H); 5.96 (m, 1H); 5.26 (dq, J = 1.7, 17.3 Hz, 1H); 5.16 (m, 1H); 4.53 (dt, J = 1.4, 5.5 Hz, 2H); 2.96 (t, J = 6.6 Hz, 2H); 2.79 (t, J = 6.6 Hz, 2H); 1.50 (s, 6H). MS (ESI, m/z): 340.2 [M+H+] for C18H21N502.
Example 88 : 2-amino-9,9-dimethyl-8- [(E)-prop-2-ynyloxyimino] -6,7,8,9-tetrahydro- benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (67 mg, 0.31 mmol) and O-(prop-2-ynyl)hydroxylamine hydrochloride (52 mg, 0.48 mmol), the title compound was obtained as a yellow solid (8 mg) using the typical procedures described in Example 11, step l l.i (oxime formation: 54% yield) and Example 1, steps l.iii and l.iv (Mn02 oxidation: 64% yield, cyclization: 24%yield).
1H NMR (ί 6-DMSO) δ: 8.41 (s, 1H); 8.20 (br. s, 1H); 7.80 (s, 1H); 7.58 (br. s, 1H); 7.40 (br. s, 2H); 4.65 (d, J = 2.2 Hz, 2H); 2.96 (t, J = 6.9 Hz, 2H); 2.79 (t, J = 6.9 Hz, 2H); 1.51 (s, 6H).
MS (ESI, m/z): 338.0 [M+H+] for Ci8Hi9N502.
Example 89: 2-amino-6-bromo-7-trifluoromethyl-5-vinyl-[l,8]naphthyridine- 3-carboxylic acid amide: Starting from ethyl 2-amino-5-bromo-6-(trifluoromethyl)-4-vinylnicotinate (323 mg, 0.95 mmol), the title compound (175 mg) was obtained as a yellow solid using the typical procedures described in Example 1, steps l.ii to l.iv (ester reduction: 95%> yield, Mn02 oxidation: 79%> yield, cyclization: 68%> yield).
1H NMR (ί 6-DMSO) δ: 8.52 (s, 1H); 8.43 (br. s, 1H); 7.77 (br. s, 3H); 6.91 (dd, J = 11.7, 17.7 Hz, 1H); 6.01 (dd, J = 1.0, 11.7 Hz, 1H); 5.73 (dd, J = 1.0, 17.7 Hz, 1H). MS (ESI, m/z): 361.1 [M+H+] for Ci2H8N4OBrF3.
Example 90 : 2-amino-8-[(E)-(Z)-4-hydroxy-but-2-enyloxyimino]-9,9-dimethyl- 6,7,8,9-tetrahydro-benzo[6] [l,8]naphthyridine-3-carboxylic acid amide:
Starting from intermediate F.iii (160 mg, 0.72 mmol) and (Z)-O-(4-((tert-butyldimethylsilyl)oxy)but-2-en-l-yl)hydroxylamine (316 mg, 1.45 mmol), the title compound was obtained as a yellow solid (0.103 g) using the typical procedures described in Example 11, step l l.i (oxime formation) and Example 1, steps l.iii and l.iv (Mn02 oxidation and cyclization: 61% yield (over 3 steps)) and Preparation F, step F.iii (deprotection: 75% yield).
1H NMR (ί 6-DMSO) δ: 8.45 (s, 1H); 8.25 (br. s, 1H); 7.83 (s, 1H), 7.65 (br. s, 1H); 7.48 (br. s, 2H); 5.55-5.70 (m, 2H); 4.75 (t, J = 6.1 Hz, 1H); 4.61 (d, J = 6.1 Hz, 2H); 4.06 (t, J = 5.0 Hz, 2H); 2.98 (t, J = 6.7 Hz, 2H); 2.78 (t, J = 6.7 Hz, 2H); 1.51 (s, 6H). MS (ESI, m/z): 370.0 [M+H+] for C19H23N5O3.
HIGH RESOLUTION LC-MS ANALYSIS
Materials and methods:
Pump: Waters Acquity Binary
MS: SYNAPT G2 MS, (Waters)
DAD: Acquity UPLC PDA Detector.
Column: Acquity UPLC BEH C18 1.7 um 2.1x50 mm from Waters, thermostated in the Acquity UPLC Column Manager at +60°C.
Eluents: Al : H20 + 0.05% HC02H; Bl : MeCN + 0.05% HC02H.
Method: Gradient: 2% B 98% B over 3.0 min.
Flow: 0.6mL/min.
Detection: UV 214nm
Results: tR are given in min.
Example No. Exact Mass Observed Mass tR
1 284.1273 285.1354 0.68
2 328.1535 329.1618 0.82
3 286.143 287.1512 0.62
4 258.1117 259.1192 0.47
5 286.143 287.151 0.59
6 400.1859 401.1944 0.59
7 357.1437 358.1519 0.76
8 413.2063 414.2145 1.08
9 373.175 374.1831 0.69 Example No. Exact Mass Observed Mass tR
11 423.1462 424.1536 1.44
12 423.1462 424.1539 1.44
13 299.1382 300.1458 0.67
14 313.1539 314.1622 0.94
15 446.1525 447.1608 1.27
19 384.191 385.1985 0.87
20 418.1753 419.1827 0.93
24 385.2114 386.2193 1.02
25 379.1644 380.1725 0.77
27 339.1695 340.1781 0.47
28 382.1576 383.1659 0.87
29 405.2165 406.2238 0.74
30 436.1482 437.1562 1.23
31 309.159 310.167 0.51
32 454.9721 455.9796 1.09
33 483.972 484.9791 1.01
34 483.972 484.9797 1.03
35 479.0263 480.0331 1.11
36 387.0001 388.0084 0.82
37 244.096 245.1039 0.49
38 260.0732 261.0814 0.59
40R 256.1324 257.1399 0.72
40S 256.1324 257.1407 0.73
43 242.1168 243.1250 0.68
44 258.1117 259.1191 0.54
46 314.1743 315.1827 0.71
48 286.143 287.1512 0.71
49 272.1273 273.1359 0.64
50 349.9626 350.9708 0.96
51 294.0116 295.0198 0.76
52 337.0538 338.0616 0.75 Example No. Exact Mass Observed Mass tR
53 326.0934 327.1015 1.23
54 327.0887 328.0964 0.56
55 276.0778 277.0861 1.02
58 393.9888 394.9967 1.11
59 367.9287 368.9367 1.38
60 389.0099 390.0174 1.2
62 393.0048 394.0125 0.9
63 407.0205 408.0287 0.96
66 377.9939 379.0018 1.08
67 270.0728 271.0811 0.93
68 363.9783 364.9865 1.01
Pharmacological properties of the invention compounds
In vitro assays Experimmtal_meth ds;
Minimal inhibitory concentrations (MICs; mg/1) are determined in cation-adjusted Mueller-Hinton Broth (supplemented with 3% (v/v) lysed horse blood for testing Streptococcus pneumoniae) by a microdilution method following the description given in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA, 2006. Results;
All Example compounds are tested against several Gram positive and Gram negative bacteria.
Typical antibacterial test results are given in the table hereafter (MIC in mg/1). Example MIC for MIC for Example MIC for MIC for No. S. aureus H. No. S. aureus H.
ATCC influenzae ATCC influenzae 29213 A921 29213 A921
1 8 2 2 32 8
3 32 4 4 >32 4
5 >32 1 6 >32 8
7 >32 8 8 32 8
9 >32 2 10 >32 2
11 >32 8 12 >32 4
13 8 0.5 14 8 2
15 8 4 16 4 2
17 4 8 18 16 0.5
19 16 1 20 16 1
21 8 1 22 8 2
23 >32 8 24 16 8
25 32 4 26 >32 8
27 >32 4 28 32 8
29 32 8 30 >32 8
31 8 0.5 32 >32 4
33 >32 8 34 >32 8
35 >32 8 36 >32 2
37 32 8 38 8 8
39 0.25 1 40A 8 4
40B 2 4 41 4 8
42 8 16 43 8 8 Example MIC for MIC for Example MIC for MIC for No. S. aureus H. No. S. aureus H.
ATCC influenzae ATCC influenzae 29213 A921 29213 A921
44 8 8 45 16 4
46 32 4 47 32 8
48 8 8 49 4 2
50 >32 8 51 4 2
52 0.5 >32 53 2 0.25
54 32 1 55 8 8
56 0.125 <0.06 57 4 16
58 16 4 59 4 4
60 8 8 61 >32 2
62 >32 2 63 32 4
64 16 8 65 16 0.5
66 32 0.125 67 16 <0.06
68 16 0.5 69 1 0.5
70 1 16 71 0.5 4
72 0.5 0.5 73 1 0.125
74 1 0.125 75 2 4
76 0.5 1 77 2 1
78 2 4 79 8 8
80 0.5 2 81 0.125 <0.063
82 1 8 83 2 2
84 2 2 85 8 8
86 16 4 87 2 2 Example MIC for MIC for Example MIC for MIC for
No. S. aureus H. No. S. aureus H.
ATCC influenzae ATCC influenzae
29213 A921 29213 A921
88 4 4 89 1 1
90 8 1

Claims

Claims
1. A compound of formula I
Figure imgf000129_0001
I wherein
R1 represents (CrC4)alkyl, (CrC3)haloalkyl, CH(Me)NHS02Ra or halogen;
R2 represents H, halogen, (CrC4)alkyl, cyclopropyl, (C2-C4)alkenyl, arylmethyl or heteorarylmethyl; or
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*, #-CRdRe-CH2-B-CH2-*, #-C(Me)2-D=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*; "#" representing the point of attachment of R 1 and "*" representing the point of attachment of R 2 ;
R3 represents hydrogen, halogen, hydroxy, -NHRb, 2-(hydroxy)ethoxy, (CrC4)alkyl, (C2- C4)alkenyl, ro-hydroxy(Ci-C3)alkyl, methoxymethyl or 2-carboxy-azetidin-l-yl; or
R2 and R3 together represent -CH2CH2CH2CH2-;
R4 represents hydrogen or hydroxy;
A represents C=NORf, C=N-NHRg, C=0, CHNHCORh, CHR\ NRj or l,3-dioxolan-2-yl; B represents CH2CH2, CH2, CH(OH), O, S or a bond;
D represents CH(CH2OH);
Ra represents (CrC4)alkyl, aryl or heteroaryl;
Rb represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, <»-hydroxy(C2-C3)alkyl or -CH2CH2CH(NH2)COOH;
Rc represents hydrogen or methyl;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-;
Rf represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, (C3-C4)alkynyl or -CH2RX; Rg represents hydrogen, (Ci-C4)alkyl, aryl, heteroaryl or -CH2Ry;
Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl;
RJ represents heteroarylmethyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2- (hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, aryl, heteroaryl or 5-phenyl-thiazol-2-yl;
Ry represents CH2OH, (Ci-C4)alkoxycarbonyl;
with the proviso that 2-amino-5,7-dimethyl-[l,8]naphthyridine-3-carboxylic acid amide is disclaimed;
or a salt (in particular a pharmaceutically acceptable salt) of such a compound.
2. A compound of formula I according to claim 1, wherein
R1 represents (CrC4)alkyl, (CrC3)haloalkyl, halogen, or -CH(Me)NHS02Ra; and
Ra represents methyl, 2-chloro-pyridin-3-yl, 4-chloro-pyridin-3-yl, 4-methoxy-phenyl, or thiophen-2-yl;
or a salt of such a compound.
3. A compound of formula I according to claim 1 or 2, wherein
R represents H, halogen, (CrC4)alkyl, cyclopropyl, (C2-C4)alkenyl, benzyl or pyridin-4- yl-methyl; or R2 and R3 together represent -CH2CH2CH2CH2-;
or a salt of such a compound.
4. A compound of formula I according to claim 1, wherein the residues
R1 and R2 together represent #-CRc(Me)-A-CH2-CH2-*; "#" representing the point of
1 2
attachment of R and "*" representing the point of attachment of R ;
A represents C=NORf, C=N-NHRg, CO, CHNHCORh, CHR\ NRj or 1 ,3-dioxolan-2-yl; Rc represents methyl;
Rf represents hydrogen, (CrC4)alkyl, (C2-C4)alkenyl, (C3-C4)alkynyl or -CH2RX;
R§represents hydrogen, (Ci-C4)alkyl, -CH2Ry, phthalazin-l-yl or 4-carboxy-phen-l-yl; Rh represents tert-butoxy or furan-2-yl;
R1 represents hydroxy or 2-(hydroxy)ethyl; RJ represents (6-fluorobenzo[d]thiazol-2-yl)methyl, (4-methylthiazol-2-yl)methyl, 2-(benzyloxy)ethyl, propargyl, 4-hydroxybut-2-yn-l-yl, 2-(hydroxy)ethyl;
Rx represents -CH(OH)CH2OH, -CH=CHCH2OH, 2,2-dimethyl-l,3-dioxolan-4-yl, cyclopropyl, -CH2NHCOCH3, -COOH, -CH2CH(NH2)COOH, 5-phenyl-thiazol-2-yl, benzothiazol-2-yl, thiazol-2-yl, 2-chlorophen-l-yl, or 3-chlorophen-l-yl;
Ry represents -CH2OH or -COOEt;
or a salt of such a compound.
5. A compound of formula I according to claim 1, wherein the residues
R1 and R2 together represent #-CRdRe-CH2-B-CH2-*; "#" representing the point of attachment of R1 and "*" representing the point of attachment of R2;
B represents CH2CH2, CH2, CH(OH), O, S or a bond;
Rd represents hydrogen or methyl;
Re represents hydrogen, methyl, hydroxymethyl or hydroxy; or
Rd and Re together represent -CH2CH2CH2CH2-;
or a salt of such a compound.
6. A compound of formula I according to claim 1, wherein the residues
R1 and R2 together represent #-C(Me)2-CH(OH)=CH-CH2-* or #-C(Me)=CH-CH2-CH2-*; "#" representing the point of attachment of R1 and "*" representing the point of attachment of R2;
or a salt of such a compound.
7. A compound of formula I according to any one of claims 1 to 6, wherein
R3 represents hydrogen, CI, hydroxy, -NHRb, 2-(hydroxy)ethoxy, methyl, ethyl, vinyl, hydroxymethyl, (2-hydroxy)ethyl, (3-hydroxy)propyl, methoxymethyl or 2-carboxy- azetidin-l-yl; and
Rb represents hydrogen, methyl, allyl, (2-hydroxy)ethyl, (3-hydroxy)propyl or -CH2CH2CH(NH2)COOH;
or a salt of such a compound.
8. A compound of formula I according to any one of claims 1 to 7, wherein when R4 is OH, R3 is H; or a salt of such a compound.
9. A compound of formula I according to claim 1, which is selected from the following:
- 2-amino-6-bromo-7-(trifluoromethyl)-l,8-naphthyridine-3-carboxamide;
- 2-amino-6-bromo-5,7-dichloro-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-benzyl-7-chloro-5-methyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-methyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide.
- 2-amino-9,9-dimethyl-6,7,8,9-tetrahydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-chloro-5-ethyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-cyclopropyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide; - 2-amino-7-trifluoromethyl-6-vinyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-ethyl-7-trifluoromethyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6,7,8,9-tetrahydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-9-methyl-6,7-dihydro-benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-tert-butyl-[l,8]naphthyridine-3-carboxylic acid amide;
- 8-[(E)-allyloxyimino]-2-amino-9,9-dimethyl-6,7,8,9-tetrahydro- benzo[b][l,8]naphthyridine-3-carboxylic acid amide;
- 2-amino-6-bromo-7-trifluoromethyl-5-vinyl-[l,8]naphthyridine-3-carboxylic acid amide; or a salt of such a compound.
10. A compound of formula I according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.
11. A pharmaceutical composition containing, as active principle, a compound of formula I according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
12. A compound of formula I according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a bacterial infection.
13. A compound of formula I according to claim 12, or a pharmaceutically acceptable salt thereof, for the prevention of treatment of community acquired pneumonias including hospital acquired pneumonia, skin and skin structure infections, blood and tissue infections, including bacteremia, endocarditis and osteomyelitis, foreign body infections, meningitis, gastrointestinal infections including those caused by Clostridium difficile or Helicobacter pylory infections, topical infections, acne vulgaris, infected atopic dermatitis and opthalmological infections.
14. A compound of formula I according to claim 12, or a pharmaceutically acceptable salt thereof, for the use as a medicament in humans, pigs, ruminants, horses, dogs, cats and poultry.
15. Use of a compound of formula I according to any one of claims 1 to 9, or a salt thereof, for cleaning purposes.
PCT/IB2012/056487 2011-11-18 2012-11-16 2 -amino- 1, 8 -naphthyridine-3 -carboxamide derivatives as antimicrobial agents WO2013072882A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018521061A (en) * 2015-07-02 2018-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング General process for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid
WO2019137995A1 (en) 2018-01-11 2019-07-18 Basf Se Novel pyridazine compounds for controlling invertebrate pests
RU2785141C1 (en) * 2022-02-25 2022-12-05 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Application of 1-(6-tosyl-5,6,7,8-tetrahydro-2,6-naphthiridin-3-yl)ethan-1-one as antibacterial agent against gram-positive microorganisms

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064685A2 (en) 2000-02-29 2001-09-07 Takeda Chemical Industries, Ltd. Thienopyridine derivatives and their use as anti-inflammatory agents
WO2005111030A1 (en) * 2004-05-12 2005-11-24 Warner-Lambert Company Llc Quinolone antibacterial agents
WO2006059103A2 (en) 2004-12-03 2006-06-08 Peakdale Molecular Limited Pyridine based compounds useful as intermediates for pharmaceutical or agricultural end-products
WO2006124490A2 (en) 2005-05-17 2006-11-23 Schering Corporation Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20070082920A1 (en) 2005-10-06 2007-04-12 Yongsheng Song NAD+-dependent DNA ligase inhibitors
WO2007045868A1 (en) 2005-10-20 2007-04-26 Biolipox Ab Pyrazoles useful in the treatment of inflammation
WO2007093901A1 (en) 2006-02-17 2007-08-23 Pfizer Limited 3 -deazapurine derivatives as tlr7 modulators
WO2008128962A1 (en) 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic compounds as antibacterials
US20090253678A1 (en) 2008-04-03 2009-10-08 Abbott Laboratories Macrocyclic pyrimidine derivatives
US20100144782A1 (en) * 2007-06-13 2010-06-10 Sanofi-Aventis Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
WO2010123945A2 (en) 2009-04-20 2010-10-28 Allergan, Inc. Silk fibroin hydrogels and uses thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064685A2 (en) 2000-02-29 2001-09-07 Takeda Chemical Industries, Ltd. Thienopyridine derivatives and their use as anti-inflammatory agents
WO2005111030A1 (en) * 2004-05-12 2005-11-24 Warner-Lambert Company Llc Quinolone antibacterial agents
WO2006059103A2 (en) 2004-12-03 2006-06-08 Peakdale Molecular Limited Pyridine based compounds useful as intermediates for pharmaceutical or agricultural end-products
WO2006124490A2 (en) 2005-05-17 2006-11-23 Schering Corporation Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20070082920A1 (en) 2005-10-06 2007-04-12 Yongsheng Song NAD+-dependent DNA ligase inhibitors
WO2007045868A1 (en) 2005-10-20 2007-04-26 Biolipox Ab Pyrazoles useful in the treatment of inflammation
WO2007093901A1 (en) 2006-02-17 2007-08-23 Pfizer Limited 3 -deazapurine derivatives as tlr7 modulators
WO2008128962A1 (en) 2007-04-20 2008-10-30 Glaxo Group Limited Tricyclic compounds as antibacterials
US20100144782A1 (en) * 2007-06-13 2010-06-10 Sanofi-Aventis Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics
US20090253678A1 (en) 2008-04-03 2009-10-08 Abbott Laboratories Macrocyclic pyrimidine derivatives
WO2010123945A2 (en) 2009-04-20 2010-10-28 Allergan, Inc. Silk fibroin hydrogels and uses thereof

Non-Patent Citations (50)

* Cited by examiner, † Cited by third party
Title
"A guide to Functional Group Preparations", 1999, WILEY-VC, article "Comprehensive Organic Transformations", pages: 1075 - 1087,109
"Clinical and Laboratory Standards Institute (CLSI) Document M7-A7", 2006, article "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically"
"Comprehensive Organic Transformations. A guide to Functional Group Preparations", 1999, WILEY-VC, pages: 1234 - 1236
"Comprehensive Organic Transformations. A guide to Functional Group Preparations", 1999, WILEY-VC, pages: 1941 - 1949
"Salt selection for basic drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
ACC. CHEM. RES., vol. 41, 2008, pages 1555 - 1564
ALDRICHIMICA ACTA, vol. 39, 2006, pages 17 - 24,97-111
ALDRICHIMICA ACTA, vol. 39, 2006, pages 97 - 111
ANGEW. CHEM. INT. ED. ENGL., vol. 43, 2004, pages 4704 - 4734
ANGEW. CHEM. INT. ED., vol. 44, 2005, pages 1371 - 1375
ANGEW. CHEM. INT. ED., vol. 47, 2008, pages 6338 - 6361
BROETZ-OESTERHELT ET AL., J. BIOL. CHEM., vol. 278, no. 41, 2003, pages 39435 - 39442
BULL. CHEM. SOC. JAP., vol. 72, 1999, pages 2307 - 2313
BULL. SOC. CHIM. FR., 1957, pages 1499
CHEM. PHARM. BULL., vol. 43, 1995, pages 797 - 817
CHEM. REV., vol. 93, 1993, pages 2117 - 2188
CHEM. REV., vol. 95, 1995, pages 2457 - 2483
CHEM. SOC. REV., vol. 38, 2009, pages 1598 - 1607
DORNOW A ET AL: "UBER SYNTHESEN UND UMSETZUNGEN VON 1,8-NAPHYYRIDINEN. ÖSYNTHESEN STICKSTOFFHALTIGER HETEROCYCLEN", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 290, no. 3, 1 January 1957 (1957-01-01), pages 136 - 153, XP000562106, ISSN: 0365-6233, DOI: 10.1002/ARDP.19572900305 *
EDWARD M. HAWES ET AL: "2,3-Disubstituted 1,8-naphthyridines as potential diuretic agents. 2. 5,7-Dimethyl derivatives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 20, no. 6, 1 June 1977 (1977-06-01), pages 838 - 841, XP055053985, ISSN: 0022-2623, DOI: 10.1021/jm00216a021 *
G. BENZ: "Comprehensive Organic Synthesis", vol. 6, 1991, PERGAMON PRESS, pages: 381
HAWES ET AL., J. MED. CHEM., vol. 20, no. 6, 1977, pages 838 - 41
J ORG. CHEM., vol. 58, 1993, pages 2931 - 2932
J ORG. CHEM., vol. 65, 2000, pages 1144 - 1157
J. HETEROCYCLIC CHEM., vol. 21, 1984, pages 1441 - 1444
J. HETEROCYCLIC CHEM., vol. 26, no. 3, 1989, pages 705 - 708
J. MED. CHEM., vol. 34, 1991, pages 2468 - 2473
J. MED. CHEM., vol. 40, no. 15, 1997, pages 2347 - 2362
J. ORG. CHEM., vol. 61, 1996, pages 7681
J. ORG. CHEM., vol. 62, 1997, pages 6888 - 6896
J. ORG. CHEM., vol. 75, 2010, pages 7146 - 7158
JEAN-PHILIPPE SURIVET ET AL: "Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 21, 1 November 2012 (2012-11-01), pages 6705 - 6711, XP055054121, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2012.08.094 *
MEIER ET AL., FEBS JOURNAL, vol. 275, no. 21, 2008, pages 5258 - 5271
P.J. KOCIENSKI: "Protecting Groups", 1994, GEORG THIEME VERLAG, pages: 118 - 143
R. C. LAROCK: "Comprehensive Organic Transformations. A guide to Functional Group Preparations", 1999, WILEY-VC, pages: 703
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
SYNLETT, 2004, pages 2111 - 2114
SYNTH. COMMUN., vol. 38, 1984, pages 851 - 854
SYNTHESIS, 2004, pages 2419 - 2440
T.W. GREENE; P.G.M. WUTS: "Protecting Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS, INC., pages: 133 - 139,142-
T.W. GREENE; P.G.M. WUTS: "Protecting Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS, INC., pages: 23 - 147
T.W. GREENE; P.G.M. WUTS: "Protecting Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS, INC., pages: 494 - 653
T.W.GREENE; P.G.M. WUTS;: "Protecting Groups in Organic Synthesis", 1999, JOHN WILEY AND SONS, INC., pages: 23 - 147
TETRAHEDRON ASYMMETRY, 1996, pages 2497 - 2450
TETRAHEDRON, vol. 59, no. 27, 2003, pages 5115 - 5121
TETRAHEDRON, vol. 60, 2004, pages 7899 - 7906
TETRAHEDRON, vol. 61, 2005, pages 2779 - 2794
TETRAHEDRON, vol. 62, 2006, pages 6361
TETRAHEDRON, vol. 62, no. 26, 2006, pages 6361 - 6369
YAKUGAKU ZASSHI, vol. 4, 1979, pages 342 - 348

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018521061A (en) * 2015-07-02 2018-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング General process for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid
US10106506B2 (en) * 2015-07-02 2018-10-23 Boehringer Ingelheim International Gmbh General process for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid
WO2019137995A1 (en) 2018-01-11 2019-07-18 Basf Se Novel pyridazine compounds for controlling invertebrate pests
RU2785141C1 (en) * 2022-02-25 2022-12-05 Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" Application of 1-(6-tosyl-5,6,7,8-tetrahydro-2,6-naphthiridin-3-yl)ethan-1-one as antibacterial agent against gram-positive microorganisms

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