WO2002002565A2 - Glucocortiocoid-selective antiinflammatory agents - Google Patents

Glucocortiocoid-selective antiinflammatory agents Download PDF

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Publication number
WO2002002565A2
WO2002002565A2 PCT/US2001/020423 US0120423W WO0202565A2 WO 2002002565 A2 WO2002002565 A2 WO 2002002565A2 US 0120423 W US0120423 W US 0120423W WO 0202565 A2 WO0202565 A2 WO 0202565A2
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WO
WIPO (PCT)
Prior art keywords
dihydro
trimethyl
methoxy
jbenzopyrano
quinoline
Prior art date
Application number
PCT/US2001/020423
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French (fr)
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WO2002002565A3 (en
Inventor
Michael J Coghlan
James P Edwards
Steven W Elmore
Todd K Jones
Michael E Kort
Philip R Kym
Jimmie L Moore
John K Pratt
Alan X Wang
Original Assignee
Abbott Laboratories
Ligand Pharmaceuticals Incorporated
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Publication date
Application filed by Abbott Laboratories, Ligand Pharmaceuticals Incorporated filed Critical Abbott Laboratories
Priority to MXPA03000183A priority Critical patent/MXPA03000183A/en
Priority to BR0112160-0A priority patent/BR0112160A/en
Priority to AU2001270194A priority patent/AU2001270194A1/en
Priority to JP2002507817A priority patent/JP2004502693A/en
Priority to CA002415037A priority patent/CA2415037A1/en
Priority to EP01948754A priority patent/EP1299392A2/en
Publication of WO2002002565A2 publication Critical patent/WO2002002565A2/en
Publication of WO2002002565A3 publication Critical patent/WO2002002565A3/en
Priority to HK03106700.5A priority patent/HK1056165A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to glucocorticoid receptor-selective benzopyrano[3,4-f]quinolines that are useful for treating immune or autoimmune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation, inflammatory disease, immune, and autoimmune diseases in a mammal.
  • Intracellular receptors are a class of structurally related proteins involved in the regulation of gene expression.
  • the steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol.
  • Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response.
  • GR glucocorticoid receptor
  • Steroids which interact with GR have been shown to be potent antiinflammatory agents. Despite this benefit, steroidal GR ligands are not selective. Side effects associated with chronic dosing are believed to be the result of cross- reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains.
  • Selective GR modulators e.g. repressors, agonists, partial agonists and antagonists
  • GR modulators can be used to influence the basic, life-sustaining systems ofthe body, including carbohydrate, protein and lipid metabolism, and the functions ofthe cardiovascular, kidney, central nervous, immune, skeletal muscle, and other organ and tissue systems
  • prior art GR modulators have proven useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Gushing 's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal in
  • GR modulators are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis , osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstractive pulmonary disease, asthma, tendonitis , bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis.
  • GR active compounds have also been used as immunostimulants and repressors, and as wound healing and tissue repair agents.
  • GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T
  • glucocorticoid receptor has been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIV), cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IL-1 expression, anti-retro viral therapy, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa.
  • Cogitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, and anxiety.
  • Rl is -LI-RA where Li is selected from (1) a covalent bond
  • alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups
  • R20 is hydrogen or alkyl of one to twelve carbons
  • alkanoyl where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups
  • alkyl of one to twelve carbons (15) alkenyl of two to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Li when Li is other than a covalent bond,
  • alkanoyl where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons substituted by 1 or 2 aryl groups
  • alkyl of one to twelve carbons (viii) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons
  • alkenyl of three to twelve carbons provided that a carbon-carbon double bond is not attached directly to nitrogen
  • alkynyl of three to twelve carbons provided that a carbon-carbon triple bond is not attached directly to nitrogen
  • -CO2 10 where Rio is selected from
  • aryl (i) aryl, (ii) aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (ii) cycloalkyl of three to twelve carbons, (iii) alkyl of one to twelve carbons, and (iv) alkyl of one to twelve carbons substituted with aryl or cycloalkyl of three to twelve carbons,
  • (17) and (18) can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from (a) alkyl of one to twelve carbons, (b) aryl,
  • alkanoyloxy where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons
  • R2; R3 > an R4 are independently hydrogen or Rl ; or
  • Rl and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or -(C(Rl2)(Rl3))v - where R12 and R13 are independently hydrogen or alkyl of one to twelve carbons and v is 1, 2, or 3, and Z* is selected from -CH2-, -CH2S(O)t-, -CH2O-,
  • L2 is selected from
  • R5 is selected from (1) halo
  • alkanoyl where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted with 1 or 2 phenyl substituents, (v) cycloalkyl of three to twelve carbons, (vi) alkyl of one to twelve carbons,
  • alkyl of one to twelve carbons substituted with 1, 2, or 3 substituents independently selected from alkoxy of one to twelve carbons, cycloalkyl of three to twelve carbons, aryl, and alkoxycarbonyl where the alkyl group is one to twelve carbons,
  • R30 is selected from
  • alkynyl of one to twelve carbons provided that a carbon of a carbon-carbon triple bond is not attached directly to L ⁇ when L ⁇ is other than a covalent bond, where (i), (ii), and (iii) can be optionally substituted with cycloalkyl of three to twelve carbons, -OH, provided that no two -OH groups are attached to the same carbon, halo, alkoxy of one to twelve carbons, thioalkoxy of one to twelve carbons, -NR 8 'R9', -O-(CH 2 ) q -Z-Rio, alkoxycarbonyl where the alkyl group is one to twelve carbons, alkanoyloxy where the alkyl group is one to twelve carbons, -NR7SO2-(alkyl of one to twelve carbons),
  • -OSO2-(alkyl of one to twelve carbons), aryl, and heterocycle (iv) aryl, (v) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo,
  • L3 is other than -NR7- or -O-, where the carbon-carbon double bond is in the Z or E configuration
  • R-19? R-20 > nd R-21 are independently selected from
  • alkanoyloxy where the alkyl group is one to twelve carbons
  • (xxiv) -OSO2Rl l, and (xxv) -NR7(X)NR 8 -R9', or R20 and R21 together are selected from
  • R6 is hydrogen or alkyl of one to twelve carbon atoms
  • R ⁇ 6 and R ⁇ 6' are independently hydrogen or alkyl of one to six carbons; or R ⁇ 6 and Rl6' together are alkenyl of two carbons;
  • a broken line represents the optional presence of a double bond, provided that when Ri6 and R ⁇ 6' together are alkenyl of two carbons, the double bond is not present;
  • R ⁇ 8 and R ⁇ 8' are independently hydrogen or alkyl of one to six carbons; or R ⁇ 8 and R ⁇ 8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.
  • R ⁇ 5 R2, R3, R4, R5, R6, and L2, are defined above.
  • R ⁇ 5 R2, R3, R4, R5, R6, and L2, are defined above.
  • R ⁇ 5 R5, R6, and L2, are defined above.
  • R ⁇ 6 and R ⁇ 7 are independently hydrogen or alkyl of one to six carbons.
  • R ⁇ 8 and R ⁇ 8' are independently hydrogen or alkyl of one to six carbons;
  • R ⁇ 8 and R ⁇ 8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
  • glucocorticoid receptor In another embodiment ofthe invention are disclosed methods of selectively partially antagonizing, antagonizing, agonizing or modulating the glucocorticoid receptor. In another embodiment ofthe invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I. In yet another embodiment ofthe invention are disclosed pharmaceutical compositions containing compounds of Formula I.
  • Compounds of this invention include, but are not limited to, 2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-5 -phenyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline-
  • alkanoyl refers to an alkyl group attached to the parent molecular group through a carbonyl group.
  • alkanoyloxy refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • alkenyl refers to a monovalent straight or branched chain group of two to twelve carbons derived from a hydrocarbon having at least one carbon-carbon double bond.
  • alkoxy refers to an alkyl group attached to the parent molecular group through an oxygen atom.
  • alkoxycarbonyl refers to an ester group, i.e. an alkoxy group attached to the parent molecular moiety through a carbonyl group.
  • alkyl refers to a monovalent straight or branched chain group of one to twelve carbons derived from a saturated hydrocarbon.
  • alkylene refers to a divalent straight or branched chain group of one to twelve carbons derived from an alkane.
  • alkynyl refers to a monovalent straight or branched chain hydrocarbon of two to twelve carbons with at least one carbon-carbon triple bond.
  • alkynylene refers to a divalent straight or branched chain group of two to twelve carbons derived from an alkyne.
  • amino refers to -NH2-
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings.
  • the aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.
  • carboxy refers to -CO2H.
  • cycloalkenyl refers to a monovalent group derived from a cyclic or bicyclic hydrocarbon of three to twelve carbons that has at least one carbon-carbon double bond.
  • cycloalkyl refers to a monovalent group three to twelve carbons derived from a saturated cyclic or bicyclic hydrocarbon.
  • halo refers to F, Cl, Br, or I.
  • heterocycle represents a represents a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
  • heterocycle also includes bicyclic, tricyclic and tetracyclic groups in which any ofthe above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring.
  • Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrid
  • Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
  • Heterocyclics also include compounds ofthe formula
  • X* is selected from -CH2-, -CH2O- and -O-
  • Y* is selected from -C(O)- and -(C(R")2)v -
  • R" is hydrogen or alkyl of one to four carbons
  • v is 1-3.
  • heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like.
  • heterocycloalkyl refers to a non-aromatic, partially unsaturated or fully saturated 4- to 8-membered ring having from one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quatemized.
  • N-protected amino refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)). Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • O-protected carboxy refers to a carboxylic acid protecting ester or amide group typically employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites ofthe compound are performed.
  • Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” (1981). Additionally, a carboxy protecting group can be used as a prodrag whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields as described in U.S. Pat. No. 3,840,556 and 3,719,667.
  • pharmaceutically acceptable prodrugs represents those prodrags of the compounds ofthe present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, ofthe compounds ofthe invention.
  • prodrag represents compounds which are rapidly transformed in vivo to the parent compound ofthe above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art . For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail inJ Pharmaceutical Sciences, 1977, 66:1 - 19 .
  • the salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Stereoisomers include enantiomers and diastereomers, and equal mixtures of enantiomers are designated ( — ).
  • Individual stereoisomers of compounds ofthe present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art.
  • Geometric isomers can also exist in the compounds ofthe present invention.
  • the present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a ring.
  • Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration where the term “Z” represents substituents on the same side ofthe carbon-carbon double bond and the term “E” represents substituents on opposite sides ofthe carbon-carbon double bond.
  • the arrangement of substituents around a ring are designated as cis or trans where the term “cis” represents substituents on the same side ofthe plane ofthe ring and the term “trans” represents substituents on opposite sides ofthe plane ofthe ring.
  • Mixtures of compounds where the substitutients are disposed on both the same and opposite sides of plane ofthe ring are designated cis/trans.
  • Glass fiber type C multiscreen MAFC NOB plates were from Millipore ( Burlington, MA). Hydroxyapatide Bio-Gel HTP gel was from Bio-Rad Laboratories (Hercules, CA). Tris(hydroxymethyl)aminomethane (Tris), ethylenediaminetetraacetic acid (EDTA), glycerol, dithiothreitol (DTT) and sodium moylybdate were obtained from Sigma Chemicals (St. Louis, MO). Microscint-20 scintillation fluid was from Packard Instrument (Meriden, CT).
  • GRX and PRA binding reactions were performed in Millipore Multiscreen plates.
  • [ 3 HJ-Dex (-35,000 dpm (-0.9 nM)), GRX cytosol (-35 ⁇ g protein), test compounds and binding buffer were mixed in a total volume of 200 ⁇ L and incubated at 4 °C overnight in a plate shaker. Specific binding was defined as the difference between binding of [ ⁇ HJDex in the absence and in the presence of l ⁇ M unlabelled Dex.
  • [ 3 H]Prog (-36,000 dpm (-0.8 nM)), PRA cytosol (-40 ⁇ g protein), test compounds and binding buffer were mixed in a total volume of 200 ⁇ L and incubated at 4 °C at overnight in a plate shaker. Specific binding was defined as the difference between binding of [ 3 H]Prog in the absence and in the presence of 3 ⁇ M unlabelled Prog.
  • hydroxyapatite (25 % weight/volume) slurry were added to each well and plates were incubated for 10 min at °C in a plate shaker. Plates were suctioned with a Millipore vacuum manifold and each well was rinsed with 300 ⁇ L of ice-cold binding buffer. A 250 ⁇ L aliquot of Packard Microscint- 20 was added to each well and the wells were shaken at room temperature for 20 minutes. The amount of radioactivity was determined with a Packard TopCount plate reader.
  • the concentration of test compounds that inhibited 50% of specific binding was determined from a Hill analysis ofthe competitive binding experiments.
  • L* is the concentration of radioligand
  • K is the dissociation constant ofthe radioligand determined from saturation analysis.
  • K was -1.5 nM
  • KL was -4.5 nM.
  • the inhibitory potencies of compounds of this invention and their selectivity for GR and PR receptors are shown in Table 1.
  • the present invention also provides pharmaceutical compositions which comprise compounds ofthe present invention formulated together with one or more non- toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, arid the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants. Conversely, reduced particle size may maintain biological activity.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect ofthe drug, it is desirable to slow the absorption ofthe drag from subcutaneous or intramuscular injection.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices ofthe drag in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers , such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound ofthe present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity ofthe particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical history ofthe patient being treated. However, it is within the skill ofthe art to start doses ofthe compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • resorcinol dimethyl ether was metallated with a strong base such as n- or sec-butyllithium, treated with a trialkoxyborate such as trimethyl- or triisopropylborate and hydrolyzed with acid such as 2M HC1 to provide boronic acid 1 A.
  • a strong base such as n- or sec-butyllithium
  • a trialkoxyborate such as trimethyl- or triisopropylborate
  • acid such as 2M HC1
  • Treatment of 1 A with methyl 5-nitro-2-bromobenzoate in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or dichlorobis(triphenylphosphine)palladium (II) provided biphenyl IB.
  • Demethylation of IB was accomplished with reagents such as BBr3, to provide hydroxylactone 1C, which was treated with alkylating agents such as methyl iodide to provide ID.
  • Conversion of ID to amine IE was accomplished using hydrogen gas and a palladium catalyst such as 10% palladium on carbon.
  • IE was converted to quinoline IF by a Skraup ring annulation reaction.
  • Introduction of functionalization at the C-5 position of IF to provide 1 was achieved through addition of organometallic reagents such as phenyllithium to the C-5 carbonyl to provide IG, followed by deoxygenation with Lewis acids such as BF3-OEt3 and reducing agents such as triethylsilane to provide 1.
  • IF was converted to methyl acetal 2B, via hemiacetal 2A, using a two-step procedure comprising conversion of IF to 2 A with reagents such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane followed by acid-catalyzed acetal formation with acids such as p-toluenesulfonic acid monohydrate and alcohols such as methanol to provide 2B.
  • 2B was treated with nucleophiles such as allyltrimethylsilane in the presence of a Lewis acid such as boron trifluoride diethyl etherate to form C-5 allyl analogs such as Example 2.
  • the Lewis acid/methyl acetal complex was also condensed with organomagnesium chlorides, bromides or iodides to provide compounds of this invention such as Example 11.
  • Halo alkoxy analogs were prepared from 3B by nucleophillic displacement using a polyhalogenated alkylating agent such as CF2HCI to provide 8A followed by functionalization at the C-5 position of 8A, as described in Schemes 1-3, to provide 8.
  • a polyhalogenated alkylating agent such as CF2HCI
  • IF was treated with lithiated, O-protected phenol reagents, such as 3-(methoxymethoxy)phenyllithium, to provide 12 A.
  • the protecting group was cleaved in acidic media, such as methanolic or aqueous HCl, to provide diol 12B which was converted to phenyl acetates 12C with reagents such as acetyl chloride and base such as pyridine, triethylamine or diisopropylethylamine.
  • the tertiary alcohol was then reduced as described in Scheme 1, and the acetate group of Example 12 was removed to provide Example 13.
  • Example 13 was alkylated or acylated as described in Scheme 4 to provide examples 14 and 15.
  • IF was treated with magnesium halides, preferably bromides, to provide an intermediate hemiketal which was treated with acid catalysts such as para-toluenesulfonic acid, methanesulfonic acid or aqueous hydrochloric acid to provide optionally substituted analogs such as 18 as mixtures of E and Z isomers.
  • acid catalysts such as para-toluenesulfonic acid, methanesulfonic acid or aqueous hydrochloric acid to provide optionally substituted analogs such as 18 as mixtures of E and Z isomers.
  • Scheme 8 shows the applicability ofthe chemistry described in Scheme 1 and Examples 1-131 to the synthesis of new cores with substituents other than alkoxy at the
  • Scheme 10 shows additional selective bromination chemistry.
  • Regiochemical bromination of Example IF as directed by the C-10 methoxy group and choice of brominating agent, provided Cores 9, 10, and 11. These brominated rings were further derivatized at the brominated position(s) by transition metal-catalyzed introduction of a variety of functional groups.
  • cores bearing phenolic hydroxyl functionality were either dehydroxylated (as shown for Core 2), acetylated, or alkylated by transformations well-known in the art. See Larock, “Comprehensive Organic Transformations. A Guide to Functional Group Preparations,” VCH Publishers, New York (1989), hereby, incorporated by reference.
  • Example 148 Example 149
  • Example 150
  • Scheme 12 shows the introduction ofthe substituted cyclohexenyl group by Lewis acid catalyzed addition ofthe tert-butyldimethylsilyl-protected enol ether to the C- 5 position of Example 2B. Once introduced, the diastereomers and rearrangement products were separated, and the alkoxycarbonyl group was optionally reduced to a hydroxyalkyl group.
  • Example 147 Examples 171 , 172 and 173
  • the vinylic bromide group of compounds such as Example 147 were further derivatized at the brominated position(s) to provide a number of R19 substituents by transition metal-catalyzed introduction of a variety of functional groups such as those described in Scheme 10.
  • Example IF was converted to a ring-opened aldehyde using a two-step sequence involving treatment with a reducing agent such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane followed by treatment with a silylating reagent such as tert-butyldimethylsilyl chloride in the presence of a base such as potassium tert-butoxide.
  • a reducing agent such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane
  • silylating reagent such as tert-butyldimethylsilyl chloride in the presence of a base such as potassium tert-butoxide.
  • organolithium reagents such as lithiopyridines
  • R pyridyl
  • analogs such as Examples 213-215 using a two-step sequence comprising removal ofthe silicon group with reagents such as tetrabutylammonium fluoride and subsequent cyclization using reagent combinations such as triethylphosphine and l,l'-(azodicarbonyl)dipiperidine.
  • Example X, : R H
  • Example 7 was converted to the triflate derivative with reagents such as trifluoromethanesulfonic anhydride, then derivatized at the C-10 position using the methods described in Scheme 3.
  • reagents such as trifluoromethanesulfonic anhydride
  • Reduction of Example 335 with reagents such as diisobutylaluminum hydride provided Example 336.
  • Example 336 with oxidizing reagents such as tetrapropylammonium perrathenate afforded Example 337.
  • Alkylation of Example 336 could be accomplished with reagents such as iodomethane in the presence of a base such as potassium bis(trimethylsilyl)amide to provide analogs such as Example 338.
  • Example 339 and subsequently to its methyl acetal using the methods described in
  • Example 3B was treated with reagents such as dimethylcarbamoyl chloride to give a thionocarbamate which underwent thermal rearrangement to provide the sulfur-carbon bond at C-10.
  • the allyl group at C-5 was introduced as described in Scheme 2.
  • Hydrolysis with a strong base such as potassium hydroxide and alkylation of sulfur with electrophiles such as iodomethane in the presence of a base such as cesium carbonate provided analogs bearing thioalkoxy functionality at C-10, such as Example 343.
  • Example 2B was treated with nucleophiles such as tributylvinyltin in the presence of Lewis acids such as boron trifluoride diethyl etherate to provide Example 320 which was then coupled with aryl halides such as iodobenzene in the presence of catalysts such as palladium (II) acetate to provide trans isomer Example 321.
  • the Lewis acid/methyl acetal complex was also condensed with tributylphenylacetylenyltin to provide Example 322 which was then partially hydrogenated in the presence of catalysts such as palladium on BaSO4 to provide cis isomer Example 323.
  • substituents Rl, R2, R3, R4, R-5, R-6, Rl6, R-16', R-17, Rl8, R-18', Y, R-2, and L2 can be determined by selection ofthe appropriate commercially available or known starting materials (e.g., substituted methoxybenzenes) or introduced synthetically by known chemical methods such as those disclosed in Larock, "Comprehensive Organic Transformations. A Guide to Functional Group Preparations," VCH Publishers, New York (1989), hereby incorporated by reference.
  • Example 1A A solution of 1,3-dimethoxybenzene (33.2 g, 240 mmol) in hexanes (20 mL) at -20 °C was treated sequentially with n-butyllithium (100 mL of a 2.4 M solution in hexanes, 240 mmol) and N,N,N',N'-tetramethylethylenediamine (1.81 mL, 12 mmol), stirred at 23 °C for 1.5 hours, cooled to -78 °C, treated with triisopropylborate (60.9 mL,
  • Example IB A mixture of Example 1 A, methyl 5-nitro-2-bromobenzoate (25.8 g, 99.2 mmol),
  • Example 1C A solution of Example IB (11.1 g, 35.1 mmol) in dichloromethane (60 mL) at -
  • Example IE A suspension of Example ID (11.2 g, 41.3 mmol) in dioxane (400 mL) at 23 °C was treated with 10% palladium on carbon (580 mg), heated at 65° C, treated with hydrogen, stirred under atmospheric pressure for 60 hours, filtered through powdered sea shells (Celite®) while hot, and concentrated during which a precipitate formed. The product was filtered and dried under vacuum to provide the desired compound. Concentration ofthe mother liquor to half of its original volume afforded a second crop of desired compound.
  • Example IF A solution of Example IE (4.0 g, 16.6 mmol) and iodine (1.7 g, 6.64 mmol) in acetone (380 mL) in a IL sealed ACE glass high pressure vessel at 105 °C was stirred for 48 hours, cooled to room temperature, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 12%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 322 (M+H)+.
  • Example IG A solution of Example IF (1.02 g, 3.18 mmol) in THF (20 mL) at -78 °C was treated with a solution of phenyllithium (10.9 mL, 19.6 mmol) in cyclohexanes/diethyl ether, warmed to -50 °C, stirred for 2 hours, treated with saturated NH4CI, warmed to 25 °C, and extracted with ethyl acetate The extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 20%> ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 400 (M+H)+.
  • Example IG 2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- f
  • Example 2A A solution of Example IF (6.65 g, 20.69 mmol) in dichloromethane (500 mL) at - 78 °C was treated dropwise with 1M diisobutylaluminum hydride in hexanes (47.6 mL,
  • Example 2B A solution of Example 2A (4.20 g, 12.99 mmol) in methanol (150 mL) at 0° C was treated with p-toluenesulfonic acid-H2 ⁇ (1.2 g, 20 wt %), stirred for 30 minutes, stirred at room temperature for 1 hour, cooled to 0 °C for 30 minutes, and filtered. The solid was rinsed with hexanes and dried under vacuum to provide the desired compound. The filtrate was poured into saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10-20% ethyl acetate/hexanes to provide additional desired compound.
  • Example 2 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- f]quinoline
  • a solution of Example 2B (2.50 g, 7.41 mmol) in dichloromethane (225 mL) was treated with allyltrimethylsilane (4.0 mL, 25.2 mmol), cooled to - 78 °C, treated dropwise with BF3-OEt2 (3.1 mL, 25.2 mmol), stirred for 15 minutes at -78 °C, warmed to 0 °C for 30 minutes, treated with saturated NaHCO3, and extracted with ethyl acetate.
  • Example 3A A solution of Example 1C was processed as in Example IE to provide the desired compound. MS (DCI/NH3) m/z 227 (M+H)+.
  • Example 3B A solution of Example 3 A was processed according to the procedure in Example IF to provide the desired compound. MS (DCI/NH3) m/z 308 (M+H)+.
  • Example 3C A solution of Example 3B (1.38 g, 4.49 mmol), triethylamine (1.92 mL, 13.77 mmol) and 4-dimethylaminopyridine (100 mg) in dichloromethane (50 mL) at -78°C, was treated dropwise with trifluoromethanesulfonic anhydride (1.39 g, 4.94 mmol), stirred 30 minutes at -78° C, warmed slowly to room temperature over 1.5 hours, poured into saturated NH4CI, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10%> ethyl acetate/hexanes to provide the desired compound.
  • Example 3C was processed according to the procedures in examples 2A, 2B and 2 to provide the desired compound. MS (DCI/NH3) m/z 466 (M+H)+.
  • Example 4 methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fjquinoline- 10-carboxylate
  • a solution of Example 3D (263 mg, 0.565 mmol), triethylamine (0.10 mL, 0.717 mmol), l,3-bis(diphenylphosphino)propane (26 mg, 0.063 mmol) and DMSO (1.5 mL) in methanol (8 mL) was treated with palladium acetate (12.7 mg, 0.056 mmol), saturated with carbon monoxide, stirred under carbon monoxide (1 atm) for 20 minutes, heated at 65 °C for 3 hours, cooled, diluted with ethyl acetate (100 mL), and filtered.
  • Example 5 10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[llbenzopyrano[3,4- fjquinoline
  • a solution of Example 3D (103 mg, 0.221 mmol) and (1,3- bis(diphenylphosphino)ferrocene)palladium (II) chloride-dichloromethane (22 mg, 0.027 mmol) in l-methyl-2-pyrrolidinone (2 mL) was treated with vinyl tributylstannane (0.110 mL, 119 mg, 0.376 mmol), heated at 65 °C for 24 hours, cooled to room temperature, treated with saturated KF, and extracted with ethyl acetate.
  • Example 6A A solution of Example 3D (25 mg, 0.054 mmol), tetra-n-butylammonium iodide (40 mg, 0.108 mmol), bis(triphenylphosphine)palladium chloride (7.0 mg, 0.010 mmol), copper(I) iodide (3.8 mg, 0.020 mmol) and triethylamine (0.15 mL, 0.717 mmol) in DMF (0.75 mL) was treated with trimethylsilylacetylene (174 mg, 1.76 mmol), heated at 55 °C for 3 hours, diluted with ethyl acetate (20 mL), and filtered.
  • Example 3D 25 mg, 0.054 mmol
  • tetra-n-butylammonium iodide 40 mg, 0.108 mmol
  • bis(triphenylphosphine)palladium chloride 7.0 mg, 0.010 mmol
  • Example 6 10-ethynyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[11benzopyrano[3,4- f
  • a solution of Example 6 A in THF (2.5 mL) was treated sequentially with glacial acetic acid (0.005 mL) and IM tetra-n-butylammonium fluoride in THF (0.050 mL,
  • Example 7A A solution of Example 3B (569 mg, 1.85 mmol) in DMF (8 mL) at 23 °C was treated sequentially with imidazole (379 mg, 5.55 mmol) and t-butyldimethylsilyl chloride (418 mg, 2.78 mmol), stirred for 3 hours, poured into water, and extracted with
  • Example 7A was processed as in examples IG and lto provide the desired compound.
  • Example 3B A solution of Example 3B (1.11 g, 3.6 mmol) in DMF (10 mL) at 0 °C was treated sequentially with sodium t-butoxide (0.38 g, 3.6 mmol) and bromodifluoromethane (10 mL), stirred at 0 °C for 6 hours, warmed to room temperature for 1 hour, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 5%> ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 436 (M+H)+.
  • Example 8A 10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [1 Jbenzopyrano [3 ,4-f]quinoline
  • Example 8A was processed as in examples 2B and 2 to provide the desired compound.
  • Example 9 10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl- lH-fl jbenzopyranor3,4- fjquinoline
  • Example 9A A solution of Example 3B (28 mg, .09 mmol) in DMF (1.0 mL) at 0 °C was treated with sodium hydride (2.4 mg of a 60% dispersion in mineral oil, 0.01 mmol), stirred for 1 hour, treated with ethyl bromide (20 mg, .182 mmol), stirred for 30 minutes at room temperature, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired compound.
  • Example 9 10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl- 1 H- ⁇ 1 Jbenzopyrano [3 ,4- f]quinoline
  • Example 9 A was processed as in examples IG and 1 to provide the desired compound.
  • Example 10 2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[11benzopyrano[3,4-f]quinoline-10-ol acetate (ester)
  • a solution of Example 7 (20 mg, 0.05 mmol) in pyridine (1 mL) at 0 °C was treated with acetic anhydride (0.1 mL, 1.05 mmol), stirred at room temperature 14 hours, and concentrated. The residue was purified by flash chromatography on silica gel with 20%) ethyl acetate/hexanes to provide the desired compound.
  • Example 12A A solution of 3-methoxymethoxyphenyl bromide (10.85 g, 50.00 mmol) in THF (300 mL) at -78 °C was treated with n-butyllithium (2.5 M in hexane, 20 mL), warmed to -30 °C, recooled to -78 °C, treated with Example IF, warmed to -50 °C, quenched with saturated NH4CI, warmed to ambient temperature, decanted, and concentrated. The residue was treated with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 20-25% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 460 (M+H)+.
  • Example 12B A solution of Example 12A (2.30 g, 5.00 mmol) in methanol (10 mL) was treated with HCl-saturated methanol (50 mL), stirred for 18 hours, poured into 1 :1 ethyl acetate/saturated NH4CI, and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m/z 416 (M+H)+.
  • Example 12C A solution of Example 12B (2.45 g, 5.89 mmol) and pyridine (2.33 g, 29.4 mmol) in THF (100 mL) was treated with acetyl chloride (0.51 g, 6.48 mmol), stirred for 4 hours, allowed to settle, decanted, and concentrated. The residue was treated with saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25-33% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 458 (M+H)+.
  • Example 12C was processed as in Example 1 to provide the desired compound.
  • Example 13 3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinolin- 5 - yl)phenol
  • a solution of Example 12 (0.81 g, 1.84 mmol) in THF (20 mL) and methanol (20 mL) was treated with K2CO3 ( 2.00 g, 14.5 mmol) in water (6 mL), stirred for 12 hours, quenched with saturated NH4CI, decanted, concentrated, treated with saturated NaHCO3, and extracted with ethyl acetate.
  • Example 14 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-r[3-(methylthio)methoxy]phenylJ-lH- ri Ibenzopyrano [3 ,4-fjquinoline
  • Example 16 5-[3-(2-furanyl)-5-methylphenyl1-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- r 1 Ibenzopyrano [3 ,4-fjquinoline
  • a solution of Example 11 (0.253 g, 0.531 mmol) in l-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85 °C for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate.
  • Example 11 1 H-[ 1 Jbenzopyrano [3 ,4-f]quinoline
  • Toluene 5 mL
  • bis(dibenzylideneacetone)palladium(0) 0.007 g, 0.012mmol
  • S)-(-)- bis(diphenylphospino)-l,l'-binaphthyl 0.022 g, 0.035 mmol
  • morpholine 15DL, 0.173 mmol
  • sodium tert-butoxide 0.028 g, 0.289 mmol
  • Example IF and n-butyllithium were processed as in examples IG and 1 to provide the desired compound.

Abstract

Compounds having formula I are useful for partially or fully antagonizing, repressing, agonizing, or modulating the glucocorticoid receptor and treating immune, autoimmune and inflammatory diseases in a mammal. Also disclosed are pharmaceutical compositions comprising compounds of formula I and methods of inhibiting immune or autoimmune diseases in a mammal.

Description

GLUCOCORTIOCOID-SELECTIVE ANTIINFLAMMATORY AGENTS
Technical Field
The present invention relates to glucocorticoid receptor-selective benzopyrano[3,4-f]quinolines that are useful for treating immune or autoimmune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation, inflammatory disease, immune, and autoimmune diseases in a mammal.
Background of The Invention
Intracellular receptors (IR's) are a class of structurally related proteins involved in the regulation of gene expression. The steroid hormone receptors are a subset of this superfamily whose natural ligands are typically comprised of endogenous steroids such as estradiol, progesterone, and cortisol. Man-made ligands to these receptors play an important role in human health and, of these receptors, the glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent antiinflammatory agents. Despite this benefit, steroidal GR ligands are not selective. Side effects associated with chronic dosing are believed to be the result of cross- reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains.
Selective GR modulators (e.g. repressors, agonists, partial agonists and antagonists) of the present disclosure can be used to influence the basic, life-sustaining systems ofthe body, including carbohydrate, protein and lipid metabolism, and the functions ofthe cardiovascular, kidney, central nervous, immune, skeletal muscle, and other organ and tissue systems, In this regard, prior art GR modulators have proven useful in the treatment of inflammation, tissue rejection, auto-immunity, various malignancies, such as leukemias and lymphomas, Gushing 's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous polyarteritis, inhibition of myeloid cell lines, immune proliferation/apoptosis, HPA axis suppression and regulation, hypercortisolemia, modulation of the Thl/Th2 cytokine balance, chronic kidney disease, stroke and spinal cord injury, hypercalcemia, hypergylcemia, acute adrenal insufficiency, chronic primary adrenal insufficiency, secondary adrenal insufficiency, congenital adrenal hyperplasia, cerebral edema, thrombocytopenia, and Little's syndrome.
GR modulators are especially useful in disease states involving systemic inflammation such as inflammatory bowel disease, systemic lupus erythematosus, polyartitis nodosa, Wegener's granulomatosis, giant cell arteritis, rheumatoid arthritis , osteoarthritis, hay fever, allergic rhinitis, urticaria, angioneurotic edema, chronic obstractive pulmonary disease, asthma, tendonitis , bursitis, Crohn's disease, ulcerative colitis, autoimmune chronic active hepatitis, organ transplantation, hepatitis, and cirrhosis. GR active compounds have also been used as immunostimulants and repressors, and as wound healing and tissue repair agents.
GR modulators have also found use in a variety of topical diseases such as inflammatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, herpes gestationis, eosinophilic fasciitis, relapsing polychondritis, inflammatory vasculitis, sarcoidosis, Sweet's disease, type 1 reactive leprosy, capillary hemangiomas, contact dermatitis, atopic dermatitis, lichen planus, exfoliative dermatitus, erythema nodosum, acne, hirsutism, toxic epidermal necrolysis, erythema multiform, cutaneous T-cell lymphoma.
Selective antagonists ofthe glucocorticoid receptor have been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIV), cell apoptosis, and cancer including, but not limited to, Kaposi's sarcoma, immune system activation and modulation, desensitization of inflammatory responses, IL-1 expression, anti-retro viral therapy, natural killer cell development, lymphocytic leukemia, and treatment of retinitis pigmentosa. Cogitive and behavioral processes are also susceptible to glucocorticoid therapy where antagonists would potentially be useful in the treatment of processes such as cognitive performance, memory and learning enhancement, depression, addiction, mood disorders, chronic fatigue syndrome, schizophrenia, stroke, sleep disorders, and anxiety.
Summary of The Invention
In one embodimentof the present invention are compounds represented by Formula I
Figure imgf000003_0001
I, or a pharmaceutically acceptable salt or prodrug thereof, where Rl is -LI-RA where Li is selected from (1) a covalent bond,
(2) -O-,
(3) -S(O)t- where t is 0, 1 , or 2,
(4) -C(X)-, (5) -NR7- where R7 is selected from
(a) hydrogen,
(b) aryl
(c) cycloalkyl of three to twelve carbons, (d) alkanoyl where the alkyl part is one to twelve carbons,
(e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons, (h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from
(i) aryl and
(ii) cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (6) -NR8C(X)NR9- where X is O or S and Rs and R9 are independently selected from
(a) hydrogen,
(b) aryl,
(c) cycloalkyl of three to twelve carbons, (d) alkyl of one to twelve carbons,
(e) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons,
(f) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(g) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (7) -X'C(X)- where X is previously defined and X' is O or S, (8) -C(X)X'-,
(9) -X'C(X)X"- where X and X' are previously defined and X" is O or S, provided that when X is O, at least one of X' or X" is O, (10) -NR8C(X)-,
(11) -C(X)NR8-,
(12) -NRsC(X)X*-,
(13) -X'C(X)NRs-, (14) -SO2NR8-,
(15) -NRgSO2-, and
(16) -NR8SO2NR9- where (6)-(16) are drawn with their right ends attached to RA and RA is selected from (1) -OH,
(2) -OG where G is a -OH protecting group,
(3) -SH,
(4) -CO2 2O where R20 is hydrogen or alkyl of one to twelve carbons,
(5) alkoxylcarbonyl, (6) -CN,
(7) halo,
(8) haloalkoxy of one to twelve carbons,
(9) perfluoroalkoxy of one to twelve carbons,
(10) -CHO, (11) -NR7R7' where R7 is defined previously and R71 is selected from
(a) hydrogen,
(b) aryl,
(c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons, (e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons,
(h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from
(i) aryl and
(ii) cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (12) -C(X)NR8R9,
(13) -OSO2R11 where Ri 1 is selected from
(a) aryl,
(b) cycloalkyl of three to twelve carbons, (c) alkyl of one to twelve carbons,
(d) alkyl of one to twelve carbons substituted with 1, 2, 3, or 4 halo substituents, and
(e) perfluoroalkyl of one to twelve carbons,
(14) alkyl of one to twelve carbons, (15) alkenyl of two to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Li when Li is other than a covalent bond,
(16) alkynyl of two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to Li when Li is other than a covalent bond, where (14), (15), and (16) can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) alkoxy of one to twelve carbons,
(b) -OH, provided that no two -OH groups are attached to the same carbon,
(c) -SH,
(d) thioalkoxy of one to twelve carbons, provided that no two -SH groups are attached to the same carbon,
(e) -CN, (f) halo,
(g) -CHO, (h) -NO2,
(i) haloalkoxy of one to twelve carbons,
(j) perfluoroalkoxy of one to twelve carbons, (k) -NR7R7,
(1) =NNR7R7-,
(m) -NR7NR7'R7" where R7 and R7» are defined previously and R7" is selected from (i) hydrogen, (ii) aryl,
(iii) cycloalkyl of three to twelve carbons,
(vi) alkanoyl where the alkyl part is one to twelve carbons,
(v) alkoxycarbonyl where the alkyl part is one to twelve carbons, (vi) alkoxycarbonyl where the alkyl part is one to twelve carbons substituted by 1 or 2 aryl groups, (vii) alkyl of one to twelve carbons, (viii) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (ix) alkenyl of three to twelve carbons, provided that a carbon-carbon double bond is not attached directly to nitrogen, and (x) alkynyl of three to twelve carbons, provided that a carbon-carbon triple bond is not attached directly to nitrogen, (n) -CO2 10 where Rio is selected from
(i) aryl, (ii) aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (ii) cycloalkyl of three to twelve carbons, (iii) alkyl of one to twelve carbons, and (iv) alkyl of one to twelve carbons substituted with aryl or cycloalkyl of three to twelve carbons,
(o) -C(X)NR8R9, (p) =N-ORιo, (q) =NRio, (r) -S(O)tRlθ, (s) -X'C(X)Rio,
(t) (=X), and (u) -OSO2R1 I,
(17) cycloalkyl of three to twelve carbons,
(18) cycloalkenyl of four to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to L] when L\ is other than a covalent bond, where (17) and (18) can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from (a) alkyl of one to twelve carbons, (b) aryl,
(c) alkoxy of one to twelve carbons,
(d) halo,
(e) alkoxycarbonyl where the alkyl group is one to twelve carbons, and (f) -OH, provided that no two -OH groups are attached to the same carbon,
(19) perfluoroalkyl of one to twelve carbons,
(20) aryl, and (21) heterocycle where (20) and (21) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) alkyl of one to twelve carbons,
(b) alkanoyloxy where the alkyl part is one to twelve carbons, (c) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(d) alkoxy of one to twelve carbons,
(e) halo,
( ) -OH, provided that no two -OH groups are attached to the same carbon, (g) thioalkoxy of one to twelve carbons,
(h) perfluoroalkyl of one to twelve carbons, (i) -NR7R7-,
G) -CO2RlO,
(k) -OSO2Rl l, and (1) (=X);
R2; R3> an R4 are independently hydrogen or Rl ; or
Rl and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or -(C(Rl2)(Rl3))v - where R12 and R13 are independently hydrogen or alkyl of one to twelve carbons and v is 1, 2, or 3, and Z* is selected from -CH2-, -CH2S(O)t-, -CH2O-,
-CH2NR7-, -NR7-, and -O-;
L2 is selected from
(1) a covalent bond,
(2) alkylene of one to twelve carbons,
(3) alkylene of one to twelve carbons substituted with 1 or 2 substituents independently selected from (a) spiroalkyl of three to eight carbon atoms,
(b) spiroalkenyl of five or eight carbon atoms,
(c) oxo,
(d) halo, and (e) -OH, provided that no two -OH groups are attached to the same carbon,
(4) alkynylene of two to twelve carbons,
(5) -NR7-, (6) -C(X)-,
(7) -O-, and
(8) -S(O)t-; and
R5 is selected from (1) halo,
(2) hydrogen,
(3) -C(=NR7)ORio,
(4) -CN, provided that when R5 is (1), (2), or (3), L2 is a covalent bond, (5) alkyl of one to twelve carbons,
(6) alkynyl two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to L3 when L3 is other than a covalent bond,
(7) cycloalkyl of three to twelve carbons, (8) heterocycle,
(9) aryl where (5)-(9) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) -OH, provided that no two -OH groups are attached to the same carbon,
(b) -SH, provided that no two -SH groups are attached to the same carbon,
(c) -CN,
(d) halo, (e) -CHO,
(f) -NO2,
(g) haloalkoxy of one to twelve carbons,
(h) perfluoroalkoxy of one to twelve carbons, (i) -NR8'R9 where R8' and R91 are selected from (i) hydrogen,
(ii) alkanoyl where the alkyl part is one to twelve carbons,
(iii) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(iv) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted with 1 or 2 phenyl substituents, (v) cycloalkyl of three to twelve carbons, (vi) alkyl of one to twelve carbons,
(vii) alkyl of one to twelve carbons substituted with 1, 2, or 3 substituents independently selected from alkoxy of one to twelve carbons, cycloalkyl of three to twelve carbons, aryl, and alkoxycarbonyl where the alkyl group is one to twelve carbons,
(viii) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not directly attached to nitrogen, (ix) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not directly attached to nitrogen, (x) -C(O)NRχRγ where Rx and Ry are independently selected from hydrogen and alkyl of one to twelve carbons, (xi) alkoxy of one to twelve carbons, (xii) aryl, and
(xiii) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, alkanoyloxy where the alkyl part is one to twelve carbons, alkoxycarbonyl where the alkyl part is one to twelve carbons, alkoxy of one to twelve carbons, halo,
-OH provided that no two -OH groups are attached to the same carbon, thioalkoxy of one to twelve carbons, perfluoroalkyl of one to twelve carbons,
-NR7R7',
-CO2R10, -OSO2Rl l, and
(=X), or Rδ' and R9' together with the nitrogen atom to which they are attached form a ring selected from (i) aziridine,
(ii) azetidine,
(iii) pyrrolidine,
(iv) piperidine, (v) pyrazine,
(vi) morpholine,
(vii) phthalimide,
(viii) thiomorpholine, and
(ix) thiomorpholine sulfone where (i)-(ix) can be optionally substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (j) =NNR8'R9', (k) -NR7NR8-R9', (1) -CO2R8, (m) -C(X)NR8'R9',
(n) =N-OR«, (o) =NR8, (p) -S(O)tRlθ, (q) -X'C(X)R8, (r) (=X),
(s) -O-(CH2)q-Z-Rιo where Rio is defined previously, q is 1, 2, or 3, and Z is O or -S(O)t-, (t) -OC(X)NR8'R9-, (u) -OSO2Rl l, (v) alkanoyloxy where the alkyl group is one to twelve carbons,
(w) -L 3 30 where Lβ is selected from
(i) a covalent bond,
(ϋ) -O-,
(iii) -S(O)t-, and (iv) -C(X)- and
R30 is selected from
(i) alkyl of one to twelve carbons, (ii) alkenyl of one to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Lβ when Lβ is other than a covalent bond,
(iii) alkynyl of one to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to Lβ when Lβ is other than a covalent bond, where (i), (ii), and (iii) can be optionally substituted with cycloalkyl of three to twelve carbons, -OH, provided that no two -OH groups are attached to the same carbon, halo, alkoxy of one to twelve carbons, thioalkoxy of one to twelve carbons, -NR8'R9', -O-(CH2)q-Z-Rio, alkoxycarbonyl where the alkyl group is one to twelve carbons, alkanoyloxy where the alkyl group is one to twelve carbons, -NR7SO2-(alkyl of one to twelve carbons),
-OSO2-(alkyl of one to twelve carbons), aryl, and heterocycle, (iv) aryl, (v) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo,
-NO2, and -OH, provided that no two -OH groups are attached to the same carbon, (vi) heterocycle, and
(vii) heterocycle substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo,
-NO2, and
-OH, provided that no two -OH groups are attached to the same carbon,
Figure imgf000012_0001
(y) -NHC(O)NHNH2, (z) alkenyl of two carbons,
(aa) -C(=NR7)ORio, and
Figure imgf000013_0001
provided that when R5 is (9), L3 is other than -NR7- or -O-, where the carbon-carbon double bond is in the Z or E configuration, and
R-19? R-20> nd R-21 are independently selected from
(a) hydrogen,
(b) halo,
(c) alkoxycarbonyl where the alkyl group is of one to twelve carbons,
(d) alkyl of one to twelve carbons, and
(e) alkyl of one to twelve carbons substituted with
(i) alkoxy of one to twelve carbons,
(ϋ) -OH, provided that no two -OH groups are attached to the same carbon,
(ϋi) -SH, provided that no two -SH groups are attached to the same carbon,
(iv) -CN,
(v) halo,
(vi) -CHO,
(vii) -NO2,
(viii) haloalkoxy of one to twelve carbons,
(ix) perfluoroalkoxy of one to twelve carbons,
(x) -NR8'R9'
(xi) =NNR8'R9',
(xii) -NR7NR8'R9',
(xiii) -CO2R10,
Figure imgf000013_0002
(xvi) =NRlo,
(xvii) -S(O)tRl0,
(xviii) -X'C(X)Riθ,
(xix) (=X),
(xx) -O-(CH2)q-Z-Rlθ, (xxi) -OC(X)NR8'R9', (xxii) -LβR30,
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons, (xxiv) -OSO2Rl l, and (xxv) -NR7(X)NR8-R9', or R20 and R21 together are selected from
(a) cycloalkyl of three to twelve carbon atoms,
(b) cycloalkenyl of four to twelve carbon atoms, and P-22
<
(c) 23 (allene) where R22 and R23 are independently hydrogen or alkyl of one to twelve carbons, and
(11) cycloalkenyl of four to twelve carbons where the cycloalkenyl group or the ring formed by R20 and R21 together can be optionally substituted with one or two substituents independently selected
(a) alkoxy of one to twelve carbons,
(b) -OH, provided that no two -OH groups are attached to the same carbon,
(c) -SH, provided that no two -SH groups are attached to the same carbon, (d) -CN,
(e) halo,
(f) -CHO,
(g) -NO2,
(h) haloalkoxy of one to twelve carbons, (i) perfluoroalkoxy of one to twelve carbons,
0) -NR8'R9<
(k) =NNR8'R9',
(1) -NR7NR8'R9',
(m) -CO2R10, (n) -C(X)NR8-R9',
Figure imgf000014_0001
(P) =NR10,
(q) -S(O)tRlθ,
(r) -X'C(X)Rio, (s) (=X),
(t) -O-(CH )q-Z-Rio, (u) -OC(X)NR8'R9',
(v) -LβR30,
(w) alkanoyloxy where the alkyl group is one to twelve carbons,
(x) -OSO2Rl l, and
(y) -NR7(X)NR8'R9';
R6 is hydrogen or alkyl of one to twelve carbon atoms; or
-L2-R5 and R6 together are selected from
Figure imgf000015_0001
where Dis 1, 2, 3, or 4 and A is selected from
(a) -CH2-,
(b) -O-,
(c) -S(O)t, and (d) -NR7-, and
R, 26
R
(3) 26 where the carbon-carbon double bond can be in the E or Z configuration and R26 and R26' are independently selected from
(a) hydrogen,
(b) alkenyl of three to twelve carbons, (c) aryl, (d) heterocycle, (e) alkyl of one to twelve carbons, (f) cycloalkyl of three to twelve carbons, (g) cycloalkenyl of four to twelve carbons, and (h) cycloalkenyl of four to twelve carbons where (a)-(f) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(i) alkoxy of one to twelve carbons,
(ϋ) -OH, provided that no two -OH groups are attached to the same carbon, (iii) -SH, provided that no two -SH groups are attached to the same carbon, (iv) -CN,
(v) halo,
(vi) -CHO,
( ii) -NO2,
(viii) haloalkoxy of one to twelve carbons,
(ix) perfluoroalkoxy of one to twelve carbons,
(X) -NR8'R9-
(xi) =NNR8'R9',
(xϋ) -NR7NR8'R9*,
(xiii) -CO2RlO,
(xiv) -C(X)NR8'R9',
Figure imgf000016_0001
(xvi) =NRιo,
Figure imgf000016_0002
(xviii) -X'C(X)Rio,
(xix) (=X),
(xx) -O-(CH2)q-Z-RiO,
(xxi) -OC(X)NR8'R9',
(xxii) -LBR30,
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiii) -OSO2Rl l, and
(xxiv) -NR7(X)NR8-R9';
Rχ6 and Rχ6' are independently hydrogen or alkyl of one to six carbons; or Rχ6 and Rl6' together are alkenyl of two carbons;
a broken line represents the optional presence of a double bond, provided that when Ri6 and Rχ6' together are alkenyl of two carbons, the double bond is not present;
Y is selected from carbon, nitrogen, and N+(=O_);
Rl7 is absent or hydrogen or alkyl of one to six carbons, provided that when the double bond is present, and Y is nitrogen or N+(=O_), Rχ7 is absent; and
Rχ8 and Rχ8' are independently hydrogen or alkyl of one to six carbons; or Rχ8 and Rχ8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.
In another embodiment ofthe invention are disclosed compounds of Formula II
Figure imgf000017_0001
H, or a pharmaceutically acceptable salt or prodrag thereof, where Rχ5 R2, R3, R4, R5, R6, and L2, are defined above.
In another embodiment ofthe invention are disclosed compounds of Formula III
Figure imgf000017_0002
or a pharmaceutically acceptable salt or prodrag thereof, where Rχ5 R2, R3, R4, R5, R6, and L2, are defined above.
In another embodiment ofthe invention are discolsed compounds of Formula IV
Figure imgf000017_0003
IN, or a pharmaceutically acceptable salt or prodrag thereof, where
Y is nitrogen or Ν+(=O"), and
Rχ5 R5, R6, and L2, are defined above.
In another embodiment ofthe invention are disclosed compounds of Formula V
Figure imgf000018_0001
N, or a pharmaceutically acceptable salt or prodrag thereof, where Rχ; R5, and L2, are defined above;
Rχ6 and Rχ7 are independently hydrogen or alkyl of one to six carbons; and
Rχ8 and Rχ8' are independently hydrogen or alkyl of one to six carbons; or
Rχ8 and Rχ8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
In another embodiment ofthe invention are disclosed methods of selectively partially antagonizing, antagonizing, agonizing or modulating the glucocorticoid receptor. In another embodiment ofthe invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I. In yet another embodiment ofthe invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of this invention include, but are not limited to, 2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-5 -phenyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline-
1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fj quinoline,
2,5-dihydro-2,2,4,Ν-tetramethyl-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fJquinolin- 10- amine, methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fJquinoline-
10-carboxylate,
10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 ]benzopyrano [3 ,4f] quinoline, 10-ethynyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinolin-10-ol, 10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[1 ]benzopyrano[3,4-f]quinoline,
10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline-10-ol acetate (ester),
5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)- phenol,acetate (ester), 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)- phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(methylthio)methoxy]phenyl]-lH-
[l]benzopyrano[3,4-f]quinoline,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)- phenyl] dimethylcarbamate,
5-[3-(2-furanyl)-5-methylphenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-5 - [3 -methyl-5 -(1 -morpholiny l)phenyl] - 1 H-
[1 jbenzopyrano [3 ,4-f]quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)-lH-[l]benzopyrano[3,4- f] quinoline,
5-(3 ,5-dichIorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 ]benzopyrano [3 ,4-f]quinoline,
5-butyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f]quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl]-lH-
[ 1 ]benzopyrano [3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
5-(3-chlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(3-methylphenyl)-lH-[l]benzopyrano[3,4- f] quinoline,
(± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- f] quinoline, (± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- f] quinoline,
5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, 5-(4-chlorophenyl)-2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 ]benzopyrano [3 ,4- fj quinoline,
5-(3 ,4-dimethylphenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 ]benzopyrano [3 ,4-f] quinoline, 5-(4-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 ]benzopyrano [3 ,4- f] quinoline,
5-[3,5-bis(trifluoromethyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[1 ]benzopyrano [3 ,4-f]quinoline,
(-)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
(+)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f]quinoline,
5-(3 ,5-difluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l]benzopyrano[3 ,4- f] quinoline, 2,5-dihydro-10-methoxy-2,2,4,N-tetramethyl-N-phenyl-lH-[l]benzopyrano[3,4- f]quinolin-5-amine,
(-)2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
(+)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
4-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l ]benzopyrano[3 ,4-f]quinolin-5-yl)-
N,N-dimethylbenzenamine,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(l-morpholinyl)phenyl]-lH-
[1 ]benzopyrano[3,4-f]quinoline, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-3,3- dimethyl-2-butanone,
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline-5 - carbonitrile, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-2- propanone, methyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- acetate, 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-l- phenylethanone,
5-[2-(chloromethyl)-2-propenyl]-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 ]benzopyrano [3 ,4-f] quinoline, 2 ,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-(-methylene- 1 H- [ 1 jbenzopyrano [3 ,4- f]quinoline-5-propanol, acetate (ester),
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-5 -(4-methylphenyl)- 1 H- [ 1 ]benzopyrano[3 ,4- fjquinoline,
5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
5-(3-bromophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethyl)-lH-[l]benzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-propyl-lH-[l]benzopyrano[3,4-f]quinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
5-(3 -fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4- f] quinoline, 2,5-dihydro-10-methoxy-2,2,4,5-tetramethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(l-methylethyl)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H- [ 1 ]benzopyrano [3 ,4- f] quinoline, 5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l]benzopyrano[3 ,4-f]quinoline-5- carboximidic acid ethyl ester,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-(-methylene 1 H- [1 jbenzopyrano [3,4- f]quinoline-5-propanol, 2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- acetamide,
2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- ethanamine,
N-cyclopropyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinoline-5-acetamide,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propynyl)-lH-[l]benzopyrano[3,4- f] quinoline, 5-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-
2(5H)-furanone,
5-(3-butenyl)-2,5-dihdyro- 10-methoxy-2,2,4-trimethyl- 1 H-[l ]benzopyrano[3,4- f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-5-propanol,
10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-2,2,4, 10-tetrametnyl-5-phenyl- 1 H- [1 ]benzopyrano [3 ,4-f]quinoline,
5-(3,5-dichlorophenyl)-10-ethyl-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline, 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl-lH-[l]benzopyrano[3,4- f] quinolin- 10-amine,
5-(3 ,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)- 1 H-
[l]benzopyrano[3,4-f]quinolin-10-amine,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propynyloxy)-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propenyloxy)-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fJquinoline-10- methanol, 2,5 -dihy dro-2,2,4-trimethy 1-5 -(2propenyl)- 1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline- 10- carboxylic acid,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
5 -(3 , 5 -dichlorophenyl)-2 , 5 -dihy dro-2,2,4-trimethy 1- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinolin- lO-ol,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
10-yl]methylcarbonate,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinolin-10-ol,
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
[3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano[3 ,4-f]quinolin-5-yl)- phenyl] methylcarbonate,
2,5-dihydro- 10-methoxy-5-(3 -methoxyphenyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenyl]-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenyl]-lH-
[ 1 jbeήzopyrano [3 ,4-f] quinoline, 5-[3-(cyclopropylmethoxy)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[2-(l-piperidinyl)ethoxy]pheny]-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 5 -(3 -hexyloxyphenyl)-2 , 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3,4- f] quinoline,
5-[3-(2,4-dinitrophenoxy)phenyl]-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propynyloxy)phenyl]-lH- [ljbenzopyrano [3 ,4-f] quinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenol, 4-methylbenzenesulfonate (ester),
4-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l ]benzopyrano[3 ,4-f]quinolin-5- yl)phenolacetate (ester), 4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)- phenol,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxy]phenyl]- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
[4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl] dimethylcarbamate,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenyl]- 1 H-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenyl]-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, [(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl] 1 -morpholinecarboxylate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[(methylsulfinyl)methoxy]phenyl]-lH-
[ 1 jbenzopyrano [3 ,4-f]quinoline,
O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl] ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenyl]-lH-
[ 1 ]benzopyrano [3 ,4-f]quinoline,
O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl] methylcarbonothioate, [3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl]-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl] trifluoromethanesulfonate,
5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4- trimethy 1- 1 H- [ 1 jbenzopy rano [3 ,4-f] quinoline, ethyl 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yijbenzoate,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)benzoic acid, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(2-propenyl)phenyl]-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-
5 -methy lpheny 1] ethanone,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-5- trimethylbenzenemefhanol,
5- [3 -(2-furanyl)phenyl] -2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(lH-pyrrolidin-l-yl)phenyl]-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l ]benzopyrano[3 ,4-f]quinolin-5- methyl)-5,N-dimethylbenzenamine,
3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinolin-5-yl)-5- methyl-N-(2-propenyl)benzamide,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-N- (2-methoxyethyl)-5-methylbenzenamine,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-N-
(2-propenyl)benzenamine,
N'- [3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinolin-5-yl)-
5 -methylphenyl] -N,N-dimethy lurea, N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyl]benzenemethanamine,
5-[(3 ,5-dichlorphenyl)methylene]-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[1 ]benzopyrano [3 ,4-fjquinoline,
5-[(4-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(trifluoromethyl)-phenyl]methylene]-lH-
[ 1 ] -benzopyrano [3 ,4-f] quinoline,
5-[(2,6-difluorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, 5-[(2-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f]quinoline,
5-[(2,6-dichlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f]quinoline, 5-[(2-fluorophenyl)methylene]-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[(4,5-dihydro-4,4-dimethyl-2- oxazoly l)methylene] - 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-9,10-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- f] quinoline,
5-(2-cyclohexen-l-yl)-2,5-dihydro-9,10-dimethoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, 2,5-dihydro- 10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl- 1 H-
[1 ]benzopyrano[3 ,4-f] quinoline, re/ (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, anti(5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro- 10-methoxy-5-(3 -cyclohexenyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- f] quinoline, 2,5-dihydro- 10-methoxy-5-(3 -butenyl)-2,2,4-trimethyl- 1 H- [1 ]benzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-5 -( 1 -ethenyl- 1 -cyclohexyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(l-methylene-2-cyclohexyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(l -oxo-2-cyclohexyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(3-cyclooctenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-10-methoxy-5-(3-cycloheptenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline, 2,5-dihydro-10-methoxy-5-(l-cyclohexenylmethyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3,3-dimethyl-6-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, re/(5R,3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, re/(5R,3 ' S) 2,5-dihydro- 10-methoxy-5-(l -hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(3 -hydroxymethyl-3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(3 -indolyl)-2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano [3 ,4- fjquinoline, rel (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, re/ (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
(-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
(+) (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[l ]benzopyrano[3,4-f]quinoline, (-)-(5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
(+)-(5R, 3 ' S) 2,5 -dihy dro- 10-methoxy-5-( 1 -methyl-3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N,N-dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-mo holino)methyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methyl-N-methylsulfonylamino)methyl- 3-cyclohexenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-(N,N dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-( 1 ,3 -butadien-2-yl)-2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(l,2-dihydroxy-3-propyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(l-(N-phthalimido)-3-propyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(l-amino-3-propyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
(E) 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-l-ethenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(Z)-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline, (E) 2,5-dihydro-10-methoxy-5-(3-hydroxy-l-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)- 1 -propenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, (E) 2,5-dihydro-10-methoxy-5-(3-methoxymethoxy-l-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl) acetyl hydroxamate,
2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl) acetaldehyde,
2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2 ,5 -dihy dro- 10-methoxy- 5 -(2-cy cloheptylidenylethyl)-2,2 ,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3 ,4-fjquinoline, trans 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[l]benzopyr ano[3,4- f] quinoline, trans 2,5-dihydro-10-methoxy-5-(2-penten-l-yI)-2,2,4-trimethyI-lH- [1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l,l-difluoro-l-propen-3-yl)-2,2,4-trimethyl-lH-
[ljbenzopyrano[3,4-fjquinoIine,
(E) methyl 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4- f]quinolin-5-yl) 2-butenoate, (E) 2,5-dihydro- 10-methoxy-5-(4-hydroxy-2-buten- 1 -yl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro-l 0-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten-l -yl)-
2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-fJquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- 1 -yl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(E) 2,5-dihydro-l 0-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[l ]benzopyrano[3,4- f] quinoline,
2,5-dihydro-10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline, 2,5-dihydro- 10-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-morpholinocarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[1 ]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-l 0-methoxy-5-(2-(N-methyaminocarbonyloxyoxy)ethyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(aminomethyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-10-methoxy-5-(ethoxycarbonylamino)methyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(carboethoxy)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fj quinoline,
2,5-dihydro- 10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(l -methylpropa- 1 ,2-dienyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fj quinoline,
2,5-dihydro-10-methoxy-5-(3-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
(10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-fj quinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-[l]benzopyrano[3,4- fjquinoline, 10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
10-chloro-9-hydroxy-5-(3 ,5-dimethylphenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[1 jbenzopyrano [3 ,4-fjquinoline, rel-(5S, 3 *i?)-9-hydroxy- 10-methoxy-5- [1 -hydroxymethyl-3 -cyclohexenyl] -2,2,4- trimethyl-2,5-dihydro- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(-) 2,5 (S)-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3 S-cyclopenteny 1 )- 1 H-
[ 1 jbenzopyrano [3 ,4-fj quinoline, (-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3R-cyclopentenyl)-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3-cyclopentenyl)-lH- [l]benzopyrano[3 ,4-fjquinoline,
(+)-(5R, 3 ' R)2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3 -cyclopenteny 1 )- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 9-10-methylenedioxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-[l]benzopyrano[3,4- fjquinoline,
5-(3 -propenyl)-9-chloro- 10-ethenyl-2,2,4-trimethyl-2,5-dihydro- 1 H- [1 jbenzopyrano [3 ,4- fjquinoline,
9-chloro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3,4- fj quinoline,
5-(3-propenyl)-9-chloro-10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
9-chloro- 10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1 H-
[l]benzopyrano[3,4-f]quinoline, 8-fluoro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
(10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
10-methoxy-9-hydroxy-5 -(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-methylcyclohexen-3-yl)-
1 H-[ 1 Jbenzopyrano[3 ,4-fjquinoline,
(-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H-[l Jbenzopyrano[3,4-fjquinoline, (+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(+) (5R,3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H-[l Jbenzopyrano [3 ,4-fjquinoline, 5 (-) (5S,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenylJ-10-methoxy-2,2,4- trimethyl-2, 5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- 10 methylcy clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, re/-(5S,3 'R)-9-hydroxy-5-[l -methoxymethyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethyl-2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-5-propyl-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4- fjquinoline, 15 (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cycloheptenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cycloheptenyl)- lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy -2,2,4-trimethyl-5-phenyl-lH-[ljbenzopyrano[3,4- 20 fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3 ,5-difluorophenyl)- 1 H-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 25 5-butyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- lH-[ 1 jbenzopyrano [3 ,4- fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)- 30 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3 ,4-difluorophenyl)- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-fluorophenyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 35. 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethylphenyl)-lH-
[1 Jbenzopyrano[3,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-bistrifluoromethylphenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4- chlorophenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4-chlorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-butenyl)- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-5-(phenylmethyl)-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fj quinoline,
(-) (5S,3 'R) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-[l -ethyl-3- cy clohexenylj - 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
(-) (S) 5-cyclopentyl-2,5 -dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline, (+) (R) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyI-5-(5-methoxy-2-thienyl)- 1 H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6-pentafluorophenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- hy droxymethylcy clopenten-3 -yl)-lH-[l Jbenzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methylcarboxy latecy clopenten-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[1 ]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimefhyl-5-(2-thienyl)- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline, (±) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) - 1 H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3-propenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3 ' S) 2,5 -dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5- [ 1 -ethyl-3 - cy clohexeny 1 J - 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-cyclohexyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5,5-trihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-hydroxymethyl-3-propenyl)-
1 H- [ 1 jbenzopyrano [3,4-f] quinoline, methyl 2-[2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]-5-quinolinyl] acetate,
(Z) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-butenyl)-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, (+) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-
1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
(+) (5R,3 'R) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3-cyclohexeny 1)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 ]benzopyrano [3 ,4-fjquinoline,
(+) (5R,3 'R) 2,5(R)-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- cy clopenteny 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l -methoxycarbonyl)cyclohexen-3-yl]- 10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H-[l ]benzopyrano[3,4-fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methyl-3-propenyl)-lH-.
[1 jbenzopyrano [3 ,4-fjquinoline,
9,10-Dimethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3 ,4- fj quinoline,
9,10-Dimethoxy-5-[3-cyclohexenyl]-methoxy-2,2,4-trimethyl-2,5-dihydro-lH- [l]benzopyrano[3,4-f]quinoline,
10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-fjquinoline>
10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-acetoxy-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-
5-(2-propenyl)-lH-[l]benzopyrano[3 ,4-fjquinoline,
7-bromo -5-[3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
7-bromo-5-[l -methyl-3 -cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [1 jbenzopyrano [3 ,4-fjquinoline,
7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
7,9-Dibromo-5-[cyclohexen-3-ylj- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 ]benzopyrano [3 ,4-fjquinoline, 7,9-Dibromo-5-[l-methyl-3-cyclohexenyl]-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
10-methoxy-7-acetyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-methyl-10-methoxy-2,2,4-trimethyl-5-(l-methylcyclohexen-3-yl)-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
10-chloro-5-(3-propenyl)-2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4- fjquinoline,
(+/-) 2,5-dihydro- 10-chloro-2,2,4-trimethyl-5-phenyl- 1 H-[ 1 Jbenzopyrano [3 ,4- fj quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-
(carbomethoxymethyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methylcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4-trimethyl-lH- [ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylaminocarbonyloxy)ethyl)phenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro- 10-methoxy-5 -cyclopropyl-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-ethenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, trans 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f] quinoline, cis 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline, trans 2,5-dihydro- 10-methoxy-5-(l -cyclohexenyl)-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, 2,5-dihydro- 10-(2-furanyl)-5-(3 -propenyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fj quinoline,
2,5-dihydro- 10-carboxy-5-(3 -propenyl)-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-formyl-5 -(3-propenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-aminomethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxymethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fj quinoline, 2,5-dihydro-10-ethenyl-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinoline, 2,5-dihydro-10-ethynyl-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline, methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-10- carboxylate,
2,5-dihydro- 10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-formyl-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fj quinoline,
2,5 -dihy dro- 10-ethenyl-5 -oxo-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-ethenyl-5-[l-methyl-3-cyclohexenyl]-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline,
2,5-dihydro-5-(3 -propenyl)- 10-methylthio-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline,
(+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline, 10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fj quinoline,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3 ,4,5 -tetrahydro- 1 H- chromeno [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) -lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-5-(3 -methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 ] benzopyrano [3,4-f] quinoline,
10-methoxy-5-(4,5-dimethyl-l,3-oxazol-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline,
10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-fj quinoline, 10-methoxy-5-(l -butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-3-oxide-5-phenyl-lH-[ljbenzopyrano[3,4- fjquinazoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fjquinazoline,
2,5-dihydro-10-methoxy-2,2-[spiro(tetrahydro-4-pyranyl)]-4-methyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-2,2- [spiro(hexyl)]-5-allyl- 1 H- [ 1 ]benzopyran [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2-diethyl-4-methyl-5-allyl-lH-[ljbenzopyrano[3,4- fjquinoline,
2,5-dihydro-l O-methoxy-2,2,3 ,4-tetramethyl-5 -allyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2 , 5 -dihy dro- 10-methoxy-2,2-dimethyl-4-ethy 1-5 -allyl- 1 H- [ 1 jbenzopyrano [3 ,4- fj quinoline,
2,5-dihydro-l O-methoxy-2,2,3 -trimethyl-5-allyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline, Z-5-(benzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro-
[1 jbenzopyrano [3 ,4-fjquinoline,
Z-5-(2,5-difluorobenzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
Z-5-(3-fluorobenzylidenyl)-10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH- [lJbenzopyrano[3,4-f]quinoline,
Z- 10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
Z-9-hydroxy- 10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline, 9-hydroxy- 10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fj quinoline,
(Z) 9-hydroxy- 10-methoxy-5-((4-fluorophenyl)methylene)-2,2,4-trimethyl- 1 H-2,5- dihydro- [ljbenzopyrano[3,4-f]quinoline,
(Z)-9-hydroxy-10-methoxy-5-([2,3-difluorophenylJmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 Jbenzopyrano [3 ,4-f] quinoline, Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, re/-(5 S,3 'R)-9-hydroxy-5-[l -methoxymethyl-3-cyclohexenylj- 10-chloro-2,2,4-trimethyl-
2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 9-hydroxy-10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4- fj quinoline,
(+/-) 2,5-dihydro-9-cyanomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-5- (2-propenyl)- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N-piperidino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-(4-N-morpholino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propeny 1)- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-
5 -(3 ,4, 5 -trifluorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-difluorophenylmethyl)-lH-
[ 1 ]benzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-thienyl)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclopentyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) - 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxymethyl- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(l -pentenyl)- 1 H- '
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-allyl-lH- [1 ]benzopyrano [3 ,4-fjquinoline,
2,5 -dihy dro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-allenyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, (-) (5S, 3'S) 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[ 1 jbenzopyrano [3,4-fj quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, (-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH- ■
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) -lH-
[1 ]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl) -1H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
10-difluoromethoxy-5-[[3-(methylthio)methoxy]phenyl]-2,2,4-trimethyl-lH-2,5- dihydro- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-7-bromo-9-hydroxy-10-chloro-2,2,4-trimethyl-5-allyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3-
(methylthio)methoxyphenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-(methylthiomethoxy)phenyl)-
1 H- [ 1 ]benzopyrano [3 ,4-fjquinoline,
9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimefhyl-5-([2-N,N- dimethylcarbamoyloxy]phenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyjphenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5 -ethyl- 1 H-[ 1 Jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-isopropyl-lH-[ljbenzopyrano[3,4- fj quinoline,
9-hydroxy- 10-methoxy-5 -(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5 -dihydro-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-butyl- 1 H- [ 1 ]benzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(l -thiazol-2-yl)- 1 H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-hydroxymethyl- 10-chloro-2,2,4-trimethyl-5-allyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-propyl- 1 H- [1 jbenzopyrano [3 ,4- fjquinoline, 9-hydroxy-10-methoxy-5-([3-fluorophenyl]methylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline,
9-hydroxy-10-chloro-5-([2-pyridyl]methylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3,4-f] quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-hydroxymethyl)cyclohexen-3-ylj- 10-methoxy-2,2,4- trimethyl-2, 5 -dihy dro- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-methoxycarbonyl)cyclohexen-3-ylJ- 10-methoxy-2,2,4- trimethy 1-2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-dichlprophenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l-methylcyclohexen-3- yl)-lH-[lJbenzopyrano[3 ,4-fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l-methylcyclohexen-3- y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l-methylcyclohexen-3- y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
(+) (5R,3 'R) 2,5-dihydro-9-hydroxy-l 0-chloro-2,2,4-trimethyl-5-(l -methylcyclohexen-
3 -y 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-chloro-2,2,4- trimethyl-5 -ally 1- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
(-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-cyclopentyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-
5 -( 1 -methy lethyl)- 1 H- [ 1 ] benzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-5-
(phenylmethyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-
5-(2-thienyl)-lH-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy- 10-methoxy-5-(3 -propenyl)-2,2,4- trimethyl- 1 H-2,5-dihydro- [ 1 ]benzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-(3 -acetamido-propanoyloxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline, (+/-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-benzyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[1 jbenzopyrano [3 ,4-fjquinoline, 9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 Jbenzopyrano [3,4-f] quinoline,
(+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)-10-methoxy-2,2,4-trimethyl-5-allyl-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, (+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 ]benzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3 ,4,5-trifluorophenyl)- 1 H- [1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-
5-(2-propenyl)- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline, - 2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-(4-N-morpholino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-2,2,4- trimethyl-5 (S)-(3 (S)- 1 -cy clopenten-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH-
[1 Jbenzopyrano [3 ,4-f] quinoline, and
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- 1 H- [l]benzopyrano[3,4-f]quinoline.
Detailed Description of The Invention
Definition of Terms
The term "alkanoyl" refers to an alkyl group attached to the parent molecular group through a carbonyl group. The term "alkanoyloxy" refers to an alkanoyl group attached to the parent molecular group through an oxygen atom. The term "alkenyl" refers to a monovalent straight or branched chain group of two to twelve carbons derived from a hydrocarbon having at least one carbon-carbon double bond.
The term "alkoxy" refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term "alkoxycarbonyl" refers to an ester group, i.e. an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term "alkyl" refers to a monovalent straight or branched chain group of one to twelve carbons derived from a saturated hydrocarbon. The term "alkylene" refers to a divalent straight or branched chain group of one to twelve carbons derived from an alkane.
The term "alkynyl" refers to a monovalent straight or branched chain hydrocarbon of two to twelve carbons with at least one carbon-carbon triple bond.
The term "alkynylene" refers to a divalent straight or branched chain group of two to twelve carbons derived from an alkyne.
The term "amino refers to -NH2-
The term "aryl" refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The term "carboxy" refers to -CO2H.
The term "cycloalkenyl" refers to a monovalent group derived from a cyclic or bicyclic hydrocarbon of three to twelve carbons that has at least one carbon-carbon double bond.
The term "cycloalkyl" refers to a monovalent group three to twelve carbons derived from a saturated cyclic or bicyclic hydrocarbon.
The term "halo" refers to F, Cl, Br, or I.
The term "heterocycle" represents a represents a 4-, 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds.
The term "heterocycle" also includes bicyclic, tricyclic and tetracyclic groups in which any ofthe above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring. Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like.
Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
Figure imgf000043_0001
, and the like. Heterocyclics also include compounds ofthe formula
Figure imgf000043_0002
where X* is selected from -CH2-, -CH2O- and -O-, and Y* is selected from -C(O)- and -(C(R")2)v -, where R" is hydrogen or alkyl of one to four carbons, and v is 1-3. These heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like. The term "heterocycloalkyl" as used herein, refers to a non-aromatic, partially unsaturated or fully saturated 4- to 8-membered ring having from one or two heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatom can optionally be quatemized.
The term "N-protected amino" refers to groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)). Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). The term "O-protected carboxy" refers to a carboxylic acid protecting ester or amide group typically employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites ofthe compound are performed. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis" (1981). Additionally, a carboxy protecting group can be used as a prodrag whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields as described in U.S. Pat. No. 3,840,556 and 3,719,667. The term "oxo" refers to (=O).
The term "pharmaceutically acceptable prodrugs" represents those prodrags of the compounds ofthe present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, ofthe compounds ofthe invention.
The term "prodrag" represents compounds which are rapidly transformed in vivo to the parent compound ofthe above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery
Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drag Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
The term "pharmaceutically acceptable salt" represents those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art . For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail inJ Pharmaceutical Sciences, 1977, 66:1 - 19 . The salts can be prepared in situ during the final isolation and purification ofthe compounds ofthe invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
Compounds ofthe present invention can exist as stereoisomers where asymmetric or chiral centers are present. These compounds are designated by the symbols "R" or "S," depending on the configuration of substitiuents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and equal mixtures of enantiomers are designated ( — ). Individual stereoisomers of compounds ofthe present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation ofthe resulting mixture of diastereomers by recrystallization or chromatography and liberation ofthe optically pure product from the auxiliary or (2) direct separation ofthe mixture of enantiomers on chiral chromatographic columns.
Geometric isomers can also exist in the compounds ofthe present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a ring. Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration where the term "Z" represents substituents on the same side ofthe carbon-carbon double bond and the term "E" represents substituents on opposite sides ofthe carbon-carbon double bond. The arrangement of substituents around a ring are designated as cis or trans where the term "cis" represents substituents on the same side ofthe plane ofthe ring and the term "trans" represents substituents on opposite sides ofthe plane ofthe ring. Mixtures of compounds where the substitutients are disposed on both the same and opposite sides of plane ofthe ring are designated cis/trans.
Methods for Radioligand Binding Studies with Human Glucocorticoid and Progesterone Receptor Cytosol
The procedure described in Anal. Biochem. 1970, 37, 244-252, hereby incorporated by reference, was used. Briefly, cytosol preparations of human glucocorticoid receptor- D DGRXQisoform and human progesterone receptor-A [PRAJ isoform were obtained from Ligand Pharmaceuticals (San Diego, CA). Both receptor cDNAs were cloned into baculovirus expression vectors and expressed in insect SF21 cells. [^HJ-dexamethasone (Dex, specific activity 82-86 Ci/mmole) and [-1HJ- progesterone (Prog, specific activity 97-102 Ci/mmol) were purchased from Amersham Life Sciences (Arlington Heights, IL). Glass fiber type C multiscreen MAFC NOB plates were from Millipore ( Burlington, MA). Hydroxyapatide Bio-Gel HTP gel was from Bio-Rad Laboratories (Hercules, CA). Tris(hydroxymethyl)aminomethane (Tris), ethylenediaminetetraacetic acid (EDTA), glycerol, dithiothreitol (DTT) and sodium moylybdate were obtained from Sigma Chemicals (St. Louis, MO). Microscint-20 scintillation fluid was from Packard Instrument (Meriden, CT). Stock solutions (32 mM) of compounds were prepared in dimethylsulfoxide (DMSO), and 50X solutions of test compounds were prepared from the 32 mM solution with a 50:50 mixture of DMSO/ethanol. The 5 OX solution was then diluted with binding buffer that contained 10 mM Tri-HCl, 1.5 mM EDTA, 10% glycerol, 1 mM DTT, 20 mM sodium molybdate, pH 7.5 @ 4 C. 1% DMSO/ethanol was present in the binding assay.
GRX and PRA binding reactions were performed in Millipore Multiscreen plates. For GR binding assays, [3HJ-Dex (-35,000 dpm (-0.9 nM)), GRX cytosol (-35 μg protein), test compounds and binding buffer were mixed in a total volume of 200 μL and incubated at 4 °C overnight in a plate shaker. Specific binding was defined as the difference between binding of [^HJDex in the absence and in the presence of lμM unlabelled Dex.
For PR binding assays, [3H]Prog (-36,000 dpm (-0.8 nM)), PRA cytosol (-40 μg protein), test compounds and binding buffer were mixed in a total volume of 200 μL and incubated at 4 °C at overnight in a plate shaker. Specific binding was defined as the difference between binding of [3H]Prog in the absence and in the presence of 3 μM unlabelled Prog.
After an overnight incubation, 50 μL of hydroxyapatite (25 % weight/volume) slurry were added to each well and plates were incubated for 10 min at °C in a plate shaker. Plates were suctioned with a Millipore vacuum manifold and each well was rinsed with 300 μL of ice-cold binding buffer. A 250 μL aliquot of Packard Microscint- 20 was added to each well and the wells were shaken at room temperature for 20 minutes. The amount of radioactivity was determined with a Packard TopCount plate reader.
Determination of Inhibition Constant (Ki)
The concentration of test compounds that inhibited 50% of specific binding (IC50) was determined from a Hill analysis ofthe competitive binding experiments. The Ki of test compounds was determined using the Cheng-Prusoff equation Ki =IC50 /(l+[L*]/[KLj) where L* is the concentration of radioligand and K is the dissociation constant ofthe radioligand determined from saturation analysis. For GRX, K was -1.5 nM, and for PRA, KL was -4.5 nM. The inhibitory potencies of compounds of this invention and their selectivity for GR and PR receptors are shown in Table 1.
Table 1
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
The present invention also provides pharmaceutical compositions which comprise compounds ofthe present invention formulated together with one or more non- toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, arid the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance ofthe required particle size in the case of dispersions, and by the use of surfactants. Conversely, reduced particle size may maintain biological activity.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect ofthe drug, it is desirable to slow the absorption ofthe drag from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption ofthe drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drag form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices ofthe drag in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part ofthe intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds ofthe present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound ofthe present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for .example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount ofthe active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity ofthe particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical history ofthe patient being treated. However, it is within the skill ofthe art to start doses ofthe compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Abbreviations
Abbreviations that have been used in the descriptions ofthe scheme and the examples that follow are: BF3OE12 for boron trifluoride diethyl ether complex; DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide; and THF for tetrahydrofuran.
Synthetic Methods
The compounds and processes ofthe present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds ofthe invention can be prepared.
Syntheses ofthe compounds ofthe present invention are described in Schemes 1-21.
Scheme 1
Figure imgf000064_0001
As exemplified in Scheme 1, resorcinol dimethyl ether was metallated with a strong base such as n- or sec-butyllithium, treated with a trialkoxyborate such as trimethyl- or triisopropylborate and hydrolyzed with acid such as 2M HC1 to provide boronic acid 1 A. Treatment of 1 A with methyl 5-nitro-2-bromobenzoate in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) or dichlorobis(triphenylphosphine)palladium (II) provided biphenyl IB. Demethylation of IB was accomplished with reagents such as BBr3, to provide hydroxylactone 1C, which was treated with alkylating agents such as methyl iodide to provide ID. Conversion of ID to amine IE was accomplished using hydrogen gas and a palladium catalyst such as 10% palladium on carbon. IE was converted to quinoline IF by a Skraup ring annulation reaction. Introduction of functionalization at the C-5 position of IF to provide 1 was achieved through addition of organometallic reagents such as phenyllithium to the C-5 carbonyl to provide IG, followed by deoxygenation with Lewis acids such as BF3-OEt3 and reducing agents such as triethylsilane to provide 1. Scheme 2
Figure imgf000065_0001
A more preferred route to compounds of this invention is exemplified in Scheme 2. IF was converted to methyl acetal 2B, via hemiacetal 2A, using a two-step procedure comprising conversion of IF to 2 A with reagents such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane followed by acid-catalyzed acetal formation with acids such as p-toluenesulfonic acid monohydrate and alcohols such as methanol to provide 2B. 2B was treated with nucleophiles such as allyltrimethylsilane in the presence of a Lewis acid such as boron trifluoride diethyl etherate to form C-5 allyl analogs such as Example 2. The Lewis acid/methyl acetal complex was also condensed with organomagnesium chlorides, bromides or iodides to provide compounds of this invention such as Example 11.
Figure imgf000066_0001
3: R=NHMe 4: R=CO2Me 5: R=CH=CH2 6: R=C≡CH
As exemplified in Scheme 3, the C-10 position of 1C was subjected the same reduction Skraup conditions described in Scheme 1 to afford hydroxyquinoline 3B. 3B was converted to triflate derivative 3C with reagents such as trifluoromethanesulfonic anhydride then derivatized at the C-5 position as described in schemes 1 and 2 to provide analogs such as 3D. The functionalized C-10 triflates were used in coupling reactions mediated by palladium catalysts for animations, carbonylations, Stille couplings and modified Sonagashira reactions and provided aminomethyl, carbomethoxy, vinyl and acetylenic derivatives of 3D such as the C-5 allyl- substituted examples 3, 4, 5, and 6, respectively.
Scheme 4
Figure imgf000067_0001
8: R=OCF2H
As shown in Scheme 4, treatment of 3B with tert-butyl dimethylsilyl (TBS) ether and a base such as imidazole, triethylamine or diisopropylethylamine and functionalization ofthe C-5 position as described in schemes 1-3 provided silane 7B. Removal ofthe silane group with reagents such as tetra n-butylammonium fluoride in THF, to provide phenol 7, and treatment with R-X or RC(O)X, where R is an alkyl group and X is a leaving group such as halogen, provided alkoxy and carboxy compounds such as examples 9 and 10. Halo alkoxy analogs were prepared from 3B by nucleophillic displacement using a polyhalogenated alkylating agent such as CF2HCI to provide 8A followed by functionalization at the C-5 position of 8A, as described in Schemes 1-3, to provide 8.
Figure imgf000068_0001
12C: R=C(O)CH3 14: R=CH2SMe 15: R=C(O)NMe2
As exemplified in Scheme 5, IF was treated with lithiated, O-protected phenol reagents, such as 3-(methoxymethoxy)phenyllithium, to provide 12 A. The protecting group was cleaved in acidic media, such as methanolic or aqueous HCl, to provide diol 12B which was converted to phenyl acetates 12C with reagents such as acetyl chloride and base such as pyridine, triethylamine or diisopropylethylamine. The tertiary alcohol was then reduced as described in Scheme 1, and the acetate group of Example 12 was removed to provide Example 13. Example 13 was alkylated or acylated as described in Scheme 4 to provide examples 14 and 15.
Figure imgf000069_0001
17 As shown in Scheme 6, functionality in the meta position ofthe phenyl ring in the C-5 position was introduced using meta-halophenyl analogs such as Example 11, prepared as described in Scheme 2. Stille or Suzuki couplings or aminations with palladium catalysts such as [l,l-bis(diphenylphosphino)ferroceneJdichloropalladium(II) or tetrakis(triphenylphosphine)palladium(0) in the presence of ligands such as tributylstaimylfuran or morpholine provided carbon- or nitrogen-bound groups in the meta position ofthe aromatic ring at the C-5 position as exemplified in examples 16 and 17, respectively.
Scheme 7
Figure imgf000070_0001
1F 18
As shown in Scheme 7, IF was treated with magnesium halides, preferably bromides, to provide an intermediate hemiketal which was treated with acid catalysts such as para-toluenesulfonic acid, methanesulfonic acid or aqueous hydrochloric acid to provide optionally substituted analogs such as 18 as mixtures of E and Z isomers.
The chemistry shown in Scheme 1 was found to be general. Thus, a variety of tetracyclic cores could be prepared from an assortment of substituted anisoles via their corresponding boronic acids according to Scheme 8. >
Scheme 8
Figure imgf000070_0002
Scheme 8 shows the applicability ofthe chemistry described in Scheme 1 and Examples 1-131 to the synthesis of new cores with substituents other than alkoxy at the
C-10 position. Ortho metallation of substituted anisoles with a strong base such as n- or sec-butyllithium, followed by sequential treatment with a trialkoxyborate such as trimethyl- or triisopropylborate and hydrolysis with acid, as described in Scheme 1, provided the appropriately substituted boronic acids which were then elaborated to compounds of Formula I using chemistry described above. Further elaboration of the ring to provide Cores 1-17 is described below. Examples of novel tetracyclic cores prepared using the chemistry described in
Scheme 8 are shown below.
Figure imgf000071_0001
Core 1 Core 7 Core 8
Further derivatization of Core 1 using methods well-known in the art provide additional tetracyclic coumarins for subsequent elaboration at the C-5 position, as shown in Scheme 9. For example, selective alkylation ofthe C-10 hydroxyl of Core 1 with alkylating agents (e.g., methyl iodide) and base, such as potassium carbonate, provided Core 7. Selective derivitization of Core 1 at the C-7 position with halogenating agents such as bromine or N-bromosuccinimide provided the compound of Formula I precursor Core 8.
Example IF
Figure imgf000072_0001
Scheme 10 shows additional selective bromination chemistry. Regiochemical bromination of Example IF, as directed by the C-10 methoxy group and choice of brominating agent, provided Cores 9, 10, and 11. These brominated rings were further derivatized at the brominated position(s) by transition metal-catalyzed introduction of a variety of functional groups.
Scheme 11
Figure imgf000073_0001
R = lower acyl R = lower alkyl
As shown in Scheme 11 , cores bearing phenolic hydroxyl functionality were either dehydroxylated (as shown for Core 2), acetylated, or alkylated by transformations well-known in the art. See Larock, "Comprehensive Organic Transformations. A Guide to Functional Group Preparations," VCH Publishers, New York (1989), hereby, incorporated by reference.
Figure imgf000073_0002
Example 148 Example 149 Example 150
Scheme 12 shows the introduction ofthe substituted cyclohexenyl group by Lewis acid catalyzed addition ofthe tert-butyldimethylsilyl-protected enol ether to the C- 5 position of Example 2B. Once introduced, the diastereomers and rearrangement products were separated, and the alkoxycarbonyl group was optionally reduced to a hydroxyalkyl group.
Figure imgf000074_0001
Example 147 Examples 171 , 172 and 173
As shown in Scheme 13, the vinylic bromide group of compounds such as Example 147 were further derivatized at the brominated position(s) to provide a number of R19 substituents by transition metal-catalyzed introduction of a variety of functional groups such as those described in Scheme 10.
Example 69
Figure imgf000074_0002
Example 176
Figure imgf000074_0003
Example 177 Example 178
As shown in Scheme 14, Mitsunobu introduction of phthalimide to Example 69 and removal ofthe imide group with hydrazine provided alkylamino Example 177 which was further derivatized to Example 178 by treatment with di(tert-butyl)dicarbonate. Example 44
Figure imgf000075_0001
Example 179 X1=CON(CH3)2 (Example 182)
X,=CH2OCH3 (Example 183)
As shown in Scheme 15, elaboration ofthe C-5 nitrile of Example 44 to the D,D- unsaturated ester Example 179 followed by selective reduction ofthe alkoxycarbonyl group to the alkeneyl alcohol (Xi is H) provided precursors for carbamates and methoxymethyl ethers Examples 182 and 183, respectively.
Example 46
Figure imgf000076_0001
Example 185 Example 186
Figure imgf000076_0002
Figure imgf000076_0003
Example 187
Figure imgf000076_0004
Example 195
Figure imgf000076_0005
As shown in Scheme 16, conversion of ester Example 46 to its Weinreb amide derivative Example 185 and subsequent reduction to aldehyde Example 186 provided precursors for alkene Examples 187, 194, 195, and 200 by treatment ofthe aldehydes with a number of commercially available Wittig of Homer- Wadsworth-Emmons reagents.
Figure imgf000077_0001
As shown in Scheme 17, Example IF was converted to a ring-opened aldehyde using a two-step sequence involving treatment with a reducing agent such as diisobutylaluminum hydride in an aprotic solvent such as dichloromethane followed by treatment with a silylating reagent such as tert-butyldimethylsilyl chloride in the presence of a base such as potassium tert-butoxide. Addition of organolithium reagents such as lithiopyridines to the aldehyde produced benzylic alcohols (R=pyridyl) which could then be converted to analogs such as Examples 213-215 using a two-step sequence comprising removal ofthe silicon group with reagents such as tetrabutylammonium fluoride and subsequent cyclization using reagent combinations such as triethylphosphine and l,l'-(azodicarbonyl)dipiperidine.
Figure imgf000078_0001
Example 335: X1=-OCH3 Example X, : R=H
Example 337: X j=H Example Xj : R=Me
As shown in Scheme 18, Example 7 was converted to the triflate derivative with reagents such as trifluoromethanesulfonic anhydride, then derivatized at the C-10 position using the methods described in Scheme 3. Reduction of Example 335 with reagents such as diisobutylaluminum hydride provided Example 336. Treatment of
Example 336 with oxidizing reagents such as tetrapropylammonium perrathenate afforded Example 337. Alkylation of Example 336 could be accomplished with reagents such as iodomethane in the presence of a base such as potassium bis(trimethylsilyl)amide to provide analogs such as Example 338.
Figure imgf000079_0001
Example 340: R=H Example 341: R=Me
As shown in Scheme 19, triflate 3C was also converted to a C-10 vinyl derivative
Example 339 and subsequently to its methyl acetal using the methods described in
Schemes 3 and 2, respectively. The acetal was treated with nucleophiles such as 3-
(trimethylsilyl)cyclohexene or 3-(dimethylphenylsilyl)-3-methylcyclohexene in the presence of a Lewis acid such as boron trifluoride etherate to provide analogs such as
Examples 340 and 341, respectively.
Scheme 20
Figure imgf000079_0002
Introduction of sulfur at C-10 position of Example 3B is shown in Scheme 20. Example 3B was treated with reagents such as dimethylcarbamoyl chloride to give a thionocarbamate which underwent thermal rearrangement to provide the sulfur-carbon bond at C-10. The allyl group at C-5 was introduced as described in Scheme 2. Hydrolysis with a strong base such as potassium hydroxide and alkylation of sulfur with electrophiles such as iodomethane in the presence of a base such as cesium carbonate provided analogs bearing thioalkoxy functionality at C-10, such as Example 343.
Figure imgf000080_0002
Example 2B
Figure imgf000080_0003
Figure imgf000080_0001
Example 322 Example 323
A route to make Examples 320-323 is shown in Scheme 21. Example 2B was treated with nucleophiles such as tributylvinyltin in the presence of Lewis acids such as boron trifluoride diethyl etherate to provide Example 320 which was then coupled with aryl halides such as iodobenzene in the presence of catalysts such as palladium (II) acetate to provide trans isomer Example 321. The Lewis acid/methyl acetal complex was also condensed with tributylphenylacetylenyltin to provide Example 322 which was then partially hydrogenated in the presence of catalysts such as palladium on BaSO4 to provide cis isomer Example 323.
It is understood from the preceeding schemes and the following examples that the substituents Rl, R2, R3, R4, R-5, R-6, Rl6, R-16', R-17, Rl8, R-18', Y, R-2, and L2 can be determined by selection ofthe appropriate commercially available or known starting materials (e.g., substituted methoxybenzenes) or introduced synthetically by known chemical methods such as those disclosed in Larock, "Comprehensive Organic Transformations. A Guide to Functional Group Preparations," VCH Publishers, New York (1989), hereby incorporated by reference. Also, it will be appreciated by one skilled in the art that selective protection and deprotection steps depending on the nature of Rl, R2, R3, R4, R5, R6, Rl6, Rl6', R-17, R-18, Rl8', Y, R-25 and L2 can be carried out in varying order or number of steps to successfully complete the synthetic sequences. Commonly used protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," John Wiley & Sons, New York (1981), hereby incorporated by reference.
Example 1 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1H-[1 Jbenzopyrano \3 ,4- f]quinolinelH-ri]benzopyrano[3,4-f]quinoline
Example 1A A solution of 1,3-dimethoxybenzene (33.2 g, 240 mmol) in hexanes (20 mL) at -20 °C was treated sequentially with n-butyllithium (100 mL of a 2.4 M solution in hexanes, 240 mmol) and N,N,N',N'-tetramethylethylenediamine (1.81 mL, 12 mmol), stirred at 23 °C for 1.5 hours, cooled to -78 °C, treated with triisopropylborate (60.9 mL,
264 mmol) in diethyl ether (60 mL) over 1.5 hours with additional diethyl ether (150 mL) added to maintain stirring, stirred at 23 °C for 2 hours, poured into ice (150 mL) and 3M HCl (150 mL), and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated, during which a white solid precipitated from solution. The solid was collected by filtration and washed with hexanes to provide the desired compound. MS (DCI/NH3) m/z 200 (M+NH4)+.
Example IB A mixture of Example 1 A, methyl 5-nitro-2-bromobenzoate (25.8 g, 99.2 mmol),
(21.7 g, 119 mmol), cesium carbonate (97.1 g, 298 mmol), and dichlorobis- (triphenylphosphine)palladium(II) (3.5 g, 5.0 mmol) in DMF (300 mL) was stirred for 24 hours at 80 °C, cooled to 23 °C, treated with water (600 mL), and extracted with ethyl acetate (800 mL). The extract was dried (Na2SO4) and concentrated, during which a light yellow solid precipitated from solution. The mixture was placed in a freezer (-20
°C) for 2 hours then filtered to provide the desired compound. MS (DCI/NH3) m/z 318 (M+H)+ and 335 (M+NH4)+.
Example 1C A solution of Example IB (11.1 g, 35.1 mmol) in dichloromethane (60 mL) at -
78 °C was treated with boron tribromide (25.0 g, 99.8 mmol),warmed to 23 °C for 1 hour, recooled to -78 °C, and treated with methanol (100 mL). The mixture was warmed to 0 °C, and the precipitate was collected by filtration and recrystallized from methanol to provide the desired compound. MS (DCI/NH3) m/z 275 (M+NH4)+.
Example ID A mixture of Example 1C (10.7 g, 41.6 mmol) and CS2CO3 (20.0 g, 61.4 mmol) in DMF (130 mL) at 23 °C was treated dropwise with methyl iodide (22.8 g, 161 mmol), stirred for 4 hours, treated with water, and extracted with 1:1 ethyl acetate/hexane. The extract was concentrated, and the resulting solid was filtered, washed with water (100 mL), and dried under vacuum to provide the desired compound.
MS (DCI/NH3) m/z 289 (M+NH4)+.
Example IE A suspension of Example ID (11.2 g, 41.3 mmol) in dioxane (400 mL) at 23 °C was treated with 10% palladium on carbon (580 mg), heated at 65° C, treated with hydrogen, stirred under atmospheric pressure for 60 hours, filtered through powdered sea shells (Celite®) while hot, and concentrated during which a precipitate formed. The product was filtered and dried under vacuum to provide the desired compound. Concentration ofthe mother liquor to half of its original volume afforded a second crop of desired compound.
MS (DCI/NH3) m/z 242 (M+H)+ and 259 (M+NH4)+.
Example IF A solution of Example IE (4.0 g, 16.6 mmol) and iodine (1.7 g, 6.64 mmol) in acetone (380 mL) in a IL sealed ACE glass high pressure vessel at 105 °C was stirred for 48 hours, cooled to room temperature, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 12%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 322 (M+H)+.
Example IG A solution of Example IF (1.02 g, 3.18 mmol) in THF (20 mL) at -78 °C was treated with a solution of phenyllithium (10.9 mL, 19.6 mmol) in cyclohexanes/diethyl ether, warmed to -50 °C, stirred for 2 hours, treated with saturated NH4CI, warmed to 25 °C, and extracted with ethyl acetate The extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 20%> ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 400 (M+H)+.
Example 1
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- f|quinolinelH-[lJbenzopyrano[3,4-f|quinoline A solution of Example IG (0.67 g, 1.67 mmol) in dichloromethane (30 mL) at - 78 °C was treated with triethylsilane (2.91 g, 25.05 mmol) and BF3-OEt2 (0.95 g, 6.68 mmol), warmed to room temperature, stirred for 16 hours, and treated with saturated NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m/z 384 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.00 (d, 1H), 7.19 (m, 5H), 6.9 (dd, 1H), 6.76 (s, 1H),
6.69 (dd, 1H), 6.55 (d, 1H), 6.43 (d, 1H), 6.2 (s, 1H), 5.38 (s, 1H), 3.8 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H);
Anal, calcd for C26H25NO2: C, 81.42; H, 6.58; N, 3.65. Found C, 81.28; H, 6.30; N,
3.47.
Example 2 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fj quinoline
Example 2A A solution of Example IF (6.65 g, 20.69 mmol) in dichloromethane (500 mL) at - 78 °C was treated dropwise with 1M diisobutylaluminum hydride in hexanes (47.6 mL,
47.6 mmol), stirred for 2 hours, treated sequentially with saturated aqueous sodium potassium tartrate (300 mL) and ethyl acetate (600 mL), and stirred vigorously for 4 hours. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m/z 306 (M-OH)+.
Example 2B A solution of Example 2A (4.20 g, 12.99 mmol) in methanol (150 mL) at 0° C was treated with p-toluenesulfonic acid-H2θ (1.2 g, 20 wt %), stirred for 30 minutes, stirred at room temperature for 1 hour, cooled to 0 °C for 30 minutes, and filtered. The solid was rinsed with hexanes and dried under vacuum to provide the desired compound. The filtrate was poured into saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10-20% ethyl acetate/hexanes to provide additional desired compound.
MS (DCI/NH3) m/z 306 (M-OCH3)+.
Example 2 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- f]quinoline A solution of Example 2B (2.50 g, 7.41 mmol) in dichloromethane (225 mL) was treated with allyltrimethylsilane (4.0 mL, 25.2 mmol), cooled to - 78 °C, treated dropwise with BF3-OEt2 (3.1 mL, 25.2 mmol), stirred for 15 minutes at -78 °C, warmed to 0 °C for 30 minutes, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-20% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 348 (M+H)+; iH NMR (300 MHz, DMSO-dfS)D7.96 (d, 1H), 7.07 (t, 1H), 6.71 (d, 1H), 6.60 (d, 1H), 6.52 (d, 1H), 6.12 (br s, 1H), 5.82 (m, 1H), 5.76 (dd, 1H), 5.44 (br s, 1H), 5.01 (m, 2H), 3.86 (s, 3H), 2.44 (m, 1H), 2.20 (m, 1H), 2.16 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); Anal, calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C, 79.35; H, 7.30; N, 3.89.
Example 3 Claim 2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)-lH-[llbenzopyrano[3,4- f]quinolin-l 0-amine
Example 3A A solution of Example 1C was processed as in Example IE to provide the desired compound. MS (DCI/NH3) m/z 227 (M+H)+.
Example 3B A solution of Example 3 A was processed according to the procedure in Example IF to provide the desired compound. MS (DCI/NH3) m/z 308 (M+H)+.
Example 3C A solution of Example 3B (1.38 g, 4.49 mmol), triethylamine (1.92 mL, 13.77 mmol) and 4-dimethylaminopyridine (100 mg) in dichloromethane (50 mL) at -78°C, was treated dropwise with trifluoromethanesulfonic anhydride (1.39 g, 4.94 mmol), stirred 30 minutes at -78° C, warmed slowly to room temperature over 1.5 hours, poured into saturated NH4CI, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10%> ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m z 440 (M+H)+.
Example 3D
Example 3C was processed according to the procedures in examples 2A, 2B and 2 to provide the desired compound. MS (DCI/NH3) m/z 466 (M+H)+.
Example 3
2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)- 1 H-[l Jbenzopyrano [3 ,4- fjquinolin- 10-amine A solution of Example 3D (0.165 g, 0.36 mmol), palladium(II) acetate (0.0016 g, 0.007 mmol), (S)-(-)-2,2'-bis(phenylphosphino)-l,l,-binapthyl (0.0055, 0.008 mmol), sodium tert-butoxide (0.051 g, 0.53 mmol), methylamine (0.44 mL of a 2.0M solution in
THF, 0.88 mmol) in toluene (0.5 mL) was heated at 90 °C for 4 hours in a sealed ACE- glass high pressure vessel, cooled to 0 °C, diluted with ethyl acetate (5 mL), and washed with 0.5M HCl. The organic extract was dried (Na2SO4), filtered, and concentrated.
The residue was purified by flash chromatography on silica gel with 5-12% ethyl acetate/hexanes to provide the desired compound.
MS (DCI NH3) m/z 347 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.83 (d, 1H), 6.94 (dd, 1H), 6.62 (d, 1H), 6.28 (dd, 1H), 6.25 (dd, 1H), 6.05 (d, 1H), 5.86-5.74 (m, 2H), 5.67 (dd, 1H), 5.45 (s, 1H), 5.40 (q, 1H), 5.03 (dd, 1H), 4.98 (dd, 1H), 2.72 (d, 3H), 2.16 (s, 3H), 1.17, (s, 3H), 1.15 (s, 3H); HRMS m/z calcd for C23H26N2O: 346.2045 (M+H)+. Found: 346.2049.
Example 4 methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fjquinoline- 10-carboxylate A solution of Example 3D (263 mg, 0.565 mmol), triethylamine (0.10 mL, 0.717 mmol), l,3-bis(diphenylphosphino)propane (26 mg, 0.063 mmol) and DMSO (1.5 mL) in methanol (8 mL) was treated with palladium acetate (12.7 mg, 0.056 mmol), saturated with carbon monoxide, stirred under carbon monoxide (1 atm) for 20 minutes, heated at 65 °C for 3 hours, cooled, diluted with ethyl acetate (100 mL), and filtered. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 376 (M+H)+; !H NMRD7.19 (m, 2H), 7.03 (dd, IH), 6.78 (d, IH), 6.60 (d, IH), 6.30 (m, IH), 5.85 (m, 2H), 5.46 (m, IH), 5.05 (dm, IH), 4.98 (dm, IH), 3.77 (s, 3H), 2.30 (m, 2H), 2.19 (d, 3H), 1.21 (s, 3H), 1.15 (s, 3H); HRMS m/z calcd for C24H25NO3: 375.1834 (M+H)+. Found: 375.1841.
Example 5 10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[llbenzopyrano[3,4- fjquinoline A solution of Example 3D (103 mg, 0.221 mmol) and (1,3- bis(diphenylphosphino)ferrocene)palladium (II) chloride-dichloromethane (22 mg, 0.027 mmol) in l-methyl-2-pyrrolidinone (2 mL) was treated with vinyl tributylstannane (0.110 mL, 119 mg, 0.376 mmol), heated at 65 °C for 24 hours, cooled to room temperature, treated with saturated KF, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 344 (M+H)+;
1H NMRD7.22 (d, IH), 7.15 (m, 2H), 6.99 (dd, IH), 6.83 (dd, IH), 6.63 (d, IH), 6.23 (m, IH), 5.87 (ddm, IH), 5.73 (dd, IH), 5.76 (dd, IH), 5.47 (m, IH), 5.33 (dd, IH), 5.03 (dd, IH), 4.98 (dm, IH), 3.77 (s, 3H), 2.44 (m, IH), 2.28 (m, IH), 2.18 (d, 3H), 1.21 (s,
3H), 1.15 (s, 3H); HRMS m/z calcd for C24H26NO: 344.2014 (M+H)+. Found: 344.2011
Example 6 10-ethvnyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline
Example 6A A solution of Example 3D (25 mg, 0.054 mmol), tetra-n-butylammonium iodide (40 mg, 0.108 mmol), bis(triphenylphosphine)palladium chloride (7.0 mg, 0.010 mmol), copper(I) iodide (3.8 mg, 0.020 mmol) and triethylamine (0.15 mL, 0.717 mmol) in DMF (0.75 mL) was treated with trimethylsilylacetylene (174 mg, 1.76 mmol), heated at 55 °C for 3 hours, diluted with ethyl acetate (20 mL), and filtered. The filtrate was washed with saturated NH4CI, and the aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was applied to a 10 x 20 cm, 0.25 mm silica gel TLC plate and eluted twice with 10%> ethyl acetate/hexane. Extraction ofthe silica gel with ethyl acetate provided the desired compound. MS (DCI/NH3) m/z 414 (M+H)+; iHNMR (300 MHz, DMSO-d6)D8.36 (d, IH), 7.07 (m, 2H), 6.90 (dd, IH), 6.60 (d, IH), 6.34 (m, IH), 5.80 (m, 2H), 5.46 (m, IH), 5.04 (dm, IH), 4.97 (dm, IH), 2.35 (m, IH), 2.26 (m, IH), 2.17 (d, 3H), 1.18 (s, 3H), 1.17 (s, 3H), 0.26 (s, 9H).
Example 6 10-ethynyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[11benzopyrano[3,4- f| quinoline A solution of Example 6 A in THF (2.5 mL) was treated sequentially with glacial acetic acid (0.005 mL) and IM tetra-n-butylammonium fluoride in THF (0.050 mL,
0.050 mmol), stirred at room temperature for 18 hours, and purified according to the procedure in Example 6A to provide the desired compound. MS (DCI/NH3) m/z 342 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 8.27 (dd, IH), 7.15 (t, IH), 7.07 (d, IH), 6.91 (dm, IH), 6.62 (d, IH), 6.34 (m, IH), 5.80 (m, IH), 5.46 (m, IH), 5.03 (dm, IH), 4.98 (dm,
IH), 4.41 (s, IH), 2.44 (m, 2H), 2.17 (s, 3H), 1.18 (s, 6H); HRMS calcd m/z for C24H23NO: 341.1780 (M+H)+. Found: 341.1788.
Example 7 2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinolin-10-ol
Example 7A A solution of Example 3B (569 mg, 1.85 mmol) in DMF (8 mL) at 23 °C was treated sequentially with imidazole (379 mg, 5.55 mmol) and t-butyldimethylsilyl chloride (418 mg, 2.78 mmol), stirred for 3 hours, poured into water, and extracted with
2:1 hexane/ethyl acetate (22 mL). The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25%> ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 422 (M+H)+.
Example 7B
Example 7A was processed as in examples IG and lto provide the desired compound.
Example 7
2,5-dihvdro-2,2,4-trimethyl-5-phenyl-lH-[11benzopyrano[3,4-fjquinolin-10-ol A solution of Example 7B (0.90 g, 1.87 mmol) in THF (12 mL) at 0 °C was treated with IM tetra-n-butylammonium fluoride in THF (3.37 mL, 3.37 mmol), warmed to 23 °C with over 1 hour, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m/z 370 (M+H)+;
*H NMR (300 MHz, DMSO-d6)Q9.63 (s, IH), 9.16 (d, IH), 7.13-7.24 (m, 5H), 6.74 (s,
IH), 6.70 (d,lH), 6.8 (d,lH), 6.39 (dd, IH), 6.26 (dd, IH), 6.11 (d, IH), 5.37 (s, IH),
1.85 (d, 3H), 1.22 (s, 3H), 1.11 (s, 3H);
HRMS calcd m/z for C25H23NO2: 369.1729 (M+H)+. Found 369.1736.
Example 8 10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline
Example 8A
A solution of Example 3B (1.11 g, 3.6 mmol) in DMF (10 mL) at 0 °C was treated sequentially with sodium t-butoxide (0.38 g, 3.6 mmol) and bromodifluoromethane (10 mL), stirred at 0 °C for 6 hours, warmed to room temperature for 1 hour, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel with 5%> ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 436 (M+H)+.
Example 8
10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [1 Jbenzopyrano [3 ,4-f]quinoline Example 8A was processed as in examples 2B and 2 to provide the desired compound. MS (DCI/NH3) m/z 384 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.75 (d, IH), 7.20 (t, IH), 7.15 (t, IH), 6.83 (dd, IH), 6.81 (dd, IH), 6.63 (d, IH), 6.28 (s, IH), 5.89-5.75 (m, 2H), 5.46 (s, IH), 5.04 (dd, IH), 4.96 (dd, IH), 2.48-2.40 (m, IH), 2.29-2.20 (m, IH), 2.18 (s, 3H), 1.17 (s, 6H); HRMS calcd for C23H23F2NO2: 383.1697 (M+H)+. Found 383.1693.
Example 9 10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl- lH-fl jbenzopyranor3,4- fjquinoline Example 9A A solution of Example 3B (28 mg, .09 mmol) in DMF (1.0 mL) at 0 °C was treated with sodium hydride (2.4 mg of a 60% dispersion in mineral oil, 0.01 mmol), stirred for 1 hour, treated with ethyl bromide (20 mg, .182 mmol), stirred for 30 minutes at room temperature, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired compound.
Example 9 10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl- 1 H- \ 1 Jbenzopyrano [3 ,4- f]quinoline Example 9 A was processed as in examples IG and 1 to provide the desired compound.
MS (DCI/NH3) m/z 398 (M+H)+;
1H NMR (300 MHz, DMSO-d6)Q8.09 (d, IH), 7.20-7.15 (m, 5H), 6.78 (dd, 2H), 6.77 (s, IH), 6.69 (d, IH), 6.53 (dd, IH), 6.43 (dd, IH), 6.18 (d, IH), 5.39 (d, IH), 3.99-4.06 (m, IH), 1.85 (d, 3H), 1.38 (t, 3H), 1.22 (s, 3H), 1.16 (s, 3H); HRMS calcd m/z for C27H27NO2: 397.2042 (M+H)+. Found 397.2034.
Example 10 2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[11benzopyrano[3,4-f]quinoline-10-ol acetate (ester) A solution of Example 7 (20 mg, 0.05 mmol) in pyridine (1 mL) at 0 °C was treated with acetic anhydride (0.1 mL, 1.05 mmol), stirred at room temperature 14 hours, and concentrated. The residue was purified by flash chromatography on silica gel with 20%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m z 412 (M+H)+; 'H NMR (300 MHz, DMSO-d6)D7.62 (d, IH), 7.21-7.16 (m, 5H), 6.93 (t, IH), 6.77 (s,
IH), 6.73 (d, IH), 6.65 (dd, IH), 6.62 (dd, IH), 6.32 (s, IH), 5.37 (s, IH), 2.30 (s, 3H), 1.79 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H); HRMS calcd m/z for C27H25NO3: 411.1834 (M+H)+. Found: 411.1842.
Example 11
5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- π Jbenzopyrano[3 ,4-fjquinoline A solution of Example 2B and (0.520 g, 1.54 mmol) in dichloromethane (50 mL) was cooled to -10 °C, treated dropwise with BF3-OEt2 (0.57 mL, 4.62 mmol), stirred for
30 minutes at -10 °C, treated dropwise with a 0.49 M solution of 3-bromo-5- methylphenylmagnesium bromide in diethyl ether (12.6 mL), stirred for 15 minutes, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5% ethyl acetate/hexanes to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)D8.02 (d, IH), 7.22 (s, IH), 7.03 (br d,lH), 6.95 (t, IH), 6.74 (s, IH), 6.71 (d, IH), 6.59 (d, IH), 6.50 (d, IH), 6.26 (d, IH), 5.42 (s, IH), 4.04 (s, IH), 3.80 (s, 3H), 2.18 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H); HRMS m/z calculated for C27H26Nθ2Br: 475.1147 (M+H)+. Found 475.1143.
Example 12 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[11benzopyranor3,4-flquinolin-5- yl)phenol,acetate (ester)
Example 12A A solution of 3-methoxymethoxyphenyl bromide (10.85 g, 50.00 mmol) in THF (300 mL) at -78 °C was treated with n-butyllithium (2.5 M in hexane, 20 mL), warmed to -30 °C, recooled to -78 °C, treated with Example IF, warmed to -50 °C, quenched with saturated NH4CI, warmed to ambient temperature, decanted, and concentrated. The residue was treated with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 20-25% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 460 (M+H)+.
Example 12B A solution of Example 12A (2.30 g, 5.00 mmol) in methanol (10 mL) was treated with HCl-saturated methanol (50 mL), stirred for 18 hours, poured into 1 :1 ethyl acetate/saturated NH4CI, and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m/z 416 (M+H)+.
Example 12C A solution of Example 12B (2.45 g, 5.89 mmol) and pyridine (2.33 g, 29.4 mmol) in THF (100 mL) was treated with acetyl chloride (0.51 g, 6.48 mmol), stirred for 4 hours, allowed to settle, decanted, and concentrated. The residue was treated with saturated NaHCO3 and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25-33% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 458 (M+H)+.
Example 12
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-rilbenzopyranor3,4-f]quinolin-5- yl)phenol,acetate (ester) Example 12C was processed as in Example 1 to provide the desired compound. MS (DCI/NH3) m/z 442 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.26 (t, IH), 7.07 (d, IH), 6.98-6.90 (m,
2H), 6.85 (s, IH), 6.77 (s, IH), 6.71 (d, IH), 6.58 (d, IH), 6.46 (dd, IH), 6.23 (s, IH), 5.40 (s, IH), 3.79 (s, 3H), 2.19 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H); Anal, calcd for C28H27NO4-0.25H2O: C, 75.40; H, 6.21; N, 3.14. Found: C, 75.76; H,
6.21; N, 2.84.
Example 13 3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinolin- 5 - yl)phenol A solution of Example 12 (0.81 g, 1.84 mmol) in THF (20 mL) and methanol (20 mL) was treated with K2CO3 ( 2.00 g, 14.5 mmol) in water (6 mL), stirred for 12 hours, quenched with saturated NH4CI, decanted, concentrated, treated with saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m z 400 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q9.26 (s, IH), 8.00 (d, IH), 7.00 (t, IH), 6.92 (t, IH),
6.71-6.66 (m, 2H), 6.63 (d, IH), 6.58-6.51 (m, 3H), 6.44 (dd, IH), 6.15 (s, IH), 5.38 (s, IH), 3.80 (s, 3H), 1.88 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H); Anal, calcd for C26H25NO3: C, 78.17; H, 6.30; N, 3.50. Found: C, 77.82; H, 6.42; N,
3.26.
Example 14 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-r[3-(methylthio)methoxy]phenylJ-lH- ri Ibenzopyrano [3 ,4-fjquinoline A solution of Example 13 (420 mg, 1.05 mmol) in DMF (40 mL) at 0 °C was treated with NaH (50 mg, 2.10 mmol) portionwise over 5 minutes, stirred for 10 minutes, treated with chloromethyl methyl sulfide (152 mg, 1.58 mmol), warmed to room temperature, treated with saturated NH4CI, and extracted with ethyl acetate. The extract was washed sequentially with IM NaOH and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-
17% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m/z 460 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.14 (t, IH), 6.92 (t, IH), 6.83-6.68 (m, 5H), 6.56 (d, IH), 6.47 (d, IH), 6.21 (s, IH), 5.40 (s, IH), 5.13 (s, 2H), 3.80 (s, 3H), 2.09
(s, 3H), 1.97 (s 3H), 1.24 (s, 3H), 1.16 (s, 3H); Anal, calcd for O28H29NO3S-0.5H2O: C, 71.76; H, 6.45; N, 2.98. Found: C, 71.93; H,
6.61; N, 2.68.
Example 15
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-ri1benzopyrano[3,4-f]quinolin-
5-yl)phenylJ dimethylcarbamate Example 13 and N,N-dimethylcarbamoyl chloride were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 471 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.22 (t, IH), 7.05 (d, IH), 6.93 (t, 2H), 6.83 (s, IH), 6.77 (s, IH), 6.71 (d, IH), 6.57 (d, IH), 6.48 (d, IH), 6.23 (d, IH), 5.40 (s, IH), 3.80 (s, 3H), 2.97 (s, 3H), 2.85 (s, 3H), 1.86 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H); Anal, calcd for C29H30N2O4: C, 74.02; H, 6.42; N, 5.95. Found: C, 74.05; H, 6.36; N, 5.86.
Example 16 5-[3-(2-furanyl)-5-methylphenyl1-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- r 1 Ibenzopyrano [3 ,4-fjquinoline A solution of Example 11 (0.253 g, 0.531 mmol) in l-methyl-2-pyrrolidinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.045 g, 0.005 mmol), heated to 85 °C for 13 hours, cooled to room temperature, diluted with ethyl acetate and saturated KF, stirred for 3 hours, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 464 (M+H); iH NMR (300 MHz, DMSO-d6)D8.02 (d, IH), 7.67 (m, IH), 7.31 (d, 2H), 6.92 (t, IH), 6.92 (s, IH), 6.75 (m, 2H), 6.72 (d, IH), 6.57-6.50 (m, 3H), 6.23 (m, IH), 5.41 (s, IH), 3.78 (s, 3H), 2.20 (s, 3H), 1.89 (s, 3H), 1.24 (s, 3H), 1.17 (s, 3H); Anal, calcd for C31H29NO3: C, 80.32; H, 6.31; N, 3.02. Found: C, 80.08; H, 6.25; N, 2.83.
Example 17 2,5 -dihy dro- 10-methoxy-2,2 ,4-trimethyl-5 - [3 -methyl-5 -( 1 -morpholinyrjphenylj -
1 H-[ 1 Jbenzopyrano [3 ,4-f]quinoline A solution of Example 11 (0.055 g, 0.115 mmol) in toluene (5 mL) was treated sequentially with bis(dibenzylideneacetone)palladium(0) (0.007 g, 0.012mmol), (S)-(-)- bis(diphenylphospino)-l,l'-binaphthyl (0.022 g, 0.035 mmol), morpholine (15DL, 0.173 mmol), and sodium tert-butoxide (0.028 g, 0.289 mmol), stirred at 85 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate and water, and filtered through powdered sea shells (Celite®). The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10-33%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 483 (M+H); iH NMR (300 MHz, DMSO-d6)Q7.97 (d, IH), 6.93 (t, IH), 6.68 (m, 2H), 6.54-6.60 (m, 3H), 6.49 (d, IH), 6.40 (s, IH), 6.18 (br s, IH), 5.40 (s, IH), 3.78 (s, 3H), 3.65 (m, 4H),
2.91 (m, 4H), 2.09 (s, 3H), 1.89 (s, 3H), 1.21 (s, 3H), 1.16 (s, 3H); Anal, calcd for C31H34N2O3-0.25H2O: C, 76.44; H, 7.14; N, 5.75. Found: C, 76.61 ; H,
7.35; N, 5.47.
Example 18
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline A solution of Example IF (0.100 g, 0.31 mmol) in THF (5 mL) at -78 °C was treated with a solution of benzylmagnesium bromide (10 mL of 0.44 M solution in ether, 4.4 mmol) dropwise over 10 minutes, warmed to room temperature, stirred for 14 hours, treated with saturated NH4CI, and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was dissolved in dichloromethane (10 mL), treated with p-toluenesulfonic acid-H2θ (0.059 g, 0.31 mmol), stirred for 14 hours at room temperature, treated with 2% NaOH (10 mL), and extracted with ethyl acetate. The residue was purified by flash chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired compound as a mixture of regioisomers. The regioisomers were separated by HPLC (Microsorb, 5% acetone/hexanes) but rapidly interconverted at room temperature to a 1 :1 regioisomeric mixture. MS (DCI NH3) m/z 396 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1:D8.12 (d, IH), 7.16-7.03 (m, 5H), 6.80-6.66 (m, 4H), 6.45 (s, IH), 6.34 (s, IH), 5.0 (s, IH), 3.90 (s, 3H), 1.84 (s, 3H), 1.20 (s, 3H), 0.91 (s, 3H); isomer 2:D8.23 (d, IH), 7.70 (d, 2H), 7.37 (t, 2H), 7.22 (m, IH), 7.03-7.16 (m, 3H), 6.86 (d, IH), 6.55 (s, IH), 5.53 (s, IH), 5.45 (s, IH), 3.90 (s, 3H), 1.97 (s, 3H),
1.25 (s, 6H); HRMS calcd m/z for C27H25NO2: 395.1885 (M+H)+. Found: 395.1884.
Example 19 5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[lJbenzopyrano[3 ,4-f]quinoline Example IF and 3,5-dichlorophenyl magnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 452 (M+H)+; *H NMR (300 MHz, DMSQ)D8.10 (d, IH), 7.51 (t, Hz, IH), 7.19 (d, 2H), 7.03 (dd,
IH), 6.87 (s, IH), 6.80 (d, IH), 6.67 (d, IH), 6.59 (d, IH), 6.36 (s, IH), 5.50 (s, IH), 3.87 (s, 3H), 1.93 (s, 3H), 1.29 (s, 3H), 1.22 (s, 3H);
13C NMR (75 MHz, DMSO) 156.1, 151.1, 145.6, 143.8, 133.8, 133.8, 133.5, 128.1, 127.6, 127.3, 127.2, 127.1, 126.7, 126.7, 117.8, 116.9, 114.1. 113.4, 110.2, 105.9, 73.3, 55.6, 49.7, 29.2, 28.5, 23.2;
HRMS calcd for C26H23NO2CI2 : 451.1106 (M+H)+. Found 451.1113.
Example 20 5-butyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[llbenzopyrano[3,4- fjquinoline
Example IF and n-butyllithium were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 364 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.94 (d, IH), 7.06 (dd,lH), 6.68 (dd, IH), 6.58 (d, IH), 6.54 (dd, IH), 6.08 (s, IH), 5.67 (m, IH), 5.44 (s, IH), 3.85 (s, 3H), 2.15 (s, 3H),
1.68 (m, IH), 1.41-1.22 (m, 5H), 1.17 (s, 3H), 1.14 (s, 3H), 0.78 (t, 3H); Anal, calcd for C24H29NO2:C, 79.30; H, 8.04; N, 3.85. Found C, 79.10; H, 8.14; N,
3.72.
Example 21
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-5 - [3 -(trifluoromethyl)phenylj - 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline Example IF and 3-trifluoromethylphenyl-magnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 452 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.03 (d, IH), 7.55 (m, IH), 7.47 (m, 3H), 6.93 (dd, IH), 6.88 (s, IH), 6.73 (d, IH), 6.58 (d, IH), 6.48 (d, IH), 6.29 (s, IH), 5.43 (s, IH),
3.79 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.17 (s, 3H); Anal, calcd for C27H24F3NO2: C, 71.82; H, 5.35; N, 3.10. Found: C, 71.73; H, 5.44;
N, 3.05.
Example 22
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-flquinoline Example 2B and anisole were processed as in Example 2C to provide the desired compound. MS (DCI/NH3) m/z 414 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.00 (d, IH), 7.04 (d, 2H), 6.90 (dd, IH), 6.78 (dd, 2H), 6.70 (dd, 2H), 6.60 (dd, IH), 6.41 (dd, IH), 6.18 (s, IH), 5.37 (s, IH), 3.79 (s, 3H), 3.65 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H); HRMS calcd m/z for C27H27NO3: 413.1991 (M+H)+. Found: 413.1987.
Example 23 5-(3 -chlorophenyl)-2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4- fjquinoline Example IF and 3-chlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound.
MS (DCI/NH3) m/z 418 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.23-7.12 (m, 4H), 6.90 (dd, IH), 6.77 (s, IH), 6.70 (d, IH), 6.55 (dd, IH), 6.44 (dd, IH), 6.18 (d, IH), 5.38 (s, IH), 3.79 (s, 3H), 1.84 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H); HRMS calcd m/z for C26H24NO2CI: 417.1496 (M+H)+. Found: 417.1490.
Example 24 2 ,5 -dihy dro- 10-methoxy-2,2 ,4-trimethyl-5 -(3 -methylphenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline Example IF and 3-methylphenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 398 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.94 (d, IH), 7.01-6.91 (m, 4H), 6.84 (dd, IH), 6.66 (s, IH), 6.62 (d, IH), 6.48 (dd, IH), 6.38 (dd, IH), 6.11 (d, IH), 5.31 (d, IH), 3.72 (s, 3H), 2.10 (s, 3H), 1.78 (d, 3H), 1.15 (s, 3H), 1.09 (s, 3H); Anal, calcd for C28H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C, 81.23; H, 7.18; N, 3.36.
Example 25 (± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano-
[3,4-f]quinoline Enantiomer of Example 1.
Spectral data are identical to Example 1. [D]D = + 85.1;
Retention time = 11.68 minutes on a Chiralcel OJ 4.6 x 250 mm HPLC column; Solvent: 95:5 hexane:ethanol; Flow rate: 1 mL/minute.
Example 26 (± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fjquinoline Enantiomer of Example 1. Spectral data are identical to Example 1.
[D]D = - 84.9;
Retention time = 15.27 minutes on a Chiralcel OJ 4.6 x 250 mm HPLC column; Solvent: 95:5 hexane:ethanol; Flow rate: 1 mL/minute.
Example 27 5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Ibenzopyrano [3 ,4-fjquinoline Example IF (0.052 g, 0.162 mmol) in THF (5 mL) was cooled to 0 °C, treated dropwise with 0.38 M 3,5-dimethylphenyl magnesium bromide in dimethylether (4.4 mL, 1.68 mmol), warmed to room temperature, stirred for 14 hours, partitioned between saturated NH4CI and ethyl acetate, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with a gradient from 10-25% ethyl acetate/hexanes to provide the desired lactol.
The lactol (0.043 g, 0.101 mmol) was dissolved in dichloromethane (7 mL), treated with triethylsilane (0.16 mL, 1.01 mmol), cooled to 0 °C, treated with BF3-OEt2
(0.12 mL, 1.01 mmol), warmed to room temperature, stirred for 19 hours, and treated withNaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m/z 412 (M+H)+; iH NMR (300 MHz, DMSO-dfS)D8.00 (d, IH), 6.92 (t, IH), 6.78 (m, 3H), 6.70 (d, IH),
6.69 (s, IH), 6.56 (dd, IH), 6.47 (dd, IH), 6.19 (d, IH), 5.39 (s, IH), 3.79 (s, 3H), 2.11
(s, 6H), 1.85 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H);
Anal, calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C, 81.59; H, 7.54; N,
3.16.
Example 28 5 -(4-chlorophenyl)-2 , 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano \3 ,4- f] quinoline Example IF and 4-chlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound.
MS (DCI/NH3) m/z 418 (M+H)+; iH NMR (300 MHz, DMSO-d<s)Q8.01 (d, IH), 7.24 (q, 4H), 6.92 (t, IH), 6.76 (s, IH), 6.70 (d, IH), 6.57 (d, IH), 6.43 (d, IH), 6.24 (br s, IH), 5.20 (br s, IH), 3.79 (s, 3H), 1.83 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H); Anal, calcd for C26H24NO2CI: C, 74.72; H, 5.79; N, 3.35. Found: C, 74.73; H, 5.68; N,
3.29.
Example 29 5-(3,4-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Ibenzopyrano \3 ,4-fj quinoline
Example IF and 3,4-dimethylphenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 412 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.98 (d, IH), 6.94 (s, IH), 6.82 (q, 2H), 6.78 (d, IH), 6.67 (d, IH), 6.53 (d, IH), 6.42 (d, IH), 6.17 (s, IH), 5.37 (s, IH), 3.78 (s, 3H), 2.08 (s,
6H), 1.84 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H); Anal, calcd for C28H29O2N-0.5H2O: C, 79.97; H, 7.19; N, 3.33. Found: C, 79.94; H,
7.25; N, 2.98.
Example 30
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyranor3,4- f] quinoline Example 2B and 4-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/z 402 (M+H)+; iH NMR (300 MHz, DMSO-dβ)Q8.03 (d, IH), 7.16 (m, 2H), 7.03 (t, 2H), 6.88 (t, IH), 6.71 (s, IH), 6.68 (d, IH), 6.55 (d, IH), 6.41 (d, IH), 6.22 (s, IH), 5.38 (s, IH), 3.79 (s,
3H), 1.82 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H).
Example 31 5-[3,5-bis(trifluoromethyl)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[11benzopyrano[3,4-f]quinoline
Example 2B and 4-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q8.02 (d, IH), 7.98 (s, IH), 7.00 (s, IH), 6.93 (d, IH),
6.75 (d, IH), 6.59 (d, IH), 6.49 (d, IH), 6.38 (s, IH), 5.46 (s, IH), 3.79 (s, 3H), 1.87 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H);
HRMS calcd m z for C28H23O2F6N: 519.1633 (M+H)+. Found: 519.1646;
Anal, calcd for O28H23NO2F6'1.25H2O: C, 62.05; H, 4.74; N, 2.58. Found: C, 61.96; H, 4.70; N, 2.35.
Example 32
(-)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ 1 Jbenzopyrano 3 ,4-f]quinoline Enantiomer of Example 19. Spectal data are identical to Example 19. ' [DJD = - 208.0;
Retention time = 6.89 minutes on a Regis (R,R)-WhelkOl Kromasil 4.6x250mm HPLC column;
Solvent: 86:10:3 hexane:dichloromethane:ethanol; Flow rate: 1 mL/minute.
Example 33 (+)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ 1 Jbenzopyrano [3 ,4-f]quinoline
-Enantiomer of Example 19. Spectal data are identical to Example 19. [D]D = + 210.7;
Retention time = 8.63 min on a Regis (R,R)-WhelkOl Kromasil 4.6 x 250mm HPLC column;
Solvent: 86:10:3 hexane: dichloromethane :ethanol; Flow rate: 1 mL/minute.
Example 34 5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-ri]benzopyrano[3,4-f]quinoline
Example 2B and 3,5-difluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. iHNMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.05 (m, IH), 6.93 (t, IH), 6.79 (s, 3H),
6.71 (d, IH), 6.59 (9, IH), 6.50 (d, IH), 6.30 (s, IH), 5.43 (s, IH), 3.81 (s, 3H), 1.87 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H);
HRMS calcd m/z for C26H23O2F2N: 419.1697 (M+H)+. Found: 419.1702;
Anal, calcd for C26H23O2F2N-0.5H2O: C, 72.88; H, 5.65; N, 3.27. Found: C, 72.62; H,
5.58; N, 3.06.
Example 35
2,5-dihydro- 10-methoxy-2,2,4,N-tetramethyl-N-phenyl- 1 H- [ 1 Ibenzopyrano [3 ,4-f]quinolin-5-amine Example IF and N-methylaniline were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 306 (M-NMePh)+; iH NMR (300 MHz, DMSO-d6)Q8.03 (d, IH), 7.25 (t, 2H), 7.08 (m, 2H), 6.99 (t, IH), 6.86 (s, IH), 6.80 (t, IH), 6.70-6.65 (m, 2H), 6.41 (d, IH), 6.26 (br s, IH), 5.39 (br s, IH), 3.87 (s, 3H), 2.47 (s, 3H), 1.74 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H).
. Example 36
(-)2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-rilbenzopyranor3 ,4- fjquinoline Example 2 was purified by flash chromatography on Chiralcel OJ with 10% ethanol/hexanes to provide the desired compound. [DJD = -1.8 (C 1.2,' CHC13);
MS (DCI/NH3) m/z 348 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.96 (d, IH), 7.07 (t, IH), 6.71 (d, IH), 6.60 (d, IH), 6.52 (d, IH), 6.12 (br s, IH), 5.82 (m, IH), 5.76 (dd, IH), 5.44 (br s, IH), 5.01 (m, 2H), 3.86 (s, 3H), 2.44 (m, IH), 2.20 (m, IH), 2.16 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); Anal, calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C, 9.34; H, 7.00; N,
4.07.
Example 37 (+)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-riJbenzopyrano[3,4- flquinoline Example 2 was purified by flash chromatography on Chiralcel OJ with 10% ethanol/hexanes to provide the desired compound. [DJD= +2.1(c l.l, CHCl3);
MS (DCI/NH3) m/z 348 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.96 (d, IH), 7.07 (t, IH), 6.71 (d, IH), 6.60 (d, IH), 6.52 (d, IH), 6.12 (br s, IH), 5.82 (m, IH), 5.76 (dd, IH), 5.44 (br s, IH), 5.01 (m, 2H), 3.86 (s, 3H), 2.44 (m, IH), 2.20 (m, IH), 2.16 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); Anal, calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C, 79.29; H, 7.01; N,
3.92.
Example 38 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[11benzopyrano[3,4-f1quinoline Example 2B and triethylsilane were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 308 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.82 (d, IH), 7.05 (t, IH), 6.72 (dd, IH), 6.58 (d, IH), 6.57 (dd, IH), 6.13 (d, IH), 5.39 (t, IH), 5.10 (s, 2H), 3.84 (s, 3H), 2.02 (d, 3H), 1.18 (s, 6H);
Anal, calcd for C2θH2lNθ2-0.1H2θ: C, 77.69; H, 6.91; N, 4.53. Found: C, 77.60; H,
7.15; N, 4.33.
Example 39 4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)-N,N-dimethylbenzenamine Example 2B and N,N-dimethylaniline were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 427 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D7.98 (d, IH), 6.95 (d, 2H), 6.88 (t, IH), 6.57 (d, IH),
6.64 (s, IH), 6.53 (m, 3H), 6.39 (d, IH), 6.14 (d, IH), 5.35 (s, IH), 3.79 (s, 3H), 2.80 (s, 6H), 1.84 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H); Anal, calcd for C28H30N2O2O.25H2O: C, 78.02; H, 7.13; N, 6.50. Found: C, 78.29; H,
7.38; N, 6.01.
Example 40
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-
1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline Example 2B and 2-methoxythiophene were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 420 (M+H)+; iH NMR (500 MHz, DMSO-d6)D7.98 (d, IH), 6.97 (d, IH), 6.73 (s, IH), 6.67 (d, IH), 6.63 (d, IH), 6.46 (d, IH), 6.20 (d, IH), 6.18 (s, IH), 5.96 (d, 4H), 5.39 (s, IH), 3.82 (s,
3H), 3.72 (s, 3H), 1.98 (s, 3H), 1.21 (s, 3H), 1.13 (s, 3H); Anal, calcd for C25H25NO3S: C, 71.57; H, 6.01; N, 3.34. Found: C, 71.54; H, 5.99; N,
3.17.
Example 41
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)- 1 H-[ 1 Ibenzopyrano [3 ,4-f]quinoline Example 2B and 2-propylthiophene were processed as in Example 2 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 6.95 (t, IH), 6.84 (s, IH), 6.67 (d, IH),
6.61 (d, IH), 6.51 (d, IH), 6.46 (d, IH), 6.41 (d, IH), 6.18 (m, IH), 5.39 (s, IH), 3.82 (s, 3H), 2.59 (t, 2H), 1.96 (s, 3H), 1.50 (h, 2H), 1.20 (s, 3H), 1.14 (s, 3H), 0.83 (t, 3H); HRMS calcd m/z for C27H29NO2S : 431.1919 (M+H)+. Found: 431.1911.
Example 42
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-r4-(l-morpholinyl)phenylJ- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline Example 2B and 4-phenylmorpholine were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 469 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.00 (d, IH), 7.00 (d, 2H), 6.92 (t, IH), 6.76 (d, 2H), 6.68 (d, 2H), 6.55 (d, IH), 6.40 (d, IH), 6.16 (m, IH), 5.36 (s, IH), 3.79 (s, 3H), 3.62 (m, 4H), 3.05 (m, 4H), 1.81 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H); Anal, calcd for C30H32N2O2-0.5H2O: C, 75.45; H, 6.96; N, 5.87. Found: C, 75.46; H, 6.69; N, 5.31.
Example 43 1 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f]quinolin-
5-yl)-3 ,3 -dimethyl-2-butanone Example 2B and (2,2-dimethyl-l-methylenepropoxy)trimethylsilane were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.95 (d, IH), 7.04 (t, IH), 6.71 (d, IH), 6.60 (d, IH), 6.41 (d, IH), 6.33 (d, IH), 6.15 (br s, IH), 5.43 (s, IH), 3.87 (s, 3H), 3.26 (m, IH), 2.36 (m, IH), 2.13 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H), 0.89 (s, 9H); Anal, calcd for C26H3lNθ3-0.33H2θ: C, 75.90; H, 7.76; N, 3.40. Found: C, 75.91; H, 8.17; N, 3.62.
Example 44 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[11benzopyrano[3,4-f]quinoline-5- carbonitrile Example 2B and cyanotrimethylsilane were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 333 (M+H)+; H NMR (300 MHz, DMSO-d6)D7.96 (d, IH), 7.20 (t, IH), 6.89 (d, IH), 6.84 (s, IH), 6.74 (d, 8H), 6.73 (d, IH), 6.46 (s, IH), 5.51 (s, IH), 3.90 (s, 3H), 2.22 (s, 3H), 1.29 (s, 3H), 1.09 (s, 3H);
Anal, calcd for C2lH2θN2θ2-0.25H2θ: C, 74.87; H, 6.13; N, 8.31. Found: C, 75.00; H,
6.23; N, 8.34.
Example 45 l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyranor3,4-fjquinolin-
5 -yl)-2-propanone Example 2B and 2-(trimethylsiloxy)-propene were processed as in Example 2 to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)D7.96 (t, IH), 7.04 (t, IH,), 6.71 (d, IH), 6.58 (d, IH), 6.48 (d, IH), 6.20 (dd, IH), 6.16 (s, IH), 5.4 (s, IH), 3.87 (s, 3H), 2.91 (q, IH), 2.16 (s,
3H), 2.04 (s, 3H), 1.15 (d, 6H);
HRMS calcd m/z for C23H25O3N: 363.1834 (M+H)+. Found: 363.1843; Anal, calcd for C23H25NO3-0.33H2O: C, 74.79; H, 7.00; N, 3.79. Found: C, 74.77; H, 7.14; N, 3.67.
Example 46 methyl 2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline-
5 -acetate Example 2B and 1 -methoxy- l-(tert-butyldimethylsiloxy)ethylene were processed as in Example 2 to provide the desired compound.
MS (DCI /NH3) m/z 380 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.11 (t, IH), 6.78 (d, IH), 6.66 (d, IH), 6.53 (d, IH), 6.27 (d, IH), 6.22 (s, 2H), 5.52 (s, IH), 3.93 (s, 3H), 3.67 (s, 3H), 2.70 (dd, IH), 2.64 (d, IH), 2.27 (s, 3H), 1.22 (d, 6H); Anal, calcd for C23H25O4N-0.5H2O: C, 71.12; H, 6.75; N, 3.61. Found: C, 71.46; H, 6.81; N, 3.45.
Example 47 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l Jbenzopyrano[3 ,4-f]quinolin-
5-yl)- 1 -phenylethanone Example 2B and 1 -phenyl- l-(trimethylsiloxy)ethylene were processed as in
Example 2 to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)Q8.01 (d, IH), 7.72 (d, 2H), 7.59 (t, IH), 7.40 (t, 2H),
6.93 (t, IH), 6.70 (d, IH), 6.61 (d, IH), 6.43 (d, IH), 6.25 (d, IH), 6.18 (s, IH), 5.44 (s, IH), 3.90 (s, 3H), 3.66 (q, IH), 2.95 (d, IH), 2.16 (s, 3H), 1.16 (s, 6H); HRMS calcd m/z for C28H27O3N: 425.1991 (M+H)+. Found: 425.2005.
Example 48 5-r2-(chloromethyl)-2-propenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[l]benzopyrano[3 ,4-fjquinoline Example 2B and 2-chloromethyl-3-trimethylsilyl-l-propene were processed as in
Example 2 to provide the desired compound. iH NMR (300 MHz, DMSO-dβ)Q7.96 (d, IH), 7.03 (t, IH), 6.69 (d, IH), 6.59 (d, IH),
6.44 (d, IH), 6.15 (s, IH), 5.96 (dd, IH), 5.45 (s, IH), 5.27 (s, IH), 4.95 (s, IH), 4.17 (q, 2H), 3.87 (s, 3H), 2.55 (d, IH), 2.26 (dd, IH), 2.20 (s, 3H), 1.15 (d, 6H); HRMS m/z calcd for C24H26O2CIN: 395.1652 (M+H)+. Found: 395.1645;
Anal, calcd for O24H26O2 N-0.333H2O: C, 71.73; H, 6.69; N, 3.49. Found: C, 71.71; H, 6.32; N, 3.35.
Example 49 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-(-methylene- 1H-[1 Jbenzopyrano [3 ,4- flquinoline-5-propanol, acetate (ester) Example 2B and 2-[(trimethylsilyl)methylj-2-propen-l-yl acetate were processed as in Example 2 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q8.02 (d, IH), 7.10 (t, IH), 6.75 (dd, IH), 6.65 (d, IH), 6.50 (d, IH), 6.18 (s, IH), 5.98 (dd, IH), 5.51 (s, IH), 5.16 (s, IH), 4.98 (s, IH), 4.48 (q,
2H), 3.93 (s, 3H), 2.25 (s, 3H), 1.22 (s, 6H); HRMS calcd m/z for C26H29O4N: 419.2097 (M+H)+. Found: 419.2095; Anal, calcd for C26H-29O4N-0.25H2O: C, 73.65; H, 7.01; N, 3.30. Found: C, 73.83; H, 6.91; N, 3.20.
Example 50 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(4-methylphenyl)- 1 H- [1 Jbenzopyrano [3 ,4- fjquinoline Example IF and 4-methylphenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 398 (M+H); iH NMR (300 MHz, DMSO-d6)Q8.00 (d, IH), 7.02 (q, 4H), 6.89 (t, IH), 6.72 (s, IH),
6.69 (d, IH), 6.55 (d, IH), 6.41 (d, IH), 6.18 (br s, IH), 5.37 (br s, IH), 3.79 (s, 3H), 2.18 (s, 3H), 1.83 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H); Anal, calcd for C27H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C, 81.56; H, 7.25; N,
3.29.
Example 51 5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H-f 1 jbenzopyrano ["3 ,4-f]quinoline Example 2B and 3-fluoro-4-methylphenylmagnesium bromide were processed as in Example 11 to provide the desired compound.
MS (DCI/NH3) m/z 416 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.11 (t, IH), 6.95-6.84 (m, 3H), 6.74 (s, IH), 6.71 (d, IH), 6.57 (d, IH), 6.46 (d, IH), 6.23 (s, IH), 5.39 (s, IH), 3.79 (s, 3H), 2.11 (s, 3H), 1.85 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H); Anal, calcd for C27H26NO2F: C, 78.05; H, 6.31; N, 3.37. Found: C, 77.80; H, 6.51; N,
3.06.
Example 52 5-(3-bromophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline
Example IF and 3-bromophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI/NH3) m/z 462 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.02 (d, IH), 7.36 (m, IH), 7.30 (m, IH), 7.17 (m, 2H), 6.93 (t, IH), 6.79 (s, IH), 6.72 (d, IH), 6.58 (d, IH), 6.48 (d, IH), 6.24 (br s, IH),
5.41 (br s, IH), 3.80 (s, IH), 1.85 (s, 3H), 1.23 (s, IH), 1.16 (s, IH).
Example 53 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethyl)-lH-[11benzopyrano[3 ,4- fj quinoline Example 2B and benzylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/z 398 (M+H); iH NMR (300 MHz, DMSO-d6)Q8.02 (d, IH), 7.31 - 7.18 (m, 3H), 7.12 (m, 3H), 6.75 (d, IH), 6.63 (d, IH), 6.46 (d, IH), 6.15 (d, IH), 5.93 (dd, IH), 5.43 (s, IH), 3.89 (s, 3H), 2.98 (dd, IH), 2.74 (dd, IH), 2.23 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H); Anal, calcd for O27H27NO2-0.25H2O: C, 80.67; H, 6.89; N, 3.48. Found: C, 80.78; H, 7.08; N, 3.26.
Example 54 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-propyl-lH-riJbenzopyrano[3,4-f1quinoline Example 2B and propylmagnesium bromide were processed as in Example 11 to provide the desired compound.
MS (DCI/NH3) m/z 350 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.94 (d, IH), 7.05 (t, IH), 6.69 (d, IH), 6.58 (d, IH), 6.54 (d, IH), 6.10 (d, IH), 5.70 (m, IH), 5.44 (s, IH), 3.85 (s, 3H), 2.16 (s, 3H), 1.70 (m, IH), 1.43 - 1.31 (m, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 0.83 (t, 3H); Anal, calcd for C23H27NO2: C, 79.05; H, 7.79; N, 4.01. Found: C, 78.76; H, 7.86; N,
3.84.
Example 55 5-(4-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline
Example 2B and 4-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)D7.99 (d, IH), 7.11 (d, IH), 6.92 (m, 2H), 6.71 (s, IH),
6.68 (s, IH), 6.55 (d, IH), 6.43 (d, IH), 6.21 (s, IH), 5.39 (s, IH), 3.99 (s, 3H), 2.11 (s, 3H), 1.84 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H);
HRMS calcd m/z for C27H26O2NF: 415.1948 (M+H)+. Found: 415.1947.
Example 56 5 -(3 -fluorophenyl)-2, 5 -dihy dro- 10-methoxy-2 ,2 ,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3,4- fjquinoline
Example 2B and 3-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q8.03 (d, IH), 7.22 (q, IH), 6.90 (m, 4H), 6.78 (s, IH), 6.73 (d, IH), 6.56 (d, IH), 6.46 (d, IH), 6.24 (s, IH), 5.40 (s, IH), 3.79 (s, 3H), 1.85 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H);
HRMS calcd m/z for C26H24O2NF: 402.1869 (M+H)+. Found: 402.1865; Anal, calcd for C26H24O2FN-2.25H2O: C, 70.65; H, 6.50; N, 3.17. Found: C, 70.56; H,
6.18; N, 2.83.
Example 57 2,5-dihydro-10-methoxy-2,2,4,5-tetramethyl-lH-riJbenzopyrano[3,4-f]quinoline Example 2B and methylmagnesium iodide were processed as in Example 11 to provide the desired compound. iHNMR (300 MHz, DMSO-d6)Q7.91 (d, IH), 7.02 (8, IH), 6.67 (d, IH), 6.54 (s, IH),
6.52 (d, IH), 6.08 (s, IH), 5.87 (q, IH), 5.43 (s, IH), 3.85 (s, 3H), 2.16 (s, 3H), 1.25 (d, 3H), 1.18 (s, 3H), 1.13 (s, 3H); HRMS calcd m/z for C21H23O2N: 321.1729 (M+H)+. Found: 321.1728.
Example 58 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-( 1 -methylethyP)- 1 H- [ 1 Jbenzopyrano [3 ,4- fj quinoline Example 2B and 2-propylmagnesium chloride were processed as in Example 11 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q7.99 (d, IH), 7.03 (t, IH), 6.57 (d, IH), 6.45 (d, IH),
6.53 (d, IH), 6.18 (s, IH), 5.45 (s, IH), 5.31 (d, IH), 3.85 (s, IH), 2.16 (s, 3H), 1.79 (m, IH), 1.30 (s, 3H), 1.01 (s, 3H), 0.93 (d, 3H), 0.62 (d, 3H); HRMS calcd m/z for C23H27O2N: 349.2042 (M+H)+. Found: 349.2041.
Example 59 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH- [ljbenzopyranor3,4-f]quinoline Example 2B and sec-butylmagnesium chloride were processed as in Example
1 lto provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q7.93 (d, IH), 7.03 (t, IH), 6.67 (d, IH), 6.51 (q, 2H),
6.08 (s, IH), 5.77 (dd, IH), 5.43 (s, IH), 3.85 (s, 3H), 2.18 (s, 3H), 1.72 (m, 2H), 1.76 (d, 6H), 0.86 (d, 3H), 0.74 (d, 3H); HRMS calcd m/z for C24H29O2N: 363.2198 (M+H)+. Found: 363.2208;
Anal, calcd for C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C, 79.63; H, 7.83; N, 3.89. Example 60 5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fj quinoline Example 2B and ethylmagnesium bromide were processed as in Example 11 to provide the desired compound.
MS (DCI/NH3) m/z 336 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.92 (d, IH), 7.03 (t, IH), 6.67 (d, IH), 6.54 (t, 2H), 6.10 (s, IH), 5.55 (dd, IH), 5.44 (s, IH), 3.84 (s, 3H), 2.16 (s, 3H), 1.63 (m, IH), 1.44 (m, IH), 1.15 (s, 6H), 0.84 (t, 3H); Anal, calcd for O22H25O2N-2.25 H2O: C, 77.73; H, 7.56; N, 4.12. Found: C, 77.95; H,
7.60; N, 4.07.
Example 61 2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline-5 - carboximidic acid ethyl ester
A solution of Example 44 (0.040 g, 0.120 mmol) in ethanol (5 mL) was cooled to -5 °C, saturated with hydrogen chloride gas, stirred for 10 minutes at -5 °C, stirred 14 hours at room temperature, neutralized with NaHCO3, and extracted with diethyl ether. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired compound.
MS (DCI/NH3) m/z 379 (M+H); iH NMR (300 MHz, DMSO-d6)D7.95 (d, IH), 7.32 (s, IH), 7.05 (t, IH), 6.69 (t, 2H), 6.61 (d, IH), 6.22 (s, IH), 6.14 (s, IH), 5.44 (s, IH), 3.92 (m, 2H), 3.82 (s, 3H), 2.06 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H), 1.02 (t, 3H).
Example 62 2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene lH-[ljbenzopyrano[3,4- fjquinoline-5-propanol A solution of Example 49 (0.060 g, 0.143 mmol) in 1:1 methanol/water (10 mL) was treated with K2CO3 (0.080 g, 1.0 mmol), stirred for 24 hours at room temperature, neutralized with 10% HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25%> dichloromethane/ethyl acetate to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)Q8.01 (d, IH), 7.72 (d, 2H), 7.59 (t, IH), 7.40 (t, 2H),
6.93 (t, IH), 6.70 (d, IH), 6.61 (d, IH), 6.43 (d, IH), 6.25 (d, IH), 6.18 (s, IH), 5.44 (s, IH), 3.90 (s, 3H), 3.66 (q, IH), 2.95 (d, IH), 2.16 (s, 3H), 1.16 (s, 6H); HRMS calcd m/z for C28H27O3N: 425.1991 (M+H)+. Found: 425.2005. Example 63 2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-rijbenzopyranor3,4-f|quinoline-5- acetamide Example 46 was hydrolyzed with lithium hydroxide in THF to provide the corresponding acid which was then coupled to N,N-dimethylamine with l-(3- dimethylaminopropyI)-3-ethyIcarbodiimide to provide the desired compound. iHNMR (300 MHz, DMSO-d6)D7.94 (d, IH), 7.04 (t, IH), 6.70 (d, IH), 6.59 (d, IH),
6.46 (d, IH), 6.26 (d, IH), 6.15 (s, IH), 5.44 (s, IH), 3.86 (s, 3H), 2.88 (q, IH), 2.81 (s, 3H), 2.55 (s, 3H), 2.25 (s, IH), 2.19 (s, 3H), 1.15 (s, 6H);
HRMS calcd m/z for C24H28O3N2: 392.2100 (M+H)+. Found: 392.2104;
Anal, calcd for C24H28 2O3: C, 73.44; H 7.19, 7.35; N, 7.14. Found: C, 73.17; H,
7.19; N, 6.85.
Example 64
2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[lJbenzopyrano[3,4-f]quinoline-
5-ethanamine A solution of Example 63 in diethyl ether was reduced at room temperature with lithium aluminum hydride to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)Q7.93 (d, IH), 7.03 (t, IH), 6.68 (8, IH), 6.54 (t, IH),
6.12 (s, IH), 5.76 (dd, IH), 5.44 (s, IH), 3.85 (s, 3H), 2.18 (s, 3H), 2.05 (s, 6H), 1.18 (s,
3H), 1.14 (s, 3H);
HRMS m z calcd for C24H30O2N2: 378.2307 (M+H)+. Found: 378.2307.
Example 65
N-cyclopropyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fj quinoline-5 -acetamide Example 46 and cyclopropylmethylamine were processed as in Example 63 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)D7.94 (d, IH), 7.70 (d, IH), 7.03 (t, IH), 6.68 (d, IH),
6.58 (d, IH), 6.43 (d,), 6.23 (dd, IH), 6.13 (s, IH), 5.43 (s, IH), 3.85 (s, 3H), 2.51 (m, 2H), 2.07 (d, IH), 2.03 (s, 3H), 1.17 (s, 3H), 1.13 (s, 3H), 0.60 (m, 2H), 0.31 (s, 2H); HRMS m/z calcd for C25H28O3N2: 404.2100 (M+H)+. Found: 404.2092.
Example 66
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propynyl)-lH-[lJbenzopyrano[3,4- f]quinoline Example 2B and 2-propynylmagnesium bromide were processed as in Example 11 to provide the desired compound. iH NMR (300 MHz, DMSO-d(3)Q7.97 (d, IH), 7.06 (t, IH), 6.71 (d, IH), 6.56 (q, 2H),
6.16 (s, IH), 5.88 (q, IH), 5.44 (s, IH), 3.86 (s, 3H), 2.82 (q, IH), 2.41 (q, IH), 2.19 (s, 3H), 1.16 (s, 3H);
HRMS m/z calcd for C23H23O2N: 345.1729 (M+H)+. Found: 345.1738.
Example 67 5-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-ri1benzopyrano[3,4-f]quinolin-5- yl)-2(5H)-furanone
Example 2B and 2-trimethylsiloxyfuran were processed as in Example 2C to provide the desired compound. MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.11 (d, IH), 7.13 (dd, IH), 6.75 (d, IH), 6.72 (d, IH), 6.64 (d, IH), 6.37 (d, IH), 6.25 (dd, IH), 6.23 (d, IH), 5.83 (d, IH), 5.47 (s, IH), 5.12
(dd, IH), 3.87 (s, 3H), 2.03 (s, 3H), 1.30 (s, 3H), 1.09 (s, 3H); Anal, calcd for C24H23NO4: C, 74.02; H, 5.95; N, 3.60. Found: C, 73.89; H, 5.94; N,
3.51.
Example 68
5-(3-butenyl)-2,5-dihdyro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fjquinoline Example 2B and 3-butenylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/z 362 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.94 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.57 (d, IH), 6.10 (s, IH), (5.78 (dddd, IH), 5.65 (dd, IH), 5.44 (s, IH), 5.00 (dd, IH), 4.93 (dd, IH), 3.85 (s, 3H), 2.16 (s, 3H), 2.10 (m, 2H), 1.78 (m, IH), 1.45 (bm, IH), 1.16 (s, 3H), 1.14 (s, 3H); HRMS calcd m z for C24H27NO2: 361.2042 (M+H)+. Found: 361.2039.
Example 69 2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-lH-ri1benzopyrano[3,4-f]quinoline-5-propanol Example 2 (52.0 mg, 0.15 mmol) in THF (4 mL) at 0 °C was treated dropwise with 0.5M 9-BBN (600 OL, 0.30 mmol), stirred overnight at room temperature, cooled to 0 °C, treated sequentially with 2.5M NaOH (400 DL, 1.0 mmol), and 30% H2O2 (250
DL), stirred for 2 hours at room temperature, partitioned between 1:1 ethyl acetate/water, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 30%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m z 366 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D7.94 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.53 (d, IH), 6.10 (s, IH), 5.70 (dd, IH), 5.44 (s, IH), 4.36 (t, IH), 3.85 (s, 3H), 3.33 (m,
2H), 2.16 (s, 3H), 1.40-1.75 (bm, 4H), 1.17 (s, 3H), 1.14 (s, 3H); HRMS calcd m/z for C23H27NO3: 365.1991 (M+H)+. Found: 365.1991
Example 70 10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[11benzopyrano[3,4-f]quinoline
Example 70A Example 3C (0.208 g, 0.493 mmol) and tetraethyltin (0,444 g, 1.89 mmol) were combined with (1 ,3-bis(diphenylphosphino)ferrocene)palladium(II)- chloride-dichloromethane (0.039 g, 0.047 mmol) in l-methyl-2-pyrrolidinone (3 mL) at
80 °C for 16 hours and concentrated to provide the desired compound. MS
Example 70 10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline
Example 70A was processed as in examples IF, IG, and 1 to provide the desired compound. MS (DCI/NH3) m/z 382 (M+H)+; iH NMR (300 MHz, DMSO)D7.37 (d, IH), 7.21-7.16 (m, 5H), 6.85, (dd, IH), 6.75 (s, IH), 6.73 (dd, IH), 6.68 d, IH), 6.58 (dd, IH), 6.21 (s, IH), 5.39 (s, IH), 3.02-2.75 (m,
2H), 1.79 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H), 1.15 (m, 3H); HRMS calcd for C27H27NO: 381.2093 (M+H)+. Found 381.2096.
Example 71 2,5 -dihydro-2,2 ,4, 10-tetrametnyl-5 -phenyl- 1 H- [ 1 J benzopyrano [3 ,4-f] quinoline
Example 3C and tetramethyltin were processed as in Example 70 to provide the desired compound. MS (DCI/NH3) m/z 368 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.44 (d, IH), 7.21-7.12 (m, 5H), 6.82 (dd, IH), 6.74 (d, IH), 6.71 (s, IH), 6.69 (dd, IH), 6.59 (dd, IH), 6.21 (s, IH), 5.39 (s, IH), 2.51 (s,
3H), 1.80 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H); HRMS calcd m/z for C26H25NO: 367.1936 (M+H)+. Found: 367.1931. Example 72 5-(3,5-dichlorophenyl)- 10-ethyl-2,5-dihydro-2,2,4-trimethyl- 1 H- T 1 Jbenzopyrano [3 ,4-f] quinoline Example 70A and 3,5-dichlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound.
MS (DCI/NH3) m/z 450 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.43 (d, IH), 7.43 (t, IH), 7.18 (d, 2H), 6.91 (dd, IH), 6.80 (dd, IH), 6.78 (d, IH), 6.72 (s, IH), 6.62 (dd, IH), 6.35 (s, IH), 5.42 (s, IH), 3.15- 2.75 (m, 2H), 1.79 (s, 3H), 1.27 (s, 3H), 1.14 (s, 3H), 1.13 (t, 3H); HRMS calcd m/z for C27H25NOCI2: 449.1313 (M+H)+. Found: 449.1330.
Example 73 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl- 1 H- [ 1 Ibenzopyrano [3 ,4-fj quinolin- 10-amine
Figure imgf000112_0001
Example 73A Example 3C and 3,5-dichlorophenylmagnesium bromide were processed as in Example 72 to provide the desired compound. MS (DCI/NH3) m/z 539 (M+H)+.
Example 73 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl- 1 H- [ 1 Jbenzopyrano \3 ,4-f]quinolin- 10-amine Example 73A was processed as in Example 3 to provide the desired compound. MS (DCI/NH3) m/z 451 (M+H)+; iHNMR (300 MHz, DMSO-d6)Q7.91 (d, IH), 7.45 (dd, IH), 7.20 (m, 2H), 6.83 (dd, IH), 6.75 (d, IH), 6.71 (s, IH), 6.22 (dd, IH), 6.18 (s, IH), 6.17 (dd, IH), 5.57 (d, IH), 5.44 (s, IH), 2.65 (d, 3H), 1.85 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H); HRMS calcd m/z for C26H24N2OCI2: 450.1266 (M+H)+. Found: 450.1267.
Example 74 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH- [ 1 jbenzopyrano [3 ,4-f] quinolin- 10-amine Example 73 A and allylamine were processed as in Example 3 to provide the desired compound. MS (DCI/NH3) m/z 477 (M+H)+; iH NMR (300 MHz, DMSO-dfS)D7.99 (d, IH), 7.49 (dd, IH), 7.27 (d, 2H), 6.82 (dd, IH), 6.77 ( d, IH), 6.75 (s, IH), ), 6.25 (dd, IH), 6.21 (s, IH), 6.20 (dd, IH), 5.95-5.86
(m, IH), 5.69-5.65 (m, IH), 5.48 (s, IH), 5.18-5.12 (m, IH), 5.11-5.06 (m, IH), 3.78- 3.70 (m, 2H), 1.88 (s, 3H), 1.30 (s, 3H), 1.20 (s, 3H); HRMS calcd m/z for C28H26N2OCI2: 476.1422 (M+H)+. Found: 476.1428.
Example 75
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propynyloxy)-lH-rijbenzopyrano[3,4- fjquinoline Example 7 and propargyl bromide were processed as in Example 9A to provide the desired compound. MS (DCI/NH3) m/z 408 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 1.12 (s, 3H), 1.23 (s, 3H), 1.83 (s, 3H), 3.59 (t, IH,), 4.81 (d, 2H), 5.39 (br s, IH), 6.19 (br s, IH), 6.47 (d, IH), 6.61 (d, IH), 6.71 (d, IH), 6.78 (s, IH), 6.90 (t, IH), 7.14-7.22 (m, 5H), 8.02 (d, IH); Anal, calcd for C28H25NO2: C, 82.53; H, 6.18; N, 3.44. Found: C, 82.64; H 6.31; N, 3.38.
Example 76 2,5 -dihy dro-2,2,4-trimethyl-5 -phenyl- 10-(2-propenyloxy)- 1H-[1 jbenzopyrano [3,4- fjquinoline Example 7 and allyl bromide were processed as in Example 9A to provide the desired compound. MS (DCI) m/z 410 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 1.15 (s, 3H), 1.23 (s, 3H), 1.84 (s, 3H), 4.51-4.64 (m,
2H), 5.26 (dq, IH), 5.39 (br s, IH), 5.40 (dq, IH), 6.12 (ddt, IH), 6.21 (br s, IH), 6.44 (dd, IH), 6.55 (dd, IH), 6.69 (d, IH), 6.77 (s, IH), 6.88 (t, IH), 7.15-7.24 (m, 5H), 8.06
(d, IH); HRMS calcd m z for C28H27NO2: 409.2042 (M+H)+. Found: 409.2039.
Example 77 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline-
10-methanol A solution of Example 4 (32 mg, 0.085 mmol) in dichloromethane (3 mL) under argon, at -78° C, was treated dropwise with diisobutylaluminum hydride (1.0 M) in . cyclohexanes (0.400 mL, 0.40 mmol), warmed to 0 °C for 3.5 hours, treated with Rochelle's salt, separated, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The residue was applied to two 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted three times with hexane, then ethyl acetate/hexanes (10:90). The product band was scraped off and extracted with ethyl acetate to provide the desired compound. MS (DCI/NH3) m/z 348 (M+H)+; iH NMR.D7.47 (d, IH), 7.14 (m, 2H), 6.80 (dd, IH), 6.64 (d, IH), 6.17 (m, IH), 5.81 (ddm, IH), 5.73 (dd, IH), 5.46 (m, IH), 5.32 (dd, IH), 5.02 (dm, IH), 4.94 (dm, IH), 4.62 (m, 2H), 2.30 (m, 2H), 2.17 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H);
HRMS Calcd m/z for C23H25NO2: 347.1885 (M+H)+. Found: 347.1897.
Example 78 2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[ljbenzopyrano[3,4-f]quinoline- 10-carboxy lie acid
Example 74 and chlorotris(triphenylphosphate)rhodium(I) chloride were processed as in Example 3 to provide the desired compound. MS (DCI/NH3) m/z 437 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.91 (d, IH), 7.44 (dd, IH), 7.19 (d, 2H), 6.74 (d, IH), 6.70 (s, IH), 6.69 (dd, IH), 6.26 (dd, IH), 6.22 (s, IH), 6.11 (dd, 1.0 Hz, IH), 5.43 (s,
IH), 5.15 (s, 2H), 1.84 (s, 3H), 1.23 (s, 3H), 1.15 (s, 3H).
Example 79 5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline
Example 9A and 3,5-dichlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DCI) m/z 466 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.10 (d, IH), 7.46 (t, IH), 7.13 (d, 2H), 6.95 (dd, IH), 6.81 (s, IH), 6.72 (d, IH), 6.60 (d, IH), 6.51 (d, IH), 6.32 (d, IH), 5.44 ( s, IH), 3.99-
4.12 (m, IH), 1.87 (s, 3H), 1.37 (t, 3H), 1.23 (s, 3H), 1.20 (s, 3H); HRMS calcd m/z for C27H25NO2CI2: 465.1262 (M+H)+. Found 465.1277.
Example 80 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin- lO-ol Example 7A and 3,5-dichlorobenzylmagnesium bromide were processed as in examples 7B and 7 to provide the desired compound. MS (DCI) m/z 438, 440 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D9.79 (s, IH), 8.18 (d, IH), 7.44 (t, IH), 7.12 (dd, 2H),
6.79 (d, IH), 6.77 (s, IH), 6.73 (d, IH), 6.45 (d, IH), 6.28 (dd, IH), 6.23 (d, IH), 5.43 (s, IH), 1.87 (d, 3H), 1.22 (s, 3H), 1.16 (s, 3H); HRMS calcd m/z for C25H21CI2NO2: 437.0949 (M+H)+. Found: 437.0955.
Example 81 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
10-ylJmethylcarbonate Example 80 and methylchloroformate were processed as in examples 7B and 7 to provide the desired compound. MS (DCI/NH3) m/z 496 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.58 (d, IH), 7.45 (t, IH), 7.24 (m, 2H), 7.02 (t, IH), 6.82 (s, IH), 6.80 (dd, IH), 6.75 (dd, IH), 6.74 (d, IH), 6.48 (s, IH), 5.43 (s, IH), 3.79 (s, 3H), 1.79 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H);
Anal, calcd for C27H23NO4C12 C, 65.33; H, 4.67; N, 2.82. Found: C, 65.12; H, 4.55,
N, 2.79.
Example 82 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[11benzopyranor3,4-fjquinolin-10-ol
Example 7A and allylmagnesium bromide were processed as in examples 7B and
7 to provide the desired compound.
MS (DCI/NH3) m/z 334 (M+H)+; iH NMR (300 MHz, DMSO-dβ)D9.77 (s, IH), 8.10 (d, IH), 6.88 (t, IH), 6.58 (d, IH), 6.53 (d, IH), 6.35 (d, IH), 6.05 (s, IH), 5.89-5.72 (m, 2H), 5.44 (s, IH), 5.03 (d, IH),
4.99 (d, IH), 2.50-2.40 (m, IH), 2. 25-2.18 (m, IH), 2.16 (s, 3H), 1.16, (s, 3H), 1.15 (s,
3H);
HRMS calcd m/z for C22H23NO2: 333.1729 (M+H)+. Found 333,1734.
Example 83
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [11benzopyrano[3,4-f]quinoline Example 82 and dibromodifluoromethane were processed as in examples 7B and 7 to provide the desired compound. MS (DCI/NH3) m/z 462 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.60 (d, IH), 7.21 (t, IH), 7.0 (m, IH), 6.95 (dd, IH), 6.64 (d, IH), 6.35 (s, IH), 5.89-5.76 (m, 2H), 5.46 (s, IH), 5.04 (dd, IH), 4.96 (dd, IH), 2.55-2.44 (m, IH), 2.33-2.25 (m, IH), 2.18 (s, 3H), 1.19, (s, 3H), 1.17 (s, 3H); HRMS calcd m/z for C23H22F2NO2Br: 461.0802 (M+H)+. Found 461.0815.
Example 84 [3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f]quinolin- 5-yl)phenylj methylcarbonate
Example 13 and methylchloroformate were processed as in Example 10 to provide the desired compound. MS (DCI/NH3) m z 458 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.25 (t, IH), 7.12 (d, IH), 7.01 (q, IH), 6.90 (q, 2H), 6.78 (s, IH), 6.72 (d, IH), 6.57 (q, IH), 6.44 (q, IH), 6.20 (d, IH), 5.39 (s,
IH), 3.80 (s, 3H), 3.63 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.16 (s, 3H); Anal, calcd for C28H27NO5: C, 73.50; H, 5.94; N, 3.06. Found: C, 73.63; H, 6.20; N,
2.86.
Example 85
2,5-dihydro-l 0-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline Example 13 and methyl iodide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 414 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.01 (d, IH), 7.13 (t, IH), 6.92 (t, IH), 6.75-6.67 (m, 5H), 6.57 (dd, IH), 6.46 (dd, IH), 6.20 (d, IH), 5.39 (s, IH), 3.80 (s, 3H), 3.63 (s, 3H), 1.88 (s, 3H), 1.22 (s, 3H), 1.16 (s, 3H); Anal, calcd for C27H27NO3: C, 78.42; H, 6.58; N, 3.38. Found: C, 78.58; H, 6.55; N, 3.23.
Example 86 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenylJ- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline Example 13 and allyl bromide were processed as in Example 14 to provide the desired compound. MS (DCI NH3) m/z 440 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, IH), 7.13 (t, IH), 6.92 (t, IH), 6.78-6.67 (m, 5H), 6.56 (d, IH), 6.46 (d, IH), 6.20 (d, IH), 5.95 (m, IH), 5.40 (s, IH), 5.31 (dd, IH), 5.21 (dd, IH), 4.42 (d, 2H), 3.80 (s, 3H), 1.86 Cs, 3H), 1.23 (s, 3H), 1.16 Cs, 3H);
Anal, calcd for C29H29NO3: C, 79.24; H, 6.64; N, 3.18. Found: C, 78.87; H, 6.46; N,
3.07. Example 87 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenylJ- lH-[11benzopyrano[3,4-f]quinoline Example 13 and benzyl bromide were processed as in Example 14 to provide the desired compound.
MS (DCI/NH3) m/z 490 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.06 (d, IH), 7.40 (m, 5H), 7.18 (t, IH), 6.97 (t, IH), 6.90-6.85 (m, 2H), 6.80-6.74 (m, 3H), 6.62 (d, IH), 6.48 (d, IH), 6.24 (d, IH), 5.45 (s, IH), 5.03 (d, 2H), 3.85 (s, 3H), 1.92 (s, 3H), 1.29 (s, 3H), 1.21 (s, 3H); Anal, calcd for C33H31NO3: C, 80.95; H, 6.38; N, 2.86. Found: C, 80.81; H, 6.24; N,
2.96.
Example 88 5-[3-(cyclopropylmethoxy)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-fjquinoline
Example 13 and cyclopropylmethyl bromiode were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 454 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.01 (d, IH), 7.12 (t, IH), 6.92 (t, IH), 6.74-6.68 (m, 5H), 6.55 (d, IH), 6.46 (d, IH), 6.20 (s, IH), 5.39 (s, 3H), 3.79 (s, 3H), 3.66 (d, 2H),
1.86 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H), 1.12 (m, IH), 0.50 (q, 2H), 0.24 (q, 2H); Anal, calcd for C30H31NO3: C, 79.44; H, 6.88; N, 3.08. Found: C, 79.12; H, 6.72; N,
2.99.
Example 89
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-r3-[2-(l-piperidinyl)ethoxyJphenyj- 1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline Example 13 and l-(2-chloroethyl)piperidine were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m z 511 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.01 (d, IH), 7.12 (t, IH), 6.92 (t, IH), 6.77-6.68 (m, 5H), 6.57 (d, IH), 6.46 (d, IH), 6.20 (d, IH), 5.39 (s, IH), 3.91 (t, 2H), 3.80 (s, 3H), 2.55 (t, 2H), 2.35 (b, 4H), 1.92 (s, 3H), 1.46 (b, 4H), 1.36 (b, 2H), 1.22 (s, 3H), 1.16 (s, 3H); Anal, calcd for C33H38N2θ3-0.5H2θ: C, 76.27; H, 7.56; N, 5.39. Found: C, 76.26; H, 7.38; N, 5.28.
Example 90 5-(3-hexyloxyphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline Example 13 and hexyl iodide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 484 (M+H)+; iH NMR (300 MHz, DMSO-d<s)Q8.01 (d, IH), 7.09 (t, IH), 6.92 (t, IH), 6.75-6.67 (m,
5H), 6.56 (dd, IH), 6.46 (dd, IH), 6.18 (d, IH), 5.40 (s, IH), 3.81 (t, 2H), 3.79 (s, 3H), 1.87 (s, 3H), 1.60 (m, 2H), 1.36-1.23 (b, 6H), 1.22 (s, 3H), 1.16 (s, 3H), 0.86 (t, 3H); HRMS calcd m/z for C32H37NO3: 483.2773 (M+H)+. Found: 483.2776.
Example 91
5-r3-(2,4-dinitrophenoxy)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-
1 H- r 1 Jbenzopyrano [3 ,4-fjquinoline Example 13 and l-fluoro-2,4-dinitrobenzene were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 566 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.87 (d, IH), 8.38 (dd, IH), 7.88 (d, IH), 7.40 (t, IH), 7.20-7.08 (m, 2H), 7.20-7.08 (m, 2H), 6.81 (s, IH), 6.72 (d, IH), 6.68 (d, IH), 6.62 (d, IH), 6.46 (dd, IH), 6.24 (d, IH), 5.40 (s, IH), 3.78 (s, 3H), 1.90 (s, 3H), 1.19 (s, 3H),
1.13 (s, 3H); Anal, calcd for C32H27N3O7: C, 67.95; H, 4.81; N, 7.42. Found: C, 68.20; H, 5.05; N,
7.20.
Example 92 2 ,5 -dihy dro- 10-methoxy-2 ,2 ,4-trimethyl-5 - [3 -(2-propynyloxy)phenylJ - lH-[l]benzopyranor3,4-f]quinoιine
Example 13 and propargyl bromide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 566 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.00 (d, IH), 7.13 (t, IH), 6.92 (t, IH), 6.80-6.68(m, 5H), 6.56 (d, IH), 6.48 (d, IH), 6.18 (d, IH), 5.39 (s, IH), 4.67 (d, 2H), 3.80 (s, 3H),
3.50 (t, IH), 1.87 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H);
Example 93 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5-yl)phenol 4-methylbenzenesulfonate (ester)
Example 13 and p-toluenesulfonyl chloride were processed as in Example 15 to provide the desired compound. MS (DCI/NH3) m/z 554 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D7.99 (d, IH), 7.47 (d, 2H), 7.36 (d, 4H), 7.22 (t, IH), 7.13 (d, IH), 6.97 (t, IH), 6.85-6.78 (m, 2H), 6.70 (d, IH), 6.68 (s, IH), 6.59 (dd, IH), 6.37 (dd, IH), 6.24 (d, IH), 5.39 (s, IH), 3.80 (s, 3H), 2.43 (s, 3H), 1.74 (s, 3H), 1.24 (s, 3H), 1.18 (s, 3H); Anal, calcd for C33H31NO5S: C, 71.58; H, 5.64; N, 2.52. Found: C, 71.49; H, 5.75; N,
2.40.
Example 94 4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-f|quinolin- 5-yl)phenolacetate (ester)
Example IF and 4-methoxymethoxyphenyl bromide were processed as in examples 12A-C to provide the desired compound. MS (DCI/NH3) m/z 442 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.02 (d, IH), 7.19 (d, 2H), 6.99 (d, 2H), 6.91 (t, IH), 6.79 (s, IH), 6.71 (d, IH), 6.58 (d, IH), 6.46 (dd, IH), 6.21 (d, IH), 5.39 (s, IH), 3.79 (s,
3H), 2..19 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H); Anal, calcd for C28H27NO4: C, 76.16; H, 6.16; N, 3.17. Found: C, 75.79; H, 6.24; N,
3.03.
Example 95
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-fjquinolin-
5-yl)phenol Example 94 was processed as in Example 13 to provide the desired compound. MS (DCI/NH3) m/z 400 (M+H)+; iH NMR (300 MHz, DMSO-d6)D9.29 (s, IH), 8.05 (d, IH), 7.00 (d, 2H), 6.95 (t, IH),
6.74 (d, 2H), 6.72 (s, IH), 6.63-6.58 (m, 3H), 6.44 (dd, IH), 6.15 (s, IH), 5.41 (s, IH), 3.83 (s, 3H), 1.90 (s, 3H), 1.28 (s, 3H), 1.20 (s, 3H); Anal, calcd for C26H25NO3: C, 78.17; H, 6.30; N, 3.50. Found: C, 78.59; H, 6.20; N,
3.12.
Example 96 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxyjphenyl1- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline Example 95 was processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 460 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.17 (d, 2H), 6.90 (t, IH), 6.82 (d, 2H), 6.72 (s, IH), 6.69 (d, IH), 6.56 (d, IH), 6.42 (d, IH), 6.17 (s, IH), 5.38 (s, IH), 5.16 (s, 2H), 3.80 (s, 3H), 2.11 (s, 3H), 1.85 (s 3H), 1.23 (s, 3H), 1.16 (s, 3H); Anal, calcd for C28H29 O3S: C, 73.17; H, 6.35; N, 3.04. Found: C, 72.86; H, 6.62; N, 2.69.
Example 97 [4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)phenylJ dimethylcarbamate Example 95 and dimethylcarbanoylchloride were processed as in Example 15 to provide the desired compound.1 MS (DCI/NH3) m/z 471 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.15 (d, 2H), 6.98 (d, 2H), 6.90 (d, IH),
6.76 (s, IH), 6.70 (d, IH), 6.57 (d, IH), 6.44 (d, IH), 6.22 (d, IH), 5.40 (s, IH), 3.80 (s, 3H), 2.98 (s, 3H), 2.85 (s, 3H), 1.86 (s, 3H), 1.23 (s, 3H), 1.15 (s, 3H).
Example 98 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenylj-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline Example 95 and benzyl bromide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 490 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, IH), 7.40-7.28 (m, 4H), 7.08 (d, 2H), 6.90 (t,
IH), 6.84 (d, 2H), 6.72 (s, IH), 6.70 (d, IH), 6.55 (d, IH), 6.41 (d, IH), 6.15 (s, IH), 5.37 (s, IH), 4.96 (s, 2H), 3.80 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.15 (s, 3H); Anal, calcd for C33H31NO3: C, 80.95; H, 6.38; N, 2.86. Found: C, 81.02; H, 6.25; N,
2.76.
Example 99 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenylJ- 1 H-
[ 1 Jbenzopyrano [3 ,4-fj quinoline Example 13 and methoxymethyl chloride were processed as in Example 14 to provide the desired compound.
MS (DCI/NH3) m/z 444 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.14 (t, IH), 6.92 (t, IH), 6.83-6.75 (m, 4H), 6.70 (d, IH), 6.58 (d, IH), 6.47 (q, IH), 6.21 (s, IH), 5.40 (s, IH), 5.06 (s, 2H), 3.80 (s, 3H), 3.30 (s, 3H), 1.89 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H); HRMS calcd m/z for C28H29NO4: 443.2097 (M+H)+. Found: 443.2098.
Example 100 r(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fjquinolin-5- yl)phenylj 1 -morpholinecarboxylate Example 13 and morpholine were processed as in Example 15 to provide the desired compound. MS (DCI/NH3) m/z 513 (M+H)+; iHNMR (300 MHz, DMSO-d($)Q8.01 (d, IH), 7.22 (t, IH), 7.05 (d, IH), 6.93 (t, 2H), 6.83 (s, IH), 6.77 (s, IH), 6.71 (d, IH), 6.57 (d, IH), 6.48 (q, IH), 6.23 (d, IH), 5.40 (s, IH), 3.80 (s, 3H), 3.60 (t, 4H), 3.50 (b, 4H), 1.86 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H); HRMS calcd m/z for C31H32N2O5: 512.2311 (M+H)+. Found: 512.2328.
Example 101 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[(methylsulfinyl)methoxyJphenylJ-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline A solution of Example 14 (12 mg, 0.005 mmol) in methanol (1 mL) at 0 °C was treated sequentially with Teθ2 (1.6 mg, 0.01 mmol) and acetic acid (50 mg, 0.83 mmol), stirred at ambient temperature overnight, treated with saturated NaHCO3 and extracted with dichloromethane. The extract was washed with water and brine, dried (MgSO4), filtered, and concentrated to yield MS (DCI/NH3) m/z 476 (M+H)+; iH NMR (300 MHz, DMSO-dfS)D8.01 (dd, IH), 7.15 (dt, IH), 6.92 (m, 3H), 6.78 (t,
IH), 6.74 (s, IH), 6.70 (d, IH), 6.58 (d, IH), 6.47 (d, IH), 6.19 (d, IH), 5.40 (d, IH), 5.12 (dd, IH), 4.93 (q, IH), 3.79 (d, 3H), 2.57 (d, 3H), 1.87 (d 3H), 1.24 (d, 3H), 1.16 (d, 3H); HRMS calcd m/z for C28H29NO4S: 475.1817 (M+H)+. Found: 475.1819.
Example 102 O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinolin-5-yl)phenylJ ester Example 13 and thiocarbanoyl chloride were processed as in Example 16 to provide the desired compound.
MS (DCI/NH3) m/z 487 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.22 (t, IH), 7.13 (d, IH), 6.92 (t, IH), 6.85 (d, IH), 6.78 (s, IH), 6.72 (s, IH), 6.59 (d, IH), 6.57 (d, IH), 6.45 (d, IH), 6.21 (s, IH), 5.39 (s, IH), 3.80 (s, 3H), 3.29 (s, 3H), 3.22 (s, 3H), 1.86 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H).
Example 103 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-r3-(methylthio)phenylJ-lH- [ 1 Ibenzopyrano [3 ,4-fjquinoline
Example 103 A A solution of 3-bromophenylmethoxymethyl ether (3.50 g, 15.0 mmol) in THF
(150 mL) at -78 °C was treated with n-butyllithium (2.5 M in hexanes, 6.00 mL) over 5 minutes, warmed to -30 °C, cooled to -78 °C, treated with Example IF in one portion, warmed to -40 °C, quenched with saturated NH4CI, warmed to ambient temperature, and allowed to settle. The supernatant was decanted and concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed sequentially with water and brine, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 20-25%) ethyl acetate/hexane provided the desired compound. MS (DCI/NH3) m/z 476 (M+H)+
Example 103
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenyl1-lH- [ 1 Jbenzopyrano [3 ,4-f] quinoline A solution of Example 103 A (20 mg, 0.042 mmol) and triethylsilane (49 mg, 0.42 mmol) in dichloromethane (1 mL) at ambient temperature was treated with BF3-OEt2 (60 mg, 0.42 mmol), stirred for 24 hours, and treated with saturated NaHCO3.
The aqueous layer was extracted with dichloromethane, and the combined extracts were washed sequentially with IM NaOH and brine, dried (Na2SO4), filtered, and concentrated. Flash chromatography ofthe residue on silica gel with 10-25% ethyl acetate/hexane provided the desired compound. MS (DCI/NH3) m/z 430 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.15 (t, IH), 7.05 (s, IH), 7.03 (d, IH), 6.93 (t, IH), 6.89 (s, IH), 6.74 (s, IH), 6.70 (d, IH), 6.57 (d, IH), 6.46 (d, IH), 6.19 (d, IH), 5.40 (s, IH), 3.78 (s, 3H), 3.33 (s, 3H), 1.88 (s, 3H), 1.22 (s, 3H), 1.16 (s, 3H); HRMS calcd m z for C27H27NO2S: 429.1763 (M+H)+. Found: 429.1764.
Example 104 O-r3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl-l H-[lJbenzopyrano [3 ,4- f]quinolin-5-yl)phenylj methylcarbonothioate Example 95 and methyl thiochloroformate were processed as in Example 15 to provide the desired compound.
MS (DCI/NH3) m z 474 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.00 (d, IH), 7.26 (t, IH), 7.12 (d, IH), 7.01 (q, IH), 6.89 (t, IH), 6.87 (s, IH), 6.78 (s, IH), 6.72 (d, IH), 6.57 (q, IH), 6.44 (q, IH), 6.20 (d, IH), 5.39 (s, IH), 3.78 (s, 3H), 2.35 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.16 (s, 3H); Anal, calcd for C28H27NO4S: C, 71.01; H, 5.74; N, 2.95. Found: C, 70.77; H, 5.74; N, 2.79.
Example 105 [3 -(2, 5 -dihy dro- 10-methoxy-2,2 ,4-trimethylj - 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinolin- 5 -yl)pheny 1J trifluoromethanesulfonate A solution of Example 13 (100 mg, 0.25 mmol), triethylamine (70 uL, 0.5 mmol), and 4-dimethylaminopyridine (catalytic) in dichloromethane (10 mL) at -78 °C was treated dropwise with trifluoromethanesulfonic anhydride (50 DL, 0.30 mmol), stirred for 30 minutes at -78 °C, poured into saturated NaHCO3, and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 15-85%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 532 (M+H)+; iH NMR (300 MHz, DMSO-dβ)D8.02 (d, IH), 7.44 (t, IH), 7.30 (m, 2H), 7.17 (s, IH), 6.93 (t, IH), 6.83 (s, IH), 6.71 (d, IH), 6.57 (d, IH), 6.43 (d, IH), 6.28 (d, IH), 5.40 (s, IH), 3.78 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H);
Anal, calcd for C27H24NO5SF3: C, 61.01; H, 4.55; N, 2.64. Found: C, 61.17; H, 4.60;
N, 2.51.
Example 106 5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenylJ-2,5-dihydro-10-methoxy-
2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline Example 52 (92.9 mg, 0.20 mmol), 2-trimethylstannyl-4,4-dimethyloxazoline (210 mg, 0.80 mmol), and [l, -is(diphenylphosphino)-ferrocene]dichloropalladium(II) (16 mg, 0.02 mmol) in l-methyl-2-pyrrolidinone (2 mL) were purged with 2, heated at 85 °C for 3 hours, partitioned between ethyl acetate (50 mL) and saturated KF (30 mL), stirred for 1 hour, and filtered through a pad of powdered sea shells (Celite®). The filtrate was washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0-30%) ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 481 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.02 (d, IH), 7.64 (d, IH), 7.62 (s, IH), 7.41 (d, IH), 7.32 (t, IH), 6.92 (t, IH), 6.82 (s, IH), 6.71 (d, IH), 6.56 (dd, IH), 6.47 (dd, IH), 6.25 (d, IH), 5.40 (s, IH), 4.02 (s, 2H), 3.78 (s, 3H), 1.84 (s, 3H), 1.25 (s, 3H), 1.22 (s, 6H),
1.16 (s, 3H);
Anal, calcd for C3iH32N2θ3-0.7H2θ: C, 75.49; H, 6.85; N, 5.68. Found: C, 75.83; H,
6.88; N, 5.29.
Example 107 ethyl 3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- f]quinolin-5-yl)benzoate Example 106 (48 mg, 0.1 mmol) in 1.5 M sulfuric acid in ethanol (5 mL) was refluxed for 16 hours, cooled, poured into saturated NaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 456 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, IH), 7.76 (m, 2H), 7.48 (d, IH), 7.38 (t, IH),
6.91 (t, IH), 6.85 (s, IH), 6.72 (d, IH), 6.56 (dd, IH), 6.46 (dd, IH), 6.26 (d, IH), 5.40 (s, IH), 4.23 (q, 2H), 3.78 (s, 3H), 1.84 (s, 3H), 1.25 (t, 3H), 1.24 (s, 3H), 1.16 (s, 3H); HRMS m/z calcd for C29H30NO4: 456.2175 (M+H)+. Found: 456.2175
Example 108
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-5- yl)benzoic acid Example 107 (20 mg, 0.04 mmol) and LiOH-H2θ (16.8 mg, 0.4 mmol) in 1:1 :1
THF/methanol/water (3 mL) was stirred for 48 hours, and concentrated. The residue was dissolved in IM NaOH (2 mL), washed with diethyl ether, treated with IM HCl to pH 3, and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m/z 428 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.02 (d, IH), 7.73 (m, 2H), 7.46 (d, IH), 7.35 (t, IH), 6.91 (t, IH), 6.83 (s, IH), 6.71 (d, IH), 6.55 (dd, IH), 6.46 (dd, IH), 6.22 (d, IH), 5.40
(s, IH), 3.78 (s, 3H), 1.83 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H); Anal, calcd for C27H25NO4: C, 72.86; H, 5.89; N, 3.28. Found: C, 72.89; H, 6.00; N,
2.94.
Example 109
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(2-propenyl)phenylj- lH-[llbenzopyrano[3,4-f]quinoline Example 52 and allyltributyltin were processed as in Example 16 to provide the desired compound. MS (DCI/NH3) m/z 438 (M+H); iH NMR (300 MHz, DMSO-d6)D7.99 (d, IH), 6.91 (t, IH), 6.80 (m, 3H), 6.70 (s, IH), 6.68 (d, IH), 6.56 (dd, IH), 6.44 (dd, IH), 6.16 (d, IH), 5.78 (ddt, IH), 5.39 (s, IH), 4.94 (dq, IH), 4.88 (dq, IH), 3.78 (s, 3H), 3.17 (d, 2H), 2.13 (s, 3H), 1.86 (s, 3H), 1.22 (s, 3H), 1.16 (s, 3H); Anal, calcd for C30H31NO2: C, 82.35; H, 7.14; N, 3.20. Found: C, 81.99; H, 7.14; N,
2.98.
Example 110 l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[11benzopyrano[3,4-f]quinolin-5-yl)-
5-methylphenyljethanone Example 52 and tributyl(l-ethoxyvinyl)tin in dichloroethane (20 mL) was treated • with silica gel (1.0 g) and formic acid (10 drops), heated to 40 °C for 6 hours, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 5-10% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 440 (M+H); iH NMR (300 MHz, DMSO-d6)Q8.01 (d, IH), 7.61 (s, IH), 7.51 (s, IH), 7.28 (s, IH),
6.92 (t, IH), 6.80 (s, IH), 6.72 (d, IH), 6.56 (dd, IH), 6.49 (dd, IH), 6.24 (m, IH), 5.40 (s, IH), 3.78 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 1.84 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H).
Example 111 3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4-f]quinolin-5-yι)-
5 -trimethy lbenzenemethanol A solution of Example 110 (0.022 g, 0.050 mmol) in THF (5 mL) at 0 °C was treated with methylmagnesium chloride (3M in THF, 0.83 DL), warmed to room temperature, stirred for 1 hour, treated with saturated NH4CI, separated, and extracted with ethyl acetate. The extract was washed with brine and dried (MgSO4), filtered, and concentrated to provide the desired compound. MS (DCI/NH3) m/z 456 (M+H); iHNMR (300 MHz, DMSO-dβ)D7.98 (d, IH), 7.11 (s, IH), 7.08 (s, IH), 6.91 (t, 8H), 6.78-6.63 (m, 3H), 6.55 (d, IH), 6.46 (d, IH), 6.18 (m, IH), 5.39 (s, IH), 4.84 (s, IH), 3.73 (s, 3H), 2.14 (s, 3H), 1.88 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H), 1.22 (s, 3H), 1.16 (s,
3H).
Example 112 5-[3-(2-furanyl)phenyll-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-rilbenzopyrano[3,4-f]quinoline Example 52 and 2-(tributylstannyl)furan were processed as in Example 16 to provide the desired compound. MS (DCI/NH3) m/z 456, 450 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.0 (d, IH), 7.69 (s, IH), 7.48 (d, IH), 7.23 (t, IH), 7.05 (d, IH), 6.88 (t, IH), 6.81 (s, 2H), 6.70 (d, IH), 6.54 (m, 2H), 6.47 (d, IH), 6.23 (s, IH), 5.41 (s, IH), 3.78 (s, 3H), 1.88 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H); Anal, calcd for C30H27NO3Η2O: C, 77.07; H, 6.25; N, 3.00. Found: C, 77.27; H, 5.97; N, 3.23.
Example 113 2,5 -dihy dro- 10-methoxy-2 ,2,4-trimethyl-5 - [3 -methyl-5 -(1 H-pyrrolidin- 1 -y l)phenylj -
1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline Example 11 and pyrrolidine were processed as in Example 17 to provide the desired compound. MS (DCI/NH3) m/z 467 (M+H)+; iH NMR (300 MHz, DMSO-df )D7.97 (d, IH), 6.93 (t, IH), 6.67 (s, IH), 6.67 (d, IH), 6.56 (d, IH), 6.49 (d, IH), 6.22 (s, IH), 6.14 (m, 3H), 5.39 (s, IH), 3.79 (s, 3H), 3.04 (m, 4H), 2.07 (s, 3H), 1.92 (s, 3H), 1.87 (m, 4H), 1.21 (s, 3H), 1.17 (s, 3H).
Example 114 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fjquinolin- 5-methyl)-5,N-dimethylbenzenamine Example 11 and methylamine were processed as in Example 17 to provide the desired compound. MS (DCI/NH3) m/z 427 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.98 (d, IH), 6.92 (t, IH), 6.67 (d, IH), 6.61 (s, IH), 6.56 (d, IH), 6.46 (d, IH), 6.18 (br s, 2H), 6.14 (br s, IH), 6.10 (s, IH), 5.58 (q, IH), 5.38 (br s, IH), 3.79 (s, 3H), 2.50 (d, 3H), 2.04 (s, 3H), 1.90 (s, 3H), 1.22 (s, 3H), 1.15
(s, 3H);
Anal, calcd for C28H30N2O2-0.5H2O: C, 77.21; H, 7.17; N, 6.43. Found: C, 77.65; H,
7.13; N, 5.97.
Example 115
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[llbenzopyrano[3,4-f]quinolin-5-yl)-5- methyl-N-(2-propenyl)benzamide Example 11 and allylamine were processed as in Example 17 to provide the desired compound. MS (DCI/NH3) m/z 453 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.98 (d, IH), 6.92 (t, IH), 6.67 (d, IH), 6.56 (d, H), 6.45 (d, IH), 6.24 (br s, IH), 6.14 (m, 3H), 5.76 (m, IH), 5.63 (t, IH), 5.37 (br s, IH), 5.10 (qd, IH), 5.02 (qd, IH), 3.79 (s, 3H), 3.50 (m, 2H), 2.02 (s, 3H), 1.89 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H); Anal, calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C, 79.35; H, 7.30; N,
3.89.
Example 116
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)-N-(2-methoxyethyl)-5-methylbenzenamine
Example 11 and 2-methoxyethylamine were processed as in Example 17 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q7.98 (d, IH), 6.95 (t, IH), 6.65 (d, IH), 6.60 (s, IH),
6.54 (d, IH), 6.44 (d, IH), 6.22 (s, IH), 6.17 (s, 2H), 6.13 (s, IH), 5.41 (t, 10H), 5.38 (s, IH), 3.79 (s, 3H), 3.26 (q, 2H), 3.20 (s, 3H,), 2.98 (q, 2H), 2.03 (s, 3H), 1.90 (s, 3H), 1.22 (s, 3H), 1.15 (s, 3H).
Example 117 3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4-fjquinolin-
5-yl)-N-(2-propenyl)benzenamine Example 52 and allylamine were processed as in Example 17 to provide the desired compound.
MS (DCI/NH3) m/z 439 (M+H)+; iHNMR (300 MHz, DMSO-d6)D7.99 (d, IH), 6.91 (t, IH), 6.86 (t, IH), 6.67 (d, IH), 6.63 (s, IH), 6.55 (d, IH), 6.44 (m, 2H), 6.33 (m, 2H), 6.14 (d, IH), 5.78 (m, 2H), 5.37 (s, IH), 5.12 (qd, IH), 5.03 (qd, IH), 3.79 (s, 3H), 3.51 (m, 2H), 1.88 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H);
Anal, calcd for C29H30N2O2: C, 79.42; H, 6.89; N, 6.39. Found: C, 79.03; H, 7.05; N,
6.17.
Example 118 N'-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-ri]benzopyrano[3,4-fjquinolin-5-yl)-
5 -methylphenyl] -N,N-dimethylurea A solution of Example 115 (0.112 g, 0.247 mmol) in 10% ethanol/water (10 mL) was treated with l,4-diazabicyclo[2.2.2]octane (0.056 g, 0.495 mmol) and chlorotris(triphenylphosphine)rhodium(I) (0.115 g, 0.124 mmol), refluxed for 15 hours, poured into 5% HCl, stirred 20 minutes, neutralized with NaHCO3, and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 20- 33% ethyl acetate/hexanes to provide the desired aniline.
The aniline (0.030 g, 0.073 mmol) was dissolved in 2;l/toluene:THF (7 mL), treated sequentially with diisopropylethylamine (38 DL, 0.218 mmol) and N,N-dimethylcarbamoyl chloride (20 DL, 0.218 mmol), refluxed for 18 hours, cooled, treated with water, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25-50% ethyl acetate/hexanes to provide the desired compound. iH NMR (300 MHz, DMSO-d6)Q8.15 (s, IH), 7.98 (d, IH), 7.10 (br s, 2H), 6.91 (t,
IH), 6.69 (d, IH), 6.63 (s, IH), 6.56 (d, IH), 6.54 (s, IH), 6.46 (d, IH), 6.16 (br s, IH), 5.38 (s, IH), 2.85 (s, 6H), 2.09 (s, 3H), 1.86 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H);
HRMS m/z calcd for C30H39N3O3: 484.2600 (M+H)+. Found: 484.2601.
Example 119 N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin- 5 -y Pjpheny ljbenzenemethanamine
Example 11 and benzylamine were processed as in Example 17 to provide the desired compound. iHNMR (300 MHz, DMSO-d6)Q7.97 (d, IH), 7.23 (m, 5H), 6.80 (m, 2H), 6.65 (d,
IH), 6.59 (s, IH), 6.53 (d, 2H), 6.49 (s, IH), 6.20 (m, 3H), 6.16 (t, IH), 6.12 (s, IH), 5.35 (s, IH), 4.10 (b, 2H), 3.78 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H);
HRMS m/z calcd for C33H32O2N2: 488.2464 (M+H)+. Found: 488.2468.
Example 120 5-[(3 ,5-dichlorphenyl)methylene]-2,5-dihydro- 10-methoxy-2,2,4- trimethyl- 1H-[1 Jbenzopyrano [3 ,4-fjquinoline
Example IF and 3,5-dichlorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 464 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer l.:D8.17 (d, IH), 7.32 (s, IH), 6.96 (s, 2H), 6.81-6.74 (m, 4H), 6.45 (s, 2H), 5.11 (s, IH), 3.93 (s, 3H), 1.88 (s, 3H), 1.22 (s, 3H),
0.89 (s, 3H); isomer 2:D8.29 (d, IH), 7.78 (s, 2H), 7.45 (s, IH), 7.23 (t, IH), 7.18 (d, IH), 7.16 (d, IH), 6.84 (d, IH), 6.66 (s, IH), 5.59 (s, IH), 5.47 (s, IH), 3.93 (s, 3H), 1.96 (s, 3H), 1.27 (s, 6H); HRMS calcd m/z for C27H23CI2NO2: 463.1106 (M+H)+. Found: 463.1112.
Example 121 5-[(4-chlorophenyl)methylenej-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline
Example IF and 4-chlorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 430 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1 :D8.26 (d, IH), 7.75 (d, Hz, 2H), 7.42 (d, 2H), 7.18 (t, 2H), 6.89 (d, IH), 6.74 (d, IH), 6.61 (s, IH), 5.54 (s, IH), 5.46 (s, IH), 3.91 (s,
3H), 1.97 (s, 3H), 1.26 (s, 6H); isomer 2:Q8.13 (s, IH), 7.18 (t, IH), 7.04 (d, 2H), 6.82- 6.71 (m, 5H), 6.46 (s, IH), 6.41 (s, IH), 5.04 (s, IH), 3.91 (s, 3H), 1.84 (s, 3H), 1.22 (s, 3H), 0.90 (s, 3H); HRMS calcd m/z for C27H24CINO2: 429.1496 (M+H)+. Found: 429.1500.
Example 122 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3- (trifluoromethyl)phenyl Jmethylenej - 1 H- [ 1 J -benzopyrano ,4-fjquinoline Example IF and 3-trifluoromethylmagnesium bromide were processed as in Example IB to provide the desired compound.
MS (DCI/NH3) m/z 464 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1 :Q8.28 (d, IH), 8.13 (s, IH), 7.98 (d, IH), 7.65-7.56 (m, IH), 7.33-7.39 (m, IH), 7.21 (t, IH), 6.83-6.78 (m, 2H), 6.75 (t, IH), 6.64 (s, IH), 5.68 (s, IH), 5.48 (s, IH), 3.92 (s, 3H), 1.99 (s, 3H), 1.27 (s, 6H); isomer 2: D 8.17 (d, IH), 7.65-7.56 (m, IH), 7.45 (d, IH), 7.39-7.33 (m, IH), 7.27 (d, IH), 7.17
(t, IH), 6.83-6.78 (m, 2H), 6.75 (t, IH), 6.56 (s, IH), 6.40 (s, IH), 5.01 (s, IH), 3.92 (s, 3H), 1.88 (s, 3H), 1.19 (s, 3H), 0.78 (s, 3H); HRMS calcd m/z for C28H24F3NO2: 463.1759 (M+H)+. Found: 463.1762.
Example 123
5-[(2,6-difluorophenyl)methylenej-2,5-dihydro-10-methoxy-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline Example IF and 2,6-difluorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 432 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1 :D8.32 (d, IH), 7.19 -7.08 (m, 3H), 6.92 (t, IH), 6.81 - 6.76 (m, 2H), 6.64 (s, IH), 6.54 (d, IH), 5.49 (s, IH), 5.46 (s, IH), 3.92 (s, 3H), 2.11 (s, 3H), 1.25 (s, 6H); isomer 2: D8.18 (d, IH), 7.38 (t, IH), 7.19-7.08 (m, 3H), 6.81-6.76 (m, 2H), 6.67 (d, IH), 6.21 (s, IH), 6.19 (s, IH), 4.96 (s, IH), 3.93 (s, 3H),
1.91 (s, 3H), 1.16 (s, 3H), 0.61 (s, 3H);
HRMS calcd m/z for C27H23F2NO2: 431.1697 (M+H)+. Found: 431.1704.
Example 124
5-[(2-chlorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline Example IF and 2-chlorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 430 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1:Q8.11 (d, IH), 7.47 (d, IH), 7.40 (d, IH), 7.23-7.10 (m, 3H), 6.84-6.74 (m, 2H), 6.71 (s, IH), 6.66 (s, IH), 6.01 (s, IH), 5.47 (s, IH), 3.93 (s, 3H), 2.02 (s, 3H), 1.25 (s, 6H); isomer 2:D8.27 (d, IH), 8.18 (d, IH), 7.41 (t, IH), 7.26 (d, IH), 7.01 (t, IH), 6.84-6.74 (m, 4H), 6.47 (s, IH), 6.37 (s, IH), 5.00 (s, IH), 3.93 (s, 3H), 1.88 (s, 3H), 1.18 (s, 3H), 0.73 (s, 3H);
HRMS calcd m/z for C27H24CINO2: 429.1496 (M+H)+. Found: 429.1497.
Example 125 5-[(2,6-dichlorophenyl)methylenej-2,5-dihydro-10-methoxy-2,2,4- trimethyl- 1H-T1 Ibenzopyrano [3 ,4-fj quinoline
Example IF and 2,6-dichlorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 464 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer LD8.27 (d, IH), 7.16 (m, 2H), 7.07 (t, IH), 6.81-6.76 (m, 3H), 6.68 (d, IH), 6.30 (s, IH), 5.47 (s, IH), 4.90 (s, IH), 3.93 (s, 3H),
1.96 (s, 3H), 1.15 (s, 3H), 0.59 (s, 3H); isomer 2: D 8.37 (d, IH), 7.45 (d, 2H), 7.31 (t, IH), 7.16 (m, 2H), 6.77 (m, IH), 6.65 (s, IH), 6.44 (d, IH), 6.34 (s, IH), 5.60 (s, IH), 3.91 (s, 3H), 2.20 (s, 3H), 1.25 (s, 6H); HRMS calcd m/z for C27H23CI2NO2: 463.1106 (M+H)+. Found: 463.1114.
Example 126 5-r(2-fluorophenyl)methylene1-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline Example IF and 2-fluorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound.
MS (DCI/NH3) m/z 414 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1:D8.30 (d, IH), 8.23 (m, IH), 7.28 (m, IH), 7.19 (t, IH), 7.18 (d, IH), 6.93 -6.75 (m, 3H), 6.76 (d, IH), 6.65 (s, IH), 5.77 (s, IH), 5.49 (s, IH), 3.93 (s, 3H), 2.01 (s, 3H), 1.25 (s, 6H); isomer 2:D8.17 (d, IH), 7.28 (m, 2H), 7.18 (d, IH), 7.14-7.06 (m, 2H), 6.79 (m, 2H), 6.72 (d, IH), 6.41 (s, IH), 6.38 (s, IH), 5.00 (s, IH), 3.93 (s, 3H), 1.87 (s, 3H), 1.18 (s, 3H), 0.76 (s, 3H); HRMS calcd m/z for C27H24FNO2: 413.1791 (M+H)+. Found: 413.1788.
Example 127 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-r(4,5-dihydro-4,4-dimethyl-2- oxazolyl)methyleneJ - 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline Example IF and 4,4-dimethyl-2-oxazoline-2-methyllithium were processed as in Example IB to provide the desired compound.
MS (DCI/NH3) m/z 417 (M+H)+; iH NMR (300 MHz, DMSO-d6) isomer 1:D8.34 (d, IH), 7.19 (t, IH), 6.83-6.78 (m, 2H), 6.74-6.70 (m, 2H), 5.48 (s, IH), 5.08 (s, IH), 3.98 (s, 2H), 3.92 (s, 3H), 1.99 (s, 3H), 1.22 (s, 3H), 1.20 (s, 9H); isomer 2:D8.06 (d, IH), 7.14 (m, IH), 6.80 (m, IH), 6.76 (m, IH), 6.72 (m, IH), 6.42 (s, IH), 5.96 (s, IH), 5.35 (s, IH), 3.90 (s, 3H), 3.72 (m,
2H), 1.93 (s, 3H), 1.32 (s, 3H), 1.20 (s, 6H), 1.11 (s, 3H); HRMS calcd m z for C26H28N2O3: 417.2178 (M+H)+. Found: 417.2176.
Example 128 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline Example IF and 2-methylpyridyllithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 397 (M+H)+; % iH NMR (300 MHz, DMSO-d6) isomer 1 :D8.50 (m, IH), 8.31 (d, IH), 8.25 (d, IH),
7.83 (t, IH), 7.20 (d, IH), 7.19 (m, IH), 6.95 (d, IH), 6.83 (d, 1 H,), 6.78 (d, IH), 6.64 (s, IH), 5.77 (s, IH), 5.49 (s, IH), 3.92 (s, 3H), 2.00 (s, 3H), 1.27 (s, 6H). isomer 2:D8.43 (m, IH), 8.15 (d, IH), 7.48 (t, IH), 7.22 (d, IH), 7.15 (d, IH), 7.08 (m, IH), 6.88 (d, IH), 6.78 (d, IH), 6.77 (t, IH), 6.46 (s, IH), 6.38 (s, IH), 4.99 (s, IH), 3.92 (s, 3H), 1.87 (s, 3H), 1.21 (s, 3H), 0.89 (s, 3H);
HRMS calcd m/z for C26H24N2O2: 397.1916 (M+H)+. Found: 397.1923.
Example 129 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-[11benzopyrano[3,4- fjquinoline
Example IF and 2-thienyllithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 391 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.38 (d, IH), 6.95 (dd, IH), 6.93 (s, IH), 6.81 (dd, IH), 6.68 (d, IH), 6.65 (d, IH), 6.64 (d, IH), 6.46 (d, IH), 6.21 (d, IH), 5.39 (s, IH), 3.81 (s, 3H), 1.95 (d, 3H), 1.21 (s, 3H), 1.15 (s, 3H).
Example 130
2,5-dihydro-9, 10-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-[l jbenzopyrano [3 ,4- fjquinoline 1,2,4-trimethoxybenzene was processed as described in Schemes 1 and 2 to provide the desired compound. MS (DCI/NH3) m/e 378 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.93 (d, IH), 6.82 (d, IH), 6.61 (dd, 2H), 6.22 (d, IH), 5.81 (ddt, IH), 5.70 (dd, IH), 5.44 (s, IH), 5.01 (m, 2H), 3.76 (s, 3H), 3.67 (s, 3H), 2.35 (m, 2H), 2.16 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H).
Example 131
5-(2-cyclohexen- 1 -yl)-2,5-dihydro-9, 10-dimethoxy-2,2,4-trimethyl- 1H-
[ 1 Ibenzopyrano [3 ,4-fjquinoline 1,2,4-trimethoxybenzene was processed as described in Example 130 but substituting 3-trimethylsilylcyclohexene for allyltrimethylsilane to provide the desired compound.
MS (DCI/NH3) m/e 418 (M+H)+; iHNMR (300 MHz, DMSO d6)D8.03 (d, IH), 8.01 (d, IH), 6.83 (d, IH), 6.82 (d, IH), 6.60 - 6.69 (m, 4H), 6.31 (d, IH), 6.27 (d, IH), 5.6-5.8 (m, 4H), 5.35-5.52 (m, 4H), 5.11 (m, IH), 5.09 (m, IH), 3.77 (s, 6H), 3.69 (s, 3H), 3.68 (s, 3H), 2.25 (m, 4H), 2.13 (s, 3H), 2.10 (s, 3H), 1.95 (m, 4H), 1.6 (m, 4H),1.31 (s, 3H), 1.29 (s, 3H), 1.07 (s, 3H), 1.04
(s, 3H).
Example 132 2,5-dihydro- 10-methoxy-5-(3 -methyl-3 -butenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline
Example 2B and 3 -methyl- l-trimethylsilyl-2-butene (prepared according to Fleming, et. al. Synthesis 1979, 446.) were processed as in example 2 to provide the desired compound. MS (DCI/NH3) m/e (M+H)+ 376; iH NMR (300 MHz, DMSO-d6)D8.10 (d, J=8 Hz, IH), 7.01 (t, J=8 Hz, IH), 6.65 (d,
J=8 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.49 (d, J=8 Hz, IH), 6.25 (br s, IH), 5.57 (s, IH), 5.55 (dd, J=17, 11 Hz, IH), 5.41 (s, IH), 4.64-4.56 (m, 2H), 3.83 (s, 3H), 2.14 (s, 3H),
1.31 (s, 3H), 1.01 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H);
13C NMR (100 MHz, DMSO-d6)D 156.31, 153.48, 145.02, 143.74, 133.05, 128.73,
127.10, 126.82, 126.27, 119.20, 118.15, 114.05, 113.11, 110.85, 109.36, 105.24, 78.33, 55.69, 49.12, 44.84, 29.53, 26.14, 23.53, 23.43, 23.35;
Anal, calcd for O25H29NO2'1/4H2O: C, 79.02; H, 7.82; N, 3.69. Found: C, 79.09; H,
7.94; N, 3.59.
Example 133 2,5-dihydro-10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline Example 2B and 5,5-dimethyl-l-trimethylsilyl-2-cyclohexene (prepared from
5,5-dimethyl-2-cyclohexene-l-ol by the method of Tsuji, et. al. J. Org. Chem. 1996, 61,
5779) were processed as in example 2 to provide the desired compound as a 1.8:1 inseparable mixture of diastereomers.
MAJOR:
MS (DCI/NH3) m/e (M+H)+ 416; iH NMR (300 MHz, DMSO-d6)D8.08 (d, J=8 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.69 (d,
J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.25 (br s, IH), 5.85 (m, IH), 5.62-5.71 (m, IH), 5.46 (s, IH), 5.45 (d, J=10 Hz, IH), 3.86 (s, 3H), 2.41-2.33 (m, IH), 2.11 (s, 3H), 1.84-1.72
(m, IH), 1.68-1.48 (m, 2H), 1.30 (s, 3H), 1.35-1.21 (m, IH), 1.01 (s, 3H), 0.76 (s, 3H),
0.53 (s, 3H);
Anal, calcd for O28H33NO2'1/2H2O: C, 79.21; H, 8.07; N, 3.30. Found: C, 79.31; H,
7.75; N, 3.11. MINOR: iH NMR (300 MHz, DMSO-d6)Q8.02 (d, J=8 Hz, IH), 7.09 (t, J=8 Hz, IH), 6.70 (d,
J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.20 (br s, IH), 5.60-5.52 (m, IH), 5.50 (d, J=10 Hz, IH), 5.14 (m, IH), 5.41 (m, IH), 3.86 (s, 3H), 2.41-2.33 (m, IH), 2.09 (s, 3H), 1.91-1.78 (m, IH), 1.68-1.48 (m, 2H), 1.35-1.21 (m, IH), 1.28 (s, 3H), 1.07 (s, 3H), 0.92 (s, 3H), 0.51 (s, 3H).
Example 134 re/ (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline Example 2B and 3,4-dihydro-6-(trimethylsiloxy)-2H-pyran were processed as in
Example 2 to give 41 > Example 134 and 48% Example 135. MS (DCI/NH3) m/e 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.12 (d, J=8 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.67 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.49 (d, J=8 Hz, IH), 6.42 (d, J=5 Hz, IH), 6.21 (d, J=2 Hz, IH), 5.44 (br s, IH), 4.35-4.00 (m, 2H), 3.86 (s, 3H), 2.77-2.67 (m, IH), 2.17 (s, 3H), 2.01-1.50 (m, 4H), 1.27 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, DMSO-d6)P 169.93, 156.40, 152.16, 145.53, 133.80, 128.46,
127.75, 127.20, 126.66, 117.38, 116.74, 113.45, 112.07, 109.23, 109.19, 105.44, 98.19, 72.79, 69.09, 55.62, 49.44, 46.37, 29.45, 27.13, 23.20, 21.46, 20.22, 19.61; Anal, calcd for C25H27NO4-1/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.66; H, 6.92; N, 2.91.
Example 135 anti (5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl-
1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline Example 2B and 3,4-dihydro-6-(trimethylsiloxy)-2H-pyran were processed as in Example 2 to give 41% Example 135 and 48% Example 135 A. MS (DCI NH3) m/e 406 (M+H)+; iHNMR (300 MHz, DMSO-d6)D8.12 (d, J=8 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.67 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.49 (d, J=8 Hz, IH), 6.42 (d, J=5 Hz, IH), 6.21 (d, J=2 Hz, IH), 5.44 (br s, IH), 4.35-4.00 (m, 2H), 3.86 (s, 3H), 2.77-2.67 (m, IH), 2.17 (s, 3H), 2.01-1.50 (m, 4H), 1.27 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, DMSO-d6)D 169.93, 156.40, 152.16, 145.53, 133.80, 128.46,
127.75, 127.20, 126.66, 117.38, 116.74, 113.45, 112.07, 109.23, 109.19, 105.44, 98.19, 72.79, 69.09, 55.62, 49.44, 46.37, 29.45, 27.13, 23.20, 21.46, 20.22, 19.61; Anal, calcd for O25H27NO4«1/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.66; H, 6.92; N, 2.91.
Example 135A anti (5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl- lH-[11benzopyrano[3,4-fjquinoline MS (DCI/NH3) m/e 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.06 (d, J=9 Hz, IH), 7.06 (t, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.65 (d, J=9 Hz, IH), 6.50 (d, J=8 Hz, IH), 6.27 (d, J=8 Hz, IH), 6.21 (d,
J=2 Hz, IH), 5.46 (s, IH), 4.01-4.10 (m, 2H), 3.87 (s, 3H), 2.81 (m, IH), 2.14 (m, 3H), 1.68 -1.61 (m, 2H), 1.27 (s, 3H), 1.16-1.36 (m, 2H), 1.03 (s, 3H); 13C NMR (100 MHz, DMSO-d6)D 172.14, 156.33, 150.95, 145.21, 134.18, 127.71,
127.38, 127.20, 126.73, 118.09, 116.66, 113.53, 112.78, 110.56, 105.45, 71.40, 66.76, 55.52, 49.49, 29.46, 27.38, 23.69, 21.05, 20.79;
Anal, calcd for C25H27NO4'l/4H2O: C, 73.24; H, 6.76; N, 3.42. Found: C, 72.89; H,
7.07; N, 3.05. Example 136 2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fj quinoline Example 2B and cyclopenten-2-yltrimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of two diastereomers (1.5:1). MS (DCI/NH3) m/z 374 (M+H)+; iH NMR (300 MHz, DMSO-d6)
Major diastereomer:D8.05 (d, IH), 7.09 (t, IH), 6.72 (d, IH), 6.66 (d, IH), 6.58 (d, IH), 6.19 (s, IH), 5.77 (ddd, IH), 5.50 (d, IH), 5.43 (s, IH), 5.19 (ddd, IH), 3.87 (s, 3H), 2.90
(m, IH), 2.43-2.15 (m, 2H), 2.09 (s, 3H), 1.97-1.70 (m, 2H), 1.31 (s, 3H), 1.09 (s, 3H); Minor diastereomer:D8.07 (d, IH), 7.08 (t, IH), 6.70 (d, IH), 6.66 (d, IH), 6.61 (d, IH), 6.22 (s, IH), 5.82-5.70 (m, 2H), 5.48 (d, IH), 5.41 (d, IH), 3.88 (s, 3H), 2.92 (m, IH), 2.30 (m, IH), 2.20 (m, IH), 2.15 (s, 3H), 1.50 (m, 2H), 1.33 (s, 3H), 1.05 (s, 3H); HRMS calcd m/z for C25H27NO2: 373.2042. Found: 373.2049.
Example 137 2,5-dihydro- 10-methoxy-5-(3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline Example 2B and cyclohexen-2-yltrimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of two diastereomers (1.1:1).
MS (DCI/NH3) m/z 388 (M+H)+; iH NMR (300 MHz, DMSO-d6)
Major diastereomer:D8.05 (d, IH), 7.06 (t, IH), 6.67 (d, IH), 6.64 (d, IH), 6.59 (d, IH), 6.19 (s, IH), 5.82 (m, IH), 5.72 (m, IH), 5.41 (s, IH), 5.40 (d, IH), 3.87 (s, 3H), 2.29
(m, IH), 2.13 (s, 3H), 1.95-1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1.10 (m, 2H), 1.30 (s,
3H), 1.02 (s, 3H);
Minor diastereomer:Q8.03 (d, IH), 7.07 (t, IH), 6.68 (d, IH), 6.63 (d, IH), 6.57 (d, IH),
6.15 (s, IH), 5.62 (m, IH), 5.54 (m, IH), 5.46 (s, IH), 5.09 (m, IH), 3.85 (s, 3H), 2.29 (m, IH), 2.10 (s, 3H), 1.95-1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1.10 (m, 2H), 1.28 (s,
3H), 1.05 (s, 3H);
HRMS calcd m/z for C26H29NO2: 387.2198. Found: 387.2206.
Example 138 2,5-dihydro- 10-methoxy-5-(3-butenyl)-2,2,4-trimethyl- 1 H-[l Ibenzopyrano [3 ,4- fjquinoline Example 2B and 2-butenyltrimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of two diastereomers (1.3:1). MS (DCI/NH3) m z 362 (M+H)+; iH NMR (300 MHz, DMSO-d6) Major diastereomer: D8.04 (d, IH), 7.05 (t, IH), 6.69 (d, IH), 6.64 (d, IH), 6.47 (d, IH), 6.16 (s, IH), 5.88 (ddd, IH), 5.54 (d, IH), 5.46 (s, IH), 4.93 (ddd, IH), 4.74 (ddd, IH), 3.86 (s, 3H), 2.37 (bm, IH), 2.17 (s, 3H), 1.30 (s, 3H), 1.02 (s, 3H), 0.71(d, 3H); Minor diastereomer:D8.03 (d, IH), 7.08 (t, IH), 6.67 (d, IH), 6.64 (d, IH), 6.58 (d, IH), 6.10 (s, IH), 5.51 (ddd, IH), 5.47 (d, IH), 5.40 (s, IH), 4.78 (ddd, IH), 4.74 (ddd, IH), 3.86 (s, 3H), 2.38 (bm, IH), 2.11 (s, 3H), 1.28 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H); Anal, calcd for C24H27N O2: C, 79.74; H, 7.53; N, 3.87. Found: C, 79.41; H, 7.63; N, 3.43.
Example 139 2,5-dihydro-l 0-methoxy-5-(l -ethenyl-1 -cyclohexyl)-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3 ,4-fjquinoline Example 2B and 2-cyclohexylideneethyl trimethylsilane were processed as in
Example 2 to provide the desired compound. MS (DCI/NH3) m/z 416 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.10 (d, IH), 7.00 ( t, IH), 6.63 (d, IH), 6.60 (dd, IH), 6.47(dd, IH), 6.20 (dd, IH), 5.45 (s, IH), 5.40 (s, IH), 5.14 (dd, IH), 4.81 (dd, IH), 4.53 (dd, IH), 3.85 (s, 3H), 2.15 (s, 3H), 1.78 (m, IH), 1.45-0.80 (m, 9H), 1.32 (s, 3H),
1.03 (s, 3H); Anal, calcd for C28H33NO2: C, 80.93; H, 8.00; N, 3.37. Found: C, 80.57; H, 8.02; N,
3.22.
Example 140
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline Example 2B and (4,4-dimethylcyclohexen-2-yl)trimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of diastereomers (2: 1).
MS (DCI/NH3) m/z 416 (M+H)+; iH NMR (300 MHz, DMSO-d6)
Major diastereomerD8.07 (d, IH), 6.99 (t, IH), 6.63 (d, IH), 6.62 (d, IH), 6.48 (d, IH), 6.23 (s, IH), 5.72 (d, IH), 5.48 (m, IH), 5.40 (m, 2H), 3.84 (s, 3H), 2.16 (s, 3H), 2.05 (m, IH), 1.75 (bm, 2H), 1.30 (s, 3H), 1.12 (m, 2H), 1.02 (s, 6H), 0.51 (s, 3H);
Minor diastereomerQ8.04(d, IH), 7.06 (t, IH), 6.68 (d, IH), 6.62 (d, IH), 6.57 (d, IH), 6.19 (s, IH), 5.68 (dd, IH), 5.50-5.38 (m, 3H), 3.86 (s, 3H), 2.14 (s, 3H), 2.08 (m, IH), 1.71 (m, IH), 1.42 (m, IH), 1.30 (s, 3H), 1.07 (m, 2H), 1.02 (s, 3H), 0.91 (s, 3H), 0.84
(s, 3H);
HRMS calcd m/z for C28H33NO2: 415.2511. Found: 415.2527.
Example 141
2,5-dihydro- 10-methoxy-5-( 1 -methylene-2-cyclohexyl)-2,2,4-trimethyl- 1 H-
T 1 Ibenzopyrano [3 ,4-f] quinoline Example 2B and l-(trimethylsilylmethyl)cyclohexene were processed as in Example 2 to provide the desired compound as an inseparble mixture of diastereomers (4:1).
MS (DCI/NH3) m/z 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)
Major diastereomerD8.07 (d, IH), 7.03 (t, IH), 6.65 (d, IH), 6.63 (d, IH), 6.40 (d, IH),
6.22 (s, IH), 5.89 (d, IH), 4.75 (d, IH), 4.56 (d, IH), 3.87 (s, 3H), 2.38 (m, IH), 2.23 (m, IH), 2.21 (s, 3H), 1.97 (bm, 2H), 1.55-1.05 (m, 6H), 1.34 (s, 3H), 1.01 (s, 3H);
Minor diastereomerD8.09 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.57 (d, IH), 6.56 (d, IH), 6.11 (s, IH), 5.86 (d, IH), 5.40 (s, IH), 4.33 (d, IH), 3.91 (d, IH), 3.87 (s, 3H), 2.48 (m, IH), 2.22 (m, IH), 2.20 (s, 3H), 1.94 (bm, IH), 1.75-1.05 (m, 6H), 1.29 (s, 3H), 0.97 (s, 3H); HRMS calcd m z for C27H31NO2: 401.2355. Found: 401.2351.
Example 142 2,5-dihydro-10-methoxy-5-(l-oxo-2-cyclohexyl)-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-fjquinoline Example 2B and l-(trimethylsilyloxy)cyclohexene were processed as in Example
2 to provide the desired compound as single diastereomer. MS (DCI/NH3) m/z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.04 (d, IH), 7.02 ( t, IH), 6.67 (d, IH), 6.63 (d, IH), 6.39 (d, IH), 6.37 (d, IH), 6.17 (s, IH), 5.44 (s, IH), 3.80 (s, 3H), 2.70 (ddd, IH), 2.25 (m, 2H), 2.15 (s, 3H), 1.84 (bm, IH), 1.62-1.25 (m, 4H), 1.28 (s, 3H), 1.09 (m, IH), 1.00
(s, 3H). HRMS calcd m/z for C26H29NO3: 403.2147. Found: 403.2142.
Example 143 2,5-dihydro-10-methoxy-5-(3-cyclooctenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline Example 2B and cycloocten-2-yltrimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of two diastereomers (7:5). MS (DCI/NH3) m/z 416 (M+H)+; iH NMR (300 MHz, DMSO-d6)
Major diastereomer: D 8.03 (dd, IH), 7.07 (t, IH), 6.62 (d, IH), 6.57 (d, IH), 6.39 (d,
IH), 6.17 (s, IH), 5.59 (m, 2H), 5.44 (s, IH), 5.14 (dd, IH), 3.88 (s, 3H), 2.18 (s, 3H),
2.04-0.84 (m, 17H);
Minor diastereomer: D 8.00 (d, IH), 7.00 (t, IH), 6.70 (d, IH), 6.66 (d, IH), 6.58 (d, IH),
6.12 (s, IH), 5.59 (m, 2H), 5.48 (s, IH), 5.38 (dd, IH), 3.88 (s, 3H), 2.18 (s, 3H), 2.04-
0.84 (m, 17H);
HRMS calcd m/z for C28H33NO2: 415.2511. Found: 415.2498.
Example 144 2,5-dihydro-10-methoxy-5-(3-cycloheptenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fjquinoline Example 2B and cyclohepten-2-yltrimethylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of two diastereomers (1:1).
MS (DCI/NH3) m/z 402 (M+H)+; iH NMR (300 MHz, DMSO-d6) diastereomer A: D 8.04 (d, 1H0, 7.04 (t, IH), 6.68 (d, IH), 6.63 (d, IH), 6.51 (d, IH), 6.22 (s, IH), 5.97 (m, IH), 5.73 (m, IH), 5.58 (m, IH), 5.47 (s, IH), 3.87 (s, 3H), 2.42- 0.98 (m, 18H); diastereomer B:D 8.01 (d, IH), 7.08 (t, IH), 6.70 (d, IH), 6.62 (d,lH), 6.56 (d, IH), 6.21 (s, IH), 5.58 (m, 2H), 5.49 (s, IH), 5.32 (m, IH), 3.87 (s, 3H), 2.42-0.98 (m, 18H); HRMS calcd m/z for C27H31NO2: 401.2355. Found: 401.2351..
Example 145
2,5-dihydro-10-methoxy-5-(l-cyclohexenylmethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline Example 2B and 2-methylenecyclohexyldimethylphenylsilane were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.96 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.45 (d, IH), 6.10 (s, IH), 5.85 (dd, IH), 5.43 (s, IH), 5.18 (bs, IH), 3.85 (s, 3H), 2.45- 1.12 (m, 19H);
HRMS calcd m/z for C27H31NO2: 401.2355. Found: 401.2342; Anal, calcd for C27H31NO2: C, 80.76; H, 7.78; N, 3.49. Found: C, 80.76; H, 8.00; N,
3.25. Example 146 2,5-dihydro- 10-methoxy-5-(3 ,3 -dimethyl-6-cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline Example 2B and (6,6-dimethylcyclohexen-2-yl)dimethylphenylsilane were processed as in Example 2 to provide the desired compound as an inseparable mixture of diastereomers (5:1).
MS (DCI/NH3) m/z 416 (M+H)+; iH NMR (300 MHz, DMSO-d6) major diastereomer: D 8.04 (d, IH), 7.06 (t, IH), 6.68 (d, IH), 6.63 (d, IH), 6.58 (d, IH), 6.21 (s, IH), 5.67 (dd, IH), 5.49-5.38 (m, 3H), 3.86
(s, 3H), 2.29-0.82 (m, 20H); minor diastereomer: D 8.01 (d, IH), 7.07 (t, IH), 6.68' (d,
IH), 6.63 (d, IH), 6.57 (d, IH), 6.16 (s, IH), 5.56-5.33 (m, 3H), 4.97 (dd, IH), 3.86 (s,
3H), 2.29-0.82 (m, 20H);
HRMS calcd m/z for C28H33NO2: 415.2511. Found: 415.2527; Anal, calcd for O28H33NO2: C, 80.93; H, 8.00; N, 3.37. Found: C, 80.92; H, 7.98; N,
3.25.
Example 147 2,5-dihydro-l 0-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-fjquinoline
Example 2B and (2-bromoallyl)trimethylsilane were processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 426 (M+H)+; iHNMR (300 MHz, DMSO-d6)D8.00 (d, IH), 7.08 ( t, IH), 6.72 (d, IH), 6.62 (d, IH), 6.47 (d, IH), 6.17 (s, IH), 6.02 (dd, IH), 5.51 (d, IH), 5.47 (s, IH), 5.42 (s, IH), 3.87 (s,
3H), 2.89 (dd, IH), 2.44 (dd, IH), 2.26 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H). Anal, calcd for C23H24NO2Br: C, 64.79; H, 5.67; N, 3.29. Found: C, 64.70; H, 5.65; N,
3.09.
Examples 148-150 Example 2B (1.25g, 3.70 mmol) and Hl'-t-butyldimethylsiloxy-l'- methoxyalkylidene]-2-cyclohexene were processed as in example 2 to provide a diastereomeric mixture of unsaturated ester adducts (1.21 g, 73%) that was carried on to the next step.
The mixture above (1.20 g, 2.69 mmol) was dissolved in THF (100 ml), cooled to 0 °C, treated slowly with Dibal-H (13.5 ml of lM/hex solution, 13.5 mmol) by syringe, stirred 30 minutes, diluted with 250 ml saturated aqueous sodium pottasium tartrate and 300 ml ethyl acetate and stirred overnight. The layers were separated, aqueous phase extracted twice with ethyl acetate, combined organics washed with brine and dried (MgSO4). The resulting residue was purified by silica gel chromatography eluting with from 20% to 30% methyl t-butylether in hexanes to give Examples 148-150.
Example 148 rel (5R,3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, J=8 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.17 (d, J=2 Hz, IH), 5.50 (d, J=10 Hz, IH), 5.39 (br s, IH), 5.05 (br s, IH), 4.42 (t, IH), 3.85 (s, 3H), 3.64 (d, J=6 Hz,
2H), 2.27 (n, IH), 2.05 (s, 3H), 1.95-1.86 (m, 2H), 1.78-1.21 (m, 4H), 1.28 (s, 3H), 1.09
(s, 3H);
Anal, calcd for C27H3lNO3»l/2H2O: C, 76.03; H, 7.56; N, 3.28. Found: C, 76.34; H,
7.71; N, 3.20.
Example 149 rel (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline
MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.40 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.67 (d,
J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.20 (d, J=8 Hz, IH), 6.20 (s, IH), 5 (78, J=s Hz, IH), 5.45 (s, IH), 5.37 (d, J=10 Hz, IH), 4.60 (dd, J=5 Hz, IH), 3.85 (s, 3H), 3.75 (s, 2H), 2.37 (m, IH), 2.12 (s, 3H), 1.70 (m, 2H), 1.60 (m, IH), 1.30 (s, 3H), 1.15 (m, 2H), 1.02 (s, 3H); 13C NMR (75 MHz, DMSO-d6)D 156.3, 151.5, 145.0, 139.6, 133.7, 130.2, 128.0, 127.1,
126.9, 120.8, 120.3, 118.5, 116.5, 113.0, 110.2, 105.2, 105.2, 76.2, 65.1, 55.6, 49.4, 36.9, 29.6, 26.8, 23.7, 21.3.
Example 150 2,5-dihydro-l 0-methoxy-5-(3-hydroxymethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.06 (d, J=8 Hz, IH), 7.01 (t, J=8 Hz, IH), 6.59 (d,
J=8 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.27 (s, IH), 6.03 (s, IH), 5.38 (s, IH), 5.23 (m, IH), 4.75 (m, 2H), 3.81 (s, 3H), 3.47 (m, IH), 2.95 (m, IH), 2.19 (s, 3H), 1.70-1.35 (m, 6H),
1.31 (s, 3H), 1.03 (s, 3H); 13C NMR (75 MHz, DMSO-d6)D 156.4, 154.4 (145.1), 132.9, 129.2, 128.0, 127.6, 126.9, 126.1, 119.3, 118.6, 114.3, 113.1, 109.0, 105.5, 73.5, 64.4,
55.9, 49.2, 48.6, 29.7, 26.5, 25.6, 24.3, 23.5, 18.3;
Anal, calcd for C27H31NO3-1/4H2O: C, 76.84; H, 7.52; N, 3.32. Found: C, 76.93; H,
7.73; N, 3.18.
Example 151 2,5-dihydro-10-methoxy-5-(3-indolyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline Example 2B and indole were processed as in Example 2 to provide the desired compound.
MS (DCI/NH3) m/e 423 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 10.89 (d, IH), 8.01 (d, IH), 7.83 (dd, IH), 7.27 (dd, IH), 7.04 (m, 3H), 6.80 (t, IH), 6.68 (d, IH), 6.54 (s, IH), 6.53 (d, IH), 6.28 (d, IH), 6.12 (s, IH), 5.35 (s, IH), 3.83 (s, 3H), 1.89 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H) Anal, calcd for C28H26 2O2: C, 79.59; H, 6.20; N, 6.62. Found: C, 79.58; H, 6.28; N,
6.36.
Example 152 re/ (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- [11benzopyrano[3,4-f]quinoline
Example 148 (0.512 g, 1.23 mmol) was dissolved in CH2CI2 (5 ml), cooled to 0 °C, treated with (i-Pr)2NEt (0.32 ml, 1.84 mmol), methanesulfonyl chloride (0.11 ml, 1.47 mmol) and stirred for 1 hour. The reaction mixture was treated dropwise with lithium triethylborohydride (4.70 ml of 1M/THF solution, 4.70 mmol), stirred 60 minutes, treated with 10 ml IM NaOH, 0.6 ml 30 % H2O2, stirred 2 hours and extracted with ethyl acetate. The organic layer was washed with H2O, saturated aqueous NaHCO3, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography eluting with 5 % then 7 % ethyl acetate in hexanes to give 0.362 g (74%) ofthe desired product as a colorless foam. MS (DCI/NH3) m/e 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.02 (d, J=8 Hz, IH), 7.06 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.56 (d, J=8 Hz, IH), 6.16 (s, IH), 5.49 (d, J=10 Hz, IH), 5.41 (br s, IH), 4.83 (br s, IH), 3.85 (s, 3H), 2.31-2.17 (m, IH), 2.06 (s, 3H), 1.99- 1.21 (m, 6H), 1.49 (s, 3H), 1.29 (s, 3H), 1.08 (s, 3H). • Example 153 re/ (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ljbenzopyrano[3 ,4-fjquinoline Example 149 was processed as in Example 152 to provide the desired compound.
MS (DCI/NH3) m/e 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.04 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.22 (d, J=2 Hz, IH), 5.55 (br s, IH), 5.45 (br s, IH), 5.35 (d, J=10 Hz, IH), 3.86 (s, 3H), 2.34-2.18 (m, IH), 2.12 (s, 3H), 1.97-0.88 (m, 6H), 1.61 (s, 3H), 1.30 (s, 3H), 1.02 (s, 3H);
Anal, calcd for C27H-3lNθ2'l/4H2θ: C, 79.87; H, 7.82; N, 3.45. Found: C, 79.81; H,
8.28; N, 3.39.
Example 154 (-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline Example 152 was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 2%> EtOH in hexanes to provide the desired compound. [DJD20 -155.9° (c 0.85, CHCI3); MS (DCI/NH3) m/e 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.02 (d, J=9 Hz, IH), 7.06 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.64 (d, J=9 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.20 (d, J=2 Hz, IH), 5.49 (d, J=10 Hz, IH), 5.42 (br s, IH), 4.83 (br s, IH), 3.85 (s, 3H), 2.30-2.18 (m, IH), 2.06 (s, 3H), 1.97-1.20 (m, 6H), 1.49 (s, 3H), 1.29 (s, 3H), 1.08 (s, 3H); Anal, calcd for C27H3lNO2'l/4H2O: C, 79.87; H, 7.82; N, 3.45. Found: C, 79.80; H,
8.15; N, 3.41.
Example 155 (-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline
Example 149 was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 6% EtOH in hexanes to provide the desired product. [D]D20 -233.9° (c 1.27, CHCI3); MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO-df5)D8.05 (d, J=9 Hz, IH), 7.08 (d, J=8 Hz, IH), 6.68 (d,
J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.23 (br s, IH), 5.78 (br s, IH), 5.46 (br s, IH), 5.37 (d, J=10 Hz, IH), 4.65 (t, J=6 Hz, IH), 3.86 (s, 3H), 3.76 (m, 2H), 2.36-2.22 (m, 2H), 2.12 (s, 3H), 1.87-1.77 (m, 2H), 1.65-1.53 (m, IH), 1.30 (s, 3H), 1.27-0.92 (m, 2H), 1.02 (s, 3H).
Example 156 (+) (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline Example 149 was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 6% EtOH in hexanes to provide the desired product. [DJD20 +234.6° (c 1.10, CHCI3); MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO-dfS)D8.05 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.22 (br s, IH), 5.78 (br s, IH), 5.45 (br s, IH), 5.37 (d, J=10 Hz, IH), 4.63 (t, J=6 Hz, IH), 3.86 (s, 3H), 3.78-3.73 (m, 2H), 2.36-2.22 (m, 2H), 2.12 (s, 3H), 1.87-1.77 (m, 2H), 1.65-1.52 (m, IH), 1.34-0.93 (m, 2H), 1.30 (s, 3H), 1.02 (s, 3H).
Example 157
(-H5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- f 1 Jbenzopyrano [3 ,4-fjquinoline Example 155 was processed as in Example 152 to provide the desired compound.
MS (DCI/NH3) m/e (M+H)+ 402; iH NMR (300 MHz, DMSO-d6)D8.04 (d, J=8 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d,
J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.23 (br s, IH), 5.55 (br s, IH),
5.45 (br s, IH), 5.35 (d, J=10 Hz, IH), 3.86 (s, 3H), 2.33-2.18 (m, IH), 2.12 (s, 3H), 1.95-1.45 (m, 4H), 1.61 (s, 3H), 1.34-0.88 (m, 2H), 1.30 (s, 3H), 1.02 (s, 3H); [DJD20 -
224.1° (c 0.73, CHCI3);
Anal, calcd for O27H31NO2 "1/2^0: C, 78.99; H, 7.86; N, 3.41. Found: C, 79.14; H,
8.07; N, 3.03.
Example 158
(+)-(5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline Example 156 was processed as in Example 152 to provide the desired compound. MS (DCI/NH3) m/e 402 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.04 (d, J=9 Hz, IH), 7.07 (d, J=8 Hz, IH), 6.67 (d,
J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.22 (br s, IH), 5.55 (m, IH), 5.45 (br s, IH), 5.35 (d, J=10 Hz, IH), 3.86 (s, 3H), 2.27 (m, IH), 2.12 (s, 3H), 1.94-1.05 (m, 6H), 1.61 (s, 3H), 1.30 (s, 3H), 1.02 (s, 3H). Example 159 2,5-dihydro- 10-methoxy-5-( 1 -chloromefhyl-3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[11benzopyrano[3,4-f]quinoline Example 148 (0.110 g, 0.264 mmol) was combined with methanesulfonyl chloride (49 μl, 0.632 mmol), (i-Pr)2NEt (53 μL, 0.695 mmol), Lithium chloride (11 mg, 0.264 mmol) in 2 mL of THF containing 2 drops of DMF and the reaction mixture was stirred at room temperature for several hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous bicarbonate, brine, dried over MgSO4 and purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 106 mg (92%>) ofthe desired compound as a foam.
MS (DCI/NH3) m/e 436 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.03 (d, J=8 Hz, IH), 7.08 (t, J=8 Hz, IH), 6.66 (dd,
J=8 Hz, 2H), 6.55 (d, J=8 Hz, IH), 6.25 (br s, IH), 5.53 (d, J=10 Hz, IH), 5.39 (s, IH), 5.25 (s, IH), 3.91 (s, 2H), 3.84 (s, 3H), 2.30 (m, IH), 2.05 (s, 3H), 1.35-2.00 (m, 6H),
1.30 (s, 3H), 1.10 (s, 3H).
Example 160 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1H-[1 jbenzopyrano [3 ,4-fj quinoline
Example 148 was processed according to Example 152 using sodium methoxide instead of lithium triethylborohydride to give the desired compound. MS (DCI/NH3) m/e 432 (M+H)+; iHNMR (400 MHz, DMSO-df5)D8.02 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.69 (d, J=9 Hz, IH), 6.64 (d, J=9 Hz, IH), 6.57 (d, J=9 Hz, IH), 5.53 (d, J=10 Hz, IH), 5.11 (s,
IH), 3.85 (s, 3H), 3.58 (dd, J=12+32 Hz, IH), 3.06 (s, 3H), 2.30 (br m, IH), 2.07 (s, 3H), 1.50-2.00 (br m, 4H), 1.35 (m, IH), 1.30 (s, 3H), 1.10 (s, 3H); i3C NMR (100 MHz, DMSO-d<s)D 156.2, 150.9, 145.0, 137.0, 133.7, 133.6, 130.4,
128.1, 127.1, 127.1, 123.5, 117.9, 116.4, 113.5, 113.1, 110.1, 105.4, 105.3, 105.0, 76.2, 75.4, 56.4, 55.6, 49.5, 36.9, 29.7, 23.4, 25.5, 25.3, 25.2, 24.2, 20.2.
Example 161 rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline Example 148 was processed according to Example 152 using sodium thiomethoxide instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 448 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, J=8 Hz, IH), 7.08 ( t, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.65 (d, J=9 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.23 (s, IH), 5.49 (d, J=10 Hz, IH), 5.40 (s, IH), 5.00 (s, IH), 3.86 (s, 2H), 2.30 (br m, 2H), 2.07 (s, 3H), 1.81 (s, 3H), 1.40-1.78 (br m, 6H), 1.30 (s, 3H), 1.09 (s, 3H);
13C NMR (100 MHz, DMSO-d6)P 156.2, 151.0, 145.0, 135.7, 133.8, 130.3, 128.2,
127.1, 127.1, 123.5, 118.1, 116.5, 113.4, 113.1, 110.1, 105.3, 75.7, 55.5, 49.5, 40.8, 37.5, 29.7, 27.3, 26.2, 25.7 (24.2), 20.6, 13.7.
Example 162 rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline Example 149 (0.100 g, 0.239 mmol) was combined with acetic anhydride ( 27 μL, 0.288 mmol), DMAP (2 mg, catalytic), (i-Pr)2NEt (50 μL, 0.288 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 1 hour at room temperature, diluted with ethyl acetate and washed with saturated aqueous bicarbonate, brine, dried (MgSO4)and purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 89 mg (81%>) ofthe desired compound as a white solid.
MS (DCI/NH3) m/e 460 (M+H)+; iH NMR (300 MHz, DMSO-df )D8.05 (d, J=8 Hz, IH), 7.08 (t, J=8 Hz, IH), 6.68 (d,
J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.23 (s, IH), 5.82 (s, IH), 5.46
(s, IH), 5.40 (d, J-10 Hz, IH), 4.38 (s, 2H), 3.86 (s, 3H), 2.33 (br m, IH), 2.12 (s, 3H),
2.03 (s, 3H), 1.85 (br m, 2H), 1.60 (br m, IH), 1.30 (s, 3H), 1.02-1.28 (br m, 3H), 1.02
(s, 3H); Anal, calcd for C29H33NO4: C, 75.79; H, 7.24; N, 3.05. Found: C, 76.14; H, 7.47; N,
3.02.
Example 163 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline
Example 148 was processed as in Example 162 to provide the desired compound as a white solid.
MS (DCI/NH3) m/e 460 (M+H)+; iHNMR (300 MHz, DMSO-d<s)D8.02 (d, J=8 Hz, IH), 7.08 (t, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.65 (d, J=8 Hz, IH), 6.58 (d, J=8 Hz, IH), 6.18 (s, IH), 5.55 (d, J=10 Hz, IH), 5.39 (s, IH), 5.16 (s, IH), 4.22 (s, 2H), 3.85 (s, 3H), 2.40 (br, J=8 Hz, IH), 2.06 (s, 3H), 1.96 (s, 3H), 1.32-1.95 (br m, 3H), 1.28 (s, 3H), 1.06 (s, 3H); Anal, calcd for C29H33NO4: C, 75.79; H, 7.24; N, 3.05. Found: C, 75.53; H, 7.32; N, 2.84.
Example 164 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline Example 149 was processed according to Example 152 using sodium methoxide instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 432 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.05 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.67 (d,
J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.20 (s, IH), 5.78 (s, IH), 5.45 (s, IH), 5.39 (d, J=10 Hz, IH), 3.70 (s, 2H), 3.14 (s, 3H), 2.30 (br m, IH), 2.12 (s, 3H), 1.81 (br m, 2H), 1.60 (br m, IH), 1.30 (s, 3H), 1.15 (brm, 2H), 1.02 (s, 3H); Anal, calcd for O28H33NO3-1/4H2O: C, 77.12; H, 7.74; N, 3.21. Found: C, 77.17; H,
7.55; N, 3.15.
Example 165 rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-(N,N-dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline
Example 148 was processed according to Example 152 using dimethylamine instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 445 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, J=8 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.22 (s, IH), 5.50 (d, J=10 Hz,
IH), 5.39 (s, IH), 5.03 (s, IH), 3.85 (s, 3H), 2.62 (d, J=ll Hz, IH), 2.50 (d, J-l l Hz, IH), 2.25 (br s, IH), 2.06 (s, 6H), 1.98 (s, 3H), 1.40-1.95 (br m, 6H), 1.30 (s, 3H), 1.25 (br m, IH), 1.11 (s, 3H); Anal, calcd for C29H36N2O2-3/4H2O: C, 76.03; H, 8.25; N, 6.11. Found: C, 75.90; H, 7.81; N, 5.90.
Example 166 rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline Example 149 was processed according to Example 152 using sodium thiomethoxide instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 448 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.05 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.24 (s, IH), 5.71 (s, IH), 5.46 (s, IH), 5.39 (d, J=10 Hz, IH), 3.86 (s, 3H), 3.02 (s, 2H), 2.17-2.41 (br m, 2H), 2.11 (s, 3H), 1.91-2.10 (br m, 2H), 1.88 (s, 3H), 1.30 (s, 3H), 1.25 (s, 3H), 1.05-1.25 (br m, 3H),
1.02 (s, 3H); Anal, calcd for C28H33NO2S-I/2H2O: C, 73.65; H, 7.50; N, 3.07. Found: C, 73.37; H,
7.46; N, 2.97.
Example 167 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-momholino)methyl-3-cyclohexenyl)- 2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline Example 148 was processed according to Example 152 using morpholine instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 487 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.01 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.65 (d, J=8 Hz, IH), 6.56 (d, J=8 Hz, IH), 6.22 (s, IH), 5.49 (d, J=l l Hz, IH), 5.41 (s, IH), 5.04 (s, IH), 3.85 (s, 3H), 3.52 (br s, 3H), 2.68 (d, J=12 Hz, IH), 2.56 (d, J=12 Hz, IH), 2.25 (br s, IH), 2.15 (br s, 2H), 2.05 (s, 3H), 1.40-2.00 (br m, 6H), 1.32 (s, 3H), 1.20- 1.28 (br m, 6H), 1.17 (s, 3H);
Anal, calcd for C31H38N2O3: C, 76.51; H, 7.87; N, 5.76. Found: C, 76.24; H, 8.05; N,
5.52.
. Example 168 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methyl-N-methylsulfonylamino)methyl-
3-cyclohexenyl)-2,2,4-trimethyl-lH-πjbenzopyrano[3 ,4-fjquinoline Example 170 (0.80 g, 0.186 mmol) was combined with methanesulfonyl chloride (15 μL, 0.195 mmol), (i-Pr)2NEt (48 μl, 0.279 mmol) and THF at 0 °C for 1.5 hours.
The product was added directly to a silica gel plug and eluted with hexane then 40%) ethyl acetate in hexane to give 88 mg (93%) ofthe desired compound as a white solid.
MS (DCI/NH3) m/e 509 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, J=9 Hz, IH), 7.08 (t, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.65 (d, J=9 Hz, IH), 6.58 (d, J=9 Hz, IH), 6.20 (s, IH), 5.53 (d, J=5 Hz, IH), 5.41 (s, IH), 5.11 (s, IH), 3.85 (s, 3H), 3.46 (d, J=13 Hz, IH), 3.24 (d, J=13 Hz, IH), 2.82 (s, 3H), 2.53 (s, 3H), 2.30 (br, IH), 2.08 (s, 2H), 1.5-2.0 (br m, 6H), 1.35 (br m, IH), 1.30 (s, 3H), 1.25 (m, IH), 1.11 (s, 3H); Anal, calcd for C29H36N2O4S: C, 68.47; H, 7.13; N, 5.51. Found: C, 68.20; H, 7.09; N, 5.36.
Example 169 rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-(N,N dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-ιjquinoline Example 149 was processed according to Example 152 using dimethylamine instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 445 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.05 (d, J=9 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.67 (d,
J=8 Hz, IH), 6.63 (d, J-8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.213 (s, IH), 5.69 (s, IH), 5.46 (s, IH), 5.42 (d, J=10 Hz, IH), 3.86 (s, 3H), 2.70 (br, IH), 2.30 (br m, IH), 2.11 (s, 3H), 2.05 (br, 4H), 1.85 (br, 2H), 1.56 (m, IH), 1.30 (s, 3H), 1.10-1.25 (m, 3H), 1.02 (s, 3H); Anal, calcd for C29H36N2O2-1/2H2O: C, 76.79; H, 8.22; N, 6.18. Found: C, 76.49; H, 8.23; N, 5.95.
Example 170 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3-cyclohexenyl)- 2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4-fjquinoline Example 148 was processed according to Example 152 using methylamine instead of lithium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 431 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q8.00 (d, J=8 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.68 (d, J=7 Hz, IH), 6.63 (d, J=7 Hz, IH), 6.57 (d, J=7 Hz, IH), 6.22 (s, IH), 5.76 (s, IH), 5.53 (d, J=10 Hz, IH), 5.41 (s, IH), 5.14 (br s, IH), 3.85 (s, 3H), 3.02 (s, 2H), 2.30 (br m,
IH), 2.22 (s, 3H), 2.07 (s, 3H), 1.74 (br m, 2H), 1.80-1.4 (br m, 4H), 1.30 (s, 3H), 1.25 (s, IH), 1.10 (s, 3H); Anal, calcd for C28H33N2O2T.25H2O: C, 74.22; H, 8.12; N, 6.18. Found: C, 74.05; H,
7.81; N, 6.00.
Example 171 2,5-dihydro-l 0-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl-lH- [11benzopyrano[3,4-fjquinoline A solution of Example 147 (51 mg, 0.12 mmol) and tetramethyltin (66.5 μl, 0.048 mmol) in 1ml HMPA was degassed with N2 for 20 minutes.
Dichlorobis(triphenylphosphine)palladium(II) (9.8 mg, 0.012 mmol) was added and the reaction mix was heated at 85°C for 60 hours, cooled to room temperature, and stirred vigorously with 30 ml of ethyl acetate and 30 ml of saturated KF aqueous solution for 3 hours. The mixture was then filtered through a plug of celite and the layers were separated. The organic layer was washed with water, brine and dried (Na2SO4).
Concentration followed by silica gel chromatography (15%) ethyl acetate/hexanes) provided the desired compound.
MS (DCI/NH3) m z 362 (M+H)+; iH NMR (300 MHz, DMSO-d6)Q7.94 (d, IH), 7.05 ( t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.42 (d, IH), 6.12 (d, IH), 5.91 (dd, IH), 5.44 (s, IH), 4.77 (s, IH), 4.54 (s, IH), 3.87 (s, 3H), 2.43 (m, IH), 2.20 (s, 3H), 2.09 (in, IH), 1.74 (s, 3H), 1.16 (s, 3H). HRMS calcd m/z for C24H27NO2: 361.2042. Found: 361.2047.
Example 172
2,5-dihydro- 10-methoxy-5-( 1 ,3 -butadien-2-yl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline Example 147 and tributyl(vinyl)tin were processed as in the previous example to give the desired compound.
MS (DCI NH3) m z 374 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.00 (d, IH), 7.05 ( t, IH), 6.70 (dd, IH), 6.60 (d,
IH), 6.47 (dd, IH), 6.36 (dd, IH), 6.18 (d, IH), 5.95 (dd, IH), 5.43 (s, IH), 5.16 (s, IH), 5.12 (s, IH), 5.05 (d, IH), 5.00 (d, IH), 3.87 (s, 3H), 2.55 (dd, IH), 2.22 (dd, IH), 2.10
(s, 3H), 1.20 (s, 3H), 1.12 (s, 3H).
Example 173 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH- [ 1 Jbenzopyrano [3 ,4-fj quinoline
A mixture of Example 147 (64 mg, 0.15 mmol), bis(triphenylphosphine)dicarbonylnickel (144 mg, 0.225 mmol) and triethylamine (42uL, 0.30 mmol) in 5 mL of MeOH was refluxed for 16 hours, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash silica gel chromatography (15% ethyl acetate/hexanes) to give the desired compound. MS (DCI/NH3) m z 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, IH), 7.06 ( t, IH), 6.70 (dd, IH), 6.60 (d, IH), 6.41 (dd, IH), 6.12 (dd, IH), 6.01 (dd, IH), 5.43 (s, IH), 5.36 (s, IH), 3.87 (s, 3H), 3.68 (s, 3H), 2.60 (dd, IH), 2.43 (dd, IH), 2.21 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H);
Anal, calcd for C25H27NO4: C, 74.05; H, 6.71; N, 3.45. Found: C, 73.81; H, 6.61; N,
3.38. Example 174 2,5-dihydro-10-methoxy-5-(l,2-dihydroxy-3-propyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline A solution of Example 2 (50 mg, 0.144 mmol) in pyridine (3 mL) at 0 °C was treated with Osθ4 (370 uL, 0.144 mmol), stirred at ambient temperature for 48 hours, treated with saturated aqueous sodium bisulfite (3 mL), stirred for 4 hours and filtered through Celite. The Celite plug was washed repeatedly with EtOAc. The organic filtrate was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by flash silica gel chromatography (95:5 methylene chloride/methanol) to give the desired compound as an inseparable mixture of two diastereomers (2:1).
MS (DCI/NH3) m/z 382 (M+H)+; iH NMR (300 MHz, DMSO-d6);
Major diastereomer: D 7.94 (d, IH), 7.05 (t, IH), 6.67 (d, IH), 6.57 (d, IH), 6.53 (d, IH), 6.13-6.05 (m, 2H), 5.42 (s, IH), 4.80 (d, IH), 4.38 (t, IH), 3.85 (s, 3H), 3.65 (bm, IH), 3.19-3.00 (m, 2H), 2.21 (s, 3H), 1.83 (m, 2H), 1.19 (s, 3H), 1.11 (s, 3H);
Minor diastereomer: D 7.96 (d, IH), 7.07 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.55 (d, IH), 6.13 (s, IH), 5.97 (dd, IH), 5.42 (s, IH), 4.50 (t, IH), 4.45 (d, IH), 3.85 (s, 3H), 3.45- 3.30 (m, 3H), 2.23 (s, 3H), 1.80-1.58 (m, 2H), 1.21 (s, 3H), 1.09 (s, 3H); Anal, calcd for C23H27NO4O.35 H2O: C/71.24; H, 7.20; N, 3.61. Found: C, 71.24; H, 7.28; N, 3.49.
Example 175 2,5-dihydro-10-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-fjquinoline A mixture of Example 174 (50 mg, 0.13 mmol), triphenylphosphine (38 mg, 0.14 mmol), diethyl azodicarboxylate (25 mg, 0.14 mmol) and 3 angstrom molecular sieves (50 mg) in benzene (5 mL) was refluxed for 48 hours, cooled and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by flash silica gel chromatography (8:2 hexane/EtOAc) to give the desired compound as an inseparable mixture of two diastereomers (1.3:1).
MS (DCI/NH3) m/z 364 (M+H)+; iH NMR (300 MHz, DMSO-d6);
Major diastereomer: D 7.93 (d, IH), 7.09 (t, IH), 6.72 (d, IH), 6.60 (d, IH), 6.58 (d, IH), 6.14 (s IH), 5.95 (m, IH), 5.44 (s, IH), 3.85 (s, 3H), 3.04 (m, IH), 2.72 (dd, IH), 2.35
(dd, IH), 2.17 (s, 3H), 2.05-1.35 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); Minor diastereomer: D 7.95 (d, IH), 7.08 (t, IH), 6.71 (d, IH), 6.59 (d, IH), 6.57 (d, IH), 6.15 (s IH), 5.93 (m, IH), 5.44 (s, IH), 3.85 (s, 3H), 2.90 (m, IH), 2.65 (dd, IH), 2.28 (m, IH), 2.17 (s, 3H), 2.05-1.58 (m, 2H), 1.17 (s, 3H), 1.13 (s, 3H); HRMS calcd m/z for C23H35NO3: 363.1834. Found: 363.1846.
Example 176 2,5-dihydro-10-methoxy-5-(l-(N-phthalimido)-3-propyl)-2,2,4-ttimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline Example 69 (250 mg, 0.68 mmol), phthalimide (103 mg, 0.7 mmol), triphenylphosphine (184 mg, 0.7 mmol) and diethyl azodicarboxylate (110 uL, 0.7 mmol) in THF (15 mL) was stirred for 24 hours and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by flash silica gel chromatography (3:1 hexane/EtOAc) to give the desired compound. MS (DCI/NH3) m/z 495 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.88 (d, IH), 7.81 (s, 4H), 6.82 (t, IH), 6.58 (d, IH), 6.42 (d, IH), 6.40 (d, IH), 6.10 (s, IH), 5.61 (dd, IH), 5.40 (s, IH), 3.78 (s, 3H), 3.48 (t, 2H), 2.16 (s, 3H), 1.75-1.40 (bm, 4H), 1.22 (s, 3H), 1.16 (s, 3H); HRMS calcd m/z for C31H30N2O4: 494.2206. Found: 494.2198. Example 177
2,5-dihydro-10-methoxy-5-(l-amino-3-propyl)-2,2,4-trimethyl-lH-[11benzopyrano[3 ,4- fj quinoline Example 176 (118 mg, 0.24 mmol) was treated with hydrazine (12.8 mg, 0.4 mmol) in refluxing ethanol (8 mL) for 16 hours, cooled and filtered to remove a solid. The filtrate was concentrated and purified by flash silica gel chromatography (9.5:0.5 methylene chloride/methanol) to give the desired compound.
MS (DCI/NH3) m/z 365 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.94 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.57 (d, IH),
6.54(d, IH), 6.08 (s, IH), 5.66 (dd, IH), 5.43 (s, IH), 3.85 (s, 3H), 2.43 (t, 2H), 2.17 (s, 3H), 1.80-1.22 (m, 4H), 1.16 (s, 3H), 1.15 (s, 3H);
Anal, calcd for C23H28N2O2 • 0.30 H2O: C,74.69; H, 7.79; N, 7.57. Found: C, 74.50;
H, 7.78; N, 7.31. Example 178
2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline Example 177 (65 mg, 0.178 mmol) was treated with triphosgene (19 mg, 0.0646 mmol) and triethylamine (50 uL, 0.36 mmol) in refluxing THF (6 mL) for 3 hours, cooled and concentrated to give the crude isocyanate.
The crude isocyanate (0.089 mmol) in THF (10 mL) was treated with hydrazine
(4.5 mmol), stirred for 2 hours under nitrogen, concentrated and the resulting residue was purified by flash silica gel chromatography( 9: 1 dichloromethane / methanol) to give the desired compound.
MS (DCI/NH3) m/z 423 (M+H)+; iH NMR (300 MHz, DMSO-d6)L17.94 (d, IH), 7.06 (t, IH), 6.79 (bs, IH), 6.68 (dd,
IH), 6.57 (d, IH), 6.54 (dd, IH), 6.22 (bt, IH), 6.10 (d, IH), 5.63 (dd, IH), 5.44 (s, IH), 3.96 (bs, 2H), 3.85 (s, 3H), 2.92 (m, 2H), 2.15 (s, 3H), 1.58-1.20 (m, 4H), 1.16 (s, 3H),
1.15 (s, 3H);
HRMS (M+H)+ calcd m/z for C24H30N4O3: 423.2396 . Found: 423.2413.
Example 179 (E) 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-l-ethenyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline Example 44 (0.087 g, 0.26 mmol) was dissolved in CH2CI2 (10ml), cooled to-23
°C, treated dropwise with 0.52 ml IM Dibal-H / heptane solution (0.52 mmol) and stirred for 1 h. The reaction mixture was poured into 30 ml 0.5 M HCl, stirred 30 min, extracted with ethyl acetate, the combined organics washed with brine and dried
(Na2SO4) to give the intermediate aldehyde as a yellow foam.
The resulting yellow foam was dissolved in THF (8 ml), cooled to 0 °C, treated with methyl (triphenylphosphoranylidene)acetate (0.130 g, 0.39 mmol),i stirred overnight at room temperature and then at 45 °C for 1 hour. The reaction mixture was allowed to cool, diluted with saturated aqueous NH4CI, extracted with ethyl acetate, and the combined organics washed with brine and dried (MgSO4). The resulting residue was purified by column chromatography on silica gel eluting with 90:10-hexane:ethyl acetate to give 0.043 g (42%>) the desired compound as a yellow foam. MS (DCI/NH3) m/e 392 (M+H)+; JH NMR (300 MHz, DMSO-d6)Q7.99 (d, J=9 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.86 (dd,
J=4, 16 Hz, IH), 6.69 (d, J=7 Hz, IH), 6.67 (d, J=9 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.41 (dd, J=2, 4 Hz, IH), 6.26 (d, J=2 Hz, IH), 5.63 (dd, J=2, 16 Hz, IH), 5.45 (br s, IH), 3.84 (s, 3H), 3.56 (s, 3H), 2.08 (s, 3H), 1.19 (s, 3H), 1.15 (s, 3H); l C NMR (100 MHz, DMSO-d6)P 165.19, 156.18, 151.64, 146.45, 145.59, 133.53, 128.39, 127.17, 123.57, 117.17, 116.54, 113.85, 109.82, 105.78, 71.93, 55.80, 55.59, 51.57, 49.75, 29.56, 29.15, 28.70, 23.45; Anal, calcd for O24H25NO4»1/4H2O: C, 72.80; H, 6.49; N, 3.54. Found: C, 73.00; H, 6.56; N, 3.34.
Example 180 (Z)-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline The intermediate aldehyde from Example 179 and ethyltriphenylphosphonium iodide were processed according to Example 187 to provide the desired compound. MS (DCI/NH3) m/e 348 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.90 (d, J=8 Hz, IH), 6.97 (t, J=6 Hz, IH), 6.67 (d, J=8 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.48 (d, J=12 Hz, IH), 6.26 (d, J=7 Hz, IH), 6.10 (s, IH), 5.59 (m, IH), 5.41 (s, 2H), 3.83 (s, 3H), 2.08 (s, 3H), 1.79 (d, J=7 Hz, 3H), 1.23 (s,
3H), l.ll (s, 3H); 13C NMR (125 MHz, DMSO-d6)P 156.1, 152.4, 145.4, 132.4, 131.0, 130.2, 127.7,
127.2, 127.0, 126.7, 116.9, 116.4, 113.7, 113.0, 109.9, 105.4, 69.4, 55.6, 49.7, 29.6, 28.3, 23.0, 13.8; Anal, calcd for C23H25θ2N»1.0H2θ: C, 75.59; H, 7.45; N, 3.83. Found: C, 75.53; H,
7.20; N, 3.62.
Example 181 (E) 2,5-dihydro-10-methoxy-5-(3-hydroxy-l-propenyl)-2,2,4-trimethyl-lH- [11benzopyranor3,4-f]quinoline
A 20 ml ethereal suspension of L1AIH4 (0.200 g, 5.17 mmol) was treated dropwise at room temperature with a 15 ml ethereal solution of AICI3 (0.230 g, 1.72 mmol), stirred for 15 minutes and treated dropwise with a 20 ml ethereal solution of Example 179. After stirring 1 hour at room temperature, 2 ml H2O was carefully added followed by the dropwise addition of 15 % NaOH until a white paste deposited on the bottom ofthe vessel. The ether solution was decanted, the paste washed several times with ether and the combined organics washed with brine and dried (MgSO4). The residue was purified by column chromatography on silica gel eluting with 25% then 33% ethyl acetate in hexanes to give 0.195 g (78%>) ofthe desired compound as a colorless foam. iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=8 Hz, IH), 7.01 (t, J=8 Hz, IH), 6.64 (d,
J=9 Hz, IH), 6.61 (d, J=9 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.18 (br d, J=4 Hz, IH), 6.08 (s, IH), 5.73-5.66 (m, IH), 5.51 (5.43, J=m Hz, IH), 5.41 (s, IH), 4.65 (t, J=5 Hz, IH), 3.83 (s, 3H), 3.77 (t, J=5 Hz, 2H), 2.12 (s, 3H), 1.19 (s, 3H), 1.13 (s, 3H); MS (FAB) m/e calcd for C23H25NO3: 363.183. Found 363.1839.
Example 182
(E) 2,5-dihydro-l 0-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)-l -propenyl)-2,2,4- trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline Example 181 (0.035 g, 0.096 mmol) was dissoved in DMF (5 ml), treated with NaH (0.012 g 60%> dispersion in oil, 0.289 mmol) at room temperature, stirred for 10 minutes, treated dropwise with N,N-dimethylcarbamoyl chloride (44 Dl, 0.481 mmol) and stirred for 30 minutes. The reaction mixture was diluted with 10 ml saturated aqueous NH4CI, extracted with ethyl acetate, the organic layers washed with H2O, brine, dried (MgSO4), concentrated, and purified by silica gel chromatography eluting with 25%) then 33%> ethyl acetate in hexanes to give 0.033 g (79%) ofthe desired compound as a colorless foam. :
MS (DCI/NH3) m/e 509 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.94 (d, J=9 Hz, IH), 7.02 (t, J=8 Hz, IH), 6.66 (d, J=8 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.53 (d, J=8 Hz, IH), 6.17 (m, 2H), 5.82 (dd, J=16, 4 Hz, IH), 5.49-5.42 (m, IH), 5.42 (s, IH), 4.31 (d, J=6 Hz, 2H), 3.82 (s, 3H), 2.71 (m, 6H), 2.09 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H);
13C NMR (100 MHz, DMSO-d6)D 156.1, 155.1, 151.8, 145.4, 133.0, 131.5, 130.0, 129.8, 127.6, 127.0, 126.8, 117.3, 116.9, 113.7, 113.5, 110.0, 105.6, 72.9, 63.8, 55.7, 55.6, 49.7, 29.3, 28.5, 28.4, 23.3; MS (FAB) m/e calcd for C26H30N2O4: 434.2206. Found 434.2209.
Example 183 (E) 2,5-dihydro-10-methoxy-5-(3-methoxymethoxy-l-propenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline Example 181 ( 0.026 g, 0.072 mmol) was dissolved in dichloroethane (5 ml), cooled to 0 °C, treated with (i-Pr)2NEt (62 Dl, 0.358 mmol) followed by chloromethyl methyl ether (16 Dl, 0.215 mmol) the bath removed and the mixture heated to 55 °C for 14 hours. The mixutre was partitioned between ethyl acetate and saturated aqueous NH4CI, the organic layer washed with brine, dried (MgSO4) and purified by silica gel chromatography eluting with 10 % ethyl acetate in hexanes to give 0.012 g (41%) ofthe desired compound as an amber oil. iH NMR (300 MHz, DMSO-d6)D7.94 (d, J=8 Hz, IH), 7.02 (t, J=8 Hz, IH), 6.66 (d,
J=9 Hz, IH), 6.63 (d, J=9 Hz, IH), 6.53 (d, J=8 Hz, IH), 6.19 (br d, J=3 Hz, IH), 6.14 (d, J=2 Hz, IH), 5.78 (dd, J=16, 4 Hz, IH), 5.42 (s, IH), 4.31 (ABq, J=8, 6 Hz, 2H), 3.84 (m, 2H), 3.82 (s, 3H), 3.09 (s, 3H), 2.11 (s, 3H), 1.20 (s, 3H), 1.13 (s, 3H); MS (FAB) m/e calcd for C25H29NO4: 407.2097. Found 407.2090.
Example 184
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH- f 1 Jbenzopyrano \3 ,4-fjquinoline Example 44 (0.58 g, 1.74 mmol) was dissolved in CH2CI2 (40 ml), cooled to-45
°C, treated dropwise with 2.09 ml IM Dibal-H / heptane solution (2.09 mmol) and stirred for 1 h. The reaction mixture was poured into 75 ml 0.5 M HCl, stirred 30 min, extracted with ethyl acetate, the combined organics washed with brine, dried (Na2SO4) and concentrated to give 0.55 g crude aldehyde as a yellow foam. The resulting aldehyde (0.048 g, 0.143 mmol) was dissolved in THF (5 ml) cooled to 0 °C, and treated slowly with vinylmagnesium bromide (0.72 ml 1M/THF, 0.72 mmol). After stirring 15 minutes, the mixture was partitioned between ethyl acetate and brine, the aqueous layer extracted with ethyl acetate and combined organics washed with brine, dried (Na2SO4), concentrated and purified by silica gel chromatography eluting with 20
%> ethyl acetate in hexanes to give the desired compound (0.027 g, 53%) as an inseparable 1 : 1 mixture of diastereomers. MAJOR: iH NMR (300 MHz, DMSO-d6)D7.97 (d, J=8 Hz, IH), 7.04 (t, J=8 Hz, IH), 6.68 (d,
J=8 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.03 (br s, IH), 5.61 (s, IH), 5.46 (m, IH), 5.36 (m, IH), 4.97-5.10 (m, IH), 4.87 (m, IH), 3.94 (m, IH), 3.85 (s, 3H), 2.19 (s, 3H), 1.23 (s, 3H), 1.10 (s, 3H); MINOR:
MS (DCI/NH3) m/e 364 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.02 (d, J=8 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.68 (d, J=8 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.16 (br s, IH), 5.95 (m, IH), 5.58 (s, IH), 5.41 (s, IH), 4.97-5.10 (m, 2H), 3.94 (m, IH), 3.85 (s, 3H), 2.11 (s, 3H), 1.27 (s, 3H), 1.01 (s, 3H); MS (DCI/NH3) m/e (M+H)+ 364; Anal, calcd for
C23H25NO3*3/4H2O: C, 73.29; H, 7.09; N, 3.72. Found: C, 73.67; H, 6.80; N, 3.81.
Example 185 methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-rijbenzopyrano[3,4-fjquinolin-5- yl) acetyl hydroxamate
Example 46 ( 0.150 g, 0.395 mmol) was added dropwise to a solution of N,O- dimethylhydroxylamine hydrochloride ( 0.192 g, 1.98 mmol) and trimethylaluminium ( 1.0 mL, 2.0 mmoland the resulting mixture heated at 40 °C for 2 hours, quenched with methanol and partitioned between methylene chloride and saturated aqueous Rochelle's salt. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, and dried (MgSO4). The crude product was purified by flash chromatography on silica gel eluting with 4% then 10% ethyl acetate in methylene chloride to give the desired compound (62 %>) as a white foam.
MS (DCI/NH3) m/e 409 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.79 (d, J=8 Hz, IH), 7.05 (dd, J=8 Hz, IH), 6.73 (d, J=8 Hz, IH), 6.61 (d, J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.25 (dd, J=2+10 Hz, IH), 6.16 (s, IH), 5.43 (s, IH), 3.87 (s, 3H), 3.25 (br s, 3H), 3.04 (br s, 3H), 2.34 (m, IH), 2.18 (s, 3H), 1.17 (s, 6H);
Anal, calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.74; H, 7.11; N,
6.59.
Example 186 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f]quinolin-5-yl) acetaldehyde Example 185 (0.334 g, 0.817 mmol) was dissolved in THF (20 ml), cooled to -78
°C, and treated with IM Dibal-H in toluene (1.71 mL, 1.71 mmol) over 5 minutes and stirred for 1 hour. The reaction mixture was poured into saturated potassium sodium tartrate, the layers separated, the aqueous phase extracted with CH2CI2, the combined organics washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give
0.265 g (93%>) ofthe desired product as a colorless foam.
MS (DCI/NH3) m/e 350 (M+H)+; iH NMR (300 MHz, DMSO-d6)D9.65 (s, IH), 7.95 (d, J=9 Hz, IH), 7.05 (dd, J=8 Hz,
IH), 6.73 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.45 (d, J=8 Hz, IH), 6.35 (dd, J=3+10
Hz, IH), 6.20 (s, IH), 5.45 (s, IH), 3.85 (s, 3H), 2.85 (m, IH), 2.60 (m, IH), 2.15 (s,
3H), 1.17 (s, 3H), 1.15 (s, 3H);
Anal, calcd for O22H23NO3»1/4H2O: C, 74.66; H, 6.69; N, 3.96. Found: C, 74.32; H, 6.30; N, 3.86.
Example 187 2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline Cyclohexyltriphenylphosphonium bromide ( Grim, S. O.; Ambras, J. H.; J.Org.
Chem. 1968, 33, 2993-2994.) (0.234 g,0.55 mol) was suspended in (5:3) THF:Ether (8.0 ml), cooled to-10 °C, treated with 220D1 of 2.5 M n-butyl lithium, stirred for 10 minutes. Example 186 was added as a solution in THF and the reaction was allowed to stir at room temperature 12 hours, refluxed for 15 minutes and allowed to cool. Diethyl ether was added and the reaction was filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10:1 to 5:1 hexanes:ethyl acetate to afford 0.033 g (51% ) desired compound. : m.p. 130-135 C°; MS (DCI/NH3) m/e 416 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.03 (t, J=9 Hz, IH), 6.67 (d, J-8 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.50 (d, J=8 Hz, IH), 6.11 (s, IH), 5.64 (dd, J=10, 10 Hz, IH), 5.43 (s, IH), 5.04 (t, J=7 Hz, IH), 3.85 (s, 3H), 2.10 (s, 3H), 2.0 (b, 2H), 1.81 (t, J=7 Hz, 2H), 1.45 (b, 3H), 1.3 (b, 3H), 1.17 (s, 3H), 1.15 (s, 3H); i 3C NMR (100 MHz, DMSO-d6)P 165.0, 151.1, 145.4, 140.5, 133.41, 132.2, 127.5,
127.0, 126.8, 116.5, 116.3, 116.0, 113.0, 110.3, 105.3, 73.9, 55.5, 49.6, 36.6, 30.5, 28.9, 28.7, 28.1, 27.9, 27.0, 26.2, 23.8.
Example 188 2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl-lH- ri1benzopyrano[3,4-f]quinoline Example 186 and cyclopentyltriphenylphosphonium bromide (Ramirez, F.; Levy, S. JACS 1957, 79, 67-69. ) were processed according to Example 187 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)D7.94 (d, J=9 Hz, IH), 7.02 (t, J=8 Hz, IH), 6.67 (d,
J=8 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.48 (d, J=7 Hz, IH), 6.10 (s, IH), 5,56 (dd, J=10, 8 Hz, IH), 5.43 (s, IH), 5.22 (b, IH), 3.85 (s, 3H), 2.14 (s, 6H), 1.77 (b, 2H), 1.49 (b, 4H), 1.17 (s, 3H), 1.14 (s, 3H); i 3C NMR (75 MHz, DMSO-d6)D 156.1, 151.2, 145.4, 144.6,
133.4, 132.3, 127.6, 127.0, 126.8, 116.4, 116.1, 115.3, 113.3, 113.1, 110.3, 105.3, 73.6, 55.6, 49.6, 33.1, 29.0, 28.7, 28.0, 25.8, 25.7, 23.8;
HRMS (FAB)w/e calcd for C27H32O2N: 401.2355. Found 401.2342.
Example 189 2,5-dihydro-l 0-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fjquinoline
Example 186 and cycloheptyltriphenylphoshonium bromide (Albright, T. A.; Freeman, W. J.; Schweizer, E.E. JACS 1974, 97, 2942-2943.) were processed according to example 186 to provide the desired compound. MS (DCI/NH3) m/e 430 (M+H)+; iH NMR (300 MHz, DMSO-d< )P7.94 (d, J=9 Hz, IH), 7.02 (t, J=8 Hz,TH), 6.67 (d,
J=8 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.49 (d, J=8 Hz, IH), 6.12 (s, IH), 5.69 (dd, J=10, 9 Hz, IH), 5.43 (s, IH), 5.12 (t, J=7 Hz, IH), 3.85 (s, 3H), 2.13 (s, 6H), 1.90 (b, 2H), 1.38
(b, 3H), 1.27 (m, 4H), 1.17 (s, 3H), 1.14 (s, 3H), 0.82 (m, 3H);
13C NMR (75 MHz, DMSO-d6)P 156.1, 151.1, 145.4, 142.2, 133.4, 132.2, 128.6, 127.6,
127.0, 126.8, 120.0, 116.3, 116.0, 113.0, 110.3, 105.3, 73.6, 65.7, 55.6, 49.6, 37.3, 33.2, 31.1, 29.8, 29.3, 29.2, 29.0, 28.6, 28.5, 26.2, 23.8, 23.2;
Anal, calcd for C29H35θ2N2'3/4H2θ: C, 72.70; H, 8.52; N, 2.92. Found: C, 72.50; H,
8.11; N, 2.47.
Example 190 2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-
[ljbenzopyrano[3 ,4-fjquinoline Example 186 a d isopropyltriphenylphosphonium iodide were processed according to Example 187 to provide the desired compound. iH NMR (300 MHz, DMSO-d<s)D7.94 (d, J=8 Hz, IH), 7.37 (s, IH), 7.03 (t, J=8 Hz, IH), 6.67 (d, J=7 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.49 (d, J=8 Hz, IH), 6.11 (s, IH), 5.65
(dd, J=10, 9 Hz, IH), 5.43 (s, IH), 5.12 (t, J=7 Hz, IH), 3.85 (s, 3H), 2.14 (s, 3H), 1.63 (s, 3H), 1.31 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6)P 156.1, 151.1, 145.4, 133.4, 132.8, 132.2, 127.6,
127.0, 126.9, 119.8, 116.4, 116.1, 113.3, 113.1, 110.3, 105.3, 73.7, 55.6, 49.6, 31.5, 29.0, 28.7, 25.6, 23.8, 17.5;
HRMS (FA )m/e calc'd for C25H29O2N: 375.2198. Found 375.2189.
Example 191 trans 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- flquinoline
Example 186 and ethyltriphenylphosphonium bromide were processed according to example 186 to provide the desired compound. MS (DCI/NH3) m/e 362 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.96 (d, J=8 Hz, IH), 7.05 (dd, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.51 (d, J=8 Hz, IH), 6.10 (s, IH), 5.72 (dd, J=4+10
Hz, IH), 5.45 (m, 3H), 3.86 (s, 3H), 2.43 (m, IH), 2.20 (m, IH), 2.15 (s, 3H), 1.30 (d, J=5 Hz, 3H), 1.17 (s, 3H), 1.15 (s, 3H). Example 192 trans 2,5-dihydro-10-methoxy-5-(2-penten-l-yl)-2,2,4-trimethyl-lH- [11benzopyrano[3,4-fjquinoline Example 186 (0.050 g, 0.143 mmol) and propyltriphenylphosphonium bromide
(165.6 mg, 0.429 mmol) were processed as in example 187 to give the desired compound.
MS (DCI/NH3) m/e 376 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.05 (dd, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.50 (d, J=8 Hz, IH), 6.09 (s, IH), 5.70 (dd, J=3, 10
Hz, IH), 5.44 (s, IH), 5.38 (ss, J=5 Hz, 2H), 3.86 (s, 3H), 2.41 (m, IH), 2.19 (m, IH), 2.15 (s, 3H), 1.70 (m, 2H), 1.15 (s, 6H), 0.75 (t, J=7 Hz, 3H).
Example 193 2,5-dihydro- 10-methoxy-5-( 1 , 1 -difluoro- 1 -propen-3 -yl)-2,2,4-trimethyl- 1 H-
[1 ]benzopyrano[3 ,4-fjquinoline Example 186 (0.050 g, 0.143 mmol) and diphenylphosphoranyl difluromethane (Edwards, M.L., et. al. Tet. Let. 1990,57, 5571-74) were processed as in example 187 to give the desired compound. iH NMR (300 MHz, DMSO-d6)D7.98 (d, J=8 Hz, IH), 7.08 (t, J=8 Hz, IH), 6.71 (d,
J-9 Hz, IH), 6.62 (d, J=9 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.17 (s, IH), 5.73 (dd, J=4,10 Hz, IH), 5.46 (s, IH), 4.53 (m, IH), 3.86 (s, 3H), 2.32 (m, IH), 2.16 (s, 3H), 2.11 (m, IH), 1.17 (s, 3H), 1.15 (s, 3H); HRMS (FAB) /e calc'd 383.1697. Found 383.1689.
Example 194 (E) methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[11benzopyrano[3,4- f]quinolin-5-yl) 2-butenoate Example 186 ( 0.040 g, 0.115 mmol) and methyl (triphenylphosphoranylidene)acetate (115 mg, 0.344 mmol, Aldrich) were processed according to example 179 to give 0.037 g (80%) ofthe desired compound as a white foam.
MS (DCI/NH3) m/e 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.07 (dd, J=8 Hz, IH), 6.85 (m, IH), 6.72 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.50 (d, J=8 Hz, IH), 6.15 (s, IH), 5.87
(dd, J=3+10 Hz, IH), 5.80 (d, J-14 Hz, IH), 5.45 (s, IH), 3.88 (s, 3H), 3.65 (s, 3H), 2.60 (m, IH), 2.45 (m, IH), 2.15 (s, 3H), 1.15 (br s, 6H); 13C NMR (75 MHz, DMSO- dfS)D 165.8, 156.2, 150.5, 145.6, 144.8, 133.6, 131.3, 127.4, 127.2, 122.7, 116.3, 115.9,
113.4, 113.1, 110.2, 105.7, 72.4, 55.6, 51.3, 49.7, 34.9, 29.0, 28.9, 28.9, 23.9;
Anal, calcd for C25H-27NO4-1/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.55; H,
6.71; N, 3.22.
Example 195 (E) 2,5-dihydro- 10-methoxy-5-(4-hydroxy-2-buten- 1 -yl)-2,2,4-trimethyl- 1 H-
[ 1 Ibenzopyrano [3 ,4-fj quinoline Example 194 ( 0.063 g, 0.155 mmol) in Et2θ was treated dropwise with a slurry containing L1AIH4 ( 0.044 g, 1.16 mmol) and AICI3 (0.041 g, 0.308 mmol) for 1 hour.
The reaction mixture was diluted with Et2θ and treated with 2 drops of H2O followed by 15% NaOH until a white paste formed. The Et2θ was decanted and the paste washed 2 times with Et2θ. The combined organics were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and purified by silica gel chromatography eluting with 6% then 10% ethyl acetate in methylene chloride to give 0.031 g (53%) ofthe desired compound. MS (DCI/NH3) m/e 378 (M+H)+; iHNMR (300 MHz, DMSO-d6)D7.94 (d, J=9 Hz, IH), 7.07 (dd, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.54 (d, J=8 Hz, IH), 6.12 (s, IH), 5.70 (dd, J=3+10 Hz, IH), 5.4-5.69 (m, 3H), 4.63 (dd, J=6 Hz, IH), 3.87 (m, 5H), 3.31 (s, 3H), 2.40 (m, lH), 2.15 (s, 3H), 1.15 (s, 6H); Anal, calcd for C24H27NO3«l/4H2O: C, 75.47; H, 7.26; N, 3.67. Found: C, 75.62; H,
7.40; N, 3.59.
Example 196
(E) 2,5-dihydro- 10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten- 1 -yl)- 2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline Example 195 and disuccinimidyl carbonate were processed as in Example 200 to give the an intermediate succinate ester. The intermediate succinate ester and N,N-dimethylamine were processed as in
Example 200 to give the desired compound. MS (DCI/NH3) m/e 449 (M+H)+; iH NMR (400 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.09 (s, IH), 5.74 (dd, J=3,10 Hz, IH), 5.65 (m, IH), 5.48 (m, IH), 5.43 (s, IH), 3.85 (s, 3H), 3.79 (d, J=5 Hz, 2H), 2.45 (m, IH), 2.20 (m, IH), 2.15 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); 1 C NMR (100 MHz, DMSO-d6)D 156.1, 150.9, 145.5, 133.6, 132.0, 129.0, 128.6, 127.4, 127.1, 127.0,
116.2, 115.9, 113 (3), 113.2, 110.3, 105.4, 73.5, 72.0, 56.9, 55.6, 49.7, 35.0, 28.9, 23.3; Anal, calcd for C27H32N2O4: C, 72.30; H, 7.19; N, 6.25. Found: C, 72.10; H, 7.11; N,
5.98.
Example 197 (E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- 1 -yl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline The intermediate succinate ester from Example 196 and methylamine were processed as in Example 200 to give the desired compound.
MS (DCI/NH3) m/e 435 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=8 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.95 (m, IH), 6.70 (d, J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.08 (s, IH), 5.70 (m, 2H), 5.50 (m, IH), 5.43 (s, IH), 4.35 (d, J=5 Hz, 2H), 3.85 (s, 3H), 2.56 (d, J=5 Hz, 3H), 2.42 (m, IH), 2.20 (m, IH), 2.15 (s, 3H), 1.15 (s, 6H);
Anal, calcd for C26H30N2O4: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.66; H, 7.25; N,
6.07.
Example 198 (E) 2,5-dihydro- 10-methoxy-5-(2-butenyl)-2,2,4-trimethyl- 1 H-[lJbenzopyrano[3 ,4- fjquinoline Example 195 (0.080 g , 0.212 mmol) was dissolved in CH2CI2 (10 ml), cooled to -10 °C, treated with (i-Pr)2NEt (55 DL , 0.318 mmol) followed by methanesulfonyl chloride (20 DL, 0.255 mmol), stirred for lhr and allowed to warm to room temperature. The mixture was recooled to -10 °C and treated dropwise with lithium triethylborohydride (635 DL, 0.635 mmol), stirred for 1 hr, allowed to warm to room temperature, treated with 5.0 ml of IN NaOH followed by 0.11 ml of 30%> H2O2 and stirred for 30 minutes. The mixture was partitioned between water and ethyl acetate, the aqueous extacted with ethyl acetate and the combined organics washed with water, brine, and dried (Na2SO4). Purification by silica gel chromatography eluting with 15:1 then
7:1 hexanes:ethyl acetate provided 0.029 g (38%) desired compound. iH NMR (360 MHz, DMSO-d6)D7.93 (d, J=9 Hz, IH), 7.04 (t, J=8 Hz, IH), 6.68 (d,
J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.51 (d, J=7 Hz, IH), 6.11 (s, IH), 5.67 (dd, J=10 Hz, IH), 5.41 (t, J=9 Hz, IH), 5.34 (t, J=l 1 Hz, IH), 3.85 (s, 3H), 2.34 (m, IH), 2.15 (s, 3H), 1.59 (dd, J=5 Hz, 3H), 1.17 (s, 3H), 1.15 (s, 3H);
13C NMR (100 MHz, DMSO-d6)P 156.2, 151.0, 145.4, 133.4, 132.1, 127.1, 127.0,
126.9, 126.6, 125.5, 115.9, 113.2, 110.0, 105.3, 73.7, 55.5, 49.6, 35.4, 28.9, 28.8, 23.9, 17.8; HRMS (FAB) calc'd for C24H28O2N: m/e 362.2120. Found 362.2119.
Example 199 2,5-dihydro-10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline
Example 46 (0.100 g, 0.264mmol) was treated with IM Dibal-H in toluene (0.544 ml, 0.544mmol) at -78° C, warmed to room temperature, quenched with methanol and the partitioned between methylene chloride and saturated aqueous Rochelle's salt. The organic layer was washed with IN HCl, saturated aqueous sodium bicarbonate, brine, and dried (MgSO4). The resulting crude product was purified by flash chromatography on silica gel eluting with 10% ethyl acetate in methylene chloride to give (87%) ofthe desired compound as a white solid. MS (DCI/NH3) m/e 352 (M+H)+; iH NMR (300 MHz, DMSO-dβ)P7.95 (d, J=8 Hz, IH), 7.05 (dd, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.59 (d, J=8 Hz, IH), 6.55 (d, J=8 Hz, IH), 610 (s, IH), 5.95 (dd, J=2,10
Hz, IH), 5.43 (s, IH), 4.61 (t, J=6 Hz, IH), 3.84 (s, 3H), 3.52 (m, IH), 2.20 (s, 3H), 1.80 (m, IH), 1.50 (m, IH), 1.19 (s, 3H), 1.16 (s, 3H).
Example 200 2,5-dihydro-l 0-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ljbenzopyrano[3 ,4-fjquinoline Example 199 ( 0.200 g, 0.57 mmol) was combined with N,N'-disuccinimidyl carbonate ( 0.217 g, 0.85 mmol), (i-Pr)2NEt (0.30 ml, 1.71mmol), and acetonitrile (2mL), stirred at room temperature 2 hours and partitioned between CH2CI2 and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried
(MgSO4), and purified by silica gel chromatography eluting with 6% ethyl acetate in dichloromethane to give 0.252 g (90%) ofthe succinate ester as a white foam.
The succinate ester (0.020 g, 0.041mmol), benzyl amine (6.6 μl, 0.061mmol), and CH2CI2 (3 ml) were combined and stirred for 20 minutes at room temperature. The reaction mixture was diluted with CH2CI2 and the organic layers washed with H2O, saturated aqueous sodium bicarbonate, brine, dried (MgSO4) and purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 19 mg (97%>) ofthe desired compound as a white solid.
MS (DCI/NH3) m/e 485 (M+H)+; iH NMR (400 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.68 (t, J=6 Hz, IH), 7.25 (m,
3H), 7.07 (t, J=8 Hz, IH), 6.71 (d, J=8 Hz, IH), 6.59 (dd, J=8 Hz, IH), 6.11 (s, IH), 5.86 (d, J=8 Hz, IH), 5.40 (s, IH), 4.18 (m, 2H), 4.00 (m, 2H), 3.85 (s, 3H), 2.12 (s, 3H), 1.90
(m, IH), 1.71 (m, IH), 1.17 (s, 3H), 1.15 (s, 3H);
13C NMR (100 MHz, DMSO-d6)P 156.3, 156.1, 150.7, 145.6, 139.7, 133.5, 131.9,
128.2, 127.5, 127.2, 127.1, 127.0, 126.7, 116.3, 115.9, 113.2, 113.2, 110.2, 110.1, 105.6, 70.3, 60.2, 55.6, 49.6, 43.7, 31.5, 28.8, 28.7, 23.8;
Anal, calcd for C30H32N2O5-H2O: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.45; H,
6.83; N, 5.56.
Example 201 2,5-dihydro-l 0-methoxy-5-(2-(N-mo holinocarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline The intermediate succinate ester from Example 200 and morpholine were processed as in Example 200 to give the desired compound. MS (DCI/NH3) m/e 465 (M+H)+; iH NMR (400 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.07 (t, J=8 Hz, IH), 6.71 (d,
J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.10 (s, IH), 5.88 (dd, J=3+10 Hz, IH), 5.44 (s, IH), 4.05 (m, 2H), 3.85 (s, 3H), 3.75 (m, 4H), 2.16 (s, 3H), 1.85 (m, IH), 1.78 (m, IH), 1.16 (s, 3H), 1.15 (s, 3H); i C NMR (100 MHz, DMSO-d6)P 156.2, 154.4, 150.6, 145.6, 133.5, 131.8, 127.3, 127.2, 127.1, 116 (1), 115.9, 113.2, 113.2, 110.1, 105.6, 70.3, 65.8, 61 (2), 55.6, 49.7,
43.7, 43.6, 31.3, 29.0, 28.9, 23..8; Anal, calcd for C27H32N2O5-1/4H2O: C, 69.14; H, 6.98; N, 5.97. Found: C, 68.96; H,
7.05; N, 5.94.
Example 202
2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline The intermediate succinate ester from Example 200 and 2-methoxyethyl aminewere processed as in Example 200 to give the desired compound. MS (DCI/NH3) m/e 453 (M+H)+; iH NMR (500 MHz, DMSO-d<s)D7.95 (d, J=8 Hz, IH), 7.13 (m, IH), 7.04 (t, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.56 (d, J=8 Hz, IH), 6.08 (s, IH), 5.85d (10, IH), 5.45 (s, IH), 3.95 (m, 2H), 3.85 (s, 3H), 3.25 (s, 3H), 3.12 (m, 2H), 2.15 (s, 3H), 1.92 (m, IH), 1.72 (m, IH), 1.15 (d, 6H); 13C NMR (125 MHz, DMSO-d6)D 156.1, 156.1, 150.7, 145.6, 133.5, 131.9, 127.6,
127.1, 127.1, 116.3, 116.0, 113.2, 113.2, 110.2, 105.6, 70.7, 70.3, 60.0, 57.8, 55.6, 49.6, 31.5, 28.8, 28.8, 23.8. Example 203 2,5-dihydro-10-methoxy-5-(2-(N-methyaminocarbonyloxyoxy)ethyl)-2,2,4-trimethyl-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline The intermediate succinate ester from Example 200 and methylamine were processed as in Example 200to give the desired compound. MS (DCI/NH3) m/e 409 (M+H)+; iH NMR (500 MHz, DMSO-d6)D7.95 (d, J=8 Hz, IH), 7.04 (t, J=8 Hz, IH), 6.93 (m, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.56 (d, J=8 Hz, IH), 6.08 (s, IH), 5.85d (10, IH), 5.45 (s, IH), 3.95 (m, 2H), 3.85 (s, 3H), 2.59 (d, 3H), 2.15 (s, 3H), 1.92
(m, IH), 1.72 (m, IH), 1.15 (d, 6H); i 3C NMR (125 MHz, DMSO-d6)P 156.6, 156.1, 150.7, 145.6, 133.5, 131.9, 127.5,
127.2, 127.1, 116.3 (116.0), 113.2, 113.2, 113.2, 105.6, 70.3, 60.0, 55.6, 49.6, 31.5, 28.8, 28.8, 26.9, 23.7; Anal, calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86. Found: C, 70.30; H, 6.91; N,
6.58.
Example 204
2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4-trimethyl- lH-[11benzopyranor3,4-f]quinoline
The intermediate succinate ester from Example 200 and N,N-dimethylamine were processed as in Example 200 to give the desired compound as a white solid.
MS (DCI/NH3) m/e 423 (M+H)+; iHNMR (300 MHz, DMSO-d6)D7.95 (d, J=8 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.69 (d, J=8 Hz, IH), 6.56 (dd, J=8 Hz, 2H), 6.12 (s, IH), 5.86 (dd, J=3+10 Hz, IH), 5.44 (s,
IH), 3.96 (m, 2H), 3.85 (s, 3H), 2.86 (s, 3H), 2.83 (s, 3H), 2.18 (s, 3H), 1.95 (m, IH),
1.76 (m, IH), 1.15 (s, 6H).
Example 205 2,5-dihydro-10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl-lH-
[11benzopyrano[3,4-fjquinoline Example 199 (0.040 g, 0.114 mmol) was combined with chloromethyl methyl ether ( 13 μL, 0.171 mmol), (i-Pr)2NEt ( 40 μL, 0.228 mmol), and methylene chloride (5ml) and heated to reflux for 3 hours. The reaction was partitioned between H2O and ethyl acetate, the aqueous layer extracted with ethyl acetate and the combined organic layers washed with saturated aqueous sodium bicarbonate, brine, dried over MgSO4, and purified by silica gel chromatography eluting with 2%> then 5% ethyl acetate in methylene chloride to give 45 mg (40%>) ofthe desired product. MS (DCI/NH3) m/e 396 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=9 Hz, IH), 7.05 (t, J=8 Hz, IH), 6.70 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.55 (d, J=8 Hz, IH), 6.14 (s, IH), 5.89 (dd, J=3+10 Hz, IH), 5.45 (s, IH), 4.55 (s, 2H), 3.85 (s, 3H), 3.58 (m, IH), 3.25 (s, 3H), 2.18 (s, 3H), 1.85 (m, IH), 1.65 (m, IH), 1.19 (s, 3H), 1.13 (s, 3H);
Anal, calcd for C24H29NO4-1/4H2O: C, 72.07; H, 7.43; N, 3.50. Found: C, 71.90; H,
7.33; N, 3.24.
Example 206 2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4-trimethyl-
1 H- [ 1 Ibenzopyrano [3 ,4-fjquinoline
Example 206A 2,5-dihydro- 10-methoxy-5-(aminomethyl)-2,2,4-trimethyl- 1 H-[l Jbenzopyrano [3 ,4- fjquinoline A 10 ml ethereal suspension of LiAlHg (0.050 g, 1.31 mmol) was treated dropwise at room temperature with a 5.0 ml ethereal solution of AICIQ (0.59 g, 4.4 mmol), strirred for 30 minutes and treated dropwise with a 4.0 ml ethereal solution of Example 44. After stirring for 1 hour at room temperature , 2.0 ml of HgO carefully added followed by dropwise addition of 15 % NaOH until a white paste formed. The ether solution was decanted, the paste washed several times with ether and combined organics washed with brine and dried (Nag SOQ). The residue was purified by silica gel column chromatography eluting with CHπClπ'CHrjOH (8:i) to give 0.031 g (69 %>) aminomethyl analog that was carried directly to the next step.
Example 206 2,5-dihydro-l 0-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline The aminomethyl analog above (0.065 g, 0.19 mmol) was dissolved in dichloromethane ( 6.0 ml ),cooled to 0 °C, treated with BOCQO (0.93 g, 0.42 mmol ). Allowed to warm to room temperature overnight. 10 ml HQO was added and the phases separated. The organic layer was washed with brine and dried (NaπSOπ). The residue was purified by silica gel column chromatography eluting with CH ]Cl[]:CHr OH (8:1) to give 0.080 g (95 %) desired compound : m.p. 130-135 °C; iH NMR (400 MHz, DMSO-d6)D7.98 (d, J=9 Hz, IH), 7.70 (t, J=9 Hz, IH), 6.79 (t, J=5 Hz, IH), 6.67 (d, J=9 Hz, IH), 6.60 (d, J=9 Hz, IH), 6.53 (d, J=8 Hz, IH), 6.12 (s, IH), 5.80 (dd, J=10, 10 Hz, IH), 5.42 (s, IH), 3.85 (s, 3H), 3.14 (m, IH), 2.86 (m, IH), 2.19 (s, 3H), 1.47 (s, 3H), 1.21 (s, 3H), 1.12 (s, 3H), .84 (m, IH); 13C NMR (100 MHz, DMSO-d6)P 156.1, 155.5, 150.9, 145.4, 133.4, 131.5, 129.5,
128.6, 127.8, 126.9, 117.1, 116.4, 113.4, 112.7, 110.5, 105.3, 77.7, 72.3, 67.4, 55.6, 49.5,
41.5, 29.8, 29.2, 28.3, 28.2, 23.4, 23.2, 22.3;
HRMS (FAB) m/e calc'd for C26H32N2O4: 436.2362. Found 436.2360.
Example 207
2,5-dihydro- 10-methoxy-5-(ethoxycarbonylamino)methyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline Example 206A (0.047 g, 0.14mmole) in THF (10 ml) was treated with triethylamine (21.0 DL, 0.14 mmol). Followed by dropwise addition of ethyl chloroformate ( 14.1 DL, 0.14 mmol.). After 30 minutes the reaction was poured into
H O, the aqueous layer extracted with ethyl acetate and the combined organic layers washed IX with H2O, IX with brine, and dried (NaπSOg)- The residue was purified by silica gel column chromatography eluting with 3:2 hexanes:ethyl acetate to give 0.047 g (80%) ofthe desired compound as a solid. iH NMR (300 MHz, DMSO-d6)D7.98 (d, J=8 Hz, IH), 7.13 (t, IH), 7.03 (t, J=8 Hz,
IH), 6.67 (d, J=8 Hz, IH), 6.57 (d, J=8 Hz, IH), 6.54 (d, J-8 Hz, IH), 6.13 (s, 3H), 5.83 (dd, IH), 5.43 (s, IH), 3.94 (m, 2H), 3.85 (s, 3H), 3.13 (m, IH), 2.94 (m, IH), 2.21 (s, 3H), 1.2o (s, 3H), 1.17 (s, 3H), 1.11 (s, 3H); 13C NMR (75 MHz, DMSO-d6)P 156.1, 150.8, 145.5, 133.4, 129.4, 127.7, 127.0, 117.0, 116.4, 113.5, 112.7, 110.6, 105.4, 72.2, 59.7, 55.6, 49.6, 41.8, 29.2, 28.3, 23.5, 14.6;
HRMS m/e calc'd for C24H28N2O4: 408.2049. Found 408.2044.
Example 208 2,5-dihydro-10-methoxy-5-(carboethoxy)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline
To Example 61 was added 2.0 ml of 5 % aqueous HCl, 5.0 ml HgO, and enough efhanol to make the solution homogenous.This was warmed at 35 °C for 1 hour, quenched with saturated aqueous sodium bicarbonate to a pH of 7.0. The reaction was extracted with ethyl acetate. The organics were washed with HQO, brine, and dried ( Nag SO π )• The residue was purified by silca gel column chromatography eluting with
7:1-5:1-3:2 hexanes:ethyl acetate to give 0.041 g (48 %>) ofthe desired compound as a solid. MS (DCI/NH3) m/e 380 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.90 (d, J=9 Hz, IH), 7.04 (t, J=8 Hz, IH), 6.64 (d, J=8 Hz, IH), 6.61 (m, 2H), 6.32 (s, IH), 6.21 (s, IH), 5.45 (s, IH), 3.90 (m, 2H), 3.84 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H), .93 (t, J=7 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)P 169.4, 156.2, 152.5, 145.4, 133.1, 127.6, 126.9,
126.0, 118.2, 117.7, 114.7, 109.8, 105.7, 73.0, 60.7, 55.6, 49.9, 28.9, 28.7, 22.8, 13.7; Anal, calcd for O23H25NO4-1/4H2O: C, 71.95; H, 6.68; N, 3.65. Found: C, 72.21; H,
6.41; N, 3.85.
• Example 209
2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline Example 2B and cyclopentylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/e 376 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.01 (d, J-8 Hz, IH), 7.03 (t, J=8 Hz, IH), 6.65 (d, J=8 Hz, IH), 6.59 (d, J=9 Hz, IH), 6.52 (d, J=8 Hz, IH), 6.20 (s, IH), 5.46 (s, 3H), 3.85 (s, 3H), 2.16 (s, 3H), 1.50 (m, 5H), 1.30 (s, 3H), 1.16 (m, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, DMSO-d6)P 156.2, 151.7, 145.0, 133.7, 131.6, 128.1, 126.7, 117.7, 116.4, 113.3, 112.6, 109.9, 105.0, 76.5, 49.2, 42.5, 29.8, 29.5, 27.5, 26.6, 24.8, 24.6, 23.6;
Anal, calcd for C25H29O2N-1/2H2O: C, 78.09; H, 7.86; N, 3.64. Found: C, 78.09; H,
7.52; N, 3.42.
Example 210 2,5-dihydro-10-methoxy-5-(l-methylpropa-l,2-dienyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3,4-f] quinoline Example 2B and propargylmagnesium bromide (Gaoni,Y.; Leznoff, C. C; Sondheimer, F. J. Am. Chem. Soc. 1968, 90, 4940-4945. ) were processed as in example 11 to provide the desired compound. m.p. 59-63°; iH NMR (300 MHz, DMSO-d6)D7.84 (d, J=8 Hz, IH), 7.03 (t, J=6 Hz, IH), 6.68 (d, j=6 Hz, IH), 6.55 (d, J=8 Hz, 2H), 6.04 (s, IH), 5.97 (s, IH), 5.40 (s, IH), 4.94 (m, IH), 4.23 (m, IH), 3.82 (s, 3H), 2.11 (s, 3H), 1.70 (s, 3H), 1.21 (s, 3H), 1.10 (s, 3H); 13C NMR (100 MHz, DMSO-d6)P 156.1, 151.2, 150.5, 145.1, 132.6, 130.5, 127.9, 127.1, 127.0, 126.7, 126.5, 117 (5), 117.1, 114.7, 113.3, 112.9, 110.1, 106.3, 98.6, 76.2, 75.6,
55.9, 49.6, 29.4, 28.4, 22.5, 16.0; MS m/e calc'd for C24H25O2N: 359.1885. Found 359.1893. Example 211 2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-fjquinoline Example 2B and 3,4,5-trifluorophenylmagnesium bromide were processed as in
Example 11 to provide the desired compound. MS (DCI/NH3) m/e 438 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.04 (d, J=8 Hz, IH), 6.94 -7.02 (m, 3H), 6.77 (s, IH), 6.74 (d, J-9 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.51 (d, J=8 Hz, IH), 6.31 (br s, IH), 5.43 (s, IH), 3.81 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.15 (s, 3H);
Anal, calcd for C26H22N02F3»1/4H2O: C, 70.66; H, 5.13; N, 3.17. Found: C, 70.89; H,
5.19; N, 2.93.
Example 212 2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline Example 2B and cyclohexylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/e 308 (M+H)+; MAJOR: iH NMR (300 MHz, DMSO-d6)D8.03 (d, J=9 Hz, IH), 7.05 (t, J=8 Hz, IH),
6.72 (d, J=8 Hz, IH), 6.61 (d, J=9 Hz, IH), 6.59 (s, IH), 6.15 (d, J=8 Hz, IH), 5.40 (m, 2H), 3.86 (s, 3H), 2.01 (s, 3H), 1.61 (m, IH), 1.56-1.41 (m, 2H), 1.35-0.96 (m, 6H), 1.29 (s, 3H), 1.18 (s, 3H), 0.95-0.77 (m, 2H); Anal, calcd for C26H3lNO2'l/2H2O: C, 78.36; H, 8.09; N, 3.51. Found: C, 78.24; H, 7.72; N, 3.70.
Example 213 2,5-dihydro- 10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano[3 ,4-fjquinoline Example 213 A 2,5-dihydro- 10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl- 1 H- [ 1 Ibenzopyrano [3 ,4- fjquinoline To a solution of Example 2A (1.42 g, 4.39 mmol) in THF (40 mL) at 0 °C was added a solution of potassium tert-butoxide (1.48 g, 13.2 mmol) in THF (13 mL). The mixture was stirred 45 min at 0 °C then a solution of TBSC1 (1.46 g, 9.66 mmol) in THF (9.5 mL) was introduced in dropwise fashion. The solution was stirred at 0 °C for 30 min then was quenched by addition of saturated aqueous NH4CI (10 mL) and was extracted with EtOAc (2 x 30 mL). The combined organic portions were washed with brine (8 mL) and were dried (Na2SO4). Filtration and concentration gave a brown residue which was purified via flash chromatography (elution with 2% EtOAc/CH2Cl2) to give the desired product as a yellow solid (994 mg, 2.28 mmol, 52%). MS (DCI/NH3) m/z 438 (M+H)+.
Example 213
2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[nbenzopyrano[3,4- fjquinoline A solution ofthe 2-lithiopyridine (nominally 1 M in THF) was formed by addition of «-BuLi (680 DL of a 2.5 M solution in hexane, 1.70 mmol) to a solution of 2- bromopyridine (285 mg, 1.80 mmol) in THF (17 mL) at -78 °C. This solution was stirred for 20 min then a solution ofthe aldehyde prepared above (211 mg, 0.480 mmol) in THF (2.0mL)was added in drop wise fashion at -78 °C. The solution was stirred at - 78 °C for 30 min then was quenched by addition of saturated aqueous NH4CI (7 mL) and was extracted with EtOAc (2 x 30 mL). The combined organic portions were washed with brine (10 mL) and were dried (Na2SO4). Filtration and concentration gave a brown residue which was used without further purification.
The crude material prepared above was dissolved in THF (10 mL) at 23 °C and was treated with tetrabutylammonium fluoride (500 DL of a 1 M solution in THF, 0.500 mmol). After 1 h, the reaction mixture was concentrated in vacuo, was resuspended in EtOAc (20 mL) and then was washed with water (5 mL) and brine (5 mL), and was dried
(Na2SO4). Filtration and concentration gave a brown residue which was used without further purification.
This crude residue was dissolved in THF (10 mL), and the solution was cooled to 0 °C. To this solution was added triethylphosphine (48 mg, 0.410 mmol) followed by a solution of 1,1 '-(azodicarbonyl)dipiperidine (103 mg, 0.410 mmol) in THF (1.5 mL).
The solution was stirred for 30 min at 0 °C then at 23 °C for 7 h. The reaction mixture was concentrated and was purified by flash chromoatography (elution with 25% EtOAc/hexane) to give the desired product (13 mg, 0.034 mmol, 8%>) as a colorless solid. MS (DCI/NH3) m/z 385 (M+H)+; lU NMR (300 MHz, DMSO)D8.45 (br d, J=6.6 Hz, 1 H), 7.98 (d, J=8.0 Hz, 1 H), 7.61
(td, J=6.5, 1.8 Hz, 1 H), 7.19-7.13 (m, 2 H), 6.91 (t, J=6.6 Hz, 1 H), 6.72 (s, 1 H), 6.68 (d, J=7.9 Hz, 1 H), 6.57 (br d, J=6.7 Hz, 1 H), 6.44 (dd, J=6.5, 1.0 Hz, 1 H), 6.17 (br s, 1 H), 5.37 (br s, 1 H), 3.80 (s, 3 H), 1.80 (s, 3 H), 1.23 (s, 3 H), 1.13 (s, 3 H); HRMS (FAB) calcd (M+H)+ for C25H25N2O2: 385.1916 . Found: 385.1910. Example 214 2,5-dihydro- 10-methoxy-5-(3 -pyridyl)-2,2,4-trimefhyl- 1 H-[ 1 Jbenzopyrano [3 ,4- flquinoline The desired compound was prepared as described in Example 213 in 49% yield.
MS (DCI/NH3) m/z 385 (M+H)+;
*H NMR (300 MHz, DMSO)Q8.38 (d, J=2.4 Hz, 1 H), 8.35 (dd, J=5.6, 2.0 Hz, 1 H), 8.02 (d, J=8.0 Hz, 1 H), 7.49 (br d, J=6.9 Hz, 1 H), 7.25 (dd, J=6.9, 5.5 Hz, 1 H), 6.92 (t, J=6.9 Hz, 1 H), 6.86 (s, 1 H), 6.72 (d, J=8.1 Hz, 1 H), 6.58 (d, J=6.7 Hz, 1 H), 6.45 (d, J=6.4 Hz, 1 H), 6.38 (br s, 1 H), 5.41 (br s, 1 H), 3.80 (s, 3 H), 1.83 (s, 3 H), 1.23 (s, 3
H), 1.15 (s, 3 H);
13C NMR (125 MHz, DMSQ)P 156.0, 151.2, 149.4, 148.8, 145.6, 135.7, 134.7, 133.2, 128.5, 127.3, 127.2, 127.0, 123.2, 117.7, 117.2, 113.9, 113.7, 110.2, 105.7, 73.0, 55.5, 49.8, 29.5, 28.5, 23.4; HRMS (FAB) calcd m/z for C25H25N2O2: 385.1916 (M+H)+. Found: 385.1915.
Anal, calcd for C25H24N2O2: C, 78.09; H, 6. 29; N, 7.28. Found: C, 76.98; H, 6.60; N, 6.93.
Example 215 2,5-dihydro-10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline The desired compound was prepared as described in Example 213 in 20% yield. MS (DCI/NH3) m/z 385 (M+H)+;
*H NMR (300 MHz, DMSO)D8.43 (br d, J=4.3 Hz, 2 H), 8.04 (d, J=8.0 Hz, 1 H), 7.15 (d, J=4.2 Hz, 2 H), 6.96 (t, J=6.7 Hz, 1 H), 6.81 (s, 1 H), 6.75 (d, J=7.9 Hz, 1 H), 6.59
(d, J=6.8 Hz, 1 H), 6.53 (d, J=6.8 Hz, 1 H), 6.37 (br s, 1 H), 5.43 (br s, 1 H), 3.79 (s, 3
H), 1.88 (s, 3 H), 1.26 (s, 3 H), 1.18 (s, 3 H);
13C NMR (125 MHz, DMSQ)D 156.1, 151.4, 149.4 (2), 148.2, 145.6, 133.4, 133.3,
128.3, 127.3 (2), 127.0, 122.9, 117.9, 117.0, 113.9, 110.2, 105.6, 105.0, 103.0, 73.4, 49.8, 29.4, 28.6, 23.2;
HRMS (FAB) calcd m/z for C25H25N2O2: 385.1916 (M+H)+. Found: 385.1906.
The chemistry described in Schemes 1-21 and Examples 1-215 was used with Core 2 to prepare Examples 216-226. Example 216 10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [ 1 Ibenzopyrano [3 ,4-f] quinoline MS (DCI/NH3) m/z 368 (M+H)+; H NMR (300 MHz, DMSO)D9.34 (s, 1 H), 7.87 (d, J=8 Hz, 1 H), 6.72 (d, J=8 Hz, 1 H), 6.66 (d, J=8 Hz, 1 H), 6.58 (d, J=8 Hz, 1 H), 6.21 (br s, 1 H), 5.81-5.71 (m, 1 H), 5.62 (dd, J=10, 3 Hz, 1 H), 5.41 (br s, 1 H), 4.98 (dd, J=10, 2 Hz, 1 H), 4.93 (dd, J=17, 2 Hz, 1 H), 2.42-2.34 (m, 1 H), 2.26-2.20 (m, 1 H), 2.11 (s, 3 H), 1.16 (s, 3 H), 1.11 (s, 3 H);
HRMS (FAB) calcd m/z for C22H22CINO2: 367.1339. Found: 367.1336.
Example 217 10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Ibenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 404 (M+H)+;
!H NMR (300 MHz, DMSO)D9.46 (s, 1 H), 7.96 (d, J=8 Hz, 1 H), 7.26-7.12 (m, 3 H), 7.14-7.07 (m, 1 H), 6.87 (dd, J=8, 2 Hz, 1 H), 6.72 (d, J=8 Hz, 1 H), 6.68 (s, 1 H), 6.58 (app s, 2 H), 6.37 (br s, 1 H), 5.40 (br s, 1 H), 1.80 (s, 3 H), 1.26 (s, 3 H), 1.17 (s, 3 H); HRMS (FAB) calcd m/z for C25H22CINO2: 403.1339. Found: 403.1344.
Example 218 10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-
2,5-dihydro- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 472 (M+H)+; IH NMRD9.45 (s, IH), 7.98 (d, IH, J=8.5Hz), 7.54 (m, 4H), 6.85 (d, IH, J=8.5Hz), 6.75
(m, 2H), 6.57 (d, IH, J=8.5Hz), 6.42 (m, IH), 5.39 (m, IH), 1.91 (s, 3H), 1.24 (s, 3H), ,1.11 (s, 3H); Anal, calcd for C26H21CIF3NO2: 471.1213. Found: 471.1216.
Example 219
10-chloro-9-hydroxy-5-(3,5-dimethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyranor3,4-fjquinoline MS (DCI/NH3) m/z 432 (M+H)+;
1H NMRD9.52 (s, IH), 7.95 (d, IH, J=8.5Hz), 6.82 (m, 2H), 6.71 (m, 2H), 6.61 (s, 2H), 6.36 (m, IH), 6.42 (m, IH), 5.40 (m, IH), 2.31 (s, 6H), 1.92 (d, 3H, J=1.4Hz), 1.24 (s,
2H), 1.14 (s, 2H); HRMS (FAB) calcd m/z for C27H26CINO2: 421.1652. Found: 431.1650. Example 220 rel-(5S, 'R)-9-hydroxy- 10-methoxy-5-[l -hydroxymethyl-3-cyclohexenyl]- 2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3 ,4-fjquinoline MS (DCI/NH3) m/z 438 (M+H)+;
*H NMR (300 MHz, DMSO)D9.56 (s, 1 H), 8.01 (d, J=8 Hz, 1 H), 6.77 (app s, 2 H), 6.67 (d, J=8 Hz, 1 H), 6.39 (br s, 1 H), 5.48 (d, J=10 Hz, 1 H), 5.42 (br s, 1 H), 5.10 (br s, 1 H), 4.42 (t, J=6 Hz, 1 H), 3.65 (br d, J=6 Hz, 2 H), 2.28-2.18 (m, 2 H), 2.05 (br s, 3 H), 1.94-1.87 (m, 2 H), 1.75-1.64 (m, 1 H), 1.52-1.42 (m, 1 H), 1.36-1.27 (m, 1 H), 1.29 (s, 3 H), 1.10 (s, 3 H);
HRMS (FAB) calcd m/z for C26H28CINO3: 437.1758. Found: 437.1756.
The C-5 lactol-9-tert-butyldimethylsilyl ether of Core 2 and 3-cyclopentenyl trimethylsilane were processed as above to give a 2:1 diastereomeric product mixture which was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 2%> ETOH in hexanes to provide the individual enantiomers.
Example 221 (-) 2,5(S)-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3 S-cyclopenteny 1 )-l H-
[ 1 jbenzopyrano [3 ,4-fjquinoline
[D]23D=-220° (c 0.012, CHCI3);
MS (DCI/NH3) m/z 394 (M+H)+; iH NMR (300 MHz, DMSO-d6)P9.55 (s, IH), 8.00 (d, IH), 6.75 (d, IH), 6.72 (d, IH), 6.63 (d, IH), 6.36 (s, IH), 5.73 (ddd, IH), 5.44 (d, IH), 5.40 (s, IH), 5.17 (ddd,
IH), 2.78 (m, IH), 2.35 (m, IH), 2.15 (m, IH), 2.05 (s, 3H), 1.80 (m, IH), 1.72 (m, IH),
1.27 (s, 3H), 1.05 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 148.7, 146.0, 144.0, 134.0, 133.6, 132.7, 129.9,
127.9, 127.0, 123.7, 116.6, 115.8, 115.4, 114.2, 112.4, 76.1, 49.6, 48.2, 31.7, 29.8, 27.8, 27.3, 24.4.
Example 222 (-) 2,5(S)-dihydro-9-hydroxy-l 0-chloro-2,2,4-trimethyl-5-(3R- cyclopenteny 1 )- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline [D]23D=-232° (c 0.010, CHCI3); MS (DCI/NH3) m/z 394 (M+H)+; iH NMR (300 MHz, DMSO-d<s)P9.50 (bs, IH), 8.02 (d, IH), 6.75 (d, IH), 6.72 (d, IH), 6.63 (d, IH), 6.39 (s, IH), 5.74 (ddd, IH), 5.60 (ddd, IH), 5.46 (s, IH), 5.39 (d, IH), 2.83 (m, IH), 2.26 (m, IH), 2.14 (m, IH), 2.09 (s, 3H), 1.55-1.40 (m, 2H), 1.27 (s, 3H), 1.01 (s, 3H); 13C NMR (400 MHz, DMSO-d6)P 148.7, 146.0, 144.6, 134.1, 132.8, 132.0, 131.7, 127.8, 126.8, 123.6, 117.4, 115.9, 115.8, 115.5, 114.2, 112.3, 76.4, 49.4, 48.0, 31.7, 29.5,
27.2, 24.5, 23.8.
Example 223 10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 Ibenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m z 472 (M+H)+;
1H NMRD9.40 (s, IH), 8.01 (d, IH, J=8.5Hz), 7.43 (m, 4H), 6.85 (d, IH, J=8.5Hz), 6.71 (m, IH), 6.57 (d, IH, J=8.5Hz), 6.42 (m, IH), 5.47 (m, IH), 1.81 (s, 3H), 1.29 (s, 3H), 1.09 (s, 3H); HRMS (FAB) calcd m/z for C25H20CI3NO2: 471.0559. Found: 471.0556.
Example 224 (+)-(5R, 3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3-cyclopentenyl -lH-
T 1 jbenzopyrano [3 ,4-fj quinoline [D]23D=+ 256° (c 0.046, CHCI3).
MS (DCI/NH3) m/z 394 (M+H)+; iH NMR (300 MHz, DMSO-d6)D9.50 (bs, IH), 8.02 (d, IH), 6.75 (d, IH), 6.72 (d, IH), 6.63 (d, IH), 6.39 (s, IH), 5.74 (ddd, IH), 5.60 (ddd, IH), 5.46 (s, IH), 5.39 (d, IH), 2.83 (m, IH), 2.26 (m, IH), 2.14 (m, IH), 2.09 (s, 3H), 1.55-1.40 (m, 2H), 1.27 (s, 3H), 1.01 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 148.7, 146.0, 144.6, 134.1, 132.8, 132.0, 131.7,
127.8, 126.8, 123.6, 117.4, 115.9, 115.8, 115.5, 114.2, 112.3, 76.4, 49.4, 48.0, 31.7, 29.5, 27.2, 24.5, 23.8.
Example 225
(+)-(5R, 3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3-cyclopentenyl)- lH-[ljbenzopyrano[3 ,4-fjquinoline [D]23D=+244° (c 0.165, CHCI3); MS (DCI/NH3) m/z 394 (M+H)+; iH NMR (300 MHz, DMSO-d6)D9.55 (s, IH), 8.00 (d, IH), 6.75 (d, IH), 6.72 (d, IH), 6.63 (d, IH), 6.36 (s, IH), 5.73 (ddd, IH), 5.44 (d, IH), 5.40 (s, IH), 5.17 (ddd, IH), 2.78 (m, IH), 2.35 (m, IH), 2.15 (m, IH), 2.05 (s, 3H), 1.80 (m, IH), 1.72 (m, IH), 1.27 (s, 3H), 1.05 (s, 3H); 1 C NMR (400 MHz, DMSO-dφQ 148.7, 146.0, 144.0, 134.0, 133.6, 132.7, 129.9, 127.9, 127.0, 123.7, 116.6, 115.8, 115.4, 114.2, 112.4, 76.1, 49.6, 48.2, 31.7, 29.8, 27.8,
27.3, 24.4.
Example 226 10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [11benzopyrano[3,4-f|quinoline
MS (DCI/NH3) m/z 440 (M+H)+;
1H NMRD9.41 (s, IH), 7.94 (d, IH, J=8.5Hz), 6.96 (m, 3H), 6.75 (m, 3H), 6.57 (d, IH, J=8.5Hz), 6.45 (m, IH), 5.47 (m, IH), 1.81 (s, 3H), 1.29 (s, 3H), 1.09 (s, 3H); HRMS (FAB) calcd m/z for C25H20CIF2NO2: 429.1150. Found: 429.1152.
The chemistry described in Schemes 1-21 and Examples 1-215 was used with Core 3 to prepare Example 227.
Example 227 9- 10-methylenedioxy-5 -phenyl-2,2,4-trimethyl- 1 H-2,5-dihy dro- [1 Jbenzopyrano [3 ,4- fjquinoline MS (DCI/NH3) m/z 298 (M+H)+; IH NMR (200 MHz, DMSO-dό) 7.72 (d, J=8.1 Hz, IH), 7.20 (m, 5H), 6.82 (s, IH), 6.75
(d, J=8.8 Hz, IH), 6.50 (d, J=8.1 Hz, IH), 6.26 (s, IH). 6.27 (d, J=8.8 Hz, IH), 6.05 (s, IH), 5.98 (s, IH), 5.4 (s, IH), 1.87 (s, 2H), 1.20 (s, 2H), 1.17 (s, 2H).
The chemistry described in Schemes 1-21 and Examples 1-215 was used with Core 4 to prepare Examples 228-231.
Example 228 5-(3-propenyl)-9-chloro-10-ethenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Ibenzopyrano [3 ,4-f] quinoline lH NMR.D7.93 (d, IH, J=8.5Hz), 7.20 (d, IH, J=8.5Hz), 6.70 (d, IH, J=8.5Hz), 6.64 (d, IH, J=8.5Hz), 6.34 (m, IH), 5.81 (m, 2H), 5.46 (m, IH), 5.03 (dm, IH, J=10.5Hz), 4.98 (dm, IH, J=17.1Hz), 3.65 (s, 3H), 2.44 (m, IH), 2.28 (m, IH), 2.18 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H);
HRMS (ESI) m/z calc'd for O23H25CINO2: 381.1495. Found: 381.1490. Example 229 9-chloro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH- [ 1 Jbenzopyrano [3 ,4-fjquinoline iH NMRD7.98 (d, IH, J=8.5Hz), 7.42 (m, IH), 7.21 (m, 5H), 7.00 (d, IH, J=8.5Hz),
6.75 (m, IH), 6.57 (d, IH, J=8.5Hz), 6.42 (m, IH), 5.47 (m, IH), 3.65 (s, 3H), 1.81 (s, 3H), 1.29 (s, 3H), 1.09 (s, 3H); HRMS (ESI) m/z calc'd for for C26H24CINO2: 417.1495. Found: 417.1497.
Example 230
5-(3-propenyl)-9-chloro-10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline 1H NMRD7.58 (d, IH, J=8.5Hz), 7.14 (m, 2H), 6.80 (dd, IH, J=7.3Hz), 6.64 (d, IH, J=8.5Hz), 6.24 (m, IH), 5.81 (m, 2H), 5.46 (m, IH), 5.02 (dm, IH, J=10.5Hz), 4.94 (dm, IH, J=17.1Hz), 2.30 (m, 2H), 2.17 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H); mass spectrum
(ESI) m/z: 418 (M+H); Calcd for C23H22CIF2NO2: 417.1307. Found: 417.1304.
Example 231 9-chloro-10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH- [ 1 jbenzopyrano [3 ,4-f] quinoline
1H NMRD7.77 (d, IH, J=8.5Hz), 7.44 (m, IH), 7.22 (m, 5H), 7.12 (d, IH, J=8.5Hz), 6.84 (s, IH), 6.76 (t, IH, J=75Hz), 6.74 (d, IH, J=8.5Hz), 6.51 (m, IH), 5.39 (m, IH), 1.78 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H); mass spectrum (ESI) m/z: 454 (M + 1); Calcd for C26H22CIF2NO2: 453.1307. Found: 453.1304.
The chemistry described in Schemes 1-21 and Examples 1-215 was used with Core 5 to prepare Examples 232-233.
Example 232 8-fluoro- 10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1 H-
[1 Jbenzopyrano [3 ,4-fjquinoline IH NMRD7.95 (d, IH, J=8.5Hz), 7.30 (m, 2H), 7.20 (m, 5H), 7.00 (d, IH, J=8.5Hz), 6.82 (s, IH), 6.43 (m, IH), 5.38 (m, IH), 3.56 (s, 3H), 2.17 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H); mass spectrum (ESI) m z: 402 (M+H); Calcd for C26H24FNO2: 401.1791. Found: 401.1795.
Anal. Calcd for C26H24FNO2: C, 77.78; H, 6.02; N, 2.49. Found: C, 77.66; H, 5.90; N,
2.28. Example 233 5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH- T 1 Jbenzopyrano [3 ,4-f|quinoline iH NMR.D7.95 (d, IH, J=8.5Hz), 7.30 (m, 2H), 7.20 (m, 5H), 7.00 (d, IH, J=8.5Hz),
6.82 (s, IH), 6.43 (m, IH), 5.38 (m, IH), 3.56 (s, 3H), 2.17 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H); mass spectrum (ESI) m/z: 402 (M+l); Calcd for C26H24FNO2: 401.1791. Found:
401.1795.
The chemistry described in Schemes 1-21 and Examples 1-215 was used with
Core 6 to prepare Example 234.
Example 234 10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro- ri jbenzopyrano[3,4-f]quinoline
MS (DCI/NH3) m/z 366 (M+H)+; lU NMR (300 MHz, DMSO)D7.87 (d, J=8.5 Hz, 1 H), 7.00 (dd, J=8.8, 2.2 Hz, 1 H), 6.64 (d, J=8.1 Hz, 1 H), 6.63 (d, J=8.8 Hz, 1 H), 6.31 (d, J=l.l Hz, 1 H), 5.90-5.80 (m, 1 H), 5.79-5.75 (m, 1 H), 5.46 (s, 1 H), 5.05-4.95 (m, 2 H), 3.79 (s, 3 H), 2.17 (d, J=l.l Hz, I H), 1.17 (s, 6 H);
HRMS calcd for C23H24FNO2 is 366.1869. Found 366.1869.
The chemistry described in Schemes 1-21 and Examples 1-215 was used with Core 7 to prepare Examples 235-296.
Example 235 10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [ 1 jbenzopyrano [3,4-f] quinoline iH NMR (300 MHz, DMSOJD8.69 (s, 1 H), 7.92 (d, J=8.5, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.48 (d, J=8.5, 1 H), 6.16 (d, J=1.7 Hz, 1 H), 5.81 (ddt,
J=17.3, 10.3, 6.6 Hz, 1 H), 5.67 (dd, J=9.8, 3.3 Hz), 5.44 (s, 1 H), 5.02 (dd, J=10.3, 1.8 Hz, 1 H), 4.98 (dd, J=17.3, 1.8 Hz, 1 H), 2.47-2.41 (m, 1 H), 2.34-2.27 (m, 1 H), 2.16 (s, 3 H), 1.18 (s, 3 H), 1.16 (s, 3 H);
13C NMR (75 MHz, DMSQ)P 145.8, 145.1, 143.9, 142.9, 134.4, 133.4, 132.7, 127.5, 126.5, 117.8, 117.0, 116.3, 116.1, 114.3, 113.6, 112.4, 73.3, 59.3, 49.7, 36.4, 29.2, 28.9,
23.9. MS (DCI/NH3) m/z 364 (M+H)+; Anal, calcd for C23H24N2O2: C, 76.01; H, 6.93; N, 3.85. Found C, 75.85; H, 7.18; N, 3.66.
Example 236 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m/z 404 (M+H)+; iH MR (300 MHz, DMSO-d6)D8.70 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.53 (d, IH), 6.27 (d, IH), 5.82-5.65 (m, 2H), 5.45 (s, IH), 5.33 (d, IH), 3.65 (s, 3H), 2.28 (m, IH), 2.12 (s, 3H), 1.86 (m, 2H), 1.55 (m, IH), 1.31 (s, 3H), 1.26-1.14 (m, 3H), 1.03 (s, 3H);
13C NMR (400 MHz, DMSO-dfS)P 145.4, 145.0, 144.1, 143.5, 133.6, 130.7, 128.1,
127.9, 127.7, 126.1, 1 18.4, 1 17.8, 116.5, 1 14.4, 113.4, 112.1, 75.9, 59.3, 49.4, 37.2, 29.6, 27.1, 24.7, 24.6, 23.7, 21.2.
Example 237 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H-[ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 8.66 (s, 1 H), 8.00 (d, J= 8.5 Hz, 1 H), 6.65 (d, J=
8.5 Hz, 1 H), 6.62 (d, J= 8.5 Hz, 1 H), 6.55 (d, J= 8.5 Hz, 1 H), 6.24 (d, J= 1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, J= 9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30 - 2.20
(m, 1 H), 2.11 (s, 3 H), 1.80 -1.54 (m, 3 H), 1.60, (s, 3 H), 1.30 (s, 3 H), 1.28 - 1.08 (m, 3
H), 1.03 (s, 3 H);
13C NMR (75 MHz, DMSO-d<s)P 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0,
126.1, 121.8, 118.3, 1 17.9, 116.5, 114.3, 113.3, 112.1, 76.2, 59.3, 49.4, 37.5, 29.6, 29.5, 27.1, 24.5, 23.8, 23.7, 21.6.
Example 238 (-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline [D]D=-158.8°;
MS (DCI/NH3) m/z 118 (M+H)+; iH NMR (300 MHz, DMSO-d6)D 8.66 (s, 1 H), 8.00 (d, J=8.5 Hz, 1 H), 6.65 (d, J=8.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.55 (d, J=8.5 Hz, 1 H), 6.24 (d, J=1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, J=9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30-2.20 (m, 1 H), 2.11 (s, 3 H), 1.80 -1.54 (m, 3 H), 1.60, (s, 3 H), 1.30 (s, 3 H), 1.28-1.08 (m, 3 H), 1.03
(s, 3 H); 13C NMR (75 MHz, DMSO-d6)D 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0,
126.1, 121.8, 118.3, 117.9, 116.5, 114.3, 113.3, 112.1, 76.2, 59.3, 49.4, 37.5, 29.6, 29.5,
27.1, 24.5, 23.8, 23.7, 21.6.
Anal, calcd for C27H31NO3: C, 77.67; H, 7.48; N, 3.35. Found C, 77.65; H, 7.67; N, 3.36.
Example 239 (+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenyn- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline [D]D=+157.9°
MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d<s)D8.66 (s, 1 H), 8.00 (d, J=8.5 Hz, 1 H), 6.65 (d, J=8.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.55 (d, J=8.5 Hz, 1 H), 6.24 (d, J=1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, J=9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30-2.20 (m, 1 H), 2.11 (s, 3 H), 1.80 -1.54 (m, 3 H), 1.60, (s, 3 H), 1.30 (s, 3 H), 1.28-1.08 (m, 3 H), 1.03
(s, 3 H); 13C NMR (75 MHz, DMSO-d6)p 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0,
126.1, 121.8, 118.3, 117.9, 116.5, 114.3, 113.3, 112.1, 76.2, 59.3, 49.4, 37.5, 29.6, 29.5, 27.1, 24.5, 23.8, 23.7, 21.6. Anal, calcd for C27H31NO3: C, 77.67; H, 7.48; N, 3.35. Found C, 77.65; H, 7.67; N,
3.36.
Example 240 (+) (5R,3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- [D]D=+78.0°
MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.74 (s, 1 H), 7.99 (d, J=8.8 Hz, 1 H), 6.66 (d, J=8.8 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.52 (d, J=8.5 Hz, 1 H), 6.24 (d, J=1.5 Hz, 1 H), 5.41 (br s, 1 H), 5.41 (d, J=10.3 Hz, 1 H), 4.84 (br s, 1 H), 3.63 (s, 3 H), 2.34-1.35 (m, 7 H), 2.06 (s, 3 H), 1.49, (s, 3 H), 1.30 (s, 3 H), 1.09 (s, 3 H);
13C NMR (75 MHz, DMSO-d6)D 145.3, 145.0, 144.0, 143.2, 135.5, 133.3, 131.3, 128.4,
126.2, 120.5, 118.1, 117.9, 116.5, 114.4, 113.5, 112.0, 75.3, 59.3, 49.5, 36.8, 29.4, 27.5,
25.0, 24.1, 23.7, 20.2.
HRMS calcd for C27H31NO3 417.2304. Found: 417.2305. Example 241 (-) (5S,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenyn- 10-methoxy-2,2,4-trimethyl-2,5- dihy dro- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline [DJD=-79.4°
MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d<s) 8.74 (s, 1 H), 7.99 (d, J=8.8 Hz, 1 H), 6.66 (d, J=8.8 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.52 (d, J=8.5 Hz, 1 H), 6.24 (d, J=1.5 Hz, 1 H), 5.41 (br s, 1 H), 5.41 (d, J=10.3 Hz, 1 H), 4.84 (br s, 1 H), 3.63 (s, 3 H), 2.34-1.35 (m, 7 H), 2.06 (s, 3 H), 1.49, (s, 3 H), 1.30 (s, 3 H), 1.09 (s, 3 H); i3C NMR (75 MHz, DMSO-d6)D 145.3, 145.0, 144.0, 143.2, 135.5, 133.3, 131.3, 128.4,
126.2, 120.5, 118.1, 117.9, 116.5, 114.4, 113.5, 112.0, 75.3, 59.3, 49.5, 36.8, 29.4, 27.5,
25.0, 24.1, 23.7, 20.2.
Anal, calcd for C27H31NO3: C, 77.67; H, 7.48; N, 3.35. Found C, 77.55; H, 7.56; N, 3.34.
Example 242 re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenylj-10-methoxy-2,2,4- trimethyl-2, 5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 434 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.72 (s, 1 H), 7.98 (d, J=8.8 Hz, 1 H), 6.65 (d, J=8.8 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.52 (d, J=8.8 Hz, 1 H), 6.23 (br s, 1 H), 5.43-5.39 (m, 2 H), 5.06 (br s, 1 H), ), 4.44 (t, J=5.1 Hz, 1 H), 3.69-3.67 (m, 1 H), 3.67 (s, 3 H), 2.32-2.22 (m, 1 H), 2.05 (s, 3 H), 1.94 -1.88 (m, 2 H), 1.74-1.61 (m, 2 H), 1.55-1.45 (m, 2 H), 1.29 (s, 3 H), 1.10 (s, 3 H);
13C NMR (75 MHz, DMSO-d6)P 145.4, 145.0, 144.0, 143.1, 140.4, 133.5, 131.2, 128.2,
126.2, 120.5, 118.0, 118.0, 116.5, 114.4, 113.5, 112.1, 75.4, 65.6, 59.4, 49.5, 37.0, 29.8,
27.8, 25.8, 25.1, 24.3, 20.3.
Anal, calcd for C27H31NO4: C, 74.80; H, 7.21; N, 3.23. Found: C, 74.59; H, 7.21; N, 3.22.
Example 243 (+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d6)P8.66 (s, 1 H), 8.00 (d, J= 8.5 Hz, 1 H), 6.65 (d, J= 8.5 Hz, 1 H), 6.62 (d, J= 8.5 Hz, 1 H), 6.55 (d, J= 8.5 Hz, 1 H), 6.24 (d, J= 1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, J= 9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30 - 2.20 (m, 1 H), 2.11 (s, 3 H), 1.80 -1.54 (m, 3 H), 1.60, (s, 3 H), 1.30 (s, 3 H), 1.28 - 1.08 (m, 3 H), 1.03 (s, 3 H); 13C NMR (75 MHz, DMSO-d6)D 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0, 126.1, 121.8, 118.3, 117.9, 116.5, 114.3, 113.3, 112.1, 76.2, 59.3, 49.4, 37.5, 29.6, 29.5,
27.1, 24.5, 23.8, 23.7, 21.6.
Example 244 re/-(5S,3 'R)-9-hydroxy-5-[l -methoxymethyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethyl-2, 5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 448 (M+H)+; iH NMR (300 MHz, DMSO-d<s)P8.75 (s, 1 H), 8.00 (d, J=8.5 Hz, 1 H), 6.67 (d, J=8.5
Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.54 (d, J=8.5 Hz, 1 H), 6.27 (d, J=1.5 Hz, 1 H), 5.46
(d, J=9.9 Hz, 1 H), 5.38 (br s, 1 H), 5.21 (br s, 1 H), 4.33-4.29 (m, 1 H), 3.66-3.63 (m, 1 H), 3.65 (s, 3 H), 3.64 (s, 3 H), 2.32-1.45 (m, 7 H), 2.04 (s, 3 H), 1.29 (s, 3 H), 1.07 (s, 3
H);
Anal, calcd for C28H33NO4: C, 75.14; H, 7.43; N, 3.13. Found C, 74.81; H, 7.35; N,
3.05.
Example 245
2,5-dihydro-9-hydroxy-10-methoxy-5-propyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fjquinoline The C-5 lactol-9-TBS ether of core 7 and «-propylmagnesium chloride were processed as in example 251 to provide the desired compound: iH NMR (300 MHz, DMSO-d<s)p8.66 (s, IH), 7.90 (d, J=9 Hz, IH), 6.60 (d, J=8 Hz,
IH), 6.59 (s, IH), 6.49 (d, J=9 Hz, IH), 6.14 (br s, IH), 5.57 (m, IH), 5.44 (br s, IH), 3.63 (s, 3H), 2.15 (s, 3H), 1.79-1.61 (m, IH), 1.48-1.08 (m, 5H), 1.16 (s, 6H), 0.78 (t, J=7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)P 145.7, 144.9, 143.9, 143.1, 133.5, 127.5,
126.4, 117.9, 116.3, 116.2, 114.2, 113.4, 112.1, 73.6, 59.3, 49.7, 31.9, 29.1, 28.8, 27.7, 23.8, 21.7, 13.9; MS (DCI/NH3) m/e (M+H)+ 380; Anal, calcd for
C24H29Nθ3«l/4H2θ: CC, 75.07; H, 7.74; N, 3.65. Found: C, 74.78; H, 7.86; N, 3.29.
The C-5 lactol-9-TBS ether of core 7 and 3-cycloheptenyl trimethylsilane were processed as above to give a 5:1 diastereomeric product mixture which was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 2% ETOH in hexanes to provide two levarotary enantiomers. Example 246 (-) (5S,3'S) 2,5-dihydro-9-hvdroxy-10-methoxy-2,2,4-trimethyl-5-(3-cycloheptenyl)-
1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 418 (M+H)+; , iH NMR (300 MHz, DMSO-d6) 08.70 (s, IH), 7.96 (d, IH), 6.65 (d, IH), 6.64 (d, IH), 6.21 (s, IH), 5.55 (ddd, IH), 5.53 (d, IH), 5.46 (s, IH), 5.31 (ddd, IH), 3.65 (s, 3H), 2.45 (m, IH), 2.14 (m, 3H), 2-05-1.84 (m, 4H), 1.46 (m, IH), 1.29 (s, 3H), 1.27- 1.15 (m, 4H), 1.04 (s, 3H); 13C NMR (400 MHz, DMSO-d6)D 145.3, 144.9, 144.0, 143.1, 133.7, 132.1, 131.6,
131.2, 128.1, 126.1, 118.3, 117.9, 116.5, 114.4, 113.3, 112.1, 74.5, 59.3, 49.5, 38.9, 29.5, 29.0, 28.7, 27.8, 27.2, 26.3, 23.8;
HRMS calcd m/z for C27H31NO3: 417.2304 (M*)+. Found: 417.2319. [D]23D=-134° (c 1.15, CHCI3).
Example 247 (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cycloheptenyl)-
1 H- r 1 Ibenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 418 (M+H)+; iH NMR (300 MHz, DMSO-d6) D8.66 (s, IH), 7.97 (d, IH), 6.65 (d, IH), 6.59 (d,
IH), 6.45 (d, IH), 6.22 (s, IH), 5.93 (ddd, IH), 5.72 (ddd, IH), 5.50 (d, IH), 5.45 (s, IH), 3.65 (s, 3H), 2.38 (m, IH), 2.13 (s, 3H), 2.04 (m,lH), 1.82-1.70 (m, 2H), 1.50-1.05 (m, 5H), 1.30 (s, 3H), 1.02 (s, 3H); 13C NMR (400 MHz, DMSO-d6)P 145.2, 144.8, 143.8, 143.2, 133.9, 133.6, 131.1, 130.8, 128.0, 126.1, 118.6, 118.0, 116.5, 114.4, 113.4, 112.2, 75.3, 59.2, 49.4, 41.9, 30.0,
29.6, 28.3, 28.0, 27.3, 26.1, 23.9;
HRMS calcd m/z for C27H31NO3: 417.2304 (M*)+. Found: 417.2288. [Dj23D=-122° (c 0.74, CHCI3).
Example 248 2,5-dihydro-9-hydroxy- 10-methoxy -2,2,4-trimethyl-5-phenyl- 1 H-
[1 Jbenzopyrano [3 ,4-fjquinoline iH NMR (300 MHz, DMSO),D8.53 (s, 1 H), 7.93 (d, J=8.7 Hz, 1 H), 7.20-7.14 (m, 5 H), 6.73 (d, J=8.7 Hz, 1 H), 6.66 (s, 1 H), 6.42 (d, J=8.9 Hz, 1 H), 6.33 (d, J=8.7 Hz, 1 H), 6.22 (d, J=1.7 Hz, 1 H), 5.37 (s, 1 H), 3.55 (s, 3 H), 1.80 (s, 3 H), 1.24 (s, 3 H), 1.14 (s, 3 H); 13C NMR (300 MHz, DMSO),D 145.7, 144.8, 143.8, 143.6, 139.3, 133.1,
132.7, 130.2, 128.3, 127.8, 127.6, 127.5, 126.4, 126.1, 123.8, 118.4, 117.8, 114.1, 114.0, 112.8, 112.2, 74.9, 59.0, 49.7, 29.7, 28.4, 23.2; MS, ESI m/z 400 (M+H)+; HRMS calcd for C26H-25NO2 is 399.1834. Found 399.1839.
Example 249 2,5-dihvdro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5- difluorophenyl)- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline
IH NMR (300 MHz, DMSO), 08.68 (s, 1 H), 7.95 (d, J=8.4 Hz, 1 H), 7.06 (tt, J=9.2, 2.2 Hz, 1 H), 6.82 (dd, J=8.1, 1.8 Hz, 2 H); 6.77 (d, J=8.4 Hz, 1 H), 6.70 (s, 1 H), 6.48 (d, J=8.4 Hz, 1 H), 6.42 (d, J=8.4 Hz, 1 H), 6.32 (d, J=1.5 Hz), 5.42 (s, 1 H), 3.56 (s, 3 H), 1.84 (d, J=l.l Hz, 3 H), 1.25 (s, 3 H), 1.15 (s, 3 H); 13C NMR (300 MHz, DMSO),D 163.6 (d, J=12.81 Hz), 160.4 (d, J=12.81 Hz), 145.9, 145.2, 144.5, 144.4 (t,
J=7.93 Hz), 143.6, 143.3, 133.1, 129.0, 127.3, 126.6, 118.2, 117.9, 117.2, 114.5 (d, J=6.1
Hz), 112.4, 111.4, 103.5, 73.8, 64.9, 59.1, 49.9, 29.6, 28.5, 23.2; MS ESI m/z 436
(M+H)+;
HRMS calcd for C26H22F2NO2 is 435.1646. Found 435.1657.
Example 250 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5- trifluorophenyl)- 1 H-[ 1 Ibenzopyrano \3 ,4-fjquinoline IHNMR (300 MHz, DMSO), 08.76 (s, 1 H), 8.02 (d, J=8.4 Hz, 1 H), 7.08 (dd, J=6.98, 1.8 Hz, 1 H), 6.86 (dd, J=7.3, 2.2 Hz, 1 H), 6.83 (d, J=8.8 Hz, IH), 6.73 (s, 1 H), 6.55 (d, J=8.8 Hz, 1 H), 6.47 (d, J=8.8 Hz, 1 H), 6.38 (d, J=1.5 Hz, 1 H), 5.46 (s, 1 H), 3.62 (s, 3
H), 1.88 (d, J=l.l Hz, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H); 13C NMR (300 MHz, DMSO),D 146.0, 145.3, 143.6, 143.1, 133.1, 128.7, 127.3, 126.7, 118.1 (d, J=15.87 Hz), 117.1, 116.0, 115.9, 115.8, 114.05 (d, J=9.16 Hz), 113.0, 112.7, 112.4, 73.5, 59.1, 49.8, 29.7, 28.4, 23.3, MS ESI m/z 454 (M+H)+;
HRMS calcd for C26H22F2NO2 is 453.1552. Found 453.1571.
Example 251
5-butyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline
The C-5 lactol-9-tert-butyldimethylsilyl ether of core 7 (0.057 g, 0.122 mmol) was dissolved in 1 ,2-dichloroethane (5 ml), cooled to -10°C, and treated dropwise with BF3»OEt2 (46 mL, 0.366 mmol). The resulting deep green solution was treated dropwise with an ethereal solution of «-butylmagnesium chloride (0.19 ml of a 2M / Et2θ solution, 0.380 mmol). The color changed to yellow-brown. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, the aqueous layer extracted with ethyl acetate, the combined organics washed with brine, dried (MgSO4), and concentrated to a yellow oil. The resulting yellow oil was dissolved in THF (5 ml), cooled to 0°C, and treated with tetrabutylammonium fluoride solution (0.14 ml of a IM / THF solution, 0.14 mmol). After 10 minutes, the mixture was quenched by the addition of saturated aqueous ammonium chloride and pH 7.0 buffer, and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organics washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexanes to give 0.032 g (72%) ofthe desired compound. iH NMR (300 MHz, DMSO-d6)D8.70 (s, IH), 7.90 (d, J=8 Hz, IH), 6.60 (d, J=8 Hz, IH), 6.59 (s, IH), 6.49 (d, J=8 Hz, IH), 6.16 (br s, IH), 5.61 (m, IH), 5.44 (br s, IH),
3.63 (s, 3H), 2.16 (s, 3H), 1.77-1.63 (m, IH), 1.47-1.26 (m, 3H), 1.17 (s, 3H), 1.16 (s, 3H), 0.83 (m, 3H); i 3C NMR (75 MHz, DMSO-d6)P 145.7, 144.9, 143.9, 143.1, 133.5,
133.3, 127.5, 126.4, 117.9, 116.3, 114.2, 113.4, 112.1, 73.2, 59.3, 49.7, 34.1, 29.1, 28.9, 23.9, 18.6, 13.4; MS (DCI/NH3) m/e (M+H)+ 366; Anal, calcd for C23H27NO3-1.25H2O: C, 71.20; H, 7.66; N, 3.61. Found: C, 71.48; H, 7.32; N, 3.52.
The C-5 lactol-9-TBS ether of core 7 and 3-cyclopentenyl trimethylsilane were processed as above to give a 1:1 diastereomeric product mixture which was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 2% ETOH in hexanes to provide the individual enantiomers.
Example 252 (-) (5S,3'S) 2,5-dihvdro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)-
1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6) 08.68 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.51 (d, IH), 6.22 (s, IH), 5.72 (dd, IH), 5.41 (d, IH), 5.40 (s, IH), 5.17 (dd, IH), 3.63 (s, 3H), 2.90-2.80 (m, IH), 2.41-2.32 (m, IH), 2.23-2.10 (m, IH), 2.06 (s, 3H), 1.89-1.71 (m, 2H), 1.30 (s, 3H), 1.08 (s, 3H); 13C NMR (400 MHz, DMSO-d6)P 145.5, 145.0, 143.9, 143.4, 133.5, 132.3, 132.2,
130.2, 128.1, 126.4, 117.8, 116.9, 116.4, 114.4, 113.4, 111.9, 75.7, 59.3, 49.5, 48.7, 31.6,
29.8, 27.6, 27.1, 24.2;
HRMS calcd m/z for C25H27NO3: 389.1991 (M*)+. Found: 389.1994.
[D]23D=-120° (c 0.800, CHCI3). Example 253 (-) (5S,3 'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-cyclopenteny 1 )-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6)08.67 (s, IH), 8.02 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.53 (d, IH), 6.25 (s, IH), 5.77 (ddd, IH), 5.69 (ddd, IH), 5.47 (s, IH), 5.37 (s, IH), 3.66 (s, 3H), 2.90 (m, IH), 2.34-2.13 (m, 2H), 2.10 (s, 3H), 1.55-1.41 (m, 2H), 1.31 (s, 3H), 1.04 (s, 3H); 1 C NMR (400 MHz, DMSO-d6)P 145.5, 144.9, 144.0, 143.9, 133.6, 132.0, 131.7,
131.5, 127.9, 126.2, 117.7, 117.6, 116.5, 114.4, 113.3, 111.9, 76.1, 59.3, 49.4, 48.6, 31.7, 29.5, 27.1, 24.6, 23.7;
HRMS calcd m/z for C25H27NO3: 389.1991. Found: 389.1998.
[0]23D=-132° (c 0.76, CHCI3).
Example 254 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4- difluoropheny 1)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline IH NMR (300 MHz, DMSO-d6), 08.65 (s, 1 H), 7.96 (d, J=8.8 Hz, 1 H), 7.31-7.17 (m, 2 H), 6.98-6.95 (m, 1 H), 6.76 (d, J=8.8 Hz, 1 H), 6.67 (s, 1 H), 6.48 (d, J=8.4 Hz, 1 H), 6.38 (d, J=8.4 Hz, 1 H), 6.29 (d, J=1.5 Hz), 5.40 (s, 1 H), 3.57 (s, 3 H), 1.82 (d, J=1.5
Hz), 1.25 (s, 3 H), 1.14 (s, 3 H); 12C-NMR (75 MHz, DMSO-d6)D 145.9, 145.1, 143.6, 143.3, 137.3, 132.9, 129.5, 127.4,
126.6, 125.2, 118.3, 117.8, 117.3, 117.1, 117.0, 116.8, 114.4, 114.3, 112.3, 73.8, 59.1, 49.8, 29.7, 28.4, 23.3; HRMS calcd for C26H22NO2F2 is 435.1646. Found 435.1638.
Example 255 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-fluorophenyl)-
1 H- [ 1 Ibenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) 418 (M+H)+; IH NMR (300 MHz, DMSO-d6), 08.58 (s, 1 H), 7.95 (d, J=8.8 Hz, 1 H), 7.23-7.19 (m, 2
H), 7.03 (dd, J=8.8, 8.8 Hz, 2 H), 6.74 (d, J=8.8 Hz, 1 H), 6.66 (s, 1 H), 6.44 (d, J=8.8 Hz, 1 H), 6.34 (d, J=8.8 Hz, 1 H), 6.24 (d, J=1.5 Hz), 5.38 (s, 1 H), 3.57 (s, 3 H), 1.80 (d, J=1.5 Hz), 1.24 (s, 3 H), 1.14 (s, 3 H); HRMS calcd for C26H24NO2F is 417.1740. Found 417.1745. Example 256 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethylphenyl)-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline MS APCI m/z 468 (M+H)+; iHNMR (300 MHz, DMSO),08.62 (s, 1 H), 7.97 (d, J=8.8 Hz, 1 H), 7.61-7.41 (m, 3 H), 7.36 (s, 1 H), 6.75 (s, 1 H), 6.44 (d, J=8.4 Hz, 1 H), 6.35 (d, J=8.4, 1 H), 6.30 (d, J=1.5 Hz, 1 H), 5.40 (s, 1 H), 3.52 (s, 3 H), 1.80 (d, J=1.5 Hz, 3 H), 1.24 (s, 3 H), 1.15 (s, 3 H); 13C NMR (300 MHz, DMSO),0145.9, 145.0, 143.5, 140.9 (d, J=17.01 Hz), 140.9, 133.0, 132.6, 129.3, 129.2, 127.4, 126.6, 124.4, 118.3, 118.0, 117.4, 114.5 (d,
J=7.32 Hz), 112.3, 74.2, 58.9, 49.8, 29.5, 29.4, 23.3. HRMS calcd for C27H24F2NO2 is 467.1708. Found 467.1708.
Example 257 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5- bistrifluoromethylphenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
MS APCI m/z 536 (M+H)+;
IH NMR (300 MHz, DMSO), 08.69 (s, 1 H), 8.00 (d, J=8.8 Hz, 1 H), 7.96 (s, 1 H), 7.80
(s, 2 H), 6.90 (s, IH), 6.79 (d, J=8.4 Hz, 1 H), 6.46 (d, J=8.8 Hz, 1 H), 6.39 (d, J=1.3 Hz,
1 H), 6.37 (d, J=8.4 Hz, 1 H), 5.43 (s, 1 H), 3.51 (s, 3 H), 1.80 (d, J=0.73 Hz, 3 H), 1.24 (s, 3 H), 1.15 (s, 3 H); 13C NMR (300 MHz, DMSO),0146.1, 145.3, 143.6, 142.9,
133.2, 130.1, 129.7, 129.5, 127.2, 126.7, 124.9, 118.2, 117.2, 114.8, 112.3, 73.5, 58.8,
49.8, 29.4, 28.3, 23.3.
HRMS calcd for C28H22F6NO2 is 535.1582. Found 535.1573.
Example 258
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4- chlorophenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline MS (APCI) m/z 502 (M+H)+; IH NMR (300 MHz, DMSO),D8.70 (s, 1 H), 7.97 (d, J=8.8 Hz, 1 H), 7.70-7.60 (m, 3 H), 6.78 (s, 1 H), 7.55 (s, 1 H), 6.46 (d, J=8.8 Hz, 1 H), 6.38 (s, 1 H), 6.36 (d, J=8.8 Hz, 1 H), 5.41 (s, 1 H), 3.53 (s, 3 H), 1.79 (s, 3 H) 1.28 (s, 3 H), 1.14 (s, 3 H); 13C NMR (300 MHz, DMSO), p 166.9, 146.0, 145.2, 143.6, 143.1, 139.6, 134.1, 133.0, 131.7, 131.5, 128.6, 127.3, 126.7, 114.6, 112.3, 73.7, 59.0, 49.8, 67.4, 29.6, 29.8, 28.3, 23.3, 23.2, 22.4, 13.8, 10.8. HRMS calcd for C27H22CIF2NO2 501.1319. Found 501.1326. Example 259 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[lJbenzopyrano[3,4-f]quinoline The C-5 lactol-9-tert-butyldimethylsilyl ether of core 7 and wo-butylmagnesium chloride were processed as in example 251 to provide the desired compound: iH NMR (300 MHz, DMSO-d6)08.69 (s, IH), 7.90 (d, J=8 Hz, IH), 6.61 (d, J=8 Hz,
IH), 6.59 (d, J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.16 (br s, IH), 5.71 (m, IH), 5.44 (br s, IH), 3.63 (s, 3H), 2.17 (s, 3H), 1.82-1.60 (m, 2H), 1.43-1.18 (m, IH), 1.17 (s, 3H), 1.16 (s, 3H), 0.97 (d, J=7 Hz, 3H), 0.76 (d, J=7 Hz, 3H); 13C NMR (75 MHz, DMSO- d6)P 145.8, 144.8, 143.8, 143.0, 133.5, 133.3, 127.5, 126.4, 117.9, 116.3, 116.1, 114.2,
113.4, 112.1, 71.8, 59.3, 49.6, 29.1, 28.9, 24.6, 24.0, 23.3, 21.2; MS (FAB Hi Res) m/e calc'd for C24H29NO3: 379.2147. Found 379.2159.
Example 260
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4-chlorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline The C-5 lactol-9-tert-butyldimethylsilyl ether of core 7 and 3-fluoro-4- chlorophenyl magnesium bromide were processed according to Example 251 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)D8.72 (s, IH), 7.91 (d, J=8 Hz, IH), 6.59 (d, J=8 Hz,
IH), 6.59 6.48 (d, J=8 Hz, IH), 6.16 (br s, IH), 5.71 (m, IH), 5.44 (br s, IH), 3.63 (s, 3H), 2.17 (s, 3H), 1.82-1.60 (m, 2H), 1.43-1.18 (m, IH), 1.17 (s, 3H), 1.16 (s, 3H), 0.97 (d, J=7 Hz, 3H), 0.76 (d, J=7 Hz, 3H).
Example 261 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-butenyl)- 1 H-
[ 1 Ibenzopyrano [3 ,4-fjquinoline The C-5 lactol-9-tert-butyldimethylsilyl ether of core 7 and l-butenyl-4- magnesium bromide were processed according to Example 251 to provide the desired compound.
Example 262 2,5-dihydro-9-hydroxy-10-methoxy-5-(phenylmethyl)-2,2,4-trimethyl-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline The C-5 lactol-9-TBS ether of core 7 and benzylmagnesium bromide were processed as in example 251 to provide the desired compound: iH NMR (300 MHz, DMSO-d6)08.77 (s, IH), 7.97 (d, J=9 Hz, IH), 7.34-7.13 (m, 3H),
7.11 (s, IH), 7.10 (d, J=7 Hz, IH), 6.67 (m, J=8 Hz, IH), 6.65 (m, J=8 Hz, IH), 6.42 (d, J=9 Hz, IH), 6.20 (br s, IH), 5.86 (dd, J=10, 3 Hz, IH), 5.42 (br s, IH), 3.69 (s, 3H), 2.99 (dd, J=10, 14 Hz, IH), 2.77 (dd, J=3, 15 Hz, IH), 2.23 (s, 3H), 1.16 (s, 3H), 1.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6)D 145.8, 145.0, 144.0, 142.8, 138.0, 133.3, 132.4,
128.9 (2C), 121.1 (2C), 127.4, 126.4, 126.1, 117.9, 116.3, 116.2, 114.4, 113.7, 112.5, 74.5, 59.4, 49.7, 37.9, 29.2, 29.0, 24.3; MS (DCI/NH3) m/e (M+H)+ 414; Anal, calcd for O27H27NO3»1/4H2O: C, 77.58; H, 6.63; N, 3.35. Found: C, 77.70; H, 7.07; N, 3.19.
Example 263 (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l- ethyl-3 -cy clohexenylj - 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline The mixture of diastereomers from example 277 were resolved on a Chiracel OJ HPLC column eluting with hexane :2-propanol (95:5) to give the desired product. iH NMR (300 MHz, DMSO-d6.)D8.67 (s, IH), 7.99 (d, J=9 Hz, IH), 6.65 (d, J=9 Hz, IH),
6.62 (d, J=9 Hz, IH), 6.53 (d, J=8 Hz, IH), 6.22 (s, IH), 5.44 (d, J=12 Hz, 2H), 5.30 (d, J=10 Hz, IH), 3.62 (s, 3H), 3.50-2.26 (m, IH), 2.11 (s, 3H), 1.89-1.72 (m, 3H), 1.25- 1.17 (m, 2H), 1.03 (2, 3H), .088 (t, J=7 Hz, 3H); 13C NMR (75 MHz, DMSO- dfS)D 145.4, 144.9, 144.0, 143.7, 140.1, 133.6, 130.9, 127.9, 126.1, 120.0, 118.2, 117.8,
116.6, 114.3, 113.3, 112.0, 76.2, 59.3, 49.4, 37.7, 30.2, 29.6, 27.7, 27.2, 24.9, 23.7, 21.6, 12.3.
Example 264 (-) (S) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-mefhoxy-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
The C-5 lactol-9-TBS ether of core 7 and cyclopentylmagnesium chloride were processed as in Example 251. The resulting racemic product was resolved into its constituent enantiomers by HPLC on a (R, R)- WHELK-O 1 column eluting with 2%
EtOH in hexanes to give the desired compound as the first eluent: iH NMR (300 MHz, DMSO-d6)D8.66 (s, IH), 8.00 (d8, IH), 6.63 (d8, IH), 6.61 (d,
J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.24 (br s, IH), 5.45 (br s, IH), 5.35 (d, J=10 Hz, IH), 3.65 (s, 3H), 2.15 (s, 3H), 2.12-1.97 (m, IH), 1.60-1.43 (m, 4H), 1.42-1.22 (m, 2H), 1.19-1.07 (m, 2H), 1.31 (s, 3H), 1.02 (s, 3H); MS (DCI/NH3) m/e (M+H)+ 392.
Example 265 (+) (R) 5-cyclopentyl-2,5-dihydro-9-hvdroxy-10-methoxy-2,2,4- trimethyl- 1H-[1 jbenzopyrano [3 ,4-fjquinoline
The racemic product from Example 264 was resolved into its constituent enantiomers by HPLC on a (R, R)-WHELK-Oι column eluting with 2% EtOH in hexanes to give the desired compound as the second eluent: iH NMR (300 MHz, DMSO-d6)08.66 (s, IH), 8.00 (d8, IH), 6.63 (d8, IH), 6.61 (d,
J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.24 (br s, IH), 5.45 (br s, IH), 5.35 (d, J=10 Hz, IH), 3.65 (s, 3H), 2.15 (s, 3H), 2.12-1.97 (m, IH), 1.60-1.43 (m, 4H), 1.42-1.22 (m, 2H), 1.19-1.07 (m, 2H), 1.31 (s, 3H), 1.02 (s, 3H); MS (DCI/NH3) m/e (M+H)+ 392. Example 266 2,5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline The C-5 lactol-9-TBS ether of core 7 and propargylmagnesium bromide (Gaoni,Y:, Leznoff, C.C:,Sondheimer. J Am. Chem. Soc. 1968, 90, 4940-4945.) were processed as in Example 251 to give the desired compound. 1H NMR (300 MHz, DMSO-d6)D8.77 (s, IH), 7.92 (d, J=9 Hz, IH), 6.63 (dd, j=9, 8 Hz, 2H), 6.54 (m, IH),
6.17 (s, IH), 5.82 (dd, J=9, 9 Hz, IH), 5.44 (s, IH), 3.68 (s, 3H), 2.78 (t, IH), 2.44-2.36 (m, 2H), 2.18 (s, 3H), 1.17 (d, J=5 Hz, 6H); 13C NMR (75 MHz, DMSO-d6)0145.9, 145.5, 145.4, 145.2, 143.9, 142.3, 133.5, 132.6, 131.4, 127.4, 126.5, 117.4, 116.5, 115.8,
114.5, 1 14.0, 112.6, 91.4, 80.7, 72.5, 59.4, 49.8, 29.3, 29.0, 23.9, 23.3, 22.4.
Example 267 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH-
[1 ]benzopyranor3 ,4-fjquinoline The C-5 lactol-9-TBS ether of core 7 and wo-propylmagnesium chloride were processed as in Example 251 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)D8.65 (s, IH), 7.99 (d8, IH), 6.64 (d, J=8 Hz, IH), 6.61
(d, j=8 Hz, IH), 6.51 (d, J=8 Hz, IH), 6.22 (br s, IH), 5.44 (br s, IH), 5.26 (d, j=10 Hz, IH), 3.64 (s, 3H), 2.16 (s, 3H), 1.85-1.67 (m, IH), 1.30 (s, 3H), 1.02 (s, 3H), 0.93 (d, J=6 Hz, 3H), 0.64 (7, 3H); 13C NMR (75 MHz, DMSO-d6)D 145.3, 144.8, 144.0, 143.7,
133.5, 131.6, 128.2, 126.1, 118.4, 117.9, 116.5, 114.3, 113.2, 112.0, 77.7, 59.3, 49.4, 30.7, 29.7, 27.2, 23.9, 19.5, 17.9; MS (DCI/NH3) m/e (M+H)+ 366; Anal, calcd for C23H27Nθ3»l/4H2θ: C, 74.67; H, 7.49; N, 3.79. Found: C, 74.81; H, 7.39; N, 3.67.
Example 268
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline The C-5 lactol-9-TBS ether of core 7 and 2-methoxyfhiophene were processed according to Example 276 to provide the desired compound. iH NMR (300 MHz, DMSO-d6)08.63 (s, IH), 7.93 (d, J=8 Hz, IH), 6.70 (d, j=8 Hz,
IH), 6.65 (s, IH), 6.50 (d, J=8 Hz, IH), 6.39 (d, J=9 Hz, IH), 6.28 (d, J=3 Hz, IH), 6.23 (br s, IH), 5.97 (d, J=3 Hz, IH), 5.38 (br s, IH), 3.72 (s3), 3.59 (s, 3H), 1.97 (s, 3H), 1.22 (s, 3H), 1.13 (s, 3H); i 3C NMR (75 MHz, DMSO-d6)P 166.2, 145.7, 145.1, 143.6,
143.5, 132.9, 130.2, 128.7, 127.6, 126.4, 126.0, 118.3, 117.2, 117.2, 114.2, 112.4, 102.7, 71.5, 59.7, 59.1, 49.8, 29.8, 28.6, 22.9; MS (DCI/NH3) m/e (M+H)+ 436; Anal, calcd for
C25H25Nθ4S»l/4H2θ: C, 68.24; H, 5.84; N, 3.18. Found: C, 68.52; H, 6.19; N, 3.00. Example 269 (±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6- pentafluorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline The C-5 lactol-9-TBS ether of core 7 and pentafluorophenylmagnesium bromide were processed to give the desired compound which was purified by flash chromatography eluting with 4:1 hexane/EtOAc. MS (DCI/NH3) m/z 490 (M+H)+; iH NMR (300 MHz, DMSO-d6) D8.75 (s, IH), 7.83 (d, IH), 6.82 (S, IH), 6.67 (d, IH), 6.44 (d, IH), 6.33 (d, IH), 6.19 (s, IH), 5.37 (s, IH), 3.53 (s, 3H), 1.77 (s, 3H), 1.17 (s, 3H), 1.06 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 146.1, 145.8, 143.8, 142.9, 133.4, 128.4, 127.0,
126.2, 118.6, 118.1, 117.6, 114.5, 114.2, 113.3, 112.2, 105.0, 68.6, 58.9, 49.9, 29.8, 28.3,
23.1;
Anal, calcd for C26H20NO3F5 • 0.5 H2O: C, 62.65; H, 4.25; N, 2.81. Found: C, 62.4; H, 4.28; N, 2.73.
Example 270 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- hydroxymethylcyclopenten-3-yl)-lH-[lJbenzopyrano[3,4-f]quinoline
MS (DCI/NH3) m/z 420(M+H)+; IH NMR (400 MHz, DMSO-d6) IH NMR (200 MHz, DMSO-d6)08.77 (s, IH), 8.04 (d,
IH), 6.67 (d, IH), 6.62 (d, IH), 6.52 (d, IH), 6.24 (bs, IH), 6.12 (dd, IH), 5.50 (d, IH),
5.42 (bs, IH), 2.64 (s, 2H), 2.57 (s, 2H), 2.75-1.09 (m, 14H).
Example 271 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methylcarboxylatecyclopenten-3-y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
The C-5 lactol-9-TBS ether of core 7 and 3-cyclohexenyl trimethylsilane were processed as above to give a 3:2 diastereomeric product mixture which was subjected to HPLC on an (R,R) WHELK-O 1 column eluting with 2% EtOH in hexanes to provide the individual enantiomers.
Example 272 (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexenyl)-lH-πjbenzopyrano[3,4-fjquinoline MS (DCI/NH3) m z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6) D8.70 (s, IH), 7.99 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.52 (d, IH), 6.20 (d, IH), 5.61 (ddd, IH), 5.46 (d, IH), 5.41 (s, IH), 5.10 (dd, IH),
3.66 (s, 3H), 2.27 (m, IH), 2.10 (s, 3H), 1.99-1.72 (m, 2H), 1.70-1.55 (m, 3H), 1.35 (m, IH), 1.29 (s, 3H), 1.06 (s, 3H); 13C NMR (400 MHz, DMSO-d6)P 145.4, 145.0, 143.4, 143.0, 133.5, 131.0, 128.9,
128.1, 126.4, 126.3, 117.9, 116.5, 114.4, 113.5, 112.1, 75.2, 59.3, 49.5, 36.9, 29.7, 27.6,
25.5, 24.6, 24.3, 20.0;
[0]23D=-162° (c 0.11, CHCI3).
Example 273 (-) (5S,3'R) 2,5-dihvdro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline
MS (DCI/NH3) m/z 404 (M+H)+; iH NM (300 MHz, DMSO-d6) D8.70 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.53 (d, IH), 6.27 (d, IH), 5.82-5.65 (m, 2H), 5.45 (s, IH), 5.33 (d, IH), 3.65 (s,
3H), 2.28 (m, IH), 2.12 (s, 3H), 1.86 (m, 2H), 1.55 (m, IH), 1.31 (s, 3H), 1.26-1.14 (m,
3H), 1.03 (s, 3H);
13C NMR (400 MHz, DMSO-d6)D 145.4, 145.0, 144.1, 143.5, 133.6, 130.7, 128.1,
127.9, 127.7, 126.1, 118.4, 117.8, 116.5, 114.4, 113.4, 112.1, 75.9, 59.3, 49.4, 37.2, 29.6, 27.1, 24.7, 24.6, 23.7, 21.2;
[D]23D=-158° (c 0.50, CHCI3).
Example 274 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ljbenzopyrano[3 ,4-fjquinoline A 0.24 M solution of 2-thienylzinc chloride was prepared by diluting 2-thienyl lithium (1.0 ml of a IM/THF solution, 1.0 mmol) with ethyl ether (2 ml), cooling to 0°C, treating with ZnCi2 (1.1 ml of a lM/EtjO solution, 1.10 mmol), and allowing to come to room temperature. The resulting heterogeneous mixture was stirred vigorously.
The C-5 lactol-9-TBS ether of core 7 and the 2-thienylzinc chloride from above were processed according to Example 251 to provide the desired compound: iH NMR (300 MHz, DMSO-d6)08.65 (s, IH), 7.95 (d, J=9 Hz, IH), 7.39 (dd, J=5, 1
Hz, IH), 6.85-6.82 (m, 2H), 6.74 (m, IH), 6.72 (d, J=8 Hz, IH), 6.48 (d, J=8 Hz, IH), 6.37 (d, J=9 Hz, IH), 6.28 (br s, IH), 5.39 (br s, IH), 3.59 (s, 3H), 1.93.(s, 3H), 1.22 (s, 3H), 1.14 (s, 3H); i 3C NMR (75 MHz, DMSO-d(S)P 145.7, 145.1, 143.7, 143.6, 143.5, 133.0, 130.8, 127.9, 127.5, 127.0, 126.5, 126.4, 118.3, 117.1, 114.4, 114.2, 112.4, 70.9,
59.0, 49.8, 29.7, 28.6, 23.0; MS (DCI/NH3) m/e (M+H)+ 406; Anal, calcd for C24H23NO3S: C, 71.09; H, 5.72; N, 3.45. Found: C, 70.93; H, 6.00; N, 3.27. Example 275 (±) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2- methy lphenyl) - 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline The C-5 lactol-9-TBS ether of core 7 and o-tolylmagnesium bromide were processed to give the desired product which was purified by flash chromatography eluting with 4:1 hexane/EtOAc. MS (DCI/NH3) m/z 414 (M+H)+; iH NMR (300 MHz, DMSO-d6) 08.43 (s, IH), 7.79 (d, IH), 7.02 (d, IH), 6.92 (dt, IH), 6.72 (t, IH), 6.59 (d, IH), 6.55 (s, IH), 6.54 (d, IH), 6.24 (d, IH), 6.12 (d, IH), 6.07 (s, IH), 5.20 (s, IH), 3.48 (s, 3H), 2.44 (s, 3H), 1.54 (s, 3H), 1.09 (s, 3H), 0.98 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 145.9, 145.0, 143.9, 143.6, 137.5, 136.6, 132.6,
130.6, 130.5, 128.8, 128.1, 127.6, 126.4, 124.9, 118.7, 118.2, 117.8, 114.1, 114.0, 111.7,
73.7, 59.2, 49.8, 30.0, 28.3, 22.5, 19.3;
Anal, calcd for C27H27NO3: C, 78.42; H, 6.58; N,3.39. Found: C, 78.07; H, 6.85; N, 3.09.
Example 276 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-
3 -propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
The C-5 lactol-9-TBS ether of core 7 (0.150 g, 0.321 mmol) was dissolved in dichloromethane (15 ml), treated with 2-[(trimethylsilyl)methyl]-2-propene-l-yl acetate
(0.180 g, 0.962 mmol), cooled to -78°C, treated dropwise with BF3»Et2θ and allowed to warm to 0°C. After 10 minutes, the reaction mixture was partitioned between saturated aqueous bicarbonate and ethyl acetate, layers separated, aqueous layer extracted with ethyl acetate, the combined organics washed with brine, dried (MgSO4) and concentrated.
The resulting yellow oil was dissolved in THF (10 ml), cooled to 0°C, and treated with tetrabutylammonium fluoride solution (0.35 ml of a IM / THF solution, 0.35 mmol). After 10 minutes, the mixture was quenched by the addition of saturated aqueous ammonium chloride and pH 7.0 buffer, and the layers were separated. The aqueous layer was extracted with ethyl acetate, the combined organics washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluting with 25%> ethyl acetate in hexanes to provide 0.125 g (89%) of the desired compound. iH NMR (300 MHz, DMSO-d6)D8.74 (s, IH), 7.92 (d, J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 6.62 (d, J=8 Hz, IH), 6.41 (d, J=9 Hz, IH), 6.21 (br s, IH), 5.85 (dd, J=2, 10 Hz,
IH), 5.44 (s, IH), 5.08 (s, IH), 4.92 (s, IH), 4.58 (ABq, J=13, 30 Hz, 2H), 3.65 (s, 3H), 2.23 (m, 2H), 2.17 (s, 3H), 1.99 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H); MS (DCI/NH3) m/e (M+H)+ 436; Anal, calcd for C26H29NO5: C, 71.71; H, 6.71; N, 3.22. Found: C, 71.34; H, 6.98; N, 3.12.
Example 277 (+) (5R,3 ' S) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-[ 1 - ethyl-3 -cy clohexenylj - 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline
To 77 ml of a 0.36 M THF solution of dimethylphenylsilyl methyl cuprate (27.7 mmol) ( Flemingi.; Newton, T. W.J. Chem. Soc. Perkin Trans. 1 , 1984, 1805.) at - 23°C was added 3-ethyl-cyclohex-2-ene-l-one (2.73 g, 27.0 mmol). The mixture was stirred for 1 hr at -23 °C, then for 2 hr at 0°C, treated with N-phenyl-bis- (trifluoromethanesulfonimide) (4.43 g, 26.4 mmol), allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was quenched with saturated aqueous sodium bicarbonate, filtered through celite, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, and dried (Na2SO4). The product was purified by silica gel column chromatography eluting with hexanes to give the intermediate triflate as a light yellow oil.
The above triflate (0.70 g, 1.28 mmol) was combined with tributyltin hydride (0.92 g, 2.13 mmol) in THF and added dropwise to a THF solution of tetrakistriphenylphosphinepalladium(O) (0.44 g, 3.5 mmol) and LiCl (0.45 g, 10.7 mmol) at room temperature. After the addition, the reaction was refluxed for 24 hr, cooled, filtered through a pad of celite, and stirred vigorously with saturated potassium fluoride solution for 2 hours. The mixture was filtered through celite, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, brine, and dried (Na2SO4). The product was purified by silica gel column chromatography eluting with hexanes to give 3 -ethyl-3 - dimethylphenylsilyl-cyclohexene as a colorless oil.
The C-5 lactol-9-TBS ether of core 7 and 3 -ethyl-3 -dimethylphenylsilyl- cyclohexene were processed according to example 276 to give the product as a mixture of diastereomers that was separated on a (R,R,)-Whelk-Ol HPLC column eluting with hexane:ethanol (98:2) to give the desired compound. : iH NMR (500 MHz, DMSO- d6)D8.01 (d, J=8 Hz, IH), 6.63 (d, J=8 Hz, IH), 6.61 (d, J=9 Hz, IH), 6.53 (d, J=9 Hz,
IH), 6.20 (s, IH), 5.48 (s, IH), 5.44 (s, IH), 5.32 (d, J=9 Hz, IH), 3.64 (s, 3H), 2.26 (m, IH), 1.90-1.73 (m, 3H), 1.60 (m, IH), 1.26-1.18 (m, 2H), 1.03 (s, 3H), .088 (t, J=7 Hz, 3H); 13C NMR (50 MHz, DMSO-d6)0145.3, 144.8, 144.0, 143.6, 140.3, 133.5, 130.8,
127.8, 126.0, 120.0, 118.1, 117.8, 116.5, 114.2, 113.2, 111.9, 76.1, 59.2, 49.4, 37.5, 30.1, 29.5, 27.7, 27.1, 24.8, 23.6, 21.6, 12.2; MS m/e calc'd for C28H33O3N: 431.2460.
Found 431.2467. The C-5 lactol-9-TBS ether of core 7 and cyclohexylmagnesium chloride were processed to give a mixture of Examples 278 and 279 which were separated by flash chromatography eluting with 4: 1 hexane/EtOAc.
Example 278 2,5-dihvdro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclohexyl-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m/z 406 (M+H)+; iH NMR (300 MHz, DMSO-d6)08.66 (s, IH), 7.96 (d, IH), 6.61 (d, IH), 6.59 (d,
IH), 6.47 (d, IH), 6.18 (d, IH), 5.42 (s, IH), 5.30 (d, IH), 3.64 (s, 3H), 2.13 (s, 3H), 1.87 (m, IH), 1.60-1.48 (m, 3H), 1.28 (s, 3H), 1.20-0.80 (m, 7H), 1.00 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 145.3, 144.8, 144.1, 143.8, 133.5, 131.1, 128.1,
126.1, 118.5, 117.9, 116.6, 114.4, 113.2, 112.0, 76.8, 59.3, 49.4, 29.7, 29.5, 28.0, 27.2, 25.8, 25.6, 25.3, 23.8;
Example 279 2,5,5-trihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 324 (M+H)+; iH NMR (300 MHz, DMSO-d6) 08.78 (s, IH), 7.81 (d, IH), 6.62 (d, IH), 6.57 (d,
IH), 6.53 (d, IH), 6.22 (s, IH), 5.40 (s, IH), 5.05 (s, 2H), 3.62 (s, 3H), 2.01 (s, 3H), 1.19 (s, 6H);
13C NMR (400 MHz, DMSO-d6)P 146.6, 145.4, 145.3, 144.0, 131.5, 130.8, 128.1,
126.2, 118.2, 118.0, 117.2, 113.9, 113.2, 111.2, 67.1, 59.4, 49.9, 29.0, 22.9;
Example 280 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-hydroxymethyl- 3 -propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline
Example 276 (0.032g, 0.074 mmol) was dissolved in THF/MeOH/H2θ (5ml/lml/0.5ml), cooled to 0°C, treated with K2CO3 (0.051 g, 0.367 mmol), and allowed to warm to room temperature and stir for 12 h. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate, the aqueous layer extracted with ethyl acetate, the combined organics washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluting with 25% then 50%> ethyl acetate in hexanes to give 0.022 g (76%>) ofthe desired compound. iHNMR (300 MHz, DMSO-d6)D8.71 (s, IH), 7.92 (s, J=9 Hz, IH), 6.62 (d, J=9 Hz,
IH), 6.61 (d, J=8 Hz, IH), 6.41 (d, J=8 Hz, IH), 6.18 (d, J=l Hz, IH), 5.86 (dd, J=l l, 1 Hz, IH), 5.43 (br s, IH), 5.02 (m, IH), 4.80 (t, J=6 Hz, IH), 4.74 (br s, IH), 3.90-3.78
(m, 2H), 3.65 (s, 3H), 2.50-2.36 (m, IH), 2.23-2.10 (m, IH), 2.19 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); 13C NMR (125 MHz, DMSO-dft) 0145.9, 145.8, 144.9, 143.8, 142.8, 133.2, 132.8, 127.6, 126.4, 117.7, 116.2, 116.2, 114.2, 113.6, 112.6, 110.6, 72.1, 63.7, 59.4, 49.7, 35.4, 29.2, 28.9, 23.9; MS (DCI/NH3) m/e (M+H)+ 394.
Example 281 methyl 2- [2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H- [lJbenzopyrano[3,4-fj-5-quinolinyl1 acetate
The C-5 lactol-9-TBS ether of core 7 was processed as in example 46 to provide the intermediate silylated product. iH NMR (300 MHz, DMSO-d6)07.94 (d, J=9 Hz, IH), 6.64 (dd, J=9, 3 Hz, IH), 6.49
(d, J=9 Hz, IH), 6.27 (s, IH), 6.14 (dd, J=10, 3 Hz, IH), 4.45 (s, IH), 3.63 (s, 3H), 3.61 (s, 3H), 2.76-2.55 (m, 2H), 2.20 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H), 1.00 (s, 9H), 0.21 (s,
3H), 0.16 (s, 3H); MS (APCI) m/e (M+H)+ 510, (M-H)" 508.
The intermediate silylated compound above (0.030 g, 0.058) was dissolved THF
(1 ml) cooled to 0°C, and treated with tetrabutylammonium fluoride (58μL of a IM/THF solution, 0.058 mmol). After 5 minutes, the mixture was poured over saturated aqueous NH4CI and extracted with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). The product was purified by silica gel chromatography eluting with 40%> methyl t-butyl ether in hexane to provide the desired compound (0.019 g, 82%) as a white solid. iH NMR (300 MHz, DMSO-dfi) 08.80 (s, IH), 7.93 (d, J=9
Hz, IH), 6.64 (d, J=9 Hz, IH), 6.61 (d, J=9 Hz, IH), 6.43 (d, J=9 Hz, IH), 6.25 (s, IH), 6.10 (dd, J=10, 3 Hz, IH), 5.45 (s, IH), 3.66 (s, 3H), 3.60 (s, 3H), 2.77-2.52 (m, 2H),
2.21 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 396, (M-H)" 394.
Example 282 (Z) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-butenyl)-lH- [ 1 Jbenzopyrano[3 ,4-fjquinoline
The intermediate silylated product from example 281 (0.445 g, 0.87 mmol) was dissolved in THF (4 ml), cooled to 0° C, treated dropwise with Dibal-H (2.69 mL of a IM/THF solution, 2.69mmol), and stirred for 30 minutes. The reaction mixture was poured over a rapidly stirring mixture of 100 mL of saturated aqueous potassium sodium tartrate and 100 mL of ethyl acetate and stirred for 1 hour. The layers were separated, the aqueous layer extracted with ethyl acetate, the combined organic layers washed with saturated aqueous sodium bicarbonate, brine and dried (MgSO4). The residue was purified by silica gel chromatography eluting with 20% then 30% methyl t-butyl ether in hexane followed by 6%> ethyl acetate in dichloromethane to give the primary alcohol (0.293 g, 70%) as a white solid. iH NMR (300 MHz, DMSO-dft) 07.92 (d, J=9 Hz, IH),
6.65 (d, J=9 Hz, IH), 6.61 (d, J=9 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.21 (s, IH), 5.88 (dd, J=10, 3 Hz, IH), 5.43 (s, IH), 4.62 (t, J=5 Hz, IH), 3.61 (s, 3H), 2.19 (s, 3H), 1.90-1.75 (m, 2H), 1.62-1.47 (m, 2H), 1.17 (s, 3H), 1.15 (s, 3H), 0.99 (s, 9H), 0.20 (s, 3H), 0.15 (s, 3H); MS (APCI) m/e (M+H)+ 482, (M-H)" 480.
A stirring solution of oxalyl chloride (22 μL, 0.249 mmol) in THF (2 mL) was cooled to -78°C, treated with DMSO (24 μL, 0.332 mmol), stirred for 5 minutes and treated dropwise with a solution ofthe above primary alcohol (0.080 g, 0.166 mmol) in 2 mL of THF. The resulting mixture was stirred for 40 minutes, treated with triethylamine (92.5 μL, 0.664 mmol) stirred a further 10 minutes and allowed to warm to 0° C. After 30 minutes at 0°C the reaction mixture was partitioned between water and dichloromethane, the aqueous layer extracted with dichloromethane, and the combined organic layers dried (MgSO4). The product was purified by silica gel chromatography eluting with 20%) then 30% ethyl acetate in hexane to give the aldehyde (0.059 g, 73%) as a white solid. 1H NMR (300 MHz, DMSO-d6)09.65 (s, IH), 7.93 (d, J=9 Hz, IH),
6.67 (d, J=9 Hz, IH), 6.65 (d, J=9 Hz, IH), 6.48 (d, J=9 Hz, IH), 6.33 (m, 2H), 5.46 (s, IH), 3.63 (s, 3H), 2.87 (m, IH), 2.65 (m, IH), 2.18 (s, 3H), 1.19 (s, 3H), 1.14 (s, 3H), 1.00 (s, 9H), 0.21 (s, 3H), 0.15 (s, 3H); MS (APCI) m/e (M+H)+ 480, (M-H)" 478.
A solution of ethyltriphenylphosphonium bromide (0.130 g, 0.351 mmol) in THF:Et2θ (3 ml, 3:2) was cooled to 0°C and treated dropwise with n-BuLi (140 μL of a
2.5 M/hexanes, 0.351 mmol). The resulting deep red solution was stirred for 30 minutes at 0 C, cooled to -78°C and treated with the above aldehyde (0.056 g, 0.117 mmol) in THF (2 mL). The reaction mixture was stirred for 5 minutes at -78° C, warmed to 0 C for 40 minutes and quenched by the addition of water. The layers were separated, the aqueous layer extracted with dichoromethane, the combined organic layers washed with brine and dried (MgSO4). The product was purified by silica gel chromatography eluting with a gradient from 5% to 20%> ethyl acetate in hexane to provide the intermediate silyl ether (0.050 g, 87%) as a white solid. iH NMR (300 MHz, DMSO- d6)D7.92 (d, J=9 Hz, IH), 6.65 (d, J=9 Hz, IH,), 6.63 (d, J=9 Hz, IH), 6.20 (s, IH,),
5.68 (dd, J=10, 3 Hz, IH), 5.43 (m, 3H), 3.64 (s, 3H), 2.15 (s, 3H), 1.26 (d, J=5 Hz, 3H), 1.17 (s, 6H), 1.00 (s, 9H), 0.20 (s, 3H), 0.15 (s, 3H); MS (APCI) m/e (M+H)+ 492, (M- H)- 490. The intermediate silyl ether (0.038 g, 0.077 mmol) was dissolved in THF (3 ml), cooled to 0°C, treated with tetrabutylammonium fluoride (80 ml of a 1 M/THF solution,
0.080 mmol), and the mixture was partitioned between ethyl acetate and saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate, the combined organics were washed with brine, dried (MgSO4) and purified by silica gel chromatography eluting with 25 % ethyl acetate in hexanes to give the desired compound (0.024 g, 83%). iH NMR (300 MHz, DMSO-d6)D8.71 (s, IH), 7.93 (d, J=9
Hz, IH), 6.62 (d, J=9 Hz, IH), 6.60 (d, J=9 Hz, IH), 6.47 (d, J=9 Hz, IH), 6.18 (s, IH), 5.62 (dd, J=10, 3 Hz, IH), 5.43 (m, 3H), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.30 (d, J=5 Hz, 3H), 1.15 (s, 6H); MS (APCI) m/e calc'd for : 377.20. Found ; (M+H)+ 378, (M-H)" 376.
Example 283 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH-
[ 1 Ibenzopyrano [3,4-f] quinoline The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. iH MR (300 MHz, DMSO-d6)D8.65 (s, IH), 7.91 (d, J=9 Hz,
IH), 6.62 (d, J=9 Hz, IH), 6.60 (d, J=9 Hz, IH), 6.46 (d, J=9 Hz, IH), 6.14 (s, IH), 5.60 (dd, J=9, 3 Hz, IH), 5.43 (s, IH), 5.15 (m, IH), 3.64 (s, 3H), 2.45-2.18 (m, 2H), 2.15 (s, 3H), 1.63 (s, 3H), 1.32 (s, 3H), 1.17 (s, 3H), 1.16 (s, 3H); MS (APCI) m/e (M+H)+ 392, (M-H)" 390.
Example 284 (+) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexenyl)-lH-[11benzopyrano[3,4-fjquinoline
MS (DCI/NH3) m/z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6) 08.70 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d,
IH), 6.53 (d, IH), 6.27 (d, IH), 5.82-5.65 (m, 2H), 5.45 (s, IH), 5.33 (d, IH), 3.65 (s, 3H), 2.28 (m, IH), 2.12 (s, 3H), 1.86 (m, 2H), 1.55 (m, IH), 1.31 (s, 3H), 1.26-1.14 (m,
3H), 1.03 (s, 3H);
13C NMR (400 MHz, DMSO-d6)0145.4, 145.0, 144.1, 143.5, 133.6, 130.7, 128.1,
127.9, 127.7, 126.1, 118.4, 117.8, 116.5, 114.4, 113.4, 112.1, 75.9, 59.3, 49.4, 37.2, 29.6, 27.1, 24.7, 24.6, 23.7, 21.2; [Dj23D=+184° (c 0.33, CHCI3).
Example 285 (+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6) D8.70 (s, IH), 7.99 (d, IH), 6.65 (d, IH), 6.62 (d,
IH), 6.52 (d, IH), 6.20 (d, IH), 5.61 (ddd, IH), 5.46 (d, IH), 5.41 (s, IH), 5.10 (dd, IH), 3.66 (s, 3H), 2.27 (m, IH), 2.10 (s, 3H), 1.99-1.72 (m, 2H), 1.70-1.55 (m, 3H), 1.35 (m, IH), 1.29 (s, 3H), 1.06 (s, 3H); 13C NMR (400 MHz, DMSO-d6)P 145.4, 145.0, 143.4, 143.0, 133.5, 131.0, 128.9, 128.1, 126.4, 126.3, 117.9, 116.5, 114.4, 113.5, 112.1, 75.2, 59.3, 49.5, 36.9, 29.7, 27.6,
25.5, 24.6, 24.3, 20.0; [OJ23D=+170° (c 0.23, CHCI3). Example 286 (+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5- (3 -cyclopenteny 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6) P8.67 (s, IH), 8.02 (d, IH), 6.65 (d, IH), 6.62 (d,
IH), 6.53 (d, IH), 6.25 (s, IH), 5.77 (ddd, IH), 5.69 (ddd, IH), 5.47 (s, IH), 5.37 (s, IH), 3.66 (s, 3H), 2.90 (m, IH), 2.34-2.13 (m, 2H), 2.10 (s, 3H), 1.55-1.41 (m, 2H), 1.31 (s, 3H), 1.04 (s, 3H); 13C NMR (400 MHz, DMSO-d6)0145.5, 144.9, 144.0, 143.9, 133.6, 132.0, 131.7, 131.5, 127.9, 126.2, 117.7, 117.6, 116.5, 114.4, 113.3, 111.9, 76.1, 59.3, 49.4, 48.6, 31.7,
29.5, 27.1, 24.6, 23.7; [Oj23D=+136° (c 0.355, CHCI3).
Example 287 (+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5- (3 -cyclopenteny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6) 08.68 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d, IH), 6.51 (d, IH), 6.22 (s, IH), 5.72 (dd, IH), 5.41 (d, IH), 5.40 (s, IH), 5.17 (dd, IH), 3.63 (s, 3H), 2.90-2.80 (m, IH), 2.41-2.32 (m, IH), 2.23-2.10 (m, IH), 2.06 (s, 3H), 1.89-1.71 (m, 2H), 1.30 (s, 3H), 1.08 (s, 3H);
13C NMR (400 MHz, DMSO-d6)P 145.5, 145.0, 143.9, 143.4, 133.5, 132.3, 132.2,
130.2, 128.1, 126.4, 117.8, 116.9, 116.4, 114.4, 113.4, 111.9, 75.7, 59.3, 49.5, 48.7, 31.6, 29.8, 27.6, 27.1, 24.2;
[Dj23D=+H6° (c 0.800, CHCI3).
Example 288 rel-(5S)-9-hydroxy-5-r(3R)-(l -methoxycarbonyl)cyclohexen-3-ylj- 10- methoxy-2,2 ,4-trimethyl-2 ,5 -dihydro- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) 462 (M+H)+;
IH NMR (200 MHz, DMSO-d6), 08.81 (s, 1 H), 8.07 (d, J=8.5 Hz, 1 H), 6.72 (d, J=8.5 Hz, 1 H), 6.70 (d, J=8.5 Hz, 1 H), 6.60 (d, J=8.5 Hz, 1 H), 6.42-6.41 (m, 1 H), 6.21 (d,
J=1.2 Hz), 5.57 (d, J=10.2 Hz, 1 H), 1 H), 5.45 (s, 1 H), 2.71 (s, 2 H), 2.58 (s, 2 H), 2.56- 2.48 (m, 2 H), 2.20-2.16 (m, 2 H), 2.08 (d, J=1.2 Hz), 1.80-1.40 (m, 4 H), 1.25 (s, 2 H), 1.18 (s, 2 H); HRMS calcd for C28H2INO5 is 461.2202. Found 461.2212. Example 289 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methyl-3- propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline
Example 276 (0.040 g, 0.092 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.006 g, 0.009 mmol) were dissolved in dioxane (5 ml), heated to 100 °C and treated with sodium borohydride ( 0.017 g, 0.460 mmol). The resulting black solution was allowed to cool to room temperature, diluted with water and ethyl acetate and filtered through celite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organics were washed with brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography eluting with 25% ethyl acetate in hexanes provided the desired product (0.028 g, 80%) as a colorless foam. iH NMR (300 MHz, DMSO-d6)08.71 (s, IH), 7.92 (d, J=8 Hz, IH), 6.62 (d, J=8 Hz,
IH), 6.61 (d, J=8 Hz, IH), 6.41 (d, J=8 Hz, IH), 6.18 (d, J=l Hz, IH), 5.83 (dd, J=3, 10 Hz, IH), 5.44 (br s, IH), 4.75 (br s, IH), 4.56 (br s, IH), 3.65 (s, 3H), 2.50-2.41 (m, IH),
2.19 (s, 3H), 2.16-2.07 (m, IH), 1.73 (s, 3H), 1.18 (s, 3H), 1.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6)D 145.8, 144.9, 143.8, 142.8, 141.6, 133.3, 132.7, 127.5, 126.4, 117.8,
116.3, 116.2, 114.2, 113.6, 112.8, 112.7, 72.0, 59.4, 49.7, 29.2, 28.8, 24.0, 22.4; MS (DCI/NH3) m/e (M+H)+ 378; Anal, calcd for C24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found: C, 76.06; H, 7.17; N, 3.39.
Example 290 9, 10-Dimethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fjquinoline MS (ESI) m/z 378 (M+H)+; lR NMR (300 MHz, DMSO)D7.93 (d, J=8.5 Hz, 1 H), 6.82 (d, J=8.8 Hz, 1 H), 6.61
(dd, J=4.4, 4.4 Hz, 2 H), 6.22 (d, J=1.4 Hz, 1 H), 5.83 (ddt, J=16.9, 10.3, 3.1 Hz, 1 H), 5.70 (dd, J=10.3, 3.3 Hz, 1 H), 5.44 (s, 1 H), 5.44-4.96 (m, 2 H), 3.77 (s, 3 H), 3.67 (s, 3 H), 2.16 (s, 3 H), 1.17 (s, 3 H), 1.16 (s, 3 H); HRMS calcd for C24H27NO3 377.1991. Found 377.2001.
Example 291 9,10-Dimethoxy-5-[3-cyclohexenylj-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline MS (ESI) m/z 418 (M+H)+;
!H NMR (300 MHz, DMSO), isomer 1 :D8.02 (d, J=8.8 Hz, 1 H), 6.84 (d, J=1.7 Hz, 1 H), 6.70 -6.60 (m, 2 H), 6.27 (d, J=0.6 Hz, 1 H), 5.80 -5.60 (m, 2 H), 5.16-5.15 (m, 1 H),
3.77 (s, 3 H), 3.69 (s, 3 H), 2.13 (s, 3 H), 1.31 (s, 3 H), 1.07 (s, 3 H); isomer 2:08.01 (d, J=8.81 Hz, 1 H), 6.80 (d, J=0.7 Hz, 1 H), 6.64 (m, 2 H), 6.26 (d, J=0.7 Hz, 1 H), 5.60 - 5.30 (m, 2 H), 5.09 (s, 1 H), 3.77 (s, 3 H), 3.68 (s, 3 H), 2.10 (s, 3 H), 1.29 (s, 3 H), 1.04
(s, 3 H);
HRMS calcd for C27H31NO3 417.2304. Found 417.2299.
Example 292 10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline iH NMR (300 MHz, DMSO)07.94 (d, J=8.8 Hz, 1 H), 6.79 (d, J=8.8 Hz, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.55 (d, J=8.8, 1 H), 6.45 (s, 1 H), 5.85 (ddt, J=17.3, 10.3, 6.6 Hz, 1 H), 5.43 (d, J=9.2 Hz), 5.16 (s, 1 H), 5.09 (dd, J=10.3, 1.1 Hz, 1 H), 5.06 (dd, J=17.3, 1.1 Hz, 1 H), 4.91 (s, 1 H), 4.06-3.97 (m, 2 H), 2.62-2.52 (m, 1 H), 2.31-2.15 (m, 1 H), 2.24
(s, 3 H), 1.35 (t, J=7.0 Hz, 3 H), 1.26 (s, 3 H), 1.07 (s, 3 H);
MS (DCI/NH3) m/z 392 (M+H)+;
HRMS calcd for C26H27NO3 391.2147. Found 391.2138.
Example 293 10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 404 (M+H)+. iH NMR (300 MHz, DMSO)D7.93 (d, J=9.0 Hz, 1 H), 6.83 (d, J=8.8 Hz, 1 H), 6.61 (d,
J=9.0 Hz, 1 H), 6.59 (d, J=8.8 Hz, 1 H), 6.23 (d, J=1.5 Hz, 1 H), 6.15-6.02 (m, 1 H), 5.81 (ddt, J=17.3, 10.3, 6.6 Hz, 1 H), 5.67 (dd, J=9.8, 3.3 Hz), 5.45 (s, 1 H), 5.44 (dd,
J=16.0, 2.0 Hz, 1 H), 5.27 (dd, 10.6, 2.0 Hz, 1 H), 5.03 (dd, J=10.3, 1.8 Hz, 1 H), 4.98
(dd, J=17.3, 1.8 Hz, 1 H), 4.56-4.53 (m, 1 H), 2.47-2.41 (m, 1 H), 2.34-2.27 (m, 1 H),
2.16 (s, 3 H), 1.17 (s, 3 H), 1.16 (s, 3 H);
HRMS calcd for C26H29NO3 403.2147. Found 403.2150.
Example 294 10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 402 (M+H)+; iH NMR (300 MHz, DMSO)D7.92 (d, J=8.8 Hz, 1 H), 6.88 (d, J=8.8 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.61 (d, J=8.8, 1 H), 6.24 (d, J=1.7 Hz, 1 H), 5.81 (ddt, J=17.3, 10.3, 6.6
Hz, 1 H), 5.72 (dd, J=9.8, 3.3 Hz), 5.44 (s, 1 H), 5.03 (dd, J=10.3, 1.8 Hz, 1 H), 4.99 (dd,
J=17.3, 1.8 Hz, 1 H), 4.79 (d, J=2.3 Hz, 2 H), 3.57 (t, J=2.3 Hz, 1 H), 2.47-2.41 (m, 1
H), 2.34-2.27 (m, 1 H), 2.16 (s, 3 H), 1.17 (s, 3 H), 1.16 (s, 3 H);
HRMS calcd for C26H27NO3 401.1991. Found 401.1978
Example 295 2,5-dihydro-9-acetoxy-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline iH NMR (400 MHz, DMSO-d6)D7.78 (d, J=8.5, IH), 6.81 (d, J=8.5, IH), 6.60 (d, J=8.5, IH), 6.57 (d, J=8.9, IH), 6.18 (d, J=1.7, IH), 5.80-5.70 (m, 2H), 5.39 (s, IH), 4.99-4.90 (m, 2H), 3.55 (s, 3H), 2.39 (br dd, 2H), 2.23 (s, 3H), 2.10 (d, J=0.9, 3H), 1.11 (s, 3H), 1.10 (s, 3H); ! C NMR (100 MHz, DMSO-d6)D 169.3, 148.5, 148.0, 146.4, 138.6, 134.1, 133.7, 132.2, 127.4, 126.3, 120.8, 118.3, 117.4, 116.3, 115.1, 113.9, 112.7,
73.7, 60.0, 49.9, 36.7, 29.4, 29.1, 23.9, 20.6; MS (DCI NH3) m/e 406(M+H)+; Anal. Calcd for C25H27NO4: C 74.05, H 6.71, N 3.45. Found: C 73.91, H 6.79, N 3.31.
Example 296 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(2-propenyl)-lH-[ljbenzopyrano[3 ,4-fjquinoline
IH NMR (300 MHz, DMSO-d6)D7.86 (d, J=8.8, IH), 6.85 (d, J=8.8, IH), 6.68- 6.62 (m, 2H), 6.25 (d, J=1.5, IH), 5.89-5.75 (m, 2H), 5.46 (s, IH), 5.06-4.96 (m, 2H), 3.62 (s, 3H), 3.00 (s, 3H), 2.85 (s, 3H), 2.83-2.67 (m, 4H), 2.48 (m, IH), 2.26 (m, IH), 2.17 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H); 13C NMR (75 MHz, DMSO-d6) 0171.5, 170.4, 148.3, 148.0, 146.2, 138.5, 134.1, 133.5, 132.1, 127.3, 126.2, 120.8, 118.1, 117.2, 116.2,
115.0, 113.8, 112.5, 73.6, 60.0, 49.8, 36.6, 36.5, 34.9, 29.3, 29.0, 27.6, 23.8; MS (DCI/NH3) m/e 491(M+H)+, 508(M+NH4)+; Anal. Calcd for C29H24N2O5: C 71.00,
H 6.99, N 5.71. Found: C 70.88, H 7.10, N 5.49.
The chemistry described above was used with Core 9 to prepare Examples 297-299.
Example 297 7-bromo -5-[3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5-dihydro- lH-[lJbenzopyranor3 ,4-fjquinoline MS (APCI) m/z A66 (M+H)+; *H NMR (300 MHz, DMSO), isomer 1 : 08.03 (d, J=8.8 Hz, 1 H), 7.33 (d, J=9.2 Hz, 1
H), 6.65 (dd, J=8.8, 1.7 Hz, 2 H), 6.35 (d, J=1.3 Hz, 1 H), 5.91-5.43 (m, 4 H), 3.86 (s, 3 H), 2.14 (s, 3 H), 1.99 (s, 3 H), 1.31 (s, 3 H), 1.06 (s, 3 H); isomer 2: 08.00 (dd, J=8.8 Hz, 1 H), 7.33 (d, J=9.2 Hz, 1 H), 6.65 (dd, J=8.8, 1.7 Hz, 1 H), 6.35 (d, J=1.3 Hz, 1 H), 6.31 (d, J=1.3 Hz, 1 H), 5.91-5.43 (m, 4 H), 2.12 (s, 3 H), 1.28 (s, 3 H), 1.03 (s, 3 H); 13C NMR (300 MHz, DMSQ)P 155.5, 145.5, 133.9, 133.7, 129.5, 129.4, 128.5, 127.9,
127.7, 127.2, 127.0, 125.6, 118.1, 115.5, 113.2, 113.1, 106.9, 102.3, 77.2, 76.5, 55.8, 49.4, 37.6, 36.7, 29.6, 29.5, 27.4, 26.9, 25.6, 24.6, 24.2, 23.6, 21.1, 19.8; HRMS cald for C26H28NO2?9Br 465.1303. Found 465.1284; Cald for
C26H28NO281Br 467.1283. Found 467.1281. Anal, calcd for C26H28BrNO2: C, 66.95; H, 6.05; N, 3.00; found C, 66.77; H,
6.20; N, 2.88. Example 298 10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-f] quinoline
MS (APCI) m/z 426 (M+H)+; h Η NMR (300 MHz, DMSQ)D7.93 (d, J=8.8 Hz, 1 H), 7.33 (d, J=9.2 Hz, 1 H), 6.71 (d, J=9.2 Hz, 1 H), 6.60 (d, J=8.5 Hz, 1 H), 6.25 (d, J=1.5 Hz, 1 H), 5.94-5.80 (m, 2 H),
5.45 (s, 1 H), 5.0 (m, 2 H), 3.86 (s, 3 H), 2.17 (d, J=1.5 Hz, 3 H), 1.17 (s, 6 H). 13C NMR (300 MHz, DMSO) 155.3, 147.0, 146.0, 133.8, 133.6, 131.8, 129.5, 127.3, 127.2, 117.4, 116.0, 115.1, 113.2, 107.1, 102.6, 74.8, 55.9, 49.8, 29.0, 23.8. HRMS calcd for C23H24?9BrNO2 426,3502. Found 426.3496.
Anal, calcd for C23H24BrNO2: C, 64.79; H, 5.67; N, 3.29; found C, 65.08; H, • 5.73; N, 3.18.
Example 299 7-bromo-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5- dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (APCI) m/z 480 (M+H)+;
*HNMR (300 MHz, DMSO) isomer 1:D8.02 (d, J=8.5 Hz, 1 H), 7.55 (d, J=5.9 Hz, 1 H), 7.37 (d, J=2.6 Hz, 1 H), 7.31 (d, J=1.8 Hz, 1 H), 6.67 (dd, J=14.7, 8.8 Hz, 1 H), 6.35 (d, J=1.5 Hz, 1 H), 5.63 (d, J=5.9 Hz, 1 H), 5.56-5.45 (m, 2 H), 3.86 (s, 3 H), 2.13 (s, 3 H), 1.61 (s, 3 H), 1.30 (s, 3 H), 1.02 (s, 3 H); isomer 2:08.00 (d, J=8.5 Hz, 1 H), 7.54
(d, J=5.9 Hz, 1 H), 7.35 (d, J=1.8 Hz, 2 H), 6.67 (dd, J=14.7, 8.8 Hz, 2 H), 6.31 (d, .7=1.5 Hz, 1 H), 5.51 (m, 2 3.86 (s, 3 H), 2.08 (s, 3 H), 1.50 (s, 3 H), 1.09 (s, 3 H), 0.92 (s, 3 H); HRMS calcd for C27H3θNθ2?9Br 479.1460. Found 479.1463; HRMS calcd for C27H30NO281Br 481.1439. Found 481.1456.
Anal, calcd for C27H3θNθ2?9Br: C, 67.5; H, 6.29; N, 2.92; found C, 67.08; H, 6.38; N,
2.54.
The chemistry described above was used with Core 10 to prepare Example 300.
Example 300 10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ljbenzopyrano[3,4-f]quinoline MS (DCI/NH3) m/z 428 (M+H)+; 426;
!H NMR (300 MHz, DMSO)D7.93 (d, J=8.8 Hz, 1 H), 7.33 (d, J=8.5 Hz, 1 H), 6.67 (d, J=8.5 Hz, 1 H), 6.65 (d, J=8.5 Hz, 1 H), 6.36 (d, .7=1.1 Hz, 1 H), 5.88-5.74 (m, 2 H),
5.46 (s, 1 H), 5.05-4.95 (m, 2 H), 3.62 (s, 3 H), 2.18 (d, .7=1.1 Hz, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H); 13C NMR (300 MHz, DMSO)0152.7, 150.8, 146.5, 134.0, 133.6, 132.1, 130.0, 127.3, 126.1, 119.3, 117.4, 116.2, 115.0, 114.6, 114.0, 109.5, 73.7, 59.6, 49.9,
36.7, 29.4, 29.1, 23.9;
HRMS calcd for C23H24NO2?9Br 425.0990. Found 425.0998; HRMS calcd for
C23H24NO281Br 427.0970. Found 427.0974.
Anal, calcd for C23H24BrNθ2: C, 64.79; H, 5.67; N, 3.29; found C, 64.99; H, 5.98; N,
3.13.
The chemistry detailed above was used with Core 11 to prepare Examples 301-303.
Example 301 7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [ljbenzopyrano[3,4-f]quinoline
MS (ESI) m/z 504 (M+H)+;
*H NMR (300 MHz, DMSO)D7.57 (d, J=8.9 Hz, 1 H), 7.65 (s, 1 H), 6.66 (d, J=8.8 Hz,
1 H), 6.44 (s, 1 H), 5.95 (dd, J=10.1, 3.1 Hz, 1 H), 5.97-5.78 (m, 2 H), 5.47 (s, 1 H), 5.08-4.99 (m, 2 H), 3.62 (s, 3 H), 2.19 (s, 3 H), 1.20 (s, 3 H), 1.17 (s, 3 H); 13C NMR
(300 MHz, DMSO) D l 52.1, 147.4, 147.0, 133.6, 132.7, 132.0, 131.7, 128.3, 127.1,
126.3, 120.5, 117.6, 115.9, 115.3, 114.0, 113.8, 110.0, 106.6, 75.2, 59.7, 49.9, 36.8, 29.6,
29.2, 23.7;
HRMS calcd for C23H2379Br2NO2 503.0096. Found 503.0086; HRMS calcd for C23H2379Br81BrNθ2 505.0075. Found 505.0075.
Example 302 7,9-Dibromo-5-rcyclohexen-3-yU- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (ESI) m/z 544 (M+H)+; IH NMR (300 Mhz, DMSO), 1st isomer: 08.81 (d, IH, J=8.83 Hz), 7.67 (s, IH), 6.70 (d,
IH, J=8.83 Hz), 6.59 (s, IH), 5.82-5.59 (m, 4H), 5.50 (s, IH), 3.61 (s, 3H), 2.49-2.27 (m, 2H), 2.15 (s, 3H), 2.04-1.81 (m, 2H), 1.79-1.41 (m, 2H), 1.32 (s, 3H), 1.08 (s, 3H); 2nd isomer 07.9 (d, IH, J=8.83 Hz), 7.66 (s, IH), 6.69 (d, IH, J=8.83 Hz), 6.54 (s, IH), 5.82-5.59 (m, 4H), 5.45 (s, IH), 3.60 (s, 3H), 2.49-2.27 (m, 2H), 2.13 (s, 3H), 2.04-1.81 (m, 2H), 1.79-1.41 (m, 2H), 1.30 (s, 3H), 1.05 (s, 3H);
HRMS calcd for C26H2779Br2NO2 is 543.0409. Found 543.0385; HRMS calcd for C26H2779Br81BrN02 545.0388. Found 545.0396.
Example 303 7,9-Dibromo-5-[l-methyl-3-cyclohexenylj-10-methoxy-2,2,4-trimethyl- 2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline
MS (ESI) m/z 560 (M+H)+; IH NMR (300 MHz, DMSO), isomer 1:D8.83 (d, J=8.0 Hz, 1 H), 7.37 (s, 1 H), 6.70 (d, J=8.8 Hz, 1 H), 6.58 (s, 1 H), 5.58 (d, .7=9.2 Hz, 1 H), 5.49 (s, 1 H), 3.61 (s, 3 H), 2.51- 2.49 (m, 4 H), 2.14 (s, 3 H), 1.31 (s, 3 H), 1.29-1.20 (m, 4 H), 1.26 (s, 3 H); isomer 2:07.99 (d, J=8.0 Hz, 1 H), 7.37 (s, 1 H), 6.71 (d, J=8.8 Hz, 1 H), 6.55 (s, 1 H), 5.57 (d, J=9.2 Hz, 1 H), 5.45 (s, 1 H), 3.59 (s, 3 H), 2.51-2.49 (m, 4 H), 2.09 (s, 3 H), 1.30 (s, 3
H), 1.29-1.20 (m, 4 H), 1.21 (s, 3 H); HRMS calcd for C27H29Br2NO2 557.0565. Found 557.0548.
The chemistry described above was used with Cores 12-17 to prepare Examples 304-310.
Example 304 10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [11benzopyrano[3,4-f]quinoline MS (ESI) m/z 373 (M+H)+; H NMR (300 MHz, DMSO) 07.82 (d,J=8.9 Hz, 1 H), 7.23 (d, J=8.9 Hz, 1 H), 6.78 (dd, .7=11.0, 6.8 Hz, 1 H), 6.61 (d, J=8.9 Hz, 1 H), 6.49 (d, J=8.5 Hz, 1 H), 5.99 (d, .7=1.7 Hz, 1 H), 5.74 (dd, .7=7.6, 3.0 Hz, 1 H), 5.71-5.63 (m, 1 H), 5.57 (dd, .7=7.6, 1.7 Hz, 1 H), 5.32 (s, 1 H), 5.00 (dd, .7=9.3, 1.7 Hz, 1 H), 4.92 (dd, .7=10.2, 1.7 Hz, 1 H), 4.83 (dd, .7=16.9, 1.7 Hz, 1 H), 3.75 (s, 3 H), 2.06 (s, 3 H), 1.53-1.41 (m, 2 H), 1.24-1.15 (m, 3 H),
1.05 (d, J=2.1 Hz, 1 H); 13C NMR (300 MHz, DMSO)D 155.66, 147.91, 145.55, 134.17, 133.45, 131.98, 130.77, 127.37, 127.28, 123.88, 119.52, 117.21, 115.99, 115.80, 113.20, 113.18, 112.12, 105.59, 74.01, 55.59, 49.69, 36.40, 29.03, 28.83, 27.67, 26.19, 23.83, 13.55; HRMS calcd for C25H27NO2 373.2042. Found 373.2048.
Example 305 10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline MS (ESI) m/z 362 (M+H)+; ]H NMR (300 MHz, DMSO)D7.92 (d, J=8.5 Hz, 1 H), 6.93 (d, J=8.5 Hz, 1 H), 6.59
(dd, .7=5.5, 2.6 Hz, 1 H), 6.10 (s, 1 H), 5.90-5.76 (m, 2 H), 5.44 (s, 1 H), 5.07-4.90 (m, 2 H), 3.82 (s, 3 H), 2.17 (s, 3 H), 2.08 (s, 3 H), 1.99 (s, 3 H), 1.16 (s, 3 H), 1.15 (s, 3H); 13C NMR (300 MHz, DMSO), 154.2, 148.5, 145.4, 134.5, 133.4, 131.9, 127.8, 127.4, 127.1, 118.2, 117.0, 116.3, 116.0, 113.1, 112.9, 104.8, 73.6, 55.5, 49.6, 36.5, 28.9, 28.8, 23.8, 15.0;
HRMS calcd for C24H27NO2 361.2042. Found 361.2045. Example 306 10-methoxy-7-acetyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[11benzopyrano[3,4-f|quinoline MS (ESI) m/z 390 (M+H)+. H NMR (300 MHz, DMSO), 7.88 (d, J=8.8 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 6.84 (d,
J=8.8 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.22 (d, .7=1.5 Hz, 1 H), 6.01-5.97 (m, 1 H), 5.90-5.69 (m, 1 H), 5.46 (s, 1 H), 5.03-4.83 (m, 2 H), 3.93 (s, 3 H), 2.53 (s, 3 H), 2.20 (d, .7=1.5 Hz, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H).
Example 307 (+/-) 2,5-dihydro-9-methyl- 10-methoxy-2,2,4-trimethyl-5-(l - methylcy clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 416 (M+H)+.
Example 308 10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 376 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, J=8.5 Hz, 1 H), 6.81 (s, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.17 (d , .7=1.5 Hz, 1 H), 5.89-5.76 (m, 2 H), 5.44 (br s, 1 H), 5.04 (dd, .7=10.3, 1.8 Hz, 1 H), 4.94 (dd, .7=17.3, 1.8 Hz, 1 H), 3.52 (s, 3 H), 2.46-2.40 (m, 1 H), 2.28-2.24 (m, 1 H), 2.18 (s, 3 H), 2.17 (s, 3 H), 2.07 (s, 3 H), 1.19 (s, 3 H), 1.14 (s, 3 H);
HRMS calcd for C25H29NO2 375.2198. Found: 375.2214.
Example 309 10-chloro-5-(3 -propenyl)-2,2,4-trimethyl-2,5-dihydro- 1 H- T 1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 352 (M+H)+;
*H NMR (300 MHz, DMSO)07.93 (d, J=8 Hz, 1 H), 7.12-7.10 (m, 2 H), 6.90-6.84 (m, 1 H), 6.65 (10, 2 Hz, 1 H), 4.97 (dd, .7=17, 2 Hz, 1 H), 2.47-2.26 (m, 2 H), 2.16 (s, 3 H), 1.23 (s, 3 H), 1.17 (s, 3 H); HRMS (FAB) calcd m/z for C22H22CINO: 351.1390 (M)+. Found: 351.1385.
Example 310 (+/-) 2,5-dihydro-10-chloro-2,2,4-trimethyl-5-phenyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m/z 288 (M+H)+;
IH NMR (200 MHz, DMSO)07.98 (d, J=8 Hz, 1 H), 7.27-7.14 (m, 5 H), 6.97-6.80 (m, 2 H), 6.81 (br s, 1 H), 6.78-6.72 (m, 2 H), 6.44 (br s, 1 H), 5.40 (br s, 1 H), 1.81 (br s, 2
H), 1.26 (s, 2 H), 1.16 (s, 2 H);
HRMS (FAB) calcd m/z for C25H23CINO: 387.1390 (M)+. Found: 287.1286. Example 311 2,5-dihydro-10-methoxy-5-(3-(N-methyl-N- (carbomethoxymethyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3 ,4-fj quinoline
Example 13 and N-methyl-N-(methylglycinate)carbamoyl chloride were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/e 529 (M+H)+ iH NMR (300 MHz, DMSO-d6)O8.00(d, IH), 7.21(m, IH), 7.03(d, IH), 6.92(m, 3H), 6.72(m, 3H), 6.55(d, IH), 6.45(t, IH), 5.40(s, IH), 4.15(s, IH), 4.05(s, IH), 3.78(s, 3H),
3.65(s, 3H), 3.00(s, IH), 2.88(s, 2H), 1.84(s, 3H), 1.22(s, 3H), 1.13(s, 3H). Anal, calcd for C31H32N2O6: C, 70.43; H, 6.10; N, 5.29. Found: C, 70.98; H, 6.33; N,
4.85
Example 312
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methylcarbonyl)aminocarbonyloxy)phenyl)-2,2 ,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline Example 13 and methylisocyanate were processed as in Example 14 to provide the desired compound.
MS (DCI/NH3) m/e 514 (M+H)+ iH NMR (300 MHz, DMSO-d6)08.18(q, IH), 8.01(d, IH), 7.27(t, IH), 7.06(t, 2H), 6.98(s, IH), 6.91(t, IH), 6.77(s, IH), 6.70(d, IH), 6.56(d, IH), 6.46(d, IH), 6.19(s, IH), 5.38(s, IH), 3.78(s, 3H), 3.19(s, 3H), 2.70(d, 3H), 1.84(s, 3H), 1.22(s, 3H), 1.14(s, 3H). Anal, calcd for C3θH3iN3θ5-2H2θ: C, 65.55; H, 6.41; N, 7.60. Found: C, 65.71; H,
6.20; N, 7.05
Example 313
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline
Example 13 and methylisocyanate were processed as in Example 14 to provide the desired compound.
MS (DCI/NH3) m/e 457 (M+H)+ lH NMR (300 MHz, DMSO-d6)D8.01(d, IH), 7.50(q, IH), 7.21(t, IH), 7.02(d, IH), 6.92(dd, 2H), 6.80(s, IH), 6.77(s, IH), 6.70(dd, IH), 6.56(d, IH), 6.46(d, IH), 6.18(s,
IH), 5.40(s, IH), 3.80(s, 3H), 2.60(d, 3H), 1.86(s, 3H), 1.23(s, 3H), 1.15(s, 3H)
Anal, calcd for C28H28 2O4-0.50H2O: C, 72.33; H, 6.27; N, 6.01. Found: C, 72.20; H,
6.38; N, 5.78 Example 314 2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline A solution of 3-(2'-methoxymethoxy)ethylphenyl bromide (3.55 g, 14.5 mmol) in
THF (150 ml) at -78 °C was treated with n-butyllithium (2.5 M in hexane, 5.80 ml) over 15 minutes, warmed to -30 °C, cooled down to -78 °C, treated with compound IF in one portion, warmed to -50 °C, quenched with saturated ammonium chloride, and allowed to warm to ambient temperature and settle. The supernatant was decanted and concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed sequentially with water and brine, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 20-35% ethyl acetate/hexane provided 0.82 g (56%) ofthe title 5-(3'-MOMO-phenyl)hemiketal. MS (DCI/NH3) m/e 489 (M+H)+ A solution of ofthe hemiketal prepared above (0.70 g, 1.43 mmol) in methanol
(10 ml) was treated with saturated hydrogen chloride in methanol (20 ml) at ambient temperature, stirred for 18 hours, poured into 1 : 1 ethyl acetate/saturated ammonium chloride. The separated aqueous layer was extracted with ethyl acetate, and the combined acetate layers were sequentially washed with water and brine, dried (Na2SO4) and concentrated to provide 0.52 g (82%o) ofthe unmasked hemiketal.
MS (DCI/NH3) m/e 444 (M+H)+.
A solution ofthe unmasked hemiketal prepared above (0.45 g, 1.00 mmol) and triefhylsilane (1.16 g, 10 mmol) in dichloromethane (20 mL) was treated with boron trifluoride etherate (1.42 g, 10 mmol) at ambient temperature, stirred for 18 hours, and poured into 1:1 ethyl acetate/saturated NaHCO3. The separated aqueous layer was extracted with ethyl acetate, and the combined extracts were washed sequentially with water and brine, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 25-45%) ethyl acetate in hexane provided 0.342 ofthe title compound. MS (DCI/NH3) m/e 428 (M+H)+; iH NMR (300 MHz, DMSO-d6)O8.00(d, IH), 7.00(m, 5H), 6.74(s, IH), 6.70(d, IH),
6.55(d, IH), 6.45(d, IH), 6.16(s, IH), 5.39(s, IH), 4.54(t, IH), 3.79(s, 3H), 3.44(q, 4H), 2.59(t, 2H), 1.86(s, 3H), 1.22(s, 3H), 1.1 l(s, 3H); Anal, calcd for C28H29NO3: C, 78.66; H,6.83; N, 3.27. Found: C, 78.48; H, 6.85; N,
3.29. Example 315 2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4-trimethyl-lH-
[11benzopyrano[3,4-fjquinoline A solution of Example 314 (200 mg, 0.47 mmole) and triethylamine (94 mg, 0.94 mmol) in CH2CI2 (6 ml) at 0 °C was treated with methanesulfonyl chloride (64 mg, 0.56 mmol), stirred for 30 minutes, and quenched with saturated NaHCO3. The separated aqueous layer was extracted with CH2CI2 , and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 10-30% ethyl acetate/hexane provided 0.30 g (97%) ofthe title compound.
MS (DCI/NH3) m/e 506 (M+H)+; lH NMR (300 MHz, DMSO-d6)D8.00(d, lH), 7.18(s, lH), 7.14(d, IH), 7.09(d, IH), 6.96(d, IH), 6.90(t, IH), 6.75(s, IH), 6.70(d, IH), 6.55(d, IH), 6.45(d, IH), 6.21(s, IH), 5.39(s, IH), 4.27(t, 2H), 3.79(s, 3H), 2.88(s, 3H), 2.87(t, 2H), 1.84(s, 3H), 1.24(s, 3H), 1.14(s, 3H)
Anal, calcd for C29H31NO5S: C, 68.88; H,6.17; N, 2.77. Found: C, 69.08; H, 6.14; N,
2.63.
Example 316 2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH- ■
[ 1 Jbenzopyrano [3,4-f] quinoline A solution of Example 315 (10 mg, 0.02 mmol) in DMF (1 ml) was treated with NaSMe (14 mg, 0.20 mmol) at ambient temperature, stirred for 2 hr, quenched with saturated NaHCO3, and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 10-30%) ethyl acetate/hexane provided 9 mg (99%>) ofthe title compound. MS (DCI/NH3) m/e 458 (M+H)+
1H NMR (300 MHz, DMSO-d6)O8.00(d, IH), 7.1 l(t, IH), 7.07(s, IH), 7.02(d, IH), 6.96(d, IH), 6.90(t, IH), 6.75(s, IH), 6.70(d, IH), 6.54(d, IH), 6.44(d, 1H0, 6.16(s, IH), 5.39(s, IH), 3.77(s, 3H), 2.70(t, 2H), 2.54(t, 2H), 1.91(s, 3H), 1.95(s, 3H), 1.21(s, 3H),
1.15(s, 3H)
Example 317 2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylaminocarbonyloxy)ethyl)phenyl)-2,2,4- trimethyl-lH-[ljbenzopyrano[3,4-f]quinoline
Example 314 and N,N-dimethylcarbamoyl chloride were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/e 499 (M+H)+ iH NMR (300 MHz, DMSO-d6)O8.01(d, IH), 7.00(m, 5H), 6.76(s, IH), 6.70(d, IH), 6.55(s, IH), 6.44(d, IH), 6.15(s, IH), 5.39(s, IH), 4.01(t, 2H), 3.78(s, 3H), 2.79(t, 2H), 2.77(s, 3H), 2.65(s, 3H), 1.84(s, s, 3H), 1.23(s, 3H), 1.15(s, 3H) Anal, calcd for C31H34N2O4: C, 74.67; H, 6.87; N, 5.61. Found: C, 74.45; H, 6.73; N, 5.45.
Example 318 2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-f] quinoline Example 315 and dimethylamine were processed as in Example 316 to provide the desired compound. MS (DCI/NH3) m/e 455 (M+H)+ iH NMR (300 MHz, DMSO-d6)O8.00(d, IH), 7.09(t, IH), 7.01(d, IH), 6.97(m, 2H), 6.90(t, IH), 6.73(s, IH), 6.69(d, IH), 6.55(d, IH), 6.44(d, IH), 6.16(s, IH), 5.39(s, IH), 3.79(s, 3H), 2.54(t, 2H), 2.25(t, 2H), 2.08(s, 6H), 1.87(s, 3H), 1.22(s, 3H), 1.17(s, 3H).
Example 319 2,5-dihydro-10-methoxy-5-cyclopropyl-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline
Example 319A A mixture of ExamplelF (4.43 g, 13.7 mmol), 4-chlorophenol (9.28 g, 72.1 mmol) and MgSO4 (8.69 g, 72.1 mmol) in CH2CI2 (100 ml) at ambient temperature was stirred for 12 hr, diluted with ethyl acetate (200 ml), washed with IM aq NaOH twice and brine respectively, dried (Na2SO4) and concentrated. The residue was triturated with hot ethyl acetate (25 ml) to provide the desired phenyl acetal. MS (DCI/NH3) m/e 306 (M-4-Cl-ph)+
Example 319B A solution ofthe Example 319A (131 mg, 0.30 mmol) in toluene (20 ml) at 0 °C was treated with cyclopropylmagnesium bromide made by refluxing cyclopropyl bromide (363 mg, 3.0 mmol) and Mg (73 mg, 3.0 mmol) in THF (1.5 ml) for 30 min.
The final solution was allowed to warm to ambient temperature and stirred for 12 hr, quenched with sat. NH4CL The organic layer was washed with IM aq NaOH twice and brine respectively, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 5-15% ethyl acetate/hexane provided 18 mg (17%>) ofthe title compound.
MS (DCI/NH3) m/e 348 (M+H)+ iHNMR (300 MHz, DMSO-d6)D8.01(d, IH), 7.04(t, IH), 6.67(d, IH), 6.60(d, IH), 6.57(d, IH), 6.16(s, IH), 5.44(s, IH), 5.42(d, IH), 3.85(s, 3H), 2.12(s, 3H), 1.26(s, 3H), 1.05(s, 3H), 0.28(m, 4H), 0.08(m, IH).
Example 320
2,5-dihydro- 10-methoxy-5-ethenyl-2,2,4-trimethyl- 1 H-[l Jbenzopyrano [3 ,4-fjquinoline A solution of 2B (34 mg, 0.1 mmol) and tributylvinyltin (96 mg) in CH2CI2 (2 ml) was treated with boron trifluoride etherate (43 mg, 0.3 mmol) at -78 °C, and allowed to warm to ambient temperature with stirring for 2 hr. The reaction was then quenched with sat. NaHCO3, and the organic layer was washed with sat. NaHCO3 and brine respectively, dried (Na2SO4) and concentrated. Flash chromatography ofthe residue on silica gel with 5-15% ethyl acetate/hexane provided 27 mg (81%>) ofthe title compound. MS (DCI/NH3) m/e 334 (M+H)+ iH NMR (300 MHz, DMSO-d6)07.93(d, IH), 7.02(t, IH), 6.63(dd, 2H), 6.54(d, IH), 6.19(d, IH), 6.10(s, IH), 5.93(m, IH), 5.42(s, IH), 5.16(dt, IH), 4.91(dt, IH), 3.83(s,
3H), 2.11(s, 3H), 1.21(s, 3H), 1.13(s, 3H).
Example 321 trans 2,5-dihydro-l 0-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline
A mixture of Example 320 (13 mg, 0.039 mmol), iodobenzene (12 mg, 0.058 mmol), palladium (II) acetate (18 mg, 0.008 mmol), tri(o-tolyl)phosphine (3.6 mg, 0.012 mmol), triethylamine (12 mg, 0.12 mmol) in CH3CN (1 ml) was heated to 80 °C for 4 hr in a sealed tube. After solvent removal, flash chromatography ofthe residue on silica gel with 5-15%) ethyl acetate/hexane provided 7 mg (44%) ofthe title compound.
MS (DCI/NH3) m/e 410 (M+H)+ iH NMR (300 MHz, DMSO-d6)D7.99(d, IH), 7.22(m, 4H), 7.19(m, IH), 7.00(t, IH), 6.67(d, IH), 6.63(d, IH), 6.57(d, IH), 6.38(q, IH), 6.34(d, IH), 6.27(d, IH), 6.14(s, IH), 5.43(s, IH), 3.82(s, IH), 2.12(s, 3H), 1.22(s, 3H), 1.13(s, 3H).
Example 322 2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fj quinoline Example 2B and tributylphenylacetylenyltin were processed as in Example 320 to provide the desired compound.
MS (DCI/NH3) m/e 408 (M+H)+ iH NMR (300 MHz, DMSO-d6)D7.92(d, IH), 7.29(m, 3H), 7.16(m, 2H), 7.10(d, IH), 6.78(d, IH), 6.65(dd, IH), 6.59(s, IH), 6.23(s, IH), 5.45(s, IH), 3.87(s, 3H), 2.33(s, 3H), 1.28(s, 3H), 1.12(s, 3H)
Example 323 cis 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline A mixture of Example 322 (20 mg, 0.049 mmol), palladium/BaS04 (20 mg) in pyridine (2 ml) was stirred at ambient temperature for 12 hr, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried(Na2SO4), and concentrated. Flash chromatography ofthe residue on silica gel with 5-15% ethyl acetate/hexane provided 13 mg (75%) ofthe title compound. MS (DCI/NH3) m/e 410 (M+H)+ iH MR (300 MHz, DMSO-d6)D7.97(d, IH), 7.62(d, 2H), 7.48(t, 2H), 7.39(t, IH), 7.03(t, IH), 6.72(d, IH), 6.63(d, IH), 6.61(d, IH), 6.52(d, IH), 6.12(d, IH), 6.10(s, IH),
5.70(dd, IH), 5.27(s, IH), 3.87(s, 3H), 1.55(s, 3H), 1.17(s, 3H), 1.079s, 3H)
Example 324
2,5-dihydro- 10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4- fjquinoline
Example 2B and tributyl-(2-methylpropenyl)tin were processed as in Example
320 to provide the desired compound.
MS (DCI/NH3) m/e 362 (M+H)+ iH NMR (300 MHz, DMSO-d6)07.92(d, IH), 6.99(t, IH), 6.65(d, IH), 6.58(d, IH), 6.44(d, IH), 6.24(d, IH), 6.21(s, IH), 5.40(s, IH), 5.18(d, IH), 3.85(s, 3H), 2.07(s, 3H),
1.84(s, 3H), 1.58(s, 3H), 1.23(s, 3H), 1.10(s, 3H)
Anal, calcd for C24H27NO2: C, 79.74; H, 7.52; N, 3.87. Found: C, 79.34; H, 7.25; N,
3.68
Example 325 trans 2,5-dihydro-10-methoxy-5-(l-cyclohexenyl)-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-fjquinoline Example 2B and tributyl-(l-cyclohexenyl)tin were processed as in Example 320 to provide the desired compound. MS (DCI/NH3) m/e 388 (M+H)+ iH NMR (300 MHz, DMSO-d6)07.91(d, IH), 7.00(t, IH), 6.64(d, IH), 6.60(d, IH), 6.49(d, IH), 6.02(s, IH), 5.85(s, IH), 5.39(s, IH), 5.14(s, IH), 3.81(s, 3H), 2.18(m, IH), 2.03(s, 3H), 1.98(m, IH), 1.81(m, IH), 1.64(m, IH), 1.42(m, 3H), 1.24(m, IH), 1.22(s,
3H), 1.13(s, 3H)
Anal, calcd for C26H29 O2-1.25H2O: C, 76.15; H, 7.74; N, 3.41. Found: C, 76.12; H,
7.34; N, 3.21
Example 326 2,5-dihydro- 10-(2-furanyl)-5-(3-propenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline A magnetically stirred mixture of triflate 3C [from the original patent applicationj (196 mg, 0.421 mmol) and 2-(ttibutylstannyl)furan (0.250 mL, 0.79 mmol) and [l,r-bis(diphenylphosphino)ferroceneJdicloropalladium(II) methylene chloride complex (25 mg, 0.031 mmol) and tetrabutylammonium iodide (25 mg, 0.068 mmol) in dry NMP (6.5 mL) was heated at 70°C for 5h under argon. The reaction was allowed to cool to room temperature, was diluted with satd aq NaCl and extracted with ethyl acetate (5 x 20 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated.
The crude material was chromatographed on silica gel (16g) using ethyl acetate-hexane (10:90) to give product contaminated with starting material. The material was applied to three 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted four times with EtOAc-hexane (5:95). The product band was scraped off and extracted with ethyl acetate to furnish 23 mg (0.044 mmol, 14%>) of desired furan as a viscous syrap: iH NMR07.67
(d, IH, J=1.0Hz), 7.18 (t, IH, J=7.8Hz), 7.08 (m, IH), 6.91 (dd, IH, J=8.1Hz, J=1.4Hz), 6.64 (m, 2H), 6.35 (d, IH, J=8.5Hz), 6.25 (d, IH, J=8.5Hz), 6.14 (m, IH), 5.82 (m, 2H), 5.43 (s, IH), 5.05 (dd, IH, J=10.5Hz, J=1.5Hz), 4.99 (dd, IH, J=17.3Hz, J=1.5Hz), 2.40 (m, 2H), 2.19 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H); mass spectrum (DCI) m/z 384 (M + 1). Anal. Calcd for C26H25 O2: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.24; H, 6.62; N,
3.66.
Example 327 2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline
A magnetically stirred mixture of triflate 3C (195 mg, 0.419 mmol), 36 mg (0.031 mmol) of tetrakis(triphenylphosphine)palladium(0) and zinc cyanide (36 mg, 0.31 mmol) in dry dioxane (4.0 mL) and water (1.0 mL) was heated at 80°C for 48h under argon. The reaction was allowed to cool to room temperature, was diluted with ethyl acetate (25 mL) and washed with satd aq NaCl. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated. The crude material was chromatographed on silica gel (20 g) using ethyl acetate-hexane (10:90) to give product contaminated with starting triflate. The partially pure nitrile was applied to two 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted five times with EtOAc-hexane (5:95). The product band was scraped off and extracted with ethyl acetate to furnish 17.3 mg (0.0505 mmol, 12%) of desired nitrile: 1H NMR07.87 (d, IH, J=8.5Hz), 7.46 (dd, IH, J=7.5Hz, J=1.5Hz), 7.27 (t, IH, J=7.8Hz), 7.19 (dd, IH, J=8.1Hz, J=1.4Hz), 6.71 (d, IH, J=8.5Hz), 6.57 (m, IH), 5.90 (dd, IH, J=10Hz, J=3.6Hz), 5.82 (m, IH), 5.49 (m, IH), 5.04 (dm, IH, J=10.5Hz), 4.98 (dm, IH, J=17.3Hz), 2.38 (m, IH), 2.30 (m, IH), 2.19 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H); mass spectrum (APCI) m/z 343 (M + 1); Calcd for C23H22N2O: 342.1732. Found:
342.1730.
Example 328 2,5-dihydro-10-carboxy-5-(3-propenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline A magnetically stirred mixture ofthe Example 4 (31 mg, 0.082 mmol) and sodium cyanide (51 mg, 0.78 mmol) in dry dimethylsulfoxide (2.5 mL) was heated at
110°C for 5h under argon. The reaction was allowed to cool to room temperature, was diluted with satd aq NaCl and extracted with ethyl acetate (5 x 20 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated. The crude material was applied to two 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted twice with EtOAc-hexane (10:90), then EtOAc-hexane (50:50) three times. The product band was scraped off and extracted with ethyl acetate to furnish 16 mg (0.044 mmol, 54%) of desired carboxylic acid as a viscous syrap: iH NMR07.16 (m, 2H), 7.02 (d, IH, J=8.5Hz), 6.98 (dd, IH, J=5.5Hz, J=3.7Hz), 6.58 (d, IH, J=8.5Hz), 6.29 (m, IH), 5.82 (m, 2H), 5.45 (s, IH), 5.05 (dd, IH, J=10.5Hz, J=1.5Hz), 4.98 (dd, IH, J=17.3Hz, J=l .5Hz), 2.30 (m, 2H), 2.18 (s, 3H), 1.20 (s, 3H), 1.16 (s, 3H); mass spectrum (APCI) m/z 362 (M + 1). Anal. Calcd for C23H23NO3: C, 76.43; H, 6.41; N, 3.88. Found: C, 76.24; H, 6.46; N,
3.66.
Example 329
2,5-dihydro-10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-fj quinoline To a magnetically stirred solution of example 4 (32 mg, 0.085 mmol) in dry methylene chloride (3 mL), cooled to -78°, was added dropwise 1.0M diisobutylaluminum hydride in cyclohexane (0.400 mL, 0.40 mmol) under dry argon.
The temperature ofthe reaction was allowed to rise to 0°C. After 3.5h, the reaction was quenched by addition to aqueous Rochelle's salt and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 40 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated. The crude material was applied to two 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted with hexane, then EtOAc- hexane (10:90) three times. The product band was scraped off and extracted with ethyl acetate to furnish 27 mg (0.078 mmol, 91%) of desired alcohol as a viscous syrap: iH NMRD7.47 (d, IH, J=8.5Hz), 7.14 (m, 2H), 6.80 (dd, IH, J=7.3Hz, J=1.8Hz), 6.64 (d,
IH, J=8.5Hz), 6.17 (m, IH), 5.81 (ddm, IH, J=10.5Hz, J=17.1Hz), 5.73 (dd, IH, J=3.4Hz, J=10.5Hz), 5.46 (m, IH), 5.32 (dd, IH, J=6.3Hz, J=4.2Hz), 5.02 (dm, IH, J=10.5Hz), 4.94 (dm, IH, J=17.1Hz), 4.62 (m, 2H), 2.30 (m, 2H), 2.17 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H); mass spectrum (ESI) m/z: 348 (M + 1); Calcd for C23H25NO2: 347.1885. Found: 347.1897.
Example 330 2,5-dihydro-10-formyl-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fj quinoline A magnetically stirred mixture ofthe Example 329 (185 mg, 0.532 mmol) and tetrapropylammonium perrathenate (205 mg, 0.583 mmol) in dry methylene chloride (10 mL) was stirred for 1.5h under argon. The reaction was filtered through celite, the filter pad was washed with ethyl acetate and the filtrate was concentrated. The crade material was chromatographed on silica gel (20 g) using EtOAc-hexane (10:90) to furnish 144 mg (0.417 mmol, 78%) of desired aldehyde: !H NMRD 10.11 (s, IH), 7.45 (dd, IH,
J=7.8Hz, J=1.2Hz), 7.29 (t, IH, J=7.8Hz), 7.16 (dd, IH, J=7.8Hz, J=1.4Hz), 6.84 (d, IH, J=8.5Hz), 6.70 (d, IH, J=8.5Hz), 6.53 (m, IH), 5.91 (dm, IH, J=10.0Hz), 5.84 (m, IH), 5.51 (s, IH), 5.05 (dm, IH, J=10.5Hz), 4.97 (dm, IH, J=17.3Hz), 2.40 (m, 2H), 2.21 (s, 3H), 1.22 (s, 3H), 1.18 (s, 3H); mass spectrum (APCI) m/z 346 (M + 1); Calcd for C23H23NO2: 345.1729. Found: 345.1732.
Example 331 2,5-dihydro- 10-aminomethyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline To a magnetically stirred solution of Example 330 (40 mg, 0.116 mmol) and ammonium acetate (77 mg, 1.0 mmol) in dry methanol (10 mL) was added sodium cyanoborohydride (14 mg, 0.23 mmol) under nitrogen. After 5h, the reaction was quenched by addition to 10% sodium carbonate and extracted with ethyl acetate (3 x 40 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated. The crade material was applied to two 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted with hexane, then EtOAc-hexane (20:80) four times. The product band was scraped off and extracted with ethyl acetate to furnish 8.0 mg (0.023 mmol, 20%) of desired amine as a viscous syrup: iH NMRD 7.55 (d, IH, J=8.5Hz), 7.14 (m, 2H), 6.80 (dd, IH, J=7.3Hz, J=1.8Hz), 6.64 (d, IH, J=8.5Hz), 6.17 (m, IH), 5.81 (ddm, IH, J=10.5Hz, J=17.1Hz), 5.73 (dd, IH, J=3.4Hz, J=10.5Hz), 5.46 (m, IH), 5.02 (dm, IH, J=10.5Hz), 4.94 (dm, IH, J=17.1Hz), 4.62 (m, 2H), 3.88 (m, 2H), 2.30 (m, 2H), 2.17 (s, 3H), 1.19 (s, 3H), 1.16 (s, 3H); mass spectrum (ESI) m/z: 347 (M + 1); Calcd for C23H26N2O: 346.2045. Found: 346.2047.
Example 332 2,5-dihydro-10-methoxymethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-ri1benzopyranor3,4- fjquinoline To a magnetically stirred solution of Example 329 (26 mg, 0.075 mmol) in dry
THF (2.0 mL), cooled in an ice bath, was added 0.14 mL of IM potassium hexamethyldisilazide in hexane under argon. Methyl iodide (13.8 mg, 0.097 mmol) was added and the reaction was allowed to slowly come to room temperature. The reaction was quenched with satd aq NH4CI and extracted with ethyl acetate (3 x 10 mL). The extracts were dried (MgSO4), filtered, and concentrated. The crade material was applied to three 10 x 20 cm, 0.25 mm thick silica gel plates which were eluted four times with EtOAc-hexane (5:95). The product band was extracted using EtOAc to furnish 25 mg (0.069 mmol, 92%) of desired methyl ether: 1H NMRD7.34 (d, IH, J=8.5Hz), 7.11 (m, 2H), 6.85 (dd, IH, J=7.1Hz, J=2.4Hz), 6.64 (d, IH, J=8.5Hz), 6.20 (m, IH), 5.81 (dm, IH, J=10.2Hz), 5.75 (m, IH), 5.46 (s, IH), 5.02 (dm, IH, J=10.2Hz), 4.93 (dm, IH,
J=17.3Hz), 4.61 (d, IH, J=11.2Hz), 4.43 (d, IH, J=11.2Hz), 3.37 (s, 3H), 2.33 (m, IH), 2.27 (m, IH), 2.17 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H); mass spectrum (ESI) m/z 362 (M + 1); Calcd for C24H27NO2: 361.2042. Found: 361.2047.
Example 333 2,5-dihydro-10-ethenyl-5-phenyl-2,2,4-trimethyl-lH-
[ljbenzopyrano[3 ,4-fjquinoline
Example 333 A 2,5-dihydro-l 0-ethenyl-5-phenyl-2,2,4-trimethyl-lH-riJbenzopyrano[3 ,4-fjquinoline Example 7 and trifluoromethanesulfonic anhydride were processed as in Example
3C to provide the desired triflate. MS (ESI) m/z 502 (M+H) +.
Example 333 2,5-dihydro-10-ethenyl-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline
Example 333 A and vinyl tributylstannane were processed as in Example 5 to provide the desired compound. MS (DCI/NH3) m/z 380 (M+H)+; iH NMR (300 MHz, CDCI3.) D7.30-7.l l (m, 6 H), 7.02-6.89 (m, 3 H), 6.78 (s, 1 H), 6.76-6.68 (m, 2 H), 6.32 (br s, 1 H), 5.72 (br d, .7=11.4 Hz, 1 H), 5.40 (br s, 1 H), 5.30 (br d, .7=15.9 Hz, 1 H), 1.81 (s, 3 H), 1.26 (s, 3 H), 1.15 (s, 3 H);
13C NMR (125 MHz, DMSO)D 151.3, 145.7, 138.8, 137.3, 133.3, 133.0, 131.2, 128.5 (2), 128.3, 128.2, 128.0 (2), 127.8, 127.4, 126.6, 123.9, 120.8, 118.1, 116.2, 114.5,
113.6, 75.3, 50.0, 30.0, 28.7, 23.2; HRMS (FAB) calcd m/z for C27H25NO: 379.1936 (M)+. Found: 379.1924.
Example 334 2,5-dihydro-10-ethynyl-5-phenyl-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline
Example 333 A and (trimethylsilyl)acetylene were processed as in Example 6 A and Example 6 to provide the desired compound. MS (DCI/NH3) m/z 378 (M+H)+; iH NMR (300 MHz, DMSO)08.32 (d, J=8.8 Hz, 1 H), 7.27-7.16 (m, 5 H), 7.01 (dd, .7=8.7, 1.8 Hz, 1 H), 6.83 (t, J=8.6 Hz, 1 H), 6.84-6.79 (m, 1 H), 6.81 (br s, 1 H), 6.74 (d,
J=8.6 Hz, 1 H), 6.42 (br s, 1 H), 5.41 (br s, 1 H), 4.38 (s, 1 H), 2.03 (s, 3 H), 1.24 (s, 3
H), 1.18 (s, 3 H);
13C NMR (125 MHz, DMSO)D 150.9, 146.4, 138.8, 133.1, 130.7, 128.6, 128.2 (2),
128.0 (2), 127.9, 127.4, 126.6, 126.5, 126.4, 126.3, 118.3, 117.6, 117.5, 115.7, 113.4, 84.3, 75.1, 50.0, 30.0, 28.8, 23.2;
HRMS (FAB) calcd m/z for C27H23NO: 377.1780 (M)+. Found: 377.1779.
Example 335 methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l jbenzopyrano[3 ,4- fjquinoline-10-carboxylate Example 333A was processed as in Example 4 to provide the desired compound, mp 150-2 °C; MS (DCI/NH3) m/z 412 (M+H)+;
!H NMR (300 MHz, DMSO) 07.36-7.30 (m, 2 H), 7.28-7.17 (m, 3 H), 7.12-7.01 (m, 2 H), 6.93-6.88 (m, 2 H), 6.84 (d, J=8.7 Hz, 1 H), 6.70 (d, J=8.9 Hz, 1 H), 6.40 (br s, 1 H), 5.40 (br s, 1 H), 3.79 (s, 3 H), 1.81 (s, 3 H), 1.26 (s, 3 H), 1.17 (s, 3 H);
13C NMR (125 MHz, DMSO)D 169.9, 151.2, 146.1, 138.3, 132.5, 130.3, 128.8 (2), 128.1, 128.0 (2), 127.7, 127.4, 127.0, 126.6, 124.9, 122.9, 119.6, 117.7, 117.5, 114.2, 75.7, 52.2, 50.0, 30.0, 28.6, 23.2; Anal, calcd for C27H25NO3: C, 78.81; H, 6.12; N, 3.40. Found: C, 78.84; H, 6.25; N, 3.24. Example 336 2,5-dihydro- 10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline To a solution of Example 335 (136 mg, 0.330 mmol) in anhydrous CH2CI2 (12 mL) at -50 °C was added Dibal-H (1.65 mL of a 1.0 M solution in heptane, 1.65 mmol).
The resulting orange solution was warmed gradually to 0 °C over a 30 min period, then was stirred at 0 °C for 2 h. EtOAc (5 mL) was then added to the solution at 0 °C to quench the excess Dibal-H reagent (indicated by a color change ofthe solution from orange to light yellow) and the reaction mixture was then treated with saturated aqueous NH4CI (5 mL). The reaction mixture was partitioned between EtOAc (40 mL) and saturated aqueous Rochelle's salt (sodium potassium tartrate; 35 mL) and the resulting mixture was stirred vigorously until a clear separation of layers was observed (ca. 1 h). The layers were partitioned and the aqueous layer was extractedwith EtOAc (15 mL). The organics were combined and were washed with brine (10 mL) and then were dried (Na2SO4). Filtration and concentration gave the desired compound (116 mg, 0.302 mmol, 92%>) as a colorless foamy solid. MS (DCI/NH3) m/z 384 (M+H)+; iH NMR (300 MHz, DMSQ)D7.58 (d, J=8.9 Hz, 1 H), 7.23-7.11 (m, 5 H), 6.98 (dd,
J=8.7, 1.7 Hz, 1 H), 6.84 (t, J=8.7 Hz, 1 H), 6.76 (br s, 1 H), 6.75 (d, J=8.6 Hz, 1 H), 6.69 (dd, J=8.7, 1.8 Hz, 1 H), 6.26 (br s, 1 H), 5.40 (br s, 1 H), 5.37 (dd, J=6.0, 4.0 Hz, 1
H), 4.65 (dd, .7=11.5, 6.0 Hz, 1 H), 4.54 (dd, .7=11.6, 4.4 Hz, 1 H), 1.80 (s, 3 H), 1.24 (s,
3 H), 1.17 (s, 3 H);
13C NMR (125 MHz, DMSO)0151.0, 145.6, 139.0, 137.0, 133.1, 131.4, 128.4 (2),
128.1, 128.0 (2), 127.7, 127.6, 126.2, 124.8, 123.7, 118.6, 118.0, 116.0, 113.9, 75.1, 61.9, 49.9, 29.9, 28.7, 23.3;
Anal, calcd for C26H25NO2: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.53; H, 6.86; N,
3.41.
Example 337 2,5-dihydro-10-formyl-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline
To a solution of Example 336 (50 mg, 0.130 mmol) in CH2CI2 (6 mL) at 23 °C was added a solution of tetrapropylammonium perrathenate (60 mg, 0.16 mmol) in CH2CI2 (14 mL). After 15 min, the reaction mixture was filtered through a small plug of silica gel, rinsing with CH2CI2 followed by 1:1 EtOAc-hexanes. The filtrate was concentrated to give a gold symp which was purified by preparative thin layer chromatography (elution with 3%o EtO Ac/toluene) to afford the desired product (19 mg, 0.050 mmol, 38%>) as a pale yellow foam. MS (DCI/NH3) m/z 382 (M+H)+; iH NMR (300 MHz, DMSO)D 10.13 (s, 1 H), 7.31 (dd, J=8.8, 1.9 Hz, 1 H), 7.28-7.16 (m, 5 H), 7.12 (d, J=8.7 Hz, 1 H), 7.05 (dd, J=8.7, 2.0 Hz, 1 H), 6.95 (d, J=8.8 Hz, 1 H), 6.92 (br s, 1 H), 6.81 (d, J=8.8 Hz, 1 H), 6.59 (br s, 1 H), 5.43 (br s, 1 H), 1.85 (s, 3 H), 1.27 (s, 3 H), 1.18 (s, 3 H); 13C NMR (125 MHz, DMSO)D 191.4, 151.9, 146.8, 138.3, 133.2, 131.5, 131.4, 130.8,
128.6 (2), 128.1 (2), 128.0, 127.2, 126.6, 121.5, 121.4, 118.1, 115.5, 114.2 (2), 75.8, 50.2, 30.1, 29.0, 23.1; HRMS (FAB) calcd m/z for C26H24NO: 382.1807 (M+H)+. Found: 382.1816.
Example 338
2,5-dihydro-10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl-lH-rijbenzopyrano[3 ,4- fjquinoline To a solution of Example 336 (22 mg, 0.057 mmol) in THF (2.0 mL) at 0 °C was added KHMDS (110 mL of a 0.5 M solution in toluene, 0.057 mmol). After 15 min, a solution of iodomethane was added as a solution in DMF (100 mL of a solution of 81 mg iodomethane in 1.0 mL DMF, 0.057 mmol) was added and the solution was stirred additionally at 0 °C for 30 min, the cooling bath was removed, and the reaction was stirred additionally at 23 °C for 1.5 h. The reaction was then quenched with water (3 mL) and was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (5 mL), then were dried (MgSO4), and were concentrated in vacuo to provide a brown oil. Purification of this residue by preparative thin layer chromatography (elution with 10%> EtOAc/hexanes) afforded the desired product (15 mg, 0.038 mmol, 66%>) as a colorless foam. MS (DCI/NH3) m/z 98 (M+H)+; iH NMR (300 MHz, DMSO)O7.40 (d, J=8.9 Hz, 1 H), 7.19-7.10 (m, 5 H), 6.97-6.92
(m, 1 H), 6.94 (s, 1 H), 6.77-6.70 (m, 3 H), 6.29 (br s, 1 H), 5.39 (br s, 1 H), 4.58 (d, .7=11.1 Hz, 1 H), 4.39 (d, .7=11.1 Hz, 1 H), 3.28 (s, 3 H), 1.81 (s, 3 H), 1.26 (s, 3 H), 1.17 (s, 3 H); 13C NMR (125 MHz, DMSQ)D 151.0, 145.7, 138.8, 132.9, 132.6, 131.5, 128.4 (2), 127.8 (2), 127.8, 127.7, 127.5, 126.1, 125.7, 124.4, 118.3, 117.9, 116.6, 113.9, 75.2,
72.5, 57.2, 49.9, 29.9, 28.7, 23.3; HRMS (FAB) calcd m/z for C27H27NO2: 397.2042 (M)+. Found: 397.2039.
Example 339 2,5-dihydro- 10-ethenyl-5-oxo-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline
Example 3C and vinyl tributylstannane were processed as in Example 5 to provide the desired compound, mp 218-224 °C; MS (DCI/NH3) m/z 318 (M+H)+, 335 (M+NH4)+; iH NMR (300 MHz, DMSO)07.88 (d, J=8.8 Hz, 1 H), 7.38 (dd, J=8.8, 6.6 Hz, 1 H),
7.29 (s, 1 H), 7.28 (d, J=8.6 Hz, 1 H), 7.19 (dd, J=17.3, 11.1 Hz, 1 H), 7.13 (d, J=8.7 Hz,
1 H), 7.03 (br s, 1 H), 5.75 (dd, J=17.3, 1.2 Hz, 1 H), 5.52-5.47 (m, 2 H), 1.97 (s, 3 H),
1.24 (s, 6 H);
13C NMR (125 MHz, CDCl3.)D 160.1, 150.0, 145.4, 138.5, 136.3, 132.2, 131.0, 127.1,
126.7, 126.6, 125.5, 124.1, 119.9, 118.5, 117.2, 115.9, 115.7, 50.0, 27.9 (2), 21.0;
Anal, calcd for C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.28; H, 5.97; N,
4.20.
Example 340 5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline To a magnetically stirred solution of Example 339 (100 mg, 0.300 mmol) and 3- (trimethylsilyl)cyclohexene (139 mg, 0.900 mmol) in CH2CI2 (6 mL) at -78 °C was added freshly distilled BF3»OEt2 (80 mL, 0.600 mmol). The resulting greenish brown solution was stirred at -78 °C for 15 min then slowly warmed to 23 °C with continued stirring over a period of 1 h. The reaction mixture was poured into 10% NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic portions were washed with brine (8 mL) and were dried (Na2SO4). Filtration and concentration gave a brown residue which was purified via flash chromatography (elution with 5%>
EtOAc/hexanes) to give the desired product as a tan foam (356 mg, 0.186 mmol, 62%>). MS (DCI/NH3) m/z 384 (M+H)+; iH NMR (300 MHz, DMSO) (data for major syn diastereomer)D7.30 (d, J=8.0 Hz, 1 H),
7.16-6.97 (m, 3 H), 6.95-6.88 (m, 1 H), 6.67 (d, J=8.0 Hz, 1 H), 6.42 (br s, 1 H), 5.82- 5.60 (m, 3 H), 5.52-5.44 (m, 2 H), 5.33 (d, J=7.6 Hz, 1 H), 2.40-2.26 (m, 1 H), 2.17 (s, 3
H), 2.05-1.82 (m, 2 H), 1.70-1.53 (m, 2 H), 1.32 (s, 3 H), 1.31-1.07 (m, 2 H), 1.05 (s, 3
H);
13C NMR (125 MHz, CDCI3.) 0138.8, 134.2, 129.3 (2), 128.1 (2), 127.9 (2), 126.7,
121.3, 116.4, 114.1, 37.2, 37.0, 34.7, 31.6, 30.2, 27.2, 26.1, 25.2, 24.7, 22.6, 24.1, 21.8 (2), 20.5, 14.1;
Anal, calcd for C27H29NO: C, 83.57; H, 7.66; N, 3.60. Found: C, 83.55; H, 7.38; N,
3.45.
Example 341 2,5-dihydro- 10-ethenyl-5-[l -methyl-3-cyclohexenylj-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f]quinoline Example 339 and 3-(dimethylphenylsilyl)-3-methylcyclohexene were processed as in Example 339 to provide the desired compound. mp 198-201 °C;
MS (DCI/NH3) m/z 398 (M+H)+; iH NMR (300 MHz, DMSO) (data for major syn diastereomer) D 7.30 (d, J=7.9 Hz, 1 H), 7.16-7.00 (m, 3 H), 6.92 (dd, J=7.1, 2.6 Hz, 1 H), 6.66 (d, J=8.0 Hz, 1 H), 6.39 (br s, 1 H), 5.73 (d, J=12.4 Hz, 1 H), 5.52-5.41 (m, 3 H), 5.32 (d, J=10.2 Hz, 1 H), 2.33-2.22 (m, 1 H), 2.14 (s, 3 H), 1.91-1.70 (m, 1 H), 1.87-1.65 (m, 1 H), 1.63-1.51 (m, 1 H), 1.60 (s, 3 H), 1.34-1.15 (m, 2 H), 1.31 (s, 3 H), 1.13-0.98 (m, 1 H), 1.04 (s, 3 H); Anal, calcd for C28H31NO: C, 84.59; H, 7.85; N, 3.52. Found: C, 84.46; H, 7.81; N,
3.37.
Example 342 2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fj quinoline To a magnetically stirred solution of Example 3B (120 mg, 0.390 mmol) in anhydrous DMF (1.0 mL) at 0 °C was added sodium hydride (17 mg of a 60% dispersion in mineral oil, 0.430 mmol). The mixture was stirred under an atmosphere of nitrogen until evolution of hydrogen had ceased (1 h). Solid dimethylthiocarbamoyl choride (64 mg, 0.520 mmol) was then introduced in a single portion and stirring was continued at 0 °C for 30 min. The cooling bath was removed and the mixture heated at 80 °C for 45 min. The reaction mixture was then poured into 1% NaOH (10 mL) and extracted with
EtOAc (2 x 25 mL). The combined organics portions were washed with water (3 x 5 mL) and with brine (3 mL) then dried (MgSO4), filtered and concentrated. The resulting brown residue was purified flash chromatography (elution with 25% EtOAc/hexanes) to provide the resulting thionocarbamate (43 mg, 0.109 mmol, 28%>) as a yellow solid. MS (DCI/NH3) m/z 348 (M+H)+.
The compound prepared above (113 mg, 0.280 mmol) was placed in an open vial and immersed in a Woods metal bath heated to 270-280 °C for 6 min. The reaction was cooled and the resulting dark brown residue was purified flash chromatography (gradient elution: 20%MA0% EtOAc/hexanes) to provide the thermally rearranged thiocarbamate product (67 mg, 0.165 mmol, 59%>) as a yellow solid.
MS (DCI/NH3) m/z 348 (M+H)+.
To a solution ofthe rearranged product (500 mg, 1.26 mmol) in anhydrous toluene (70 mL) at -78 °C under N2 was added dropwise Dibal-H (2.02 mL of a 1.0 M solution in heptane, 2.02 mmol) maintaining the temperature at -78 °C. The resulting orange-red solution was stirred at -78 °C for 1.5h at which time a TLC of an aliquot
(quenched with satd. ammonium chloride) indicated conversion to desired product.. Some lower Rf material (diol resulting from over-reduction) was also observed. EtOAc
(10 mL) was added to the solution at -78 °C to quench the excess DIBAL-H reagent (indicated by a color change ofthe solution from orange-red to light yellow), followed by addition of saturated aqueous NH4CI solution (15 mL). The reaction mixture was partitioned between EtOAc (150 mL) and aqueous Rochelle's salt (sodium potassium tartrate, 40 mL) and the resulting mixture was stirred vigorously until a clear separation of layers was observed. The layers were separated and the organic layer was washed with brine (20 mL), was dried (Na2SO4), and was filtered. Removal of solvent gave the lactol as a light yellow foam (512 mg) which was used without further purification.
The lactol was dissolved in MeOH (30 mL) at 23 ° C andp-TsOH^O (50 mg,
25% w/w) was added portionwise as a solid. The mixture was stirred for 14 h at 23 ° C and then was quenched with saturated aqueous sodium bicarbonate (10 mL) and was extracted with EtOAc (2 x 50 mL). The organics portions were combined and were washed with brine (20 mL) and were dried (Na2SO4). Filtration and concentration provided a yellow residue which was purified by flash chromatography (elution with 5% EtOAc/CH2Cl2) to provide the product methylacetal (157 mg, 0.416 mmol, 33% over two steps) as a yellow foam.
MS (DCI/NH3) m/z 379 (M-OCH3)+.
The lactol prepared above and allyltrimethylsilane were processed as in Example 2 to give a C-5 allyl compound. MS (DCI/NH3) m/z 421 (M+H)+.
Example 343 2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-rijbenzopyranor3,4- fjquinoline A suspension ofthe thiocarbamate (249 mg, 0.590 mmol) and KOH (90 mg, 1.20 mmol) in ethylene glycol (6 mL) containing water (1.5 mL) was heated at reflux
(homogeneous solution) for 1.5 h. The solution was cooled and poured onto ice (10 g). The mixture was acidified (pH 4) with 10%> HCl and was then extracted with CH2CI2 (2 x 20 mL). The extracts were dried (Na2SO4), were filtered, and were concentrated. The resulting residue was purified by flash chromatography (elution with 5% EtOAc/CH2Cl2) to provide nearly homogeneous thiophenol adduct (183 mg) as an off- yellow solid that was used immediately: H NMR (300 MHz, DMSO-cfe) D7.72 (d, J=8.0 Hz, 1 H), 7.08 (dd, J=7.6, 1.1 Hz, 1 H), 6.96 (t, J=7.5 Hz, 1 H), 6.67 (d, J=8.1 Hz, 1 H), 6.63 (dd, J=7.5, 1.2 Hz, 1 H), 6.28 (br s, 1 H), 5.88-5.70 (m, 2 H), 5.47 (br s, 1 H), 5.41 (s, IH), 5.03 (dd, J=13.2, 1.3 Hz, 1 H), 4.98 (dd, J=18.4, 1.3 Hz, 1 H), 2.48-2.21 (m, 2 H), 2.17 (s, 3 H), 1.20 (s, 3 H), 1.17 (s, 3 H); MS (DCI/NH3) m/e 350 (M+H)+.
A solution ofthe crude thiophenol (183 mg) in DMF (10 mL) at 0 °C was treated with cesium carbonate (50 mg, 0.153 mmol). After 10 min, a solution of iodomethane (25 mg, 0.176 mmol) in DMF (0.7 mL) was added, and the solution was stirred at 0 °C for 30 min then at 23 °C for 2 h. The mixture was diluted with 1:1 EtOAc-hexane (100 mL) and was washed with water (3 x 25 mL) then washed with brine (25 mL). The organic portion was dried (Na2SO4), was filtered, and was concentrated. The resulting residue was purified by flash chromatography (elution with 5%> EtOAc/hexanes) to provide the thioether (65 mg, 0.179 mmol, 34%) as an off-yellow solid: 1H NMR (300
MHz, DMSO- 6) P7.82 (d, .7=8.1 Hz, 1 H), 7.11 (t, J=7.6 Hz, 1 H), 6.98 (br d, J=7.7 Hz,
1 H), 6.72 (br d, J=7.6 Hz, 1 H), 6.62 (d, J=8.0 Hz, 1 H), 6.27 (br s, 1 H), 5.88-5.70 (m,
2 H), 5.47 (br s, 1 H), 5.03 (dd, .7=13.3, 1.1 Hz, 1 H), 4.99 (dd, .7=18.3, 1.1 Hz, 1 H), 2.47 (s, 3 H), 2.46-2.33 (m, 1 H), 2.32-2.22 (m, 1 H), 2.18 (s, 3 H), 1.21 (s, 3 H), 1.17 (s, 3 H); MS (CI/NH3) m/e 364 (M+H)+.
Example 344 (+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)- 10-methoxy-2,2,4- trimethyl-5-allyl-lH-[lJbenzopyrano[3,4-fjquinoline MS (APCI) m/z 491 (M+H)+; IH NMR (200 MHz, DMSO-d6) 07.94 (t, IH), 7.84 (d, IH), 6.88 (d, IH), 6.67 (d, IH),
6.64 (d, IH), 6.21 (s, IH), 5.87-5.78 (m, 2H), 5.46 (s, IH), 5.06-4.96 (m, 2H), 2.60 (s, 2H), 2.16 (dt, 2H), 2.62 (t, 2H), 2.21-2.27 (m, 2H), 2.18 (s, 2H), 1.82 (s, 2H), 1.79 (m, 2H), 1.18 (s, 2H), 1.17 (s, 2H).
Example 345
10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fjquinoline Example 7 and bromodifluoromethane were processed as in Example 8A to provide the desired compound. MS (CI/NH3) m/z 420 (M+H)+;
*H NMR (300 MHz, DMSO-d6)D7.80 (s, J=8.8 Hz, 1 H), 7.26-7.15 (m, 5 H), 7.16-7.13 (m, 1 H), 6.97 (t, j=8.1 Hz, 1 H), 6.82 (br s, 1 H), 6.74 (d, J=8.9 Hz, 1 H), 6.72-6.67 (m, 1 H), 6.38 (br s, 1 H), 5.39 (br s, 1 H), 1.82 (s, 3 H), 1.24 (s, 3 H), 1.15 (s, 3 H); HRMS (FAB) calcd m/z for C26H23F2NO2: 419.1697 (M)+. Found: 419.1714.
Example 346 10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl- 1 H-[l Ibenzopyrano [3 ,4-fjquinoline MS (ESI) m/z 498 (M+H) + *H NMR (300 MHz, DMSO-d6)P7.68 (s, J=8.8 Hz, 1 H), 7.25-7.14 (m, 5 H), 7.03 (t, j=8.2 Hz, 1 H), 6.89-6.84 (m, 1 H), 6.85 (br s, 1 H), 6.83-6.79 (m, 1 H), 6.74 (d, J=8.6 Hz, 1 H), 6.46 (br s, 1 H), 5.40 (br s, 1 H), 1.81 (s, 3 H), 1.25 (s, 3 H), 1.15 (s, 3 H); 13C NMR (125 MHz, DMSO-d6)P 152.34, 146.44, 145.97, 138.38, 133.02, 130.51, 128.61 (2), 128.07, 127.92 (2), 127.33, 126.86 (2), 119.16, 117.82, 116.68, 115.84, 115.32, 114.28, 114.12, 75.60, 49.93, 29.90, 28.72, 23.26;
HRMS (FAB) calcd m/z for C26H2279BrF2NO2: 497.0802 (M+H)+. Found: 497.0790. HRMS (FAB) calcd m/z for C26H2281BrF2Nθ2: 499.0782 (M+H)+. Found: 499.0793.
Example 347 10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3 ,4,5-tetrahydro- 1 H- chromeno[3 ,4-fjquinoline MS (ESI) m/z 498 (M+H) +. H NMR (300 MHz, CDCl3.)D7.88 (s, J=8.4 Hz, 1 H), 7.31-7.26 (m, 2 H), 7.19-7.12 (m, 3 H), 6.95 (t, J=8.1 Hz, 1 H), 6.86-6.78 (m, 2 H), 6.64 (br s, 1 H), 6.58 (d, J=8.5 Hz, 1 H), 4.94 (s, 1 H), 4.61 (s, 1 H), 4.17 (br s, 1 H), 2.45 (br d, J=12.0 Hz, 1 H), 2.19 (d, J=12.4 Hz, 1 H), 1.35 (s, 3 H), 1.14 (s, 3 H); HRMS (FAB) calcd m/z for C26H22?9BrF2NO2: 497.0802 (M+H)+. Found: 497.0790.
HRMS (FAB) calcd m/z for C26H2281BrF2NO2: 499.0782 (M+H)+. Found: 499.0771.
Example 348 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) -1H- [1 Jbenzopyrano[3,4-f]quinoline
Example 349 10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline
Example IF and the lithium anion of 3,5-dimethylisoxazole were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 401 (M+H)+;
!H NMR (300 MHz, DMSO-d6)D8.33 (d, IH, J=8.83 Hz), 7.7-7.5 (m, IH), 7.22 (t, IH, J=8.09), 7.05 (d, IH, J=l.l Hz), 6.85 (s, IH), 6.79 (d, IH, J=8.82 Hz), 5.61 (s, IH), 5.5
(s, IH), 3.93 (s, 3H), 2.45 (s, 3H), 1.96 (d, 3H, J=l.l Hz), 1.20-1.30 (s, 6H). Example 350 10-methoxy-5-(3-methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- lH-[ljbenzopyrano[3,4-fjquinoline
Example IF and the lithium anion of 3,5-dimethylisoxazole were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 401 (M+H)+;
!H NMR (300 MHz, DMSO-d6), isomer l.:D8.38 (d, IH, J=8.83 Hz), 7.22 (t, IH, J=8 Hz), 7.09 (s, IH), 6.87-6.81 (m, 2H), 6.56 (s, IH), 5.65 (s, IH), 5.51 (s, IH), 3.93 (s,
3H), 2.28 (s, 3H), 1.95 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H); isomer 2:08.16 (d, IH, J=8.83 Hz), 7.18 (t, 2H, J=8 Hz), 7.06 (s, IH), 6.80-6.76 (m, 2H), 6.46 (s, IH), 5.90 (s, IH), 5.21 (s, IH), 3.91(s, 3H), 2.08 (s, 3H), 1.84 (s, 3H), 1.26 (s, 3H), 1.12 (s, 3H).
Example 351
10-methoxy-5-(4,5-dimethyl-l,3-oxazol-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl-lH-[lJbenzopyrano[3 ,4-fjquinoline Example IF and the lithium anion of 2,4,5-trimethyloxazole were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 415 (M+H)+; H NMR (300 MHz, DMSO-dό), isomer 1 :08.36 (d, IH, J=8.82 Hz), 7.24-7.20 (m, IH), 6.82 (m, 3H), 6.25 (s, IH), 5.49 (s, IH), 3.92 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.28 (s, 3H), 1.2 (m, 6H); 2nd isomerO8.09 (d, IH, J=8.82 Hz), 7.16 (m, IH), 6.78-6.73 (m, 2H), 5.41 (s, IH), 5.21 (s, IH), 3.91 (s, 3H), 2.03 (s, 3H), 1.89 (s, 3H), 1.88 (s, 3H), 1.25-1.15 (m, 6H).
Example 352 10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-
1 H- [ 1 Ibenzopyrano [3 ,4-fjquinoline Example IF and the lithium anion of 6-chloro-2-methylpyridine were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 431 (M+H)+;
*HNMR (300 MHz, DMSO-d6)D8.35 (d, IH, J=4.7 Hz), 8.25 (d, IH, J=8.1 Hz), 7.9 (t, IH, J=7.7 Hz), 7.30 (d, IH, J=7.7 Hz), 7.21 (d, IH, J=8 Hz), 7.00 (d, IH, J=8.1 Hz), 6.8 (dd, 2H, J=8.4, 2.6 Hz), 6.72 (s, IH), 5.65 (s, IH), 5.51 (s, 3H), 3.93 (s, 3H), 1.99 (s,
3H), 1.2 (s, 6H). Example 353 10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline Example IF and the 4-picolinyllithium were processed as in Example IB to provide the desired compound. MS (DCI NH3) m/z 397 (M+H)+; H NMR (300 MHz, DMSO-d6), isomer 1:08.52 (d, 2H, J=6.1 Hz), 8.17 (d, IH, J=8.8 Hz), 7.2 (t, IH, J=8.2 Hz), 6.96 (s, IH), 6.7 (m, 3H), 6.66 (s, 2H), 5.55 (s, IH), 4.53 (s, IH), 3.93 (s, 3H), 1.81 (d, 3H, J=1.4 Hz), 1.27 (s, 6H); isomer 2:08.32 (d, 2H, J=6.1
Hz), 8.19 (d, IH, J=8.8 Hz), 7.17 (t, IH, J=8.2 Hz), 6.99 (s, IH), 6.77 (m, 3H), 6.45 (s, 2H), 5.48 (s, IH), 5.05 (s, IH), 3.93 (s, 3H), 1.81 (d, 3H, J=1.4 Hz), 1.27 (s, 6H).
Example 354 10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline Example IF and the lithium anion of cylopropylmethylbromide were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 360 (M+H)+; !H NMR (300 MHz, DMSO-d6)08.16 (d, IH, J=8.8 Hz), 7.10 (t, IH, J=7.7 Hz), 6.8-6.6
(m, 4H), 6.47 (s, IH), 5.89-5.75 (m, IH), 5.41 (s, IH), 5.10-4.93 (m, 2H), 4.67 (t, IH, J=7.5 Hz), 3.88 (s, 3H), 1.97 (d, 3H, J=1.3 Hz), 1.20 (s, 6H).
Example 355 10-methoxy-5-(l -methylpropylidene)-2,5 -dihydro-5-phenyl-2,2,4-trimethyl- 1 H-
[ 1 Ibenzopyrano [3 ,4-fj quinoline Example IF and the sec-butyllithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 362 (M+H)+; lU NMR (300 MHz, DMSO-d6)O8.01 (d, IH, J=8.09 Hz), 7.09 (t, 2H, J=8.09 Hz), 6.7
(dd, 2H, J=8.5, 2.6 Hz), 6.65 (d, IH, J=8.46 Hz), 6.37 (d, IH, J=0.8 Hz), 5.4 (s, IH), 3.87 (s, 3H), 1.86 (d, 3H, J=l.l Hz), 1.48 (s, 3H), 1.33 (s, 3H), 1.08 (s, 3H), 0.9 (t, 3H, J=7.3 Hz). Example 356 10-methoxy-5-(l-butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- [ 1 Ibenzopyrano [3 ,4-f] quinoline Example IF and the «-butyllithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 362 (M+H)+;
*H NMR (300 MHz, DMSO-d6)D8.14 (d, IH), 7.07 (t, IH), 6.67 (m, 3H), 6.07 (s, IH), 5.40 (s, IH), 4.71 (t, IH), 3.88 (s, 3H), 2.29 (q, IH), 2.00 (s, 3H), 1.43-1.36 (m, 2H), 1.21 (s, 6H), 0.88 (t, 3H).
Example 357 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-3 -oxide-5 -phenyl- 1 H- [1 Jbenzopyrano [3 ,4-f|quinazoline
Example 357A
8-amino-7-bromo-l-methoxy-6H-benzo[c1chromen-6-one A solution of Example IE (3.0 g, 12.0 mmol) in DMF (100 mL) was treated with N-bromosuccinimide (2.2 g, 12.0 mmol), stirred for 40 minutes, poured into 900 mL of water, stirred for 5 minutes and the resulting solid was collected by filtration and dried to give the desired compound.
Example 357B 7-bromo- 1 -methoxy-6-phenyl-6H-benzo[cJchromen-8-ylamine Example 357A (2.0 g, 6.25 mmol) and phenyllithium were processed as in Examples 1 G and 1 to provide the desired compound.
Example 357C 1 -(7-bromo-l -methoxy-6-phenyl-6H-benzo[cjchromen-8-yl)ethan-l -one Example 357B (1.23 g, 3.22 mmol), tributyl(l-ethoxyvinyl)tin, (1.4 g, 3.86 mmol), and dichlorobis(triphenylphosphine)palladium (II) (263 mg, 0.322 mmol) in
NMP (30 mL) were heated at 85 °C for 24 hours under nitrogen. The mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate and filtered through Celite. The EtoAc layer was concentrated and the residue was dissolved in acetonitrile, washed 5 X 20 mL with hexanes and concentrated. The resulting residue was treated with a 1 : 1 volume of IN HCl / THF, stirred for 30 minutes, poured into cold, saturated sodium bicarbonate and extracted with EtOAc (5 X 25 mL). The organics were washed with brine, dried (Na2SO4) and flash chromatographed on silica eluting with 4:1 hexane/EtOAc to give the desired compound. Example 357D 1 -(7-bromo- 1 -methoxy-6-phenyl-6H-benzo [cJchromen-8-yl)ethan- 1 -one oxime A solution of Example 357C (700 mg, 2.03 mmol) and hydroxylamine hydrochloride (2.45 g, 30.4 mmol) in a mixture of EtOH (70 mL) and pyridine (70 mL) was refluxed for 8 hours, cooled and concentrated. The residue was dissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to provide the desired compound without purifiction.
Example 357
2,5-dihydro- 10-methoxy-2,2,4-trimefhyl-3 -oxide-5 -phenyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fj quinazoline Example 357D (700 mg, 1.94 mmol), CuSO4 (105 mg) and acetic acid (3 drops ) were combined in acetone (30 mL) and refluxed for 8 hours. The mixture was cooled, poured into water and extracted with EtOAc (3 X 50 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with
EtOAc (30 mL) and the yellow solid was collected by filtration to provide the desired compound.
MS (DCI/NH3) m/z 401 (M+H)+; iH NMR (300 MHz, DMSO-d6)D8.21 (d, IH), 7.30 (s, IH), 7.29-7.16 (m, 5H), 7.00-
6.92 (m, 2H), 6.61 (d, IH), 6.57 (s, IH), 6.44 (d, IH), 3.72 (s, 3H), 2.01 (s, 3H), 1.55 (s, 3H), 1.28 (s, 3H); HRMS calcd m/z for C24H27NO2: 400.1787 (M*)+. Found: 400.1786
Example 358 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinazoline A solution of Example 357E (80 mg, 0.2 mmol) in MeOH under 4 atmospheres of hydrogen was treated with Raney nickel and stirred for 24 hours. The mixture was filtered through Celite, concentrated and the resulting residue was flash chromatographed on silica eluting with 99:1 EtOAc/MeOH to provide the desired compound.
MS (DCI/NH3) m/z 385 (M+H)+; iH NMR (300 MHz, DMSO-d6)08.22 (d, IH), 7.26-7.15 (m, 5H), 6.93 (t, IH), 6.79 (s,
IH), 6.76 (d, IH), 6.73 (s, IH), 6.57 (d, IH), 6.44 (d, IH), 3.81 (s, 3H), 2.00 (s, 3H), 1.36 (s, 3H), 1.21 (s, 3H).
HRMS calcd m/z for C25H24N2O2: 385.1916 (M+H)+. Found: 385.1930. Example 359 2,5-dihydro-10-methoxy-2,2-[spiro (tetrahydro-4-pyranyl)j-4-methyl-5- allyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
Example 359 A Example 357A (1.3 g, 4.08 mmol), isopropenyltrimetl yltin (3.3 g, 16.3 mmol) and dichlorobis(triphenylphosphine)palladium (II) (330 mg, 0.40 mmol) in NMP (30 mL) were heated at 85 °C for 24 hours under nitrogen. The mixture was partitioned between EtOAc and saturated aqueous potassium fluoride, stirred for 3 hours and filtered through Celite. The EtOAc layer was washed 5 X 50 mL with water, 5 x 50 mL with brine, dried (Na2SO4) and concentrated. Flash chromatography on silica eluting with
3:1 hexane/EtOAc provided the desired product.
Example 359 A mixture ofthe 2-isopropenyl aniline (56 mg, 0.2 mmol), tetrahydro-4H-pyran- 4-one (160 mg, 1.6 mmol) and iodine (25 mg, 0.1 mmol) in 5 mL of toluene in an ACE sealed tube was heated at 80 °C for 1 hour, cooled and the mixture was partitioned between EtOAc and 10% aqueous Na2S2θ3. The EtOAc layer was washed with water, brine, dried (Na2SO4) and concentrated. Flash chromatography on silica eluting with 3 :2 hexane/EtOAc provided the desired coumarin as a bright yellow powder. This resulting coumarin was processed as in Example 2 to provide the desired compound. MS (DCI/NH3) m/z 390 (M+H)+; iH NMR (300 MHz, DMSO-d6)07.92 (d, IH), 7.07 (t, IH), 6.75 (d, IH), 6.70 (d, IH), 6.52 (d, IH), 6.24 (s, IH), 5.87-5.73 (m, 2H), 5.71 (s, IH), 5.01 (dd, IH), 4.96 (dd, IH), 3.86 (s, 3H), 3.75-3.39 (m, 4H), 2.51-2.14 (m, 2H), 2.20 (s, 3H), 1.69-1.49 (m, 4H); HRMS calcd m/z for C25H27NO3: 389.1991 (M)+. Found: 389.1974. Anal, calcd for C25H27NO3: C, 77.07; H, 6.99; N, 3.60. Found: C/76.92; H, 7.28; N,
3.64.
Example 360 2,5-dihydro- 10-methoxy-2,2-[spiro(hexyl)j-5-allyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline Example 357 A was treated sequentially with isopropenyltributyltin and cyclohexanone as in the previous example to give the desired compound. MS (DCI/NH3) m/z 388 (M+H)+; iH NMR (300 MHz, DMSO-d6)D7.95 (d, IH), 7.06 (t, IH), 6.74 (d, IH), 6.70 (d, IH), 6.52 (d, IH), 6.05 (s, IH), 5.85-5.72 (m, 2H), 5.58 (s, IH), 5.02 (dd, IH), 4.97 (dd, IH), 3.86 (s, 3H), 2.42 (m, IH), 2.18 (s, 3H), 2.16 (m, IH), 1.56-1.25 (m, 10H);
HRMS calcd m/z for C26H29NO2: 387.2198 (M)+. Found: 387.2196. Example 361 2,5-dihydro-10-methoxy-2,2-diethyl-4-methyl-5-allyl-lH-[lJbenzopyrano[3,4- f] quinoline Example 357 A was treated sequentially with isopropenyltributyltin and 3- pentanone as in the previous example to give the desired compound. MS (DCI/NH3) m/z 376 (M+H)+; iH NMR (300 MHz, DMSO-d6) 07.92 (d, IH), 7.05 (t, J=8 Hz, IH), 6.68 (d, IH), 6.59 (d, IH), 6.51 (d, IH), 5.98 (s, IH), 5.86-5.77 (m, 2H), 5.27 (s, IH), 5.04-4.95 (m, 2H), 3.85 (s, 3H), 2.42 (m, IH), 2.21 (s, 3H), 2.15 (m, IH), 1.42-1.35 (m, 4H), 0.83 (t, 3H),
0.82 (t, 3H);
HRMS calcd m/z for C25H29NO2: 375.2198 (M*)+. Found: 375.2191. Anal, calcd for C25H29 O2: C, 79.96; H, 7.78; N, 3.73. Found: C, 79.74; H, 7.89; N, 3.54.
Example 362 2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[ljbenzopyrano[3 ,4-fjquinoline Example 357 A was treated sequentially with 1 -methyl- 1-propenyltributyltin and acetone as in the previous example to give the desired compound MS (DCI/NH3) m/z 362 (M+H)+; iH NMR (300 MHz, DMSO-d6) D7.97 (d, IH), 7.07 (t, IH), 6.70 (d, IH), 6.62 (d, IH), 6.53 (d, IH), 5.90 (s, IH), 5.76 (m, IH), 5.61 (dd, IH), 5.01-4.90 (m, 2H), 3.87 (s, 3H), 2.47 (m, IH), 2.18 (m, IH), 2.04 (s, 3H), 1.76 (s, 3H), 1.13 (s, 3H), 1.09 (s, 3H); HRMS calcd m/z for C24H27NO2: 361.2042 (M")+. Found: 361.2055.
Example 363 2,5-dihydro-l 0-methoxy-2,2-dimethyl-4-ethyl-5-allyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline Example 357 A was treated sequentially with 1-methylenepropyltributyltin and acetone as in the previous example to give the desired compound.
MS (DCI/NH3) m/z 362 (M+H)+; iH NMR (300 MHz, DMSO-d6) D7.98 (d, IH), 7.07 (t, IH), 6.70 (dd, IH), 6.63 (d, IH), 6.53 (dd, IH), 6.12 (bs, IH), 5.78 (m, IH), 5.59 (dd, IH), 5.50 (bs, IH), 5.03-4.92 (m, 2H), 3.86 (s, 3H), 2.54-2.41 (m, 3H), 2.11 (m, IH), 1.20 (s, 3H), 1.10 (s, 3H), 1.03 (t, 3H);
HRMS calcd m/z for C24H27NO2: 361.2042 (M*)+. Found: 361.2034. Example 364 2,5-dihydro-10-methoxy-2,2,3-trimethyl-5-allyl-lH-[lJbenzopyranor3,4-fjquinoline Example 357A was treated sequentially with (Z)-l-propenyltributyltin and acetone as in the previous example to give the desired compound.
MS (DCI/NH3) m/z 348 (M+H)+; iH NMR (300 MHz, DMSO-d6) 07.89 (d, IH), 7.04 (t, IH), 6.68 (d, IH), 6.52 (d, IH),
6.47 (d, IH), 6.21 (s, IH), 5.96 (s, IH), 5.88 (m, IH), 5.43 (dd, IH), 5.03 (m, IH), 4.96 (m, IH), 3.84 (s, 3H), 2.35 (m, IH), 2.08 (m, IH), 1.83 (s, 3H), 1.23 (s, 6H); HRMS calcd m/z for C23H25NO2: 347.1885 (M*)+. Found: 347.1879.
Example 365 Z-5-(benzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro- MS (DCI/NH3) 412 (M+H)+; iH NMR (300 MHz, DMSO-d6),D8.93 (s, 1 H), 8.13 (d, J=8.8 Hz, 1 H), 7.63 (d, J=8.8
Hz, 2 H), 7.32-7.15 (m, 3 H), 6.77 (d, 1 H), 6.69 (d, 1 H), 6.66 (d, 1 H), 6.52 (s, 1 H), 5.46 (s, 1 H), 5.39 (s, 1 H), 3.65 (s, 3 H), 1.90 (s, 3 H), 1.20 (s, 6 H); HRMS calcd for C27H25NO3 is 411.1834. Found 411.1821.
Example 366
Z-5-(2,5-difluorobenzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro-
[1 jbenzopyrano[3 ,4-fjquinoline MS (DCI/NH3) m/e (M+H)+ 448. iH NMR (300 MHz, DMSO-d6)D9.06 (s, IH), 8.29 (d, J=9 Hz, IH), 7.96 (m, IH), 7.24 (m, IH), 7.11 (m, IH), 6.86 (d, J=9 Hz, IH), 6.82 (d, J=9 Hz, IH), 6.78 (d, J=9 Hz, IH),
6.72 (br s, IH), 5.75 (s, IH), 5.48 (s, IH), 3.75 (s, 3H), 1.99 (s, 3H), 1.26 (br s, 6H); Anal, calcd for C27H23NO3F2 : C, 72.47; H, 5.18; N, 3.13. Found: C, 72.21; H, 5.31;
N, 3.09.
Example 367
Z-5 -(3 -fluorobenzylidenyl)- 10-chloro-9-hydroxy-2 ,2 ,4-trimethyl-2, 5-dihydro- 1 H-
[l]benzopyrano[3,4-f]quinorine MS (DCI/NH3) m/z 434 (M+H)+;
!H NMR (300 MHz, DMSO)09.86 (br s, 1 H), 8.40 (d, J=8.5 Hz, 1 H), 7.61 (dt, J=8.6, 1.8 Hz, 1 H), 7.60-7.52 (m, 1 H), 7.46-7.38 (m, IH), 7.15-7.02 (m, 1 H), 7.09 (d, J=8.4
Hz, 1 H), 6.85 (d, J=8.6 Hz, 1 H), 6.84 (s, 1 H), 6.78 (d, J=8.6 Hz, 1 H), 5.68 (s, 1 H),
5.48 (br s, 1 H), 1.97 (br s, 3 H), 1.16 (br s, 6 H); 13C NMR (125 MHz, DMSO)0163.8, 160.6, 149.9, 149.2, 148.2, 146.4, 132.0, 130.3,
128.1, 127.3, 126.2, 125.3, 124.5, 118.7, 117.7, 117.3, 116.1, 115.5, 114.6, 114.3, 114.0,
113.7, 62.1, 29.8, 28.2, 21.2;
HRMS (FAB) calcd m/z for C26H21CIFNO2: 433.1245 (M)+. Found: 433.1237.
Example 368 Z-10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
T 1 Ibenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 417 (M+H)+; *H NMR (300 MHz, DMSO)09.79 (br s, 1 H), 8.51 (ddd, J=5.9, 1.6, 1.0 Hz, 1 H), 8.43
(d, J=8.6 Hz, 1 H), 8.24 (dt, J=7.8, 1.0 Hz, 1 H), 7.53 (td, J=7.8, 1.7 Hz, 1 H), 7.22 (ddd, J=7.7, 5.8, 1.2 Hz, 1 H), 7.00 (d, J=8.5 Hz, 1 H), 6.88 (d, J=8.6 Hz, 1 H), 6.81 (d, J=8.5 Hz, 1 H), 6.63 (br s, 1 H), 5.71 (s, 1 H), 5.51 (br s, 1 H), 2.00 (br s, 3 H), 1.28 (br s, 6 H); 13C NMR (125 MHz, DMSO-d6)P 153.5, 149.7, 146.4, 145.7, 136.5, 136.1, 132.7, 128.7, 128.2, 123.0, 122.4, 121.5, 118.3, 117.7, 117.6, 116.5, 115.5, 114.8, 114.4, 114.1,
113.9, 49.5, 29.7, 28.1, 21.2; HRMS (FAB) calcd m/z for C25H21CIN2O2: 416.1291 (M)+. Found: 416.1288.
Example 369 Z-9-hydroxy-10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[1 jbenzopyranoP,4-fjquinoline MS (DCI/NH3) m/z 413 (M+H)+;
*H NMR (300 MHz, DMSO)D9.08 (br s, 1 H), 8.55 (ddd, J=5.3, 1.4, 1.0 Hz, 1 H), 8.32
(d, J=8.6 Hz, 1 H), 8.30 (br t, J=7.7 Hz, 1 H), 7.83 (td, J=7.8, 1.4 Hz, 1 H), 7.21 (ddd, J=7.6, 5.3, 1.2 Hz, 1 H), 6.97 (d, J=8.6 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 6.81 (d, J=8.6
Hz, 1 H), 6.73 (br s, 1 H), 5.80 (s, 1 H), 5.54 (br s, 1 H), 3.78 (s, 3 H), 2.03 (br s, 3 H),
1.31 (br s, 6 H);
13C NMR (125 MHz, DMSO-d6)P 158.4, 149.1, 148.2, 146.6, 139.5, 136.0, 133.1,
128.8, 125.7, 124.6, 122.9, 121.0, 119.4, 118.2, 117.3, 116.9, 115.8, 115.1, 114.7, 114.0, 111.5, 73.3, 50.2, 29.9, 28.1, 22.3;
HRMS (FAB) calcd m/z for C26H25N2O3: 413.1865 (M+H)+. Found: 413.1849.
Anal, calcd for C26H24N2O3: C, 75.71; H, 5.86; N, 6.79. Found: C, 75.61; H, 6.05; N,
6.75. Example 370 9-hydroxy-10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline IH NMR (300 MHz, DMSO-d6)D9.05 (s, IH), 8.24 (d, J=9 Hz, IH), 7.41 (m, 2H), 7.07
(m, IH), 6.85 (d, J=8 Hz, IH), 6.80 (d, J=9 Hz, IH), 6.76 (d, J=9 Hz, IH), 6.70 (br s, IH), 5.57 (s, IH), 5.46 (s, IH), 3.72 (s, 3H), 1.96 (s, 3H), 1.27 (br s, 6H); 12C NMR (75 MHz, DMSO-d6)D 164.0 (d), 160.8 (d), 150.1, 146.2, 146.1, 144.6, 144.4, 132.1, 128.8, 125.2, 125.0, 117.9, 117.8, 115.2, 115.0, 114.8, 112.1, 110.9, 110.8, 110.5, 101.9, 101.6, 101.2, 29.3, 49.5, 21.1 (2xC); MS (DCI/NH3) m/e (M+H)+ 448.
Example 371 9-hydroxy- 10-methoxy-5 -(3 ,4-difluorophenyl)methylidene-2,5-dihydro-5 -phenyl-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline iH NMR (300 MHz, DMSO-d6)D9.03 (s, IH), 8.22 (d, J=9 Hz, IH), 7.79 (m, IH), 7.52
(m, IH), 7.41 (m, IH), 6.86 (d, J=9 Hz, IH), 6.77 (d, J=9 Hz, IH), 6.74 (d, J=9 Hz, IH), 6.68 (br s, IH), 5.53 (s, IH), 5.45 (s, IH), 3.33 (s, 3H), 1.95 (s, 3H), 1.27 (br s, 6H); MS (DCI/NH3) m/e (M+H)+ 448. FAB HRMS calculated for C27H23NO3F2.
Example 372 (Z) 9-hydroxy- 10-methoxy-5 -((4-fluorophenyl)methylene)-2,2,4- trimethy 1- 1 H-2 , 5 -dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline iH NMR (300 MHz, DMSO-d6)O9.01 (s, IH), 8.19 (d, J=9 Hz, IH), 7.77 ( d, J=9 Hz,
IH), 7.76 (d, J=9 Hz, IH), 7.22 (d, J=9 Hz, IH), 7.18 (d, J=9 Hz, IH), 6.84 (d, J=8 Hz, IH), 6.75 (d, J=9 Hz, IH), 6.72 (d, J=9 Hz, IH), 6.66 (s, IH), 5.53 (s, IH), 5.45 (s, IH), 3.71 (s, 3H), 1.96 (s, 3H), 1.26 (s, 6H); 13C NMR (75 MHz, DMSO-d6)D 161.8, 159.4,
147.4, 146.0, 145.1, 144.4, 132.0, 131.4, 130.2, 130.1, 129.0, 126.2, 125.0, 117.8, 115.4, 115.3, 115.2, 114.6, 114.5, 113.3, 111.0, 59.3, 59.2, 49.5, 21.0; . MS (DCI/NH3) m/z 430 (M+H)+; Anal, calcd for C27H24NO3F: C, 75.51; H, 5.63; N, 3.26. Found: C, 75.64; H, 5.97; N, 3.03.
Example 373 (Z)-9-hydroxy-10-methoxy-5-(r2,3-difluorophenyljmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 jbenzopyrano [3,4-f] quinoline iH NMR (300 MHz, DMSO-d6)D9.09 (s, IH), 8.27 (d, J=9 Hz, IH), 8.04 ( d, J=9 Hz, IH), 7.33-7.20 (m, 2H), 6.87 (d, J=9 Hz, IH), 6.82 (d, J=9 Hz, IH), 6.76 (s, IH), 6.75
(d, J=9 Hz, IH), 5.75 (s, IH), 5.49 (s, IH), 3.73 (s, 3H), 1.99 (s, 3H), 1.26 (s, 6H); MS (DCI NH3) m/z 448 (M+H)+; Anal, calcd for C27H23NO3F2: C, 72.47; H, 5.18; N,
3.13. Found: C, 72.17; H, 5.03; N, 2.95. Example 374 Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline iH NMR (300 MHz, DMSO-d6)D9.04 (s, IH), 8.22 (d, IH), 7.62-7.37 (m, 3H), 7.10-
7.02 (m, IH), 6.86 (d, IH), 6.78 (d, IH), 6.73 (d, IH), 6.70 (s, IH), 5.56 (s, IH), 5.46 (s, IH), 3.72 (s, 3H), 1.96 (s, 3H), 1.27 (s, 3H). MS (DCI/NH3) m/z 430 (M+H)+; Anal, calcd for C27H24NO3F' 0.25 H2O: C, 75.51; H, 5.63; N, 3.26. Found: C, 74.84; H, 6.17; N,2.91.
Example 375 re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenylJ-10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m/z 452 (M + H)+; NMR (300 MHz, DMSO)D8.02 (d, J= 8.6 Hz, 1 H), 6.93 (app s, 2 H), 6.68 (d, J=
8.3 Hz, 1 H), 6.48 (br s, 1 H), 5.52 (d, J= 10.3 Hz, 1 H), 5.42 (br s, 1 H), 5.10 (br s, 1 H), 4.46 (t, J= 5.5 Hz, 1 H), 3.81 (s, 3 H), 3.65 (br d, J= 5.5 Hz, 2 H), 2.26-2.16 (m, 1 H), 2.08 (br s, 3 H), 1.95-1.88 (m, 2 H), 1.77-1.62 (m, 2 H), 1.57-1.44 (m, 1 H), 1.37- 1.28 (m, 1 H), 1.30 (s, 3 H), 1.11 (s, 3 H); 13C NMR (125 MHz, DMSO)0150.4, 146.0, 144.9, 140.7, 133.9, 132.7, 127.9, 127.0,
124.3, 119.8, 117.7, 116.7, 115.7, 115.4, 112.5, 110.7, 75.9, 65.5, 56.4, 49.6, 36.6, 29.7, 27.9, 25.9, 25.0, 24.4, 20.3; HRMS (FAB) calcd m/z for C27H30CINO3: 451.1915 (M)+. Found: 451.1922.
Example 376
9-hydroxy-10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3,4- fjquinoline IH NMR (200 MHz, DMSO-d6)O8.70 (s, IH), 7.90 (d, j=8 Hz, IH), 6.61 (m, 2H), 6.51 (d, J=8 Hz, IH), 6.16 (br s, IH), 5.52-5.40 (m, 2H), 2.62 (s, 2H), 2.09 (s, 2H), 1.79-1.58 (m, IH), 1.52-1.27 (m, IH), 1.17 (s, 2H), 1.15 (s, 2H), 0.89 (t, J=7 Hz, 2H); 12C NMR
(75 MHz, DMSO-d6)D 145.8, 145.0, 142.9, 142.0, 122.5, 122.4, 127.6, 126.4, 118.0, 116.4, 116.1, 114.2, 112.5, 112.2, 75.1, 59.2, 49.7, 29.2, 28.8, 25.5, 22.8, 10.4; MS (DCI NH3) m/e (M+H)+ 252; Anal, calcd for C22H25NO2»l/2H2O: C, 72.94; H, 7.24; N, 2.92. Found: C, 72.78; H, 7.40; N, 2.74. Example 377 (+/-) 2,5-dihydro-9-cyanomethoxy- 10-methoxy-2,2,4-trimethyl-5-allyl-
1 H- [ 1 Ibenzopyrano [3 ,4-fjquinoline IH NMR (200 MHz, DMSO-d6)07.92 (d, IH), 6.95 (d, IH), 6.66 (d, IH), 6.62 (d, IH), 6.26 (d, IH), 5.86 (m, 2H), 5.45 (s, IH) 5.12 (s, 2H), 5.00 (m, 2H), 2.69 (s, 2H), 2.42 (m, IH), 2.26 (m, IH), 2.17 (s, 2H), 1.18 (s, 2H), 1.17 (s, 2H).
Example 378 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-butanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(2-propenyl)-lH-[11benzopyranor3,4-f]quinoline IH NMR (400 MHz, DMSO-d6)D7.78 (d, J=8.5, IH), 6.76 (d, J=8.9, IH), 6.60- 6.55 (m, 2H), 6.18 (d, J=1.7, IH), 5.80-5.70 (m, 2H), 5.28 (s, IH), 4.98-4.90 (m, 2H), 2.55 (s, 2H), 2.28-2.17 (m, 4H), 2.77-2.69 (m, 2H), 2.68-2.57 (m, 2H), 2.29 (m, IH),
2.19 (m, IH), 2.10 (s, 2H), 1.11 (s, 2H), 1.10 (s, 2H), 1.06 (t, J=7.2, 2H), 0.95 (t, J=7.2, 2H); 13C NMR (100 MHz, DMSO-d6)0171.5, 169.5, 148.2, 148.0, 146.2, 128.5, 124.1, 122.5, 122.1, 127.2, 126.2, 120.8, 118.2, 117.2, 116.2, 115.0, 112.8, 112.5, 72.6, 60.0, 49.8, 41.1, 26.6, 29.2, 29.0, 27.4, 22.8, 14.0, 12.1; MS (ESI/NH3) m/e 519(M+H)+, 541(M+Na)+; Anal. Calcd for C31H38N2O5: C 71.79, H 7.28, N 5.40. Found: C
71.50, H 7.28, N 5.28.
Example 379 2,5-dihydro-9-(4-N-piperidino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[ljbenzopyrano[3 ,4-fjquinoline IH MR (200 MHz, DMSO-d6)D7.78 (d, J=8.4, IH), 6.76 (d, J=8.8, IH), 6.61- 6.55 (m, 2H), 6.17 (d, J=1.5, IH), 5.82-5.68 (m, 2H), 5.28 (s, IH), 4.99-4.89 (m, 2H),
2.55 (s, 2H), 2.27 (m, 4H), 2.74 (m, 2H), 2.61 (m, 2H), 2.41 (m, IH), 2.18 (m, IH), 2.10 (s, 2H), 1.51-1.16 (m, 6H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (75 MHz, DMSO- d6)D 171.7, 168.9, 148.5, 148.2, 146.5, 128.7, 124.2, 122.8, 122.2, 127.5, 126.5, 121.0, 118.4, 117.5, 116.4, 115.2, 114.0, 112.8, 72.8, 60.2, 50.0, 45.9, 42.4, 26.8, 29.5, 29.2, 27.7, 26.1, 25.5, 24.2, 24.1 ; MS (ESI/NH3) m/e 521(M+H)+, 552(M+Na)+; Anal. Calcd for C32H38N2O5: C 72.42, H 7.22, N 5.28. Found: C 72.16, H 7.26, N 5.09.
Example 380 2,5-dihydro-9-(4-N-morpholino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline IH NMR (400 MHz, DMSO-d6)D7.78 (d, J=8.9, IH), 6.77 (d, J=8.5, IH), 6.60- 6.55 (m, 2H), 6.18 (s, IH), 5.80-5.70 (m, 2H), 5.28 (s, IH), 4.98-4.90 (m, 2H), 2.55 (s,
2H), 2.52-2.42 (m, 4H), 2.40 (m, 4H), 2.76 (m, 2H), 2.65 (m, 2H), 2.40 (m, IH), 2.20 (m, IH), 2.10 (s, 2H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (100 MHz, DMSO- d6)D 171.4, 169.4, 148.2, 148.0, 146.2, 128.5, 124.1, 122.5, 122.1, 127.2, 126.2, 120.8, 118.2, 117.2, 116.2, 115.0, 112.8, 112.6, 72.6, 66.1, 60.0, 49.8, 45.1, 41.6, 26.6, 29.2, 29.0, 28.8, 27.2, 22.8; MS (ESI/NH3) m/e 522(M+H)+, 555(M+Na)+; Anal. Calcd for
C31H36N2O6: C 69.90, H 6.81, N 5.26. Found: C 69.61, H 6.84, N 5.04. Example 381 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-[ljbenzopyrano[3,4-fjquinoline IH NMR (400 MHz, DMSO-d6)O7.90 (d, J=8.5, IH), 7.07-7.02 (m, 2H), 6.80- 6.70 (m, 2H), 6.62 (d, J=8.9, IH), 6.44 (s, IH), 5.42 (d, J=1.2, IH), 2.54 (s, 2H), 2.97 (s, 2H), 2.82 (s, 2H), 2.76-2.72 (m, 2H), 2.67-2.64 (m, 2H), 1.84 (s, 2H), 1.25 (s, 2H), 1.15
(s, 2H); 13C NMR (100 MHz, DMSO-d6)0171.4, 170.4, 150.1 (d, J=248), 148.4, 147.9, 146.4, 128.7, 128.2 (dd, J=251, 49), 126.5, 122.2, 128.2, 127.1, 126.5, 121.0, 118.5, 117.9, 116.1, 114.8, 112.0, 112.8, 112.6, 72.7, 59.7, 49.9, 26.5, 24.9, 29.7, 28.9, 28.6, 27.6, 22.2; MS (ESI/NH3) m/e 581(M+H)+, 602(M+Na)+; Anal. Calcd for C32H3iF3N2θ5* C 66.20, H 5.28, N 4.82. Found: C 66.17, H 5.46, N 4.65.
Example 382 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5- difluorophenylmethyl)- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline iH NMR (300 MHz, DMSO-d6)08.81 (s, IH), 7.95 (d, J= 8 Hz, IH), 7.10-7.03 (m,
IH), 6.78 (d, J= 9 Hz, 2H), 6.63 (dd, J= 9, 9 Hz, 2H), 6.41 (d, J= 9 Hz, IH), 6.22 (s, IH), 5.91 (dd, J= 10, 10 Hz, IH), 5.40 (s, IH), 3.69 (s, 3H), 3.06-2.98 (m, IH), 2.90-
2.84 (m, IH), 2.19 (s, 3H), 1.15 (s, 3H), 1.12 (s, 3H); 13C NMR (75 MHz, DMSO- d6)0163.8, 163.6, 160.6, 160.4, 145.9, 145.2, 144.1, 142.6, 142.4, 142.3, 133.4, 131.7,
127.4, 126.5, 117.8, 116.5, 116.2, 114.5, 113.9, 112.3, 112.2, 111.9, 102.1, 101.7, 101.4,
73.5, 59.5, 49.7, 29.1, 29.0, 24.1; HRMS calc'd for C27H25O3F2N: m/e 449.1803, found 449.1801 ; Analysis calc'd for C27H25O3F2N 0.05H2O: C, 70.73; H, 5.72; N,
3.05; found: C, 70.52; H, 5.79; N, 2.91.
Example 383 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-thienyl)-lH-
[1 Ibenzopyrano [3 ,4-fjquinoline
1H NMRQ9.51 (s, IH), 7.95 (d, IH, J=8.5Hz), 7.40 (dd, IH, J=5.1Hz, J=1.4Hz), 6.82 (m, 2H), 6.71 (m, 2H), 6.61 (s, 2H), 6.26 (m, IH), 5.40 (m, IH), 1.92 (d, 2H, J=1.4Hz),
1.24 (s, 2H), 1.14 (s, 2H); mass spectrum (ESI) m/z: 410 (M + 1); Calcd for ,
C22H20C1NO2S: 409.0902. Found: 409.0902.
Example 384 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclopentyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)D8.70 (s, IH), 7.99 (d, J= 8 Hz, IH), 6.63 (d, J= 9 Hz,
IH), 6.61 (d, J= 9 Hz, IH), 6.48 (d, J= 8 Hz, IH), 6.27 (br s, IH), 5.45 (br s, IH), 5.35 (d, J= 10 Hz, IH), 3.65 (s, 3H), 2.15 (s, 3H), 2.11 - 1.97 (m, IH), 1.62 - 1.43 (m, 4H), 1.41 - 1.26 (m, 2H), 1.30 (s, 3H), 1.21 - 1.06 (m, 2H), 1.02 (s, 3H); MS (DCI NH3)
(M+H)+ 392. Example 385 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2- fluorophenyl)methyl) - 1 H-[l JbenzopyranoP ,4-fjquinoline MS (DCI/NH3) m/z 418 (M+H)+. Example 386 2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 378 (M+H)+;
*H NMR (500 MHz, DMSO)07.93 (d, J= 8.2 Hz, 1 H), 7.16 (d, J= 8.3 Hz, 1 H), 6.67 (d, J= 8.1 Hz, 1 H), 6.63 (d, J= 8.3 Hz, 1 H), 6.27 (br s, 1 H), 5.87-5.75 (m, 2 H), 5.44
(br s, 1 H), 5.03 (br d, J= 10.3 Hz, 1 H), 4.98 (br d, J= 15.1 Hz, 1 H), 4.97-4.93 (m, 1
H), 4.57-4.48 (m, 2 H), 3.59 (s, 3 H), 2.55-2.46 (m, 1 H), 2.30-2.22 (m, 1 H), 2.19 (s, 3
H), 1.19 (s, 3 H), 1.16 (s, 3 H);
13C NMR (125 MHz, DMSO) 0154.0, 150.2, 145.9, 134.2, 133.4, 132.1, 128.9, 127.4, 126.6, 125.9, 117.2, 116.8, 116.3, 115.6, 113.9, 112.6, 73.6, 60.0, 58.1, 49.8, 36.4, 29.4,
28.9, 23.9;
HRMS (FAB) calcd m/z for C24H27NO3: 377.1991 (M)+. Found: 377.1985.
Example 387 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-pentenyl)-lH-
[11benzopyrano[3,4-fjquinoline iH NMR (300 MHz, DMSO-d6)P8.67 (s, IH), 7.88 (d, J= 9 Hz, IH), 6.59 (d, J= 9 Hz,
2H), 6.48 (d, J= 8 Hz, IH), 6.14 (s, IH), 5.73-5.65 (m, IH), 5.61-5.57 (m, IH), 5.43 (s, IH), 4.94-4.86 (m, 2H), 3.63 (s, 3H), 2.15 (s, 3H), 1.99-1.93 (m, 2H), 1.73-1.69 (m, IH), 1.45-1.41 (m, 3H), 1.16 (s, 6H); 13C NMR (75 MHz, DMSO-d6)P 145.7, 144.9, 143.9,
143.0, 138.4, 133.4, 133.3, 127.5, 126.4, 117.9, 116.2, 116.1, 114.7, 114.2, 113.4, 112.1, 73.5, 59.3, 49.7, 32.5, 31.7, 29.1, 28.9, 24.6, 23.8; MS calc'd for C25H29O3N: m/e
391.2147, found 391.2153; Analysis calc'd for C25H29O3N 0.50 H2O: C, 74.97; H, 7.55; N, 3.50; found: C, 75.20; H, 7.45; N, 3.49.
Example 388 2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-allyl-
1H-[1 jbenzopyrano [3, 4-f]quinoline MS (DCI/NH3) m/z 406 (M+H)+;
!H NMR (125 MHz, DMSO)07.92 (d, J= 8.1 Hz, 1 H), 6.48 (d, J= 8.3 Hz, 1 H), 6.75 (d, J= 8.2 Hz, 1 H), 6.65 (d, J= 8.2 Hz, 1 H), 6.33 (br s, 1 H), 5.90-5.75 (m, 2 H), 5.46 (br s, 1 H), 5.04 (dd, J= 10.5, 1.0 Hz, 1 H), 4.98 (dd, J= 15.4, 1.0 Hz, 1 H), 3.82 (s, 3 H), 3.67 (s, 3 H), 2.54-2.42 (m, 1 H), 2.38-2.27 (m, 1 H), 2.18 (s, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H);
13C NMR (300 MHz, DMSO) 0166.1, 156.5, 154.6, 146.3, 133.9, 133.5, 131.9, 129.0,
127.2, 126.2, 119.1, 118.1, 117.4, 116.2, 114.5, 114.0, 113.0, 74.0, 60.7, 51.8, 49.8, 36.8,
29.4, 29.0, 23.8;
HRMS (FAB) calcd m/z for C25H27NO4: 405.1940 (M)+. Found: 405.1939. Example 389 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-allenyl-lH-
[11benzopyrano[3,4-f]quinoline iHNMR (300 MHz, DMSO-d6)08.67 (s, IH), 7.93 (d, J= 9 Hz, IH), 6.57 (dd, J= 10,
9 Hz, 2H), 6.48 (d, J= 9 Hz, IH), 6.15-6.12 (m, 2H), 5.41 (s, IH), 5.31 (q, J= 12 Hz, IH), 4.72-4.69 (m, IH), 4.59-4.49 (m, IH), 3.58 (s, 3H), 2.14 (s, 3H), 1.23 (s, 3H), 1.10 (s, 3H); MS calc'd for C23H23O3N: m/e 361.1678, found 361.1671; Analysis calc'd for
C23H23O3N 0.5 H2O: C, 74.58; H, 6.53; N, 3.78; found: C, 74.98; H, 6.56; N, 3.83. Example 390 (-) (5S, 3'S) 2,5-dihvdro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3- yl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6) 08.05 (d, J= 9 Hz, IH), 7.09 (t, J= 8 Hz, IH), 6.72
(d, J= 8 Hz, IH), 6.66 (d, J= 9 Hz, IH), 6.58 (d, J= 8 Hz, IH), 6.19 (s, IH), 5.77 (dd, J = 6,3 Hz, IH), 5.50 (d, J= 10 Hz, IH), 5.43 (s, IH), 5.19 (dd, J= 6, 2 Hz, IH), 3.87 (s, 3H), 2.90 (m, IH), 2.43-2.15 (m, 2H), 2.09 (s, 3H), 1.97-1.70 (m, 2H), 1.31 (s, 3H), 1.09 (s, 3H); 13C NMR (75 MHz, DMSO-d6)P 156.2, 151.4, 145.2, 133.7, 132.5, 131.6,
130.0, 128.1, 127.2, 127.1, 117.0, 116.4, 113.4, 113.1, 110.0, 105.3, 75.9, 55.6, 49.5,
48.6, 31.6, 29.7, 27.3, 27.2, 24.2;
(DCI NH3) m/z 374 (M+H)+; MS (FAB HRMS) calc'd for C25H27NO2: m/e
373.2042, found: 373.2047. Example 391 (- (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3- y 1)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline iHNMR (300 MHz, DMSO-d6)D8.03 (d, J= 9 Hz, IH), 7.07 (t, J= 8 Hz, IH), 6.68 (d,
J= 8 Hz, IH), 6.63 (d, J= 9 Hz, IH), 6.57 (d, J= 8 Hz, IH), 6.15 (s, IH), 5.62 (m, IH), 5.54 (m, IH), 5.46 (s, IH), 5.09 (m, IH), 3.85 (s, 3H), 2.29 (m, IH), 2.10 (s, 3H), 1.95- 1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1.10 (m, 2H), 1.28 (s, 3H), 1.05 (s, 3H); i3C
NMR (75 MHz, DMSO-d6)D 156.2, 151.0, 145.0, 133.7, 130.4, 129.1, 128.1, 127.1,
126.1, 117.9, 116.5, 113.5, 113.1, 110.1, 105.4, 75.3, 55.6, 49.5, 36.8, 29.7, 27.3, 25.5,
24.6, 24.3, 20.0; MS (DCI/NH3) m/z 388 (M+H)+; MS (FAB HRMS) calc'd for C26H29NO2: m/e 387.2198, found: 387.2204. [a]23D = -138° (c 0.114, CHCI3).
Example 392 (-) (5S, 3'R) 2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-(cyclohexen-3- yl)- 1 H- [ 1 Ibenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)O8.05 (d, J= 9 Hz, IH), 7.06 (t, J= 8 Hz, IH), 6.67 (d,
J= 8 Hz, IH), 6.64 (d, J= 9 Hz, IH), 6.59 (d, J= 8 Hz, IH), 6.19 (s, IH), 5.82 (m, IH), 5.72 (m, IH), 5.41 (s, IH), 5.40 (d, J= 10 Hz, IH), 3.87 (s, 3H), 2.29 (m, IH), 2.13 (s,
3H), 1.95-1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1.10 (m, 2H), 1.30 (s, 3H), 1.02 (s, 3H); 13C NMR (75 MHz, DMSO-d6)P 156.3, 151.4, 145.0, 133.8, 130.0, 128.3, 127.9, 127.5,
127.1, 126.9, 118.5, 116.4, 113.4, 113.0, 110.2, 105.3, 76.1, 55.6, 49.4, 37.1, 29.6, 26.8,
24.7, 23.6, 21.2; ; MS (DCI/NH3) m/z 388 (M+H)+; ); MS (FAB HRMS) calc'd for C26H29NO2: m/e 387.2198, found: 387.2206.
[Dj23D = -147° (c 0.080, CHCI3). Example 393 (-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3- yl)-lH-[11benzopyranoP,4-fjquinoline iH NMR (300 MHz, DMSO-d6)P8.07 (d, J= 9 Hz, IH), 7.08 (t, J= 8 Hz, IH), 6.70 (d,
J= 8 Hz, IH), 6.66 (d, J= 9 Hz, IH), 6.61 (d, J= 8 Hz, IH), 6.22 (s, IH), 5.82-5.70 (m, 2H), 5.48 (d, J= 13 Hz, IH), 5.41 (d, J= 10 Hz, IH), 3.88 (s, 3H), 2.92 (m, IH), 2.30
(m, IH), 2.20 (m, IH), 2.15 (s, 3H), 1.50-1.40 (m, 2H), 1.33 (s, 3H), 1.05 (s, 3H); 13C NMR (75 MHz, DMSO-d6.)P 156.3, 151.8, 145.1, 133.8, 132.0, 131.8, 130.8, 127.9,
127.0, 117.7, 117.0, 116.5, 113.4, 113.3, 112.9, 109.9, 105.2, 105.0, 76.3, 49.3, 48.4, 32.4, 31.6, 26.7, 24.6, 23.9, 23.6; MS (DCI/NH3) m/z 374 (M+H)+; MS (FAB HRMS) calc'd for C25H27NO2: m/e 373.2042, found: 373.2049.
Example 394 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) - lH-[11benzopyrano[3,4-fjquinoline iH NMR (300 MHz, DMSO-d6)D8.71 (s, IH), 7.92 (d, J= 8 Hz, 1 H), 6.62 (d, J= 9
Hz, IH), 6.60 (d, J= 9 Hz, IH), 6.47 (d, J= 9 Hz, IH), 6.18 (br s, IH), 5.63 (dd, J= 4, 9 Hz, IH), 5.43 (br s, IH), 5.36 (m, 2H), 3.64 (s, 3H), 2.44 - 2.33 (m, IH), 2.33 - 2.19 (m,
IH), 2.15 (s, 3H), 1.70 (m, 2H), 1.16 (s, 6H), 0.75 (t, J= 8 Hz, 3H); MS (DCI/NH3)
(M+H)+ 392. Example 395 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl)
- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline MS (DCI/NH3) m/z 458(M+H)+;
IH NMR (400 MHz, DMSO-d6) 8.62(S, IH), 7.92(d, IH), 7.27(t, IH), 7.12(d, IH), 6.94(dd, IH), 6.82(s, IH), 6.72(d, IH), 6.67(s, IH), 6.44(d, IH), 6.27(d, IH), 6.20(s, IH), 5.29(s, IH), 2.55(s, 2H), 2.18(s, 2H), 1.81(s, 2H), ϊ.25(s, 2H), 1.12(s, 2H). Example 396 10-difluoromethoxy-5-[P-(methylthio)methoxyJphenylj-2,2,4-trimethyl- 1 H-2, 5 -dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) 496 (M+H)+;
IH NMR (200 MHz, DMSO-d6), 07.80 (d, J=8.5 Hz, 1 H), 7.21 (t, JH-F= 56 Hz, 1 H), 7.20-7.12 (m, 2 H), 6.99 (t, IH), 6.82-6.68 (m, 7 H), 6.29 (d, J=l.l Hz, 1 H), 5.40 (s, 1 H), 5.14 (s, 2 H), 2.08 (s, 2 H), 1.85 (s, 2 H), 1.22 (s, 2 H), 1.16 (s, 2 H); HRMS calcd for C28H27NO2F2S is 495.1680. Found 495.1682.
Example 397 2,5-dihydro-7-bromo-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-alIyl- 1 H-
[ljbenzopyranoP,4-fjquinoline MS (DCI/NH3) m/z 448 (M+H)+;
!H NMR (300 MHz, DMSO)010.03 (s, 1 H), 7.90 (d, J= 8.5 Hz, 1 H), 7.00 (app s, 2 H), 6.63 (d, J= 8.4 Hz, 1 H), 6.43 (br s, 1 H), 5.92-5.77 (m, 2 H), 5.47 (br s, 1 H), 5.11-
4.97 (m, 1 H), 2.44-2.26 (m, 2 H), 2.19 (s, 3 H), 1.22 (s, 3 H), 1.18 (s, 3 H); 13C NMR (125 MHz, DMSO-d6)P 156.7, 150.2, 148.6, 144.0, 139.1, 136.3, 135.5,
130.8, 129.2, 124.4, 117.6, 115.9, 115.2, 114.0, 111.6, 75.9, 51.6, 48.3, 35.5, 29.8, 27.9,
24.0;
HRMS (FAB) calcd m/z for C22H2177BrClNO2: 445.0444 (M)+. Found: 445.0436. HRMS (FAB) calcd m/z for C22H2179BrClNO2: 447.0424 (M)+. Found: 447.0413.
Anal. Calcd for C22H2lBrClNO2* C, 59.15; H, 4.74; N, 3.14. Found: C, 59.31; H, 4.85; N, 3.22.
Example 398 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- hydroxyphenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 416(M+H)+;
IH NMR (400 MHz, DMSO-d6) 9.22(s, IH), 8.56(s, IH), 7.92(d, IH), 6.98(t, IH), 6.71(d, IH), 6.64(d, IH), 6.58(m, 2H), 6.54(dd, IH), 6.44(d, IH), 6.22(d, IH), 6.22(s, IH), 5.27(s, IH), 2.56(s, 2H), 1.82(s, 2H), 1.24(s, 2H), 1.12(s, 2H).
Example 399 2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3- (methy lthio)methoxyphenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline
MS (DCI/NH3) m/z 526(M+H)+
IH NMR (400 MHz, DMSO-d6) 7.94(d, IH), 7.14(t, IH), 6.82-6.70(m, 6H), 6.50(d, IH), 6.24(s, IH), 5.29(s, IH), 5.16(s, 2H), 5.14(s, 2H), 2.6 l(s, 2H), 2.14(s, 2H), 2.08(s, 2H), 1.82(s, 2H), 1.24(s, 2H), 1.16(s, 2H). Example 400 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-
(methylthiomethoxy)phenyl)- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 476(M+H)+;
IH NMR (400 MHz, DMSO-d6) 8.58(s, IH), 7.92(d, IH), 7.12(t, IH), 6.82-6.6.71(m, 4H), 6.62(s, IH), 6.42(d, IH), 6.26(d, IH), 6.25(s, IH), 5.28(s, IH), 5.12(s, 2H), 2.55(s, 2H), 2.07(s, 2H), 1.84(s, 2H), 1.22(s, 2H), 1.15(s, 2H).
Example 401 9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5- dihydro-[ 1 Jbenzopyrano [3 ,4-fjquinoline 1H NMRD9.48 (s, IH), 7.98 (m, IH), 7.42 (m, IH), 7.22 (m, 5H), 7.00 (m, IH), 6.71 (m, IH), 6.52 (m, IH), 6.42 (m, IH), 5.47 (m, 0.5H), 5.12 (m, 0.5H), 1.96 (s, 2H), 1.02 (s, 2H), 0.85 (s, 2H); mass spectrum (DCI) m/z: 416 (M + 1); Calcd for C26H22CINO2:
415.1229. Found: 415.1229.
Example 402 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoy loxyjphenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline MS (DCI/NH3) 504(M+NH4)+, 487(M+H)+; IH NMR (400 MHz, DMSO-d6) 8.59(s, IH), 7.92(d, IH), 7.22(t, IH), 7.09(d, IH),
6.91(dd, IH), 6.81(t, IH), 6.72(d, IH), 6.66(d, IH), 6.44(d, IH), 6.24(d, IH), 6.27(s, IH), 5.28(s, IH), 2.55(s, 2H), 2.949s, 2H), 2.82(s, 2H), 1.81(s, IH), 1.24(s, 2H), 1.12(s, 2H). Example 403 2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trimethyl- 5-([2-N,N-dimethylcarbamoyloxy1phenyl)-lH-[lJbenzopyrano[3 ,4-fjquinoline MS (DCI/NH3) 575(M+MH4)+; IH NMR (400 MHz, DMSO-d6) 7.90(d, IH), 7.25(t,
IH), 7.1 l(d, IH), 6.95(dd, IH), 6.85(s, IH), 6.79(s, IH), 6.75(d, IH), 6.71(d, IH), 6.52(d, IH), 6.49(s, IH), 5.41(s, IH), 2.52(s, 2H), 2.02(s, 2H), 2.94(s, 2H), 2.89(s, 2H), 2.85(s, 2H), 1.84(s, 2H), 1.25(s, 2H), 1.15(s, 2H).
Example 404 2,5-dihvdro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-ethyl-lH- [ 1 Jbenzopyrano [3 ,4-fjquinoline iH NMR (300 MHz, DMSO-d6)D9.59 (s, IH), 7.91 (d, J= 8 Hz, IH), 6.75 (s, 2H), 6.62
(d, J= 8 Hz, IH), 6.29 (d, J= 2 Hz, IH), 5.46 (m, 2H), 2.14 (s, 3H), 1.57 (m, 2H), 1.19 (s, 3H), 1.15 (s, 3H), 0.89 (t, J= 7 Hz, 3H); Hi Res MS (APCI) m/e calc'd for C21H22 O2CI: 355.1339, found 355.1353. Example 405 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-isopropyl-lH-
[ 1 Ibenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)09.57 (s, IH), 8.02 (d, J= 8 Hz, IH), 6.76 (s, 2H), 6.65
(d, J= 9 Hz, IH), 6.45 (s, IH), 5.45 (s, IH), 5.32 (d, J= 9 Hz, IH), 2.17 (s, 3H), 1.70 (m, IH), 1.30 (s, 3H), 1.02 (s, 3H), 0.92 (d, J= 6 Hz, 3H), 0.67 (d, J= 6 Hz, 3H); HRMS(APCI) m/e calc'd for C22H24NO2CI: 369.1496, found 369.1492.
Example 406 9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) 412 (M+H)+;
IH NMR (200 MHz, DMSO-d6),D8.92 (s, 1 H), 8.12 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 Hz, 2 H), 7.22-7.15 (m, 2 H), 6.77 (d, 1 H), 6.69 (d, 1 H), 6.66 (d, 1 H), 6.52 (s, 1 H),
5.46 (s, 1 H), 5.29 (s, 1 H), 2.65 (s, 2 H), 1.90 (s, 2 H), 1.20 (s, 6 H); HRMS calcd for C27H25NO2 is 411.1824. Found 411.1821.
Example 407 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-butyl- 1H- [ 1 jbenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)09.55 (br s, IH), 7.91 (d, J= 9 Hz, IH), 6.74 (s, 2H),
6.61 (d, J= 8 Hz, IH), 6.26 (d, J= 1 Hz, IH), 5.56 (dd, J= 11, 2 Hz, IH), 5.45 (br s, IH), 2.15 (m, 3H), 1.64 ( , IH), 1.46 (m, IH), 1.31 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H), 0.78 (t, J= 7 Hz, 3H); MS (DCI/NH3) m/e (M+H)+ 384.
Example 408 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(l -thiazol-2-yl)- 1 H- [ 1 Ibenzopyrano [3,4-f] quinoline iH NMR (300 MHz, DMSO-d6)08.72 (s, IH), 8.02 (d, J= 8 Hz, IH), 6.88 (s, IH), 6.70
(d, J= 8 Hz, IH), 6.68 (d, J= 8 Hz, IH), 6.61 (d, J= 9 Hz, IH), 6.54 (s, IH), 6.20 (s, IH), 5.49 (s, IH), 3.72 (s, 3H), 2.57 (s, 3H), 2.30 (s, 3H), 1.33 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6)P 182.9, 182.5, 181.3, 179.8, 169.8, 167.9, 165.5, 163.8, 154.6, 154.4, 153.6, 151.7, 151.3, 150.0, 127.0, 96.8, 87.2, 67.6, 65.7, 60.3; MS (DCI/NH3) (M+H)+ 322.
Example 409 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline iH NMR (300 MHz, DMSO-d6)09.59 (br s, IH), 7.91 (d, J= 9 Hz, IH), 6.75 (d, J= 8
Hz, IH), 6.73 (d, J= 8 Hz, IH), 6.62 (d, J= 8 Hz, IH), 6.28 (d, J= 2 Hz, IH), 5.70 (dd, J= 12, 2 Hz, IH), 5.45 (br s, IH), 2.17 (s, 3H), 1.68 (m, 2H), 1.23 (m, 2H), 1.19 (s, 3H), 1.15 (s, 3H), 0.98 (d, J= 6 Hz, 3H), 0.75 (d, J= 1 Hz, 3H); MS (DCI NH3) m/e (M+H)+ 384.
Example 410 2,5-dihydro-9-hydroxymethyl-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 Ibenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 381 (M)+;
*H NMR (500 MHz, DMSO) Q 7.91 (d, J= 8.4 Hz, 1 H), 7.30 (d, J= 8.5 Hz, 1 H), 6.90 (d, J= 8.4 Hz, 1 H), 6.64 (d, J= 8.5 Hz, 1 H), 6.32 (br s, 1 H), 5.90-5.73 (m, 2 H), 5.47
(br s, 1 H), 5.28 (t, J= 5.1 Hz, 1 H), 5.04 (dd, J= 10.2, 1.1 Hz, 1 H), 4.97 (dd, J= 10.2,
1.1 Hz, 1 H), 4.64-4.50 (m, 2 H), 2.46-2.25 (m, 2 H), 2.17 (br s, 3 H), 1.21 (s, 3 H), 1.16 (s, 3 H);
HRMS (FAB) calcd m/z for C23H24CINO2: 381.1496 (M)+. Found: 381.1495. Example 411 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-propyl- 1 H-
[ 1 Ibenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)09.55 (s, IH), 7.90 (d, J= 9 Hz, IH), 6.74 (s, 2H), 6.60
(d, J= 9 Hz, IH), 6.26 (s, IH), 5.59 (d, J= 9 Hz, IH), 5.45 (s, IH), 2.15 (s, 3H), 1.65 (m, IH), 1.38 (m, 3H), 1.19 (s, 3H), 1.15 (s, 3H), 0.82 (t, J= 7 Hz, 3H); 1 C NMR (75 MHz, DMSO-d6) Q 148.6, 146.1, 143.6, 134.8, 133.4, 127.4, 127.0, 123.9, 116.2, 115.9,
115.9, 115.2, 113.9, 112.5, 73.9, 49.8, 33.4, 29.4, 28.8, 23.8, 18.7, 13.4; Hi Res MS (APCI) m/e calc'd for C22H24NO2CI: 369.1496, found 369.1504.
Example 412 9-hydroxy-10-methoxy-5-([3-fluorophenylJmethylene)-2,2,4-trimethyl- lH-2,5-dihydro- [1 JbenzopyranoP,4-f]quinoline IH NMR (200 MHz, DMSO-d6)D9.04 (s, IH), 8.22 (d, IH), 7.62-7.27 (m, 2H), 7.10-
7.02 (m, IH), 6.86 (d, IH), 6.78 (d, IH), 6.72 (d, IH), 6.70 (s, IH), 5.56 (s, IH), 5.46 (s, IH), 2.72 (s, 2H), 1.96 (s, 2H), 1.27 (s, 2H). MS (DCI/NH3) m/z 420 (M+H)+;
Anal, calcd for C27H24NO2F' 0.25 H2O: C, 75.51; H, 5.62; N, 2.26. Found: C, 74.84;
H, 6.17; N,2.91. Example 413 9-hydroxy-10-chloro-5-([2-pyridylJmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) m/z 417 (M+H)+; IH NMR (200 MHz, DMSO)D9.79 (br s, 1 H), 8.51 (ddd, J=5.9, 1.6, 1.0 Hz, 1 H), 8.42 (d, J=8.6 Hz, 1 H), 8.24 (dt, J=7.8, 1.0 Hz, 1 H), 7.52 (td, J=7.8, 1.7 Hz, 1 H), 7.22 (ddd, J=7.7, 5.8, 1.2 Hz, 1 H), 7.00 (d, J=8.5 Hz, 1 H), 6.88 (d, J=8.6 Hz, 1 H), 6.81 (d, J=8.5 Hz, 1 H), 6.62 (br s, 1 H), 5.71 (s, 1 H), 5.51 (br s, 1 H), 2.00 (br s, 2 H), 1.28 (br s, 6 H); 13C NMR (125 MHz, DMSO-d6)0152.5, 149.7, 146.4, 145.7, 126.5, 126.1, 122.7,
128.7, 128.2, 122.0, 122.4, 121.5, 118.2, 117.7, 117.6, 116.5, 115.5, 114.8, 114.4, 1 14.1,
112.9, 49.5, 29.7, 28.1, 21.2;
HRMS (FAB) calcd m/z for C25H21CIN2O2: 416.1291 (M)+. Found: 416.1288.
Example 414 rel-(5S)-9-hydroxy-5-[(3S)-(l-hydroxymethyl)cyclohexen-3-ylj- 10- methoxy-2,2,4-trimethyl-2,5-dihydro-lH-[llbenzopyrano[3,4-f]quinoline
IH NMR (200 MHz, DMSO-d6), 08.49 (s, 1 H), 7.99 (d, J=8.5 Hz, 1 H), 6.64 (d, J=8.5 Hz, 1 H), 6.58 (d, J=8.5 Hz, 1 H), 6.47 (d, J=8.5 Hz, 1 H), 6.21 (br s, 1 H), 5.99 (br s, 1 H), 5.40 (br s, 1 H), 5.26-5.21 (m, 1 H), 4.81-4.72 (m, 2 H), 4.02-4.02 (m, 1 H), 2.61- 2.58 (m, 1 H), 2.52 (s, 2 H), 2.00-2.95 (m, 1 h), 2.21 (s, 2 H), 1.61-1.40 (m, 4 H), 1.22 (s, 2 H), 1.28-1.24 (m, 2 H), 1.04 (s, 2 H);
Anal, calcd for C27H21NO4: C, 74.80; H, 7.21; N, 2.22. Found: C, 74.77; H, 7.15; N,
2.12.
Example 415 rel-(5 S)-9-hydroxy-5 - [(3 S)-( 1 -methoxycarbonyl)cyclohexen-3 -ylj- 10- methoxy-2,2,4-trimethyl-2,5-dihydro-lH-[11benzopyranoP,4-fjquinoline MS (DCI/NH3) 462 (M+H)+;
IH NMR (200 MHz, DMSO-d6), 08.72 (s, 1 H), 8.04 (d, J=8.5 Hz, 1 H), 6.90-6.87 (m, 1 H), 6.67 (d, J=8.5 Hz, 1 H), 6.64 (d, J=8.5 Hz, 1 H), 6.52 (d, J=8.5 Hz, 1 H), 6.25-6.29 (m, 1 H), 5.50-5.44 (m, 2 H), 4.06-4.00 (m, 1 H), 2.66 (s, 2 H), 2.62 (s, 2 H), 2.20-2.27 (m, 1 H), 2.18-2.05 (m, 1 H), 2.12 (s, 2 H), 1.72-1.60 (m, 2 H), 1.25-1.24 (m, 2 H), 1.20 (s, 2 H), 1.04 (s, 2 H);
HRMS calcd for C28H21NO5 is 461.2202. Found 461.2196.
Anal, calcd for C28H21NO5 . 0.25 H2O: C, 72.15; H, 6.81; N, 2.00. Found: C, 72.06;
H, 7.06; N, 2.82.
Example 416 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5- dichlorophenyl)- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline
MS DCI m/z 468 (M+H)+;
IH NMR (200 MHz, DMSO),08.69 (s, 1 H), 7.96 (d, J=8.8 Hz, 1 H), 7.44 (t, J=1.8 Hz, 1 H), 7.17 (d, J=1.8 Hz, 2 H), 6.76 (d, J=8.4 Hz, 1 H), 6.70 (s, 1 H), 6.48 (d, J=8.8 Hz, 1 H), 6.28 (d, J=8.8 Hz, 1 H), 6.25 (d, J=1.5 Hz, 1 H), 5.41 (s, 1 H), 2.57 (s, 2 H), 1.82 (s, 2 H), 1.25 (s, 2 H), 1.14 (s, 2 H); 13C NMR (200 MHz, DMSO), 0145.9, 145.2, 142.6,
142.1, 122.7, 122.0, 128.8, 127.6, 127.2, 127.1, 126.6, 118.2, 117.9, 117.2, 114.5, 112.2, 72.7, 59.0, 49.8, 29.6, 28.2, 22.2. HRMS calcd for C26H23CIFNO3 is 467.1066. Found 467.1064. Example 417 (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline MS (DCI/NH3) m/z 422 (M + H)+;
*H NMR (300 MHz, DMSO)09.55 (s, 1 H), 8.02 (d, J= 8.4 Hz, 1 H), 6.77 (app s, 2 H), 6.68 (d, J= 8.4 Hz, 1 H), 6.41 (br s, 1 H), 5.50-5.42 (m, 2 H), 4.88 (br s, 1 H), 2.23-2.15
(m, 1 H), 2.07 (br s, 3 H), 1.91-1.80 (m, 2 H), 1.76-1.63 (m, 2 H), 1.60-1.46 (m, 1 H), 1.50 (br s, 3 H), 1.38-1.28 (m, 1 H), 1.30 (s, 3 H), 1.09 (s, 3 H); 13C NMR (125 MHz, DMSQ)P 148.6, 145.7, 143.7, 135.8, 133.7, 132.6, 128.2, 126.8, 123.7, 120.2, 117.7, 115.9 (2), 115.3, 114.1, 112.4, 75.6, 49.5, 36.3, 29.6, 29.3, 27.5, 25.1, 24.2, 23.7, 20.2;
HRMS (FAB) calcd m/z for C26H28CINO2: 421.1809 (M)+. Found: 421.1810.
Example 418 (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 422 (M + H)+; *H NMR (300 MHz, DMSO)D9.58 (s, 1 H), 8.05 (d, J= 8.4 Hz, 1 H), 6.79 (ABq, J=
8.0 Hz, ΔnAB = 14.4 Hz, 2 H), 6.67 (d, J= 8.3 Hz, 1 H), 6.47 (br s, 1 H), 5.49-5.46 (m,
2 H), 5.35 (d, J= 8.9 Hz, 1 H), 2.28-2.15 (m, 1 H), 2.12 (br s, 3 H), 1.93-1.80 (m, 1 H), 1.78-1.63 (m, 2 H), 1.64-1.51 (m, 1 H), 1.62 (br s, 3 H), 1.31 (s, 3 H),1.25-1.13 (m, 2 H), 1.04 (s, 3 H); 13C NMR (125 MHz, DMSO)0148.7, 145.8, 144.2, 135.1, 134.0, 132.1, 127.9, 126.7,
123.7, 121.4, 118.0, 116.0 (2), 115.4, 114.2, 112.4, 103.4, 76.4, 49.5, 37.1, 29.5, 27.2, 24.5, 23.8 (2), 21.6; HRMS (FAB) calcd m/z for C26H28CINO2: 421.1809 (M)+. Found: 421.1816.
Example 419 (+) (5R,3 'S) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(l - methylcy clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline
[OJD25 +237.8 ° (c = 0.5, CHCI3); MS (DCI/NH3) m/z 422 (M + H)+; H NMR (300 MHz, DMSO)D9.58 (s, 1 H), 8.05 (d, J= 8.4 Hz, 1 H), 6.79 (ABq, J= 8.0 Hz, ΔnAB = 14.4 Hz, 2 H), 6.67 (d, J= 8.3 Hz, 1 H), 6.47 (br s, 1 H), 5.49-5.46 (m, 2 H), 5.35 (d, J= 8.9 Hz, 1 H), 2.28-2.15 (m, 1 H), 2.12 (br s, 3 H), 1.93-1.80 (m, 1 H),
1.78-1.63 (m, 2 H), 1.64-1.51 (m, 1 H), 1.62 (br s, 3 H), 1.31 (s, 3 H),1.25-1.13 (m, 2 H), 1.04 (s, 3 H);
13C NMR (125 MHz, DMSO) P 148.7, 145.8, 144.2, 135.1, 134.0, 132.1, 127.9, 126.7, 123.7, 121.4, 118.0, 116.0 (2), 115.4, 114.2, 112.4, 103.4, 76.4, 49.5, 37.1, 29.5, 27.2, 24.5, 23.8 (2), 21.6;
HRMS (FAB) calcd m/z for C26H28CINO2: 421.1809 (M)+. Found: 421.1806. Example 420 (+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano P ,4-fjquinoline [D]D25 +147.5 ° (c = 0.2, CHCI3); MS (DCI/NH3) m/z 422 (M + H)+; *H NMR (300 MHz, DMSO)D9.55 (s, 1 H), 8.02 (d, J= 8.4 Hz, 1 H), 6.77 (app s, 2 H),
6.68 (d, J= 8.4 Hz, 1 H), 6.41 (br s, 1 H), 5.50-5.42 (m, 2 H), 4.88 (br s, 1 H), 2.23-2.15 (m, 1 H), 2.07 (br s, 3 H), 1.91-1.80 (m, 2 H), 1.76-1.63 (m, 2 H), 1.60-1.46 (m, 1 H), 1.50 (br s, 3 H), 1.38-1.28 (m, 1 H), 1.30 (s, 3 H), 1.09 (s, 3 H); 13C NMR (125 MHz, DMSO)p 148.6, 145.7, 143.7, 135.8, 133.7, 132.6, 128.2, 126.8, 123.7, 120.2, 117.7, 115.9 (2), 115.3, 114.1, 112.4, 75.6, 49.5, 36.3, 29.6, 29.3, 27.5,
25.1, 24.2, 23.7, 20.2; HRMS (FAB) calcd m/z for C26H28CINO2: 421.1809 (M)+. Found: 421.1794.
Example 421 (+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-l 0- chloro-2,2,4-trimethyl-5-allyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline MS (ESI) m/z 495 (M+H)+;
IH NMR (200 MHz, DMSO-d6)D7.90 (d, IH), 6.99 (d, IH), 6.92 (d, IH), 6.64 (d,lH), 6.42 (s, IH), 5.81-5.76 (m, 2H), 5.48 (s, IH), 5.07-4.94 (m, 2H), 2.99 (s, 2H), 2.84 (s, 2H), 2.82-2.68 (m, 4H), 2.41-2.27 (m, 2H), 2.18 (s, 2H), 1.20 (s, 2H), 1.17 (s, 2H). Example 422 (-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-cyclopentyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline
MS (DCI/NH3) m/z 296(M+H)+;
IH NMR (400 MHz, DMSO-d6) IH NMR (200 MHz, DMSO-d6)O9.50 (bs, IH), 8.04 (s, IH), 6.77 (d, IH), 6.72 (d, IH), 6.65 (d, IH), 6.42 (d, IH), 5.50 (s, IH), 5.42 (d, IH) 2.18-1.08 (m, 18H). Example 423 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-
2 ,2,4-trimethy 1-5 -( 1 -methylethyl)- 1H-[1 Jbenzopyrano [3 ,4-fj quinoline iH NMR (400 MHz, DMSO-d6)07.92 (d, J=8.5, IH), 6.83 (d, J=8.5, IH), 6.71- 6.65 (m, 2H), 6.31 (d, J=1.7, IH), 5.46 (br m, IH), 5.37 (d, J=9.7, IH), 3.61 (s, 3H), 3.00 (s, 3H), 2.84 (s, 3H), 2.80 (m, 2H), 2.70 (m, 2H), 2.17 (s, 3H), 1.80 (m, IH), 1.31 (s, 3H), 1.03 (s, 3H), 0.95 (d, J=6.4, 3H), 0.65 (d, J=6.8, 3H); 13C NMR (125 MHz,
DMSO-d6)D 171.5, 170.4, 149.0, 148.0, 145.6, 138.3, 133.6, 131.0, 127.9, 125.8, 120.7, 118.2, 118.2, 115.4, 113.4, 112.1, 78.0, 60.0, 49.4, 36.4, 34.9, 30.9, 29.6, 28.9, 27.6, 27.3, 23.8, 19.4, 17.8; MS (ESI/NH3) m/e 493(M+H)+, 515(M+Na)+; HRMS calcd m/z for C29H26N2O5: 492.2624. Found: 492.2613. Example 424 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-
5-(phenylmethyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4-fjquinoline IH NMR (500 MHz, DMSO-d6)D7.90 (d, J=8.8, IH), 7.29-7.26 ( , 2H), 7.21 (m, IH), 7.09 (d, J=7.0, 2H), 6.89 (d, J=8.8, IH), 6.66 (d, J=8.8, IH), 6.60 (d, J=8.8, IH), 6.25 (d, J=1.8, IH), 5.98 (dd, J=10.1, 2.5, IH), 5.42 (s, IH), 2.67 (s, 2H), 2.01 (s, 2H), 2.97 (m, IH), 2.85 (s, 2H), 2.84-2.81 (m, 2H), 2.72-2.69 (m, 2H), 2.22 (s, 2H), 1.17 (s, 2H), 1.14 (s, 2H); 13C NMR (125 MHz, DMSO-d6)0171.5, 170.4, 148.2, 148.1, 146.2, 128.4, 127.6, 122.4, 121.9, 128.9, 128.2, 127.2, 126.2, 126.2, 120.8, 118.2, 116.2, 115.2, 112.9, 112.6, 74.8, 60.1, 49.7, 28.2, 24.9, 29.2, 29.1, 28.9, 27.6, 24.2; MS (ESI NH3) m/e 541(M+H)+, 562(M+Na)+; Anal. Calcd for C33H36N2O5: C 72.21, H 6.71, N 5.18.
Found: C 72.87, H 6.97, N 4.90. Example 425 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(2-thienyl)-lH-[lJbenzopyrano[3,4-f|quinoline iHNMR (500 MHz, DMSO-d6)D7.90 (d, J=8.4, IH), 7.40 (dd, J=5.0, 1.3, IH),
6.96 (s, IH), 6.86 (m, IH), 6.80 (m, IH), 6.74-6.71 (m, 2H), 6.57 (d, J=8.4, IH), 6.32 (d, J=1.8, IH), 5.41 (s, IH), 3.58 (s, 3H), 2.98 (s, 3H), 2.83 (s, 3H), 2.77-2.74 (m, 2H), 2.68- 2.65 (m, 2H), 1.95 (d, J=l.l, 3H), 1.23 (s, 3H), 1.15 (s, 3H); 13C NMR (125 MHz, DMSO-d6)D 171.1, 170.2, 148.6, 147.5, 146.0, 142.8, 138.4, 132.8, 130.1, 128.0, 127.2, 126.3, 126.1, 125.9, 125.8, 120.4, 118.4, 116.8, 115.8, 114.3, 112.3, 70.9, 59.5, 49.7,
36.2, 34.7, 29.5, 28.7, 28.5, 27.4, 22.8; MS (ESI/NH3) m/e 533(M+H)+, 555(M+Na)+; Anal. Calcd for C20H22N2O5S: C 67.65, H 6.06, N 5.26. Found: C 67.48, H 6.16, N 5.07.
Example 426 2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3 ,4-fjquinoline
IH NMR (500 MHz, DMSO-d6)D7.85 (d, J=8.4, IH), 6.86 (d, J=8.4, IH), 6.68- 6.61 (m, 2H), 6.25 (d, J=1.5, IH), 5.86-5.78 (m, 2H), 5.46 (s, IH), 5.06-4.98 (m, 2H), 2.61 (s, 2H), 2.62 (t, J=7.1, 2H), 2.47 (m, IH), 2.22 (t, J=7.0, 2H), 2.25 (m, IH), 2.18 (s, 2H), 2.16 (s, 6H), 1.80 (m, 2H), 1.18 (s, 2H), 1.17 (s, 2H); 13C NMR (125 MHz, DMSO-d6)D171.8, 148.4, 147.9, 146.2, 128.5, 124.0, 122.5, 122.1, 127.2, 126.2, 120.7,
118.2, 117.2, 116.2, 115.0, 112.8, 112.6, 72.6, 59.9, 58.0, 45.1, 26.6, 21.1, 29.2, 29.0, 22.8, 22.5; MS (ESI/NH3) m/e 477(M+H)+; Anal. Calcd for C29H36N2O4: C 72.08, H
7.61, N 5.88. Found: C 72.77, H 7.74, N 5.64.
Example 427 9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy- 10-methoxy-5-(3- propenyl)-2 ,2 ,4-trimethy 1- 1 H-2, 5 -dihy dro- [ 1 Jbenzopyrano [3 ,4-fj quinoline
MS (DCI/NH3) 510 (M+NH4)+, 492 (M+H)+, 264;
IH NMR (200 MHz, DMSO-d6),0 8.21 (t, J=6.0 Hz, 1 H), 7.86 (d J=8.5 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 6.64 (d, J=8.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 1 H), 6.29 (d, J=l.l Hz, 1 H), 5.90-5.76 (m, 2 H), 5.45 (br s, 1 H), 5.04 (dd, J=10.2, 1.8 Hz, 1 H), 4.99 (dd, J=17.2, 1.8 Hz, 1 H), 4.12 (q, J=7.0 Hz, 2 H), 2.85 (d, J=6.0 Hz, 2 Hz), 2.65 (s, 2 H), 2.20-2.22
(m, 2 H), 2.17 (d, J=l.l Hz, 2 H), 1.21 (t, J=7.0 Hz, 2 H), 1.18 (s, 2 H), 1.17 (s, 2 H); Anal, calcd for C28H22N2O6: C, 68.28; H, 6.55; N, 5.69. Found: C, 67.97; H, 6.59; N,
5.62. Example 428 (+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)-l 0-methoxy-2,2,4- trimethy 1-5 -ally 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline MS (APCI) m/z 477 (M+H)+;
IH NMR (200 MHz, DMSO-d6)p8.04 (t, IH), 7.85 (d, IH), 6.90 (d, IH), 6.68 (d, IH), 6.64 (d, IH), 6.26 (s, IH), 5.87-5.77 (m, 2H), 5.46 (s, IH), 5.04 (dd, IH), 4.98 (dd, IH),
2.61 (s, 2H), 2.40 (q, 2H), 2.76 (t, 2H), 2.52-2.44 ( , IH), 2.20-2.24 (m, IH), 2.18 (s, 2H), 1.84 (s, 2H), 1.18 (s, 2H), 1.17 (s, 2H).
Example 429 (+/-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-benzyl-lH- [ljbenzopyranoP,4-fjquinoline
MS (DCI/NH3) m/z 418(M+H)+;
IH NMR (400 MHz, DMSO-d6) IH NMR (200 MHz, DMSO-d6)D9.70 (bs, IH), 7.99
(s, IH), 7.20-7.08 (m, 5H), 6.79 (d, IH), 6.67 (d, IH), 6.62 (d, IH), 6.19 (d, IH), 5.86
(dd, IH), 5.44 (s, IH) 2.98-2.84 (m, 2H), 2.22 (s, 2H), 1.19 (s, 2H), 1.17 (s, 2H). Example 430 9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [1 Jbenzopyrano[3,4-fjquinoline (DCI/NH3) 412 (M + H)+; iH NMR (300 MHz, DMSO-d6), 08.93 (s, 1 H), 8.13 (d, J= 8.8 Hz, 1 H), 7.63 (d, J= 8.8 Hz, 2 H), 7.32 - 7.15 (m, 3 H), 6.77 (d, 1 H), 6.69 (d, 1 H), 6.66 (d, 1 H), 6.52 (s, 1 H), 5.46 (s, 1 H), 5.39 (s, 1 H), 3.65 (s, 3 H), 1.90 (s, 3 H), 1.20 (s, 6 H);
HRMS calcd for C27H25NO3 is 411.1834, found 411.1821.
Example 431 9-(dimethylaminothiocarbonyl)-oxy- 10-methoxy-5-(3 -propenyl)-2,2,4- trimethyl- 1 H-2,5-dihydro- [1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) 451 (M+H)+; IH NMR (200 MHz, DMSO-d6),0 7.84 (d J=8.8 Hz, 1 H), 6.80 (d, J=8.8 Hz, 1 H), 6.65
(d, j=8.8 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.26 (d, J=1.7 Hz, 1 H), 5.90-5.76 (m, 2 H), 5.46 (br s, 1 H), 5.04 (dd, J=10.2, 1.8 Hz, 1 H), 4.98 (dd, J=17.2, 1.8 Hz, 1 H), 2.64 (s, 2 H), 2.29 (s, 2 H), 2.26 (s, 2 H), 2.22-2.22 (m, 2 H), 2.18 (d, j=1.7 Hz, 2 H), 1.18 (s, 2 H), 1.16 (s, 2 H); Anal, calcd for C26H20 2O2S.O.5 H2O: C, 67.94; H, 6.79; N, 6.09. Found: C, 68.06;
H, 6.80; N, 6.12.
Example 432 (+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)- 10-methoxy-2,2,4- trimethyl-5-allyl- 1H-[1 jbenzopyrano [3 ,4-fjquinoline MS (APCI) m/z 464 (M+H)+; IHNMR (200 MHz, DMSO-d6) D7.78 (d, IH), 6.79 (d, IH), 6.60 (d, IH), 6.57 (d, IH),
6.27 (t, IH), 6.18 (bs, IH), 5.80-5.70 (m, 2H), 5.67 (s, 2H), 5.28 (s, IH), 4.97 (dd, IH), 4.92 (dd, IH), 4.01 (d, 2H), 2.55 (s, 2H), 2.42-2.27 (m, IH), 2.22-2.16 (m, IH), 2.10 (s, 2H), 1.11 (s, 2H), 1.10 (s, 2H). Example 433 (+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)-l 0-methoxy-2,2,4- trimethyl-5-allyl-lH-[lJbenzopyrano[3,4-fjquinoline IH NMR (200 MHz, DMSO-d6)07.92 (d, IH, J=8Hz), 6.79 (d, IH), 6.62 (d, IH, J=8Hz), 6.58 (d, IH, J=8Hz), 6.18 (d, IH, J=2Hz), 5.82 (m, IH), 5.72 (dd, IH, J=2Hz, J=9Hz) 5.45 (s, IH), 5.05-4.97 (m, 2H), 4.08 (q, 2H, J=5Hz), 4.02-2.91 (m, 2H), 2.70 (s,
2H), 2.50 (t, 2H, J=5Hz), 2.45 (m, IH), 2.21 (m, IH), 2.16 (s, 2H), 2.00 (quin, 2H, J=5Hz), 1.19 (t, 2H, J=5Hz), 1.17 (s, 6H). Example 434 (+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)- 10-methoxy-2,2,4-trimethyl-5- allyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline MS (APCI) m/z 462 (M+H)+;
IH NMR (200 MHz, DMSO-d6) 07.78 (d, IH), 6.77 (d, IH), 6.59 (d, IH), 6.57 (d, IH), 6.18 (s, IH), 5.80-5.68 (m, 2H), 5.28 (s, IH), 4.96 (dd, IH), 4.92 (dd, IH), 2.54 (s, 2H), 2.79 (dd, 2H), 2.70 (dd, 2H), 2.41-2.16 (m, 2H), 2.10 (s, 2H), 2.09 (s, 2H), 1.11 (s, 2H), 1.10 (s, 2H). Example 435 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5- trifluorophenyl)- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline 1H NMRD9.20 (s, IH), 7.91 (d, IH, J=8.5Hz), 6.92 (m, 2H), 6.88 (m, 2H), 6.57 (d, IH, J=8.5Hz), 6.28 (m, IH), 5.45 (m, IH), 1.81 (s, 2H), 1.29 (s, 2H), 1.09 (s, 2H); mass spectrum (DCI) m/z: 458 (M + 1); Calcd for C25H19CIF2NO2: 457.1056. Found: 457.1054.
Example 436 2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-
1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline MS (DCI/NH3) m/z 424(M+H)+;
IH NMR (400 MHz, DMSO-d6) 7.92(d, IH), 6.88(d, IH), 6.62(d, IH), 6.60(d, IH), 6.20(s, IH), 5.81(m, IH), 5.74(dd, IH), 5.45(s, IH), 5.24(s, IH), 5.02(d, IH), 4.99(d,
IH), 2.70(s, 2H), 2.45 (m, 2H), 2.22(s, 2H), 2.18(s, 2H), 1.18(s, 2H), 1.17(s, 2H). Example 437 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(2-propenyl)- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline iH NMR (400 MHz, DMSO-d6)07.84 (d, J=8.5, IH), 6.88 (d, J=8.9, IH), 6.68- 6.62 (m, 2H), 6.26 (br s, IH), 5.85-5.77 (m, 2H), 5.45 (br s, IH), 5.05-4.97 (m, 2H), 3.60
(s, 3H), 3.34-3.21 (m, 4H), 2.65 (t, J=7.4, 2H), 2.45-2.41 (m, 3H), 2.27 (m, IH), 2.17 (s, 3H), 1.90 (m, 2H), 1.18 (s, 3H), 1.17 (s, 3H), 1.12 (t, J=7.0, 3H), 1.02 (t, J=7.2, 3H); 13C NMR (100 MHz, DMSO-d6)D 171.7, 170.3, 148.4, 147.9, 146.3, 138.4, 134.0, 133.5, 132.1, 127.3, 126.1, 120.7, 118.2, 117.2, 116.2, 114.9, 113.8, 112.6, 73.6, 59.9, 49.8, 41.2, 36.6, 32.7, 30.9, 29.3, 29.0, 23.8, 20.4, 14.2, 13.1; MS (ESI/NH2) m/e 533(M+H)+,
555(M+Na)+; Anal. Calcd for C22H4θN2θ5: C 72.15, H 7.57, N 5.26. Found: C
72.16, H 7.76, N 5.06. Example 438 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy- 2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyranoP,4-fJquinoline IH NMR (400 MHz, DMSO-d6)D7.77 (d, J=8.5, IH), 6.81 (d, J=8.9, IH), 6.61- 6.56 (m, 2H), 6.19 (d, J=1.7, IH), 5.80-5.70 (m, 2H), 5.28 (s, IH), 4.98-4.90 (m, 2H), 2.71 (s, 2H), 2.90 (s, 2H), 2.76 (s, 2H), 2.58 (t, J=7.4, 2H), 2.28-2.25 (m, 2H), 2.20 (m,
IH), 2.10 (s, 2H), 1.84 (m, 2H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (100 MHz, DMSO-d6) p 171.7, 171.2, 148.4, 147.9, 146.2, 128.4, 124.1, 122.5, 122.1, 127.2, 126.2, 120.7, 118.2, 117.2, 116.2, 114.9, 112.8, 112.6, 72.6, 59.9, 49.8, 26.6, 24.8, 22.8, 21.2, 29.2, 29.0, 22.8, 20.2; MS (ESI/NH3) m/e 505(M+H)+, 527(M+Na)+; Anal. Calcd for C30H36N2O5: C 71.40, H 7.19, N 5.55. Found: C 71.20, H 7.19, N 5.29.
Example 439 2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[11benzopyrano[3,4-fjquinoline IH NMR (400 MHz, DMSO-d6)D7.78 (d, J=8.9, IH), 6.81 (d, J=8.5, IH), 6.61- 6.55 (m, 2H), 6.19 (d, J=1.7, IH), 5.80-5.70 (m, 2H), 5.28 (s, IH), 4.98-4.90 (m, 2H),
2.52 (s, 2H), 2.25 (m, 4H), 2.58 (t, J=7.2, 2H), 2.29-2.25 (m, 2H), 2.20 (m, IH), 2.10 (s, 2H), 1.82 (m, 2H), 1.51 (m, 2H), 1.42 (m, 2H), 1.26 (m, 2H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (100 MHz, DMSO-d6)0171.7, 169.6, 148.4, 147.9, 146.2, 128.4, 124.0, 122.5, 122.1, 127.2, 126.1, 120.7, 118.2, 117.2, 116.2, 114.9, 112.8, 112.6, 72.6, 59.9, 49.8, 45.8, 41.9, 26.6, 22.8, ,21.2, 29.2, 29.0, 26.0, 25.2, 24.0, 22.8, 20.4; MS (ESI/NH3) m/e 545(M+H)+, 567(M+Na)+; Anal. Calcd for C33H40N2O5: C 72.77, H 7.40, N 5.14.
Found: C 72.50, H 7.42, N 4.99.
Example 440 2,5-dihydro-9-(4-N-morpholino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline
IH NMR (400 MHz, DMSO-d6)07.77 (d, J=8.5, IH), 6.81 (d, J=8.5, IH), 6.61- 6.56 (m, 2H), 6.19 (s, IH), 5.78-5.70 (m, 2H), 5.28 (s, IH), 4.98-4.90 (m, 2H), 2.52 (s, 2H), 2.50 (m, 4H), 2.29 (t, J=4.7, 4H), 2.59 (t, J=7.4, 2H), 2.41-2.27 (m, 2H), 2.20 (m, IH), 2.10 (s, 2H), 1.82 (m, 2H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (100 MHz, DMSO-d6)D 171.6, 170.2, 148.4, 147.9, 146.2, 128.4, 124.0, 122.5, 122.1, 127.2, 126.1,
120.7, 118.2, 117.2, 116.2, 114.9, 112.8, 112.6, 72.6, 66.1, 60.0, 49.8, 45.2, 41.4, 26.6, 22.7, 21.0, 29.2, 29.0, 22.8, 20.2; MS (ESI/NH3) m/e 547(M+H)+, 569(M+Na)+; Anal. Calcd for C32H38N2O6: C 70.21, H 7.01, N 5.12. Found: C 69.99, H 7.06, N 4.91.
Example 441 (-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-l 0- methoxy-2,2,4-trimethyl-5(S)-(3 (S)- 1 -cyclopenten-3-y 1 )- 1 H- [ 1 Ibenzopyrano [3 ,4- fjquinoline MS (APCI) m/z 517 (M+H)+; IH NMR (200 MHz, DMSO-d6)07.94 (d, IH), 6.84 (d, IH), 6.69 (d, IH), 6.67 (d, IH), 6.22 (s, IH), 5.75 (dd, IH), 5.52 (d, IH), 5.42 (s, IH), 5.17 (dd, IH), 2.62 (s, 2H), 2.99 (s, 2H), 2.90-2.85 (m, IH), 2.84 (s, 2H), 2.80 (t, 2H), 2.68 (t, 2H), 2.29-2.21 (m, IH), 2.25-2.12 (m, IH), 2.08 (s, 2H), 1.92-1.74 (m, 2H), 1.20 (s, 2H), 1.08 (s, 2H). Example 442 10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl- lH-2,5-dihydro- [1 jbenzopyrano [3 ,4-fjquinoline MS (DCI/NH3) 464 (M+NH4)+, 447 (M+H)+, 264.
IH NMR (200 MHz, DMSO-d6),0 7.96 (t, J=5.9 Hz, 1 H), 7.86 (d, J=8.5 Hz, 1 H), 6.86 (d, J=8.5 Hz, 1 H), 6.62 (d, J=8.5 Hz, 2 H), 6.28 (d, J=1.5 Hz, 1 H), 5.90-5.76 (m, 2 H), 5.45 (br s, 1 H), 5.27-4.97 (m, 4 H), 2.71 (m, 1 H), 2.64 (s, 2 H), 2.41-2.22 (m, 2 H),
2.17 (d, J=1.5 Hz, 2 H), 1.18 (s, 2 H), 1.17 (s, 2 H); Anal, calcd for C27H20N2O4 . 0.25 H2O: C, 71.89; H, 6.81; N, 6.21. Found: C, 72.18;
H, 7.08; N, 5.98.
Example 443 10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5 -(3 -propenyl)-2,2,4- trimethyl-lH-2,5-dihydro-[ljbenzopyrano[3 ,4-fjquinoline
MS (DCI/NH3) 506 (M+NH4)+, 489 (M+H)+, 264.
IH NMR (200 MHz, DMSO-d6),0 7.86 (d J=8.8 Hz, 1 H), 7.67 (d, J=7.8 Hz, 1 H), 6.84
(d, J=8.8 Hz, 1 H), 6.62 (d, J=8.8 Hz, 1 H), 6.61 (d, J=8.8 Hz, 1 H), 6.25 (d, J=1.0 Hz, 1
H), 5.90-5.76 (m, 2 H), 5.45 (br s, 1 H), 5.04 (dd, J=10.2, 1.8 Hz, 1 H), 4.99 (dd, J=17.2, 1.8 Hz, 1 H), 4.02 (br s, 1 H), 2.62 (s, 2 H), 2.20-2.22 (m, 2 H), 2.17 (d, J=l .0 Hz, 2 H),
1.86-1.52 (m, 5 H), 1.21-1.22 (m, 5 H), 1.18 (s, 2 H), 1.17 (s, 2 H);
HRMS calcd for C20H26N2O4 is 488.2675. Found 488.2670.
Example 444 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline iH NMR (300 MHz, DMSO-d6)08.57 (s, IH), 7.91 (d, J= 9 Hz, IH), 7.35 (dd, J= 5, 5
Hz, IH), 6.99 (d, J= 5 Hz, IH), 6.92 (s, IH), 6.68 (d, J= 9 Hz, IH), 6.64 (s, IH), 6.44 (d, J= 9 Hz, IH), 6.34 (d, J= 9 Hz, IH), 6.21 (s, IH), 5.38 (s, IH), 3.57 (s, 3H), 1.87 (s, 3H), 1.23 (s, 3H), 1.13 (s, 3H); 13C NMR (125 MHz, DMSO-d6)P 183.2, 182.4, 181.4,
181.1, 170.3, 168.8, 165.3, 165.2, 164.1, 163.9, 163.5, 163.4, 162.6, 155.8, 154.7, 151.6, 149.6, 108.9, 96.6, 87.3, 67.3, 66.0, 60.6; MS (DCI/NH3) (M+H)+406.
Example 445 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(4- (fluorophenyl)methyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline iH NMR (300 MHz, DMSO-d6)D8.47 (s, IH), 7.94 (d, J= 8 Hz, IH), 7.33-7.31 (m, IH), 7.13-7.04 (m, 3H), 6.62 (dd, J= 9, 8 Hz, 2H), 6.41 (d, J= 9 Hz, IH), 6.41 (s, IH),
5.82 (dd, J= 10, 9 Hz, IH), 5.40 (s, IH), 3.69 (s, 3H), 3.01-2.93 (m, IH), 2.81-2.76 (m, IH), 2.20 (s, IH), 1.15 (s, 3H), 1.13 (s, 3H); 13C NMR (75 MHz, DMSO-d6JP 162.5,
159.2, 145.8, 145.1, 144.0, 142.8, 134.1, 133.4, 132.2, 130.8, 130.7, 127.4, 126.4, 117.9, 116.4, 116.2, 115.0, 114.7, 114.4, 113.8, 112.5, 74.4, 59.5, 49.7, 37.1, 29.2, 29.0, 24.3; MS calc'd for C27H26O3NF: m/e 431.1897, found 431.1905; Analysis calc'd for C27H26O3NF 0.30 H2O: C, 74.23; H, 6.14; N, 3.21; found: C, 74.16; H, 6.44; N, 2.96.

Claims

WHAT IS CLAIMED IS:
1. A compound having Formula I
Figure imgf000250_0001
I, or a pharmaceutically acceptable salt or prodrag thereof, where RX is -LI-RA where Li is selected from
( 1 ) a covalent bond,
(2) -O-, (3) -S(O)t- where t is 0, 1 , or 2,
(4) -C(X)-,
(5) -NR7- where R7 is selected from
(a) hydrogen,
(b) aryl (c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons,
(e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons,
(h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from (i) aryl and
(ii) cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen, (j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen, (6) -NRsC(X)NR9- where X is O or S and R8 and R9 are independently selected from
(a) hydrogen,
(b) aryl, (c) cycloalkyl of three to twelve carbons,
(d) alkyl of one to twelve carbons,
(e) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons,
(f) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(g) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(7) -X'C(X)- where X is previously defined and X' is O or S,
(8) -C(X)X'-,
(9) -X'C(X)X"- where X and X' are previously defined and X" is O or S, provided that when X is O, at least one of X' or X" is O,
(10) -NR8C(X)-,
(11) -C(X)NR8-,
(12) -NR8C(X)X'-, (13) -X'C(X)NR8-,
(14) -SO2NR8-,
(15) -NR8SO2-, and
(16) -NR8SO2NR9- where (6)-(16) are drawn with their right ends attached to RA and R is selected from
(1) -OH,
(2) -OG where G is a -OH protecting group,
(3) -SH,
(4) -CO2R2O where R20 is hydrogen or alkyl of one to twelve carbons, (5) alkoxylcarbonyl,
(6) -CN,
(7) halo,
(8) haloalkoxy of one to twelve carbons, (9) perfluoroalkoxy of one to twelve carbons,
(10) -CHO,
(11) -NR7R7' where R7 is defined previously and R7" is selected from
(a) hydrogen, *(b) aryl,
(c) cycloalkyl of three to twelve carbons,
(d) alkanoyl where the alkyl part is one to twelve carbons,
(e) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(f) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted by 1 or 2 aryl groups,
(g) alkyl of one to twelve carbons,
(h) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from
(i) aryl and
(ii) cycloalkyl of three to twelve carbons, (i) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to nitrogen,
(j) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to nitrogen,
(12) -C(X)NR8R9, (13) -OSO2R11 where Rl is' selected from
(a) aryl,
(b) cycloalkyl of three to twelve carbons,
(c) alkyl of one to twelve carbons,
(d) alkyl of one to twelve carbons substituted with 1, 2, 3, or 4 halo substituents, and
(e) perfluoroalkyl of one to twelve carbons,
(14) alkyl of one to twelve carbons,
(15) alkenyl of two to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Ll when L is other than a covalent bond,
(16) alkynyl of two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to Ll when Li is other than a covalent bond, where (14), (15), and (16) can be optionally substituted with 1, 2, or 3 substituents independently selected from
(a) alkoxy of one to twelve carbons,
(b) -OH, provided that no two -OH groups are attached to the same carbon,
(c) -SH,
(d) thioalkoxy of one to twelve carbons, provided that no two -SH groups are attached to the same carbon,
(e) -CN,
(f) halo,
(g) -CHO, (h) -NO2,
(i) haloalkoxy of one to twelve carbons, (j) perfluoroalkoxy of one to twelve carbons, (k) -NR7R7', (1) =NNR7R7',
(m) -NR7NR7'R7" where R7 and R7' are defined previously and R7" is selected from (i) hydrogen, (ii) aryl,
(iii) cycloalkyl of three to twelve carbons, (vi) alkanoyl where the alkyl part is one to twelve carbons, (v) alkoxycarbonyl where the alkyl part is one to twelve carbons, (vi) alkoxycarbonyl where the alkyl part is one to twelve carbons substituted by 1 or 2 aryl groups, (vii) alkyl of one to twelve carbons, (viii) alkyl of one to twelve carbons substituted with 1 or 2 substituents independently selected from aryl or cycloalkyl of three to twelve carbons, (ix) alkenyl of three to twelve carbons, provided that a carbon-carbon double bond is not attached directly to nitrogen, and
(x) alkynyl of three to twelve carbons, provided that a carbon-carbon triple bond is not attached directly to nitrogen, (n) -CO2R10 where Rl 0 is selected from
(i) aryl,
(ii) aryl substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (ii) cycloalkyl of three to twelve carbons, (iii) alkyl of one to twelve carbons, and (iv) alkyl of one to twelve carbons substituted with aryl or cycloalkyl of three to twelve carbons,
(o) -C(X)NR8R9,
Figure imgf000254_0001
(q) =NRlo,
(r) -S(O)tRl0,
(s) -X'C(X)Rιo,
(t) (=X), and
(u) -OSO2RH,
(17) cycloalkyl of three to twelve carbons,
(18) cycloalkenyl of four to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Li when L is other than a covalent bond, where (17) and (18) can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from
(a) alkyl of one to twelve carbons,
(b) aryl,
(c) alkoxy of one to twelve carbons,
(d) halo,
(e) alkoxycarbonyl where the alkyl group is one to twelve carbons, and
(f) -OH, provided that no two -OH groups are attached to the same carbon,
(19) perfluoroalkyl of one to twelve carbons,
(20) aryl, and
(21) heterocycle where (20) and (21) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) alkyl of one to twelve carbons,
(b) alkanoyloxy where the alkyl part is one to twelve carbons,
(c) alkoxycarbonyl where the alkyl part is one to twelve carbons, (d) alkoxy of one to twelve carbons,
(e) halo,
(f) -OH, provided that no two -OH groups are attached to the same carbon, (g) thioalkoxy of one to twelve carbons,
(h) perfluoroalkyl of one to twelve carbons, (i) -NR7R7',
G) -co2Rio,
(k) -OSO2Rl l, and (1) (=X);
R2, R3, and R4 are independently hydrogen or Ri; or
R and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or -(C(Rl2)(Rl3))v - where R12 and R13 are independently hydrogen or alkyl of one to twelve carbons and v is 1, 2, or 3, and Z* is selected from -CH2-, -CH2S(O)f, -CH2O-, -CH2NR7-, -NR7-, and -O-;
L2 is selected from (1) a covalent bond,
(2) alkylene of one to twelve carbons,
(3) alkylene of one to twelve carbons substituted with 1 or 2 substituents independently selected from
(a) spiroalkyl of three to eight carbon atoms, (b) spiroalkenyl of five or eight carbon atoms,
(c) oxo,
(d) halo, and
(e) -OH, provided that no two -OH groups are attached to the same carbon,
(4) alkynylene of two to twelve carbons,
(5) -NR7-,
(6) -C(X)-, (7) -O-, and (8) -S(O)t-; and
R5 is selected from
(1) halo,
(2) hydrogen,
(3) -C(=NR7)ORlθ,
(4) -CN, provided that when R5 is (1), (2), or (3), L2 is a covalent bond,
(5) alkyl of one to twelve carbons,
(6) alkynyl two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to L3 when L3 is other than a covalent bond,
(7) cycloalkyl of three to twelve carbons,
(8) heterocycle,
(9) aryl where (5)-(9) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) -OH, provided that no two -OH groups are attached to the same carbon,
(b) -SH, provided that no two -SH groups are attached to the same carbon,
(c) -CN,
(d) halo,
(e) -CHO,
(f) -NO2,
(g) haloalkoxy of one to twelve carbons,
(h) perfluoroalkoxy of one to twelve carbons,
(i) -NR8'R9' where R8' and R9' are selected from
(i) hydrogen,
(ii) alkanoyl where the alkyl part is one to twelve carbons,
(iii) alkoxycarbonyl where the alkyl part is one to twelve carbons,
(iv) alkoxycarbonyl where the alkyl part is one to twelve carbons and is substituted with 1 or 2 phenyl substituents, (v) cycloalkyl of three to twelve carbons, (vi) alkyl of one to twelve carbons, (vii) alkyl of one to twelve carbons substituted with 1, 2, or 3 substituents independently selected from alkoxy of one to twelve carbons, cycloalkyl of three to twelve carbons, aryl, and alkoxycarbonyl where the alkyl group is one to twelve carbons, (viii) alkenyl of three to twelve carbons, provided that a carbon of a carbon-carbon double bond is not directly attached to nitrogen, (ix) alkynyl of three to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not directly attached to nitrogen, (x) -C(O)NRχRγ where Rx and Ry are independently selected from hydrogen and alkyl of one to twelve carbons, (xi) alkoxy of one to twelve carbons, (xii) aryl, and (xiii) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, alkanoyloxy where the alkyl part is one to twelve carbons, alkoxycarbonyl where the alkyl part is one to twelve carbons, alkoxy of one to twelve carbons, halo,
-OH provided that no two -OH groups are attached to the same carbon, thioalkoxy of one to twelve carbons, perfluoroalkyl of one to twelve carbons,
-NR7R7-, -CO2R10,
-OSO2Rl l, and
(=X), or R8' and R9» together with the nitrogen atom to which they are attached form a ring selected from
(i) aziridine,
(ii) azetidine,
(iii) pyrrolidine,
(iv) piperidine, (v) pyrazine,
(vi) morpholine,
(vii) phthalimide,
(viii) thiomorpholine, and
(ix) thiomorpholine sulfone where (i)-(ix) can be optionally substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents,
(j) =NNR8'R9',
(k) -NR7NR8'R9*,
(1) -CO2R8,
(m) -C(X)NR8-R9',
(n) =N-OR8,
(0) =NR8,
(P) -S(O)tRlθ,
(q) -X'C(X)R8,
(r) HO,
(s) -O-(CH2)q-Z-Rιo where Rio is defined previously, q is 1, 2, or
3, and Z is O or -S(O)x-,
(t) -OC(X)NR8-R9',
0*0 -OSO2RH,
(v) alkanoyloxy where the alkyl group is one to twelve carbons,
(w) -LβR30 where Lβ is selected from
(i) a covalent bond, (ii) -O-,
(iii) -S(O)t-, and
(iv) -C(X)- and R30 is selected from (i) alkyl of one to twelve carbons, (ii) alkenyl of one to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directly to Lβ when Lβ is other than a covalent bond,
(iii) alkynyl of one to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directly to Lβ when Lβ is other than a covalent bond, where (i), (ii), and (iii) can be optionally substituted with cycloalkyl of three to twelve carbons,
-OH, provided that no two -OH groups are attached to the same carbon, halo, alkoxy of one to twelve carbons, thioalkoxy of one to twelve carbons, -NR8'R9',
-O-(CH2)q-Z-Rio, alkoxycarbonyl where the alkyl group is one to twelve carbons, alkanoyloxy where the alkyl group is one to twelve carbons,
-NR7SO2-(alkyl of one to twelve carbons),
-OSO2-(alkyl of one to twelve carbons), aryl, and heterocycle, (iv) aryl,
(v) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo, ' -NO2, and
-OH, provided that no two -OH groups are attached to the same carbon, (vi) heterocycle, and
(vii) heterocycle substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo, -NO2, and
-OH, provided that no two -OH groups are attached to the same carbon, (x) -X'C(X)X"Rio, (y) -NHC(O)NHNH2, (z) alkenyl of two carbons, (aa) -C(=NR7)ORio, and
(10)
Figure imgf000260_0001
provided that when R5 is (9), L3 is other than -NR7- or -O-, where the carbon-carbon double bond is in the Z or E configuration, and Rl9, R20, and R21 are independently selected from
(a) hydrogen,
(b) halo,
(c) alkoxycarbonyl where the alkyl group is of one to twelve carbons,
(d) alkyl of one to twelve carbons, and
(e) alkyl of one to twelve carbons substituted with (i) alkoxy of one to twelve carbons,
(ϋ) -OH, provided that no two -OH groups are attached to the same carbon,
(iii) -SH, provided that no two -SH groups are attached to the same carbon,
(iv) -CN,
(v) halo,
(vi) -CHO, (vii) -NO2,
(viii) haloalkoxy of one to twelve carbons,
(ix) perfluoroalkoxy of one to twelve carbons,
(x) -NR8'R9«
(xi) =NNR8'R9',
( ii) -NR7NR8-R9',
(xiii) -CO2RlO,
(xiv) -C(X)NR8'R9',
Figure imgf000261_0001
(xvi) =NRio,
(xvii) -S(O)tRlθ,
(xviii) -X'C(X)Ri0,
(xix) (=X),
Figure imgf000261_0002
(xxi) -OC(X)NR8'R9',
(xxii) -LBR30,
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiv) -OSO2Rl l, and (xxv) -NR7(X)NR8'R9', or R20 and R21 together are selected from
(a) cycloalkyl of three to twelve carbon atoms,
(b) cycloalkenyl of four to twelve carbon atoms, and
Figure imgf000261_0003
hydrogen or alkyl of one to twelve carbons, and (11) cycloalkenyl of four to twelve carbons where the cycloalkenyl group or the ring formed by R20 and R21 together can be optionally substituted with one or two substituents independently selected from
(a) alkoxy of one to twelve carbons,
(b) -OH, provided that no two -OH groups are attached to the same carbon,
(c) -SH, provided that no two -SH groups are attached to the same carbon,
(d) -CN,
(e) halo,
(f) -CHO,
(g) -NO2,
(h) haloalkoxy of one to twelve carbons,
(i) perfluoroalkoxy of one to twelve carbons,
G) -NR8'R9'
(k) =NNR8*R9',
(1) -NR7NR8'R9',
(m) -CO2R10,
(n) -C(X)NR8-R9',
(o) =N-ORl0,
(P) =NRlO,
(q) -S(O)tRlO,
(r) -X'C(X)Rio,
(s) (=X),
(t) -O-(CH2)q-Z-Rio,
(u) -OC(X)NR8'R9',
(v) -LβR30,
(w) alkanoyloxy where the alkyl group is one to twelve carbons,
(x) -OSO2Rl l, and
(y) -NR7(X)NR8'R9-;
R6 is hydrogen or alkyl of one to twelve carbon atoms; or
-L2-R5 and R6 together are selected from
Figure imgf000262_0001
where Ois 1, 2, 3, or 4 and A is selected from
(a) -CH2-,
(b) -O-,
(c) -S(O)t, and
(d ) -NR7-, and ✓R26
(3) R 26 ' where the carbon-carbon double bond can be in the E or Z configuration and R26 and R26' are independently selected from
(a) hydrogen,
(b) alkenyl of three to twelve carbons, (c) aryl,
(d) heterocycle,
(e) alkyl of one to twelve carbons,
(f) cycloalkyl of three to twelve carbons,
(g) cycloalkenyl of four to twelve carbons, and (h) cycloalkenyl of four to twelve carbons where (a)-(f) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (i) alkoxy of one to twelve carbons, (ϋ) -OH, provided that no two -OH groups are attached to the same carbon, (iii) -SH, provided that no two -SH groups are attached to the same carbon, (iv) -CN,
(v) halo, (vi) -CHO, (vii) -NO2,
(viii) haloalkoxy of one to twelve carbons, (ix) perfluoroalkoxy of one to twelve carbons,
(x) -NR8'R9'
(xi) =NNR8'R9',
(xii) -NR7NR8'R9»,
(xiii) -CO2R10, (xiv) -C(X)NR8'R9',
(xv) =N-ORio,
(xvi) =NRio,
(xvii) -S(O)tRio,
(xviii) -X'C(X)Rio, (xix) (=X),
(xx) -O-(CH2)q-Z-Rl0, (xxi) -OC(X)NR8'R9',
(xxii) -LβR30,
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiii) -OSO2Rl l, and
(xxiv) -NR7(X)NR8'R9':
Rχ6 and Rχ6' are independently hydrogen or alkyl of one to six carbons; or Rχ6 and Rχ6' together are alkenyl of two carbons;
a broken line represents the optional presence of a double bond, provided that when Rχ6 and Rχ6' together are alkenyl of two carbons, the double bond is not present;
Y is selected from carbon, nitrogen, and N+(=O");
Rχ7 is absent or hydrogen or alkyl of one to six carbons, provided that when the double bond is present, and Y is nitrogen or N+(=O"), R 7 is absent; and
Rχ8 and Rχ8' are independently hydrogen or alkyl of one to six carbons; or Rχ8 and Rχ8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.
2. A compound according to Claim 1 of Formula II
Figure imgf000264_0001
II, or a pharmaceutically acceptable salt or prodrag thereof, where Rχ3 R2, R3, R4, R5, R6, and L2, are defined above.
3. A compound according to Claim 2 where Rl is -LI-RA, LI is -O- or -S-, and RA is alkyl of one to twelve carbons that can be optionally substituted, or Rx and R2 together are -X*-Y*-Z*-.
4. A compound according to Claim 3 selected from
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5 -phenyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH- [ 1 Jbenzopyrano [3 ,4- fjquinoline,
10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)- 1 H- [ 1 J benzopy rano [3,4-f] quinoline,
10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3 ,4- fj quinoline, 5-(3 -bromo-5 -methylphenyl)-2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-f]quinolin- 5- yl)phenol,acetate (ester), 3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinolin-
5- yl)phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(methylthio)methoxyJphenylJ- 1H- [lJbenzopyrano[3,4-f]quinoline,
[3 -(2,5-dihydro-l 0-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinolin-5- yl)phenyl] dimethylcarbamate,
5-[3-(2-furanyl)-5-methylphenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(l- morpholiny l)pheny 1] -
1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)-lH- [ 1 jbenzopyrano [3 ,4-f] quinoline, 5-(3 ,5-dichlorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 ] benzopy rano [3 , 4-fj quinoline,
5 -butyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl]-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 5-(3 -chlorophenyl)-2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(3-methylphenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(± )-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
(± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- fj quinoline,
5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 5-(4-chlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
5-(3,4-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
5-[3,5-bis(trifluoromethyl)phenylj-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
(-)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline, (+)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro- 10-methoxy-2,2,4,N-tetramethyl-N-phenyl- 1 H- [l]benzopyrano[3,4- f]quinolin-5-amine,
(-)2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-proρenyl)-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(+)-2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinoline,
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5- yl)-N,N-dimethylbenzenamine, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)- 1 H-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(l-morpholinyl)phenylj-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
1 -(2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinolin-
5 -y l)-3 ,3 -dimethyl-2-butanone,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- carbonitrile,
1 -(2,5-dihydro- 10-methoxy-2,2,4-trimethy 1- 1 H- [ 1 Jbenzopyrano [3,4-f] quinolin-
5-yl)-2-propanone, methyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline-5-acetate, 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)- 1 -phenylethanone,
5-[2-(chloromethyl)-2-propenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-
1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene-lH-[l]benzopyrano[3,4- fjquinoline-5-propanol, acetate (ester),
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(4-methylphenyl)-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 5 -(3 -bromophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethyl)-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-propyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline,
5 -(4-fluorophenyl)-2,5 -dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
5-(3-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[1 ]benzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-2,2,4,5-tetramethyl-lH-[l]benzopyrano[3,4- fj quinoline,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-(l -methylethyl)-lH-
[ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinoline-5- carboximidic acid ethyl ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene lH-[l]benzopyrano[3,4- fjquinoline-5-propanol,
2,5 -dihy dro- 10-methoxy-2,2,4,N,N-pentamethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- f]quinoline-5-acetamide,
2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[l]benzopyrano[3 ,4- fj quinoline-5 -ethanamine,
N-cyclopropyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3,4- f]quinoline-5-acetamide,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propynyl)- 1 H- [1 Jbenzopyrano [3 ,4- fj quinolin.e,
5-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5- yl)-2(5H)-furanone,
5-(3 -butenyl)-2,5-dihdyro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- propanol,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline, [3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinolin-
5- yl)phenyl] methylcarbonate,
2,5-dihydro-10-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenyl]-lH- [ljbenzopyrano[3,4-fjquinoline,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5- [3 -(phenylmethoxy)phenyl]- 1 H-
[ 1 jbenzopyrano [3,4-f] quinoline,
5-[3-(cyclopropylmethoxy)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[2-(l-piperidinyl)ethoxyjphenyj-
1 H-[l jbenzopyrano[3,4-fjquinoline,
5-(3 -hexyloxyphenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
5-[3-(2,4-dinitrophenoxy)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propynyloxy)phenylj-lH-
[ 1 Jbenzopyrano [3 ,4-fJ quinoline, 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5 -yl)phenol-4-methylbenzenesulfonate (ester),
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinolin-
5-yl)phenolacetate (ester),
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin- 5-yl)phenol, •
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxyJphenylj-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
[4-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinolin-
5-yl)phenylj dimethylcarbamate, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenyl]-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenyl]-lH-
[1 Jbenzopyrano [3 ,4-fj quinoline, .
[(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzoρyrano[3,4-fJquinolin- 5- yl)phenylj 1 -morpholinecarboxylate,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-[3- [(methylsulfinyl)methoxyjphenyl]- lH-[l]benzopyrano[3 ,4-fjquinoline, O- [3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fj quinolin-5-yl)phenylJ ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenyl]-lH-
[ljbenzopyrano[3 ,4-fjquinoline,
O- [3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4- fjquinolin-5-yl)phenylJ methylcarbonothioate,
[3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl] - 1 H- [ 1 jbenzopyrano [3 ,4- fjquinolin-
5 -y l)phenyl] trifluoromethanesulf onate, 5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]-2,5-dihydro-10-methoxy-
2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, ethyl 3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4- f]quinolin-5-yl)benzoate, 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5- yl)benzoic acid,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(2-propenyl)phenyl]-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline, l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinolin- 5-yl)-5-methylphenyl]ethanone,
3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjqumolin- 5- yl)-5 -trimethylbenzenemethanol, 5-[3-(2-furanyl)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(lH-pyrrolidin-l- yl)phenyl] - 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5-methyl)-5,N-dimethylbenzenamine,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin- 5- yl)-5-methyl-N-(2-propenyl)benzamide,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin- 5-yl)-N-(2-methoxyethyl)-5-methylbenzenamine,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)-N-(2-propenyl)benzenamine,
N'-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fj quinolin-5 -y l)-5 -methylphenylj -N,N-dimethylurea, N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinolin-5-yl)phenyl]benzenemethanamine,
5-[(3,5-dichlorphenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
5-[(4-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-
(trifluoromethyl)phenyljmethylene]- 1 H- [ 1 J -benzopyrano [3,4-f] quinoline, 5-[(2,6-difluorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
5-[(2-chlorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ 1 jbenzopyrano [3 ,4-fjquinoline, 5-[(2,6-dichlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- H-
[1 Jbenzopyrano [3 ,4-fjquinoline,
5-[(2-fluorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[(4,5-dihydro-4,4-dimethyl-2- oxazoly l)methy lene J - 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-thienyl)- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9,10-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
5-(2-cyclohexen- 1 -yl)-2,5-dihydro-9, 10-dimethoxy-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-fjquinoline, rel (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, anti(5R, 2'S) 2,5-dihydro-l 0-methoxy-5-(2 -oxo-3-tetrahydropyranyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-(3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-butenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fj quinoline, 2,5-dihydro- 10-methoxy-5-( 1 -ethenyl- 1 -cyclohexyl)-2,2,4-trimefhyl- 1 H-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro- 10-methoxy-5-( 1 -methylene-2-cyclohexyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(l -oxo-2-cyclohexyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-fJquinoline, 2,5-dihydro-10-methoxy-5-(3-cyclooctenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-cycloheptenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(l-cyclohexenylmethyl)-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3,3-dimethyl-6-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, re/(5R,3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, re/(5R,3 ' S) 2,5-dihydro- 10-methoxy-5-( 1 -hydroxymethyl-3 -cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxymethyl-3-cyclohexenyl)-2,2,4-trimethyl- lH-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-indolyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fj quinoline, rel (5 S,3 ' S) 2,5-dihydro- 10-methoxy-5 -( 1 -methyl-3 -cy clohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, rel (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [1 ]benzopyrano [3 ,4-fjquinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)- 2,2,4-trimethyl- 1 H-[l ]benzopyrano[3 ,4-fjquinoline,
(+) (5R, 3'S) 2,5-dihydro-l 0-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline,
(-)-(5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline, (+)-(5R, 3 ' S) 2,5-dihydro-l 0-methoxy-5-(l -methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3,4-f] quinoline, rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoline, rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, rel (5R, 3'S) 2,5-dihydro-l 0-methoxy-5-(l -acetoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)- 2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l -(N,N-dimethylamino)methyl-3 - cyclohexenyl)-2,2,4-trimethy 1- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, rel (5R, 3'S) 2,5-dihydro-l 0-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-morpholino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methyl-N- methylsulfonylamino)methyl-3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline, rel (5R, 3'S) 2,5-dihydro- 10-methoxy-5-(l-(N,N dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-methyl-3 -propenyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l,3-butadien-2-yl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro- 10-methoxy-5 -( 1 ,2-dihydroxy-3 -propyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -(N-phthalimido)-3 -propyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-l 0-methoxy-5-(l -amino-3-propyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-l-ethenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, (Z)-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano[3,4-fJquinoline,
(E) 2,5-dihydro-10-methoxy-5-(3-hydroxy-l-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)-l - propenyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro-10-methoxy-5-(3-methoxymethoxy-l-propenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, methyl 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fj quinolin-5-yl) acetyl hydroxamate,
2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fjquinolin-
5-yl) acetaldehyde,
2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, trans 2,5-dihydro-l 0-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, trans 2,5-dihydro- 10-methoxy-5-(2-penten- 1 -yl)-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5 -( 1 , 1 -difluoro- 1 -propen-3-yl)-2,2,4-trimethyl- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
(E) methyl 2-(2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-lH-[l jbenzopyrano [3,4- f]quinolin-5-yl) 2-butenoate, (E) 2,5-dihydro-10-methoxy-5-(4-hydroxy-2-buten-l-yl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
(E) 2,5-dihydro-10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten-l- yl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, (E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- 1 -yl)-
2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(2-butenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-(N-morpholinocarbonyloxy)ethyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)-
2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-(N-methyaminocarbonyloxyoxy)ethyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4- trimethy 1- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, ,5-dihydro-10-methoxy-5-(aminomethyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(ethoxycarbonylamino)methyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-l 0-methoxy-5-(carboethoxy)-2,2,4-trimethyl- 1 H-
[ljbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-( 1 -methylpropa- 1 ,2-dienyl)-2,2,4-trimethyl- 1 H- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-methoxy-5-(3-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- f] quinoline, 2,5-dihydro- 10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fjquinoline,
9-10-methylenedioxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro- [ 1 jbenzopyrano [3 ,4-fjquinoline, 5-(3-propenyl)-9-chloro-10-ethenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
9-chloro- 10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, 5-(3 -propenyl)-9-chloro- 10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
9-chloro-10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH- [1 jbenzopyrano [3 ,4-fjquinoline,
8-fluoro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH- [ 1 jbenzopyrano [3 ,4-f] quinoline, 5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
(10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [ 1 Jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(l - methy ley clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, (-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H- [1 jbenzopyrano [3 ,4-f] quinoline, (+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenyl]- 10-methoxy-2,2,4- trimethy 1-2, 5 -dihy dro- 1 H- [1 jbenzopyrano [3 ,4-f] quinoline, (+) (5R,3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethyl-2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(-) (5S,3 'R)-9-hydroxy-5-[l -methyl-3-cyclohexenyl]- 10-methoxy-2,2,4- trimethy 1-2, 5 -dihy dro- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenyl]-10-methoxy- 2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3 ,4-fjquinoline, (+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, re/-(5S,3 'R)-9-hydroxy-5-[l -methoxymethyl-3-cyclohexenyl]- 10-methoxy- 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-5-propyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(-) (5S,3 ' S) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimefhyl-5-(3- cy clohepteny 1 )- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clohepteny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy -2,2,4-trimethyl-5-phenyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-difluorophenyl)-lH- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
5-butyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clopenteny 1 )- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
(-) (5S,3 'R) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4-difluorophenyl)-lH- [ljbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(4-fluorophenyl)- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- trifiuoromethylphenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-5- bistrifluoromethylphenyl)- 1 H-[ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4- chlorophenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4- chlorophenyl)- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-butenyl)-lH-
[1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-5-(phenylmethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenylj- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline, (-) (S) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(+) (R) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6- pentafluorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l - hydroxymethylcy clopenten-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methylcarboxylatecyclopenten-3 -y 1 )- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
(-) (5S,3 'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
(±) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) -
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3- propenyl)- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline,
(+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenylj-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-cyclohexyl- 1 H- [lJbenzopyrano[3,4-fjquinoline,
2,5 ,5 -trihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-hydroxymethyl-3- propenyl)-lH-[l]benzopyrano[3,4-f]quinoline, methyl 2- [2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] -5 -quinolinyl] acetate,
(Z) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-butenyl)-lH-
[ 1 jbenzopyrano [3 , 4-fj quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(+) (5S,3 ' S) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1)-1H-[1 Jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clopenteny 1 )- 1 H- [ljbenzopyrano [3 ,4-fj quinoline,
(+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l -methoxycarbonyl)cyclohexen-3-ylj- 10-methoxy-
2 ,2,4-trimethyl-2 , 5 -dihy dro- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methyl-3-propenyl)-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, 9,10-Dimethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
9,10-Dimethoxy-5-[3-cyclohexenyl]-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [ljbenzopyrano [3 ,4-f] quinoline,
10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ] benzopyrano [3,4-f] quinoline,
10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-acetoxy-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 ]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
7-bromo -5-[3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH- [lJbenzopyrano[3,4-fjquinoline,
10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[1 ]benzopyrano[3 ,4-fjquinoline,
7-bromo-5-[l -methyl-3 -cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihydro- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-fj quinoline,
7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline, 7,9-Dibromo-5-[cyclohexen-3-ylj- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
7,9-Dibromo-5-[l-methyl-3-cyclohexenyl]-10-methoxy-2,2,4-trimethyl-2,5- dihy dro- 1 H- [1 jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-7-(2-ethenyl)-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-methoxy-7-acetyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-fjquinoline,
(+/-) 2,5-dihydro-9-methyl- 10-methoxy-2,2,4-trimethyl-5-(l -methylcyclohexen-
3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-
(carbomethoxymethyl)aminocarbonyloxy)phenyl)-2 ,2,4-trimethyl- 1 H-
[lJbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methylcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl- 1 H- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[ ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N- dimethylaminocarbonyloxy)ethyl)phenyl)-2,2,4-trimethyl- 1 H-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-l 0-methoxy-5-cyclopropyl-2,2,4-trimethyl-lH-[l Jbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-ethenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, trans 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, cis 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3,4-f] quinoline, trans 2,5-dihydro-l 0-methoxy-5-(l -cy clohexeny l)-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, (+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)- 10-methoxy-2,2,4-trimethyl-5- allyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 jbenzopy rano [3 ,4-fjquinoline, 10-methoxy-5-(3 -methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-5-(4,5-dimethyl-l,3-oxazol-2-yl)methyidene-2,5-dihydro-5-phenyl-
2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline,
10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-
1 H-[l Jbenzopyrano[3,4-fjquinoline,
10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, 10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-methoxy-5-(l-butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, Z-5-(benzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline,
Z-5-(2,5-difluorobenzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline, Z-9-hydroxy-10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
9-hydroxy- 10-methoxy-5-(3 ,5-difluorophenyl)methylidene-2,5-dihydro-5- phenyl-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5- phenyl-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(Z) 9-hydroxy-10-methoxy-5-((4-fluorophenyl)methylene)-2,2,4-trimethyl-lH-
2,5 -dihy dro- [ 1 ]benzopyrano [3 ,4-fj quinoline,
(Z)-9-hydroxy-10-methoxy-5-([2,3-difluorophenyl]methylene)-2,2,4-trimethyl-
1 H-2, 5 -dihy dro- [ 1 Jbenzopyrano [3 ,4-f] quinoline, Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-cyanomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH- [ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N-piperidino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-9-(4-N-morpholino-4-oxo-butanoyloxy)- 10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[ljbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(3 ,4,5 -trifluorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5- difluorophenylmethyl)- lH-[ ljbenzopyrano [3 ,4-fjquinoline,
2,5 -dihy dro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-cyclopentyl- 1 H-
[ 1 Jbenzopyrano[3 ,4-fjquinoline,
2,5 -dihy dro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
- 1 H-[ 1 Jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-pentenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-allenyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline, (-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cycIohexen-3-yl)-lH- [ljbenzopyrano [3 ,4-f] quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) -lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl) -1H-
[ 1 jbenzopyrano [3,4-fJ quinoline,
10-difluoromethoxy-5-[[3-(methylthio)methoxy]phenyl]-2,2,4-trimethyl-lH-
2,5-dihydro- [ljbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)-lH- [l]benzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3-
(methy lthio)methoxyphenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-
(methylthiomethoxy)phenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trimethyl-5-([2-
N,N-dimethylcarbamoyloxy jpheny 1)- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[1 ]benzopyrano[3 ,4-fjquinoline,
9-hydroxy- 10-methoxy-5-([3 -fluorophenyl]methylene)-2,2,4-trimethyl- 1 H-2,5- dihydro- [l]benzopyrano[3,4-f]quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-methoxycarbonyl)cyclohexen-3-ylj- 10-methoxy-
2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-dichlorophenyl)-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-2,2,4- trimethyl-5 -(1 -methylethyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-(4-N,N-dimethyIamino-4-oxo-butanoyloxy)-10-methoxy-5-
(phenylmethyl)-2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4-fjquinoline, 2,5 -dihy dro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-2,2,4- trimethyl-5-(2 -thienyl)- 1 H- [ 1 jbenzopyrano [3,4-fJ quinoline, 2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl- 5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, 9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4- trimethy 1- 1 H-2, 5 -dihy dro- [ 1 ]benzopyrano [3 ,4-f] quinoline, (+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)-10-methoxy-2,2,4-trimethyl-5- ally 1- 1 H- [ 1 ]benzopyrano [3 ,4-fj quinoline, 9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4- trimethy 1- 1 H-2,5 -dihy dro- [ 1 jbenzopyrano [3,4-f] quinoline, (+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)-10-methoxy-2,2,4- trimethy 1-5 -allyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, (+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)-10-methoxy-2,2,4-trimethyl-5- allyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH- [ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)- 10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-(4-N-morpholino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, (-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy- 2,2,4-trimethyl-5(S)-(3(S)-l-cyclopenten-3-yl)-lH-[l]benzopyrano[3,4- fjquinoline,
10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5- dihydro- [ 1 jbenzopyrano [3 ,4-fj quinoline, 10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5 -(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5 -dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH- [ ljbenzopyrano [3 ,4-fjquinoline, and 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline.
5. A compound according to Claim 2 where R is -LI-RA, Ll is a covalent bond and RA is -NR7R7'.
6. A compound according to Claim 5 selected from 2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fjquinolin- 10-amine, 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinolin- 10-amine,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH-
[1 ]benzopyrano[3 ,4-fjquinolin- 10-amine, and
2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[l]benzopyrano[3,4- fjquinoline- 10-carboxylic acid.
7. A compound according to Claim 2 where Rl is -LI-RA, Ll is -C(X)X'-, X and X' are -O-, and RA is alkyl of one to twelve carbons that can be optionally substituted.
8. A compound according to Claim 7 selected from methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l ]benzopyrano[3,4- f] quinoline- 10-carboxylate and methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline- 10-carboxylate.
9. A compound according to Claim 2 where Rl is -LI-RA, Ll is -X'C(X)-, X and X' are -O-, and RA is alkyl of one to twelve carbons that can be optionally substituted.
10. A compound according to Claim 9 that is
2,5 -dihydro-2 ,2,4-trimethyl-5 -phenyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline- 10-ol acetate (ester).
11. A compound according to Claim 2 where Rl is -LI-RA, Ll is a covalent bond and R is alkyl of two to twelve carbons that can be optionally substituted.
12. A compound according to Claim 11 selected from 10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
2,5-dihydro-2,2,4,10-tetrametnyl-5-phenyl-lH-[l]benzopyrano[3,4-fJquinoline,
5-(3,5-dichlorophenyl)-10-ethyl-2,5-dihydro-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-f] quinoline,
2 , 5 -dihy dro-2,2,4-trimethyl-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline-
10-methanol,
2,5-dihydro-10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-aminomethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxymethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro- 10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl-lH-
[1 jbenzopyrano[3 ,4-fjquinoline, and
2,5-dihydro-10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline .
13. A compound according to Claim 2 where Rl is -LI-RA, LI is a covalent bond, and
RA is alkenyl of two to twelve carbons that can be optionally substituted.
14. A compound according to Claim 13 selected from 10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fjquinoline.
2,5-dihydro-10-ethenyl-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-ethenyl-5-oxo-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, and
2,5 -dihy dro- 10-ethenyl-5 - [ 1 -methyl-3 -cy clohexeny 1] -2 ,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fj quinoline.
15. A compound according to Claim 2 where Rl is -LI-RA, Ll is a covalent bond and RA is alkynyl of two to twelve carbons that can be optionally substituted.
16. A compound according to Claim 15 selected from 10-ethynyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH- [l]benzopyrano[3,4-fJquinoline and
2,5-dihydro-10-ethynyl-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline.
17. A compound according to Claim 2 where Rl is -LI-RA, Ll is a covalent bond and RA is -OH, halo, heterocycle, -CN, -CO2H, or -CHO.
18. A compound according to Claim 17 selected from
2,5-dihydrό-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinolin-10-ol,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fj quinolin- lO-ol,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fjquin olin-10-ol,
(10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl- 1 H-2,5 -dihy dro-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3 ,4-fj quinoline,
10-chloro-9-hydroxy-5-(3 ,5-dimethylphenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline, rel-(5S, 3 '7?)-9-hydroxy- 10-methoxy-5- [ 1 -hydroxymethyl-3 -cyclohexenylj - 2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3,4-fJquinoline,
(-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3S-cyclopentenyl)-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
(-) 2,5 (S)-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3R-cyclopenteny 1 )-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, 10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-fjquinoline,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(+)-(5R, 3 'R)2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4-f]quinoline, 10-chloro-5-(3-propenyl)-2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-10-chloro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- fj quinoline, 2,5-dihydro- 10-(2-furanyl)-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3 ,4- fj quinoline,
2,5-dihydro- 10-carboxy-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-formyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-formyl-5-phenyl-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline, Z-5-(3-fluorobenzylidenyl)-10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro- [1 jbenzopyrano [3 ,4-fjquinoline,
Z- 10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline, re/-(5S,3 'R)-9-hydroxy-5-[l -methoxymethyl-3-cy clohexeny 1]-10-chloro-2,2,4- trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, and 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[ 1 jbenzopyrano [3,4-f] quinoline .
2,5-dihydro-7-bromo-9-hydroxy-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyjpheny 1)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy- 10-chIoro-2,2,4-trimethyl-5-ethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-isopropyl- 1H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-l 0-chloro-2,2,4-trimethyl-5-butyl-lH-
[1 Jbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-thiazol-2-yl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxymethyl-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hy droxy- 10-chloro-2,2,4-trimethyl-5-propyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
9-hydroxy-10-chloro-5-([2-pyridyljmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-f] quinoline, rel-(5 S)-9-hydroxy-5 - [(3 S)-( 1 -hydroxymethyl)cyclohexen-3 -ylj- 10-chloro- 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3 -y 1 )- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-chloro- 2,2,4-trimethyl-5-allyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(-) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-cyclopentyl- 1 H-
[ ljbenzopyrano [3 ,4-fj quinoline, and
(+/-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-benzyl-lH-
[ 1 j benzopy rano [3 ,4-fj quinoline .
19. A compound according to Claim 2 where Rl is -LI-RA, Ll is O and RA is alkenyl of three to twelve carbons that can be optionally substituted.
20. A compound according to Claim 19 that is 2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propenyloxy)-lH-
[l]benzopyrano[3,4- fjquinoline.
21. A compound according to Claim 2 where Rl is -LI-RA, LI is O and RA is alkynyl of three to twelve carbons that can be optionally substituted.
22. A compound according to Claim 21 that is
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propynyloxy)-lH-[l]benzo pyrano [3 ,4-fjquinoline .
23. A compound according to Claim 2 where Rl is -LI-RA, Ll is -X'C(X)X"-, X, X' and X" are O.
24. A compound according to Claim 23 that is
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fjquinolin- 10-ylJmethylcarbonate.
25. A compound according to Claim 1 of Formula III
Figure imgf000290_0001
III, or a pharmaceutically acceptable salt or prodrag thereof, where RX, R2, R3, R4, R5, R6, and L2, are defined above.
26. A compound according to Claim 25 where Ri is -LI-RA, Ll is -O-, and RA is alkyl of one to twelve carbons that can be optionally substituted.
27. A compound according to Claim 26 that is 10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3,4,5- tetrahydro- 1 H-chromeno [3 ,4-fjquinoline.
28. A compound according to Claim 1 of Formula IV
Figure imgf000290_0002
IN, or a pharmaceutically acceptable salt or prodrag thereof, where
Y is nitrogen or Ν+(=O"), and RX, R2, R3, R4, R5, R6, and L2, are defined above.
29. A compound according to Claim 28 where Ri is -Ll-RA, Ll is -O-, and RA is alkyl of one to twelve carbons that can be optionally substituted.
30. A compound according to Claim 29 selected from 2,5-dihydro-10-methoxy-2,2,4-trimethyl-3-oxide-5-phenyl-lH- [l]benzopyrano[3,4-f]quinazoline and 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H- [1 jbenzopyrano [3 ,4- fjquinazoline.
31. A compound according to Claim 1 of Formula V
Figure imgf000291_0001
V, or a pharmaceutically acceptable salt or prodrag thereof, where
RX, R2, R3, R4, R5, R6, and L2, are defined above.
Rχ6 and Rχ7 are independently hydrogen or alkyl of one to six carbons; and
Rχ8 and Rχ8' are independently hydrogen or alkyl of one to six carbons; or Rχ8 and Rχ8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
32. A compound according to Claim 31 where Rl is -LI-RA, Ll is -O-, and RA is alkyl of one to twelve carbons that can be optionally substituted.
33. A compound according to Claim 32 selected from 2,5-dihydro-10-methoxy-2,2-[spiro (tetrahydro-4-pyranyl)J-4-methyl-5-allyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-2,2-[spiro(hexyl)]-5-allyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5 -dihy dro- 10-methoxy-2,2-diethyl-4-methyl-5 -allyl- 1 H- [ 1 ]benzopyrano [3 ,4- fj quinoline, 2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[l]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-2,2-dimethyl-4-ethyl-5 -allyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline, and 2,5-dihydro-l O-methoxy-2,2,3 -trimethyl-5-allyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline.
34. A compound selected from
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3 ,4- fj quinoline 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[1 jbenzopyrano [3 ,4- fjquinoline,
2,5 -dihydro-2 ,2,4,N-tetramethyl-5 -(2-propenyl)- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinolin- 10-amine, methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3 ,4- fjquinoline-10-carboxylate,
10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- f] quinoline, 10-ethynyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-fjqumolin-10-ol,
10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[1 ]benzopyrano[3 ,4-fjquinoline,
10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline-10-ol acetate (ester),
5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ 1 Jbenzopyrano [3 ,4-f] quinoline, 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5- yl)phenol,acetate (ester), 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fjquinolin- 5- yl)phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(methylthio)methoxyJphenylJ- 1H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinolin-5- yl)phenylj dimethylcarbamate,
5-[3-(2-furanyl)-5-methylphenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(l - morpholiny l)phenyl] -
1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)- 1 H- [1 ]benzopyrano [3 ,4-f] quinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
5-butyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl]-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
5-(3-chlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(3-methylphenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(± )-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H-[ 1 Jbenzopyrano [3 ,4- fjquinoline, (± )-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
5-(4-chlorophenyl)-2,5 -dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ljbenzopyrano [3 ,4-fjquinoline,
5-(3 ,4-dimethylphenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3 ,4-fjquinoline,
5-(4-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
5-[3,5-bis(trifluoromethyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(-)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
(+)-5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro- 10-methoxy-2,2,4,N-tetramethyl-N-phenyl- 1 H-
[ljbenzopyrano[3,4- f]quinolin-5-amine,
(-)2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ljbenzopyrano[3 ,4-fjquinoline,
(+)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH- [ljbenzopyrano [3 ,4-fjquinoline,
2,5 -dihy dro- 10-methoxy-2 ,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5- yl)-N,N-dimethylbenzenamine, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(l-mo holinyl)phenylj- lH-[l]benzopyrano[3 ,4-fjquinoline,
1 -(2,5-dihydro-l 0-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinolin-
5-yl)-3,3-dimethyl-2-butanone,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4-fjquinoline-5- carbonitrile, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5 -y l)-2-propanone, methyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline-5-acetate,
2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin- 5-yl)-l-phenylethanone,
5- [2-(chloromethyl)-2-propenylJ-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline,
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl-(-methy lene- 1 H- [ 1 Jbenzopyrano [3 ,4- fJquinoline-5-propanol, acetate (ester),
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(4-methylphenyl)- 1 H-
[lJbenzopyrano[3,4-fjquinoline,
5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fjquinoline,
5-(3-bromophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(phenylmethyl)- 1 H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-propyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
5-(3-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4,5-tetramethyl-lH-[l]benzopyrano[3,4- fj quinoline,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-(l -methylethyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[l]benzopyrano[3,4-fjquinoline,
5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- f] quinoline,
2,5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline-5 - carboximidic acid ethyl ester,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-(-methylene 1 H- [ 1 Jbenzopyrano [3,4- fjquinoline-5-propanol,
2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[l]benzopyrano[3,4- fj quinoline-5 -acetamide, 2,5-dihydro- 10-methoxy-2,2,4,N,N-pentamethyl- 1 H- [ 1 Jbenzopyrano [3 ,4- fj quinoline-5 -ethanamine,
N-cyclopropyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fj quinoline-5 -acetamide, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propynyι)-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinoline, 5-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinolin- 5- yl)-2(5H)-furanone,
5-(3 -butenyl)-2,5-dihdyro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- fjquinoline,
2 , 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline-5 - propanol,
10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- f] quinoline, 2,5-dihydro-2,2,4, 10-tetrametnyl-5-phenyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline,
5-(3,5-dichlorophenyl)-10-ethyl-2,5-dihydro-2,2,4-trimethyl-lH- [1 jbenzopyrano
[3 ,4-f] quinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl- 1 H- [1 jbenzopyrano [3 ,4-f] quinolin- 10-amine,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH-
[1 Jbenzopyrano [3 ,4-fjquinolin- 10-amine,
2,5-dihydro-2,2,4-trimethyl-5-phenyl- 10-(2-propynyloxy)- 1 H- [1 Jbenzo pyrano [3,4-f] quinoline, 2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propenyloxy)-lH-[l]benzo- pyrano [3 ,4- fj quinoline,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fjquinoline- 10-methanol,
2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[l]benzopyrano[3 ,4- fj quinoline- 10-carboxy lie acid,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinolin-10-ol,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinolin- 10-ylJmethylcarbonate,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fjquin olin-10-ol,
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, [3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin- - yijphenyij methylcarbonate,
2,5-dihydro-10-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenylj-
1 H-[l Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenylj-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
5 -[3 -(cy clopropy lmethoxy)phenylj -2, 5 -dihy dro- 10-methoxy-2,2,4-trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[2-(l-piperidinyl)ethoxyJphenyj-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
5-(3-hexyloxyphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 5-[3-(2,4-dinitrophenoxy)phenyl]-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propynyloxy)phenylj-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fJquinolin- 5-yl)phenol 4-methylbenzenesulfonate (ester),
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5-yl)phenolacetate (ester),
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5-yl)phenol, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxy]phenyl]-
1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
[4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)phenylj dimethylcarbamate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenylj- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenyl]-lH-
[ljbenzopyrano[3,4-f|quinoline,
[(2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin- 5- yl)phenylj 1-morpholinecarboxylate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3- [(methylsulfinyl)methoxyjphenylj-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- f]quinolin-5-yl)phenylj ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenyl]-lH-
[1 ]benzopyrano[3 ,4-fjquinoline, O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinoIin-5-yI)phenylj methylcarbonothioate,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl]-lH-[lJbenzopyrano[3,4- fjquinolin-
5 -y l)pheny 1 J trifluoromethanesulfonate, 5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenylJ-2,5-dihydro-10-methoxy-
2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline, ethyl 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- f]quinolin-5-yl)benzoate,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin- 5- yl)benzoic acid,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(2-propenyl)phenyl]-
1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
1 - [3 -(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4- fj quinolin- 5-yl)-5-methylphenyl]ethanone,
3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l ]benzopyrano[3,4-fjquinolin- 5- yl)-5-trimethylbenzenemethanol,
5-[3-(2-furanyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(l H-pyrrolidin- 1 - yl)phenylj- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinolin-
5-methyl)-5,N-dimethylbenzenamine, 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5- yl)-5-methyl-N-(2-propenyl)benzamide,
3 -(2, 5 -dihy dro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinolin-
5-yl)-N-(2-methoxyethyl)-5-methylbenzenamine, 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinolin-
5-yl)-N-(2-propenyl)benzenamine,
N'-[3-(2,5 -dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4- fj quinolin-5 -yl)-5 -methylphenyl] -N,N-dimethy lurea, N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinolin-5-yl)phenylJbenzenemethanamine,
5-[(3,5-dichlorphenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
5-[(4-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-
(trifluoromethyl)phenylj methylene] - 1 H- [ 1 ] -benzopyrano [3 ,4-fjquinoline,
5-[(2,6-difluorophenyl)methylenej-2,5-dihydro-10-methoxy-2,2,4-trimethyl- H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
5-[(2-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [1 jbenzopyrano [3 ,4-fjquinoline, 5-[(2,6-dichlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- H-
[ 1 ]benzopyrano [3,4-f] quinoline,
5-[(2-fluorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[(4,5-dihydro-4,4-dimethyl-2- oxazolyl)methylene] - 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-[l]benzopyrano[3 ,4- fjquinoline, 2,5-dihydro-9, 10-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
5-(2-cyclohexen-l-yl)-2,5-dihydro-9,10-dimethoxy-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, re/ (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, anti(5R, S) 2,5-dihydro-l 0-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH-
[ljbenzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-5-(3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-butenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(l-ethenyl-l-cyclohexyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-(l -methylene-2-cyclohexyl)-2,2,4-trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(l-oxo-2-cyclohexyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-cyclooctenyl)-2,2,4-trimethyl-lH-
[ ljbenzopyrano [3 ,4-fjquinoline, , 2,5-dihydro- 10-methoxy-5-(3 -cycloheptenyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(l-cyclohexenylmethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3,3-dimethyl-6-cyclohexenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, re/(5R,3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, re/(5R,3 ' S) 2,5-dihydro- 10-methoxy-5-( 1 -hydroxymethyl-3 -cy clohexeny 1)-
2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxymethyl-3-cyclohexenyl)-2,2,4-trimethyl-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-(3 -indolyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline, re/ (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, rel (5R,3 ' S) 2,5-dihydro- 10-methoxy-5-( 1 -methyl-3 -cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, (-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, (+) (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinoline,
(-)-(5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, (+)-(5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4-trimethyl-
1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, rel (5R, 3'R) 2,5-dihydro-l 0-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)- 2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-l 0-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-l 0-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-
2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-(N,N-dimethylamino)methyl-3- cy clohexeny l)-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-
2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-morpholino)methyl-3- cy clohexeny l)-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3 'R) 2,5-dihydro- 10-methoxy-5-(l -(N-methyl-N- methylsulfonylamino)methyl-3 -cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-(N,N dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(l,3-butadien-2-yl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-l 0-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-5-(l,2-dihydroxy-3-propyl)-2,2,4-trimethyl-lH-
[ 1 J benzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro- 10-methoxy-5-( 1 -(N-phthalimido)-3-propyl)-2,2,4-trimethyl- 1 H-
[1 Jbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l-amino-3-propyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(2-carbomethoxy- 1 -ethenyl)-2,2,4-trimethyl-l H-
[ 1 jbenzopyrano [3,4-f] quinoline,
(Z)-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, (E) 2,5-dihydro- 10-methoxy-5-(3-hydroxy- 1 -propenyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro-10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)-l- propenyl)-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3 -methoxymethoxy- 1 -propenyl)-2,2,4- trimethyl- 1 H-[l jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, methyl 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4- f]quinolin-5-yl) acetyl hydroxamate, 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[l Jbenzopyrano [3 ,4-fjquinolin-
5-yl) acetaldehyde,
2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-l 0-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, trans 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline, trans 2,5-dihydro-10-methoxy-5-(2-penten-l-yl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-l 0-methoxy-5-(l , 1 -difluoro- 1 -propen-3 -yl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(E) methyl 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinolin-5-yl) 2-butenoate, (E) 2,5-dihydro- 10-methoxy-5-(4-hydroxy-2-buten- 1 -yl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopy rano [3,4-f] quinoline,
(E) 2,5-dihydro-10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten-l- yl)-2,2,4-trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- 1 -yl)- 2,2,4-trimethyl- 1 H-[l jbenzopyrano [3 ,4-fjquinoline,
(7JT) 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-morpholinocarbonyloxy)ethyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)- 2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-(N-methyaminocarbonyloxyoxy)ethyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4- trimethy 1- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(aminomethyl)-2,2,4-trimethyl-lH-[l]benzopyrano- [3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(ethoxycarbonylamino)methyl)-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(carboethoxy)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -methylpropa- 1 ,2-dienyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
2,5 -dihy dro- 10-methoxy-5 -(3 -pyridyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
(10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[1 Jbenzopyrano [3 ,4-fjquinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3,4-f] quinoline, 10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
10-chloro-9-hydroxy-5-(3,5-dimethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-f] quinoline, rel-(5S, 3 '7?)-9-hy droxy- 10-methoxy-5 - [ 1 -hy droxymethyl-3 -cy clohexeny 1] - 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4-fjquinoline,
(-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3S-cyclopentenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3R-cyclopentenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(+)-(5R, 3'R)2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3,4-f] quinoline,
9-10-methylenedioxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ]benzopyrano [3 ,4-fj quinoline, 5-(3-propenyl)-9-chloro-10-ethenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
9-chloro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 5-(3-propenyl)-9-chloro-10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
9-chloro- 10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, 8-fluoro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
5 -(3 -propenyl)-8-fluoro- 10-methoxy-2,2,4-trimethyl-2,5-dihydro- 1 H-
[1 jbenzopyrano [3 ,4-fjquinoline,
( 10-methoxy-9-fluoro-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro- [ljbenzopyrano [3 ,4-fjquinoline,
10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-cyclohexeny 1)-
1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
(-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethy 1-2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4- trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylj- 10-methoxy-2,2,4- trimethy 1-2,5 -dihy dro- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(-) (5S,3 'R)-9-hydroxy-5-[l -methyl-3 -cyclohexenylj- 10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, re/-(5S,3'R)-9-hydroxy-5-[l -hydroxymethyl-3-cyclohexenylj-l 0-methoxy-
2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4-fjquinoline,
(+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- methylcyclohexen-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenylj- 10-methoxy- 2,2,4-trimethyl-2, 5 -dihy dro- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-5-propyl-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clohepteny 1 )- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohepteny 1 )- 1 H- [1 ]benzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-l 0-methoxy -2,2,4-trimethyl-5-phenyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-difluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, 5-butyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1H-
[1 jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4-difluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-fluorophenyl)-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- trifluoromethylphenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5 -dihy dro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5 -(3 -5- bistrifluoromethy lpheny 1)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4- chlorophenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4- chlorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-butenyl)-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-5-(phenylmethyl)-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3,4-f] quinoline,
(-) (5S,3 'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-[l -ethyl-3- cy clohexeny 1] - 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
(-) (S) 5-cyclopentyl-2,5 -dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[1 ]benzopyrano[3 ,4-fjquinoline,
(+) (R) 5 -cyclopentyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2,2,4-trimethyl-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-
1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6- pentafluorophenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, (+/-) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5(S)-(3(S)- 1 - hydroxymethylcy clopenten-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methy lcarboxy latecy clopenten-3 -y 1 )- 1 H- [ 1 ]benzopyrano [3 ,4-fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
(-) (5S,3 'R) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ ljbenzopyrano [3 ,4-fjquinoline, (±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) -
1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3- propeny 1)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline,
(+) (5R,3 ' S) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-[l -ethyl-3- cy clohexeny 1] - 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclohexyl-lH-
[l]benzopyrano[3,4-fjquinoline, ;
2,5,5-trihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-hydroxymethyl-3- propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, methyl 2-[2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3 ,4-f] -5 -quinolinyl] acetate,
(Z) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-butenyl)-lH- [ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(+) (5 S,3 ' S) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3 'R) 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3- cy clohexeny 1 )- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
(+) (5R,3 ' S) 2,5(R)-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, (+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cy clopenteny 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l -methoxycarbonyl)cy clohexen-3 -ylj- 10-methoxy-
2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3,4-fJquinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-methyl-3-propenyl)-
1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
9, 10-Dimethoxy-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopy rano [3 ,4-f] quinoline,
9,10-Dimethoxy-5-[3-cyclohexenyl]-methoxy-2,2,4-trimethyl-2,5-dihydro-lH- [ljbenzopyrano[3,4-fjquinoline,
10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3,4-f] quinoline'
10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopy rano [3,4-f] quinoline, 10-methoxy- 9-(3 -propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-acetoxy-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)- lH-[ ljbenzopyrano [3 ,4-fjquinoline,
7-bromo -5-[3-cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[1 Jbenzopyrano [3 ,4-fjquinoline, 7-bromo-5-[l -methyl-3 -cyclohexenylj- 10-methoxy-2,2,4-trimethyl-2,5- dihy dro- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
7,9-Dibromo-5-[cyclohexen-3-ylj- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
7,9-Dibromo-5-[l-methyl-3-cyclohexenyl]-10-methoxy-2,2,4-trimethyl-2,5- dihy dro- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, 10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopy rano [3 ,4-fjquinoline,
10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 10-methoxy-7-acetyl-5-(3 -propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-methyl- 10-methoxy-2,2,4-trimethyl-5-(l -methylcyclohexen-
3-yl)-lH-[l Jbenzopyrano [3 ,4-fjquinoline, 10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-fj quinoline,
10-chloro-5-(3-propenyl)-2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4- f] quinoline,
(+/-) 2,5-dihydro-10-chloro-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-
(carbomethoxymethyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methy lcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl- 1 H- [ljbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-l 0-methoxy-5-(3-(2-(N,N- dimethylaminocarbonyloxy)ethyl)phenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro- 10-methoxy-5 -cyclopropyl-2,2,4-trimethyl- 1 H- [1 Jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-ethenyl-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fjquinoline, trans 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH- [ljbenzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline, cis 2,5-dihydro-10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline, trans 2,5-dihydro-10-methoxy-5-(l-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano [3 , 4-fj quinoline,
2,5-dihydro-10-(2-furanyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-carboxy-5-(3-propenyl)-2,2,4-trimethyl-lH-[ljbenzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro- 10-formyl-5 -(3 -propenyl)-2,2,4-trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-aminomethyl-5-(3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxymethyl-5-(3-propenyl)-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-ethenyl-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-ethynyl-5-phenyl-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- f] quinoline, methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- f] quinoline- 10-carboxylate,
2,5-dihydro-10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro- 10-formyl-5-phenyl-2,2,4-trimethyl- 1 H-[ 1 Jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-10-ethenyl-5-oxo-2,2,4-trimethyl-lH-[ljbenzopyrano[3,4- fj quinoline, 5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-10-ethenyl-5-[l-methyl-3-cyclohexenylj-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-5-(3 -propenyl)- 10-methylthio-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3,4-f] quinoline, (+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)- 10-methoxy-2,2,4-trimethyl-5- allyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,,4-trimethyl-lH-
[ 1 ]benzopyrano [3,4-f] quinoline,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- [ljbenzopyrano [3 ,4-fjquinoline,
10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3,4,5- tetrahydro- 1 H-chromeno [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
10-methoxy-5-(3-methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-5-(4,5-dimethyl- 1 ,3-oxazol-2-yl)methyidene-2,5-dihydro-5-phenyl- 2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethy 1- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-
1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, 10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
10-methoxy-5-(l-butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-3-oxide-5-phenyl-lH-
[ 1 Jbenzopyrano [3 ,4-f]quinazoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H- [1 Jbenzopyrano [3 ,4- fj quinazoline, 2,5-dihydro-10-methoxy-2,2-[spiro(tetrahydro-4-pyranyl)]-4-methyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-2,2-[spiro(hexyl)]-5-allyl-lH-[l]benzopyrano[3,4- f] quinoline, 2,5-dihydro- 10-methoxy-2,2-diethyl-4-methyl-5-allyl- 1 H-[l jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[l]benzopyrano[3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2-dimethyl-4-ethyl-5-allyl-lH-[l]benzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-methoxy-2,2,3-trimethyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
Z-5-(benzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
Z-5-(2,5-difluorobenzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3 ,4-fjquinoline,
Z-5-(3-fluorobenzylidenyl)-10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-
1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, Z-l 0-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
Z-9-hydroxy-10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
9-hydroxy-10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5- phenyl-2,2,4-trimethyl- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5- phenyl-2,2,4-trimethyl- 1 H-[ 1 jbenzopyrano [3 ,4-f] quinoline,
(Z) 9-hydroxy-10-methoxy-5-((4-fluorophenyl)methylene)-2,2,4-trimethyl-lH-
2,5-dihydro- [l]benzopyrano[3,4-f]quinoline, (Z)-9-hydroxy-10-methoxy-5-([2,3-difluorophenyl]methylene)-2,2,4-trimethyl- lH-2,5-dihydro-[lJbenzopyrano[3,4-fjquinoline,
Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-
1 H- [ 1 jbenzopyrano [3,4-f] quinoline, re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenyl]-10-chloro-2,2,4- trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-fjquinoline,
9-hydroxy-10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-cyanomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)- 1 H-[l Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N-piperidino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)- 1 H-[l Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N-morpholino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(3 ,4,5-trifluorophenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-l 0-methoxy-2,2,4-trimethyl-5-(3-5- difluorophenylmethyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclopentyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
- 1 H- [ 1 Jbenzopyrano[3 ,4-fjquinoline,
2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-pentenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-allenyl-lH- [l]benzopyrano[3,4-f]quinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[ 1 Jbenzopyrano [3,4-f] quinoline, (-) (5S, 3 'R) 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)- 1H-
[ 1 ]benzopyrano [3 ,4-fj quinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) - 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl) -1H-
[l]benzopyrano[3 ,4-fjquinoline,
10-difluoromethoxy-5-[[3-(methylthio)methoxyjphenyl]-2,2,4-trimethyl-lH-
2,5 -dihy dro- [ 1 jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-7-bromo-9-hydroxy-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 ]benzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)-lH-
[1 Jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3-
(methylthio)methoxyphenyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-
(methy lthiomethoxy)phenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyjphenyl)- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trimethyl-5-([2- N,N-dimethylcarbamoy loxyjphenyl)- 1 H- [ 1 ]benzopyrano [3,4-f] quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-ethyl- 1 H-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-isopropyl-lH-
[ 1 jbenzopyrano [3 ,4-fjquinoline, 9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-butyI-lH-
[1 jbenzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l-thiazol-2-yl)-lH- [ljbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxymethyl-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 ]benzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-propyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-methoxy-5-([3-fluorophenyl]methylene)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 jbenzopyrano [3 ,4-f] quinoline,
9-hydroxy-10-chloro-5-([2-pyridyl]methylene)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline, rel-(5 S)-9-hydroxy-5-[(3 S)-( 1 -hydroxymethyl)cy clohexen-3 -yl] - 10-chloro-
2,2,4-trimethyl-2,5-dihydro-lH-[ljbenzopyrano[3,4-fjquinoline, rel-(5 S)-9-hydroxy-5 - [(3 S)-( 1 -methoxycarbonyl)cy clohexen-3 -ylj- 10-methoxy-
2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-dichlorophenyl)-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoline,
(-) (5S,3 ' S) 2,5-dihydro-9-hydroxy-l 0-chloro-2,2,4-trimethyl-5-(l - methy ley clohexen-3 -y 1 )- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline, (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methy ley clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, (+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, (+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcy clohexen-3 -y 1 )- 1 H- [ 1 Jbenzopyrano [3 ,4-fjquinoline, (+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-chloro- 2,2,4-trimethyl-5 -allyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline, (-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-cyclopentyl-lH- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5 -(1 -methylethyl)- 1 H- [ 1 jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-5- (phenylmethyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-thienyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl- 5-(2-propenyl)-lH-[ljbenzopyrano[3 ,4-fjquinoline, 9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy- 10-methoxy-5-(3 -propenyl)-2,2,4- trimethyl-lH-2,5-dihydro- [ljbenzopyrano [3 ,4-fj quinoline,
(+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)-10-methoxy-2,2,4-trimethyl-5- allyl- 1 H-[ 1 Jbenzopyrano [3 ,4-fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-benzyl-lH- [ 1 jbenzopyrano [3,4-f] quinoline, 9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[1 jbenzopyrano [3 ,4-fjquinoline,
9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4- trimethyl- 1 H-2,5 -dihy dro- [ 1 jbenzopyrano [3,4-f] quinoline, (+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)- 10-methoxy-2,2,4- trimethy 1-5 -allyl- 1 H- [ 1 ]benzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)- 10-methoxy-2,2,4-trimethyl-5- allyl- 1 H- [ 1 jbenzopyrano [3 ,4-f] quinoline,
(+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H- [ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH- [ 1 jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)- 1 H- [1 jbenzopyrano [3 ,4-fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethy 1-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fj quinoline, 2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)- 10-methoxy-2,2,4- trimethyl-5 -(2-propenyl)- 1 H- [ 1 Jbenzopyrano [3,4-f] quinoline, 2,5-dihydro-9-(4-N-morpholino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fjquinoline, (-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy- 2,2,4-trimethy 1-5 (S)-(3 (S)- 1 -cy clopenten-3 -y 1 )- 1 H- [ 1 jbenzopyrano [3 ,4- fjquinoline,
10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihy dro- [ 1 jbenzopyrano [3,4-f] quinoline, 10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5 -dihy dro- [ 1 jbenzopyrano [3 ,4-fj quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH- [l]benzopyrano[3 ,4-fjquinoline, and
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- 1 H- [ 1 jbenzopyrano [3 ,4-fjquinoline.
35. A method of selectively modulating the activation, repression, agonism, and antagonism effects ofthe glucocorticoid receptor in a mammal comprising administering an effective amount of a compound of Claim 1.
36. A method of treating inflammation and immune, autoimmune and inflammatory diseases in a mammal comprising administering an effective amount of a compound of Claim 1.
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CA002415037A CA2415037A1 (en) 2000-07-05 2001-06-27 Glucocortiocoid-selective antiinflammatory agents
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