WO2004047836A1 - Use of phosphodiesterase-4 inhibitors as enhancers of cognition - Google Patents

Use of phosphodiesterase-4 inhibitors as enhancers of cognition Download PDF

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Publication number
WO2004047836A1
WO2004047836A1 PCT/CA2003/001799 CA0301799W WO2004047836A1 WO 2004047836 A1 WO2004047836 A1 WO 2004047836A1 CA 0301799 W CA0301799 W CA 0301799W WO 2004047836 A1 WO2004047836 A1 WO 2004047836A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
carboxamide
dihydro
naphthyridin
isopropyl
Prior art date
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PCT/CA2003/001799
Other languages
French (fr)
Inventor
Daniel Dube
Michel Gallant
Patrick Lacombe
Yves Girard
Dwight Macdonald
Richard Friesen
Yves Ducharme
Bernard Cote
Marc Blouin
Evelyn Martins
Daniel Guay
Mario Girard
Richard Frenette
Sebastien Laliberte
Annette Robichaud
Anthony Mastracchio
Helene Perrier
Original Assignee
Merck Frosst Canada & Co.
Hamel, Pierre
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Filing date
Publication date
Application filed by Merck Frosst Canada & Co., Hamel, Pierre filed Critical Merck Frosst Canada & Co.
Priority to US10/536,250 priority Critical patent/US20060040981A1/en
Priority to AU2003286024A priority patent/AU2003286024A1/en
Priority to EP03776698A priority patent/EP1592419A1/en
Publication of WO2004047836A1 publication Critical patent/WO2004047836A1/en

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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • 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

Definitions

  • the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor.
  • this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and effective amount of a phosphodiesterase-4 inhibitor.
  • Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger.
  • Cyclic adenosine monophosphate (adenosine 3', 5'-cyclic monophosphate, "cAMP” or “cyclic AMP”) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid- stimulating hormone, and vasopressin.
  • cAMP mediates cellular responses to hormones.
  • Cyclic AMP also mediates cellular responses to various neurotransmitters.
  • Phosphodiesterases are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity.
  • PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses.
  • PDE4 inhibition can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
  • a major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C.Burnouf et al., ("Burnouf '), Ann. Rep. In Med. Chem., 33:91-109(1998). B.Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996); M .Perry et al., Cell Biochem.
  • A.H.Cook, et al., J.Chem. Soc, 413-417(1943) describes gamma- pyridylquinolines.
  • Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(24V.6692-6700(1993 ; Kei Manabe et al., J.Am. Chem. Soc, 115(12 :5324- 5325(1993); and Kei Manabe et al., J.Am. Chem. Soc, 114(17): 6940-6941(1992).
  • U.S. Patent Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri -substituted aryl or heteroaryl phenyl derivatives.
  • U.S. Patent No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives.
  • U.S. Patent No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives.
  • U.S. Patent No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives.
  • International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors.
  • U.S. Patent No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
  • the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor.
  • this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and effective amount of a phosphodiesterase-4 inhibitor.
  • the invention is directed to a method of enhancing cognition in healthy subjects comprising administering a safe cognition enhancing amount of compound of
  • Examples IA through 34D or a parmaceutically salt thereof, to the health subject.
  • the compounds of Examples IA through 34D are:
  • the invention encompass a method of of enhancing cognition in healthy subjects comprising administering a safe cognition enhancing amount of compound of the compounds below to the healthy subject:
  • the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor.
  • this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and cognition enhancing amount of a phosphodiesterase-4 inhibitor.
  • a method of enhancing cognition in a healthy subject comprising administering a safe, non-emetic, cognition enhancing amount of a phosphodiesterase-4 inhibitor.
  • cognition For purposes of this application is defined as a subject with cognition in the normal range for the subjects age or other classification. Cognition of a healthy subject as well as cognition enhancement of the healthy subject is illustrated shown by testing the compounds in the Morris water maze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-
  • classes of healthy subjects includes juveniles, adults and seniors of average cognition; juveniles, adults and seniors of above average cognition; and juveniles, adults and seniors of below average cognition.
  • juvenile human subjects is defined as a human subject less than 18 years of age.
  • adult human subject is defined as a human subject 18 years of age or older.
  • a human adult 18 to 40 years of age For purposes of this specification, senior human subjects is defined as a human subject 40 years of age or older.
  • CAmbridge Neuropsychological Test Automated -Sattery CANTAB, de Jager CA, Milwain E, Budge M.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non- toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • compositions of the present invention comprise a compound (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) HI receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAID”), and ix) M2/M3 antagonists.
  • NSAID non-steroidal anti-inflammatory drugs
  • compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
  • Dosage levels from about O.OOOlmg/kg to about 50mg/kg of body weight per day are useful for enhancing cognition or about 0.005mg to about 2.5g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005mg to about 2.5g of active agent, compounded with an appropriate and convenient amount of carrier materia.
  • Unit dosage forms will generally contain between from about 0.005mg to about lOOOmg of the active ingredient, typically 0.005, O.Olmg, 0.05mg, 0.25mg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of a compound of the Examples.
  • the compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • the compound of this invention can be utilized in combination with other therapeutic compounds.
  • the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) HI (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
  • cognition can be conveniently enhanced with capsules, cachets or tablets each containing 0.005, O.Olmg, 0.05mg, 0.25mg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
  • IC50 values should be less than about 5 ⁇ M, advantageously less than about 2.5 ⁇ M.
  • the IC50 values of Examples 1 to 33 ranged from O.Ol ⁇ M to 2.4 ⁇ M.
  • BAL bronchial alveolar lavages
  • test compound was added (dissolved in 2 ⁇ L DMSO), 188 ⁇ L of substrate buffer containing [2,8- H] adenosine 3 ',5 '-cyclic phosphate
  • IC50 values of Examples 1 to 33 were determined with lOOnM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase -Na (met-248) produced from a baculovirus/Sf-9 expression system. IC50 values should be less than about lOOOnM, advantageously less than about 250nM, and even more advantageously less than about lOOnM. The IC50 values of Examples 1 to 33 ranged from O.lnM to 90.0nM.
  • TLC mass spectrometry
  • ⁇ MR nuclear magnetic resonance
  • microanalytical data When given, yields are for illustration only.
  • NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.
  • TMS tetramethylsilane
  • Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.
  • “Ar” signifies an aromatic signal.
  • the Examples are comprised of four sub-sets - Example set A, Example set B, Example set C and Example Set D.
  • Examples 1 A through 42A are characterized and prepared as disclosed in US 6,410,563 Bl, issued June 25, 2002, which is hereby iincorporated by reference.
  • IA. and 2A 6-isopropyl-8-(3- ⁇ (Z/E)-2-[4-(methylsulfonyl)phenyl]-2- phenylethenyl ⁇ phenyl )quinoline;
  • 9A 2-methyl-2-[8-(3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl ⁇ phenyl)-6-quinolinyl]propanenitrile; 10A. 6-[l-(methylsulfonyl)ethyl]-8- ⁇ 3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l,3- thiazol-2-yl)ethenyl]phenyl ⁇ quinoline;
  • 11 A 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- ⁇ 3-[(E)-2-[4- (methylsulfonyl)phenyl]-2-(l,3-thiazol-2-yl)ethenyl]phenyl ⁇ quinoline; 12A. 8-(3- ⁇ (Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-
  • 26A 6-isopropyl-8-(3- ⁇ (E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl ⁇ phenyl)quinoline;
  • 29A (E)-N-(tert-butyl)-3-(3- ⁇ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl ⁇ phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide; 30A. 8- ⁇ 3-[2,2-bis(4-chlorophenyl)vinyl]phenyl ⁇ -6-isopropylquinoline;
  • 33 A. and 34A 6-iso ⁇ ropyl-8-(3- ⁇ (E/Z)-2-(5-methyl-2- ⁇ yridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl ⁇ phenyl)quinoline; 35A. 8-(3- ⁇ 2,2-bis[4-(methylsulfonyl)phenyl]vinyl ⁇ phenyl)-6- i sopropylquinoline;
  • 40A. and 41 A 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3- ⁇ (E/Z)-2-(5-methyl-2- pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl ⁇ phenyl)quinoline; 42A. 2-(6- ⁇ (E)-2-(3- ⁇ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinylJphenyl)-l-[4-(methylsulfonyl)phenyl]ethenyl ⁇ -3-pyridinyl)-2-propanol;
  • Examples IB through 36 are characterized and prepared as disclosed in US 6,399,636 B2, issued June 4, 2002, which is hereby incorporated by reference.
  • c-but represents cyclobutyl
  • c-pr represents cyclopropyl
  • c-pent represents cyclopentyl
  • c-Hex represents cyclohexyl
  • 4-EtPh represents 4- ethylphenyl
  • 4-FPh represents 4-fluorophenyl
  • Ph represents phenyl
  • Pyr represents pyridyl
  • 2-(5-Br)Pyr represents 2-(5-bromo)pyridyl
  • 3-(6-Br)Pyr represents 3-(6-bromo)pyridyl.
  • Step 1 Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.
  • Step 2 Ethyl l-(3-bromophenyl)- 4-dihydrori.81naphthyridin-4-one-3-carboxylate.
  • the crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil , 9.4g, 235mmol) was added in portions. After stirring at 0° for 1 hour, the mixture was allowed to warm up to room temperature. After 2 hours, water (400mL) was added to the suspension and and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150mL) at room temperature for 24 hours and filtered to afford the title compound as a cream-colored solid.
  • a suspension of ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylate from Step 2 (52.5g, 140.7mmol) in a mixture of tetrahydrofuran (400mL), methanol (400mL) and IN aqueous sodium hydroxide (280mL) was heated at ca 50°C with stirring for 20 minutes. After cooling, the mixture was diluted with water (300mL) and IN aqueous HC1 (325mL) was added. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the title acid as a cream-colored solid.
  • Step 4 N-Isopropyl-l-(3-bromophenyl)-l,4-dihydrori,81naphthyridin-4-one-3-carboxamide.
  • Step 5 N-Isopropyl-l-r3-(3-acetylphenyl)phenyl1-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide
  • Step 1 Anion of 4-amino-3-5-dichloropyridine.
  • Step 2 Acid chloride of l-(3-bromophenyl)-1.4-dihvdro
  • Step 3 N-(2.6-Dichloropyridin-4-y0- l-(3-bromophenyl)- 1 ,4-dihvdror 1 ,81naphthyridin-4-one-3- carboxamide.
  • Step 4 N-(2,6-Dichloropyridin-4-yl)-l-r3-(3-acetylphenyl)phenyl1-1.4- dihvdrori.81naphthyridin-4-one-3-carboxamide.
  • Step 1 N-Isopropyl-N-methyl-l-(3-bromophenyl)- 4-dihvdron.81naphthyridin-4-one-3- carboxamide
  • Step 2 N-Isopropyl-N-methyl-l-r3-(4-acetylphenyl)phenyl1-1.4-dihydrori.81naphthyridin-4- one-3-carboxamide
  • Step 1 N-tert-Butyl-l-(3-bromopher.ylV 1.4-dihydrof 1.8]naphthyridm-4-one-3-carboxamide
  • Step 2 N-tert-Butyl-l-[3-(4-acetylphenyl)phenvn-1.4-dihvdrori.81naphthyridin-4-one-3- carboxamide
  • Aqueous saturated ammonium chloride 400mL
  • water 1 equivalent of H3PO4 (20mL)
  • the mixture was stirred for 15 minutes and then concentrated to a volume of approximately 200mL (at which stage the mixture became bluish and a precipitate formed).
  • the mixture was slowly diluted with heptane (800mL) and the resulting suspension was stirred overnight.
  • the suspension was filtered, the solid was washed with heptane and dried to afford the title boronic acid.
  • Step 3 N-Isopropyl-l- ⁇ 3-F 4-(4-tertbutyloxycarbonylpi ⁇ erazin-l-yl)phenvn-phenyl 1-1.4- dihvdrori.81naphthyridin-4-one-3-carboxamide
  • Step 1 N-Cvclopropyl-l-(3-bromophenyl)-1.4-dihvdror 81naphthyridin-4-one-3-carboxamide
  • Step 4 substituting cyclopropylamine for isopropylamine the N-Cyclopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide was obtained as a fluffy white solid.
  • Step 2 N-Cyclopropyl-l-F3-(pyridin-3-yl)phenyl1- 4-dihvdroF 81naphthyridin-4-one-3- carboxamide
  • Step 2 N-Cyclopropyl-l-r3-(4-sulfamoylphenyl)phenyl1-1.4-dihydroFl,8]naphthyridin-4-one-3- carboxamide
  • Step 1 Ethyl l-F3-(3-ethoxyphenyl)phenyl1-l,4-dihydroF1.81naphthyridin-4-one-3-carboxylate
  • Step 2 l-F3-(3-Ethoxyphenyl)phenyl1-1.4-dihydroF 81naphthyridin-4-one-3-carboxylic acid
  • Step 3 of Example IC substituting ethyl l-[3-(3- ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from step 1 for ethyl 1- (3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate the l-[3-(3- Ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid compound was obtained and used without purification in the next step.
  • Step 3 N-Isopropyl- l-F3-(3-ethoxyphenyl)phenyl1-1.4-dihydroF1.81naphthyridin-4-one-3- carboxamide
  • Step 1 Ethyl l-r3-(4-methylthiophenyl)phenyl1-1.4-dihvdroF 81naphthyridin-4-one-3- .. carboxylate
  • Step 2 l-F3-(4-methylthiophenyl)phenyl1-l,4-dihvdroF 81naphthyridin-4-one-3-carboxylic acid
  • Step 3 ethyl l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from Step 1 for ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate the l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid compound was obtained as a solid.
  • Step 3 N-Isopropyl-l-
  • Step 2 N-Isopropyl- 1 - ( 3-F5-( 1 -hydroxy- 1 -methylethyl)pyridin-3-yl1phenyl I - 1.4- dihvdroF1.81naphthyridin-4-one-3-carboxamide.
  • Step 2 N-Isopropyl-l-
  • Step 2 N-Isopropyl-l-F3-(5-acetylpyridin-3-yl)phenyll-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
  • Step 2 N-Isopropyl-l-F3-(6-methylpyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
  • Step 2 N-Cyclopropyl-l-F3-(l-oxidopyrimidinyl-5-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
  • Step 1 5-Bromo-2-(l-hydroxy-l-methylethyl) pyridine
  • Step 3 1 -(3-bromophenyl)- l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 4 1 - ( 3-F6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yllphenyl 1-1.4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 N-Isopropyl-l-F3-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyll-l,4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
  • Step 3 N-Isopropyl-l- ⁇ 3-F4-(pyridin-3-yl,phenyl1phenyl
  • Step 1 N-Cvclopropyl-l-F3-(4,4,5,5,-tetramethyl-1.3.2-dioxaborolan-2-yl)phenyl1-l,4- dihvdroF1.81naphthyridin-4-one-3-carboxamide
  • Step 2 3-Bromo-5-methylsulfonylpyridine
  • diethyl ether 70ml
  • n-butyllithium 1.6M in hexanes
  • Dimethyl disulfide (1.12ml, 12.5mmol) was added and the mixture was warmed to room temperature, then partitioned between ether and water.
  • Step 3 N-Cyclopropyl-l-F3-(5-methylsulfonylpyridin-3-yl)1phenyl1-l,4- dihvdroF 1 ,81naphth yridin-4-one-3-carboxamide
  • Step 2 2-Bromo-4-( 1 -hydroxy- 1 -methylethvDpyridine
  • Step 4 N-Cvclopropyl-l- ⁇ 3-F4-(l-hvdroxy-l-methylethyl)-l-oxidopyridin-2-yllphenyl ⁇ -l,4- dihvdrori.81naphthyridin-4-one-3-carboxamide
  • Step 2 N-Cvclopropyl-l-l3-F5-(l-hvdroxy-l-methylethyl)pyridin-2-vnphenyl ⁇ -1.4- dihydroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 4-Bromo-2-(l-hvdroxy-l-methylethyl)pyridine
  • Step 2 N-Cyclopropyl- 1- ⁇ 3-F3-(l-hvdroxy-l-methylethyl)pyridin-4-yl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 4-Bromo-2-( 1 -hydroxy- 1 -methylethvDpyridine N-oxide
  • Step 2 N-Cvclopropyl-l- ⁇ 3-F3-(l-hydroxy-l-methylethyl)-l-oxidopyridin-4-yl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 2 5-Bromo-2-isopropylsulfonylpyridine
  • oxone 15.8g, 25.8mmol
  • aqueous sodium bicarbonate 25ml
  • Step 3 N-Cyclopropyl-l-F3-(6-isopropylsulfonylpyridin-3-yl)1phenyll-l,4- dihydrof 1 ,81naphthyridin-4-one-3-carboxamide Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- isopropylsulfonylpyridine from Step 2 for 3-bromo-5-methylsulfonylpyridine, the N-
  • Step 2 N-Cyclopropyl-l-F3-(6-methoxypyridin-3-yl)phenyll-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
  • Step 1 5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine
  • Step 2 N-Cvclopropyl-l- ⁇ 3-F6-(2.2.2-trifluoroethoxy ' )pyridin-3-yl1phenyl 1-1.4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
  • Step 2 N-Cvclopropyl-l-[3-(6-benzyloxypyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4- , one-3-carboxamide
  • Step 2 N-Cyclopropyl- 1- ⁇ 3-F6-dicvclopropyl(hvdroxy)methyl-l-oxidopyridin-3-yl1phenyl 1- l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 2 N-Cvclopropyl-l-(3-[5-(l-hydroxy-l-methylethyl)-l-oxidopyridin-2-yl1phenyl ⁇ -l,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 5-(3-Aminophenyl)- 2-(l -hydroxy- 1 -methylethyl) pyridine
  • 3- aminophenylboronic acid for 3-acetyl phenylboronic acid and 5-bromo-2-( 1 -hydroxy- 1- methylethyl)pyridine from Step 1 of Example 30C for N-isopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide
  • the 5-(3-Aminophenyl)- 2-( 1 -hydroxy- 1- methylethyl) pyridine compound was obtained as a solid.
  • Step 2 l- ⁇ 3-F6-(l-Hvdroxy-l-methylethyl)pyridin-3-yl1phenyll-1.4-dihvdroFl,81naphthyridin- 4-one-3-carboxylic acid
  • Step 3 N-Isobutyl- 1 - ⁇ 3-f6-( 1 -hvdroxy-l-methylethyl)pyridin-3-yl1phenyl 1-1.4- dihydroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 l-(3,5-Dibromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxylic acid
  • Step 2 N-Cvclopropyl-l-(3,5-dibromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
  • Step 4 of Example IC substituting the l-(3,5- Dibromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid from Step 1 for l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid, and cyclopropylamine for isopropylamine, the N-Cyclopropyl-l-(3,5-dibromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one- 3-carboxamide compound was obtained as a solid.
  • Step 3 2-(l-Hydroxy-l-methylethyl)-5-tributylstannylpyridine
  • n-butyllithium 2.5M in hexanes leq
  • Acetone leq
  • n-butyllithium was added along with ether (2ml/mmol).
  • tributyltin chloride (l.leq) was added and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 2-( 1 -Hydroxy- 1- methylethyl)-5-tributylstannylpyridine compound as a colorless liquid.
  • Step 4 N-Cyclopropyl- 1 - ⁇ 5-bromo-3- F6-( 1 -hydroxy- 1 -meth ylethyl)pyridin-3-yl1phenyl ⁇ - 1 ,4- dihydroFl,81naphthyridin-4-one-3-carboxamide
  • Step 1 2-(l -Hydroxy- l-methylethyl)-6-tributylstannylpyridine
  • Step 2 N-Cvclopropyl-l-
  • Step 2 N-Cyclopropyl-l-F3-(6-methylthiopyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4- one-3-carboxamide
  • Step 2 N-Cyclopropyl-l-F3-(6-methylthiopyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4- one-3-carboxamide
  • Step 3 N-Cvclopropyl-l-F3-(6-methylsulfonylpyridin-3-yl) ⁇ henyll-l,4- dihydroF 1.81naphthyridin-4-one-3-carboxamide
  • Example 49C Following the procedure of Example 49C, but substituting N-isopropyl- 1-[3-(5- methylthiopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 15C for N-isopropyl-l-[3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide, the title compound was obtained as a solid.
  • Step 1 N-Cvclopropyl-l-F3-(4-bromomethylphenyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
  • Step 2 N-Cvclopropyl-l-F3-(4-methylsulfonylmethylphenyl)phenyl1-l,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
  • Example 69C From the procedure of Example 69C, the title compound was also obtained as a white solid.
  • Example 69C From the procedure of Example 69C the title compound was also obtained as a white solid.
  • a mixture of 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine N-oxide from step 2 of example 30 (1.29g) and 25% aqueous sulfuric acid was heated at 130°C for 2 days. After cooling, the mixture was made slightly basic using ION aqueous sodium hydroxide and partitioned between ethyl acetate and water. The crude product from evaporation of the organic phase was used as such in step 2.
  • Step 2 5-bromo-2-(l,2-dihydroxy-l-methylethyl) pyridine N-oxide
  • the crude product from step 1 was dissolved in a 3 : 1 mixture of acetone and water
  • Step 3 N-Cyclopropyl- 1 - ⁇ 3-F6-( 1 ,2-dihydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-vHphenyl ⁇ - l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide.
  • step 2 of example 32 substituting 5-bromo-2-(l,2- dihydroxy-1 -methylethyl) pyridine N-oxide from step 2 for 3-bromo-5-methylsulfonylpyridine the title compound was obtained as a white solid.
  • Step 1 Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.
  • Step 2 Ethyl l-(3-bromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxylate.
  • the crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil , 9.4g, 235mmol) was added in portions. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm up to room temperature. After 2 hours, water (400mL) was added to the resulting suspension and the insoluble solid was filtered and washed copiously with water.
  • Step 3 l-(3-Bromopheny1)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxylic acid.
  • Step 4 N-Isopropyl-l-(3-bromophenyl)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxamide.
  • 1 -(3-bromophenyl)- l,4-dihydro[l, 8]naphthyri din-4-one-3- carboxylic acid from Step 3 (26.3g, 76mmol) and triethylamine (23.2g, 230mmol) in tetrahydrofuran (lOOOmL) at 0°C was added isobutyl chloroformate (18.85g, 138mmol).
  • Step 5 N-Isopropyl-l-F(3-phenylethynyl)phenyl1-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide.
  • Step 1 N-Isopropyl-l-r3-(trimethylsilylethvnyl)phenyl1-l,4-dihvdrofl,81naphthyridin-4-one-3- carboxamide.
  • Step 2 N-Isopropyl-l-(3-ethvnylphenyl)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxamide.
  • the crude product from Step 1 was dissolved in methanol (12mL mmol) and IN aqueous sodium hydroxide was added (3 eq), resulting in a suspension.
  • the suspension mixture was stirred at room temperature for 2 hours and the methanol was evaporated.
  • the resulting aqueous suspension was diluted with water and the product was extracted out with ethyl acetate.
  • Step 1 N-Cyclopropyl- l-(3-bromophenyl)-l,4-dihvdrori,81naphthyridin-4-one-3-carboxamide.
  • Step 1 1-Ethynylcyclopropanol.
  • the 1-ethynylcyclopropanol was prepared following the procedure described in J. Org.Chem. 916, 41, 1237 from [(l-ethoxycyclopropyl)oxy]trimethylsilane and ethynyl magnesium bromide and was obtained as a liquid.
  • Step 2 N-Isopropyl-l-F3-(l-hvdro ⁇ vcvclopropyl)ethynylphenyn-l,4-dihvdroFl,81naphthyridin- 4-one-3-carboxamide.
  • Step 1 l.l,l-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol.
  • Step 2 N-Isopropyl-l-(3-F4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-l-ynyl1phenyl ⁇ -l,4- dihydrof 1 ,81naphthyridin-4-one-3-carboxamide.
  • Step 5 of EXAMPLE ID was then applied, but substituting this solution for phenylacetylene to afford the N-Isopropyl-l- ⁇ 3-[4,4,4-trifluoro-3-hydroxy-3- (trifluoromethyl)but-l-ynyl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as a solid.
  • Step 1 3-Ethynylpyridine N-oxide.
  • Step 2 N-Cyclopropyl-l-[3-(l-oxido-3-pyridinylethvnyl)phenyll-1.4-dihydro[l,81naphthyridin-
  • Step 1 3-Bromo-5-(l-hydroxy-l-rnethylethyl)pyridine.
  • Step 2 3-Bromo-5-(l-hvdroxy-l-methylethyl)pyridine-N-oxide.
  • Step 3 N-Isopropyl- 1 - ⁇ 3- r5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridin yleth vn yllphenyl J - l,4-dihvdroll,81naphthyridin-4-one-3-carboxamide.
  • N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide the N- isopropyl-l- ⁇ 3-[5-(l-hydroxy-l-methylethyl)-l-oxido-3-pyridinylethynyl]phenyl ⁇ -l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
  • Step 1 5-Bromo-2-(l-hvdroxy-l-methylethyl) pyridine.
  • Step 2 5-Bromo-2-(l-methyl-l- ⁇ r2-(trimethylsilyl)ethoxy1methoxy lethvDpyridine.
  • Step 3 2-(l -Methyl- 1-1 r2-(trimethv1siIyl)ethoxylmethoxylethyl)-5- [(trimethylsilyl)ethynyllpyridine.
  • Step 4 5-Ethvnyl-2-(l-methyl-l-( [2-(trimethylsilyl)ethoxy1methoxy lethvDpyridine.
  • Step 5 N-Isopropyl-l-(3-
  • Step 6 N-Isopropyl-l- ⁇ 3-[6-(l-hvdroxy-l-methylethyl)-3-pyridinylethvnyl1phenyl 1-1,4- dihvdro[l,81naphthyridin-4-one-3-carboxamide.
  • Step 1 Methyl 2-bromoisonicotinate.
  • Step 2 2-Bromo-4-(l-hvdroxy-l-methylethyl)pyridine.
  • Step 3 N-Isopropyl-l- ⁇ 3-r4-(l-hydroxy-l-methylethyl)-2-pyridinylethvnyllphenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide.
  • Step 1 2-Bromo-5-(l-hvdroxy-l-methylethyl)pyridine.
  • Step 2 5-(l-Hvdroxy-l-methylethyl)-2-F(trimethylsilvI)ethvnyllpyridine.
  • Step 3 2-Ethvnyl-5-(l -hydroxy- l-methylethyl)pyridine.
  • Step 4 N-Isopropyl- 1 - ⁇ 3-F5-( 1 -hydroxy- 1 -methyleth yl)-2-pyridinylethyn yllphenyl 1 - 1 ,4- dihydroFl,81naphthyridin-4-one-3-carboxamide.
  • Step 1 2-Bromo-6-(l-hydroxy-l-methylethyl)pyridine.
  • Step 2 N-Isopropyl- 1 - ⁇ 3- F6-( 1 -hydroxy- 1 -methylethyl)-2-pyri dinyleth vnyllphenyl J - 1 ,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide.
  • Step 1 5-Bromo-2-(l-hvdroxy-l-methylethyl)pyridine N-oxide.
  • Step 2 N-Cvclopropyl-l- ⁇ 3-F6-(l-hvdroxy-l-methylethyl)-l-oxido-3-pyridinylethvnyl1phenyl 1- l,4-dihvdroll.81naphthyridin-4-one-3-carboxamide.
  • Step 1 3-(4-Bromophenyl)pyridine.
  • Step 2 N-Isopropyl-l- ⁇ 3-F(4-pyridin-3-ylphenyl)ethvnyl1phenyll-l,4-dihvdro ⁇ ,8]naphthyridin- 4-one-3-carboxamide.
  • Step 1 2-Bromo-5-( 1 -hydroxy- 1 -methylethyPthiophene.
  • Step 2 2-(l-Hvdroxy-l-methylethv1)-5-trimethvIsilyIethvnyl thiophene.
  • Step 3 2-Ethynyl-5-(l-hvdroxy-l-methylethyl)thiophene.
  • Step 4 N-Isopropyl- 1 -(3- ⁇ F5-(l -hydroxy- 1 -methylethyl .thien-2-v ⁇ ethvnyl ⁇ phenyl)-l,4- dihvdroF1.81naphthyridin-4-one-3-carboxamide.
  • Step 1 2-( 1 -hydroxy- 1 -methylethyl) thi azole.
  • Step 2 2-(l-methyl-l-l r2-(trimethvIsilyl,ethoxylmethoxylethyl. thiazole.
  • Step 3 5-Bromo-2-(l -hydroxy- l-methylethyl)thiazole.
  • Step 4 N-Isopropyl- 1 -(3-1 F2-(l-hvdroxy-l-methylethyl .-1.3-th ⁇ azol-5-yl1ethvnyl lphenyl)-l,4- d ⁇ hydroF1.81naphthynd ⁇ n-4-one-3-carboxam ⁇ de.
  • Step 1 l-(3-Bromophenyl)-l,4-d ⁇ hydroFl,81naphthvnd ⁇ n-4-one-3-carboxam ⁇ de.
  • Step 2 l-F3-(Tnmethyls ⁇ lv1ethynyl)phenyl1-l,4-d ⁇ hvdroFl,81naphthvnd ⁇ n-4-one-3-carboxam ⁇ de.
  • Step 3 l-(3-Ethvnylphenyl)-l,4-dihvdroFl,81naphthyridin
  • Step 4 l-F3-(l-oxido-3-pyridinylethvnyl)phenyl1-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide.
  • Step 1 Ethyl l-(3-Ethvnylphenyl)-1.4-dihvdroFl,81naphthyridin-4-one-3-carboxylate.
  • Step 2 of EXAMPLE 5D substituting ethyl 1 -(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from Step 2 of EXAMPLE 1 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide as the starting material, the Ethyl l-(3-Ethynylphenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxylate compound was obtained as a solid.
  • Step 2 Ethyl l-F3-(l-oxido-3-pyridinylethvnyl)phenv ⁇ -l,4-dihvdroFl,8]naphthyridin-4-one-3- carboxylate.
  • Step 3 l-F3-(l-Oxido-3-pyridinylethynyl)phenyll-l,4-dihydroFl,81naphthyridin-4-one-3- carboxylic acid.
  • Step 2 Following the procedure of Step 3 of EXAMPLE ID, but substituting the ethyl 1- [3-( 1 -oxido-3-pyridinylethynyl)phenyl] - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxylate ester from present Step 2 for ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylate, the l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylic acid was obtained as a white solid.

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Abstract

The present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and effective amount of a phosphodiesterase-4 inhibitor.

Description

TITLE OF THE INVENTION
USE OF PHOSPHODIESTERASE-4 INHIBITORS AS ENHANCERS OF COGNITION
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and effective amount of a phosphodiesterase-4 inhibitor.
RELATED BACKGROUND
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3', 5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid- stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases ("PDE") are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 ("PDE4", also known as "PDE- IV"), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity. A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C.Burnouf et al., ("Burnouf '), Ann. Rep. In Med. Chem., 33:91-109(1998). B.Hughes et al., Br. J.Pharmacol., 118:1183-1191(1996); M .Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S.B.Christensen et al., J.Med. Chem., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M.D.Houslay et al., Adv. In Pharmacol, 44:225-342(1998) and D.Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors. International Patent Publication WO9907704 describes l-aryl-l,8-naphthylidin-4-one derivatives as PDE4 inhibitors.
A.H.Cook, et al., J.Chem. Soc, 413-417(1943) describes gamma- pyridylquinolines. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(24V.6692-6700(1993 ; Kei Manabe et al., J.Am. Chem. Soc, 115(12 :5324- 5325(1993); and Kei Manabe et al., J.Am. Chem. Soc, 114(17): 6940-6941(1992).
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Patent Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Patent No. 5,736,297 describes ring systems useful as a photosensitive composition.
U.S. Patent Nos. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri -substituted aryl or heteroaryl phenyl derivatives. U.S. Patent No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Patent No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Patent No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Patent No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Patent No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
SUMMARY OF THE INVENTION
The present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and effective amount of a phosphodiesterase-4 inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the invention is directed to a method of enhancing cognition in healthy subjects comprising administering a safe cognition enhancing amount of compound of
Examples IA through 34D, or a parmaceutically salt thereof, to the health subject. The compounds of Examples IA through 34D are:
6-isopropyl-8-(3-{(Z E)-2-[4-(methylsulfonyl)phenyl]-2-phenylethenyl}phenyl)quinoline;
6-isopropyl-8-{3-[(E/Z)-2-[4-(methylsulfonyl)phenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl}quinoline;
6-isopropyl-8-(3-{(E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
6-isopropyl-8-(3-{(Z/E)-2-(4-fluorophenyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 2-(2-{(E/Z)-2-[3-(6-isopropyl-8-quinolinyl)phenyl]-l-[4-(methylsulfonyl)phenyl]ethenyl}-l,3- thiazol-5-yl)-2-propanol;
2-[8-(3- { (E/Z)-2-[5-( 1 -hydroxy- 1 -methylethyl)- 1 ,3-thiazol-2-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]-2-methylpropanenitrile;
2-methyl-2-[8-(3- { (E)-2-( 1 -methyl- lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile;
6-[l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl Jquinoline; 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)ρhenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl}quinoline;
8-(3-{(Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-
(methylsulfonyl)ethyl]quinoline; 8-(3-{(Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l- methyl-l-(methylsulfonyl)ethyl]quinoline;
6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
(E/Z)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenyl}-N-isopropyl-2-[4- (methylsulfonyl)phenyl]-2-propenamide;
8-(3-{(E)-2-{3-[(4-methoxyphenoxy)methyl]-l,2,4-oxadiazol-5-yl}-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-methyl-l-(methylsulfonyl)ethyl]quinoline;
(5- { (E)-2-(3- { 6- [ 1 -methyl- 1 -(methylsulfonyl)ethyl] -8-quinolinyl } phenyl)- 1 - [4-
(methylsulfonyl)phenyl]ethenyl}-l,2,4-oxadiazol-3-yl)methanol; (E)-N-isopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide;
(E)-3- { 3- [6-( 1 -cyano- 1 -methylethyl)-8-quinolinyl]phenyl } -2- [4-(methylsulfonyl)phenyl] -2- propenoic acid;
2-methyl-2-[8-(3-{ (E)-2-(3-methyl-l ,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile;
(E)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenyl}-2-[4-(methylsulfonyl)phenyl]-2- propenamide;
E)-N-(tert-butyl)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenyl}-2-[4-
(methylsulfonyl)phenyl]-2-propenamide; (E)-3-[3-(6-isopropyl-8-quinolinyl)phenyl]-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid;
6-isopropyl-8-(3-{(E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl } phenyl )quinoline ;
(E)-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-l-(l-pyrrolidinyl)-2-propen-l-one; (E)-N-cyclopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide;
(E)-N-(tert-butyl)-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide; 8-{3-[2,2-bis(4-chlorophenyl)vinyl]phenyl}-6-isopropylquinoline;
6-isopropyl-8-(3-{(E/Z)-2-(6-methyl-3-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
6-isopropyl-8-(3- { (E/Z)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phenyl)quinoline;
8-(3-{2,2-bis[4-(methylsulfonyl)phenyl] vinyl }phenyl)-6-isopropylquinoline;
2-methyl-2-[8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-
6-quinolinyl]propanenitrile;
2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6-quinolinyl]-2-methylpropanenitrile; 2-methyl-2-(8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(2-pyridinyl)ethenyl]phenyl}-6- quinolinyl)propanenitrile;
6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
2-(6- { (E)-2-(3- { 6- [ 1 -methyl- 1 -(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)- 1 -[4- (methylsulfonyl)phenyl]ethenyl }-3-pyridinyl)-2-propanol;
2-[8-(3-{(lE/Z)-3-(dimethylamino)-2-[4-(methylsulfonyl)phenyl]prop-l-enyl}phenyl)quinolin-6- yl]-2-methylpropanenitrile;
(±)-4-{2-[3,4-Bis(difluoromethoxy)ρhenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl } ethyl }pyri dine N-oxide; chiral 4- { 2-[3,4-Bis(difluoromethoxy)phenyl] -2- { 5-[2-( 1 -hydroxy- 1 - methyl)ethyl]thiazolyl }ethyl }pyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl } pyridine;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl}pyridine n-oxide;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl jpyridine;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl }ethyl }pyridine n-oxide; (±/±)-4- { 2- [3,4-Bi s(difluoromethoxy)phenyl] -2- { 5- [2-( 1 -hydroxy- 1 - trifluoromethyl)ethyl]thiazolyl }ethyl } pyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl }pyridine n-oxide; (±/±)-4- { 2- [3 ,4-Bi s(difluoromethoxy)phenyl]-2- [5-(2-( 1 -hydroxy- 1 - phenyl)ethyl)thiazolyl]ethyl }pyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4- { 2- [3 ,4-Bis(difluoromethoxy)phenyl] -2-[5-(2-( 1 -hydroxy- 1 - phenyl)propyl)thiazolyl]ethyl Jpyridine n-oxide;
(± ±)-4- { 2- [3 ,4-Bis(difluoromethoxy)phenyl] -2-[5-(2- cyclohexylmethanol)thiazolyl]ethyl Jpyridine;
(± ±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-cyclohexyl-2,2,2- trifluoromethyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4- { 2- [3 ,4-Bis(difluoromethoxy)phenyl] -2-[5-(2-( 1 -hydroxy- 1 -(4- ethyl)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(± ±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-ethyl)ρhenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4- fluoro)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-Fluoro)phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(5-bromopyridin-2-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(6-bromopyridin-3-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l- hydroxy)cyclobutyl]thiazolyl } ethyl Jpyridine N-oxide; (±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l- hydroxy)cyclohexyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine; (±)-4- { 2- [(3-cyclobutyloxy-4-difluoromethoxy)phenyl] -2- { 5- [2-( 1 -hydroxy- 1 -trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine; chiral 3-{ 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-( 1 -hydroxy- 1- methyl)ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{ 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl- 2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
Ν-Isopropyl-l-[3-(3-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-(2,6-Dichloropyridin-4-yl)-l-[3-(3-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide ; N-Isopropyl-l-[3-(4-n-propylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(4-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide
N-Isopropyl-l-[3-(2-methylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-N-methyl-l-[3-(4-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(indol-5-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-tert-Butyl-l-[3-(4-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-(2,6-Dichloropyridin-4-yl)-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-{3-[ 4-(4-tertbutyloxycarbonylpiperazin-l-yl)phenyl]-phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(quinolin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-carboxamide; N-Isopropyl-l-[3-(pyrimidin-5-yl) phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-carboxamide;
N-Cyclopropyl-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 -[3-(5-methylthiopyridin-3-yl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(4-hydroxymethylρhenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(pyridin-4-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(4-ethylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide ; N-Cyclopropyl-l-[3-(3-thienyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 -[3-(4-sulfamoylphenyl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 -[3-(4-methylthiophenyl)phenyl] - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-acetyl-4-hydroxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(5-carboethoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl- l-{3-[5-(l -hydroxy- 1 -methylethyl)pyridin-3-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-{3-[6-(2-methylpropyl)pyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Isopropyl-l-[3-(5-acetylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(6-methylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyrimidin-5-yl) phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; l-{3-[6-(l-Hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]phenyl J-l,4-dihydro[l,8]naphthyridin-
4-one-3-carboxamide;
N-Isopropyl- 1- { 3-[4-(pyridin-3-yl)phenyl]phenyl } - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(5-methylsulfonylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Cyclopropyl- 1 - { 3- [4-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydrof 1 ,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl- 1- { 3-[5-( 1 -hydroxy- 1 -methylethyl)pyridin-2-yl]phenyl J 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3- [3-( 1 -hydroxy- 1 -methylethyl)pyridin-4-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3- [3-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-4-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-isopropylsulfonylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-methoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(6-methylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl- 1 - { 3-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 -[3-(5-bromopyridin-3-yl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(6-benzyloxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-{3-[6-dicyclopropyl(hydroxy)methyl-l-oxidopyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl- 1 - { 3- [5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl)pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isobutyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl )pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-{5-bromo-3-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)pyridin-2-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 -[3-(4-methylsulfonylphenyl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphth yridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Isopropyl-l-[3-(5-methylsulfonylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(4-ethylsulfonylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl- 1 -[3-(4-ethylsulfinylphenyl)phenylJ- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-{3-[4-(l-oximidoethyl)phenyl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl- 1 - { 3-[ 4-(4-piperazin- 1 -yl)phenyl] -phenyl J - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(4-methylsulfonylmethylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Cyclopropyl-l-[3-(l,6-dihydro-6-oxopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]pyridin-3-yl}phenyl]]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-(2,6-Dichloropyridin-4-yl)-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Isopropyl- l-[3-(5-carboethoxy- l-oxidopyridin-3-yl)phenyl]- 1 ,4-dihydro[l ,8]naphthyridin-4- one-3-carboxamide;
N-Isopropyl- 1 - { 3- [5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl jphenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1- { 3-[6-(2-methylpropyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(6-methyl-l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyridin-4-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(5-bromo-l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one- 3-carboxamide;
N-Cyclopropyl- 1 -[ [3- { 5- [6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]pyridin-3- ylJphenyl]]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]-l-oxidopyridin-3- yl } phenyl]]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]-l-oxidopyridin-3- ylJphenyl]]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(l-oxidoquinolin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one- carboxamide;
N-Isobutyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-methyl-l-oxidopyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-methylsulfonyl-l oxidopyridin-3-yl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-l-{5-bromo-3-[6-(l-hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-{3-[6-(l,2-dihydroxy-l-methylethyl)-l-oxidopyridin-3-yl]phenyl}-l,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1-[ 3-(phenylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(2-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(4-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carbox amide; N-Isopropyl-l-[3-(l-oxido-4-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1 -(3-ethynylphenyl)- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-hydroxy-3-methylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(3-hydroxy-3-methylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide; N-Isopropyl-l-[3-(l-hydroxycyclopentyl)ethynylphenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(l-hydroxycyclopropyl)ethynylphenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-l-ynyl]phenylJ-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(3-hydroxy-3-phenylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl-l-[3-(3-amino-3-ethylpent-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carbox amide; or
N-Cyclopropyl-l-[3-(3-amino-3-ethylpent-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-quinolinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(l-oxido-3-quinolinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl- l-[3-(cyclopropylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(6-amino-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl- l-{3-[5-(l -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl )-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 - { 3-[4-( 1 -hydroxy- 1 -methylethyl)-2-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- l-{3-[5-(l -hydroxy- 1 -methylethyl)-2-pyridinylethynyl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-{ 3-[6-(l-hydroxy-l-methylethyl)-2-pyridinylethynyl]phenyl J-l ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1 -(3- { [5-( 1 -hydroxy- 1 -methylethyl )thien-2-yl]ethynyl } phenyl)- 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-(3-{[2-(l-hydroxy-l-methylethyl)-l,3-thiazol-5-yl]ethynyl}phenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; l-[3-(l-Oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; and l-[3-(l-Oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention encompass a method of of enhancing cognition in healthy subjects comprising administering a safe cognition enhancing amount of compound of the compounds below to the healthy subject:
Figure imgf000015_0001
X
Figure imgf000015_0002
Figure imgf000015_0003
or a pharmaceutically acceptable salt thereof.
Compounds X, Y and Z may be prepared as disclosed in US 5,552,438, US 5,712,298 and US 6,448,274, which are hereby incorporated by reference.
As mentioned above, the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of a phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and cognition enhancing amount of a phosphodiesterase-4 inhibitor. Within this aspect there is a method of enhancing cognition in a healthy subject comprising administering a safe, non-emetic, cognition enhancing amount of a phosphodiesterase-4 inhibitor.
For purposes of this application is defined as a subject with cognition in the normal range for the subjects age or other classification. Cognition of a healthy subject as well as cognition enhancement of the healthy subject is illustrated shown by testing the compounds in the Morris water maze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-
108. Further details of relevant methodology are described in WO 96/25948. Other assessments for measuring cognition enhancement include, but are not limited to the "T" Maze Test; Radial Arm Maze Test; Delayed Non-Match or Delayed Match Test; Passive Avoidance Procedure; 5 Choice Test, disclosed in WO 01/87281 A2, published November 22. 2001.
For purposes of this specification, classes of healthy subjects includes juveniles, adults and seniors of average cognition; juveniles, adults and seniors of above average cognition; and juveniles, adults and seniors of below average cognition.
For purposes of this specification, juvenile human subjects is defined as a human subject less than 18 years of age. For purposes of this specification, adult human subject is defined as a human subject 18 years of age or older. Within this classification is a human adult 18 to 40 years of age. For purposes of this specification, senior human subjects is defined as a human subject 40 years of age or older. Within this classification is a human subject 55 years of age or older; 65 years of age or older; and 70 years of age or older. As appreciated by those of skill in the art, beginning at about age 25, the cognition of the healthy human declines at a measurable and reproducible rates, as for example, measured by CAmbridge Neuropsychological Test Automated -Sattery (CANTAB, de Jager CA, Milwain E, Budge M. Early detection of isolated memory deficits in the elderly: the need for more sensitive neuropsychological tests. Psychol Med 2002 Apr;32(3):483-91) or the Cognitive Drug Reseach Battery (CDR, Barker A, Jones R, Simpson P, Wesnes K. (1995). Scopolamine induced cognitive impairment as a predictor of cognitive decline in healthy elderly volunteers. International Journal of Geriatric Psychiatry 10: 1059-1062). Thus, by the time a human subject becomes a senior 40 years of age the decline in cognitive function has declined significant and would benefit from a method of memory enhancement.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non- toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The pharmaceutical compositions of the present invention comprise a compound (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) HI receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAID"), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
Dosage levels from about O.OOOlmg/kg to about 50mg/kg of body weight per day are useful for enhancing cognition or about 0.005mg to about 2.5g per patient per day. Alternatively, dosage levels from about 0.00 lmg to lOmg of the compound per kilogram of body weight per day, or alternatively about 0.05mg to about 500mg per patient per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.005mg to about 2.5g of active agent, compounded with an appropriate and convenient amount of carrier materia. Unit dosage forms will generally contain between from about 0.005mg to about lOOOmg of the active ingredient, typically 0.005, O.Olmg, 0.05mg, 0.25mg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of a compound of the Examples. The compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Further, the compound of this invention can be utilized in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) HI (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
Thus, for example, cognition can be conveniently enhanced with capsules, cachets or tablets each containing 0.005, O.Olmg, 0.05mg, 0.25mg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg of the active ingredient of the compound of the present application, or a pharmaceutically acceptable salt thereof, administered once, twice, or three times daily.
The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
Figure imgf000021_0001
Figure imgf000022_0001
ALKYL GROUP ABBREVIATIONS
Figure imgf000023_0001
ASSAYS DEMONSTRATING BIOLOGICAL ACTIVITY
LPS AND FMLP-INDUCED TNF-α AND LTB4 ASSAYS IN HUMAN WHOLE BLOOD Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-α and LTB4.
Upon stimulation with LPS, activated monocytes express and secrete TNF-α up to 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, by using the same blood sample, it is possible to evaluate the potency of a compound on two surrogate markers of PDE4 activity in the whole blood by the following procedure. Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. 500μL aliquots of blood were pre-incubated with either 2μL of vehicle (DMSO) or 2μL of test compound at varying concentrations for 15 minutes at 37°C. This was followed by the addition of either lOμL vehicle (PBS) as blanks or lOμL LPS (lμg/mL final concentration, #L-2630 (Sigma Chemical Co., St. Louis, MO) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37°C, another lOμL of PBS (blank) or lOμL of LPS (lμg/mL final concentration) was added to blood and incubated for 30 minutes at 37°C. The blood was then challenged with either lOμL of PBS (blank) or lOμL of fMLP (lμM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37°C. The blood samples were centrifuged at 1500xg for 10 minutes at 4°C to obtain plasma. A 50μL aliquot of plasma was mixed with 200μL methanol for protein precipitation and centrifuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS) using an ΕLISA kit (Cistron Biotechnology, Pine Brook, NJ) according to manufacturer's procedure. IC50 values should be less than about 5μM, advantageously less than about 2.5μM. The IC50 values of Examples 1 to 33 ranged from O.OlμM to 2.4μM.
ANTI- ALLERGIC ACTIVITY 7N VIVO
Compounds of the invention have been tested for effects on an IgE-mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, animals were challenged with aerosolized ovalbumin while under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-lOmg kg i.p. or p.o.), up to three times during the 48h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. SPA BASED PDE ACTIVITY ASSAY PROTOCOL Compounds which inhibit the hydrolysis of cAMP to AMP by the type-JN cAMP- specific phosphodiesterases were screened in a 96-well plate format as follows:
In a 96 well-plate at 30°C the test compound was added (dissolved in 2μL DMSO), 188μL of substrate buffer containing [2,8- H] adenosine 3 ',5 '-cyclic phosphate
(cAMP, lOOnM to 50μM), lOmM MgCl2, ImM EDTA, 50mM Tris, pH 7.5. The reaction was initiated by the addition of human recombinant PDE4 (the amount was controlled so that -10% product was formed in lOmin.). The reaction was stopped after lOmin. by the addition of lmg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, ΝJ). The product AMP generated was quantified on a Wallac Microbeta® 96-well plate counter (EG&G Wallac Co., Gaithersburg, MD). The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point titration.
The IC50 values of Examples 1 to 33 were determined with lOOnM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase -Na (met-248) produced from a baculovirus/Sf-9 expression system. IC50 values should be less than about lOOOnM, advantageously less than about 250nM, and even more advantageously less than about lOOnM. The IC50 values of Examples 1 to 33 ranged from O.lnM to 90.0nM.
The Examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperature - that is, at a temperature in the range of 18-25°C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000pascals: 4.5-30mm Hg) with a bath temperature of up to 60°C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and "d" indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (ΝMR) spectrometry or microanalytical data. When given, yields are for illustration only. When given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, "Ar" signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)),mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles),mmol (millimoles), eq (equivalent(s)).
EXAMPLES
The Examples are comprised of four sub-sets - Example set A, Example set B, Example set C and Example Set D.
EXAMPLES A 1 Through A 42
The compounds of Examples 1 A through 42A are characterized and prepared as disclosed in US 6,410,563 Bl, issued June 25, 2002, which is hereby iincorporated by reference.
IA. and 2A. 6-isopropyl-8-(3-{(Z/E)-2-[4-(methylsulfonyl)phenyl]-2- phenylethenyl } phenyl )quinoline;
3A. 6-isoρropyl-8-{3-[(E/Z)-2-[4-(methylsulfonyl)phenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl Jquinoline;
4A. 6-isopropyl-8-(3- { (E)-2-( 1 -methyl- 1 H-imidazol-2-yl)-2- [4- (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 5A. and 6A. 6-isopropyl-8-(3-{(Z E)-2-(4-fluorophenyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
7A. 2-(2-{(E/Z)-2-[3-(6-isoρropyl-8-quinolinyl)phenyl]-l-[4- (methylsulfonyl)phenyl]ethenyl}-l,3-thiazol-5-yl)-2-propanol;
8 A. 2-[8-(3- { (E/Z)-2-[5-( 1 -hydroxy- 1 -methylethyl)- 1 ,3-thiazol-2-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl }phenyl)-6-quinolinyl]-2-methylpropanenitrile;
9A. 2-methyl-2-[8-(3-{ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile; 10A. 6-[l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l,3- thiazol-2-yl)ethenyl]phenyl}quinoline;
11 A. 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4- (methylsulfonyl)phenyl]-2-(l,3-thiazol-2-yl)ethenyl]phenyl}quinoline; 12A. 8-(3-{(Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-(methylsulfonyl)ethyl]quinoline;
13 A. 8-(3- { (Z)-2-( 1 -methyl- lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-methyl-l-(methylsulfonyl)ethyl]quinoline;
14A. and 15. 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(3-methyl- l,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
16A. and 17A. (E/Z)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]ρhenyl }-N- isopropyl-2-[4-(methylsulfonyl)phenyl]-2-propenamide;
18A. 8-(3-{(E)-2-{3-[(4-methoxyphenoxy)methyl]-l,2,4-oxadiazol-5-yl}-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-methyl-l-(methylsulfonyl)ethyl]quinoline; 19 A. (5- { (E)-2-(3- { 6- [ 1 -methyl- 1 -(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)- l-[4-(methylsulfonyl)phenyl]ethenyl}-l,2,4-oxadiazol-3-yl)methanol;
20A. (E)-N-isopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide;
21 A. (E)-3- { 3-[6-( 1 -cyano- 1 -methylethyl)-8-quinolinyl]phenyl } -2-[4- (methylsulfonyl)phenyl]-2-propenoic acid;
22A. 2-methyl-2-[8-(3-{(E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile;
23A. (E)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenyl}-2-[4- (methylsulfonyl)phenyl]-2-propenamide; 24A. E)-N-(tert-butyl)-3- { 3-[6-( 1-cyano- 1 -methylethyl)-8-quinolinyl]phenyl } -2-
[4-(methylsulfonyl)phenyl]-2-propenamide;
25A. (E)-3-[3-(6-isopropyl-8-quinolinyl)phenyl]-2-[4-(methylsulfonyl)phenyl]-2- propenoic acid;
26A. 6-isopropyl-8-(3-{(E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phenyl)quinoline;
27A. (E)-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4- (methylsulfonyl)phenyl]-l-(l-pyrrolidinyl)-2-propen-l-one; 28A. (E)-N-cyclopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide;
29A. (E)-N-(tert-butyl)-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl}phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide; 30A. 8-{3-[2,2-bis(4-chlorophenyl)vinyl]phenyl }-6-isopropylquinoline;
31 A. and 32A. 6-isopropyl-8-(3-{(E/Z)-2-(6-methyl-3-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
33 A. and 34A. 6-isoρropyl-8-(3-{(E/Z)-2-(5-methyl-2-ρyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 35A. 8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6- i sopropylquinoline;
36A. and 37A. 2-methyl-2-[8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile;
38A. 2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6-quinolinyl]-2- methylpropanenitrile;
39A. 2-methyl-2-(8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(2- pyridinyl)ethenyl]phenylJ-6-quinolinyl)propanenitrile;
40A. and 41 A. 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(5-methyl-2- pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 42A. 2-(6-{(E)-2-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinylJphenyl)-l-[4-(methylsulfonyl)phenyl]ethenyl}-3-pyridinyl)-2-propanol;
The compounds of Examples IB through 36 are characterized and prepared as disclosed in US 6,399,636 B2, issued June 4, 2002, which is hereby incorporated by reference.
Examples 1B-36B are summarized in the table below:
Figure imgf000028_0001
Figure imgf000029_0001
In the table above, "c-but" represents cyclobutyl, "c-pr" represents cyclopropyl, "c-pent" represents cyclopentyl, "c-Hex" represents cyclohexyl, "4-EtPh" represents 4- ethylphenyl, "4-FPh" represents 4-fluorophenyl, "Ph" represents phenyl, "Pyr" represents pyridyl, "2-(5-Br)Pyr" represents 2-(5-bromo)pyridyl, and "3-(6-Br)Pyr" represents 3-(6-bromo)pyridyl.
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl Jpyridine;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- trifluoromethyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l- phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)ρhenyl]-2-[5-(2-(l-hydroxy-l-phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4- { 2-[3 ,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-( 1 -hydroxy- 1 - phenyl)propyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2- cyclohexylmethanol)thiazolyl]ethyl Jpyridine;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-cyclohexyl-2,2,2- trifluoromethyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4- ethyl)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-ethyl)phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)ρhenyl]-2-[5-(2-(l-hydroxy-l-(4- fluoro)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-Fluoro)phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(5-bromopyridin-2-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(6-bromopyridin-3-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l- hydroxy)cyclobutyl]thiazolyl Jethyl Jpyridine N-oxide; (±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l- hydroxy)cyclohexyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine;
(±)-4- { 2- [(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2- { 5- [2-( 1 -hydroxy- 1 -trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine n-oxide; Chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine;
Chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine n-oxide;
Chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine n-oxide;
Chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2, 2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide; (±)-4-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methy])ethyl]thiazoly] Jethyl Jpyridine N-oxide;
(±)-3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- trifluoro methyl- 2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide; and chiral 3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- trifluoro methyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide.
Table IC
Figure imgf000032_0001
Figure imgf000032_0002
Figure imgf000033_0002
Table 2
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0002
Table 3
Figure imgf000035_0001
Figure imgf000036_0002
Table 4
Figure imgf000036_0001
Figure imgf000036_0003
Figure imgf000037_0001
EXAMPLE IC
N-Isopropyl-l-r3-(3-acetylphenyl)phenyl1-1.4-dihydron.81naphthyridin-4-one-3-carboxamide
Step 1: Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.
A mixture of ethyl 2-chloronicotinoyl acetate (41.1g, 180.5mmol), triethyl orthoformate (40.12g, 271mmol) and acetic anhydride (92.05g, 902.5mmol) was heated at 130°C for 2.5 hours. The volatile components were distilled off and the residue was co-evaporated twice with xylene. The oily residue was dissolved in methylene chloride (250mL) and 3- bromoaniline (37.25g, 216.6mmol) was added slowly. The resulting solution was stirred at room temperature for 18 hours, and the solvent evaporated away. The resulting crude compound was used as such in the next step.
Step 2: Ethyl l-(3-bromophenyl)- 4-dihydrori.81naphthyridin-4-one-3-carboxylate.
The crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil , 9.4g, 235mmol) was added in portions. After stirring at 0° for 1 hour, the mixture was allowed to warm up to room temperature. After 2 hours, water (400mL) was added to the suspension and and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150mL) at room temperature for 24 hours and filtered to afford the title compound as a cream-colored solid.
1H NMR (Acetone-dό) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.78 (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H). Step 3: l-(3-Bromophenyl)-l-4-dihvdrori,81naphthyridin-4-one-3-carboxylic acid
A suspension of ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylate from Step 2 (52.5g, 140.7mmol) in a mixture of tetrahydrofuran (400mL), methanol (400mL) and IN aqueous sodium hydroxide (280mL) was heated at ca 50°C with stirring for 20 minutes. After cooling, the mixture was diluted with water (300mL) and IN aqueous HC1 (325mL) was added. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the title acid as a cream-colored solid.
Η NMR (Acetone-de) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H).
Step 4: N-Isopropyl-l-(3-bromophenyl)-l,4-dihydrori,81naphthyridin-4-one-3-carboxamide.
To a suspension of l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylic acid from Step 3 (26.3g, 76mmol) and triethylamine (23.2g, 230mmol) in tetrahydrofuran (lOOOmL) at 0°C was added isobutyl chloroformate (18.85g, 138mmol). After stirring at 0°C for 2 hours, isopropylamine (23g, 390mmol) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N- Isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide as a white solid.
1H NMR (Acetone-d 6) δ 1.25 (d, 6H), 4.17 (m, 1H), 7.59-7.63 (m, 2H), 7.70 (d, 1H), 7.80 (d, 1H), 7.94 (s, 1H), 8.73 (m, 1H), 8.78 (d, 1H), 8.85 (s, 1H), 9.61 (br, NH).
Step 5: N-Isopropyl-l-r3-(3-acetylphenyl)phenyl1-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide
A mixture of N-Isopropyl- l-(3-bromophenyl)- 1 ,4-dihydro[ 1 ,8]naphthyridin-4- one-3-carboxamide from Step 4, 3-acetylphenylboronic acid (1.2eq.), trans- dibromobis(triphenylphosphine)palladium (II) (0.05eq.), toluene (όmlJmmol ), ethanol (2mIJmmol ) and 2M aqueous sodium carbonate (8eq.) was refluxed for 1 hour under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and the organic phase was washed with water and brine, dried and evaporated. The crude product was chromatographed on silica gel eluting with a gradient of 20-40% ether in methylene chloride to afford the N-Isopropyl-l-[3-(3- acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide product as a solid.
Η NMR (CDCI3) δ 1.29 (d, 6H), 2.65 (s, 3H), 4.28 (m, IH), 7.47 (m, 2H), 7.55 (t, IH), 7.65 (m, 2H), 7.80 (m, 2H), 7.95 (dd, IH), 8.19 (brs, IH), 8.70 (dd, IH), 8.81 (dd, IH), 9.05 (s, IH), 9.65 (br, NH).
EXAMPLE 2C
N-(2.6-Dichloropyridin-4-yl)- l-H-G-acetylphenyDphenyl]- 1 ,4-dihvdror 1 ,81naphthyridin-4-one- 3-carboxamide
Step 1: Anion of 4-amino-3-5-dichloropyridine.
A suspension of sodium hydride as 60% dispersion in oil (360mg, 9mmol) in tetrahydrofuran (15mL) was cooled to 0°C. A solution of 4-amino-3,5-dichloropyridine (978mg, 6mmol) in tetrahydrofuran (15mL) was added slowly. The resulting mixture was kept at 0° for 2.5 hours.
Step 2: Acid chloride of l-(3-bromophenyl)-1.4-dihvdro|T.81naphthyridin-4-one-3-carboxylic acid.
A suspension of l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylic acid from Step 3 of Example IC (690mg, 2mmol) in tetrahydrofuran (12mL) was cooled to 0°C, and oxalyl chloride (38 lmg, 3mmol) was added, followed by 2 drops of N,N- dimethylformamide. The resulting mixture was then stirred at room temperature for 1 hour then refluxed for 45 minutes and cooled to room temperature.
Step 3 : N-(2.6-Dichloropyridin-4-y0- l-(3-bromophenyl)- 1 ,4-dihvdror 1 ,81naphthyridin-4-one-3- carboxamide.
The mixture from Step 2 above, as a brown suspension, was added via syringe to the cold suspension of Step 1. The resulting mixture was stirred at room temperature for 18 hours, quenched with aqueous saturated ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from evaporation of the organic phase was triturated with ether (50mL) and filtered, affording the N-(2,6-Dichloropyridin-4-yl)-l-(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide as a beige solid. Η NMR (Acetone-dβ) δ 7.61-7.70 (m, 2H), 7.76 (d, IH), 7.81 (d, IH), 8.00 (s,
IH), 8.62 (s, 2H), 8.80 (br s, IH), 8.86 (d, IH), 8.99 (s, IH), 12.1 (br, NH).
Step 4: N-(2,6-Dichloropyridin-4-yl)-l-r3-(3-acetylphenyl)phenyl1-1.4- dihvdrori.81naphthyridin-4-one-3-carboxamide. Following the procedure of Step 5 of Example IC, but substituting N-(2,6- dichloropyridin-4-yl)- 1 -(3-bromophenyl)- 1 ,4-dihydro[l ,8]naphthyridin-4-one-3-carboxamide from step 3 for N-isopropyl 1 -(3-bromophenyl)- l,4-dihydro[l, 8]naphthyridin-4-one-3- carboxamide, the N-(2,6-Dichloropyridin-4-yl)-l-[3-(3-acetylphenyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid. 1H NMR (CDC13) δ 2.65 (s, 3H), 7.47 (d, IH), 7.50-7.60 (m, 2H), 7.70 (m, 2H),
7.82 (d, 2H), 7.98 (d, IH), 8.20 (s, IH), 8.55 (s, 2H) 8.75 (brs, IH), 8.92 (dd, IH), 9.14 (s, IH), 12.08 (br, NH).
EXAMPLE 3C
N-Isopropyl-l-[3-(4-n-propylphenyl)phenyl1-l,4-dihvdroπ.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 4-n- propylphenylboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a white solid.
Η NMR (Acetone-d6) δ 0.93 (t, 3H), 1.24 (d, 6H), 1.65 (m, 2H), 2.62 (t, 2H), 4.18 (m, IH), 7.31 (d, 2H), 7.58-7.61 (m, 2H), 7.68-7.72 (m, 3H), 7.87 (d, IH), 7.95 (s, IH), 8.72 (m, IH), 8.78 (dd, IH), 8.92 (s, IH), 9.66 (br, NH). EXAMPLE 4C
N-Isopropyl-l-r3-(4-acetylphenyl)phenyl1-1.4-dihvdron,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 4- acetylphenylboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a solid.
1H NMR (Acetone-de) δ 1.25 (d, 6H), 2.61 (s, 3H), 4.17 (m, IH), 7.59 (m, IH), 7.70 (d, IH), 7.76 (t, IH), 7.92 (d, 2H), 7.97 (d, IH), 8.07-8.10 (m, 3H), 8.72 (brs, IH), 8.78 (dd, IH), 8.92 (s, IH), 9.65 (br, NH).
EXAMPLE 5C
N-Isopropyl-l-r3-(2-methylphenyl)phenyn-l,4-dihvdrori,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 2- methylphenylboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a solid. 1H NMR (Acetone-d6) δ 1.24 (d, 6H), 2.35 (s, 3H), 4.17 (m, IH), 7.27-7.34 (m,
4H), 7.56-7.60 (m, 2H), 7.65 (m, 2H), 7.70 (t, IH), 8.74 (m, IH). 8.78 (dd, IH), 8.92 (s, IH), 9.64 (br, NH).
EXAMPLE 6C
N-Isopropyl-N-methyl-l-r3-(4-acetylphenyl)phenyn- 4-dihydrofl.81naphthyridin-4-one-3- carboxamide
Step 1: N-Isopropyl-N-methyl-l-(3-bromophenyl)- 4-dihvdron.81naphthyridin-4-one-3- carboxamide
Following the procedure of Example IC, Step 4, but substituting N-isopropyl-N- methylamine for isopropylamine the N-Isopropyl -N-methyl-1 -(3-bromophenyl)- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide was obtained in as a yellow solid.
1H NMR (Acetone-c-6) (Appears as two rotamers of the amide) δ 1.18 (m, 6H), 2.85 (s, 3H), 4.05 (m, 0.5H), 4.84 (m, 0.5H), 7.49-7.64 (m, 3H), 7.72 (d, IH), 7.86 (s, IH), 8.14 (s, IH), 8.65 (d, 2H).
Step 2: N-Isopropyl-N-methyl-l-r3-(4-acetylphenyl)phenyl1-1.4-dihydrori.81naphthyridin-4- one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting N-isopropyl-
N-methyl-1 -(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from step 1 for
N-isopropyl 1 -(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide and 4- acetylphenylboronic acid for 3-acetylphenylboronic acid the N-Isopropyl-N-methyl-l-[3-(4- acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (CDC13) (Appears as two rotomers of the amide) δ 1.23 (m, 6H), 2.62 (s,
3H), 4.00 (m, 0.5H), 4.92 (m, 0.5H), 7.38-7.55 (m, 2H), 7.63-7.77 (m, 5H), 8.03 (d, 2H), 8.14 (s, 0.5H), 8.21 (s, 0.5H), 8.65 (m, IH), 8.75-8.80 (m, IH).
EXAMPLE 7C
N-Isopropyl-l-r3-(pyridin-3-yl)phenvn-1.4-dihydrofl.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting pyridine-3- boronic acid 1,3-propanediol cyclic ester for 3-acetylphenylboronic acid and [l,l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) for trans- dibromobis(triphenylphosphine)palladium (II) the title compound was obtained as a beige solid. 1H NMR (Acetone-dβ) δ 1.24 (d, 6H), 4.17 (m, IH), 7.48 (m, IH), 7.60 (m, IH), 7.71 (dd, IH), 7.78 (t, IH), 7.95 (dd, IH), 8.05 (brs, IH), 8.15 (m, IH), 8.60 (m, IH), 8.72 (m, IH), 8.78 (dd, IH), 8.92 (s, IH), 8.99 (brs, IH), 9.65 (br, NH).
EXAMPLE 8C
N-Isopropyl- l-[3-(indol-5-yl)phenyll-l,4-dihvdrori.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 5- indolylboronic acid for 3-acetylphenylboronic acid the title compound was obtained as an off- white solid. 1H NMR ((DMSO-de) δ 1.20 (d, 6H), 4.10 (m, IH), 6.47 (s, IH), 7.38 (brs, IH),
7.46-7.52 (m, 3H), 7.59-7.66 (m, 2H), 7.87-7.93 (m, 3H), 8.72-8.81 (m, 3H), 9.67 (br, NH), 11.2 (br, NH).
EXAMPLE 9C
N-tert-Butyl-l-f3-(4-acetylphenyl)phenyn-1.4-dihvdrori.81naphthyridin-4-one-3-carboxamide
Step 1 : N-tert-Butyl-l-(3-bromopher.ylV 1.4-dihydrof 1.8]naphthyridm-4-one-3-carboxamide
Following the procedure of Example IC, Step 4, but substituting tert-butylamine for isopropylamine the N-tert-Butyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide was obtained as a yellow solid.
1H NMR (Acetone-dβ) δ 1.44 (s, 9H), 7.58-7.62 (m, 2H), 7.70 (dd, IH), 7.78 (dd, IH), 7.93 (br s, IH), 8.72 (m, IH), 8.77 (dd, IH), 8.81 (s, IH), 9.73 (br, NH).
Step 2: N-tert-Butyl-l-[3-(4-acetylphenyl)phenvn-1.4-dihvdrori.81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of Example IC, but substituting N-tert butyl-1- (3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from step 1 for N- isopropyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide and 4- acetylphenylboronic acid for 3-acetylphenylboronic acid the N-tert-Butyl-l-[3-(4- acetylphenyl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide compound was obtained in 93% yield as a white solid. 1H NMR (Acetone-dδ ) δ 1.45 (s, 9H), 2.61 (s, 3H), 7.59 (m, IH), 7.69-7.72 (m,
IH), 7.77 (t, IH), 7.92-7.99 (m, 3H), 8.07-8.11 (m, 3H), 8.72 (m, IH), 8.78 (dd, IH), 8.91 (s,
IH), 9.79 (br, NH).
EXAMPLE 10C
N-(2,6-Dichloroρyridin-4-yl)-l-F3-(pyridin-3-yl)phenyll-1.4-dihvdror 81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 4 of Example 2C but substituting [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(II) for trans- dibromobis(triphenylphosphine)palladium (H) and pyridine-3-boronic acid 1,3-propanediol cyclic ester for 3-acetylphenylboronic acid the title compound was obtained as a glassy solid.
H NMR (Acetone-d6 ) δ 7.48 (m, IH), 7.68 (m, IH), 7.77-7.82 (m, 2H), 7.98 (m, IH), 8.12-8.17 (m, 2H), 8.61 (m, IH), 8.62 (s, 2H), 8.80 (m, IH), 8.88 (dd, IH), 8.99 (brs, IH), 9.06 (s, IH), 12.2 (br, NH).
EXAMPLE 11C
N-Isopropyl- 1- { 3-f 4-(4-tertbutyloxycarbonylpiperazin- 1 -yPphenyll-phenyl I - 1.4- dihvdrori,81naphthyridin-4-one-3-carboxamide
Step 1: 4-tert-Butyloxycarbonyl-l-(3-bromophenyl)piperazine
To a suspension of l-(4-bromophenyl)piperazine hydrochloride (103.15g, 371.59mmol) in acetonitrile (1.5 L) at 0°C under a nitrogen atmosphere was added a catalytic amount of 4-dimethylaminopyridine (4.54g, 37.159mmol) followed by triethylamine (155mL, 1114.77mmol) and di-tert-butyl dicarbonate (121.65g, 557.385mmol, dissolved in a minimum amount of acetonitrile) and the resulting reaction mixture was warmed to room temperature and stirred for 5.5 hours. The reaction mixture was filtered, ethyl acetate was added and the organic phase was washed with 10 % aqueous citric acid, water (2X) and brine, then dried and evaporated to afford the crude 4-tert-Butyloxycarbonyl-l-(3-bromophenyl)piperazine product which was used as such in the next step.
Step 2: 3-(4-tert-Butyloxycarbonylpiperazin-l-yl)phenylboronic acid
To the 4-tert-Butyloxycarbonyl-l-(3-bromophenyl)piperazine from Step 1 (118.30g, 346.9mmol) in tetrahydrofuran /toluene (1/1, 1.5 L) at -78°C under nitrogen was added n-butyllithium (2.5M, 160mL, 398.9mmol) dropwise and the resulting reaction mixture was stirred at -78°C for 20 minutes. Triisopropyl borate (96.1mL, 416.3mmol) was added dropwise and the reaction was warmed to 0°C and stirred for 2 hours. Aqueous saturated ammonium chloride (400mL), water (lOOmL) and 1 equivalent of H3PO4 (20mL) were added and the mixture was stirred for 15 minutes and then concentrated to a volume of approximately 200mL (at which stage the mixture became bluish and a precipitate formed). The mixture was slowly diluted with heptane (800mL) and the resulting suspension was stirred overnight. The suspension was filtered, the solid was washed with heptane and dried to afford the title boronic acid.
Step 3: N-Isopropyl-l-{3-F 4-(4-tertbutyloxycarbonylpiρerazin-l-yl)phenvn-phenyl 1-1.4- dihvdrori.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC but substituting [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(II) for trans- dibromobis(triphenylphosphine)palladium (II) and the boronic acid from Step 2 above for 3- acetylphenylboronic acid the 4-tert-Butyloxycarbonyl-l-(3-bromophenyl)piperazine compound was obtained as a solid.
1H NMR (CDC13 ) δ 1.30 (d, 6H), 1.49 (s, 9H), 3.18 (m, 4H), 3.58 (m, 4H), 4.29 (m, IH), 6.98 (d, 2H), 7.32 (d, IH), 7.45 (m, IH), 7.53 (d, 2H), 7.55-7.62 (m, 2H), 7.72 (d, IH), 8.70 (m, IH), 8.82 (d, IH), 9.07 (s, IH), 9.68 (br, NH).
EXAMPLE 12C
N-Isopropyl-l-[3-(quinolin-3-yl)phenyl1-l,4-dihvdroFl,8]naphthyridin-4-one-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 3- quinolineboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a solid.
1H NMR (CDC13) δ 1.29 (d, 6H), 4.29 (m, IH), 7.49 (m, 2H), 7.61 (t, IH), 7.70- 7.78 (m, 3H), 7.86-7.92 (m, 2H), 8.14 (d, IH), 8.36 (s, IH), 8.71 (m, IH), 8.84 (dd, IH), 9.10 (s, IH), 9.19 (s, IH), 9.67 (br, NH).
EXAMPLE 13C
N-Isopropyl-l-F3-(pyrimidin-5-yl) phenyl1-l-4-dihvdroF 81naphthyridin-4-one-carboxamide
Following the procedure of Step 5 of Example IC, but substituting 5- pyrimidineboronic acid for 3-acetylboronic acid the title compound was obtained as a solid. 1H NMR (CDCI3) δ 1.28 (d, 6H), 4.27 (m, IH), 7.48 (dd, IH), 7.52 (m, IH), 7.65 (s, IH), 7.74 (m, 2H), 8.68 (m, IH), 8.72 (d, IH), 8.98 (s, 2H) 9.03 (s, IH), 9.22 (s, IH), 9.62 (br, NH).
EXAMPLE 14C
N-Cvclopropyl-l-F3-(pyridin-3-yl)phenyl]- 4-dihvdroF 81naphthyridin-4-one-3-carboxamide
Step 1: N-Cvclopropyl-l-(3-bromophenyl)-1.4-dihvdror 81naphthyridin-4-one-3-carboxamide Following the procedure of Example IC, Step 4, but substituting cyclopropylamine for isopropylamine the N-Cyclopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide was obtained as a fluffy white solid.
1H NMR (Acetone-de) δ 0.59 (m, 2H), 0.80 (m, 2h), 2.96 (m, IH), 7.59-7.68 (m,
2H), 7.72 (dd, IH), 7.82 (dd, IH), 7.97 (s, IH), 8.72-8.81 (m, 2H), 8.89 (s, IH), 9.70 (br, NH).
Step 2: N-Cyclopropyl-l-F3-(pyridin-3-yl)phenyl1- 4-dihvdroF 81naphthyridin-4-one-3- carboxamide
Following the procedure of Example 7C but substituting N-cyclopropyl-l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from step 1 for N-isopropyl - l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the N-Cyclopropyl- 1-
[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a cream-coloured solid.
1H NMR (DMSO-d 6 ) δ 0.57 (m, 2H), 0.78 (m, 2H), 2.91 (m, IH), 7.52 (m, IH),
7.63-7.69 (m, 2H), 7.74 (t, IH), 7.97 (d, IH), 8.07 (brs, IH), 8.17 (d, IH), 8.61 (m, IH), 8.73 (dd, IH), 8.79 (m, IH), 8.85 (s, IH), 8.99 (brs, IH), 9.74 (br, NH).
EXAMPLE 15C
N-Isopropyl-l-F3-(5-methylthiopyridin-3-yl)phenvn-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of Example IC but substituting 5- methylthiopyridine-3-boronic acid for 3-acetylphenylboronic acid and [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(II) for trans- dibromobis(triphenylphosphine)palladium (II) the title compound was obtained as a solid. 1H NMR (CDC13 ) δ 1.33 (d, 6H) 2.60 (s, 3H), 4.33 (m, IH), 7.48-7.54 (m, 2H),
7.66 (m, IH), 7.73 (t, IH), 7.78-7.81 (m, 2H), 8.55 (s, IH), 8.66 (s, IH), 8.74 (m, IH), 8.87 (d, IH), 9.09 (s, IH), 9.69 (br, NH).
EXAMPLE 16C
N-Cvclopropyl-l-F3-(4-hvdroxymethylphenyl)phenvn-l,4-dihvdroF 81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 14C but substituting 4- hydroxymethylphenyl boronic acid for pyridine-3-boronic acid 1,3-propanediol cyclic ester the title compound was obtained as a solid.
Η NMR (CDC13 ) δ 0.71 (m, 2H), 0.89 (m, 2H), 1.88 (t, IH), 3.03 (m, IH), 4.78 (d, 2H), 7.43 (d, IH), 7.46-7.52 (m, 3H), 7.61-7.69 (m, 4H), 7.80 (d, IH), 8.73 (m, IH), 8.83 (dd, IH), 9.10 (s, IH), 9.82 (br, NH).
EXAMPLE 17C
N-Cvclopropyl-l-F3-(pyridin-4-yl)phenyll-1.4-dihvdroF 81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 5 of Example IC but substituting N- cyclopropyl- l-(3-bromophenyl)- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide for N- isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide and 4- pyridineboronic acid for 3-acetylphenylboronic acid the title compound was obtained as a white solid. 1H NMR ((DMSO-de ) δ 0.57 (m, 2H), 0.77 (m, 2H), 2.90 (m, IH), 7.64 (m, IH),
7.72-7.89 (m, 4H), 8.03 (d, IH), 8.13 (s, IH), 8.66-8.78 (m, 4H), 8.84 (s, IH), 9.72 (br, NH).
EXAMPLE 18C
N-Cvclopropyl-l-F3-(4-ethylthiophenyl)phenyn- 4-dihydroF1.81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 14C but substituting 4- ethylthiobenzeneboronic acid for pyridine-3-boronic acid 1,3-propanediol cyclic ester the title compound was obtained as a solid.
1H NMR (CDC13 ) δ 0.72 (m, 2H), 0.90 (m, 2H), 1.48 (t, 3H), 3.03 (m, 3H), 7.42 (d, 3H), 7.50 (m, IH), 7.57 (d, 2H), 7.64 (s, IH), 7.68 (t, IH), 7.78 (d, IH), 8.75 (m, IH), 8.85 (d, IH), 9.10 (s, IH), 9.83 (br, NH).
EXAMPLE 19C
N-Cvclopropyl-l-F3-(3-thienyl)phenyl1-1.4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 14C but substituting 3- thiopheneboronic acid for pyridine-3-boronic acid 1,3-propanediol cyclic ester the title compound was obtained as a white solid.
1H NMR (Acetone-d 6 ) δ 0.60 (m, 2H), 0.79 (m, 2H), 2.96 (m, IH), 7.57-7.72 (m, 5H), 7.92-7.98 (m, 2H), 8.05 (s, IH), 8.74 (s, IH), 8.78 (d, IH), 8.93 (s, IH), 9.74 (br, NH).
EXAMPLE 20C
N-Cyclopropyl-l-F3-(4-sulfamoylphenyl)phenyl1-l,4-dihvdroF 81naphthyridin-4-one-3- carboxamide
Step 1: 4-Sulfamoylbenzeneboronic acid pinacol ester
A mixture of 4-bromobenzenesulfonamide, diboron pinacol ester (l.leq), potassium acetate (3.5eq) and 1,1' -bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05eq) im N,N-dimethylformamide (4ml/mmol) was heated at 85°C for 18 hours. After quenching with saturated aqueous ammonium chloride solution the mixture was partitioned between ethyl acetate and water and the product from the organic phase was chromatographed on silica gel eluting with a 1 : 1 mixture of ethyl acetate and hexane to afford the 4- Sulfamoylbenzeneboronic acid pinacol ester as a solid.
Step 2: N-Cyclopropyl-l-r3-(4-sulfamoylphenyl)phenyl1-1.4-dihydroFl,8]naphthyridin-4-one-3- carboxamide
A mixture of N-cyclopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide, boronate from Step 1 (1.2eq), palladium acetate (O.leq), triphenylphosphine
(0.35eq) and 2M aqueous sodium carbonate (3.5eq) in n-propanol (lOml/mmol) was stirred at 85°C for 1 hour. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with a 1:5:4 mixture of ethanol, ethyl acetate and methylene chloride to afford the N-Cyclopropyl-l-[3-(4-sulfamoylphenyl)phenyl]- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as a solid.
Η NMR (Acetone-d 6 ) δ 0.62 (m, 2H), 0.82 (m, 2H), 2.98 (m, IH), 6.66 (br, NH2), 7.64 (m, IH), 7.74 (m, IH), 7.80 (t, IH), 7.97-8.05 (m, 5H), 8.10 (m, IH), 8.76 (m, IH), 8.81 (dd, IH), 8.97 (s, IH), 9.77 (br, NH).
EXAMPLE 21C
N-Isopropyl-l-F3-(3-ethoxyphenyl)phenyl1-1.4-dihvdroF 81naphthyridin-4-one-3-carboxamide
Step 1: Ethyl l-F3-(3-ethoxyphenyl)phenyl1-l,4-dihydroF1.81naphthyridin-4-one-3-carboxylate
Following the procedure of Step 5 of Example IC, but substituting ethyl l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from Step 2 of Example 1 for N-isopropyl- 1 -(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, and 3- ethoxybenzeneboronic acid for 3-acetylbenzeneboronic acid, the Ethyl l-[3-(3- ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate compound was obtained as a solid.
Step 2: l-F3-(3-Ethoxyphenyl)phenyl1-1.4-dihydroF 81naphthyridin-4-one-3-carboxylic acid Following the procedure of Step 3 of Example IC but substituting ethyl l-[3-(3- ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from step 1 for ethyl 1- (3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate the l-[3-(3- Ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid compound was obtained and used without purification in the next step.
Step 3: N-Isopropyl- l-F3-(3-ethoxyphenyl)phenyl1-1.4-dihydroF1.81naphthyridin-4-one-3- carboxamide
A mixture of l-[3-(3-ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one- 3-carboxylic acid from Step 2 and thionyl chloride (4eq) in tetrahydrofuran (lOml/mmol) was refluxed for 45 minutes, then evaporated. The residue was dissolved in the same volume of tetrahydrofuran, isopropylamine (5eq) was added and the mixture was stirred at room temperature for 18 hours. After quenching with saturated aqueous ammonium chloride solution, the resulting mixture was partitioned between ethyl acetate and water, and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-Isopropyl- l-[3-(3-ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound as a solid.
1H NMR (CDC13 ) δ 1.29 (d, 6H), 1.42 (t, 3H), 4.08 (q, 2H), 4.28 (m, IH), 6.91 (d, IH), 7.12 (s, IH), 7.18 (d, IH), 7.34 (t, IH), 7.40 (d, IH), 7.46 (m, IH), 7.60-7.65 (m, 2H), 7.75 (d, IH), 8.71 (brs, IH), 8.82 (dd, IH), 9.08 (s, IH), 9,70 (br, NH).
EXAMPLE 22C
N-Isopropyl-l-F3-(4-methylthiophenyl)phenvn-1.4-dihvdrori,81naphthyridin-4-one-3- carboxamide
Step 1: Ethyl l-r3-(4-methylthiophenyl)phenyl1-1.4-dihvdroF 81naphthyridin-4-one-3- .. carboxylate
Following the procedure of Step 5 of Example IC, but substituting ethyl l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from step 2 of example 1 for
N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, and 4- methylthiobenzeneboronic acid for 3-acetylbenzeneboronic acid, the Ethyl l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate compound was obtained as a solid.
Step 2: l-F3-(4-methylthiophenyl)phenyl1-l,4-dihvdroF 81naphthyridin-4-one-3-carboxylic acid Following the procedure of Step 3 of Example IC but substituting ethyl l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from Step 1 for ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate the l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid compound was obtained as a solid. Step 3: N-Isopropyl-l-F3-(4-methylthiophenyl)phenvn-1.4-dihvdroF 81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 3 of Example 21C but substituting l-[3-(4- methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid for l-[3-(3- ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid the N-Isopropyl- 1 - [3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxami de compound was obtained as a white solid.
1H NMR (Acetone-d 6 ) δ 1.24 (d, 6H), 2.52 (s, 3H), 4.18 (m, IH), 7.37 (d, 2H), 7.58-7.62 (m, 2H), 7.69-7.73 (m, 3H), 7.87 (d, IH), 7.96 (s, IH), 8.72 (m, IH), 8.78 (dd, IH), 8.91 (s, IH), 9.65 (br, NH).
EXAMPLE 23C
N-Isopropyl-l-F3-(3-acetyl-4-hvdroxyphenyl)phenvn-l-4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
A mixture of 5'-bromo-2'-hydroxyacetophenone, diboron pinacol ester (1.25eq), potassium acetate (3eq) and [l,l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05eq) in N,N-dimethylformamide (lOml/mmol) was stirred at 80°C for 3 hours and cooled down. A solution of N-Isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide from Example 1, Step 4 (0.75eq) in N,N-dimethylformamide (7ml/mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05eq) and 2M aqueous sodium carbonate (8.5eq) were added and the resulting mixture was stirred at 80°C for 2.5 hours. The cooled mixture was partitioned between ethyl acetate and water and the product from the organic phase was chromatographed on silica gel eluting with 60% ethyl acetate in hexane to afford the title compound as a light yellow solid.
1H NMR (Acetone-d 6 ) δ 1.24 (d, 6H), 2.75 (s, 3H), 4.19 (m, IH), 7.06 (d, IH), 7.59-7.63 (m, 2H), 7.72 (t, IH), 7.92 (d, IH), 7.97 (d, IH), 8.02 (s, IH), 8.33 (s, IH), 8.73 (m, IH), 8.78 (dd, IH), 8.90 (s, IH), 9.65 (br, NH). EXAMPLE 24C
N-Isopropyl-l-F3-(5-carboethoxypyridin-3-yl)phenyl1-l-4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Example 23C but substituting N-isopropyl-l-(3- bromophenyl)- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide for 5 ' -bromo-2' - hydroxyacetophenone and ethyl 5-bromonicotinate for N-isopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide the title compound was obtained as a beige solid.
1H NMR (CDC13) δ 1.29 (d, 6H), 1.40 (t, 3H), 4.28 (m, IH), 4.42 (q, 2H), 7.45- 7.51 (m, 2H), 7.68 (s, IH), 7.71 (t, IH), 7.80 (d, IH), 8.49 (s, IH), 8.59 (m, IH), 8.82 (d, IH), 9.03 (s, IH), 9.07 (s, IH), 9.23 (s, IH), 9.64 (br, NH).
EXAMPLE 25C
N-Isopropyl- 1 - { 3- F5-( 1 -hydroxy- 1 -methylethvDpyri din-3-yllphen yl J - 1.4-dihydroF 1.81 naphthyridin-4-one-3-carboxamide
Step 1: 3-Bromo-5-(l-hydroxy-l-methylethyl,pyridine
To a solution of ethyl 5-bromonicotinate (1.02g, 4.4mmol) in diethyl ether (15ml) at -30°C was added a 3M solution of methyl magnesium bromide (4ml, 12mmol)in ether. The resulting slurry was then refluxed for 2 hours then cooled and quenched with an excess of 0.5M aqueous monobasic sodium phosphate and partitioned between ether and water. The product from the organic phase was chromatographed on silica gel eluting with a 2: 1 :2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-Bromo-5-(l-hydroxy-l- methylethyl)pyridine compound as a yellow oil. Step 2: N-Isopropyl- 1 - ( 3-F5-( 1 -hydroxy- 1 -methylethyl)pyridin-3-yl1phenyl I - 1.4- dihvdroF1.81naphthyridin-4-one-3-carboxamide.
Following the procedure of Example 24C, but substituting the 3-bromo-5-(l- hydroxy-l-methylethyl)pyridine from Step 1 for ethyl 5-bromonicotinate, the title compound was obtained as a yellow foam.
1H NMR (CDC13) δ 1.28 (d, 6H), 1.62 (s, 6H), 2.52 (brs, IH), 4.25 (m, IH), 7.41- 7.48 (m, 2H), 7.60-7.68 (m, 2H), 7.75 (d, IH), 8.05 (s, IH), 8.67-8.71 (m, 3H), 8.80 (dd, IH), 9.03 (s, IH), 9.66 (br, NH).
EXAMPLE 26C
N-Isopropyl-l-{3-F6-(2-methylpropyl)pyridin-3-yl1phenylJ-1.4-dihydroF 81naphthyridin-4-one- 3-carboxamide
Step 1: 5-Bromo-2-(2-methylpropyl)pyridine
To a solution of 2,5-dibromopyridine (4.5g, 19mmol) in tetrahydrofuran (50ml) was added [l.l'-bis (diphenylphosphino)ferrocene]dichloronickel (II) (103mg, 0.19mmol) and the resulting mixture was cooled to -10°C. A 2M solution of isobutylmagnesium bromide in ether (12.4ml, 24.7mmol) was added slowly and the mixture was stirred at -10 to 10°C for 3.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel eluting with 10% ether in pentane to afford the 5-Bromo-2-(2- methylpropyl)pyridine compound as a volatile oil.
Step 2: N-Isopropyl-l-|3-F6-(2-methylpropyl)pyridin-3-yllphenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Example 24C but substituting 5-bromo-2-(2- methylpropyl)pyridine from Step 1 for ethyl 5-bromonicotinate the N-Isopropyl-l-{3-[6-(2- methylpropyl)pyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid. Η NMR (CDCI3) δ 0.92 (d, 6H), 1.28 (d, 6H), 2.10 (m, IH), 2.69 (d, 2H), 4.28 (m, IH), 7.19 (d, IH), 7.40-7.47 (m, 2H), 7.60 (s, IH), 7.64 (t, IH), 7.73 (d, IH), 7.79 (dd, IH), 8.68 (m, IH), 8.77-8.83 (m, 2H), 9.05 (s, IH), 9.66 (br, NH).
EXAMPLE 27C
N-Isopropyl-l-F3-(5-acetylpyridin-3-yl)phenyll-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 3-Acetyl-5-bromopyridine
To a solution of ethyl 5-bromonicotinate (3.9g, 16.9mmol) in ether (50ml) at 0°C was added a 3M solution of methylmagnesium bromide (16.9ml, 50.8mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of IM aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluting with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(l- hydroxy-1 -methylethyl )pyri dine described in Example 25C.
Step 2: N-Isopropyl-l-F3-(5-acetylpyridin-3-yl)phenyll-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Example 23C but substituting 3-acetyl-5- bromopyridine from Step 1 for ethyl 5-bromonicotinate the N-isopropyl-l-[3-(5-acetylpyridin-3- yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (CDCI3) δ 1.29 (d, 6H), 2.69 (s, 3H), 4.28 (m, IH), 7.48 (dd, IH), 7.51 (d, IH), 7.69 (s, IH), 7.72 (t, IH), 7.80 (d, IH), 8.42 (s, IH), 8.69 (m, IH), 8.82 (d, IH), 9.05 (s, 2H) 9.17 (s, IH), 9.63 (br, NH). EXAMPLE 28C
N-Isopropyl-l-F3-(6-methvIpyridin-3-yl)phenyl1-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 5-Bromo-2-methylpyridine
Following the procedure of Step 1 of Example 26C but substituting methylmagnesium chloride for isobutylmagnesium bromide the 5-bromo-2-methylpyridine compound was obtained as a solid.
Step 2: N-Isopropyl-l-F3-(6-methylpyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Example 24C but substituting 5-bromo-2- methylpyridine from Step 1 for ethyl 5-bromonicotinate the N-Isopropyl- 1- [3-(6-methylpyridin- 3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 1.32 (d, 6H), 2.63 (m, 3H), 4.30 (m, IH), 7.25 (d, IH), 7.45- 7.51 ( , 2H), 7.63 (s, IH), 7.69 (t, IH), 7.77 (d, IH), 7.82 (dd, IH), 8.72 (m, IH), 8.78 (s, IH), 8.85 (d, IH), 9.08 (s, IH), 9.68 (br, NH).
EXAMPLE 29C
N-Cvclopropyl-l-F3-(l-oxidopyrimidin-5-yl) phenyll-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 5-Bromo-l-oxidopyrimidine
To 5-bromopyrimidine (2.05g, 12.9mmol) in methylene chloride (25ml) was added m-chloroperoxybenzoic acid (ca 70% pure, 3.17g, 12.9mmol) and the resulting mixture was stirred at room temperature for 5 days. Calcium hydroxide (lg) was added and after 10 minutes the mixture was filtered through celite. The product from evaporation of the filtrate was chromatographed on silica gel eluting with ethyl acetate to afford the 5-bromo-l- oxidopyrimidine compound as a white solid.
Step 2: N-Cyclopropyl-l-F3-(l-oxidopyrimidinyl-5-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Following the procedure of Example 24C but substituting 5-bromo-l- oxidopyrimidine from Step 1 for ethyl 5-bromonicotinate and N-cyclopropyl-l-(3- bromophenyl)- l,4-dihydro[l, 8]naphthyridin-4-one-3-carboxamide for N-isopropyl- 1 -(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the N-Cyclopropyl- l-[3-(l- oxidopyrimidinyl-5-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (CDC13 ) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.97 (m, IH), 7.48 (m, IH), 7.58 (d, IH), 7.65 (s, IH), 7.71 (d, IH), 7.77 (t, IH), 8.46 (s, IH), 8.60 (s, IH), 8.68 (brs, IH), 8.81 (dd, IH), 8.98 (s, IH), 9.02 (s, IH), 9.72 (br, NH).
EXAMPLE 30C
l-l3-F6-(l-Hvdroxy-l-methylethyl)-l-oxidopyridin-3-yllphenylJ-l,4-dihydroFl,81naphthyridin- 4-one-3-carboxamide
Step 1: 5-Bromo-2-(l-hydroxy-l-methylethyl) pyridine
To a suspension of 2,5-dibromopyridine in toluene (12ml/mmol) cooled to -78°C was added n-butyllithium 2.5M in hexanes (1.05eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2eq) was added and stirring was continued for 1.5h. After quenching with saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-Bromo-2-(l-hydroxy-l-methylethyl) pyridine compound as a syrup.
Step 2: 5-Bromo-2-(l -hydroxy- 1 -methylethyl) pyridine N-oxide
To a solution of 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine from Step 1 in methylene chloride (5ml/mmol) at room temperature was added m-chloroperoxybenzoic acid 70% (l.leq) and the resulting mixture was stirred at room temperature for 18 hours. An excess of calcium hydroxide was added and after 5 minutes the mixture was filtered through a bed of celite. The crude product from evaporation of the filtrate was chromatographed on silica gel eluting with 80% ethyl acetate in hexane and the 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine N-oxide compound was obtained as a white solid.
Step 3: 1 -(3-bromophenyl)- l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 4 of Example IC but substituting 28% aqueous ammonium hydroxide for isopropylamine the l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide compound was obtained as a solid.
Step 4: 1 - ( 3-F6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yllphenyl 1-1.4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Example 24C but substituting 5-bromo-2-(l-hydroxy- 1 -methylethyl) pyridine N-oxide from Step 2 above for ethyl 5-bromonicotinate and l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide for N-isopropyl-l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the l-{ 3-[6-(l -hydroxy- 1- methylethyl)-l-oxidopyridin-3-yl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid. 1H NMR (CDC13 ) δ 1.76 (s, 6H), 5.83 (br, IH, NH). 7.50 (d, IH), 7.55 (m, IH),
7.57-7.62 (m, 2H), 7.65 (m, 2H), 7.72-7.78 (m, 2H), 8.55 (s, IH, OH), 8.75 (m, IH), 8.90 (dd,
IH), 9.08 (s, IH), 9.52 (br, IH, NH).
EXAMPLE 3 IC
N-Isopropyl-l-{3-F4-(pyridin-3-yl)phenyl1phenylj-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Step 1: N-Isopropyl-l-F3-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyll-l,4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
A mixture of N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide from Step 4 of Example IC, diboron pinacol ester (l.leq), potassium acetate (3.5eq) and [l,l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05eq) in N,N- dimethylformamide (5ml/mmol) was stirred at 85°C for 18 hours. A further amount of diboron pinacol ester (0.4eq) and palladium catalyst (0.05eq) were added and heating and stirring were continued for a further 24 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the crude product from the organic phase was chromatographed on silica gel eluting with a 1 : 1 mixture of ethyl acetate and hexane. The product was then stirred in hexane at room temperature for several hours and filtered to afford the N-Isopropyl- 1- [3- (4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound as a white solid.
Step 2: 3-(4-Bromophenyl)pyridine
A mixture of pyridine-3 -boronic acid 1,3-propanediol cyclic ester, 4- bromoiodobenzene (l.leq), [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(π) (0.05eq) and 2M aqueous sodium carbonate (5eq) in N,N-dimethylformamide (2ml/mmol) was stirred at 85°C for 4 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ethyl acetate and water, and the crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 3-(4-Bromophenyl)pyridine compound as a solid.
Step 3: N-Isopropyl-l-{3-F4-(pyridin-3-yl,phenyl1phenyl|-l,4-dihydroFl,81naphthyridin-4-one- 3-carboxamide
A mixture of the boronate from Step 1, 3-(4-bromophenyl)pyridine from Step 2 (1.5eq), [l,l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05eq) and 2M aqueous sodium carbonate (5eq) in N,N-dimethylformamide (7ml/mmol) was stirred at 85°C for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 7:3 mixture of ethyl acetate and methylene chloride to afford the N-Isopropyl-l-{3-[4-(pyridin-3-yl)phenyl]phenylJ- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as a solid.
1H NMR (CDC13 ) δ 1.30 (d, 6H), 4.25 (m, IH), 7.35 (m, IH), 7.39-7.48 (m, 2H), 7.60-7.75 (m, 6H), 7.80 (d, IH), 7.90 (d, IH), 8.58 (d, IH), 8.70 (m, IH), 8.82 (d, IH), 8.88 (s, IH), 9.08 (s, IH), 9.68 (br, NH). EXAMPLE 32C
N-Cvclopropyl-l-[3-(5-methylsulfonylρyridin-3-vmphenyn-l,4-dihvdro[l,81naphthyridin-4- one-3-carboxamide
Step 1: N-Cvclopropyl-l-F3-(4,4,5,5,-tetramethyl-1.3.2-dioxaborolan-2-yl)phenyl1-l,4- dihvdroF1.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 1 of Example 31C but substituting N- cyclopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from step 1 of example 14 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide the N-Cyclopropyl-l-[3-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
Step 2: 3-Bromo-5-methylsulfonylpyridine To 3,5-dibromopyridine (2.96g, 12.5mmol) in diethyl ether (70ml) at -78°C was added n-butyllithium 1.6M in hexanes (8.6ml, 13.7mmol) and the resulting mixture was stirred in the cold for 3 hours. Dimethyl disulfide (1.12ml, 12.5mmol) was added and the mixture was warmed to room temperature, then partitioned between ether and water. To the crude product from evaporation of the organic phase was added tetrahydrofuran (80ml), methanol (20ml), oxone (17g) and enough saturated aqueous sodium bicarbonate to afford a slightly basic medium. After stirring for 4 hours at room temperature, an excess of IM aqueous sodium metabisulfite was added, the organic solvents were evaporated, and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was stirred in a small volume of ethyl acetate and filtered to afford the 3-Bromo-5-methylsulfonylpyridine compound as a solid.
Step 3: N-Cyclopropyl-l-F3-(5-methylsulfonylpyridin-3-yl)1phenyl1-l,4- dihvdroF 1 ,81naphth yridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 31C but substituting 3-bromo-5- methylsulfonylpyridine from Step 2 above for 3-(4-bromophenyl)pyridine, and N-cyclopropyl-1- [3-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide from Step 1 for N-isopropyl-l-[3-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the N-Cyclopropyl-l-[3-(5- methylsulfonylρyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDCI3) δ 0.71 (m, 2H), 0.90 (m, 2H), 3.03 (m, IH), 3.21 (s, 3H), 7.53 (m, IH), 7.60 (d, IH), 7.74 (s, IH), 7.80 (t, IH), 7.86 (d, IH), 8.45 (m, IH), 8.74 (m, IH), 8.86 (d, IH), 9.09 (s, IH), 9.20 (d, 2H), 9.78 (br, NH).
EXAMPLE 33C
N-C vclopropyl- 1 - { 3-F4-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-vHphenyl J - 1 ,4- dihvdroF 1 ,81naphthyridin-4-one-3-carboxamide
Step 1 : Methyl 2-bromoisonicotinate
To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Bull., 38:2446(1990)) (2.0g) in tetrahydrofuran (100ml) was added excess ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate and hexane to afford the Methyl 2-bromoisonicotinate ester as a colorless liquid.
Step 2 : 2-Bromo-4-( 1 -hydroxy- 1 -methylethvDpyridine
Following the procedure of Step 1 of Example 25C, but substituting methyl 2- bromoisonicotinate from Step 1 for ethyl 5-bromonicotinate, the 2-Bromo-4-(l -hydroxy- 1- methylethy pyridine compound was obtained as a white solid.
Step 3: 2-Bromo-4-(l-hydroxy-l-methylethyl)pyridine-N-oxide
Following the procedure of Step 2 of Example 30C but substituting 2-bromo-4- (1 -hydroxy- l-methylethyl)pyridine from Step 2 for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine the 2-Bromo-4-(l -hydroxy- l-methylethyl)pyridine-N-oxide compound was obtained as a white solid. Step 4: N-Cvclopropyl-l-{3-F4-(l-hvdroxy-l-methylethyl)-l-oxidopyridin-2-yllphenyl}-l,4- dihvdrori.81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 2-bromo-4- (l-hydroxy-l-methylethyl)pyridine-N-oxide from Step 3 for 3-bromo-5-methylsulfonylpyridine, the N-Cyclopropyl- 1 - { 3- [4-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a beige solid.
1H NMR (DMSO-dβ) δ 0.57 (m, 2H), 0.79 (m, 2H), 1.45 (s, 6H), 2.90 (m, IH), 5.35 (s, IH, OH), 7.48 (m, IH), 7.64 (m, IH), 7.72 (m, 3H), 8.11 (m, 2H), 8.30 (d, IH), 8.72 (dd, IH), 8.78 (m, IH), 8.82 (s, IH), 9.72 (br, NH).
EXAMPLE 34C
N-Cyclopropyl-l-(3-F5-(l-hvdroxy-l-methylethyl)pyridin-2-yl1phenyll 1,4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 2-Bromo-5-(l-hydroxy-l-methylethyl)pyridine
A solution of 2,5-dibromopyridine in diethyl ether (5ml/mmol) was cooled to - 78°C, and n-butyllithium 2.5M in hexanes (1.05eq) was added slowly. After 2h in the cold, acetone (1.3eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product from the organic phase was triturated with 1:1 ether-hexane and filtered to afford the 2-Bromo-5-(l -hydroxy- 1- methylethy pyridine compound as a solid.
Step 2: N-Cvclopropyl-l-l3-F5-(l-hvdroxy-l-methylethyl)pyridin-2-vnphenyl}-1.4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 2-bromo-5- (1 -hydroxy- l-methylethyl)pyri dine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N- Cyclopropyl- 1 - { 3-[5-( 1 -hydroxy- 1 -methylethyl)pyridin-2-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid. Η NMR (CDCI3) δ 0.71 (m, 2H), 0.90 (m, 2H), 1.68 (s, 6H), 1.85 (s, IH, OH), 3.04 (m, IH), 7.45-7.52 (m, 2H), 7.71 (t, IH), 7.79 (d, IH), 7.95 (dd, IH), 8.16 (s, IH), 8.20 (d, IH), 8.72 (m, IH), 8.80-8.87 (m, 2H), 9.12 (s, IH), 9.82 (br, NH).
EXAMPLE 35C
N-Cvclopropyl-l-{ 3-F3-(l-hvdroxy-l-methylethyl)pyridin-4-yl1phenyl J-l ,4-dihydro Fl,81naphthyridin-4-one-3-carboxamide
Step 1 : 4-Bromo-2-(l-hvdroxy-l-methylethyl)pyridine
Following the sequence described in Steps 1-2 of Example 33C, but substituting 4-bromopicolinic acid (Aust. J. Chem. 24:390(1971)) for 2-bromoisonicotinic acid in Step 1, the 4-Bromo-2-(l -hydroxy- l-methylethyl)pyri dine compound was obtained as a white solid.
Step 2: N-Cyclopropyl- 1-{ 3-F3-(l-hvdroxy-l-methylethyl)pyridin-4-yl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 4-bromo-2- (1 -hydroxy- l-methylethyl)pyri dine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N- Cyclopropyl-l-{3-[3-(l-hydroxy-l-methylethyl)pyridin-4-yl]phenylJ-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a beige solid.
1H NMR (DMSO-de) δ 0.57 (m, 2H), 0.78 (m, 2H), 1.48 (s, 6H), 2.91 (m, IH), 5.27 (s, IH, OH), 7.62-7.66 (m, 2H), 7.72 7.79 (m, 2H), 8.01 (m, IH), 8.10 (s, IH), 8.58 (d, IH), 8.73-8.79 (m, 2H), 8.84 (s, IH), 9.73 (br, NH).
EXAMPLE 36C
Synthesis of N-Cvclopropyl-l-{ 3-F3-(l-hvdroxy-l-methylethyl)-l-oxidopyridin-4-yl1phenylJ- l,4-dihydroF1.81naphthyridin-4-one-3-carboxamide
Step 1 : 4-Bromo-2-( 1 -hydroxy- 1 -methylethvDpyridine N-oxide
Following the procedure of Step 2 of Example 30C, but substituting 4-bromo-2- (l-hydroxy-l-methylethyl)pyridine from Step 1 of Example 35C for 5-bromo-2-(l-hydroxy-l- methylethyl) pyridine, the 4-Bromo-2-(l-hydroxy-l-methylethyl)pyridine N-oxide compound was obtained as a white solid.
Step 2: N-Cvclopropyl-l-{3-F3-(l-hydroxy-l-methylethyl)-l-oxidopyridin-4-yl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 4-bromo-2- (1 -hydroxy- l-methylethyl)pyridine-N-oxide from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N-Cyclopropyl- 1 - { 3-[3-( 1 -hydroxy- 1-methylethyl)- 1 -oxidopyridin-4-yl]phenyl J - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a beige solid.
1H NMR (DMSO-de) δ 0.57 (m, 2H), 0.78 (m, 2H), 1.62 (s, 6H), 2.90 (m, IH), 6.99 (s, IH, OH), 7.65-7.84 (m, 4H), 7.94 (s, IH), 8.03 (dd, IH), 8.15 (s, IH), 8.38 (d, IH), 8.73-8.78 (m, 2H), 8.83 (s, IH), 9.73 (br, NH).
EXAMPLE 37C
N-Cyclopropyl- l-F3-(6-isopropylsulfonylpyridin-3-yl)1phenvn-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Step 1: 5-Bromo-2-isopropylthiopyridine
To a mixture of 2,5-dibromopyridine (2.07g, 8.73mmol) and 2-propanethiol (0.97ml, 10.4mmol) in N,N-dimethylformamide (20ml) at 0°C was added portionwise sodium hydride 60% dispersed in oil (450mg, 11.3mmol). The resulting mixture was stirred at room temperature for 1 hour, then partitioned between ether and water. The crude product from the organic phase was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to afford the 5-Bromo-2-isopropylthiopyridine compound as a solid.
Step 2: 5-Bromo-2-isopropylsulfonylpyridine To a solution of 5-bromo-2-isopropylthiopyridine from Step 1 (2.03g, 8.75mmol) in tetrahydrofuran (50ml) and methanol (25ml) at 0°C was added oxone (15.8g, 25.8mmol) and then saturated aqueous sodium bicarbonate (25ml). The resulting mixture was stirred at room temperature for 6 hours. The mixture was quenched with aqueous sodium bicarbonate and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-Bromo-2- isopropylsulfonylpyridine compound as a white solid.
Step 3: N-Cyclopropyl-l-F3-(6-isopropylsulfonylpyridin-3-yl)1phenyll-l,4- dihydrof 1 ,81naphthyridin-4-one-3-carboxamide Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- isopropylsulfonylpyridine from Step 2 for 3-bromo-5-methylsulfonylpyridine, the N-
Cyclopropyl-l-[3-(6-isopropylsulfonylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide compound was obtained as a solid.
Η NMR (CDC13) δ 0.70 (m, 2H), 0.89 (m, 2H), 1.39 (d, 6H), 3.00 (m, IH), 3.82 (m, IH), 7.51 (m, IH), 7.60 (d, IH), 7.72 (s, IH), 7.80 (t, IH), 7.83 (d, IH), 8.15-8.24 (m, 2H),
8.72 (m, IH), 8.86 (dd, IH), 9.03 (s, IH), 9.10 (s, IH), 9.77 (br, NH).
EXAMPLE 38C
N-Cvclopropyl-l-F3-(6-methoxypyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 5-Bromo-2-methoxypyridine
To a solution of 2,5-dibromopyridine (6.95g, 29mmol) in N,N- dimethylformamide (5ml) was added methanol (3.56ml) and IM potassium tert-butoxide
(32.3ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting slurry was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ether and hexane to afford the 5- Bromo-2-methoxypyridine compound as an oil.
Step 2: N-Cyclopropyl-l-F3-(6-methoxypyridin-3-yl)phenyll-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- methoxypyridine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N-cyclopropyl-l-[3-(6- methoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 0.71 (m, 2H), 0.89 (m, 2H), 3.00 (m, IH), 4.00 (s, 3H), 6.85 (d, IH), 7.44 (d, IH), 7.50 (m, IH), 7.62 (s, IH), 7.68 (t, IH), 7.73 (d, IH), 7.83 (dd, IH), 8.44 (s, IH), 8.73 (m, IH), 8.85 (dd, IH), 9.10 (s, IH), 9.82 (br, NH).
EXAMPLE 39C
N-Cvclopropyl-l-F3-(6-methylpyridin-3-yl)phenyll-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- methylpyridine from Step 1 of Example 28C for 3-bromo-5-methylsulfonylpyridine, the title compound was obtained as a solid.
1H NMR (CDC13) δ 0.72 (m, 2H), 0.90 (m, 2H), 2.65 (s, 3H), 3.03 (m, IH), 7.28 (d, IH), 7.45-7.53 (m, 2H), 7.66 (s, IH), 7.72 (t, IH), 7.80 (d, IH), 7.84 (dd, IH), 8.73 (m, IH), 8.80 (s, IH), 8.86 (dd, IH), 9.11 (s, IH), 9.82 (br, NH).
EXAMPLE 40C
N-Cvclopropyl-l-{3-F6-(2,2,2-trifluoroethoxy)pyridin-3-yllphenyl}-l,4-dihvdro F 1 ,81naphthyridin-4-one-3-carboxamide
Step 1 : 5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine
Following the procedure of Step 1 of Example 38C, but substituting 2,2,2- trifluoroethanol for methanol, with heating at 70°C for 18 hours, the 5-Bromo-2-(2,2,2- trifluoroethoxy)pyridine compound was obtained as an oil.
Step 2: N-Cvclopropyl-l-<3-F6-(2.2.2-trifluoroethoxy')pyridin-3-yl1phenyl 1-1.4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- (2,2,2-trifluoroethoxy)pyridine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N- Cyclopropyl-l-{3-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide compound was obtained as a solid.
Η NMR (CDC13) δ 0.72 (m, 2H), 0.90 (m, 2H), 3.03 (m, IH), 4.85 (q, 2H), 7.00 (d, IH), 7.43-7.53 (m, 2H), 7.62 (s, IH), 7.69-7.78 (m, 2H), 7.92 (dd, IH), 8.42 (s, IH), 8.73 (m, IH), 8.85 (dd, IH), 9.10 (s, IH), 9.80 (br, NH).
EXAMPLE 41C
N-Cvclopropyl-l-F3-(5-bromopyridin-3-yl)phenyl1-l,4-dihydrori,8]naphthyridin-4-one-3- carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 3,5- dibromopyridine for 3-bromo-5-methylsulfonylpyridine, the title compound was obtained as a white solid.
Η NMR (DMSO-d6) δ 0.58 (m, 2H), 0.79 (m, 2H), 2.90 (m, 1H), 7.65 (m, IH), 7.71-7.77 (m, 2H), 8.03 (d, IH), 8.14 (s, IH), 8.49 (s, IH), 8.74 (brs, IH), 8.79 (brs, IH), 8.86 (s, 1H), 9.01 (s, IH), 9.73 (br, NH). EXAMPLE 42C
N-Cvclopropyl-l-F3-(6-benzyloxypyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 2-Benzyloxy-5-bromopyridine
A mixture of 2,5-dibromopyridine, benzyl alcohol (1.3eq), potassium hydroxide pellets (2.4eq) and dibenzo-18-crown-6 (0.05eq) in toluene (4ml/mmol) was refluxed with azeotropic removal of water for 3 hours. After evaporation of the toluene, the resulting mixture was partitioned between chloroform and water. The crude product from the organic phase was recrystallized from ether-hexane to afford the 2-Benzyloxy-5-bromopyridine compound as a solid.
Step 2: N-Cvclopropyl-l-[3-(6-benzyloxypyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4- , one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 2-benzyloxy- 5-bromopyridine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N-Cyclopropyl-l-[3-(6- benzyloxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (DMSO-de) δ 0.57 (m, 2H), 0.79 (m, 2H), 2.91 (m, IH), 5.42 (s, 2H) 7.00 (d, IH), 7.32-7.48 (m, 5H), 7.61-7.72 (m, 3H), 7.90 (d, IH), 7.99 (s, IH), 8.14 (d, IH), 8.59 (s, IH), 8.73-8.84 (m, 3H), 9.73 (br, NH).
EXAMPLE 43C
N-Cvclopropyl-l-{3-F6-dicvclopropyl(hvdroxy)methyl-l-oxidopyridin-3-yl1phenyl 1-1.4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 5-Bromo-2-dicvclopropyl(hvdroxy)methylpyridine N-oxide
Following the procedure of Steps 1 and 2 of Example 30C, but substituting dicyclopropyl ketone for acetone in Step 1, the 5-Bromo-2- dicyclopropyl(hydroxy)methylpyridine N-oxide compound was obtained as a solid.
Step 2: N-Cyclopropyl- 1-{ 3-F6-dicvclopropyl(hvdroxy)methyl-l-oxidopyridin-3-yl1phenyl 1- l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- dicyclopropyl(hydroxy)methylpyridine N-oxide from Step 1 for 3-bromo-5- methylsulfonylpyridine, the N-Cyclopropyl-l-{3-[6-dicyclopropyl(hydroxy)methyl-l- oxidopyridin-3-yl]phenyl }-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (CDC13) δ 0.52 (m, 4H), 0.70 (m, 4H), 0.76 (m, 2H), 0.89 (m, 2H), 1.35
(m, 2H), 3.02 (m, IH), 7.52 (m, IH), 7.58 (m, IH), 7.62 (dd, IH), 7.68 (s, IH), 7.73-7.80 (m, 3H), 8.15 (br, IH, OH), 8.49 (s, IH), 8.72 (m, IH), 8.85 (dd, IH), 9.09 (s, IH), 9.78 (br, NH).
EXAMPLE 44C
N-Cvclopropyl-l-(3-15-(l-hvdroxy-l-methylethyl)-l-oxidopyridin-2-y11phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 2-Bromo-5-( 1 -hydroxy- l-methylethvDpyri dine N-oxide
Following the procedure of Step 2 of Example 30, but substituting 2-bromo-5-(l- hydroxy-l-methylethyl)pyridine from Step 1 of Example 34C for 5-bromo-2-(l -hydroxy- 1- methylethyl) pyridine, the 2-Bromo-5-(l -hydroxy- l-methylethyl)pyri dine N-oxide compound was obtained as a white solid. Step 2: N-Cvclopropyl-l-(3-[5-(l-hydroxy-l-methylethyl)-l-oxidopyridin-2-yl1phenyl }-l,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 2-bromo-5- (1 -hydroxy- l-methylethyl)pyri dine N-oxide from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N-Cyclopropyl- 1 - { 3-[5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 0.69 (m, 2H), 0.88 (m, 2H), 1.63 (s, 6H), 2.20 (s, IH, OH), 2.98 (m, IH), 7.38-7.49 (m, 3H), 7.52 (d, IH), 7.70 (t, IH), 7.98-8.04 (m, 2H), 8.50 (s, IH), 8.69 (m, IH), 8.80 (dd, IH), 9.08 (s, IH), 9.75 (br, NH).
EXAMPLE 45C
N-Cvclopropyl-l-(3-F6-(l-hvdroxy-l-methylethyl)pyridin-3-yl1phenyl l-l,4-dihvdro Fl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- (1-hydroxy-l-methylethyl) pyridine from Step 1 of Example 30C for 3-bromo-5- methylsulfonylpyridine, the title compound was obtained as a solid. Η NMR (CDC13) δ 0.72 (m, 2H), 090 (m, 2H), 1.62 (s, 6H), 3.02 (m, IH), 4.85
(s, IH, OH), 7.48-7.53 (m, 3H), 7.68 (s, IH), 7.73 (t, IH), 7.80 (d, IH), 7.95 (dd, IH), 8.72 (m, IH), 8.81 (s, IH), 8.86 (dd, IH), 9.10 (s, IH), 9.78 (br, NH).
EXAMPLE 46C
N-Isobutyl-l-{3-F6-(l-hvdroxy-l-methylethyl)pyridin-3-vnphenyl l-l,4-dihvdro Fl,81naphthyridin-4-one-3-carboxamide
Step 1: 5-(3-Aminophenyl)- 2-(l -hydroxy- 1 -methylethyl) pyridine Following the procedure of Step 5 of Example IC, but substituting 3- aminophenylboronic acid for 3-acetyl phenylboronic acid and 5-bromo-2-( 1 -hydroxy- 1- methylethyl)pyridine from Step 1 of Example 30C for N-isopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the 5-(3-Aminophenyl)- 2-( 1 -hydroxy- 1- methylethyl) pyridine compound was obtained as a solid.
Step 2: l-{3-F6-(l-Hvdroxy-l-methylethyl)pyridin-3-yl1phenyll-1.4-dihvdroFl,81naphthyridin- 4-one-3-carboxylic acid
Following the procedures of Steps 1-3 of Example IC, but substituting 5-(3- aminophenyl)- 2-(l -hydroxy- l-methylethyl)pyri dine for 3-bromoaniline from Step 1 in the First Step, the l-{3-[6-(l-Hydroxy-l-methylethyl)pyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxylic acid compound was obtained as a solid.
Step 3 : N-Isobutyl- 1 - { 3-f6-( 1 -hvdroxy-l-methylethyl)pyridin-3-yl1phenyl 1-1.4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 4 of Example IC, but substituting the acid from Step 2 for l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid, and isobutylamine for isopropylamine, the N-Isobutyl-l-{3-[6-(l-hydroxy-l-methylethyl)pyridin-3- yl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a cream-colored solid.
1H NMR (Acetone-d*) δ 0.98 (d, 6H), 1.53 (s, 6H), 1.88 (m, IH), 3.26 (t, 2H), 4.66 (s, IH, OH), 7.60 (m, IH), 7.69 (d, IH), 7.76-7.79 (m, 2H), 7.95 (d, IH), 8.05 (s, IH), 8.16
(dd, IH), 8.73 (m, IH), 8.79 (dd, IH), 8.90 (s, IH), 8.94 (s, IH), 9.83 (br, NH).
EXAMPLE 47C
N-Cvclopropyl-l-{5-bromo-3-F6-(l-hvdroxy-l-methylethyl)pyridin-3-yl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: l-(3,5-Dibromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxylic acid
Following the procedures of Steps 1-3 of Example IC, but substituting 3,5- dibromoaniline for 3-bromoaniline in Step 1, the l-(3,5-Dibromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxylic acid compound was obtained as a beige solid. Step 2: N-Cvclopropyl-l-(3,5-dibromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 4 of Example IC, but substituting the l-(3,5- Dibromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid from Step 1 for l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid, and cyclopropylamine for isopropylamine, the N-Cyclopropyl-l-(3,5-dibromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one- 3-carboxamide compound was obtained as a solid.
Step 3: 2-(l-Hydroxy-l-methylethyl)-5-tributylstannylpyridine To a suspension of 2,5-dibromopyridine in toluene (5ml/mmol) at -78°C, was added n-butyllithium 2.5M in hexanes (leq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (leq) was added, and the mixture was warmed to -50°C and became a brown solution. After cooling down to -78°C, more n-butyllithium (leq) was added along with ether (2ml/mmol). After stirring in the cold for a further hour, tributyltin chloride (l.leq) was added and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 2-( 1 -Hydroxy- 1- methylethyl)-5-tributylstannylpyridine compound as a colorless liquid.
Step 4: N-Cyclopropyl- 1 - { 5-bromo-3- F6-( 1 -hydroxy- 1 -meth ylethyl)pyridin-3-yl1phenyl } - 1 ,4- dihydroFl,81naphthyridin-4-one-3-carboxamide
A mixture of N-cyclopropyl-l-(3,5-dibromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 2, 2-(l-hydroxy-l-methylethyl)-5- tributylstannylpyridine from Step 3 (1.4eq), l,l'-bis (diphenylphosphino)ferrocene]dichloro- palladium(II) (0.05eq), and cuprous iodide (0.05eq) in N,N-dimethylformamide (15ml/mmol) was stirred at 85°C for 5 hours. After cooling the resulting mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:6:3 mixture of ethanol, ethyl acetate and methylene chloride to afford the N-Cyclopropyl- 1 - { 5-bromo-3-[6-(l -hydroxy- 1 -methylethyl)pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as a solid. Η NMR (CDCI3) δ 0.72 (m, 2H), 0.90 ( , 2H), 1.62 (s, 6H), 3.02 (m, IH), 4.76 (s, IH, OH), 7.50-7.56 (m, 2H), 7.62 (s, IH), 7.69 (s, IH), 7.90-7.96 (m, 2H), 8.74 (m, IH), 8.79 (s, IH), 8.86 (dd, IH), 9.07 (s, IH), 9.74 (br, NH).
EXAMPLE 48C
N-Cvclopropyl-l-(3-F6-(l-hydroxy-l-methylethyl)pyridin-2-yl1phenyll-l,4-dihvdro Fl,81naphthyridin-4-one-3-carboxamide
Step 1: 2-(l -Hydroxy- l-methylethyl)-6-tributylstannylpyridine
Following the procedure of Step 3 of Example 47C, but substituting 2,6- dibromopyridine for 2,5-dibromopyridine, the 2-(l -Hydroxy- l-methylethyl)-6- tributylstannylpyridine compound was obtained.
Step 2: N-Cvclopropyl-l-|3-F6-(l-hvdroxy-l-methylethyl)pyridin-2-yl1phenyl 1-1,4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 4 of Example 47C, but substituting 2-(l- hydroxy-l-methylethyl)-6 tributylstannyl pyridine from Step 1 for 2-(l -hydroxy- 1-methylethyl)-
5-tributylstannylpyridine, the N-Cyclopropyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl )pyridin-2- yl]phenyl }-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDCI3) δ 0.72 (m, 2H), 0.90 (m, 2H), 1.61 (s, 6H), 3.04 (m, IH), 5.13
(s, IH, OH), 7.40 (d, IH), 7.46-7.53 (m, 2H), 7.70-7.76 (m, 2H), 7.85 (t, IH), 8.13 (s, IH), 8.22
(d, IH), 8.73 (m, IH), 8.87 (d, IH), 9,12 (s, IH), 9.83 (br, NH).
EXAMPLE 49C
N-Isopropyl-l-F3-(4-methylsulfonylphenyl)phenyl1-1.4-dihydrori,81naphthyridin-4-one-3- carboxamide
To a mixture of N-isopropyl- l-[3-(4-methylthiophenyl)phenyl]- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 22C in tetrahydrofuran (24ml/mmol), methanol (12ml/mmol), and water (12ml/mmol), was added oxone (2.24eq) and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 30% ether in methylene chloride to afford the title compound as a white solid.
1H NMR (Acetone-d6) δ 1.25 (d, 6H), 3.16 (s, 3H), 4.18 (m, IH), 7.60 (m, IH), 7.74 (d, IH), 7.79 (t, IH), 7.99 (d, IH), 8.05 (s, 4H), 8.09 (s, IH), 8.72 (m, IH), 8.78 (dd, IH), 8.93 (s, IH), 9.64 (br, NH).
EXAMPLE 50C
N-Cvclopropyl-l-F3-(6-methylsulfonylpyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4-one- 3-carboxamide
Step 1: 5-Bromo-2-methylthiopyridine
A mixture of 2,5-dibromopyridine and sodium thiomethoxide (1.3eq) in N,N- dimethylformamide (2ml/mmol) was stirred at room temperature for 20 minutes then cooled to 0°C. After diluting with cold water the precipitate was filtered to afford the 5-Bromo-2- methylthiopyridine compound as a solid.
Step 2: N-Cyclopropyl-l-F3-(6-methylthiopyridin-3-yl)phenyl1-l,4-dihydroFl,81naphthyridin-4- one-3-carboxamide Following the procedure of Step 3 of Example 32C, but substituting 5-bromo-2- methylthiopyridine from Step 1 for 3-bromo-5-methylsulfonylpyridine, the N-Cyclopropyl-l-[3- (6-methylthiopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
Step 3: N-Cvclopropyl-l-F3-(6-methylsulfonylpyridin-3-yl)ρhenyll-l,4- dihydroF 1.81naphthyridin-4-one-3-carboxamide
Following the procedure of Example 49C, but substituting N-cyclopropyl-l-[3- (6-methylthiopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 2 for N-isopropyl-l-[3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide, the N-Cyclopropyl-l-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.97 (m, IH), 3.26 (s, 3H), 7.48 (m, IH), 7.55 (d, IH), 7.67 (s, IH), 7.74-7.80 (m, 2H), 8.14-8.19 (m, 2H), 8.68 (m, IH), 8.81 (dd, IH), 8.96 (s, IH), 9.05 (s, IH), 9.73 (br, NH).
EXAMPLE 5 IC
N-Isopropyl-l-F3-(5-methylsulfonylpyridin-3-yl)phenyl1-l,4-dihvdro[l,81naphthyridin-4-one-3- carboxamide
Following the procedure of Example 49C, but substituting N-isopropyl- 1-[3-(5- methylthiopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 15C for N-isopropyl-l-[3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDCI3) δ 1.33 (d, 6H), 3.20 (s, 3H), 4.31 (m, IH), 7.52 (m, IH), 7.60 (d, IH), 7.73 (s, IH), 7.79 (t, IH), 7.86 (d, IH), 8.48 (m, IH), 8.73 (m, IH), 8.88 (d, IH), 9.08 (s, IH), 9.19 (d, 2H), 9.68 (br, NH).
EXAMPLE 52C
N-Cvclopropyl-l-F3-(4-ethylsulfonylphenyl)phenyl1-l,4-dihydroFl,8]naphthyridin-4-one-3- carboxamide
Following the procedure of Example 49C, but substituting N-cyclopropyl-l-[3- (4-ethylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 18C for N-isopropyl-l-[3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide, the title compound was obtained as a solid. 1H NMR (CDCI3) δ 0.72 (m, 2H), 0.90 (m, 2H), 1.35 (t, 3H), 3.02 (m, IH), 3.18
(q, 2H), 7.48-7.56 (m, 2H), 7.70 (s, IH), 7.75 (t, IH), 7.84 (m, 3H), 8.03 (d, 2H), 8.73 (m, IH), 8.85 (dd, IH), 9.10 (s, IH), 9.80 (br, NH).
EXAMPLE 53C
N-Cvclopropyl-l-F3-(4-ethylsulfinylphenyl)phenyl1-l,4-dihvdroFl,8]naphthyridin-4-one-3- carboxamide
To a solution of N-cyclopropyl-l-[3-(4-ethylthiophenyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 18C, in a 1:1 mixture of methylene chloride and methanol (9ml/mmol), was added at 0°C magnesium monoperoxyphthalate hexahydrate (MMPP, 0.5molareq) and the resulting mixture was stirred in the cold for 2 hours. The mixture was quenched with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 90:9:1 mixture of methylene chloride, ethanol and 28% aqueous ammonium hydroxide to afford the title compound as a solid.
1H NMR (CDCI3) δ 0.68 (m, 2H), 0.85 (m, 2H), 1.15 (m, 3H), 2.80 (m, IH), 2.94 (m, IH), 2.98 (m, IH), 7.45-7.50 (m, 2H), 7.65-7.73 (m, 4H), 7.76-7.82 (m, 3H), 8.71 (m, IH), 8.83 (dd, IH), 9.06 (s, IH), 9.78 (br, NH). EXAMPLE 54C
N-Isopropyl-l-(3-F4-(l-oximidoethyl)phenyl1phenyl}-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
To a solution of N-isopropyl-l-[3-(4-acetylphenyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 4C in pyridine (llml/mmol) at room temperature was added hydroxylamine hydrochloride (2. leq) and the resulting mixture was stirred for 16 hours. The mixture was filtered through celite and the filtrate evaporated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium carbonate and then water, dried and evaporated. The residue was stirred in a small volume of acetone and filtered to afford the title compound as a solid.
1H NMR (CDC13) δ 1.29 (d, 6H), 2.27 (s, 3H), 4.30 (m, IH), 7.39 (d, IH), 7.46 (m, IH), 7.56 (d, 2H), 7.59-7.63 (m, 2H), 7.66 (d, 2H), 7.72 (d, IH), 8.17 (s, IH, OH), 8.69 (brs, IH), 8.82 (d, IH), 9.10 (s, IH), 9.71 (br, NH).
EXAMPLE 55C
N-Isopropyl-l-{3-F 4-(4-piperazin-l-yl)phenyl1-phenyl }-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
To a solution of N-isopropyl-l-{3-[ 4-(4-tertbutyloxycarbonylpiperazin-l- yl)phenyl]-phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 11C in methylene chloride (lOml/mmol) was added trifluororacetic acid (6ml/mmol) and the resulting mixture was stirred at room temperature for 2 hours, then warmed gently for 15 minutes. The mixture was evaporated and the crude product was chromatographed on silica gel eluting with a 9:0.9:0.1 mixture of methylene chloride, methanol and 28% aqueous ammonium hydroxide to afford the title compound as a solid.
1H NMR (CDC13) δ 1.29 (d, 6H), 2.99 (m, 4H), 3.16 (m, 4H), 4.25 (m, IH), 6.94 (d, 2H), 7.29 (d, IH), 7.42 (m, IH), 7.50 (d, 2H), 7.52-7.58 (m, 2H), 7.69 (d, IH), 8.66 ( , IH), 8.78 (dd, IH), 9.04 (s, IH), 9.69 (br, NH). EXAMPLE 56C
N-Cvclopropyl-l-F3-(4-methylsulfonylmethylphenyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Step 1: N-Cvclopropyl-l-F3-(4-bromomethylphenyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
A mixture of N-cyclopropyl-l-[3-(4-hydroxymethylphenyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 16C, carbon tetrabromide (2eq), and diphos (0.6 molareq) in methylene chloride (15ml/mmol) was stirred at room temperature for 3 hours. The mixture was concentrated at room temperature and chromatographed on silica gel eluting with a 1: 1 mixture of ethyl acetate and methylene chloride to afford the N- Cyclopropyl-l-[3-(4-bromomethylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound.
Step 2: N-Cvclopropyl-l-F3-(4-methylsulfonylmethylphenyl)phenyl1-l,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
To a solution of N-Cyclopropyl-l-[3-(4-bromomethylphenyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 1 in N,N-dimethylformamide
(20ml/mmol) was added methanesulfinic acid sodium salt (1.3eq) and the resulting mixture was stirred at room temperature for 18 hours. To the mixture was added saturated aqueous ammonium chloride solution and ethyl acetate, and the insoluble solid was filtered and washed well with water, hexane, ether and ethyl acetate to afford the title compound as a solid. 1H NMR (CDC13) δ 0.72 (m, 2H), 0.89 (m, 2H), 2.85 (s, 3H), 3.04 (m, IH), 4.34
(s, 2H) 7.46-7.52 (m, 2H), 7.55 (d, 2H), 7.65-7.73 (m, 4H), 7.80 (d, IH), 8.76 (m, IH), 8.85 (d, IH), 9.12 (s, lH), 9.82 (br, NH). EXAMPLE 57
N-Cvclopropyl-l-F3-(l,6-dihvdro-6-oxopyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
To a solution of N-cyclopropyl-l-[3-(6-benzyloxypyridin-3-yl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 42C in 1,2-dichloroethane (25ml/mmol) was added trifluoroacetic acid (1.5ml/mmol) and the resulting mixture was stirred at 60°C for 18 hours. More trifluoroacetic acid was added (0.75ml/mmol) and heating was continued for a further 24 hours. The cooled mixture was diluted with methylene chloride and saturated aqueous sodium bicarbonate was added, resulting in precipitation of a solid which was filtered. From the filtrate the organic phase was collected and evaporated to a solid which was combined with the previous filtered solid. This mixture was chromatographed on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a white fluffy solid.
1H NMR (DMSO-d6) δ 0.57 (m, 2H), 0.78 (m, 2H), 2.90 (m, IH), 6.45 (d, IH), 7.52 (m, IH), 7.61-7.65 (m, 2H), 7.78 (d, IH), 7.85 (s, IH), 7.89-7.93 (m, 2H), 8.74 (d, IH), 8.78-8.81 (m, 2H), 9.73 (br, NH), other NH >1 lppm.
EXAMPLE 58C
N-Cvclopropyl-l-FF3-|5-F6-(l-hvdroxy-l-methylethyl)pyridin-3-yl1pyridin-3-yllphenyl11-l,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 4 of Example 47C, but substituting N- cyclopropyl-l-[3-(5-bromopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide from Example 41C for N-cyclopropyl-l-(3,5-dibromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a white solid. Η NMR (DMSO-de) δ 0.58 (m, 2H), 0.79 (m, 2H), 2.91 (m, IH), 5.30 (s, IH, OH), 7.65 (m, IH), 7.71-7.79 (m, 3H), 8.12 (d, IH), 8.23-8.26 (m, 2H), 8.49 (s, IH), 8.75 (dd, IH), 8.80 (m, IH), 8.87 (s, IH), 8.97 (m, 2H), 9.04 (s, IH), 9.74 (br, NH).
EXAMPLE 59C
N-Isopropyl-l-F3-(l-oxidopyridin-3-yl)phenyl1-l-4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 30, but substituting N-isopropyl- 1 -
[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 7C for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a white solid.
Η NMR (DMSO-de) δ 1.21 (d, 6H), 4.10 (m, IH), 7.51 (t, IH), 7.64 (m, IH), 7.71-7.75 (m, 3H), 7.97 (m, IH), 8.09 (s, IH), 8.23 (d, IH), 8.69-8.77 (m, 3H), 8.84 (s, IH), . 9.66 (br, NH).
EXAMPLE 60C
N-(2,6-Dichloropyridin-4-yl)-l-F3-(l-oxidopyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N-(2,6- dichloropyridin-4-yl)-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide from Example 10 for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a white solid.
Η NMR (DMSO-d6) δ 7.51 (m, IH), 7.69-7.78 (m, 4H), 7.99 (dd, IH), 8.14 (s, IH), 8.24 (dd, IH), 8.70 (s, IH), 8.73 (s, 2H), 8.84 (m, 2H), 8.99 (s, IH), 12.05 (br, NH). EXAMPLE 6 IC
N-Isopropyl-l-F3-(5-carboethoxy-l-oxidopyridin-3-yl)phenyl1-l,4-dihvdro[l,81naphthyridin-4- one-3-carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N-isopropyl- l-[3-(5-carboethoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 24C for 5-bromo-2-(l-hydroxy-l-methylethyl)pyridine, the title compound was obtained as a white solid. 1H NMR (CDC13) δ 1.28 (d, 6H), 1.40 (t, 3H), 4.28 (m, IH), 4.43 (q, 2H), 7.49
(dd, IH), 7.56 (m, IH), 7.68 (s, IH), 7.73 (d, 2H), 8.04 (s, IH), 8.60 (s, IH), 8.68 (dd, IH), 8.77 (s, IH), 8.82 (d, IH), 9.01 (s, IH), 9.61 (br, NH).
EXAMPLE 62C
N-Isopropyl- 1 - { 3-F5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yπphenyl 1-1-4- dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N-isopropyl- l-{3-[5-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide from Example 25C for 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine, the title compound was obtained as a white solid
1H NMR (CDC13) δ 1.29 (d, 6H), 1.60 (s, 6H), 4.11 (brs, IH), 4.23 (m, IH), 7.42- 7.51 (m, 2H), 7.58 (s, 2H) 7.65 (m, 2H), 8.28 (s, IH), 8.33 (s, IH), 8.64 (m, IH), 8.80 (d, IH), 8.98 (s, IH), 9.61 (br, NH). EXAMPLE 63C
N-Isopropyl-l-{3-F6-(2-methylpropyl)-l-oxidopyridin-3-yl1phenyll-l,4-dihydro F 1 ,8]naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 30, but substituting N-isopropyl- 1- { 3-[6-(2-methylpropyl)pyridin-3-yl]phenyl } - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide from Example 26C for 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine, the title compound was obtained as an off- white solid.
1H NMR (CDC13) δ 0.98 (d, 6H), 1.29 (d, 6H), 2.29 (m, IH), 2.32 (d, 2H), 4.26 (m, IH), 7.28 (d, IH), 7.38 (d, IH), 7.47-7.52 (m, 2H), 7.60 (s, IH), 7.69 (m, 2H), 8.53 (s, IH), 8.69 (m, IH), 8.82 (dd, IH), 9.03 (s, IH), 9.62 (br, NH).
EXAMPLE 64C
N-Isopropyl-l-F3-(6-methyl-l-oxidopyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 30, but substituting N-isopropyl-1-
[3-(6-methylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 28C for 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine, the title compound was obtained as an off-white solid.
1H NMR (CDCI3) δ 1.32 (d, 6H), 2.60 (s, 3H), 4.30 (m, IH), 7.35-7.45 (m, 2H), 7.50 (m, 2H), 7.62 (s, IH), 7.72 (d, 2H), 8.58 (s, IH), 8.72 (m, IH), 8.85 (dd, IH), 9.06 (s, IH), 9.66 (br, NH). EXAMPLE 65C
N-CvcIopropyl-l-F3-(l-oxidopyridin-3-yl)phenyll-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N- cyclopropyl-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 14C for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a white solid. 1H NMR (DMSO-d ) δ 0.57 (m, 2H), 0.78 (m, 2H), 2.90 (m, IH), 7.52 (t, IH),
7.65 (m, IH), 7.72-7.76 (m, 3H), 7.98 (m, IH), 8.10 (s, IH), 8.25 (d, IH), 8.70-8.79 (m, 3H), 8.85 (s, IH), 9.72 (br, NH).
EXAMPLE 66C
N-Cyclopropyl- 1 - { 3- F6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl 1 - 1 ,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 29C but substituting 5-bromo-2- (1 -hydroxy- 1 -methylethyl) pyridine N-oxide from Step 2 of Example 30C for 5-bromo-l- oxidopyrimidine, the title compound was obtained as a white solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.85 (m, 2H), 1.70 (s, 6H), 2.97 (m, IH), 7.43-7.49 (m, 2H), 7.52-7.56 (m, 2H), 7.61 (s, 2H) 7.71-7.74 (m, 2H), 8.49 (s, IH), 8.68 (m, IH), 8.80 (d, IH), 9.02 (s, IH), 9.74 (br, NH).
EXAMPLE 67C
N-Cvclopropyl-l-F3-(l-oxidopyridin-4-yl)phenvn-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N- cyclopropyl-l-[3-(pyridin-4-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 17C for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a white solid. 1H NMR (DMSO-de) δ 0.57 (m, 2H), 0.79 (m, 2H), 2.92 (m, IH), 7.62-7.70 (m,
2H), 7.75 (t, IH), 7.88 (d, 2H), 8.03 (d, IH), 8.15 (s, IH), 8.30 (d, 2H), 8.75 (d, IH), 8.80 (m, IH), 8.86 (s, IH), 9.73 (br, NH).
EXAMPLE 68C
N-Cvclopropyl-l-F3-(5-bromo-l-oxidopyridin-3-yl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one- 3-carboxamide
Following the procedure of Step 2 of Example 30, but substituting N-cyclopropyl- l-[3-(5-bromopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 41C for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a light yellow solid.
1H NMR (DMSO-de) δ 0.56 (m, 2H), 0.78 (m, 2H), 2.91 (m, IH), 7.65 (m, IH), 7.71-7.74 (m, 2H), 8.02-8.06 (m, 2H), 8.15 (s, IH), 8.60 (s, IH), 8.73-8.79 (m, 3H), 8.86 (s, IH), 9.73 (br, NH). EXAMPLE 69C
N-Cvclopropyl- 1 -FF3- { 5-F6-(l -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl1pyridin-3-yl 1 phenvπi-l-4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N- cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]pyridin-3-yl Jphenyl]]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 58 for 5-bromo-2-(l-hydroxy-l- methylethyl) pyridine, and using 1.6eq. of m-chloroperoxybenzoic acid, the title compound was obtained as a white solid.
1H NMR (DMSO-d6) δ 0.57 (m, 2H), 0.78 (m, 2H), 2.91 (m, IH), 6.94 (s, IH, OH), 7.65 (m, IH), 7.71-7.79 (m, 3H), 7.97 (dd, IH), 8.13 (d, IH), 8.25 (s, IH), 8.55 (s, IH), 8.74 (dd, IH), 8.80 (m, IH), 8.87 (s, IH), 8.91 (s, IH), 9.00 (s, IH), 9.09 (s, IH), 9.73 (br, NH).
EXAMPLE 70C
N-Cyclopropyl-1 -FF3- { 5-F6-( 1 -hydroxy- 1 -methylethyl)pyridin-3-yl1- 1 -oxidopyridin-3-yl 1 phenvin-1.4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
From the procedure of Example 69C, the title compound was also obtained as a white solid.
1H NMR (DMSO-de) δ 0.57 (m, 2H), 0.79 (m, 2H), 2.92 (m, IH), 5.32 (s, IH,
OH), 7.65 (m, IH), 7.72-7.80 (m, 3H), 8.08-8.17 (m, 2H), 8.27 (m, 2H), 8.70-8.82 (m, 4H), 8.88
(s, IH), 8.98 (s, IH), 9.73 (br, NH).
EXAMPLE 7 IC
N-Cyclopropyl- 1 -FF3- { 5-F6-(l -hydroxy- 1 -methylethyl)-l -oxidopyridin-3-yll- 1 -oxidopyridin-3- yl Jphenvin-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
From the procedure of Example 69C the title compound was also obtained as a white solid.
1H NMR (DMSO-de) δ 0.58 (m, 2H), 0.80 (m, 2H), 2.92 (m, IH), 6.85 (brs, IH, OH), 7.65 (m, IH), 7.70-7.80 (m, 3H), 7.96 (d, IH), 8.13 (m, 2H), 8.29 (s, IH), 8.71-8.84 (m, 4H), 8.89 (s, IH), 8.92 (s, IH), 9.73 (br, NH).
EXAMPLE 72C
N-Isopropyl-l-F3-(l-oxidoquinolin-3-yl)phenyll-l,4-dihydroFl,81naphthyridin-4-one- carboxamide
Following the procedure of Step 2 of Example 30, but substituting N-isopropyl- 1 - [3-(quinolin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-carboxamide from Example 12C for 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine, the title compound was obtained as a solid. 1H NMR (CDC13) δ 1.30 (d, 6H), 4.28 (m, IH), 7.49 (dd, IH), 7.54 (d, IH),
7.66-7.85 (m, 5H), 7.92 (m, 2H), 8.69-8.75 (m, 2H), 8.84 (d, IH), 8.86 (s, IH), 9.08 (s, IH), 9.64 (br, NH).
EXAMPLE 73C
N-Isobutyl- 1 - 13- F6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-vHphen yl } - 1 ,4-dihvdro Fl,81naphthyridin-4-one-3-carboxamide
To a mixture of N-isobutyl-l-{3-[6-(l-hydroxy-l-methylethyl)pyridin-3- yl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 46 in 13:1 methylene chloride/methanol (33ml/mmol) at room temperature was added magnesium monoperoxyphthalate hexahydrate (MMPP, 1.1 molareq) and the resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered through a bed of celite and the filtrate was washed with aqueous sodium carbonate, then water and dried. The crude product was chromatographed on silica gel eluting with 8% ethanol in ethyl acetate and the solid obtained was stirred at room temperature in ether for several hours and filtered to afford the title compound as a light pink solid. 1H NMR (Acetone-de) δ 0.98 (d, 6H), 1.61 (s, 6H), 1.88 (m, IH), 3.26 (t, 2H),
7.52 (s, IH, OH), 7.61 (m, IH), 7.66 (d, IH), 7.77-7.82 (m, 2H), 7.88 (d, IH), 7.99 (d, IH), 8.12 (s, IH), 8.68 (s, IH), 8.73 (m, IH), 8.80 (dd, IH), 8.93 (s, IH), 9.81 (br, NH).
EXAMPLE 74C
N-Cvclopropyl-l-F3-(6-methyl-l-oxidopyridin-3-yl)1phenyll-l,4-dihvdroFl,81naphthyridin-4- one-3-carboxamide
Following the procedure of Example 73, but substituting N-cyclopropyl-l-[3-(6- methylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 39C for N-isobutyl-l{ [3-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl }-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
Η NMR (CDC13) δ 0.72 (m, 2H), 0.91 (m, 2H), 2.61 (s, 3H), 3.02 (m, IH), 7.38 (d, IH), 7.45 (dd, IH), 7.49-7.58 ( , 2H), 7.66 (s, IH), 7.75 (m, 2H), 8.61 (s, IH), 8.72 (m, IH), 8.87 (dd, IH), 9.08 (s, IH), 9.78 (br, NH). EXAMPLE 75C
N-Cvclopropyl-l-F3-(6-methylsulfonyl-l oxidopyridin-3-yl)phenyl1-l,4-dihydro F 1 ,81naphthyridin-4-one-3-carboxamide
To a suspension of N-cyclopropyl-l-[3-(6-methylsulfonylpyridin-3-yl)phenyl]- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 51 in methylene chloride (30ml/mmol) was added urea-hydrogen peroxide (8eq) and the resulting mixture was cooled to 0°C. Trifluoroacetic acid (4.7eq) was added and the mixture was warmed to room temperature as a solution was obtained. After 18 hours, more urea-hydrogen peroxide (2.6eq) and trifluoroacetic acid (2eq) were added and stirring was continued for 2 hours. The mixture was quenched with saturated aqueous sodium metabisulfite, diluted with methylene chloride and the organic phase was washed with IN aqueous HC1, then brine and water, dried and evaporated. The crude product was chromatographed on silica gel eluting with 40% toluene in acetone to afford the title compound as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, IH), 3.52 (s, 3H), 7.48 (m, IH), 7.58-7.65 (m, 3H), 7.72-7-78 (m, 2H), 8.15 (d, IH), 8.54 (s, IH), 8.68 (brs, IH), 8.81 (d, IH), 9.01 (s, IH), 9.71 (br, NH).
EXAMPLE 76C
N-Cyclopropyl- 1 - 15-bromo-3- F6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yllphenyl 1-1.4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of Example 30C, but substituting N- cyclopropyl-l-{5-bromo-3-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from Example 47C for 5-bromo-2-(l-hydroxy- 1 -methylethyl) pyridine, the title compound was obtained as a solid.
1H NMR (CDC13) δ 0.71 (m, 2H), 0.90 (m, 2H), 1.75 (s, 6H), 3.02 (m, IH), 7.48-7.60 (m, 5H), 7.73 (s, IH), 7.88 (s, IH), 8.52 (s, IH), 8.72 (m, IH), 8.84 (dd, IH), 9.04 (s, lH), 9.71 (br, NH). EXAMPLE 77C
N-Cvclopropyl-l-|3-F6-(l,2-dihvdroxy-l-methylethyl)-l-oxidopyridin-3-yl1phenyll -l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide.
Step 1: 5-Bromo-2-(l-methylvinyl)pyridine N-oxide
A mixture of 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine N-oxide from step 2 of example 30 (1.29g) and 25% aqueous sulfuric acid was heated at 130°C for 2 days. After cooling, the mixture was made slightly basic using ION aqueous sodium hydroxide and partitioned between ethyl acetate and water. The crude product from evaporation of the organic phase was used as such in step 2.
Step 2: 5-bromo-2-(l,2-dihydroxy-l-methylethyl) pyridine N-oxide The crude product from step 1 was dissolved in a 3 : 1 mixture of acetone and water
(16mL) and 4-methylmorpholine N-oxide (lg) and potassium osmate dihydrate (90mg) were added. The resulting mixture was stirred at room temperature for 3 days then excess solid sodium bisulfite was added and the mixture was evaporated. The residue was diluted with methylene chloride and filtered. The filtrate was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate to afford the title compound as a white solid.
Step 3 : N-Cyclopropyl- 1 - { 3-F6-( 1 ,2-dihydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-vHphenyl } - l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide.
Following the procedure of step 2 of example 32 but substituting 5-bromo-2-(l,2- dihydroxy-1 -methylethyl) pyridine N-oxide from step 2 for 3-bromo-5-methylsulfonylpyridine the title compound was obtained as a white solid.
Η NMR (CDCI3) δ 0.66 (m, 2H), 0.85 (m, 2H), 1.61 (s, 3H), 2.78 (m, IH, OH), 2.97 (m, IH), 3.90 (m, IH), 3.97 (m, IH), 7.48 (m, IH), 7.53 ( , 2H), 7.60 (m, 2H), 7.69-7.72 (m, 2H), 7.92 (s, IH, OH), 8.49 (s, IH), 8.68 (m, IH), 8.80 (dd, IH), 9.02 (s, IH), 9.73 (br, NH). Referring to the formula below, Examples lD-33Dare summarized in TABLE ID below.
TABLE 1
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
EXAMPLE ID
N-Isopropyl-1-F 3-(phenylethvnyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.
A mixture of ethyl 2-chloronicotinoyl acetate (41. lg, 180.5mmol), triethyl orthoformate (40.12g, 271mmol) and acetic anhydride (92.05g, 902.5mmol) was heated at 130°C for 2.5 hours. The volatile components were distilled off and the resulting residue was co- evaporated twice with xylene. The oily residue was dissolved in methylene chloride (250mL) and 3-bromoaniline (37.25g, 216.6mmol) was added slowly. The resulting solution was stirred at room temperature for 18 hours, and the solvent evaporated away. The resulting crude compound was used as such in the next step.
Step 2: Ethyl l-(3-bromophenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxylate. The crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil , 9.4g, 235mmol) was added in portions. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm up to room temperature. After 2 hours, water (400mL) was added to the resulting suspension and the insoluble solid was filtered and washed copiously with water. When dry, the solid was stirred in ether (150mL) at room temperature for 24 hours and filtered to afford the ethyl l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate compound as a cream-colored solid.
1H NMR (Acetone-de) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, IH), 7.78 (dd, IH), 7.93 (s, IH), 8.66-8.71 (m, 3H).
Step 3: l-(3-Bromopheny1)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxylic acid.
A suspension of ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylate from Step 2 (52.5 g, 140.7mmol) in a mixture of tetrahydrofuran (400mL), methanol (400mL) and IN aqueous sodium hydroxide (280mL) was heated at ca 50°C with stirring for 20 minutes. After cooling, the mixture was diluted with water (300mL) and IN aqueous HC1
(325mL) was added. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylic acid as a cream-colored solid.
1H NMR (Acetone-do) δ 7.65 (t, IH), 7.76 (m, 2H), 7.84 (d, IH), 7.99 (s, IH), 8.87 (m, 2H), 9.01 (s, IH).
Step 4: N-Isopropyl-l-(3-bromophenyl)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxamide. To a suspension of 1 -(3-bromophenyl)- l,4-dihydro[l, 8]naphthyri din-4-one-3- carboxylic acid from Step 3 (26.3g, 76mmol) and triethylamine (23.2g, 230mmol) in tetrahydrofuran (lOOOmL) at 0°C was added isobutyl chloroformate (18.85g, 138mmol). After stirring at 0°C for 2 hours, isopropylamine (23g, 390mmol) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N- isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide as a white solid.
Η NMR (Acetone-d 6) δ 1.25 (d, 6H), 4.17 (m, IH), 7.59-7.63 (m, 2H), 7.70 (d, IH), 7.80 (d, IH), 7.94 (s, IH), 8.73 (m, IH), 8.78 (d, IH), 8.85 (s, IH), 9.61 (br, NH).
Step 5: N-Isopropyl-l-F(3-phenylethynyl)phenyl1-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide.
A mixture of amide from Step 4, phenylacetylene (1.9 eq), triethylamine (1.6 eq), triphenylphosphine (0.06 eq) and bis(triphenylphosphine)palladium (II) chloride (0.05 eq) in THF (lόmlJmmol) was stirred at room temperature for 20 minutes. Copper (I) iodide (5 mg/mmol) was added and the mixture was stirred at reflux for 18 hours. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the crude product was chromatographed on silica gel eluting with a 1:9 mixture of ether and methylene chloride to afford a solid which was stirred in ether at room temperature and filtered to yield the N-Isopropyl-l-[(3-phenylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound as a solid.
Η NMR (Acetone-dό) δ 1.24 (d, 6H), 4.18 (m, IH), 7.42 (m, 3H), 7.56-7.61 (m, 3H), 7.69 (m, 2H), 7.76 (m, IH), 7.85 (s, IH), 8.73 (m, IH), 8.77 (dd, IH), 8.88 (s, IH), 9.62 (br, NH).
EXAMPLE 2D
N-Isopropyl- l-F3-(2-pyri dinylethyn yl)phenyl1-l, 4-dihydroFl, 81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting 2- ethynylpyridine for phenylacetylene, the title compound was obtained as a brown solid. Η NMR (Acetone-dό) δ 1.25 (d, 6H), 4.18 (m, IH), 7.38 (m, IH), 7.59-7.64 (m,
2H), 7.71-7.76 (m, 2H), 7.81-7.85 (m, 2H), 7.92 (s, IH), 8.61 (m, IH), 8.74 (m, IH), 8.78 (dd, IH), 8.89 (s, IH), 9.62 (br, NH). EXAMPLE 3D
N-Isopropyl-l-F3-(4-pyridinylethvnyl)phenyll-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting 4- ethynylpyridine (J.Org.Chem. 1996, 61, 6535) for phenylacetylene, the title compound was obtained as a solid.
1H NMR (Acetone-d6) δ 1.24 (d, 6H), 4.18 (m, IH), 7.49 (m, 2H), 7.61 (m, IH), 7.71-7.78 (m, 2H), 7.81 (m, IH), 7.92 (s, IH), 8.62 (m, 2H), 8.73 (m, IH), 8.78 (dd, IH), 8.87 (s, IH), 9.62 (br, NH).
EXAMPLE 4D
N-Isopropyl-l-F3-(l-oxido-4-pyridinylethynyl)phenvn-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
To a solution of N-Isopropyl-l-[3-(4-pyridinylethynyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 3D in methylene chloride (36mLmmol) and methanol (3mIJmmol) was added magnesium monoperoxyphthalate hexahydrate (MMPP, 3.6 eq) and the mixture was stirred at room temperature overnight. A further amount of MMPP (2 eq) was added and stirring was continued for 24 hours. The resulting mixture was filtered through a bed of celite, the filtrate was diluted with methylene chloride and washed with aqueous sodium bicarbonate and water. After drying, the organic phase was evaporated and the crude product was purified by chromatography on silica gel eluting with 10% methanol in methylene chloride to afford the title compound as a solid.
1H NMR (CDCI3) δ 1.28 (d, 6H), 4.28 (m, IH), 7.35 (d, 2H), 7.46 (m, 2H), 7.58 (m, 2H), 7.67 (m, IH), 8.14 (d, 2H), 8.69 (m, IH), 8.81 (dd, IH), 8.99 (s, IH), 9.62 (br, NH). EXAMPLE 5D
N-Isopropyl-l-(3-ethvnylphenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: N-Isopropyl-l-r3-(trimethylsilylethvnyl)phenyl1-l,4-dihvdrofl,81naphthyridin-4-one-3- carboxamide.
Following the procedure of Step 5 of EXAMPLE ID, but substituting trimethylsilylacetylene for phenylacetylene, the N-isopropyl-l-[3-(trimethylsilylethynyl)phenyl]- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide product was obtained and used in the next step without further purification.
Step 2: N-Isopropyl-l-(3-ethvnylphenyl)-l,4-dihydroFl,81naphthyridin-4-one-3-carboxamide. The crude product from Step 1 was dissolved in methanol (12mL mmol) and IN aqueous sodium hydroxide was added (3 eq), resulting in a suspension. The suspension mixture was stirred at room temperature for 2 hours and the methanol was evaporated. The resulting aqueous suspension was diluted with water and the product was extracted out with ethyl acetate.
The crude product was chromatographed on silica gel eluting with 10% ether in methylene chloride to afford the N-isopropyl-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound as a solid. Η NMR (Acetone-de) 8 1.24 (d, 6H), 3.81 (s, IH), 4.17 (m, IH), 7.59 (m, IH),
7.64-7.71 (m, 3H), 7.81 (s, IH), 8.72 (m, IH), 8.76 (dd, IH), 8.84 (s, IH), 9.61 (br, NH).
EXAMPLE 6D
N-Cvclopropyl- 1 -(3-ethynylphenyD-l ,4-dihydroF 1 ,81naphthyridin-4-one-3-carboxamide
Step 1: N-Cyclopropyl- l-(3-bromophenyl)-l,4-dihvdrori,81naphthyridin-4-one-3-carboxamide.
Following the procedure of Step 4 of EXAMPLE ID, but substituting cyclopropylamine for isopropylamine, the N-cyclopropyl-1 -(3-bromophenyl)- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide was obtained as a fluffy white solid.
1H NMR (Acetone-d6) δ 0.59 (m, 2H), 0.80 (m, 2h), 2.96 (m, IH), 7.59-7.68 (m, 2H), 7.72 (dd, IH), 7.82 (dd, IH), 7.97 (s, IH), 8.72-8.81 (m, 2H), 8.89 (s, IH), 9.70 (br, NH). Steps 2 and 3: N-Cvclopropyl-l-(3-ethvnylphenyl)-1.4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedures of Steps 1 and 2 of EXAMPLE 5D, but substituting the product from step 1 for N-isopropyl- 1 -(3-bromophenyl)- l,4-dihydro[l, 8]naphthyridin-4-one-3- carboxamide, the N-Cyclopropyl-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, IH), 3.18 (s, IH), 7.42 (d, IH), 7.47 (m, IH), 7.52-7.58 (m, 2H), 7.65 (d, IH), 8.70 (m, IH), 8.80 (dd, IH), 8.98 (s, IH), 9.74 (br, NH).
EXAMPLE 7D
N-Isopropyl-l-F3-(3-pyridinylethynyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting N- isopropyl-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5 for phenylacetylene and 3-bromopyridine for N-isopropyl- 1 -(3-bromophenyl)- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a light brown solid.
1H NMR (Acetone-de) δ 1.24 (d, 6H), 4.18 (m, IH), 7.43 (m, IH), 7.61 (m, IH), 7.70-7.75 (m, 2H), 7.80 (d, IH), 7.90 (s, IH), 7.94 (d, IH), 8.58 (m, IH), 8.74-8.79 (m, 3H), 8.88 (s, IH), 9.62 (br, NH).
EXAMPLE 8D
N-Isopropyl-l-F3-(l-oxido-3-pyridinylethynyl)phenyl1-l,4-dihydrori,81naphthyridin-4-one-3- carbox amide
Following the procedure of EXAMPLE 4D, but substituting N-isopropyl-l-[3-(3- pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 7D for N-isopropyl-l-[3-(4-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide, the title compound was obtained as a solid. 1H NMR (CDCI3) δ 1.28 (d, 6H), 4.28 (m, IH), 7.26(m, IH), 7.36 (d, IH), 7.45- 7.49 (m, 2H), 7.57-7.62 (m, 2H), 7.69 (d, IH), 8.16 (d, IH), 8.31 (s, IH), 8.69 (m, IH), 8.81 (dd, IH), 8.99 (s, IH), 9.63 (br, NH).
EXAMPLE 9D
N-Cvclopropyl-l-F3-(3-pyridinylethynyl)phenyl1-l,4-dihvdroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting N- cyclopropyl-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for phenylacetylene and 3-bromopyridine for N-isopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, IH), 7.28 (m, IH), 7.43- 7.48 (m, 2H), 7.57 (t, IH), 7.62 (s, IH), 7.70 (d, IH), 7.79 (d, IH), 8.55 (m, IH), 8.70 (m, IH), 8.75 (s, IH), 8.79 (dd, IH), 9.01 (s, IH), 9.74 (br, NH).
EXAMPLE 10D
N-Isopropyl-l-r3-(3-hvdroxy-3-methylbut-l-vnyl)phenyl1-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting 2-methyl-3- butyn-2-ol for phenylacetylene, the title compound was obtained as a white solid. 1H NMR (Acetone-d^) δ 1.24 (d, 6H), 1.53 (s, 6H), 4.17 (m, IH), 4.52 (s, IH,
OH), 7.58-7.65 (m, 4H), 7.68 (s, IH), 8.72 (m, IH), 8.77 (dd, IH), 8.84 (s, IH), 9.62 (br, NH).
EXAMPLE 1 ID
N-Cvclopropyl-l-F3-(3-hydroxy-3-methylbut-l-vnyl)phenyl1-l,4-dihydroFl,81naphthyridin-4- one-3-carboxamide
Following the procedure of EXAMPLE 10D, but substituting N-cyclopropyl-l-(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6D for N- isopropyI-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a white solid. 1H NMR (Acetone-de) δ 0.57 (m, 2H), 0.78 (m, 2H), 1.53 (s, 6H), 2.93 (m, IH),
4.53 (s, IH, OH), 7.58-7.65 (m, 4H), 7.67 (s, IH), 8.72 ( , IH), 8.76 (dd, IH), 8.85 (s, IH), 9.69 (br, NH).
EXAMPLE 12D
N-Isopropyl-l-f3-(l-hvdroxycvclopentyl)ethvnylphenyl1-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Following the procedure of Step 5 of EXAMPLE ID, but substituting 1- ethynylcyclopentanol for phenylacetylene, the title compound was obtained as a white solid.
'H NMR (CDC13) δ 1.28 (d, 6H), 1.76-1.80 ( , 2H), 1.84-1.88 (m, 3H), 1.98-2.06 (m, 4H), 4.27 (m, IH), 7.36 (d, IH), 7.44-7.50 (m, 3H), 7.56 (d, IH), 8.68 ( , IH), 8.79 (dd, IH), 8.97 (s, IH), 9.63 (br, NH).
EXAMPLE 13D
N-Isopropyl-l-F3-(l-hvdroxycvcloρropyl)ethvnylphenyl1-l,4-dihydroFl,81naphthyridin-4-one-3- carboxamide
Step 1: 1-Ethynylcyclopropanol.
The 1-ethynylcyclopropanol was prepared following the procedure described in J. Org.Chem. 916, 41, 1237 from [(l-ethoxycyclopropyl)oxy]trimethylsilane and ethynyl magnesium bromide and was obtained as a liquid. Step 2: N-Isopropyl-l-F3-(l-hvdroχvcvclopropyl)ethynylphenyn-l,4-dihvdroFl,81naphthyridin- 4-one-3-carboxamide.
Following the procedure of Step 5 of EXAMPLE ID, but substituting the product from present Step 1 for phenylacetylene, the N-isopropyl-l-[3-(l- hydroxycyclopropyl)ethynylphenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 1.09 (m, 2H), 1.17 (m, 2H), 1.28 (d, 6H), 2.57 (s, IH, OH), 4.28 (m, IH), 7.35 (d, IH), 7.44-7.50 (m, 3H), 7.54 (d, IH), 8.68 (m, IH), 8.79 (dd, IH), 8.96 (s, IH), 9.63 (br, NH).
EXAMPLE 14D
N-Isopropyl-l-l3-F4.4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-l-ynvnphenvU-l,4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Step 1: l.l,l-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol.
To a solution of trimethylsilylacetylene (4mL) in THF (30mL) at -78°C was added
2.5M n-butyllithium in hexanes (14mL) and the resulting mixture was stirred for 1 hour. An excess of hexafluoroacetone was bubbled into the cold mixture and stirring was continued for 4 hours. After warming to room temperature, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ether and water. The organic phase was dried and evaporated to afford the l,l,l-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-
2-ol as a liquid.
Step 2: N-Isopropyl-l-(3-F4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-l-ynyl1phenyl }-l,4- dihydrof 1 ,81naphthyridin-4-one-3-carboxamide.
To a solution of l,l,l-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol from present Step 1 (6.8mmol) in lOmL of THF was added IM tetrabutyl ammonium fluoride (8.5mL) and the resulting mixture was refluxed for 30 minutes to remove the TMS protecting group. The procedure of Step 5 of EXAMPLE ID was then applied, but substituting this solution for phenylacetylene to afford the N-Isopropyl-l-{3-[4,4,4-trifluoro-3-hydroxy-3- (trifluoromethyl)but-l-ynyl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as a solid.
1H NMR (Acetone-d6) δ 1.24 (d, 6H), 4.17 (m, IH), 7.60 (m, IH), 7.72-7.79 (m, 2H), 7.83 (d, IH), 7.90 (s, IH), 8.14 (s, IH, OH), 8.72 (m, IH), 8.77 (dd, IH), 8.85 (s, IH), 9.62 (br, NH).
EXAMPLE 15D
N-Isopropyl-l-[3-(3-hydroxy-3-phenylbut-l-ynyl)phenyl1-l,4-dihvdro[l,81naphthyridin-4-one-3- carboxamide
A mixture of N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide from Step 4 of EXAMPLE ID, 2-phenyl-3-butyn-2-ol (2 eq), triethylamine (1.66 eq), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq), and copper (I) iodide (5mg/mmol) in DMF (20mIJmmol) was heated at 85°C for 18 hours. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with 20% ether in methylene chloride. The purified product was stirred in ether at room temperature for 3 hours and filtered to afford the title compound as a white solid.
1H NMR (Acetone-de) δ 1.24 (d, 6H), 1.79 (s, 3H), 4.18 (m, IH), 5.22 (s, IH, OH), 7.26 (t, IH), 7.35 (t, 2H), 7.59 (m, IH), 7.66 (m, 3H), 7.73 (d, 2H), 7.76 (s, IH), 8.72 (m, IH), 8.77 (dd, IH), 8.84 (s, IH), 9.62 (br, NH).
EXAMPLE 16D
N-Cyc1opropyl-l-r3-(l-oxido-3-pyridinylethynyl)phenyl1-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide
Step 1: 3-Ethynylpyridine N-oxide.
To a solution of 3-ethynylpyridine in methylene chloride (5mlJmmol) at room temperature was added m-chloroperoxybenzoic acid (m-CPBA, 70% purity, 1.2 eq) and the resulting mixture was stirred for 2 hours. A further amount of m-CPBA was added (0.25 eq) and stirring was continued for 1 hour. Calcium hydroxide was added (2 eq) and after 15 minutes the mixture was filtered through celite and the filtrate was evaporated. The solid residue was stirred in ether for 3 hours and filtered to afford the 3-ethynylpyridine N-oxide compound as a white solid.
Step 2: N-Cyclopropyl-l-[3-(l-oxido-3-pyridinylethvnyl)phenyll-1.4-dihydro[l,81naphthyridin-
4-one-3-carboxamide.
Following the procedure of EXAMPLE 15D, but substituting N-cyclopropyl-l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 1 of EXAMPLE 6D for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, and
3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, the N-cyclopropyl-l-[3-(l- oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.96 (m, IH), 7.26 (m, IH), 7.37 (d, IH), 7.45-7.48 (m, 2H), 7.58-7.62 (m, 2H), 7.69 (d, IH), 8.16 (d, IH), 8.31 (s, IH), 8.69 (m,
IH), 8.79 (dd, IH), 8.99 (s, IH), 9.73 (br, NH).
EXAMPLE 17D
N-Isopropyl-l-f3-(3-amino-3-ethylpent-l-vnyl)phenvn-l,4-dihvdron,81naphthyridin-4-one-3- carboxamide
Following the procedure of EXAMPLE 15D, but substituting 1,1- diethylpropargylamine for 2-phenyl-3-butyn-2-ol, the title compound was obtained as a solid. 1H NMR (CDCI3) δ 1.05 (t, 6H), 1.28 (d, 6H), 1.57 (m, 2H), 1.69 (m, 2H), 4.27
(m, IH), 7.33 (d, IH), 7.44-7.49 (m, 3H), 7.53 (d, IH), 8.69 (m, IH), 8.79 (dd, IH), 8.97 (s, IH), 9.63 (br, NH). (NH2 not observed).
EXAMPLE 18D
N-Cyclopropyl-l-[3-(3-amino-3-ethylpent-l-vnyl)phenyll-l,4-dihvdro[l,81naphthyridin-4-one-3- carboxamide Following the procedure of EXAMPLE 17D, but substituting N-cyclopropyl-l-(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 1 of EXAMPLE 6D for N-isopropyl- l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.05 (t, 6H), 1.57 (m, 2H), 1.70 (m, 2H), 2.96 (m, IH), 7.33 (d, IH), 7.44-7.49 (m, 3H), 7.54 (d, IH), 8.69 (m, IH), 8.77 (dd, IH), 8.97 (s, IH), 9.75 (br, NH). (NH2 not observed).
EXAMPLE 19D
N-Isopropyl-l-r3-(3-quinolinylethynyl)phenvn-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide
Following the procedure of EXAMPLE 15D, but substituting N-isopropyl-l-(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 2 of EXAMPLE 5D for 2-phenyl-3-butyn-2-ol, and 3-bromoquinoline for N-isopropyl- 1 -(3-bromophenyl)- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.
1H NMR (CDCI3) δ 1.32 (d, 6H), 4.32 (m, IH), 7.48-7.51 (m, 2H), 7.58-7.65 (m, 2H), 7.71 (s, IH), 7.73-7.80 (m, 2H), 7.83 (d, IH), 8.12 (d, IH), 8.35 (s, IH), 8.75 (m, IH), 8.85 (dd, IH), 9.02 (s, IH), 9.06 (s, IH), 9.65 (br, NH).
EXAMPLE 20D
N-IsopropyI-l-f3-(l-oxido-3-quinolinylethvnyl)phenvn-l,4-dihvdro[l,81naphthyridin-4-one-3- carboxamide
Following the procedure of EXAMPLE 19D, but substituting 3-bromoquinoline N-oxide for 3-bromoquinoline, the title compound was obtained as a solid.
Η NMR (CDCI3) δ 1.33 (d, 6H), 4.32 (m, IH), 7.49-7.53 (m, 2H), 7.63 (t, IH), 7.68-7.73 (m, 2H), 7.75-7.83 (m, 2H), 7.88-7.92 (m, 2H), 8.63 (s, IH), 8.73-8.78 (m, 2H), 8.86 (dd, IH), 9.05 (s, IH), 9.67 (br, NH). EXAMPLE 2 ID
N-Isopropyl-l-[3-(cvclopropylethvnyl)phenyl1-l,4-dihvdrori.81naphthyridin-4-one-3- carboxamide
Following the procedure of EXAMPLE 15D, but substituting cyclopropylacetylene (Tetrahedron letters 2000, 41, 4007) for 2-phenyl-3-butyn-2-ol, the title compound was obtained as a gray solid.
1H NMR (CDC13) δ 0.83 (m, 2H), 0.90 (m, 2H), 1.31 (d, 6H), 1.48 (m, IH), 4.31 (m, IH), 7.33 (m, IH), 7.45-7.51 (m, 3H), 7.55 (d, IH), 8.72 (m, IH), 8.83 (dd, IH), 9.01 (s, IH), 9.68 (br, NH).
EXAMPLE 22D
N-Isopropyl-l-r3-(6-amino-3-pyridinylethvnyl)phenyl1-l,4-dihvdro[l,81naphthyridin-4-one-3- carboxamide
Following the procedure of EXAMPLE 19D, but substituting but substituting 5- bromo-2-aminopyridine for 3-bromoquinoline, the title compound was obtained as a solid. 1H NMR (CDC13) δ 1.33 (d, 6H), 4.31 (m, IH), 4.71 (br, NH2), 6.49 (d, IH), 7.40
(m, IH), 7.48 (m, IH), 7.54-7.60 (m, 3H), 7.68 (d, IH), 8.28 (s, IH), 8.72 (m, IH), 8.83 (dd, IH), 9.04 (s, IH), 9.67 (br, NH).
EXAMPLE 23D
N-Isopropyl-l-|3-[5-(l-hvdroxy-l-methylethyl)-l-oxido-3-pyridinylethynvnphenyl 1-1,4- dihvdro[l,81naphthyridin-4-one-3-carboxanιide
Step 1: 3-Bromo-5-(l-hydroxy-l-rnethylethyl)pyridine. To a solution of ethyl 5-bromonicotinate (1.02g, 4.4mmol) in diethyl ether
(15mL) at -30°C was added a 3M solution of methyl magnesium brorηide in ether (4mL, 12mmol). The resulting slurry was refluxed for 2 hours then cooled and quenched with an excess of 0.5M aqueous monobasic sodium phosphate and partitioned between ether and water. The product from the organic phase was chromatographed on silica gel eluting with a 2:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-bromo-5-(l- hydroxy-l-methylethyl)pyridine compound as a yellow oil.
Step 2: 3-Bromo-5-(l-hvdroxy-l-methylethyl)pyridine-N-oxide.
To a solution of 3-bromo-5-(l -hydroxy- l-methylethyl)pyri dine from Step 1 (3.1mmol) in chloroform (lOmL) was added m-chloroperoxybenzoic acid 70% (1.5 eq) and the resulting mixture was stirred at room temperature for 18 hours. An excess of calcium hydroxide was added and after stirring for 5 minutes, the mixture was filtered through celite and the filtrate was evaporated. The crude material was chromatographed on silica gel eluting with 10% ethanol in methylene chloride (saturated with ammonia) to afford the 3-bromo-5-(l-hydroxy-l- methylethyl)pyridine-N-oxide compound as a solid.
Step 3 : N-Isopropyl- 1 - { 3- r5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridin yleth vn yllphenyl J - l,4-dihvdroll,81naphthyridin-4-one-3-carboxamide.
Following the procedure of EXAMPLE 15D, but substituting N-isopropyl- 1 -(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5D for 2- phenyl-3-butyn-2-ol, and 3-bromo-5-(l-hydroxy-l-methylethyl)pyridine-N-oxide from Step 2 for
N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the N- isopropyl-l-{3-[5-(l-hydroxy-l-methylethyl)-l-oxido-3-pyridinylethynyl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 1.32 (d, 6H), 1.64 (s, 6H), 2.22 (br, IH, OH), 4.30 (m, IH),
7.45-7.52 (m, 2H), 7.60 (t, IH), 7.66 (s, IH), 7.72 (d, IH), 7.98 (s, IH), 8.70 (br, 2H), 8.73 (m,
IH), 8.84 (dd, IH), 9.03 (s, IH), 9.68 (br, NH).
EXAMPLE 24D
N-Isopropyl-l-{3-[6-(l-hvdroxy-l-methylethyl)-3-pyridinylethynyl1phenyl 1-1,4- dihydroF 1 ,81naphth yridin-4-one-3-carboxamide
Step 1: 5-Bromo-2-(l-hvdroxy-l-methylethyl) pyridine.
To a suspension of 2,5-dibromopyridine in toluene (12mL/mmol) cooled to -78°C was added n-butyllithium 2.5M in hexanes (1.05eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2eq) was added and stirring was continued for 1.5h. After quenching with saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-bromo-2-(l-hydroxy-l-methylethyl) pyridine compound as a syrup.
Step 2: 5-Bromo-2-(l-methyl-l-{ r2-(trimethylsilyl)ethoxy1methoxy lethvDpyridine.
To a solution of 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine from Step 1 (14mmol) in methylene chloride (50mL) at 0°C was added N,N-diisopropylethylamine (37.3mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15.3mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with 6% ethyl acetate in hexane to afford the 5- bromo-2-(l-methyl-l-{ [2-(trimethylsilyl)ethoxy]methoxyJethyl)pyridine compound.
Step 3: 2-(l -Methyl- 1-1 r2-(trimethv1siIyl)ethoxylmethoxylethyl)-5- [(trimethylsilyl)ethynyllpyridine.
Following the procedure of Step 5 of EXAMPLE ID, but substituting the product from present Step 2 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide and trimethylsilylacetylene for phenylacetylene, the 2-(l-methyl-l-{ [2- (trimethylsilyl)ethoxy]methoxy}ethyl)-5-[(trimethylsilyl)ethynyl]pyridine compound was obtained .
Step 4: 5-Ethvnyl-2-(l-methyl-l-( [2-(trimethylsilyl)ethoxy1methoxy lethvDpyridine.
Following the procedure of Step 2 of EXAMPLE 5D, but substituting the product from present Step 3 for N-isopropyl- l-[3-(trimethylsilylethynyl)phenyl]- 1,4- dihydro[l ,8]naphthyridin-4-one-3-carboxamide, the 5-ethynyl-2-(l-methyl-l-{ [2- (trimethylsilyl)ethoxy]methoxyJethyl)pyridine compound was obtained. Step 5: N-Isopropyl-l-(3-| [6-(l-methyl-l-π2-trimethylsilyl)ethoxy1methoxyJethyl)pyridin-3- yl1ethvnvπphenyl)-l,4-dihvdro[l,81naphthyridin-4-one-3-carboxamide.
Following the procedure of Step 5 of EXAMPLE ID, but substituting the product from present Step 4 for phenylacetylene, the N-isopropyl-l-(3-{ [6-(l-methyl-l-{ {2- trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl }phenyl)-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide compound was obtained.
Step 6: N-Isopropyl-l-{3-[6-(l-hvdroxy-l-methylethyl)-3-pyridinylethvnyl1phenyl 1-1,4- dihvdro[l,81naphthyridin-4-one-3-carboxamide. To a solution of N-isopropyl-l-(3-{ [6-(l-methyl-l-{ {2- trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl}phenyl)-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide product from present Step 5 in methylene chloride (32mL/mmol) at 0°C was added trifluoroacetic acid (3.2mL/mmol). The resulting mixture was stirred at 0°C for 2 hours then at room temperature for 2 hours. The mixture was neutralized slowly with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude material from the organic phase was chromatographed on silica gel eluting with 40% ether in methylene chloride and the purified product was stirred in ether at room temperature for 2 hours and filtered to afford the N-isopropyl-l-{3-[6-(l-hydroxy-l-methylethyl)-3- pyridinylethynyl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound as solid.
1H NMR (Acetone-d6) δ 1.24 (d, 6H), 1.50 (s, 6H), 4.18 (m, IH), 4.57 (s, IH, OH), 7.61 (m, IH), 7.69-7.74 (m, 3H), 7.78 (m, IH), 7.88 (s, IH), 7.93 (dd, IH), 8.68 (s, IH), 8.74 (m, IH), 8.78 (dd, IH), 8.88 (s, IH), 9.63 (br, NH).
EXAMPLE 25D
N-Isopropyl- 1- { 3-[6-(l-hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridin ylethynyllphenyl 1-1.4- dihydro[l,81naphthyridin-4-one-3-carboxamide
Following the procedure of Step 2 of EXAMPLE 23D, but substituting N- isopropyl-l-{3-[6-(l-hydroxy-l-methylethyl)-3-pyridinylethynyl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide from example 24D for 3-bromo-5-(l -hydroxy- 1- methylethyl)pyridine, the title compound was obtained as a solid. 1H NMR (Acetone-dβ) δ 1.25 (d, 6H), 1.60 (s, 6H), 4.18 (m, IH), 7.24 (s, IH, OH), 7.60-7.63 (m, 3H), 7.72-7.78 (m, 2H), 7.82 (d, IH), 7.91 (s, IH), 8.46 (s, IH), 8.74 (m, IH), 8.78 (dd, IH), 8.87 (s, IH), 9.62 (br, NH).
EXAMPLE 26D
N-Isopropyl- 1 - { 3- F4-( 1 -hydroxy- 1 -methylethyl)-2-pyridinylethvnyllphenyl 1 - 1.4- dihvdro[l,8]naphthyridin-4-one-3-carboxamide
Step 1: Methyl 2-bromoisonicotinate.
To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Bull. 1990, 38, 2446) (2.0g) in tetrahydrofuran (lOOmL) was added excess ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate and hexane to afford the methyl 2-bromoisonicotinate ester as a colorless liquid.
Step 2: 2-Bromo-4-(l-hvdroxy-l-methylethyl)pyridine.
Following the procedure of Step 1 of EXAMPLE 23D, but substituting methyl 2- bromoisonicotinate from present Step 1 for ethyl 5-bromonicotinate, the 2-bromo-4-(l-hydroxy- l-methylethyl)pyridine compound was obtained as a white solid.
Step 3: N-Isopropyl-l-{3-r4-(l-hydroxy-l-methylethyl)-2-pyridinylethvnyllphenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide.
Following the procedure of EXAMPLE 19D, but substituting the 2-bromo-4-(l- hydroxy- l-methylethyl)pyri dine from present Step 2 for 3-bromoquinoline, the N-isopropyl- 1- {3-[4-(l-hydroxy-l-methylethyl)-2-pyridinylethynyl]phenyl}-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide compound was obtained as a yellow foam.
1H NMR (Acetone-d6) δ 1.27 (d, 6H), 1.55 (s, 6H), 4.20 (m, IH), 4.42 (s, IH, OH), 7.52 (m, IH), 7.63 (m, IH), 7.72-7.79 (m, 3H), 7.84 (d, IH), 7.95 (s, IH), 8.55 (d, IH), 8.77 (m, IH), 8.80 (dd, IH), 8.92 (s, IH), 9.65 (br, NH). EXAMPLE 27D
N-Isopropyl-l-f 3-F5-(l-hvdroxy-l-methylethyl)-2-pyridinylethynyl1phenyl 1-1,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 2-Bromo-5-(l-hvdroxy-l-methylethyl)pyridine.
A solution of 2,5-dibromopyridine in diethyl ether (5mIJmmol) was cooled to - 78°C, and n-butyllithium 2.5M in hexanes (1.05 eq) was added slowly. After 2 hrs in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product from the organic phase was triturated with 1:1 ether-hexane and filtered to afford the 2-bromo-5-(l -hydroxy- 1- methylethyl)pyridine compound as a solid.
Step 2: 5-(l-Hvdroxy-l-methylethyl)-2-F(trimethylsilvI)ethvnyllpyridine.
Following the procedure of EXAMPLE 15D, but substituting the product 2- bromo-5-(l -hydroxy- 1 -methylethyl )pyri dine from present Step 1 for N-isopropyl- 1 -(3- bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl-3-butyn-2-ol, the 5-(l-hydroxy-l-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine compound was obtained.
Step 3: 2-Ethvnyl-5-(l -hydroxy- l-methylethyl)pyridine.
Following the procedure of Step 2 of EXAMPLE 5D, but substituting the product 5-(l-hydroxy-l-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine from present Step 2 for N- isopropyl-l-[3-(trimethylsilylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide, the 2-ethynyl-5-(l-hydroxy-l-methylethyl)pyridine compound was obtained.
Step 4: N-Isopropyl- 1 - { 3-F5-( 1 -hydroxy- 1 -methyleth yl)-2-pyridinylethyn yllphenyl 1 - 1 ,4- dihydroFl,81naphthyridin-4-one-3-carboxamide. Following the procedure of EXAMPLE 15D but substituting the product 2- ethynyl-5-(l -hydroxy- l-methylethyl)pyridine from present Step 3 for 2-phenyl-3-butyn-2-ol, the N-Isopropyl-l-{3-[5-(l-hydroxy-l-methylethyl)-2-pyridinylethynyl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained. Η NMR (CDCI3) δ 1.32 (d, 6H), 1.66 (s, 6H), 2.08 (s, IH, OH), 4.31 (m, IH), 7.46-7.55 (m, 3H), 7.61 (t, IH), 7.71 (s, IH), 7.78 (d, IH), 7.86 (dd, IH), 8.73 (m, IH), 8.77 (m, IH), 8.83 (dd, IH), 9.04 (s, IH), 9.67 (br, NH).
EXAMPLE 28D
N-Isopropyl- 1 - { 3- F6-( 1 -hydroxy- 1 -methylethyl)-2-pyridinylethvnyllphenyl 1 - 1 ,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 2-Bromo-6-(l-hydroxy-l-methylethyl)pyridine.
Following the procedure of Step 1 of EXAMPLE 27D, but substituting 2,6- dibromopyridine for 2,5-dibromopyridine, the 2-Bromo-6-(l-hydroxy-l-methylethyl)pyridine compound was obtained as a solid.
Step 2: N-Isopropyl- 1 - { 3- F6-( 1 -hydroxy- 1 -methylethyl)-2-pyri dinyleth vnyllphenyl J - 1 ,4- dihvdroFl,81naphthyridin-4-one-3-carboxamide.
Following the procedure of EXAMPLE 19D, but substituting the product 2- Bromo-6-(l-hydroxy-l-methylethyl)pyridine from present Step 1 for 3-bromoquinoline, the N- Isopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)-2-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained.
Η NMR (CDC13) δ 1.31 (d, 6H), 1.58 (s, 6H), 4.32 (m, IH), 4.83 (s, IH, OH), 7.38 (d, IH), 7.43-7.52 (m, 3H), 7.60 (t, IH), 7.70-7.75 (m, 2H), 7.79 (d, IH), 8.74 (m, IH), 8.84 (dd, IH), 9.03 (s, IH), 9.66 (br, NH).
EXAMPLE 29D
N-Cyclopropyl- 1 - { 3- 16-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinyleth vnyllphenyl 1 - 1.4- dihvdroFl,81naphthyridin-4-one-3-carboxamide
Step 1: 5-Bromo-2-(l-hvdroxy-l-methylethyl)pyridine N-oxide.
Following the procedure of Step 2 of EXAMPLE 23D, but substituting 5-bromo- 2-(l -hydroxy- l-methylethyl)pyridine from Step 1 of EXAMPLE 24D for 3-bromo-5-(l-hydroxy- l-methylethyl)ρyridine, the 5-Bromo-2-(l -hydroxy- l-methylethyl)ρyridine N-oxide compound was obtained.
Step 2: N-Cvclopropyl-l-{3-F6-(l-hvdroxy-l-methylethyl)-l-oxido-3-pyridinylethvnyl1phenyl 1- l,4-dihvdroll.81naphthyridin-4-one-3-carboxamide.
Following the procedure of EXAMPLE 15D, but substituting N-cyclopropyl- 1 -(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6D for 2- phenyl-3-butyn-2-ol and 5-bromo-2-(l-hydroxy-l-methylethyl)pyridine-N-oxide from present Step 1 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide, the N-cyclopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } -1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC13) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.66 (s, 6H), 2.96 (m, IH), 7.34 (d, IH), 7.43-7.50 (m, 4H), 7.58-7.62 (m, 2H), 7.69 (d, IH), 8.33 (s, IH, OH), 8.69 (m, IH), 8.79 (dd, IH), 8.99 (s, IH), 9.73 (br, NH).
EXAMPLE 30D
N-Isopropyl-l-(3-F(4-pyridin-3-ylphenyl)ethvnyllphenyll-l,4-dihvdroFl,81naρhthyridin-4-one-3- carboxamide
Step 1: 3-(4-Bromophenyl)pyridine.
A mixture of pyridine-3 -boronic acid 1,3-propanediol cyclic ester, 4- bromoiodobenzene (l.leq), [l.l'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (2mIJmmol) was stirred at 85°C for 4 hours. After quenching with saturated aqueous ammonium chloride solution the mixture was partitioned between ethyl acetate and water and the crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ethyl acetate and hexane to afford the 3-(4-bromophenyl)pyridine compound as a solid.
Step 2: N-Isopropyl-l-{3-F(4-pyridin-3-ylphenyl)ethvnyl1phenyll-l,4-dihvdro π,8]naphthyridin- 4-one-3-carboxamide.
Following the procedure of EXAMPLE 19D, but substituting the product from present Step 1 for 3-bromoquinoline, the N-isopropyl-l-{3-[(4-pyridin-3- ylphenyl)ethynyl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained .
1H NMR (CDCI3) δ 1.28 (d, 6H), 4.28 (m, IH), 7.38 (m, IH), 7.42 (d, IH), 7.48 (m, IH), 7.53-7.64 (m, 6H), 7.70 (d, IH), 7.88 (d, IH), 8.60 (m, IH), 8.71 (m, IH), 8.82 (dd, IH), 8.86 (s, IH), 9.02 (s, IH), 9.63 (br, NH).
EXAMPLE 3 ID
N-Isopropyl- l-(3-F F5-(l -hydroxy- 1 -methylethyl)thien-2-yl1eth vnyl ] phenyl)- 1 ,4- dihydroFl,81naphthyridin-4-one-3-carboxamide
Step 1 : 2-Bromo-5-( 1 -hydroxy- 1 -methylethyPthiophene.
To a solution of 2-acetyl-5-bromothiophene in THF (2.5mIJmmol) at -30°C was added 1.4M methylmagnesium bromide in 3:1 toluene-THF (1.5 eq) and the resulting mixture was warmed to -10°C and stirred for 1.5 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ether and water. The organic fraction was dried and evaporated, and the crude material was chromatographed on silica gel eluting with a 1:4 mixture of ether and hexane to afford the 2-bromo-5-(l-hydroxy-l- methylethyl)thiophene compound.
Step 2: 2-(l-Hvdroxy-l-methylethv1)-5-trimethvIsilyIethvnyl thiophene.
Following the procedure of EXAMPLE 15D, but substituting the product from present Step 1 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide and trimethylsilylacetylene for 2-phenyl-3-butyn-2-ol, the 2-( 1 -hydroxy- 1- methylethyl)-5-trimethylsilylethynyl thiophene compound was obtained.
Step 3: 2-Ethynyl-5-(l-hvdroxy-l-methylethyl)thiophene.
Following the procedure of Step 2 of EXAMPLE 5D, but substituting the product from present Step 2 for N-isopropyl-l-[3-(trimethylsilylethynyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the 2-ethynyl-5-(l-hydroxy-l- methylethyl)thiophene compound was obtained. Step 4: N-Isopropyl- 1 -(3- { F5-(l -hydroxy- 1 -methylethyl .thien-2-vπethvnyl }phenyl)-l,4- dihvdroF1.81naphthyridin-4-one-3-carboxamide.
Following the procedure of EXAMPLE 15D, but substituting the 2-ethynyl-5-(l- hydroxy-l-methylethyl)thiophene product from present Step 3 for 2-phenyl-3-butyn-2-ol, the N- isopropyl-l-(3-{ [5-(l-hydroxy-l-methylethyl)thien-2-yl]ethynyl}phenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.
1H NMR (CDC1 ) δ 1.31 (d, 6H), 1.70 (s, 6H), 2.42 (s, IH, OH), 4.31 (m, IH), 6.87 (d, IH), 7.16 (d, IH), 7.42 (d, IH), 7.48 (m, IH), 7.59 (t, IH), 7.63 (s, IH), 7.68 (d, IH), 8.73 (m, IH), 8.84 (dd, IH), 9.02 (s, IH), 9.68 (br, NH).
EXAMPLE 32D
N-Isopropyl-l-(3-{ F2-(l-hvdroxy-l-methylethyl)-l,3-thiazol-5-yl1ethvnyl)phenyl)-l,4- dihvdroF1.81naphthyridin-4-one-3-carboxamide
Step 1: 2-( 1 -hydroxy- 1 -methylethyl) thi azole.
To a solution of thiazole in ether (lmL/mmol) at -78°C was added 2.2M n- butyllithium in hexanes (1.1 eq) and the resulting mixture was stirred for 30 minutes. Acetone (1.2 eq) was added and the mixture was stirred at -78°C for a further 30 minutes. The mixture was quenched in the cold with saturated aqueous ammonium chloride solution and warmed to room temperature, then partitioned between ether and water. The organic phase was dried and evaporated to yield the crude product as an orange-brown oil which was used as such in the next step.
Step 2: 2-(l-methyl-l-l r2-(trimethvIsilyl,ethoxylmethoxylethyl. thiazole.
Following the procedure of Step 2 of EXAMPLE 24D, but substituting the product from present Step 1 for 5-bromo-2-(l -hydroxy- 1 -methylethyl) pyridine, the 2-(l -methyl - l-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole compound was obtained as an oil.
Step 3: 5-Bromo-2-(l -hydroxy- l-methylethyl)thiazole.
To a solution of 2-(l-methyl-l-{ [2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole from Step 2 in chloroform (2mL/mmol) at room temperature was added bromine (2 molar eq) and the resulting mixture was stirred for 1 hour. Solid sodium bicarbonate (0.55 eq) was added and the mixture was stirred for 5 hours. More sodium bicarbonate was added (0.55 eq) and stirring was continued for 18 hours. After a final addition of sodium bicarbonate (0 55 eq) the mixture was stirred for a further 5 hours, diluted with chloroform and the organic phase was washed with saturated aqueous sodium bicarbonate, then with water, dπed and evaporated. The crude material was chromatographed, eluting with a 3:7 mixture of ethyl acetate and hexane to afford the desired product.
Step 4: N-Isopropyl- 1 -(3-1 F2-(l-hvdroxy-l-methylethyl .-1.3-thιazol-5-yl1ethvnyl lphenyl)-l,4- dιhydroF1.81naphthyndιn-4-one-3-carboxamιde. Following the procedure of EXAMPLE 19D, but substituting the product from present Step 3 for 3-bromoquιnolιne, the N-isopropyl- 1 -(3- {[2-(l -hydroxy- 1 -methylethyl)- 1, 3- thιazol-5-yl]ethynyl}phenyl)-l,4-dιhydro[l,8]naphthyπdιn-4-one-3-carboxamιde compound was obtained as a solid.
Η NMR (CDC13) δ 1.29 (d, 6H), 1.68 (s, 6H), 2 90 (s, IH, OH), 4 28 (m, IH), 7.42 (d, IH), 7.46 (m, IH), 7.54-7.60 (m, 2H), 7.66 (d, IH), 7.82 (s, IH), 8.70 (m, IH), 8.80 (dd,
IH), 8.99 (s, IH), 9.63 (br, NH).
EXAMPLE 33D
l-F3-(l-Oxιdo-3-pyndιnylethvnyl)phenyl1-l,4-dιhvdroF1.81naphthvndm-4-one-3-carboxamιde
Step 1: l-(3-Bromophenyl)-l,4-dιhydroFl,81naphthvndιn-4-one-3-carboxamιde.
Following the procedure of Step 4 of EXAMPLE ID, but substituting 28% aqueous ammonium hydroxide for isopropylamine, the 1 -(3-bromophenyl)- 1,4- dιhydro[l,8]naphthyπdιn-4-one-3-carboxamιde compound was obtained as a solid.
Step 2: l-F3-(Tnmethylsιlv1ethynyl)phenyl1-l,4-dιhvdroFl,81naphthvndιn-4-one-3-carboxamιde.
Following the procedure of Step 5 of EXAMPLE ID, but substituting the l-(3- Bromophenyl)-l,4-dιhydro[l,8]naphthyπdιn-4-one-3-carboxamιde from present Step 1 for N- ιsopropyl-l-(3-bromophenyl)-l,4-dιhydro[l,8]naphthyπdιn-4-one-3-carboxamιde and tπmethylsilylacetylene for phenylacetylene, the l-[3-(tπmethylsιlylethynyl)phenyl]-l,4- dιhydro[l,8]naphthyπdιn-4-one-3-carboxamιde product was obtained as a solid Step 3: l-(3-Ethvnylphenyl)-l,4-dihvdroFl,81naphthyridin-4-one-3-carboxamide.
To a solution of l-[3-(trimethylsilylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin- 4-one-3-carboxamide from Step 2 in THF (30mL/mmol) at 0°C was added IM tetrabutylammonium fluoride in THF (1.5 eq) and the resulting mixture was stirred at 0°C for 30 minutes. The mixture was partitioned between methylene chloride and water and the organic phase was dried and evaporated. The crude l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide product was used as such in the next step.
Step 4: l-F3-(l-oxido-3-pyridinylethvnyl)phenyl1-l,4-dihvdrori,81naphthyridin-4-one-3- carboxamide.
Following the procedure of example 19D, but substituting the l-(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide from Step 3 for N-Isopropyl- l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide and 3-bromopyridine N- oxide for 3-bromoquinoline, the l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide was obtained as a white solid.
1H NMR (CDC13) δ 5.84 (br, IH, NH), 7.30 (m, IH), 7.41 (d, IH), 7.53 (m, 2H), 7.64 (t, IH), 7.67 (s, IH), 7.74 (d, IH), 8.21 (d, IH), 8.35 (s, IH), 8.75 (m, IH), 8.88 (dd, IH), 9.05 (s, IH), 9.52 (br, IH, NH).
EXAMPLE 34D
l-F3-(l-Oxido-3-pyridinylethvnyl)phenyll-l,4-dihydroF1.81naphthyridin-4-one-3-carboxylic acid
Step 1: Ethyl l-(3-Ethvnylphenyl)-1.4-dihvdroFl,81naphthyridin-4-one-3-carboxylate. Following the procedures of Steps 1 and 2 of EXAMPLE 5D, but substituting ethyl 1 -(3-bromophenyl)- l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from Step 2 of EXAMPLE 1 for N-isopropyl-l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide as the starting material, the Ethyl l-(3-Ethynylphenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxylate compound was obtained as a solid. Step 2: Ethyl l-F3-(l-oxido-3-pyridinylethvnyl)phenvπ-l,4-dihvdroFl,8]naphthyridin-4-one-3- carboxylate.
Following the procedure of EXAMPLE 15D, but substituting the ethyl l-(3- ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate from present Step 1 for 2- phenyl-3-butyn-2-ol and 3-bromopyridine N-oxide for N-isopropyl-l-(3-bromophenyl)-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide, the ethyl l-[3-(l-oxido-3- pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylate was obtained as a solid.
Step 3: l-F3-(l-Oxido-3-pyridinylethynyl)phenyll-l,4-dihydroFl,81naphthyridin-4-one-3- carboxylic acid.
Following the procedure of Step 3 of EXAMPLE ID, but substituting the ethyl 1- [3-( 1 -oxido-3-pyridinylethynyl)phenyl] - 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxylate ester from present Step 2 for ethyl l-(3-bromophenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylate, the l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxylic acid was obtained as a white solid.
1H NMR (DMSO-dό) δ 7.46 (t, IH), 7.51 (d, IH), 7.70 (t, IH), 7.75 (m, 2H), 7.80 (d, IH), 7.92 (s, IH), 8.26 (d, IH), 8.47 (s, IH), 8.81 (dd, IH), 8.89 (m, IH), 8.97 (s, IH).
Other variations or modifications, which will be obvious to those skilled in the art, are within the scope and teachings of this invention. This invention is not to be limited except as set forth in the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of compound selected from the group consisting of:
6-isopropyl-8-(3-{(Z/E)-2-[4-(methylsulfonyl)phenyl]-2-phenylethenyl}phenyl)quinoline;
6-isoρropyl-8-{3-[(E/Z)-2-[4-(methylsulfonyl)ρhenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl Jquinoline;
6-isopropyl-8-(3-{(E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl }phenyl)quinoline;
6-isopropyl-8-(3-{(Z/E)-2-(4-fluorophenyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
2-(2-{(E/Z)-2-[3-(6-isopropyl-8-quinolinyl)phenyl]-l-[4-(methylsulfonyl)ρhenyl]ethenyl}-l,3- thiazol-5-yl)-2-propanol; 2-[8-(3-{(E/Z)-2-[5-(l-hydroxy-l-methylethyl)-l,3-thiazol-2-yl]-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]-2-methylpropanenitrile;
2-methyl-2-[8-(3-{(E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)-6-quinolinyl]propanenitrile;
6-[l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl Jquinoline;
6-[l-methyl-l-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(l,3-thiazol-2- yl)ethenyl]phenyl Jquinoline;
8-(3-{(Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-
(methylsulfonyl)ethyl]quinoline; 8-(3-{(Z)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l- methyl-l-(methylsulfonyl)ethyl]quinoline;
6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
(E/Z)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenyl}-N-isopropyl-2-[4- (methylsulfonyl)phenyl]-2-propenamide;
8-(3-{(E)-2-{3-[(4-methoxyphenoxy)methyl]-l,2,4-oxadiazol-5-yl}-2-[4-
(methylsulfonyl)phenyl]ethenyl }phenyl)-6-[l-methyl-l-(methylsulfonyl)ethyl]quinoline; (5- { (E)-2-(3- { 6-[ 1-methyl- 1 -(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)- 1 -[4-
(methylsulfonyl)phenyl]ethenyl }-l,2,4-oxadiazol-3-yl)methanol;
(E)-N-isopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide; (E)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]phenylJ-2-[4-(methylsulfonyl)phenyl]-2- propenoic acid;
2-methyl-2-[8-(3-{(E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4-
(methylsulfonyl)phenyl]ethenyl Jphenyl)-6-quinolinyl]propanenitrile;
(E)-3- { 3-[6-( 1 -cyano- 1 -methylethyl)-8-quinolinyl]phenyl } -2-[4-(methylsulfonyl)phenyl]-2- propenamide;
E)-N-(tert-butyl)-3-{3-[6-(l-cyano-l-methylethyl)-8-quinolinyl]ρhenyl }-2-[4-
(methylsulfonyl)phenyl]-2-propenamide;
(E)-3-[3-(6-isopropyl-8-quinolinyl)phenyl]-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid;
6-isopropyl-8-(3-{(E)-2-(3-methyl-l,2,4-oxadiazol-5-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
(E)-3-(3- { 6-[ 1 -methyl- 1 -(methylsulfonyl)ethyl]-8-quinolinyl } phenyl)-2- [4-
(methylsulfonyl)phenyl]- 1 -(1 -pyrrolidinyl)-2-propen- 1 -one;
(E)-N-cyclopropyl-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide; (E)-N-(tert-butyl)-3-(3-{6-[l-methyl-l-(methylsulfonyl)ethyl]-8-quinolinyl}phenyl)-2-[4-
(methylsulfonyl)phenyl]-2-propenamide;
8-{3-[2,2-bis(4-chlorophenyl)vinyl]phenyl}-6-isopropylquinoline;
6-isopropyl-8-(3-{(E/Z)-2-(6-methyl-3-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline; 6-isopropyl-8-(3-{ (E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6-isopropylquinoline;
2-methyl-2-[8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-
6-quinolinyl]propanenitrile; 2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6-quinolinyl]-2-methylpropanenitrile;
2-methyl-2-(8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(2-pyridinyl)ethenyl]phenyl}-6- quinolinyl)propanenitrile; 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-
(methylsulfonyl)phenyl]ethenyl}phenyl)quinoline;
2-(6- { (E)-2-(3- { 6-[ 1 -methyl- 1 -(methylsulfonyl)ethyl]-8-quinolinyl Jphenyl)- 1 -[4-
(methylsulfonyl)phenyl]ethenyl}-3-pyridinyl)-2-propanol; 2-[8-(3-{(lE/Z)-3-(dimethylamino)-2-[4-(methylsulfonyl)phenyl]prop-l-enyl }phenyl)quinolin-6- yl]-2-methylpropanenitrile;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 4- { 2-[3 ,4-Bis(difluoromethoxy)phenyl] -2- { 5- [2-( 1 -hydroxy- 1 - methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±)-4- { 2-[3 ,4-Bis(difluoromethoxy)phenyl]-2- { 5- [2-( 1 -hydroxy- 1 -trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl Jpyridine;
(±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-2,2,2- trifluoro)ethyl]thiazolyl Jethyl Jpyridine n-oxide;
(± ±)-4- { 2-[3 ,4-Bis(difluoromethoxy)phenyl]-2- { 5-[2-( 1 -hydroxy- 1 - trifluoromethyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-phenylmethanol)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l- phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l- phenyl)propyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2- cyclohexylmethanol)thiazolyl]ethyl Jpyridine;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-cyclohexyl-2,2,2- trifluoromethyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4- ethyl)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-ethyl)phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide; (±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4- fluoro)phenyl)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(± ±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(4-Huoro)phenyl-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-[5-(2-(l-hydroxy-l-(5-bromopyridin-2-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±/±)-4-{2-[3,4-Bis(difluoromethoxy)ρhenyl]-2-[5-(2-(l-hydroxy-l-(6-bromoρyridin-3-yl)-2,2,2- trifluoro)ethyl)thiazolyl]ethyl Jpyridine n-oxide;
(±)-4- { 2- [3 ,4-Bis(difluoromethoxy)ρhenyl] -2- { 5- [2-( 1 - hydroxy)cyclobutyl]thiazolyl Jethyl Jpyridine N-oxide; (±)-4-{2-[3,4-Bis(difluoromethoxy)phenyl]-2-{5-[2-(l- hydroxy)cyclohexyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{ 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 4-{ 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine;
(±)-4- { 2- [(3-cyclobutyloxy-4-difluoromethoxy)phenyl] -2- { 5-[2-( 1 -hydroxy- 1 -trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine; chiral 3- { 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2- { 5- [2-(l -hydroxy- 1 - methyl )ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine n-oxide; chiral 3-{ 2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide; (±)-4-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l- methyl)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
(±)-3-{2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{5-[2-(l-hydroxy-l-trifluoromethyl-
2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide; chiral 3-{ 2-[(3-cyclopropyloxy-4-difluoromethoxy)phenyl]-2-{ 5-[2-(l-hydroxy-l- trifluoromethyl-2,2,2-trifluoro)ethyl]thiazolyl Jethyl Jpyridine N-oxide;
Ν-Isopropyl-l-[3-(3-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-(2,6-Dichloropyridin-4-yl)-l-[3-(3-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide ; N-Isopropyl-l-[3-(4-n-propylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1 -[3-(4-acetylphenyl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide
N-Isopropyl-l-[3-(2-methylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-N-methyl-l-[3-(4-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(indol-5-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-tert-Butyl-l-[3-(4-acetylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-(2,6-Dichloropyridin-4-yl)-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1- { 3-[ 4-(4-tertbutyloxycarbonylpiperazin- 1 -yl)phenyl]-phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- l-[3-(quinolin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-carboxamide;
N-Isopropyl-l-[3-(pyrimidin-5-yl) phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-carboxamide; N-Cyclopropyl-l-[3-(pyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(5-methylthiopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(4-hydroxymethylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(pyridin-4-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(4-ethylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide ;
N-Cyclopropyl-l-[3-(3-thienyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-l-[3-(4-sulfamoylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- l-[3-(3-ethoxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- l-[3-(4-methylthiophenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-acetyl-4-hydroxyphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(5-carboethoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl- 1 - { 3-[5-(l-hydroxy- 1 -methylethyl)pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-{3-[6-(2-methylpropyl)pyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Isopropyl- l-[3-(5-acetylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(6-methylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyrimidin-5-yl) phenyl]- l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; l-{3-[6-(l-Hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]phenylJ-l,4-dihydro[l,8]naphthyridin-
4-one-3-carboxamide;
N-Isopropyl-l-{3-[4-(pyridin-3-yl)phenyl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl- l-[3-(5-methylsulfonylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Cyclopropyl- 1 - { 3-[4-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-{ 3-[5-(l-hydroxy-l-methylethyl)pyridin-2-yl]phenyl } 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3-[3-(l -hydroxy- 1 -methylethyl)pyridin-4-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-l-{3-[3-(l-hydroxy-l-methylethyl)-l-oxidopyridin-4-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-isopropylsulfonylpyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide; N-Cyclopropyl-l-[3-(6-methoxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl- l-[3-(6-methylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-{3-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(5-bromopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(6-benzyloxypyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-{3-[6-dicyclopropyl(hydroxy)methyl-l-oxidopyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3-[5-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-2-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-{3-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isobutyl-l-{3-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]phenyl}-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 5-bromo-3-[6-( 1 -hydroxy- 1 -methylethyl )pyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl- l-{3-[6-(l-hydroxy-l-methylethyl)pyridin-2-yl]phenyl}-l, 4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(4-methylsulfonylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(6-methylsulfonylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one- 3-carboxamide;
N-Isopropyl-l-[3-(5-methylsulfonylpyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(4-ethylsulfonylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(4-ethylsulfinylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl-l-{3-[4-(l-oximidoethyl)phenyl]phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-{3-[ 4-(4-piperazin-l-yl)phenyl]-phenyl}-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(4-methylsulfonylmethylphenyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Cyclopropyl-l-[3-(l,6-dihydro-6-oxopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3 -carbox amide ;
N-Cyclopropyl- 1 -[ [3- { 5- [6-( 1 -hydroxy- 1 -methylethyl)pyridin-3-yl]pyridin-3-yl } phenyl] ]- 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-(2,6-Dichloropyridin-4-yl)-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Isopropyl-l-[3-(5-carboethoxy-l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Isopropyl- 1 - { 3-[5-(l -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1- { 3-[6-(2-methylpropyl)- l-oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(6-methyl-l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Cyclopropyl-l-{3-[6-(l-hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]phenyl }-l,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(l-oxidopyridin-4-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(5-bromo-l-oxidopyridin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-
3-carboxamide;
N-Cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)-l-oxidopyridin-3-yl]pyridin-3- yl}phenyl]]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Cyclopropyl-l-[[3-{5-[6-(l-hydroxy-l-methylethyl)pyridin-3-yl]-l-oxidopyridin-3- ylJphenyl]]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 -[[3- { 5- [6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl] - 1 -oxidopyridin-3- yl}phenyl]]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(l-oxidoquinolin-3-yl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one- carboxamide;
N-Isobutyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-[3-(6-methyl-l-oxidopyridin-3-yl)]phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide; N-Cyclopropyl- l-[3-(6-methylsulfonyl-l oxidopyridin-3-yl)phenyl]-l,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 5-bromo-3-[6-( 1-hydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3-[6-( 1 ,2-dihydroxy- 1 -methylethyl)- 1 -oxidopyridin-3-yl]phenyl J - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide.
N-Isopropyl-l-[ 3-(phenylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(2-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(4-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(l-oxido-4-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl-l-(3-ethynylphenyl)-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-l-[3-(3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carbox amide;
N-Isopropyl-l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-hydroxy-3-methylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(3-hydroxy-3-methylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4- one-3-carboxamide;
N-Isopropyl-l-[3-(l-hydroxycyclopentyl)ethynylphenyl]-l ,4-dihydro[ 1 ,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(l-hydroxycyclopropyl)ethynylphenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-l-ynyl]phenyl}-l,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-[3-(3-hydroxy-3-phenylbut-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Cyclopropyl-l-[3-(l-oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(3-amino-3-ethylpent-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; or
N-Cyclopropyl-l-[3-(3-amino-3-ethylpent-l-ynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1 - [3-(3-quinolinylethynyl)phenyl] - 1 ,4-dihydro [ 1 ,8]naphthyridin-4-one-3- carboxamide; or
N-Isopropyl-l-[3-(l-oxido-3-quinolinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide; N-Isopropyl-l-[3-(cyclopropylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl-l-[3-(6-amino-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1- { 3-[5-( 1 -hydroxy- 1 -methylethyl)- l-oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl- 1 - { 3-[6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- l-{3-[4-(l-hydroxy-l-methylethyl)-2-pyridinylethynyl]phenyl}- 1,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl- l-{3-[5-(l -hydroxy- 1 -methylethyl)-2-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl)-2-pyridinylethynyl]phenyl } - 1 ,4- dihydro[ 1 ,8]naphthyridin-4-one-3-carboxamide;
N-Cyclopropyl- 1 - { 3- [6-( 1 -hydroxy- 1 -methylethyl)- 1 -oxido-3-pyridinylethynyl]phenyl } - 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide;
N-Isopropyl-l-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenylJ-l,4-dihydro[l,8]naphthyridin-4-one-3- carboxamide;
N-Isopropyl- 1 -(3- { [5-( 1 -hydroxy- 1 -methylethyl)thien-2-yl]ethynyl } phenyl)- 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl- 1 -(3- { [2-( 1 -hydroxy- 1 -methylethyl)- 1 ,3-thiazol-5-yl]ethynyl } phenyl)- 1 ,4- dihydro[l,8]naphthyridin-4-one-3-carboxamide; l-[3-(l-Oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxamide; or l-[3-(l-Oxido-3-pyridinylethynyl)phenyl]-l,4-dihydro[l,8]naphthyridin-4-one-3-carboxylic acid; or a pharmaceutically acceptable salt thereof.
2. A method of enhancing cognition in a healthy subject according to claim 1 comprising administering a safe, non-emetic, cognition enhancing amount of compound.
3. A method of enhancing cognition in a healthy subject according to claim
2, wherein the healthy subject is a human 40 years of age or older.
4. A method of enhancing cognition in a healthy subject according to claim
2, wherein the healthy subject is a human 55 years of age or older.
5. A method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of compound selected from the group consisting of:
Figure imgf000129_0001
X
Figure imgf000129_0002
Figure imgf000129_0003
or a pharmaceutically acceptable salt thereof.
6. A method of enhancing cognition in a healthy subject according to claim 1 comprising administering a safe, non-emetic, cognition enhancing amount of compound.
7. A method of enhancing cognition in a healthy subject according to claim 2, wherein the healthy subject is a human 40 years of age or older.
8. A method of enhancing cognition in a healthy subject according to claim 2, wherein the healthy subject is a human 55 years of age or older.
9. Use of a compound as set forth in claim 1 or 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing cognition in a healthy subject.
10. A compound as set forth in claim 1 or 6, or a pharmaceutically acceptable salt thereof for use in enhancing cognition in a healthy subject.
11. A pharmaceutical composition for enhancing cognition in a healthy subject comprising an effective cognition enhancing amount of a compound as set forth in claim 1 or 6, or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
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