WO2008094473A1 - Substituted pyrano[2,3-b]pyridine derivatives as cannabinoid-1 receptor modulators - Google Patents

Substituted pyrano[2,3-b]pyridine derivatives as cannabinoid-1 receptor modulators Download PDF

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WO2008094473A1
WO2008094473A1 PCT/US2008/001033 US2008001033W WO2008094473A1 WO 2008094473 A1 WO2008094473 A1 WO 2008094473A1 US 2008001033 W US2008001033 W US 2008001033W WO 2008094473 A1 WO2008094473 A1 WO 2008094473A1
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Prior art keywords
chlorophenyl
pyrano
pyridin
dihydro
dimethyl
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PCT/US2008/001033
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French (fr)
Inventor
John S. Debenham
Jeffrey J. Hale
Pei Huo
Christina B. Madsen-Duggan
Thomas F. Walsh
Lin Yan
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Merck & Co., Inc.
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Publication of WO2008094473A1 publication Critical patent/WO2008094473A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • C07D491/044Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/18Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/22Anxiolytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems
    • C07D491/107Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10Spiro-condensed systems
    • C07D491/113Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20Spiro-condensed systems

Definitions

  • Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes.
  • a major active ingredient in marijuana and hashish has been determined to be ⁇ 9-tetrahydrocannabinol ( ⁇ 9-THC).
  • ⁇ 9-THC ⁇ 9-tetrahydrocannabinol
  • CBl and CB2 G-protein coupled receptors
  • the CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
  • the CB2 receptor is found primarily in lymphoid tissues and cells.
  • CBl modulators characterized as inverse agonists/antagonists, ACOMPLIA (rimonabant, N-( 1 -piperidinyl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide, SRl 41716A), and 3-(4-chlorophenyl- ⁇ -(4- chlorophenyl)sulfonyl-7V-methyl-4-phenyl-4,5-dihydro- 1 H-pyrazole- 1 -carboxamide (SLV-319), and taranabant, N-[( 1 S,2S)-3 -(4-Chlorophenyl)-2-(3 -cyanophenyl)- 1 -methylpropyl] -2-methyl-2- [[5-(trifluoromethyl)-2-pyridinyl]oxy]propanamide, in clinical development for treatment of eating disorders and/or smoking
  • Naphthyridone CBl antagonists/inverse agonists are described in Debenham, et al., Bioorg. Med. Chem. Lett. 16: 681-685 (2006) and in WO 05/047285.
  • Pyranopyridine derivatives are described in the following publications: EP 895994, WO 98/09969, WO 99/03859, WO 01/98306, WO 03/032897, WO 05/000250, WO 05/042697, and WO 06/045096.
  • the present invention is concerned with pyrano[2,3- ⁇ ]pyridines of general formula I:
  • the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor.
  • compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, Huntington's disease, movement disorders, and schizophrenia.
  • the compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, and complications associated therewith, including left ventricular hypertrophy, as well as the treatment of asthma, constipation, chronic intestinal pseudoobstruction, and cirrhosis of the liver.
  • the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
  • the present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
  • the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient, as well as processes for preparing the compounds of this invention.
  • X is selected from: (1) halogen,
  • heteroaryl-Ci-3alkyl unsubstituted or substituted on heteroaryl with one, two, or three substituents independently selected from Rb,
  • X is selected from:
  • Xl is hydrogen, or
  • X is selected from: (1) oxadiazolyl, unsubstituted or substituted on a carbon atom with methyl,
  • Rl is selected from: hydrogen, Ci-6alkyl, C3_7cycloalkyl, C3-8cycloalkenyl, C3-7cycloalkyl-Ci_4alkyl, C3- 8cycloalkenyl-Ci-4alkyl, cycloheteroalkyl, cycloheteroalkyl-Ci-4alkyl, phenyl, benzyl, heteroaryl, heteroaryl-Ci-4alkyl, -C(O)NH-S(O)2-CH3, wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from R a , and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to four substituents independently selected from Rb;
  • Rl is selected from: (1) hydrogen,
  • Ci-6alkyl unsubstituted or substituted with hydroxy, fluoro, or methylsulfonylmethyl
  • R2 is selected from: (1) Ci-6alkyl, unsubstituted or substituted with hydroxy, fluoro, or methylsulfonyl,
  • ROl is selected0 from:.- hyd>roOgen, m0ethyl-, and ethyl
  • R2 is selected from: methyl, ethyl, isopropyl, and t-butyl; or Rl and R2 together with the carbon to which they are attached form the spiroannulated ring system:
  • Rl and R2 are each methyl or together form:
  • R4 is selected from: -H; halo-; -CN; Ci- 3alkyl-, unsubstituted or substituted with one, two or three Rh substitutents; -CF3; -ORd; and - OCF3.
  • R4 is selected from: halo-; -CN; C1.3a.kyl-, unsubstituted or substituted with one, two or three Rh substitutents; -CF3; -ORd; and -OCF3.
  • R4 is selected from: halo-, -CN, -CH3, -CF3, -OCH3, -OCH2CF3, and -OCF3.
  • R4 is chloro.
  • R6 is selected from:
  • cycloalkyl unsubstituted or substituted with one or two Rh substitutents
  • cycloheteroalkyl unsubstituted or substituted with one or two Rh substitutents
  • R6 is not hydrogen.
  • R6 is selected from: -F; -Cl; -Br; -I; -CN; -CH3; -CF3; oxadiazolyl, unsubstituted or substituted with one or two Rh substitutents; pyrazolyl; thienyl; furyl; oxazolyl; -OH; -OCH3; -OCF3; -OCH2CF3; and -CO2CH3.
  • R6 is selected from: -Cl, -Br, -CN, -CH3, -CF3, and 1,2,4-oxadiazolyl. hi a subclass, R6 is chloro.
  • R? is selected from:
  • R6 is hydrogen
  • R? is not hydrogen
  • R7 is selected from:
  • R7 is selected from: -H, -F; -Cl; -Br; -I; -CN; -CH 3 ; -CF 3 ; oxadiazolyl, unsubstituted or substituted with one or two Rh substitutents; pyrazolyl; thienyl; furyl; oxazolyl; -OH; -OCH 3 ; -OCF 3 ; -OCH2CF3 ; and -CO2CH 3 ; PROVIDED THAT, if R6 is hydrogen, R? is not hydrogen.
  • R? is hydrogen or chloro;.
  • each R a is independently selected from: -OH, -OCH3, halogen, — SH, -S ⁇ 2R d , -NH2, -CN, -C ⁇ 2R d , -C(O)NRCRd, -CF 3 , and -OCF 3 .
  • each R a is independently selected from: -OH, -F, -SO2CH 3 , -CO2-C1-
  • each R a is independently selected from: -OH, -F, and -CF 3 .
  • each R ⁇ is independently selected from: -OH, -OCH 3 , halogen, - SH, -S ⁇ 2R d , -NH2, -CN, -C ⁇ 2R d , -C(O)NRCRd, -CF 3 , -OCF 3 , oxo, Ci-ioalkyl, C2-10 alkenyl, cycloalkyl, cycloalkyl-C 1.1 Oalkyl, cycloheteroalkyl, cycloheteroalkyl-C 1.10 alkyl, aryl, heteroaryl, aryl-Ci-K)alkyl, and heteroaryl-Ci_io a lkyl; wherein alkyl and alkenyl moieties are unsubstituted or substituted
  • each EP is independently selected from: -OH, -OCH3, halogen, — N(CH3)2, -CH(O), -C(O)Rd 5 -CO2CH3, -CO2CH2C6H5, -CN, -CF3, -OCF3, oxo, Ci_3alkyl, C2-3 alkenyl, cyclopropyl, oxadiazolyl, pyrazolyl, tetrazolyl, and phenyl; wherein alkyl and alkenyl moieties are unsubstituted or substituted with one, two, or three Rk substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rk substituents.
  • each R c is independently selected from: hydrogen, Ci_ioalkyl, C2- 10 alkenyl, cycloalkyl, cycloalkyl-C 1.1 oalkyl-, cycloheteroalkyl, cycloheteroalkyl-C 1.10 alkyl-, aryl, heteroaryl, aryl-Ci-i oalkyl-, and heteroaryl-Ci-i oalkyl-; wherein each Rc and Rd moiety, other than hydrogen, may be unsubstituted or substituted with one to three substituents selected
  • each R c is independently selected from: hydrogen, and methyl.
  • each Rd is independently selected from: hydrogen, Ci _i oalkyl, C2-
  • each Rd is independently selected from: hydrogen, Ci-6alkyl, C2-6alkenyl, cycloalkyl, cycloalkyl-Ci-i oalkyl-, cycloheteroalkyl, cycloheteroalkyl-C i-i o alkyl-, aryl, heteroaryl, aryl-Ci-3alkyl-, and heteroaryl-Ci_3alkyl-; wherein each Rd moiety, other than hydrogen, may be unsubstituted or substituted with one, two or three substituents selected from Rh.
  • each R ⁇ is independently selected from: halogen, Ci_6alkyl, unsubstituted or substituted with one or two Ri substituents, and -N(CH3)2.
  • each R ⁇ is independently selected from: chloro, ethyl, n-propyl, chloropropyl, and -N(CH3)2.
  • each R ⁇ is independently selected from: hydrogen, -OH, and methyl.
  • each Rh is independently selected from: halogen, Ci_6alkyl, 4-methylbenzyl-, -OH, -O-Ci-4alkyl, benzyloxy-, -oxo, -OC(O)-C 1. oalkyl, -C(O)O-Ci -oalkyl, -S-Ci_4alkyl, -NH2, -NH(CH3), -N(CH3)2, -NO2, -CN, -CF3, and -OCF3; wherein alkyl may be unsubstituted or substituted with one, two or three substituents selected from Ri.
  • each R 1 is independently selected from: halogen, -O-Ci_4alkyl, -OH, -S-Ci-4alkyl, -CN, -CF3, and -OCF3.
  • each R ⁇ is independently selected from: halogen, oxo, amino, hydroxy, Ci-4alkyl, -O-Ci_4alkyl, -S-Ci-4alkyl, -CN, -CF3, and -OCF3.
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
  • Cycloalkyl means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooxtyl, tetrahydronaphthyl, decahydronaphthyl, bicycloand the like.
  • cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 1,2,3,4-tetrahydronaphthyl.
  • Cycloalkenyl means nonaromatic, mono- or bicyclic or bridged carbocyclic rings, each having from 3 to 10 carbon atoms and at least one degree of unsaturation.
  • Examples of cycloalkyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl, decahydronaphthyl, bicyclo[2.2.1]hept-5-en-2-yl, and the like.
  • cycloalkenyl is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and bicyclo[2.2.1]hept-5-en-2-yl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteratom selected from O, S, and N. Heteroaryls thus inclue heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and cycloheteroalkyls that are not aromatic.
  • heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazaolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, dibenzylfuranyl, isobenzylfuranyl, benzopyrazolyl, benzothienyl, benzothiazolyl, furo(2,3- ⁇ )pyridyl, quinolyl, indolyl, isoquinolyl, oxazolidinyl, imidazothiathiazolyl, pyrazolylpyridyl,
  • heteroaryl is selected from pyridyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, indazolyl, oxadiazolyl, tetrazolyl, imidazolyl, indolyl, benzimidazolyl, triazolyl, and benzopyrazolyl.
  • Cycloheteroalkyl refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S and N, further including the oxidized forms of sulfur, namely SO and SO2, in which the point of attachment may be carbon or nitrogen.
  • heterocycloalkyl examples include tetrahydrofuranyl, azetidinyl, perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, piperidinyl, 1,3- dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl, thiomo ⁇ holinyl, dioxidoisothiazolidinyl, azacycloheptyl, diazobicyclo[3.2.1]-octane, and hexahydroindazolyl.
  • cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens, hi one embodiment of the present invention, cycloheteroalkyl is selected from tetrahydrofuranyl, imidazolidinyl, piperidinyl, pyrrolidinyl, isothiazolidinyl, morpholinyl and thiomorpholinyl.
  • “Spiroannulated Ring system” refers to a compound having two rings which have only one atom in common, and the two rings are not linked by a bridge. These systems can be part of larger polycyclic ring systems.
  • the common atom is known as a spiro atom.
  • Particular spiroannulated substituents of the present invention include:
  • any variable e.g., Rl, Rd, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • a squiggly line across a bond in a substituent variable represents the point of attachment.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound.
  • Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
  • crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. 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, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • pharmaceutically acceptable salt further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolly
  • Compounds of the present invention are modulators of the CBl receptor.
  • the compounds of structural formula I are antagonists or inverse agonists of the CBl receptor.
  • Compounds of this invention are modulators of the CBl receptor as antagonists/inverse agonists and as such are useful as centrally acting drugs in the treatment of psychosis; memory deficits; cognitive disorders; Alzheimer's disease; migraine; neuropathy; neuro-inflamrnatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma; anxiety disorders; stress; epilepsy; Parkinson's disease; Huntington's disease; movement disorders; schizophrenia; substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine; obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy, as well as treating or preventing obesity in other mammalian species, including canines and felines; cirrhosis of the liver; non-alcoholic fatty liver disease (NAFLD
  • prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a mammal, particularly a human or companion animal such as a dog or cat, with an effective dosage of a compound of the present invention.
  • a mammal particularly a human or companion animal such as a dog or cat
  • an effective dosage of a compound of the present invention for example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient.
  • Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like.
  • the topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. hi practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • capsules including timed release and sustained release formulations
  • pills including timed release and sustained release formulations
  • cachets powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion or a water-in-
  • each tablet, cachet, or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular, intranasal and topical, with or without occlusion.
  • Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier.
  • Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
  • the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
  • Lactose Powder 573.5 Microcrystalline Cellulose 415 MMaaggnneessiiuumm SStteeaarraattee 11..55 Povidone 14.0
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, antimigraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti -Parkinson's agents, anti-Huntington's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, other anti-obesity agents, as well as antidiabetic agents, lipid lowering agents, and antihypertensive agents which may be administered separately or in the same pharmaceutical compositions.
  • Specific compounds of use in combination with a compound of the present invention include: simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, and losartan, losartan with hydrochlorothiazide.
  • Specific CBl antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO03/077847, including: N-[3- (4-chlorophenyl)-2(5)-phenyl- 1 (5)-methylpropyl] -2-(4-trifluoromethyl-2-pyrimidyloxy)-2- methylpropanamide, N- [3 -(4-chlorophenyl)-2-(3 -cyanophenyl)- 1 -methylpropyl] -2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(5-chloro-3- pyridyl)-l-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically acceptable salts thereof; as well as those in WO05/000809, which includes the following: 3- ⁇
  • NPY5 antagonists of use in combination with a compound of the present invention include: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-l(3 ⁇ ),4'-piperidine]-r- carboxamide, 3 -oxo-N-(7-trifluoromethylpyrido [3 ,2-b]pyridin-2-yl)spiro- [isobenzofuran- l(3H),4'-piperidine]-r-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro- [isobenzofuran- 1 (3 H),4 ' -piperidine] - 1 ' -carboxamide, trans-3 ' -oxo-N-(5 -phenyl-2- pyrimidinyl)spiro [cyclohexane- 1 , 1' (3 ' H)-
  • Specific ACC- 1/2 inhibitors of use in combination with a compound of the present invention include: r-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(lH-tetrazol-5-yl)spiro[chroman- 2,4'-piperidin]-4-one; (5- ⁇ r-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4'- piperidin]-6-yl ⁇ -2H-tetrazol-2-yl)methyl pivalate; 5- ⁇ l'-[(8-cyclopropyl-4-methoxyquinolin-2- yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6-yl ⁇ nicotinic acid; 1 '-(8-methoxy-4- mo ⁇ holin-4-yl-2-naphthoyl)-6 : (l//-te
  • Specific MC ⁇ 1R antagonist compounds of use in combination with a compound of the present invention include: l- ⁇ 4-[(l-ethylazetidin-3-yl)oxy]phenyl ⁇ -4-[(4- fluorobenzyl)oxy]pyridin-2( 1 H)-one, 4-[(4-fluorobenzyl)oxy] - 1 - ⁇ 4- [( 1 -isopropylazetidin-3 - yl)oxy]phenyl ⁇ pyridin-2(lH)-one, l-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one, 4-[(5-chloropyridin-2-yl)methoxy]-l- ⁇ 4-[(l-ethylazetidin-3- yl)oxy]phenyl ⁇ pyridin-2(lH)-one,
  • a specific DP-FV inhibitors of use in combination with a compound of the present invention is 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8- tetrahydro-l,2,4-triazolo[4,3-a]pyrazine, or a pharmaceutically acceptable salt thereof.
  • ⁇ 3 (histamine H3) antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO05/077905, including:3- ⁇ 4- [(l-cyclobutyl-4-piperidinyl)oxy]phenyl ⁇ -2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one, 3- ⁇ 4-[(l- cyclobutyl-4-piperidinyl)oxy]phenyl ⁇ -2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-ethyl-3-(4- ⁇ 3 - [(3 S)-3 -methylpiperidin- 1 -yljpropoxy ⁇ phenyl)pyrido [2,3 -d]pyrimidin-4(3H)-one 2-methyl-3 - (4- ⁇ 3-[(3S)-3-methylpiperidin-l-yl]propoxy ⁇ phenyl)pyrido[
  • Specific CCKlR agonists of use in combination with a compound of the present invention include: 3-(4- ⁇ [l-(3-ethoxyphenyl)-2-(4-methylphenyl)-lH-imidazol-4-yl]carbonyl ⁇ - 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- ⁇ [ 1 -(3 -ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)- IH- imidazol-4-yl]carbonyl ⁇ - 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- ⁇ [ 1 -(3 -ethoxyphenyl)-2-(4- fluorophenyl)- 1 H -imidazol-4-yl]carbonyl ⁇ - 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- ⁇
  • Specific MC4R agonists of use in combination with a compound of the present invention include: 1 ) (55)- 1 '- ⁇ [(3R,4R)- 1 -tert-butyl-3 -(2,3 ,4-trifluorophenyl)piperidin-4-yl]carbonyl ⁇ -3 - chloro-2-methyl-5-[ 1 -methyl- 1 -( 1 -methyl- 1 H- 1 ,2,4-triazol-5 -yl)ethyl] -5H-spiro [furo [3 ,4- ⁇ ]pyridine-7,4'-piperidine] ; 2) (5R)- 1 '- ⁇ [(3R,4R)- 1 -tert-butyl-3 -(2,3 ,4-trifluorophenyl)-piperidin- 4-yl]carbonyl ⁇ -3-chloro-2-methyl-5-[l-methyl-l-(l-methyl-lH-l,2,4-
  • the obesity-related disorders herein are associated with, caused by, or result from obesity.
  • obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, G ⁇ -deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat- free mass, e.g, children with acute lymphoblastic leukemia.
  • obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
  • the compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
  • the compounds of formula I are also useful for treating or preventing obesity and obesity-related disorders in cats and dogs.
  • the term “mammal” includes companion animals such as cats and dogs.
  • substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
  • the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
  • compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependence and nicotine withdrawal.
  • the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist, including varenicline and selective alpha-4 beta 2 nicotinic partial agonists such as SSR 591813, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.
  • a nicotine agonist or a partial nicotine agonist including varenicline and selective alpha-4 beta 2 nicotinic partial agonists such as SSR 591813, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption
  • an antidepressant such as bupropion, doxepine, ornortriptyline
  • an anxiolytic such as buspirone
  • the method of treatment of this invention comprises a method of modulating the CBl receptor and treating CBl receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CB 1 receptor in preference to the other CB or G-protein coupled receptors.
  • reaction schemes illustrate methods which may be employed for the synthesis of the novel pyrano[2,3-6]pyridines of structural formula I described in this invention. All substituents are as defined above unless indicated otherwise.
  • Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the title compounds of general formula I.
  • a preferred synthetic process which is shown in the retrosynthetic sense in reaction Scheme 1 proceeds through a suitably substituted 3- cyano-2-pyridone of general formula 2.
  • the 3-cyano-2-pyridone of general formula 2 is in turn derived from a 1 ,2-diarylethanone of general formula 1.
  • Reaction Schemes 2-7 illustrate the preferred methods for the synthesis of the novel compounds of general formula I in the forward sense.
  • group Ar 1 refers to the aryl group substituted by the substituent R 4 position 6 of the pyrano[2,3- ⁇ ]pyridine of general formula I
  • Ar 2 refers to the aryl group substituted by the substituents R 6 and R 7 at position 7 of the pyrano[2,3-6]pyridine of general formula I.
  • 1 ,2-Diarylethanones of general formula 1 may be available commercially or they can be synthesized using one of several methods known in the art of organic synthesis.
  • Scheme 2 illustrates three methods for the synthesis of the 1 ,2-diarylethanones of general formula 1.
  • a substituted arylmethyl bromide of general formula 3 is converted to a Grignard reagent with magnesium metal in a solvent such as THF at a temperature between room temperature and the refluxing temperature of the solvent.
  • the resulting Grignard reagent is then added to a substituted arylnitrile of general formula 4.
  • a third method for the preparation of the 1 ,2-diarylethanones of general formula 1 involves the palladium-catalyzed ⁇ -arylation of an acetophenone derivative of general formula 8 with an aryl halide, such as the aryl bromide of general formula 7, as illustrated in equation 3 (Fox, J.M.; Huang, X.; Chieffi, A.; Buchwald, S.L. J. Am. Chem. Soc. 2000, 122, 1360-70).
  • Reaction Scheme 3 illustrates two methods for the conversion of the 1 ,2-diarylethanone of general formula 1 into the 3-cyano-2-pyridones of general formula 2.
  • the 1 ,2-diarylethanone of general formula 1 is first converted to a vinylogous amide of general formula 9 by reaction with an ⁇ yV-dimethylformamide dimethylacetal.
  • the condensation reaction may be conducted using a solvent such as acetonitrile or simply by using the DMF acetal as the reaction solvent at an elevated temperature, typically between room temperature and 150 0 C, and the vinylogous amide 9 is produced as a mixture of E and Z diastereoisomers.
  • the vinylogous amide 9 is condensed with cyanoacetamide to afford the 3-cyano-2- pyridone of general formula 2.
  • the reaction is usually conducted in a polar aprotic solvent such as DMF in the presence of a strong base such as an alkali metal hydride or alkoxide.
  • reaction Schemes 4 A preferred method for the next stage of the synthesis of the novel compounds of general formula I is illustrated in reaction Schemes 4.
  • a 3-cyano-2-pyridone of general formula 2 is converted to an ⁇ , ⁇ -unsaturated ketone of general formula 13, which can undergo a spontaneous intramolecular Michael addition with the adjacent nucleophilic pyridone oxygen atom.
  • the resulting product is the substituted 2,3-dihydro-4//-pyrano[2,3- ⁇ ]pyridin-4-one 17, which corresponds to the title compounds of general formula I wherein the X and X 1 substituents together form a carbonyl group, and there is a single bond between the carbon atoms at positions 3 and 4 of the pyran ring.
  • the 3 -cyano-2 -pyridone of general formula 2 may be converted to the intermediate ⁇ , ⁇ -unsaturated ketone of general formula 13, using one of several synthetic methods. For instance, reaction of 2 with a vinyl Grignard reagent of general formula 12 followed by acidic hydrolysis of the reaction mixture affords the ⁇ , ⁇ -unsaturated ketones of general formula 13 which in turn undergo the intramolecular cyclization that leads to compounds of general formula 17.
  • the 3-cyano-2-pyridones (2) may be first converted to a ketone general formula 15, typically by reaction with an organometallic species, such as the Grignard reagent of general formula 14, followed by acidic hydrolysis.
  • Reaction of the resulting ketone 15 under basic conditions with a carbonyl compound of general formula 16 effects an aldol condensation.
  • a preferred method for conducting the aldol condensation involves using a secondary or tertiary amine as the base and conducting the reaction at an elevated temperature, for instance at temperatures between room temperature and 150°C. Under these conditions, the aldol condensation results in concomitant loss of water to initially afford an ⁇ , ⁇ -unsaturated ketone of general formula 13, which in turn may undergo the intramolecular cyclization that leads to compounds of general formula 17 as described above.
  • reaction Schemes 5-7 illustrate some of the preferred synthetic methods for the conversion of compounds (17) to the novel compounds of general formula I described in this invention.
  • reaction Scheme 5 reduction of the carbonyl group at the 4-position of the pyran ring in compounds of general formula 17 results in a secondary alcohol of general formula 18.
  • the reduction of 17 can be accomplished using a variety of metal hydride reducing agents such as sodium borohydride in suitable solvent systems such as T ⁇ F/methanol.
  • the resulting secondary alcohols of general formula 18 contain a new stereogenic center and are formed as either a racemic mixture or as a mixture of diastereoisomers when an additional stereogenic center is present in the compound.
  • Racemic mixtures of general formula 18 may be separated into their component enantiomerically pure alcohols by classical resolution methods, or by separation using chiral stationary phase ⁇ PLC columns.
  • the reduction of the carbonyl group in compounds of general formula 17 may also be accomplished using asymmetric reduction methods such as hydrogenation in the presence of a chiral organometallic catalyst ( ⁇ aack, K.J.; ⁇ ashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. Engl.
  • the hydroxyl group of compounds of general formula 18 may also be displaced by a new functional group.
  • One preferred method for the hydroxyl displacement is the Mitsunobu reaction with a zinc azide complex (Viaud, M.C.; Rollin, P. Synthesis 1990, 130-2) which affords the azido compound of general formula 20.
  • the amino group may also be N-alkylated using reductive amination reactions or N-arylated using palladium catalyzed coupling reactions with suitable aryl or heteroaryl halides (Muci, A.R.; Buchwald, S. L. Topics in Current Chemistry 2002, 219 Cross-Coupling Reactions, 131-209. Hartwig, J.F. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 1051-96).
  • the amino group of compounds of general formula 21 may also be incorporated into various nitrogen heterocyclic systems when it is desired that either the X or X 1 substituent in the compounds of general formula I be such a heterocyclic element.
  • Reaction Scheme 6 illustrates two additional methods for the synthetic modification of the substituted 2,3-dihydro-4H-pyrano[2,3- ⁇ ]pyridin-4-ones of general formula 17 when it is desired that either the X or X 1 substituent be an amino or optionally substituted amino group.
  • the carbonyl group of compounds of general formula 17 may be subjected to reductive amination reactions with primary or secondary amino compounds 22, for instance using either sodium cyanoborohydride, sodium triacetoxy borohydride, or sodium borohydride in combination with titanium tetraisopropoxide as the reducing agent, and the substituted 4- aminopyrano[2,3- ⁇ ]pyridine derivatives of general formula 21 are again produced.
  • the substituted amino compounds of general formula 21 may be further modified into the title compounds of general formula I using the methods described above.
  • Reaction Scheme 7 illustrates methods for the synthetic modification of the substituted 2,3-dihydro-4H-pyrano[2,3-Z>]pyridin-4-ones of general formula 17 when it is desired that either the X or X 1 be a carbon substituent.
  • the carbonyl group of compounds of general formula 17 undergo carbon-carbon bond forming reactions with nucleophilic carbon reagents that are commonly employed in organic synthesis.
  • the compounds of general formula 17 may react in Wittig or ⁇ orner-Emmons olefination reactions, with organometallic reagents such as Grignard reagents or with a variety of stabilized carbanionic species such as enolates, and the like.
  • Scheme 7 illustrates the reaction of a compound of general formula 17 with a Reformatsky reagent (25) which produces the tertiary alcohol of general formula 26.
  • the alcohols of general formula 26 may be further synthetically modified, for instance they may be dehydrated to afford derivatives containing a new double bond, which is generally produced as a separable mixture of the endocyclic and exocyclic isomers.
  • the carbonyl group of compounds of general formula 17 may also be converted to vinyl triflates of general formula 27 by treatment with a reagent such as trifluoromethansulfonic anhydride or N-phenyl-bis(trifluoromethane-sulfonimide) in the presence of a suitable base.
  • Vinyl triflates of general formula 27 may then be employed in a variety of palladium-catalyzed cross coupling reactions to afford compounds of general formula 28. For instance, when triflates of general formula 27 are reacted with aryl, heteroaryl, or vinylboronic acids in the presence of a palladium catalyst, the compounds of general formula 28 are produced wherein the X group is an aryl, heteroaryl or vinyl substituent. Additionally, the triflates of general formula 27 may be converted to carboxylic acid derivatives. Hydroxycarboxylation of compounds of general formula 27 using potassium acetate, carbon monoxide and a palladium catalyst in DMSO (Cacchi, S.; Lupi, A. Tetrahedron Lett.
  • Reaction Scheme 8 illustrates a preferred method for the synthesis of the novel compounds of general formula I described in this invention when it is desired that the R 1 and R 2 substituents together form a carbonyl group.
  • the cyano group of the substituted 3-cyano-2-pyridone of general formula 2 is first reduced to an aldehyde using a reagent such as diisobutylaluminum hydride in a solvent such as toluene.
  • the resulting substituted 2-pyridone-3-carboxaldehydes of general formula 29 may then be condensed with a variety of substituted acetic ester derivatives of general formula 30 under basic reaction conditions.
  • the group Y is typically an electron-withdrawing group such as a carbonyl, cyano group or the like, which is capable of further stabilizing the enolate of the ester of general formula 30.
  • the deprotonated form of the ester 30 condenses with the formyl group of the 2-pyridone-3-carboxaldehydes of general formula 29.
  • This condensation reaction is typically conducted at an elevated temperature, such as the boiling point of the solvent used, and under these conditions the resulting intermediate from this condensation (eg. 31) may then further cyclize to form the pyrone ring of the 2//-pyrano[2,3- ⁇ ]pyridin-2-one of general formula 32.
  • Compounds of general formula 32 correspond to the title compounds of general formula I wherein the R 1 and R 2 taken together form a carbonyl group, the X group is a hydrogen atom, X 1 is absent, and there is a double bond between the carbon atoms at positions 3 and 4 of the pyran ring.
  • the compounds of general formula 32 described in Scheme 8 may be further modified into the novel compounds of general formula I using the methods described in the preceding reaction Schemes for the compounds of general formula 17, or by using other synthetic reactions known in organic chemistry.
  • Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents.
  • the progress of reactions was determined by either analytical thin layer chromatography (TLC) performed with E. Merck precoated TLC plates, silica gel 60F- 254, layer thickness 0.25 mm or liquid chromatography-mass spectrum (LC-MS). Mass analysis was performed on a Waters Micromass ® ZQTM with electrospray ionization in positive ion detection mode.
  • HPLC High performance liquid chromatography
  • Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IP A/Hep) as isocratic solvent systems.
  • Chiral preparative chromatography was conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography.
  • Step A 3-Dimethylamino-l-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-l-one
  • a solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4 mmol) and dimethylformamide dimethyl acetal (7.7 mL, 58 mmol) in DMF (60 mL) was heated at 75°C for 20 h. The volatiles were removed in vacuo to provide the product which was used directly in the next step.
  • Step B 6-(2,4-DichlorophenylV5-(4-chlorophenv ⁇ -2-oxo-K2-dihvdropyridine-3-carbonitrile
  • cyanoacetamide (1.33 g, 15.8 mmol)
  • MeOH 1.3 mL, 32 mmol
  • DMF 35 mL
  • NaH 60% in mineral oil
  • DMF 16 mL
  • the reaction was heated to 95°C for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aq 18% citric acid solution.
  • Step B To the product of Step B (13.15g, 35 mmol) in THF (160 mL) was added MeMgBr (1.4 M in toluene/THF, 26.25 mL, 36.75 mmol). After stirring 3 min, 2- methylprop-1-enylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) was added and the temperature was increased to 50 °C. After 20 min the reaction was cooled, quenched with 2 M HCl and diluted with EtOAc. The reaction was stirred for 3 days before work up. The solution was washed twice with brine, followed by twice with saturated aq NaHCO 3 .
  • Step B 7'-(2-Chlorophenyl)-6'-(4-chlorophenyl)spiro[cvclohexane-l,2'-pyranor2,3-
  • Example 39 The product of Example 39 was resolved on an AD column using 4%EtOH/Hexane.
  • Step A ethyl 2-(6-(4-chlorophenyl)-7-(2,4-dichlorophenv ⁇ -4-hvdroxy-2,2-dimethyl-3.4- dihydro-2H-pyranor2,3-61pyridin-4-yl ' )acetate.
  • a mixture of ethyl 2-bromoacetate (0.334 mL 3.01 mmol), 1 ,2-dibromoethane (0.02 mL, 0.23 mmol), Zn powder (0.227 g, 3.47 mmol) and T ⁇ F (2.5 mL) was heated to 65 °C for 2 min before cooling to rt.
  • Step B Ethyl 2-r6-(4-chlorophenyl)-7-(2.4-dichlorophenyl)-2.2-dimethyl-2.3-dihvdro-4H- pyranof2,3-6 "
  • this example (192 mg, 0.382 mmol) was added /»-toluenesulfonic acid monohydrate (72.6 mg, 0.276 mmol) in toluene (3 mL). The reaction was heated to 104 °C. After 80 min the reaction was cooled and diluted with EtOAc. The solution was washed with brine and saturated aq NaHCO 3 .
  • Step A 2-(6-(4-Chlorophenvn-7-(2,4-dichlorophenyl ' )-2,2-dimethyl-3,4-dihvdro-2H- pyrano [2,3 -6]pyridin-4-vDacetic acid.
  • KO ⁇ (10.3 mg, 0.184 mmol) in T ⁇ F (1.5 mL), MeOH (0.2 mL) and water (0.075 mL). The reaction was heated to 50 °C. After 27 min the reaction was cooled and diluted with EtOAc.
  • Step B 5- ( r6-(4-CMorophenyl>7-(2.4-dicMorophenvn-2.2-dimethyl-3 ,4-dihydro-2H- pyranor2,3-61 pyridine-4-v ⁇ methvU-1.3,4-oxadiazol-2(3H)-one.
  • step A of this example To the product of step A of this example (40.0 mg, 0.084 mmol) was added ⁇ OBt (lH-l,2,3-benzotriazol-l-ol hydrate) (15.4 mg, 0.101 mmol), EDAC (N 1 -((emylimino)methylene)-N 3 ,N 3 -dimethylpropane-l,3-diamine hydrochloride) (19.3 mg, 0.101 mmol) in CH 2 Cl 2 (1.5 mL). The reaction was stirred 1 min before hydrazine hydrate (8.1 ⁇ L, 0.168 mmol) was added. After 10 min EDAC (19.3 mg) and hydrazine hydrate (16.3, ⁇ L, 0.336 mmol) were added.
  • Example 26 The following example was prepared utilizing the product of Example 26 using a procedure similar to that of Example 44.
  • the enantiomers were separated by chiral chromatography on an AD column elutin with 15%EtOH/He tane into two isomers.
  • Example 46 r2y)-N-r7'-r2-ChlorophenylV6'-(4-chlorophenyl)-3'.4'-dihvdrospirorcvclohexane-1.2'-pyranor2.3- 61pyridin1-4'-yll-2-hydroxypropanamide .
  • L-lactic acid sodium salt 18 mg, 0.16 mmol
  • 1- hydroxybenzotriazole HOBt
  • PYBOP 125 mg, 0.24 mmol
  • DIEA 80 ⁇ L, 0.48 mmol
  • Step B l-r6-(4-Chlorophenvn-7-( ' 2.4-dichlorophenylV2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- Z?lpyridin-4-yl "
  • the product obtained in Step A (127 mg, 0.23 mmol) was dissolved in DMSO (2 mL). NaH (20 mg, 0.51 mmol) was added and the reaction was stirred at rt for 1 h.
  • Step A The product of Step A (40 mg, 0.075 mmol) was dissolved in DME (0.9 mL), water (0.4 mL) and ethanol (0.2 mL) in a 10 mL reaction tube of a CEM Corporation Discover microwave reactor.
  • Example 66 (1.9 g, 3.36 mmol) was added DMF (2OmL), MeOH (6 mL), NEt 3 (1.4 mL, 10 mmol) and dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium (II) dichlorormethane adduct (275 mg, 0.336 mmol).
  • the flask was evacuated and backfilled with carbon monoxide 3 times. The mixture was stirred under a carbon monoxide atmosphere at 70°C overnight.
  • the reaction was cooled and 2 M HCl and EtOAc were added.
  • the organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated.
  • Step A Methyl 7-(2-chlorophenylV6-f4-cMorophenvn-2,2-dimethyl-3.4-dihydro-2H- pyrano[2,3-61pyridine-4-carboxylate. Powdered tellurium (70 mg, 0.57 mmol) was dissolved in EtOH (1.5 mL) at rt and NaBH 4 (50 mg, 1.4 mmol) was added. The reaction was heated to 70°C for 20 min. The reaction was cooled to -20 0 C and deoxygenated AcOH (0.07 mL, 1.21 mmol) was added. The mixture was stirred for 5 min and the product of Example 71 (150 mg, 0.34 mmol) was added.
  • the reaction was allowed to come to rt and was stirred an additional 30 min.
  • the reaction was filtered through Celite with CH 2 Cl 2 and the filtrate was concentrated.
  • the residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound.
  • Step B 7-(2-Chlorophenyl)-6-(4-cMorophenyiy2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 61pyridine-4-carboxylic acid.
  • Product from Step A (66mg, 0.14 mmol) was dissolved in T ⁇ F (1 mL) and 10 % KO ⁇ (1 mL) was added. The reaction was heated to 70 °C for 1 hr. The reaction was diluted with EtOAc and washed with 10 % NaHSO 4.
  • Step C 7-r2-ChlorophenylV6-r4-chlorophenyl)-N-(2-hvdroxyethyl)-2.2-dimethyl-3.4-dihvdro- 2H-pyrano [2.3-61 pyridine-4-carboxamide .
  • Step B 7-r2-ChlorophenylV6-r4-chlorophenyl)-N-(2-hvdroxyethyl)-2.2-dimethyl-3.4-dihvdro- 2H-pyrano [2.3-61 pyridine-4-carboxamide .
  • Example 73 Step B Using- the product of Example 73 Step B and following a procedure similar to Example 73 Step C with the appropriate amine the following compounds were afforded. Where noted the enantiomers were separated on chiral chromatography with conditions as indicated.
  • To the product of Example 19 50 mg, 0.12 mmol) was added (3iS)-2,5-dioxotetrahydrofuran-3-yl acetate (0.5 g) and the reaction was heated to 85°C for 1 hr. The reaction was cooled and AcOH was added (1 mL). Heating was continued at 85°C an additional 2 h.
  • Step B r3.S r )-l-r6-(4-Chlorophenvn-7-r2.4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H- pyranor23-61pyridin-4-yl1-3-hvdroxypyrrolidine-2,5-dione.
  • the product of Step A (38 mg, 0.7 mmol) was dissolved in MeOH (2 mL) andp-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction was heated at 85°C for 2 h and concentrated.
  • Step A 7V-r6-r4-chlorophenyl)-7-r2,4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H-pyranor2.3-
  • Step B N-r6-(4-Chlorophenvn-7-(2.4-dichlorophenvn-2.2-dimethyl-3.4-dihvdro-2H- pyrano[2.3-61pyridin-4-yll-3-oxobutanethioamide.
  • a solution of the product of Step A (136 mg, 0.26 mmol) and Lawesson's reagent (106 mg, 0.26 mmol) in 5.0 mL of toluene was stirred at 120 0 C for 3 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 1 :3 v/v EtOAc/hexanes as the eluant afforded the title compound.
  • Step C 6-r4-Chlorophenvn-7-r2.4-dichlorophenvn-2.2-dimethyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 3 ,4-dihydro-2//-pyrano [2,3 -Z)] pyridin-4-amine .
  • Example 132 The racemic mixture of Example 132 was resolved by chiral preparative chromatography with conditions indicated to afford the enantiomers listed in the followin exam les.
  • Step A 4-Bromo-N-r7-(4-bromo-2-chlorophenyl)-6-( ' 4-chlorophenyl)-2,2-diniethyl-3,4- dihvdro-2i/-pyrano[2,3-61pyridin-4-vnbutanamide.
  • Step B l-[7-(4-Bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyranor2,3-61pyridin-4-vHpyrrolidin-2-one.
  • Step A fert-Butyl (2- ⁇ r6-(4-chlorophenvn-7-(2.4-dichlorophenyl)-2.2-dimethyl-3 A- dihvdro-2H-pyranof2.3-61pyridin-4-yl1amino ⁇ ethv ⁇ carbamate.
  • Step B N-r6-(4-Chlorophenvn-7-(2,4-dichlorophenvn-2.2-dimethyl-3.4-dihydro-2//- pyranor2,3-6]pyridin-4-yl1ethane-l,2-diamine.
  • Step C l-r6-(4-ChlorophenylV7-r2.4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H- pyranor2,3-61 pyridin-4-yl "
  • 1 ' -carbonyldiimidazole (18.1 mg, 0.11 mmol) in 5.0 mL of CHCl 3 was added the product of Step B (0.07 mmol) and NEt 3
  • Step A fert-Butyl (2- ⁇ (bromoacetvnr6-(4-chlorophenylV7-(2.4-dichlorophenvn-2.2- dimethyl-3,4-dihvdro-2H-pyrano[2,3-61pyridin-4-yl1amino ⁇ ethyl)carbamate.
  • Step A a solution of the product of Example 166, Step A (90.5 mg, 0.16 mmol) in 5.0 mL of CH 2 Cl 2 at 0 0 C was added NEt 3 (54.7 ⁇ L, 0.39 mmol) and bromoacetyl bromide (15.0 ⁇ L, 0.17 mmol). The mixture was allowed to stir at rt for 1 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 7:13 v:v EtOAc/hexanes as the eluant afforded the product.
  • Step B fert-Butyl 4-r6-(4-chlorophenyn-7-(2.4-dichlorophenylV2.2-dimethyl-3.4-dihydro-2H- pyranor2,3-61pyridin-4-yl1-3-oxopiperazine-l-carboxylate.
  • 60 % NaH 4.8 mg, 0.12 mmol
  • the mixture was allowed to stir at rt for 30 min and then diluted with EtOAc (50 mL). The resulting mixture was washed with brine (50 mL). The organic layer was separated, dried over MgSO 4 , and concentrated. Chromatography on a Biotage 40+S cartridge using 9:11 v:v EtOAc/hexanes as the eluant afforded the product.
  • Step C l-r6-( " 4-Chlorophenyl)-7-(2.4-dichlorophenyl)-2.2-dimethyl-3,4-dihydro-2i/-pyranor23- b] pyridin-4-vH piperazin-2-one .
  • Step B N-r6-(4-ChlorophenylV7-(2,4-dicMorophenylV2,2-dimethyl-3.4-dihvdro-2H- pyrano [2,3-61 pyridin-4-yll hydrazinecarboxamide.
  • Step C 4-r6-(4-ChlorophenylV7-( ' 2.4-dichlorophenv ⁇ -2.2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 61pyridin-4-yl "
  • Step B Methyl 3-chloro-4- ⁇ 6-( " 4-chlorophenylV4-[(2,2-dimethylpropanoly)amino]-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-61pyridin-7-yllbenzoate.
  • Step C N-r7-r2-Chloro-4-( ' hvdrazinocarbonvnphenyll-6-r4-chlorophenylV2.2-dimethyl-3,4- dihydro-2//-pyrano[2,3-61pyridin-4-yll-2,2-dimethylpropanamide.
  • a solution of the product of Step B (22 mmol) and 2.0 mL of hydrazine hydrate in 10 mL Of CH 3 OH was refluxed for 10 h. After cooling to rt, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification.
  • Step D N-
  • Step A 7V-r7-r4-Bromo-2-chlorophenyl)-6-(4-chlorophenylV2,2-dimethyl-3,4-dihvdro-2H- pyranor2,3-61pyridin-4-yll-2,2-dimethylpropanamide.
  • Step B N-r7-( f 2-Chloro-4-cvanophenyl)-6-(4-chlorophenyl)-2.2-dimethyl-3,4-dihydro-2H- pyranor2,3-61pyridin-4-yl1-2,2-dimethylpropanamide.
  • Step B N-r7-r2-Chloro-4- ⁇ ,2,4-oxadiazol-3-vnphenyl1-6-(4-chlorophenvn-2,2-dimethyl-3,4- dihvdro-2H-pyrano[2,3- ⁇ lpyridin-4-yl1-2,2-dimethylpropanamide.
  • This example was prepared using procedures analogous to those described for Example 173 substituting Example 127 for N- [7-(2-chloro-4-cyanophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ⁇ ]pyridin-4-yl]-2,2-dimethylpropanamide in Step A.
  • (LC-2) ⁇ PLC/MS: 553.1 (M+l), 555.1 (M+3); R 1 3.45 min.
  • Step A fert-Butyl r7-(2-chloro-4-(1.2.4-oxadiazol-3-v ⁇ phenyl)-6-(4-chlorophenylV2.2- dimethyl-3,4-dihvdro-2H-pyrano
  • Step B 7-(2-Chloro-4-( 1.2.4-oxadiazol-3 -vDphenyl V6-(4-chlorophenyl)-2,2-dimethyl-3.4- dihvdro-2H-pyrano
  • Step C N-r7-r2-Chloro-4-d.2.4-oxadiazol-3-vnphenyll-6-(4-chlorophenvn-2.2-dimethyl-3.4- dihvdro-2H-pyrano( " 2,3-61pyridin-4-yll-3,3,3-trifluoro-2-hvdroxypropanamide.
  • Step A (4 ⁇ -6-(4-ChlorophenylV7-(2.4-dichlorophenylV2.2-dimethyl-3.4-dihvdro-2H- pyrano[2.,3-6]pyridin-4-ol.
  • Step B (4 ⁇ -6-(4-Chlorophenvn-7-(2,4-dichlorophenylV2.2-dimethyl-3,4-dihydro-2H- pyrano[2,3-Z>lpyridin-4-yl benzoate.
  • NEt 3 21 ⁇ L, 0.15 mmol
  • DMAP catalytic amount of DMAP in 10 mL Of CH 2 Cl 2 at rt
  • benzoyl chloride (11.5 ⁇ L, 0.10 mmol)
  • the reaction was quenched by adding saturated aq NaHCO 3 (5 mL) and the resulting mixture was stirred at rt for 30 min.
  • reaction mixture was partitioned between CH 2 Cl 2 (50 mL) and saturated aq NaHCO 3 (50 mL). The aq layer was separated and extracted with CH 2 Cl 2 (3x10 mL). The organic layers were combined, dried over MgSO 4 , and concentrated.
  • Step A (4 J /?V4-Azido-6-( ' 4-chlorophenyl)-7-(2.4-dichlorophenylV2.2-dimethyl-3.4- dihvdro-2H-pyrano-[2.,3-fr]pyridine.
  • Step A To a mixture of the product of Example 180, Step A (9.8 g, 22.5 mmol), Zn(N 3 ) 2 /bis-pyridine complex ⁇ Synthesis 1990, 130) (13.9 g, 45.1 mmol), triphenylphosphine (11.8 g, 45.1 mmol), and imidazole (6.1 g, 90 mmol) in 100 mL of CH 2 Cl 2 was added diisopropyl azodicarboxylate (8.8 mL, 45.1 mmol) dropwise at it. The mixture was allowed to stir at rt for 16 h.
  • Step B (4i?V6-(4-Chlorophenv ⁇ -7-(2,4-dichlorophenyl)-2.2-dimethyl-3,4-dihvdro-2H-pyrano- [2,3-&]pyridin-4-amine.
  • Step C N-r(4i?V6-(4-Chlorophenvn-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano
  • reaction mixture was diluted with Et 2 O (50 mL), washed with saturated aq NaHCO 3 (3x50 mL) and brine (3x50 mL). The organic layer was separated, dried over MgSO 4 and concentrated.
  • Example 182 The product was prepared using the procedures analogous to those described for Example 180, Example 182 and Example 170 substituting 7-(4-bromo-2-chlorophenyl)-6-(4- chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrazo[2,3-Zj]pyridin-4-one for 6-(4-chlorophenyl)- 7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrazo[2,3-6]pyridin-4-one in Step A of Example 180.
  • Step B tert-Butyl F( ' 4i?V7-r2-chloro-4-( ' hvdrazinocarbonyl ' )phenyll-6-(4-chloropheny ⁇ -2.2- dimethyl-3,4-dihydro-2H-pyrano[ " 2.3-61pyridin-4-yllcarbamate.
  • Step C tert-Butyl r(4J?)-7-r2-chloro-4-(1.3,4-oxadia2ol-2-vnphenyll-6-( ' 4-chlorophenvn-2.2- dimethyl-3,4-dihydro-2//-pyrano[2,3-61pyridin-4-yl1carbamate.
  • Step D N-r(47?V7-r2-Chloro-4- ⁇ .3,4-oxadiazol-2-vnphenvn-6-( ' 4-chlorophenyn-2,2-dimethyl- 3.4-dihvdro-2H-pyranor2,3-61pyridin-4-yl1-3,3,3-trifluoro-2-hvdroxypropanamide.
  • the reaction mixture was cooled and diluted with CH 2 Cl 2 (50 mL) and filtered through a cake of Celite. The filtrate was washed with H 2 O (50 mL) and brine (50 mL). After the phases separated, the organic layer was dried over MgSO 4 and concentrated.
  • Step B r2i?/ ⁇ )-N-r(4 ⁇ V6-(4-Chlorophenyl)-7-r2-chloro-4-(lH-pyrazol-l-yl)phenyll-2,2- dimethyl-3,4-dihvdro-2H-pyrano
  • Example 169 To a solution of Example 169 (1.5 g, 2.59 mmol) in a mixed solvent of 9.0 mL of DMF, 1.0 mL of H 2 O, and 2.0 mL of EtOH was added ter/-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (1.53 g, 5.19 mmol), Na 2 CO 3 (830 mg, 7.78 mmol), and tetrakis(triphenylphosphino)palladium(0) (150 mg, 0.13 mmol). The mixture was stirred at 120 0 C under microwave irradiation for 30 min.
  • Step B (AR V 6-(4-Chlorophenyl)-7- r2-chloro-4-( 1 H-pyrazol-4-vnphenyll -2,2-dimethyl-3 ,4- dihvdro-2H-pyrano[2,3-61pyridin-4-amine.
  • a solution of the product of Step A (364 mg, 0.64 mmol) in 10 mL of 20% TFA in CH 2 Cl 2 was stirred at rt for 2 h. The reaction mixture was concentrated to give the product, which was used in the next step without further purification.
  • Step C N- ⁇ r4ig)-6-(4-Chlorophenvn-7-r2-chloro-4-(l//-pyrazol-4-vnphenyll-2.2-dimethyl-3.4- dihydro-2H-pyrano [2,3 -Z>lpyridin-4-yl ⁇ benzamide.
  • Step B To a solution of the product of Step B (35.6 mg, 0.08 mmol) and NEt 3 (43 ⁇ L, 0.31 mmol) in 10 mL Of CH 2 Cl 2 was added benzoyl chloride (20 ⁇ L, 0.17 mmol). After stirring at rt for 1 h, 2.0 mL of CH 3 OH and 100 ⁇ L of 5.0 N NaOH was added to the reaction mixture.
  • Example 237 substituting the appropriate boronic acids or boronic esters for tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate in Step A and substituting appropriate acyl chlorides or acids for benzoyl chloride in Step C.
  • Example 268 N- ⁇ 1 ' -(2-Chlorophenyl V6 ' -(4-cyanophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1 ,2 ' -pyrano [2,3 - 61pyridine1-4'-yll-2-hydroxy-2-methylpropanamide.
  • Step B (4" ⁇ -4"-Azido-7"-(4-bromo-2-chlorophenylV6"-f4-chlorophenvn-3".4"- dihvdrodispiro[13-dioxolane-2,r-cvclohexane-4%2"-pyrano[2,3-61pyridine1.
  • Step A The product was prepared using procedures analogous to those described for Example 180 and Example 182 substituting the product of Step A for 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl- 2,3-dihydro-4H-pyrano[2,3- ⁇ ]pyridine-4-one in Step A of Example 180.
  • Step C (4'i?V4 ; -Azido-7 ; -(4-bromo-2-chlorophenvn-6'-(4-chlorophenvn-3 ⁇ 4'-dihvdro-4H- spiro[cyclohexane-l,2'-pyrano[2,3-fr1pyridine1-4-one.
  • Step D (4'i?)-4'-Azido-7'-( ' 4-bromo-2-chlorophenv ⁇ -6'-(4-chlorophenyl)-4,4-difluoro- 3 ⁇ 4'-dihydro-4//-spiro[cvclohexane-l ,2'-pyrano[2,3-Z>1pyridine].
  • Step E ( " 4'i?V7'-(4-Bromo-2-chlorophenv ⁇ -6'-r4-chlorophenv ⁇ -4.4-difluoro-3'.4'-dihvdro-4H- spiro[cvclohexane-l,2'-pyranor2,3-6]pyridinl-4'-amine.
  • Step F ⁇ V-rf4'igV7 > -(4-Bromo-2-chlorophenvn-6 > -r4-chlorophenvn-4.4-difluoro-3'.4 > - dihvdrospiro[cyclohexane-l,2'-pyranor2,3-6]pyridine1-4'-yl]-5-methyl-lH-pyrazole-3- carboxamide
  • This assay is described in Biological Example 1 of WO 05/00809.
  • Compounds of the present invention have have IC50s of less than 5 micromolar in the CBl binding assay.
  • the compounds of the present invention are selective CBl antagonist/inverse agonist compounds having IC50s greater in the CB2 binding assay than in the CBl assay.
  • the compounds of Examples 1 to 17 and 19-274 were assayed in the CBl Binding assay and found to have IC50 values for the human CBl receptor less than 1 micromolar.
  • Cannabinoid Receptor- 1 (CBl) Functional Activity Assay.
  • mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food is removed from rodent cages. Experimental compounds or their vehicles are administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals.
  • Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the compounds are compared to the effect of vehicle, hi these experiments many strains of mouse or rat, and several standard rodent chows can be used.
  • Rats or mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet.
  • the rat strains commonly used include the Sprague Dawley bred through Charles River Laboratories. Although several mouse strains may be used, c57Bl/6 mice are more prone to obesity and hyperinsulinemia than other strains.
  • Common diets used to induce obesity include: Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282 (60% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks.
  • the rodents receive injections (1 to 4 per day) or continuous infusions of experimental compounds or their vehicles either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effects of the compounds are compared to the effects of vehicle. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the compounds of the invention indicated above.

Abstract

Novel compounds of the structural Formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, Huntington's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.

Description

TITLE OF THE INVENTION
SUBSTITUTED P YRANO [2, 3 -B] P YRIDINE DERIVATIVES AS CANNABINOID-1
RECEPTOR MODULATORS
BACKGROUND OF THE INVENTION
Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes. A major active ingredient in marijuana and hashish has been determined to be Δ9-tetrahydrocannabinol (Δ9-THC). Detailed research has revealed that the biological action of Δ9-THC and other members of the cannabinoid family occurs through two G-protein coupled receptors termed CBl and CB2. The CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs. The CB2 receptor is found primarily in lymphoid tissues and cells. Three endogenous ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2- arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to Δ9-THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.
There are at least three CBl modulators characterized as inverse agonists/antagonists, ACOMPLIA (rimonabant, N-( 1 -piperidinyl)-5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4- methylpyrazole-3-carboxamide, SRl 41716A), and 3-(4-chlorophenyl-Λ^-(4- chlorophenyl)sulfonyl-7V-methyl-4-phenyl-4,5-dihydro- 1 H-pyrazole- 1 -carboxamide (SLV-319), and taranabant, N-[( 1 S,2S)-3 -(4-Chlorophenyl)-2-(3 -cyanophenyl)- 1 -methylpropyl] -2-methyl-2- [[5-(trifluoromethyl)-2-pyridinyl]oxy]propanamide, in clinical development for treatment of eating disorders and/or smoking cessation at this time. There still remains a need for potent low molecular weight CBl modulators that have pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.
Naphthyridone CBl antagonists/inverse agonists are described in Debenham, et al., Bioorg. Med. Chem. Lett. 16: 681-685 (2006) and in WO 05/047285. Pyranopyridine derivatives are described in the following publications: EP 895994, WO 98/09969, WO 99/03859, WO 01/98306, WO 03/032897, WO 05/000250, WO 05/042697, and WO 06/045096. SUMMARY OF THE INVENTION
The present invention is concerned with pyrano[2,3-ό]pyridines of general formula I:
Figure imgf000002_0001
and pharmaceutically acceptable salts thereof which are modulators of and, in particular, antagonists and/or inverse agonists of the Cannabinoid- 1 (CBl) receptor and are useful in the treatment, prevention or suppression of diseases mediated by the Cannabinoid-1 (CBl) receptor. In one aspect, the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor. As such, compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, Huntington's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, and complications associated therewith, including left ventricular hypertrophy, as well as the treatment of asthma, constipation, chronic intestinal pseudoobstruction, and cirrhosis of the liver.
The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. The present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
The invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient, as well as processes for preparing the compounds of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are represented by structural formula I:
Figure imgf000003_0001
hi one class are compounds of structural formula ID-I :
Figure imgf000003_0002
In another class are compounds of structural formula ID-2:
Figure imgf000004_0001
In still another class are compounds of structural formula ID-3:
Figure imgf000004_0002
In one embodiment of the present invention, X is selected from: (1) halogen,
(2) -Ci-βalkyl, unsubstituted or substituted with one, two or three substituents independently selected from Ra,
(3) aryl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb, (4) cycloalkyl, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(5) heteroaryl-, unsubstituted or substituted with one, two, or three substituents independently selected from Rb,
(6) heterocycloalkyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(7) heteroaryl-Ci-3alkyl, unsubstituted or substituted on heteroaryl with one, two, or three substituents independently selected from Rb,
(8) -Cθ2Rd,
(9) -CO-NRCRd, (10) -CN,
(H) -ORd,
(12) -0-C(O)Rd,
(13) -NRCRd,
Figure imgf000004_0003
(15) -NRcC(=O)ORd,
(16) -NRcC(=O)-C(=O)NRcRd ,
(17) -NH-Sθ2-Rf, and
(18) -S-Ci-6alkyl,
Xl is selected from hydrogen, halogen and Ci-6alkyl, or together X and Xl form =0, =NRg, or ^CH-C(O)-O-Rd.
In one class of this embodiment, X is selected from:
(1) methyl, ethyl, isopropyl or t-butyl, substituted with one, two or three substituents independently selected from Ra, (2) phenyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(3) heteroaryl-, unsubstituted or substituted with one, two, or three substituents independently selected from Rb,
(4) heterocycloalkyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(5) heteroaryl-methyl-, unsubstituted or substituted on heteroaryl with one, two, or three substituents independently selected from Rb,
(6) -CO2Rd,
(7) -CO-NRCRd, (8) -ORd,
(9) -0-C(O)Rd,
(10) -NRCRd5
(11) -NRcC(=O)Rd,
(12) -NHC(=O)ORd, (13) -NHC(=O)-C(=O)NHRd , and
(14) -NH-SO2-Rf,
Xl is hydrogen, or
X and Xl together form =O, =N-OH, or -CH-C(O)-O-CH2CHs. hi a subclass of this class, X is selected from: (1) oxadiazolyl, unsubstituted or substituted on a carbon atom with methyl,
(2) piperidinyl, unsubstituted or substituted on carbon with oxo,
(3) oxadiazolyl-methyl-, unsubstituted or substituted on an oxadiazolyl carbon atom with methyl or oxo,
(4) -NH-pyridyl, (5) -NH(pyrazolyl), wherein the pyrazole is unsubstituted or substituted on a carbon atom with methyl,
(6) -NH-C(O)-CH2-OH,
(7) -NH-C(0)-CH(CH3)-0H,
(8) -NH-C(O)-C(CH3)2-OH, (9) -NH-C(O)-N(CH3)2,
(10) isoxazolyl-carboxamide, (11) pyrazolylcarboxamide, wherein the pyrazole is unsubstituted or substituted on a carbon atom with methyl,
(12) triazolyl-carboxamide, wherein the triazole is unsubstituted or substituted on a carbon atom with methyl, (13) imidazolyl-carboxamide,
(14) cyclopropylcarboxamide, wherein the cyclopropyl group is unsubstituted or substituted with hydroxy,
(15) -NH-C(O)-C(O)-NH(CH3), and
Xl is hydrogen, or X and X 1 together form =0.
In one embodiment of the present invention, Rl is selected from: hydrogen, Ci-6alkyl, C3_7cycloalkyl, C3-8cycloalkenyl, C3-7cycloalkyl-Ci_4alkyl, C3- 8cycloalkenyl-Ci-4alkyl, cycloheteroalkyl, cycloheteroalkyl-Ci-4alkyl, phenyl, benzyl, heteroaryl, heteroaryl-Ci-4alkyl, -C(O)NH-S(O)2-CH3, wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to four substituents independently selected from Rb;
R2 is selected from: Ci-6alkyl, C3-7cycloalkyl, C3-8cycloalkenyl, C3-7cycloalkyl-Ci-4alkyl, C3-8cycloalkenyl-Ci-4alkyl, cycloheteroalkyl, cycloheteroalkyl-Ci_4alkyl, phenyl, benzyl, heteroaryl, heteroaryl-Ci-4alkyl, -C(O)NH-S(O)2-CH3, wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to four substituents independently selected from Rb; or Rl and R2 together with the carbon to which they are attached form a carbonyl group (C=O) or a spiroannulated ring system of 5 to 10 members containing 0, 1, or 2 heteroatoms independently selected from -O-, and -S, optionally substituted with an Rb substituent.
In one class, Rl is selected from: (1) hydrogen,
(2) Ci-6alkyl, unsubstituted or substituted with hydroxy, fluoro, or methylsulfonylmethyl,
(3) bicyclo[2.2. l]hept-5-en-2-yl,
(4) cycloheteroalkyl, (5) cycloheteroalkyl-Ci-4alkyl, and
(6) phenyl, unsubstituted or substituted with fluoro; R2 is selected from: (1) Ci-6alkyl, unsubstituted or substituted with hydroxy, fluoro, or methylsulfonyl,
(2) bicyclo[2.2. l]hept-5-en-2-yl,
(3) cycloheteroalkyl,
(4) cycloheteroalkyl-Ci_4alkyl, and (5) phenyl, unsubstituted or substituted with fluoro; or Rl and R2 together with the carbon to which they are attached form a carbonyl group (C=O) or a spiroannulated ring system selected from:
)O In. a)nother class of tXhe p)reOsent inCventi)onO, Rl is selectOed fro .m-: hXydrogen, meth-yl, hydroxymethyl-, methylsulfonylmethyl-, ethyl, isopropyl, t-butyl, bicyclo[2.2.1]hept-5-en-2-yl-, and 3 -fluorophenyl-; R2 is selected from: methyl, hydroxymethyl-, methylsulfonylmethyl-, ethyl, isopropyl, t-butyl, bicyclo[2.2.1]hept-5-en-2-yl-, and 3 -fluorophenyl-; or Rl and R2 together with the carbon to which they are attached form a carbonyl group (C=O) or a spiroannulated ring system selected from: )O In. a) subclass oXf th}e pre.s)enOt inveCntion), ROl is selected0 from:.- hyd>roOgen, m0ethyl-, and ethyl; R2 is selected from: methyl, ethyl, isopropyl, and t-butyl; or Rl and R2 together with the carbon to which they are attached form the spiroannulated ring system:
Figure imgf000007_0001
In a.nother subclass, Rl and R2 are each methyl or together form:
hi one e >mbodimen.t of the present invention, R4 is selected from: -H; halo-; -CN; Ci- 3alkyl-, unsubstituted or substituted with one, two or three Rh substitutents; -CF3; -ORd; and - OCF3. In one class of the present invention, R4 is selected from: halo-; -CN; C1.3a.kyl-, unsubstituted or substituted with one, two or three Rh substitutents; -CF3; -ORd; and -OCF3.
In another class, R4 is selected from: halo-, -CN, -CH3, -CF3, -OCH3, -OCH2CF3, and -OCF3. hi a subclass, R4 is chloro. hi one embodiment, R6 is selected from:
(1) -H,
(2) halo-,
(3) -CN, (4) Ci-3alkyl-, unsubstituted or substituted with one, two, or three Rh substitutents,
(5) -CF3,
(6) cycloalkyl, unsubstituted or substituted with one or two Rh substitutents, (7) cycloheteroalkyl, unsubstituted or substituted with one or two Rh substitutents,
(8) aryl, unsubstituted or substituted with one or two Rk substitutents,
(9) heteroaryl, unsubstituted or substituted with one or two Rk substitutents,
(10) -OH, (11) -OCH3,
(12) -OCF3,
(13) -OCH2CF3,
(14) -C(O)Rd,
(15) -Cθ2Rd, (16) -C(O)NRCRd, and
(17) -NRCRd.
In another embodiment of the present invention, if R? is hydrogen, R6 is not hydrogen. In one class, R6 is selected from: -F; -Cl; -Br; -I; -CN; -CH3; -CF3; oxadiazolyl, unsubstituted or substituted with one or two Rh substitutents; pyrazolyl; thienyl; furyl; oxazolyl; -OH; -OCH3; -OCF3; -OCH2CF3; and -CO2CH3.
In another class, R6 is selected from: -Cl, -Br, -CN, -CH3, -CF3, and 1,2,4-oxadiazolyl. hi a subclass, R6 is chloro.
In one embodiment, R? is selected from:
(1) -H, (2) halo-,
(3) -CN,
(4) Ci_3alkyl-, unsubstituted or substituted with one, two, or three Rh substitutents,
(5) -CF3, (6) cycloalkyl, unsubstituted or substituted with one or two Rh substitutents,
(7) cycloheteroalkyl, unsubstituted or substituted with one or two Rh substitutents,
(8) aryl, unsubstituted or substituted with one or two Rk substitutents,
(9) heteroaryl, unsubstituted or substituted with one or two Rk substitutents, (10) -OH,
(H) -OCH3, (12) -OCF3, (13) -OCH2CF3,
(14) -C(O)Rd
(15) -Cθ2Rd,
(16) -C(O)NRCRd, and (17) -NRCRd.
In one embodiment of the present invention, if R6 is hydrogen, R? is not hydrogen. In one class, R7 is selected from:
(1) -H,
(2) halo-, (3) -CN,
(4) -Ci_3alkyl-, unsubstituted or substituted with one, two, or three Rh substitutents,
(5) -CF3,
(6) cycloheteroalkyl, unsubstituted or substituted with one or two Rh substitutents,
(7) heteroaryl, unsubstituted or substituted with one or two Rk substitutents,
(8) -OH,
(9) -OCH3,
(10) -OCF3, (11) -OCH2CF3, and
Figure imgf000009_0001
hi one class, if R6 is hydrogen, R7 is not hydrogen.
In another class, R7 is selected from: -H, -F; -Cl; -Br; -I; -CN; -CH3; -CF3; oxadiazolyl, unsubstituted or substituted with one or two Rh substitutents; pyrazolyl; thienyl; furyl; oxazolyl; -OH; -OCH3 ; -OCF3 ; -OCH2CF3 ; and -CO2CH3 ; PROVIDED THAT, if R6 is hydrogen, R? is not hydrogen.
In a subclass, R? is hydrogen or chloro;. hi one embodiment, each Ra is independently selected from: -OH, -OCH3, halogen, — SH, -Sθ2Rd, -NH2, -CN, -Cθ2Rd, -C(O)NRCRd, -CF3, and -OCF3. hi one class, each Ra is independently selected from: -OH, -F, -SO2CH3, -CO2-C1-
6alkyl, and -CF3. hi a subclass, each Ra is independently selected from: -OH, -F, and -CF3. hi one embodiment, each R^ is independently selected from: -OH, -OCH3, halogen, - SH, -Sθ2Rd, -NH2, -CN, -Cθ2Rd, -C(O)NRCRd, -CF3, -OCF3, oxo, Ci-ioalkyl, C2-10 alkenyl, cycloalkyl, cycloalkyl-C 1.1 Oalkyl, cycloheteroalkyl, cycloheteroalkyl-C 1.10 alkyl, aryl, heteroaryl, aryl-Ci-K)alkyl, and heteroaryl-Ci_ioalkyl; wherein alkyl and alkenyl moieties are unsubstituted or substituted with one, two, three or four Rk substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rk substituents.
In one class, each EP is independently selected from: -OH, -OCH3, halogen, — N(CH3)2, -CH(O), -C(O)Rd5 -CO2CH3, -CO2CH2C6H5, -CN, -CF3, -OCF3, oxo, Ci_3alkyl, C2-3 alkenyl, cyclopropyl, oxadiazolyl, pyrazolyl, tetrazolyl, and phenyl; wherein alkyl and alkenyl moieties are unsubstituted or substituted with one, two, or three Rk substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rk substituents.
In one embodiment, each Rc is independently selected from: hydrogen, Ci_ioalkyl, C2- 10 alkenyl, cycloalkyl, cycloalkyl-C 1.1 oalkyl-, cycloheteroalkyl, cycloheteroalkyl-C 1.10 alkyl-, aryl, heteroaryl, aryl-Ci-i oalkyl-, and heteroaryl-Ci-i oalkyl-; wherein each Rc and Rd moiety, other than hydrogen, may be unsubstituted or substituted with one to three substituents selected
In one class, each Rc is independently selected from: hydrogen, and methyl. In one embodiment, each Rd is independently selected from: hydrogen, Ci _i oalkyl, C2-
10 alkenyl, cycloalkyl, cycloalkyl-Ci-ioalkyl-, cycloheteroalkyl, cycloheteroalkyl-Ci-i o alkyl-, aryl, heteroaryl, aryl-Ci-ioalkyl-, and heteroaryl-Ci-i oalkyl-; wherein each Rc and Rd moiety, other than hydrogen, may be unsubstituted or substituted with one to three substituents selected from Rh. In one class, each Rd is independently selected from: hydrogen, Ci-6alkyl, C2-6alkenyl, cycloalkyl, cycloalkyl-Ci-i oalkyl-, cycloheteroalkyl, cycloheteroalkyl-C i-i o alkyl-, aryl, heteroaryl, aryl-Ci-3alkyl-, and heteroaryl-Ci_3alkyl-; wherein each Rd moiety, other than hydrogen, may be unsubstituted or substituted with one, two or three substituents selected from Rh. hi one embodiment of the present invention, each R^ is independently selected from: halogen, Ci_6alkyl, unsubstituted or substituted with one or two Ri substituents, and -N(CH3)2.
In one class, each R^ is independently selected from: chloro, ethyl, n-propyl, chloropropyl, and -N(CH3)2. hi one embodiment of the present invention, each R§ is independently selected from: hydrogen, -OH, and methyl.
In one embodiment of the present invention, each Rh is independently selected from: halogen, Ci_6alkyl, 4-methylbenzyl-, -OH, -O-Ci-4alkyl, benzyloxy-, -oxo, -OC(O)-C 1. oalkyl, -C(O)O-Ci -oalkyl, -S-Ci_4alkyl, -NH2, -NH(CH3), -N(CH3)2, -NO2, -CN, -CF3, and -OCF3; wherein alkyl may be unsubstituted or substituted with one, two or three substituents selected from Ri. hi one embodiment of the present invention, each R1 is independently selected from: halogen, -O-Ci_4alkyl, -OH, -S-Ci-4alkyl, -CN, -CF3, and -OCF3. In one embodiment of the present invention, each R^ is independently selected from: halogen, oxo, amino, hydroxy, Ci-4alkyl, -O-Ci_4alkyl, -S-Ci-4alkyl, -CN, -CF3, and -OCF3.
"Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl.
"Alkenyl" means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.
"Cycloalkyl" means mono- or bicyclic or bridged saturated carbocyclic rings, each having from 3 to 10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooxtyl, tetrahydronaphthyl, decahydronaphthyl, bicycloand the like. In one embodiment of the present invention, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and 1,2,3,4-tetrahydronaphthyl.
"Cycloalkenyl" means nonaromatic, mono- or bicyclic or bridged carbocyclic rings, each having from 3 to 10 carbon atoms and at least one degree of unsaturation. Examples of cycloalkyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl, decahydronaphthyl, bicyclo[2.2.1]hept-5-en-2-yl, and the like. In one embodiment of the present invention, cycloalkenyl is selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and bicyclo[2.2.1]hept-5-en-2-yl, and the like.
"Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteratom selected from O, S, and N. Heteroaryls thus inclue heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls, and cycloheteroalkyls that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazaolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, dibenzylfuranyl, isobenzylfuranyl, benzopyrazolyl, benzothienyl, benzothiazolyl, furo(2,3- ό)pyridyl, quinolyl, indolyl, isoquinolyl, oxazolidinyl, imidazothiathiazolyl, pyrazolylpyridyl, benzotriazolyl, methylenedioxyphenyl, hexahydrothieno-pyridinyl, thienopyridinyl, and the like. In one embodiment of the present invention, heteroaryl is selected from pyridyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, indazolyl, oxadiazolyl, tetrazolyl, imidazolyl, indolyl, benzimidazolyl, triazolyl, and benzopyrazolyl.
"Cycloheteroalkyl" refers to a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S and N, further including the oxidized forms of sulfur, namely SO and SO2, in which the point of attachment may be carbon or nitrogen. Examples of heterocycloalkyl include tetrahydrofuranyl, azetidinyl, perhydroazepinyl, dihydrofuranyl, dioxanyl, oxanyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, piperidinyl, 1,3- dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1,3-dithianyl, oxathianyl, thiomoφholinyl, dioxidoisothiazolidinyl, azacycloheptyl, diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. The cycloheteroalkyl ring may be substituted on the ring carbons and/or the ring nitrogens, hi one embodiment of the present invention, cycloheteroalkyl is selected from tetrahydrofuranyl, imidazolidinyl, piperidinyl, pyrrolidinyl, isothiazolidinyl, morpholinyl and thiomorpholinyl. "Spiroannulated Ring system" refers to a compound having two rings which have only one atom in common, and the two rings are not linked by a bridge. These systems can be part of larger polycyclic ring systems. The common atom is known as a spiro atom. Particular spiroannulated substituents of the present invention include:
>o "H.)alogen" inc>luodes flu.oXrin3e, ch<lori.nex, bromine an:d>α iodine..-)θθ-
When any variable (e.g., Rl, Rd, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A squiggly line across a bond in a substituent variable represents the point of attachment.
Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column. Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. 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, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The term "pharmaceutically acceptable salt" further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N- methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used as a dosage form for modifying the solubility or hydrolysis characteristics or can be used in sustained release or pro-drug formulations. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Compounds of the present invention are modulators of the CBl receptor. In particular, the compounds of structural formula I are antagonists or inverse agonists of the CBl receptor. Compounds of this invention are modulators of the CBl receptor as antagonists/inverse agonists and as such are useful as centrally acting drugs in the treatment of psychosis; memory deficits; cognitive disorders; Alzheimer's disease; migraine; neuropathy; neuro-inflamrnatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma; anxiety disorders; stress; epilepsy; Parkinson's disease; Huntington's disease; movement disorders; schizophrenia; substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine; obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy, as well as treating or preventing obesity in other mammalian species, including canines and felines; cirrhosis of the liver; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); asthma; constipation; and chronic intestinal pseudo-obstruction. In particular, the compounds of this invention are antagonists/inverse agonists of the CBl receptor. In particular, the compounds of the invention are useful for smoking cessation.
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
Another aspect of the present invention provides pharmaceutical compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
Any suitable route of administration may be employed for providing a mammal, particularly a human or companion animal such as a dog or cat, with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like. The topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle. Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art. hi practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in- water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions. Desirably, each tablet, cachet, or capsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular, intranasal and topical, with or without occlusion. Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
The dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:
Capsule mg/capsule Tablet mg/tablet
Compound of Formula I 25 Compound of Formula I 25
Lactose Powder 573.5 Microcrystalline Cellulose 415 MMaaggnneessiiuumm SStteeaarraattee 11..55 Povidone 14.0
600 Pregelatinized Starch 43.5
Magnesium Stearate 2.5
500
Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, antimigraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti -Parkinson's agents, anti-Huntington's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, other anti-obesity agents, as well as antidiabetic agents, lipid lowering agents, and antihypertensive agents which may be administered separately or in the same pharmaceutical compositions.
Specific compounds of use in combination with a compound of the present invention include: simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate, naltrexone, bupriopion, phentermine, and losartan, losartan with hydrochlorothiazide. Specific CBl antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO03/077847, including: N-[3- (4-chlorophenyl)-2(5)-phenyl- 1 (5)-methylpropyl] -2-(4-trifluoromethyl-2-pyrimidyloxy)-2- methylpropanamide, N- [3 -(4-chlorophenyl)-2-(3 -cyanophenyl)- 1 -methylpropyl] -2-(5- trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, N-[3-(4-chlorophenyl)-2-(5-chloro-3- pyridyl)-l-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide, and pharmaceutically acceptable salts thereof; as well as those in WO05/000809, which includes the following: 3-{l-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2- dimethylpropanenitrile, 1 -{ 1 -[I -(4-chlorophenyl)pentyl]azetidin-3-yl}-l-(3,5-difluorophenyl)-2- methylpropan-2-ol. 3-((S)-(4-chlorophenyl){3-[(lS)-l-(3,5-difluorophenyl)-2-hydroxy-2- methylpropyl]azetidin- 1 -yl } methyl)benzonitrile, 3 -((S)-(4-chlorophenyl) { 3 - [( 1 S)- 1 -(3 ,5 - difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-l-yl}methyl)benzonitrile, 3-((4- chlorophenyl) { 3 - [ 1 -(3 ,5 -difluorophenyl)-2 ,2-dimethylpropyl] azetidin- 1 -yl } methyl)benzonitrile, 3-((1S)-I-(I -[(S)-(3 -cyanophenyl)(4-cyanophenyl)methyl]azetidin-3 -yl } -2-fluoro-2- methylpropyl)-5-fluorobenzonitrile, 3 - [(S)-(4-chlorophenyl)(3 - { ( 1 S)-2-fluoro- 1 - [3 -fluoro-5- (4H- 1 ,2,4-triazol-4-yl)phenyl]-2-methylpropyl} azetidin- 1 -yl)methyl]benzonitrile, and 5-((4- chlorophenyl){3-[(lS)-l-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-l- yl}methyl)thiophene-3-carbonitrile, and pharamecueitcally acceptable salts thereof; as well as: 3-[(5)-(4-chloroρhenyl)(3-{(l1S)-2-fluoro-l-[3-fluoro-5-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)phenyl] -2-methylpropyl } azetidin- 1 -yl)methyl]benzonitrile, 3 - [(5)-(4-chlorophenyl)(3 - { ( 1 S)-2- fluoro-l-[3-fluoro-5-(l,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-l- yl)methyl]benzonitrile, 3 -[(S)-(3 - { ( 1 S)- 1 - [3 -(5-amino- 1 ,3 ,4-oxadiazol-2-yl)-5-fluorophenyl] -2- fluoro-2-methylpropyl} azetidin- l-yl)(4-chlorophenyl)methyl]benzonitrile, 3-[(5)-(4- cyanophenyl)(3-{(15)-2-fluoro-l-[3-fluoro-5-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]-2- methylpropyl } azetidin- 1 -yl)methyl]benzonitrile, 3- [(5)-(3- { ( 1 S)- 1 - [3-(5-amino- 1 ,3 ,4-oxadiazol- 2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl} azetidin- l-yl)(4- cyanophenyl)methyl]benzonitrile, 3 -[(S)-(4-cyanophenyl)(3 - { ( 15)-2-fluoro- 1 - [3 -fluoro-5 -( 1,3,4- oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-l-yl)methyl]benzonitrile, 3-[(S)-(A- chlorophenyl)(3-{(15)-2-fluoro-l-[3-fluoro-5-(l,2,4-oxadiazol-3-yl)phenyl]-2- methylpropyl } azetidin- 1 -yl)methyl]benzonitrile, 3- [( 1 S)- 1 -( 1 - { (5)-(4-cyanophenyl) [3 -( 1 ,2,4- oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 5- (3- { 1 - [ 1 -(diphenyhnethyl)azetidin-3 -yl] -2-fluoro-2-methylpropyl } -5-fluorophenyl)- 1 H-tetrazole, 5-(3-{l-[l -(diphenylmethyl)azetidin-3 -yl] -2 -fluoro-2-methy lpropyl } -5 -fluorophenyl)- 1 -methyl - lH-tetrazole, 5-(3-{l-[l-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5- fluorophenyl)-2-methyl-2H-tetrazole, 3 - [(4-chlorophenyl)(3 - { 2-fluoro- 1 - [3 -fluoro-5-(2-methyl- 2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-l-yl)methyl]benzonitrile, 3-[(4- chlorophenyl)(3- {2-fluoro- 1 - [3 -fluoro-5 -( 1 -methyl- 1 H-tetrazol-5 -yl)phenyl] -2- methylpropyl } azetidin- 1 -yl)methyl]benzonitrile, 3 -[(4-cyanophenyl)(3 - {2-fluoro- 1 - [3 -fluoro-5-
( 1 -methyl- 1 H-tetrazol-5-yl)phenyl] -2-methylpropyl } azetidin- 1 -yl)methyl]benzonitrile, 3 - [(4- cyanophenyl)(3-{2-fluoro-l-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2- methylpropyl } azetidin- 1 -y l)methyl] benzonitrile, 5 - { 3 - [(S)- { 3 - [( 1 S)- 1 -(3 -bromo-5 -fluorophenyl)- 2-fluoro-2-methylpropyl]azetidin- 1 -yl } (4-chlorophenyl)methyl]phenyl } - 1 ,3 ,4-oxadiazol-2(3H)- one, 3 - [( 1 S)- 1 -( 1 - { (S)-(4-chlorophenyl) [3 -(5 -oxo-4 , 5 -dihydro- 1 ,3 ,4-oxadiazol-2- yl)phenyl]methyl} azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(1S)-I -(I - { (S)-(4-cyanophenyl) [3 -(5 -oxo-4,5 -dihydro- 1 ,3 ,4-oxadiazol-2-yl)phenyl]methyl } azetidin-3 -yl)- 2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3-[(lS)-l-(l-{(S)-(4-cyanophenyl)[3-(l,3,4- oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile, 3- [( 1 S)- 1 -( 1 - { (S)-(4-chlorophenyl) [3 -( 1 ,3 ,4-oxadiazol-2-yl)phenyl]methyl } azetidin-3 -yl)-2-fluoro- 2-methylpropyl]-5-fluorobenzonitrile, 3-((lS)-l-{l-[(S)-[3-(5-amino-l,3,4-oxadiazol-2- yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3 -(( 1 S)- 1 - { 1 -[(S)- [3 -(5 -amino- 1 ,3 ,4-oxadiazol-2-yl)phenyl] (4-cyanophenyl)methyl]azetidin-3 - yl } -2-fluoro-2-methylpropyl)-5-fluorobenzonitrile, 3 - [( 1 S)- 1 -( 1 - { (S)-(4-cyanophenyl)[3 -( 1 ,2,4- oxadiazol-3 -yl)phenyl] methyl } azetidin-3 -yl)-2-fluoro-2-methylpropyl] -5 -fluorobenzonitrile, 3 - [( 1 S)- 1 -( 1 - { (S)-(4-chlorophenyl)[3 -( 1 ,2,4-oxadiazol-3-yl)phenyl]methyl } azetidin-3 -yl)-2-fluoro- 2-methylpropyl] -5 -fluorobenzonitrile, 5 - [3 -((S)-(4-chlorophenyl) { 3 -[( 1 S)- 1 -(3 ,5 -difluorophenyl)- 2-fluoro-2-methylpropyl] azetidin-1 -yl}methyl)phenyl]-l ,3,4-oxadiazol-2(3H)-one, 5-[3-((S)-(4- chlorophenyl) { 3 - [( 1 S)- 1 -(3 ,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin- 1 - yl } methyl)phenyl] - 1 ,3 ,4-oxadiazol-2(3H)-one, 4- { (S)- { 3- [( 1 S)- 1 -(3 ,5-difluorophenyl)-2-fluoro- 2-methylpropyl]azetidin-l-yl}[3-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]methyl}- benzonitrile, and pharmaceutically acceptable salts thereof.
Specific NPY5 antagonists of use in combination with a compound of the present invention include: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-l(3Η),4'-piperidine]-r- carboxamide, 3 -oxo-N-(7-trifluoromethylpyrido [3 ,2-b]pyridin-2-yl)spiro- [isobenzofuran- l(3H),4'-piperidine]-r-carboxamide, N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro- [isobenzofuran- 1 (3 H),4 ' -piperidine] - 1 ' -carboxamide, trans-3 ' -oxo-N-(5 -phenyl-2- pyrimidinyl)spiro [cyclohexane- 1 , 1' (3 ' H)-isobenzofuran] -4-carboxamide, trans-3 ' -oxo-N-[ 1 -(3 - quinolyl)-4-imidazolyl]spiro[cyclohexane-l,r(3'H)-isobenzofuran]-4-carboxamide, trans-3-oxo- N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran- 1 (3H), 1 '-cyclohexane] -4 '-carboxamide, trans-N- [5 -(3 -fluorophenyl)-2-pyrimidinyl] -3 -oxospiro [5 -azaisobenzofuran- 1 (3 H), 1 ' - cyclohexane]-4'-carboxamide, trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5- azaisobenzofuran-l(3H),r-cyclohexane]-4'-carboxamide, trans-N-[l-(3,5-difluorophenyl)-4- imidazolylJ-S-oxospirotT-azaisobenzofuran-^S^^'-cyclohexaneJ^'-carboxamide, trans-3-oxo- N-(I -phenyl-4-pyrazolyl)spiro[4-azaisobenzo furan-l(3 H)5I '-cyclohexane]-4'-carboxamide, trans-N- [ 1 -(2-fluorophenyl)-3 -pyrazolyl] -3 -oxospiro [6-azaisobenzofiiran- 1 (3 H), 1 ' -cyclohexane] - 4'-carboxamide, trans-3-oxo-N-(l-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-l(3H),r- cyclohexane]-4'-carboxamide, trans-3-oxo-N-(2-phenyl-l,2,3-triazol-4-yl)spiro[6- azaisobenzofuran-l(3H),r-cyclohexane]-4'-carboxamide, and pharmaceutically acceptable salts and esters thereof. Specific ACC- 1/2 inhibitors of use in combination with a compound of the present invention include: r-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(lH-tetrazol-5-yl)spiro[chroman- 2,4'-piperidin]-4-one; (5-{r-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4'- piperidin]-6-yl}-2H-tetrazol-2-yl)methyl pivalate; 5-{ l'-[(8-cyclopropyl-4-methoxyquinolin-2- yl)carbonyl]-4-oxospiro[chroman-2,4'-piperidin]-6-yl} nicotinic acid; 1 '-(8-methoxy-4- moφholin-4-yl-2-naphthoyl)-6:(l//-tetrazol-5-yl)spiro[chroman-2,4'-piperidin]-4-one; and 1'- [(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(lH-tetrazol-5-yl)spiro[chroman-2,4'-piperidin]-4- one; and pharmaceutically acceptable salts and esters thereof.
Specific MCΗ1R antagonist compounds of use in combination with a compound of the present invention include: l-{4-[(l-ethylazetidin-3-yl)oxy]phenyl}-4-[(4- fluorobenzyl)oxy]pyridin-2( 1 H)-one, 4-[(4-fluorobenzyl)oxy] - 1 - {4- [( 1 -isopropylazetidin-3 - yl)oxy]phenyl}pyridin-2(lH)-one, l-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2- yl)methoxy]pyridin-2(lH)-one, 4-[(5-chloropyridin-2-yl)methoxy]-l-{4-[(l-ethylazetidin-3- yl)oxy]phenyl}pyridin-2(lH)-one, 4-[(5-chloropyridin-2-yl)methoxy]-l-{4-[(l-propylazetidin-3- yl)oxy]phenyl } pyridin-2( 1 H)-one, and 4-[(5 -chloropyridin-2-yl)methoxy] - 1 -(4- { [(2S)- 1 - ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(l//)-one, or a pharmaceutically acceptable salt thereof.
A specific DP-FV inhibitors of use in combination with a compound of the present invention is 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8- tetrahydro-l,2,4-triazolo[4,3-a]pyrazine, or a pharmaceutically acceptable salt thereof. Specific Η3 (histamine H3) antagonists/inverse agonists of use in combination with a compound of the present invention include: those described in WO05/077905, including:3-{4- [(l-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one, 3-{4-[(l- cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-ethyl-3-(4- { 3 - [(3 S)-3 -methylpiperidin- 1 -yljpropoxy } phenyl)pyrido [2,3 -d]pyrimidin-4(3H)-one 2-methyl-3 - (4-{3-[(3S)-3-methylpiperidin-l-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 3-{4- [(I -cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone, 3-{4-[(l - cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone, 3-{4- [(l-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(l- cyclobutylpiperidin-4-yl)oxy]phenyl } -5 -fluoro-2-methyl-4(3H)-quinazolinone, 3 - {4- [( 1 - cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(l- cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone, 3-{4-[(l- cyclobutylpiperidin-4-yl)oxy]phenyl} -6-fluoro-2-methyl-4(3H)-quinazolinone, 3 - {4-[( 1 - cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone, 3-{4-[(l-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 3- {4-[( 1 -cyclobutylpiperidin-4-yl)oxy]phenyl } -6-fluoro-2-methylpyrido[3 ,4-d]pyrimidin-4(3H)- one, 3- {4-[(l -cyclobutyl-4-piperidinyl)oxy]phenyl} -2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one, 6- methoxy-2-methyl-3-{4-[3-(l-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one, 6- methoxy-2-methyl-3 - {4-[3 -( 1 -pyrrolidinyl)propoxy]phenyl } pyϊido [3 ,4-d]pyrimidin-4(3H)-one, 2,5-dimethyl-3-{4-[3-(l-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 2-methyl-3-{4-[3- (l-pyiτolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone, 5-fluoro-2-methyl-3- {4-[3-(l-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 6-methoxy-2-methyl-3-{4-[3-(l- piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone, 5-methoxy-2-methyl-3-(4-{3-[(3S)-3- methylpiperidin-l-yl]propoxy}phenyl)-4(3H)-quinazolinone, 7-methoxy-2-methyl-3-(4-{3-[(3S)- 3-methylpiperidin-l-yl]propoxy}phenyl)-4(3H)-quinazolinone, 2-methyl-3-(4-{3-[(3S)-3- methylpiperidin- 1 -yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one, 5-fluoro-2-methyl-3- (4- { 3 - [(2R)-2-methylpyrrolidin- 1 -yl]propoxy }phenyl)-4(3H)-quinazolinone, 2-methyl-3 -(4- { 3 - [(2R)-2-methylpyrrolidin- 1 -yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 6-methoxy-2- methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-l-yl]propoxy}phenyl)-4(3H)-quinazolinone, 6- methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-l-yl]propoxy}phenyl)-4(3H)-quinazolinone, and pharmaceutically acceptable salts thereof.
Specific CCKlR agonists of use in combination with a compound of the present invention include: 3-(4-{[l-(3-ethoxyphenyl)-2-(4-methylphenyl)-lH-imidazol-4-yl]carbonyl}- 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- { [ 1 -(3 -ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)- IH- imidazol-4-yl]carbonyl} - 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- { [ 1 -(3 -ethoxyphenyl)-2-(4- fluorophenyl)- 1 H -imidazol-4-yl]carbonyl } - 1 -piperazinyl)- 1 -naphthoic acid; 3 -(4- { [ 1 -(3 - ethoxyphenyl)-2-(2,4-difluorophenyl)- \H -imidazol-4-yl]carbonyl}- 1 -piperazinyl)- 1 -naphthoic acid; and 3-(4-{[l-(2,3-dihydro-l,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-li/-imidazol-4- yl]carbonyl}-l-piperazinyl)-l-naphthoic acid; and pharmaceutically acceptable salts thereof.
Specific MC4R agonists of use in combination with a compound of the present invention include: 1 ) (55)- 1 '- { [(3R,4R)- 1 -tert-butyl-3 -(2,3 ,4-trifluorophenyl)piperidin-4-yl]carbonyl } -3 - chloro-2-methyl-5-[ 1 -methyl- 1 -( 1 -methyl- 1 H- 1 ,2,4-triazol-5 -yl)ethyl] -5H-spiro [furo [3 ,4- ό]pyridine-7,4'-piperidine] ; 2) (5R)- 1 '- { [(3R,4R)- 1 -tert-butyl-3 -(2,3 ,4-trifluorophenyl)-piperidin- 4-yl]carbonyl}-3-chloro-2-methyl-5-[l-methyl-l-(l-methyl-lH-l,2,4-triazol-5-yl)ethyl]-5H- spirotfurotS^-όlpyridine-T^'-piperidine]; 3) 2-(l'-{[(35,4i?)-l-rerr-butyl-4-(2,4- difluorophenyl)pyrrolidin-3 -yl] carbonyl } -3 -chloro-2-methyl-5H-spiro [furo [3 ,4-£]pyridine-7,4'- piperidin]-5-yl)-2-methylpropanenitrile; 4) 1 '- { [(35,4i?)- 1 -tert-butyl-4-(2,4- difluorophenyl)pyrrolidin-3-yl] carbonyl } -3 -chloro-2-methyl-5 -[ 1 -methyl- 1 -( 1 -methyl- 1 H- 1 ,2,4- triazol-5-yl)ethyl] -5H-spiro [furo [3 ,4-ό]pyridine-7,4'-piperidine] ; 5) N- [(3i?,4i?)-3 -( { 3 -chloro-2- methyl-5-[ 1 -methyl- 1 -( 1 -methyl- 1 H- 1 ,2,4-triazol-5 -yl)ethyl] - 1 'H,5H-spiro [furo- [3 ,4-6]pyridine- 7,4'-piperidin]-r-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H- pyran-4-amine; 6) 2- [3 -chloro- 1 '-( { ( 1 i?,2i?)-2-(2,4-difluorophenyl)-4- [methyl(tetrahydro-2H- pyran-4-yl)amino] -cyclopentyl } -carbonyl)-2-methyl-5H-spiro [furo [3 ,4-ό]pyridine-7,4'- piperidin]-5-yl]-2-methyl-propane-m'trile; and pharmaceutically acceptable salts thereof. The obesity-related disorders herein are associated with, caused by, or result from obesity. Examples of obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GΗ-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat- free mass, e.g, children with acute lymphoblastic leukemia. Further examples of obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro-esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer. The compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
The compounds of formula I are also useful for treating or preventing obesity and obesity-related disorders in cats and dogs. As such, the term "mammal" includes companion animals such as cats and dogs.
As used herein, the term "substance abuse disorders" includes substance dependence or abuse with or without physiological dependence. The substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above. In particular, compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependence and nicotine withdrawal. For smoking cessation, the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist, including varenicline and selective alpha-4 beta 2 nicotinic partial agonists such as SSR 591813, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.
The method of treatment of this invention comprises a method of modulating the CBl receptor and treating CBl receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CB 1 receptor in preference to the other CB or G-protein coupled receptors.
The following reaction schemes illustrate methods which may be employed for the synthesis of the novel pyrano[2,3-6]pyridines of structural formula I described in this invention. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the title compounds of general formula I. A preferred synthetic process which is shown in the retrosynthetic sense in reaction Scheme 1 proceeds through a suitably substituted 3- cyano-2-pyridone of general formula 2. The 3-cyano-2-pyridone of general formula 2 is in turn derived from a 1 ,2-diarylethanone of general formula 1. Reaction Schemes 2-7 illustrate the preferred methods for the synthesis of the novel compounds of general formula I in the forward sense. In these schemes, group Ar1 refers to the aryl group substituted by the substituent R4 position 6 of the pyrano[2,3-ό]pyridine of general formula I, and Ar2 refers to the aryl group substituted by the substituents R6 and R7 at position 7 of the pyrano[2,3-6]pyridine of general formula I.
Scheme 1
Figure imgf000022_0001
1 ,2-Diarylethanones of general formula 1 may be available commercially or they can be synthesized using one of several methods known in the art of organic synthesis. Scheme 2 illustrates three methods for the synthesis of the 1 ,2-diarylethanones of general formula 1. In the first example (equation 1), a substituted arylmethyl bromide of general formula 3 is converted to a Grignard reagent with magnesium metal in a solvent such as THF at a temperature between room temperature and the refluxing temperature of the solvent. The resulting Grignard reagent is then added to a substituted arylnitrile of general formula 4. Acidic hydrolysis of the reaction mixture followed by extraction of the organic product affords a 1 ,2-diarylethanone of general formula 1 as shown. An alternative synthesis of 1 ,2-diarylethanones 1 which is preferred when either of the aryl groups ArI or Ar2 are optionally substituted with functional groups that are reactive with Grignard reagents is shown in equation 2 of reaction Scheme 2. Here a substituted arylacetic acid of general formula 5 is reacted at low temperature (-78° to -50°C) with two equivalents of a strong base such as lithium bis(trimethylsilylamide) in an aprotic solvent such as THF. This deprotonates the arylacetic acid 5, and generates a dianion which undergoes a Dieckmann reaction when the substituted arylcarboxylate ester of general formula 6 is added. In this modification of the Dieckmann reaction, the intermediate β-keto acid smoothly decarboxylates and a 1 ,2-diarylethanone of general formula 1 is produced. A third method for the preparation of the 1 ,2-diarylethanones of general formula 1 involves the palladium-catalyzed α-arylation of an acetophenone derivative of general formula 8 with an aryl halide, such as the aryl bromide of general formula 7, as illustrated in equation 3 (Fox, J.M.; Huang, X.; Chieffi, A.; Buchwald, S.L. J. Am. Chem. Soc. 2000, 122, 1360-70).
Scheme 2
Figure imgf000023_0001
O LiN(TMS)2, THF Λ, ^^ OH (2)
Ar2 ^CO2CH3 Ar* "S)
5 6 1
7 8 1
Reaction Scheme 3 illustrates two methods for the conversion of the 1 ,2-diarylethanone of general formula 1 into the 3-cyano-2-pyridones of general formula 2. The 1 ,2-diarylethanone of general formula 1 is first converted to a vinylogous amide of general formula 9 by reaction with an ΛyV-dimethylformamide dimethylacetal. The condensation reaction may be conducted using a solvent such as acetonitrile or simply by using the DMF acetal as the reaction solvent at an elevated temperature, typically between room temperature and 1500C, and the vinylogous amide 9 is produced as a mixture of E and Z diastereoisomers. In the second step of this sequence, the vinylogous amide 9 is condensed with cyanoacetamide to afford the 3-cyano-2- pyridone of general formula 2. The reaction is usually conducted in a polar aprotic solvent such as DMF in the presence of a strong base such as an alkali metal hydride or alkoxide.
Me2NCH(OMe)2
Figure imgf000024_0002
Figure imgf000024_0001
1 9 2 (R3 = H)
A preferred method for the next stage of the synthesis of the novel compounds of general formula I is illustrated in reaction Schemes 4. hi this Scheme, a 3-cyano-2-pyridone of general formula 2 is converted to an α,β -unsaturated ketone of general formula 13, which can undergo a spontaneous intramolecular Michael addition with the adjacent nucleophilic pyridone oxygen atom. The resulting product is the substituted 2,3-dihydro-4//-pyrano[2,3-ό]pyridin-4-one 17, which corresponds to the title compounds of general formula I wherein the X and X1 substituents together form a carbonyl group, and there is a single bond between the carbon atoms at positions 3 and 4 of the pyran ring. The 3 -cyano-2 -pyridone of general formula 2 may be converted to the intermediate α,β -unsaturated ketone of general formula 13, using one of several synthetic methods. For instance, reaction of 2 with a vinyl Grignard reagent of general formula 12 followed by acidic hydrolysis of the reaction mixture affords the α,β -unsaturated ketones of general formula 13 which in turn undergo the intramolecular cyclization that leads to compounds of general formula 17. Alternatively, the 3-cyano-2-pyridones (2) may be first converted to a ketone general formula 15, typically by reaction with an organometallic species, such as the Grignard reagent of general formula 14, followed by acidic hydrolysis. Reaction of the resulting ketone 15 under basic conditions with a carbonyl compound of general formula 16 effects an aldol condensation. A preferred method for conducting the aldol condensation involves using a secondary or tertiary amine as the base and conducting the reaction at an elevated temperature, for instance at temperatures between room temperature and 150°C. Under these conditions, the aldol condensation results in concomitant loss of water to initially afford an α,β-unsaturated ketone of general formula 13, which in turn may undergo the intramolecular cyclization that leads to compounds of general formula 17 as described above. Scheme 4
Figure imgf000025_0001
17
The substituted 2,3-dihydro-4H-pyrano[2,3-ό]pyridin-4-ones of general formula 17 are versatile intermediates, and reaction Schemes 5-7 illustrate some of the preferred synthetic methods for the conversion of compounds (17) to the novel compounds of general formula I described in this invention. For instance, in reaction Scheme 5, reduction of the carbonyl group at the 4-position of the pyran ring in compounds of general formula 17 results in a secondary alcohol of general formula 18. The reduction of 17 can be accomplished using a variety of metal hydride reducing agents such as sodium borohydride in suitable solvent systems such as TΗF/methanol. The resulting secondary alcohols of general formula 18 contain a new stereogenic center and are formed as either a racemic mixture or as a mixture of diastereoisomers when an additional stereogenic center is present in the compound. Racemic mixtures of general formula 18 may be separated into their component enantiomerically pure alcohols by classical resolution methods, or by separation using chiral stationary phase ΗPLC columns. The reduction of the carbonyl group in compounds of general formula 17 may also be accomplished using asymmetric reduction methods such as hydrogenation in the presence of a chiral organometallic catalyst (Ηaack, K.J.; Ηashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. Engl. 1997, 36, 285-8). The secondary alcohols of general formula 18 may be further modified as shown in Scheme 5, for instance by conversion to ethers (R = alkyl), esters (R = acyl), and carbamates (R = CONR2) of general formula 19. The hydroxyl group of compounds of general formula 18 may also be displaced by a new functional group. One preferred method for the hydroxyl displacement is the Mitsunobu reaction with a zinc azide complex (Viaud, M.C.; Rollin, P. Synthesis 1990, 130-2) which affords the azido compound of general formula 20. Reduction of the azido group in the compounds of general formula 20, for instance using Staudinger's conditions (PPh3, H2O), then affords amino derivatives of general formula 21 (R2 = H). The primary amino compounds of general formula 21 may in turn be further modified to incorporate additional substituents on the nitrogen atom that are within the scope of this invention using a variety of synthetic methods. For instance, the amino group may be reacted with acid chlorides or sulfonyl chlorides to afford the corresponding amides or sulfonamides respectively. The amino group may also be N-alkylated using reductive amination reactions or N-arylated using palladium catalyzed coupling reactions with suitable aryl or heteroaryl halides (Muci, A.R.; Buchwald, S. L. Topics in Current Chemistry 2002, 219 Cross-Coupling Reactions, 131-209. Hartwig, J.F. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 1051-96). Finally the amino group of compounds of general formula 21 may also be incorporated into various nitrogen heterocyclic systems when it is desired that either the X or X1 substituent in the compounds of general formula I be such a heterocyclic element. The resulting compounds of general formula 21 correspond to the title compounds of general formula I wherein the X = NR2, X1 = H and there is a single bond between the carbon atoms at positions 3 and 4 of the pyran ring.
Figure imgf000026_0001
19 20 21
Reaction Scheme 6 illustrates two additional methods for the synthetic modification of the substituted 2,3-dihydro-4H-pyrano[2,3-ό]pyridin-4-ones of general formula 17 when it is desired that either the X or X1 substituent be an amino or optionally substituted amino group. The carbonyl group of compounds of general formula 17 may be subjected to reductive amination reactions with primary or secondary amino compounds 22, for instance using either sodium cyanoborohydride, sodium triacetoxy borohydride, or sodium borohydride in combination with titanium tetraisopropoxide as the reducing agent, and the substituted 4- aminopyrano[2,3-ό]pyridine derivatives of general formula 21 are again produced. The substituted amino compounds of general formula 21 may be further modified into the title compounds of general formula I using the methods described above. The carbonyl group of compounds of general formula 17 may also be converted to the corresponding oximes 23 using hydroxylamine hydrochloride. These oximes may in turn be reduced to afford primary amine 21 (R2 = H), or be employed in a reductive amidation reaction (Burk, M.J.; Casy, G.; Johnson, N.B. J. Org. Chem. 1998, 63, 6084) which produces the enamides of general formula 24. Compounds of general formula 24 correspond to the title compounds of general formula I wherein the X = NHR2, X1 is absent and there is a double bond between the carbon atoms at positions 3 and 4 of the pyran ring.
Figure imgf000027_0001
21 23 24
Reaction Scheme 7 illustrates methods for the synthetic modification of the substituted 2,3-dihydro-4H-pyrano[2,3-Z>]pyridin-4-ones of general formula 17 when it is desired that either the X or X1 be a carbon substituent. The carbonyl group of compounds of general formula 17 undergo carbon-carbon bond forming reactions with nucleophilic carbon reagents that are commonly employed in organic synthesis. For instance, the compounds of general formula 17 may react in Wittig or Ηorner-Emmons olefination reactions, with organometallic reagents such as Grignard reagents or with a variety of stabilized carbanionic species such as enolates, and the like. Scheme 7 illustrates the reaction of a compound of general formula 17 with a Reformatsky reagent (25) which produces the tertiary alcohol of general formula 26. The alcohols of general formula 26 may be further synthetically modified, for instance they may be dehydrated to afford derivatives containing a new double bond, which is generally produced as a separable mixture of the endocyclic and exocyclic isomers. The carbonyl group of compounds of general formula 17 may also be converted to vinyl triflates of general formula 27 by treatment with a reagent such as trifluoromethansulfonic anhydride or N-phenyl-bis(trifluoromethane-sulfonimide) in the presence of a suitable base. Vinyl triflates of general formula 27 may then be employed in a variety of palladium-catalyzed cross coupling reactions to afford compounds of general formula 28. For instance, when triflates of general formula 27 are reacted with aryl, heteroaryl, or vinylboronic acids in the presence of a palladium catalyst, the compounds of general formula 28 are produced wherein the X group is an aryl, heteroaryl or vinyl substituent. Additionally, the triflates of general formula 27 may be converted to carboxylic acid derivatives. Hydroxycarboxylation of compounds of general formula 27 using potassium acetate, carbon monoxide and a palladium catalyst in DMSO (Cacchi, S.; Lupi, A. Tetrahedron Lett. 1992, 33, 3939-42) afford the corresponding carboxylic acids (28, X = CO2H). Similarly, compounds of general formula 27 may be converted directly to esters (28, X = CO2R) or amides (28, X = CONR2) by reaction with either an alcohol or a primary or secondary amine with a palladium catalyst in the presence of carbon monoxide. Compounds of general formula 28 correspond to the title compounds of general formula I wherein the X group is a directly bonded carbon substituent as described above, X1 is absent and there is a double bond between the carbon atoms at positions 3 and 4 of the pyran ring.
Figure imgf000028_0001
26 27 28
Reaction Scheme 8 illustrates a preferred method for the synthesis of the novel compounds of general formula I described in this invention when it is desired that the R1 and R2 substituents together form a carbonyl group. In this synthetic process, the cyano group of the substituted 3-cyano-2-pyridone of general formula 2 is first reduced to an aldehyde using a reagent such as diisobutylaluminum hydride in a solvent such as toluene. The resulting substituted 2-pyridone-3-carboxaldehydes of general formula 29 may then be condensed with a variety of substituted acetic ester derivatives of general formula 30 under basic reaction conditions. In these reactions the group Y is typically an electron-withdrawing group such as a carbonyl, cyano group or the like, which is capable of further stabilizing the enolate of the ester of general formula 30. The deprotonated form of the ester 30 condenses with the formyl group of the 2-pyridone-3-carboxaldehydes of general formula 29. This condensation reaction is typically conducted at an elevated temperature, such as the boiling point of the solvent used, and under these conditions the resulting intermediate from this condensation (eg. 31) may then further cyclize to form the pyrone ring of the 2//-pyrano[2,3-ό]pyridin-2-one of general formula 32. Compounds of general formula 32 correspond to the title compounds of general formula I wherein the R1 and R2 taken together form a carbonyl group, the X group is a hydrogen atom, X1 is absent, and there is a double bond between the carbon atoms at positions 3 and 4 of the pyran ring. The compounds of general formula 32 described in Scheme 8 may be further modified into the novel compounds of general formula I using the methods described in the preceding reaction Schemes for the compounds of general formula 17, or by using other synthetic reactions known in organic chemistry.
Scheme 8
Figure imgf000029_0001
29
Figure imgf000029_0002
31 32
In order to illustrate the invention, the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of reducing the invention to practice. Those skilled in the art may find other methods of practicing the invention which are readily apparent to them. However, those methods are also deemed to be within the scope of this invention. General Procedures.
Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) performed with E. Merck precoated TLC plates, silica gel 60F- 254, layer thickness 0.25 mm or liquid chromatography-mass spectrum (LC-MS). Mass analysis was performed on a Waters Micromass® ZQ™ with electrospray ionization in positive ion detection mode. High performance liquid chromatography (HPLC) was conducted on an Agilent 1100 series HPLC on Waters C18 XTerra 3.5 μm 2.1x20 mm column with gradient 10:90-98:2 v/v CH3CN/H2O + v 0.05 % TFA over 3.25 min then hold at 98:2 v/v CH3CN/H2O + v 0.05 % TFA for 0.75 min; flow rate 1.5 mL/min, UV wavelength 254 nm. Two other HPLC conditions applied were noted as LC-I (Waters C18 XTerra 3.5 μm 2.1x20 mm column with gradient 10:90-98:2 v/v CH3CN/H2O + v 0.05 % TFA over 1.25 min then hold at 98:2 v/v CH3CN/H2O + v 0.05 % TFA for 0.75 min; flow rate 1.5 mL/min, UV wavelength 254 nm) and LC-2 (Waters C18 XTerra 3.5 μm 30 x50 mm column with gradient 10:90-98:2 v/v CH3CN/H2O + v 0.05 % TFA over 3.75 min then hold at 98:2 v/v CH3CN/H2O + v 0.05 % TFA for 1.75 min; flow rate 1.0 mL/min, UV wavelength 254 nm). Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (32-63 mM, 60 A pore size) in pre-packed cartridges of the size noted. 1H NMR spectra were acquired at 500 MHz spectrometers in CDCl3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CD3Cl solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IP A/Hep) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography.
Abbreviations: acetic acid (AcOH), aqueous (aq), (benzotriazol-l-yloxy)tripyrrolidino- phosphonium hexafiuorophosphate (PyBOP), 2,2 ' -bis(diphenylphosphino)- 1,1' -binaphthalene (BINAP), l,l'-bis(diphenylphosphino)ferrocene (dppf),
Figure imgf000030_0001
(DMAP), ethyl acetate (EtOAc), diethyl ether (ether or Et2O), ΛζiV-diisopropylethylamine (DIEA), NJV- dimethylformamide (DMF), gram(s) (g), hour(s) (h or hr), microliter(s) (μL), milligram(s) (mg), milliliter(s) (mL), millimole (mmol), mass spectrum (ms or MS), 2-propanol (IPA), retention time (R1), room temperature (rt), saturated aq sodium chloride solution (brine), trifluoroacetic acid (TFA), tetrahydrofuran (THF), and minute(s) (min).
Figure imgf000030_0002
6-(4-Chlorophenyl)-7-(2,4-dichlorophenyl)-2.2-dimethyl-2,3-dihvdro-4H-pyrano[2.3-61pyridin- 4-one
Step A: 3-Dimethylamino-l-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-l-one A solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4 mmol) and dimethylformamide dimethyl acetal (7.7 mL, 58 mmol) in DMF (60 mL) was heated at 75°C for 20 h. The volatiles were removed in vacuo to provide the product which was used directly in the next step. (LC-2) HPLC/MS: 354 (M+l), 356 (M+3); Rt = 3.47 min.
Step B: 6-(2,4-DichlorophenylV5-(4-chlorophenvπ-2-oxo-K2-dihvdropyridine-3-carbonitrile To a solution of the product of Step A, cyanoacetamide (1.33 g, 15.8 mmol), and MeOH (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to a suspension of NaH (60% in mineral oil) (1.45 g, 36 mmol) in DMF (16 mL) at rt. After the slow addition was complete, the reaction was heated to 95°C for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aq 18% citric acid solution. The mixture was extracted twice with CH2Cl2 and the organic layers were washed with brine. The combined organic layers were dried (Na2SO4) and concentrated. The solid residue was triturated with ether, filtered, and air dried to afford the product. (LC-2) HPLC/MS: 375 (M+l), 377 (M+3); R, = 3.47 min. Step C: 6-(4-Chlorophenyl)-7-("2.4-dichlorophenylV2.2-dimethyl-23-dihvdro-4H- pyrano \23-b] pyridin-4-one . To the product of Step B (13.15g, 35 mmol) in THF (160 mL) was added MeMgBr (1.4 M in toluene/THF, 26.25 mL, 36.75 mmol). After stirring 3 min, 2- methylprop-1-enylmagnesium bromide (0.5 M in THF, 100 mL, 50 mmol) was added and the temperature was increased to 50 °C. After 20 min the reaction was cooled, quenched with 2 M HCl and diluted with EtOAc. The reaction was stirred for 3 days before work up. The solution was washed twice with brine, followed by twice with saturated aq NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 432.2 (M+l), 434.2 (M+3); Rt = 4.15 min.
Example 2
Figure imgf000031_0001
7-(2-Chlorophenvπ-6-(4-chlorophenyl)-2,2-dimethyl-2,3-dihvdro-4H-pyrano[2,3-61pyridin-4-one Starting with 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile prepared in similar fashion to Step B Example 1 and following a similar procedure as described in Example 1 step C the title compound was prepared. (LC-2) HPLC/MS: 398.1 (M+l), 400.1 (M+3); Rt = 4.09 min.
Example 3
Figure imgf000031_0002
7'-(2-ChlorophenylV6'-(4-chlorophenyl')spiro [cyclohexane- 1.2'-pyrano [2,3 -άlpyridinl -4Y3 'H)-one Step A: 3 - Acetyl-6-(2-chlorophenyl >5 -(4-chlorophenyl)pyridin-2( 1 H)-one. To 6-(2- chlorophenyl)-5-(4-chlorophenyl)-2-oxo-l,2-dihydropyridine-3- carbonitrile (15.02 g, 44.0 mmol) prepared in similar fashion to Step B Example 1 was added THF (100 mL). The mixture was reacted with MeMgBr (70 mL, 1.4 M in toluene/THF) slowly over 30 min. The reaction mixture warmed, becoming homogenous yellow-orange, and the addition was maintained at a rate to keep the temperature below the boiling point of THF. After the addition was complete, the reaction stirred an additional 1 h at rt. The reaction mixture was quenched with 1.0 N HCl and the organic layer was separated and concentrated. The residue was dissolved in hot EtOAc and washed with water, brine, dried (MgSO4), filtered and concentrated to afford the title compound which was used in the next step without further purification. (LC-2) HPLC/MS: 358.1 (M+l), 360.1 (M+3); Rt = 3.62 min.
Step B: 7'-(2-Chlorophenyl)-6'-(4-chlorophenyl)spiro[cvclohexane-l,2'-pyranor2,3-
6"|pyridin| -4Ϊ3 'HVone To the product of Example 3 Step A (6.25 g, 17.5 mmol), was added cyclohexanone (20 mL) and pyrrolidine (1.44 mL, 17.4 mmol). The reaction was heated to 155 °C for 30 min in a sealed 80 mL tube in a CEM Corporation Discover microwave system. The reaction was then concentrated and the residue was purified directly by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane to afford the title compound. (LC-2) ΗPLC/MS: 438.3 (M+l), 440.3 (M+3); R1 = 4.39 min.
Starting with the product of Example 3 Step A and using procedures similar to that of Example 3 Ste B the following additional compounds were prepared using the appropriate ketones.
Figure imgf000032_0001
Figure imgf000033_0001
Example 11
Figure imgf000033_0002
2-fert-Butyl-7-(2-chlorophenyl)-6-(4-chlorophenylV23-dihvdro-4H-pyrano[2,3-61pyridin-4-one To the product of Example 3 Step A (0.75 g, 2.09 mmol) was added pivalaldehyde (2. mL, 20.9 mmol), pyrrolidine (0.26 mL, 3.14 mmol) and acetonitrile (15 mL). The reaction was heated to 70 °C for 19 h. The reaction was then concentrated and the residue was purified directly by flash chromatography on silica gel gradient eluted with 0-35% EtOAc in hexane to afford the title compound. (LC-2) ΗPLC/MS: 426.3 (M+l), 428.3 (M+3); R, = 4.32 min.
Starting with the product of Example 3 Step A or 3-acetyl-6-(4-bromo-2-chlorophenyl)-5-(4- chlorophenyl)pyridin-2(lH)-one and using procedures similar to that of Example 11 the following compounds were prepared using the appropriate aldeh des.
Figure imgf000033_0003
Figure imgf000034_0001
Example 15
Figure imgf000034_0002
7'-(2-ChlorophenylV6'-(4-chlorophenyl)spiro [cyclohexane- 1 ,2'-pyrano [2,3 -άipyridini -4'(3 'HVone oxime (E/Z mixture). To the product of Example 3 Step B (414 mg, 0.945 mmol), was added hydroxylamine hydrochloride (262 mg, 3.78 mmol), NEt3 (0.527 mL, 3.78 mmol), potassium acetate (370 mg, 3.77 mmol) and methanol (23 mL). The reaction was heated to 65 °C for 90 min. The reaction was then concentrated and the residue was diluted with EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound which used without further purification. (LC-2) ΗPLC/MS: 453.1 (M+l), 455.1 (M+3); R1 = 4.09 and 4.12 min.
The following compounds were prepared using conditions similar to that of Example 15 and the a ro riate ketone.
Figure imgf000034_0003
Figure imgf000035_0001
Example 18
Figure imgf000035_0002
7'-(2-Chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihvdrospiro[cvclohexane-l,2'-pyrano|"2,3- 61pyridin1-4'-amine. To the product of Example 15 (453 mg) was added Zn powder (196 mg, 3.0 mmol) and AcOH (10 mL). The reaction was heated to 95 °C for 15 min and then concentrated. The residue was diluted with EtOAc and washed with saturated aq NaHCO3, dried (Na2SO4), filtered and concentrated to afford the title compound. (LC-2) HPLC/MS: 439.2 (M+l), 441.2
Figure imgf000035_0003
The following compounds were prepared from the appropriate oximes utilizing similar
Figure imgf000035_0004
Example 21
Figure imgf000036_0001
N-[7'-(2-Chlorophenyl')-6'-(4-chlorophenyl)-3'.4'-dihvdrospirorcvclohexane-l,2'-pyranof2,3- 61pyridinl-4'-yl]acetamide. To the product of Example 18 (50 mg, 0.114mmol) in CH2Cl2 (1 mL) was added acetyl chloride (9 μL, 0.127 mmol) and NEt3 (40 μL, 0.286 mmol). The reaction was stirred 30 min and was purified directly by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 481.2 (M+l), 483.2 (M+3); R4 = 3.79 min.
Example 22
Figure imgf000036_0002
N-r6-(4-Chlorophenyl)-7-(2,4-dichlorophenvπ-2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- b] pyridin-4-yl] acetamide . To the product of Example 16 (102 mg, 0.228 mmol) in AcOH (2 mL) was added Zn powder (75 mg, 1.15 mmol). The reaction was heated to 95 °C for 10 min before adding acetic anhydride (0.5mL). After 15 min the reaction was concentrated. The residue was diluted with EtOAc and washed with IM aq Na2CO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane to afford the title compound. (LC-2) ΗPLC/MS: 475.2 (M+l), 477.1 (M+3); R, = 3.83 min.
Figure imgf000036_0003
N-[7'-(2-ChlorophenylV6'-(4-chlorophenyπ-3'.4'-dihydrospiro[cyclohexane-L2'-pyranor2,3- &1pyridin'|-4'-yl'|-2-hvdroxyacetamide. To the product of Example 18 (50 mg, 0.114mmol) in CH2Cl2 (1 mL) was added acetoxyacetyl chloride (14.7 μL, 0.137 mmol) and NEt3 (15.9 μL, 0.114 mmol). The reaction was stirred 20 min and was treated with sodium methoxide solution (0.3 mL, 30 wt%) and MeOH (1 mL). The reaction was stirred 90 min and was concentrated. The residue was diluted with CH2Cl2 and washed with aq NaHSO4 (1 M). The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 497.2 (M+ 1), 499.1 (M+3); R, = 3.61 min.
The following examples were prepared utilizing the appropriate amine and carboxylic acid or acid chloride in procedures similar to those of Example 21 and Example 46. Preparation of hydroxy acetamide compounds were carried out as per Example 23. Where noted the enantiomers, or the diastereomers, were separated either by chiral chromatography or via silica gel purification with the conditions as indicated:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
1 -["7'-(2-Chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihvdrospiro|"cvclohexane- 1 ,2'-pyrano[23-
Figure imgf000039_0002
To the product of Example 29 (34 mg, 0.0652 mmol) in DMF (1 mL) was added Cs2CO3 (20 mg, O.Oόlmmol). The reaction was heated to 80 °C for 1 h. The reaction was diluted with EtOAc and washed with brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 521.3 (M+l), 523.2 (M+3); R1 = 4.20 min.
Example 39
Figure imgf000039_0003
N-r6-(4-Chlorophenvn-7-(2,4-dichlorophenylV2,2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 61pyridin-4-yl1-3-hvdroxy-2,2-dimethylpropanamide. To the product of Example 37 (168 mg, 0.269mmol) was added FeCl3 (235 mg, 1.45 mmol) in CH2Cl2 (3.5 mL). The reaction was stirred 130 min at 30 °C and was then diluted with EtOAc. The reaction was washed with brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 533.3 (M+l), 535.3 (M+3); R1 = 3.86 min.
The product of Example 39 was resolved on an AD column using 4%EtOH/Hexane.
Example 40
Figure imgf000040_0001
N-r6-(4-ChlorophenylV7-(2,4-dichlorophenylV2,2-dimethyl-3.4-dihvdro-2//-pyranor2.3- 61pyridin-4-yll-iV-methylethanediamide. To the product of Example 19 (110 mg, 0.254 mmol) in CH2Cl2 (2mL) was added oxalyl chloride (0.5 mL, 5.71 mmol). After 10 min, the reaction was concentrated. The residue was diluted with 6 mL of 2 M methylamine in THF. After 30 min the reaction was concentrated The residue was diluted with EtOAc and washed with saturated aq NaHCO3 /brine (1 :1). The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 518.0(M+l), 520.0 (M+3); R1 = 3.67 min.
Example 41
Figure imgf000040_0002
Ethyl 2-r6-(r4-chlorophenylV7-('2,4-dichlorophenyl)-2,2-dimethyl-2.3-dihvdro-4H-pyranor2.3- b] pyridin-4-ylidenel acetate (E or Z).
Step A: ethyl 2-(6-(4-chlorophenyl)-7-(2,4-dichlorophenvπ-4-hvdroxy-2,2-dimethyl-3.4- dihydro-2H-pyranor2,3-61pyridin-4-yl')acetate. A mixture of ethyl 2-bromoacetate (0.334 mL 3.01 mmol), 1 ,2-dibromoethane (0.02 mL, 0.23 mmol), Zn powder (0.227 g, 3.47 mmol) and TΗF (2.5 mL) was heated to 65 °C for 2 min before cooling to rt. Chlorotrimethylsilane (0.015 mL, 0.116 mmol) was added and the reaction was stirred for 5 min at which point the product of Example 1 (1 g, 2.315 mmol) in TΗF 10 mL was added. The reaction was heated to 70 °C. After 1 h the reaction was cooled to rt. The reaction was diluted with EtOAc and washed with 2 M aq HCl and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-10% EtOAc in CH2Cl2 affording the product (LC-2) HPLC/MS: 520.2 (M+l), 522.2 (M+3); R, = 3.97 min.
Step B: Ethyl 2-r6-(4-chlorophenyl)-7-(2.4-dichlorophenyl)-2.2-dimethyl-2.3-dihvdro-4H- pyranof2,3-6"|pyridin-4-ylidenelacetate (E or Z). To the product of Step A this example (192 mg, 0.382 mmol) was added /»-toluenesulfonic acid monohydrate (72.6 mg, 0.276 mmol) in toluene (3 mL). The reaction was heated to 104 °C. After 80 min the reaction was cooled and diluted with EtOAc. The solution was washed with brine and saturated aq NaHCO3. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-25% EtOAc in hexane affording the title compound as the faster eluting isomer on silica gel. (LC-2) HPLC/MS: 502.1 (M+l), 504.1 (M+3); R1 = 4.52 min.
Example 42
Figure imgf000041_0001
Ethyl 2-(6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2//-pyrano[2,3- 6}pyridin-4-yl)acetate. The product Example 41 (63.7 mg, 0.127 mmol) was added Zn powder (120 mg, 1.835 mmol) in AcOH (2 mL). The reaction was heated to 100 0C. After 20 min the reaction was cooled and diluted with EtOAc. The solution was filtered and washed with 10 % aq Na2CO3 and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-40% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 504.0 (M+l), 506.0 (M+3); Rt = 4.38 min.
Example 43
Figure imgf000041_0002
5-{r6-(4-ChlorophenylV7-(2,4-dichlorophenylV2,2-dimethyl-3,4-dihvdro-2H-pyranor2.3- 61pyridine-4-yl]methyl}-l,3,4-oxadiazol-2(3H)-one.
Step A: 2-(6-(4-Chlorophenvn-7-(2,4-dichlorophenyl')-2,2-dimethyl-3,4-dihvdro-2H- pyrano [2,3 -6]pyridin-4-vDacetic acid. To the product of Example 42 (46.5 mg, 0.127 mmol) was added KOΗ (10.3 mg, 0.184 mmol) in TΗF (1.5 mL), MeOH (0.2 mL) and water (0.075 mL). The reaction was heated to 50 °C. After 27 min the reaction was cooled and diluted with EtOAc. The solution was washed with aq 2 M HCl and brine, dried (Na2SO4), filtered and concentrated to afford the product that was not purified further (LC-2) ΗPLC/MS: 476.0 (M+l), 478.0 (M+3); R, = 3.96 min.
Step B: 5- ( r6-(4-CMorophenyl>7-(2.4-dicMorophenvn-2.2-dimethyl-3 ,4-dihydro-2H- pyranor2,3-61 pyridine-4-vπmethvU-1.3,4-oxadiazol-2(3H)-one. To the product of step A of this example (40.0 mg, 0.084 mmol) was added ΗOBt (lH-l,2,3-benzotriazol-l-ol hydrate) (15.4 mg, 0.101 mmol), EDAC (N1-((emylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride) (19.3 mg, 0.101 mmol) in CH2Cl2 (1.5 mL). The reaction was stirred 1 min before hydrazine hydrate (8.1 μL, 0.168 mmol) was added. After 10 min EDAC (19.3 mg) and hydrazine hydrate (16.3, μL, 0.336 mmol) were added. The reaction was stirred an additional 3.5 h and then diluted with EtOAc. The solution was washed with brine, dried (Na2SO4), and filtered. The concentrated residue was diluted with CH2Cl2 (1.5 mL) and reacted with trichloromethyl chloridocarbonate (0.02 mL, 0.167 mmol). After 20 min the reaction was diluted with EtOAc. The solution was washed with saturated aq NaHCO3 and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 516.0.0 (M+l), 518.0 (M+3); R, = 4.04 min. The product was resolved on an AD column eluting with 23 %IP A/Heptane to give two isomers.
Example 44
Figure imgf000042_0001
7-(2-Chlorophenyl')-6-(4-chlorophenyl)-2',3',5',6'-tetrahvdrospiro|'pyrano[2,3-άlpyridine-2,4'- thiopyran1-4(3//)-one lM'-dioxide. The product of Example 5 (75 mg, 0.165 mmol) in CH2Cl2 (2 mL) and MeOH (3 mL) reacted with magnesium bis(monoperoxyphthalate) hexahydrate (254 mg, 0.41 mmol, 80%) at rt for 90 min. The reaction was concentrated, and the residue was diluted with EtOAc and washed with saturated aq NaHCO3 and brine. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc in hexane affording the title compound. (LC-2) HPLC/MS: 488.1 (M+l), 490.0 (M+3); R1 = 3.74 min.
The following example was prepared utilizing the product of Example 26 using a procedure similar to that of Example 44. The enantiomers were separated by chiral chromatography on an AD column elutin with 15%EtOH/He tane into two isomers.
Figure imgf000042_0002
Example 46
Figure imgf000043_0001
r2y)-N-r7'-r2-ChlorophenylV6'-(4-chlorophenyl)-3'.4'-dihvdrospirorcvclohexane-1.2'-pyranor2.3- 61pyridin1-4'-yll-2-hydroxypropanamide . To the product of Example 18 (70 mg, 0.16 mmol) in DMF (2 mL) was added L-lactic acid sodium salt (18 mg, 0.16 mmol), 1- hydroxybenzotriazole (HOBt) (32 mg, 0.24 mmol), PYBOP (125 mg, 0.24 mmol) and DIEA (80 μL, 0.48 mmol) and the reaction was stirred at rt for 30 min. EtOAc was added and the solution was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 60 % EtOAc in CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded the two diastereomers. (LC-2) HPLC/MS (less polar isomer on silica): 511.2 (M+l), 513.2 (M+3); R1 = 3.73 min and (LC-2) HPLC/MS (more polar isomer on silica): 511.2 (M+l), 513.2 (M+3); Rt = 3.73 min
Using the procedure described in Example 46, and the appropriate amine and carboxylic acid, the following compounds were prepared. Where noted the enantiomers, or the diastereomers, were separated either on chiral chromatography or via silica gel purification with conditions as indicated:
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000046_0002
Example 64
Figure imgf000046_0001
7'-(2-CMorophenvD-6'-(4-chlorophenvO-4'-α .1 -dioxidoisothiazolidin-2-ylV3',4'- dihydrospiro [cyclohexane- 1 ,2'-pyrano [2.3 -fripyridine. The product from Example 60 (48 mg, 0.08 mmol) was dissolved in DMF (1 mL) and Cs2CO3 (40 mg, 0.13 mmol) was added. The reaction was stirred for 1 h. The reaction was diluted with EtOAc and washed with a saturated NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0 to 40 % EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 543.2 (M+ 1), 545.2 (M+3); R1 = 4.05 min Example 65
Figure imgf000047_0001
l-r6-r4-Chlorophenvn-7-r2.4-dichlorophenylV2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- 6]pyridin-4-yl]imidazolidine-2,4-dione Step A: 2-Chloro-N-r{r6-r4-chlorophenvn-7-r2,4-dichlorophenvn-2.2-dimethyl-3.4-dihvdro-2H- pyrano [2,3-61 pyridin-4- yl] amino } carbonyDacetamide. The product from Example 19 (100 mg, 0.23 mmol) was dissolved in THF (2 mL). Chloroacetyl isocyanate (40 mg, 0.34 mmol) was added and the reaction was stirred at rt for 30 min. The product was concentrated and used without further purification. Step B: l-r6-(4-Chlorophenvn-7-('2.4-dichlorophenylV2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- Z?lpyridin-4-yl"|imidazolidine-2,4-dione. The product obtained in Step A (127 mg, 0.23 mmol) was dissolved in DMSO (2 mL). NaH (20 mg, 0.51 mmol) was added and the reaction was stirred at rt for 1 h. The reaction was diluted with EtOAc and washed with a saturated NaHCO3 solution, 10 % NaHSO4, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0 - 70 % EtOAc in hexane to afford the title compound. HPLC /MS m/z (M+ 1) 516.0, m/z (M+3) 518.3, 1^3.49 min. (LC-2). Further purification on an AD column, eluting with 12 % IP A/heptane provided the two pure enantiomers.
Example 66
Figure imgf000047_0002
7-(2-ChlorophenylV6-(4-chlorophenyl)-2,2-dimethyl-4-pyridin-4-yl-2H-pyranor23-61pyridine Step A: 7-(2-Chlorophenvπ-6-(4-chlorophenvπ-2.2-dimethyl-2//-pyranor2,3-61pyridin-4-yl trifluoromethanesulfonate. To the product of Example 2 (0.47 g, 1.2 mmol) in DMF (9 mL) at - 78°C, was added 1 M LiΗMDS in TΗF (1.3 mL, 1.3 mmol) and the reaction was stirred for 5 min. N-phenyl trifluoromethanesulfonamide (0.47 g, 1.3 mmol) was added and the reaction was allowed to come to rt. The reaction was stirred an additional 15 min, concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound. Step B: 7-(2-Chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-4- pyridin-4-yl-2H-pyrano|"2,3-61pyridine
The product of Step A (40 mg, 0.075 mmol) was dissolved in DME (0.9 mL), water (0.4 mL) and ethanol (0.2 mL) in a 10 mL reaction tube of a CEM Corporation Discover microwave reactor. A 2 M solution OfNa2CO3 (0.11 mL), pyridinyl-4-yl boronic acid (10 mg, 0.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.0075 mmol) were added and the tube was purged with nitrogen, capped and inserted into the microwave reactor and heated at 120°C, at 50 Watts, for 10 min. The reaction was diluted with EtOAc and washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-70% EtOAc in hexane to afford the title compound. (LC-2) ΗPLC/MS: 459.2 (M+ 1), 461.2 (M+3); Rt = 3.45 min.
Using the procedure described in Example 66 Step B with the appropriate boronic acid and the roduct of Exam le 66 Ste A, the followin com ounds were afforded:
Figure imgf000048_0001
Example 71
Figure imgf000049_0001
Methyl 7-(2-chlorophenyl')-6-('4-chlorophenyl)-2.,2-dimethyl-2H-pyrano[2,3-6]pyridine-4- carboxylate
To the product of Step A, Example 66 (1.9 g, 3.36 mmol) was added DMF (2OmL), MeOH (6 mL), NEt3 (1.4 mL, 10 mmol) and dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium (II) dichlorormethane adduct (275 mg, 0.336 mmol). The flask was evacuated and backfilled with carbon monoxide 3 times. The mixture was stirred under a carbon monoxide atmosphere at 70°C overnight. The reaction was cooled and 2 M HCl and EtOAc were added. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 442.3 (M+l), 444.3 (M+3); R1 = 3.87 min.
The triflate derived from the product of Example 1 using a procedure similar to Example 66 Step A was used in a procedure similar to that described in Example 71 to afford the following com ound:
Figure imgf000049_0003
Example 73
Figure imgf000049_0002
7-r2-ChlorophenylV6-('4-chlorophenvn-7V-r2-hvdroxyethyl)-2.2-dimethyl-3,4-dihvdro-2H- pyrano[2.3-6"lpyridine-4-carboxamide.
Step A: Methyl 7-(2-chlorophenylV6-f4-cMorophenvn-2,2-dimethyl-3.4-dihydro-2H- pyrano[2,3-61pyridine-4-carboxylate. Powdered tellurium (70 mg, 0.57 mmol) was dissolved in EtOH (1.5 mL) at rt and NaBH4 (50 mg, 1.4 mmol) was added. The reaction was heated to 70°C for 20 min. The reaction was cooled to -20 0C and deoxygenated AcOH (0.07 mL, 1.21 mmol) was added. The mixture was stirred for 5 min and the product of Example 71 (150 mg, 0.34 mmol) was added. The reaction was allowed to come to rt and was stirred an additional 30 min. The reaction was filtered through Celite with CH2Cl2 and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound.
Step B: 7-(2-Chlorophenyl)-6-(4-cMorophenyiy2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 61pyridine-4-carboxylic acid. Product from Step A (66mg, 0.14 mmol) was dissolved in TΗF (1 mL) and 10 % KOΗ (1 mL) was added. The reaction was heated to 70 °C for 1 hr. The reaction was diluted with EtOAc and washed with 10 % NaHSO4. The organic layer was separated, dried (Na2SO4), filtered and concentrated and used without any further purification Step C: 7-r2-ChlorophenylV6-r4-chlorophenyl)-N-(2-hvdroxyethyl)-2.2-dimethyl-3.4-dihvdro- 2H-pyrano [2.3-61 pyridine-4-carboxamide . Using the product of Step B and ethanolamine, along with the procedure described in Example 46, the title compound was afforded. Further separation on an AS chiral column, eluting with 7 % EtOH/heptane, afforded the enantiomers: (LC-2) HPLC/MS (fast isomer on AS): 471.3 (M+l), 473.3 (M+3); Rt = 3.13 min. (LC-2) HPLC/MS(slow isomer on AS): 471.3 (M+l), 473.3 (M+3); R, = 3.13 min.
Using- the product of Example 73 Step B and following a procedure similar to Example 73 Step C with the appropriate amine the following compounds were afforded. Where noted the enantiomers were separated on chiral chromatography with conditions as indicated.
Figure imgf000050_0001
Figure imgf000051_0002
Example 78
Figure imgf000051_0001
6-(4-ChlorophenylV7-(2.4-dichlorophenvπ-2,2-dimethyl-4-(5-methyl-1.3.4-oxadiazol-2-vn-3.4- dihydro-2H-pyranor2,3-61pyridine. To 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl- 3,4-dihydro-2H-pyrano[2,3-ό]pyridine-4-carboxylic acid prepared in similar fashion to the product of Example 73 Step B (20 mg, 0.05 mmol) in MeCN (1 mL) was added 1- hydroxybenzotriazole (ΗOBt) (7 mg, 0.005 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarboddimide hydrochloride (EDAC) (10 mg, 0.05 mmol) and the reaction was stirred at rt for 30 min. The reaction was cooled to 00C and hydrazine hydrate (0.005 mL, 0.09 mmol) was added and the reaction was stirred for 5 min. EtOAc was added and the organic portion was washed with saturated aq NaHCO3 and water, dried (Na2SO4), filtered and concentrated. The residue was dissolved in CH2Cl2 (2 mL). Acetyl chloride (0.025 mL, 0.35 mmol) was added and the reaction was stirred 10 min. EtOAc was added and the solution was washed with saturated aq NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was dissolved in toluene (0.5 mL) and POCl3 (0.2 mL) was added. The reaction was refluxed overnight, diluted with CH2Cl2, washed with a saturated aq solution OfNaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-50 % EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 500.2 (M+l), 502.2 (M+3); R, = 3.91 min.
Using the procedure described in Example 78, and the appropriate acid chloride, the following compounds were afforded. The enantiomers were separated by chiral chromatography with conditions as indicated:
Figure imgf000052_0002
Example 81
Figure imgf000052_0001
6-C4-Chlorophenyl)-7-('2,4-dichlorophenylV4-('5-isopropyl-L3,4-oxadiazol-2-yl)-2,2-dimethyl- 2H-pyrano|"2,3-6]pyridine. The title compound was isolated as an unanticipated side product from Example 80. (LC-2) HPLC/MS: 526.2 (M+l), 528.2 (M+3); R1 = 4.42 min.
Figure imgf000053_0001
r3^-l-r6-(4-Chlorophenyl)-7-('2,4-dichlorophenylV2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- 6]pyridin-4-vH -3 -hvdroxypyrrolidine-2,5 -dione
Step A: r3S)-l-r6-(4-Chlorophenvn-7-r2.4-dichlorophenyl)-2.2-dimethyl-3.4-dihvdro-2H- pyrano [2,3 -&lpyridin-4-yl] -2,5-dioxopyrrolidin-3 -yl acetate. To the product of Example 19 (50 mg, 0.12 mmol) was added (3iS)-2,5-dioxotetrahydrofuran-3-yl acetate (0.5 g) and the reaction was heated to 85°C for 1 hr. The reaction was cooled and AcOH was added (1 mL). Heating was continued at 85°C an additional 2 h. The reaction was diluted with EtOAc, washed with saturated aq NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-30 % EtOAc in hexane to afford the title compound. (LC-2) HPLC/MS: 573.0 (M+l), 575.0 (M+3); R1 = 3.80.
Step B: r3.Sr)-l-r6-(4-Chlorophenvn-7-r2.4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H- pyranor23-61pyridin-4-yl1-3-hvdroxypyrrolidine-2,5-dione. The product of Step A (38 mg, 0.7 mmol) was dissolved in MeOH (2 mL) andp-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction was heated at 85°C for 2 h and concentrated. The residue was dissolved in EtOAc and the solution was washed with saturated aq NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-60 % EtOAc in hexane to afford the title compound. Further separation on an AD chiral column, eluting with 50 % IP A/heptane, afforded the diastereomers: (LC-2) HPLC/MS (fast isomer on AD): 531.0 (M+l), 533.0 (M+3); R1 = 3.58 min. (LC-2) HPLC/MS(slow isomer): 531.0 (M+l), 533.0 (M+3); R, = 3.59 min.
The following examples were prepared utilizing the appropriate amine and carboxylic acid or acid chloride in procedures similar to that described for Example 21 and Example 46.
Figure imgf000053_0002
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Example 131
Figure imgf000058_0001
6-(4-ChlorophenylV7-(2.4-dichloroρhenyl)-2.2-dimethyl-N-rpyridine-2-ylV3,4-dihvdro-2//- pyrano[2,3-6]pyridin-4-amine.
A mixture of the product of Example 19 (160 mg, 0.37 mmol), 2-bromopyridine (35 μL, 0.37 mmol), palladium(II) acetate (4.1 mg, 0.02 mmol), (±)-BINAP (11.5 mg, 0.02 mmol), and sodium tert-butoxide (39.0 mg, 0.41 mmol) in 10 mL of toluene was degassed and allowed to stir at 70 0C for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL) and filtered through a cake of Celite. The filtrate was concentrated and purified by chromatography on preparative TLC plates (Analtech TLC Uniplates™, silica gel, 20x20 cm, 1000 μm) using 9: 11 v/v Et2O/hexanes as the mobile phase afforded the title compound: 1H NMR δ 1.52 (s, 3H), 1.56 (s, 3H), 1.86 (m, IH), 2.38 (dd, J= 6.1, 13.4, IH), 4.58 (br. s, IH), 5.54 (m, IH), 6.47 (d, J = 8.5, IH), 6.65 (dd, J= 5.4, 6.8, IH), 6.97-6.99 (m, 2H), 7.13-7.26 (m, 4H), 7.42-7.46 (m, IH), 7.79 (s, IH), 8.13 (d, J= 4.2, IH).
Example 132
Figure imgf000058_0002
6-(4-Chlorophenyl)-7-('2,4-dichlorophenvn-2,2-dimethyl-N-("5-methyl-lH-pyrazol-3-ylV3.4- dihvdro-2H-pyrano[2,3-61pyridin-4-amine.
Step A: 7V-r6-r4-chlorophenyl)-7-r2,4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H-pyranor2.3-
61pyridin-4-yl"|-3-oxobutanamide. To a solution of the product of Example 19 (129.5 mg, 0.30 mmol) in 10 mL OfCH2Cl2 at 0 0C was added diketene (50 μL, 0.66 mmol). The mixture was allowed to stir at rt for 1 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 3:2 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.46 (s, 3H), 1.55 (s, 3H), 1.87 (m, IH), 2.24-2.29 (m, 4H), 3.54 (s, 2H), 5.48 (m, IH), 7.01 (d, J= 8.4, 2H), 7.17-7.26 (m, 4H), 7.40 (br. s, 1 H), 7.63 (s, 1 H). Step B: N-r6-(4-Chlorophenvn-7-(2.4-dichlorophenvn-2.2-dimethyl-3.4-dihvdro-2H- pyrano[2.3-61pyridin-4-yll-3-oxobutanethioamide. A solution of the product of Step A (136 mg, 0.26 mmol) and Lawesson's reagent (106 mg, 0.26 mmol) in 5.0 mL of toluene was stirred at 120 0C for 3 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 1 :3 v/v EtOAc/hexanes as the eluant afforded the title compound.
Step C: 6-r4-Chlorophenvn-7-r2.4-dichlorophenvn-2.2-dimethyl-N-(5 -methyl- lH-pyrazol-3 -yl)- 3 ,4-dihydro-2//-pyrano [2,3 -Z)] pyridin-4-amine . A mixture of the product of Step B (56 mg, 0.11 mmol), hydrazine (6.6 μL, 0.21 mmol), and AcOH (12.0 μL, 0.21 mmol) in 5.0 mL of EtOH was refluxed for 16 h. The reaction mixture was then cooled to rt, diluted with Et2O (50 mL), and washed with saturated aq NaHCO3 (2x50 mL) and brine (50 mL). After phase separation, the organic phase was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 2:3 v/v acetone/hexanes as the eluant afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.54 (s, 3H), 1.82 (JL3 J= 12.4, IH), 2.26 (s, 3H), 2.41 (dd, J= 5.9, 13.3, IH), 3.86 (br. s, IH), 4.92 (m, IH), 5.45 (s, IH), 7.00 (d, J= 8.4, 2H), 7.15-7.26 (m, 5H), 7.97 (s, IH).
The racemic mixture of Example 132 was resolved by chiral preparative chromatography with conditions indicated to afford the enantiomers listed in the followin exam les.
Figure imgf000059_0002
The following examples were prepared utilizing the appropriate amine and carboxylic acid or acid chloride in procedures similar to those described for Example 21 or Example 46.
Figure imgf000059_0001
Figure imgf000059_0003
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0003
Example 160
Figure imgf000062_0001
l-[7-(4-Bromo-2-chlorophenyl)-6-('4-chlorophenyl)-2,2-dimethyl-3,4-dihvdro-2H-pyrano[2,3- 6]pyridin-4-yl]pyrrolidin-2-one.
Step A: 4-Bromo-N-r7-(4-bromo-2-chlorophenyl)-6-('4-chlorophenyl)-2,2-diniethyl-3,4- dihvdro-2i/-pyrano[2,3-61pyridin-4-vnbutanamide. To a mixture of 7-(4-bromo-2- chlorophenyl)-6-(4-chloro-phenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4-amine (303 mg, 0.63 mmol) and NEt3 (221 μL, 1.6 mmol) in 10 niL of CH2Cl2 was added 4- bromobutyryl chloride (110 μL, 0.95 mmol). After stirring at rt for 16 h, the reaction mixture was combined with saturated aq NaHCO3 (20 mL). The aq layer was separated and extracted with CH2Cl2 (3x20 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford the product.
Step B: l-[7-(4-Bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyranor2,3-61pyridin-4-vHpyrrolidin-2-one. To a solution of the product of Step A (133 mg, 0.21 mmol) in 5.0 mL of THF was added 60 % NaH (12.7 mg, 0.32 mmol) at rt. After stirring for 16 h, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was separated, dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 4:1 v:v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.48 (s, 3H), 1.58 (s, 3H), 1.96-2.10 (m, 4H), 2.50-2.54 (m, 2H), 3.13 (m, IH), 3.30-3.33 (m, IH), 5.65-5.69 (m, IH), 6.98 (d, J= 8.5, 2H), 7.19-7.42 (m, 6H).
Example 161
Figure imgf000062_0002
l-r6-(4-ChlorophenylV7-(2.4-dichlorophenylV2.2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 61pyridin-4-yl1piperidin-2-one. This example was prepared using procedures analogous to those described for Example 160 substituting 5-chlorovaleroyl chloride for 4-bromobutyryl chloride and 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- Z>]pyridin-4-amine for 7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro- 2H-pyrano[2,3-δ]pyridin-4-amine, respectively, in Step A. HPLC/MS: 515.2 (M+l), 517.2
Figure imgf000063_0001
The following examples were prepared using procedures analogous to those described for Example 160 using either (2/?)-4-bromo-2-hydroxybutanoic acid or (2S)-4-bromo-2- hydroxybutanoic acid {Tetrahedron Lett. 1997, 55,4935) for 4-bromobutyryl chloride and using PyBOP as the coupling reagent in Step A. All four enantiomers were separated by silica gel chromatography.
Figure imgf000063_0002
Example 166 NHH
Figure imgf000063_0003
l-r6-(4-Chlorophenyl)-7-(2.4-dichlorophenyl)-2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3-
61pyridin-4-yllimidazolidin-2-one.
Step A: fert-Butyl (2- { r6-(4-chlorophenvn-7-(2.4-dichlorophenyl)-2.2-dimethyl-3 A- dihvdro-2H-pyranof2.3-61pyridin-4-yl1amino}ethvπcarbamate. To the product of Example 2 (407 mg, 0.94 mmol) in 10 mL of EtOH was added tert-butyl (2-aminoethyl)carbamate (223 μL, 1.41 mmol) and titanium(IV) isopropoxide (1.4 mL, 4.70 mmol). After refluxing for 16 h, the reaction mixture was cooled to it and NaBH4 (78.2 mg, 2.07 mmol) was added. After stirring at rt for 2 h, NH4OH (10 mL, -28% NH3 content) and Et2O (20 mL) were added sequentially. After stirring for 30 min, the solid was filtered off and washed with copious EtOAc. The filtrate was washed with brine (2x50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 11 :9 v/v EtOAc/hexanes as the eluant afforded the product. Step B: N-r6-(4-Chlorophenvn-7-(2,4-dichlorophenvn-2.2-dimethyl-3.4-dihydro-2//- pyranor2,3-6]pyridin-4-yl1ethane-l,2-diamine. A solution of the product of Step A (42.9 mg,
0.07 mmol) in 2.5 mL of 20 % TFA in CH2Cl2 was stirred at rt for 1 h. The reaction mixture was concentrated to give the product which was used without further purification. Step C: l-r6-(4-ChlorophenylV7-r2.4-dichlorophenyl)-2,2-dimethyl-3.4-dihvdro-2H- pyranor2,3-61 pyridin-4-yl"|imidazolidin-2-one. To a solution of 1 , 1 ' -carbonyldiimidazole (18.1 mg, 0.11 mmol) in 5.0 mL of CHCl3 was added the product of Step B (0.07 mmol) and NEt3
(51.8 μL, 0.37 mmol) in 5.0 mL of CHCl3. The mixture was allowed to stir at rt for 2 h and then refluxed for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (50 mL) and washed with brine (2x50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge eluting with EtOAc afforded the title compound: 1H NMR δ 1.48 (s, 3H), 1.58 (s, 3H), 2.00-2.09 (m, 2H), 3.18-3.50 (m, 4H), 4.70 (br. s, IH), 5.44 (m, IH), 7.00 (d, J= 8.5, 2H), 7.18-7.27 (m, 4H), 7.50 (s, IH).
Example 167
Figure imgf000064_0001
l-r6-(4-Chlorophenvn-7-(2.4-dichlorophenvn-2.2-dimethyl-3.4-dihydro-2H-pyranor2.3- b] pyridin-4-yl] piperazin-2-one .
Step A: fert-Butyl (2-{(bromoacetvnr6-(4-chlorophenylV7-(2.4-dichlorophenvn-2.2- dimethyl-3,4-dihvdro-2H-pyrano[2,3-61pyridin-4-yl1amino}ethyl)carbamate. To a solution of the product of Example 166, Step A (90.5 mg, 0.16 mmol) in 5.0 mL of CH2Cl2 at 0 0C was added NEt3 (54.7 μL, 0.39 mmol) and bromoacetyl bromide (15.0 μL, 0.17 mmol). The mixture was allowed to stir at rt for 1 h and then concentrated. Chromatography on a Biotage 40+S cartridge using 7:13 v:v EtOAc/hexanes as the eluant afforded the product.
Step B: fert-Butyl 4-r6-(4-chlorophenyn-7-(2.4-dichlorophenylV2.2-dimethyl-3.4-dihydro-2H- pyranor2,3-61pyridin-4-yl1-3-oxopiperazine-l-carboxylate. To a solution of the product of Step A (42 mg, 0.06 mmol) in 5.0 niL of THF at rt was added 60 % NaH (4.8 mg, 0.12 mmol). The mixture was allowed to stir at rt for 30 min and then diluted with EtOAc (50 mL). The resulting mixture was washed with brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 9:11 v:v EtOAc/hexanes as the eluant afforded the product.
Step C: l-r6-("4-Chlorophenyl)-7-(2.4-dichlorophenyl)-2.2-dimethyl-3,4-dihydro-2i/-pyranor23- b] pyridin-4-vH piperazin-2-one . A solution of the product of Step B (31 mg, 0.05 mmol) in 5.0 mL of 20 % TFA in CH2Cl2 was stirred at rt for 30 min and then concentrated. HPLC purification afforded the title compound: 1H NMR δ 1.47 (s, 3H), 1.59 (s, 3H), 2.10-2.23 (m, 2H), 3.30-3.56 (m, 4H), 3.94-4.07 (m, 2H), 7.10 (d, J= 8.5, 2H), 7.23-7.41 (m, 4H), 7.69 (s, IH).
Example 168
Figure imgf000065_0001
4-r6-(4-Chlorophenyl)-7-(2,4-dichlorophenvπ-2,2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 61pyridin-4-yll2.4-dihvdro-3H- 1.2.4-triazol-3-one Step A: Phenyl F6-('4-chlorophenylV7-('2,4-dichlorophenylV2,2-dimethyl-3.4-dihvdro-2H- pyrano[2,3-άlpyridin-4-yllcarbamate. To a solution of the product of Example 19 (176 mg, 0.41 mmol) and NEt3 (68 μL, 0.49 mmol) in 10 mL Of CH2Cl2 at 0 0C was added phenyl chloroformate (61 μL, 0.49 mmol). After stirring at rt for Ih, the reaction mixture was concentrated. Chromatography on a Biotage 40+S cartridges using 1 :4 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.47 (s, 3H), 1.58 (s, 3H), 1.94 (t, J= 12.0, IH), 2.39 (dd, J= 5.7, 13.4, IH), 5.21-5.26 (m, 2H), 7.04 (8.4, 2H), 7.15-7.40 (m, 9H), 7.79 (s, IH). Step B: N-r6-(4-ChlorophenylV7-(2,4-dicMorophenylV2,2-dimethyl-3.4-dihvdro-2H- pyrano [2,3-61 pyridin-4-yll hydrazinecarboxamide. A solution of the product of Step A (77 mg, 0.14 mmol) and hydrazine (8.7 μL, 0.28 mmol) in 5.0 mL of EtOH was refluxed for 3 h. The reaction mixture was then concentrated to give the product, which was used directly in the next step without further purification.
Step C: 4-r6-(4-ChlorophenylV7-('2.4-dichlorophenvπ-2.2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 61pyridin-4-yl"|2,4-dihydro-3H-L2,4-triazol-3-one. A mixture of the product of Step B (0.14 mmol) and formamidine acetate (72 mg, 0.70 mmol) in 5.0 mL of DMF was allowed to stir at rt for 2 h. AcOH (40 μL, 0.70 mmol) was then added. The resulting mixture was stirred at 80 0C for 16 h. After cooling to rt, the reaction mixture was diluted with EtOAc (20 mL) and washed with brine (3x20 mL). The organic phase was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridges using 1 :99 v/v CH3OHZCH2Cl2 as the eluant afforded the title compound: 1H NMR δ 1.53 (s, 3H), 1.62 (s, 3H), 2.18 (t, J= 12.7, IH), 2.36 (dd, J= 6.3, 13.1, IH), 5.56 (m, IH), 6.95 (d, J= 8.3, 2H), 7.16-7.38 (m, 7H), 10.1 (br. s, IH).
Example 169
Figure imgf000066_0001
fert-Butyl r7-r4-bromo-2-chlorophenvπ-6-(4-chlorophenvπ-2,2-dimethyl-3.4-dihvdro-2H- pyrano[2,3-Z>lpyridin-4-yllcarbamate. To a solution of 7-(4-bromo-2-chlorophenyl)-6-(4- chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4-amine (1.4 g, 2.93 mmol) and NEt3 (816 μL, 5.86 mmol) in 10 mL of CH2Cl2 was added di-tert-butyl dicarbonate (958 mg, 4.39 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated. Chromatography on a Biotage 40+M cartridge using 1 : 1 v/v EtOAc/hexanes as the eluant afforded the title compound as a white solid: 1H NMR δ 1.40 (s, 3H), 1.44 (s, 9H), 1.48 (s, 3H), 1.75 (t, J= 12.4, IH), 2.22 (dd, J= 5.8, 13.2, IH), 5.06 (m, 2H), 6.98 (d, J= 8.5, 2H), 7.13-7.34 (m, 5H), 7.68 (s, IH).
Example 170
Figure imgf000066_0002
Methyl 3-chloro-4-r6-(4-chlorophenylV4-({r(U-dimethylethyl)oxylcarbonvUamino)-2,2- dimethyl-3.4-dihydro-2H-pyrano[2,3-61pyridin-7-yl]benzoate. A solution of Example 169 (840 mg, 1.45 mmol), palladium(II) acetate (16.3 mg, 0.07 mmol), dppf (81 mg, 0.15 mmol), and NEt3 (405 μL, 2.90 mmol) in 20 mL of CH3OH was stirred at 100 0C under 50 psi of CO for 24 h. After cooling to rt, the reaction mixture was filtered. The filtrate was concentrated and chromatography on a Biotage 25+M cartridge using 1 : 1 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.46 (s, 3H), 1.49 (s, 9H), 1.54 (s, 3H), 1.82 (m, IH), 2.29 (dd, J= 6.2, 13.3, IH), 3.90 (s, 3H), 4.89 (br. s, IH), 5.12 (m, IH), 7.01 (d, J= 8.5, 2H), 7.16 (d, J= 8.4, 2H), 7.40 (m, IH), 7.73-7.92 (m, 3H). Example 171
Figure imgf000067_0001
N-r7-r2-Chloro-4-r5-oxo-4,5-dihvdro-l,3,4-oxadiazol-2-yl>)phenyl]-6-('4-chlorophenvπ-2,2- dimethyl-3,4-dihvdro-2.H-pyrano|'2,3-6]pyridin-4-yll-2,2-dimethylpropanamide Step A: Methyl 4-r4-amino-6-('4-chlorophenvπ-2.2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 6]pyridin-7-yll -3 -chlorobenzoate. To a solution of Example 170 (200 mg, 0.36 mmol) in 5.0 mL Of CH2Cl2 was added 500 μL of TFA. After stirring at rt for 16 h, the reaction mixture was concentrated. The amine TFA salt was taken onto next step without further purification. Step B: Methyl 3-chloro-4-{6-("4-chlorophenylV4-[(2,2-dimethylpropanoly)amino]-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-61pyridin-7-yllbenzoate. To a solution of the product of Step A (100 mg, 0.22 mmol) in 5.0 mL OfCH2Cl2 was added pivaloyl chloride (32 μL, 0.26 mmol) and NEt3 (46 μL, 0.33 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1 :1 v/v EtOAc/hexanes as the eluant afforded the product as a white solid. Step C: N-r7-r2-Chloro-4-('hvdrazinocarbonvnphenyll-6-r4-chlorophenylV2.2-dimethyl-3,4- dihydro-2//-pyrano[2,3-61pyridin-4-yll-2,2-dimethylpropanamide. A solution of the product of Step B (22 mmol) and 2.0 mL of hydrazine hydrate in 10 mL Of CH3OH was refluxed for 10 h. After cooling to rt, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification. Step D: N-|"7-[2-Chloro-4-(5-oxo-4,5-dihvdro-L3,4-oxadiazol-2-yl')phenyl1-6-(4-chlorophenyl)- 2,2-dimethyl-3,4-dihvdro-2H-pyrano|"2,3-61pyridin-4-yl1-2,2-dimethylpropanamide. To a solution of the product of Step C (22 mmol) in 10 mL Of CH2Cl2 at - 78 0C was added 300 μL of phosgene (20 % in toluene). After stirring at - 78 0C for 15 min and at 0 0C for 30 min, the reaction mixture was concentrated. Chromatography on a Biotage 40+S cartridge using 1 : 1 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.86 (t, J= 12.2, IH), 2.27 (m, IH), 5.50 (m, IH), 5.87 (m, IH), 6.99 (d, J= 8.0, 2H), 7.17 (d, J= 8.0, 2H), 7.39 (m, IH), 7.58-7.72 (m, 3H), 9.87 (br. s, IH).
Example 172
Figure imgf000068_0001
JV-f7-('2-Chloro-4-cvanophenyl')-6-('4-chlorophenyl)-2.,2-dimethyl-3,4-dihvdro-2H-pyranor2,3- 61pyridin-4-yl]-2,2-dimethylpropanamide
Step A: 7V-r7-r4-Bromo-2-chlorophenyl)-6-(4-chlorophenylV2,2-dimethyl-3,4-dihvdro-2H- pyranor2,3-61pyridin-4-yll-2,2-dimethylpropanamide. To a solution of the 7-(4-bromo-2- chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3 ,4-dihydro-2H-pyrano [2,3 -6]pyridin-4-amine (536.2 mg, 1.12 mmol) in 10 mL of CH2Cl2 at 0 0C was added pivaloyl chloride (166 μL, 1.34 mmol) and NEt3 (313 μL, 2.24 mmol). After stirring at it for 1 h, the reaction mixture was concentrated. Chromatography on a Biotage 40+M cartridge using 1 :3 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.26 (s, 9H), 1.47 (s, 3H), 1.55 (s, 3H), 1.82 (t, J= 12.3, IH), 2.26 (dd, J= 6.2, 13.3, IH), 5.48 (m, IH), 5.81 (br. s, IH), 6.97 (d, J= 8.5, 2H), 7.16-7.20 (m, 3H), 7.33-7.42 (m, 2H), 7.55 (s, IH).
Step B: N-r7-(f2-Chloro-4-cvanophenyl)-6-(4-chlorophenyl)-2.2-dimethyl-3,4-dihydro-2H- pyranor2,3-61pyridin-4-yl1-2,2-dimethylpropanamide. To a suspension of the product of Step A (141 mg, 0.25 mmol), Zn(CN)2 (29.4 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (5.2 mg, 0.005 mmol), and dppf (6.9 mg, 0.01 mmol) in 5.0 mL of DMF was added one drop of H2O. The solution was degassed and stirred at 120 °C for 16 h, the reaction mixture was cooled to rt and diluted with EtOAc (20 mL). The solid was filtered off and washed with EtOAc. The filtrate was concentrated and chromatography on a Biotage 40+M cartridge using 2:3 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.84 (m, IH), 2.26 (m, IH), 5.50 (m, IH), 5.82 (br. s, IH), 6.95 (d, J= 8.2, 2H), 7.19 (d, J= 8.3, 2H), 7.41-7.58 (m, 4H).
Example 173
Figure imgf000068_0002
N-r7-r2-Chloro-4-(1.2.4-oxadiazol-3-vnphenvn-6-('4-chlorophenvn-2.2-dimethyl-3,4-dihvdro- 2H-pyranor2.3-61pyridin-4-yll-2.2-dimethylpropanamide Step A: iV-[7-{2-Chloro-4-[(hvdroxyaminoyimino)methyllphenyl|-6-(4-chlorophenyl)-
2,2-dimethyl-3,4-dihvdro-2//-pyrano[2,3-61pyridin-4-vn-2,2-dimethylpropanainide. A solution of Example 172 (120 mg, 0.24 mmol), hydroxylamine hydrochloride (65.6 mg, 0.94 mmol), and NaHCO3 (119 mg, 1.42 mmol) in 10 mL of EtOH was refluxed for 16 h. The reaction mixture was partitioned between brine (50 mL) and CH2Cl2 (50 mL). The aq layer was separated and extracted with CH2Cl2 (2x50 mL). The organic layers were combined, dried over MgSO4, and concentrated to give the product, which was taken into the next step without further purification. Step B: N-r7-r2-Chloro-4-π,2,4-oxadiazol-3-vnphenyl1-6-(4-chlorophenvn-2,2-dimethyl-3,4- dihvdro-2H-pyrano[2,3-άlpyridin-4-yl1-2,2-dimethylpropanamide. To a suspension of the product of Step A (61 mg, 0.11 mmol) in 5.0 mL of triethyl orthoformate was added one drop of BF3-Et2O. After stirring at 110 0C for 1 h, the reaction mixture was diluted with EtOAc"(20 mL) and washed with saturated aq NaHCO3 (2x50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 7:13 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.84 (t, J= 11.4, IH), 2.27 (dd, J= 6.2, 13.0, IH), 5.50 (m, IH), 5.84 (br. s, IH), 7.01 (d, J= 8.3, 2H), 7.16 (d, J= 8.2, 2H), 7.45 (m, IH), 7.58 (s, IH), 7.96-8.04 (m, 2H), 8.77 (s, IH).
Example 174
Figure imgf000069_0001
N-r7-r4-Chloro-2-π.2.4-oxadiazol-3-yl>)phenyll-6-(4-chlorophenylV2.2-dimethyl-3.4-dihvdro- 2H-pyranor2,3-61pyridin-4-yl1-2-hvdroxy-2-methylpropanamide. This example was prepared using procedures analogous to those described for Example 173 substituting Example 127 for N- [7-(2-chloro-4-cyanophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-2,2-dimethylpropanamide in Step A. (LC-2) ΗPLC/MS: 553.1 (M+l), 555.1 (M+3); R1 = 3.45 min.
Example 175
Figure imgf000069_0002
7V-r7-r2-Chloro-4-(5-methyl-1.2.4-oxadiazol-3-vπphenyll-6-("4-chlorophenylV2.2-dimethyl-3.4- dihvdro-2H-pyrano[2,3-Z?1pyridin-4-yl1-2,2-dimethylpropanamide. This example was prepared using procedures analogous to those described for Example 173 substituting triethyl orthoacetate for triethyl orthoformate in Step B: 1H NMR δ 1.27 (s, 9H), 1.51 (s, 3H), 1.59 (s, 3H), 2.82 (m, IH), 2.28 (m, IH), 2.68 (s, 3H), 5.50 (m, IH), 5.83 (br. s, IH), 7.02 (d, J= 8.5, 2H), 7.18 (d, J= 8.4, 2H), 7.44 (m, IH), 7.60 (s, IH), 7.93 (m, IH), 8.00 (s, IH).
Examples 176, 177, 178, and 179
Figure imgf000070_0001
r2i?/^)-N-rr4^/^)-7-f2-Chloro-4-(1.2.4-oxadiazol-3-vnphenyl1-6-r4-chlorophenvn-2,2-dimethyl- 3,4-dihvdro-2H-pyrano[2,3-61pyridin-4-yl]-33,3-trifluoro-2-hvdroxypropanamide
Step A: fert-Butyl r7-(2-chloro-4-(1.2.4-oxadiazol-3-vπphenyl)-6-(4-chlorophenylV2.2- dimethyl-3,4-dihvdro-2H-pyrano|"2,3-61pyridin-4-yllcarbamate. The product was prepared using procedures analogous to those described for Example 173 substituting tert-butyl [7-(2-chloro-4- cyanophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-2H-pyrazo[2,3-6]pyridine-4-yl]carbamate for N- [7-(2-chloro-4-cyanophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-2//-pyrazo[2,3-ό]pyridine-4-yl]- 2,2-dimethylpropanamide in Step A: 1U NMR δ 1.51 (s, 3Η), 1.58 (s, 3H), 1.91 (m, IH), 2.31 (m, IH), 4.59 (m, IH), 4.61 (br. s, IH), 5.56 (m, IH), 6.65 (m, IH), 7.02 (d, J= 8.4, 2H), 7.18 (d, J= 8.5, 2H), 7.46 (m, IH), 7.61 (s, IH), 8.0 (m, IH), 8.05 (s, IH), 8.80 (s, IH). Step B: 7-(2-Chloro-4-( 1.2.4-oxadiazol-3 -vDphenyl V6-(4-chlorophenyl)-2,2-dimethyl-3.4- dihvdro-2H-pyrano|"2,3-61pyridine-4-amine. To a solution of the product of Step A (130 mg,
0.23 mmol) in 5.0 mL of CH2Cl2 was added TFA (200 μL, 2.60 mmol). After stirring at rt for 16 h, the mixture was concentrated to give the title compound, which was taken into the next step without further purification. Step C: N-r7-r2-Chloro-4-d.2.4-oxadiazol-3-vnphenyll-6-(4-chlorophenvn-2.2-dimethyl-3.4- dihvdro-2H-pyrano("2,3-61pyridin-4-yll-3,3,3-trifluoro-2-hvdroxypropanamide. To a solution of the product of Step B (107 mg, 0.23 mmol), 3,3,3-trifluoro-2-hydroxypropionic acid (39 mg, 0.27 mmol), and NEt3 (63 μL, 0.45 mmol) in 10 mL of CH2Cl2 was added PyBOP (140 mg, 0.27 mmol). After stirring at rt for 16 h, the mixture was concentrated. Chromatography on a Biotage 25+M cartridge using 1 : 1 v/v EtOAc/hexanes as the eluant afforded two enantiomeric mixtures, which were subsequently resolved (the one having higher Rf value on TLC was resolved by AD using 13% EtOH/hex, and the other by AD using 20% IPA/hept) to afford the title compounds.
Example 180
Figure imgf000071_0001
(45r)-6-(4-ChlorophenylV7-('2.4-dichlorophenvn-2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- Z?]pyridin-4-yl benzoate.
Step A: (4^-6-(4-ChlorophenylV7-(2.4-dichlorophenylV2.2-dimethyl-3.4-dihvdro-2H- pyrano[2.,3-6]pyridin-4-ol. A solution of Example 1 (14.1 g, 32.5 mmol) and the (S, S) catalyst described by Noyori in Angew. Chem. Int. Ed. Engl. 1997, 36, 285 (998 mg, 1.62 mmol) in IPA (20 mL) and CH2Cl2 (10 mL) was stirred at rt. After 16 h, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification: 1H NMR δ 1.43 (s, 3H), 1.56 (s, 3H), 1.96 (dd, J= 9.7, 13.4, IH), 2.06 (d, J= 7.3, IH), 2.28 (dd, J= 6.2, 13.5, IH), 5.00 (m, IH), 7.03 (d, J= 8.5, 2H), 7.18-7.26 (m, 5H), 7.90 (s, IH).
Step B: (4^-6-(4-Chlorophenvn-7-(2,4-dichlorophenylV2.2-dimethyl-3,4-dihydro-2H- pyrano[2,3-Z>lpyridin-4-yl benzoate. To a solution of the product of Step A (21.6 mg, 0.05 mmol), NEt3 (21 μL, 0.15 mmol), and catalytic amount of DMAP in 10 mL Of CH2Cl2 at rt was added benzoyl chloride (11.5 μL, 0.10 mmol). After stirring for 2 h, the reaction was quenched by adding saturated aq NaHCO3 (5 mL) and the resulting mixture was stirred at rt for 30 min. The reaction mixture was partitioned between CH2Cl2 (50 mL) and saturated aq NaHCO3 (50 mL). The aq layer was separated and extracted with CH2Cl2 (3x10 mL). The organic layers were combined, dried over MgSO4, and concentrated. Chromatography on Biotage 40+S cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.57 (s, 3H), 1.65 (s, 3H), 2.24 (dd, J= 6.7, 14.2, IH), 2.46 (dd, J= 5.9, 14.3, IH), 6.40 (t, J= 6.2, IH), 7.00 (d, J= 8.4, 2H), 7.16-7.28 (m, 5H), 7.45-7.60 (m, 3H), 7.77 (s, IH), 8.07 (d, J= 7.5, 2H).
Example 181
Figure imgf000071_0002
(4^V6-(4-Chlorophenyn-7-(2,4-dichlorophenvn-2.2-dimethyl-3,4-dihvdro-2H-pyranor2.3- 6]pyridin-4-yl benzoate. This example was prepared using procedures analogous to those described for Example 180 substituting the (RJl) catalyst described by Noyori in Angew. Chem.
Int. Ed Engl. 1997, 36, 285 in Step A: 1H NMR δ 1.57 (s, 3H), 1.65 (s, 3H), 2.24 (dd, J= 6.7,
14.2, IH), 2.46 (dd, J= 5.9, 14.3, IH), 6.40 (t, J= 6.2, IH), 7.00 (d, J= 8.4, 2H), 7.16-7.28 (m,
5H), 7.45-7.60 (m, 3H), 7.77 (s, IH), 8.07 (d, J= 7.5, 2H). Example 182
Figure imgf000072_0001
N-r(4/?V6-('4-Chlorophenvn-7-(2.4-dichlorophenvn-2.2-dimethyl-3.4-dihvdro-2H-pyranor2.3- 6]pyridin-4-yl]-5-methyl-lH-pyrazole-3-carboxamide
Step A: (4J/?V4-Azido-6-('4-chlorophenyl)-7-(2.4-dichlorophenylV2.2-dimethyl-3.4- dihvdro-2H-pyrano-[2.,3-fr]pyridine. To a mixture of the product of Example 180, Step A (9.8 g, 22.5 mmol), Zn(N3)2/bis-pyridine complex {Synthesis 1990, 130) (13.9 g, 45.1 mmol), triphenylphosphine (11.8 g, 45.1 mmol), and imidazole (6.1 g, 90 mmol) in 100 mL of CH2Cl2 was added diisopropyl azodicarboxylate (8.8 mL, 45.1 mmol) dropwise at it. The mixture was allowed to stir at rt for 16 h. The supernatant was separated and washed with diluted HCl (1.0 N, 3x50 mL), saturated aq NaHCO3 (3x50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on Biotage 40+M cartridges using 3:17 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.47 (s, 3H), 1.59 (s, 3H), 2.11 (dd, J= 9.6, 13.5, IH), 2.32 (dd, J= 6.1, 13.6, IH), 4.75 (dd, J= 6.0, 9.6, IH), 7.04 (d, J= 8.5, 2H), 7.19-7.28 (m, 5H), 7.78 (s, IH). Step B (4i?V6-(4-Chlorophenvπ-7-(2,4-dichlorophenyl)-2.2-dimethyl-3,4-dihvdro-2H-pyrano- [2,3-&]pyridin-4-amine. To a solution of the product of Step A (9.5 g, 20.7 mmol) in 50 mL of TΗF was added 2.5 mL of H2O and 31.0 mL of trimethylphosphine in THF (1.0 M, 31.0 mmol). After stirring at rt for 3 h, the solvent was evaporated. Chromatography on a Biotage 40+M cartridge using 1 : 19 v/v CH3OH/CH2C12 as the eluant afforded the product: 1H NMR δ 1.42 (s, 3H), 1.54 (s, 3H), 1.78 (t, J= 12.5, IH), 2.18 (dd, J= 5.9, 13.4, IH), 4.16 (dd, J= 6.0, 11.7, IH), 7.04 (d, J= 8.5, 2H), 7.17-7..26 (m, 5H), 7.93 (s, IH).
Step C N-r(4i?V6-(4-Chlorophenvn-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano|"2,3-61pyridin-4-yl]-5-methyl-l.H-pyrazole-3-carboxamide. A mixture of the product of Step B (300 mg, 0.69 mmol), S-methylpyrazole-S-carboxylic acid (105 mg, 0.83 mmol), PyBOP (540 mg, 1.04 mmol), and NEt3 (0.19 mL, 1.38 mmol) in 20 mL of CH2Cl2 was stirred at rt. After 16 h, the reaction mixture was diluted with Et2O (50 mL), washed with saturated aq NaHCO3 (3x50 mL) and brine (3x50 mL). The organic layer was separated, dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 1 : 1 v/v EtOAc/Hexanes as the eluant afforded the title compound: 1H NMR δ 1.44 (s, 3H), 1.51 (s, 3H), 1.94 (t, J= 12.5, IH), 2.26-2.30 (m, 4H), 5.62 (m, IH), 6.58 (s, IH), 6.96 (d, J= 8.5, 2H), 7.12-7.29 (m, 5H), 7.69 (s, IH).
The following examples were prepared using procedures analogous to those described for Example 182 substituting the appropriate amine for (4i?)-6-(4-chlorophenyl)-7-(2,4- dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano-[2,3-ό]pyridin-4-amine and the appropriate carboxylic acid for S-methylpyrazole-S-carboxylic acid, respectively, in Step C.
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Examples 233, 234
Figure imgf000077_0001
r2i?/5)-N-rr4J?V7-r2-Chloro-4-d3.4-oxadiazol-2-vnphenyll-6-(4-chlorophenvn-2,2-dimethyl- 3.4-dihydro-2H-pyrano [2,3-6] pyridin-4-yl] -3 ,3 ,3 -trifluoro-2-hvdroxypropanamide Step A: Methyl 3 -chloro-4-rf 4i? V 6-(4-chlorophenyl )-4( U(I Λ- dimethylethyl')oxy1carbonyU-aniino)-2,2-dimethyl-3,4-dihvdro-2H-pyrano[2,3-6]pyridin-7- ylibenzoate. The product was prepared using the procedures analogous to those described for Example 180, Example 182 and Example 170 substituting 7-(4-bromo-2-chlorophenyl)-6-(4- chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrazo[2,3-Zj]pyridin-4-one for 6-(4-chlorophenyl)- 7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrazo[2,3-6]pyridin-4-one in Step A of Example 180.
Step B: tert-Butyl F('4i?V7-r2-chloro-4-('hvdrazinocarbonyl')phenyll-6-(4-chlorophenyπ-2.2- dimethyl-3,4-dihydro-2H-pyrano["2.3-61pyridin-4-yllcarbamate. The product was prepared using the procedures analogous to those described for Example 171 substituting methyl 3-chloro-4- [(4i?)-6-(4-chlorophenyl)-4({ [( 1 , 1 -dimethylethyl)oxy]carbonyl} amino)-2,2-dimethyl-3 ,4- dihydro-2H-pyrano[2,3-ό]pyridin-7-yl]benzoate for methyl 3-chloro-4-{6-(4-chlorophenyl)- 4[(2,2-dimethylpropanoly)amino]-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-7- yljbenzoate in Step C.
Step C: tert-Butyl r(4J?)-7-r2-chloro-4-(1.3,4-oxadia2ol-2-vnphenyll-6-('4-chlorophenvn-2.2- dimethyl-3,4-dihydro-2//-pyrano[2,3-61pyridin-4-yl1carbamate. The product was prepared using the procedures analogous to those described for Example 173 substituting tert-butyl [(4i?)-7-[2- chloro-4-(hydrazinocarbonyl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-yl]carbamate for N-[7-{2-chloro-4-
[(hydroxyamino)(imino)methyl]phenyl}-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-yl]-2,2-dimethylpropanamide in Step B except without addition of boron trifluoride-diethyl etherate.
Step D: N-r(47?V7-r2-Chloro-4-π.3,4-oxadiazol-2-vnphenvn-6-('4-chlorophenyn-2,2-dimethyl- 3.4-dihvdro-2H-pyranor2,3-61pyridin-4-yl1-3,3,3-trifluoro-2-hvdroxypropanamide. The title compound was prepared using the procedures analogous to those described for Examples 176, 177, 178, and 179 substituting the product of Step C for tert-butyl [7-(2-chloro-4-( 1,2,4- oxadiazol-3-yl)phenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4- yl] carbamate in Step B.
Examples 235, and 236
Figure imgf000078_0001
r2i?/y>-N-rr4i?V6-(4-ClilorophenylV7-r2-chloro-4-(lH-pyrazol-l-vnphenyl1-2,2-dimethyl-3,4- dihvdro-2H-pyrano[2,3-61pyridin-4-vn-3,3,3-trifluoro-2-hvdroxypropanamide Step A: tert-butyl (r4i?V6-('4-chlorophenyl)-7-r2-chloro-4-('lH-pyrazol-l-vnphenyll-2,2- dimethyl-3,4-dihydro-2H-pyrano [2,3 -6]pyridin-4-vU carbamate. A solution of Example 169(280 mg, 0.48 mmol), pyrazole (65.8 mg, 0.97 mmol), copper(I) oxide (3.5 mg, 0.02 mmol), 2- hydroxybenzaldehyde oxime (33.1 mg, 0.24 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in 10 mL Of CH3CN was degassed and stirred at 85 0C for 16 h. The reaction mixture was cooled and diluted with CH2Cl2 (50 mL) and filtered through a cake of Celite. The filtrate was washed with H2O (50 mL) and brine (50 mL). After the phases separated, the organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 3:7 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.46 (s, 3H), 1.50 (s, 9H), 1.55 (s, 3H), 1.18 (m, IH), 2.29 (m, IH), 4.76 (br. s, IH), 5.13 (m, IH), 6.38 (m, IH), 6.47 (m, IH), 7.05 (d, J= 8.5, 2H), 7.18 (d, J= 8.5, 2H), 7.39-7.72 (m, 5H), 7.90 (m, IH). Step B: r2i?/^)-N-r(4^V6-(4-Chlorophenyl)-7-r2-chloro-4-(lH-pyrazol-l-yl)phenyll-2,2- dimethyl-3,4-dihvdro-2H-pyrano|"2,3-61pyridin-4-yll-3,3,3-trifluoro-2-hydroxypropanamide. The title compounds were prepared using procedures analogous to those described in Examples 176, 177, 178, and 179 substituting the product of Step A for tert-butyl [7-(2-chloro-4-(l,2,4- oxadiazol-3-yl)phenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2//-pyrano[2,3-ό]pyridine- 4-yl] carbamate in Step B.
Example 237
Figure imgf000078_0002
jV-{C4j;)-6-('4-Chlorophenvn-7-r2-chloro-4-(lH-pyrazol-4-vnphenyll-2,2-dimethyl-3,4-dihvdro- 2H-pyrano \1 ,3 -b\ pyridin-4-yl } benzamide Step A: fert-Butyl {(4/g)-6-(4-chlorophenvπ-7-r2-chloro-4-(l//-pyrazol-4-vπphenyll-2,2- dimethyl-3 ,4-dihydro-2H-pyrano|"2,3-61pyridin-4-yl } carbamate. To a solution of Example 169 (1.5 g, 2.59 mmol) in a mixed solvent of 9.0 mL of DMF, 1.0 mL of H2O, and 2.0 mL of EtOH was added ter/-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (1.53 g, 5.19 mmol), Na2CO3 (830 mg, 7.78 mmol), and tetrakis(triphenylphosphino)palladium(0) (150 mg, 0.13 mmol). The mixture was stirred at 120 0C under microwave irradiation for 30 min. After cooling, the mixture was diluted with EtOAc (200 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 1 : 1 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.49 (s, 3H), 1.52 (s, 9H), 1.58 (s, 3H), 1.84 (t, J= 12.7, IH), 2.33 (dd, J= 6.2, 13.2, IH), 4.78 (m, IH), 5.15 (m, IH), 7.09 (d, J = 8.4, 2H), 7.20 (d, J= 8.5, 2H), 7.26-7.41 (m, 3H), 7.74 (s, IH), 7.85 (s, 2H). Step B: (AR V 6-(4-Chlorophenyl)-7- r2-chloro-4-( 1 H-pyrazol-4-vnphenyll -2,2-dimethyl-3 ,4- dihvdro-2H-pyrano[2,3-61pyridin-4-amine. A solution of the product of Step A (364 mg, 0.64 mmol) in 10 mL of 20% TFA in CH2Cl2 was stirred at rt for 2 h. The reaction mixture was concentrated to give the product, which was used in the next step without further purification. Step C: N-{r4ig)-6-(4-Chlorophenvn-7-r2-chloro-4-(l//-pyrazol-4-vnphenyll-2.2-dimethyl-3.4- dihydro-2H-pyrano [2,3 -Z>lpyridin-4-yl } benzamide. To a solution of the product of Step B (35.6 mg, 0.08 mmol) and NEt3 (43 μL, 0.31 mmol) in 10 mL Of CH2Cl2 was added benzoyl chloride (20 μL, 0.17 mmol). After stirring at rt for 1 h, 2.0 mL of CH3OH and 100 μL of 5.0 N NaOH was added to the reaction mixture. After stirring for 30 min, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aq NaHCO3 (20 mL). The organic layer was separated and washed with brine (20 mL). After the phases separated, the organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 7:3 v/v
EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.50 (s, 3H), 1.56 (s, 3H), 1.96 (t, J= 12.4, IH), 2.36 (dd, J= 6.4, 13.2, IH), 5.73 (m, 2H), 6.61 (d, J= 8.7, IH), 7.02 (d, J = 8.5, 2H), 7.13 (d, J= 8.5, 2H), 7.14-7.55 (m, 6H), 7.72-7.83 (m, 5H).
The following examples were prepared using procedures analogous to those described for
Example 237 substituting the appropriate boronic acids or boronic esters for tert-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate in Step A and substituting appropriate acyl chlorides or acids for benzoyl chloride in Step C.
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0003
The following examples were prepared utilizing the appropriate amine and carboxylic acid or acid chloride in procedures similar to those described for Example 21 and Example 46.
Figure imgf000081_0001
The following examples were prepared utilizing the appropriate amine and carboxylic acid or acid chloride in procedures similar to those described for Example 21 and Example 46.
Figure imgf000081_0002
Figure imgf000081_0004
Figure imgf000082_0003
The following examples were prepared using procedures analogous to those described for Example 131 substituting (4i?)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4- dihydro-2H-pyrano-[2,3-ό]pyridin-4-amine for the corresponding racemic amine and the appropriate aryl halide for 2-bromopyridine, respectively, in Step A.
Figure imgf000082_0001
Figure imgf000082_0004
Example 267
Figure imgf000082_0002
6 ' -(4-Bromophenyl)-7 ' -(2-chlorophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1.2' -pyrano [2.3- 61pyridine1-4'-amine. The title compound was prepared from 6'-(4-bromophenyl)-7'-(2- chlorophenyl)spiro [cyclohexane-l,2'-pyrano[2,3-Z)]pyridin]-4'(3lH)-one oxime using a procedure similar to that of Example 18. ΗPLC/MS: 483.1 (M+l), 485.1 (M+3); R1 = 3.39 min. Example 268
Figure imgf000083_0001
N- [6' -(4-Bromophenyl)-7 ' -(2-chlorophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1,2' -pyrano ["2,3 - fclpyridinei^'-yli^-hydroxy^-methylpropanamide. The title compound was prepared using the product of Example 267 and the appropriate carboxylic acid in a procedure similar to that described for Example 46. HPLC/MS: 571.2 (M+l), 573.2 (M+3); Rt = 3.82 min. The enantiomers were resulved using chiral chromatography on an AD column eluting with 10% EtOH/Hexane.
Example 269
Figure imgf000083_0002
N- \1 ' -(2-Chlorophenyl V6 ' -(4-cyanophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1 ,2 ' -pyrano [2,3 - 61pyridine1-4'-yll-2-hydroxy-2-methylpropanamide. The product of Example 268 was treated under conditions similar to that of Example 172 Step B to afford the title compound: HPLC/MS: 516.4 (M+l), 518.4 (M+3); Rt = 3.62 min.
The following examples were prepared utilizing the appropriate amine and carboxylic acid following the general procedure of Example 46.
Figure imgf000083_0003
Figure imgf000083_0004
Example 272
Figure imgf000084_0001
N-r(4'i?V7'-(4-Bromo-2-clilorophenvn-6;-(4-chlorophenvn-4,4-difluoro-3',4'- dihvdrospiro[cvclohexane-l,2'-pyrano[2,3-Z>lpyridinel-4'-yl1-5-methyl-l//-pyrazole-3- carboxamide Step A: 7"-(4-Bromo-2-chlorophenylV6"-(4-chlorophenyls)dispiro|'l,3-dioxolane-2.,r- cyclohexane-4 ' ,2"-pyrano [2,3 -6]pyridine] -4"(3 "HVone. Starting with 3-acetyl-6-(4-bromo-2- chlorophenyl)-5-(4-chlorophenyl)pyridin-2(l//)-one and utilizing a procedure similar to that of Example 3 step B substituting l,4-dioxaspiro[4.5]decan-8-one for cyclohexanone the product was prepared. Step B: (4"^-4"-Azido-7"-(4-bromo-2-chlorophenylV6"-f4-chlorophenvn-3".4"- dihvdrodispiro[13-dioxolane-2,r-cvclohexane-4%2"-pyrano[2,3-61pyridine1. The product was prepared using procedures analogous to those described for Example 180 and Example 182 substituting the product of Step A for 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl- 2,3-dihydro-4H-pyrano[2,3-ό]pyridine-4-one in Step A of Example 180. Step C: (4'i?V4;-Azido-7;-(4-bromo-2-chlorophenvn-6'-(4-chlorophenvn-3\4'-dihvdro-4H- spiro[cyclohexane-l,2'-pyrano[2,3-fr1pyridine1-4-one. A solution of the product of Step B (300 mg, 0.54 mmol) andp-toluenesulfonic acid monohydrate (5.1 mg, 0.03 mmol) in 10 mL of acetone was allowed to stir at it for 16 h. The reaction mixture was diluted with Et2O (50 mL), washed with saturated aq NaHCO3 (2x50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 3:7 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.93-2.07 (m, 2H), 2.21-2.53 (m, 6H), 2.86-3.03 (m, 2H), 4.82 (m, IH), 7.04 (d, J= 8.4, 2H), 7.15-7.24 (m, 3H), 7.37 (dd, J= 2.1, 8.3, IH), 7.46 (d, J= 1.8, IH), 7.81 (s, IH). Step D: (4'i?)-4'-Azido-7'-('4-bromo-2-chlorophenvπ-6'-(4-chlorophenyl)-4,4-difluoro- 3 \4'-dihydro-4//-spiro[cvclohexane-l ,2'-pyrano[2,3-Z>1pyridine]. A mixture of [bis(2- methoxyethyl)amino] sulfur trifluoride (65 μL, 0.35 mmol) and BF3-Et2O (3.2 μL, 0.03 mmol) in 5.0 mL of toluene was allowed to stir for 45 min at 0 0C. A solution of the product of Step C (129 mg, 0.25 mmol) in 5.0 mL of toluene was added. The resulting mixture was stirred at 55 0C for 2 days. After cooling, the mixture was partitioned between 2N NaOH (50 mL) and Et2O (40 mL) at 0 0C and stirred for 30 min. After the phases separated, the organic layer was washed with saturated aq NaHCO3 (50 mL) and brine (50 mL). The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+S cartridge using 3:17 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.82-2.33 (m, 10H), 4.78 (m, IH), 7.02 (d, J= 8.5, 2H), 7.14-7.45 (m, 5H), 7.78 (s, IH).
Step E: ("4'i?V7'-(4-Bromo-2-chlorophenvπ-6'-r4-chlorophenvπ-4.4-difluoro-3'.4'-dihvdro-4H- spiro[cvclohexane-l,2'-pyranor2,3-6]pyridinl-4'-amine. The product was prepared using procedures analogous to those described for Example 182 substituting the product of Step D this example for (4i?)-4-azido-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3 ,4-dihdyro- 2H-pyrano[2,3-&]pyridine in Step B.
Step F: ■V-rf4'igV7>-(4-Bromo-2-chlorophenvn-6>-r4-chlorophenvn-4.4-difluoro-3'.4>- dihvdrospiro[cyclohexane-l,2'-pyranor2,3-6]pyridine1-4'-yl]-5-methyl-lH-pyrazole-3- carboxamide
The title compound was prepared using procedures analogous to those described for Example 182 substituting the product of Step E for (4i?)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2- dimethyl-3,4-dihdyro-2H-pyrano[2,3-6]pyridine-4-amine in Step C: 1H NMR δ 1.82-2.46 (m, 13H), 5.65 (m, IH), 6.64 (s, IH), 6.97 (d, J= 8.4, 2H), 7.14-7.45 (m, 5H), 7.70 (s, IH). Example 273
Figure imgf000085_0001
N- \(4 'R)-7 ' -C2-ChlorophenylV6 ' -(4-chlorophenyl V4.4-difluoro-3 ' .4 ' -dihvdrospiro Fcyclohexane- l,2'-pyranor2,3-61pyridinel-4'-yl]-5-methyl-lH-pyra2ole-3-carboxamide. A mixture of Example 273 (68 mg, 0.10 mmol), NEt3 (29 μL, 0.21 mmol), 11 mg of 5% Pd/C in 5.0 niL of EtOAc was degassed and stirred under 1 atm of H2 for 5 h. The solids were filtered and washed with EtOAc. The filtrate was concentrated and chromatography on a Biotage 40+S cartridge using 9:11 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.81-2.49 (m, 13H), 5.64 (m, IH), 6.61 (s, IH), 6.97 (d, J= 8.5, 2H), 7.11-7.30 (m, 6H), 7.71 (s, IH).
Figure imgf000085_0002
N- \(4 ' RV 7 * -f 4-Bromo-2-chlorophenyl>6' -(4-chlorophenvn-4.4-difluoro-3 * .4 ' - dihvdrospiro [cyclohexane- 1.2' -pyrano [2.3-6] pyridine] -4 ' -yll -5 -methyl- 1 H-pyrazole-3 - acetamide. The title compound was prepared from the product of Step E Example 272 and acetic anhydride. HPLC/MS: 594.9 (M+l), 596.9 (M+3); R1 = 2.51 min. BIOLOGICAL EXAMPLE 1 Cannabinoid Receptor- 1 (CBl) Binding Assay.
This assay is described in Biological Example 1 of WO 05/00809. Compounds of the present invention have have IC50s of less than 5 micromolar in the CBl binding assay. The compounds of the present invention are selective CBl antagonist/inverse agonist compounds having IC50s greater in the CB2 binding assay than in the CBl assay. The compounds of Examples 1 to 17 and 19-274 were assayed in the CBl Binding assay and found to have IC50 values for the human CBl receptor less than 1 micromolar.
CBl Receptor Binding for Selected Compounds
Figure imgf000086_0001
BIOLOGICAL EXAMPLE 2
Cannabinoid Receptor- 1 (CBl) Functional Activity Assay.
This assay is described in Biological Example 2 of WO 05/00809. The compounds of Examples 3, 11, 40, 54, 63, 131, 132, and 182 were all tested in the CBl functional activity assay and found to have EC50s less than 20 nM and were functional inverse agonists. BIOLOGICAL EXAMPLE 3
Acute food intake studies in rats or mice: General Procedure
Adult rats or mice are used in these studies. After at least 2 days of acclimation to the vivarium conditions (controlled humidity and temperature, lights on for 12 hours out of 24 hours) food is removed from rodent cages. Experimental compounds or their vehicles are administered orally, intraperitoneally, subcutaneously or intravenously before the return of a known amount of food to cage. The optimal interval between dosing and food presentation is based on the half-life of the compound based on when brain concentrations of the compound is the highest. Food remaining is measured at several intervals. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant effect of the compounds are compared to the effect of vehicle, hi these experiments many strains of mouse or rat, and several standard rodent chows can be used.
BIOLOGICAL EXAMPLE 4 Chronic weight reduction studies in rats or mice: General Procedure
Adult rats or mice are used in these studies. Upon or soon after weaning, rats or mice are made obese due to exclusive access to diets containing fat and sucrose in higher proportions than in the control diet. The rat strains commonly used include the Sprague Dawley bred through Charles River Laboratories. Although several mouse strains may be used, c57Bl/6 mice are more prone to obesity and hyperinsulinemia than other strains. Common diets used to induce obesity include: Research Diets D12266B (32% fat) or D12451 (45% fat) and BioServ S3282 (60% fat). The rodents ingest chow until they are significantly heavier and have a higher proportion of body fat than control diet rats, often 9 weeks. The rodents receive injections (1 to 4 per day) or continuous infusions of experimental compounds or their vehicles either orally, intraperitoneally, subcutaneously or intravenously. Food intake and body weights are measured daily or more frequently. Food intake is calculated as grams of food eaten per gram of body weight within each time interval and the appetite-suppressant and weight loss effects of the compounds are compared to the effects of vehicle. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications for the compounds of the invention indicated above.
Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of structural formula I:
Figure imgf000088_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from:
(1) halogen, -
(2) -Ci -6alkyl, unsubstituted or substituted with one, two or three substituents independently selected from Ra, (3) aryl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(4) cycloalkyl, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(5) heteroaryl-, unsubstituted or substituted with one, two, or three substituents independently selected from Rb,
(6) heterocycloalkyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(7) heteroaryl-Ci-3alkyl, unsubstituted or substituted on heteroaryl with one, two, or three substituents independently selected from Rb, (8) -Cθ2Rd,
(9) -CO-NRCRd,
(10) -CN,
(11) -ORd,
(12) -0-C(O)Rd, (13) -NRCRd,
(14) -NRcC(=O)Rd,
(15) -NRcC(=O)ORd,
(16) -NRcC(=O)-C(=O)NRCRd ,
(17) -NH-Sθ2-Rf, and (18) -S-Ci-6alkyl,
XI is selected from hydrogen, halogen and Ci-βalkyl, or together X and X 1 form =0, =NRg, or =CH-C(O)-O-Rd; Rl is selected from:
(1) hydrogen, (2) Ci-βalkyl,
(3) C3_7cycloalkyl,
(4) C3-8cycloalkenyl,
(5) C3-7cycloalkyl-Ci_4alkyl, (6) Cs-δcycloalkenyl-Ci^alkyl,
(7) cycloheteroalkyl,
(8) cycloheteroalkyl-C i -4alkyl,
(9) phenyl,
(10) benzyl, (11) heteroaryl,
(12) heteroaryl-Ci_4alkyl,
(13) -C(O)NH-S(O)2-CH3, wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to four substituents independently selected from Rb; R2 is selected from:
(1) Ci-6alkyl,
(2) C3-7cycloalkyl, (3) C3-8cycloalkenyl,
(4) C3-7cycloalkyl-Ci-4alkyl,
(5) C3-8cycloalkenyl-Ci_4alkyl,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C i-4alkyl, (8) phenyl,
(9) benzyl,
(10) heteroaryl,
(11) heteroaryl-C i _4alkyl,
(12) -C(O)NH-S(O)2-CH3, wherein each alkyl is unsubstituted or substituted with one to four substituents independently selected from Ra, and each cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is optionally substituted with one to four substituents independently selected from Rb; or Rl and R2 together with the carbon to which they are attached form a carbonyl group (C=O) or a spiroannulated ring system of 5 to 10 members containing 0, 1, or 2 heteroatoms independently selected from -O-, and -S, optionally substituted with an Rb substituent; R4 is selected from: (1) -H,
(2) halo-,
(3) -CN,
(4) Ci-3alkyl-, unsubstituted or substituted with one, two or three Rh substitutents, (5) -CF3,
(6) -ORd, and
(7) -OCF3;
R6 and R? are each independently selected from:
(1) -H, (2) halo-,
(3) -CN,
(4) Ci-3alkyl-, unsubstituted or substituted with one, two, or three Rh substitutents,
(5) -CF3,
(6) cycloalkyl, unsubstituted or substituted with one or two Rh substitutents, (7) cycloheteroalkyl, unsubstituted or substituted with one or two Rh substitutents,
(8) aryl, unsubstituted or substituted with one or two Rk substitutents,
(9) heteroaryl, unsubstituted or substituted with one or two Rk substitutents,
(10) -OH,
(11) -OCH3, (12) -OCF3,
(13) -OCH2CF3,
(14) -C(O)Rd5
(15) -CO2Rd,
(16) -C(O)NRCRd, and (17) -NRCRd; each Ra is independently selected from: -OH, -OCH3, halogen, -SH, -SO2Rd, -NH2, -CN,
CO2Rd, -C(O)NRCRd, -CF3, and -OCF3;. each R^ is independently selected from: -Ra, oxo, Ci-ioalkyl, C2-IO alkenyl, cycloalkyl, cycloalkyl-Ci-ioalkyl, cycloheteroalkyl, cycloheteroalkyl-Ci-io alkyl, aryl, heteroaryl, aryl-Ci- loalkyl, and heteroaryl-Ci-ioalkyl, wherein alkyl and alkenyl moieties are unsubstituted or substituted with one, two, three or four Rk substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rk substituents;
RC and Rd are each independently selected from:
(1) hydrogen, (2) Ci-ioalkyl,
(3) C2-IO alkenyl,
(4) cycloalkyl, (5) cycloalkyl-Ci-ioalkyl-,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C i .10 alkyl-,
(8) aryl, (9) heteroaryl,
(10) aryl-Ci-ioalkyl-, and
(11) heteroaryl-C i . i Oalkyl-, wherein each Rc and Rd moiety, other than hydrogen, may be unsubstituted or substituted with one to three substituents selected from Rh; each R^ is independently selected from:
(1) halogen,
(2) Ci-6alkyl, unsubstituted or substituted with one or two Ri substituents, and
(3) -N(CH3)2; each Rg is independently selected from: hydrogen, -OH, and methyl; each Rn is independently selected from:
(1) halogen,
(2) Ci-6alkyl,
(3) 4-methylbenzyl-,
(4) -OH, (5) -O-Ci_4alkyl,
(6) benzyloxy-,
(7) -oxo,
(8) -OC(O)-C l-6alkyl,
(9) -C(O)O-Ci-6alkyl, (10) -S-Ci_4alkyl,
(11) -NH2,
(12) -NH(CH3),
(13) -N(CH3)2,
(14) -NO2, (15) -CN,
(16) -CF3, and
(17) -OCF3, wherein alkyl may be unsubstituted or substituted with one, two or three substituents selected from Ri; each Ri is independently selected from: halogen, -O-Ci-4alkyl, -OH, -S-Ci-4alkyl, -CN, -CF3, and -OCF3; and each RΛ is independently selected from: halogen, oxo, amino, hydroxy, Ci-4alkyl, -O-Ci_4alkyl, -S-Ci_4alkyl, -CN, -CF3, and -OCF3.
2. The compound according to Claim 1, wherein: X is selected from:
(1) methyl, ethyl, isopropyl or t-butyl, substituted with one, two or three substituents independently selected from Ra,
(2) phenyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb, (3) heteroaryl-, unsubstituted or substituted with one, two, or three substituents independently selected from Rb,
(4) heterocycloalkyl-, unsubstituted or substituted with one, two or three substituents independently selected from Rb,
(5) heteroaryl-methyl-, unsubstituted or substituted on heteroaryl with one, two, or three substituents independently selected from Rb,
(6) -CO2Rd,
(7) -CO-NRCRd,
(8) -ORd,
(9) -0-C(O)Rd, (10) -NRCRd,
(11) -NRcC(=O)Rd,
(12) -NHC(=O)ORd,
(13) -NHC(=O)-C(=O)NHRd , and
(14) -NH-Sθ2-Rf, Xl is hydrogen, or
X and Xl together form =O, =N-0H, or =CH-C(O)-O-CH2CH3;
Rl is selected from:
(1) hydrogen,
(2) Ci-6alkyl, unsubstituted or substituted with hydroxy, fluoro, or methylsulfonylmethyl, (3) bicyclo[2.2.1]hept-5-en-2-yl,
(4) cycloheteroalkyl,
(5) cycloheteroalkyl-Ci^alkyl, and
(6) phenyl, unsubstituted or substituted with fluoro; R2 is selected from: (1) Ci-6alkyl, unsubstituted or substituted with hydroxy, fluoro, or methylsulfonyl,
(2) bicyclo[2.2.1]hept-5-en-2-yl,
(3) cycloheteroalkyl, (4) cycloheteroalkyl-Ci^alkyl, and
(5) phenyl, unsubstituted or substituted with fluoro; or Rl and R2 together with the carbon to which they are attached form a carbonyl group (C=O) or a spiroannulated ring system selected from:
R :4 is sele.c)ted from:}θ.} ;.>o<.x >oθ:
(1) halo-,
(2) -CN,
(3) -CH3, (4) -CF3,
(5) -OCH3,
(6) -OCH2CF3, and
(7) -OCF3;
R6 is selected from: -Cl, -Br, -CN, -CH3, -CF3, and 1,2,4-oxadiazolyl; R7 is selected from:
(1) -H,
(2) -F,
(3) -Cl,
(4) -Br,
(5) -I,
(6) -CN,
(7) -CH3,
(8) -CF3,
(9) oxadiazolyl, unsubstituted or substituted with one or two Rh substitutents,
(10) pyrazolyl,
(H) thienyl,
(12) furyl,
(13) oxazolyl,
(14) -OH,
(15) -OCH3,
(16) -OCF3,
(17) -OCH2CF3, and
(18) -CO2CH3; each Ra is independently selected from: -OH, -F, -SO2CH3, -CO2-C l-6alkyl, and -CF3; each Rb is independently selected from: -OH, -OCH3, halogen, -N(CH3)2, -CH(O), -C(O)Rd5 -CN, -CO2CH3, -CO2CH2C6H5, -CF3, -OCF3, oxo, Ci_3alkyl, C2-3 alkenyl, cyclopropyl, oxadiazolyl, pyrazolyl, tetrazolyl, and phenyl, wherein: alkyl and alkenyl moieties are unsubstituted or substituted with one, two, or three Rk substituents, and cycloalkyl, cycloheteroalkyl, aryl and heteroaryl moieties are unsubstituted or substituted with one, two or three Rk substituents; each Rc is independently selected from: hydrogen, and methyl, each Rd is independently selected from:
(I) hydrogen, (2) Ci-6alkyl,
(3) C2-6alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-Ci-ioalkyl-,
(6) cycloheteroalkyl, (7) cycloheteroalkyl-C 1.10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-3 alkyl-, and
(I I) heteroaryl-Ci-3alkyl-, wherein each Rd moiety, other than hydrogen, may be unsubstituted or substituted with one, two or three substituents selected from Rh; each R^ is independently selected from: chloro, ethyl, n-propyl, chloropropyl, and -N(CH3)2;
Rg, Rh, Ri and Rk are as defined in Claim 1, or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 2, of structural formula ID-I :
Figure imgf000094_0001
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 3, wherein:
Rl and R2 are each methyl or together form:
Figure imgf000094_0002
R4 is chloro, R6 is chloro, R7 is hydrogen or chloro, and X and Xl are as according to Claim 3, or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 4, wherein:
X is selected from:
(I) oxadiazolyl, unsubstituted or substituted on a carbon atom with methyl, (2) piperidinyl, unsubstituted or substituted on carbon with oxo,
(3) oxadiazolyl-methyl-, unsubstituted or substituted on an oxadiazolyl carbon atom with methyl or oxo,
(4) -NH-pyridyl,
(5) -NH(pyrazolyl), wherein the pyrazole is unsubstituted or substituted on a carbon atom with methyl,
(6) -NH-C(O)-CH2-OH,
(7) -NH-C(O)-CH(CH3)-OH,
(8) -NH-C(O)-C(CH3)2-OH,
(9) -NH-C(O)-N(CH3)2, (10) isoxazolyl-carboxamide,
(I I) pyrazolylcarboxamide, wherein the pyrazole is unsubstituted or substituted on a carbon atom with methyl,
(12) triazolyl-carboxamide, wherein the triazole is unsubstituted or substituted on a carbon atom with methyl, (13) imidazolyl-carboxamide,
(14) cyclopropylcarboxamide, wherein the cyclopropyl group is unsubstituted or substituted with hydroxy,
(15) -NH-C(O)-C(O)-NH(CH3), and
XI is hydrogen, or X and Xl together form =0; or a pharmaceutically acceptable salt thereof.
6. The compound according to Claim 1, selected from:
(1) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-2,3-dihydro-4H-pyrano[2,3- ό]pyridin-4-one;
(2) 7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-2,3-dihydro-4H-pyrano[2,3-6]pyridin- 4-one; 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)spiro[cyclohexane- 1 ,2'-pyrano[2,3- ό]pyridin] -4'(3 'H)-one; 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)spiro [cyclopentane- 1 ,2'- pyrano [2,3 -ό]pyridin]-4'(3 'H)-one; 7-(2-chlorophenyl)-6-(4-chlorophenyl)-2',3 ',5 ',6'- tetrahydrospiro[pyrano[2,3-6]pyridine-2,4'-thiopyran]-4(3H)-one;
(6) 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-2,3,5,6-tetrahydrospiro[pyran-4,2'-pyrano[2,3- 6]pyridin]-4'(3Η)-one;
(7) 7"-(2-chlorophenyl)-6"-(4-chlorophenyl)dispiro[l,3-dioxolane-2,r-cyclohexane-4',2"- pyrano[2,3-6]pyridin]-4"(3"H)-one;
(8) 7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,2-diethyl-2,3-dihydro-4H-pyrano[2,3-ό]pyridin-4- one; (9) 7-(2-chlorophenyl)-6-(4-chlorophenyl)-2-isopropyl-2-methyl-2,3-dihydro-4//-pyrano[2,3- ό]pyridin-4-one; (10)7-(2-chlorophenyl)-6-(4-chlorophenyl)-2-ethyl-2-methyl-2,3-dihydro-4H-pyrano[2,3-
6]pyridin-4-one;
(l l)2-tert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,3-dihydro-4H-pyrano[2,3-ό]pyridin- 4-one;
(12)7-(2-chlorophenyl)-6-(4-chlorophenyl)-2-isopropyl-2,3-dihydro-4H-pyrano[2,3-ό]pyridin-
4-one; (13) 2-bicyclo[2.2. l]hept-5-en-2-yl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,3-dihydro-4H- pyrano[2,3-6]pyridin-4-one; (14)7-(4-bromo-2-chlorophenyl)-2-te/-t-butyl-6-(4-chlorophenyl)-2,3-dihydro-4H-pyrano[2,3-
6]pyridin-4-one; (15) 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)spiro[cyclohexane-l ,2'-pyrano[2,3-Z>]pyridin]-
4'(3'H)-one oxime;
(16)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-2,3-dihydro-4H-pyrano[2,3- 6]pyridin-4-one oxime;
(17)7-(2-chlorophenyl)-6-(4-chlorophenyl)-2',3',5',6'-tetrahydrospiro[pyrano[2,3-o]pyridine-
2,4'-thiopyran]-4(3H)-one oxime; (18) 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane- 1 ,2'-pyrano[2,3-
6]pyridin]-4'-amine; (19)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dmiethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-amine; (20)2-tert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-3,4-dih.ydro-2H-pyrano[2,3-ό]pyridin-
4-amine;
(21)N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'-pyrano[2,3- ό]pyridin]-4'-yl]acetamide;
(22)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyτano[2,3- Z?]pyridin-4-yl] acetamide; (23)N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'-pyrano[2,3-
6]pyridin] -4'-yl] -2-hydroxyacetamide; (24) N- [7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3 ',4'-dihydrospiro[cyclohexane- 1 ,2'-pyrano [2,3 -
&]pyridin]-4'-yl]isoxazole-5-carboxamide; (25)N-[7-(2-chlorophenyl)-6-(4-chlorophenyl)-2',3,3',4,5',6'-hexahydrospiro[pyrano[2,3- δ]pyridine-2,4'-thiopyran]-4-yl]-2-hydroxyacetamide; (26)N-[7-(2-chlorophenyl)-6-(4-chlorophenyl)-2',3,3',4,5',6'-hexahydrospiro[pyrano[2,3- ό]pyridine-2,4'-thiopyran]-4-yl]-2-hydroxyacetamide;
(27)iV-[7l-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4l-dihydrospiro[cyclopentane-l,2l- pyrano[2,3-6]pyridin]-4'-yl]-2-hydroxyacetamide;
(28) ethyl [7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospifo[cyclohexane- 1 ,2'- pyrano[2,3-ό]pyridin]-4'-yl]carbamate; (29) 3 -chloro-iV- [7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3 ',4'-dihydrospiro [cyclohexane- 1 ,2'- pyrano[2,3-ό]pyridin]-4'-yl]-2,2-dimethylpropanamide; (30)N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane- 1 ,2'-pyrano[2,3- b] pyridin] -4'-yl] cyclopropanecarboxamide ; (31)4-bromo-N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'- pyrano[2,3-ό]pyridin]-4'-yl]butanamide;
(32)iV-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-2-hydroxyacetamide;
(33)iV-[7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-2-hydroxyacetamide; (34)(2i?)-N-[2-tert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-2-hydroxypropanamide; (35)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-
Z»]pyridin-4-yl]-4,4,4-trifluoro-3-hydroxybutanamide; (36)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-
6]pyridin-4-yl]-4,4,4-trifluoro-3-hydroxybutanamide;
(37)3-(benzyloxy)-N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano [2,3 -6]pyridin-4-yl] -2,2-dimethylpropanamide;
(38) 1 -[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l ,2'-pyrano[2,3- ό]pyridin]-4'-yl]-3,3-dimethylazetidin-2-one; (39) N- [6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3 ,4-dihydro-2H-pyrano [2,3 -
6]pyridin-4-yl]-3-hydroxy-2,2-dimethylpropanaπiide; (40)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-N'-methylethanediamide; (41 ) ethyl 2-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-2,3-dihydro-4H- pyrano [2,3 -δ]pyridin-4-ylidene] acetate; (42)ethyl 2-(6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano [2,3 -6]pyridin-4-yl)acetate; (43)5-{[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-
&]pyridine-4-yl]methyl}-l,3,4-oxadiazol-2(3H)-one; (44)7-(2-chlorophenyl)-6-(4-chlorophenyl)-2',3',5',6'-tetrahydrospiro[pyrano[2,3-ό]pyridine-
2,4'-thiopyran]-4(3H)-one l',l '-dioxide;
(45)N-[7-(2-chlorophenyl)-6-(4-chlorophenyl)-l',l'-dioxido-2',3,3l,4,5',61- hexahydrospiro[pyrano[2,3-6]pyridine-2,4'-thiopyran]-4-yl]-2-hydroxyacetamide;
(46)(25)-N-[71-(2-chlorophenyl)-6l-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,21- pyrano [2,3 -6]pyridin] -4'-yl] -2-hydroxypropanamide; (47) (2J?)-N-[7l-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro [cyclohexane-1 ,2'- pyrano [2,3-6] pyridin] -4'-yl] -2-hydroxypropanamide; (48)iV-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro [cyclohexane-1 ,2'- pyrano[2,3-ό] pyridin]-4'-yl]-2-hydroxy-2-methylpropanamide; (49)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-
Z)]pyridin-4-yl]-2-hydroxy-2-methylpropanamide;
(50)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl] -2-hydroxypropanamide;
(51)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-4,4,4-trifluoro-3-hydroxybutanamide; (52) N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'- pyrano [2,3 -6]pyridin] -4'-yl] -2-methylpropanamide; (53) N- [7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4l-dihydrospiro [cyclohexane-1, T- pyrano[2,3-ό]pyridin]-4'-yl]propanamide; (54) N- [7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3 ',4'-dihydrospiro [cyclohexane- 1 ,T- pyrano[2,3-6]pyridin]-4'-yl]propane- 1 -sulfonamide;
(55)3 -chloro-N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3 ',4'-dihydrospiro [cyclohexane- 1 ,T- pyrano[2,3-ό]pyridin]-4'-yl]propane-l -sulfonamide;
(56)N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]methanesulfonamide; (57)N'-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- olpyridin^-ylj-N^-dimethylsulfamide; (58)iV-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl] -N^/V-dimethylurea; (59) 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-4'-(l , 1 -dioxidoisothiazolidin-2-yl)-3',4'- dihydrospiro[cyclohexane- 1 ,2'-pyrano[2,3-ό]pyridine; (60) l-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]imidazolidine-2,4-dione; (61) 7-(2-chlorophenyl)-6-(4-chlorophenyl)-N-(2-hydroxyethyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-ό]pyridine-4-carboxamide;
(62) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-N-(2-hydroxyethyl)-2,2-dimethyl-3,4-dihydro- 2H-pyrano[2,3-6]pyridine-4-carboxamide;
(63) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-N-(2-hydroxy-l,l-dimethylethyl)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridine-4-carboxarnide;
(64) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-N-isopropyl-2,2-dimethyl-3,4-dihydro-2H- pyrano [2,3 -Z>]pyridine-4-carboxamide;
(65) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-N-(3,3,3-trifluoro-2- hydroxypropyl)-3,4-dihydro-2H-pyrano[2,3-ό]pyridine-4-carboxamide; (66)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)-
3 ,4-dihydro-2H-pyrano [2,3 -ό]pyridine; (67)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-4-(5-isopropyl-l,3,4-oxadiazol-2-yl)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridine;
(68)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-4-(5-isopropyl-l,3,4-oxadiazol-2-yl)-2,2- dimethyl-2H-pyrano [2,3-6] pyridine ;
(69) (35)- 1 -[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-6]pyridin-4-yl]-3-hydroxypyrrolidine-2,5-dione; (70)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-iV-(pyridine-2-yl)-3,4-dihydro-2H- pyrano [2,3 -&]pyridin-4-amine; (71)6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-7V-(5-methyl-lH-pyrazol-3-yl)-
3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4-amine; (72) 1 - [7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3 ,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-yl]pyrrolidin-2-one;
(73) l-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]piperidin-2-one;
(74) l-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]imidazolidin-2-one; (75) l-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]piperazin-2-one; (76)4-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]2,4-dihydro-3H- 1 ,2,4-triazol-3-one; (77) tert-butyl [7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3 ,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-yl]carbamate; (78) methyl 3-chloro-4-[6-(4-chlorophenyl)-4-({ [(1 , 1 -dimethylethyl)oxy]carbonyl} amino)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-7-yl]benzoate; (79)N-[7-[2-chloro-4-(5-oxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)phenyl]-6-(4-chlorophenyl)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4-yl]-2,2-dimethylpropanamide; (80)N-[7-(2-chloro-4-cyanophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-yl]-2,2-dimethylpropanamide;
(81)N-[7-[2-chloro-4-(l,2,4-oxadiazol-3-yl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4- dihydro-2H-pyrano[2,3-6]pyridin-4-yl]-2,2-dimethylpropanamide;
(82)N-[7-[4-chloro-2-(l,2,4-oxadiazol-3-yl)phenyl]-6-(4-chloropheriyl)-2,2-dimethyl-3,4- " " dihydro-2H-pyrano[2,3-Z>]pyridin-4-yl]-2-hydroxy-2-methylpropanamide; (83)N-[7-[2-chloro-4-(5-methyl-l,2,4-oxadiazol-3-yl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-
3,4-dihydro-2H-pyrano[2,3-Z>]pyridin-4-yl]-2,2-dimethylpropanamide; (84)N-[7-[2-chloro-4-(l ,2,4-oxadiazol-3-yl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4- dihydro-2//-pyrano[2,3-ό]pyridin-4-yl]-3,3,3-trifluoro-2-hydroxypropanamide; (85)(45)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-
6]pyridin-4-yl benzoate;
(86)(4/?)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- &]pyridin-4-yl benzoate;
(87)N-[(4i?)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano [2,3 -6]pyridin-4-yl] -5-methyl- 1 //-pyrazole-3 -carboxamide; (88)N-[(4i?)-7-[2-chloro-4-(l,3,4-oxadiazol-2-yl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4- dihydro-2//-pyrano[2,3-Z>]pyridin-4-yl]-3,3,3-trifluoro-2-hydroxypropanamide; (89)N-[(4i?)-6-(4-chlorophenyl)-7-[2-chloro-4-(l//-pyrazol-l-yl)phenyl]-2,2-dimethyl-3,4- dihydro-2H-pyrano [2,3-6] pyridin-4-yl] -3,3,3 -trifluoro-2-hydroxypropanamide ; (90)N-{(4/?)-6-(4-chlorophenyl)-7-[2-chloro-4-(lH-pyrazol-4-yl)phenyl]-2,2-dimethyl-3,4- dihydro-2H-pyrano [2,3 -ό]pyridin-4-yl } benzamide;
(91) 6' -(4-bromophenyl)-7' -(2-chlorophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1,2' -pyrano [2,3 - 6]pyridine]-4'-amine;
(92) N- [6 ' -(4-bromophenyl)-7' -(2-chlorophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1,2'- pyrano [2,3 -ό]pyridine] -4' -yl] -2-hydroxy-2-methylpropanamide;
(93) N- [7' -(2-chlorophenyl)-6 ' -(4-cyanophenyl)-3 ' ,4 ' -dihydrospiro [cyclohexane- 1,2'- pyrano [2,3 -Z?]pyridine]-4 ' -yl] -2-hydroxy-2-methylpropanamide; (94)N-[(4'i?)-7'-(4-bromo-2-chlorophenyl)-6'-(4-chlorophenyl)-4,4-difluoro-3',4'- dihydrospiro [cyclohexane- 1 ,2 ' -pyrano [2,3 -ό]pyridine] -4' -yl] -5-methyl- 1 H-pyrazole-3 - carboxamide; (95)N-[(4'J?)-7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-4,4-difluoro-3',4'- dihydrospirofcyclohexane-l^'-pyranoPjS-δjpyridineJ^'-ylJ-S-methyl-lH-pyrazole-S- carboxamide; and
(96)N-[(4'R)-7'-(4-bromo-2-chlorophenyl)-6'-(4-chlorophenyl)-4,4-difluoro-3',4'- dihydrospiro [cyclohexane- 1 ,2 ' -pyrano [2,3 -6]pyridine] -4' -yl] -5-methyl- 1 H-pyrazole-3 - acetamide; or a pharmaceutically acceptable salt thereof.
7. A compound according to Claim 1 selected from: (1) 7'-(2-chlorophenyl)-6'-(4-chlorophenyl)spiro [cyclohexane- l,2'-pyrano [2,3 -6]pyridin]- 4'(3'H)-one; "
(2) 2-tert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,3-dihydro-4H-pyrano[2,3-ό]pyridin- 4-one;
(3) N-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'-pyrano[2,3- 6]pyridin]-4'-yl]-2-hydroxyacetamide;
(4) 7V-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'-pyrano[2,3- δ]pyridin]-4'-yl]isoxazole-5-carboxamide;
(5) iV-[7'-(2-chlorophenyl)-6'-(4-chlorophenyl)-3',4'-dihydrospiro[cyclohexane-l,2'-pyrano[2,3- &]pyridin]-4'-yl]-2-hydroxy-2-methylpropanamide; (6) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-2-hydroxyacetamide;
(7) (25f)-N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-Z)]pyridin-4-yl]-2-hydroxypropanamide;
(8) (2i?)-N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano [2,3 -&]pyridin-4-yl] -2-hydroxypropanamide;
(9) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2//-pyrano[2,3- ό]pyridin-4-yl]-2-hydroxy-2-methylpropanamide;
(10) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]-N'-methylethanediamide; (11) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)- 3 ,4-dihydro-2H-pyrano [2,3 -&]pyridine;
(12) 5-{[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- ό]pyridin-4-yl]methyl } - 1 ,3 ,4-oxadiazol-2(3H)-one;
(13) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-N-pyridin-2-yl-3,4-dihydro-2H- pyrano[2,3-ό]pyridin-4-amine;
(14) 6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-N-(5-methyl-lH-pyrazol-3-yl)- 3,4-dihydro-2H-pyrano[2,3-ό]pyridin-4-amine; (15) 1 -[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2//-pyrano[2,3- 6]pyridin-4-yl]piperidin-2-one;
(16) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- δ]pyridin-4-yl] - 5 -methyl- 1 H-pyrazole-3 -carboxamide ; (17) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- δ]pyridin-4-yl] -3 -methyl- IH- 1 ,2,4-triazole-5-carboxamide;
(18) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- Z>]pyridin-4-yl]-lH-imidazole-4-carboxamide;
(19) N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- Z)]pyridin-4-yl]-l-hydroxycyclopropanecarboxamide; and
(20) iV-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- b] pyridin-4-yl] -N, N-dimethylurea; or a pharmaceutically acceptable salt thereof.
8. The compound according to Claim 1 which is:
7'-(2-chlorophenyl)-6'-(4-chlorophenyl)spiro[cyclohexane-l,2'-pyrano[2,3-Z7]pyridin]-4'(3'H)-one; or a pharmaceutically acceptable salt thereof.
9. The compound according to Claim 1 which is: 2-tert-butyl-7-(2-chlorophenyl)-6-(4-chlorophenyl)-2,3-dihydro-4H-pyrano[2,3-ό]pyridin-4-one; or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 1 which is: N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 6]pyridin-4-yl]-iV'-methylethanediamide; or a pharmaceutically acceptable salt thereof.
11. The compound according to Claim 1 which is: iV-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 6]pyridin-4-yl]-5-methyl-l//-pyrazole-3-carboxamide; or a pharmaceutically acceptable salt thereof.
12. The compound according to Claim 1 which is:
N-[6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 6]pyridin-4-yl]-3-methyl-lH-l,2,4-triazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.
13. A composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.
14. A composition comprising a compound according to Claim 7 and a pharmaceutically acceptable carrier.
15. The use of a compound according to Claim 1 for the preparation of a medicament useful for the treatment of a condition ameliorated by antagonism or inverse agonism of the CBl receptor.
16. The use according to Claim 10 wherein the condition is selected from: psychosis, memory deficit, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflammatory disorders, cerebral vascular accidents, head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, schizophrenia, substance abuse disorders, constipation, chronic intestinal pseudo-obstruction, cirrhosis of the liver, asthma, obesity, and other eating disorders associated with excessive food intake.
17. The use according to Claim 11 , wherein the substance abuse disorder is abuse of or addiction to a substance selected from: opiates, alcohol, marijuana, and nicotine, and the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.
18. The use of a compound according to Claim 1 for the manufacture of a medicament useful for preventing obesity in a person at risk for obesity.
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WO2013014587A1 (en) * 2011-07-22 2013-01-31 Actelion Pharmaceuticals Ltd Heterocyclic amide derivatives as p2x7 receptor antagonists
US9409917B2 (en) 2012-01-20 2016-08-09 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9718774B2 (en) 2012-12-12 2017-08-01 Idorsia Pharmaceuticals Ltd Indole carboxamide derivatives as P2X7 receptor antagonist
US9388198B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9388197B2 (en) 2013-01-22 2016-07-12 Actelion Pharmaceuticals Ltd. Heterocyclic amide derivatives as P2X7 receptor antagonists
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
CN110724151A (en) * 2019-11-18 2020-01-24 成都睿智化学研究有限公司 Synthesis method of (3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-6-yl) methanol
CN110724151B (en) * 2019-11-18 2022-03-04 成都睿智化学研究有限公司 Synthesis method of (3, 4-dihydro-2H-pyrano [2,3-b ] pyridine-6-yl) methanol

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