WO2018102885A1 - Modulators of nicotinic acetylcholine receptors and uses thereof - Google Patents

Modulators of nicotinic acetylcholine receptors and uses thereof Download PDF

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WO2018102885A1
WO2018102885A1 PCT/AU2017/051358 AU2017051358W WO2018102885A1 WO 2018102885 A1 WO2018102885 A1 WO 2018102885A1 AU 2017051358 W AU2017051358 W AU 2017051358W WO 2018102885 A1 WO2018102885 A1 WO 2018102885A1
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optionally substituted
alkyl
mmol
heterocyclyl
ethyl
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PCT/AU2017/051358
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French (fr)
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Justin Anthony Ripper
Lorna Helen Mitchell
Andrew John Harvey
Patrick BAZZINI
Jean-Marie Contreras
Nicolas FEICHTER
Christophe Morice
Laurent Schaeffer
Cindy STAHL
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Bionomics Limited
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Priority claimed from AU2016905080A external-priority patent/AU2016905080A0/en
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Publication of WO2018102885A1 publication Critical patent/WO2018102885A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to chemical compounds and methods for their use and preparation in relation to the treatment of diseases, disorders or conditions which would benefit from the modulation of the alpha 7 nicotinic acetylcholine receptor (a.7 nAChR).
  • the invention thus also relates to the use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
  • a.7 nAChRs are rapidly desensitizing cation channels belonging to the cis-loop ligand- gated family.
  • a7 nAChRs play an important role in the regulation of neuronal excitability in different brain regions either by presynaptically modulating neurotransmitter release or by their position on somato-dendritic sites of intemeurons and pyramidal cells, where they directly regulate neuronal activity. They are abundantly expressed in the brain, modulate neurotransmitter release and are responsible for direct fast excitatory neurotransmission.
  • o7 nAChRs At the cellular level, activation of o7 nAChRs can regulate interneuron excitability, modulate the release of excitatory and inhibitory neurotransmitters, and contribute to neuroprotective effects. Positive modulation of a7 nAChRs can enhance hippocampal long term potentiation (LTP), and a7 nAChRs are associated with attentional processes and working memory. As a consequence, a7 nAChRs are a therapeutic target for treating cognitive impairment, notably in Alzheimer's disease and schizophrenia (1-4).
  • a human imaging study has shown that ACh levels are elevated in patients who are depressed, and remain high in patients who have a history of depression (8).
  • other clinical and preclinical studies have shown that blockers of cholinergic receptors can induce antidepressant-like responses (9).
  • physostigmine an inhibitor of acetylcholinesterase, increased depressive symptoms in individuals with or without a history of depression.
  • hyperactivity of brain cholinergic systems can contribute to the pathophysiology of depression (10).
  • Other studies have shown that a7 nAChRs in both the hippocampus and the amygdala are implicated in the regulation of depression and anxiety.
  • the basolateral amygdala receives dense cholinergic input from the basal forebrain, affecting both normal functions and dysfunctions of the amygdala.
  • Neuronal excitability in the BLA is particularly relevant to anxiety.
  • a7 nAChRs are present on somatodendritic regions of glutamatergic neurons (12), and on somatic and/or dendritic regions of GABAergic interneurons (13).
  • ⁇ 2 subunit-containing ( ⁇ 2*) and a7 nAChRs have implicated both ⁇ 2 subunit-containing ( ⁇ 2*) and a7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviours.
  • Viral-mediated down-regulation of the ⁇ 2 or a7 nAChR subunit in the amygdala induced robust anxiolytic- and antidepressant- like effects in several mouse behavioral models (14).
  • a7 nAChR subunit knockdown was effective at decreasing anxiety-like behaviour, and reversed the effect of increased ACh signaling in a mouse model of depression.
  • the present invention provides compounds of formula (A), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
  • Z, Y, G and D are independently CR' (where R' is selected from H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacy
  • Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optional
  • L represents halogen, heteroaromatic, OR 7 , or NR 7 R" (where R" is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, and optionally substituted sulfonyl);
  • R 7 represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl, or R 7 and R" together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl; and
  • X represents NR, O, S, SO, or S0 2 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted amino
  • the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
  • X represents NR, O, S, SO, or S0 2 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted al
  • Y, and Z are independently selected from C, or N, and wherein at least one of Y and Z is N;
  • Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substitute
  • R 2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optional
  • R 3 and R 4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, and optionally substituted thioacyl; or R 3 and R4 together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl.
  • the present invention provides compounds of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof for use in treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR, including the step of administering to a patient in need of an effective amount of said compound or salt.
  • the invention also provides for the use of compounds of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR.
  • the present invention also provides methods of treatment for diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR comprising the administration of an effective amount of at least one compound of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof to a subject in need thereof.
  • the modulation of a7 nAChR involves negative allosteric modulation of a7 nAChR.
  • the compounds are useful in the treatment of anxiety, depression, or stress-related disorders. Detailed Description of the Invention
  • the present invention is primarily based on the discovery that the compounds of the general formula (A) or (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof have useful properties as selective negative allosteric modulators of alpha 7 nicotinic acetylcholine receptors.
  • Such compounds have significant potential for the treatment of mood disorders such as anxiety, depression and stress related disorders whether they occur alone or as comorbidities with other conditions.
  • “Alkyl” refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms.
  • alkyl groups examples include methyl, ethyl, n-propyl, z ' so-propyl, n-butyl, iso- butyl, ft-hexyl, and the like.
  • Alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), and the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms.
  • aryl groups include phenyl, naphthyl and the like.
  • Arylene refers to a divalent aryl group wherein the aryl group is as described above.
  • Aryloxy refers to the group aryl-O- wherein the aryl group is as described above.
  • Arylalkyl refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
  • Arylalkoxy refers to the group arylalkyl-O- wherein the arylalkyl group are as described above. Such arylalkoxy groups are exemplified by benzyloxy and the like. "Alkoxy” refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, z ' so-propoxy, n-butoxy, ieri-butoxy, sec- butoxy, ft-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Alkoxyalkyl refers to alkoxy-alkyl- group wherein the alkoxy group and alkyl group are as described above.
  • (Alkoxy) 2 alkyl refers to alkoxy-alkoxy-alkyl- group wherein the alkoxy group and alkyl group are as described above.
  • the alkoxy groups may be the same alkoxy group, or may be different alkoxy groups.
  • Olethy alkoxy alkyl refers to oxy- alkoxy- alkyl- group wherein the oxy group is -OH, and the alkoxy group and alkyl group are as described above.
  • Alkenyl refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds.
  • Alkenyloxy refers to the group alkenyl-O- wherein the alkenyl group is as described above.
  • Alkenylene refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethenylene
  • Alkynyl refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds.
  • alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), pent-2-ynyl (-CH 2 C ⁇ CCH 2 -CH 3 ), and the like.
  • Alkynyloxy refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
  • Alkynylene refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C ⁇ C-), propynylene (-CH 2 -C ⁇ C-), and the like.
  • Acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxyalkyl refers to the group alkyl-OH wherein the alkyl group is as described above. Examples include hydroxymethyl, hydroxyethyl, hydroxypropyl and the likes.
  • Oxyacyl refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Amino refers to the group -NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • aminoalkyl refers to the amino-alkyl- group wherein the amino group and alkyl group are as described above.
  • Aminoacyl refers to the group -C(0)NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Acylamino refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-aryl, -C(0)0-heteroaryl, and
  • aminoacyloxy refers to the groups -OC(0)NR"-alkyl, -OC(0)NR"-aryl,
  • R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxyacylamino refers to the groups -NR"C(0)0-alkyl, -NR"C(0)0-aryl,
  • R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxyacyloxy refers to the groups -OC(0)0-alkyl, -0-C(0)0-aryl, -OC(0)0- heteroaryl, and -OC(0)0-heterocyclyl where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acylimino refers to the groups -C(NR")-R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Acyliminoxy refers to the groups -0-C(NR")-R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Oxyacylimino refers to the groups -C(NR")-OR” where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Cycloalkyl refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.
  • Cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 11 carbon atoms.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.
  • Halo or “halogen” refers to fluoro, chloro, bromo and iodo.
  • Heteroaryl refers to a monovalent aromatic heterocyclic group which fulfils the Hiickel criteria for aromaticity (i.e. contains 4n + 2 ⁇ electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen).
  • Such heteroaryl groups can have a single ring (e.g. pyridyl, pyrrolyl or N- oxides thereof or furyl) or multiple condensed rings (e.g. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).
  • R 2 or R' is an optionally substituted heteroaryl which has one or more ring heteroatoms
  • the heteroaryl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
  • Heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R 2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
  • heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7
  • Heteroaryloxy refers to the group heteroaryl-O- wherein heteroaryl is described as above.
  • Heteroarylalkyl refers to the group heteroaryl-alkyl- wherein heteroaryl and alkyl are described as above.
  • Heteroarylene refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.
  • Heterocyclylalkyl refers to the heterocyclyl-alkyl- group wherein the heterocyclyl group and alkyl group are as described above.
  • Heterocyclylene refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.
  • Thio refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Thioacyl refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxythioacyl refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Oxythioacyloxy refers to groups HO-C(S)-0-, alkylO-C(S)-0-, cycloalkylO-C(S)-0-, arylO-C(S)-0-, heteroarylO-C(S)-0-, and heterocyclylO-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Phosphorylamino refers to the groups -NR"-P(0)(R"')(OR"") where R" represents H, alkyl, cycloalkyl, alkenyl, or aryl, R'" represents OR"" or is hydroxy or amino and R"" is alkyl, cycloalkyl, aryl or arylalkyl, where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are as described herein.
  • Thioacyloxy refers to groups H-C(S)-0-, alkyl-C(S)-0-, cycloalkyl-C(S)-0-, aryl- C(S)-0-, heteroaryl-C(S)-0-, and heterocyclyl-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
  • Sulfinyl refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • Sulfonyl refers to groups H-S(0) 2 -, alkyl-S(0) 2 -, cycloalkyl-S(0) 2 -, aryl-S(0) 2 -, heteroaryl-S(0) 2 -, and heterocyclyl-S(0) 2 -, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • “Sulfinylamino” refers to groups H-S(0)-NR"-, alkyl-S(0)-NR”-, cycloalkyl-S(O)- NR"-, aryl-S(0)-NR"-, heteroaryl-S(0)-NR”-, and heterocyclyl-S(0)-NR”-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • “Sulfonylamino” refers to groups H-S(0) 2 -NR"-, alkyl-S(0) 2 -NR"-, cycloalkyl-S(0) 2 - NR"-, aryl-S(0) 2 -NR"-, heteroaryl-S(0) 2 -NR”-, and heterocyclyl-S(0) 2 -NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxysulfinylamino refers to groups HO-S(0)-NR"-, alkylO-S(0)-NR"-, cycloalkylO- S(0)-NR"-, arylO-S(0)-NR"-, heteroarylO-S(0)-NR”-, and heterocyclylO-S(0)-NR”-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Oxysulfonylamino refers to groups HO-S(0) 2 -NR"-, alkylO-S(0) 2 -NR"-, cycloalkylO-S(0) 2 -NR"-, arylO-S(0) 2 -NR"-, heteroarylO-S(0) 2 -NR”-, and heterocyclylO-S(0) 2 -NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminothioacyl refers to groups R"R"N-C(S)-, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Thioacylamino refers to groups H-C(S)-NR"-, alkyl-C(S)-NR"-, cycloalkyl-C(S)- NR"-, aryl-C(S)-NR"-, heteroaryl-C(S)-NR”-, and heterocyclyl-C(S)-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminosulfinyl refers to groups R"R"N-S(0)-, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • Aminosulfonyl refers to groups R"R"N-S(0) 2 -, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from oxo/hydroxy, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trial
  • the term "optionally substituted” is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of oxo/hydroxy, halogen (in particular CI, Br, F), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 oxyalkyl, C 1-6 alkoxyalkyl, C 1-6 oxyalkoxyalkyl, C 1-6 (alkoxy)2-alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl (in particular -CF 3 ), Ci_ 6 haloalkoxy (such as -OCF 3 ), C 2 -6 alkenyloxy, C 2 -6 alkynyloxy, arylalkyl (wherein alkyl is C 1-6 ), arylalkoxy (wherein alkyl is C 1-6 ), aryl, cyano, nitro, heteroaryl, Ci_ 6 heteroarylalkyl (wherein alkyl is
  • the term "optionally substituted” is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of hydroxy, halogen (in particular CI, Br, F), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 oxyalkyl, C 1-6 alkoxyalkyl, C 1-6 oxyalkoxyalkyl, C 1-6 (alkoxy) 2 -alkyl, C 2 -6 alkenyl, C 1-6 haloalkyl (in particular -CF 3 ), Ci_ 6 haloalkoxy (such as -OCF 3 ), arylalkyl (wherein alkyl is C 1-6 ), arylalkoxy (wherein alkyl is C 1-6 ), aryl, cyano, nitro, heteroaryl, heterocyclyl, heterocyclylalkyl, trialkylsilyl, amino, mono- and di-alkylamino, mono-and di- substituted alkyl)amin
  • the term "optionally substituted” is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of hydroxy, hydroxymethyl, hydroxethyl, hydroxpropyl, methyl, methoxy, methoxymethyl, hydroxyethoxymethyl, methoxyethoxymethyl, cyano, pyridinyl, pyridinylmethyl, pyrazinyl, methylphenyl, benzyl, trimethylsilyl, phenyl, methylpyrazoyl, dimethylamino, fluorophenyl, morpholinyl, morpholinylmethyl, morpholinylethyl, ie/t-butyloxycarbonyl, amino, dimethylaminomethyl, dimethylaminoethyl, methyldifluoroethylamino, methyltrifluoroethylamino, methylmethoxyethylamino, di(methoxyethy
  • the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
  • X represents NR, O, S, SO, or S0 2 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted al
  • Y and Z are independently selected from C, or N, and wherein at least one of Y and Z is N;
  • Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted
  • R 2 represents H, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally
  • R 3 and R 4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, and optionally substituted thioacyl; or R 3 and R4 together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl.
  • R when present is selected from H, dihalomethoxy, halogen, hydroxy, pentahaloethyl, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted arylalkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally
  • R when present is selected from the following groups:
  • Ci-C 6 alkyl group for instance methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl, methoxymethyl or methoxyethyl; optionally substituted aminoalkyl, for instance dimethylaminoethyl, methyldifluoroethylaminoethyl, methyltrifluoroethylaminoethyl, methylmethoxyethylaminoethyl, di(methoxyethyl)aminoethyl;
  • heterocyclylalkyl for instance morpholinylethyl
  • R when present is optionally substituted Ci-C 6 alkyl, optionally substituted aminoalkyl, or optionally substituted heterocyclylalkyl. In a further embodiment, and with reference to formula (A) and (I), R when present is ethyl.
  • R when present is morpholinylethyl .
  • R when present is dimethylaminoethyl .
  • Ri is selected from H, cyano, optionally substituted oxo/hydroxy, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Q- C 6 alkoxy, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkyl, optionally substituted
  • Ri is selected from the following groups: hydrogen;
  • Ci-C 6 alkyl group for instance N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl;
  • C 2 -C6 alkenyl group for instance ⁇ - ⁇ 2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl;
  • C 2 -C 6 alkynyl group for instance ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy )butynyl ;
  • amino for instance 2-pyrazinyl amino, N,N-(2- pyridinyl)methylamino ;
  • acylamino for instance (2-pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2-benzyl)acylamino, 4-(methylphenyl)acylamino;
  • cycloalkenyl for instance 3-cyclopentenyl
  • heterocyclyl for instance N-(4-hydroxy)piperidinyl, N-morpholinyl,
  • aryl for instance phenyl, 2-(methylphenyl), 4-(methylphenyl), 2- (methoxyphenyl), 3-(methoxyphenyl), 4-(methoxyphenyl), 3-(cyanophenyl), 4- (cyanophenyl);
  • heteroaryl preferably 2-furanyl, 3-furanyl, 3-(2-methylfuranyl), 5- (2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N- methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N- morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-triazolyl), N-methyl-2-pyrrolyl, 2-methyl- N-pyrrolyl, N-pyrazolyl, l-methyl-2-pyrazolyl, N-methyl-4-pyrazolyl, 4-(N- dimethylaminoethyl)pyrazolyl, 4-(N-morpholinyleth
  • heteroarylalkyl for instance 1,2,3-triazolylmethyl, 4- (hydroxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5 -hydroxy ethoxymethyl( 1 ,2,3- triazolyl)methyl, 4-(hydroxyethyl- 1 ,2,3-triazolyl)methyl, 5-hydroxyethyl( 1 ,2,3- triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5-
  • heterocyclylalkyl for instance N,N'-(2-pyridinyl)piperazinylmethyl, (N-morpholinyl)methyl;
  • arylalkyl for instance phenylethyl
  • aryloxy for instance phenoxy, (4-methoxyphenyl)oxy
  • heteroaryloxy for instance (3-pyridinyl)oxy
  • arylalkyloxy for instance (4-methoxybenzyl)oxy
  • R' is optionally substituted Ci-C 6 alkyl or optionally substituted phenyl, for instance phenylacyl, methylacyl, ethylacyl.
  • Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4- pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-( 1 -benzyl- 1,2,3 - triazolyl), phenoxy, phenylacyl, 5-thiazolyl, (N-morpholinyl)methyl, 4- hydroxymethyl(l,2,3-triazolyl)methyl, 5-methoxymethyl(l,2,3-triazolyl)methyl, 4-(N- dimethylaminoethyl)pyrazolyl, or 1,2,3
  • R' when present and R 2 are independently selected from H, cyano, hydroxyl, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryl
  • Ci-C 6 alkyl for instance ie/t-butyl
  • aryl for instance phenyl
  • cycloalkyl for instance cyclohexanyl
  • heterocyclyl for instance piperidinyl, N-(ie/t-butyloxycarbonyl- piperidinyl).
  • R' when present and R 2 are independently selected from H or tert-butyl.
  • R 7 when present and R 3 are independently selected from H, optionally substituted Ci-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C 6 ).
  • R 3 are independently selected from the following groups:
  • cycloalkyl for instance indanyl
  • arylalkyl wherein alkyl is Ci-C 6 ), for instance phenylmethyl;
  • heterocyclyl for instance tetrahydropyranyl
  • heterocyclylalkyl wherein alkyl is Ci-C 6 , for instance tetrahydropyran methyl.
  • R 7 when present and R 3 are independently indanyl.
  • R 4 is selected from Q-C 6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is CrC 6 ).
  • R4 are independently selected from the following groups:
  • Ci-C 6 alkyl for instance methyl
  • R" when present and R 4 are independently H.
  • R' (when present) and R 2 are independently selected from ie/t-butyl, phenyl, cyclohexanyl, piperidinyl, N-(ieri-butyloxycarbonyl-piperidinyl) .
  • Ri is selected from N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl, ⁇ - ⁇ 2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl, ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy)butynyl, 2-pyr
  • Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N- methylimidazolyl), 2-oxazolyl, 4-(l-benzyl-l,2,3-triazolyl), phenoxy, phenylacyl, 5- thiazolyl, or (N-morpholinyl)methyl, 1,2,3-triazolylmethyl, 5-methoxymethyl( 1,2,3- triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl
  • Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl-l,2,3-triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 5- methoxymethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl or 4-(N- dimethylaminoe
  • Ri is 1,2,3-triazolylmethyl.
  • R 3 and R4 together with the N-atom form an optionally substituted heteroaryl or optionally substituted heterocyclyl.
  • R 7 and R" together with the N-atom form an optionally substituted heteroaryl or optionally substituted heterocyclyl.
  • the present invention relates to compounds of formula (I) which are represented by formulae (la), (lb), (Ic), (Id), (Ie) or (If):
  • the compounds of formula (I) are represented by formula (la), or (lb), wherein R, Ri, R 2, R 3 and R4 are as defined above for compounds of formula (I).
  • the compounds of formula (I) are represented by formula (la), wherein R, Ri, R 2 , R 3 and R4 are as defined above for compounds of formula (I).
  • the compounds of the present invention are represented by the formula ( ⁇ ) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof
  • the invention provides compounds of formula ( ⁇ ) represented by formula (I'a), (I'b), (I'c), (I'd), (I'e) or (I'f):
  • the compounds of formula (I) are represented by formula (I'a), (I'b), wherein R, Ri, R 2 and R4 are as described above for compounds of formula (I).
  • the compounds of formula (I) are represented by formula (I'a), wherein R, Ri, R 2 and R4 are as described above for compounds of formula (I).
  • the compounds of the present invention are represented by the formula (I") or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof wherein X, Y, Z, R, Ri and R 2 are as described above for the compounds of formula (I). Accordingly, in other embodiments the invention provides compounds of formula (I") represented by formula (Fa), (I"b), (I"c) or (I"d):
  • compounds of formula (I) are represented by formula (I"a), or (I"b), wherein R, Ri and R 2 are as described above for compounds of formula (I).
  • compounds of formula (I) are represented by formula (I" a), wherein R, Ri and R 2 are as described above for compounds of formula (I).
  • the present invention also provides compound of formula (I"a) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
  • R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminoacy
  • Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optional
  • R is selected from H, dihalomethoxy, halogen, hydroxy, pentahaloethyl, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted arylalkoxy, optionally substituted C 2 -C6 alkenyl, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted Ci-C 6 alkoxy, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, optionally substituted aryloxy, optionally substituted cycloal
  • R is selected from the following groups:
  • Ci-C 6 alkyl group for instance methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl, methoxymethyl or methoxyethyl;
  • aminoalkyl for instance dimethylaminoethyl, methyldifluoroethylaminoethyl, methyltrifluoroethylaminoethyl, methylmethoxyethylaminoethyl, di(methoxyethyl)aminoethyl;
  • heterocyclylalkyl for instance morpholinylethyl
  • R is selected from optionally substituted Ci-C 6 alkyl, optionally substituted aminoalkyl, or optionally substituted heterocyclylalkyl.
  • R is ethyl
  • R is morpholinylethyl.
  • R is dimethylaminoethyl.
  • Ri is selected from H, cyano, optionally substituted oxo/hydroxy, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C ⁇ - C 6 alkoxy, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkyl,
  • Ri is selected from the following groups:
  • Ci-C 6 alkyl group for instance N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl;
  • C 2 -C 6 alkenyl group for instance ⁇ - ⁇ 2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl;
  • C 2 -C 6 alkynyl group for instance ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy )butynyl ;
  • amino for instance 2-pyrazinyl amino, N,N-(2- pyridinyl)methylamino
  • acylamino for instance (2-pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2-benzyl)acylamino, 4-(methylphenyl)acylamino;
  • cycloalkenyl for instance 3-cyclopentenyl
  • heterocyclyl for instance N-(4-hydroxy)piperidinyl, N-morpholinyl, 2-benzofuanyl, N-morpholinonyl;
  • aryl for instance phenyl, 2-(methylphenyl), 4-(methylphenyl), 2- (methoxyphenyl), 3-(methoxyphenyl), 4-(methoxyphenyl), 3-(cyanophenyl), 4- (cyanophenyl); optionally substituted heteroaryl, preferably 2-furanyl, 3-furanyl, 3-(2-methylfuranyl), 5- (2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N- methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N- morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-triazolyl), N-methyl-2-(l,
  • heteroarylalkyl for instance 1,2,3-triazolylmethyl, 4- (hydroxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5 -hydroxy ethoxymethyl( 1 ,2,3- triazolyl)methyl, 4-(hydroxyethyl-l,2,3-triazolyl)methyl, 5-hydroxyethyl( 1,2,3 - triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5- (methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 4-(methoxymethyl- 1 ,2,3-triazolyl)methyl, 5-morpholinylethyl( 1 ,2,3-triazolyl)methyl, 5-methoxymethyl( 1 ,2,3-triazolyl)methyl, 4- dimethylaminoethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5- dimethyl
  • heterocyclylalkyl for instance N,N'-(2-pyridinyl)piperazinylmethyl, (N-morpholinyl)methyl;
  • arylalkyl for instance phenylethyl
  • aryloxy for instance phenoxy, (4-methoxyphenyl)oxy
  • heteroaryloxy for instance (3-pyridinyl)oxy
  • arylalkyloxy for instance (4-methoxybenzyl)oxy
  • R' is optionally substituted Ci-C 6 alkyl or optionally substituted phenyl, for instance phenylacyl, methylacyl, ethylacyl.
  • Ri is selected from ethynyl, 1- (3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2- imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2- furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l -benzyl- 1,2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, (N-morpholinyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5-methoxymethyl(l,2,3-triazolyl)methyl, 4-(N-dimethylaminoethyl)pyrazolyl, or 1,2,3- triazolylmethyl
  • R 2 is selected from H, cyano, hydroxyl, optionally substituted Ci-C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted Ci-C 6 alkoxy, optionally substituted C 2 -C 6 alkenyloxy, optionally substituted C 2 -C 6 alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C 6 ), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted ary
  • R 2 is selected from the following groups:
  • Ci-C 6 alkyl for instance ie/t-butyl
  • aryl for instance phenyl
  • cycloalkyl for instance cyclohexanyl
  • heterocyclyl for instance piperidinyl, N-(ie/t-butyloxycarbonyl- piperidinyl).
  • R 2 is selected from H or tert- butyl.
  • R 2 when Ri is H, R 2 is selected from ie/ -butyl, phenyl, cyclohexanyl, piperidinyl, N-(ieri-butyloxycarbonyl-piperidinyl).
  • Ri is selected from N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (1,2,3- triazolyl)methyl, l-(2-ie/t-butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl, ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2- imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3- hydroxyl)propanyl, l-(4-hydroxy)butynyl, 2-pyrazinyl amino, N,N,N
  • Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl- 1, 2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 1,2,3- triazolylmethyl, 5-methoxymethyl( 1 ,2,3 -triazolyl)methyl, 4-hydroxymethyl( 1,2,3- triazolyl)methyl or 4-(N-dimethyla
  • Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl- 1,2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 5- methoxymethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl or 4-(N- dimethylaminoethyl)pyrazolyl
  • Ri is 1 ,2,3-triazolylmethyl.
  • Ri is 1,2,3-triazolylmethyl.
  • the structures contain one or more stereogenic centers, the respective structures are depicted in an arbitrary absolute configuration. These structures also include the respective structure such as salts, tautomers, opposite stereoisomers as well as mixtures of isomers in all ratios including racemates:
  • an amino substituted N-containing heteroaryl e.g. a 2-substituted- 5-amino-pyridine
  • a diethyl ethoxymethylene malonate in a suitable solvent (e.g. diethyl ether) to afford the desired diethyl aminomethylene malonate.
  • This product may then be cyclised at temperatures above 200°C (for instance in diphenyl ether) to afford the corresponding ring closed product. Hydrolysis of the ethyl ester under standard conditions may afford the corresponding carboxylic acid.
  • the ring closed product may be reacted with a suitable electrophilic group (e.g. alkylation with an alkylhalide) under standard conditions.
  • Coupling of the acid with HNR'R" may be achieved under typical peptide coupling conditions.
  • the carboxylic acid can be initially converted to an activated ester with ethyl chloroformate or HBTU in the presence of a suitable non-nucleophilic base (e.g. triethylamine, Hiinigs base, etc).
  • a suitable non-nucleophilic base e.g. triethylamine, Hiinigs base, etc.
  • a carboxy-substituted N-containing heteroaryl (e.g. a 2,5- disubstituted nicotinic acid) may be converted to the malonate ester by reaction with thionyl chloride and potassium ethyl malonate under standard conditions.
  • the L group depicted in Scheme 2 represents any suitable leaving group which may be halogen, methoxy, tosylate, mesylate, etc.
  • the malonate ester may be reacted with triethylorthoformate in acetic acid followed by the addition of a nucleophilic amine (HNR 2 ) to afford the ethylene amine which may be subsequently cyclised or be promoted to cyclise (e.g.
  • NR 3 R j group may be accomplished by nucleophilic substitution chemistry with an effective nucleophilie e.g. 9 NHRi or 9 0Ri or may be introduced using palladium catalysed coupling chemistry.
  • X may be an oxygen based leaving group (or precursor thereof) such as a tosylate or mesylate, or a halogen for instance, CI, Br, or I.
  • X may alternatively be N0 2 .
  • the N0 2 group may be reduced to NH 2 with the use of, for instance, Raney nickel/H 2 .
  • the corresponding NH 2 group may be reacted with RL' (L' is a leaving group) to produce compounds where -XRi is -NHRi.
  • Examples of functional group inter-conversions are: -C(0)NR*R** from -C0 2 CH 3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR*R** in CH 3 OH; - OC(0)R from -OH with e.g., C1C(0)R in pyridine; -NC(S)NR*R** from -NHR with an alkylisothiocyanate or thiocyanic acid; -NRC(0)OR* from -NHR with alkyl chloroformate; -NRC(0)NR*R** from -NHR by treatment with an isocyanate, e.g.
  • the present invention may be used in the treatment of a variety of diseases, disorders or conditions which would benefit from the negative modulation of a.7 nAChR, including the step of administering to a patient in need of an effective amount of said compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof.
  • diseases, disorders or conditions include:
  • anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder;
  • depressive or bipolar disorders for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder;
  • emesis anxiety and/or depression associated with emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting;
  • anxiety and/or depression associated with eating disorders including anorexia nervosa and bulimia nervosa;
  • Compounds of the invention may be beneficial as pre-medication prior to anaesthesia minor procedures such as endoscopy, including gastric endoscopy.
  • the invention also provides for the use of compounds of formula (I), ( ⁇ ) or (I") (and sub- formulae) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of medicaments for treating diseases, disorders or conditions which would benefit from the modulation of al nAChR.
  • chemotherapeutic treatments e.g. muscle relaxants, anticonvulants, hypnotics, anaesthetics, analgesics, antidepressants, antipsychotics, or other anxiolytics, etc.
  • chemotherapeutic treatments e.g. muscle relaxants, anticonvulants, hypnotics, anaesthetics, analgesics, antidepressants, antipsychotics, or other anxiolytics, etc.
  • the compounds of the invention can be used in the treatment of any disease state which may be ameliorated by negative modulation of the alpha 7 nicotinic receptor complex.
  • a treatment effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular disease of condition being treated.
  • the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • the dosage may be in the range of 1 ⁇ to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another preferred embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject.
  • the active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition.
  • the formulation of such compositions is well known to those skilled in the art.
  • the composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
  • a binder e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like.
  • Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Transdermal patches may also be used to administer the compounds of the invention.
  • compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage compositions are those containing a daily dose or unit, daily sub- dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.
  • the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • the compounds of the present invention may be administered to a subject as a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt also fall within the scope of the present invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • the present invention includes within its scope cationic salts e.g. sodium or potassium salts, or alkyl esters (e.g. methyl, ethyl) of the phosphate group.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention.
  • Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group (for instance at the Ri or R 2 position) is converted into an ester, such as an acetate or phosphate ester, or where a free amino group is (for instance at the Ri, R 2 or R 4 position) converted into an amide (e.g. a-aminoacid amide).
  • Procedures for esterifying, e.g. acylating, the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
  • the compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
  • compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres e.g., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, e.g., chromatography, or use of a resolving agent.
  • the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention.
  • Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope.
  • the invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
  • Mass spectral data and purity of all compounds were acquired on an Agilent LCMS-Ion Trap- 1200 Series. Mass spectra were obtained on an Agilent Ion Trap applying electrospray ionization (ESI). Purity of all compounds was obtained using a Nucleodur 3 ⁇ 4.6 x 150 mm reverse-phase column. The eluent was a linear gradient with a flow rate of 1.3 mL/min from 95% A and 5% B to 5% A and 95% B in 8.5 min (solvent A, H 2 0 with 0.1% HC0 2 H; solvent B, acetonitrile with 0.1% HC0 2 H). The compounds were detected at their maximum of absorbance.
  • the crude solid obtained was purified by flash chromatography (Si0 2 , CH 2 Cl 2 /AcOEt 100:0 ⁇ 30:70 then CH 2 Cl 2 /MeOH 100:0 ⁇ 80:20) leading to the expected product as a yellow solid (1.44 g, 38%) and to unreacted starting material (960 mg, 32%).
  • Acetophenone (1.20 g, 10.0 mmol) in dry THF (10 ml) was added dropwise to a suspension of methyl 5-bromo-2-chloropyridine-3-carboxylate (2.50 g, 10.0 mmol) and sodium hydride (800 mg, 20.0 mmol) in dry THF (20 ml).
  • the mixture was allowed to stir at RT for 2h and heated under reflux for 16h. After cooling to RT, the solution was put into water (40 ml) and extracted with AcOEt (40 ml). The combined organic layers were washed with a saturated solution of NH 4 C1 (15 ml), brine (40 ml), and dried over Na 2 S0 4 .
  • This compound was solubilized in DMF (100 ml) in presence of diisopropylethylamine (5.20 ml, 30.0 mmol) before addition of tert-butyldimethylsilyl chloride (3.9 g, 25.7 mmol).
  • the mixture was heated at 60°C for 7 days. After cooling, water (400 ml) and IN HC1 (50 ml) were added. The suspension was filtered off. The grey solid recovered was dried leading to the title compound (7.8 g, 94%).
  • the crude was purified by flash chromatography (cyclohexane/AcOEt 100:0 ⁇ 0: 100 then AcOEt/CH 3 OH 100:0 ⁇ 80:20) to furnish the expected compound as a yellow solid (700 mg, 41%).
  • Example 1 l-Ethyl-6-(indan-2-ylamino)-3-trimethylsilanylethynyl-lH-[l,8] naphthyridin-4-one
  • Example 7 l-Ethyl-6-(indan-2-ylamino)-3-(3-methyl-3H-imidazol-4-ylethynyl)-lH- [l,8]naphthyridin-4-one
  • Example 8 l-Ethyl-3-ethynyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
  • Example 16 l-Ethyl-6-(indan-2-ylamino)-3-(2-methyl-2H-pyrazol-3-yl)-lH-[l,8] naphthyridin-4-one
  • Example 17 l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-pyrazol-4-yl)-lH-[l,8] naphthyridin-4-one
  • Example 22 l-Ethyl-6-(indan-2-ylamino)-3-pyrimidin-5-yl-lH-[l,8]naphthyri-din-4- one
  • Example 24 l-Ethyl-6-(indan-2-ylamino)-3-thiophen-2-yl-lH-[l,8]naphthyri-din-4- one
  • Example 25 l-Ethyl-6-(indan-2-ylamino)-3-(2-methyl-pyrrol-l-yl)-lH-[l,8] na hthyridin-4-one
  • Example 31 l-Ethyl-3-[l-(3-hydroxy-propyl)-lH-[l,2,3]triazol-4-yl]-6-(indan-2- ylamino)- 1H- [l,8]naphthyridin-4-one
  • Example 37 l-Ethyl-6-(indan-2-ylamino)-3-(3-methoxy-phenyl)-lH-[l,8]naph- th ridin-4-one
  • the filtrate was decanted.
  • the aqueous layer was extracted with AcOEt (3 x 30 ml).
  • the combined organic fractions were dried over MgS0 4 , filtered and concentrated under reduced pressure.
  • the crude obtained was purified by flash chromatography (Si0 2 , CH 2 Cl 2 /acetone 100:0 ⁇ 30:70) leading to a yellow solid which was triturated in DMSO to furnish after filtration and drying the pure expected product as a yellow powder (50 mg, 6%).
  • Example 46 l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-2-yl)-lH-[l,8] naphthyridin-4-one
  • Example 50 l-Ethyl-6-(indan-2-ylamino)-3-thiazol-2-yl-lH-[l,7]naphthyridin-4-one l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,7]naphthyridin-4-one (300 mg, 0.78 mmol) and 2-(tributylstannyl)thiazole (350 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (150 mg, 49%) as an orange solid.
  • Example 51 l-Ethyl-6-(indan-2-ylamino)-3-(3-methoxy-phenyl)-lH-[l,7]naph- thyridin-4-one
  • the reaction mixture was heated under microwaves for 2h at 180°C.
  • the resulting suspension was cooled to RT and filtered through a pad of Celite eluting with AcOEt.
  • the filtrate was concentrated and purified by flash chromatography (Si0 2 , cyclohexane/AcOEt 100:0 ⁇ 30:70) leading to the expected product as a yellow oil (32 mg, 14%).
  • Example 60 l-Ethyl-3-hydroxymethyl-6-(indan-2-yl-methyl-amino)-lH-[l,8] naphthyridin-4-one
  • Example 63 4-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- ylmethyl]-piperazine-l-carboxylic acid tert-butyl ester
  • Example 64 l-Ethyl-6-(indan-2-ylamino)-3-piperazin-l-ylmethyl-lH-[l,8] naphthyridin-4-one
  • Example 66 l-Ethyl-6-(indan-2-ylamino)-3-methoxymethyl-lH-[l,8]naphthyri-din-4- one
  • triethylsilane (68 mg, 0.58 mmol) was slowly added to a solution of l-ethyl-6- (indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one (40 mg, 0.11 mmol) in trifluoroacetic acid (5 ml). After 2h stirring at 0°C, the solvent was removed under vacuum and the crude was purified by semi-preparative HPLC leading to the pure expected product as a yellow foam (21 mg, 54%).
  • Example 72 l-Ethyl-6-(indan-2-ylamino)-3-[l,2,3]triazol-l-ylmethyl-lH-[l,8] na hthyridin-4-one
  • Example 74 l-Ethyl-3-(3-hydroxy-propyl)-6-(indan-2-ylamino)-lH-[l,8]naph- thyridin-4-one
  • Example 75 l-Ethyl-6-(indan-2-ylamino)-3-(2-oxo-pyrrolidin-l-yl)-lH-[l,8] na hthyridin-4-one
  • Example 76 l-Ethyl-6-(indan-2-ylamino)-3-(3-oxo-morpholin-4-yl)-lH-[l,8] naphthyridin-4-one
  • Example 77 N-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- yl]-4-meth l-benzamide
  • Example 78 Pyridine-2-carboxylic acid [l-ethyl-6-(indan-2-ylamino) dihydro-[l,8]naphthyridin-3-yl]-amide
  • Example 83 l-Ethyl-6-(indan-2-ylamino)-3-(thiazol-2-ylamino)-lH-[l,8]naph- thyridin-4-one
  • Example 84 l-Ethyl-3-(4-hydroxy-piperidin-l-yl)-6-(indan-2-ylamino)-lH-[l,8] naphthyridin-4-one
  • Example 85 l-Ethyl-6-(indan-2-ylamino)-3-morpholin-4-yl-lH-[l,8]naphthyri-din-4- one
  • Example 88 l-Ethyl-6-(indan-2-ylamino)-3-(4-methoxy-phenoxy)-lH-[l,8] naphthyridin-4-one
  • the filtrate was concentrated and purified by flash chromatography (Si0 2 , cyclohexane/AcOEt 100:0 ⁇ 0: 100) to furnish after a semi -preparative HPLC the pure coupling product (27 mg, 10%) as yellow foam.
  • Example 91 l-Ethyl-3-furan-2-yl-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8] naphthyridin-4-one l-Ethyl-3-iodo-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8]naphthyridin-4-one (200 mg, 0.50 mmol) and 2-(tributylstannyl)furan (215 mg, 0.60 mmol) were reacted as described under General Procedure B (24h at 90°C) to furnish the title compound (57 mg, 34%) as a yellow foam.

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Abstract

The present invention relates generally to chemical compounds and methods for their use and preparation in relation to the treatment of diseases, disorders or conditions which would benefit from the modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR). The invention thus also relates to the use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.

Description

MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS AND USES
THEREOF
Field of the Invention
The present invention relates generally to chemical compounds and methods for their use and preparation in relation to the treatment of diseases, disorders or conditions which would benefit from the modulation of the alpha 7 nicotinic acetylcholine receptor (a.7 nAChR). The invention thus also relates to the use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds.
Background of the Invention The a.7 nAChRs are rapidly desensitizing cation channels belonging to the cis-loop ligand- gated family. a7 nAChRs play an important role in the regulation of neuronal excitability in different brain regions either by presynaptically modulating neurotransmitter release or by their position on somato-dendritic sites of intemeurons and pyramidal cells, where they directly regulate neuronal activity. They are abundantly expressed in the brain, modulate neurotransmitter release and are responsible for direct fast excitatory neurotransmission. At the cellular level, activation of o7 nAChRs can regulate interneuron excitability, modulate the release of excitatory and inhibitory neurotransmitters, and contribute to neuroprotective effects. Positive modulation of a7 nAChRs can enhance hippocampal long term potentiation (LTP), and a7 nAChRs are associated with attentional processes and working memory. As a consequence, a7 nAChRs are a therapeutic target for treating cognitive impairment, notably in Alzheimer's disease and schizophrenia (1-4).
However, there are several lines of evidence to suggest that excessive amounts of acetylcholine (ACh) in the brain contribute to anxious and depressed mood states (5). One of the most consistent findings in neuropsychiatry is that patients with depression have dysfunctional neuroendocrine systems possibly resulting from prolonged responses to stress (6,7), and that ACh plays a significant role in mediating neuroendocrine, emotional, and physiological responses to stress. For example, central ACh turnover is increased following stress and ACh facilitates the release of several stress-sensitive neuro-hormones and peptides including corticosterone, adrenocorticotropic hormone (ACTH), and corticotropin releasing factor (CRF). A human imaging study has shown that ACh levels are elevated in patients who are depressed, and remain high in patients who have a history of depression (8). In addition, other clinical and preclinical studies have shown that blockers of cholinergic receptors can induce antidepressant-like responses (9). In these human studies, physostigmine, an inhibitor of acetylcholinesterase, increased depressive symptoms in individuals with or without a history of depression. These observations suggest that hyperactivity of brain cholinergic systems can contribute to the pathophysiology of depression (10). Other studies have shown that a7 nAChRs in both the hippocampus and the amygdala are implicated in the regulation of depression and anxiety. The role of cholinergic signaling in the hippocampus in anxiety- and mood-related behaviours has been investigated in rodents using pharmacological (physostigmine) and molecular genetic techniques (shRNAs targeting acetylcholinesterase (AChE)) to alter AChE levels or activity in adulthood (11). In addition, direct infusion of physostigmine or shRNAs into the hippocampus decreased hippocampal AChE which correlated with increased anxiety and depression-like behaviours and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by co- infusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviours related to anxiety and depression and suggest that abnormalities in the cholinergic system may be critical for the etiology of mood disorders.
Similarly, cholinergic signaling in the basolateral amygdala has also been implicated in behaviours related to stress. The basolateral amygdala (BLA) receives dense cholinergic input from the basal forebrain, affecting both normal functions and dysfunctions of the amygdala. Neuronal excitability in the BLA is particularly relevant to anxiety. In the BLA, a7 nAChRs are present on somatodendritic regions of glutamatergic neurons (12), and on somatic and/or dendritic regions of GABAergic interneurons (13). Pre-clinical studies have implicated both β2 subunit-containing (β2*) and a7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviours. Viral-mediated down-regulation of the β2 or a7 nAChR subunit in the amygdala induced robust anxiolytic- and antidepressant- like effects in several mouse behavioral models (14). a7 nAChR subunit knockdown was effective at decreasing anxiety-like behaviour, and reversed the effect of increased ACh signaling in a mouse model of depression. These results suggested that stimulation of a7 nAChRs by acetylcholine may mediate the increased depression-like behaviours during the hyper-cholinergic state observed in depressed individuals and in those with anxiety.
In summary, there is considerable evidence in the literature to suggest that selective inhibition of a7 nAChRs has therapeutic potential for the treatment of anxiety, depression and stress-related disorders. The present invention seeks to provide such compounds.
Summary of the Invention
According to one aspect, the present invention provides compounds of formula (A), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000004_0001
where Z, Y, G and D are independently CR' (where R' is selected from H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino) or N; J represents C or N;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxy sulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
L represents halogen, heteroaromatic, OR7, or NR7R" (where R" is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, and optionally substituted sulfonyl);
R7 represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl, or R7 and R" together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl; and
X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino);
According to another aspect, the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
(I)
Figure imgf000006_0001
wherein X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino);
Y, and Z are independently selected from C, or N, and wherein at least one of Y and Z is N; Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl; wherein both Ri and R2 are not H; and
R3 and R4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, and optionally substituted thioacyl; or R3 and R4 together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl.
The present invention provides compounds of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof for use in treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR, including the step of administering to a patient in need of an effective amount of said compound or salt.
The invention also provides for the use of compounds of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of a medicament for treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR.
The present invention also provides methods of treatment for diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR comprising the administration of an effective amount of at least one compound of formula (A) or (I) or subformulae or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof to a subject in need thereof.
In certain embodiments, the modulation of a7 nAChR involves negative allosteric modulation of a7 nAChR.
In certain embodiments, the compounds are useful in the treatment of anxiety, depression, or stress-related disorders. Detailed Description of the Invention
The present invention is primarily based on the discovery that the compounds of the general formula (A) or (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof have useful properties as selective negative allosteric modulators of alpha 7 nicotinic acetylcholine receptors. Such compounds have significant potential for the treatment of mood disorders such as anxiety, depression and stress related disorders whether they occur alone or as comorbidities with other conditions. "Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, z'so-propyl, n-butyl, iso- butyl, ft-hexyl, and the like. "Alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like. "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g. phenyl) or multiple condensed rings (e.g. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.
"Arylene" refers to a divalent aryl group wherein the aryl group is as described above.
"Aryloxy" refers to the group aryl-O- wherein the aryl group is as described above.
"Arylalkyl" refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like.
"Arylalkoxy" refers to the group arylalkyl-O- wherein the arylalkyl group are as described above. Such arylalkoxy groups are exemplified by benzyloxy and the like. "Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, z'so-propoxy, n-butoxy, ieri-butoxy, sec- butoxy, ft-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
"Alkoxyalkyl" refers to alkoxy-alkyl- group wherein the alkoxy group and alkyl group are as described above.
"(Alkoxy)2alkyl" refers to alkoxy-alkoxy-alkyl- group wherein the alkoxy group and alkyl group are as described above. The alkoxy groups may be the same alkoxy group, or may be different alkoxy groups.
"Oxy alkoxy alkyl" refers to oxy- alkoxy- alkyl- group wherein the oxy group is -OH, and the alkoxy group and alkyl group are as described above. "Alkenyl" refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds. Examples include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), wo-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like.
"Alkenyloxy" refers to the group alkenyl-O- wherein the alkenyl group is as described above.
"Alkenylene" refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethenylene
(-CH=CH-), and the propenylene isomers (e.g., -CH2CH=CH- and -C(CH3)=CH-), and the like.
"Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds. Examples of alkynyl groups include ethynyl (-C≡ CH), propargyl (-CH2C≡ CH), pent-2-ynyl (-CH2C≡CCH2-CH3), and the like.
"Alkynyloxy" refers to the group alkynyl-O- wherein the alkynyl groups is as described above.
"Alkynylene" refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-C≡ C-), propynylene (-CH2-C≡ C-), and the like. "Acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxo/hydroxy" refers to groups =0/HO-.
"Oxyalkyl" refers to the group alkyl-OH wherein the alkyl group is as described above. Examples include hydroxymethyl, hydroxyethyl, hydroxypropyl and the likes.
"Oxyacyl" refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Amino" refers to the group -NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminoalkyl" refers to the amino-alkyl- group wherein the amino group and alkyl group are as described above.
"Aminoacyl" refers to the group -C(0)NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Acylamino" refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Acyloxy" refers to the groups -OC(0)-alkyl, -OC(0)-aryl, -C(0)0-heteroaryl, and
-C(0)0-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Aminoacyloxy" refers to the groups -OC(0)NR"-alkyl, -OC(0)NR"-aryl,
-OC(0)NR"-heteroaryl, and -OC(0)NR"-heterocyclyl where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Oxyacylamino" refers to the groups -NR"C(0)0-alkyl, -NR"C(0)0-aryl,
-NR"C(0)0-heteroaryl, and NR"C(0)0-heterocyclyl where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Oxyacyloxy" refers to the groups -OC(0)0-alkyl, -0-C(0)0-aryl, -OC(0)0- heteroaryl, and -OC(0)0-heterocyclyl where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Acylimino" refers to the groups -C(NR")-R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Acyliminoxy" refers to the groups -0-C(NR")-R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Oxyacylimino" refers to the groups -C(NR")-OR" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein.
"Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.
"Cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 11 carbon atoms. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"Heteroaryl" refers to a monovalent aromatic heterocyclic group which fulfils the Hiickel criteria for aromaticity (i.e. contains 4n + 2 π electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen). Such heteroaryl groups can have a single ring (e.g. pyridyl, pyrrolyl or N- oxides thereof or furyl) or multiple condensed rings (e.g. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl). It will be understood that where, for instance, R2 or R' is an optionally substituted heteroaryl which has one or more ring heteroatoms, the heteroaryl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
"Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.
Examples of heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, pyrrolidone, tetrahydrofuranyl, triazole, and the like.
"Heteroaryloxy" refers to the group heteroaryl-O- wherein heteroaryl is described as above.
"Heteroarylalkyl" refers to the group heteroaryl-alkyl- wherein heteroaryl and alkyl are described as above. "Heteroarylene" refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.
"Heterocyclylalkyl" refers to the heterocyclyl-alkyl- group wherein the heterocyclyl group and alkyl group are as described above.
"Heterocyclylene" refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above.
"Thio" refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Thioacyl" refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxythioacyl" refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO- C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Oxythioacyloxy" refers to groups HO-C(S)-0-, alkylO-C(S)-0-, cycloalkylO-C(S)-0-, arylO-C(S)-0-, heteroarylO-C(S)-0-, and heterocyclylO-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Phosphorylamino" refers to the groups -NR"-P(0)(R"')(OR"") where R" represents H, alkyl, cycloalkyl, alkenyl, or aryl, R'" represents OR"" or is hydroxy or amino and R"" is alkyl, cycloalkyl, aryl or arylalkyl, where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are as described herein.
"Thioacyloxy" refers to groups H-C(S)-0-, alkyl-C(S)-0-, cycloalkyl-C(S)-0-, aryl- C(S)-0-, heteroaryl-C(S)-0-, and heterocyclyl-C(S)-0-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Sulfinyl" refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S(O)-, aryl-S(O)-, heteroaryl-S(O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Sulfonyl" refers to groups H-S(0)2-, alkyl-S(0)2-, cycloalkyl-S(0)2-, aryl-S(0)2-, heteroaryl-S(0)2-, and heterocyclyl-S(0)2-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
"Sulfinylamino" refers to groups H-S(0)-NR"-, alkyl-S(0)-NR"-, cycloalkyl-S(O)- NR"-, aryl-S(0)-NR"-, heteroaryl-S(0)-NR"-, and heterocyclyl-S(0)-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Sulfonylamino" refers to groups H-S(0)2-NR"-, alkyl-S(0)2-NR"-, cycloalkyl-S(0)2- NR"-, aryl-S(0)2-NR"-, heteroaryl-S(0)2-NR"-, and heterocyclyl-S(0)2-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Oxysulfinylamino" refers to groups HO-S(0)-NR"-, alkylO-S(0)-NR"-, cycloalkylO- S(0)-NR"-, arylO-S(0)-NR"-, heteroarylO-S(0)-NR"-, and heterocyclylO-S(0)-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Oxysulfonylamino" refers to groups HO-S(0)2-NR"-, alkylO-S(0)2-NR"-, cycloalkylO-S(0)2-NR"-, arylO-S(0)2-NR"-, heteroarylO-S(0)2-NR"-, and heterocyclylO-S(0)2-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminothioacyl" refers to groups R"R"N-C(S)-, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Thioacylamino" refers to groups H-C(S)-NR"-, alkyl-C(S)-NR"-, cycloalkyl-C(S)- NR"-, aryl-C(S)-NR"-, heteroaryl-C(S)-NR"-, and heterocyclyl-C(S)-NR"-, where R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminosulfinyl" refers to groups R"R"N-S(0)-, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.
"Aminosulfonyl" refers to groups R"R"N-S(0)2-, where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. In this specification the term "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from oxo/hydroxy, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di- substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like. For instance, an "optionally substituted amino" group may include amino acid and peptide residues.
In an embodiment, the term "optionally substituted" is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of oxo/hydroxy, halogen (in particular CI, Br, F), C1-6 alkyl, C1-6 alkoxy, C1-6 oxyalkyl, C1-6 alkoxyalkyl, C1-6 oxyalkoxyalkyl, C1-6 (alkoxy)2-alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl (in particular -CF3), Ci_6 haloalkoxy (such as -OCF3), C2-6 alkenyloxy, C2-6 alkynyloxy, arylalkyl (wherein alkyl is C1-6), arylalkoxy (wherein alkyl is C1-6), aryl, cyano, nitro, heteroaryl, Ci_6 heteroarylalkyl (wherein alkyl is C1-6), heteroaryloxy, heterocyclyl, heterocyclylalkyl (wherein alkyl is C1-6), heterocyclyloxy, oxyacyl, trialkylsilyl, trifluoromethanethio, trifluoroethenyl, amino, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-alkylaminoalkyl (wherein alkyl is Ci-C6), mono- and di-(substituted alkyl)aminoalkyl (wherein alkyl is Ci-C6), mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl.
In an embodiment, the term "optionally substituted" is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of hydroxy, halogen (in particular CI, Br, F), C1-6 alkyl, C1-6 alkoxy, C1-6 oxyalkyl, C1-6 alkoxyalkyl, C1-6 oxyalkoxyalkyl, C1-6 (alkoxy)2-alkyl, C2-6 alkenyl, C1-6 haloalkyl (in particular -CF3), Ci_6 haloalkoxy (such as -OCF3), arylalkyl (wherein alkyl is C1-6), arylalkoxy (wherein alkyl is C1-6), aryl, cyano, nitro, heteroaryl, heterocyclyl, heterocyclylalkyl, trialkylsilyl, amino, mono- and di-alkylamino, mono-and di- substituted alkyl)amino, mono- and di-alkylaminoalkyl (wherein alkyl is Ci-C6), and mono- and di-arylamino.
In a further embodiment, the term "optionally substituted" is taken to mean that the groups may be substituted from 1 to 3 times independently selected from the groups consisting of hydroxy, hydroxymethyl, hydroxethyl, hydroxpropyl, methyl, methoxy, methoxymethyl, hydroxyethoxymethyl, methoxyethoxymethyl, cyano, pyridinyl, pyridinylmethyl, pyrazinyl, methylphenyl, benzyl, trimethylsilyl, phenyl, methylpyrazoyl, dimethylamino, fluorophenyl, morpholinyl, morpholinylmethyl, morpholinylethyl, ie/t-butyloxycarbonyl, amino, dimethylaminomethyl, dimethylaminoethyl, methyldifluoroethylamino, methyltrifluoroethylamino, methylmethoxyethylamino, di(methoxyethyl)amino, or morpholinyl.
The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000019_0001
wherein X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino);
Y and Z are independently selected from C, or N, and wherein at least one of Y and Z is N; Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxy sulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted amino sulfonyl; wherein both Ri and R2 are not H; and
R3 and R4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, and optionally substituted thioacyl; or R3 and R4 together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl.
In the above embodiment, and with reference to formula (A) and (I), R when present is selected from H, dihalomethoxy, halogen, hydroxy, pentahaloethyl, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted arylalkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkenyloxy, optionally substituted Ci-C6 alkoxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.
In a further embodiment, and with reference to formula (A) and (I), R when present is selected from the following groups:
hydrogen;
optionally substituted Ci-C6 alkyl group, for instance methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl, methoxymethyl or methoxyethyl; optionally substituted aminoalkyl, for instance dimethylaminoethyl, methyldifluoroethylaminoethyl, methyltrifluoroethylaminoethyl, methylmethoxyethylaminoethyl, di(methoxyethyl)aminoethyl;
optionally substituted heterocyclylalkyl, for instance morpholinylethyl.
In a further embodiment, and with reference to formula (A) and (I), R when present is optionally substituted Ci-C6 alkyl, optionally substituted aminoalkyl, or optionally substituted heterocyclylalkyl. In a further embodiment, and with reference to formula (A) and (I), R when present is ethyl.
In a further embodiment, and with reference to formula (A) and (I), R when present is morpholinylethyl .
In a further embodiment, and with reference to formula (A) and (I), R when present is dimethylaminoethyl .
In certain embodiments, and with reference to formula (A) and (I), Ri is selected from H, cyano, optionally substituted oxo/hydroxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Q- C6 alkoxy, optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6), optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy (wherein alkyl is Ci-C6), optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, or -C(0)R' (where R' is optionally substituted Ci-C6 alkyl, optionally substituted phenyl).
In a further embodiment, and with reference to formula (A) and (I), Ri is selected from the following groups: hydrogen;
optionally substituted Ci-C6 alkyl group, for instance N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl;
optionally substituted C2-C6 alkenyl group, for instance \-{2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl;
optionally substituted C2-C6 alkynyl group, for instance ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy )butynyl ;
optionally substituted amino, for instance 2-pyrazinyl amino, N,N-(2- pyridinyl)methylamino ;
optionally substituted acylamino, for instance (2-pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2-benzyl)acylamino, 4-(methylphenyl)acylamino;
optionally substituted cycloalkenyl, for instance 3-cyclopentenyl;
optionally substituted heterocyclyl, for instance N-(4-hydroxy)piperidinyl, N-morpholinyl,
2- benzofuanyl, N-morpholinonyl;
optionally substituted aryl, for instance phenyl, 2-(methylphenyl), 4-(methylphenyl), 2- (methoxyphenyl), 3-(methoxyphenyl), 4-(methoxyphenyl), 3-(cyanophenyl), 4- (cyanophenyl);
optionally substituted heteroaryl, preferably 2-furanyl, 3-furanyl, 3-(2-methylfuranyl), 5- (2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N- methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N- morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-triazolyl), N-methyl-2-pyrrolyl, 2-methyl- N-pyrrolyl, N-pyrazolyl, l-methyl-2-pyrazolyl, N-methyl-4-pyrazolyl, 4-(N- dimethylaminoethyl)pyrazolyl, 4-(N-morpholinylethyl)pyrazolyl, 5-(N-methylpyrazolyl), 5-(2-amino-l,3,4-oxadiazolyl), 4-(l-benzyl-l,2,3-triazolyl), 5-(l-benzyl-l,2,3-triazolyl), 4- ( 1 -hydroxypropyl- 1,2,3 -triazolyl) , 5 -( 1 -hydroxypropyl- 1 ,2,3 -triazolyl) , 5 -(4-flurophenyl)-
3- isoxazolyl, N-pyrrolidonyl;
optionally substituted heteroarylalkyl, for instance 1,2,3-triazolylmethyl, 4- (hydroxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5 -hydroxy ethoxymethyl( 1 ,2,3- triazolyl)methyl, 4-(hydroxyethyl- 1 ,2,3-triazolyl)methyl, 5-hydroxyethyl( 1 ,2,3- triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5-
(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 4-(methoxymethyl- 1 ,2,3-triazolyl)methyl, 5-morpholinylethyl( 1 ,2,3 -triazolyl)methyl, 5-methoxymethyl( 1 ,2,3-triazolyl)methyl, 4- dimethylaminoethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5- dimethylaminoethyl( 1 ,2,3-triazolyl)methyl, 5-hydroxymethyl( 1 ,2,3 -triazolyl)methyl, 5- morpholinylmethyl( 1 ,2,3 -triazolyl)methyl, 4-morpholinylmethyl( 1 ,2,3 -triazolyl)methyl, 5- dimethylaminomethyl( l,2,3-triazolyl)methyl, 4-dimethylaminomethyl( 1 ,2,3- triazolyl)methyl;
optionally substituted heterocyclylalkyl, for instance N,N'-(2-pyridinyl)piperazinylmethyl, (N-morpholinyl)methyl;
optionally substituted arylalkyl, for instance phenylethyl;
optionally substituted aryloxy, for instance phenoxy, (4-methoxyphenyl)oxy;
optionally substituted heteroaryloxy, for instance (3-pyridinyl)oxy;
optionally substituted arylalkyloxy, for instance (4-methoxybenzyl)oxy; or
-C(0)R' where R' is optionally substituted Ci-C6 alkyl or optionally substituted phenyl, for instance phenylacyl, methylacyl, ethylacyl.
In another embodiment, and with reference to formula (A) and (I), Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4- pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-( 1 -benzyl- 1,2,3 - triazolyl), phenoxy, phenylacyl, 5-thiazolyl, (N-morpholinyl)methyl, 4- hydroxymethyl(l,2,3-triazolyl)methyl, 5-methoxymethyl(l,2,3-triazolyl)methyl, 4-(N- dimethylaminoethyl)pyrazolyl, or 1,2,3-triazolylmethyl.
In certain embodiments, and with reference to formula (A) and (I), R' when present and R2 are independently selected from H, cyano, hydroxyl, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 alkoxy, optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy (wherein alkyl is Ci-C6), or optionally substituted cycloalkenyl. In a further embodiment, and with reference to formula (A) and (I), R' when present and R2 are independently selected from the following groups:
hydroxy;
hydrogen;
optionally substituted Ci-C6 alkyl, for instance ie/t-butyl;
optionally substituted aryl, for instance phenyl;
optionally substituted cycloalkyl, for instance cyclohexanyl; or
optionally substituted heterocyclyl, for instance piperidinyl, N-(ie/t-butyloxycarbonyl- piperidinyl).
In another embodiment, and with reference to formula (A) and (I), R' when present and R2 are independently selected from H or tert-butyl. In certain embodiments, and with reference to formula (A) and (I), R7 when present and R3 are independently selected from H, optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6).
In a further embodiment, and with reference to formula (A) and (I), R7 when present and
R3 are independently selected from the following groups:
hydrogen;
optionally substituted cycloalkyl, for instance indanyl;
optionally substituted arylalkyl (wherein alkyl is Ci-C6), for instance phenylmethyl;
optionally substituted heterocyclyl, for instance tetrahydropyranyl;
optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6), for instance tetrahydropyran methyl.
In a further embodiment, and with reference to formula (A) and (I), R7 when present and R3 are independently indanyl. In certain embodiment, R4 is selected from Q-C6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is CrC6).
In a further embodiment, and with reference to formula (A) and (I), R" when present and
R4 are independently selected from the following groups:
hydrogen;
optionally substituted Ci-C6 alkyl, for instance methyl.
In a further embodiment, and with reference to formula (A) and (I), R" when present and R4 are independently H. In another embodiment, and with reference to formula (A) and (I), when Ri is H, R' (when present) and R2 are independently selected from ie/t-butyl, phenyl, cyclohexanyl, piperidinyl, N-(ieri-butyloxycarbonyl-piperidinyl) .
In another embodiment, and with reference to formula (A) and (I), when R' (when present) and R2 are independently H, Ri is selected from N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl, \-{2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl, ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy)butynyl, 2-pyrazinyl amino, N,N-(2-pyridinyl)methylamino, (2- pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2-benzyl)acylamino, 4- (methylphenyl)acylamino, 3-cyclopentenyl, N-(4-hydroxy)piperidinyl, N-morpholinyl, 2- benzofuanyl, N-morpholinonyl, phenyl, 2-(methylphenyl), 4-(methylphenyl), 2- (methoxyphenyl), 3-(methoxyphenyl), 4-(methoxyphenyl), 3-(cyanophenyl), 4- (cyanophenyl), 2-furanyl, 3-furanyl, 3-(2-methylfuranyl), 5-(2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N-methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N-morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-trizolyl), N-methyl-2-pyrrolyl, 2-methyl-N-pyrrolyl, N-pyrazolyl, l-methyl-2-pyrazolyl, N-methyl- 4- pyrazolyl, 4-(N-dimethylaminoethyl)pyrazolyl, 4-(N-morpholinylethyl)pyrazolyl, 5-(N- methylpyrazolyl), 5-(2-amino-l,3,4-oxadiazolyl), 4-(l-benzyl-l,2,3-triazolyl), 5-(l-benzyl- 1,2,3-triazolyl), 4-(l-propoxy-l,2,3-triazolyl), 5-(l-propoxy-l,2,3-triazolyl), 5-(4- flurophenyl)-3-isoxazolyl, N-pyrrolidonyl, N,N'-(2-pyridinyl)piperazinylmethyl, (N- morpholinyl)methyl, phenylethyl, phenoxy, (4-methoxyphenyl)oxy, (3-pyridinyl)oxy, (4- methoxybenzyl)oxy, phenylacyl, methylacyl, ethylacyl, 1,2,3-triazolylmethyl, 4- (hydroxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5 -hydroxy ethoxymethyl( 1 ,2,3 - triazolyl)methyl, 4-(hydroxyethyl-l,2,3-triazolyl)methyl, 5-hydroxyethyl( 1,2,3- triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5- (methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 4-(methoxymethyl- 1 ,2,3-triazolyl)methyl,
5- morpholinylethyl( 1 ,2,3 -triazolyl)methyl, 5-methoxymethyl( 1 ,2,3-triazolyl)methyl, 4- dimethylaminoethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5- dimethylaminoethyl(l,2,3-triazolyl)methyl, 5-hydroxymethyl(l,2,3-triazolyl)methyl, 5- morpholinylmethyl( 1 ,2,3 -triazolyl)methyl, 4-morpholinylmethyl( 1 ,2,3 -triazolyl)methyl, 5- dimethylaminomethyl(l,2,3-triazolyl)methyl, or 4-dimethylaminomethyl( 1,2,3- triazolyl)methyl.
In a further embodiment, and with reference to formula (A) and (I), when R' (when present) and R2 are independently H, Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N- methylimidazolyl), 2-oxazolyl, 4-(l-benzyl-l,2,3-triazolyl), phenoxy, phenylacyl, 5- thiazolyl, or (N-morpholinyl)methyl, 1,2,3-triazolylmethyl, 5-methoxymethyl( 1,2,3- triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl or 4-(N- dimethylaminoethyl)pyrazolyl.
In an embodiment, and with reference to formula (A) and (I), when X is NR and R is ethyl, Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl-l,2,3-triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 5- methoxymethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl or 4-(N- dimethylaminoethyl)pyrazolyl. In an embodiment, and with reference to formula (A) and (I), when X is NR and R is morpholinylethyl, Ri is 1,2,3-triazolylmethyl.
In an embodiment, and with reference to formula (A) and (I), when X is NR and R is dimethylaminoethyl, Ri is 1,2,3-triazolylmethyl.
In an embodiment, with reference to formula (I), R3 and R4 together with the N-atom form an optionally substituted heteroaryl or optionally substituted heterocyclyl. In an embodiment, with reference to formula (A), when L is NR7R", R7 and R" together with the N-atom form an optionally substituted heteroaryl or optionally substituted heterocyclyl.
In certain embodiments, the present invention relates to compounds of formula (I) which are represented by formulae (la), (lb), (Ic), (Id), (Ie) or (If):
Figure imgf000028_0001
wherein R, Ri, R2, R3 and R4 are as defined above for compounds of formula (I).
In certain embodiments, the compounds of formula (I) are represented by formula (la), or (lb), wherein R, Ri, R2, R3 and R4 are as defined above for compounds of formula (I).
In a further embodiment, the compounds of formula (I) are represented by formula (la), wherein R, Ri, R2, R3 and R4 are as defined above for compounds of formula (I).
In an another embodiment the compounds of the present invention are represented by the formula (Γ) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof
Figure imgf000029_0001
wherein X, Y, Z, R, Ri, R2 and R4 are as described above for the compounds of formula (I).
Accordingly, in other embodiments the invention provides compounds of formula (Γ) represented by formula (I'a), (I'b), (I'c), (I'd), (I'e) or (I'f):
Figure imgf000030_0001
wherein R, Ri, R2 and R4 are as described above for compounds of formula (I).
In certain embodiments, the compounds of formula (I) are represented by formula (I'a), (I'b), wherein R, Ri, R2 and R4 are as described above for compounds of formula (I).
In another embodiment, the compounds of formula (I) are represented by formula (I'a), wherein R, Ri, R2 and R4 are as described above for compounds of formula (I).
In an another embodiment, the compounds of the present invention are represented by the formula (I") or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof
Figure imgf000031_0001
wherein X, Y, Z, R, Ri and R2 are as described above for the compounds of formula (I). Accordingly, in other embodiments the invention provides compounds of formula (I") represented by formula (Fa), (I"b), (I"c) or (I"d):
Figure imgf000031_0002
wherein R, Ri and R2 are as described above for compounds of formula (I).
In certain embodiments, compounds of formula (I) are represented by formula (I"a), or (I"b), wherein R, Ri and R2 are as described above for compounds of formula (I). In a further embodiment, compounds of formula (I) are represented by formula (I" a), wherein R, Ri and R2 are as described above for compounds of formula (I).
Accordingly, the present invention also provides compound of formula (I"a) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000032_0001
wherein R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxy sulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl); R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxy sulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl; and
wherein both Ri and R2 are not H. In the above embodiment, and with reference to formula (I"a), R is selected from H, dihalomethoxy, halogen, hydroxy, pentahaloethyl, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted arylalkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkenyloxy, optionally substituted Ci-C6 alkoxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.
In a further embodiment, and with reference to formula (I" a), R is selected from the following groups:
hydrogen;
optionally substituted Ci-C6 alkyl group, for instance methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl, methoxymethyl or methoxyethyl;
optionally substituted aminoalkyl, for instance dimethylaminoethyl, methyldifluoroethylaminoethyl, methyltrifluoroethylaminoethyl, methylmethoxyethylaminoethyl, di(methoxyethyl)aminoethyl;
optionally substituted heterocyclylalkyl, for instance morpholinylethyl.
In a further embodiment, and with reference to formula (I" a), R is selected from optionally substituted Ci-C6 alkyl, optionally substituted aminoalkyl, or optionally substituted heterocyclylalkyl.
In a further embodiment, and with reference to formula (I"a), R is ethyl.
In a further embodiment, and with reference to formula (I"a), R is morpholinylethyl.
In a further embodiment, and with reference to formula (I"a), R is dimethylaminoethyl.
In certain embodiments, and with reference to formula (I"a), Ri is selected from H, cyano, optionally substituted oxo/hydroxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C\- C6 alkoxy, optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6), optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy (wherein alkyl is Ci-C6), optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, or -C(0)R' (where R' is optionally substituted Ci-C6 alkyl, optionally substituted phenyl).
In a further embodiment, and with reference to formula (I" a), Ri is selected from the following groups:
hydrogen;
optionally substituted Ci-C6 alkyl group, for instance N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (l,2,3-triazolyl)methyl;
optionally substituted C2-C6 alkenyl group, for instance \-{2-tert- butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl;
optionally substituted C2-C6 alkynyl group, for instance ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N- methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3-hydroxyl)propanyl, l-(4- hydroxy )butynyl ;
optionally substituted amino, for instance 2-pyrazinyl amino, N,N-(2- pyridinyl)methylamino;
optionally substituted acylamino, for instance (2-pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2-benzyl)acylamino, 4-(methylphenyl)acylamino;
optionally substituted cycloalkenyl, for instance 3-cyclopentenyl;
optionally substituted heterocyclyl, for instance N-(4-hydroxy)piperidinyl, N-morpholinyl, 2-benzofuanyl, N-morpholinonyl;
optionally substituted aryl, for instance phenyl, 2-(methylphenyl), 4-(methylphenyl), 2- (methoxyphenyl), 3-(methoxyphenyl), 4-(methoxyphenyl), 3-(cyanophenyl), 4- (cyanophenyl); optionally substituted heteroaryl, preferably 2-furanyl, 3-furanyl, 3-(2-methylfuranyl), 5- (2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N- methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N- morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-triazolyl), N-methyl-2-pyrrolyl, 2-methyl- N-pyrrolyl, N-pyrazolyl, l-methyl-2-pyrazolyl, N-methyl-4-pyrazolyl, 4-(N- dimethylaminoethyl)pyrazolyl, 4-(N-morpholinylethyl)pyrazolyl, 5-(N-methylpyrazolyl), 5-(2-amino-l,3,4-oxadiazolyl), 4-(l-benzyl-l,2,3-triazolyl), 5-(l-benzyl-l,2,3-triazolyl), 4- ( 1 -hydroxypropyl- 1,2,3 -triazolyl) , 5 -( 1 -hydroxypropyl- 1 ,2,3 -triazolyl) , 5 -(4-flurophenyl)- 3-isoxazolyl, N-pyrrolidonyl;
optionally substituted heteroarylalkyl, for instance 1,2,3-triazolylmethyl, 4- (hydroxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5 -hydroxy ethoxymethyl( 1 ,2,3- triazolyl)methyl, 4-(hydroxyethyl-l,2,3-triazolyl)methyl, 5-hydroxyethyl( 1,2,3 - triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 5- (methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 4-(methoxymethyl- 1 ,2,3-triazolyl)methyl, 5-morpholinylethyl( 1 ,2,3-triazolyl)methyl, 5-methoxymethyl( 1 ,2,3-triazolyl)methyl, 4- dimethylaminoethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5- dimethylaminoethyl(l,2,3-triazolyl)methyl, 5-hydroxymethyl(l,2,3-triazolyl)methyl, 5- morpholinylmethyl( 1,2,3 -triazolyl)methyl, 4-morpholinylmethyl( 1,2,3 -triazolyl)methyl, 5 - dimethylaminomethyl( l,2,3-triazolyl)methyl, 4-dimethylaminomethyl( 1 ,2,3- triazolyl)methyl;
optionally substituted heterocyclylalkyl, for instance N,N'-(2-pyridinyl)piperazinylmethyl, (N-morpholinyl)methyl;
optionally substituted arylalkyl, for instance phenylethyl;
optionally substituted aryloxy, for instance phenoxy, (4-methoxyphenyl)oxy;
optionally substituted heteroaryloxy, for instance (3-pyridinyl)oxy;
optionally substituted arylalkyloxy, for instance (4-methoxybenzyl)oxy; or
-C(0)R' where R' is optionally substituted Ci-C6 alkyl or optionally substituted phenyl, for instance phenylacyl, methylacyl, ethylacyl.
In another embodiment, and with reference to formula (I"a), Ri is selected from ethynyl, 1- (3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3-dimethylamino)propynyl, (N-methyl-2- imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2- furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l -benzyl- 1,2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, (N-morpholinyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl, 5-methoxymethyl(l,2,3-triazolyl)methyl, 4-(N-dimethylaminoethyl)pyrazolyl, or 1,2,3- triazolylmethyl. In certain embodiments, and with reference to formula (I"a), R2 is selected from H, cyano, hydroxyl, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 alkoxy, optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy (wherein alkyl is Ci-C6), or optionally substituted cycloalkenyl.
In a further embodiment, and with reference to formula (I" a), R2 is selected from the following groups:
hydroxy;
hydrogen;
optionally substituted Ci-C6 alkyl, for instance ie/t-butyl;
optionally substituted aryl, for instance phenyl;
optionally substituted cycloalkyl, for instance cyclohexanyl; or
optionally substituted heterocyclyl, for instance piperidinyl, N-(ie/t-butyloxycarbonyl- piperidinyl).
In another embodiment, and with reference to formula (I"a), R2 is selected from H or tert- butyl. In another embodiment, and with reference to formula (I"a), when Ri is H, R2 is selected from ie/ -butyl, phenyl, cyclohexanyl, piperidinyl, N-(ieri-butyloxycarbonyl-piperidinyl).
In another embodiment, and with reference to formula (I" a), when R2 is H, Ri is selected from N-ethyoxy-N-methylamino methyl, hydroxymethyl, propyl, benzyloxybutyl, (1,2,3- triazolyl)methyl, l-(2-ie/t-butyloxycarbonyl)ethenyl, l-(4-benzyloxy)butenyl, ethynyl, (trimethylsilyl)ethynyl, (ethoxy)ethynyl, l-(3-dimethylamino)propynyl, (N-methyl-2- imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, l-(3- hydroxyl)propanyl, l-(4-hydroxy)butynyl, 2-pyrazinyl amino, N,N-(2- pyridinyl)methylamino, (2-pyridinylmethyl)acylamino, 2-pyridinyl acylamino, (2- benzyl)acylamino, 4-(methylphenyl)acylamino, 3-cyclopentenyl, N-(4- hydroxy)piperidinyl, N-morpholinyl, 2-benzofuanyl, N-morpholinonyl, phenyl, 2- (methylphenyl), 4-(methylphenyl), 2-(methoxyphenyl), 3-(methoxyphenyl), 4- (methoxyphenyl), 3-(cyanophenyl), 4-(cyanophenyl), 2-furanyl, 3-furanyl, 3-(2- methylfuranyl), 5-(2-methylfuranyl), 2-pyridinyl, 3-pyridinyl, 2-pyrazinyl, 5-pyrimidinyl, 2-thiophenyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, N-imidazoyl, 4-imidazoyl, 2-(N-methylimidazolyl), 4-(N-methylimidazolyl), 5-(N-methylimidazolyl), 4-(N- morpholinylethylimidazolyl), 5-methyl-2-(l,3,4-trizolyl), N-methyl-2-pyrrolyl, 2-methyl- N-pyrrolyl, N-pyrazolyl, l-methyl-2-pyrazolyl, N-methyl-4-pyrazolyl, 4-(N- dimethylaminoethyl)pyrazolyl, 4-(N-morpholinylethyl)pyrazolyl, 5-(N-methylpyrazolyl), 5-(2-amino- l,3,4-oxadiazolyl), 4-(l-benzyl- l,2,3-triazolyl), 5-(l-benzyl-l,2,3-triazolyl), 4- (l-propoxy- l,2,3-triazolyl), 5-(l-propoxy-l,2,3-triazolyl), 5-(4-flurophenyl)-3-isoxazolyl, N-pyrrolidonyl, N,N'-(2-pyridinyl)piperazinylmethyl, (N-morpholinyl)methyl, phenylethyl, phenoxy, (4-methoxyphenyl)oxy, (3-pyridinyl)oxy, (4-methoxybenzyl)oxy, phenylacyl, methylacyl, ethylacyl, 1,2,3-triazolylmethyl, 4-(hydroxyethoxymethyl- 1,2,3- triazolyl)methyl, 5-hydroxyethoxymethyl( 1 ,2,3-triazolyl)methyl, 4-(hydroxyethyl- 1 ,2,3- triazolyl)methyl, 5-hydroxyethyl( 1 ,2,3-triazolyl)methyl, 4-(methoxyethoxymethyl- 1 ,2,3- triazolyl)methyl, 5-(methoxyethoxymethyl- 1 ,2,3-triazolyl)methyl, 4-(methoxymethyl- 1 ,2,3-triazolyl)methyl, 5-morpholinylethyl( 1 ,2,3-triazolyl)methyl, 5-methoxymethyl( 1 ,2,3- triazolyl)methyl, 4-dimethylaminoethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl( 1,2,3- triazolyl)methyl, 5-dimethylaminoethyl(l,2,3-triazolyl)methyl, 5-hydroxymethyl( 1,2,3- triazolyl)methyl, 5 -morpholinylmethyl( 1 ,2,3 -triazolyl)methyl, 4-morpholinylmethyl( 1,2,3- triazolyl)methyl, 5-dimethylaminomethyl(l,2,3-triazolyl)methyl, or 4- dimethylaminomethyl(l,2,3-triazolyl)methyl.
In a further embodiment, and with reference to formula (I"a), when R2 is H, Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl- 1, 2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 1,2,3- triazolylmethyl, 5-methoxymethyl( 1 ,2,3 -triazolyl)methyl, 4-hydroxymethyl( 1,2,3- triazolyl)methyl or 4-(N-dimethylaminoethyl)pyrazolyl. In an embodiment, and with reference to formula (I"a), when R is ethyl, Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl- 1,2,3 -triazolyl), phenoxy, phenylacyl, 5-thiazolyl, or (N-morpholinyl)methyl, 5- methoxymethyl(l,2,3-triazolyl)methyl, 4-hydroxymethyl(l,2,3-triazolyl)methyl or 4-(N- dimethylaminoethyl)pyrazolyl.
In an embodiment, and with reference to formula (I"a), when R is morpholinylethyl, Ri is 1 ,2,3-triazolylmethyl.
In an embodiment, and with reference to formula (I"a), when R is dimethylaminoethyl, Ri is 1,2,3-triazolylmethyl.
In the list below (which are representative examples of compounds of the present invention) the structures contain one or more stereogenic centers, the respective structures are depicted in an arbitrary absolute configuration. These structures also include the respective structure such as salts, tautomers, opposite stereoisomers as well as mixtures of isomers in all ratios including racemates:
-39-
Figure imgf000040_0001
-40-
Figure imgf000041_0001
-41 -
Figure imgf000042_0001
-42-
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
The compounds of the present invention can be prepared according to Scheme 1 below:
Scheme 1
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000048_0003
Figure imgf000048_0004
As shown in Scheme 1 an amino substituted N-containing heteroaryl (e.g. a 2-substituted- 5-amino-pyridine) may be heated in the presence of a diethyl ethoxymethylene malonate in a suitable solvent (e.g. diethyl ether) to afford the desired diethyl aminomethylene malonate.
This product may then be cyclised at temperatures above 200°C (for instance in diphenyl ether) to afford the corresponding ring closed product. Hydrolysis of the ethyl ester under standard conditions may afford the corresponding carboxylic acid. Alternatively where it is desired to make compounds where R is other than H, the ring closed product may be reacted with a suitable electrophilic group (e.g. alkylation with an alkylhalide) under standard conditions.
Coupling of the acid with HNR'R" may be achieved under typical peptide coupling conditions. For example, the carboxylic acid can be initially converted to an activated ester with ethyl chloroformate or HBTU in the presence of a suitable non-nucleophilic base (e.g. triethylamine, Hiinigs base, etc).
Another approach to the compounds of the present invention is depicted in Scheme 2: Scheme 2
Figure imgf000049_0001
Figure imgf000049_0002
As shown in Scheme 2 a carboxy-substituted N-containing heteroaryl (e.g. a 2,5- disubstituted nicotinic acid) may be converted to the malonate ester by reaction with thionyl chloride and potassium ethyl malonate under standard conditions. The L group depicted in Scheme 2 represents any suitable leaving group which may be halogen, methoxy, tosylate, mesylate, etc. The malonate ester may be reacted with triethylorthoformate in acetic acid followed by the addition of a nucleophilic amine (HNR2) to afford the ethylene amine which may be subsequently cyclised or be promoted to cyclise (e.g. in the presence of a mild base (e.g. K2C03)) to afford the ring closed product. Addition of the NR3R j group may be accomplished by nucleophilic substitution chemistry with an effective nucleophilie e.g. 9NHRi or 90Ri or may be introduced using palladium catalysed coupling chemistry. Accordingly, X may be an oxygen based leaving group (or precursor thereof) such as a tosylate or mesylate, or a halogen for instance, CI, Br, or I.
In Scheme 2 X may alternatively be N02. In the final stages of the synthesis (and preferably after the ring closure step) the N02 group may be reduced to NH2 with the use of, for instance, Raney nickel/H2. The corresponding NH2 group may be reacted with RL' (L' is a leaving group) to produce compounds where -XRi is -NHRi.
It would be appreciated then that the introduction of the N-R3R4 group may take place at any convenient stage during the synthetic process and that this applies to both the strategies depicted in Schemes 1 and 2.
It would be appreciated that any of the compounds depicted in Scheme 1 and 2 may be used as starting materials to synthesize the intermediates of compounds as represented in this present invention. This is depicted in Scheme 3 to 7.
Scheme 3
Figure imgf000050_0001
Scheme 4 -50-
Figure imgf000051_0001
cheme 8
Figure imgf000052_0001
106-122, 130-135
Further modifications at the 2 and 3 positions of the naphthyridone (for Ri and R2 substitution) can be performed as exemplified in General Procedure A to N; i.e. by Sonogashira coupling, Stille coupling, Ullmann coupling (amine), copper catalyzed azide- alkyne cycloaddition, ruthenium catalyzed azide-alkyne cycloaddition, Suzuki coupling, Grignard coupling, reductive amination, nucleophilic substitution, Ullmann coupling (ether), nucleophilic addition, [l,8]naphthyridin-4-one ring closure, or Buchwald coupling.
The preparation of di- and tri- substituted N-containing heteroaryls as starting materials in the above synthetic procedures may be accomplished using conventional chemistry (see for instance, D. T. Davies, Aromatic Heterocyclic Chemistry, 1993, Oxford Press, New York). Many such starting compounds have also been reported in the literature.
Other compounds of formulae (I), (Γ) and (I") can be prepared by the addition, removal or modification of existing substituents. This could be achieved by using standard techniques for functional group inter-conversion that are well known in the industry, such as those described in "Comprehensive organic transformations: a guide to functional group preparations" by Larock R. C, New York, VCH Publishers, Inc. 1989.
Examples of functional group inter-conversions are: -C(0)NR*R** from -C02CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR*R** in CH3OH; - OC(0)R from -OH with e.g., C1C(0)R in pyridine; -NC(S)NR*R** from -NHR with an alkylisothiocyanate or thiocyanic acid; -NRC(0)OR* from -NHR with alkyl chloroformate; -NRC(0)NR*R** from -NHR by treatment with an isocyanate, e.g. HN=C=0 or RN=C=0; -NRC(0)R* from -NHR by treatment with C1C(0)R* in pyridine; -C(=NR)NR*R** from -C(NR*R**)SR with H3NR+OAc~ by heating in alcohol; - C(NR*R**)SR from -C(S)NR*R** with R-I in an inert solvent, e.g. acetone; - C(S)NR*R** (where R* or R** is not hydrogen) from -C(S)NH2 with HNR*R**; - C(=NCN)-NR*R** from -C(=NR*R**)-SR with NH2CN by heating in anhydrous alcohol, alternatively from -C(=NH)-NR*R** by treatment with BrCN and NaOEt in EtOH; -NR-C(=NCN)SR from -NHR* by treatment with (RS)2C=NCN; -NR**S02R from -NHR* by treatment with C1S02R by heating in pyridine; -NR*C(S)R from -NR*C(0)R by treatment with Lawesson's reagent [2,4-bis(4-methoxyphenyl)- 1,3,2,4- dithiadiphosphetane-2,4-disulfide]; -NRS02CF3 from -NHR with triflic anhydride and base, -CH(NH2)CHO from -CH(NH2)C(0)OR* with Na(Hg) and HCl/EtOH; - CH2C(0)OH from -C(0)OH by treatment with SOCl2 then CH2N2 then H20/Ag20; - C(0)OH from -CH2C(0)OCH3 by treatment with PhMgX/HX then acetic anhydride then Cr03; R-OC(0)R* from RC(0)R* by R**C03H; -CCH2OH from -C(0)OR* with Na / R*OH; -CHCH2 from -CH2CH2OH by the Chugaev reaction; -NH2 from -C(0)OH by the Curtius reaction; -NH2 from -C(0)NHOH with TsCl/base then H20; -CHC(0)CHR from - CHCHOHCHR by using the Dess-Martin Periodinane regent or Cr03 / aqH2S04 / acetone; -C6H5CHO from -C6H5CH3 with Cr02Cl2; -CHO from -CN with SnCl2 / HC1; -CN from - C(0)NHR with PC15; -CH2R from -C(0)R with N2¾ / KOH.
During the reactions described above a number of the moieties may need to be protected. Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T W, Wiley- Interscience, New York, 1981.
In certain embodiments, the present invention may be used in the treatment of a variety of diseases, disorders or conditions which would benefit from the negative modulation of a.7 nAChR, including the step of administering to a patient in need of an effective amount of said compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof. Such diseases, disorders or conditions include:
1) anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder;
2) depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder;
3) anxiety and/or depression associated with psychotic disorders including schizophrenia;
4) anxiety and/or depression associated with neuroses;
5) anxiety and/or depression associated with convulsions;
6) anxiety and/or depression associated with migraine;
7) anxiety and/or depression associated with neurodegeneration arising from cerebral ischemia;
8) anxiety and/or depression associated with attention deficit hyperactivity disorder;
9) anxiety and/or depression associated with Tourette's syndrome;
10) anxiety and/or depression associated with speech disorders, including stuttering;
11) anxiety and/or depression associated with disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work; and
12) stress related disorders.
Further diseases, disorders or conditions for which compounds of the invention may be of benefit include:
1) anxiety and/or depression associated with pain and nociception;
2) anxiety and/or depression associated with emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting;
3) anxiety and/or depression associated with eating disorders including anorexia nervosa and bulimia nervosa;
4) anxiety and/or depression associated with premenstrual syndrome;
5) anxiety and/or depression associated with muscle spasm or spasticity, e.g. in paraplegic patients;
6) anxiety and/or depression associated with hearing disorders, including tinnitus and age-related hearing impairment;
7) anxiety and/or depression associated with urinary incontinence; and
8) anxiety and/or depression associated with the effects of substance abuse dependency, including alcohol withdrawal.
Compounds of the invention may be beneficial as pre-medication prior to anaesthesia minor procedures such as endoscopy, including gastric endoscopy.
The invention also provides for the use of compounds of formula (I), (Γ) or (I") (and sub- formulae) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof in the manufacture of medicaments for treating diseases, disorders or conditions which would benefit from the modulation of al nAChR.
There is also provided methods of treatment of diseases, disorders or conditions which would benefit from the modulation of al nAChR comprising the administration of an effective amount of at least one compound of formula (I), (Γ) or (I") (and sub-formulae) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof to a subject in need thereof. The compounds of the invention may be particularly useful in combination therapy, e.g. combining the treatment with other chemotherapeutic treatments (e.g. muscle relaxants, anticonvulants, hypnotics, anaesthetics, analgesics, antidepressants, antipsychotics, or other anxiolytics, etc). It will be understood that the compounds of the invention can be used in the treatment of any disease state which may be ameliorated by negative modulation of the alpha 7 nicotinic receptor complex.
The compounds of the invention are administered to the subject in a treatment effective amount. As used herein, a treatment effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular disease of condition being treated. As used herein, the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage may be in the range of 1 μ to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another preferred embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject.
The active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.
The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface- active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches may also be used to administer the compounds of the invention.
Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage compositions are those containing a daily dose or unit, daily sub- dose, as herein above described, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
Preferably, the compounds of the present invention may be administered to a subject as a pharmaceutically acceptable salt. It will be appreciated however that non- pharmaceutically acceptable salts also fall within the scope of the present invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. In particular, the present invention includes within its scope cationic salts e.g. sodium or potassium salts, or alkyl esters (e.g. methyl, ethyl) of the phosphate group.
Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. It will be appreciated that any compound that is a prodrug of a compound of formula (I), (Γ) or (I") (and sub-formulae) is also within the scope and spirit of the invention. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group (for instance at the Ri or R2 position) is converted into an ester, such as an acetate or phosphate ester, or where a free amino group is (for instance at the Ri, R2 or R4 position) converted into an amide (e.g. a-aminoacid amide). Procedures for esterifying, e.g. acylating, the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.
The compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.
It will also be recognised that compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres e.g., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, e.g., chromatography, or use of a resolving agent.
Furthermore, depending on the substitution pattern the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.
Examples
A) Synthetic Procedure
All anhydrous solvents were commercially obtained and stored in Sure-Seal bottles under nitrogen. All other reagents and solvents were purchased as the highest grade available and used without further purification. Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using Merck silica gel 60 F254 TLC plates and visualized using ultraviolet light. Silica gel 60 (40-63 μιη, Merck) was used for flash chromatography. Melting points were measured using an Electrothermal 1002 apparatus and were uncorrected. 1H NMR (300MHz) and 13C NMR (75 MHz) spectra were obtained on a Bruker Advance 300 NMR spectrometer using residual signal of deuterated NMR solvent as internal reference. Mass spectral data and purity of all compounds were acquired on an Agilent LCMS-Ion Trap- 1200 Series. Mass spectra were obtained on an Agilent Ion Trap applying electrospray ionization (ESI). Purity of all compounds was obtained using a Nucleodur 3 μιη 4.6 x 150 mm reverse-phase column. The eluent was a linear gradient with a flow rate of 1.3 mL/min from 95% A and 5% B to 5% A and 95% B in 8.5 min (solvent A, H20 with 0.1% HC02H; solvent B, acetonitrile with 0.1% HC02H). The compounds were detected at their maximum of absorbance.
In the examples below, in case the structures contain one or more stereogenic centres, the respective structure is depicted in an arbitrary absolute configuration. These structures depict single enantiomers as well as mixtures of enantiomers in all ratios, and/or mixtures of diastereoisomers in all ratios.
General Procedures
General Procedure A: Sonogashira coupling reaction
Figure imgf000062_0001
1 -7 At RT, a suspension of aryl iodide (1.0 equiv.), PdCl2(PPh3)2 (0.1 equiv.), Cul (0.2 equiv.) in a THF/DIEA or DMF/DIEA mixture (0.1 M; 5: 1) was deoxygenated under Ar atmosphere. Terminal alkyne (1.2 equiv.) was added and the solution stirred at RT or at 80°C depending on the reactivity of the alkyne. The resulting mixture was concentrated under vacuum, poured into water, and extracted with AcOEt. The combined organic fractions were dried over Na2S04, filtered, and evaporated in vacuo. The crude mixture obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt) to furnish the pure internal alkyne.
General Procedure B: Stille coupling reaction
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
N or O 47-50
To a suspension of aryl iodide or aryl bromide (1.0 equiv.) in dry toluene (0.05 M), was added tributylstannyl aryl (1.2 equiv.). After 20 min stirring at RT under argon, Pd(PPh3)4 (0.05 equiv.) was added. The reaction mixture was heated overnight at 90°C in a sealed tube. After cooling, the solvent was removed. Water was added and the mixture was extracted with AcOEt. The combined organic layers were dried over Na2S04, filtered off and concentrated under vacuum. The crude was purified by flash chromatography (CH2Cl2/AcOEt) followed by a semi-preparative HPLC separation to furnish the pure coupling product.
General Procedure C: Ullmann coupling reaction (amine)
Figure imgf000063_0004
To a suspension of aryl iodide or aryl bromide (1.0 equiv.), copper powder (0.2 equiv.), potassium carbonate (1.5 equiv.), and NH nucleophile (1.2 equiv.) in dry toluene (0.2 M), was added Ν,Ν' -dimethylethylenediamine (0.2 equiv.) under argon. The reaction mixture was heated at 135°C (time indicated), cooled to RT and filtered through a pad of Celite eluting with AcOEt. The filtrate was concentrated and purified by flash chromatography (cyclohexane/ AcOEt then AcOEt/CH3OH) to furnish the pure coupling product.
General Procedure D: Copper catalyzed azide-alkyne cycloaddition
Figure imgf000064_0001
106-113, 130-133
To a solution of alkyne (1.0 equiv.) in a mixture DMSO/water (5: 1) (0.05 M) were successively added CuS04 (0.05 equiv.), sodium ascorbate (0.1 equiv.) and alkyl azide (1.1 equiv.) under argon. The reaction mixture was heated at 65°C for 18h and cooled to RT. The solvents were removed by lyophilization. The residue obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt or CH2C12/CH30H) to furnish the pure triazole.
General Procedure E: Ruthenium catalyzed azide-alkyne cycloaddition
Figure imgf000064_0002
Figure imgf000064_0003
To a solution of alkyne (1.0 equiv.) in dioxane (0.05 M) were successively added alkyl azide (1.0 equiv.) and Cp*RuCl(Cod) (0.1 equiv.) under argon. The reaction mixture was heated at 80°C for 18h, cooled to RT, and concentrated in vacuo. The crude obtained was purified by flash chromatography (Si02, CH2Cl2/AcOEt or CH2C12/CH30H) to furnish the pure triazole.
General Procedure F: Suzuki coupling reaction
Figure imgf000065_0001
124
Aryl iodide or aryl bromide (1.0 equiv.) was dissolved in DME (0.05 M). Aryl boronic acid (1.2 equiv.) and 2M Na2C03 in water (2.0 equiv.) were added at RT. The reaction mixture was purged with argon for 10 min before addition of Pd(PPh3)4 (0.05 equiv.). The solution was heated overnight at 80°C in a sealed tube. After cooling, water was added and the mixture was extracted with CH2C12. The combined organic layers were dried over MgS04, filtered off and concentrated under vacuum. The crude was purified by flash chromatography (cyclohexane/AcOEt) to furnish the pure coupling product. General Procedure G: Grignard coupling reaction
Figure imgf000065_0002
To a solution of Weinreb's amide (1.0 equiv.) in anhydrous THF was added Grignard's reactant (1.0 equiv.) at RT. The reaction mixture was stirred until completion. Water was added and the mixture was extracted with AcOEt. The combined organic layers were dried over MgS04, filtered and concentrated under vacuum. The crude was purified by flash chromatography (CH2C12/ AcOEt) to furnish the pure coupling product.
General Procedure H: Reductive amination
Figure imgf000066_0001
59, 61-62
To a solution of aldehyde (1.0 equiv.) in pyridine (0.1 M) was added amine (1.5 equiv.). The resulting mixture was stirred at 110°C for 18h. After cooling, the solvent was removed under vacuum and methanol (0.05 M) was added followed by sodium borohydride (1.6 equiv.). The new mixture was stirred at RT for 3h before concentration and addition of NaHC03 aq. and AcOEt. The aqueous layer was extracted with AcOEt. The combined organic fractions were dried over Na2S04 and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (cyclohexane/ AcOEt then AcOEt/CH3OH) to furnish the pure expected compound.
General Procedure I: Nucleophilic substitution
Figure imgf000066_0002
Thionyl chloride (2.0 equiv.) was added dropwise to a suspension of alcohol (1.0 equiv.) in dichloromethane (0.1 M) at 0°C. The reaction mixture was stirred for 2h at RT before elimination of the solvent under vacuum. The residue was dissolved in anhydrous THF (0.1 M) and nucleophile was added (3.0 to 5.0 equiv.). The resulting mixture was stirred at reflux for 3-6h. After cooling, the solvent was removed under vacuum. The crude product was purified by flash chromatography (AcOEt/CH3OH) followed by semi-preparative HPLC separation to furnish the pure substitution product.
General Procedure J: Ullmann coupling reaction (ether)
Figure imgf000067_0001
A suspension of aryl iodide or aryl bromide (1.0 equiv.), hydroxy aryl (2.0 equiv.), copper iodide (0.15 equiv.), cesium carbonate (2.4 equiv.), and N,N-dimethylglycine hydrochloride (0.7 equiv.) in dioxane (0.1 M) was heated in a sealed tube at 135°C, cooled to RT and filtered through a pad of Celite eluting with AcOEt. The filtrate was concentrated and purified by flash chromatography (cyclohexane/ AcOEt then AcOEt/CH3OH) to furnish after a semi-preparative HPLC the pure coupling product.
General Procedure K: Nucleophilic addition
Figure imgf000067_0002
AH AI-AL
5-Bromo-2-chloronicotinic acid (1.0 equiv.) was refluxed in thionyl chloride (1.0 M). After 3h, the solvent was removed in vacuo. Dry THF (1.0 M), terminal alkyne (1.05 equiv.), PdCl2(PPh3)2 (0.02 equiv.), and Cul (0.04 equiv.) were added under argon atmosphere in a sealed tube. The mixture was cooled to 0 °C and triethylamine (1.05 equiv.) was added. The reaction mixture was stirred at RT before addition of water and extracted with AcOEt. The combined organic fractions were dried over Na2S04. The solvent was removed in vacuo and the residue purified by flash chromatography (cyclohexane/CH2Cl2) leading to the pure substitution product. General Procedure L: l,8]naphthyridin-4-one ring closure
Figure imgf000068_0001
BG-BI, CF-CG
BF
Alkyl amine (2.0 or 5.0 equiv.), potassium carbonate (3.0 or 3.5 equiv.) and 2- chloropyridine (1.0 equiv.) in dry DMF (0.2 M) or acetonitrile (0.04 M) were heated (at 80°C or 130 °C, time indicated). After cooling, the solvent was removed in vacuo, water was added, and the aqueous layer was extracted with AcOEt. The combined organic fractions were dried over MgSC . The solvent was removed in vacuo and the residue purified by flash chromatography (cyclohexane/AcOEt or AcOEt/CH3OH) leading to the pure cyclization product.
Figure imgf000068_0002
Figure imgf000068_0003
BJ-BL BM-BO, CJ-CK A mixture of aryl bromide (1.0 equiv.), BrettPhos (0.05 equiv.), and BrettPhos palladacycle (0.05 equiv.) in anhydride THF (0.1 M) was degassed under argon for 15 min at RT. Then 2-aminoindan (1.2 equiv.) and LiHMDS 1M in THF (4.5 equiv.) were added. The mixture was stirred at RT until completion. Then, a saturated solution of NH4C1 was added. The aqueous layer was extracted with CH2CI2. The combined organic fractions were dried over MgS04, filtered, and concentrated under vacuum. The crude obtained was purified by flash chromatography (cyclohexane/AcOEt or AcOEt/CH3OH) leading to the pure coupling product.
General Procedure N: Ethyl ester saponification
Figure imgf000069_0001
A solution of ethyl ester (1.0 equiv.) and potassium hydroxide (2.0 equiv.) in a mixture water/ethanol (1: 10) (0.05 M) was stirred under reflux (time indicated). After cooling, the solvent was removed under vacuo. The residue was triturated in IN HC1. The solid formed was filtered off, washed with water and dried under vacuo leading to the pure saponification product.
General Procedure O: Weinreb amide formation
Figure imgf000069_0002
A, G, BM-BO, CJ-CK R-S, BP-BS, CL-CM
To a suspension of carboxylic acid (1.0 equiv.) in CH2CI2 (0.2 M) at 0°C was added triethylamine (2.3 equiv.) followed by ethylchloroformate (1.2 equiv.). The reaction mixture was stirred at 0°C for 30 min before addition of Ν,Ο-dimethylhydroxylamine hydrochloride (1.2 equiv.). The mixture was stirred at RT until completion. Then aq. NH4C1 sat. was added and the solution extracted with CH2CI2. The combined organic fractions were dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (AcOEt/CH3OH or CH2C12/CH30H) leading to the pure expected compound.
General Procedure P: Weinreb amide reduction with DIBAH
Figure imgf000070_0001
R-S, BP-BS, CL-CM T, BT-BW, CN-CO, 55
A solution of Weinreb amide (1.0 equiv.) in CH2C12 (0.05 M) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2CI2 (2.1 equiv.) dropwise over 30 min, stirred for 2h at -78°C and treated with sat. aq. NH4C1. After lh at RT, the suspension was filtered off and washed with CH2CI2 and water. The aqueous layer was extracted with CH2CI2. The combined organic fractions were dried over MgS04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Cf^CVAcOEt) leading to the expected compound.
General Procedure Q: Aldehyde reduction
Figure imgf000070_0002
55, BT-BW, CN-CO 56, BX-CA, CP-CQ
A suspension of aldehyde (1.0 equiv.) in methanol (0.2 M) at RT was treated with sodium borohydride (1.1 equiv.). The reaction mixture was stirred at RT for 3h, filtered and washed with methanol. The solvent was removed in vacuo. Work up of the reaction was either by Method A: trituration in a water/AcOEt mixture (1: 1) and drying of the precipitate recovered, or by Method B: the crude obtained was purified by flash chromatography using the solvents indicated to furnish the pure coupling product.
General Procedure R: Azido formation with DPPA
Figure imgf000071_0001
56, BX-CA, CP-CQ U, CB-CE, CR-CS
To a suspension of hydroalkyl (1.0 equiv.) in anhydrous THF (0.02 M) were successively added at 0°C diphenyl phosphoryl azide (1.1 to 2.0 equiv.) and l,8-diazabicyclo[5.4.0] undec-7-ene (1.2 equiv.). After 2h at 0°C, the reaction mixture was stirred at RT until completion. The solvent was removed under vacuum and the crude was purified by flash chromatography (cyclohexane/AcOEt, or AcOEt/CH3OH, or CH2C12/CH30H) to furnish the expected compound. Intermediate B: l-Ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000071_0002
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid (10.5 g, 30 mmol) (prepared according to WO 2008/046135) and potassium cyanide (2.15 g, 33 mmol) in DMSO (100 ml) were heated at 160°C for 18h. After cooling, water (500 ml), NaOH IN (50 ml), and AcOEt (300 ml) were added. The precipitate formed was filtered off leading to a green powder (3.21 g). The aqueous layer was extracted with AcOEt (3 x 200 ml). The combined organic fractions were dried over Na2S04, filtered, and evaporated under vacuum leading to a green solid (4.32 g). The combined solid fractions (7.53 g, 82%) furnished the expected title compound. 1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 7.98 (d, = 7.6 Hz, 1H), 7.49 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 7.52 (d, = 6.5 Hz, 1H), 5.98 (d, = 7.6 Hz, 1H), 4.35-4.26 (m, 3H), 3.37-3.29 (m, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 306.2.
Intermediate C: l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one
Figure imgf000072_0001
To a suspension of l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (3.05 g, 10 mmol) in DMF (6 ml), was added N-iodosuccinimide (2.25 g, 10 mmol) at RT. After lh stirring, water (300 ml) was added. The precipitate formed was filtered off and washed with water. The crude solid obtained was purified by flash chromatography (Si02, CH2Cl2/AcOEt 100:0→ 50:50) leading to the expected product as a yellow powder (1.71 g, 75%).
1H NMR (300 MHz, DMSO-i¾) δ 8.63 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.68 (brd, = 5.6 Hz, 1H), 4.37 (qd, = 7.0 Hz, 2H), 4.33-4.26 (m, 1H), 3.37-3.29 (m, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.29 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 432.1.
Intermediate D: l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one
Figure imgf000072_0002
To a suspension of l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (3.05 g, 10 mmol) in DMF (40 ml), was added N-bromosuccinimide (1.78 g, 10 mmol) at RT. After 6h stirring, water (300 ml) was added. The precipitate formed was filtered off and washed with water. The crude solid obtained was purified by flash chromatography (Si02, CH2Cl2/AcOEt 100:0 → 30:70 then CH2Cl2/MeOH 100:0 → 80:20) leading to the expected product as a yellow solid (1.44 g, 38%) and to unreacted starting material (960 mg, 32%).
1H NMR (300 MHz, DMSO-i¾) δ 8.60 (s, 1H), 8.37 (d, = 3.0 Hz, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.68 (d, = 6.5 Hz, 1H), 4.39 (qd, = 7.0 Hz, 2H), 4.33-4.29 (m, 1H), 3.38-3.30 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.5 Hz, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.2.
Intermediate F: l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihyd] naphthyridine-3-carboxylic acid ethyl ester
Figure imgf000073_0001
To a solution of l-ethyl-6-(indan-2-ylamino)-4-oxo- l,4-dihydro-[l,8]naphthyridine-3- carboxylic acid ethyl ester (4.0 g, 10.6 mmol) in DMF (30 ml), was added sodium hydride 60% (636 mg, 15.9 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. Iodomethane (lmL, 15.9 mmol) was added and the reaction mixture was stirred at RT for 3 days. Water was added (150 ml). The precipitate formed was filtered off (washing with water) and dried in vacuo leading to the expected product as a brown powder (4.15 g, quantitative).
1H NMR (300 MHz, DMSO-i¾) δ 8.72 (s, 1H), 8.67 (d, = 3.0 Hz, 1H), 7.75 (d, = 3.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17-7.14 (m, 2H), 4.97 (qt, = 7.6 Hz, 1H), 4.46 (qd, = 7.0 Hz, 2H), 4.20 (qd, = 7.0 Hz, 2H), 3.25-3.17 (dd, = 16.6, 8.2 Hz, 2H), 3.06-2.98 (dd, = 16.3, 6.1 Hz, 2H), 2.80 (s, 3H), 1.35 (t, = 6.8 Hz, 3H), 1.27 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 392.3.
Intermediate G: l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8] naphthyridine-3-carboxylic acid
Figure imgf000074_0001
l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylk acid ethyl ester (4.1 g, 10.6 mmol) and potassium hydroxide (1.2 g, 21.2 mmol) were reacted as described under General Procedure N (18h at 80°C) to furnish the title compound (3.74 g, 97%) as a brown powder.
1H NMR (300 MHz, DMSO-i¾) δ 15.20 (s, 1H), 9.05 (s, 1H), 8.88 (d, = 3.0 Hz, 1H), 7.76 (d, / = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.15 (m, 2H), 5.08 (qt, / = 7.5 Hz, 1H), 4.63 (qd, / = 7.0 Hz, 2H), 3.28-3.20 (dd, / = 16.4, 8.1 Hz, 2H), 3.09-3.01 (dd, / = 16.4, 6.2 Hz, 2H), 2.86 (s, 3H), 1.40 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 364.3.
Intermediate H: l-Ethyl-6-(indan-2-yl-methyl-amino)-lH-[l,8]naphthyridin-4-one
Figure imgf000074_0002
l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carbo-xylic acid (3.74 g, 10.3 mmol) and potassium cyanide (0.74 g, 11.3 mmol) in DMSO (100 ml) were heated at 160°C for 18h. After cooling, water (500 ml), NaOH IN (50 ml), and AcOEt (300 ml) were added. The precipitate formed was filtered off and purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0 → 0: 100) leading to the expected product as a green solid (2.90 g, 88%).
1H NMR (300 MHz, DMSO-i¾) δ 8.67 (d, = 3.0 Hz, 1H), 8.03 (d, = 7.6 Hz, 1H), 7.71 (d, = 3.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.15-7.12 (m, 2H), 6.01 (d, = 7.6 Hz, 1H), 4.92 (qt, / = 7.8 Hz, 1H), 4.35 (qd, / = 7.0 Hz, 2H), 3.22-3.14 (dd, = 16.4, 7.2 Hz, 2H), 3.03- 2.96 (dd, = 16.4, 6.2 Hz, 2H), 2.75 (s, 3H), 1.30 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 320.3. Intermediate I: l-Ethyl-6-(indan-2-yl-methyl-amino)-3-iodo-lH-[l,8]naphthyri-din-4- one
Figure imgf000075_0001
To a suspension of l-ethyl-6-(indan-2-yl-methyl-amino)-lH-[l,8]naphthyridin-4-one (2.00 g, 6.3 mmol) in DMF (20 ml), was added N-iodosuccinimide (1.41 g, 6.3 mmol) at RT. After lh stirring, water (100 ml) was added. The precipitate formed was filtered off, washed with water and ether, and dried under vacuum. The expected product was recovered as a yellow solid (2.02 g, 72%).
1H NMR (300 MHz, DMSO-i¾) δ 8.72 (d, = 3.0 Hz, 1H), 8.68 (d, = 37 Hz, 1H), 7.67 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 4.96 (qt, = 7.9 Hz, 1H), 4.40 (qd, = 6.9 Hz, 2H), 3.23-3.15 (dd, / = 16.4, 8.1 Hz, 2H), 3.05-2.97 (dd, / = 16.3, 6.3 Hz, 2H), 2.75 (s, 3H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 446.2.
Intermediate K: 6-Chloro-l-ethyl-4-oxo-l,4-dihydro-[l,7]naphthyridine-3-carboxylic acid
Figure imgf000075_0002
6-Chloro-l-ethyl-4-oxo-l,4-dihydro-[l,7]naphthyridine-3-carboxylic acid ethyl ester (2.60 g, 9.3 mmol) and potassium hydroxide (1.04 g, 18.5 mmol) were reacted as described under General Procedure N (3h at 75°C) to furnish the title compound (1.95 g, 83%) as a white powder.
Intermediate L: l-Ethyl-6- (indan-2-ylamino) -4-oxo- 1 ,4-dihydro- [1 ,7] naphthyri-dine- 3-carboxylic acid
Figure imgf000076_0001
A mixture of 6-chloro-l-ethyl-4-oxo-l,4-dihydro-[l,7]naphthyridine-3-carboxylic acid (990 mg, 3.9 mmol), BrettPhos (105 mg, 0.2 mmol), and BrettPhos palladacycle (156 mg, 0.2 mmol) in anhydride THF (50 ml) was degassed under argon for 15 min at RT. Then 2- aminoindan (0.67 ml, 5.1 mmol) and 1M LiHMDS in THF (22 ml, 22 mmol) were added. The mixture was stirred at RT for 3h. Then, a saturated solution of NH4C1 (50 ml) was added. The aqueous layer was extracted with CH2CI2 (2 x 40 ml). The combined organic fractions were dried over MgS04, filtered, and concentrated under vacuum. The crude was purified by flash chromatography (Si02, CH2C12/CH30H 100:0→ 80:20) leading to a brown solid which was triturated in AcOEt and filtered off to furnish the expected product as a yellow powder (1.18 g, 86%).
1H NMR (300 MHz, DMSO-i¾ δ 9.02 (s, 1H), 8.79 (s, 1H), 7.50 (brs, 1H), 7.25-7.22 (m, 2H), 7.16-7.13 (m, 2H), 4.66-4.56 (m, 3H), 3.36-3.29 (dd, / = 16.0, 7.0 Hz, 2H), 2.90-2.83 (dd, / = 15.9, 5.7 Hz, 2H), 1.42 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 350.3.
Intermediate M: 1 -Ethy 1-6- (indan-2-ylamino) - 1 H- [ 1 ,7]naphthyridin-4-one
Figure imgf000076_0002
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,7]naphthyridine-3-carboxylic acid (2.00 g, 5.7 mmol) in diphenylether (40 ml) was heated at 290°C for 6h. After cooling, the reaction mixture was purified by flash chromatography (Si02, AcOEt/MeOH 100:0→ 85: 15) leading to the expected product as brown to dark foam (1.15 g, 65%).
1H NMR (300 MHz, DMSO-i¾ δ 8.77 (s, 1H), 7.84 (d, = 7.6 Hz, 1H), 7.23-7.19 (m, 2H), 7.16-7.11 (m, 2H), 7.02 (s, 1H), 6.95 (d, = 6.6 Hz, 1H), 5.86 (d, = 7.5 Hz, 1H), 4.55 (sext, = 6.6 Hz, 1H), 4.27 (qd, = 7.0 Hz, 1H), 3.33-3.26 (dd, = 15.8, 7.2 Hz, 2H), 2.88-2.80 (dd, 7 = 15.9, 5.9 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 306.3.
Intermediate N: l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,7]naphthyridin-4-one
Figure imgf000077_0001
To a suspension of l-ethyl-6-(indan-2-ylamino)-lH-[l,7]naphthyridin-4-one (520 mg, 1.70 mmol) in DMF (7 ml), was added N-iodosuccinimide (383 mg, 1.70 mmol) at RT. After lh stirring, water (50 ml) was added. The aqueous layer was extracted with AcOEt (3 x 40 ml). The combined organic fractions were dried over MgS04, filtered, and concentrated under vacuum. The crude was purified by flash chromatography (Si02, eye lohexane/ AcOEt 100:0→ 30:70) leading to the expected product as a brown powder (500 mg, 68%).
1H NMR (300 MHz, DMSC fc) δ 8.81 (s, 1H), 8.47 (s, 1H), 7.23-7.20 (m, 2H), 7.16-7.10 (m, 3H), 7.04 (s, 1H), 4.57 (sext, / = 6.8 Hz, 1H), 4.33 (qd, / = 7.0 Hz, 1H), 3.33-3.26 (dd, = 15.6, 7.3 Hz, 2H), 2.87-2.80 (dd, = 15.1, 5.1 Hz, 2H), 1.35 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 432.3.
Intermediate O: l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,7]naphthyridin-4-one
Figure imgf000077_0002
To a suspension of l-ethyl-6-(indan-2-ylamino)-lH-[l,7]naphthyridin-4-one (1.12 g, 3.67 mmol) in DMF (15 ml), was added N-bromosuccinimide (653 mg, 3.67 mmol) at RT. After lh stirring, water (150 ml) was added. The precipitate formed was filtered off and triturated in AcOEt (100 ml). Cyclohexane (200 ml) was added and the resulting precipitate was filtered off. The solid recovered was dissolved in a mixture CH2CI2/CH3OH (1: 1) (100 ml), concentrated and dried under vacuum leading to the expected product as a yellow solid (895 mg, 63%).
1H NMR (300 MHz, DMSC ^) δ 8.83 (s, 1H), 8.45 (s, 1H), 7.23-7.20 (m, 2H), 7.14-7.11 (m, 2H), 7.02 (s, 1H), 4.57 (sext, = 6.2 Hz, 1H), 4.34 (qd, = 7.1 Hz, 2H), 3.33-3.26 (dd, = 15.7, 7.3 Hz, 2H), 2.87-2.80 (dd, = 15.9, 5.9 Hz, 2H), 1.36 (t, = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 386.1.
Intermediate P: l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-dine- 3-carboxylic acid hydrazide
Figure imgf000078_0001
To a suspension of l-ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridi-ne-3- carboxylic acid ethyl ester (2.0 g, 5.3 mmol) in ethanol (20 ml), was added hydrazine monohydrate (0.54 ml, 11.1 mmol) at RT. The reaction mixture was stirred at reflux for 7h. After cooling, the suspension obtained was filtered off and washed with EtOH leading to the expected product as a yellow solid (1.73 g, 90%). 1H NMR (300 MHz, DMSO-i¾) δ 10.65 (s, 1H), 8.82 (s, 1H), 8.40 (d, = 3.0 Hz, 1H), 7.60 (d, = 3.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.81 (d, = 6.5 Hz, 1H), 4.56-4.99 (m, 4H), 4.36-4.30 (m, 1H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 364.4. Intermediate Q: l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-dine- 3-carboxylic [l-methoxy-ethylidene]-hydrazide
Figure imgf000078_0002
In sealed tube, a suspension of l-ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro- [l,8]naphthyridine-3-carboxylic acid hydrazide (250 mg, 0.69 mmol) in triethyl orthoacetate (0.86 ml, 6.9 mmol), was stirred at 180°C for lh. After cooling, the solvent was removed and the crude obtained purified by flash chromatography (Si02, CH2Cl2/acetone 100:0→ 50:50) leading to the expected product as a yellow solid (187 mg, 64%).
1H NMR (300 MHz, DMSO-i¾) δ 10.49 (s, 1H), 8.87 (s, 1H), 8.42 (d, = 3.0 Hz, 1H), 7.61 (d, = 3.0 Hz, 1H), 7.26-7.24 (m, 2H), 7.16-7.13 (m, 2H), 6.86 (d, = 6.4 Hz, 1H), 4.56 (qd, = 7.0 Hz, 2H), 4.38-4.30 (m, 1H), 3.69 (s, 3H), 3.40-3.32 (dd, = 16.1, 6.9 Hz, 2H), 2.88-2.82 (dd, = 16.1, 4.3 Hz, 2H), 2.07 (d, = 2.9 Hz, 3H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 420.4.
Intermediate R: l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine- 3-carboxylic methoxy-methyl-amide
Figure imgf000079_0001
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid (7.00 g, 20 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (2.34 g, 24 mmol) were reacted as described under General Procedure O (2h at RT), leading after flash chromatography (AcOEt/CH3OH 100:0→ 90: 10) to the title compound as a yellow solid (7.58 g, 96%). 1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 3.0 Hz, 1H), 8.24 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.63 (d, = 6.5 Hz, 1H), 4.42-4.30 (m, 3H), 3.62 (s, 3H), 3.39-3.31 (dd, = 16.0, 7.0 Hz, 2H), 3.17 (s, 3H), 2.87-2.80 (dd, = 15.9, 4.5 Hz, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 393.3. Intermediate S: l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8] naphthyridine-3-carboxylic methoxy-methyl-amide
Figure imgf000080_0001
l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8] naphthyridine-3-carboxylic acid (3.55 g, 9.8 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (1.15 g, 11.8 mmol) were reacted as described under General Procedure O (2h at RT), leading after flash chromatography (AcOEt/CH3OH 100:0→ 90: 10) to the title compound as a brown solid (3.65 g, 91%). 1H NMR (300 MHz, DMSO-i¾) δ 8.71 (d, = 3.0 Hz, 1H), 8.30 (s, 1H), 7.73 (d, = 3.0 Hz, 1H), 7.25-7.23 (m, 2H), 7.18-7.13 (m, 2H), 4.97 (qt, = 7.4 Hz, 1H), 4.41 (qd, = 6.8 Hz, 2H), 3.61 (s, 3H), 3.24-3.17 (m, 5H), 3.05-2.98 (dd, = 16.5, 6.2 Hz, 2H), 2.78 (s, 3H), 1.37-1.31 (m, 6H). Intermediate T: l-Ethyl-6-(indan-2-yl-methyl-amino)-3-propionyl-lH-[l,8] naphthyridin-4-one
Figure imgf000080_0002
l-Ethyl-6-(indan-2-yl-methyl-amino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic methoxy-methyl-amide (1.22 g, 3.0 mmol) in CH2C12 (50 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (5.1 ml, 5.1 mmol) according to General Procedure P, leading after flash chromatography (CH2Cl2/AcOEt 100:0→ 40:60) to the title compound as an orange solid (860 mg, 82%).
1H NMR (300 MHz, DMSO-i¾) δ 10.15 (s, 1H), 8.70 (d, = 3.0 Hz, 1H), 8.64 (s, 1H), 7.77 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.18-7.14 (m, 2H), 4.97 (qt, = 8.0 Hz, 1H), 4.41 (qd, / = 7.0 Hz, 2H), 3.26-3.18 (dd, / = 16.2, 8.0 Hz, 2H), 3.06-2.99 (dd, / = 16.3, 6.3 Hz, 2H), 2.82 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 348.3.
Intermediate U: 3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4- one
Figure imgf000081_0001
To a suspension of l-ethyl-3-hydroxymethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4- one (250 mg, 0.75 mmol) in anhydrous THF (5 ml) was added diphenyl phosphoryl azide (0.32 ml, 1.50 mmol) according to General Procedure R. The crude was purified by flash chromatography (cyclohexane/AcOEt 100:0→ 50:50) to furnish the expected compound as a yellow powder (180 mg, 67%).
1H NMR (300 MHz, DMSO-i¾) δ 8.37 (d, = 3.0 Hz, 1H), 8.26 (s, 1H), 7.55 (d, = 3.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.27-7.24 (m, 2H), 7.18-7.14 (m, 2H), 6.62 (d, = 6.5 Hz, 1H), 4.40-4.31 (m, 3H), 4.24 (s, 2H), 3.40-3.32 (dd, / = 16.1, 7.0 Hz, 2H), 2.88-2.82 (dd, = 16.0, 4.4 Hz, 2H), 1.33 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 361.3.
Intermediate V: l-Ethyl-6-(indan-2-ylamino)-3-(5-trimethylsilanyl-[l,2,3]triazol-l- lmethyl)-lH-[l,8]naphthyridin-4-one
Figure imgf000081_0002
u V
Ethynyltrimethylsilane (71 μΐ, 050 mmol) and 3-azidomethyl-l-ethyl-6-(indan-2-ylamino)- 1H-[1,8] naphthyridin-4-one (180 mg, 0.50 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (24 mg, 10%) as a yellow gum.
ESIMS m/z [M+H]+ 459.2. Intermediate W: (8-Ethyl-6-iodo-5-oxo-5,8-dihydro-[l,8]naphthyridin-3-yl)-indan-2- yl-carbamic acid tert-butyl ester
Figure imgf000082_0001
To a solution of l-ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (1.00 g, 2.32 mmol) in tetrahydrofuran (20 ml), were added di-tert-butyldicarbonate (760 mg, 3.48 mmol) and 4-dimethylaminopyridine (140 mg, 1.16 mmol). The reaction mixture was stirred at RT overnight and concentrated under vacuum. The resulting material was purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 70:30) leading to the expected compound as a white foam (1.01 g, 82).
1H NMR (300 MHz, CHCl3-i/) δ 8.43-8.40 (m, 2H), 8.23 (s, 1H), 7.05 (brs, 4H), 5.14 (qt, = 7.8 Hz, 1H), 4.40 (qd, = 7.1 Hz, 2H), 3.28-3.21 (dd, = 15.5, 7.9 Hz, 2H), 3.00-2.92 (dd, = 15.5, 7.8 Hz, 2H), 1.43 (t, = 7.1 Hz, 3H), 1.37 (s, 9H). ESIMS m/z [M+H]+ 532.1.
Intermediate X: {6-[3-(tert-Butyl-dimethyl-silanyloxy)-prop-l-ynyl]-8-ethyl-5- 5,8-dihydro-[l,8]naphthyridin-3-yl)-indan-2-yl-carbamic acid tert-butyl ester
Figure imgf000082_0002
(8-Ethyl-6-iodo-5-oxo-5,8-dihydro-[l,8]naphthyridin-3-yl)-indan-2-yl-carbamic acid tert- butyl ester (531 mg, 1.00 mmol) and tert-butyl-dimethyl-prop-2-ynyloxy-silane (256 mg, 1.50 mmol) were reacted as described under General Procedure A (4h at RT) to furnish the title compound (279 mg, 48%) as an orange oil.
ESIMS m/z [M+H]+ 574.4.
Intermediate Y: {6-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-8-ethyl-5-oxo-5,8- dihydro-[l,8]naphthyridin-3-yl)-indan-2-yl-carbamic acid tert-butyl ester
Figure imgf000083_0001
A solution of { 6-[3-(tert-butyl-dimethyl-silanyloxy)-prop-l-ynyl]-8-ethyl-5-oxo-5,8- dihydro-[l,8]naphthyridin-3-yl)-indan-2-yl-carbamic acid tert-butyl ester (279 mg, 0.49 mmol) in ethanol (20 ml) was stirred at RT under hydrogen (6 atm) for 48h in presence of Pt02 (57 mg, 0.25 mmol). The suspension was filtered off over Celite and washed with ethanol. The filtrate was evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 80:20) leading a mixture of two products (100 mg).
ESIMS m/z [M+H]+ 578.5.
Intermediate AA: 6-Amino-l-ethyl-4-oxo-l,4-dihydro-[l,8]naphthyridine- carboxylic acid
Figure imgf000083_0002
6-Amino- l-ethyl-4-oxo- l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid ethyl ester (10.5 g, 40 mmol) and potassium hydroxide (4.49 g, 80 mmol) were reacted as described under General Procedure N (3h at 80°C) to furnish the title compound (8.57 g, 91%) as a white powder. 1H NMR (300 MHz, OMSO-d6) δ 15.25 (s, 1H), 8.96 (s, 1H), 8.41 (d, = 3.0 Hz, 1H), 7.67 (d, = 3.0 Hz, 1H), 6.10 (s, 2H), 4.57 (qd, = 7.0 Hz, 2H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+Na]+ 256.2.
Intermediate AB: 6-Amino-l-ethyl-lH-[l,8]naphthyridin-4-one
Figure imgf000084_0001
6-Amino- l-ethyl-4-oxo- l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid (9.00 g, 38.6 mmol) in diphenylether (100 ml) was heated at 280°C for 70h. After cooling, the suspension obtained was filtered off leading to a brown solid which was purified by flash chromatography (Si02, CH2Cl2/MeOH 100:0→ 90: 10) leading to the expected product as a yellow powder (6.30 g, 86%). 1H NMR (300 MHz, DMSO-i¾) δ 8.24 (d, = 3.0 Hz, 1H), 7.95 (d, = 7.6 Hz, 1H), 7.56 (d, = 3.0 Hz, 1H), 5.91 (d, = 7.6 Hz, 1H), 5.57 (s, 2H), 4.29 (qd, = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+Na]+ 212.1.
Intermediate AC: 6-Amino-l-ethyl-3-iodo-lH-[l,8]naphthyridin-4-one
Figure imgf000084_0002
AC
To a suspension of 6-amino- l-ethyl-lH-[l,8]naphthyridin-4-one (350 mg, 1.85 mmol) in DMF (10 ml), was added N-iodosuccinimide (416 mg, 1.85 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The organic layer was successively washed with a solution of Na2S203 in water and brine. The organic fraction was dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0 → 0: 100) leading to the expected compound as a brown solid (204 mg, 35%).
1H NMR (300 MHz, DMSO-i¾) δ 1 1.04 (s, 1H), 8.59 (s, 1H), 8.27 (d, J = 3.0 Hz, 1H), 7.57 (d, = 3.0 Hz, 1H), 5.72 (s, 2H), 4.35 (qd, = 7.0 Hz, 2H), 1.29 (t, = 7.0 Hz, 3H). ESIMS m/z [2M+Na]+ 653.0. Intermediate AD: l-Ethyl-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8]naphthyri-din-4- one
Figure imgf000085_0001
A stirred solution of 6-amino-l-ethyl-lH-[l,8]naphthyridin-4-one (946 mg, 5.0 mmol), tetrahydro-4H-pyran-4-one (750 mg, 7.5 mmol), sodium sulfate (3.55 g, 25 mmol), and acetic acid (25 ml) in 1,2-dichloroethane (75 ml) was allowed to mature for 15 min at RT. Sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added in one portion and the solution was stirred for 18h at RT. The solvents were removed under vacuum. AcOEt (30 ml) and water (60 ml) were added. The aqueous layer was extracted with AcOEt (3 x 20 ml). The combined organic fractions were dried over Na2S04, filtered off and concentrated. The crude was purified by flash chromatography (Si02, CH2Cl2/MeOH 100:0→ 90: 10) leading to a yellow solid (201 mg, 14%) corresponding to the expected product.
ESIMS m/z [2M+Na]+ 569.3.
Intermediate AE: l-Ethyl-3-iodo-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8]naph thyridin-4-
Figure imgf000085_0002
AD AE
To a suspension of l-ethyl-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8]naphthyridin-4-one (200 mg, 0.73 mmol) in DMF (5 ml), was added N-iodosuccinimide (165 mg, 0.73 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The aqueous layer was extracted with AcOEt (2 x 20 ml). The organic fractions were dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt 100:0→ 0: 100) leading to the expected compound as a brown gum (200 mg, 69%).
1H NMR (300 MHz, DMSO-i¾) δ 8.63 (s, 1H), 8.38 (d, 7 = 3.0 Hz, 1H), 7.95 (s, 1H), 7.46 (d, 7 = 3.0 Hz, 1H), 4.38 (qd, 7 = 7.0 Hz, 2H), 3.90-3.84 (m, 2H), 3.60-3.24 (m, 3H), 1.92- 1.89 (m, 2H), 1.47- 1.29 (m, 5H). ESIMS m/z [M+H]+ 400.2.
Intermediate AF: l-Ethyl-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-[l,8] naphthyridin-4-one
Figure imgf000086_0001
A stirred solution of 6-amino- l-ethyl-lH-[l,8]naphthyridin-4-one (946 mg, 5.0 mmol), 4- formyltetrahydropyran (570 mg, 5.0 mmol), sodium sulfate (3.55 g, 25 mmol), and acetic acid (25 ml) in 1,2-dichloroethane (75 ml) was allowed to mature for 15 min at RT. Sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added in one portion and the solution was stirred for 4h at RT. The solvents were removed under vacuum. Water (60 ml) and AcOEt (30 ml) were added. The precipitate formed was filtered off, washed successively with water, ethyl acetate and ether. The solid obtained was dried under vacuum leading to expected product as a yellow solid (766 mg, 53%).
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, 7 = 3.0 Hz, 1H), 7.96 (d, 7 = 7.6 Hz, 1H), 7.38 (d, 7 = 3.0 Hz, 1H), 6.28 (t, 7 = 5.4 Hz, 1H), 5.95 (d, 7 = 7.6 Hz, 1H), 4.31 (qd, 7 = 6.9 Hz, 2H), 3.87-3.82 (dd, 7 = 11.2, 3.3 Hz, 2H), 3.26 (t, 7 = 11.1 Hz, 2H), 2.97 (t, 7 = 6.1 Hz, 2H), 1.80-1.74 (m, 1H), 1.67 (brd, 7 = 13.0 Hz, 2H), 1.30-1.15 (m, 5H). ESIMS m/z [M+H]+ 288.2.
Intermediate AG: l-Ethyl-3-iodo-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH- [l,8]naphthyridin-4-one
Figure imgf000087_0001
AF AG
To a suspension of l-ethyl-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-[l,8] naph- thyridin-4-one (600 mg, 2.1 mmol) in DMF (10 ml), was added N-iodosuccinimide (470 mg, 2.1 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The suspension formed was filtered off, washed successively with water, ethyl acetate and ether. The solid obtained was dried under vacuum leading to expected product as an orange solid (623 mg, 72%). 1H NMR (300 MHz, DMSO-i¾) δ 8.61 (s, 1H), 8.37 (d, = 3.0 Hz, 1H), 7.38 (d, = 3.0 Hz, 1H), 6.42 (brs, 1H), 4.36 (qd, = 7.0 Hz, 2H), 3.87-3.82 (dd, = 11.0, 2.9 Hz, 2H), 3.26 (t, = 10.8 Hz, 2H), 2.98 (t, = 5.3 Hz, 2H), 1.84-1.74 (m, 1H), 1.67 (brd, = 12.8 Hz, 2H), 1.32-1.15 (m, 5H). ESIMS m/z [M+H]+ 414.2.
Intermediate AI: l-(5-Bromo-2-chloro-pyridin-3-yl)-3-phenyl-propynone
Figure imgf000087_0002
5-Bromo-2-chloronicotinic acid (2.36 g, 10 mmol) and phenyl acetylene (1.15 ml, 10.5 mmol) were reacted as described under General Procedure K (16h at RT) to furnish the title compound (1.95 g, 60%) as a brown solid.
1H NMR (300 MHz, CHCl3-i/) δ 8.61 (d, = 2.5 Hz, 1H), 8.40 (d, = 2.5 Hz, 1H), 7.68- 7.65 (m, 2H), 7.55-7.50 (m, 1H), 7.46-7.41 (m, 2H). ESIMS m/z [M+H]+ 322.1.
Intermediate AJ: l-(5-Bromo-2-chloro-pyridin-3-yl)-3-cyclohexyl-propynone
Figure imgf000088_0001
5-Bromo-2-chloronicotinic acid (2.12 g, 9.0 mmol) and cyclohexylacetylene (1.23 ml, 9.5 mmol) were reacted as described under General Procedure K (16h at RT) to furnish the title compound (1.43 g, 48%) as a dark oil.
1H NMR (300 MHz, DMSO-i¾) δ 8.77 (d, = 2.3 Hz, 1H), 8.51 (d, = 2.3 Hz, 1H), 2.85- 2.79 (m, 1H), 1.84- 1.75 (m, 2H), 1.64-1.31 (m, 8H). ESIMS m/z [M+H]+ 328.2. Intermediate AK: l-(5-Bromo-2-chloro-pyridin-3-yl)-3-tert-butyl-propynone
Figure imgf000088_0002
5-Bromo-2-chloronicotinic acid (3.54 g, 15 mmol) and 3, 3 -dimethyl- 1-butyne (1.94 ml, 15.8 mmol) were reacted as described under General Procedure K (16h at RT) to furnish the title compound (3.33 g, 74%) as a brown oil.
1H NMR (300 MHz, DMSO-i¾) δ 8.77 (d, = 2.5 Hz, 1H), 8.46 (d, = 2.5 Hz, 1H), 1.30 (s, 9H). ESIMS m/z [M+H]+ 302.1.
Intermediate AL: 4-[3-(5-Bromo-2-chloro-pyridin-3-yl)-3-oxo-prop-l-ynyl]- piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000088_0003
5-Bromo-2-chloronicotinic acid (1.00 g, 4.2 mmol) and l-Boc-4-ethynylpiperidine (930 mg, 4.4 mmol) were reacted as described under General Procedure K (4h at RT) to furnish the title compound (1.16 g, n.d.) as an orange gum. 1H NMR (300 MHz, DMSO-i¾) δ 8.79 (d, = 2.5 Hz, 1H), 8.54 (d, = 2.5 Hz, 1H), 3.66- 3.57 (m, 2H), 3.11-2.98 (m, 3H), 1.87-1.80 (m, 2H), 1.60- 1.52 (m, 2H), 1.37 (s, 9H). ESIMS m/z [M+Na]+ 451.2.
In rmediate AM: 6-Bromo-2-phenyl-[l,8]naphthyridin-4-one
Figure imgf000089_0001
Al l-(5-Bromo-2-chloro-pyridin-3-yl)-3-phenyl-propynone (320 mg, 1.0 mmol) and 7N ammonia in methanol (0.71 ml, 5.0 mmol) were reacted as described under General Procedure L (48h at 130°C) to furnish the title compound (122 mg, 40%) as a brown solid.
1H NMR (300 MHz, DMSO-i¾) δ 12.56 (s, 1H), 8.89 (d, = 2.4 Hz, 1H), 8.54 (d, = 2.4 Hz, 1H), 7.83-7.81 (m, 2H), 7.56-7.53 (m, 3H), 6.43 (s, 1H). ESIMS m/z [M+H]+ 301.2. Intermediate AN: 6-Bromo-l-ethyl-2-phenyl-lH-[l,8]naphthyridin-4-one
Figure imgf000089_0002
l-(5-Bromo-2-chloro-pyridin-3-yl)-3-phenyl-propynone (960 mg, 3.0 mmol) and ethylamine hydrochloride (489 mg, 6.0 mmol) were reacted as described under General Procedure L (16h at 150°C) to furnish the title compound (451 mg, 45%) as a brown solid.
1H NMR (300 MHz, CHCl3-i/) δ 8.86 (d, = 2.6 Hz, 1H), 8.79 (d, = 2.6 Hz, 1H), 7.55- 7.50 (m, 3H), 7.44-7.40 (m, 2H), 4.35 (qd, = 7.0 Hz, 2H), 1.20 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 331.1.
Intermediate AO: 6-Bromo-l-(2-methoxy-ethyl)-2-phenyl-lH-[l,8]naphthyri-din-4- one
Figure imgf000090_0001
l-(5-Bromo-2-chloro-pyridin-3-yl)-3-phenyl-propynone (320 mg, 1.0 mmol) and 2- methoxyethylamine (376 mg, 5.0 mmol) were reacted as described under General Procedure L (48h at 130°C) to furnish the title compound (171 mg, 47%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.85 (d, = 2.6 Hz, 1H), 8.77 (d, = 2.6 Hz, 1H), 7.51- 7.48 (m, 3H), 7.45-7.41 (m, 2H), 4.51 (t, = 5.9 Hz, 2H), 3.54 (t, = 5.9 Hz, 2H), 3.12 (s, 3H). ESIMS m/z [M+H]+ 359.5.
Intermediate AP: 6-Bromo-2-cyclohexyl-l-ethyl-lH-[l,8]naphthyridin-4-one
Figure imgf000090_0002
AJ AP l-(5-Bromo-2-chloro-pyridin-3-yl)-3-cyclohexyl-propynone (700 mg, 2.1 mmol) and ethylamine hydrochloride (340 mg, 4.2 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (527 mg, 73%) as a beige solid. 1H NMR (300 MHz, CHCl3-i/) δ 8.90 (d, = 2.6 Hz, 1H), 8.52 (d, = 2.6 Hz, 1H), 6.19 (s, 1H), 4.51 (qd, / = 6.8 Hz, 2H), 2.85-2.78 (m, 1H), 1.90-1.67 (m, 5H), 1.45 (qt, = 9.2 Hz, 2H), 1.29-1.24 (m, 4H). ESIMS m/z [M+H]+ 337.2. Intermediate AQ: 6-Bromo-2-cyclohexyl-l-(2-methoxy-ethyl)-lH-[l,8]naph-thyridin- 4-one
Figure imgf000091_0001
l-(5-Bromo-2-chloro-pyridin-3-yl)-3-cyclohexyl-propynone (700 mg, 2.1 mmol) and 2- methoxyethylamine (805 mg, 10.7 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (579 mg, 74%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.88 (d, = 2.6 Hz, 1H), 8.52 (d, = 2.6 Hz, 1H), 6.18 (s, 1H), 4.66 (t, = 5.3 Hz, 2H), 3.62 (t, = 5.4 Hz, 2H), 3.20 (s, 3H), 3.04-2.98 (m, 1H), 1.98- 1.65 (m, 5H), 1.49- 1.24 (m, 5H). ESIMS m/z [M+H]+ 367.2.
In rmediate AR: 6-Bromo-2-tert-butyl-l-ethyl-lH-[l,8]naphthyridin-4-one
Figure imgf000091_0002
AK AR l-(5-Bromo-2-chloro-pyridin-3-yl)-3-tert-butyl-propynone (1.20 g, 4.0 mmol) and ethylamine hydrochloride (1.66 g, 12.0 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (669 mg, 54%) as a beige solid.
1H NMR (300 MHz, CHCl3-i/) δ 8.93 (d, = 2.6 Hz, 1H), 8.51 (d, = 2.6 Hz, 1H), 6.30 (s, 1H), 4.68 (qd, / = 6.6 Hz, 2H), 1.47 (s, 9H), 1.25 (t, / = 6.7 Hz, 3H). ESIMS m/z [M+H]+ 309.5.
Intermediate AS: 6-Bromo-2-tert-butyl-l-(2-dimethylamino-ethyl)-lH-[l,8] naphthyridin-4-one
Figure imgf000092_0001
l-(5-Bromo-2-chloro-pyridin-3-yl)-3-tert-butyl-propynone (1.20 g, 4.0 mmol) and N,N- dimethylethylenediamine (710 mg, 8.0 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (1.18 g, 84%) as a dark oil.
1H NMR (300 MHz, DMSO-i¾) δ 8.92 (d, = 2.6 Hz, 1H), 8.49 (d, = 2.6 Hz, 1H), 6.31 (s, 1H), 4.70 (brs, 2H), 2.47-2.40 (m, 2H), 2.19 (s, 6H), 1.48 (s, 9H). ESIMS m/z [M+H]+ 352.5.
Intermediate AT: 4-(6-Bromo-l-ethyl-4-oxo-l,4-dihydro-[l,8]naphthyridin-2-yl)- piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000092_0002
4-[3-(5-bromo-2-chloro-pyridin-3-yl)-3-oxo-prop-l-ynyl]-piperidine-l-carboxylic acid tert-butyl ester (600 mg, 1.4 mmol) and ethylamine hydrochloride (229 mg, 2.8 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (417 mg, 68%) as an orange solid.
1H NMR (300 MHz, CHCl3-i/) δ 8.91 (d, = 2.6 Hz, 1H), 8.52 (d, = 2.6 Hz, 1H), 6.18 (s, 1H), 4.55 (qd, = 6.7 Hz, 2H), 4.07-3.99 (m, 2H), 2.85-2.78 (m, 1H), 3.10-2.99 (m, 3H), 1.89 (d, = 12.3 Hz, 2H), 1.60-1.43 (m, 2H), 1.40 (s, 9H), 1.28 (t, = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 436.7.
Intermediate AU: 4-(6-Bromo-l-(2-methoxy-ethyl)-4-oxo-l,4-dihydro-[l,8] naphthyridin-2-yl)-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000093_0001
4-[3-(5-bromo-2-chloro-pyridin-3-yl)-3-oxo-prop- l-ynyl]-piperidine-l-carboxylic acid tert-butyl ester (600 mg, 1.4 mmol) and 2-methoxyethylamine (211 mg, 2.8 mmol) were reacted as described under General Procedure L (lh at 130°C) to furnish the title compound (429 mg, 65%) as an orange solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.90 (d, = 2.6 Hz, 1H), 8.53 (d, = 2.6 Hz, 1H), 6.17 (s, 1H), 4.72 (t, J = 5.3 Hz, 2H), 4.06 (d, / = 11.8 Hz, 2H), 3.63 (t, J = 5.1 Hz, 2H), 3.27- 2.20 (m, 1H), 3.19 (s, 3H), 2.91-2.78 (m, 2H), 1.84 (d, J = 12.2 Hz, 2H), 1.55-1.52 (m, 2H), 1.40 (s, 9H). ESIMS m/z [M+H]+ 466.7.
Intermediate AV: 6-Bromo-2-phenyl-thiopyrano[2,3-b]pyridin-4-one
Figure imgf000093_0002
A suspension of l-(5-bromo-2-chloro-pyridin-3-yl)-3-phenyl-propynone (780 mg, 2.4 mmol) and sodium hydrosulfide hydrate (205 mg, 3.6 mmol) in ethanol was stirred at RT for 3h. The solvent was removed under reduced pressure and the crude purified by flash chromatography (Si02, cyclohexane/CH2Cl2 100:0 → 0: 100) leading to the expected compound as an orange solid (391 mg, 50%).
1H NMR (300 MHz, DMSO-i¾) δ 9.04 (d, J = 2.4 Hz, 1H), 8.71 (d, J = 2.4 Hz, 1H), 7.84- 7.81 (m, 2H), 7.59-7.56 (m, 3H), 7.36 (s, 1H). ESIMS m/z [M+H]+ 320.3.
Intermediate AX: l-(5-bromo-2-methoxy-pyridin-3-yl)-3-hydroxy-3-phenyl- propenone
Figure imgf000094_0001
Acetophenone (1.20 g, 10.0 mmol) in dry THF (10 ml) was added dropwise to a suspension of methyl 5-bromo-2-chloropyridine-3-carboxylate (2.50 g, 10.0 mmol) and sodium hydride (800 mg, 20.0 mmol) in dry THF (20 ml). The mixture was allowed to stir at RT for 2h and heated under reflux for 16h. After cooling to RT, the solution was put into water (40 ml) and extracted with AcOEt (40 ml). The combined organic layers were washed with a saturated solution of NH4C1 (15 ml), brine (40 ml), and dried over Na2S04. After evaporation of the solvent, the residue was purified by flash chromatography (Si02, cyclohexane/CH2Cl2 100:0→ 30:70) to afford the expected compound (1.41 g, 42%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.49 (d, = 2.6 Hz, 1H), 8.34 (d, = 2.6 Hz, 1H), 8.01 (d, J = 1.1 Hz, 2H), 7.68-7.63 (m, 1H), 7.58-7.53 (m, 2H), 7.28 (s, 1H), 4.02 (s, 3H). ESEVIS m/z [M+H]+ 336.3.
Intermediate AY: 6-Bromo-2-phenyl-pyrano[2,3-b]pyridin-4-one
Figure imgf000094_0002
l-(5-Bromo-2-methoxy-pyridin-3-yl)-3-hydroxy-3-phenyl-propenone (334 mg, 1.0 mmol) was heated at 100°C for lh in polyphosphoric acid (4 ml). After cooling, the crude was diluted with water (100 ml). The suspension formed was separated by filtration, washed with water (50 ml) and ethanol (10 ml). The solid obtained was dried under vacuum leading to the expected product (218 mg, 71%) as a beige powder.
1H NMR (300 MHz, DMSO-i¾) δ 8.91 (d, = 2.6 Hz, 1H), 8.58 (d, = 2.6 Hz, 1H), 8.10- 8.07 (m, 2H), 7.63-7.58 (m, 3H), 7.18 (s, 1H). ESIMS m/z [M+H]+ 304.2. Intermediate AZ: l-Ethyl-6-(indan-2-ylamino)-3-(l-tritylimidazol-4-yl)-lH-
[l,8]naphthyridin-4-one
Figure imgf000095_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (200 mg, 0.52 mmol) and tributyl-(l-tritylimidazol-4-yl)stannane (535 mg, 0.57 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the impure title compound (234 mg) as a yellow oil.
1H NMR (300 MHz, DMSC fc) δ 8.71 (s, 1H), 8.33 (d, / = 3.0 Hz, 1H), 7.86 (s, 1H), 7.61 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.42-7.37 (m, 9H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 6H), 7.08-7.05 (m, 2H), 6.55 (d, = 6.2 Hz, 1H), 4.49 (qd, = 7.0 Hz, 2H), 4.28-4.21 (m, 1H), 3.37-3.30 (dd, = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 614.4.
Intermediate BA: 6- Cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one
Figure imgf000095_0002
A stirred solution of 6-amino-l-ethyl-lH-[l,8]naphthyridin-4-one (500 mg, 2.6 mmol), cyclopentanone (0.28 ml, 3.2 mmol), and acetic acid (0.38 ml, 7.9 mmol) in anhydrous methanol (15 ml) was heated for 18h at 50°C. After cooling at RT, sodium cyanoborohydride (249 mg, 4.0 mmol) was added in one portion and the solution was stirred for 3h at RT. The solvents were removed under vacuum. CH2CI2 (30 ml) and aq. NaHC03 (30 ml) were added. The aqueous layer was extracted with CH2CI2 (2 x 20 ml). The combined organic fractions were dried over MgS04, filtered off and concentrated. The crude was purified by flash chromatography (Si02, CH2Cl2/MeOH 100:0→ 93 :7) leading to a yellow solid (516 mg, 76%) corresponding to the expected product. 1H NMR (300 MHz, DMSO-i¾) δ 8.29 (d, = 3.0 Hz, 1H), 7.95 (d, = 7.6 Hz, 1H), 7.39 (d, = 3.0 Hz, 1H), 6.18 (d, = 6.4 Hz, 1H), 5.95 (d, = 7.6 Hz, 1H), 4.31 (qd, = 7.0 Hz, 2H), 3.77-3.72 (m, 1H), 1.97-1.89 (m, 2H), 1.70-1.42 (m, 6H), 1.29 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 258.1. Intermediate BB: 6- Isopropylamino)-l-ethyl-[l,8]naphthyridin-4-one
Figure imgf000096_0001
A stirred solution of 6-amino-l-ethyl-lH-[l,8]naphthyridin-4-one (500 mg, 2.6 mmol), acetone (0.23 ml, 3.2 mmol), and acetic acid (0.38 ml, 7.9 mmol) in anhydrous methanol (15 ml) was heated for 3 days at 50°C. After cooling at RT, sodium cyanoborohydride (249 mg, 4.0 mmol) was added in one portion and the solution was stirred for 3h at RT. The solvents were removed under vacuum. CH2C12 (30 ml) and aq. NaHC03 (30 ml) were added. The aqueous layer was extracted with CH2C12 (2 x 20 ml). The combined organic fractions were dried over MgS04, filtered off and concentrated. The crude was purified by flash chromatography (Si02, CH2Cl2/MeOH 100:0→ 95:5) leading to a yellow oil (367 mg, 60%) corresponding to the expected product.
1H NMR (300 MHz, DMSO-i¾) δ 8.28 (d, = 3.0 Hz, 1H), 7.95 (d, = 7.6 Hz, 1H), 7.38 (d, = 3.0 Hz, 1H), 6.01 (d, = 7.8 Hz, 1H), 5.95 (d, = 7.6 Hz, 1H), 4.31 (qd, = 7.0 Hz, 2H), 3.60 (sext, = 6.3 Hz, 1H), 1.29 (t, = 7.0 Hz, 3H), 1.15 (d, = 6.3 Hz, 6H). ESIMS m/z [M+H]+ 232.1.
Intermediate BC: 3-Bromo-6-(cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one
Figure imgf000097_0001
To a suspension of 6-(cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one (300 mg, 1.17 mmol) in DMF (5 ml), was added N-bromosuccinimide (207 mg, 1.17 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The aqueous layer was extracted with AcOEt (2 x 20 ml). The organic fractions were dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt 100:0→ 50:50) leading to the expected compound as a yellow solid (255 mg, 65%).
1H NMR (300 MHz, DMSO-i¾) δ 8.60 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 7.43 (d, = 3.0 Hz, 1H), 6.39 (d, = 6.3 Hz, 1H), 4.40 (qd, = 7.0 Hz, 2H), 3.79 (sext, = 6.0 Hz, 1H), 1.99- 1.93 (m, 2H), 1.73- 1.45 (m, 6H), 1.33 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 336.3. Intermediate BD: 6-(Cyclopentylamino)-l-ethyl-3-iodo-[l,8]naphthyridin-4-one
Figure imgf000097_0002
To a suspension of 6-(cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one (175 mg, 0.68 mmol) in DMF (5 ml), was added N-iodosuccinimide (153 mg, 0.68 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The aqueous layer was extracted with AcOEt (2 x 20 ml). The organic fractions were dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt 100:0→ 50:50) leading to the expected compound as a yellow solid (148 mg, 57%).
1H NMR (300 MHz, DMSO-i¾) δ 8.62 (s, 1H), 8.35 (d, = 3.0 Hz, 1H), 7.41 (d, = 3.0 Hz, 1H), 6.38 (brs, 1H), 4.39 (qd, J = 7.0 Hz, 2H), 3.80-3.74 (m, 1H), 1.99-1.93 (m, 2H), 1.73- 1.45 (m, 6H), 1.33 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 384.1. Intermediate BE: 3-Bromo-6- isopropylamino)-l-ethyl-[l,8]naphthyridin-4-one
Figure imgf000098_0001
To a suspension of l-ethyl-6-(isopropylamino)-[l,8]naphthyridin-4-one (357 mg, 1.54 mmol) in DMF (5 ml), was added N-bromosuccinimide (275 mg, 1.54 mmol) at RT. After lh stirring, water (30 ml) and AcOEt (30 ml) were added. The aqueous layer was extracted with AcOEt (2 x 20 ml). The organic fractions were dried over Na2S04, filtered, and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, CH2C12/ AcOEt 100:0→ 50:50) leading to the expected compound as a yellow solid (293 mg, 61%).
1H NMR (300 MHz, DMSO-i¾) δ 8.60 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 7.42 (d, = 3.0 Hz, 1H), 6.23 (d, = 7.6 Hz, 1H), 4.40 (qd, = 7.0 Hz, 2H), 3.64 (sext, = 6.4 Hz, 1H), 1.33 (t, = 7.0 Hz, 3H), 1.18 (d, 7 = 6.2 Hz, 6H). ESIMS m/z [M+H]+ 312.0.
Intermediate BG: Ethyl 6-bromo-l-(2-methoxyethyl)-4-oxo-[l,8] naphthyridine-3- carboxylate
Figure imgf000098_0002
Ethyl 2-(5-bromo-2-chloro-pyridine-3-carbonyl)-3-ethoxy-prop-2-enoate (3.55 g, 9.8 mmol) and 2-methoxylethylenediamine (4.25 ml, 49.0 mmol) were reacted as described under General Procedure L (18h at 80°C) to furnish the title compound (1.81 g, 52%) as a white solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.95 (d, = 2.5 Hz, 1H), 8.77 (s, 1H), 8.62 (d, = 2.5 Hz, 1H), 4.61 (t, J = 5.1 Hz, 2H), 4.23 (qd, J = 7.0 Hz, 2H), 3.67 (t, J = 5.1 Hz, 2H), 3.21 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 357.1.
Intermediate BH: Ethyl 6-bromo-l-[2-(dimethylamino)ethyl]-4-oxo-[l,8] naphthyri- dine-3-carbox late
Figure imgf000099_0001
Ethyl 2-(5-bromo-2-chloro-pyridine-3-carbonyl)-3-ethoxy-prop-2-enoate (3.55 g, 9.8 mmol) and N,N-dimethylethylenediamine (5.30 ml, 49.0 mmol) were reacted as described under General Procedure L (18h at 80°C) to furnish the title compound (2.74 g, 76%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.97 (d, = 2.5 Hz, 1H), 8.81 (s, 1H), 8.64 (d, = 2.5 Hz, 1H), 4.54 (t, = 6.0 Hz, 2H), 4.25 (qd, = 7.0 Hz, 2H), 2.61 (t, = 6.0 Hz, 2H), 2.19 (s, 6H), 1.29 (t, = 7.0 Hz, 3H).
Intermediate BI: Ethyl 6-bromo-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridine-3- carboxylate
Figure imgf000099_0002
Ethyl 2-(5-bromo-2-chloro-pyridine-3-carbonyl)-3-ethoxy-prop-2-enoate (2.84 g, 7.8 mmol) and 4-(2-aminoethyl) morpholine (5.10 ml, 39.1 mmol) were reacted as described under General Procedure L (18h at 80°C) to furnish the title compound (2.28 g, 71%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.97 (d, = 2.5 Hz, 1H), 8.83 (s, 1H), 8.64 (d, = 2.5 Hz, 1H), 4.57 (t, = 5.7 Hz, 2H), 4.26 (qd, = 7.0 Hz, 2H), 3.51 (t, = 4.4 Hz, 4H), 2.64 (t, = 5.7 Hz, 2H), 4.44 (t, = 4.2 Hz, 4H), 1.30 (t, = 7.0 Hz, 3H).
Intermediate BJ: 6-Bromo-l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridine-3-carboxylic acid
Figure imgf000100_0001
Ethyl 6-bromo- l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridine-3-carboxylate (1.74 g, 5.2 mmol) and potassium hydroxide (583 mg, 10.4 mmol) were reacted as described under General Procedure N (2h at 80°C) to furnish the title compound (1.54 g, 91%) as a white powder.
1H NMR (300 MHz, OMSO-d6) δ 14.37 (brs, 1H), 9.13 (d, J = 2.5 Hz, 1H), 9.09 (s, 1H), 8.84 (d, = 2.5 Hz, 1H), 4.79 (t, = 5.0 Hz, 2H), 3.70 (t, = 5.0 Hz, 2H), 3.21 (s, 3H). ESIMS m/z [M+H]+ 327.2.
Intermediate BK: 6-Bromo-l-[2-(dimethylamino)ethyl]-4-oxo-[l,8]naphthyridine-3- carboxylic acid
Figure imgf000100_0002
Ethyl 6-bromo- l-[2-(dimethylamino)ethyl]-4-oxo-[l,8]naphthyridine-3-carboxylate (2.74 g, 7.4 mmol) and potassium hydroxide (835 mg, 14.9 mmol) were reacted as described under General Procedure N (3 days at RT) to furnish the title compound (2.0 g, 79%) as a white powder.
1H NMR (300 MHz, OMSO-d6) δ 14.37 (brs, 1H), 9.22 (s, 1H), 9.15 (d, J = 2.4 Hz, 1H), 8.88 (d, J = 2.1 Hz, 1H), 4.83 (brs, 2H), 3.09 (brs, 2H), 2.50 (s, 6H). ESIMS m/z [M+H]+ 342.1.
Intermediate BL: 6-Bromo-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridine-3- carboxylic acid
Figure imgf000101_0001
Ethyl 6-bromo-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridine-3-carboxylate (2.28 g, 5.6 mmol) and potassium hydroxide (624 mg, 11.1 mmol) were reacted as described under General Procedure N (18h at RT) to furnish the title compound (1.52 g, 72%) as a beige powder.
1H NMR (300 MHz, DMSO-i¾) δ 14.42 (s, 1H), 9.14 (s, 2H), 8.86 (d, J = 2.1 Hz, 1H), 4.73 (t, = 5.5 Hz, 2H), 3.49 (brs, 4H), 2.68 (t, = 5.5 Hz, 2H), 2.45 (brs, 4H). ESIMS m/z [M+H]+ 384.0. Intermediate BM: 6-(Indan-2-ylamino)-l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridine- 3-carboxylic acid
Figure imgf000101_0002
6-Bromo-l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridine-3-carboxylic acid (1.54 g, 4.71 mmol) and 2-aminoindan (0.75 ml, 6.12 mmol) were reacted as described under General Procedure M (4h at RT) to furnish without purification the title compound (865 mg) as a brown sticky oil which was directly used for next step. ESIMS m/z [M+H]+ 380.2. Intermediate BN: l-[2-(dimethylamino)ethyl]-6-(indan-2-ylamino)-4-oxo-[l,8]naph- thyridine-3-carboxylic acid
Figure imgf000102_0001
6-Bromo- 1 -[2-(dimethylamino)ethyl]-4-oxo-[ 1 ,8]naphthyridine-3-carboxylic acid (600 mg, 1.76 mmol) and 2-aminoindan (0.30 ml, 2.30 mmol) were reacted as described under General Procedure M (4h at RT) to furnish without purification the title compound (200 mg) as a yellow solid which was directly used for next step.
ESIMS m/z [M+H]+ 393.3.
Intermediate BO: 6- (Indan-2-ylamino) - 1 - (2-morpholinoethyl) -4-oxo- l,8]naphthyridi-ne-3-carboxylic acid
Figure imgf000102_0002
6-Bromo-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridine-3-carboxylic acid (800 mg, 2.09 mmol) and 2-aminoindan (0.40 ml, 2.72 mmol) were reacted as described under General Procedure M (4h at RT) to furnish without purification the title compound (890 mg) as a brown powder which was directly used for next step.
ESIMS m/z [M+H]+ 435.3. Intermediate BP: 6-amino-l-ethyl-N-methoxy-N-methyl-4-oxo-[l,8]naphthyridine-3- carboxamide
Figure imgf000103_0001
6-Amino- l-ethyl-4-oxo- l,4-dihydro-[l,8]naphthyridine-3-carboxylic acid (4.66 g, 20 mmol) and N,0-dimethylhydroxylamine hydrochloride (2.34 g, 24 mmol) were reacted as described under General Procedure O (2h at RT). The crude was purified by flash chromatography (CH2CI2/CH3OH 100:0 → 90: 10) leading to the title compound as a yellow foam (894 mg).
ESIMS m/z [M+H]+ 277.1
Intermediate BQ: 6-(Indan-2-ylamino)-N-methoxy-l-(2-methoxyethyl)-N-methyl-4- oxo- [ 1 ,8] naphthyridine-3-carboxamide
Figure imgf000103_0002
6-(Indan-2-ylamino)- l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridine-3-carboxylic acid (860 mg, 2.23 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (265 mg, 2.72 mmol) were reacted as described under General Procedure O (2h at RT). The crude was purified by flash chromatography (CH2C12/CH30H 100:0→ 97:3) leading to the title compound as a yellow-brown solid (265 mg, 13% over 2 steps).
ESIMS m/z [M+H]+ 423.3. Intermediate BR: l-[2-(Dimethylamino)ethyl]-6-(indan-2-ylamino)-N-methoxy-N- methyl-4-oxo-[l,8]naphthyridine-3-carboxamide
Figure imgf000104_0001
l-[2-(Dimethylamino)ethyl]-6-(indan-2-ylamino)-4-oxo-[l,8]naphthyridine-3-carboxylic acid (200 mg, 0.51 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (60 mg, 0.61 mmol) were reacted as described under General Procedure O (2h at RT). The crude was purified by flash chromatography (CH2C12/CH30H 100:0 → 90: 10) leading to the title compound as a yellow oil (215 mg, 28% over 2 steps).
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.15 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.62 (d, = 6.5 Hz, 1H), 4.43 (t, = 6.0 Hz, 2H), 4.33-4.27 (m, 1H), 3.60 (s, 3H), 3.38-3.30 (dd, J = 16.0, 7.0 Hz, 2H), 3.17 (s, 3H), 2.87-2.80 (dd, J = 15.9, 4.5 Hz, 2H), 2.58 (t, J = 5.6 Hz, 2H), 2.15 (s, 6H). ESIMS m/z [M+H]+ 436.3. Intermediate BS: 6-(Indan-2-ylamino)-N-methoxy-N-methyl-l-(2-morpholinoethyl)- 4-oxo-[l,8]naphthyridine-3-carboxamide
Figure imgf000104_0002
6-(Indan-2-ylamino)- l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridine-3-carboxylic acid (490 mg, 1.13 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (132 mg, 1.35 mmol) were reacted as described under General Procedure O (2h at RT). The crude was purified by flash chromatography (AcOEt/CH3OH 100:0 → 85 : 15) leading to the title compound as a brown foam (230 mg, 23% over 2 steps).
1H NMR (300 MHz, OMSO-d6) δ 8.35 (d, = 3.0 Hz, 1H), 8.18 (s, 1H), 7.55 (d, = 3.0 Hz, 1H), 7.28-7.25 (m, 2H), 7.19-7.15 (m, 2H), 6.64 (d, = 6.5 Hz, 1H), 4.48 (t, = 6.0 Hz, 2H), 4.35-4.29 (m, 1H), 3.64 (s, 3H), 3.51 (t, J = 4.3 Hz, 4H), 3.41-3.32 (dd, J = 16.0, 7.0 Hz, 2H), 3.20 (s, 3H), 2.89-2.82 (dd, J = 15.9, 4.5 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.42 (t, J = 4.3 Hz, 4H). ESJ S m/z [M+H]+ 478.4.
Intermediate BT: 6-Amino-l-ethyl-4-oxo-[l,8]naphthyridin-3-carbaldehyde
Figure imgf000105_0001
A solution of 6-amino-l-ethyl-N-methoxy-N-methyl-4-oxo-[l,8]naphthyridine-3- carboxamide (890 mg, 3.2 mmol) in CH2C12 (60 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (6.8 ml, 6.8 mmol) according to General Procedure P, leading without purification to the expected compound as a brown solid (414 mg).
1H NMR (300 MHz, DMSO-i¾) δ 8.57 (s, 1H), 8.26 (d, J = 3.0 Hz, 1H), 7.67 (d, J = 3.0 Hz, 1H), 5.90 (brs, 2H), 4.43 (qd, = 7.0 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 218.0. Intermediate BU: 6-(Indan-2-ylamino)-l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridin- 3-carbaldeh de
Figure imgf000105_0002
A solution of 6-(indan-2-ylamino)-N-methoxy- l-(2-methoxyethyl)-N-methyl-4-oxo- [l,8]naphthyridine-3-carboxamide (260 mg, 0.61 mmol) in CH2C12 (15 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (1.29 ml, 1.29 mmol) according to General Procedure P, leading without purification to the expected compound as a yellow solid (173 mg, 77%).
ESIMS m/z [M+H]+ 364.2.
Intermediate BV: l-[2-(Dimethylamino)ethyl]-6-(indan-2-ylamino)-4-oxo-[l,8]naph- thyridin-3-carbaldeh de
Figure imgf000106_0001
A solution of l-[2-(dimethylamino)ethyl]-6-(indan-2-ylamino)-N-methoxy-N-methyl-4- oxo-[l,8]naphthyridine-3-carboxamide (215 mg, 0.41 mmol) in CH2C12 (10 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (1.04 ml, 1.04 mmol) according to General Procedure P, leading without purification to the expected compound as an orange solid (183 mg).
1H NMR (300 MHz, OMSO-d6) δ 10.16 (s, 1H), 8.49 (s, 1H), 8.33 (d, = 3.0 Hz, 1H), 7.60 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.83 (d, = 6.4 Hz, 1H), 4.52 (t, = 5.7 Hz, 2H), 4.35-4.30 (m, 1H), 3.40-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, = 15.9, 4.5 Hz, 2H), 2.59 (t, = 5.7 Hz, 2H), 2.16 (s, 6H). ESIMS m/z [M+H]+ 377.2.
Intermediate BW: 6-(Indan-2-ylamino)-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyri- din-3-carbaldehyde
Figure imgf000106_0002
A solution of 6-(indan-2-ylamino)-N-methoxy-N-methyl-l-(2-morpholinoethyl)-4-oxo- [l,8]naphthyridine-3-carboxamide (230 mg, 0.48 mmol) in CH2C12 (10 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (1.01 ml, 1.01 mmol) according to General Procedure P, leading without purification to the expected compound as a brown solid used directly for next step.
ESJ S m/z [M+H]+ 419.4.
Intermediate BX: 6-Amino-l-ethyl-3-(hydroxymethyl)- [l,8]naphthyridin-4-one
Figure imgf000107_0001
BT BX
A suspension of 6-amino- l-ethyl-4-oxo-[l,8]naphthyridin-3-carbaldehyde (410 mg, 1.89 mmol) in methanol (30 ml) at RT was treated with sodium borohydride (79 mg, 2.08 mmol) according to General Procedure Q and worked up using Method B. The crude was purified by flash chromatography (CH2C12/CH30H 100:0→ 90: 10) leading to the expected compound (273 mg, 39% over 2 steps) as a red solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.24 (d, = 3.0 Hz, 1H), 7.94 (s, 1H), 7.60 (d, = 3.0 Hz, 1H), 5.53 (s, 2H), 4.86 (t, = 5.4 Hz, 1H), 4.39-4.32 (m, 4H), 1.29 (t, = 7.0 Hz, 3H). ESJMS m/z [M+H]+ 220.0.
Intermediate BY: 3-(Hydroxymethyl)-6-(indan-2-ylamino)-l-(methoxyethyl)- [l,8]naphthyridin-4-one
Figure imgf000107_0002
A suspension of 6-(indan-2-ylamino)-l-(2-methoxyethyl)-4-oxo-[l,8]naphthyridin-3- carbaldehyde (170 mg, 0.47 mmol) in methanol (10 ml) at RT was treated with sodium borohydride (35 mg, 0.94 mmol) according to General Procedure Q and worked up using Method B. The crude was purified by flash chromatography (CH2C12/CH30H 100:0→ 93:7) leading to the expected compound (125 mg, 73%) as a yellow solid.
ESIMS m/z [M+H]+ 366.2.
Intermediate BZ: l-[2-(Dimethylamino)ethyl]-3-(hydroxymethyl)-6-(indan-2-yl- amino)-[l,8]naphthyridin-4-one
A suspension of l-[2-(dimethylamino)ethyl]-6-(indan-2-ylamino)-4-oxo- [l,8]naphthyridin-3-carbaldehyde (183 mg, 0.49 mmol) in methanol (10 ml) at RT was treated with sodium borohydride (21 mg, 0.54 mmol) according to General Procedure Q and worked up using Method B. The crude was purified by flash chromatography (CH2C12/CH30H 100:0→ 80:20) leading to the expected compound (109 mg, 58% over 2 steps) as a yellow solid.
1H NMR (300 MHz, DMSC fc) δ 8.31 (d, = 3.0 Hz, 1H), 7.91 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.12 (m, 2H), 6.46 (d, = 6.5 Hz, 1H), 4.90 (t, = 5.3 Hz, 1H), 4.44-4.38 (m, 4H), 4.31-4.26 (m, 1H), 3.37-3.30 (dd, / = 16.0, 7.0 Hz, 2H), 2.86- 2.79 (dd, = 15.9, 4.5 Hz, 2H), 2.58 (t, = 6.2 Hz, 2H), 2.16 (s, 6H). ESIMS m/z [M+H]+ 379.3.
Intermediate C A : 3- (Hydroxymethyl) -6- (indan-2-ylamino) - 1 - (2-morpholinoethyl) - [l,8]naphthyridin-4-one
Figure imgf000109_0001
A suspension of 6-(indan-2-ylamino)-l-(2-morpholinoethyl)-4-oxo-[l,8]naphthyridin-3- carbaldehyde (0.48 mmol) in methanol (10 ml) at RT was treated with sodium borohydride (20 mg, 0.53 mmol) according to General Procedure Q and worked up using Method B . The crude was purified by flash chromatography (AcOEt/CH3OH 100:0→ 80:20) leading to the expected compound (104 mg, 51% over 2 steps) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.94 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.46 (d, = 6.5 Hz, 1H), 4.88 (t, = 5.3 Hz, 1H), 4.45 (t, = 6.3 Hz, 2H), 4.38 (d, = 5.2 Hz, 2H), 4.31-4.25 (m, 1H), 3.50 (t, = 4.3 Hz, 4H), 3.38-3.30 (dd, = 16.0, 7.0 Hz, 2H), 2.86-2.79 (dd, = 15.9, 4.5 Hz, 2H), 2.61 (t, J = 6.3 Hz, 2H), 2.41 (t, J = 4.1 Hz, 4H). ESIMS m/z [M+H]+ 421.3. Intermediate CB: 6-Amino-3-(azidomethyl)-l-ethyl-[l,8]naphthyridin-4-one
Figure imgf000109_0002
To a suspension of 6-amino- l-ethyl-3-(hydroxymethyl)-[l,8]naphthyridin-4-one (270 mg, 1.23 mmol) in anhydrous THF (20 ml) was diphenyl phosphoryl azide (0.53 ml, 2.46 mmol) according to General Procedure R (18h heating at 60°C). The crude was purified by flash chromatography (CH2Cl2/CH3OH 100:0→ 90: 10) to furnish the expected compound as a yellow powder (146 mg, 48%).
1H NMR (300 MHz, DMSO-i¾) δ 8.27 (d, = 3.0 Hz, 1H), 8.22 (s, 1H), 7.61 (d, = 3.0 Hz, 1H), 5.64 (s, 2H), 4.33 (qd, = 7.1 Hz, 2H), 4.21 (s, 2H), 1.30 (t, = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 245.1.
Intermediate CC: 3-Azidomethyl-6-(indan-2-ylamino)-l-(2-methoxyethyl)-[l,8]naph- thyridin-4-one
Figure imgf000110_0001
To a suspension of 3-(hydroxymethyl)-6-(indan-2-ylamino)-l-(methoxyethyl)-[l,8]naph- thyridin-4-one (125 mg, 0.34 mmol) in anhydrous THF (10 ml) was added diphenyl phosphoryl azide (0.15 ml, 0.68 mmol) according to General Procedure R (5 days heating at 60°C). The crude was purified by flash chromatography (CH2CI2/CH3OH 100:0→ 98:2) to furnish the expected compound as a yellow sticky solid (73 mg, 55%).
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.15 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.60 (d, = 6.5 Hz, 1H), 4.48 (t, = 5.1 Hz, 2H), 4.33-4.27 (m, 1H), 4.22 (s, 2H), 3.65 (t, = 5.1 Hz, 2H), 3.39-3.31 (dd, / = 16.1, 7.0 Hz, 2H), 3.19 (s, 3H), 2.87-2.80 (dd, / = 16.0, 4.4 Hz, 2H). ESIMS m/z [M+H]+ 391.2.
Intermediate CD: 3-(Azidomethyl)-l-[2-(dimethylamino)ethyl]-6-(indan-2-ylamino)- [l,8]naphthyridin-4-one
Figure imgf000110_0002
To a suspension of l-[2-(dimethylamino)ethyl]-3-(hydroxymethyl)-6-(indan-2-yl-amino)- [l,8]naphthyridin-4-one (109 mg, 0.29 mmol) in anhydrous THF (10 ml) was added diphenyl phosphoryl azide (0.12 ml, 0.58 mmol) according to General Procedure R (18h at RT). The crude was purified by flash chromatography (CH2C12/CH30H 100:0→ 90: 10) to furnish the expected compound as a yellow solid (60 mg, 51%). 1H NMR (300 MHz, OMSO-d6) δ 8.34 (d, = 3.0 Hz, 1H), 8.18 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.57 (d, = 6.5 Hz, 1H), 4.40 (t, = 6.3 Hz, 2H), 4.33-4.27 (m, 1H), 4.22 (s, 2H), 3.39-3.30 (dd, = 16.1, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.4 Hz, 2H), 2.59 (t, = 6.1 Hz, 2H), 2.15 (s, 6H). ESIMS m/z [M+H]+ 404.3.
Intermediate CE: 3-(Azidomethyl)-6-(indan-2-ylamino)-l-(2-morpholinoethyl)-[l,8] naphthyridin-4-one
Figure imgf000111_0001
To a suspension of 3-(hydroxymethyl)-6-(indan-2-ylamino)- l-(2-morpholinoethyl)-[l,8] naphthyridin-4-one (104 mg, 0.24 mmol) in anhydrous THF (10 ml) was added diphenyl phosphoryl azide (0.11 ml, 0.49 mmol) according to General Procedure R (18h at RT). The crude was purified by flash chromatography (AcOEt/CH3OH 100:0→ 80:20) to furnish the expected compound as a yellow foam (42 mg, 38%).
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.18 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.57 (d, = 6.5 Hz, 1H), 4.43 (t, = 5.9 Hz, 2H), 4.33-4.27 (m, 1H), 4.23 (s, 2H), 3.49 (t, = 4.3 Hz, 4H), 3.39-3.30 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, = 15.9, 4.5 Hz, 2H), 2.63 (t, = 5.9 Hz, 2H), 2.40 (brs, 4H). ESIMS m/z [M+H]+ 446.3. Intermediate CF: Ethyl 6-bromo-l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-4-oxo- [l,8]naphthyridine-3-carboxylate - I l l -
Figure imgf000112_0001
Ethyl 2-(5-bromo-2-chloro-pyridine-3-carbonyl)-3-ethoxy-prop-2-enoate (10.5 g, 86.9 mmol) and 2-[tert-butyl(dimethyl)silyl]oxyethyl amine (18.6 g, 261 mmol) were reacted as described under General Procedure L (18h at 80°C) to furnish the title compound (10.3 g, 80%) as a yellow sticky solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.95 (d, = 2.5 Hz, 1H), 8.74 (s, 1H), 8.64 (d, = 2.5 Hz, 1H), 4.57 (t, = 4.7 Hz, 2H), 4.23 (qd, J = 1.1 Hz, 2H), 3.88 (t, = 4.7 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 0.72 (s, 9H), -0.22 (s, 6H). ESIMS m/z [M+H]+ 455.4.
Intermediate CG: Ethyl 6-bromo-l-{2-[tert-butoxycarbonyl(methyl)amino]ethyl}-4- oxo- [ 1 ,8] naphthyridine-3-carboxylate
Figure imgf000112_0002
Ethyl 2-(5-bromo-2-chloro-pyridine-3-carbonyl)-3-ethoxy-prop-2-enoate (9.5 g, 26.1 mmol) and N-Boc-N-methylethylenediamine (10.2 ml, 57.3 mmol) were reacted as described under General Procedure L (43h at 80°C) to furnish the title compound (9.5 g, 80%) as a yellow glue.
1H NMR (300 MHz, DMSO-rf*) δ 8.99 (d, / = 2.5 Hz, 1H), 8.74-8.62 (m, 2H), 4.60 (t, / = 4.7 Hz, 2H), 4.24 (qd, = 7.1 Hz, 2H), 3.66-3.51 (m, 2H), 2.85 (2s, 3H), 1.28 (t, = 7.1 Hz, 3H), 1.13 and 0.90 (2s, 9H).
Intermediate CH: 6-Bromo-l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-4-oxo-[l,8]naph- thyridine-3-carboxylic acid
Figure imgf000113_0001
Ethyl 6-bromo- 1 - { 2- [tert-butyl(dimethyl) silyl] oxyethyl } -4-oxo- [ 1 ,8] naphthyridine-3 - carboxylate (10.3 g, 22.7 mmol) and potassium hydroxide (2.55 g, 45.5 mmol) were reacted as described under General Procedure N (3h at 80°C) to furnish a white solid (6.70 g) corresponding to the desilylated carboxylic acid. This compound was solubilized in DMF (100 ml) in presence of diisopropylethylamine (5.20 ml, 30.0 mmol) before addition of tert-butyldimethylsilyl chloride (3.9 g, 25.7 mmol). The mixture was heated at 60°C for 7 days. After cooling, water (400 ml) and IN HC1 (50 ml) were added. The suspension was filtered off. The grey solid recovered was dried leading to the title compound (7.8 g, 94%).
ESIMS m/z [M+H]+ 427.3.
Intermediate CI: 6-Bromo-l-{2-[tert-butoxycarbonyl(methyl)amino]ethyl}-4-oxo- [l,8]naphthyridine-3-carboxylic acid
Figure imgf000113_0002
Ethyl 6-bromo- l-{2-[tert-butoxycarbonyl(methyl)amino]ethyl}-4-oxo-[l,8]naphthyridine- 3-carboxylate (9.5 g, 20.9 mmol) and potassium hydroxide (2.34 g, 41.7 mmol) were reacted as described under General Procedure N (3 days at RT) to furnish the title compound (8.0 g, 90%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 14.39 and 14.36 (2s, 1H), 9.18 (s, 1H), 9.15 and 9.09 (2s, 1H), 8.92 and 8.87 (2s, 1H), 4.78 (brs, 2H), 3.70-3.53 (m, 2H), 2.89 and 2.87 (2s, 3H), 1.10 and 0.85 (2s, 9H). ESIMS m/z [M+H]+ 428.0.
Intermediate CJ: l-{2-[Tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-4- oxo- [ 1 ,8] naphthyridine-3-carboxylic acid
Figure imgf000114_0001
6-Bromo- 1 - { 2- [tert-butyl (dimethyl) silyl] oxyethyl } -4-oxo- [ 1 , 8] naph-thyridine-3 - carboxylic acid (4.9 g, 11.5 mmol) and 2-aminoindan (1.99 g, 14.9 mmol) were reacted as described under General Procedure M (4h at RT) to furnish without purification the title compound (5.14 g) as a brown solid which was directly used in the next step.
ESIMS m/z [M+H]+ 480.4.
Intermediate CK: l-{2-[Tert-butoxycarbonyl(methyl)amino]ethyl}-6-(indan-2- ylamino)-4-oxo-[l,8]naphthyridine-3-carboxylic acid
Figure imgf000114_0002
6-Bromo- 1 -{ 2-[tert-butoxycarbonyl(methyl)amino]ethyl} -4-oxo-[ 1 ,8]naphthyridine-3- carboxylic acid (2.0 g, 4.69 mmol) and 2-aminoindan (0.80 ml, 6.1 mmol) were reacted as described under General Procedure M (4h at RT) to furnish without purification the title compound (965 mg) as a yellow solid which was directly used for next step.
ESMS m/z [M+H]+ 479.3.
Intermediate CL: l-{2-[Tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-N- methoxy-N-methyl-4-oxo-[l,8]naphthyridine-3-carboxamide
Figure imgf000115_0001
l-{2-[Tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-4-oxo-[l,8]naphthyridine- 3-carboxylic acid (5.5 g, 11.5 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (1.35 g, 13.8 mmol) were reacted as described under General Procedure O (18h at RT). The crude was purified by flash chromatography (CH2Cl2/AcOEt 100:0→ 0: 100) leading to the title compound as a brown sticky foam (3.79 g, 63% over 2 steps).
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 8.08 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.63 (d, = 6.5 Hz, 1H), 4.47 (t, = 4.8 Hz, 2H), 4.35-4.28 (m, 1H), 3.88 (t, J = 4.8 Hz, 2H), 3.62 (s, 3H), 3.38-3.30 (dd, J = 16.0, 7.0 Hz, 2H), 3.15 (s, 3H), 2.86-2.79 (dd, 7 = 15.9, 4.5 Hz, 2H), 0.73 (s, 9H), -0.19 (s, 6H). ESIMS m/z [M+H]+ 523.4. Intermediate CM: Tert-butyl N-{2-{6-(indan-2-ylamino)-3-[methoxy(methyl)carba- moyl]-4-oxo-[l,8]naphthyridin-l-yl}ethyl}-N-methyl-carbamate
Figure imgf000115_0002
l-{2-[Tert-butoxycarbonyl(methyl)amino]ethyl}-6-(indan-2-ylamino)-4-oxo-[l,8]naphthy- ridine- 3-carboxylic acid (960 mg, 2.00 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (234 mg, 2.40 mmol) were reacted as described under General Procedure O (72h at RT). The crude was purified by flash chromatography (AcOEt/CH3OH 100:0→ 90: 10) leading to the title compound as a yellow foam (1.0 g, 40% over 2 steps).
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.11 and 8.07 (2s, 1H), 7.55 and 7.54 (2d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.14 (m, 2H), 6.62 (d, = 6.6 Hz, 1H), 4.49-4.42 (m, 2H), 4.35-4.28 (m, 1H), 3.61 (s, 3H), 3.59-3.55 (m, 2H), 3.39-3.30 (dd, J = 16.0, 7.0 Hz, 2H), 3.17 (s, 3H), 2.87-2.80 (dd, 7 = 15.9, 4.5 Hz, 2H), 2.79 (s, 3H), 1.22 and 0.94 (2s, 9H). ESIMS m/z [M+H]+ 522.3. Intermediate CN: l-{2-[Tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-4- oxo- 1 ,8] naphthyridine-3-carbaldehyde
Figure imgf000116_0001
A solution of l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-N-methoxy- N-methyl-4-oxo-[l,8]naphthyridine-3-carboxamide (910 mg, 1.74 mmol) in CH2C12 (50 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (3.7 ml, 3.7 mmol) according to General Procedure P, leading without purification to the expected compound as a brown solid (625 mg, 77%). 1H NMR (300 MHz, DMSO-i¾) δ 10.16 (s, 1H), 8.43 (s, 1H), 8.33 (d, = 3.0 Hz, 1H), 7.61 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.18-7.13 (m, 2H), 6.84 (d, = 6.6 Hz, 1H), 4.56 (t, = 4.8 Hz, 2H), 4.37-4.21 (m, 1H), 3.89 (t, = 4.8 Hz, 2H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, J = 15.9, 4.5 Hz, 2H), 0.70 (s, 9H), -0.23 (s, 6H). ESIMS m/z [M+H]+ 464.4.
Intermediate CO: Tert-butyl N-{2-[3-formyl-6-(indan-2-ylamino)-4-oxo- [l,8]na hthy-ridin-l-yl]ethyl}-N-methyl-carbamate
Figure imgf000116_0002
A solution of tert-butyl N-{2-[6-(indan-2-ylamino)-3-[methoxy(methyl)carbamoyl]-4-oxo- [l,8]naphthyridin-l-yl]ethyl}-N-methyl-carbamate (1.0 g, 1.92 mmol) in CH2C12 (60 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2C12 (4.0 ml, 4.0 mmol) according to General Procedure P, leading without purification to the expected compound as an orange foam (780 mg, 88%).
1H NMR (300 MHz, OMSO-d6) δ 10.15 (s, 1H), 8.42 and 8.38 (2s, 1H), 8.34 (d, J = 3.0 Hz, 1H), 7.62 and 7.60 (2d, J = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.19-7.14 (m, 2H), 6.83 (d, 7 = 6.6 Hz, 1H), 4.60-4.54 (m, 2H), 4.40-4.34 (m, 1H), 3.66-3.57 (m, 2H), 3.40-3.33 (dd, J = 16.0, 7.0 Hz, 2H), 2.88-2.79 (m, 5H), 1.16 and 0.90 (2s, 9H). ESIMS m/z [M+H]+ 463.3.
Intermediate CP: l-{2-[Tert-butyl(dimethyl)silyl]oxyethyl}-3-(hydroxymethyl)-6- (indan-2-ylamino) - [ 1 ,8] naphthyridine-4-one
Figure imgf000117_0001
A suspension of l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-4-oxo- [l,8]naphthyridine-3-carbaldehyde (625 mg, 1.35 mmol) in methanol (50 ml) at RT was treated with sodium borohydride (102 mg, 2.70 mmol) according to General Procedure Q and worked up using Method B. The crude was purified by flash chromatography (cyclohexane/AcOEt 100:0→ 0: 100 then AcOEt/CH3OH 100:0→ 80:20) leading to the expected compound (501 mg, 80%) as a yellow sticky solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.88 (s, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.25-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.46 (d, = 6.6 Hz, 1H), 4.86 (t, = 5.2 Hz, 1H), 4.43 (t, = 4.9 Hz, 2H), 4.37 (d, = 5.1 Hz, 2H), 4.37-4.22 (m, 1H), 3.87 (t, = 4.9 Hz, 2H), 3.37-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.85-2.79 (dd, = 15.9, 4.5 Hz, 2H), 0.73 (s, 9H), -0.22 (s, 6H). ESIMS m/z [M+H]+ 466.4.
Intermediate CQ: Tert-butyl N-{2-[3-(hydroxymethyl)-6-(indan-2-ylamino)-4-oxo- [l,8]naphthyridin-l-yl]ethyl}-N-methyl-carbamate
Figure imgf000118_0001
A suspension of tert-butyl N-{2-[3-formyl-6-(indan-2-ylamino)-4-oxo-[l,8]naphthyridin-l- yl] ethyl }- V-methyl-carbamate (780 mg, 1.69 mmol) in methanol (50 ml) at RT was treated with sodium borohydride (128 mg, 3.37 mmol) according to General Procedure Q and worked up using Method B. The crude was purified by flash chromatography (cyclohexane/AcOEt 100:0→ 0: 100 then AcOEt/CH3OH 100:0→ 80:20) leading to the expected compound (440 mg, 56%) as an orange solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 7.80 (s, 1H), 7.53 (brs, 1H), 7.27-7.23 (m, 2H), 7.18-7.14 (m, 2H), 6.46 (d, = 6.7 Hz, 1H), 4.95-4.91 (m, 1H), 4.47- 4.41 (m, 2H), 4.38 (d, J = 5.0 Hz, 2H), 4.33-4.26 (m, 1H), 3.60-3.53 (m, 2H), 3.38-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.86-2.70 (m, 5H), 1.24 and 0.94 (2s, 9H). ESIMS m/z [M+H]+ 465.3.
Intermediate CR: 3-(Azidomethyl)-l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan- 2-ylamino -[l,8]naphthyridine-4-one
Figure imgf000118_0002
To a suspension of l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-3-(hydroxymethyl)-6-(indan- 2-ylamino)-[l,8]naphthyridine-4-one (500 mg, 1.07 mmol) in anhydrous THF (30 ml) was added diphenyl phosphoryl azide (0.46 ml, 2.14 mmol) according to General Procedure R (18h heating at 60°C). The crude was purified by flash chromatography (cyclohexane/AcOEt 100:0 → 30:70) to furnish the expected compound as a yellow powder (142 mg, 27%).
1H NMR (300 MHz, OMSO-d6) δ 8.33 (d, = 3.0 Hz, 1H), 8.11 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.57 (d, = 6.4 Hz, 1H), 4.42 (t, = 4.8 Hz, 2H), 4.33-4.27 (m, 1H), 4.21 (s, 2H), 3.91 (t, J = 4.8 Hz, 2H), 3.39-3.31 (dd, J = 16.1, 7.0 Hz, 2H), 2.86-2.80 (dd, J = 16.0, 4.4 Hz, 2H), 0.73 (s, 9H), -0.22 (s, 6H). ESIMS m/z [M+H]+ 491.4.
Intermediate CS: Tert-butyl N-{2-[3-(azidomethyl)-6-(indan-2-ylamino)-4-oxo-[l,8] naphthyridin-l-yl]ethyl}-N-methyl-carbamate
Figure imgf000119_0001
To a suspension of tert-butyl N-{2-{3-(hydroxymethyl)-6-(indan-2-ylamino)-4-oxo- [l,8]naphthyridin-l-yl}ethyl}-N-methyl-carbamate (1.6 g, 3.44 mmol) in anhydrous THF (100 ml) was added diphenyl phosphoryl azide (1.48 ml, 6.89 mmol) according to General Procedure R (18h at RT). The crude was purified by flash chromatography (cyclohexane/AcOEt 100:0→ 0: 100 then AcOEt/CH3OH 100:0→ 80:20) to furnish the expected compound as a yellow solid (700 mg, 41%).
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.04 (s, 1H), 7.54 (d, = 2.6 Hz, 1H), 7.25-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.55 (d, = 6.5 Hz, 1H), 4.43-4.38 (m, 2H), 4.33-4.28 (m, 1H), 4.20 (s, 2H), 3.63-3.50 (m, 2H), 3.38-3.30 (dd, = 16.1, 7.0 Hz, 2H), 2.85-2.68 (m, 5H), 1.21 and 0.90 (2s, 9H). ESIMS m/z [M+H]+ 490.3.
Example 1: l-Ethyl-6-(indan-2-ylamino)-3-trimethylsilanylethynyl-lH-[l,8] naphthyridin-4-one
Figure imgf000119_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (400 mg, 0.93 mmol) and ethynyltrimethylsilane (109 mg, 1.11 mmol) were reacted as described under General Procedure A (4h at RT) to furnish the title compound (326 mg, 87%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.39 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 6.67 (brd, = 6.5 Hz, 1H), 4.36 (qd, = 6.9 Hz, 2H), 4.33-4.27 (m, 1H), 3.38-3.29 (dd, = 16.0, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 402.4. Example 2: 3-(3-Dimethylamino-prop-l-ynyl)-l-ethyl-6-(indan-2-ylamino)- 1H-[1,8]- naphthyridin-4-one
Figure imgf000120_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (300 mg, 0.70 mmol) and l-dimethylamino-2-propyne (69 mg, 0.83 mmol) were reacted as described under General Procedure A (2h at 80°C) to furnish the title compound (62 mg, 23%) as a brown-orange solid. 1H NMR (300 MHz, DMSO-i¾) δ 9.66 (s, 1H), 8.75 (d, = 3.0 Hz, 1H), 7.80 (d, = 6.7 Hz, 1H), 7.56 (d, = 3.0 Hz, 1H), 7.38 (s, 1H), 7.30-7.26 (m, 2H), 7.19-7.16 (m, 2H), 5.04 (qd, = 7.2 Hz, 2H), 4.60-4.52 (m, 1H), 3.79 (brs, 2H), 3.47-3.39 (dd, = 16.0, 6.9 Hz, 2H), 2.94-2.87 (dd, = 16.0, 4.1 Hz, 2H), 2.27 (brs, 6H), 1.55 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 387.3.
Example 3: l-Ethyl-3-(3-hydroxy-prop-l-ynyl)-6-(indan-2-ylamino)-lH-[l,8]- naphthyridin-4-one
Figure imgf000121_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and propargyl alcohol (32 mg, 0.55 mmol) were reacted as described under General Procedure A (18h at 80°C) to furnish the title compound (8 mg, 4%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 9.66 (s, 1H), 8.77 (d, = 3.0 Hz, 1H), 7.84 (d, = 6.5 Hz, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.34 (s, 1H), 7.30-7.27 (m, 2H), 7.19-7.16 (m, 2H), 5.85 (t, = 5.6 Hz, 1H), 5.04 (qd, = 7.0 Hz, 2H), 4.77 (d, = 5.6 Hz, 1H), 4.52-4.48 (m, 1H), 3.49-3.40 (dd, = 16.2, 7.1 Hz, 2H), 2.96-2.89 (dd, = 16.0, 4.2 Hz, 2H), 1.56 (t, = 7.0 Hz, 3H). ESJ S m/z [M+H]+ 360.3. l-Ethyl-3-(4-hydroxy-but-l-ynyl)-6-(indan-2-ylamino)-lH-
Figure imgf000121_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (300 mg, 0.70 mmol) and propargyl alcohol (59 mg, 0.83 mmol) were reacted as described under General Procedure A (lh at 80°C) to furnish the title compound (49 mg, 19%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 9.64 (s, 1H), 8.76 (d, = 2.8 Hz, 1H), 7.85 (d, = 6.7 Hz, 1H), 7.56 (d, / = 3.0 Hz, 1H), 7.30-7.27 (m, 2H), 7.23 (s, 1H), 7.19-7.16 (m, 2H), 5.04-4.96 (m, 3H), 4.55-4.51 (m, 1H), 4.86 (qd, = 6.0 Hz, 2H), 3.48-3.40 (dd, = 16.2, 7.1 Hz, 2H), 3.13 (t, = 6.1 Hz, 2H), 2.95-2.88 (dd, = 16.1, 4.2 Hz, 2H), 1.54 (t, J = 7.1 Hz, 3H). ESJMS m/z [M+H]+ 374.3.
Example 5: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-2-ylethynyl)-lH- [l,8]na hthyridin-4-one
Figure imgf000122_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (216 mg, 0.50 mmol) and
2- ethynyl- l -methyl- IH-imidazole (95 mg, 0.90 mmol) were reacted as described under General Procedure A (18h at RT) to furnish the title compound (41 mg, 20%) as an orange foam.
1H NMR (300 MHz, DMSC fc) δ 8.58 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 8.20 (s, 1H), 7.84 (d, = 6.5 Hz, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.28 (s, 1H), 7.27-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.96 (s, 1H), 6.73 (d, J = 6.5 Hz, 1H), 4.43-4.27 (m, 3H), 3.76 (s, 3H), 3.39-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.4 Hz, 2H), 1.35 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 410.4.
Example 6: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-pyrazol-4-ylethynyl)-lH- [l,8]naphthyridin-4-one
Figure imgf000122_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (216 mg, 0.50 mmol) and 4-ethynyl- l -methyl- lH-pyrazole (95 mg, 0.90 mmol) were reacted as described under General Procedure A (18h at RT) to furnish the title compound (16 mg, 7%) as a yellow foam.
1H NMR (300 MHz, DMSC fc) δ 9.66 (s, 1H), 8.75 (d, J = 3.0 Hz, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.86 (d, = 6.4 Hz, 1H), 7.61 (d, = 3.0 Hz, 1H), 7.50 (s, 1H), 7.31-7.28 (m, 2H), 7.20-7.17 (m, 2H), 5.04 (qd, = 6.9 Hz, 2H), 4.54-4.49 (m, 1H), 3.94 (s, 3H), 3.52-3.44 (dd, = 16.0, 7.1 Hz, 2H), 2.97-2.90 (dd, = 16.0, 4.8 Hz, 2H), 1.56 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 410.4.
Example 7: l-Ethyl-6-(indan-2-ylamino)-3-(3-methyl-3H-imidazol-4-ylethynyl)-lH- [l,8]naphthyridin-4-one
Figure imgf000123_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (300 mg, 0.67 mmol) and 5 -ethynyl-1 -methyl- IH-imidazole (111 mg, 1.04 mmol) were reacted as described under General Procedure A (18h at RT) to furnish the title compound (161 mg, 56%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.52 (s, 1H), 8.35 (d, = 3.0 Hz, 1H), 7.75 (brs, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.12 (m, 3H), 6.71 (d, = 6.4 Hz, 1H), 4.42-4.30 (m, 3H), 3.69 (s, 3H), 3.38-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.79 (dd, = 16.0, 4.3 Hz, 2H), 1.33 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 410.4.
Example 8: l-Ethyl-3-ethynyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000123_0002
To a solution of l-ethyl-6-(indan-2-ylamino)-3-trimethylsilanylethynyl-lH-[l,8] naph- thyridin-4-one (2.54 g, 6.3 mmol) in anhydrous THF (63 ml) at RT was added 1 M tetrabutylammonium fluoride in THF (7.60 ml, 7.6 mmol). The reaction mixture was stirred for lh, quenched with water (20 ml) and concentrated in vacuo. The aqueous layer was extracted with CH2CI2 (2 x 30 ml). The combined organic layers were dried over MgS04, filtered off and concentrated in vacuo. The crude obtained was purified by flash chromatography (Si02, CH2Cl2/AcOEt) to furnish the title compound (1.79 g, 86%) as yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.34 (s, 1H), 8.34 (d, J = 3.0 Hz, 1H), 7.50 (d, J = 3.0 Hz, 1H), 7.25-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.65 (d, = 6.5 Hz, 1H), 4.40-4.27 (m, 3H), 3.98 (s, 1H), 3.38-3.30 (dd, J = 16.0, 7.0 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 330.3.
Figure imgf000124_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol) and 2-(tributylstannyl)furan (335 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (195 mg, 67%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.54 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 7.62 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.19 (d, = 3.0 Hz, 1H), 7.16-7.13 (m, 2H), 6.62 (d, = 6.3 Hz, 1H), 6.55 (t, = 1.6 Hz, 1H), 4.50 (qd, = 7.0 Hz, 2H), 4.34-4.28 (m, 1H), 3.40-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.89-2.81 (dd, = 16.0, 4.4 Hz, 2H), 1.35 (t, = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 372.3.
Exam le 10: l-Ethyl-3-furan-2-yl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000124_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (500 mg, 1.16 mmol) and
2- (tributylstannyl)oxazole (498 mg, 1.39 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (140 mg, 32%) as a yellow solid. 1H NMR (300 MHz, OMSO-d6) δ 8.72 (s, 1H), 8.37 (d, / = 3.0 Hz, 1H), 8.13 (s, 1H), 7.60 (d, = 3.0 Hz, 1H), 7.28 (s, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.72 (d, = 6.5 Hz, 1H), 4.47 (qd, = 6.5 Hz, 2H), 4.35-4.31 (m, 1H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.89-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.35 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 373.3.
Example 11: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-2-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000125_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (500 mg, 1.16 mmol) and l-methyl-2-(tributylstannyl)imidazole (516 mg, 1.39 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (25 mg, 5%) as a yellow solid.
1H NMR (300 MHz, DMSC fc) δ 8.38 (d, = 3.0 Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.59 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.20 (s, 1H), 7.17-7.13 (m, 2H), 6.90 (d, = 0.8 Hz, 1H), 6.65 (d, = 6.5 Hz, 1H), 4.44 (qd, = 6.9 Hz, 2H), 4.35-4.29 (m, 1H), 3.53 (s, 3H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.4.
Exam le 12: l-Ethyl-6-(indan-2-ylamino)-3-thiazol-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000125_0002
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (280 mg, 0.73 mmol) and 2-(tributylstannyl)thiazole (327 mg, 0.87 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (100 mg, 35%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 9.13 (s, 1H), 8.40 (d, J = 3.0 Hz, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.66 (d, = 3.0 Hz, 1H), 7.58 (d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.16-7.14 (m, 2H), 6.78 (d, = 6.3 Hz, 1H), 4.58 (qd, = 6.9 Hz, 2H), 4.37-4.31 (m, 1H), 3.42-3.34 (dd, = 16.1, 7.0 Hz, 2H), 2.90-2.83 (dd, = 16.0, 4.3 Hz, 2H), 1.39 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 389.3. Example 13: l-Ethyl-6-(indan-2-ylamino)-3-thiazol-5-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000126_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 5-(tributylstannyl)- l,3-thiazole (208 mg, 0.56 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (144 mg, 80%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.98 (s, 1H), 8.90 (s, 1H), 8.46 (s, 1H), 8.38 (d, = 3.0 Hz, 1H), 7.61 (d, = 2.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.72 (d, = 6.3 Hz, 1H), 4.50 (qd, = 6.6 Hz, 2H), 4.35-4.29 (m, 1H), 3.40-3.32 (dd, = 16.1, 6.9 Hz, 2H), 2.89-2.82 (dd, J = 16.0, 4.3 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 389.3.
Example 14: l-Ethyl-6-(indan-2-ylamino)-3-thiazol-4-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000126_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 4-(tributylstannyl)- l,3-thiazole (208 mg, 0.56 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (136 mg, 75%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 9.14 (s, 1H), 9.01 (s, 1H), 8.63 (s, 1H), 8.38 (d, = 2.6 Hz, 1H), 7.67 (d, = 2.5 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.65 (d, = 6.3 Hz, 1H), 4.52 (qd, = 6.7 Hz, 2H), 4.35-4.29 (m, 1H), 3.40-3.32 (dd, = 16.1, 6.9 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.3 Hz, 2H), 1.36 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 389.3.
Example 15: l-Ethyl-6-(indan-2-ylamino)-3-(3-methyl-3H-imidazol-4-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000127_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol) and l-methyl-5-(tributylstannyl)-imidazole (347 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (126 mg, 42%) as a yellow solid. 1H NMR (300 MHz, DMSC fc) δ 8.38 (d, = 3.0 Hz, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 7.58 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.85 (d, = 0.9 Hz, 1H), 6.59 (d, = 6.5 Hz, 1H), 4.40 (qd, = 6.8 Hz, 2H), 4.35-4.29 (m, 1H), 3.52 (s, 3H), 3.39-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.3.
Example 16: l-Ethyl-6-(indan-2-ylamino)-3-(2-methyl-2H-pyrazol-3-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000128_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol) and l-methyl-5-(tributylstannyl)- lH-pyrazole (347 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (178 mg, 59%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.38 (d, = 3.0 Hz, 1H), 8.21 (s, 1H), 7.59 (d, = 3.0 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.63 (d, J = 6.5 Hz, 1H), 6.24 (d, J = 1.8 Hz, 1H), 4.41 (qd, J = 6.8 Hz, 2H), 4.35-4.29 (m, 1H), 3.69 (s, 3H), 3.39-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.4.
Example 17: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-pyrazol-4-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000128_0002
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol) and l-methyl-4-(tributylstannyl)-pyrazole (347 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (1 16 mg, 38%) as a yellow solid.
1H NMR (300 MHz, DMSC fc) δ 8.53 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 7.98 (s, 1H), 7.61 (d, = 3.0 Hz, 1H), Ί .26-1.23 (m, 2H), 7.16-7.13 (m, 2H), 6.52 (d, = 6.4 Hz, 1H), 4.43 (qd, J = 7.0 Hz, 2H), 4.33-4.27 (m, 1H), 3.85 (s, 3H), 3.39-3.32 (dd, J = 15.9, 6.9 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.6 Hz, 2H), 1.35 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.3. Example 18: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-4-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000129_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol) and N-methyl-4-(tributylstannyl)-imidazole (347 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (217 mg, 72%) as a yellow solid.
1H NMR (300 MHz, DMSC fc) δ 8.68 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.58 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.52 (d, = 6.4 Hz, 1H), 4.48 (qd, J = 6.9 Hz, 2H), 4.35-4.29 (m, 1H), 3.68 (s, 3H), 3.40-3.31 (dd, J = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.28 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.3.
Example 19: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-pyrrol-2-yl)-lH-[l,8] naphth ridin-4-one
Figure imgf000129_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (300 mg, 0.69 mmol) and l-methyl-2-(tributylstannyl)-pyrrole (309 mg, 0.83 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (24 mg, 9%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 3.0 Hz, 1H), 8.08 (s, 1H), 7.58 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.77 (s, 1H), 6.56 (d, = 6.5 Hz, 1H), 6.00-5.96 (m, 2H), 4.39-4.29 (m, 3H), 3.47 (s, 3H), 3.39-3.31 (dd, 7 = 16.2, 7.0 Hz, 2H), 2.87-2.80 (dd, 7 = 16.0, 4.4 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H). ESJ S m/z [M+H]+ 385.4.
Exam le 20: l-Ethyl-6-(indan-2-ylamino)-3-pyridin-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000130_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (300 mg, 0.69 mmol) and
2- (tributylstannyl)-pyridine (307 mg, 0.83 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (55 mg, 20%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 9.00 (s, 1H), 8.71 (d, 7 = 8.0 Hz, 1H), 8.57 (d, 7 = 3.8 Hz, 1H), 7.77 (dd, 7 = 7.8, 1.9 Hz, 1H), 7.68 (d, 7 = 3.0 Hz, 1H), 7.27-7.21 (m, 3H), 7.18- 7.13 (m, 2H), 6.66 (d, 7 = 6.4 Hz, 1H), 4.51 (qd, 7 = 7.0 Hz, 2H), 4.34-4.29 (m, 1H), 3.40- 3.32 (dd, 7 = 16.2, 6.9 Hz, 2H), 2.89-2.82 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.37 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 383.3.
Exam le 21: l-Ethyl-6-(indan-2-ylamino)-3-pyridin-3-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000130_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (400 mg, 0.93 mmol) and 3-(tributylstannyl)-pyridine (410 mg, 1.11 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (60 mg, 17%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.93 (s, 1H), 8.45 (d, 7 = 3.0 Hz, 1H), 8.44 (s, 1H), 8.37 (d, 7 = 3.0 Hz, 1H), 8.17 (dt, 7 = 7.9, 1.9 Hz, 1H), 7.62 (d, 7 = 3.0 Hz, 1H), 7.40 (dd, 7 = 7.9, 4.7 Hz, 1H), 7.26-7.24 (m, 2H), 7.17-7.13 (m, 2H), 6.62 (d, 7 = 6.5 Hz, 1H), 4.45 (qd, 7 = 7.0 Hz, 2H), 4.34-4.29 (m, 1H), 3.39-3.31 (dd, 7 = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 383.3.
Example 22: l-Ethyl-6-(indan-2-ylamino)-3-pyrimidin-5-yl-lH-[l,8]naphthyri-din-4- one
Figure imgf000131_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol) and 5-(tributylstannyl)-pyrimidine (256 mg, 0.70 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (20 mg, 9%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 9.21 (s, 2H), 9.06 (s, 1H), 8.60 (s, 1H), 8.39 (d, = 3.0 Hz, 1H), 7.62 (d, = 3.0 Hz, 1H), 7.26-7.24 (m, 2H), 7.16-7.13 (m, 2H), 6.67 (d, = 6.4 Hz, 1H), 4.45 (qd, = 6.8 Hz, 2H), 4.35-4.29 (m, 1H), 3.40-3.32 (dd, = 16.0, 6.8 Hz, 2H), 2.88-2.82 (dd, = 16.1, 4.4 Hz, 2H), 1.38 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 384.4.
Exam le 23: l-Ethyl-6-(indan-2-ylamino)-3-pyrazin-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000131_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (500 mg, 1.16 mmol) and
2- (tributylstannyl)-pyrazine (513 mg, 1.39 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (74 mg, 16%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 9.85 (d, = 1.5 Hz, 1H), 8.96 (s, 1H), 8.63 (dd, = 2.5, 1.6 Hz, 2H), 8.48 (d, = 2.5 Hz, 1H), 8.38 (d, = 3.0 Hz, 1H), 7.68 (d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.17-7.14 (m, 2H), 6.73 (d, = 6.3 Hz, 1H), 4.53 (qd, = 6.8 Hz, 2H), 4.35-4.29 (m, 1H), 3.41-3.34 (dd, = 16.0, 7.0 Hz, 2H), 2.90-2.83 (dd, = 15.9, 4.5 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 384.3.
Example 24: l-Ethyl-6-(indan-2-ylamino)-3-thiophen-2-yl-lH-[l,8]naphthyri-din-4- one
Figure imgf000132_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (200 mg, 0.52 mmol) and 2-(tributylstannyl)thiophene (233 mg, 0.63 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (166 mg, 82%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.83 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 7.63 (m, 2H), 7.39-7.37 (dd, = 5.1, 1.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 2H), 7.09-7.06 (dd, = 5.1, 3.7 Hz, 1H), 6.64 (d, = 6.4 Hz, 1H), 4.50 (qd, = 6.9 Hz, 2H), 4.35-4.28 (m, 1H), 3.41-3.33 (dd, = 16.0, 7.0 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.6 Hz, 2H), 1.38 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 388.3.
Example 25: l-Ethyl-6-(indan-2-ylamino)-3-(2-methyl-pyrrol-l-yl)-lH-[l,8] na hthyridin-4-one
Figure imgf000132_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (345 mg, 0.80 mmol) and
2- methyl-lH-pyrrole (78 mg, 0.96 mmol) were reacted as described under General Procedure C (3 days at 135°C) to furnish the title compound (50 mg, 16%) as an orange solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.40 (d, = 3.0 Hz, 1H), 8.31 (s, 1H), 7.58 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.64-6.61 (m, 2H), 5.98 (t, J = 3.1 Hz, 1H), 5.87-5.85 (m, 1H), 4.44-4.29 (m, 3H), 3.39-3.31 (dd, J = 16.0, 6.9 Hz, 2H), 2.88-2.81 (dd, J = 16.0, 4.5 Hz, 2H), 2.02 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 385.3. Exam le 26: l-Ethyl-6-(indan-2- lamino)-3-pyrazol-l-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000133_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (345 mg, 0.80 mmol) and pyrazole (65 mg, 0.96 mmol) were reacted as described under General Procedure C (6h at 135°C) to furnish the title compound (116 mg, 30%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.73 (s, 1H), 8.59 (d, = 2.3 Hz, 1H), 7.41 (d, = 3.0 Hz, 1H), 7.65 (s, 2H), 7.27-7.23 (m, 2H), 7.18-7.13 (m, 2H), 6.70 (d, J = 6.5 Hz, 1H), 6.45 (t, J = 2.1 Hz, 1H), 4.51 (qd, J = 6.9 Hz, 2H), 4.35-4.30 (m, 1H), 3.40-3.33 (dd, J = 16.0, 7.0 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.5 Hz, 2H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 372.2.
Exam le 27: l-Ethyl-3-imidazol-l-yl-6-(indan-2-ylamino)-lH-[l,8]aphthyridin-4-one
Figure imgf000133_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (345 mg, 0.80 mmol) and imidazole (65 mg, 0.96 mmol) were reacted as described under General Procedure C (24h at 135°C) to furnish the title compound (80 mg, 26%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.54 (s, 1H), 8.41 (d, J = 3.0 Hz, 1H), 7.97 (s, 1H), 7.59 (d, = 3.0 Hz, 1H), 7.45 (s, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 7.02 (s, 1H), 6.70 (d, J = 6.5 Hz, 1H), 4.43 (qd, J = 7.0 Hz, 2H), 4.35-4.29 (m, 1H), 3.39-3.32 (dd, J = 16.0, 6.9 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 372.3.
Example 28: 3-(l-Benzyl-lH-[l,2,3]triazol-4-yl)-l-ethyl-6-(indan-2-ylamino)-lH- [l,8]naphthyridin-4-one
Figure imgf000134_0001
l-Ethyl-3-ethynyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (150 mg, 0.46 mmol) and benzyl azide (67 mg, 0.50 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (121 mg, 57%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.90 (s, 1H), 8.67 (s, 1H), 8.37 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.40-7.30 (m, 5H), Ί .26-1.23 (m, 2H), 7.17-7.12 (m, 2H), 7.02 (s, 1H), 6.65 (d, J = 6.5 Hz, 1H), 5.66 (s, 2H), 4.52 (qd, J = 6.9 Hz, 2H), 4.33-4.27 (m, 1H), 3.39- 3.32 (dd, = 16.0, 6.9 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.6 Hz, 2H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 463.4. e 29: l-Ethyl-3-[l-(3-hydroxy-propyl)-lH-[l,2,3]triazol-4-yl]-6-(indan-2- - 1H- [l,8]naphthyridin-4-one
Figure imgf000134_0002
l-Ethyl-3-ethynyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (150 mg, 0.46 mmol) and 3-azido- l-propanol (51 mg, 0.50 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (149 mg, 76%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.88 (s, 1H), 8.63 (s, 1H), 8.37 (d, J = 3.0 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.65 (d, J = 6.4 Hz, 1H), 4.68 (t, 7 = 5.0 Hz, 1H), 4.56-4.45 (m, 4H), 4.35-4.29 (m, 1H), 3.43-3.34 (m, 4H), 2.89-2.82 (dd, = 16.0, 4.6 Hz, 2H), 2.02-1.93 (m, 2H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.4.
Example 30: 3-(3-Benzyl-3H-[l,2,3]triazol-4-yl)-l-ethyl-6-(indan-2-ylamino)-lH- [l,8]naphthyridin-4-one
Figure imgf000135_0001
30 l-Ethyl-3-ethynyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (170 mg, 0.52 mmol) and benzyl azide (69 mg, 0.52 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (144 mg, 60%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.38 (d, = 3.0 Hz, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.26-7.13 (m, 7H), 7.01-6.98 (m, 2H), 6.69 (d, J = 6.5 Hz, 1H), 5.60 (s, 2H), 4.36-4.30 (m, 3H), 3.39-3.32 (dd, J = 16.0, 6.9 Hz, 2H), 2.88-2.81 (dd, J = 16.0, 4.6 Hz, 2H), 1.24 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 463.4.
Example 31: l-Ethyl-3-[l-(3-hydroxy-propyl)-lH-[l,2,3]triazol-4-yl]-6-(indan-2- ylamino)- 1H- [l,8]naphthyridin-4-one
Figure imgf000135_0002
8 31 l-Ethyl-3-ethynyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (150 mg, 0.46 mmol) and 3-azido- l-propanol (46 mg, 0.46 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (164 mg, 84%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.40 (d, = 3.0 Hz, 1H), 8.32 (s, 1H), 7.69 (s, 1H), 7.56 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.70 (d, = 6.5 Hz, 1H), 4.52 (t, = 5.1 Hz, 1H), 4.50-4.29 (m, 5H), 3.38-3.31 (m, 4H), 2.87-2.81 (dd, = 16.0, 4.4 Hz, 2H), 1.92-1.83 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.4. Exam le 32: l-Ethyl-6-(indan-2-ylamino)-3-phenyl-lH-[l,8]naphthyridin-4-one
Figure imgf000136_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (100 mg, 0.23 mmol) and phenyl boronic acid (34 mg, 0.28 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (40 mg, 45%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 3.0 Hz, 1H), 8.31 (s, 1H), 7.74 (d, = 7.4 Hz, 2H), 7.63 (d, = 3.0 Hz, 1H), 7.38 (t, = 7.4 Hz, 2H), 7.28-7.24 (m, 3H), 7.16-7.13 (m, 2H), 6.57 (d, = 6.2 Hz, 1H), 4.54 (qd, = 6.7 Hz, 2H), 4.33-4.28 (m, 1H), 3.39-3.32 (dd, = 16.1, 6.8 Hz, 2H), 2.88-2.81 (dd, = 15.9, 4.4 Hz, 2H), 1.35 (t, = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 382.3. Exam le 33: l-Ethyl-6-(indan-2- lamino)-3-o-tolyl-lH-[l,8]naphthyridin-4-one
Figure imgf000136_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and
2- tolyl boronic acid (76 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (47 mg, 25%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.37 (d, = 3.0 Hz, 1H), 8.05 (s, 1H), 7.59 (d, = 3.0 Hz, 1H), 7.26-7.13 (m, 8H), 6.52 (d, / = 6.5 Hz, 1H), 4.40 (qd, / = 7.1 Hz, 2H), 4.35-4.28 (m, 1H), 3.39-3.31 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.1, 4.6 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 396.4.
Example 34: 3-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- yl]-benzonitrile
Figure imgf000137_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 3-cyanophenyl boronic acid (82 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (85 mg, 45%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.51 (s, 1H), 8.37 (d, = 3.0 Hz, 1H), 8.27 (s, 1H), 8.18 (d, = 8.0 Hz, 1H), 7.71 (d, = 7.7 Hz, 1H), 7.26-7.24 (m, 2H), 7.18-7.13 (m, 2H), 6.64 (d, / = 6.5 Hz, 1H), 4.45 (qd, / = 6.8 Hz, 2H), 4.35-4.28 (m, 1H), 3.39-3.31 (dd, / = 16.1, 7.0 Hz, 2H), 2.88-2.81 (dd, = 15.9, 4.5 Hz, 2H), 1.37 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 407.4.
Example 35: 3-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- yl]-benzonitrile
Figure imgf000137_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 4-cyanophenyl boronic acid (82 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (91 mg, 48%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.51 (s, 1H), 8.37 (d, J = 3.0 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.83 (d, = 8.5 Hz, 2H), 7.63 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.65 (d, J = 6.5 Hz, 1H), 4.46 (qd, J = 6.8 Hz, 2H), 4.35-4.28 (m, 1H), 3.39-3.31 (dd, J = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, J = 15.9, 4.5 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 407.4. Example 36: l-Ethyl-6-(indan-2-ylamino)-3-(2-methoxy-phenyl)-lH-[l,8]naph- thyridin-4-one
Figure imgf000138_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and
2- methoxyphenyl boronic acid (85 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (62 mg, 33%) as a yellow solid.
1H NMR (300 MHz, DMSO-J6) δ 8.35 (d, J = 3.0 Hz, 1H), 8.06 (s, 1H), 7.57 (d, J = 3.0 Hz, 1H), 7.31-7.24 (m, 4H), 7.16-7.13 (m, 2H), 7.04 (d, = 8.4 Hz, 1H), 6.95 (t, = 7.5 Hz, 1H), 6.52 (d, = 6.5 Hz, 1H), 4.38 (qd, = 7.0 Hz, 2H), 4.33-4.27 (m, 1H), 3.70 (s, 3H), 3.39-3.31 (dd, J = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, J = 16.0, 4.5 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 412.4.
Example 37: l-Ethyl-6-(indan-2-ylamino)-3-(3-methoxy-phenyl)-lH-[l,8]naph- th ridin-4-one
Figure imgf000138_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 3-methoxyphenyl boronic acid (85 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (92 mg, 48%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.35 (d, = 3.0 Hz, 1H), 8.33 (s, 1H), 7.63 (d, = 3.0 Hz, 1H), 7.39 (d, = 1.5 Hz, 1H), 7.33-7.23 (m, 4H), 7.17-7.13 (m, 2H), 7.85-7.81 (m,lH), 6.55 (d, = 6.4 Hz, 1H), 4.44 (qd, = 6.8 Hz, 2H), 4.34-4.28 (m, 1H), 3.77 (s, 3H), 3.40- 3.30 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.82 (dd, = 16.0, 4.6 Hz, 2H), 1.36 (t, = 6.5 Hz, 3H). ESIMS m/z [M+H]+ 412.4. Example 38: l-Ethyl-6-(indan-2-ylamino)-3-(4-methoxy-phenyl)-lH-[l,8]naph- thyridin-4-one
Figure imgf000139_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and 3-methoxyphenyl boronic acid (85 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (57 mg, 30%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.25 (s, 1H), 7.68 (d, = 8.6 Hz, 2H), 7.62 (d, = 3.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.16-7.13 (m, 2H), 6.94 (d, = 8.6 Hz, 2H), 6.52 (d, = 6.5 Hz, 1H), 4.43 (qd, = 6.8 Hz, 2H), 4.33-4.27 (m, 1H), 3.77 (s, 1H), 3.39-3.31 (dd, J = 16.1, 6.8 Hz, 2H), 2.88-2.81 (dd, / = 16.0, 4.5 Hz, 2H), 1.35 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 412.4.
Example 39: 3-Benzofuran-2-yl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyri-din-4- one
Figure imgf000139_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (200 mg, 0.46 mmol) and benzo[b]furan-2-boronic acid (90 mg, 0.56 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (127 mg, 66%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.78 (s, 1H), 8.39 (d, = 3.0 Hz, 1H), 8.25 (s, 1H), 7.69- 7.62 (m, 3H), 7.54 (d, = 8.6 Hz, 1H), 7.26-7.14 (m, 6H), 6.71 (d, = 6.3 Hz, 1H), 4.56 (qd, = 7.0 Hz, 2H), 4.13-4.06 (m, 1H), 3.41-3.32 (dd, = 16.1, 6.9 Hz, 2H), 2.90-2.83 (dd, = 16.0, 4.3 Hz, 2H), 1.39 (t, = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 422.3. Example 40: l-Ethyl-6-(indan-2-ylamino)-3-(methyl-[l,3,4]oxodiazol-2-yl)-lH- [l,8]naphthyridin-4-one
Figure imgf000140_0001
A suspension of l-ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3- carboxylic [1-methoxy-ethylidene] -hydrazide (165 mg, 0.39 mmol) in dioxane (1.2 ml) in presence of acetic acid (3 drops) was heated under microwaves at 150°C for 2h. After cooling, the solvents were removed under vacuo. The solid obtained was triturated in AcOEt (15 ml) in presence of aq. NaHC03 (5 ml) and filtered off (washings with water and AcOEt). After drying, the expected product was obtained as a yellow solid (103 mg, 39%). 1H NMR (300 MHz, DMSO-i¾) δ 8.75 (s, 1H), 8.38 (d, = 2.6 Hz, 1H), 7.58 (d, = 2.6 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.78 (d, = 6.3 Hz, 1H), 4.47 (qd, = 7.0 Hz, 2H), 4.36-4.28 (m, 1H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.87-2.81 (dd, = 16.1, 4.1 Hz, 2H), 2.53 (s, 3H), 1.35 (t, J = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 388.2. Example 41: l-Ethyl-6-(indan-2-ylamino)-3-(5-methyl-4H-[l,2,4]triazol-3-yl)-lH- [l,8]naphthyridin-4-one
Figure imgf000140_0002
A suspension of l-ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3- carboxylic acid hydrazide (750 mg, 2.06 mmol), thioacetamide (620 mg, 8.25 mmol) and triethylamine (0.57 ml, 4.13 mmol) in a mixture pyridine/ 1-butanol (1:5) (29 ml) was refluxed for 18h. After cooling, the solvents were removed under vacuo. The solid obtained was triturated in AcOEt (40 ml) in presence of aq. NaCl (20 ml) and filtered off. The filtrate was decanted. The aqueous layer was extracted with AcOEt (3 x 30 ml). The combined organic fractions were dried over MgS04, filtered and concentrated under reduced pressure. The crude obtained was purified by flash chromatography (Si02, CH2Cl2/acetone 100:0→ 30:70) leading to a yellow solid which was triturated in DMSO to furnish after filtration and drying the pure expected product as a yellow powder (50 mg, 6%). 1H NMR (300 MHz, OMSO-d6) δ 13.39 (s, 1H), 8.91 (s, 1H), 8.40 (d, = 3.0 Hz, 1H), 7.65 (d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.16-7.13 (m, 2H), 6.79 (d, = 6.4 Hz, 1H), 4.57 (qd, / = 6.7 Hz, 2H), 4.37-4.31 (m, 1H), 3.41-3.32 (dd, / = 16.1, 6.9 Hz, 2H), 2.89- 2.83 (dd, = 16.1, 4.4 Hz, 2H), 2.27 (s, 3H), 1.36 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 387.3.
Example 42: 3-(5-Amino-[l,3,4]oxadiazol-2-yl)-l-ethyl-6-(indan-2-ylamino)- 1H- [l,8]naphthyridin-4-one
Figure imgf000141_0001
A suspension of l-ethyl-6-(indan-2-ylamino)-4-oxo- l,4-dihydro-[l,8]naphthyridine-3- carboxylic acid hydrazide (300 mg, 0.83 mmol) and cyanogen bromide (874 mg, 8.3 mmol) in anhydrous methanol (15 ml) was heated at 70°C in a sealed tube for 2h. After cooling, the solvent was removed under vacuo. The solid obtained was triturated in AcOEt (20 ml) and water (20 ml) and filtered off. The solid obtained was purified by flash chromatography (Si02, CH2C12/CH30H 100:0→ 80:20) leading to the expected product as a yellow solid (184 mg, 57%).
1H NMR (300 MHz, DMSO-i¾) δ 8.55 (s, 1H), 8.37 (d, = 3.0 Hz, 1H), 7.57 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 7.01 (s, 2H), 6.73 (d, J = 6.6 Hz, 1H), 4.44 (qd, J = 6.8 Hz, 2H), 4.35-4.29 (m, 1H), 3.38-3.31 (dd, J = 16.3, 6.9 Hz, 2H), 2.87-2.80 (dd, J = 16.0, 4.5 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 389.3.
Example 43: l-Ethyl-3-[3-(4-fluoro-phenyl)-isoxazol-5-yl]-6-(indan-2-ylamino)- 1H- [l,8]naphthyridin-4-one
Figure imgf000142_0001
To a suspension of l-ethyl-3-ethynyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (150 mg, 0.46 mmol) in a mixture 1-butanol/water (5: 1) (12 ml), were successively added a-chloro-4-fluorobenzyloxime (79 mg, 0.46 mmol), copper sulfate (4 mg, 0.03 mmol), sodium ascorbate (9 mg, 0.5 mmol) and KHCO3 (205 mg, 2.05 mmol). The reaction mixture was stirred at RT for 24h. Water (50 ml) and CH2CI2 (20 ml) were added. The aqueous layer was extracted with CH2CI2 (2 x 20 ml). The combined organic fractions were dried over MgS04, filtered off and concentrated under reduced pressure. The crude obtained was purified by flash chromatography (Si02, CH2Cl2/AcOEt 100:0 → 50:50) leading to the expected product as a yellow solid (122 mg, 57%).
1H NMR (300 MHz, DMSO-i¾) δ 8.88 (s, 1H), 8.39 (d, J = 3.0 Hz, 1H), 7.98-7.93 (m, 2H), 7.64 (d, = 3.0 Hz, 1H), 7.54 (s, 1H), 7.35 (t, = 8.8 Hz, 2H), 7.27-7.24 (m, 2H), 7.16-7.13 (m, 2H), 6.78 (d, = 6.3 Hz, 1H), 4.54 (qd, = 7.0 Hz, 2H), 4.37-4.31 (m, 1H), 3.40-3.33 (dd, J = 16.1, 6.9 Hz, 2H), 2.89-2.82 (dd, J = 16.1, 4.4 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 467.4.
Example 44: l-Ethyl-3-furan-2-yl-6-(indan-2-yl-methyl-amino)-lH-[l,8]naph- thyridin-4-one
Figure imgf000142_0002
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-iodo-lH-[l,8]naphthyridin-4-one (350 mg, 0.79 mmol) and 2-(tributylstannyl)furan (337 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (270 mg, 89%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.72 (d, = 3.0 Hz, 1H), 8.59 (s, 1H), 7.83 (d, = 3.0 Hz, 1H), 7.65 (d, = 0.9 Hz, 1H), 7.26-7.14 (m, 5H), 6.62 (d, = 6.3 Hz, 1H), 6.55 (dd, = 3.1, 1.8 Hz, 1H), 4.97 (qt, = 7.5 Hz, 1H), 4.53 (qd, = 7.0 Hz, 2H), 3.25-3.16 (dd, = 16.4, 8.1 Hz, 2H), 3.07-2.99 (dd, = 16.3, 6.3 Hz, 2H), 2.80 (s, 3H), 1.37 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 386.3.
45: l-Ethyl-3-furan-2-yl-6-(indan-2-yl-methyl-amino)-lH-[l,8]naph-
Figure imgf000143_0001
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-iodo-lH-[l,8]naphthyridin-4-one (200 mg, 0.45 mmol) and 2-(tributylstannyl)oxazole (193 mg, 0.54 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (33 mg, 19%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.77 (s, 1H), 8.72 (d, = 3.0 Hz, 1H), 8.15 (s, 1H), 7.80 (d, = 3.0 Hz, 1H), 7.29 (s, 1H), 7.27-7.24 (m, 2H), 7.17-7.15 (m, 2H), 5.00 (qt, = 7.3 Hz, 1H), 4.53 (qd, / = 6.8 Hz, 2H), 3.26-3.18 (dd, = 16.4, 8.1 Hz, 2H), 3.07-3.00 (dd, = 16.4, 6.3 Hz, 2H), 2.81 (s, 3H), 1.37 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 387.3.
Example 46: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-2-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000144_0001
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-iodo-lH-[l,8]naphthyridin-4-one (200 mg, 0.45 mmol) and l-methyl-2-(tributylstannyl)imidazole (200 mg, 0.54 mmol) were reacted as described under General Procedure B (18h at 110°C) to furnish the title compound (43 mg, 24%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.75 (d, = 3.0 Hz, 1H), 8.23 (s, 1H), 7.79 (d, = 3.0 Hz, 1H), 7.65 (s, 1H), 7.26-7.23 (m, 2H), 7.17-7.14 (m, 2H), 6.87 (s, 1H), 4.98 (qt, / = 7.4 Hz, 1H), 4.43 (qd, / = 6.7 Hz, 2H), 3.52 (s, 1H), 3.25-3.17 (dd, / = 16.4, 8.1 Hz, 2H), 3.06- 2.99 (dd, = 16.4, 6.2 Hz, 2H), 2.79 (s, 3H), 1.37 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 400.4.
Exam le 47: l-Ethyl-3-furan-2-yl-6-(indan-2-ylamino)-lH-[l,7]naphthyridin-4-one
Figure imgf000144_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,7]naphthyridin-4-one (200 mg, 0.46 mmol) and
2- (tributylstannyl)furan (199 mg, 0.56 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (160 mg, 94%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.85 (s, 1H), 8.43 (s, 1H), 7.62 (d, = 0.9 Hz, 1H), 7.24- 7.21 (m, 2H), 7.15-7.07 (m, 5H), 6.53 (dd, = 3.1, 1.8 Hz, 1H), 4.57 (sext, = 6.5 Hz, 1H), 4.46 (qd, / = 7.0 Hz, 2H), 3.35-3.27 (dd, / = 15.7, 7.3 Hz, 2H), 2.90-2.82 (dd, / = 15.9, 5.9 Hz, 2H), 1.40 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 372.3. Example 48: l-Ethyl-3-furan-2-yl-6-(indan-2-ylamino)-lH-[l,7]naphthyridin-4-one
Figure imgf000145_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,7]naphthyridin-4-one (280 mg, 0.65 mmol) and
2- (tributylstannyl)oxazole (279 mg, 0.78 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (50 mg, 21%) as a yellow solid.
1H NMR (300 MHz, DMSC ^) δ 8.84 (s, 1H), 8.57 (s, 1H), 8.10 (s,lH), 7.25-7.12 (m, 7H), 4.60 (sext, = 6.6 Hz, 1H), 4.44 (qd, = 6.9 Hz, 2H), 3.34-3.27 (dd, = 15.8, 7.4 Hz, 2H), 2.90-2.82 (dd, = 15.9, 5.8 Hz, 2H), 1.40 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 373.3.
Example 49: l-Ethyl-6-(indan-2-ylamino)-3-(l-methyl-lH-imidazol-2-yl)-lH- [l,7]naphthyridin-4-one
Figure imgf000145_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,7]naphthyridin-4-one (300 mg, 0.70 mmol) and l-methyl-2-(tributylstannyl)imidazole (310 mg, 0.83 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (40 mg, 15%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.83 (s, 1H), 8.02 (s, 1H), 7.62 (s,lH), 7.23-7.21 (m, 2H), 7.16-7.11 (m, 3H), 7.03 (d, / = 6.6 Hz, 1H), 6.84 (s, 1H), 4.58 (sext, / = 6.4 Hz, 1H), 4.35 (qd, / = 6.9 Hz, 2H), 3.49 (s, 3H), 3.34-3.27 (dd, = 15.8, 7.3 Hz, 2H), 2.88-2.81 (dd, = 15.8, 5.8 Hz, 2H), 1.38 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 386.4.
Example 50: l-Ethyl-6-(indan-2-ylamino)-3-thiazol-2-yl-lH-[l,7]naphthyridin-4-one
Figure imgf000146_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,7]naphthyridin-4-one (300 mg, 0.78 mmol) and 2-(tributylstannyl)thiazole (350 mg, 0.94 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the title compound (150 mg, 49%) as an orange solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.99 (s, 1H), 8.90 (s, 1H), 7.83 (d, J = 3.3 Hz, 1H), 7.55 (d, = 3.3 Hz, 1H), 7.26-7.30 (m, 4H), 7.16-7.12 (m, 2H), 4.64-4.51 (m, 3H), 3.36-3.30 (dd, = 16.3, 7.2 Hz, 2H), 2.91-2.84 (dd, = 15.9, 5.9 Hz, 2H), 1.43 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 389.3.
Example 51: l-Ethyl-6-(indan-2-ylamino)-3-(3-methoxy-phenyl)-lH-[l,7]naph- thyridin-4-one
Figure imgf000146_0002
A flamed-dried sealed tube was charged with PdBr2 (7 mg, 0.04 mmol), bis(2- diphenylphosphinophenyl)ether (29 mg, 0.05 mmol), l-ethyl-6-(indan-2-ylamino)-4-oxo- l,4-dihydro-[l,7]naphthyridine-3-carboxylic acid (190 mg, 0.54 mmol), 3-bromoanisole (0.14 ml, 1.09 mmol) and Ag2C03 (150 mg, 0.54 mmol). The reaction vessel was backfilled with argon. Toluene/DMA (9: 1) (5 ml) were added. The reaction mixture was heated under microwaves for 2h at 180°C. The resulting suspension was cooled to RT and filtered through a pad of Celite eluting with AcOEt. The filtrate was concentrated and purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 30:70) leading to the expected product as a yellow oil (32 mg, 14%).
1H NMR (300 MHz, DMSO-i¾) δ 8.81 (s, 1H), 8.20 (s, 1H), 7.51-7.12 (m, 8H), 6.99 (d, = 6.6 Hz, 1H), 6.82 (d, = 7.2 Hz, 1H), 4.58 (sext, = 6.6 Hz, 1H), 4.39 (qd, J = 1.1 Hz, 2H), 3.77 (s, 3H), 3.32-3.27 (m, 2H), 2.89-2.82 (dd, J = 15.9, 5.9 Hz, 2H), 1.40 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 412.4. Ex -Benzoyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000147_0001
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic me- thoxy-methyl-amide (400 mg, 1.02 mmol) and 1M phenylmagnesium bromide in THF (1.02 ml, 1.02 mmol) were reacted as described under General Procedure G (24h at RT) to furnish the title compound (36 mg, 9%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.48 (s, 1H), 8.37 (d, = 3.0 Hz, 1H), 7.70 (d, = 7.2 Hz, 2H), 7.58-7.52 (m, 2H), 7.46-7.41 (m, 2H), 7.25-7.23 (m, 2H), 7.15-7.12 (m, 2H), 6.73 (d, = 6.4 Hz, 1H), 4.46 (qd, = 7.1 Hz, 2H), 4.36-4.28 (m, 1H), 3.37-3.29 (dd, = 15.9, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.5 Hz, 2H), 1.37 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 410.3.
Example 53: 3-Acetyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000147_0002
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic me- thoxy-methyl-amide (400 mg, 1.02 mmol) and 3M methylmagnesium chloride in THF (0.34 ml, 1.02 mmol) were reacted as described under General Procedure G (18h at RT) to furnish the title compound (48 mg, 14%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.64 (s, 1H), 8.34 (d, = 3.0 Hz, 1H), 7.64 (d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.18-7.14 (m, 2H), 6.77 (d, = 6.4 Hz, 1H), 4.46 (qd, = 7.0 Hz, 2H), 4.36-4.28 (m, 1H), 3.40-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.6 Hz, 2H), 2.60 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 348.3. Example 54: l-Ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one
Figure imgf000148_0001
l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyridine-3-carboxylic methoxy-methyl-amide (400 mg, 1.02 mmol) and 1M ethylmagnesium bromide in THF (1.02 ml, 1.02 mmol) were reacted as described under General Procedure G (48h at RT) to furnish the title compound (32 mg, 8%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.64 (s, 1H), 8.33 (d, = 3.0 Hz, 1H), 7.63 (d, = 3.0 Hz, 1H), 7.26-7.24 (m, 2H), 7.16-7.14 (m, 2H), 6.78 (d, = 6.4 Hz, 1H), 4.46 (qd, = 7.0 Hz, 2H), 4.35-4.28 (m, 1H), 3.39-3.32 (dd, = 16.1, 7.0 Hz, 2H), 3.09 (qd, = 7.2 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.33 (t, = 7.0 Hz, 3H), 1.03 (t, = 7.2 Hz, 3H). ESIMS m/z [M+H]+ 362.3.
Example 55: l-Ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one
Figure imgf000148_0002
A solution of l-ethyl-6-(indan-2-ylamino)-4-oxo- l,4-dihydro-[l,8]naphthyridine-3- carboxylic methoxy-methyl-amide (2.36 g, 6.0 mmol) in CH2CI2 (100 ml) at -78°C was treated with 1.0 M diisobutylaluminum hydride solution in CH2CI2 (12.6 ml, 12.6 mmol) according to General Procedure P, leading without purification to the expected compound as a yellow solid (1.41 g, 70%). 1H NMR (300 MHz, OMSO-d6) δ 10.15 (s, 1H), 8.59 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 7.59 (d, = 3.0 Hz, 1H), Ί .25-1.23 (m, 2H), 7.16-7.13 (m, 2H), 6.85 (d, = 6.3 Hz, 1H), 4.46 (qd, J = 6.6 Hz, 2H), 4.36-4.30 (m, 1H), 3.39-3.31 (dd, J = 16.3, 6.9 Hz, 2H), 2.87- 2.80 (dd, 7 = 16.1, 4.2 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 334.2.
Example 56: l-Ethyl-3-hydroxymethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4- one
Figure imgf000149_0001
A suspension of l-ethyl-6-(indan-2-ylamino)-3-propionyl- lH-[l,8]naphthyridin-4-one (667 mg, 2.0 mmol) in methanol (10 ml) at RT was treated with sodium borohydride (83 mg, 2.2 mmol) according to General Procedure Q and worked up using Method A leading to the expected compound (498 mg, 74%) as a yellow precipitate. 1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 7.96 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.50 (d, = 6.5 Hz, 1H), 4.91 (qd, = 5.3 Hz, 2H), 4.39-4.33 (m, 4H), 4.32-4.26 (m, 1H), 3.37-3.30 (dd, = 15.7, 7.0 Hz, 2H), 2.86- 2.79 (dd, 7 = 16.1, 4.6 Hz, 2H), 1.30 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 336.3. Example 57: l-Ethyl-6-(indan-2-ylamino)-3-morpholin-4-ylmethyl-lH-[l,8] naphthyridin-4-one
Figure imgf000149_0002
l-Ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one (126 mg, 0.38 mmol) and morpholine (0.07 ml, 0.76 mmol) were reacted as described under General Procedure H (5h at RT) to furnish the title compound (65 mg, 42%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, J = 3.0 Hz, 1H), 7.99 (s, 1H), 7.52 (d, J = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.50 (d, = 6.4 Hz, 1H), 4.36 (qd, = 7.0 Hz, 2H), 4.31-4.24 (m, 1H), 3.55 (t, / = 4.5 Hz, 4H), 3.37-3.30 (dd, J = 16.1, 4.9 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.6 Hz, 2H), 2.39 (brs, 4H), 1.29 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 405.3. Example 58: l-Ethyl-6-(indan-2-ylamino)-3-[(2-methoxy-ethylamino)-methyl]-lH- [l,8]naphthyridin-4-one
Figure imgf000150_0001
l-Ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one (167 mg, 0.50 mmol) and 2-methoxyethylamine (0.06 ml, 0.75 mmol) were reacted as described under General Procedure H (5h at RT) to furnish the title compound (139 mg, 70%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.02 (s, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.50 (d, = 6.4 Hz, 1H), 4.38-4.25 (m, 3H), 3.55 (s, 2H), 3.41-3.30 (m, 4H), 3.21 (s, 3H), 2.86-2.79 (dd, J = 16.0, 4.6 Hz, 2H), 2.65 (t, J = 5.5 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 393.3. Example 59: l-Ethyl-6-(indan-2-yl-methyl-amino)-3-morpholin-4-ylmethyl-lH- [l,8]naphthyridin-4-one
Figure imgf000150_0002
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-propionyl- lH-[l,8]naphthyridin-4-one (174 mg, 0.50 mmol) and morpholine (0.07 ml, 0.75 mmol) were reacted as described under General Procedure H (3h at RT) to furnish the title compound (87 mg, 41%) as a yellow foam as well as example 60 (41 mg, 23%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.69 (d, = 3.0 Hz, 1H), 8.05 (s, 1H), 7.74 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.18-7.14 (m, 2H), 4.93 (qt, = 7.0 Hz, 1H), 4.40 (qd, = 7.0 Hz, 2H), 3.55 (brs, 4H), 3.37 (brs, 2H), 3.23-3.15 (dd, J = 16.4, 8.1 Hz, 2H), 3.05-2.97 (dd, J = 16.4, 6.3 Hz, 2H), 2.76 (s, 3H), 2.38 (brs, 4H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 419.4.
Example 60: l-Ethyl-3-hydroxymethyl-6-(indan-2-yl-methyl-amino)-lH-[l,8] naphthyridin-4-one
Figure imgf000151_0001
1H NMR (300 MHz, DMSO-i¾) δ 8.69 (d, = 3.0 Hz, 1H), 8.01 (s, 1H), 7.73 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 4.98-4.86 (m, 2H), 4.46-4.39 (m, 4H), 3.23-3.14 (dd, = 16.4, 8.4 Hz, 2H), 3.04-2.97 (dd, = 16.4, 6.3 Hz, 2H), 2.76 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 350.3. Example 61: l-Ethyl-3-{[(2-hydroxy-ethyl)-methyl-amino]-methyl}-6-(indan-2-yl- methyl-amino)- 1H- [ 1 ,8 ] naphthyridin-4-one
Figure imgf000151_0002
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-propionyl- lH-[l,8]naphthyridin-4-one (175 mg, 0.50 mmol) and 2-(methylamino)ethanol (0.06 ml, 0.75 mmol) were reacted as described under General Procedure H (5h at RT) to furnish the title compound (125 mg, 61%) as a yellow foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.69 (d, = 3.0 Hz, 1H), 8.11 (s, 1H), 7.74 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 4.92 (qt, = 7.7 Hz, 1H), 4.62 (brs, 1H), 4.39 (qd, = 6.9 Hz, 2H), 3.51 (brs, 2H), 3.41 (s, 2H), 3.22-3.14 (dd, = 16.4, 8.1 Hz, 2H), 3.05-2.97 (dd, J = 16.4, 6.3 Hz, 2H), 2.75 (s, 3H), 2.49-2.43 (m, 2H), 2.19 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 407.3. Example 62: l-Ethyl-6-(indan-2-yl-methyl-amino)-3-(4-pyridin-2-yl-piperazin-l- ylmethyl)-lH-[l,8]naphthyridin-4-one
Figure imgf000152_0001
l-Ethyl-6-(indan-2-yl-methyl-amino)-3-propionyl- lH-[l,8]naphthyridin-4-one (174 mg, 0.50 mmol) and l-(2-pyridyl)piperazine (122 mg, 0.75 mmol) were reacted as described under General Procedure H (5h at RT) to furnish the title compound (163 mg, 66%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.69 (d, = 3.0 Hz, 1H), 8.08-8.06 (m, 2H), 7.75 (d, = 3.0 Hz, 1H), 7.48 (td, J = 7.2, 1.9 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.13 (m, 2H), 6.77 (d, = 8.6 Hz, 1H), 6.59 (dd, J = 7.0, 5.0 Hz, 1H), 4.92 (qt, J = 7.7 Hz, 1H), 4.41 (qd, J = 6.9 Hz, 2H), 3.43 (brs, 6H), 3.23-3.14 (dd, = 16.4, 8.1 Hz, 2H), 3.04-2.97 (dd, = 16.4, 6.3 Hz, 2H), 2.76 (s, 3H), 2.35-2.60 (m,4H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 495.3.
Example 63: 4-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- ylmethyl]-piperazine-l-carboxylic acid tert-butyl ester
Figure imgf000152_0002
l-Ethyl-3-hydroxymethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (200 mg, 0.60 mmol) and N-Boc-piperazine (335 mg, 1.79 mmol) were reacted as described under General Procedure I (4h at 70°C) to furnish the title compound (55 mg, 18%) as a yellow foam.
1H NMR (300 MHz, OMSO-d6) δ 8.34 (d, = 3.0 Hz, 1H), 8.00 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.27-7.25 (m, 2H), 7.18-7.15 (m, 2H), 6.52 (d, = 6.3 Hz, 1H), 4.43-4.26 (m, 3H), 3.55 (t, J = 4.5 Hz, 4H), 3.39-3.32 (m, 8H), 2.88-2.73 (dd, / = 16.0, 4.5 Hz, 2H), 2.35 (brs, 4H), 1.38 (s, 9H), 1.32 (t, / = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 504.3.
Example 64: l-Ethyl-6-(indan-2-ylamino)-3-piperazin-l-ylmethyl-lH-[l,8] naphthyridin-4-one
Figure imgf000153_0001
4-[ 1 -Ethyl-6-(indan-2-ylamino)-4-oxo- 1 ,4-dihydro-[ 1 ,8]naphthyridin-3 -ylmethyl] -pi- perazine-l-carboxylic acid tert-butyl ester (40 mg, 0.08 mmol) was stirred in a 4N solution of HCl in dioxane (2.0 ml) for 2h at RT. The solvent was removed under vacuum to furnish after lyophilisation a yellow foam corresponding to the expected product (36 mg, n.d. yield). 1H NMR (300 MHz, DMSO-i¾) δ 9.61 (brs, 2H), 8.51 (s, 1H), 8.42 (d, = 3.0 Hz, 1H), 8.00 (s, 1H), 7.55 (d, = 3.0 Hz, 1H), 7.27-7.25 (m, 2H), 7.18-7.15 (m, 2H), 4.41-4.30 (m, 7H), 4.22 (s, 2H), 3.45-3.32 (m, 6H), 2.89-2.82 (dd, = 16.1, 4.4 Hz, 2H), 1.40 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 404.3. Example 65: l-Ethyl-6-(indan-2-ylamino)-3-(4-methyl-piperazin-l-ylmethyl)-lH- [l,8]naphthyridin-4-one
Figure imgf000153_0002
l-Ethyl-3-hydroxymethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (250 mg, 0.75 mmol) and 1-methylpiperazine (373 mg, 3.73 mmol) were reacted as described under General Procedure I (3h at 70°C) to furnish the title compound (78 mg, 25%) as a yellow foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.27-7.24 (m, 2H), 7.17-7.14 (m, 2H), 6.51 (d, = 6.5 Hz, 1H), 4.41-4.28 (m, 3H), 3.39-3.31 (m, 4H), 2.87-2.72 (dd, J = 16.0, 4.6 Hz, 2H), 1.38 (s, 8H), 2.13 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). ESJ S m/z [M+H]+ 418.3.
Example 66: l-Ethyl-6-(indan-2-ylamino)-3-methoxymethyl-lH-[l,8]naphthyri-din-4- one
Figure imgf000154_0001
l-Ethyl-3-hydroxymethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (200 mg, 0.60 mmol) and methanol (5.0 ml) were reacted as described under General Procedure I (6h at 70°C) to furnish the title compound (105 mg, 50%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.20 (m, 2H), 7.16-7.12 (m, 2H), 6.52 (d, = 6.5 Hz, 1H), 4.36 (qd, = 7.0 Hz, 2H), 4.29-4.26 (m, 3H), 3.37-3.29 (m, 5H), 2.85-2.78 (dd, = 16.0, 4.6 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 350.3.
Example 67: 3-Ethoxymethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyri-din-4- on
Figure imgf000154_0002
l-Ethyl-3-hydroxymethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (200 mg, 0.60 mmol) and ethanol (5.0 ml) were reacted as described under General Procedure I (6h at 70°C) to furnish the title compound (37 mg, 17%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 8.01 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 6.51 (d, = 6.5 Hz, 1H), 4.36 (qd, J = 6.9 Hz, 2H), 4.31-4.24 (m, 3H), 3.49 (qd, 7 = 7.0 Hz, 2H), 3.37-3.31 (dd, 7 = 16.3, 70 Hz, 2H), 2.85-2.79 (dd, 7 = 16.0, 4.6 Hz, 2H), 1.29 (t, 7 = 7.0 Hz, 3H), 1.12 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 364.3. Examp -Ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one
Figure imgf000155_0001
To a solution of l-ethyl-6-(indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one (333 mg, 1.00 mmol) in anhydrous THF was added at -78°C 1M ethylmagnesium bromide in THF (2.4 ml, 2.40 mmol). The reaction mixture was stirred for 40 min at this temperature and 3h at RT. IN KHS04 (10 ml) was added and the mixture was extracted with AcOEt (2 x 30 ml). The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum. The crude was purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0→ 0: 100) leading to the pure expected product as a yellow foam (87 mg, 24%).
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, 7 = 3.0 Hz, 1H), 7.93 (s, 1H), 7.51 (d, 7 = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.49 (d, 7 = 6.5 Hz, 1H), 5.00 (d, 7 = 4.8 Hz, 1H), 4.71-4.66 (m, 1H), 4.44-4.26 (m, 3H), 3.37-3.30 (dd, 7 = 16.4, 7.0 Hz, 2H), 2.86- 2.79 (dd, 7 = 15.9, 4.4 Hz, 2H), 1.76-1.68 (m, 1H), 1.55-1.46 (m, 1H), 1.29 (t, 7 = 7.0 Hz, 3H), 0.82 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 364.3.
Example 69: l-Ethyl-6-(indan-2-ylamino)-3-propyl-lH-[l,8]naphthyridin-4-one
Figure imgf000155_0002
At 0°C, triethylsilane (68 mg, 0.58 mmol) was slowly added to a solution of l-ethyl-6- (indan-2-ylamino)-3-propionyl-lH-[l,8]naphthyridin-4-one (40 mg, 0.11 mmol) in trifluoroacetic acid (5 ml). After 2h stirring at 0°C, the solvent was removed under vacuum and the crude was purified by semi-preparative HPLC leading to the pure expected product as a yellow foam (21 mg, 54%). 1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.92 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.17-7.12 (m, 2H), 6.44 (d, = 6.5 Hz, 1H), 4.36-4.25 (m, 3H), 3.37-3.30 (dd, = 15.7, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 2.37 (t, = 7.1 Hz, 2H), 1.51 (sext, = 7.5 Hz, 2H), 1.28 (t, = 7.0 Hz, 3H), 0.87 (t, = 7.3 Hz, 3H). ESIMS m/z [M+H]+ 348.3.
Example 70: 3-((E)-4-Benzyloxy-but-l-enyl)-l-ethyl-6-(indan-2-ylamino)-lH- [l,8]naphthyridin-4-one
Figure imgf000156_0001
To a suspension of (3-benzyloxypropyl)triphenylphosphonium bromide (638 mg, 1.30 mmol) in THF (6 ml) was added at 0°C a 1M solution of lithium bis(trimethylsilyl)amide in THF (1.10 ml, 1.10 mmol). The reaction mixture was stirred at this temperature for 15 min before dropwise addition of a solution of l-ethyl-6-(indan-2-ylamino)-3-propionyl- lH-[l,8]naphthyridin-4-one (333 mg, 1.00 mmol) in THF (4 ml). After complete addition, the flask was slowly warmed to RT and then stirred for lh. NH4C1 aq. (30 ml) was added. The aqueous layer was extracted with AcOEt (2 x 30 ml). The combined organic fractions were dried over Na2S04, filtered and evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0→ 30:70) leading to the expected product as a yellow foam (159 mg, 34%).
1H NMR (300 MHz, DMSO-<¾) δ 8.30 (d, / = 3.0 Hz, 1H), 8.19 (s, 1H), 7.55 (d, / = 3.0 Hz, 1H), 7.34-7.21 (m, 7H), 7.17-7.13 (m, 2H), 6.65 (td, = 15.9, 7.0 Hz, 1H), 6.53 (d, = 6.5 Hz, 1H), 6.40 (d, = 16.0 Hz, 1H), 4.48 (s, 2H), 4.40-4.28 (m, 3H), 3.51 (t, = 6.8 Hz, 2H), 3.38-3.30 (dd, = 15.6, 6.5 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 2.49-2.39 (m, 2H), 1.31 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 466.4. 71: 3-(4-Benzyloxy-butyl)-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naph-
Figure imgf000157_0001
A solution of 3-((E)-4-benzyloxy-but-l-enyl)-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]- naphthyridin-4-one (110 mg, 0.24 mmol) in ethanol (10 ml) was stirred at RT under hydrogen (1 atm) for 18h in presence of Pt02 (57 mg, 0.25 mmol). The suspension was filtered off over Celite and washed with ethanol. The filtrate was evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 30:70) leading to the expected product as a yellow foam (92 mg, 83%).
1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.92 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.34-7.22 (m, 7H), 7.15-7.12 (m, 2H), 6.45 (d, = 6.4 Hz, 1H), 4.42 (s, 2H), 4.36-4.26 (m, 3H), 3.43-3.29 (m, 4H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 2.43-2.37 (m, 2H), 1.55 (brs, 4H), 1.28 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 468.4.
Example 72: l-Ethyl-6-(indan-2-ylamino)-3-[l,2,3]triazol-l-ylmethyl-lH-[l,8] na hthyridin-4-one
Figure imgf000157_0002
A mixture of tetrabutylammonium fluoride (78 μΐ, 78 μιηοΐ) and l-ethyl-6-(indan-2- ylamino)-3-(5-trimethylsilanyl-[l,2,3]triazol-l-ylmethyl)- lH-[l,8]naphthyridin-4-one (24 mg, 52 μιηοΐ) in anhydrous THF (1 ml) was stirred at RT for 2h. The solvent was removed under vacuum and the crude was purified by semi-preparative HPLC leading to the pure expected product as a yellow foam (12 mg, 60%). 1H NMR (300 MHz, OMSO-d6) δ 8.37 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.06 (d, J = 0.9 Hz, 1H), 7.64 (d, = 0.9 Hz, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.61 (d, = 6.5 Hz, 1H), 5.37 (s, 2H), 4.37 (qd, = 7.0 Hz, 2H), 4.32-4.22 (m, 1H), 3.38-3.22 (m, 2H), 2.85-2.79 (dd, = 16.0, 4.6 Hz, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 387.3.
73: l-Ethyl-6-(indan-2-yl-methyl-amino)-3-phenethyl-lH-[l,8]naph-
Figure imgf000158_0001
A mixture of l-ethyl-6-(indan-2-yl-methyl-amino)-3-iodo- lH-[l,8]naphthyridin-4-one (250 mg, 0.56 mmol), potassium phenethyltrifluoroborate (119 mg, 0.56 mmol), palladium acetate (6 mg, 0.03 mmol), XPhos (27 mg, 0.06 mmol), and cesium carbonate (547 mg, 1.68 mmol) in toluene (3 ml) was purged with argon for 10 min before addition of water (0.3 ml). The reaction mixture was heated overnight at 95°C in a sealed tube. After cooling, water was added and the mixture was extracted with AcOEt (2 x 20 ml). The combined organic layers were dried over MgS04, filtered off and concentrated under vacuum. The crude was purified by filtrate was evaporated under vacuum. The crude obtained was purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0→ 70:30) followed by semi-preparative HPLC to furnish the expected product as an orange foam (27 mg, 11%).
1H NMR (300 MHz, DMSO-i¾) δ 8.68 (d, = 3.0 Hz, 1H), 7.85 (s, 1H), 7.77 (d, = 0.9 Hz, 1H), 7.28-7.23 (m, 4H), 7.18-7.14 (m, 5H), 4.92 (qt, J = 7.0 Hz, 1H), 4.31 (qd, J = 7.0 Hz, 2H), 3.23-3.15 (dd, = 16.4, 8.2 Hz, 2H), 3.05-2.98 (dd, = 16.3, 6.3 Hz, 2H), 2.84- 2.62 (m, 7H), 1.23 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 424.4.
Example 74: l-Ethyl-3-(3-hydroxy-propyl)-6-(indan-2-ylamino)-lH-[l,8]naph- thyridin-4-one
Figure imgf000159_0001
To a solution of {6-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-8-ethyl-5-oxo-5,8-dihydro- [l,8]naphthyridin-3-yl)-indan-2-yl-carbamic acid tert-butyl ester (100 mg, 0.17 mmol) in 4N HCl in dioxane (2 ml) was added methanol (3 drops). The reaction mixture was stirred at RT for 2h. The solvent was removed under vacuum and the crude was purified by semi- preparative HPLC leading to the pure expected product as a yellow foam (38 mg, 62%).
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 7.94 (s, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.46 (d, = 6.5 Hz, 1H), 4.53 (t, = 5.4 Hz, 1H), 4.37-4.24 (m, 3H), 3.41-3.30 (m, 4H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 2.48- 2.39 (m, 2H), 1.65 (t, = 6.5 Hz, 2H), 1.29 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 364.3.
Example 75: l-Ethyl-6-(indan-2-ylamino)-3-(2-oxo-pyrrolidin-l-yl)-lH-[l,8] na hthyridin-4-one
Figure imgf000159_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (216 mg, 0.50 mmol) and
2- pyrrolidine (51 mg, 0.60 mmol) were reacted as described under General Procedure C (lh at 135°C) to furnish the title compound (47 mg, 24%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 3.0 Hz, 1H), 8.19 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.13 (m, 2H), 6.60 (d, = 6.5 Hz, 1H), 5.87-5.85 (m, 1H), 4.41-4.26 (m, 3H), 3.70 (t, / = 6.9 Hz, 2H), 3.38-3.30 (m, 2H), 2.87-2.80 (dd, / = 15.9, 4.6 Hz, 2H), 2.36 (t, = 7.8 Hz, 2H), 2.11-2.00 (m, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 389.3.
Example 76: l-Ethyl-6-(indan-2-ylamino)-3-(3-oxo-morpholin-4-yl)-lH-[l,8] naphthyridin-4-one
Figure imgf000160_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol) and morpholin-3-one (70 mg, 0.70 mmol) were reacted as described under General Procedure C (lh at 135°C) to furnish the title compound (129 mg, 55%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.38 (d, = 3.0 Hz, 1H), 8.26 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.18-7.13 (m, 2H), 6.63 (d, = 6.5 Hz, 1H), 4.42-4.26 (m, 3H), 4.17 (s, 2H), 3.94 (t, J = 4.7 Hz, 2H), 3.59 (t, J = 5.3 Hz, 2H), 3.39-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.87-2.81 (dd, J = 16.0, 4.6 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 405.4.
Example 77: N-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- yl]-4-meth l-benzamide
Figure imgf000160_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol) and p-toluamide (94 mg, 0.70 mmol) were reacted as described under General Procedure C (lh at 135°C) to furnish the title compound (89 mg, 35%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 9.27 (s, 1H), 9.02 (s, 1H), 8.41 (d, J = 3.0 Hz, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 3.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.27-7.24 (m, 2H), 7.18-7.14 (m, 2H), 6.62 (d, J = 6.5 Hz, 1H), 4.48 (qd, J = 6.9 Hz, 2H), 4.36-4.28 (m, 1H), 3.40-3.32 (dd, J = 16.0, 7.0 Hz, 2H), 2.89-2.82 (dd, J = 16.0, 4.6 Hz, 2H), 2.38 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 439.4.
Example 78: Pyridine-2-carboxylic acid [l-ethyl-6-(indan-2-ylamino) dihydro-[l,8]naphthyridin-3-yl]-amide
Figure imgf000161_0001
l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (240 mg, 0.63 mmol) and picolinamide (92 mg, 0.75 mmol) were reacted as described under General Procedure C (18h at 135°C and 48h at 165°C) to furnish the title compound (50 mg, 19%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 10.63 (s, 1H), 9.35 (s, 1H), 8.75 (d, = 4.7 Hz, 1H), 8.42 (d, = 3.0 Hz, 1H), 8.16 (d, = 8.0 Hz, 1H), 8.08 (t, = 7.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.56 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.63 (d, = 5.9 Hz, 1H), 4.50 (qd, = 6.8 Hz, 2H), 4.36-4.29 (m, 1H), 3.40-3.32 (dd, = 16.2, 7.0 Hz, 2H), 2.88-2.82 (dd, = 15.8, 4.1 Hz, 2H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 426.4.
Example 79: N-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthyri-din-3- yl]-2-pyridin-2-yl-acetamide
Figure imgf000161_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol) and
2- pyridineacetamide (95 mg, 0.70 mmol) were reacted as described under General Procedure C (2h30 at 135°C) to furnish the title compound (39 mg, 15%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 9.66 (s, 1H), 9.05 (s, 1H), 8.54 (d, J = 4.8 Hz, 1H), 8.38 (d, = 3.0 Hz, 1H), 7.76 (td, = 7.7, 1.8 Hz, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.41 (d, = 7.8 Hz, 1H), 7.31-7.23 (m, 3H), 7.18-7.13 (m, 2H), 6.57 (d, = 6.5 Hz, 1H), 4.40 (qd, J = 6.9 Hz, 2H), 4.33-4.27 (m, 1H), 3.96 (s, 2H), 3.39-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.81 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 440.3. 80: l-Ethyl-6-(indan-2-ylamino)-3-(pyridin-2-ylamino)-lH-[l,8]naph-
Figure imgf000162_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (350 mg, 0.81 mmol) and
2- aminopyridine (153 mg, 1.62 mmol) were reacted as described under General Procedure C (5h at 135°C) to furnish the title compound (64 mg, 20%) as a yellow foam.
1H NMR (300 MHz, OMSO-d6) δ 9.40 (s, 1H), 8.39 (d, = 3.0 Hz, 1H), 8.22-8.15 (m, 2H), 7.58 (d, = 3.0 Hz, 1H), 7.53 (t, = 8.6 Hz, 1H), 7.28-7.24 (m, 2H), 7.19-7.11 (m, 3H), 6.71 (t, = 5.6 Hz, 1H), 6.50 (d, = 6.6 Hz, 1H), 4.47 (qd, = 7.0 Hz, 2H), 4.36-4.28 (m, 1H), 3.41-3.33 (dd, = 16.0, 7.0 Hz, 2H), 2.90-2.83 (dd, = 16.0, 4.6 Hz, 2H), 1.37 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 398.3. Example 81: l-Ethyl-6-(indan-2-ylamino)-3-(methyl-pyridin-2-yl-amino)-lH- [l,8]naphthyridin-4-one
Figure imgf000162_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (216 mg, 0.50 mmol) and
2- (methylamino)pyridine (108 mg, 1.00 mmol) were reacted as described under General Procedure C (4h at 135°C) to furnish the title compound (29 mg, 14%) as a yellow foam.
1H NMR (300 MHz, DMSO-d6) δ 8.37 (d, J = 3.0 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 3.9 Hz, 1H), 7.53 (d, J = 3.0 Hz, 1H), 7.34 (t, J = 7.0 Hz, 1H), Ί .25-1.22 (m, 2H), 7.15-7.12 (m, 2H), 6.61-6.54 (m, 2H), 6.33 (d, J = 8.5 Hz, 1H), 4.38 (qd, J = 7.0 Hz, 2H), 4.34-4.24 (m, 1H), 3.37-3.30 (dd, J = 15.7, 6.9 Hz, 2H), 2.89-2.80 (dd, J = 15.9, 4.4 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 412.3. 82: l-Ethyl-6-(indan-2-ylamino)-3-(pyrazin-2-ylamino)-lH-[l,8]naph-
Figure imgf000163_0001
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol) and
2- aminopyrazine (66 mg, 0.70 mmol) were reacted as described under General Procedure C (3h at 135°C) to furnish the title compound (68 mg, 29%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 9.23 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.39 (d, = 3.0 Hz, 1H), 8.10 (d, = 2.7 Hz, 1H), 7.85 (d, = 3.0 Hz, 1H), 7.59 (d, = 3.0 Hz, 1H), 7.27- 7.23 (m, 2H), 7.18-7.13 (m, 2H), 6.53 (d, = 6.6 Hz, 1H), 4.45 (qd, = 7.0 Hz, 2H), 4.37- 4.28 (m, 1H), 3.40-3.32 (dd, = 16.0, 7.0 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.6 Hz, 2H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 399.3.
Example 83: l-Ethyl-6-(indan-2-ylamino)-3-(thiazol-2-ylamino)-lH-[l,8]naph- thyridin-4-one
Figure imgf000163_0002
1- Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (500 mg, 1.16 mmol) and
2- aminothiazole (232 mg, 2.32 mmol) were reacted as described under General Procedure C (18h at 135°C) to furnish the title compound (36 mg, 8%) as a yellow foam.
1H NMR (300 MHz, OMSO-d6) δ 9.60 (s, 1H), 9.34 (s, 1H), 8.38 (d, = 3.0 Hz, 1H), 7.57 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 3H), 7.17-7.13 (m, 2H), 6.81 (d, = 3.7 Hz, 1H), 6.51 (d, = 6.5 Hz, 1H), 4.43 (qd, = 6.9 Hz, 2H), 4.37-4.27 (m, 1H), 3.39-3.32 (dd, = 16.2, 6.9 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 1.34 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 404.3.
Example 84: l-Ethyl-3-(4-hydroxy-piperidin-l-yl)-6-(indan-2-ylamino)-lH-[l,8] naphthyridin-4-one
Figure imgf000164_0001
A suspension of l-ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (250 mg, 0.58 mmol), 4-hydroxypiperidine (88 mg, 0.87 mmol), copper iodide (6 mg, 0.05 mmol), cesium carbonate (378 mg, 1.16 mmol), and 2-isobutyrylcyclohexanone (20 μΐ, 0.12 mmol) in dry DMF (1 ml), was stirred at 90°C for 72h under argon. After cooling, the reaction mixture was filtered through a pad of Celite eluting successively with AcOEt, CH2CI2 and CH3OH. The filtrate was concentrated and purified by flash chromatography (Si02, AcOEt/CH3OH 100:0→ 90: 10) and semi -preparative HPLC to furnish the title compound (24 mg, 10%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.64 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.40 (d, = 6.4 Hz, 1H), 4.62 (d, = 4.2 Hz, 1H), 4.37 (qd, / = 6.8 Hz, 2H), 4.33-4.22 (m, 1H), 3.59-3.51 (m, 1H), 3.38-3.30 (dd, = 15.7, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.6 Hz, 2H), 2.62 (t, = 7.0 Hz, 2H), 1.84- 1.77 (m, 2H), 1.52 (qd, = 9.3 Hz, 2H), 1.29 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 405.4.
Example 85: l-Ethyl-6-(indan-2-ylamino)-3-morpholin-4-yl-lH-[l,8]naphthyri-din-4- one
Figure imgf000164_0002
A suspension of l-ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (300 mg, 0.78 mmol), morpholine (82 μΐ, 0.94 mmol), sodium tert-butoxide (120 mg, 1.25 mmol), and BINAP (24 mg, 0.04 mmol) in dry toluene (15 ml) was purged with argon for 15 min. Pd2(dba)3 (36 mg, 0.04 mmol) was added and the mixture stirred at 90°C for 36h. After cooling, water (20 ml) and CH2C12 (40 ml) were added. The aqueous layer was extracted with CH2C12 (2 x 30 ml). The combined organic layers were dried over MgS04, filtered and concentrated under vacuum. The crude was purified by flash chromatography (Si02, CH2Cl2/AcOEt 100:0→ 30:70 and CH2C12/CH30H 100:0→ 90: 10) and by semi- preparative HPLC to furnish the pure expected product as a yellow solid (17 mg, 5%).
1H NMR (300 MHz, DMSO-i¾) δ 8.31 (d, = 3.0 Hz, 1H), 7.65 (s, 1H), 7.53 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.41 (d, = 6.5 Hz, 1H), 4.38 (qd, = 7.0 Hz, 2H), 4.33-4.22 (m, 1H), 3.71 (t, = 4.2 Hz, 4H), 3.37-3.30 (dd, = 16.0, 7.0 Hz, 2H), 3.01 (t, = 4.2 Hz, 4H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 1.30 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 391.4. Example 86: l-Ethyl-6-(indan- -ylamino)-3-phenox -lH-[l,8]naphthyridin-4-one
Figure imgf000165_0001
D 86 l-Ethyl-6-(indan-2-ylamino)-3-bromo-lH-[l,8]naphthyridin-4-one (150 mg, 0.39 mmol) and phenol (73 mg, 0.78 mmol) were reacted as described under General Procedure J (48h at 120°C) to furnish the title compound (22 mg, 14%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.39 (d, = 3.0 Hz, 1H), 8.37 (s, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.28-7.23 (m, 4H), 7.17-7.13 (m, 2H), 6.96 (t, = 7.3 Hz, 1H), 6.86 (d, = 7.8 Hz, 1H), 6.61 (d, J = 6.5 Hz, 1H), 4.39 (qd, J = 6.9 Hz, 2H), 4.34-4.22 (m, 1H), 3.38-3.30 (dd, J = 15.6, 7.0 Hz, 2H), 2.87-2.81 (dd, J = 16.0, 4.5 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 398.4.
Example 87: l-Ethyl-6-(indan-2-ylamino)-3-(pyridin-3-yloxy)-lH-[l,8]naphthy-ridin- 4-one
Figure imgf000165_0002
C 87 l-Ethyl-6-(indan-2-ylamino)-3-iodo- lH-[l,8]naphthyridin-4-one (216 mg, 0.50 mmol) and 3-hydroxypyridine (95 mg, 1.00 mmol) were reacted as described under General Procedure J (48h at 135°C) to furnish the title compound (8 mg, 4%) as a yellow foam. 1H NMR (300 MHz, OMSO-d6) δ 8.46 (s, 1H), 8.40 (d, 7 = 3.0 Hz, 1H), 8.29 (s, 1H), 8.19 (d, 7 = 3.4 Hz, 1H), 7.51 (d, 7 = 3.0 Hz, 1H), 7.30-7.23 (m, 4H), 7.15-7.12 (m, 2H), 6.64 (d, 7 = 6.5 Hz, 1H), 4.40 (qd, J = 1.1 Hz, 2H), 4.34-4.22 (m, 1H), 3.37-3.31 (dd, 7 = 15.6, 7.1 Hz, 2H), 2.87-2.80 (dd, 7 = 16.0, 4.4 Hz, 2H), 1.35 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 399.3.
Example 88: l-Ethyl-6-(indan-2-ylamino)-3-(4-methoxy-phenoxy)-lH-[l,8] naphthyridin-4-one
Figure imgf000166_0001
D 88
A suspension of l-ethyl-6-(indan-2-ylamino)-3-bromo- lH-[l,8]naphthyridin-4-one (250 mg, 0.65 mmol), 4-methoxyphenol (121 mg, 0.98 mmol), copper iodide (6 mg, 0.03 mmol), cesium carbonate (318 mg, 0.98 mmol), and 3,4,7, 8-tetramethyl-l, 10- phenanthroline (15 mg, 0.06 mmol) in anhydrous toluene (1 ml) was heated in a sealed tube at 110°C for 48h, cooled to RT and filtered through a pad of Celite eluting with AcOEt. The filtrate was concentrated and purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 0: 100) to furnish after a semi -preparative HPLC the pure coupling product (27 mg, 10%) as yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.39 (d, 7 = 3.0 Hz, 1H), 8.32 (s, 1H), 7.52 (d, 7 = 3.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.18-7.13 (m, 2H), 6.82 (s, 4H), 6.60 (d, 7 = 6.4 Hz, 1H), 4.39 (qd, 7 = 7.0 Hz, 2H), 4.34-4.24 (m, 1H), 3.68 (s, 3H), 3.38-3.31 (dd, 7 = 15.7, 6.9 Hz, 2H), 2.88-2.81 (dd, 7 = 15.9, 4.4 Hz, 2H), 1.33 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 428.4.
Example 89: l-Ethyl-6-(indan-2-ylamino)-3-(4-methoxy-benzyloxy)-lH-[l,8] naphthyridin-4-one
Figure imgf000166_0002
D 89 A suspension of l-ethyl-6-(indan-2-ylamino)-3-bromo- lH-[l,8]naphthyridin-4-one (250 mg, 0.65 mmol), 4-methoxybenzylalcohol (135 mg, 0.98 mmol), copper iodide (6 mg, 0.03 mmol), cesium carbonate (318 mg, 0.98 mmol), and 3,4,7, 8-tetramethyl-l, 10- phenanthroline (15 mg, 0.06 mmol) in anhydrous toluene (1 ml) was heated in a sealed tube at 110°C for 48h, cooled to RT and filtered through a pad of Celite eluting with AcOEt. The filtrate was concentrated and purified by flash chromatography (Si02, cyclohexane/AcOEt 100:0→ 0: 100) to furnish the pure coupling product (108 mg, 38%) as yellow foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, 7 = 3.0 Hz, 1H), 7.96 (s, 1H), 7.55 (d, 7 = 3.0 Hz, 1H), 7.34 (d, 7 = 8.5 Hz, 2H), 7.26-7.24 (m, 2H), 7.16-7.13 (m, 2H), 6.91 (d, 7 = 8.5 Hz, 2H), 6.51 (d, 7 = 6.4 Hz, 1H), 4.99 (s, 2H), 4.37-4.24 (m, 3H), 3.73 (s, 3H), 3.39-3.32 (dd, 7 = 15.7, 6.9 Hz, 2H), 2.87-2.80 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.24 (t, 7 = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 442.4.
Example 90: 6-Amino-l-ethyl-3-furan-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000167_0001
6-Amino- l-ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (200 mg, 0.63 mmol) and 2-(tributylstannyl)furan (272 mg, 0.76 mmol) were reacted as described under General Procedure B (24h at 90°C) to furnish the title compound (26 mg, 16%) as a yellow foam. 1H NMR (300 MHz, OMSO-d6) δ 8.52 (s, 1H), 8.27 (d, 7 = 3.0 Hz, 1H), 7.68 (d, 7 = 3.0 Hz, 1H), 7.62 (d, 7 = 1.6 Hz, 1H), 7.16 (d, 7 = 3.0 Hz, 1H), 6.53 (dd, 7 = 3.1, 1.9 Hz, 1H), 5.70 (s, 2H), 4.47 (qd, 7 = 7.0 Hz, 2H), 1.34 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 278.1.
Example 91: l-Ethyl-3-furan-2-yl-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8] naphthyridin-4-one
Figure imgf000168_0001
l-Ethyl-3-iodo-6-(tetrahydro-pyran-4-ylamino)-lH-[l,8]naphthyridin-4-one (200 mg, 0.50 mmol) and 2-(tributylstannyl)furan (215 mg, 0.60 mmol) were reacted as described under General Procedure B (24h at 90°C) to furnish the title compound (57 mg, 34%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.53 (s, 1H), 8.36 (d, 7 = 3.0 Hz, 1H), 7.63 (d, 7 = 1.7 Hz, 1H), 7.57 (d, 7 = 3.0 Hz, 1H), 7.18 (d, 7 = 3.0 Hz, 1H), 6.54 (dd, 7 = 3.2, 1.9 Hz, 1H), 6.28 (d, 7 = 7.8 Hz, 1H), 4.49 (qd, 7 = 6.9 Hz, 2H), 3.90-3.85 (m, 2H), 3.60-3.43 (m, 3H), 1.94-1.90 (m, 2H), 1.47-1.32 (m, 5H). ESIMS m/z [M+H]+ 340.3.
Example 92: l-Ethyl-3-furan-2-yl-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH- [l,8]naphthyridin-4-one
Figure imgf000168_0002
l-Ethyl-3-iodo-6-[(tetrahydro-pyran-4-ylmethyl)-amino]-lH-[l,8]naphthyridin-4-one (300 mg, 0.73 mmol) and 2-(tributylstannyl)furan (311 mg, 0.87 mmol) were reacted as described under General Procedure B (24h at 90°C) to furnish the title compound (128 mg, 50%) as a yellow foam.
1H NMR (300 MHz, DMSC ^) δ 8.53 (s, 1H), 8.37 (d, 7 = 3.0 Hz, 1H), 7.63 (s, 1H), 7.51 (d, 7 = 3.0 Hz, 1H), 7.18 (d, 7 = 3.0 Hz, 1H), 6.54 (dd, 7 = 3.1, 1.9 Hz, 1H), 6.41 (t, 7 = 5.5 Hz, 1H), 4.49 (qd, 7 = 6.8 Hz, 2H), 3.88-3.83 (m, 2H), 3.26 (t, 7 = 11.4 Hz, 2H), 3.01 (t, 7 = 6.1 Hz, 2H), 1.86-1.74 (m, 1H), 1.69 (brd, 7 = 12.7 Hz, 2H), 1.35 (t, 7 = 6.9 Hz, 3H), 1.30-1.21 (m, 2H). ESIMS m/z [M+H]+ 354.3. Example 93: 6-(Indan-2-ylamino)-2-phenyl-lH-[l,8]naphthyridin-4-one
Figure imgf000169_0001
AM 93
6-Bromo-2-phenyl-[l,8]naphthyridin-4-one (122 mg, 0.41 mmol) and 2-aminoindan (65 mg, 0.49 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (52 mg, 36%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 12.09 (s, 1H), 8.32 (d, = 3.0 Hz, 1H), 7.82-7.79 (dd, = 6.1, 2.6 Hz, 2H), 7.54-7.51 (m, 3H), 7.46 (d, = 3.0 Hz, 2H), 7.26-7.25 (m, 2H), 7.18- 7.14 (m, 2H), 6.50 (d, = 6.4 Hz, 1H), 6.27 (s, 1H), 4.35-4.26 (m, 1H), 3.41-3.33 (dd, = 16.2, 7.0 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.5 Hz, 2H). ESIMS m/z [M+H]+ 354.3.
Exam le 94: l-Ethyl-6-(indan-2-ylamino)-2-phenyl-lH-[l,8]naphthyridin-4-one
Figure imgf000169_0002
6-Bromo-l-ethyl-2-phenyl-lH-[l,8]naphthyridin-4-one (450 mg, 1.37 mmol) and 2- aminoindan (219 mg, 1.64 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (227 mg, 43%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.39 (d, = 3.0 Hz, 1H), 7.56-7.53 (m, 6H), 7.28-7.25 (m, 2H), 7.19-7.14 (m, 2H), 6.60 (d, = 6.5 Hz, 1H), 5.85 (s, 1H), 4.35-4.28 (m, 1H), 4.20 (qd, = 6.8 Hz, 2H), 3.41-3.33 (dd, = 16.0, 7.0 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.4 Hz, 2H), 1.09 (t, = 6.9 Hz, 3H). ESIMS m/z [M+H]+ 382.4.
Example 95: 6-(Indan-2-ylamino)-l-(2-methoxy-ethyl)-2-phenyl-lH-[l,8]naph- thyridin-4-one
Figure imgf000170_0001
6-Bromo-l-(2-methoxy-ethyl)-2-phenyl- lH-[l,8]naphthyridin-4-one (171 mg, 0.48 mmol) and 2-aminoindan (76 mg, 0.57 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (57 mg, 29%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.37 (d, = 3.0 Hz, 1H), 7.55-7.52 (m, 6H), 7.28-7.25 (m, 2H), 7.19-7.15 (m, 2H), 6.61 (d, = 6.5 Hz, 1H), 5.86 (s, 1H), 4.40-4.28 (m, 3H), 3.47- 3.36 (m, 4H), 2.97 (s, 3H), 2.89-2.82 (dd, = 16.0, 4.5 Hz, 2H). ESIMS m/z [M+H]+ 412.4.
Exa - Cyclohexyl- 1 -ethyl-6- (indan-2-ylamino) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000170_0002
AP 96
6-Bromo-2-cyclohexyl-l -ethyl- lH-[l,8]naphthyridin-4-one (527 mg, 1.57 mmol) and 2- aminoindan (251 mg, 1.89 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (157 mg, 26%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.48 (d, = 6.5 Hz, 1H), 6.01 (s, 1H), 4.52 (brs, 2H), 4.33-4.24 (m, 1H), 3.41-3.33 (dd, = 15.9, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.90- 1.68 (m, 5H), 1.50-1.32 (m, 6H), 1.26 (t, = 6.8 Hz, 3H). ESIMS m/z [M+H]+ 388.4.
Example 97: 2-Cyclohexyl-6-(indan-2-ylamino)-l-(2-methoxy-ethyl)-lH-[l,8] naphthyridin-4-one
Figure imgf000171_0001
6-Bromo-2-cyclohexyl-l-(2-methoxy-ethyl)-lH-[l,8]naphthyridin-4-one (579 mg, 1.59 mmol) and 2-aminoindan (253 mg, 1.90 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (88 mg, 13%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.29 (d, = 3.0 Hz, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.49 (d, = 6.5 Hz, 1H), 6.00 (s, 1H), 4.64 (brs, 2H), 4.31-4.24 (m, 1H), 3.60 (t, = 5.4 Hz, 2H), 3.38-3.30 (dd, = 15.8, 7.0 Hz, 2H), 3.21 (s, 3H), 2.98 (brs, 1H), 2.86-2.79 (dd, 7 = 16.0, 4.6 Hz, 2H), 1.88-1.68 (m, 5H), 1.50-1.28 (m, 5H). ESIMS m/z [M+H]+ 418.5.
Exa -tert-Butyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one
Figure imgf000171_0002
AR 98
6-Bromo-2-tert-butyl-l-ethyl-lH-[l,8]naphthyridin-4-one (300 mg, 0.97 mmol) and 2- aminoindan (155 mg, 1.16 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (87 mg, 25%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.35 (d, = 3.0 Hz, 1H), 7.44 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.50 (d, = 6.2 Hz, 1H), 6.14 (s, 1H), 4.66 (brs, 2H), 4.30-4.24 (m, 1H), 3.38-3.31 (dd, = 15.9, 6.9 Hz, 2H), 2.87-2.80 (dd, = 15.9, 4.2 Hz, 2H), 1.47 (s, 9H), 1.24 (t, = 6.4 Hz, 3H). ESIMS m/z [M+H]+ 362.4.
Example 99: 2-tert-Butyl-l-(2-dimethylamino-ethyl)-6-(indan-2-ylamino)-lH- [l,8]naphthyridin-4-one
Figure imgf000172_0001
6-Bromo-2-tert-butyl-l-(2-methoxy-ethyl)-lH-[l,8]naphthyridin-4-one (500 mg, 1.42 mmol) and 2-aminoindan (226 mg, 1.70 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (137 mg, 24%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 7.41 (d, = 3.0 Hz, 1H), 7.25- 7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.47 (d, = 6.4 Hz, 1H), 6.14 (s, 1H), 4.68 (brs, 2H), 4.31-4.24 (m, 1H), 3.38-3.30 (dd, = 16.1, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.4 Hz, 2H), 2.46-2.40 (m, 2H), 2.19 (s, 6H), 1.47 (s, 9H). ESIMS m/z [M+H]+ 405.4.
Example 100: 4-[l-Ethyl-6-(indan-2-ylamino)-4-oxo-l,4-dihydro-[l,8]naphthy-ridin- -yl]-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000172_0002
AT 100
4-(6-Bromo- 1 -ethyl-4-oxo- 1 ,4-dihydro- [ 1 , 8] naphthyridin-2-yl)-piperidine- 1 -carboxy-lic acid tert-butyl ester (417 mg, 0.96 mmol) and 2-aminoindan (153 mg, 1.15 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (210 mg, 62%) as a brown foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.50 (d, = 6.4 Hz, 1H), 5.97 (s, 1H), 4.55 (brs, 2H), 4.31-4.26 (m, 1H), 4.06 (brd, / = 10.8 Hz, 2H), 3.38-3.32 (dd, = 15.9, 6.8 Hz, 2H), 3.06- 2.79 (m, 5H), 1.85 (brd, = 12.2 Hz, 2H), 1.60-1.43 (m, 2H), 1.42 (s, 9H), 1.27 (t, = 6.6 Hz, 3H). ESIMS m/z [M+H]+ 489.6.
Example 101: 4-[6-(Indan-2-ylamino)-l-(2-methoxy-ethyl)-4-oxo-l,4-dihydro- [l,8]naphthyridin-2-yl]-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000173_0001
4-(6-Bromo- 1 -(2-methoxy-ethyl)-4-oxo- 1 ,4-dihydro-[ 1 ,8]naphthyridin-2-yl)-piperidi-ne- 1 - carboxylic acid tert-butyl ester (429 mg, 0.92 mmol) and 2-aminoindan (147 mg, 1.10 mmol) were reacted as described under General Procedure M (4h at RT) to furnish the title compound (36 mg, 8%) as a yellow powder. 1H NMR (300 MHz, DMSO-i¾) δ 8.30 (d, = 3.0 Hz, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.49 (d, = 6.4 Hz, 1H), 5.96 (s, 1H), 4.69 (brs, 2H), 4.31-4.25 (m, 1H), 4.06 (brd, / = 11.3 Hz, 2H), 3.61 (t, = 5.3 Hz, 2H), 3.38-3.30 (dd, = 16.2, 7.0 Hz, 2H), 3.20 (s, 3H), 2.90-2.79 (m, 3H), 1.83 (brd, / = 12.3 Hz, 2H), 1.51- 1.41 (m, 2H), 1.41 (s, 9H). ESIMS m/z [M+H]+ 519.5.
Example 102: Ethyl-6-(indan-2-ylamino)-2-piperidin-4-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000173_0002
100 102
4-[l-Ethyl-6-(indan-2-ylamino)-4-oxo- l,4-dihydro-[l,8]naphthyridin-2-yl]-piperidine- l- carboxylic acid tert-butyl ester (210 mg, 0.43 mmol) was stirred in 4N HCI in dioxane (3 ml) et RT for 2h. The precipitate formed was filtered off, washed with AcOEt, dried, and purificated by semi -preparative HPLC to furnish the pure expected compound (61 mg, 37%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.32 (d, = 3.0 Hz, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.25- 7.23 (m, 2H), 7.15-7.13 (m, 2H), 6.48 (d, = 6.3 Hz, 1H), 5.94-5.90 (m, 1H), 4.53 (brs, 2H), 4.31-4.23 (m, 2H), 3.38-3.31 (dd, J = 15.9, 7.0 Hz, 2H), 2.86-2.79 (m, 3H), 2.63-2.51 (m, 4H), 1.71 (d, / = 11.6 Hz, 2H), 1.53-1.38 (m, 2H), 1.26 (t, J = 6.7 Hz, 3H). ESIMS m/z [M+H]+ 389.4. Example 103: 6-(Indan-2-ylamino)-l-(methoxy-ethyl)-2-piperidin-4-yl-lH- [l,8]naphthyridin-4-one
Figure imgf000174_0001
4-[6-(Indan-2-ylamino)-l-(2-methoxy-ethyl)-4-oxo- l,4-dihydro-[l,8]naphthyridin-2-yl]- piperidine- l-carboxylic acid tert-butyl ester (180 mg, 0.35 mmol) was stirred in 4N HCl in dioxane (2 ml) et RT for 2h. The precipitate formed was filtered off, washed with AcOEt, dried, and purificated by semi-preparative HPLC to furnish the pure expected compound (12 mg, 8%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.30 (d, = 3.0 Hz, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.26- 7.23 (m, 2H), 7.17-7.13 (m, 2H), 6.48 (d, J = 6.5 Hz, 1H), 5.96 (s, 1H), 4.67-4.63 (m, 2H), 4.32-4.25 (m, 1H), 3.61 (t, J = 5.4 Hz, 2H), 3.38-3.30 (m, 4H), 3.20 (s, 3H), 3.14-3.03 (m, 3H), 2.86-2.79 (dd, = 16.0, 4.6 Hz, 2H), 2.68-2.60 (m, 1H), 1.77 (brd, J = 11.8 Hz, 2H), 1.60- 1.50 (m, 2H). ESIMS m/z [M+H]+ 419.3.
Example 104: 6-(Indan-2-ylamino)-2-phenyl-thiopyrano[2,3-b]pyridin-4-one
Figure imgf000174_0002
A mixture of 6-bromo-2-phenyl-thiopyrano[2,3-b]pyridin-4-one (190 mg, 0.60 mmol), 2- aminoindan (95 mg, 0.72 mmol), Pd2dba3 (54 mg, 0.06 mmol), and DavePhos (33 mg, 0.09 mmol) in toluene/NMP (1 : 1) (4 ml) was degassed under argon for 15 min at RT. Sodium tert-butoxide (76 mg, 0.84 mmol) was added. The reaction mixture was heated 10 min at 120°C under microwave conditions. After cooling, the crude was directly purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0 → 80:20) leading to the expected product (54 mg, 23%) as a yellow solid.
1H NMR (300 MHz, DIVISOR) δ 8.40 (d, = 3.0 Hz, IH), 7.82-7.79 (m, 2H), 7.64 (d, = 3.0 Hz, IH), 7.57-7.54 (m, 3H), 7.27-7.24 (m, 2H), 7.22 (s, IH), 7.18-7.14 (m, 2H), 6.95 (d, = 6.5 Hz, IH), 4.38-4.31 (m, IH), 3.40-3.33 (dd, = 16.0, 7.0 Hz, 2H), 2.88-2.82 (dd, = 16.0, 4.5 Hz, 2H). ESIMS m/z [M+H]+ 371.3.
Example 105: 6-(Indan-2-ylamino)-2-phenyl-pyrano[2,3-b]pyridin-4-one
Figure imgf000175_0001
6-Bromo-2-phenyl-pyrano[2,3-b]pyridin-4-one (180 mg, 0.60 mmol), 2-aminoindan (95 mg, 0.72 mmol), Pd2dba3 (54 mg, 0.06 mmol), and DavePhos (33 mg, 0.09 mmol) in toluene/NMP (1: 1) (4 ml) was degassed under argon for 15 min at RT. Sodium tert- butoxide (76 mg, 0.84 mmol) was added. The reaction mixture was heated 10 min at 120°C under microwave conditions. After cooling, the crude was directly purified by flash chromatography (Si02, cyclohexane/ AcOEt 100:0 → 0: 100) leading to the expected product (42 mg, 20%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.22 (d, = 3.0 Hz, IH), 8.07-8.04 (m, 2H), 7.59-7.55 (m, 3H), 7.43 (d, = 3.1 Hz, IH), 7.27-7.24 (m, 2H), 7.16-7.13 (m, 2H), 7.00 (s, IH), 6.72 (d, = 6.6 Hz, IH), 4.38-4.27 (m, IH), 3.39-3.32 (dd, / = 16.0, 7.0 Hz, 2H), 2.87-2.80 (dd, = 16.0, 4.6 Hz, 2H). ESIMS m/z [M+H]+ 355.3.
Example 106: 3-(4-Dimethylaminomethyl-[l,2,3]-triazol-l-ylmethyl)-l-ethyl-6-(indan- 2-ylamino) - IH- [ 1 ,8] naphthyridin-4-one
Figure imgf000176_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (96 mg, 0.27 mmol) and l-dimethylamino-2-propyne (24 mg, 0.29 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (109 mg, 92%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 2.0 Hz, 2H), 7.89 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 6.60 (d, J = 6.4 Hz, 1H), 5.33 (s, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.40 (s, 2H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 2.09 (s, 6H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 444.2.
Example 107: l-Ethyl-6-(indan-2-ylamino)-3-(4-morpholin-4-ylmethyl-[l,2,3]-triazol- 1 - lmethyl) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000176_0002
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and 4-(prop-2-yn- l-yl)morpholine (41 mg, 0.33 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (134 mg, 91%) as an orange foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 2.0 Hz, 2H), 7.92 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.13 (m, 2H), 6.60 (d, = 6.4 Hz, 1H), 5.33 (s, 2H), 4.37 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.52-3.38 (m, 6H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 2.37-2.29 (m, 4H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 486.2. Example 108: l-Ethyl-3-(4-hydroxymethyl-[l,2,3]-triazol-l-ylmethyl)-6-(indan-2- lamino)- 1H- [l,8]naphthyridin-4-one
Figure imgf000177_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and propargyl alcohol (19 mg, 0.33 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (91 mg, 72%) as a yellow foam.
1H NMR (300 MHz,
Figure imgf000177_0002
δ 8.38 (s, 1H), 8.36 (d, J = 3.0 Hz, 1H), 7.90 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7..25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.32 (s, 2H), 5.09 (t, J = 5.7 Hz, 1H), 4.45 (d, J = 5.6 Hz, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31- 4.25 (m, 1H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 417.3. Example 109: 3-[4-(2-Dimethylamino-ethyl)-[l,2,3]-triazol-l-ylmethyl]-l-ethyl-6- (indan-2- lamino) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000177_0003
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and (but-3-yn- l-yl)dimethylamine (32 mg, 0.33 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (96 mg, 70%) as a yellow foam.
1H NMR (300 MHz, OMSO-d6) δ 8.36 (d, J = 2.8 Hz, 2H), 7.79 (s, 1H), 7.51 (d, J = 3.0 Hz, 1H), 7 '.25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.61 (d, J = 6.5 Hz, 1H), 5.29 (s, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 2.68 (t, J = 7.0 Hz, 2H), 2.44 (t, J = 7.0 Hz, 2H), 2.13 (s, 6H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 458.3. Example 110: l-Ethyl-6-(indan-2-ylamino)-3-{[4-(methoxymethyl)triazol-l- l]methyl}-[l,8]naphthyridin-4-one
Figure imgf000178_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (73 mg, 0.20 mmol) and methyl propargyl ether (16 mg, 0.22 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (51 mg, 58%) as a yellow foam.
1H NMR (300 MHz, DMSC ^) δ 8.39 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.02 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7..25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.34 (s, 2H), 4.41-4.33 (m, 4H), 4.31-4.25 (m, 1H), 3.37-3.30 (dd, = 16.0, 6.9 Hz, 2H), 3.22 (s, 3H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.2. Example 111: l-Ethyl-3-{[4-(2-hydroxyethyl)triazol-l-yl]methyl}-6-(indan-2- ylamino -[l,8]naphthyridin-4-one
Figure imgf000178_0002
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (100 mg, 0.28 mmol) and 3-butyn-l-ol (21 mg, 0.30 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (109 mg, 91%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.36 (d, = 2.1 Hz, 2H), 7.79 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.29 (s, 2H), 4.64 (t, = 5.2 Hz, 1H), 4.36 (qd, = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.56 (qd, = 6.9 Hz, 2H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.86-2.79 (dd, J = 16.0, 4.5 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.2.
Example 112: l-Ethyl-6-(indan-2-ylamino)-3-{[4-(2-methoxyethoxymethyl)triazol-l- yl]methyl}-[l,8]naphthyridin-4-one
Figure imgf000179_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (100 mg, 0.28 mmol) and 3-(2-methoxy-ethoxy)propyne (35 mg, 0.31 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (48 mg, 36%) as a yellow foam.
1H NMR (300 MHz, DMSC ^) δ 8.39 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.00 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7..25-7.22 (m, 2H), 7.17-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.34 (s, 2H), 4.45 (s, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.53-3.50 (m, 2H), 3.41-3.30 (m, 4H), 3.18 (s, 3H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 475.2.
Example 113: l-Ethyl-3-{[4-(2-hydroxyethoxymethyl)triazol-l-yl]methyl}-6-(indan-2- ylamino)-[l,8]naphthyridin-4-one
Figure imgf000179_0002
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (90 mg, 0.25 mmol) and 2-prop-2-ynoxyethanol (50 mg, 0.50 mmol) were reacted as described under General Procedure D (18h at 65°C) to furnish the title compound (46 mg, 40%) as a yellow foam.
1H NMR (300 MHz, DMSC ^) δ 8.39 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.01 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7..25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.34 (s, 2H), 4.59 (t, J = 5.5 Hz, 1H), 4.46 (s, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.49-3.42 (m, 4H), 3.40-3.30 (m, 2H), 2.86-2.79 (dd, = 16.0, 4.5 Hz, 2H), 1.32 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 461.2. Example 114: 3-(5-Dimethylaminomethyl-[l,2,3]-triazol-l-ylmethyl)-l-ethyl-6-(indan- 2-ylamino) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000180_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and l-dimethylamino-2-propyne (50 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (115 mg, 86%) as an orange foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 2H), 8.21 (s, 1H), 7.53 (s, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.16-7.12 (m, 2H), 6.58 (d, = 6.4 Hz, 1H), 5.35 (s, 2H), 4.37 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.72 (s, 2H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 2.85-2.78 (dd, = 16.0, 4.5 Hz, 2H), 2.17 (s, 6H), 1.30 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 444.3.
Example 115: l-Ethyl-6-(indan-2-ylamino)-3-(5-morpholin-4-ylmethyl-[l,2,3]-triazol- 1 - lmethyl) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000180_0002
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and 4-(prop-2-yn- l-yl)morpholine (41 mg, 0.33 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (125 mg, 85%) as an orange foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 7.49 (d, = 3.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.16-7.12 (m, 2H), 6.59 (d, = 6.4 Hz, 1H), 5.39 (s, 2H), 4.36 (qd, J = 7.0 Hz, 2H), 4.31-4.24 (m, 1H), 3.77 (s, 2H), 3.47 (t, J = 4.4 Hz, 4H), 3.37-3.30 (dd, 7 = 16.0, 6.9 Hz, 2H), 2.85-2.78 (dd, 7 = 16.0, 4.5 Hz, 2H), 2.35 (t, 7 = 4.3 Hz, 4H), 1.29 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 486.4.
Example 116: l-Ethyl-3-(5-hydroxymethyl-[l,2,3]-triazol-l-ylmethyl)-6-(indan-2- ylamino - 1H- [l,8]naphthyridin-4-one
Figure imgf000181_0001
3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and propargyl alcohol (34 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (66 mg, 52%) as an orange foam.
1H NMR (300 MHz, DMSC ^) δ 8.36 (d, 7 = 3.0 Hz, 1H), 8.31 (s, 1H), 7.54 (s, 1H), 7.48 (d, 7 = 3.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.16-7.10 (m, 2H), 6.60 (d, 7 = 6.4 Hz, 1H), 5.65 (t, 7 = 5.8 Hz, 1H), 5.31 (s, 2H), 4.77 (d, 7 = 5.3 Hz, 2H), 4.39 (qd, 7 = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.37-3.30 (dd, 7 = 16.0, 6.9 Hz, 2H), 2.85-2.78 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.32 (t, 7 = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 417.3.
Example 117: 3-[5-(2-Dimethylamino-ethyl)-[l,2,3]-triazol-l-ylmethyl]-l-ethyl-6- (indan-2-ylamino) - 1H- [ 1 ,8] naphthyridin-4-one
Figure imgf000181_0002
3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and (but-3-yn-l-yl)dimethylamine (58 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (80 mg, 58%) as an orange foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, 7 = 3.0 Hz, 1H), 8.17 (s, 1H), 7.49 (d, 7 = 3.0 Hz, 1H), 7.47 (s, 1H), 7.24-7.21 (m, 2H), 7.14-7.12 (m, 2H), 6.58 (d, 7 = 6.4 Hz, 1H), 5.26 (s, 2H), 4.37 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.36-3.30 (dd, / = 16.0, 6.9 Hz, 2H), 2.99 (t, = 7.3 Hz, 2H), 2.85-2.78 (dd, = 16.0, 4.5 Hz, 2H), 2.16 (s, 6H), 1.30 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 458.3. Example 118: l-Ethyl-6-(indan-2-ylamino)-3-{[5-(2-morpholinoethyl)-triazol-l- yl methyl}-[l,8]naphthyridin-4-one
Figure imgf000182_0001
3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and 4-(but-3-yn-l-yl)morpholine (84 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (96 mg, 64%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.20 (s, 1H), 7.49 (s, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.16-7.12 (m, 2H), 6.61 (d, = 6.4 Hz, 1H), 5.27 (s, 2H), 4.37 (qd, = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.53 (t, = 4.5 Hz, 4H), 3.36-3.29 (dd, = 16.0, 6.9 Hz, 2H), 3.03 (t, = 7.4 Hz, 2H), 2.85-2.78 (dd, = 16.0, 4.5 Hz, 2H), 2.53 (t, = 7.4 Hz, 2H), 2.39 (t, = 4.5 Hz, 4H), 1.30 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 500.3.
Example 119: l-Ethyl-6-(indan-2-ylamino)-3-5-(methoxymethyl)-[l,2,3]triazol-l- ylmethyl)-lH-[l,8]naphthyridin-4-one
Figure imgf000182_0002
3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one (108 mg, 0.30 mmol) and methyl propargyl ether (42 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (65 mg, 50%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.26 (s, 1H), 7.64 (s, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.16-7.12 (m, 2H), 6.60 (d, = 6.4 Hz, 1H), 5.31 (s, 2H), 4.76 (s, 2H), 4.38 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.38-3.30 (dd, / = 16.0, 6.9 Hz, 2H), 3.29 (s, 3H), 2.85-2.78 (dd, = 16.0, 4.5 Hz, 2H), 1.31 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.3. Example 120: l-Ethyl-3-{[4-(2-hydroxyethyl)triazol-l-yl]methyl}-6-(indan-2- ylamino)-[l,8]naphthyridin-4-one
Figure imgf000183_0001
3-Azidomethyl-l-ethyl-6-(indan-2-ylamino)-lH-[l,8]naphthyridin-4-one (100 mg, 0.28 mmol) and 3-butyn-l-ol (19 mg, 0.28 mmol) were reacted as described under General Procedure E (48h at 80°C) to furnish the title compound (78 mg, 65%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 2.1 Hz, 1H), 8.17 (s, 1H), 7.48 (d, = 3.0 Hz, 1H), 7.47 (s, 1H), 7.25-7.22 (m, 2H), 7.16-7.12 (m, 2H), 6.59 (d, = 6.4 Hz, 1H), 5.27 (s, 2H), 4.87 (t, = 5.3 Hz, 1H), 4.37 (qd, = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.66 (qd, = 6.4 Hz, 2H), 3.37-3.30 (dd, = 16.0, 6.9 Hz, 2H), 3.01 (t, = 6.4 Hz, 2H), 2.85-2.78 (dd, = 16.0, 4.5 Hz, 2H), 1.30 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 431.2.
Example 121: l-Ethyl-6-(indan-2-ylamino)-3-{[5-(2-methoxyethoxymethyl)triazol-l- yl]methyl}-[l,8]naphthyridin-4-one
-
Figure imgf000183_0002
u 3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (100 mg, 0.28 mmol) and 3-(2-methoxy-ethoxy)propyne (35 mg, 0.31 mmol) were reacted as described under General Procedure E (18h at 65°C) to furnish the title compound (48 mg, 36%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.24 (s, 1H), 7.63 (s, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.24-7.20 (m, 2H), 7.16-7.12 (m, 2H), 6.59 (d, = 6.4 Hz, 1H), 5.32 (s, 2H), 4.82 (s, 2H), 4.37 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.59-3.55 (m, 2H), 3.44-3.41 (m, 2H), 3.37-3.30 (dd, J = 16.0, 6.9 Hz, 2H), 3.19 (s, 3H), 2.85-2.78 (dd, J = 16.0, 4.5 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 475.2.
Example 122: l-Ethyl-3-{[5-(2-hydroxyethoxymethyl)triazol-l-yl]methyl}-6-(indan-2- ylamino)-[l,8]naphthyridin-4-one
H
Figure imgf000184_0001
3-Azidomethyl- l-ethyl-6-(indan-2-ylamino)- lH-[l,8]naphthyridin-4-one (100 mg, 0.30 mmol) and 2-prop-2-ynoxyethanol (56 mg, 0.60 mmol) were reacted as described under General Procedure E (18h at 80°C) to furnish the title compound (41 mg, 32%) as a yellow foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.34 (d, = 3.0 Hz, 1H), 8.27 (s, 1H), 7.63 (s, 1H), 7.47 (d, = 3.0 Hz, 1H), 7.24-7.21 (m, 2H), 7.16-7.12 (m, 2H), 6.59 (d, = 6.4 Hz, 1H), 5.33 (s, 2H), 4.82 (s, 2H), 4.69 (t, J = 5.0 Hz, 1H), 4.38 (qd, J = 7.0 Hz, 2H), 4.31-4.25 (m, 1H), 3.53-3.47 (m, 4H), 3.37-3.29 (m, 2H), 2.85-2.78 (dd, 7 = 16.0, 4.5 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 461.2.
Example 123: l-Ethyl-6-(indan-2-ylamino)-3-[l-(2-morpholin-4-yl-ethyl)-lH-pyrazol- 4-yl]-lH-[l,8]naphthyridin-4-one
Figure imgf000185_0001
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (300 mg, 0.70 mmol) and l-(2-morpholinoethyl)-lH-pyrazole-4-boronic acid pinacol ester (256 mg, 0.84 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (43 mg, 12%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.54 (s, 1H), 8.44 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 7.99 (s, 1H), 7.62 (d, = 3.0 Hz, 1H), Ί .26-1.23 (m, 2H), 7.17-7.13 (m, 2H), 6.52 (d, = 6.4 Hz, 1H), 4.43 (qd, = 7.0 Hz, 2H), 4.32-4.25 (m, 1H), 4.23 (t, = 6.6 Hz, 2H), 3.54 (t, = 4.5 Hz, 4H), 3.40-3.32 (dd, = 16.0, 6.9 Hz, 2H), 2.88-2.81 (dd, = 16.0, 4.5 Hz, 2H), 2.71 (t, = 6.6 Hz, 2H), 2.40 (t, = 4.4 Hz, 4H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 485.4. Example 124: 3-[l-(2-Dimethylamino-ethyl)-lH-pyrazol-4-yl]-l-ethyl-6-(indan-2- ylamino)- 1H- [l,8]naphthyridin-4-one
Figure imgf000185_0002
l-Ethyl-6-(indan-2-ylamino)-3-iodo-lH-[l,8]naphthyridin-4-one (339 mg, 0.79 mmol) and l-(2-dimethylamino-ethyl)-lH-pyrazole-4-boronic acid pinacol ester (250 mg, 0.94 mmol) were reacted as described under General Procedure F (18h at 80°C) to furnish the title compound (40 mg, 11%) as a yellow solid.
1H NMR (300 MHz, OMSO-d6) δ 8.54 (s, 1H), 8.42 (s, 1H), 8.33 (d, J = 3.0 Hz, 1H), 7.99 (s, 1H), 7.61 (d, = 3.0 Hz, 1H), Ί .26-1.23 (m, 2H), 7.17-7.13 (m, 2H), 6.52 (d, = 6.4 Hz, 1H), 4.43 (qd, = 7.0 Hz, 2H), 4.32-4.25 (m, 1H), 4.19 (t, = 6.5 Hz, 2H), 3.40-3.32 (dd, = 16.0, 6.9 Hz, 2H), 2.88-2.82 (dd, = 16.0, 4.5 Hz, 2H), 2.64 (t, = 6.5 Hz, 2H), 2.16 (s, 6H), 1.36 (t, J = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 443.4.
Example 125: l-Ethyl-3-(lH-imidazol-4-yl)-6-(indan-2-ylamino)-lH-[l,8]naphthy- ridin-4-one
Figure imgf000186_0001
AZ 125 l-Ethyl-6-(indan-2-ylamino)-3-(l-tritylimidazol-4-yl)-lH-[l,8]naphthyridin-4-one (234 mg, 0.38 mmol) was heated in trif uoroacetic acid (3 ml) at 80°C for 3h. After cooling, the solvent was removed under vacuum and ether (50 ml) was added. The resulting precipitate was filtered off, dissolved in CH2CI2 (50 ml) and washed with NaHC03 aq. (20 ml). The aqueous layer was extracted with CH2CI2 (2 x 20 ml). The combined organic fractions were dried over MgS04 and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography (CH2Ci2/CH3OH) to furnish the pure title compound (46 mg, 24% over 2 steps) as a yellow-green solid.
1H NMR (300 MHz, DMSO-i¾) δ 12.02 (brs, 1H), 8.70 (s, 1H), 8.34 (d, = 3.0 Hz, 1H), 7.85 (brs, 1H), 7.65 (s, 1H), 7.63 (d, = 3.0 Hz, 1H), 7.27-7.23 (m, 2H), 7.16-7.13 (m, 2H), 6.53 (d, = 6.3 Hz, 1H), 4.48 (qd, = 7.0 Hz, 2H), 4.32-4.26 (m, 1H), 3.40-3.32 (dd, = 16.0, 6.9 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.5 Hz, 2H), 1.36 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 372.3.
Example 126: l-Ethyl-6-(indan-2-ylamino)-3-[l-(2-morpholin-4-yl-ethyl)-lH- imidazol-4-yl]-lH-[l,8]naphthy-ridin-4-one
Figure imgf000187_0001
To a solution of l-ethyl-3-(lH-imidazol-4-yl)-6-(indan-2-ylamino)-lH-[l,8]naphthyridin- 4-one (140 mg, 0.38 mmol) in DMSO (8 ml) were successively added 4-(2- chloroethyl)morpholine (84 mg, 0.41 mmol) and K2C03 (260 mg, 1.88 mmol). The reaction mixture was heated at 80°C for 4 days. After cooling, water (50 ml) was added. The resulting precipitate was filtered off and purified by flash chromatography (CH2C12/CH30H) followed by semi-preparative HPLC separation to furnish the pure title compound (48 mg, 26%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.68 (s, 1H), 8.33 (d, = 3.0 Hz, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.63 (d, = 3.0 Hz, 1H), 7.26-7.22 (m, 2H), 7.17-7.13 (m, 2H), 6.52 (d, = 6.4 Hz, 1H), 4.48 (qd, = 7.0 Hz, 2H), 4.34-4.28 (m, 1H), 4.10 (t, = 6.3 Hz, 2H), 3.54 (t, = 4.5 Hz, 4H), 3.40-3.32 (dd, = 16.0, 6.9 Hz, 2H), 2.89-2.82 (dd, = 16.0, 4.5 Hz, 2H), 2.62 (t, = 6.6 Hz, 2H), 2.39 (t, = 4.5 Hz, 4H), 1.35 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 485.4.
Example 127: 6-C clopentylamino-l-ethyl-3-furan-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000187_0002
3-Bromo-6-(cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one (228 mg, 0.68 mmol) and 2-(tributylstannyl)furan (0.26 ml, 0.82 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the pure title compound (173 mg, 79%) as a yellow foam. 1H NMR (300 MHz, DMSO-i¾) δ 8.54 (s, 1H), 8.35 (d, = 3.0 Hz, 1H), 7.64 (dd, 7 = 1.8, 0.8 Hz, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.20 (dd, = 3.2, 0.8 Hz, 1H), 6.56 (dd, = 3.2, 1.8 Hz, 1H), 6.33 (d, = 6.3 Hz, 1H), 4.51 (qd, = 7.0 Hz, 2H), 3.79 (sext, = 6.2 Hz, 1H), 2.02- 1.96 (m, 2H), 1.74- 1.47 (m, 6H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 324.2.
Example 128: 6-Cyclopentylamino-l-ethyl-3-oxazol-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000188_0001
3-Iodo-6-(cyclopentylamino)-l-ethyl-[l,8]naphthyridin-4-one (148 mg, 0.39 mmol) and 2- (tributylstannyl)oxazole (0.10 ml, 0.47 mmol) were reacted as described under General Procedure B (2 days at 90°C) to furnish the pure title compound (33 mg, 26%) as a yellow foam.
1H NMR (300 MHz, DMSC ^) δ 8.71 (s, 1H), 8.35 (d, = 3.0 Hz, 1H), 8.14 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.29 (s, 1H), 6.41 (d, = 6.4 Hz, 1H), 4.48 (qd, = 7.0 Hz, 2H), 3.81 (sext, = 6.2 Hz, 1H), 2.01-1.95 (m, 2H), 1.73- 1.47 (m, 6H), 1.37 (t, = 7.0 Hz, 3H). ESIMS m/z [M+H]+ 325.2.
Example 129: l-Eth l-6-isopropylamino-3-oxazol-2-yl-lH-[l,8]naphthyridin-4-one
Figure imgf000188_0002
3-Bromo-l-ethyl-6-(isopropylamino)-[l,8]naphthyridin-4-one (293 mg, 0.94 mmol) and 2- (tributylstannyl)oxazole (0.24 ml, 1.13 mmol) were reacted as described under General Procedure B (18h at 90°C) to furnish the pure title compound (87 mg, 31%) as a yellow foam. 1H NMR (300 MHz, DMSC ^) δ 8.70 (s, 1H), 8.33 (d, 7 = 3.0 Hz, 1H), 8.13 (s, 1H), 7.51 (d, 7 = 3.0 Hz, 1H), 7.27 (s, 1H), 6.24 (d, 7 = 7.7 Hz, 1H), 4.47 (qd, 7 = 7.0 Hz, 2H), 3.65 (sext, 7 = 6.2 Hz, 1H), 1.36 (t, 7 = 7.0 Hz, 3H), 1.18 (d, 7 = 6.2 Hz, 6H). ESIMS m/z [M+H]+ 299.1.
Example 130: 6-Amino-l-ethyl-3-[l,2,3]triazol-l-ylmethyl-lH-[l,8]naphthyridin-4- one
Figure imgf000189_0001
6-Amino-3-(azidomethyl)-l-ethyl-[l,8]naphthyridin-4-one (146 mg, 0.60 mmol) and ethynyl trimethylsilane (65 mg, 0.66 mmol) were reacted as described under General Procedure D (5 days at 65°C) to furnish after flash chromatography (CH2C12/CH30H 100:0 → 90: 10) the title compound (26 mg, 16%) as a yellow foam. 1H NMR (300 MHz, DMSO-i¾ δ 8.33 (s, 1H), 8.26 (d, 7 = 3.0 Hz, 1H), 8.04 (d, 7 = 0.7 Hz, 1H), 7.63 (d, 7 = 0.7 Hz, 1H), 7.58 (d, 7 = 3.0 Hz, 1H), 5.66 (s, 2H), 5.35 (s, 2H), 4.34 (qd, 7 = 7.1 Hz, 2H), 1.31 (t, 7 = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 271.1.
Example 131: 6-(Indan-2-ylamino)-l-(2-methoxyethyl)-3-(triazol-l-ylmethyl)-[l,8] na hthyridin-4-one
Figure imgf000189_0002
3-Azidomethyl-6-(indan-2-ylamino)-l-(2-methoxyethyl)-[l,8]naphthyridin-4-one (70 mg, 0.18 mmol) and ethynyl trimethylsilane (0.07 ml, 0.54 mmol) were reacted as described under General Procedure D (5 days at 65°C) to furnish after flash chromatography (CH2C12/CH30H 100:0→ 95:5) and semipreparative HPLC the title compound (46 mg, 62%) as a yellow solid. 1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.23 (m, 2H), 7.15-7.13 (m, 2H), 6.61 (d, = 6.5 Hz, 1H), 5.38 (s, 2H), 4.49 (t, = 5.0 Hz, 2H), 4.31-4.27 (m, 1H), 3.65 (t, = 5.0 Hz, 2H), 3.37-3.30 (dd, = 16.1, 7.0 Hz, 2H), 3.19 (s, 3H), 2.85-2.79 (dd, = 16.0, 4.4 Hz, 2H). ESIMS m/z [M+H]+ 417.2.
Example 132: l-[2-(Dimethylamino)ethyl]-6-(indan-2-ylamino)-3-(triazol-l-ylmethyl)- [l,8 naphthyridin-4-one
Figure imgf000190_0001
3-(Azidomethyl)-l-[2-(dimethylamino
(60 mg, 0.15 mmol) and ethynyl trimethylsilane (16 mg, 0.16 mmol) were reacted as described under General Procedure D (3 days at 65 °C) to furnish after flash chromatography (CH2CI2/CH3OH 100:0→ 80:20) the title compound (44 mg, 68%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.58 (d, = 6.4 Hz, 1H), 5.38 (s, 2H), 4.41 (t, J = 6.4 Hz, 2H), 4.31-4.27 (m, 1H), 3.37-3.30 (dd, 7 = 16.1, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.4 Hz, 2H), 2.58 (t, = 6.2 Hz, 2H), 2.15 (s, 6H). ESIMS m/z [M+H]+ 430.3.
Example 133: 6-(Indan-2-ylamino)-l-(2-morpholinoethyl)-3-(triazol-l-ylmethyl)-[l,8] na hthyridin-4-one
Figure imgf000190_0002
3-(Azidomethyl)-6-(indan-2-ylamino)-l-(2-morpholinoethyl)-[l,8]naphthyridin-4-one (60 mg, 0.15 mmol) and ethynyl trimethylsilane (30 mg, 0.30 mmol) were reacted as described under General Procedure D (3 days at 65°C) to furnish after flash chromatography (CH2CI2/CH3OH 100:0→ 90: 10) the title compound (18 mg, 40%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.65 (s, 1H), 7.51 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.15-7.12 (m, 2H), 6.58 (d, = 6.4 Hz, 1H), 5.39 (s, 2H), 4.43 (t, = 5.9 Hz, 2H), 4.31-4.27 (m, 1H), 3.45 (t, = 4.4 Hz, 4H), 3.37-3.30 (dd, = 16.1, 7.0 Hz, 2H), 2.86-2.79 (dd, = 16.0, 4.4 Hz, 2H), 2.60 (t, = 6.0 Hz, 2H), 2.36 (brs, 4H). ESIMS m/z [M+H]+ 472.4. Example 134: l-(2-hydroxyethyl)-6-(indan-2-ylamino)-3-(triazol-l-ylmethyl)-[l,8] na hthyridine-4-one
Figure imgf000191_0001
3-(Azidomethyl)-l-{2-[tert-butyl(dimethyl)silyl]oxyethyl}-6-(indan-2-ylamino)-[l,8]naph- thyridine-4-one (140 mg, 0.28 mmol) and ethynyl trimethylsilane (0.12 ml, 0.85 mmol) were reacted as described under General Procedure D (2 days at 80°C) to furnish after flash chromatography (CH2C12/CH30H 100:0→ 95:5) the title compound (67 mg, 58%) as a yellow solid.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.24 (s, 1H), 8.03 (d, = 0.8 Hz, 1H), 7.64 (d, = 0.8 Hz, 1H), 7.52 (d, = 3.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.16-7.12 (m, 2H), 6.58 (d, = 6.5 Hz, 1H), 5.38 (s, 2H), 4.89 (t, = 5.5 Hz, 1H), 4.37 (t, = 5.2 Hz, 2H), 4.31-4.27 (m, 1H), 3.70 (qd, = 5.2 Hz, 2H), 3.37-3.30 (dd, = 16.1, 7.0 Hz, 2H), 2.85-2.79 (dd, = 16.0, 4.4 Hz, 2H). ESIMS m/z [M+H]+ 403.2. Example 135: Tert-butyl N-{2-[6-(indan-2-ylamino)-4-oxo-3-(triazol-l-ylmethyl)-[l,8] naphthyridin-l-yl]ethyl}-N-methyl-carbamate
Figure imgf000191_0002
Tert-butyl N- { 2- [3-(azidomethyl)-6-(indan-2-ylamino)-4-oxo- [ 1 ,8]naphthyridin- 1 - yl] ethyl }- V-methyl-carbamate (700 mg, 1.42 mmol) and ethynyl trimethylsilane (210 mg, 2.14 mmol) were reacted as described under General Procedure D (6 days at 110°C) to furnish after flash chromatography (AcOEt/CH3OH 100:0→ 85 : 15) the title compound (530 mg, 71%) as a yellow foam.
1H NMR (300 MHz, DMSO-i¾) δ 8.33 (d, = 3.0 Hz, 1H), 8.18 and 8.15 (2s, 1H), 8.03 and 7.96 (2s, 1H), 7.63 (d, = 0.8 Hz, 1H), 7.52 (d, = 2.6 Hz, 1H), 7.24-7.21 (m, 2H), 7.16-7.12 (m, 2H), 6.57 (d, = 6.5 Hz, 1H), 5.35 (s, 2H), 4.44-4.38 (m, 2H), 4.32-4.27 (m, 1H), 3.61-3.55 (m, 2H), 3.37-3.30 (dd, J = 16.1, 7.0 Hz, 2H), 2.85-2.69 (m, 5H), 1.16 and 0.83 (2s, 9H). ESIMS m/z [M+H]+ 516.3.
Example 136: 6-(Indan-2-ylamino)-l-[2-(methylamino)ethyl]-3-(triazol-l-ylmethyl)- [l 8]naphthyridin-4-one dihydrochloride
Figure imgf000192_0001
To a solution of tert-butyl N-{2-[6-(indan-2-ylamino)-4-oxo-3-(triazol-l-ylmethyl)-[l,8] naphthyridin-l-yl] ethyl }-N-methyl-carbamate (480 mg, 0.93 mmol) in dioxane (10 ml) was added HCl 4N in dioxane (9.3 ml, 37.2 mmol). The reaction mixture was stirred at room temperature for 2h. The suspension was filtered off and dried under vacuum to furnish the title compound (410 mg, 90%) as a yellow powder.
1H NMR (300 MHz, OMSO-d6) δ 8.94 (br s, 2H), 8.37 (s, 1H), 8.36 (d, = 3.0 Hz, 1H), 8.11 (s, 1H), 7.66 (s, 1H), 7.54 (d, = 3.0 Hz, 1H), 7.25-7.22 (m, 2H), 7.17-7.13 (m, 2H), 5.37 (s, 2H), 4.63 (t, = 5.7 Hz, 1H), 4.33-4.27 (m, 1H), 3.69-3.63 (m, 1H), 3.48-3.44 (m, 1H), 3.38-3.30 (dd, / = 16.1, 7.0 Hz, 2H), 2.86-2.79 (dd, / = 16.0, 4.6 Hz, 2H), 2.54 (t, = 5.2 Hz, 1H). ESIMS m/z [M+H]+ 416.2.
Biological Data Electrophysiology assays were performed on human a.7 nAChRs stably expressed with ric
3 in HEK cells. Assays were performed on the IonFlux . Compounds were tested with an ECgo of acetylcholine to determine IC50 values. Compound Plate Preparation
Immediately prior to assay the supplied compound(s) were prepared in DMSO to concentrations that were 300x the final assay top concentration(s) of 10 μΜ, five dose- responses were prepared by 3-fold serial dilution in DMSO from the top concentration and aliquots were taken out from the respective concentrations and diluted 300x into external buffer to give the final assay concentrations. All wells included a final DMSO concentration of 0.33% including all control wells.
Ion Channel ECso Control & Concentration
Human nAChR a7/ric3 200 μΜ ACh
Electrophysiological Recording Solutions
The solutions for recording human nAChR a7/ric3 currents were:
Figure imgf000193_0001
Experimental Protocols
hnAChR a7/ric3 Antagonist Assay Bump-in Method Schematic
Figure imgf000194_0001
All recordings were obtained from a holding potential of -60 mV.
Compounds were assayed using a bump-in protocol. The compound addition sequence that was used for all additions was the same for all assays. One addition of the ECgo concentration of ACh (200μΜ) was added to establish baseline response. The test compounds were tested on cells in increasing concentrations of 0.12, 0.37, 1.1, 3.3, 10 μΜ ± 200μΜ ACh for all compounds. Each compound was applied for one minute followed by the addition of 200μΜ ACh for 1 second. Data Analysis
Peak inward currents in response to the ACh additions in the presence of increasing concentrations of compound were measured. All compound data have been normalized to the baseline peak current induced by addition of 200μΜ ACh for 1 second:
Potentiation of ACh Response =( icompound+ACh / με^ Where / (Compound+ACh) is the peak current induced by addition of 0.12, 0.37, 1.1, 3.3, 10μΜ test compound + 200μΜ ACh after a 1 minute incubation of 0.12, 0.37, 1.1, 3.3, 10 μΜ test compound, I ACh is the baseline peak current induced by addition of 200μΜ ACh. All data were first exported to an Excel compatible data file and then analyzed using Graph Pad Prism software. Data Filters
Figure imgf000195_0002
Results
Compounds were assayed for antagonist activities on human nAChR a7/ric3 ion channel currents. All compounds were assayed as five (5) point concentration responses against human nAChR a7/ric3 ion channels. Estimated IC50 values for some example compounds are outlined below.
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
References
1. Barik J and Wonnacott S (2006) Indirect modulation by alpha7 nicotinic acetylcholine receptors of noradrenaline release in rat hippocampal slices: interaction with glutamate and GAB A systems and effect of nicotine withdrawal. Mol Pharmacol. Feb;
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2. Dickinson J A, et al. (2008) Presynaptic alpha 7- and beta 2-containing nicotinic
acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol. Aug;
74(2):348-59.
3. Livingstone P D, et al. (2009) Glutamate-dopamine crosstalk in the rat prefrontal cortex is modulated by Alpha7 nicotinic receptors and potentiated by PNU- 120596 J Mol Neurosci. 2010 Jan;40(l-2):172-6. . Quarta D, et al. (2009) Drug discrimination and neurochemical studies in alpha7 null mutant mice: tests for the role of nicotinic alpha7 receptors in dopamine release Psychopharmacology (Berl). 2009 Apr;203(2):399-410
5. Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ (1972) A cholinergic -adrenergic hypothesis of mania and depression. Lancet (7778):632-635.
6. Mitchell AJ. (1998) The role of corticotropin releasing factor in depressive illness: a critical review. Neurosci Biobehav Rev; 22:635-651. 29;
. Nemeroff CB. 1998 The neurobiology of depression. Sci Am; 278:42-49
8. Saricicek A, et al. (2012) Persistent p2*-nicotinic acetylcholinergic receptor
dysfunction in major depressive disorder. Am J Psychiatry 169(8):851-859.
9. Furey ML, Drevets WC (2006) Antidepressant efficacy of the antimuscarinic drug scopolamine: A randomized, placebo -controlled clinical trial. Arch Gen Psychiatry 63(10): 1121-1129
10. Janowsky DS, Risch SC. Cholinomimetic and anticholinergic drugs used to
investigate and acetylcholine hypothesis of affective disorders and stress. Drug Devel
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12. Klein and Yakel 2006
13. Pidoplichko V I, et al. (2013) a7-Containing nicotinic acetylcholine receptors on intemeurons of the basolateral amygdala and their role in the regulation of the network excitability. J Neurophysiol 110:2358-2369
14. Mineur Y S, et al. (2016) Multiple Nicotinic Acetylcholine Receptor Subtypes in the Mouse Amygdala Regulate Affective Behaviours and Response to Social Stress
Neurop s ychopharmacology 41(6): 1579-87.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000202_0001
wherein X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino); Y, and Z are independently selected from C, or N, and wherein at least one of Y and Z is N; Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl; wherein both Ri and R2 are not H; and
R3 and R4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl; or R3 and R4 together with the N-atom forms an optionally substituted heteroaryl or optionally substituted heterocyclyl.
2. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, as defined in claim 1, for use in treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR.
3. Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, as defined in claim 1, in the manufacture of a medicament for treating diseases, disorders or conditions which would benefit from the modulation of a.7 nAChR.
4. A method of treating a disease, disorder or condition which would benefit from the modulation of a.7 nAChR comprising the administration of an effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof, as defined in claim 1, to a subject in need thereof.
5. A use, compound or method according to any one of claims 2 to 4 in the treatment of anxiety, depression or a stress-related disorder. 6. A compound according to claim 1, wherein R, when present, is selected from H, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted arylalkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkenyloxy, optionally substituted Ci-C6 alkoxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aminoalkyl, and preferably R in NR is ethyl.
7. A compound according to claim 1 or 6, wherein R, when present is selected from H, methyl, ethyl, dimethylaminomethyl, dimethylaminoethyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, methyldifluoroethylaminoethyl, methyltrifluoroethylaminoethyl, methylmethoxyethylaminoethyl, di(methoxyethyl)aminoethyl or morpholinylethyl.
8. A compound according to any one of claims 1, 6 and 7, wherein Ri is selected from H, cyano, optionally substituted oxo/hydroxy, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ci-C6 alkoxy, optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6), optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy (wherein alkyl is Ci-C6), optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, or -C(0)R' (where R' is optionally substituted Ci-C6 alkyl, optionally substituted phenyl).
9. A compound according to any one of claims 1, 6, 7 and 8, wherein Ri is selected from ethynyl, l-(3-hydroxyl)propanyl, l-(4-hydroxy)butynyl, l-(3- dimethylamino)propynyl, (N-methyl-2-imidazole)ethynyl, (N-methyl-5-imidazole)ethynyl, (N-methyl-4-pyrazole)ethynyl, 2-furanyl, 2-(N-methylimidazolyl), 2-oxazolyl, 4-(l- benzyl-l,2,3-triazolyl), phenoxy, phenylacyl, 5-thiazolyl, (N-morpholinyl)methyl, 4- hydroxymethyl(l,2,3-triazolyl)methyl, 5-methoxymethyl(l,2,3-triazolyl)methyl, 4-(N- dimethylaminoethyl)pyrazolyl, or 1,2,3-triazolylmethyl. 10. A compound according to any one of claims 1, 6, 7, 8 and 9, wherein R2 is selected from H or ieri-butyl.
11. A compound according to any one of claims 1, 6, 7, 8, 9 and 10, wherein R3 is selected from H, optionally substituted Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is Ci-C6), and preferably R3 is indanyl. 12. A compound according to any one of claims 1, 6, 7, 8, 9, 10, and 11, wherein R4 is selected from H, Ci-C6 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl (wherein alkyl is Ci-C6), optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl (wherein alkyl is Ci- C6), and preferably H.
13. A compound according to claim 1, wherein the compound is selected from:
Figure imgf000207_0001
and wherein R, Ri, R2, R3 and R4 are as defined above for compounds of formula (I). 14. A compound according to claim 1, which is represented by formula (Γ) or a pharmaceutically acceptable salt solvate, prodrug, stereoisomer or tautomer thereof
Figure imgf000207_0002
wherein X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino);
Y, and Z are independently selected from C, or N, and wherein at least one of Y and Z is N;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl; wherein both Ri and R2 are not H; and
R4 independently represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl.
A compound according to claim 1 or 14, wherein the compound is selected from:
Figure imgf000210_0001
and wherein R, Ri, R2 and R4 are as defined above for compounds of formula (Γ) in claim 14.
16. A compound according to claim 1, which is represented by formula (I'a) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000211_0001
wherein R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl; wherein both Ri and R2 are not H; and
R4 represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl.
17. A compound according to claim 1, which is represented by formula (I") or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof
Figure imgf000213_0001
wherein X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino);
Y, and Z are independently selected from C, or N, and wherein at least one of Y and Z is N;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted amino sulfonyl; and wherein both Ri and R2 are not H.
18. A compound according to claim 1 or 17, wherein the compound is represented by formula (Fa), (I"b), (I"c), (I"d), (I"e) or (I"f):
Figure imgf000216_0001
and wherein R, Ri and R2 are as defined above for compounds of formula (I") in claim 17. 19. A compound according to claim 1, which is represented by formula (I" a) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000216_0002
wherein R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl); R2 represents H, cyano, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted oxyacyl, optionally substituted aminoacyl, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxy sulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted amino sulfonyl; and wherein both Ri and R2 are not H.
20. A compound of formula (A), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer thereof:
Figure imgf000218_0001
where Z, Y, G and D are independently CR' (where R' is selected from H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino) or N;
J represents C or N;
Ri represents H, cyano, optionally substituted oxo/hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted acylamino, optionally substituted acyloxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted cycloalkenyl, optionally substituted aminoacyloxy, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted oxyacylimino, optionally substituted thio, optionally substituted thioacyl, optionally substituted oxythioacyl, optionally substituted thioacyloxy, optionally substituted oxythioacyloxy, optionally substituted phosphorylamino, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted sulfinylamino, optionally substituted sulfonylamino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted aminothioacyl, optionally substituted thioacylamino, optionally substituted aminosulfinyl, optionally substituted aminosulfonyl, -C(0)R' (where R' is optionally substituted alkyl, optionally substituted phenyl);
L represents halogen, heteroaromatic, OR7, or NR7R" (where R" is selected from H, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted alkenyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, optionally substituted sulfinyl, and optionally substituted sulfonyl);
R7 represents H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted oxyacyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted phosphoryl, optionally substituted sulfinyl, optionally substituted sulfonyl, optionally substituted oxysulfinyl, optionally substituted oxysulfonyl, or optionally substituted thioacyl, or R7 and R" together with the N- atom forms an optionally substituted Heteroaryl or optionally substituted heterocyclyl; and
X represents NR, O, S, SO, or S02 (where R represents H, carboxyl, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphono, phosphorylamino, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethyl, trihalomethoxy, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted arylamino, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, and optionally substituted thioacylamino).
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