WO1999041256A1 - Glucocorticoid-selective anti-inflammatory agents - Google Patents

Glucocorticoid-selective anti-inflammatory agents Download PDF

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Publication number
WO1999041256A1
WO1999041256A1 PCT/US1999/003127 US9903127W WO9941256A1 WO 1999041256 A1 WO1999041256 A1 WO 1999041256A1 US 9903127 W US9903127 W US 9903127W WO 9941256 A1 WO9941256 A1 WO 9941256A1
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WO
WIPO (PCT)
Prior art keywords
dihydro
trimethyl
methoxy
benzopyrano
fjquinoline
Prior art date
Application number
PCT/US1999/003127
Other languages
French (fr)
Inventor
Michael J. Coughlan
Steven W. Elmore
Michael E. Kort
Philip R. Kym
Jimmie L. Moore
John K. Pratt
Alan X. Wang
James P. Edwards
Todd K. Jones
Original Assignee
Abbott Laboratories
Ligand Pharmaceuticals, Inc.
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Publication date
Priority to SK1197-2000A priority Critical patent/SK284689B6/en
Priority to IL13750899A priority patent/IL137508A0/en
Priority to AU26773/99A priority patent/AU766441B2/en
Priority to PL343018A priority patent/PL193323B1/en
Priority to DK99906996T priority patent/DK1053239T3/en
Priority to AT99906996T priority patent/ATE230749T1/en
Priority to EP99906996A priority patent/EP1053239B1/en
Application filed by Abbott Laboratories, Ligand Pharmaceuticals, Inc. filed Critical Abbott Laboratories
Priority to BR9907788-4A priority patent/BR9907788A/en
Priority to JP2000531449A priority patent/JP2002503665A/en
Priority to SI9930243T priority patent/SI1053239T1/en
Priority to DE69904804T priority patent/DE69904804T2/en
Priority to HU0100460A priority patent/HUP0100460A3/en
Priority to NZ506013A priority patent/NZ506013A/en
Priority to KR1020007008850A priority patent/KR20010040935A/en
Priority to CA002320943A priority patent/CA2320943A1/en
Publication of WO1999041256A1 publication Critical patent/WO1999041256A1/en
Priority to NO20004053A priority patent/NO20004053L/en
Priority to BG104719A priority patent/BG64317B1/en
Priority to HK01102793A priority patent/HK1033308A1/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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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]

Definitions

  • the present invention relates to glucocorticoid receptor-selective benzopyrano[3,4- fjquinolines that are useful for treating immune or autoimmune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation, infl-amatory 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 of the body, including carbohydrate, protein and lipid metabolism, and the functions of the 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, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous poly arteritis, 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 ins
  • 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 obstructive 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 infla. mmatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, he ⁇ es 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, erythem
  • glucocorticoid receptor has been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIN), 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-retroviral 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, (g) alkyl of one to twelve carbons,
  • 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,
  • 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,
  • alkanoyloxy where the alkyl part is one to twelve carbons
  • alkoxycarbonyl where the alkyl part is one to twelve carbons
  • R2, R3, and R4 are independently hydrogen or Ri; or
  • Rl and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or -(C(Ri2)(Ri3))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-, -CH 2 S(O) r , -CH 2 O-, -CH 2 NR 7 -, -NR7-, and -O-;
  • L is selected from (1) a covalent bond
  • 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
  • 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, (vi ⁇ ) 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)NR ⁇ R ⁇ where Rx and Ry are independently selected from hydrogen and alkyl of one to twelve carbons, (xi) alkoxy of one to twelve carbon
  • R 8 - and R9 1 together with the nitrogen atom to which they are attached form a ring selected from (i) aziridine, (ii) azetidine, (iii) pyrrolidine,
  • alkanoyloxy where the alkyl group is one to twelve carbons, (w) - ⁇ R30 where LB is selected from (i) a covalent bond, (ii) -O-,
  • -10- R30 is selected from
  • ⁇ 11- independently selected from alkyl of one to twelve carbons, halo,
  • Rl9 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
  • R20. and R21 are independently selected from
  • alkoxycarbonyl where the alkyl group is of one to twelve carbons
  • alkyl of one to twelve carbons
  • R20 and R21 tc )gether are selected from
  • 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,
  • R is hydrogen or alkyl of one to twelve carbon atoms
  • Rl6 and R ⁇ 5' are independently hydrogen or alkyl of one to six carbons; or Rl6 and Ri ⁇ 1 together are alkenyl of two carbons;
  • ⁇ 15- a broken line represents the optional presence of a double bond, provided that when Ri6 and Ri6- together are alkenyl of two carbons, the double bond is not present;
  • Rl8 and Ri ⁇ ' are independently hydrogen or alkyl of one to six carbons; or R l 8 and Ri8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.
  • R l , R5, Re, and L2 are defined above.
  • Rl ⁇ 5 and R17 are independently hydrogen or alkyl of one to six carbons.
  • R 1 8 and Ri8' are independently hydrogen or alkyl of one to six carbons; or
  • Rl8 and Ri8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
  • glucocorticoid receptor In another embodiment of the invention are disclosed methods of selectively partially antagonizing, antagonizing, agonizing or modulating the glucocorticoid receptor. In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I. In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
  • Compounds of this invention include, but are not limited to, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline- lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-
  • 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 aiyl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring.
  • 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 of the 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,
  • Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
  • Heterocyclics also include compounds of the formula X*
  • 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 quaternized.
  • 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)).
  • 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 of the 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 prodrug 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
  • prodrugs represents those prodrugs of the compounds of the 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, of the compounds of the invention.
  • prodrug repres- ents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • 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 ⁇ l. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 - 19 .
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the 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, pe
  • 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 of the 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 of the 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 of the carbon-carbon double bond and the term “E” represents substituents on opposite sides of the 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 of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds where the substitutients are disposed on both the same and opposite sides of plane of the ring are designated cis/trans.
  • Receptor Cytosol The procedure described in Anal. Biochem. 1970, 37, 244-252, hereby inco ⁇ orated by reference, was used. Briefly, cytosol preparations of human glucocorticoid receptor-cc [GRXJ isoform 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.
  • [ 3 H]-dexamethasone (Dex, specific activity 82-86 Ci/mmole) and [ 3 H] -progesterone (Prog, specific activity 97- 102 Ci ⁇ nmol) 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),
  • DMSO dimethylsulfoxide
  • 50X solutions of test compounds were prepared from the 32 mM solution with a 50:50 mixture of DMSO/ethanol.
  • the 50X 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.
  • 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 (IC 50 ) w.as determined from a Hill analysis of the competitive binding experiments.
  • L* is the concentration of radioligand
  • KL is the dissociation constant of the radioligand determined from saturation analysis.
  • K L was -1.5 nM
  • 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.

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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

GLUCOCORΉOCOID-SELECTTVΈ ANTΗNFLAMMATORY AGENTS
Technical Field The present invention relates to glucocorticoid receptor-selective benzopyrano[3,4- fjquinolines that are useful for treating immune or autoimmune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation, infl-amatory 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 of the body, including carbohydrate, protein and lipid metabolism, and the functions of the 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, Cushing's syndrome, acute adrenal insufficiency, congenital adrenal hyperplasia, rheumatic fever, polyarteritis nodosa, granulomatous poly arteritis, 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 obstructive 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 infla. mmatory scalp alopecia, panniculitis, psoriasis, discoid lupus erythematosus, inflamed cysts, atopic dermatitis, pyoderma gangrenosum, pemphigus vulgaris, bullous pemphigoid, systemic lupus erythematosus, dermatomyositis, heφes 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 of the glucocorticoid receptor have been unsuccessfully pursued for decades. These agents would potentially find application in several disease states associated with Human Immunodeficiency Virus (HIN), 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-retroviral 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 imgf000004_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,
-2- (4) -C(X)-,
(5) -NR - 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)NRc>- where X is O or S and R 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
-3- 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) -Sθ2NR8-,
(15) -NR8SO2-, 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) -CO2R20 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 Rγ 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,
-4- (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 Rn 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
Ry 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 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) =NRιo, (r) -S(O)tRιo, (s) -X'C(X)Rιo, (t) (=X), and
(u) -OSO2R11,
(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 Li is other than a covalent bond, where (17) and (18) can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from
-6- (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
(0 -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, (0 -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.
Q) -CO2R10,
(k) -OSθ2Rn, and (l) (=X);
R2, R3, and R4 are independently hydrogen or Ri; or
Rl and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or -(C(Ri2)(Ri3))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)r, -CH2O-, -CH2NR7-, -NR7-, and -O-;
L 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
-7- 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)r; and
R5 is selected from (1) halo,
(2) hydrogen,
(3) -C(=NR7)ORιo.
(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 directiy 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,
-8- (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, (iϋ) 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, (viϋ) 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- -OSO2R11, and (=X), or
R8- and R91 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) moφholine, (vii) phthalimide, (viii) thiomoφholine, and
(ix) thiomoφholine sulfone where (i)-(ix) can be optionally substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents, (j) =NNR8'R9s (k) -NR7NR8'R9-,
(1) -CO2R8, (m) -C(X)NR8-R9', (n) =N-ORg, (0) =NR8, (p) -S(O)tRιo,
(q) -X'C(X)Rg, (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)r, (t) -OC(X)NR8'R9
(u) -OSO2R11,
(v) alkanoyloxy where the alkyl group is one to twelve carbons, (w) - βR30 where LB is selected from (i) a covalent bond, (ii) -O-,
(iii) -S(O)r, and (iv) -C(X)- and
-10- 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 LB when LB 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 LB when LB 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-Rιo, alkoxycarbonyl where the alkyl group is one to twelve carbons, alkanoyloxy where the alkyl group is one to twelve carbons,
-NR7Sθ2-(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
■11- 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"Rιo.
(y) -NHC(O)NHNH2, (z) alkenyl of two carbons,
(aa) -C(=NR7)ORιo, and
(bb) -NR7(X)NR8-R9', 20
(10) Rl9 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, (ii) -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'
-12- (xi) =NNR8'R9',
(xϋ) -NR7NR8-R9-,
(xϋi) -CO2R10.
(xiv) -C(X)NR8-R9',
(XV) =N-ORιo,
(xvi) =NRι0,
(xvii) -S(O)tRιo,
(xviii) -X'C(X)RlO,
(xix) (=X),
(xx) -O-(CH2)q-Z-Rιo,
(xxi) -OC(X)NR8-R9s
(xxii) -LβR30.
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiv) -OSO2R11, and
(xxv) -NR7(X)NR8'R9-, or
R20 and R21 tc )gether are selected from
(a) cycloalkyl of three to twelve carbon atoms,
(b) cycloalkenyl of four to twelve carbon atoms, and
Figure imgf000015_0001
,R22
(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 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,
■13- (j) -NR8'R9-
(k) =NNR8'R9-,
0) -NR7NR8-R9',
(m) -CO2R10,
(n) -C(X)NR8-R9',
(o) =N-ORιo,
(P) =NRιo,
(q) -S(O)tRιo,
(r) -X'C(X)Rιo,
(s) (=X),
(t) -O-(CH2)q-Z-Rιo,
(u) -OC(X)NR8-R9',
(v) -LβR30»
( ) alkanoyloxy where
(x) -OSO2R11, and
Figure imgf000016_0001
(y) -NR7(X)NR8'R9';
R is hydrogen or alkyl of one to twelve carbon atoms; or
-L2-R5 and Re together are selected from
(1) =O,
(2) ^ where 5 is 1, 2, 3, or 4 and A is selected from
(a) -CH2-,
(b) -O-, (c) -S(O)t, and
(d) -NR7-, and
^26
R '
(3) 26 where the carbon-carbon double bond can be in the E or Z configuration and R26 and R 6' are independently selected from (a) hydrogen,
(b) alkenyl of three to twelve carbons,
(c) aryl,
(d) heterocycle,
(e) alkyl of one to twelve carbons,
-14- O 99/41256 FCT/US
( ) 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,
(ii) -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,
(«) perfluoroalkoxy of one to twelve carbons,
(x) -NR8'R9-
(xi) =NNR8-R9',
(xϋ) -NR7NR8'R -,
(xiii) -CO2Rlθ.
(xiv) -C(X)NR8-R9%
(xv) =N-ORιo,
(xvi) =NRιo,
(xvii) -S(O)tRιo,
(xviii) -X'C(X)Rιo,
(xix) (=X),
(xx) -O-(CH2)q-Z-Rιo,
(xxi) -OC(X)NR8-R9',
(xxii) -LβR30.
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiii) -OSO2R11. and
Figure imgf000017_0001
(xxiv) -NR7(X)NR8'R9-;
Rl6 and Rι<5' are independently hydrogen or alkyl of one to six carbons; or Rl6 and Riό1 together are alkenyl of two carbons;
■15- a broken line represents the optional presence of a double bond, provided that when Ri6 and Ri6- together are alkenyl of two carbons, the double bond is not present;
Y is selected from carbon, nitrogen, and N+(=OJ;
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"), R17 is absent; and
Rl8 and Riβ' are independently hydrogen or alkyl of one to six carbons; or Rl8 and Ri8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons.
In another embodiment of the invention are disclosed compounds of Formula II
Figure imgf000018_0001
II, or a pharmaceutically acceptable salt or prodrug thereof, where Rl, R2, R3, R4, R5, Re, and L2, are defined above.
In another embodiment of the invention axe disclosed compounds of Formula IH
Figure imgf000018_0002
III, or a pharmaceutically acceptable salt or prodrug thereof, where Rl, R2, R3, R4, R5, Re, and L , are defined above.
In another embodiment of the invention are discolsed compounds of Formula IV
-16-
Figure imgf000019_0001
IV, or a pharmaceutically acceptable salt or prodrug thereof, where
Y is nitrogen or N+(=O*), and
Rl, R5, Re, and L2, are defined above.
In another embodiment of the invention are disclosed compounds of Formula V
Figure imgf000019_0002
V, or a pharmaceutically acceptable salt or prodrug thereof, where Rl, R5, .and L2, are defined above;
Rl<5 and R17 are independently hydrogen or alkyl of one to six carbons; and
R18 and Ri8' are independently hydrogen or alkyl of one to six carbons; or
Rl8 and Ri8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
In another embodiment of the invention are disclosed methods of selectively partially antagonizing, antagonizing, agonizing or modulating the glucocorticoid receptor. In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I. In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
Compounds of this invention include, but are not limited to, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline- lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-
-17- f . iquinoline,
2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)-lH-tl]benzopyrano[3,4-f]quinolin-10- amine, methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fIquinoline- 10-carboxylate,
10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4f]quinoline,
10-ethynyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 ] benzopyrano [3 ,4-fjquinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinohn-10-ol, 10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 ] benzopyr.ano[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]quinoUne-10-ol acetate (ester), 5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-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)- 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-methylρhenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(l-moφholinyl)phenyl]-lH-
[ 1 ] benzopyrano[3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)- lH-[l]benzopyrano[3,4- fjquinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
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- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinohne,
■18- 5-(3-chlorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 ] 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- fjquinoline,
(± )-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 ] benzopyrano[3,4- f]quinoline,
5-(3,5-dimethylphenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[ l]benzopyrano[3,4- fjquinoline,
5-(4-chlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3,4-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinoline, 5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
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-
[ l]benzopyrano[3,4-f]quinoline,
5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-
^quinoline, 2,5-dihydro-10-methoxy-2,2,4,N-tetramethyl-N-phenyl-lH-[l]benzopyrano[3,4- fjquinolin-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)-lH-[l]benzopyr^o[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]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)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)-lH-[l]benzopyrano[3,4-
.fjquinoline,
-19- 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[4-( 1 -moφholinyl)phenyl]- 1 H-
[l]benzopyrano[3,4- fjquinoline, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-5-yl)-3,3- dimethyl-2-butanone, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline-5- carbonitrile, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-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-lH-
[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene-lH-[l]benzopyrano[3,4-f|quinoline-
5-propanol, acetate (ester),
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(4-methylphenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [lJbenzopyrano[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-fJquinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f . jquinoline, 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- f . jquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-[lJbenzopyrano[3,4- fjquinoline, 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-lH-[l]benzopyrano[3,4-f]quinoline-5- carboximidic acid ethyl ester,
-20- 2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene lH-[l]benzopyrano[3,4-fJquinoline- 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-fJquinoline-5- ethanamine,
N-cyclopropyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinoline-5-acetamide,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propynyl)- 1 H- [ 1 J benzopyrano[3,4- fjquinoline,
5-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[ 1 Jbenzopyrano[3,4-f]quinolin-5-yl)-
2(5H)-furanone,
5-(3-butenyl)-2,5-dihdyro- 10-methoxy-2,2,4-trimethyl- lH-[ l]benzopyrano[3,4-
.fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[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-2,2,4J0-tetrametnyl-5-phenyl-lH-[lJbenzopyrano[3,4-f]quinoline,
5-(3,5-dichlorophenyl)-10-ethyl-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- flquinoline, 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl-lH-[lJbenzopyrano[3,4- fjquinolin- 10- amine,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH-
[ 1 jbenzopyrano [3 ,4-f]quinolin- 10-amine,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propynyloxy)-lH-[l]benzopyrano[3,4- fjquinohne,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propenyloxy)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)- lH-[ 1 Jbenzopyrano[3,4-f]quinoline- 10- methanol, 2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[l]benzopyrano[3,4-f]quinoline-10- carboxylic acid,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-10- ol,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-10- yljmethylcarbonate,
-21- 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- fjquinoline,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-5-yl)- phenyl] methylcarbonate,
2,5-dihydro-10-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenyl]-lH-
[ 1 ] benzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenyl]-lH-
[ 1 ] benzopyrano[3,4-f]quinoline,
5-[3-(cyclopropylmethoxy)phenyl]-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-[2-(l-piperidinyl)ethoxy]phenyJ-lH- [lJbenzopyrano[3,4-f]quinoline,
5-(3-hexyloxyphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
5-[3-(2,4-dinitrophenoxy)phenyl]-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-(2-propynyloxy)phenyl]-lH-
[lJbenzopyrano[3,4-f]quinoline,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-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-f]quinolin-5-yl)- phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxy]phenyl]-lH-
[lJbenzopyrano[3,4- fjquinoline, [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)phenylJ-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenylJ-lH- [lJbenzopyrano[3,4-fJquinoline,
[(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-tlquinolin-5-yl)phenylJ
1 -moφholinecarboxylate,
-22- 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[(methylsulfinyl)methoxy]phenylJ-lH- [l]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)phenylj ester, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenylJ-lH- [ 1 ] benzopyrano[3 ,4-fJquinoline,
O-[3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[ l]benzopyrano[3,4-fJquinolin-5- yl)phenyl] methylcarbonothioate,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl]-lH-[l]benzopyrano[3,4-fJquinolin-5- yl)phenyl] trifluoromethanesulfonate,
5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4- trimethyl- lH-[ lJbenzopyrano[3,4- fjquinoline, ethyl 3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[l]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)phenylJ-lH- [lJbenzopyrano[3,4-f]quinoline, l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzoρyrano[3,4-fJquinoUn-5-yl)-5- methylphenyljethanone,
3-(2,5^dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5-yl)-5- trimethylbenzenemethanol,
5-[3-(2-furanyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(lH-pyrrolidin-l-yl)phenylJ-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-methyl)-
5,N-dimethylbenzenamine,
3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 ]benzopyrano[3,4-f]quinolin-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-[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-f]quinolin-5-yl)-
5-methylphenylJ-N,N-dimethylurea,
-23- N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenyljbenzenemethanamine,
5-[(3,5-dichlθφhenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline, 5-[(4-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 J benzopyrano [3,4-f]quinoline,
2,5-o hydro-10-memoxy-2,2,4-trimethyl-5-[[3-(trifluoromethyl)-phenyl]methyleneJ-lH-
[ 1 ] -benzopyrano[3 ,4- fjquinoline,
5-[(2,6-difluorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-fJquinoline,
5-[(2-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano[3 ,4- fjquinoline,
5-[(2,6-dichlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, 5-[(2-fluorophenyl)methyleneJ-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-[(4,5-dihydro-4,4-dimethyl-2- oxazolyl)methy lenej - 1 H- [ 1 J benzopyrano [3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH- [l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-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- f]quinohne, 5-(2-cyclohexen-l-yl)-2,5-dihydro-9J0-dimethoxy-2,2,4-trimethyl-lH-
[ 1 ] t)enzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinohne,
2,5-dihydro- 10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3,4-f]quinoline, rel (5R,2'R) 2,5-dihydro- 10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline, anti(5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4-trimethyl- 1H-
[lJbenzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
-24- 2,5-dihydro-10-methoxy-5-(3-cyclohexenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[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-( 1 -ethenyl- 1 -cyclohexyl)-2,2,4-trimethyl- 1 H-
[ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -methylene-2-cyclohexyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-( 1 -oxo-2-cyclohexyl)-2,2,4- trimethyl- 1 H-[ 1 ] benzopyrano[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-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(l-cyclohexenylmethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[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- 1 H- [ 1 ] benzopyrano[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-(l-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- 1 H-
[1] benzopyrano [3 ,4- fjquinoline,
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-( 1 -methyl-3-cyclohexenyl)-2,2,4-trimethyl- 1 H-
[ 1 ] benzopyrano[3 ,4- fjquinoline, re/ (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-fJquinoline, (-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-f]quinoline,
-25- (-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 J benzopy rano [3 ,4- fjquinoline ,
(+) (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, (-)-(5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4- fjquinoline,
(+)-(5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-fJquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 Jbenzopyrano [3 ,4-fJ quinoline , rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H- [ 1 J 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 J benzopyr.ano [3 ,4- f] quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 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-(N,N-dimethylamino)methyl-3-cyclohexenyl)-
2,2,4- trimethyl- 1 H- [ 1 J benzopyrano [3 ,4-fJ quinoline, 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-moφholino)methyl-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-methyl-N-methylsulfonylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 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-f]quinoline, 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,
2,5-dihydro-10-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinohne, 2,5-dihydro-10-methoxy-5-(l,3-butadien-2-yl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinohne.
-26- 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano[3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 ,2-dihydroxy-3-propyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano [3 ,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -(N-phthalimido)-3-propyl)-2,2,4- trimethyl- 1 H-
[ 1 ] benzopy.rano[3 ,4- .fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -amino-3-propyl)-2,2,4- trimethyl- 1 H-[ 1 J benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(2-carbomethoxy- 1 -ethenyl)-2,2,4- trimethyl- 1 H-
[l]benzopyrano[3,4- fjquinoline, (^-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(^ 2,5-dihydro-10-methoxy-5-(3-hydroxy-l-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
(E) 2,5-dihydro-10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)-l-propenyl)-2,2,4- trimethyl- 1 H- [ 1 ] benzopyrano [3 ,4-fJ quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3-methoxymethoxy- 1 -propenyl)-2,2,4- trimethyl- 1 H-
[ 1 ] benzopyrano [3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 J benzopyrano[3 ,4-f]quinoline, methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-5- yl) acetyl hydroxamate,
2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 J benzopyrano[3 ,4-f]quinolin-5-yl) acetaldehyde,
2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4- trimethyl- 1H-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
-27- U-ans 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
U-ans 2,5-dihydro-10-methoxy-5-(2-penten-l-yl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquiπoline, 2,5-dihydro- 10-methoxy-5-( 1 , 1 -difluoro- 1 -propen-3-yl)-2,2,4-trimethyl- 1 H-
[lJbenzopyrano[3,4-f]quinoline,
(E) methyl 2-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 J benzopyrano[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- [l]benzopyrano[3,4- fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten- 1 -yl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- l-yl)-2,2,4- trimethyl- IH- [ 1 ]benzopyrano[3 ,4- fjquinoline, (E) 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl- 1 H- [lJbenzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(2-(N-moφholinoc^bonyloxy)ethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(2-(N-methy--minocarbonyloxyoxy)ethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4-trimethyl- lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(aminomethyl)-2,2,4- trimethyl- 1 H-[ 1 ] benzopyrano [3,4- fJquinoUne, 2,5-dihydro-10-methoxy-5-(ethoxycarbonylamino)methyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline.
-28- 2,5-dihydro- 10-methoxy-5-(carboethoxy)-2,2,4- trimethyl- 1 H- [ 1 ] benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4- trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(l-methylpropa-l,2-dienyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(3-pyridyl)-2,2,4- trimethyl- 1 H-[ 1 ] benzopyrano[3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
( 10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4- trimethyl- lH-2,5-dihydro-
[ 1 J benzopyrano [3 ,4- fjquinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-[lJbenzopyrano[3,4- f a jquinoline,
10-cWoro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline,
10-chloro-9-hydroxy-5-(3,5-dimethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano[3,4-fjquinoline, re/-(5S, 3'R)-9-hydroxy- 10-methoxy-5-[l-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)-lH-
[ 1 J benzopyrano[3,4- fjquinoline,
(-) 2,5(S)-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3R-cyclopenteny 1 )- 1 H- [l]benzopyrano[3,4-fJquinoline,
10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3-cyclopenteny 1 )- 1 H-
[l]benzopyrano[3,4-f]quinoline, (+)-(5R, 3 'R)2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3-cyclopenteny 1 )- 1 H-
[l]benzopyrano[3,4-f]quinoline,
-29- 10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [ 1J benzopyrano [3, 4- fjquinoline,
9-10-methylenedioxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-[lJbenzopyrano[3,4- fjquinohne, 5-(3-proρenyl)-9-chloro-10-ethenyl-2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4- fjquinoline,
9-chloro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4- fjquinoline,
5-(3-propenyl)-9-chloro-10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro-lH- [l]benzopyrano[3,4-fJquinoline,
9-chloro-10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4- fjquinoline,
8-fluoro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4- fjquinoline, 5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4- fjquinoline,
(10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4-f]quinoline,
10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]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)- lH-[lJbenzopyrano[3,4-f]quinoline, (-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5- dihydro-lH-[lJbenzopyrano[3,4- fjquinoline,
(+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5- dihydro-lH-[lJbenzopyrano[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- [ 1 Jbenzopyrano[3 ,4- fjquinoline,
(-) (5S,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5- dihydro-lH-[lJbenzopyrano[3,4- fjquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenyl]-10-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-yl)-lH-[lJbenzopyrano[3,4- fjquinoline,
-30- re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenylJ- 10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H-[ 1 ]benzopyrano[3,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-5-propyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cycloheptenyl)-lH-
[ l]benzopyrano[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-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy -2,2,4- trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-difluorophenyl)-lH-
[ 1 J benzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 5-butyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinohne,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)-lH-
[ 1 ] benzopyrano[3 ,4-fJquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dilιydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3,4-difluorophenyl)- 1 H-
[ 1 ] benzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4- fluorophenyl)- 1H-
[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethylphenyl)-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-bistrifluoromethylphenyl)-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4-chlorophenyl)- lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4-chlorophenyl)- 1 H-
[l]benzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-butenyl)-lH-
[lJbenzopyrano[3,4-fJquinoline,
-31- 2,5-dihydro-9-hydroxy- 10-methoxy-5-(phenylmethyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenylJ-lH-[lJbenzopyrano[3,4-f]quinoline, (-) (S) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fJquinoline,
(+) (R) 5-cyclopentyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-5-(3-propynyl)-2,2,4-trimethyl- 1 H- [l]benzopyrano[3, 4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)-lH-
[ l]benzopyrano[3,4-f]quinoline, (±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6-pentafluorophenyl)-
1 H- [ 1 ]benzopyrano[3,4-f] quinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- hydroxymethylcyclopenten-3-yl)-lH-[l]benzopyrano[3,4-fJquinoline,
(+/-) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5(S)-(3(S)- 1- methylcarboxylatecyclopenten-3-yl)-lH-[l]benzopyrano[3,4-f]quinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[lJbenzopyrano[3,4-f]quinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-thienyl)- 1 H-[ 1 Jbenzopyr^o[3,4- fjquinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) -lH-
[ 1 jbenzopyrano [3 ,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3-propenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenylJ-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-cyclohexyl- 1 H-[ 1 ]benzopyrano[3,4- fjquinoline, 2,5,5-trihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
-32- 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-hydroxymethyl-3-propenyl)-lH-
[ 1 ] benzopyrano [3 ,4-f]quinoline, methyl 2-[2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJ-
5-quinolinyl] acetate, (Z) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-butenyl)- 1 H-
[ 1 ] benzopyrano[3 ,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-uimethyl-5-(3-methyl-2-butenyl)-lH-
[lJbenzopyrano[3,4-f]quinoline,
(+) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH- [lJbenzopyrano[3,4-fjquinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)-
1 H-[ 1 ]benzopyrano[3,4-f]quinoline, (+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclopentenyl)- lH-[l]benzopyrano[3,4- fjquinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l-methoxyc^bonyl)cyclohexen-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- [l]benzopyrano[3,4-f]quinoline,
9J0-Dimethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [lJbenzopyrano[3,4- fjquinoline,
9J0-Dimethoxy-5-[3-cyclohexenylJ-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4-f]quinoline, 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-
[l]benzopyrωo[3,4-f]quinoline,
10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [lJbenzopyrano[3,4-fjquinoline,
2,5-dihydro-9-acetoxy-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-
(2-propenyl)- 1 H- [ 1 J benzopyrano[3,4-f]quinoline, 7-bromo -5-[3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4- fjquinoline,
-33- 10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline,
7-bromo-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4- fjquinoline, 10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-[l]benzopyrano[3,4- fjquinoline,
7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano[3 ,4-f]quinoline,
7,9-Dibromo-5- [cyclohexen-3-ylJ - 10-methoxy-2,2,4-trimethyl-2,5-dihydro- 1 H- [l]benzopyrano[3,4-f]quinoline,
7,9-Dibromo-5-[l-methyl-3-cyclohexenylJ-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4-f]quinoline,
10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline, 10-methoxy-7-methyl-5- (3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro- [ 1 ] benzopyrano[3,4- flquinoline,
10-methoxy-7-acetyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-[lJbenzopyrano[3,4- fjquinohne,
(+/-) 2,5-dihydro-9-methyl-10-methoxy-2,2,4-trimethyl-5-(l-methylcyclohexen-3-yl)-lH- [l]benzopyrano[3,4-fjquinoline, _
10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ lJbenzopyrano[3,4- fjquinoline,
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-f]quinoline, 2,5-dihydro- 10-methoxy-5-(3-(N-methyl-N-
(carbomethoxymethyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-
^quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methylcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
-34- 2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylaminocarbonyloxy)ethyl)phenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-cyclopropyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-ethenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoUne, trans 2,5-dihydro- 10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl- 1H-
[ l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, cis 2,5-dihydro- 10-methoxy-5-(2-phenylethenyl)-2,2,4- trimethyl- 1 H-[ 1 J benzopyrano [3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, tr^s 2,5-dihydro-10-methoxy-5-(l-cyclohexenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-10-(2-furanyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-carboxy-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro- 10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl- 1H-
[ 1 ]benzopyrano[3 ,4- .fjquinoline,
2,5-dihydro-10-formyl-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[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-[lJbenzopyrano[3,4-
.fjquinoline,
2,5-dihydro- 10-ethenyl-5-phenyl-2,2,4- trimethyl- 1 H-[ 1 J benzopyrano[3 ,4-f]quinoline,
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-fjquinoline- 10- carboxylate,
-35- 2,5-dihydro-10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-foιmyl-5-phenyl-2,2,4-trimethyl- 1 H-[ 1 ] benzopyrano[3 ,4-fJquinoline,
2,5-dihydro-10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-ethenyl-5-oxo-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-ethenyl-5-[l-methyl-3-cyclohexenylJ-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-fjquinoline,
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-lH-[l]benzopyrano[3,4-
^quinoline, (+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 ] benzopyrano [3 ,4-fJquinoline,
10-(difluoromefhoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinohne,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3,4,5-tetrahydro-lH- chromeno[3,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) -lH-
[lJbenzopyrano[3,4- fjquinoline, 10-methoxy-5-(5-methyUsoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline,
10-methoxy-5-(3-methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-
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-f|quinoline,
10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline, 10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
-36- 10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyi-lH-
[ 1 ] benzopyrano [3 ,4-fjquinoline,
10-methoxy-5-(l-butyhdene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano[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- 1 H-[ l]benzopyrano[3,4-f]quinazoline,
2,5-dihydro-10-methoxy-2,2-[spiro(tetrahydro-4-pyr.anyl)J-4-methyl-5-allyl-lH-
[ 1 ] benzopyrano[3 ,4-fjquinoline, 2,5-dihydro-10-methoxy-2,2-[spiro(hexyl)]-5-allyl-lH-[lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-2,2-diethyl-4-methyl-5-allyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[lJbenzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-2,2-dimethyl-4-ethyl-5-allyl-lH-[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-2,2,3-trimethyl-5-allyl-lH-[lJbenzopyrano[3,4-fjquinoline, Z-5-(benzylidenyl)-9-hydroxy- 10-methoxy-2,2,4- trimethyl- 1 H-2,5-dihydro-
[ 1 ] benzopyrano [3 ,4-fjquinoline,
Z-5-(2,5-difluorobenzyUdenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4-f]quinoline,
Z-5-(3-fluorobenzylidenyl)-10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH- [lJbenzopyrano[3,4- fjquinoline,
Z-10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4- fjquinoline,
Z-9-hydroxy-10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrMo[3,4-^quinoline, 9-hydroxy-10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(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-difiuorophenylJ methylene)-2,2,4-trimethyl- 1 H-2,5- dihydro-[lJbenzopyrano[3,4-f]quinoline,
Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4- fjquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenylJ-10-chloro-2,2,4-trimethyl-
2,5-dihydro- 1 H-[ 1 J benzopyrano[3,4- fjquinoline,
-37- 9-hydroxy- 10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro- 1 H-[ 1 J benzopyrano[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)-lH-[lJbenzopyrano[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-moφholino-4-oxo-butanoyloxy)-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-trimethyl-5-
(3,4,5-trifluorophenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-difluorophenylmethyl)-lH-
[ 1 J benzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-uimethyl-5-(2-thienyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclopentyl-lH-
[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) -lH- [lJbenzopyrMθ[3,4-f]quinoline, _
2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2,4-trimethyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-pentenyl)-lH-
[lJbenzopyrano[3,4-f]quinoline, 2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[lJbenzopyrMθ[3,4-fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-allenyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH- [lJbenzopyrano[3,4-f]quinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[l]benzopyrano[3,4- fjquinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[lJbenzopyrano[3,4- fjquinoline, (-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[lJbenzopyrano[3,4-fJquinoline,
-38- 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) -lH-
[l]benzopyrano[3,4- fjquinoline,
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-dihydro-
[ 1 ] benzopyrano [3,4-fJquinoline,
2,5-dihydro-7-bromo-9-hydroxy-10-chloro-2,2,4-trimethyl-5-allyl-lH-
[ 1 ] benzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-methylthiomethoxy- 10-methoxy-2,2,4-trimethyl-5-(3-
(methylthio)methoxyphenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-(methylthiomethoxy)phenyl)-lH-
[l]benzopyrano[3,4-fJquinoline, 9-hydroxy-10-chloro-5-(phenylmethylene)-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-([2-N,N- dimethylcarbam oy loxy] phenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyjphenyl)- lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-ethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-isopropyl-lH-[lJbenzopyrano[3,4- fjquinoline, 9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-butyl- 1 H-[ 1 J benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-thiazol-2-yl)-lH- [l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxymethyl- 10-chloro-2,2,4-trimethyl-5-allyl- 1 H-[ 1 ]benzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-propyl-lH-[lJbenzopyrano[3,4-
.fjquinoline,
-39- 9-hydroxy- 10-methoxy-5-([3-fluorophenylJmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ l]benzopyrano[3,4- fjquinoline,
9-hydroxy-10-chloro-5-([2-pyridylJmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ] benzopyrano[3,4- fjquinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-hydroxymethyl)cyclohexen-3-ylJ- 10-methoxy-2,2,4- trimethyl-2,5-dihydro- lH-[ 1 Jbenzopyrano[3,4- fjquinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-methoxycarbonyl)cyclohexen-3-ylJ- 10-methoxy-2,2,4- trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-dichlorophenyl)-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-[l] benzopyrano [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 ] benzopyrano[3,4- fjquinoline, (+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l-methylcyclohexen-3- y 1 )- 1 H- [ 1 J benzopyrano [3 ,4-fJquinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(l-methylcyclohexen-3- yl)-lH-[l]benzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-chloro-2,2,4-trimethyl- 5-allyl-lH-[l]benzopyrano[3,4-fJquinoline,
(-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-cyclopentyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(l-methylethyl)-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-5-(phenylmethyl)-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-(4-N,N-dimethyl.amino-4-oxo-but∑uιoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-thienyl)- 1 H- [ 1 ] benzopyrano [3 ,4-fjquinoline,
2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl- lH-2,5-dihydro- [lJbenzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[lJbenzopyrano[3,4-f]quinoline, (+/-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-benzyl- lH-[l]benzopyrano[3,4- fjquinoline,
-40- 9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro- [ 1 ] benzopyrano[3,4- fjquinoline,
9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [lJbenzopyrano[3,4-f]quinoline, (+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- lH-[ l]benzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H-
[ 1 ] benzopyrano[3 ,4-fJquinoline,
(+/-) 2,5-dihydro-9-(4-oxo-pen ιnoyloxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[ 1 J benzopyrano [3 ,4-fJquinoline, 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)- 10-methoxy-2,2,4- trimethyl-5-
(2-propenyl)- 1 H- [ 1 J benzopyrano[3 ,4-fJquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)- lH-[ 1 Jbenzopyrano[3,4-fjquinoline,
2,5-dihydro-9-(4-N-moφholino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-(2- propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
(-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-2,2,4-tιimethyl-
5(S)-(3(S)-l-cyclopenten-3-yl)-lH-[lJbenzopyrano[3,4-f]quinoline, 10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4-f]quinoline,
10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [ 1 ] benzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-thienyl)- 1 H- [ 1 J benzopyrano[3,4- fjquinoline, and
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- 1 H-
[ 1 ] benzopyrano[3 ,4-fjquinoline.
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.
-41- 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 aiyl 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 teπn "heterocycle" also includes bicyclic, tricyclic and tetracyclic groups in which any of the 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,
-42- imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, moφholinyl, 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, thiomoφholinyl, triazolyl, .and the like.
Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as
H λ ø H , and the like.
Heterocyclics also include compounds of the formula X*
-Y*
"O 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 quaternized. 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 of the 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 prodrug 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
-43- 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 prodrugs of the compounds of the 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, of the compounds of the invention. The term "prodrug" repres- ents compounds which are rapidly transformed in vivo to the parent compound of the 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 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incoφorated 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 αl. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1 - 19 . The salts can be prepared in situ during the final isolation and purification of the compounds of the 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.
-44- Compounds of the 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 of the 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 of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of enantiomers on chiral chromatographic columns.
Geometric isomers can also exist in the compounds of the 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 of the carbon-carbon double bond and the term "E" represents substituents on opposite sides of the 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 of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds where the substitutients are disposed on both the same and opposite sides of plane of the 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 incoφorated by reference, was used. Briefly, cytosol preparations of human glucocorticoid receptor-cc [GRXJ isoform 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. [3H]-dexamethasone (Dex, specific activity 82-86 Ci/mmole) and [3H] -progesterone (Prog, specific activity 97- 102 CiΛnmol) 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),
-45- 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 50X 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, [3H]-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 [3HJDex in the absence and in the presence of lμM unlabelled Dex.
For PR binding assays, [3HJProg (-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) w.as determined from a Hill analysis of the competitive binding experiments. The Ki of test compounds was determined using the Cheng-Prusoff equation Ki =IC5o /(1+[L*J/[KLJ) where L* is the concentration of radioligand and KL is the dissociation constant of the radioligand determined from saturation analysis. For GRX, KL 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
-46- Ki (nM)
Example GR PR Number
1 8.6 10000
2 7.6 1702
3 4.8 2654
4 7 2960
5 357.5 10000
6 3.8 321
7 4.3 -5676
8 167.9 6007
9 60.5 10000
10 179.1 10925
11 4.4 288
12 8.6 10000
13 11.1 10000
14 5.2 10000
15 2.5 10000
16 8 10000
17 39 10000
18 10.5 1035
19 6.7 4967
20 3.7 1684
21 10.7 4017
22 6.5 10000
23 8.2 6153
24 3.5 14837
25 240.4 10000
26 2.1 13390
27 5.2 3580
28 4.7 3271
29 7.7 7763
30 13 7924
Figure imgf000049_0001
31 12.2 10000
-47- 32 3.3 1559
33 95.2 8318
34 4 4706
35 260 10000
36 1.4 1704
37 20 10000
38 207 10000
39 31 10000
40 18 18132
41 9.5 3303
42 99 10000
43 72 10000
44 190 19524
45 15 10000
46 2.7 3436
47 174 10000
48 5.8 2769
49 13 10000
50 4.9 9449
51 18 7333
52 3 2269
53 8.1 2912
54 6.6 7344
55 8.2 10000
56 6.2 10000
57 50 4275
58 9 8572
59 9.5 16582
60 14 10493
61 62 14393
62 12 10000
63 511 10000
64 62 1671
Figure imgf000050_0001
65 591 10000
-48- 66 2.7 502
67 21.7 10000
68 8 9054
69 15 17331
70 25.5 7301
71 7.7 484
72 17.8 1454
73 10.3 4500
74 11.9 4877
75 7.3 13800
76 152 10000
77 1.6 173
78 80.5 10000
79 19.2 10000
80 168.2 10000
81 155.3 10000
82 22.9 327
83 54.8 2210
84 17.3 10000
85 3.5 10000
86 2.1 10000
87 4.7 10000
88 6 15327
89 275 10000
90 7.6 10000
91 17 10000
92 12 10000
93 148 10000
94 43 10000
95 31 10000
96 10 9163
97 320 10000
98 9.8 10000
Figure imgf000051_0001
99 3.6 10000
-49- 100 7.8 10000 |
101 11.4 10000
102 17.7 10000
103 5.2 10000
104 8.9 10000
105 9 >10000
106 62 >10000
107 215 >10000
108 638 >10000
109 6J 10000
110 5.6 10000
111 7.2 10000
112 31 10000
113 9.7 10000
114 12 10000
115 17 10000
116 7.2 10000
117 12 10000
118 43 10000
119 6.9 10000
120 30.3 6235
121 11.3 672
122 11.8 1409
123 6.1 9568
124 3.2 1611
125 36.6 10000
126 2.9 ■ 1407
127 29.3 10000
128 5.9 10000
129 5.5 3621
130 11.9 1054
131 7.71 996
132 230 9890
Figure imgf000052_0001
133 3.6 4867
-50- 134 238 10000
135
136 37 2700
137 5.5 2410
138 2.2 5600
139 235 4800
140 13 10000
141 10 10000
142 51 10000
143 91 8100
144 7.7 10000
145 78 10000
146 8.3 8300
147 15 9300
148 2.8 10000
149 2.7 4063
150 106 10000
151 298 10000
152 1.8 10000
153 1.9 10000
154 0.7 10000
155 0.86 10000
156 0.9 4100
157 1.5 433
158 48 10000
159 3.8 1837
160 1.8 10000
161 3.3 10000
162 6.5 10000
163 2.6 10000
164 36 10000
165 14 10000
166 8J6 5631
Figure imgf000053_0001
167 21 10000
-51- 168 2.5 10000
169 300 10000
170 82 10000
171 3.3 7429
172 7 9900
173 32 10000
174 270 10000
175 44 7700
176 88 >10000
178 468 10000
179 9.5 2750
180 18 733
181 207 10000
182 23 10000
183 38 10000
184 40 10000
185 288 10000
186 90 10000
187 46 3900
188 4.9 5300
189 6.4 1700
190 6.25 1586
191 2.9 1190
192 3.1 10000
193 2.0 2184
194 7.7 10000
195 25 10000
196
197 28 10000
198 0.65 2130
199 106 10000
200 45 10000
201 114 10000
Figure imgf000054_0001
202 134 10000
-52- 203 85 10000
204 74 10000
205 11.4 10000
206 201 10000
206A 4192
207 22 10000
208 25 970
209 2.0 5462
210 21 710
211 5.3 10000
212 13 10000
213 67 10000
214 5.7 10000
215 20 10000
216 0.58 7.6
217 1 65J
218 1.6 227
219 2.4 178
220 0.66 527
221 0.66 4.2
222 0.47 9.9
223 2.6 297
224 57 786
225 155 5010
226 2.6 220
227 8.4 1930
228 5.4 29.5
229 34.7 1338
230 2.4 50.3
231 30.2 1870
232 1.6 230
233 2.5 350
234 3.8 202
235 0.94 155
Figure imgf000055_0001
-53- 236 0.89 36.2
237 1.5 18
238 1.2 11.5
239 16.8 240
240 52.2 2173
241 0.69 61J
242 0.53 3420
243 1.6 21.2
244 6.3 804
245 0.95 119
246 0.87 113
247 0.86 195
248 1 870
249 0.80 488
250 2.4 1475
251 0.87 163
252 0.39 102
253 0.38 42
254 2.2 1824
255 1.5 1434
256 3.8 266
257 10 1624
258 10.7 879
259 1.2 938
260 3.3 250
261 0.75 161
262 1.1 150
263 2.2 59.6
264 0.51 307
265 767 1499
266 0.71 102
267 0.79 938
268 0.84 486
269 17.1 2467
Figure imgf000056_0001
-54- 270 0.66 4756
271 0.82 2288
272 0.39 66.4
273 0.56 35.8
274 0.69 386
275 11.7 2873
276
277 11.3 272
278 1.1 533
279 12.4 1900
280 1.6 10000
281 0.84 526
282 0.5 42
283 1.1 60.4
284 110 2097
285 436 3757
286 64 3029
287 346 3502
288 0.86 4080
289 0.73 260
290 12.1 611
291 8.1 592
292 487 8338
293 12 3742
294 13.8 1807
295 0.67 59.3
296 0.63 476
297 4.7 4844
298 4.1 10000
298 4.1 10000
299 5.4 2900
300 5.3 34.4
301 16 113
302 5.9 99
Figure imgf000057_0001
-55- 303 4.9 58.5
304 34.5 681
305 2 6919
306 717 4455
307 4.6 27.8
308 50.8 960
309 1.9 60.7
310 4.4 382
311 15 10000
312 8.4 10000
313 6.4 10000
314 1.7 10000
315 13 10000
316 11 10000
317 6.5 10000
318 553 10000
319 16 492
320 49 3050
321 44 2880
322 107 2300
323 428 10000
324 24 10000
325 24 10000
326 228 10000
327 9.3 1457
329 2.2 192
330 2.2 53
331 142 10000
332 18 10000
333 5.6 3670
334 9.5 10000
335 652 10000
336 9.5 1564
Figure imgf000058_0001
337 3.3 702
-56- 338 61 10000
339 112 10000
340 1.8 254
341 2.5 10000
342 2586 10000
343 5.2 4700
344 0.46 76.7
345 8.7 3000
346 44 5110
347 128 10000
348 0.89 171
349 10.5 10000
350 6.22 10000
351 93 10000
352 58 10000
353 20 10000
354 32 1500
355 27 4280
356 15 2968
357 59.8 10000
358 4.2 8963
359 11.3 2219
360 33.7 10000
361 95.7 9143
362 6.5 3370
363 5 3942
364 424 10000
365 2.2 98
366 2.1 83.9
367 2.2 7.6
368 0.21 61
369 0.41 2528
Figure imgf000059_0001
-57- 372 1.8 164
373 3.1 279
374 9.0 222
375 3 1093
376 0.78 156
377 51 3085
378 1.1 440
379 1.4 175
380 1.2 204
381 7.1 9825
382 2.2 150
383 4.8 46
384 0.67 197
385 0.9 170
386 6.5 105
387 0.65 169
388 2.8 199
389 0.58 27.5
390 0.96 520
391 1.7 1087
392 1.2 487
393 0.76 589
394 0.89 109
395 2.1 1213
396 6.3 2125
397 2.3 22.8
398 6.7 1085
399 24.4 10000
400 3.5 5962
401 134 6083
402 3.3 10063
403 131 10000
404 1.3 49.7
405 1.1 75J
Figure imgf000060_0001
-58- 406 2.3 97.9
407 1.8 16.4
408 112 14138
409 2.7 42
410 1.1 25.7
411 0.68 8.4
412 9 222
413 0.22 60.8
414 93.2 21805
415 9.9 3741
416 3.1 394
417 3 10.5
418 1.4 2.1
419 56.9 286
420 125 2396
421 0.66 11.6
422 0.28 2.9
423 0.67 8184
424 0.84 1952
425 0.35 3942
426 0.85 110
427 7.8 2205
428 0.91 204
429 4.1 29.1
430 4.8 281
431 113 10000
432 1.4 207
433 30.2 1413
434 0.96 123
435 120 734
436 18.8 5919
437 0.97 449
438 0.89 129
439 1.2 202
Figure imgf000061_0001
-59- O 99/41256
440 0.70 390
441 0.42 328
442 9.1 8863
443 63.5 10000
444 1.6 406
445 4 347
Figure imgf000062_0001
The present invention also provides pharmaceutical compositions which comprise compounds of the 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, and 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 of the 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 of the 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 absoφtion of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absoφtion such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absoφtion of the drug from subcutaneous or intramuscular injection. This may be
-60- accomplished by the use of a liquid suspension of crystalline or amoφhous material with poor water solubility. The rate of absoφtion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. .Alternatively, delayed absoφtion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug 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 dnig in liposomes or microemulsions which -ire compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incoφorating 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) absoφtion 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
-61- certain part of the 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 of the 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, corn, 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 of the 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 of the 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 XIN, Academic Press, New York, N.Y. (1976), p. 33 et seq.
-62- 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 of the 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 of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the 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 puφoses of administration, e.g. two to four separate doses per day.
Abbreviations
Abbreviations that have been used in the descriptions of the scheme and the examples that follow are: BF3 OE-2 for boron trifluoride diethyl ether complex; DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide; and THF for tetrahydrofuran.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention can be prepared.
Syntheses of the compounds of the present invention are described in Schemes 1-21.
-63- Scheme 1
Figure imgf000066_0001
1 F 1G 1
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 HCl 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(triphenylphos- phine)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 BF3OE-3 and reducing agents such as triethylsilane to provide 1.
-64- Scheme 2
,OV^^_\D
M(
1 F V
Figure imgf000067_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 L . ewis 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.
-65- Scheme 3
Figure imgf000068_0001
NO,
1C
Figure imgf000068_0002
3C: R=SO2CF3
Figure imgf000068_0003
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.
-66- Scheme 4
Figure imgf000069_0002
Figure imgf000069_0003
7B: R=TBS 9 : R=Et 7: R=H 10: R=C(O) e
Figure imgf000069_0001
Figure imgf000069_0004
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 of the C-5 position as described in schemes 1-3 provided sil∑uie 7B. Removal of the 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.
-67- Scheme 5
.0
MOM
Figure imgf000070_0001
1 F 12A
Figure imgf000070_0003
Figure imgf000070_0002
12: R=C(O)CH3
12B: R=H 13: R=H
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.
-68- O 99/41256
Scheme 6
Figure imgf000071_0001
17 As shown in Scheme 6, functionality in the meta position of the 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 coupUngs or animations with palladium catalysts such as [l,l-bis(diphenylphosphino)ferroceneJdichloropalladium(II) or tetrakis(triphenylphosphine)palladium(0) in the presence of ligands such as tributylstannylfuran or moφholine provided carbon- or nitrogen-bound groups in the meta position of the aromatic ring at the C-5 position as exemplified in examples 16 and 17, respectively.
-69- Scheme 7
Figure imgf000072_0001
Figure imgf000072_0002
1 F 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
C02Me Br- OMe
:θ2Me 2- °Me >^,OMe L N02
B(OH)2 Ri N02 Ri Ri
Figure imgf000072_0003
NH2
Figure imgf000072_0004
Scheme 8 shows the applicability of the 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.
-70- Examples of novel tetracyclic cores prepared using the chemistry described in Scheme 8 are shown below.
Figure imgf000073_0001
H
Core l Core 2 Core 3
Figure imgf000073_0002
Figure imgf000073_0003
Core 4 Core 5
Figure imgf000073_0004
Scheme 9
Figure imgf000073_0005
H H
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 of the 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.
-71- O 99/41256
Scheme 10
Example IF
Figure imgf000074_0001
= Core 15 Core 16 Core 13: R = C(O)Me Core 14: R = CH=CH2
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 imgf000074_0002
Ho OMse ll^rN^T' — - Rcr OMe lrl ^NS- r^
H x H λ
Core 7 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
-72- Functional Group Preparations," VCH Publishers, New York (1989), hereby incoφorated by reference.
Scheme 12
Example 2B
Figure imgf000075_0001
Figure imgf000075_0002
Example 148 Example 149 Example 150
Scheme 12 shows the introduction of the substituted cyclohexenyl group by Lewis acid catalyzed addition of the 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.
Scheme 13
Figure imgf000075_0003
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.
-73- Scheme 14
Ex.ample 69
Figure imgf000076_0001
Eχ.ample 176 0
„A^
Figure imgf000076_0003
Figure imgf000076_0002
Example 177 Example 178
As shown in Scheme 14, Mitsunobu introduction of phthalimide to Example 69 and removal of the imide group with hydrazine provided alkylamino Example 177 which was further derivatized to Example 178 by treatment with di(tert-butyl)dicarbonate.
Scheme 15
O-Xi
Example 44
Figure imgf000076_0004
Figure imgf000076_0005
Example 179 X,=CON(CH3)2 (Example 182)
X,=CH2OCH3 (Example 183)
As shown in Scheme 15, elaboration of the C-5 nitrile of Example 44 to the α,β- unsaturated ester Example 179 followed by selective reduction of the alkoxycarbonyl group to the alkeneyl alcohol (Xi is H) provided precursors for carbamates and methoxymethyl ethers Examples 182 and 183, respectively.
-74- Scheme 16 CH3
Example 46
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0004
Example 187
Figure imgf000077_0003
Example 195
KJO
Figure imgf000077_0005
Example 200 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 of the aldehydes with a number of commercially available Wittig of Horner-Wadsworth-Emmons reagents.
-75- Scheme 17
Figure imgf000078_0001
Example 214: Y=N; X,Z=C Example 215: Z=N; X,Y=C
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 of the silicon group with reagents such as tetrabutylammonium fluoride and subsequent cyclization using reagent combinations such as triethylphosphine and 1,1'- (azodicarbonyl)dipiperidine.
-76- Scheme 18
Figure imgf000079_0001
Figure imgf000079_0002
Example 335: X1=-OCH3 Example Xt: R=H Example 337: X1=H Example Xx: 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 perruthenate 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.
-77-
Figure imgf000080_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.
-78-
Figure imgf000081_0001
o
Example343
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.
-79- Scheme 21
Figure imgf000082_0001
Figure imgf000082_0002
Example 2B Example 320 Example 321
Figure imgf000082_0003
Figure imgf000082_0004
H N
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 BaSU4 to provide cis isomer Example 323.
It is understood from the proceeding schemes and the following examples that the substituents Ri, R2, R3. R4- R5- Rό> Rl6. Rl6'. R17. R18. Rl8'. Y. R2. and L2 can be determined by .selection of the appropriate commercially available ork . nown 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 incoφorated by reference.
Also, it will be appreciated by one skilled in the art that selective protection and deprotection steps depending on the nature of Ri, R2, R3, R4, R5, Re, Ri6> Rlό'- Rl7> Rl8> Ri8', Y, R2, 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 incoφorated by reference.
-80- Example 1 2.5-dihydro-10-methoxv-2.2.4-trimethyl-5-phenyl-lH-rnbenzopyranor3.4-flquinolinelH- f 1 Jbenzopyranor3.4- fjquinoline
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 1A, methyl 5-mtro-2-bromobenzoate (25.8 g, 99.2 mmol), (21.7 g, 119 mmol), cesium carbonate (97J 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 widi 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 (11J g, 35J 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 recrystaUized from methanol to provide the desired compound. MS (DCI/NH3) m/z 275 (M+NH4)+.
Example ID
-81- 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 soUd 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% paUadium 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 of the 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+NH-ι)+.
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, 3J8 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- 10-methoxy-2.2.4-trimethyl-5-phenyl- 1 H-[ 1 Jhenzopyranor3.4- fjquinoline 1 H- f 1 lbenzopyranor3.4-flquinoline
-82- 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 NaHCOϊ. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on siUca gel with 5% ethyl acetate/hexanes to provide the desired compound.
MS (DCI NH3) m/z 384 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 8.00 (d, IH), 7.19 (m, 5H), 6.9 (dd, IH), 6.76 (s, IH), 6.69 (dd, IH), 6.55 (d, IH), 6.43 (d, IH), 6.2 (s, IH), 5.38 (s, IH), 3.8 (s, 3H), 1.83 (s, 3H), 1.22 (s, 3H), 1.14 (s, 3H);
Anal, calcd for C26H25 O2: C, 81.42; H, 6.58; N, 3.65. Found C, 81.28; H, 6.30; N, 3.47.
Example 2 2.5-dihvdro- 10-methoxv-2.2.4-trimethyl-5J2-propenyD- 1 H-f 1 Jbenzopyranor3.4- flquinoline
Example 2A A solution of Example IF (6.65 g, 20.69 mmol) in dichloromethane (500 mL) at -78 °C was treated dropwise with IM 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 2 A (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)+.
-83- Example 2 2.5-dihvdro-10-methoxv-2.2.4-trimethvl-5-('2-propenvn-lH-rnhenzopvrannn.4- fjquinoline A solution of Example 2B (2.50 g, 7.41 mmol) in dichloromethane (225 mL) was treated with allyltrimethylsUane (4.0 mL, 25.2 mmol), cooled to - 78 °C, treated dropwi.se with BF3-OEt2 (3J 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 siUca gel with 5-20% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m z 348 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 7.96 (d, IH), 7.07 (t, IH), 6.71 (d, IH), 6.60 (d, IH), 6.52 (d, IH), 6J2 (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), 2J6 (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-propenyP- 1 H-fJ lbenzopyranor3.4- flquinolin- 10- 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 3A 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
-84- (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on siUca 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)+
Exam le 3
2.5-dihvdro-2.2.4.N-tetramethyl-5-(2-propenyn-lH-[llhenzopyranof3.4- flquinolin-10-amine A solution of Example 3D (0J65 g, 0.36 mmol), palladium (II) acetate (0.0016 g, 0.007 mmol), (S)-(-)-2,2'-bis(phenylphosphino)-lJ'-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 siUca gel with 5-12% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 347 (M+H)+;
1H NMR (300 MHz, DMSO-d6) . 7.83 (d, IH), 6.94 (dd, IH), 6.62 (d, IH), 6.28 (dd, IH), 6.25 (dd, IH), 6.05 (d, IH), 5.86-5.74 (m, 2H), 5.67 (dd, IH), 5.45 (s, IH), 5.40 (q, IH), 5.03 (dd, IH), 4.98 (dd, IH), 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-[lJhenzopyranor3.4- flquinoline- 10-carhoxylate
A solution of Example 3D (263 mg, 0.565 mmol), triethylamine (0J0 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
-85- flash chromatography on siUca gel with 5-10% ethyl acetate/hexanes to provide the desired compound.
MS (DCI/NH3) m/z 376 (M+H)+;
JH NMR δ 7.19 (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), 2J9 (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-ethenvl-2.5-dihvdro-2.2.4-trimethyl-5-<'2-propenyn-lH-ri1benzopyranor3.4- JqvHnoUh A solution of Example 3D (103 mg, 0.221 mmol) and (l,3-bis(diphenylphosphino)- ferrocene)paUadium (II) chloride-dichloromethane (22 mg, 0.027 mmol) in l-methyl-2- pyrroUdinone (2 mL) w.as treated with vinyl tributylstannane (0J10 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 siUca gel with 5% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 344 (M+H)+; *H NMR δ 7.22 (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-ethynyl-2.5-dihydro-10-methoxy-2.2.4-trimethyl-5-(2-propenyl -lH- πjbenzopyranor3.4-flquinoline
Example 6A
A solution of Example 3D (25 mg, 0.054 mmol), tetra-n-butylammonium iodide (40 mg, 0J08 mmol), bis(triphenylphosphine)palladium chloride (7.0 mg, 0.010 mmol), copper(I) iodide (3.8 mg, 0.020 mmol) and triethylamine (0J5 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
-86- 20 cm, 0.25 mm silica gel TLC plate and eluted twice with 10% ethyl acetate/hexane. Extraction of the siUca gel with ethyl acetate provided the desired compound. MS (DCI NH3) m/z 414 (M+H)+;
*H NMR (300 MHz, DMSO-dό) δ 8.36 (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-ethvnyl-2.5-dihvdro-2.2.4-trimethyl-5-(2-propenyl)-lH-rilhenzopyranor3.4- flquinotine
A solution of Example 6A 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 (DCIZNH3) m/z 342 (M+H)+; H NMR (300 MHz, DMSO-d6)δ 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-flquinolin-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 w.as washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on siUca gel with 25% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 422 (M+H)+.
Example 7B Example 7 A was processed as in examples IG and lto provide the desired compound.
Example 7
-87- 2.5-dihvdro-2.2.4-trimethvl-5-phenvl-1H-f11henzopyranor3.4-flquinolin-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 witii 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 (DCIZNH3) m/z 370 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 9.63 (s, IH), 9J6 (d, IH), 7.13-7.24 (m, 5H), 6.74 (s, IH), 6.70 (dJH), 6.8 ( ,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-(difluoromethoxyV2.5-dihvdro-2.2.4-trimethyl-5-(2-propenyl -lH- ri1benzopyrano[3.4- fjquinoline
Example 8A A solution of Example 3B (1 J 1 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 sUica gel witii 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)-lH- [ 1 Jbenzopyranor3.4- fjquinoline Example 8A was processed as in examples 2B and 2 to provide the desired compound.
MS (DCI/NH3) m/z 384 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 7.75 (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.
-88- Example 9 10-ethoxv-2.5-dihvdro-2.2.4-trimethyl-5-phenyl-lH-rilbenzoρyranor3.4- flquinoline
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 ediyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on sUica gel with 5% ethyl acetate/hexanes to provide the desired compound.
Example 9
10-ethoxy-2.5-dihydro-2.2.4-trimethyl-5-phenyl-lH-rnbenzopyranor3.4- fjquinoline Example 9A was processed as in examples IG and 1 to provide the desired compound. MS (DCI NH3) m z 398 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.09 (d, IH), 7.20-7J5 (m, 5H), 6.78 (dd, 2H), 6.77 (s, IH), 6.69 (d, IH), 6.53 (dd, IH), 6.43 (dd, IH), 6J8 (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- 1 H- 1 Jbenzopyranor3.4-fJquinoline- 10-ol aςetate (ester) A solution of Example 7 (20 mg, 0.05 mmol) in pyridine (1 mL) at 0 °C was treated with acetic anhydride (0J mL, 1.05 mmol), stirred at room temperature 14 hours, and concentrated. The residue was purified by flash chromatography on sUica gel with 20% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 412 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 7.62 (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.
-89- Example 11 5-C3-bromo-5-methylphenyl)-2.5-dihydro-10-methoxy-2.2.4- trimethyl- 1H- Illbenzopyranor3.4- fjquinoline A solution of Ex.ample 2B and (0.520 g, 1.54 mmol) in dichloromethane (50 mL) was cooled to -10 °C, treated dropwise with BF3-OE-2 (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 N--HCO3, and extracted with ethyl acetate. The extract was washed wid br. ine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on sUica gel with 5% ethyl acetate hexanes to provide the desired compound. lH NMR (300 MHz, DMSO-d6) δ 8.02 (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 C27H26NO2Br: 475.1147 (M+H)+. Found 475.1143.
Example 12 3-(2.5-dihydro- 10-methoxy-2.2.4-trimethyl- 1 H-[ 1 Jbenzopyrano[3.4-fJquinolin-5- vDphenol.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
-90- 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 sUica gel with 25-33% ethyl acetate/hexanes to provide the desired compound.
MS (DCI NH3) m/z 458 (M+H)+.
Example 12
3-r2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-[lJbenzopyranor3.4-flquinolin-5- vDphenol.acetate (estert Example 12C was processed as in Example 1 to provide the desired compound. MS (DCI NH3) m/z 442 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.01 (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), 2J9 (s, 3H), 1.85 (s, 3H), 1.23 (s, 3H), 1.14 (s, 3H); Anal, calcd for C28H27NO -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-dihydro-10-methoxy-2.2.4-trimethyl-lH-|"11benzopyrano 3.4-flquinolin-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 witii 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)+; lH NMR (300 MHz, DMSO-d6) δ 9.26 (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);
-91- 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-dihvdro-10-methoxv-2.2.4-trimethyl-5-rr3-./methylthio)methoxyIphenyll-lH-
I nbenzopvranor3.4-flquinoline A solution of Example 13 (420 mg, 1.05 mmol) in DMF (40 mL) at 0 °C was treated with NaH (50 mg, 2J0 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 NΗ4CI, 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 siUca gel with 5-17% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 460 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.01 (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 C28H29NO3SO.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-πibenzopyranor3.4-fJquinolin-5- vDphenyll 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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-r3-(,2-furanyl)-5-methylphenylJ-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-πibenzopyranor3.4- fjquinoline
-92- A solution of Example 11 (0.253 g, 0.531 mmol) in l-methyl-2-pyrroUdinone (25 mL) was deoxygenated with nitrogen, treated with 2-(tributylstannyl)furan (0.33 mL, 1.06 mmol), [l, -bis(diphenylphosphino)ferroceneJdichloropaUadium(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 KP, 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 siUca gel with 5-10% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 464 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.02 (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-dihydro-10-methoxy-2.2.4-trimethyl-5-r3-methyl-5-('l-moφholinyl')phenyll- lH-fll benzopyrano [3.4- fjquinoline A solution of Example 11 (0.055 g, 0J 15 mmol) in toluene (5 mL) was treated sequentially with bis(dibenzylideneacetone)palladium(0) (0.007 g, 0.012mmol), (S)-(-)- bis(diphenylphospino)-lJ'-binaphthyl (0.022 g, 0.035 mmol), moφholine (15μL, 0J73 mmol), and sodium tert-butoxide (0.028 g, 0.289 mmol), stirred at 85 °C for 4 hours, cooled to room temperature, dUuted 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 siUca gel with 10-33% ethyl acetate/hexanes to provide the desired compound. MS (DCI NH3) m/z 483 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 7.97 (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 C31H34N2O3O.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)- lH-rnhenzopyranor3.4-flquinoline
-93- A solution of Example IF (0J00 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 siUca 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)+;
*H NMR (300 MHz, DMSO-d6) isomer 1: δ 8.12 (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: δ 8.23 (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-dichlorophenyD-2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH- T 1 Jbenzopyrano[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, DMSO) δ 8.10 (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, 1 17.8, 116.9, 1 14J. 113.4, 1 10.2, 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-[lJbenzopyranor3.4- fjquinoline
-94- Example IF and n-butylUthium were processed as in examples IG and 1 to provide the desired compound. MS (DCL/NH3) m/z 364 (M+H)+;
*H NMR (300 MHz, DMSO-de) δ 7.94 (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 Z\
2.5-dihvdro-10-methoxv-2.2.4-trimethyl-5-r3-(trifluoromethynphenyll-lH- πibenzopyranor3.4- 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.03 (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- f 1 Jbenzopyrano[3.4- fjquinoline Example 2B and anisole were processed as in Example 2C to provide the desired compound.
MS (DCI/NH3) m z 414 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.00 (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-dihydro- 10-methoxy-2.2.4- trimethyl- lH-πibenzoρyranor3.4- .fjquinoline
Example IF and 3-chlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound.
-95- MS (DCIZNH3) m/z 418 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.01 (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), 1J5 (s, 3H); HRMS calcd m/z for C26H24NO2CI: 417J496 (M+H)+. Found: 417.1490.
Example 24 2.5-dihvdro-10-methoxy-2.2.4-trimethyl-5-(3-methylphenvn-lH-πihenzopyranoI3.4- fjquinoline Example IF and 3-methylphenylmagnesium bromide were proces-sed 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) δ 7.94 (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-dihvdro-10-methoxy-2.2.4-trimethyl-5-phenyl-lH-rnbenz6pyrano- r3.4-flquinoline Enantiomer of Example 1. Spectral data are identical to Example 1. [α]D = + 85J; 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-phenyI-lH-rnbenzopyranor3.4- flquinoline Enantiomer of Example 1. Spectral data are identical to Example 1. [α]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.
-96- Example 27
5-G.5-dimethv1phenylV2.5-dihvdro-10-methoxy-2.2.4-trimethyl-
1 H-[ 1 IbenzQpyraηQrø .4-flquinQline Example IF (0.052 g, 0J62 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 ediyl acetate, and extracted witii ethyl acetate. The extract was washed with brine, dried (MgSO4), filtered, .and concentrated. The residue was purified by flash chromatography on siUca gel with a gradient from 10-25% ethyl acetate/hexanes to provide the desired lactol.
The lactol (0.043 g, 0J01 mmol) was dissolved in dichloromethane (7 mL), treated with triethylsilane (0J6 mL, 1.01 mmol), cooled to 0 °C, treated with BF3-OEt2 (0J2 mL, 1.01 mmol), warmed to room temperature, stirred for 19 hours, and treated with N-1HCO3, 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)+; H NMR (300 MHz, DMSO-d6) δ 8.00 (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), 6J9 (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, 7J0; N, 3.40. Found: C, 81.59; H, 7.54; N, 3J6.
Example 28 5-(4-chlorophenyl -2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-πibenzopyranor3.4- flquinoline 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)+; *H NMR (300 MHz, DMSO-d6) δ 8.01 (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-G.4-dimethylphenyl)-2.5-dihydro-10-methoxy-2.2.4-trimethyl-
-97- 1 H-r 1 Ihenzopvranof 3.4-f)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)+; H NMR (300 MHz, DMSO-de) δ 7.98 (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), 6J7 (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 C28H29O2NO.5H2O: C, 79.97; H, 7J9; N, 3.33. Found: C, 79.94; H, 7.25; N, 2.98.
Example 3Q 5-f4-fluorophenvl)-2.5-dihvdro-10-methoxv-2.2.4-trimethyl-lH-rilhenzopyranor3.4- flquinς>Une 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)+; lH NMR (300 MHz, DMSO-d6) δ 8.03 (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-r3.5-bis(trifluoromethyl)phenylJ-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-flJhenzopyrano[3.4- fjquinoline Example 2B and 4-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound. lH NMR (300 MHz, DMSO-d6) δ 8.02 (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 C28H23NO2F6J.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-me oxy-2.2.4-trimethyl-lH- mbenzopyrano[3.4-flquinoline
Enantiomer of Example 19.
Spectal data are identical to Example 19.
-98- [α]D = - 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-dichlorophenyn-2.5-dihydro- 10-methoxy-2.2.4-trimethyl- 1 H- rilhenzopyrano[3.4-flquinoline -Enantiomer of Example 19. Spectal data are identical to Example 19.
[α]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
5J3.5-difluorophenylV2.5-dihvdro-10-methoxy-2.2.4-trirnethyl- lH-fnbenzopyranor3.4-flquinoline Example 2B and 3,5-difluorophenylmagnesium bromide were processed as in
Example 11 to provide the desired compound.
IH NMR (300 MHz, DMSO-d6) δ 8.01 (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 C26H23O2F2NO.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- lH-|JJbenzopyranor3.4-flquinolin-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)+;
-99- IH NMR (300 MHz, DMSO-ds) δ 8.03 (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-dihvdro-10-methoxy-2.2.4-trimethyl-5-(2-propenylVlH-ri1benzopyranor3.4- flquinoline Example 2 was purified by flash chromatography on Chiralcel OJ with 10% ethanol/hexanes to provide the desired compound. [α]D = -1.8 (c 1.2, CHC13);
MS (DCI NH3) m/z 348 (M+H)+;
IH NMR (300 MHz, DMSO-de) δ 7.96 (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-fl lbenzopyranor3.4- fjquinoline
Example 2 was purified by flash chromatography on Chiralcel OJ with 10% ethanol/hexanes to provide the desired compound. [αJD= +2.1(c 1.1. CHC13); MS (DCI/NH3) m/z 348 (M+H)+; *H NMR (300 MHz, DMSO-d6) - 7.96 (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-flJbenzopyranor3.4- fjquinoline Example 2B and triethylsilane were processed as in Example 2 to provide the desired compound. MS (DCI NH3) m/z 308 (M+H)+;
-100- IH NMR (300 MHz, DMSO-d6) δ 7.82 (d, IH), 7.05 (t, IH), 6.72 (dd, IH), 6.58 (d, IH), 6.57 (dd, IH), 6J3 (d, IH), 5.39 (t, IH), 5J0 (s, 2H), 3.84 (s, 3H), 2.02 (d, 3H), 1.18 (s, 6H);
Anal, calcd for C20H21NO2 OJH2O: C, 77.69; H, 6.91; N, 4.53. Found: C, 77.60; H, 7J5; N, 4.33.
Example 39 4-('2.5-dihvdro-10-methoxv-2.2.4-trimethvl-lH-[llhenzopyranor3.4-flquinolin-
5-ylVN.N-dimethylbenzenamine Example 2B and N,N-dimethylanUine 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*;) δ 7.98 (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), 6J4 (d, IH), 5.35 (s, IH), 3.79 (s, 3H), 2.80 (s, 6H), 1.84 (s, 3H), 1.21 (s, 3H), 1J3 (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)- lH-riJbenwpyranQr3.4-f]qqino ne Example 2B and 2-methoxythiophene were processed as in Example 2 to provide the desired compound. MS (DCI NH3) m z 420 (M+H)+; l NMR (500 MHz, DMSO-d6) δ 7.98 (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-thienyD- lH-rilbenzopyranor3.4-f1quinoline Example 2B and 2-propylthiophene were processed as in Example 2 to provide the desired compound.
-101- IH NMR (300 MHz, DMSO-dβ) 8.01 (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-dihvdro-10-me-hoxy-2.2.4-trime-hyl-5-[4-π-moφholinvDphenvll- lH-fllbenzopyranof3.4-f]quinoline Example 2B and 4-phenylmoφhoUne 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) δ 8.00 (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 C30H32N2O2O.5H2O: C, 75.45; H, 6.96; N, 5.87. Found: C, 75.46; H, 6.69; N, 5.31.
Example 43 l-(2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-flJbenzopyranor3.4-f)quinolin-
5-yl -3.3-dimethvl-2-hutanone 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)+; *H NMR (300 MHz, DMSO-d6) δ 7.95 (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 C26H31NO3O.33H2O: 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-riJbenzopyranor3.4-fJquinoline-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)+;
■102- *H NMR (300 MHz, DMSO-d6) δ 7.96 (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 C21H20N2O2 O.25H2O: C, 74.87; H, 6J3; N, 8.31. Found: C, 75.00; H, 6.23; N, 8.34.
Example 45 lJ2.5-dihvdro-10-methoxv-2.2.4-trimethvl-1H-πibenzopyranor3.4-flquinolin-
5-vlV2-propannne Example 2B and 2-(trimethylsUoxy)-propene were processed as in Example 2 to provide the desired compound.
IH NMR (300 MHz, DMSO-d6) δ 7.96 (t, IH), 7.04 (t, IH,), 6.71 (d, IH), 6.58 (d, IH), 6.48 (d, IH), 6.20 (dd, IH), 6J6 (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 O.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-dihvdro-10-methoxv-2.2.4-trimethyl-lH-rnhenzopyranoI3.4-flquinoline-
5-acetøte 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)+; l NMR (300 MHz, DMSO-d6) δ 8.01 (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 O.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 HJ 1 Jbenzopyranor3.4-flquinolin-
5-yD- 1 -phenylethanone Example 2B and l-phenyl-l-(trimethylsiloxy)ethylene were processed as in Example 2 to provide the desired compound.
-103- IH NMR (300 MHz, DMSO-dβ) δ 8.01 (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), 6J8 (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-I2-(chloromethvlV2-propenvll-2.5-dihvdro-10-methoxy-2.2.4-trimethyl- lH-rnt?enzQpyrano[3,4-f]quinQline 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) δ 7.96 (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), 4J7 (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 C24H26Q2CIN: 395.1652 (M+H)+. Found: 395.1645; Anal, calcd for C24H26O2QNO.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-r-methylene-lH-[llhenzopyranor3.4-flguinoline- 5-propanol. acetate (ester)
Example 2B and 2-[(trimethylsUyl)methyl]-2-propen-l-yl acetate were processed as in Example 2 to provide the desired compound.
*H NMR (300 MHz, DMSO-d6) δ 8.02 (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 C2-5H29O4NO.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-methyIphenyl)-lH-πjhenzopyranor3.4- flquinoline 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)+;
-104- IH NMR (300 MHz, DMSO-de) 8.00 (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), 6J8 (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-methvlphenvn-2.5-dihvdro- 10-methoxv-2.2.4-trimethyl- lH-ri1benzQpyranQr3.4- jquinQline 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-dg) δ 8.01 (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-[nbenzopyranor3.4- flgwnoliηe 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)+; !H NMR (300 MHz, DMSO-de) δ 8.02 (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-fnbenzopyranor3.4- fjquinoline Example 2B .and benzylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI NH3) m/z 398 (M+H)+;
-105- IH NMR (300 MHz, DMSO-d6) δ 8.02 (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 C27H27NO2O.25H2O: C, 80.67; H, 6.89; N, 3.48. Found: C, 80.78; H, 7.08; N, 3.26.
Example 54 2,5-dihydrQ-lQ-methoxy-2,2,4-trimethyl-5-prc>pyl-lH-[lll)enzQpyrano[3,4- |quinc)line Example 2B and propylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/z 350 (M+H)+; l NMR (300 MHz, DMSO-d6) δ 7.94 (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-fluorophenyIV2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-πjhenzopyranof3.4- fjquinoline
Example 2B and 4-fluorophenylmagnesium bromide were processed as in Example 11 to provide the desired compound.
IH NMR (300 MHz, DMSO-d6) δ 7.99 (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 C27H26O2 NF: 415.1948 (M+H)+. Found: 415.1947.
Example 56 5-f3-fluorophenyl)-2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-ri1benzopyranor3.4- fjquinoline
Example 2B and 3-fluorophenylmagnesium bromide were processed as in Example
11 to provide the desired compound.
*H NMR (300 MHz, DMSO-d6) δ 8.03 (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;
■106- Anal, calcd for C26H24O2FN-2.25H2O: C, 70.65; H, 6.50; N, 3.17. Found: C, 70.56; H, 6J8; N, 2.83.
Example 57 2.5-dihvdro-10-methoxv-2.2.4.5-tetramethyl-lH-πibenzopyranor3.4-flquinoline
Example 2B and methylmagnesium iodide were processed as in Example 11 to provide the desired compound. lH N . MR (300 MHz, DMSO-dό) δ 7.91 (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), 1J8 (s, 3H), 1.13 (s, 3H);
HRMS calcd m/z for C21H23O2N: 321.1729 (M+H)+. Found: 321.1728.
Example 58 2.5-dihvdro-10-methoxv-2.2.4-trimethyl-5-(l-methylethylVlH-rilhenzopyranor3.4- flquinoline
Example 2B and 2-propylmagnesium chloride were processed as in Example 11 to provide the desired compound. lH NMR (300 MHz, DMSO-d6) δ 7.99 (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)- 1 H- rnbenzopyranor3.4- fjquinoline
Example 2B and sec- buty -magnesium chloride were processed as in Example 11 to provide the desired compound.
*H NMR (300 MHz, DMSO-d6) δ 7.93 (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- 1 H-mhenzopyranor3,4- flquinoline
■107- Example 2B and ethylmagnesium bromide were processed as in Example 11 to provide the desired compound. MS (DCI/NH3) m/z 336 (M+H)+;
*H NMR (300 MHz, DMSO-c ) δ 7.92 (d, IH), 7.03 (t, IH), 6.67 (d, IH), 6.54 (t, 2H), 6J0 (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 C22H25θ2N-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-dihvdro-10-methoxv-2.2.4-trimethvl-lH-[nhenzopyranor3.4-fJquinoline-5- carboximidic acid ethyl ester A solution of Example 44 (0.040 g, 0J20 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)+; lH NMR (300 MHz, DMSO-d6) δ 7.95 (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-trimethyI-(-methylene lH-|J1benzopyrano[3.4-flquinoline-
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, neutraUzed with 10% HCl, and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO4), fUtered, and concentrated. The residue was purified by flash chromatography on silica gel with 25% dichloromethane/ethyl acetate to provide the desired compound. l NMR (300 MHz, DMSO-d6) δ 8.01 (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
-108- 2.5-dihvdro-10-methoxv-2 7 4.N.N-pentamethvl-lH-πibenzopvranor3.4-flguinoline-5- acetamide Example 46 was hydrolyzed with Uthium hydroxide in THF to provide the corresponding acid which was then coupled to N,N-dimethylamine with l-(3- dimethyl--minopropyl)-3-ethylc--rbodiimide to provide the desired compound.
!H NMR (300 MHz, DMSO-ds) δ 7.94 (d, IH), 7.04 (t, IH), 6.70 (d, IH), 6.59 (d, IH), 6.46 (d, IH), 6.26 (d, IH), 6J5 (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-dihvdro-10-methoxv-2.2.4.N.N-pentamethyl-lH-rilbenzopyranor3.4-flquinoline- 5-ethanamine
A solution of Example 63 in diethyl ether was reduced at room temperature with lithium aluminum hydride to provide the desired compound.
1H NMR (300 MHz, DMSO-d6) δ 7.93 (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- lH-[lJbenzopyranor3.4- fJquinoline-5-acetamide
Example 46 and cyclopropylmethylamine were processed as in Example 63 to provide the desired compound.
*H NMR (300 MHz, DMSO-d6) δ 7.94 (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-trimethyI-5-(2-propynyl)-lH-[lJbenzopyranor3.4- fj uinoline
Example 2B and 2-propynylmagnesium bromide were processed as in Example 11 to provide the desired compound.
•109- IH NMR (300 MHz, DMSO-d6) δ 7.97 (d, IH), 7.06 (t, IH), 6.71 (d, IH), 6.56 (q, 2H), 6J6 (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-dihvdro-10-methoxv-2.2.4-trimethvl-1H-rnhenzopyranor3.4-flquinolin-5- vn-2(5HVfuranone Example 2B and 2-trimethylsUoxyfuran 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) δ 8.11 (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-r3-hutenyl)-2.5-dihdyro-10-methoxy-2.2.4-trimethyl-lH-ri1henzopyranor3.4- flquinoline
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) δ 7.94 (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-10-methoxy-2.2.4-trimethyl-lH-rnbenzopyranor3.4-f quinoline-5-propanol Example 2 (52.0 mg, 0J5 mmol) in THF (4 mL) at 0 °C was treated dropwise with 0.5M 9-BBN (600 μL, 0.30 mmol), stirred overnight at room temperature, cooled to 0 °C, treated sequentially with 2.5M NaOH (400 μL, 1.0 mmol), and 30% H2O2 (250 μL), 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,
-110- and concentrated. The residue w.as purified by flash chromatography on siUca gel with 30% ethyl acetate/hexanes to provide the desired compound. MS (DCI/NH3) m/z 366 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 7.94 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.53 (d, IH), 6J0 (s, IH), 5.70 (dd, IH), 5.44 (s, IH), 4.36 (t, IH), 3.85 (s, 3H), 3.33 (m, 2H), 2J6 (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-ethvl-2.5-dihvdro-2.2.4-trimethyl-5-phenyl- lH-f 1 Jbenzopyranor3.4-fJquinoline
Example 70A Example 3C (0.208 g, 0.493 mmol) and tetraethyltin (0,444 g, 1.89 mmol) were combined with (l,3-bis(diphenylphosphino)ferrocene)palladium(II)- chloride dichloromethane (0.039 g, 0.047 mmol) in l-methyl-2-pyrroUdinone (3 mL) at 80 °C for 16 hours and concentrated to provide the desired compound. MS
Example 70 10-ethyl-2.5-dihvdro-2.2.4-trimethyl-5-phenyl-lH-riJbenzopyranor3.4-flquinoline
Example 70A was processed as in examples IF, IG, and 1 to provide the desired compound.
MS (DCI/NH3) m z 382 (M+H)+; H NMR (300 MHz, DMSO) δ 7.37 (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-dihvdro-2.2.4J0-tetrametnyl-5-phenyl-lH-|"nhenzopyranor3.4-flquinoline
Example 3C and tetramethyltin were processed as in Example 70 to provide the desired compound. MS (DCI/NH3) m/z 368 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 7.44 (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.
■ I l l- Example 72
5-(3.5-dichlorophenylV10-ethyl-2.5-dihvdro-2.2.4-trimethy1-1 H-
[I]benzQpyrano[3,4-f]quipoline 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)+;
*H NMR (300 MHz, DMSO-dό) δ 7.43 (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: 449J330.
Example 73 5-(3.5-dichlorophenyl)-2.5-dihydro-2.2.4.N-tetramethyl- 1 H-[ 1 Jbenzopyrano[3.4-f|quinolin- 10-amine
Figure imgf000114_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-dichIorophenyl)-2.5-dihvdro-2.2.4.N-tetramethyl- lH-[lJbenzopyranor3.4-flquinolin-10-amine Example 73A was processed as in Example 3 to provide the desired compound.
MS (DCI NH3) m/z 451 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 7.91 (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), 6J7 (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
-112- 5-(3.5-dichlorophenvn-2.5-dihvdro-2.2,4-trimethyl-N-r2-prnpenvn-1 H- 11 lhenzopyranor3.4-flquinolin- 10-amine Example 73A and aUylamine were processed as in Example 3 to provide the desired compound. MS (DCI/NH3) m/z 477 (M+H)+; lH NMR (300 MHz, DMSO-dβ) δ 7.99 (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), 5J 1-5.06 (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-dihvdro-2.2.4-trimethvl-5-ρhenyl-10-(2-propynyloxyVlH-rilhenzopyranor3.4-
Oquinoline Example 7 and propargyl bromide were processed as in Example 9A to provide the desired compound.
MS (DCI/NH3) m/z 408 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 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 C28H25 O2: C, 82.53; H, 6.18; N, 3.44. Found: C, 82.64; H 6.31; N,
3.38.
Example 76 2.5-dihvdro-2.2.4-trimethyl-5-phenyl-10-r2-propenyloxyVlH-mhenzopvranor3.4- f] quinoline Example 7 and allyl bromide were processed as in Example 9A to provide the desired compound. MS (DCI) m/z 410 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 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
-113- 2.5-dihvdro-2.2.4-trimRthvl-5-r2-propenvn-1H-rilhenzopvranor3.4-flφiinnlinfi-
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
RocheUe's salt, separated, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The residue weis 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 (DCIZNH3) m/z 348 (M+H)+;
IH NMR δ 7.47 (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-fJquinoline-10- carboxylic 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)+;
*H NMR (300 MHz, DMSO-d6) δ 7.91 (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-dichlorophenylV10-ethoxy-2.5-dihydro-2.2.4-trimethyl-lH- [llhenzopyranor3.4- fjquinoline Example 9 A and 3,5-dichlorophenylmagnesium bromide were processed as in examples IG and 1 to provide the desired compound. MS (DO) m/z 466 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.10 (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.
-114- Example 80 5-n,5-dichlorophenvlV2.5-dihydro-2.2.4-trimethv1-lH-fnhenzopyranor3.4-f1guinolin-10-
Ωi 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)+;
!H NMR (300 MHz, DMSO-d6) δ 9.79 (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), 1J6 (s, 3H); HRMS calcd m/z for C25H21CI2NO2: 437.0949 (M+H)+. Found: 437.0955.
Example 81
5-f3.5-dichlorophenvD-2.5-dihydro-2.2.4-trimethyl-lH-rnhenzopyranol3.4-flquinolin-
10-vllmethvlcarhonate 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)+; lH NMR (300 MHz, DMSO-d6) δ 7.58 (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 C27H23NO4 2 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-rnhenzopyranor3.4-flqιιinolin-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)+;
*H NMR (300 MHz, DMSO-d6) δ 9.77 (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-proρenyπ-lH- πibenzopyranor3.4-flquinoline
■115- 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)+; H NMR (300 MHz, DMSO-d6) δ 7.60 (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-r2.5-dihvdro-10-methoxy-2.2.4-trimethyl-lH-Illbenzopyranor3.4-flguinolin-
5-vDphenvn methvlcarhonate Ex.ample 13 and methylchloroformate were processed as in Example 10 to provide the desired compound. MS (DCI/NH3) m/z 458 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.01 (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-10-methoxy-5-(3-methoxyphenyl)-2.2.4-trimethyl- lH-nibenzopyranoT.3.4-f . jquinoline Example 13 and methyl iodide were processed as in Example 14 to provide the desired compound.
MS (DCI/NH3) m z 414 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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-r3J2-propenyloxyφhenyll- lH-[lJbenzopyranor3.4- fjquinoline
Example 13 and allyl bromide were processed as in Example 14 to provide the desired compound.
-116- MS (DCI/NH3) m/z 440 (M+H)+;
IH NMR (300 MHz, DMSO-de) δ 8.02 (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, 3J8. Found: C, 78.87; H, 6.46; N, 3.07.
Example 87 2.5-dihvdro-10-methoxv-2.2.4-trimethvl-5-13-('phenvlmethoxv)phenvn- lH-πibenzopvranoI3.4-flquinoline Example 13 and benzyl bromide were processed as in Example 14 to provide the desired compound. MS (DCIZNH3) m/z 490 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.06 (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-r3-(fcvclopropylmethoxy)phenyII-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-πihenzopyranor3.4-flquinoline Example 13 and cyclopropylmethyl bromiode were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 454 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.01 (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-10-methoxy-2.2.4-trimethyl-5-r3-r2-(l-piperidinyl)ethoxylphenyl- 1 H-rnbenzopyranor3.4-f]quinoline
Example 13 and l-(2-chloroethyl)piperidine were processed as in Example 14 to provide the desired compound.
■117- MS (DCI NH3) m/z 511 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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), 1J6 (s, 3H);
Anal, calcd for C33H38N2O3-0.5H2O: 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-memoxy-2.2.4-trimethyl-
1 H-l 11henzopvranor3.4-flquinoline Example 13 and hexyl iodide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 484 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.01 (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)phenyn-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-rπhenzopyranor3.4-flquinoline 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)+; lH NMR (300 MHz, DMSO-d6) δ 8.87 (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-dihydro- 10-methoxy-2.2.4-trimethyl-5-r3-(2-propynyloxy)pheπyl1- lH-rilbenzopyranor3.4-flquinoline
-118- Example 13 and propargyl bromide were processed as in Example 14 to provide the desired compound. MS (DCIZNH3) m/z 566 (M+H)+;
!H NMR (300 MHz, DMSO-de) δ 8.00 (d, IH), 7.13 (t, IH), 6.92 (t, IH), 6.80-6.68(m, 5H), 6.56 (d, IH), 6.48 (d, IH), 6J8 (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), 1J6 (s, 3H);
Example 93 3-r2.5-dihvdro-10-methoxy-2.2.4-trimethyl-lH-πibenzopyranor3.4-fJquinolin- 5-vl 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)+;
!H NMR (300 MHz, DMSO-d6) δ 7.99 (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-ri]benzopyrano("3.4-fJquinolin-
5-yl)phenolacetate (ester) Example IF and 4-methoxymethoxyphenyl bromide were processed as in examples 12 A-C to provide the desired compound. MS (DCI NH3) m/z 442 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.02 (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 C28H27 O4: 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-fJJbenzopyranof 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)+;
-119- IH NMR (300 MHz, DMSO-d6) δ 9.29 (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-dihvdro-10-methoxy-2.2.4--rimethyl-5-rr4-.methylthio)methoxylphenyll- lH-rilhenzopyranor3.4-flquinoline 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) δ 8.01 (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 C28H29NO3S: 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-f1quinolin- 5-yl)phenylJ dimethylcarbamate
Ex.ample 95 and dimethylcarbanoylchloride were processed as in Example 15 to provide the desired compound. MS (DCI NH3) m/z 471 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.01 (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-r4-(phenylmethoxy)phenyri- lH-|JJbenzopyrano|"3.4-f1quinoline
Example 95 and benzyl bromide were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/z 490 (M+H)+; l NMR (300 MHz, DMSO-d6) δ 8.02 (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);
J20- 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-dihvdro-10-methoxv-2.2.4-trimethyl-5-r3-rmethoxymethoxy)phenyll-lH- inbenzopvranoI3.4-flquinoline Example 13 and methoxymethyl chloride were processed as in Example 14 to provide the desired compound. MS (DCI NH3) m/z 444 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.01 (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
[r2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-[11benzopyrano[3.4-fJquinolin-5- vDphenvll 1-morpholinecarhoxylate Example 13 and moφholine were processed as in Example 15 to provide the desired compound. MS (DCI/NH3) m/z 513 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.01 (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-f3-[(methylsulfinyl)methoxylphenyll- lH-[lJbenzopyrano|"3.4- fjquinoline 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 arjd 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)+;
1H NMR (300 MHz, DMSO-d6) δ 8.01 (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),
•121- 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-r3-(2.5-dihvdro-10-methoxv-2.2.4-trimethvl-lH-πihenzopvranor3.4-f1quinolin-
5-yPpher.ylJ 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)+; H NMR (300 MHz, DMSO-d6) δ 8.01 (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-I3-(methylthio')phenyll-lH- I" 1 Jbenzopyranor3.4- 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 of the residue on siUca 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-trimethyI-5-[3-(methylthio)phenylJ-lH- riIbenzopyrano[3.4- fjquinoline A solution of Example 103A (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
■122- sequentiaUy with IM NaOH and brine, dried (Na2SO4), filtered, and concentrated. Flash chromatography of the residue on siUca gel with 10-25% ethyl acetate/hexane provided the desired compound. MS (DCI/NH3) m/z 430 (M+H)+; lH NMR (300 MHz, DMSO-dό) δ 8.01 (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), 6J9 (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-f2.5-dihvdro- 10-methoxv-2.2.4- trimethvl- lH-r nhenzopyranor3.4-flquinolin-
5-vl φhenvll methvlcarhonothioate 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-d6) δ 8.00 (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 r3-r2.5-dihvdro-10-methoxy-2.2.4-trimethyn-lH-riJbenzopyranor3.4-flquinolin-5- yDphenyll 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 μL, 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)+; *H NMR (300 MHz, DMSO-d6) δ 8.02 (d, IH), 7.44 (t, IH), 7.30 (m, 2H), 7J7 (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);
-123- 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-r3-(4.5-dihydro-4.4-dimethyl-2-oxazolyl phenylJ-2.5-dihydro-10-methoxy-
2,2,4-trimethyl-lH-πJbenzQp.yraπor3,4-fJqgiπ(?line Example 52 (92.9 mg, 0.20 mmol), 2-trimethylstannyl-4,4-dimethyloxazoUne (210 mg, 0.80 mmol), and [lJ'-is(diphenylphosphino)-ferroceneJdichloropaUadium(II) (16 mg, 0.02 mmol) in l-methyl-2-pyrrolidinone (2 mL) were purged with N2, 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 sheUs (CeUte®). The filtrate was washed with water, brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on siUca gel with 0-30% ethyl acetate/hexanes to provide the desired compound. MS (DCIZNH3) m/z 481 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.02 (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 C31H32N2O3O.7H2O: 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-lQ-methoxy-2.2.4-trimethyl-lH-rnbenzopyranor3.4- fJquinolin-5-yl)benzoate
Example 106 (48 mg, 0J 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.02 (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
•124- Example 108 3-r2.5-dihvdro-10-methoxy-2.2.4-trimethyl-1H-rilbenzopyranor3.4-flquinolin-5- yPbenzoic 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)+; lH NMR (300 MHz, DMSO-d6) δ 8.02 (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-dihvdro-10-methoxy-2.2.4-trimethyl-5-13-methyl-5-r2-propenvnphenyll- lH-fllhenzopyranor3.4- fjquinoline Example 52 and aUyltributyltin were processed as in Example 16 to provide the desired compound.
MS (DCI/NH3) m/z 438 (M+H)+; l NMR (300 MHz, DMSO-d6) δ 7.99 (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 1 -r3J2.5-dihvdro- lO-methoxy-2.2.4- trimethyl- 1 HJ llhenzopyranor3.4-flquinolin-5-yr.-5- methylphenyllethanone Example 52 and tributyl(l-ethoxyvinyl)tin in dichloroe thane (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)+;
-125- IH NMR (300 MHz, DMSO-de) δ 8.01 (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-dihvdro-10-methoxv-2.2.4-trimethvl-lH-rnhenzopyranor3.4-flguinolin-5-vn-
5-trimethyIt>enzenemethanol 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 μL), wanned to room temperature, stirred for 1 hour, treated with saturated NH4CI, separated, a . nd 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)+; lH .NMR (300 MHz, DMSO-d6) δ 7.98 (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 1 12
5J3-f2-furanyl)phenyl]-2.5-dihvdro-10-methoxy-2.2.4-trimethyl- lH-[lJbenzopyranor3.4- fjquinoline 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.0 (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 C30H27NO3 H2O: C, 77.07; H, 6.25; N, 3.00. Found: C, 77.27; H, 5.97; N, 3.23.
Example 113 2.5-dihydro-10-methoxy-2.2.4-trimethyl-5-[3-methyl-5- iH-pyrrolidirf- l-yl)phenyll- lH-πjhenzopyranof3.4- fjquinoline Example 11 and pyrrolidine were processed as in Example 17 to provide the desired compound.
- 126- MS (DCI/NH3) m/z 467 (M+H)+;
!H ISTMR (300 MHz, DMSO-d6) δ 7.97 (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-dihvdro-10-methoxy-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinolin-
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)+; lH NMR (300 MHz, DMSO-d6) δ 7.98 (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 C28H30N2O2O.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-dihvdro-10-methoxy-2.2.4-trimethvI-lH-rnhenzopyranor3.4-flquinolin-5-yl)-5-
- methyl-N-(2-propenyI)benzamide
Example 11 and aUylamine were processed as in Example 17 to provide the desired compound.
MS (DCI NH3) m/z 453 (M+H)+; 1H .NMR (300 MHz, DMSO-d6) 8 7.98 (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- 1 H-[ 1 Jbenzopyranor3.4-flquinolin- 5-yl)-N-(2-methoxyethyl)-5-methylbenzenamine Example 11 and 2-methoxyethylamine were processed as in Example 17 to provide the desired compound.
-127- IH NMR (300 MHz, DMSO-d6) δ 7.98 (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-r2.5-dihvdro-10-methoxy-2.2.4- trimethyl- lH-πihenzopyranor3.4-flguinolin-
5-vl')-N-f2-ρropenyl)henzenamine
Example 52 and aUylamine were processed as in Example 17 to provide the desired compound.
MS (DCI/NH3) m/z 439 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 7.99 (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'-r3-(-2.5-dihvdro-10-methoxy-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flguinoIin-5-ylV
5-methylphenylJ-N.N-dimethylurea A solution of Example 115 (0J 12 g, 0.247 mmol) in 10% ethanol/water (10 mL) was treated with l,4-diazabicyclo[2.2.2Joctane (0.056 g, 0.495 mmol) and chlorotris(triphenylphosphine)rhodium(I) (0.115 g, 0J24 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/hex-u es to provide the desired anUine.
The aniline (0.030 g, 0.073 mmol) was dissolved in 2: l/toluene:THF (7 mL), treated sequentially with diisopropylethylamine (38 μL, 0.218 mmol) and
N,N-dimethylcarbamoyl chloride (20 μL, 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 sUica gel with 25-50% ethyl acetate/hexanes to provide the desired compound.
■128- H NMR (300 MHz, DMSO-d6) δ 8.15 (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-r3-r2.5-dihvdro-10-methoxv-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinolin-
5-yl)phenylJbenzenemethan amine Example 11 and benzylamine were processed as in Example 17 to provide the desired compound.
IH NMR (300 MHz, DMSO-dβ) δ 7.97 (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-r(3.5-dichlo henyπmethylene1-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-ri1henzopyranor3.4-flquinoline 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)+; H NMR (300 MHz, DMSO-d6) isomer 1: δ 8.17 (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: δ 8.29 (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-|Y4-chlorophenyI)methyleneJ-2.5-dihydro-10-methoxy-2.2.4-trimethyl-
1 H-r 1 !benzopyranor3.4- fjquinoline 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)+; *H NMR (300 MHz, DMSO-d6) isomer 1: δ 8.26 (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
-129- (s, 3H), 1.97 (s, 3H), 1.26 (s, 6H); isomer 2: δ 8.13 (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-dihvdro-10-methoxy-2.2.4-trimethyl-5-rr3-
(trifluorQmethyl)phenyl]methylene1-lH-[11-benzopyrano[3,4-f]quinQline 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: δ 8.28 (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: δ 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-r(2.6-difluorophenyl methyleneJ-2.5-dihydro-10-methoxy-2.2.4- trimethyl- 1 H- f" 1 Jbenzopyranor3.4-fjquinoline 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: δ 8.32 (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: δ 8.18 (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-r(2-chlorophenyPmethyleneJ-2.5-dihydro- 10-methoxy-2.2.4-trimethyl- lH-rilbenzopyranor3.4- fjquinoline
■130- 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)+; H NMR (300 MHz, DMSO-dό) isomer 1: δ 8J 1 (d, IH), 7.47 (d, IH), 7.40 (d, IH), 7.23-7J0 (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: δ 8.27 (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-r(2.6-dichlorophenynmethylenel-2.5-dihydro-10-methoxy-2.2.4- rimethyl- 1 H-r 11tenzopyrano[3.4-flqwpoline Example IF and 2,6-dichlorobenzylmagnesium bromide were processed as in Example IB to provide the desired compound. MS (DCIZNH3) m/z 464 (M+H)+;
*H NMR (300 MHz, DMSO-d6) isomer 1: δ 8.27 (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: δ 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-[(2-fluorophenyPmethylene1-2.5-dihydro-10-methoxy-2.2.4-trimethyl- lH-["lJbenzopyrano["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)+; *H N . MR (300 MHz, DMSO-d6) isomer 1: δ 8.30 (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: δ 8J7 (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
J31- 2.5-dihvdro- .0-methoxv-2.2.4-trimethvl-5J(4.5-dihvdro-4.4-dimethyl-2- oxazolyπmethylene1-lH-riJbenzopyranor3.4-flquinoline Exa. mple IF and 4,4-dimethyl-2-oxazoUne-2-methyUithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 417 (M+H)+; lH NMR (300 MHz, DMSO-dό) isomer 1: δ 8.34 (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: δ 8.06 (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- [lJbenzopyrano[3.4- fjquinoline
Example IF and 2-methylpyridyllithium 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: δ 8.50 (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: δ 8.43 (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-rilhenzopyranoH.4-flquinoUne Example IF and 2-thienyllithium were processed as in Example IB to provide the desired compound.
MS (DCI/NH3) m/z 391 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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
•132- 2.5-dihvdro-9J0-dimethoxv-2.2.4-trimethvl-5-('2-propenvn-lH-ri1benzopyranor3,4- flquinoline 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)+; H NMR (300 MHz, DMSO-d6) δ 7.93 (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), 1J6 (s, 3H).
Example 131
5-(2-cvclohexen-l-vn-2.5-dihvdro-9JO-dimethoxy-2.2.4-trimethyl-lH- rilbenzopvranor3.4-flquinoline 1,2,4-trimethoxybenzene was processed as described in Example 130 but substituting 3-trimethylsilylcyclohexene for aUyltrimethylsilane to provide the desired compound.
MS (DCI/NH3) m/e 418 (M+H)+; iH NMR (300 MHz, DMSO d6) δ 8.03 (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),L31 (s, 3H), 1.29 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H).
(249978) Example 132 Claim
2.5-dihvdro-10-methoxy-5-(3-methyl-3-hutenylV2.2.4-trimethyl-lH-rilbenzopyranor3.4- fjquinoline
Example 2B and 3-methyl-l-trimethylsUyl-2-butene (prepared according to Fleming, et. αl. Synthesis 1979, 446.) were processed as in example 2 to provide the desired compound.
MS (DCI NH3) m/e (M+H)+ 376; *H NMR (300 MHz, DMSO-d6) δ 8.10 (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);
!3C NMR (100 MHz, DMSO-d6) δ 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;
-133- Anal, calcd for C25H29NO2«l/4H2O: C, 79.02; H, 7.82; N, 3.69. Found: C, 79.09; H, 7.94; N, 3.59.
Example 133 2.5-dihvdro- 10-methoxv-5-f 5.5-dimethvl-3-cyclohexenvl V2.2.4-trimethyl- 1 H- riJbenzppyranor3,4- 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) /e (M+H)+ 416; lH NMR (300 MHz, DMSO-d6) δ 8.08 (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 C28H33NO2'l/2H2O: C, 79.21; H, 8.07; N, 3.30. Found: C, 79.31; H, 7.75; N, 3.11. MINOR:
!H NMR (300 MHz, DMSO-d6) δ 8.02 (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-dihvdro-10-methoxy-5-r2-oxo-3-tetrahvdropyranyn-2.2.4-trimethyl-lH- rilbenzopvranor3.4-flquinoline Example 2B and 3,4-dihydro-6-(trimethylsUoxy)-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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.12 (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);
• 134- 13C NMR (100 MHz, DMSO-d6) δ 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 »l/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.66; H, 6.92; N, 2.91.
Example 135 anή f5R. 2'S) 2.5-dihvdro-10-methoxy-5J2-oxo-3-tetrahvdropyranylV2.2.4-trimethyl- lH-ri1henzopyranor3.4-flquinoline Example 2B and 3,4-dihydro-6-(trimethylsUoxy)-2H-pyran were processed as in
Example 2 to give 41% Example 135 and 48% Example 135A. MS (DCIZNH3) m/e 406 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.12 (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) δ 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'l/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.66; H, 6.92;^T, 2.91.
Example 135A anή (5R. 2'S 2.5-dihvdro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2.2.4-trimethyl- lH-riJbenzopyranor3.4-flquinoline
MS (DCI/NH3) m/e 406 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.06 (d, J=9 Hz, IH), 7.06 (t, J=8 Hz, 1H), 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) δ 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 C25H 7NO4'l/4H2O: C, 73.24; H, 6.76; N, 3.42. Found: C, 72.89; H, 7.07; N, 3.05.
■135- Example 1 6 2.5-dihvdro-10-methoxv-5-(3-cvclopentenvl)-2.2.4--rimethyl-lH-πihenzopyranor3.4- flq iinolme 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)+; !H NMR (300 MHz, DMSO-c
Major diastereomer: δ 8.05 (d, IH), 7.09 (t, IH), 6.72 (d, IH), 6.66 (d, IH), 6.58 (d, IH), 6J9 (s, IH), 5.77 (ddd, IH), 5.50 (d, IH), 5.43 (s, IH), 5J9 (ddd, IH), 3.87 (s, 3H), 2.90 (m, IH), 2.43-2J5 (m, 2H), 2.09 (s, 3H), 1.97-1.70 (m, 2H), 1.31 (s, 3H), 1.09 (s, 3H);
Minor diastereomer: δ 8.07 (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), 2J5 (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.
2.5-dihydro-10-methoxy-5-(3-cyclohexenyl)-2.2.4-trimethyl-lH-riJbenzopyranor3.4- f] quinoline
Example 2B and cyclohexen-2-yltrimethylsUane 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)+; lH NMR (300 MHz, DMSO-d6) Major diastereomer: δ 8.05 (d, IH), 7.06 (t, IH), 6.67 (d, IH), 6.64 (d, IH), 6.59 (d,
IH), 6J9 (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), 2J3 (s, 3H), 1.95-1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1J0 (m, 2H),
1.30 (s, 3H), 1.02 (s, 3H);
Minor diastereomer: δ 8.03 (d, IH), 7.07 (t, IH), 6.68 (d, IH), 6.63 (d, IH), 6.57 (d, IH), 6J5 (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), 2J0 (s, 3H), 1.95-1.80 (m, 2H), 1.72-1.50 (m, 2H), 1.38-1J0 (m, 2H), 1.28 (s, 3H), 1.05 (s, 3H); HRMS calcd m/z for C26H29NO2: 387.2198. Found: 387.2206.
•136- Example 138 2.5-dihvdro-10-methoxv-5-r3-hutenvn-2.2.4-trimethyl-lH-r henzopyranor3.4-flquinoUne Example 2B and 2-butenyltrimethylsUane 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)+;
*H NMR (300 MHz, DMSO-d6) Major diastereomer: δ 8.04 (d, IH), 7.05 (t, IH), 6.69 (d, IH), 6.64 (d, IH), 6.47 (d, IH), 6J6 (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), 0.7 l(d, 3H); Minor diastereomer: δ 8.03 (d, IH), 7.08 (t, IH), 6.67 (d, IH), 6.64 (d, IH), 6.58 (d, IH), 6J0 (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-dihvdro- 10-methoxv-5-α -ethenvl- 1 -cvclohexvn-2.2.4-trimethvl- 1H- r 1 lbenzopyranof 3.4- fjquinoline Example 2B and 2-cyclohexylideneethyl trimethyls ane were processed as in
Example 2 to provide the desired compound. MS (DCI NH3) m/z 416 (M+H)+; lH .NMR (300 MHz, DMSO-d6) δ 8.10 (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-dimethyI-3-cyclohexenyl)-2.2.4-trimethyl- 1 H- r 1 j benzopyrano!3.4- fjquinoline Example 2B and (4,4-dimethylcyclohexen-2-yl)trimethylsUane 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)+; 1H NMR (300 MHz, DMSO-d6)
•137- Major diastereomer δ 8.07 (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), 2J6 (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 diastereomer δ 8.04 (d, IH), 7.06 (t, IH), 6.68 (d, IH), 6.62 (d, IH), 6.57 (d, IH), 6J9 (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-dihvdro-10-methoxv-5-ri-methvlene-2-cvclohexvlV2.2.4-trimethyl-lH- flj benzopyrano f3.4- fjquinoline 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)+; lH NMR (300 MHz, DMSO-d6)
Major diastereomer δ 8.07 (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 diastereomer δ 8.09 (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-( 1 -oxo-2-cyclohexyl)-2.2.4-trimethyl- 1 H-[ 1 lbenzopyranor3.4- fjquinoline Example 2B and l-(trimethylsilyloxy)cyclohexene were processed as in Example 2 to provide the desired compound as single diastereomer. MS (DCI/NΗ3) m/z 404 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 8.04 (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).
-138- HRMS calcd m/z for C2-3H29NO3: 403.2147. Found: 403.2142.
Example 143 2.5-dihvdro- 10-methoxv-5-(3-cvclooctenvl)-2.2.4-trimethyl-lH-rnhenzopyranor3.4- flquinoUne
Example 2B and cycloocten-2-yltrimethylsUane 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)+; lH NMR (300 MHz, DMSO-dό) Major diastereomer: δ 8.03 (dd, IH), 7.07 (t, IH), 6.62 (d, IH), 6.57 (d, IH), 6.39 (d, IH), 6J7 (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: δ 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-cycIoheptenyl)-2.2.4-trimethyl-lH-riJbenzopyranor3.4- fjquinoline
_ Example 2B and cyclohepten-2-yltrimethylsUane 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)+; *H NMR (300 MHz, DMSO-d6) diastereomer A: δ 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: δ 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-( 1 -cyclohexenylmethyl)-2.2.4-trimethyl- 1 H- πjbenzopyranor3.4- fjquinoline
Example 2B and 2-methylenecyclohexyldimethylphenylsilane were processed as in Example 2 to provide the desired compound.
■139- MS (DCI/NH3) m/z 402 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 7.96 (d, IH), 7.05 (t, IH), 6.68 (d, IH), 6.58 (d, IH), 6.45 (d, IH), 6J0 (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-dihvdro-10-methoxy-5-r3.3-dimethyl-6-cvclohexenvI)-2.2.4-trimethyl-lH-
111 henzopvranor3.4-flquinoline Example 2B and (6,6-dimethylcyclohexen-2-yl)dimethylphenylsUane 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)+;
*H NMR (300 MHz, DMSO-d6) major diastereomer: δ 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: δ 8.01 (d, IH), 7.07 (t, IH), 6.68 (d, IH), 6.63 (d, IH), 6.57 (d, IH), 6J6 (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 C28H33NO2: C, 80.93; H, 8.00; N, 3.37. Found: C, 80.92; H, 7.98; N,
3.25.
Example 147
2.5-dihvdro-10-methoxy-5-(2-bromo-3-propenyl)-2.2.4-trimethyl-lH-fnbenzopyranor3.4- 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.00 (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
-140- Example 2B (1.25g, 3.70 mmol) and l-[l'-t-butyldimethylsiloxy-l'- methoxyalkyUdene]-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 siUca gel chromatography eluting with from 20% to 30% methyl t-butylether in hexanes to give Examples 148-150.
Example 148 rel r5R.3'R 2.5-dihvdro-10-methoxy-5-fl-hvdroxymethyl-3-cvclohexenylV2.2.4- trimethyl-lH-riJbenzopyranor3.4-flquinoline
MS (DCI/NH3) m/e 418 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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), 6J7 (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 C27H3iNO3 »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-cyclohexenylV2.2.4- trimethyl- 1 H- r 1 jbenzopyranof 3.4- fjquinoline
MS (DCI/NH3) /e 418 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.40 (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), 2J2 (s, 3H), 1.70 (m, 2H), 1.60 (m, IH), 1.30
(s, 3H), 1.15 (m, 2H), 1.02 (s, 3H);
1 c NMR (75 MHz, DMSO-d6) δ 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.
•141- Example 150 2.5-dihvdro-10-methoxy-5-t3-hydroxymethyl-3-cyclohexenvn-2.2.4-trimethyl-lH- r 1 lbenzopyrano!3.4- fjquinoline MS (DCI NH3) m/e 418 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.06 (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-dβ) δ 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 C27H31NO3J/4H2O: C, 76.84; H, 7.52; N, 3.32. Found: C, 76.93; H, 7.73; N, 3.18.
Example 151
2.5-dihvdro-10-methoxy-5-r3Jndolvn-2.2.4-trimethyl-lH-rilbenzopyranor3.4-fJquinoline
Example 2B and indole were processed as in Example 2 to provide the desired compound.
MS (DCIZNH3) m e 423 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 10.89 (d, IH), 8.01 (d, IH), 7.83 (dd, 1HJ, 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 C28H26N2O2: C, 79.59; H, 6.20; N, 6.62. Found: C, 79.58; H, 6.28; N, 6.36.
Example 152 rel (5S.3 'S) 2.5-dihydro- 10-methoxy-5J 1 -methyl-3-cyclohexenyl V2.2.4-trimethyl- 1 H- ri!benzopyranor3.4- fjquinoline 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%) of the desired product as a colorless foam.
-142- MS (DCI/NH3) m/e 402 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.02 (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 r^/ C5R.3'S ) 2.5-dihvdro-10-methoxy-5-π-methyl-3-cvclohexenvn-2.2.4-trimethyl-lH- rilbenzopyranor3.4-flquinoline Example 149 was processed as in Example 152 to provide the desired compound.
MS (DCI NH3) m/e 402 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.04 (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 C27H3iNO2'l/4H2O: 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-dihvdro- 10-methoxy-5J 1 -methyl-3-cvclohexenvn-2.2.4-trimethyl- 1 H- rilhenzopvranor3.4-flquinoline 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. [αJD 20 -155.9° (c 0.85, CHCI3); MS (DCI/NH3) m/e 402 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.02 (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 C27H3iNO2*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-dihvdro- 10-methoxy-5-(l-hvdroxymethyl-3-cvclohRxenvn-2.2.4- trimethyl- lH-rilbenzopyranor3.4-flquinoline
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.
-143- [α]D 20 -233.9° (c 1.27, CHC13); MS (DCI/NH3) m/e 418 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.05 (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 (+. C5R. 3'S) 2.5-dihvdro-10-methoxy-5-n-hvdroxymethyl-3-cvclohexenyn-2.2.4- trimethvl-1 H-π lhenzopyranor3.4-flquinoUne Example 149 was subjected to HPLC on an 0 .,R) WHELK-O 1 column eluting with 6% EtOH in hexanes to provide the desired product [α]D 20 +234.6° (c 1.10, CHCI3); MS (DCI/NH3) m/e 418 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.05 (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 (-W5S. 3,R 2.5-dihvdro-10-methoxy-5-π-methyl-3-cyclohexenylV2.2.4-trimethyl-lH- πjbenzopyranor3.4-f|quinoline 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) δ 8.04 (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); [CXJD20 -224.1° (c 0.73, CHCI3);
Anal, calcd for C27H iNO2»l/2H O: C, 78.99; H, 7.86; N, 3.41. Found: C, 79.14; H, 8.07; N, 3.03.
-144- Ex.ample 158 f+ f5R. 3,S) 2.5-dihvdro-10-rnethoxy-5-fl-methyl-3-cyclohexenyn-2.2.4-trimethyl-lH-
111benzς>pyraηcT3,4- fjquinoline Example 156 was processed as in Example 152 to provide the desired compound.
MS (DCI NH3) m/e 402 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.04 (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 -chloromethyI-3-cyclohexenyl)-2.2.4-trimethyI- 1 H- flJbenzopyrano[3.4- fjquinoline 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 dUuted 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%) of the desired compound as a foam. MS (DCI NH3) m/e 436 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.03 (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- trimethyl- 1 H-f 1 Jbenzopyranor3.4- fjquinoline
Example 148 was processed according to Example 152 using sodium methoxide instead of Uthium triethylborohydride to give the desired compound. MS (DCI/NH3) m/e 432 (M+H)+;
*H NMR (400 MHz, DMSO-d6) - 8.02 (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);
-145- 1 C NMR (100 MHz, DMSO-d6) δ 156.2, 150.9, 145.0, 137.0, 133.7, 133.6, 130.4, 128J, 127.1, 127.1, 123.5, 117.9, 116.4, 113.5, 113.1, 110J, 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-dihvdro-10-methoxv-5-f l-methylthiomethyl-3-cvclohexenylV2.2.4- trimethyl- 1 H-R JbenTOpyranor3,4-flquinQline Example 148 was processed according to Example 152 using sodium thiomethoxide instead of Uthium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 448 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.02 (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) δ 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-dihvdro-10-methoxy-5-(l-acetoxymethyl-3-cvclohexenvIV2.2.4- trimethyl-lH-πibenzopyranor3.4- fjquinoline Example 149 (0J00 g, 0.239 mmol) was combined with acetic anhydride ( 27 μL,
0.288 mmol), DM.AP (2 mg, catalytic), (i-PrfcNEt (50 μL, 0.288 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 1 hour at room temperature, dUuted with ethyl acetate and washed with saturated aqueous bicarbonate, brine, dried
(MgSO4)and purified by siUca gel chromatography eluting with 20% ethyl acetate in hexane to give 89 mg (81%) of the desired compound as a white solid.
MS (DCI/NH3) m/e 460 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.05 (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.
-146- Example 163 rel T5R. 3'R-) 2.5-dihvdroJ0-methoxy-5-(J-acetoxymethyl-3-cvclohexenyl)-2.2.4- trimethyl- 1H-[1 Jbenzopyranor3.4- fjquinoline 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.02 (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), 6J8 (s, IH), 5.55 (d, J=10 Hz, IH), 5.39 (s, IH), 5J6 (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 C5R. 3'R) 2.5-dihvdro-10-methoxy-5-f l-methoxymethyl-3-cyclohexenylV2.2.4- trimethyl- 1 H- \ 1 Jbenzopyranor3.4- fjquinoline Example 149 was processed according to Example 152 using sodium methoxide instead of Uthium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) /e 432 (M+H)+;
ΪH NMR (300 MHz, DMSO-d6) δ 8.05 (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 (br m, 2H), 1.02 (s, 3H);
Anal, calcd for C28H33NO3J/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-dimethylammo)methyl-3-cyclohexenvO-
2.2.4-trimethyl-lH-[l]benzopyranof3.4- 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)+; lH NMR (300 MHz, DMSO-d6) - 8.01 (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=l l Hz, IH), 2.50 (d, j=l l
-147- 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 C29H36N2θ2-3/4H O: C, 76.03; H, 8.25; N, 6.11. Found: C, 75.90; H, 7.81; N, 5.90.
Example 166 rel T5R. 3'S) 2.5-dihvdro-10-methoxy-5Jl-methylthiomethyl-3-cvclohexenyl)-2.2.4- trimethvl- lH-fl 1henzopvranor3.4-flquinoline Example 149 was processed according to Example 152 using sodium thiomethoxide instead of Uthium triethylborohydride to give the desired compound as a white foam. MS (DCI/NH3) m/e 448 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.05 (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 C28H33NO2SJ/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-ri-rN-mo holino)methyl-3-cyclohexenyl)-2.2.4- trimethyl-lH-['lJbenzopyranor3.4- 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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.01 (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=ll 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.
-148- Example 168 rel C5R. 3'R) 2.5-dihvdro-10-methoxy-5-f l-rN-methyl-N-methylsulfonylamino)methyl-3- cyclohexenvl)-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinoline Example 170 (0.80 g, 0J86 mmol) was combined with methanesulfonyl chloride
(15 μL, 0J95 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 sUica gel plug and eluted with hexane then 40% ethyl acetate in hexane to give 88 mg (93%) of the desired compound as a white soUd. MS (DCI/NH3) m/e 509 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.02 (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-dihvdro-10-methoxy-5-π-rN.N dimethylamino)methyl-3-cyclohexenvl)- 2.2.4-trimethyl-lH-rilbenzopyranor3.4-f]quinoline
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)+; lH NMR (300 MHz, DMSO-d6) δ 8.05 (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 C29H36N2O2J/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-πibenzopyranof3.4- 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) /e 431 (M+H)+;
-149- *H NMR (300 MHz, DMSO-d6) δ 8.00 (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 C28H33N2O2J.25H2O: C, 74.22; H, 8.12; N, 6J8. Found: C, 74.05; H, 7.81; N, 6.00.
Example 171 2.5-dihvdro-10-methoxv-5-(2-methvl-3-propenvl)-2.2.4-trimethvl-lH-rilhenzopvranor3.4- fjquinoline A solution of Example 147 (51 mg, 0J2 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 foUowed by sUica gel chromatography (15% ethyl acetate/hexanes) provided the desired compound.
MS (DCI/NH3) m/z 362 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 7.94 (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 (m, 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-hutadien-2-yl)-2.2.4-trimethyl-lH-rnhen7opyranor3.4- 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-d6) δ 8.00 (d, IH), 7.05 ( , 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).
■150- Example 173 2.5-dihvdro-10-methoxv-5J2-carbomethoxv-3-propenyl)-2.2.4-trimethv1-lH- r 11benzppyranQr3.4-flquinc.line A mixture of Example 147 (64 mg, 0J5 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 sUica 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) δ 8.01 (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-dihvdro-10-methoxy-5- .2-dihvdroxy-3-propyl)-2.2.4-trimethyl-lH- fllbenzopyranor3.4- fjquinoline
_ A solution of Example 2 (50 mg, 0J44 mmol) in pyridine (3 mL) at 0 °C was treated with Osθ4 (370 uL, 0J44 mmol), stirred at ambient temperature for 48 hours, treated with saturated aqueous sodium bisulfite (3 mL), stirred for 4 hours and filtered through CeUte. 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)+; *H NMR (300 MHz, DMSO-d6); Major diastereomer: δ 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: δ 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.
-151- 99/41256
Example 175 2.5-dihvdro-10-methoxv-5J1.2-epoxv-3-propenyl)-2.2.4- trimethyl- 1H- πJbeπ?op.vrahQr3.4-flqginoIine A mixture of Example 174 (50 mg, 0J3 mmol), triphenylphosphine (38 mg, 0J4 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 siUca 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)+; *H NMR (300 MHz, DMSO-d6); Major diastereomer: δ 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: δ 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-( 1 -(N-phthalimido)-3-propyl)-2.2.4-trimethyl- 1 H- πibenzopyranor3.4- fjquinoline 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)+; lH NMR (300 MHz, DMSO-d6) δ 7.88 (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.
-152- Example 177 2.5-dihvdro- lO-methoxv-5-C 1 -amino-3-propyl)-2.2.4-trimethyl- 1 HJ 1 lhenzopyranor3.4- πgyinQling 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 siUca gel chromatography (9.5:0.5 methylene chloride methanol) to give the desired compound. MS (DCI/NH3) m/z 365 (M+H)+;
*H NMR (300 MHz, DMSO-de) δ 7.94 (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), 1J6 (s, 3H), 1.15 (s, 3H);
Anal, calcd for C23H28N2O2 • 0.30 H2O: C74.69; H, 7.79; N, 7.57. Found: C, 74.50; H, 7.78; N, 7.31.
Example 178
2.5-dihvdro-10-methoxv-5-π-rhvdrazinocarhonylamino)-3-propyl)-2.2.4-trimethyl-lH- rilhenzopvranor3.4-flquinoline Example 177 (65 mg, 0J78 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)+;
*H NMR (300 MHz, DMSO-d6) δ 7.94 (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- rilbenzopyranor3.4- 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
-153- with ethyl acetate, the combined organics washed with brine and dried (Na2SO4) to give the intermediate aldehyde as a yellow foam.
The resulting yeUow foam was dissolved in THF (8 ml), cooled to 0 °C, treated with methyl (triphenylphosphoranyUdene)acetate (0J30 g, 0.39 mmol), stirred overnight at room temperature and then at 45 °C for 1 hour. The reaction mixture was aUowed to cool, diluted with saturated aqueous NH4CI, extracted with ethyl acetate, and the combined organics washed with brine and dried ΛgS0 ). 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)+; lH NMR (300 MHz, DMSO-d6) δ 7.99 (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); 13C NMR (100 MHz, DMSO-d6) δ 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 C24H25NO «l/4H2O: C, 72.80; H, 6.49; N, 3.54. Found: C, 73.00; H, 6.56; N, 3.34.
Example 180 r^-2.5-dihvdro-10-methoxv-5- -propenvl)-2.2.4-trimethyl-lH-πihenzopyranor3.4- flquinpline 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)+;
*H NMR (300 MHz, DMSO-d6) 6 7.90 (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), 6J0 (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), 1.11 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 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 C23H 5θ2N'1.0H2O: C, 75.59; H, 7.45; N, 3.83. Found: C, 75.53; H, 7.20; N, 3.62.
•154- Example 181
(E) 2.5-dihvdro- 10-methoxy-5- -hvdroxy- 1 -propenyl)-2.2.4-trimethyl- 1 H- r 1 lhenzopvranor3.4-flquinoline A 20 ml ethereal suspension of LiAlH4 (0.200 g, 5J7 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 of the 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 sUica gel eluting with 25% then 33% ethyl acetate in hexanes to give 0J95 g (78%) of the desired compound as a colorless foam. H NMR (300 MHz, DMSO-d6) δ 7.95 (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), 6J8 (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), 2J2 (s, 3H), 1.19 (s, 3H), 1.13 (s, 3H); MS (FAB) m/e calcd for C23H25NO3: 363.183. Found 363.1839.
Example 182
(^ 2 -dihvdro-10-methoxy-5-f3-(N.N-dimethylaminocarbonyloxy)-l-propenyl)-2.2.4- trimethyl- 1 H-11 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 (44μl, 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 sUica gel chromatography eluting with 25% then 33% ethyl acetate in hexanes to give 0.033 g (79%) of the desired compound as a colorless foam. :
MS (DCI/NH3) m/e 509 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 7.94 (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);
■155- 13C NMR (100 MHz, DMSO-d6) δ 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) /e calcd for C26H30N2O4: 434.2206. Found 434.2209.
Example 183 ( E) 2.5-dihvdro- 10-methoxv-5-(3-methoxvmethoxy- 1 -propenyl)-2.2.4-trimethyl- 1 H- πibenzopvranor3.4-flquinoline Example 181 ( 0.026 g, 0.072 mmol) was dissolved in dichloroethane (5 ml), cooled to 0 °C, treated with (i-Pr)2NEt (62 μl, 0.358 mmol) foUowed by chloromethyl methyl ether (16 μl, 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 siUca gel chromatography eluting with 10 % ethyl acetate in hexanes to give 0.012 g (41%) of the desired compound as an amber oil. lH NMR (300 MHz, DMSO-d6) δ 7.94 (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), 6J9 (br d, J=3 Hz, IH), 6J4 (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- πjbenzopyrano[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, 0J43 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.
-156- MAJOR:
*H NMR (300 MHz, DMSO-d6) δ 7.97 (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)+;
*H NMR (300 MHz, DMSO-d6) δ 8.02 (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 methvl 2J2.5-dihvdro-10-methoxv-2.2.4-trimethy1-lH-rilhenzopyranor3.4-flquinolin-5- vl) acetvl hvdroxamate 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 RocheUe'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 siUca 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)+;
*H NMR (300 MHz, DMSO-d6) δ 7.79 (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-I nhenzopyranor3.4-fJquinolin-5-vI) 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
-157- stirred for 1 hour. The reaction mixture was poured into saturated potassium sodium taitrate, the layers separated, the aqueous phase extracted with CH2CI2, the combined organics washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and purified by siUca gel chromatography eluting with 30% ethyl acetate in hexane to give 0.265 g (93%) of the desired product as a colorless foam. MS (DCI/NH3) m/e 350 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 9.65 (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 C22H23 O3 »l/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-f2-cyclohexylidenylethyl)-2.2.4-trirnethyl-lH- r 1 ]henzopyranor3.4-flquinoline Cyclohexyltriphenylphosphonium bromide ( Grim, S. O.; Ambrus, 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 220 μl of 2.5 M n-butyl lithium, stirred for 10 minutes. Example 186 was added as a solution in THF and the reaction was aUowed to stirat room temperature 12 hours, refluxed for 15 minutes and aUowed to cool. Diethyl ether was added and the reaction was filtered and concentrated. The resulting residue was purified by sUica 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)+; lH NMR (300 MHz, DMSO-d6) δ 7.03 (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); 13C NMR (100 MHz, DMSO-d6) δ 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.
-158- Example 188 2.5-dihvdro-10-methoxv-5-r2-cvclθDentylidenylethyl)-2.2.4-trimethyl-lH- rilbenzopvranor3.4-flgninoline 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.
*H NMR (300 MHz, DMSO-d6) δ 7.94 (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), 6J0 (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); 13c NMR (75 MHz, DMSO-d6) δ 156J, 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)m e calcd for C27H32O2N: 401.2355. Found 401.2342.
Example 189 2.5-dihydro-10-methoxy-5-(2-cycloheptylidenylethyl)-2.2.4-trimethyl-lH- πibenzopvranor3.4-flquinoline 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-d6) δ 7.94 (d, 5=9 Hz, IH), 7.02 (t, J=8 Hz, IH), 6.67 (d, j=8 Hz, IH), 6.57 (d, J=9 Hz, IH), 6.49 (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); "C NMR (75 MHz, DMSO-d6) δ 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 C29H35O2N2 /4H2O: 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-fl Jhenzopyranor3.4- fjquinoline
Example 186 and isopropyltriphenylphosphonium iodide were processed according to Example 187 to provide the desired compound.
•159- H NMR (300 MHz, DMSO-d6) δ 7.94 (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), 6J1 (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) δ 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 (FAB) e calc'd for C25H29O2N: 375.2198. Found 375.2189.
Example 191 trans 2.5-dihvdro-10-methoxv-5-f2-hutenvl)-2.2.4-trimethvl-lH-rilhenznpyrannr3.4- 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) δ 7.96 (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), 6J0 (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-metlιoxy-5-(2-penten-l-yl)-2.2.4-trimethyl-lH-rnbenzopyranor3.4- fjquinoline Example 186 (0.050 g, 0J43 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)+; H NMR (300 MHz, DMSO-d6) δ 7.95 (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).
-160- Example 193 2.5-dihvdro- 1 Q-methoxv-5-C 1.1 -difluoro- 1 -propen-3-vI)-2.2.4-trimethyl- 1 H- rilbenzopvranor3.4- fjquinoline Example 186 (0.050 g, 0J43 mmol) and diphenylphosphoranyl difluromethane
(Edwards, M.L., et. al. 7et. let. 1990,57, 5571-74) were processed as in example 187 to give the desired compound. H NMR (300 MHz, DMSO-d6) δ 7.98 (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=4J0 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)/n/e calc'd 383.1697. Found 383.1689.
Example 194 (E) methyl 2-(2.5-dihydro-10-methoxy-2.2.4-trimethyl-lH-fllhenzopyranor3.4-f1quinolin-
5-yl) 2-butenoate Example 186 ( 0.040 g, 0.115 mmol) and methyl (triphenylphosphoranyUdene)acetate (115 mg, 0.344 mmol, Aldrich) were processed according to example 179 to give 0.037 g (80%) of the desired compound as a white foam. MS (DCI/NH3) /e 406 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 7.95 (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); 1 C NMR (75 MHz, DMSO-d6) δ 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 C25H27NO4J/2H2O: C, 72.44; H, 6.81; N, 3.38. Found: C, 72.55; H, 6.71 ; N, 3.22.
Example 195 fg) 2.5-dihydro-10-methoxy-5J4-hvdroxy-2-buten-l-yl)-2.2J-trimethyl-lH- ri1benzopyranor3.4- fjquinoline Example 194 ( 0.063 g, 0J55 mmol) in Et2θ was treated dropwise with a slurry containing L1AIH4 ( 0.044 g, 1J6 mmol) and AICI3 (0.041 g, 0.308 mmol) for 1 hour. The reaction mixture was diluted widi 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
■161- times with Et2θ. The combined organics were washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and purified by siUca gel chromatography eluting with 6% then 10% ethyl acetate in methylene chloride to give 0.031 g (53%) of the desired compound. MS (DCI/NH3) m/e 378 (M+H)+; H .NMR (300 MHz, DMSO-d6) δ 7.94 (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, IH), 2.15 (s, 3H), 1.15 (s, 6H); Anal, calcd for C24H27NO3 '1/4^0: C, 75.47; H, 7.26; N, 3.67. Found: C, 75.62; H, 7.40; N, 3.59.
Example 196 (E. 2.5-dihvdro-10-methoxy-5-r4-./N.N-dimethylaminocarbonyloxy)-2-huten-l-v1)-2.2.4- trimethyl- 1 H- r 1 Ibenzopyranof 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) δ 7.95 (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=3J0 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); "c NMR (100 MHz, DMSO-d6) δ 156.1, 150.9, 145.5, 133.6, 132.0, 129.0, 128.6, 127.4, 127.1, 127.0, 116.2, 1 15.9, 1 13 (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-f4-fN-methylaminocarbonyloxy)-2-buten-l-yl)-2.2.4- trimethyl-lH-riJbenzopyranor3.4-f1quinoline 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)+;
-162- IH NMR (300 MHz, DMSO-d6) δ 7.95 (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 rE. 2.5-dihvdro-10-methoxv-5-(2-hutenyl)-2.2.4-trimethyl-lH-'l 11benzopyranor3.4- 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 μL , 0.318 mmol) foUowed by methanesulfonyl chloride (20 μL, 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 μL, 0.635 mmol), stirred for 1 hr, allowed to warm to room temperature, treated with 5.0 ml of IN NaOH foUowed by 0J 1 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 siUca gel chromatography eluting with 15:1 then 7:1 hexanes:ethyl acetate provided 0.029 g (38%) desired compound. H NMR (360 MHz, DMSO-d6) δ 7.93 (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 l 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); 1 C NMR (100 MHz, DMSO-d6) δ 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-riJbenzopyranor3.4- fjquinoline Example 46 (0J00 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 RocheUe's salt. The organic layer was washed with IN HCl, saturated aqueous sodium bicarbonate, brine, and dried
■163- (MgSO4). The resulting crude product was purified by flash chromatography on sUica gel eluting with 10% ethyl acetate in methylene chloride to give (87%) of the desired compound as a white solid.
MS (DCI/NH3) e 352 (M+H)+; JH NMR (300 MHz, DMSO-d6) δ 7.95 (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=2J0 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), 1J6 (s, 3H).
Example 200
2.5-dihvdro-10-methoxy-5-(2-("N-benzylcarbonyloxy)ethvI)-2.2.4-trimethvl-lH-
\ 1 jbenzopyrano 3.4-flquinoline Example 199 ( 0.200 g, 0.57 mmol) was combined with N,N'-disuccinimidyl carbonate ( 0.217 g, 0.85 mmol), (i-Pr^NEt (0.30 ml, Ulmmol), 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 sUica gel chromatography eluting with 6% ethyl acetate in dichloromethane to give 0.252 g (90%) of the succinate ester as a white foam.
The succinate ester (0.020 g, 0.041mmol), benzyl amine (6.6 μl, O.Oόlmmol), 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 sUica gel chromatography eluting with 20% ethyl acetate in hexane to give 19 mg (97%) of the desired compound as a white solid. MS (DCI/NH3) m/e 485 (M+H)+;
IH NMR (400 MHz, DMSO-d6) δ 7.95 (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); 3C NMR (100 MHz, DMSO-d6) δ 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 C3θH32N2θ5-H2O: C, 71.69; H, 6.82; N, 5.57. Found: C, 71.45; H,
6.83; N, 5.56.
-164- Example 201 2.5-dihvdro-10-methoxy-5-r2-rN-morpholinocarhonyloxy)ethyl)-2.2.4- trimethyl- 1H- rnhenzopyranor3.4-flquinoline 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) δ 7.95 (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), 6J0 (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);
1 C NMR (100 MHz, DMSO-d6) δ 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 C27H32N2O5J/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-rN-(2-methoxyethyl)aminocarbonyloxy)ethyl)-2.2.4- trimethyl- 1 H- f 1 Ibenzopyranof 3.4- fjquinoline
The intenτiediate 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-d6) δ 7.95 (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); 3C NMR (125 MHz, DMSO-d6) δ 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-lH- fllbenzopyranof 3.4- fjquinoline 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+Hf;
J65- IH NMR (500 MHz, DMSO-d6) δ 7.95 (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);
1 C NMR (125 MHz, DMSO-d6) δ 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-rN.N-dimethylaminocarbonyloxy)ethyl)-2.2.4-trimethyl-lH- rnbenzopvranor3.4-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)+;
IH NMR (300 MHz, DMSO-d6) δ 7.95 (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-f2-methoxymethoxyethyl)-2.2.4-trimethyl-lH- πjbenzopyrano["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 sUica gel chromatography eluting with 2% then 5% ethyl acetate in methylene chloride to give 45 mg (40%) of the desired product. MS (DCI/NH3) m/e 396 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 7.95 (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);
-166- Anal, calcd for C24H29NO4J/4H2O: C, 72.07; H, 7.43; N, 3.50. Found: C, 71.90; H, 7.33; N, 3.24.
Example 206 2.5-dihvdro-10-methoxv-5-r2.2-dimethylethoxycarhonvlamino)methvl)-2.2.4-trimethyl-
1 H-! 1 lbenzopyranor3.4-flquinoline
Example 206A 2.5-dihvdro-10-methoxy-5-(aminomethyl)-2.2.4-trimethyl-lH-rilbenzopyranor3.4- flquinoline A 10 ml ethereal suspension of LiAlt-4 (0.050 g, 1.31 mmol) was treated dropwise at room temperature with a 5.0 ml ethereal solution of AICI3 (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 H2O carefully added foUowed by dropwise addition of 15 % NaOH untU a white paste formed. The ether solution was decanted, the paste washed several times with ether and combined organics washed with brine and dried (Na2SO4). The residue was purified by siUca gel column chromatography eluting with CH2Cl2:CH3OH (8.J) to give 0.031 g (69 %) aminomethyl analog that was carried directly to the next step.
Example 206 2.5-dihydro-10-methoxy-5-r2.2-dimethylethoxycarhonylamino)methyl)-2.2.4-trimethyl- lH-rilhenzopyranor3.4- fjquinoline The aminomethyl analog above (0.065 g, 0J9 mmol) was dissolved in dichloromethane ( 6.0 ml ),cooled to 0 °C, treated with B0C2O (0.93 g, 0.42 mmol ). Allowed to warm to room temperature overnight. 10 ml H2O was added and the phases separated. The organic layer was washed with brine and dried (Na2SO4). The residue was purified by siUca gel column chromatography eluting with CH2θ2:CH3θH (8:1) to give 0.080 g (95 %) desired compound : m.p. 130-135 °C;
IH NMR (400 MHz, DMSO-d6) δ 7.98 (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), 6J2 (s, IH), 5.80 (dd, J=10, 10 Hz, IH), 5.42 (s, IH), 3.85 (s, 3H), 3J4 (m, IH), 2.86 (m, IH), 2J9 (s, 3H), 1.47 (s, 3H), 1.21 (s, 3H), 1.12 (s, 3H), .84 (m, IH);
•167- 13C NMR (100 MHz, DMSO-d6) δ 156.1, 155.5, 150.9, 145.4, 133.4, 131.5, 129.5, 128.6, 127.8, 126.9, 117.1, 1 16.4, 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-dihvdro-10-methoxv-5-rethoxycarhonvlamino)methyl)-2.2.4-trimethyl-lH-
111 henzopvranor3.4-flquinoline Example 206A (0.047 g, 0J4mmole) in THF (10 ml) was treated with triethylamine (21.0 μL, 0J4 mmol). Followed by dropwise addition of ethyl chloroformate ( 14JμL, 0J4 mmol.). After 30 minutes the reaction was poured into H2O, the aqueous layer extracted with ethyl acetate and the combined organic layers washed IX with H2O, IX with brine, and dried (Na2SO4). The residue was purified by silica gel column chromatography eluting with 3:2 hexanes:ethyl acetate to give 0.047 g (80%) of the desired compound as a soUd.
IH NMR (300 MHz, DMSO-d6) δ 7.98 (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) δ 156.1, 150.8, 145.5, 133.4, 129.4, 127.7, 127.0, 117.0, 116.4, 113.5, 1 12.7, 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- 1 H-f 1 j henzopyranoβ .4- fjquinoline To Example 61 was added 2.0 ml of 5 % aqueous HCl, 5.0 ml H2O, and enough ethanol 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 H2O, brine, and dried ( Na2SO4 ). 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 %) of the desired compound as a soUd. MS (DCI/NH3) m/e 380 (M+H)+;
- 168- H NMR (300 MHz, DMSO-d6) δ 7.90 (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) δ 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 C23H25 O4 «l/4H O: C, 71.95; H, 6.68; N, 3.65. Found: C, 72.21; H, 6.41; N, 3.85.
Example 209
2.5-dihvdro-10-methoxv-5-('cvclopentvl)-2.2.4- trimethvl- 1H-I1 lhenzopvranor3.4- 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)+; H NMR (300 MHz, DMSO-d6) δ 8.01 (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); 3C NMR (100 MHz, DMSO-d6) δ 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 C25H29θ2N»l/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-( 1 -methylpropa- 1 ,2-dienyl)-2.2.4-trimethyl- 1 H- πjbenzopyranor3.4- fjquinoline 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) δ 7.84 (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), 2.1 1 (s, 3H), 1.70 (s, 3H), 1.21 (s, 3H), 1.10 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 156.1, 151.2, 150.5, 145.1, 132.6, 130.5, 127.9,
-169- 127.1, 127.0, 126.7, 126.5, 117 (5), 117.1, 114.7, 113.3, 112.9, 110J, 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 359J 893.
Example 211
2.5-dihvdro-10-methoxy-5J3.4.5-trifluorophenyl)-2.2.4-trimethvl-1H- rilbenzopvranor3.4-flquinoline 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) δ 8.04 (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-dihvdro-10-methoxv-5-rcvclohexyl)-2.2.4-trimethyl-lH-nihenzopyranoir3.4- 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) δ 8.03 (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 C26H3iNO2»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-pyridyI)-2.2.4-trimethyl-lH-rilbenzopyranor3.4-flquinoline
Example 213A 2.5-dihvdro-10-methoxy-5-r2-pyridyl)-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinoline To a solution of Example 2 A (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 TBSCl (1.46 g, 9.66 mmol) in THF
-170- (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-dihvdro- 10-methoxv-5-(2-pvridvl)-2.2.4-trimethyl- 1 H-f 1 lbenzopyranor3.4-fJquinoUne A solution of the 2-lithiopyridine (nominally 1 M in THF) was formed by addition of π-BuLi (680 μL 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 of the 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). FUtration 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 μL 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). FUtration 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 lJ'-(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)+;
1H NMR (300 MHz, DMSO) δ 8.45 (br d, 7=6.6 Hz, 1 H), 7.98 (d, 7=8.0 Hz, 1 H), 7.61 (td, 7=6.5, 1.8 Hz, 1 H), 7J9-7J3 (m, 2 H), 6.91 (t, 7=6.6 Hz, 1 H), 6.72 (s, 1 H), 6.68 (d, 7=7.9 Hz, 1 H), 6.57 (br d, 7=6.7 Hz, 1 H), 6.44 (dd, 7=6.5, 1.0 Hz, 1 H), 6J7 (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.
■171- Example 214 2.5-dihvdro-10-methoxv-5-r3-pvridvl)-2.2.4-trimethvl-lH-rnhenzopyranor3.4-flquinoUne The desired compound was prepared as described in Example 213 in 49% yield. MS (DCI/NH3) m/z 385 (M+H)+;
1H NMR (300 MHz, DMSO) δ 8.38 (d, 7=2.4 Hz, 1 H), 8.35 (dd, 7=5.6, 2.0 Hz, 1 H), 8.02 (d, 7=8.0 Hz, 1 H), 7.49 (br d, 7=6.9 Hz, 1 H), 7.25 (dd, 7=6.9, 5.5 Hz, 1 H), 6.92 (t, 7=6.9 Hz, 1 H), 6.86 (s, 1 H), 6.72 (d, 7=8.1 Hz, 1 H), 6.58 (d, 7=6.7 Hz, 1 H), 6.45 (d, 7=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, DMSO) δ 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-dihvdro-10-methoxy-5-r4-pyridyl)-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinoUne The desired compound was prepared as described in Example 213 in 20% yield.
MS (DCI/NH3) m/z 385 (M+H)+;
1H NMR (300 MHz, DMSO) δ 8.43 (br d, 7=4.3 Hz, 2 H), 8.04 (d, 7=8.0 Hz, 1 H), 7.15
(d, 7=4.2 Hz, 2 H), 6.96 (t, 7=6.7 Hz, 1 H), 6.81 (s, 1 H), 6.75 (d, 7=7.9 Hz, 1 H), 6.59
(d, 7=6.8 Hz, 1 H), 6.53 (d, 7=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, DMSO) δ 156.1, 151.4, 149.4 (2), 148.2, 145.6, 133.4, 133.3,
128.3, 127.3 (2), 127.0, 122.9, 1 17.9, 1 17.0, 113.9, 1 10.2, 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-dihvdro- r 1 lbenzopyranof 3.4- fjquinoline MS (DCI/NH3) m/z 368 (M+H)+;
■ 172- 1H NMR (300 MHz, DMSO) δ 9.34 (s, 1 H), 7.87 (d, 7=8 Hz, 1 H), 6.72 (d, 7=8 Hz, 1 H), 6.66 (d, 7=8 Hz, 1 H), 6.58 (d, 7=8 Hz, 1 H), 6.21 (br s, 1 H), 5.81-5.71 (m, 1 H), 5.62 (dd, 7=10, 3 Hz, 1 H), 5.41 (br s, 1 H), 4.98 (dd, 7=10, 2 Hz, 1 H), 4.93 (dd, 7=17, 2 Hz, 1 H), 2.42-2.34 (m, 1 H), 2.26-2.20 (m, 1 H), 2.11 (s, 3 H), 1J6 (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-hvdroxy-5-phenyl-2.2.4-trimethyl-lH-2.5-dihydro- mbenzopyranor3.4-fJquinoline
MS (DCI NH3) m/z 404 (M+H)+;
1H NMR (300 MHz, DMSO) δ 9.46 (s, 1 H), 7.96 (d, 7=8 Hz, 1 H), 7.26-7.12 (m, 3 H), 7.14-7.07 (m, 1 H), 6.87 (dd, 7=8, 2 Hz, 1 H), 6.72 (d, 7=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-hvdroxv-5-f3-trifluoromethvIphenyl)-2.2.4-trimethyl-1H-2.5-dihvdro- πjbenzopyranor3.4- fjquinoline
MS (DCI/NH3) m/z 472 (M+H)+;
IH NMR δ 9.45 (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-1H-2.5-dihydro- r 1 Jbenzopyrano[3.4- fjquinoline MS (DCI/NH3) m/z 432 (M+H)+;
1H NMR δ 9.52 (s, 1 H), 7.95 (d, 1 H, J=8.5Hz), 6.82 (m, 2H), 6.71 (m, 2H), 6.61 (s, 2H), 6.36 (m, 1 H), 6.42 (m, 1 H), 5.40 (m, 1 H), 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 J 650.
■173- Example 220 rg/-(5S. 3'R)-9-hvdroxv-10-methoxv-5-π-hvdroxymethyl-3-cvclohexenyll-
2.2.4-trimethyl-2,5-dihydro-lH-πibenzop.yranor3,4-flquinoline MS (DCI NH3) m/z 438 (M+H)+;
1H NMR (300 MHz, DMSO) δ 9.56 (s, 1 H), 8.01 (d, 7=8 Hz, 1 H), 6.77 (app s, 2 H), 6.67 (d, 7=8 Hz, 1 H), 6.39 (br s, 1 H), 5.48 (d, 7=10 Hz, 1 H), 5.42 (br s, 1 H), 5J0 (br s, 1 H), 4.42 (t, 7=6 Hz, 1 H), 3.65 (br d, 7=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), 1J0 (s, 3 H);
HRMS (FAB) calcd m/z for C26H28CINO3: 437.1758. Found: 437.1756.
The C-5 lactol-9-tert-butyldimethylsUyl ether of Core 2 and 3-cyclopentenyl trimethylsUane were processed as above to give a 2: 1 diastereomeric product mixmre 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 r-) 2.5(S)-dihvdro-9-hvdroxy-10-chloro-2.2.4-trimethyl-5-(3S-cyclopentenyl)-lH- r 11benzopvranor3.4-flquinoline
[α]23 D=-220° (c 0.012, CHCI3);
MS (DCI/NH3) m/z 394 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 9.55 (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) δ 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 f-) 2.5fS)-dihydro-9-hydroxy-10-chloro-2.2.4-trimethyl-5-r3R-cvclopentenyl)-lH- r 11 benzopyranor3.4-flquinoline [α]23 D=-232° (c 0.010, CHCI3); MS (DCI/NH3) m/z 394 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 9.50 (bs, IH), 8.02 (d, IH), 6.75 (d, IH), 6.72 (d,
-174- 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-dό) δ 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-chIoro-9-hvdroxv-5-(3.5-dichlorophenyl)-2.2.4-trimethyl-lH-2.5-dihvdro- mbenzopyranor3.4-flquinoline
MS (DCI NH3) m z 472 (M+H)+;
IH NMR δ 9.40 (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 f+)-(5R. 3'S) 2.5-dihvdro-9-hydroxy- 10-chloro-2.2.4-trimethyl-5-f 3-cyclopentenv 1 )- 1 H-
\ 1 Jbenzopyrano["3.4- fjquinoline [α]23 D=+ 256° (c 0.046, CHCI3). MS (DCI/NH3) m z 394 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 9.50 (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); C NMR (400 MHz, DMSO-d6) δ 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-dihvdro-9-hydroxy-10-chloro-2.2.4-trimethyl-5-(3-cyc1opentenyl)-lH- πibenzopyranor3.4- fjquinoline
[αJ23 D=+244° (c 0.165, CHCI3);
MS (DCI/NH3) m/z 394 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 9.55 (s, IH), 8.00 (d, IH), 6.75 (d, IH), 6.72 (d,
■175- 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-d6) δ 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-hvdroxv-5-(3.4-difluorophenyl)-2.2.4-trimethvl-lH-2.5-dihvdro- rilhenzopvranoB. flquinoline
MS (DCI/NH3) m/z 440 (M+H)+;
IH NMR δ 9.41 (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-methvlenedioxv-5-phenvl-2.2.4-trimethyl-lH-2.5-dihvdro-rnbenzopvranor3.4- fjquinoline
MS (DCI NH3) m/z 298 (M+H)+;
IH NMR (200 MHz, DMSO-d6) 7.72 (d, J=8J Hz, IH), 7.20 (m, 5H), 6.82 (s, IH),
6.75 (d, J=8.8 Hz, IH), 6.50 (d, J=8J 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- 1 H- πjbenzopyranor3.4- fjquinoline IH NMR δ 7.93 (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=17JHz), 3.65 (s, 3H), 2.44 (m, IH), 2.28 (m, IH), 2.18 (s, 3H), 1J9 (s, 3H), 1.17 (s, 3H); HRMS (ESI) m/z calc'd for C23H25CINO2: 381.1495. Found: 381.1490.
-176- Example 229 9-chloro- 10-methoxv-5-phenyl-2.2.4-trimethyl-2.5-dihvdro- 1 H- rnbenzopvranor3.4-flquinoline H NMR δ 7.98 (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-r3-propenvl)-9-chloro-10-difluoromethoxv-2.2.4-trimethvl-2.5-dihydro-lH-
|JJbenzopyranor3.4-flquinoline IH NMR δ 7.58 (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=17JHz), 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- f 1 j benzopyranof3.4- fjquinoline
IH NMR δ 7.77 (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- riJbenzopyranor3.4-flquinoline IH NMR δ 7.95 (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.
-177- 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-propenvl)-8-fluoro-10-methoxy-2.2.4-trimethvl-2.5-dihvdro-lH- rilbenzopvranor3.4-flquinoline iH NMR δ 7.95 (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), 1J3 (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 lQ-methoχy-9-fl»oro-5-(3-propenyI)-2.2,4-trimethyl-lH-2,5-dihydrp- (" 1 J benzopyranor3.4- fjquinoline MS (DCI NH3) m/z 366 (M+H)+;
1H NMR (300 MHz, DMSO) δ 7.87 (d, 7=8.5 Hz, 1 H), 7.00 (dd, 7=8.8, 2.2 Hz, 1 H), 6.64 (d, 7=8.1 Hz, 1 H), 6.63 (d, 7=8.8 Hz, 1 H), 6.31 (d, 7=1.1 Hz, 1 H), 5.90-5.80 (m,i 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, 7=1.1 Hz, 1 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- riJb nzpp ranor .4- fjquinoline lH NMR (300 MHz, DMSO) δ 8.69 (s, 1 H), 7.92 (d, 7=8.5, 1 H), 6.62 (d, 7=8.5 Hz, 1
H), 6.62 (d, 7=8.5 Hz, 1 H), 6.48 (d, 7=8.5, 1 H), 6.16 (d, 7=1.7 Hz, 1 H), 5.81 (ddt,
7=17.3, 10.3, 6.6 Hz, 1 H), 5.67 (dd, 7=9.8, 3.3 Hz), 5.44 (s, 1 H), 5.02 (dd, 7=10.3,
1.8 Hz, 1 H), 4.98 (dd, 7=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);
-178- 13C NMR (75 MHz, DMSO) δ 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-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethyl-5-(3-cyclohexenvl)-lH- rilbenzopvranor3.4-flguinoline
MS (DCI NH3) m/z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.70 (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) δ 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.
Example 237 r+/-) 2.5-dihvdro-9-hvdroxv-10-methoxy-2.2.4-trimethyl-5-fl-methylcyclohexen-3-vl)- lH-πjbenzopyranor3.4- fjquinoline
MS (DCI/NH3) m/z 718 (M+H)+; NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.00 (d, 7 = 8.5 Hz, 1 H), 6.65 (d, 7 = 8.5 Hz, 1 H), 6.62 (d, 7 = 8.5 Hz, 1 H), 6.55 (d, 7 = 8.5 Hz, 1 H), 6.24 (d, 7 = 1.5 Hz, 1
H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, 7 = 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) δ 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 238 (-) (5S. 3'S)-9-hvdroxy-5-π-methyl-3-cvclohexenyn- 10-methoxy-2.2.4-trimethyl-2.5- dihydro-1 H-f lJbenzopyrano!3.4- fjquinoline
[α]D=-158.8°;
-179- MS (DCI/NH3) /z 7 IS (M+H)+; l NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.00 (d, 7=8.5 Hz, 1 H), 6.65 (d, 7=8.5 Hz, 1 H), 6.62 (d, 7=8.5 Hz, 1 H), 6.55 (d, 7=8.5 Hz, 1 H), 6.24 (d, 7=1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, 7=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) δ 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0, 126J, 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 f+) C5R.3,R)-9-hvdroxy-5-ll-methyl-3-cvclohexenyl1- 10-methoxy-2.2.4-trimethyl-2.5- dihvdro- 1 HJ llbenzopyranof 3.4-flquinoline
[α]D=+157.9°
MS (DCI/NH3) m/z 718 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.00 (d, 7=8.5 Hz, 1 H), 6.65 (d, 7=8.5
Hz, 1 H), 6.62 (d, 7=8.5 Hz, 1 H), 6.55 (d, 7=8.5 Hz, 1 H), 6.24 (d, 7=1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, 7=9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30^2.20 (m, 1
H), 2J 1 (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); i3C NMR (75 MHz, DMSO-d6) δ 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-hvdroxy-5-r 1 -methyl-3-cyclohexenyn- 10-methoxy-2.2.4-trimethyl-2.5- [α]D=+78.0°
MS (DCI NH3) /z 718 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1 H), 7.99 (d, 7=8.8 Hz, 1 H), 6.66 (d, 7=8.8 Hz, 1 H), 6.62 (d, 7=8.5 Hz, 1 H), 6.52 (d, 7=8.5 Hz, 1 H), 6.24 (d, 7=1.5 Hz, 1 H), 5.41 (br s, 1 H), 5.41 (d, 7=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);
-180- 13C NMR (75 MHz, DMSO-d6) δ 145.3, 145.0, 144.0, 143.2, 135.5, 133.3, 131.3, 128.4, 126.2, 120.5, 118J, 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 f-) (5S.3'R)-9-hydroxy-5-π-methyl-3-cyclPhe enyn- lQ-methoxy-2,2,4-trimethyl-2.5- dihvdro- 1 H-M Ihenzopyranor3.4-fJquinoline [α]D=-79.4° MS (DCI NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1 H), 7.99 (d, 7=8.8 Hz, 1 H), 6.66 (d, 7=8.8
Hz, 1 H), 6.62 (d, 7=8.5 Hz, 1 H), 6.52 (d, 7=8.5 Hz, 1 H), 6.24 (d, 7=1.5 Hz, 1 H),
5.41 (br s, 1 H), 5.41 (d, 7=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); ^C NMR (75 MHz, DMSO-d6) δ 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 rg/-f5S.3'R)-9-hydroxy-5-ri-hydroxymethyl-3-cyclohexenylJ-10-methoxy-2.2.4-trimethyl- 2.5-dihydro-lH-flJhenzopyrano[3.4- fjquinoline
MS (DCI/NH3) /z 434 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1 H), 7.98 (d, 7=8.8 Hz, 1 H), 6.65 (d, 7=8.8
Hz, 1 H), 6.62 (d, 7=8.8 Hz, 1 H), 6.52 (d, 7=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, 7=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); «c NMR (75 MHz, DMSO-d6) δ 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.
-181- Example 243
(+/-) r5S.3,R) 2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethyl-5-π-methylcyclohexen-
3-v 1 )- 1 H-r 1 lhenzopvranor3.4-fJquinoline MS (DCI/NH3) m/z 718 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1 H), 8.00 (d, 7 = 8.5 Hz, 1 H), 6.65 (d, 7 = 8.5 Hz, 1 H), 6.62 (d, 7 = 8.5 Hz, 1 H), 6.55 (d, 7 = 8.5 Hz, 1 H), 6.24 (d, 7 = 1.5 Hz, 1 H), 5.51 (br s, 1 H), 5.44 (br s, 1 H), 5.30 (d, 7 = 9.5 Hz, 1 H), 3.65 (s, 3 H), 2.30 - 2.20 (m, 1 H), 2J1 (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) δ 145.3, 144.9, 144.0, 143.6, 134.7, 133.5, 130.9, 128.0, 126J, 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 rg/-(5S.3'R)-9-hvdroxv-5-π-methoxvmethvl-3-cvclohexenyll- 10-methoxv-2.2.4- trimethyl-2.5-dihydro- lH-fl JbenzopyranoP .4-fJquinoline
MS (DCI NH3) m/z 448 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1 H), 8.00 (d, 7=8.5 Hz, 1 H), 6.67 (d, 7=8.5 Hz, 1 H), 6.62 (d, 7=8.5 Hz, 1 H), 6.54 (d, 7=8.5 Hz, 1 H), 6.27 (d, 7=1.5 Hz, 1 H),
5.46 id, 7=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-πihenzopyranor3.4- fjquinoline The C-5 lactol-9-TBS ether of core 7 and /z-propylmagnesium chloride were processed as in example 251 to provide the desired compound: iH NMR (300 MHz, DMSO-d6) δ 8.66 (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); "c NMR (75 MHz, DMSO-d6) δ 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,
-182- 28.8, 27.7, 23.8, 21.7, 13.9; MS (DCI/NH3) m/e (M+H)+ 380; Anal, calcd for C24H29NO3«l/4H2O: 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 f5S.3'S) 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-r3-cvcloheptenyl)-lH- rUb pzQ yrapQr ,4-fiqqinQiin
MS (DCI/NH3) m z 418 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.70 (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), 2J4 (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) δ 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.
[α]23 D=-134° (c 1.15, CHCI3).
Example 247 (-) (5S.3,R) 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-(3-cvcloheptenyl)-lH- r 1 lbenzopyranor3.4-flquinoline
MS (DCI/NH3) m/z 418 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.66 (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);
1 C NMR (400 MHz, DMSO-d6) δ 145.2, 144.8, 143.8, 143.2, 133.9, 133.6, 131.1, 130.8, 128.0, 126.1, 118.6, 1 18.0, 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. [αJ23 D=-122° (c 0.74, CHCI3).
•183- Example 248
2.5-dihvdro-9-hvdroxv- 10-methoxv -2.2.4-trimeth vl-5-phenvl- lH-fl Ihenzopyranof 3.4- flquinoline IH NMR (300 MHz, DMSO), δ 8.53 (s, 1 H), 7.93 (d, J=8.7 Hz, 1 H), 7.20-7J4
(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), δ 145.7, 144.8, 143.8, 143.6, 139.3, 133J, 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 C26H25NO2 is 399.1834. Found 399.1839.
Example 249 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-f3.5-difluorophenyl)-lH- 11 Jbenzopyranor3.4-flquinoline
IH NMR (300 MHz, DMSO), δ 8.68 (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=8J, 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), δ 163.6 (d, J=12.81 Hz), 160.4 (d, J=12.81 Hz), 145.9, 145.2, 144.5, 144.4 (vJ=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 2f5-dihydro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-(3.4.5-trifluorophenyl)-lH- fπhenzopyranor3.4-flquinoline IH NMR (300 MHz, DMSO), δ 8.76 (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=1J Hz, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H); 13C NMR (300 MHz, DMSO), δ 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=9J6 Hz), 113.0, 112.7, 112.4, 73.5, 59J, 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.
-184- Example 251 5-butvl-2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethvl-lH-rilhenzopyranof .4- flqwnQline The C-5 lactol-9-tert-butyldimethylsUyl ether of core 7 (0.057 g, 0J22 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 /i-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 yeUow oil.
The resulting yeUow oU was dissolved in THF (5 ml), cooled to 0°C, and treated with tetrabutylammonium fluoride solution (0J4 ml of a IM / THF solution, 0J4 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%) of the desired compound. IH NMR (300 MHz, DMSO-d6) δ 8.70 (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), 6J6 (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), 1J6 (s, 3H), 0.83 (m, 3H); "C NMR (75 MHz, DMSO-d6) δ 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 trimethylsUane 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-r3-cvc1opentenyl)-lH- rπbenzopyrano|"3.4- fjquinoline
MS (DCI/NH3) m/z 390 (M+H)+; H NMR (300 MHz, DMSO-d6) δ 8.68 (s, IH), 8.01 (d, IH), 6.65 (d, IH), 6.62 (d,
-185- IH), 6.51 (d, IH), 6.22 (s, IH), 5.72 (dd, IH), 5.41 (d, IH), 5.40 (s, IH), 5J7 (dd, IH), 3.63 (s, 3H), 2.90-2.80 (m, IH), 2.41-2.32 (m, IH), 2.23-2J0 (m, IH), 2.06 (s, 3H), 1.89-1.71 (m, 2H), 1.30 (s, 3H), 1.08 (s, 3H);
1 C NMR (400 MHz, DMSO-d6) δ 145.5, 145.0, 143.9, 143.4, 133.5, 132.3, 132.2, 130.2, 128J, 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. [α]23 D=- 120° (c 0.800, CHCI3).
Example 253 f-) r5S.3,R) 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-(3-cyclopentenyl)-lH- πiben?opyranor3,4-flquinQline
MS (DCI/NH3) m z 390 (M+H)+; iH NMR (300 MHz, DMSO-de) δ 8.67 (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), 2J0 (s, 3H), 1.55-1.41 (m, 2H),
1.31 (s, 3H), 1.04 (s, 3H);
13C NMR (400 MHz, DMSO-d6) δ 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.
[α]23 D=-132° (c 0.76, CHCI3).
Example 254 2.5-dihydro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5J3.4-difluorophenyl)-lH-
[lJbenzopyrano 3.4- fjquinoline IH NMR (300 MHz, DMSO-d6), δ 8.65 (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) δ 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.
■186- Example 255 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-ιf4-fluorophenyl)-lH- riJbenzopyranof3.4- fjquinoline MS (DCI/NH3) 418 (M+H)+;
IH NMR (300 MHz, DMSO-d6), δ 8.58 (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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-(3-trifluoromethylphenyl)-lH- πjbenzopyranor3.4- fjquinoline MS APCI m/z 468 (M+H)+;
IH NMR (300 MHz, DMSO), δ 8.62 (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), δ 145.9, 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)-lH- rilhenzopyranor3.4-flquinoline
MS APCI m/z 536 (M+H)+;
IH NMR (300 MHz, DMSO), δ 8.69 (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), δ 146.1, 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.
■187- Example 258 2. -dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethyl-5-r3-trifluoromethyl-4-chlorophenyl)- lH-rilbenzopyranor3.4-flquinoline MS (APCI) m/z 502 (M+H)+; iH NMR (300 MHz, DMSO), δ 8.70 (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), δ 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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5J2-methylpropyl)-lH- r 1 J benzopyrano[3.4- fjquinoline 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) δ 8.69 (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), 6J6 (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); "c NMR (75 MHz, DMSO- d6) δ 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- rnbenzopyrano("3.4-flquinoline 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) δ 8.72 (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).
•188- Example 261 2.5-dihvdro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-f3-butenyl)-lH- rilbenzopvranor3.4-flguinoline 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-dihvdro-9-hvdroxv-10-methoxv-5-rphenylmethyl)-2.2.4-trimethyl-lH- r 1 Jbenzopyranor3,4-fJquiPθlipe
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) δ 8.77 (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) δ 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) e (M+H)+ 414; Anal, calcd for C 7H27NO3«l/4H2O: C, 77.58; H, 6.63; N, 3.35. Found: C, 77.70; H, 7.07; N, 3.19.
Example 263 r-) (5S.3,R) 2.5-dihydro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-π -ethyl-3- cyclohexenylJ-lH-[lJbenzopyranor3.4-fJquinoline
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. H NMR (300 MHz, DMSO-d6) δ 8.67 (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); ^C NMR (75 MHz, DMSO-d6) δ
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, 1 14.3, 1 13.3, 1 12.0, 76.2, 59.3, 49.4, 37.7, 30.2, 29.6, 27.7, 27.2, 24.9, 23.7, 21.6, 12.3.
■ 189- Example 264 r-) rS) 5-cvclopentyl-2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-lH- rilbenzopyranor3.4- fjquinoline The C-5 lactol-9-TBS ether of core 7 and cyclopentylmagnesium chloride were processed as in Example 25 . The resulting racemic product 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 f .irst eluent:
IH NMR (300 MHz, DMSO-d6) δ 8.66 (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), 2J5 (s, 3H), 2J2-1.97 (m, IH), 1.60-1.43 (m, 4H), 1.42-1.22 (m, 2H), 1J9-1.07 (m, 2H), 1.31 (s, 3H), 1.02 (s, 3H); MS (DCI/NΗ3) m/e (M+H)+ 392.
Example 265 (+) (R) 5-cvclopentvI-2.5-dihydro-9-h vdroxy- 10-methoxy-2.2.4-trimethvI- 1 H- πjbenzopyranor3.4-flquinoline The racemic product from Example 264 was resolved into its constituent enantiomers by HPLC on a (R, R)-WHELK-Oj column eluting with 2% EtOH in hexanes to give the desired compound as the second eluent: iH NMR (300 MHz, DMSO-d6) δ 8.66 (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), 2J5 (s, 3H), 2J2-1.97 (m, IH), 1.60-1.43 (m, 4H), 1.42-1.22 (m,
2H), 1J9-1.07 (m, 2H), 1.31 (s, 3H), 1.02 (s, 3H); MS (DCI/NH3) e (M+H)+ 392.
Example 266
2.5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2.2.4-trimethyl-lH- 11 Ibenzopyranof 3.4- fjquinoline The C-5 lactol-9-TBS ether of core 7 and propargylmagnesium bromide (Gaoni.Y:, Leznoff, C.C:,Sondheimer. 7. Am. Chem. Soc. 1968, 90, 4940-4945.) were processed as in Example 251 to give the desired compound. *H NMR (300 MHz, DMSO-dό) δ 8.77 (s, IH), 7.92 (d, J=9 Hz, IH), 6.63 (dd, J=9, 8 Hz, 2H), 6.54 (m, IH), 6J7 (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), 2J8 (s, 3H), 1.17 (d, j=5 Hz, 6H); 3C NMR (75 MHz, DMSO-d6) δ 145.9, 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, 114.0, 112.6, 91.4, 80.7, 72.5, 59.4, 49.8, 29.3, 29.0, 23.9, 23.3, 22.4.
J90- Example 267 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-r2-propyl)-lH-lllhenzopyranor3.4- flquinoline 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) δ 8.65 (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), 2J6 (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) δ 145.3, 144.8, 144.0, 143.7, 133.5, 131.6, 128.2, 126J, 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 C23H27NO3»l/4H2O: C, 74.67; H, 7.49; N, 3.79. Found: C, 74.81; H, 7.39; N, 3.67.
Example 268 2.5-dihvdro-9-hvdroxy- 10-methoxy-2.2.4-trimethyl-5-(5-methoxy-2-thienyl)- 1 H- rilbenzopyranor3.4- fjquinoline The C-5 lactol-9-TBS ether of core 7 and 2-methoxythiophene were processed according to Example 276 to provide the desired compound. iH NMR (300 MHz, DMSO-d6) δ 8.63 (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); 13C NMR (75 MHz, DMSO-d6) δ 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 C25H25NO4S«l/4H2O: 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)- lH-πihenzopyranor3.4- fjquinoline 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/EtO Ac. MS (DCI/NH3) m/z 490 (M+H)+;
-191- O 99/41256
IH NMR (300 MHz, DMSO-d6) δ 8.75 (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); 3C NMR (400 MHz, DMSO-d6) δ 146.1, 145.8, 143.8, 142.9, 133.4, 128.4, 127.0, 126.2, 118.6, 118J, 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 C26H2θNO3F5 • 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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5rS)-f3rS)-l- hydroxymethylcyclopenten-3-y 1 )- 1 H-f llhenzopyranor3.4-f*1quinoline
MS (DCI/NH3) m/z 420(M+H)+; iH NMR (400 MHz, DMSO-de) IH NMR (200 MHz, DMSO-d6) δ 8.77 (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 r+/-) 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5fS)-(3rS)-l- methylcarboxylatecyclopenten-3-yl)-lH-riJbenzopyranor3.4- fjquinoline
_The C-5 lactol-9-TBS ether of core 7 and 3-cyclohexenyl trimethylsUane 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 (-) r5S.3,S) 2.5-dihydro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-(3-cvclohexenyl)-lH- riJbenzopyranof3.4- fjquinoline MS (DCI NH3) m/z 404 (M+H)+; IH NMR (300 MHz, DMSO-d6) δ 8.70 (s, IH), 7.99 (d, IH), 6.65 (d, 1H), 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) δ 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;
■192- [α]23 D=-162° (c OJ l, CHCl3).
Example 273 f- 5S.3,R 2.5-dihvdro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-f3-cyclohexenyn-lH- rnhenzopyranor3.4-flquinoline
MS (DCI/NH3) m/z 404 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.70 (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) δ 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;
[α]23 D=-158° (c 0.50, CHCl3).
Example 274 2.5-dihydro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-('2-thienyl)-lH-riJbenzopyranor3.4- fjquinoliηe 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 ZnCl2 (1J ml of a 1M/Et20 solution, 1J0 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) δ 8.65 (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); 13C NMR (75 MHz, DMSO-d6) δ 145.7, 145.1, 143.7, 143.6, 143.5, 133.0, 130.8, 127.9, 127.5, 127.0, 126.5, 126.4, 1 18.3, 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.
■193- Example 275 r±) 2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethyl-5-f2-methylphenyl) -lH- r 1 lbenzopyranor3.4-flquinoline 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)+;
!H NMR (300 MHz, DMSO-d6) δ 8.43 (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) δ 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-f2-acetoxymethyl-3-prσpenyl)-lH- rilbenzopyranor3.4- fjquinoline The C-5 lactol-9-TBS ether of core 7 (0J50 g, 0.321 mmol) was dissolved in dichloromethane (15 ml), treated with 2-[(trimethylsilyl)methylJ-2-propene-l-yl acetate (0J80 g, 0.962 mmol), cooled to -78°C, treated dropwise with BF3«Et2O 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 yeUow 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 0J25 g (89%) of the desired compound. IH NMR (300 MHz, DMSO-d6) δ 8.74 (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,
■194- 3H), 2.23 (m, 2H), 2.17 (s, 3H), 1.99 (s, 3H), 1.18 (s, 3H), 1J5 (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
M C5R. ' S) 2.5-dihydro-9-hvdroxy- 10-methoxy-2.2.4-trimethyl-5J 1 -ethyl-3- cyclohexenyll-lH-riJbenzopyranor3.4-flquinoline To 77 ml of a 0.36 M THF solution of dimethylphenylsilyl methyl cuprate (27.7 mmol) ( Fleming .; Newton, T. W.7. 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 sUica gel column chromatography eluting with hexanes to give the intermediate triflate as a tight yeUow oil.
The above triflate (0.70 g, 1.28 mmol) was combined with tributyltin hydride (0.92 g, 2J3 mmol) in THF and added dropwise to a THF solution of tetrakistriphenylphosphinepaUadium(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 (Na2SO ). The product was purified by siUca gel column chromatography eluting with hexanes to give 3-ethyl-3-dimethylphenylsUyl-cyclohexene as a colorless oU.
The C-5 lactol-9-TBS ether of core 7 and 3-ethyl-3-dimethylphenylsUyl- 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. : lH .NMR (500 MHz, DMSO-dβ) δ 8.01 (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) δ 145.3, 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,
-195- 37.5, 30J, 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-hvdroxv-10-methoxy-2.2.4-trimethy1-5-cyc1ohexvl-lH-rilbenzopyranor3.4- fjquinoline
MS (DCI/NH3) m/z 406 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.66 (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); 1 C NMR (400 MHz, DMSO-d6) δ 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-rnbenzopyranor3.4- fjquinoline
MS (DCI/NH3) m z 324 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.78 (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); 1 C .NMR (400 MHz, DMSO-d6) δ 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-r2-hydroxymethyl-3-propenyl)-lH- πibenzopyranor3.4- fjquinoline
Example 276 (0.032g, 0.074 mmol) was dissolved in THF/MeOH/H2O (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 (MgSU4), an^ concentrated. The residue was purified by silica gel chromatography eluting with 25% then 50% ethyl acetate in hexanes to give 0.022 g (76%) of the desired compound.
J96- H NMR (300 MHz, DMSO-d6) δ 8.71 (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); "C NMR (125 MHz, DMSO-de) δ 145.9, 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) /e (M+H)+ 394.
Example 281 methyl 2- 2.5-dihydro-9-hydroxy-10-methoxy-2.2.4-trimethyl-lH-rilbenzopyranor3.4-fJ-
5-quinolinyll acetate The C-5 lactol-9-TBS ether of core 7 was processed as in example 46 to provide the intermediate sUylated product.
IH NMR (300 MHz, DMSO-d6) δ 7.94 (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-d6) δ 8.80 (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-dihvdro-9-hydroxy-10-methoxy-2.2.4-trimethyl-5-(2-butenyl)-lH- f 1 J benzopyranor3.4-f1quinoline 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
-197- 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 siUca 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-dό) δ 7.92 (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), 0J5 (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 of the above primary alcohol (0.080 g, 0J66 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 soUd. !H NMR (300 MHz, DMSO-d6) δ 9.65 (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 (0J30 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, 0J 17 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. 2H NMR (300 MHz, DMSO-d6) δ 7.92 (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,
-198- 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 (M SO4) .and purified by siUca gel chromatography eluting with 25 % ethyl acetate in hexanes to give the desired compound (0.024 g, 83%). IH NMR (300 MHz, DMSO-d6) δ 8.71 (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), 1J5 (s, 6H); MS (APC m/e calc'd for : 377.20. Found ; (M+H)+ 378, (M-H)" 376.
Example 283
2.5-dihvdro-9-hvdroxv- 10-methoxv-2.2.4-trimethyl-5J3-methyl-2-hutenyl)- 1 H- r 1 lbenzopyranor3.4-flquinoline The intermediate aldehyde from Example 282 and isopropyltriphenylphosphonium iodide were processed according to Example 282 to give the desired compound. iH NMR (300 MHz, DMSO-d6) δ 8.65 (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 f+) f5S.3'S) 2.5-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-n-cvclohexenyl)-lH- rnbenzopyranor3.4-flquinoline
MS (DCI NH3) m/z 404 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.70 (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) δ 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;
[α]23 D=+184° (c 0.33, CHCI3).
Example 285 ( +) C5R.3' R) 2.5-dihvdro-9-hydroxy- 10-methox v-2.2.4-trimethyl-5J3-cvclohexenv 1 )- 1 H- r 11 benzopyranor3.4-f . jquinoline
MS (DCI NH3) m/z 404 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.70 (s, IH), 7.99 (d, IH), 6.65 (d, IH), 6.62 (d,
-199- IH), 6.52 (d, IH), 6.20 (d, IH), 5.61 (ddd, IH), 5.46 (d, IH), 5.41 (s, IH), 5J0 (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);
1 c NMR (400 MHz, DMSO-d6) δ 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; [α]23 D=+170° (c 0.23, CHC13).
Example 286 f+) r5R.3,S) 2.5rR)-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-r3-cvclopentenyl)- lH-πjbenzopyranor3.4-flquinoline MS (DCI/NH3) m/z 390 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.67 (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) δ 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; [α]23 D=+136° (c 0.355, CHCI3).
Example 287 f+) r5R.3'R) 2.5rR)-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-r3-cvclopentenyl)- lH-πjbenzopyranor3.4-f1quinoline MS (DCI/NH3) m/z 390 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.68 (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) δ 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;
[αJ23 D=+116° (c 0.800, CHCI3).
-200- Example 288 rRl-r5S)-9-hvdroxy-5-r(3R)-f l-methoxycarhonyl)cvclohexen-3-vn- 10-methoxy-2.2.4- trimethvl-2.5-dihvdro- 1 H-r 1 lhenzopyranor3.4-f1quinoline MS (DCI NH3) 462 (M+H)+;
IH NMR (200 MHz, DMSO-d6), δ 8.81 (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), 2.20-2J6 (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 C28H2lNO5 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- mbenzopyranor3.4- fjquinoline
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 cetite. The layers were separated, the aqueous layer was extracted with ethyl acetate, the combined organics were washed with brine, dried (M SO4), 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) δ 8.71 (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) δ 145.8, 144.9, 143.8, 142.8, 141.6, 133.3, 132.7, 127.5, 126.4, 117.8, 1 16.3, 116.2, 114.2, 113.6, 1 12.8, 1 12.7, 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 9J0-Dimethoxy-5-(3-propenyl)-2.2.4-trimethyl-lH-2.5-dihydro- |Jlhenzopyranor3.4- fjquinoline
MS (ESI) m/z 378 (M+H)+;
-201- 1H NMR (300 MHz, DMSO) δ 7.93 (d, 7=8.5 Hz, 1 H), 6.82 (d, 7=8.8 Hz, 1 H), 6.61 (dd, 7=4.4, 4.4 Hz, 2 H), 6.22 (d, 7=1.4 Hz, 1 H), 5.83 (ddt, 7=16.9, 10.3, 3.1 Hz, 1 H), 5.70 (dd, 7=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
9J0-Dimethoxv-5J3-cvclohexenvl1-methoxv-2.2.4-trimethvl-2.5-dihydro-lH- rilhenzopvranor3.4-flquino1ine MS (ESI) m/z 418 (M+H)+;
1H NMR (300 MHz, DMSO), isomer 1: δ 8.02 (d, 7=8.8 Hz, 1 H), 6.84 (d, 7=1.7 Hz, 1 H), 6.70 -6.60 (m, 2 H), 6.27 (d, 7=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: δ 8.01 (d, 7=8.81 Hz, 1 H), 6.80 (d, 7=0.7 Hz, 1 H), 6.64 (m, 2 H), 6.26 (d, 7=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-f3-propenyl)-2.2.4-trimethyl-lH-2.5-dihydro-
— riJbenzopyranor3.4-flquinoline
*H .NMR (300 MHz, DMSO) δ 7.94 (d, 7=8.8 Hz, 1 H), 6.79 (d, 7=8.8 Hz, 1 H), 6.60 (d, 7=8.8 Hz, 1 H), 6.55 (d, 7=8.8, 1 H), 6.45 (s, 1 H), 5.85 (ddt, 7=17.3, 10.3, 6.6 Hz, 1 H), 5.43 (d, 7=9.2 Hz), 5.16 (s, 1 H), 5.09 (dd, 7=10.3, 1.1 Hz, 1 H), 5.06 (dd, 7=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, 7=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-propenyIoxy)-5-(3-propenyl)-2.2.4-trimethyl-lH-2.5-dihydro- πjbenzopyranor3.4- fjquinoline MS (DCI/NH3) m/z 404 (M+H)+.
*H NMR (300 MHz, DMSO) δ 7.93 (d, 7=9.0 Hz, 1 H), 6.83 (d, 7=8.8 Hz, 1 H), 6.61 (d, 7=9.0 Hz, 1 H), 6.59 (d, 7=8.8 Hz, 1 H), 6.23 (d, 7=1.5 Hz, 1 H), 6.15-6.02 (m, 1 H), 5.81 (ddt, 7=17.3, 10.3, 6.6 Hz, 1 H), 5.67 (dd, 7=9.8, 3.3 Hz), 5.45 (s, 1 H), 5.44
-202- (dd, 7=16.0, 2.0 Hz, 1 H), 5.27 (dd, 10.6, 2.0 Hz, 1 H), 5.03 (dd, 7=10.3, 1.8 Hz, 1 H), 4.98 (dd, 7=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), 2J6 (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-methoxv-9-(3-propvnyloxy)-5-r3-propenyl)-2.2.4-trimethyl-lH-2.5-dihydro- rilbenzopvranor3.4-flquinoline MS (DCI/NH3) m/z 402 (M+H)+; lH NMR (300 MHz, DMSO) δ 7.92 (d, 7=8.8 Hz, 1 H), 6.88 (d, 7=8.8 Hz, 1 H), 6.62 (d, 7=8.8 Hz, 1 H), 6.61 (d, 7=8.8, 1 H), 6.24 (d, 7=1.7 Hz, 1 H), 5.81 (ddt, 7=17.3, 10.3, 6.6 Hz, 1 H), 5.72 (dd, 7=9.8, 3.3 Hz), 5.44 (s, 1 H), 5.03 (dd, 7=10.3, 1.8 Hz, 1 H), 4.99 (dd, 7=17.3, 1.8 Hz, 1 H), 4.79 (d, 7=2.3 Hz, 2 H), 3.57 (t, 7=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- ri!benzopyranof3.4- fjquinoline
IH .NMR (400 MHz, DMSO-d6) δ 7.78 (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, 1=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) δ 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-|"lJbenzopyranof3.4- fjquinoline IH NMR (300 MHz, DMSO-d6) δ 7.86 (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) δ 171.5, 170.4, 148.3, 148.0, 146.2, 138.5, 134.1, 133.5, 132.1, 127.3, 126.2, 120.8,
-203- 118J, 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 7J0, N 5.49.
The chemistry described above was used with Core 9 to prepare Examples 297-299.
Example 297 7-hromo -5J3-cvcIohexenv11- 10-methoxv-2.2.4-trimethyl-2.5-dihydro-lH- rijbenzopyrahor3,4-f|quinc>line MS (APCI) m/z 466 (M+H)+;
1H NMR (300 MHz, DMSO), isomer 1: δ 8.03 (d, 7=8.8 Hz, 1 H), 7.33 (d, 7=9.2 Hz, 1 H), 6.65 (dd, 7=8.8, 1.7 Hz, 2 H), 6.35 (d, 7=1.3 Hz, 1 H), 5.91-5.43 (m, 4 H), 3.86 (s, 3 H), 2J4 (s, 3 H), 1.99 (s, 3 H), 1.31 (s, 3 H), 1.06 (s, 3 H); isomer 2: δ 8.00 (dd, 7=8.8 Hz, 1 H), 7.33 (d, 7=9.2 Hz, 1 H), 6.65 (dd, 7=8.8, 1.7 Hz, 1 H), 6.35 (d, 7=1.3 Hz, 1 H), 6.31 (d, 7=1.3 Hz, 1 H), 5.91-5.43 (m, 4 H), 2J2 (s, 3 H), 1.28 (s, 3 H), 1.03 (s, 3 H); 13C NMR (300 MHz, DMSO) δ 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 C2όH28NO2 79Br 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-lH-2.5-dihydro- r 11benzopyranor3.4-flquinoline
MS (APCI) m/z 426 (M+H)+;
1H NMR (300 MHz, DMSO) δ 7.93 (d, 7=8.8 Hz, 1 H), 7.33 (d, 7=9.2 Hz, 1 H), 6.71 (d, 7=9.2 Hz, 1 H), 6.60 (d, 7=8.5 Hz, 1 H), 6.25 (d, 7=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, 7=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.
-204- Example 299 7-hromo-5-r 1 -methvl-3-cvclohexenvll- 10-methoxv-2.2.4-trimethyl-2.5-dihvdro- 1 H- rnbenzopvranor3.4-flquinoline MS (APCI) m/z 480 (M+H)+;
1H NMR (300 MHz, DMSO) isomer 1: δ 8.02 (d, 7=8.5 Hz, 1 H), 7.55 (d, 7=5.9 Hz, 1 H), 7.37 (d, 7=2.6 Hz, 1 H), 7.31 (d, 7=1.8 Hz, 1 H), 6.67 (dd, 7=14.7, 8.8 Hz, 1 H), 6.35 (d, 7=1.5 Hz, 1 H), 5.63 (d, 7=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: δ 8.00 (d, 7=8.5 Hz, 1 H), 7.54 (d, 7=5.9 Hz, 1 H), 7.35 (d, 7=1.8 Hz, 2 H), 6.67 (dd, 7=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 C27H3oNO2?9Br 479.1460. Found 479.1463; HRMS calcd for C27H3oNO2 81Br 481.1439. Found 481.1456. Anal, calcd for C27H3oNO2?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- riJbenzopyranof3.4-flquinoline
MS (DCI/NH3) m/z 428 (M+H)+; 426;
1H NMR (300 MHz, DMSO) δ 7.93 (d, 7=8.8 Hz, 1 H), 7.33 (d, 7=8.5 Hz, 1 H), 6.67 (d, 7=8.5 Hz, 1 H), 6.65 (d, 7=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); I3C NMR (300 MHz, DMSO) δ 152.7, 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 C23H2 NO2 79Br 425.0990. Found 425.0998; HRMS calcd for
C23H24Nθ28IBr 427.0970. Found 427.0974.
Anal, calcd for C2 H 4BrNO2. 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.
-205- Example 301 7.9-Dihromo-10-methoxy-5-('3-propenyl)-2.2.4-trimethyl-lH-2.5-dihvdro- rilbenzopyranor3.4- fjquinoline MS (ESI) m/z 504 (M+H)+;
1H NMR (300 MHz, DMSO) δ 7.57 (d, 7=8.9 Hz, 1 H), 7.65 (s, 1 H), 6.66 (d, 7=8.8 Hz, 1 H), 6.44 (s, 1 H), 5.95 (dd, 7=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) δ 152.1, 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 C 3H2379Br2NO2 503.0096. Found 503.0086; HRMS calcd for C23H2379Br81BrNO2 505.0075. Found 505.0075.
Example 302
7.9-Dibromo-5-rcyclohexen-3-ylJ- 10-methoxy-2.2.4-trimethyl-2.5-dihydro-lH-
[ 1 Jbenzopyranor3.4-flquinoline MS (ESI) m/z 544 (M+H)+;
IH NMR (300 Mhz, DMSO), 1st isomer: δ 8.81 (d, IH, 7=8.83 Hz), 7.67 (s, IH), 6.70 (d, IH, 7=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 δ 7.9 (d, IH, 7=8.83 Hz), 7.66 (s, IH), 6.69 (d, IH, 7=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 C26H 779Br2NO2 is 543.0409. Found 543.0385; HRMS calcd for * C26H27?9Br81BrNO2 545.0388. Found 545.0396.
Example 303 7.9-Dibromo-5-ri-methyl-3-cyclohexenylJ-10-methoxy-2.2.4-trimethyl-2.5-dihydro-lH- [llhenzopyrano('3.4-flquinoline
MS (ESI) m/z 560 (M+H)+;
IH NMR (300 MHz, DMSO), isomer 1: δ 8.83 (d, 7=8.0 Hz, 1 H), 7.37 (s, 1 H), 6.70 (d, 7=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: δ 7.99 (d, 7=8.0 Hz, 1 H), 7.37 (s, 1 H), 6.71 (d, 7=8.8 Hz, 1 H), 6.55 (s, 1 H), 5.57 (d, 7=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);
-206- 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-f3-propenyl)-2.2.4-trimethyl-lH-2.5-dihvdro- |Jlbenzopyranor3.4- fjquinoline MS (ESI) m/z 373 (M+H)+; 1H NMR (300 MHz, DMSO) δ 7.82 (d,7=8.9 Hz, 1 H), 7.23 (d, 7=8.9 Hz, 1 H), 6.78 (dd, 7=11.0, 6.8 Hz, 1 H), 6.61 (d, 7=8.9 Hz, 1 H), 6.49 (d, 7=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, 7=2.1 Hz, 1 H); 13C NMR (300 MHz, DMSO) δ 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- ri]benzopyranof3.4- fjquinoline MS (ESI) m/z 362 (M+H)+; 1H NMR (300 MHz, DMSO) δ 7.92 (d, 7=8.5 Hz, 1 H), 6.93 (d, 7=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- riJbenzopyranor3.4- fjquinoline
MS (ESI) /z 390 (M+H)+.
-207- 1H NMR (300 MHz, DMSO), 7.88 (d, 7=8.8 Hz, 1 H), 7.59 (d, 7=8.8 Hz, 1 H), 6.84 (d, 7=8.8 Hz, 1 H), 6.62 (d, 7=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-dihvdro-9-meth yl- 10-methoxy-2.2.4- trimethyl-5-f 1 -methylcvclohexen-3-v 1 )- 1 H- πibenzopyranor3.4- fjquinoline MS (DCI/NH3) m/z 416 (M+H)+.
Example 308 10-methoxy-7-methyl-9-methyl-5-f3-propeπyl)-2.2.4-trimethyl-lH-2.5-dihvdro- nibenzopyranor3.4-flquinoline MS (DCI NH3) /z 376 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 7=8.5 Hz, 1 H), 6.81 (s, 1 H), 6.62 (d, 7=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), 1J9 (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-lH-riJbenzopyranor3.4-f1quinoline MS (DCI/NH3) m z 352 (M+H)+; 1H NMR (300 MHz, DMSO) δ 7.93 (d, 7=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-chIoro-2.2.4-trimethyl-5-phenyl-lH-rnbenzopyrano['3.4-flquinoline
MS (DCI/NH3) m/z 288 (M+H)+;
IH NMR (200 MHz, DMSO) δ 7.98 (d, 7=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.
-208- Example 311 2.5-dihvdro- 10-methox v-5-n-fN-τneth vl-N- Ccarbomethoxymethyl)aminocarhonyloxy)phenyl)-2.2.4-trimethyl-lH-rnbenzopyranor3.4- flquinoline
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) δ 8.00(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), 4J5(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, 6J0; N, 5.29. Found: C, 70.98; H, 6.33; N, 4.85
Example 312
2.5-dihvdro-10-methoxy-5-r3-rN-methyl-N-(,N- methylcarbonyl)aminocarbonyloxy)phenyl)-2.2.4-trimethyl-lH-riJbenzopyrano["3.4- fJqqinQline Example 13 and methylisocyanate were processed as in Example 14 to provide the desired compound. _
MS (DCI/NH3) m/e 514 (M+H)+
1H NMR (300 MHz, DMSO-d6) δ 8J8(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), 6J9(s, IH), 5.38(s, IH), 3.78(s, 3H), 3J9(s, 3H), 2.70(d, 3H), 1.84(s, 3H), 1.22(s, 3H), 1.14(s, 3H).
Anal, calcd for C3oH3iN3O5-2H2O: 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- rilbenzopyranor3.4-f)quinoline Example 13 and methylisocyanate were processed as in Example 14 to provide the desired compound. MS (DCI/NH3) m/e 457 (M+H)+ IH NMR (300 MHz, DMSO-d6) δ 8.01(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), 6J8(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)
-209- Anal, calcd for C28H28N2O4-0.50H2O: C, 72.33; H, 6.27; N, 6.01. Found: C, 72.20; H, 6.38; N, 5.78
Example 314 2.5-dihvdro-10-methoxy-5-GJ2-hvdroxyethyl)phenyl)-2.2.4-trimethyl-lH- r 11 benzopyranpβ .4-flguiηoiip 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-butylUthium (2.5 M in hexane, 5.80 ml) over 15 minutes, warmed to -30 °C, cooled down to -78 °C, treated with compound __ 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 of the residue on silica gel with 20-35% ethyl acetate/hexane provided 0.82 g (56%) of the title 5-(3'-MOMO-phenyl)hemiketal. MS (DCI/NH3) m/e 489 (M+H)+
A solution of of the 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 sequentiaUy washed with water and brine, dried (Na2SO4) and concentrated to provide 0.52 g (82%) of the unmasked hemiketal. MS (DCI/NH3) m/e 444 (M+H)+.
A solution of the unmasked hemiketal prepared above (0.45 g, 1.00 mmol) and triethylsilane (1J6 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 of the residue on silica gel with 25-45% ethyl acetate in hexane provided 0.342 of the titie compound. MS (DCI/NH3) m/e 428 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.00(d, IH), 7.00(m, 5H), 6.74(s, IH), 6.70(d, IH), 6.55(d, IH), 6.45(d, IH), 6J6(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), l.H(s, 3H); Anal, calcd for C28H29 O3: C, 78.66; H,6.83; N, 3.27. Found: C, 78.48; H, 6.85; N, 3.29.
-210- Example 315 2.5-dihvdro-10-methoxv-5-r3-f2-methanesulfonvloxvethyl)phenyl)-2.2.4-trimethyl-lH- r 1 lbenzopyranor3.4- 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 of the residue on siUca gel with 10-30% ethyl acetate/hexane provided 0.30 g (97%) of the title compound. MS (DCI/NH3) m e 506 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.00(d, IH), 7.18(s, IH), 7J4(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,6J7; N, 2.77. Found: C, 69.08; H, 6J4; N, 2.63.
Example 316 2.5-dihvdro-10-methoxy-5-r3-(,2-methythioethyl)phenyl)-2.2.4-trimethyl-lH- r 1 Jbenzopyranor3.4- fjquinoline
__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. Rash chromatography of the residue on silica gel with 10-30% ethyl acetate/hexane provided 9 mg (99%) of the title compound. MS (DCI NH3) m/e 458 (M+H)+
IH N . MR (300 MHz, DMSO-d6) δ 8.00(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, 6J6(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-riJbenzopyranor3.4-fJquinoline 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)+
-21 1- IH NMR (300 MHz, DMSO-d6) δ 8.01 (d, IH), 7.00(m, 5H), 6.76(s, IH), 6.70(d, IH), 6.55(s, IH), 6.44(d, IH), 6J5(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 31
2„ -dihydro-lQ-methpχy-5-(3-(2-(N,N-dimethylamiπo)ethyl)phenyl)-2,2,4-trimethyl-lH- riJbenzopyranor3,4-f1quinoline 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) δ 8.00(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), 6J6(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-rilbenzopyranor3.4- fjquinoline
Example 319A A mixture of ExamplelF (4.43 g, 13.7 mmol), 4-chlorophenol (9.28 g, 72J mmol) and MgSO4 (8.69 g, 72J mmol) in CH2CI2 (100 ml) at ambient temperature was stirTed for 12 lir, dUuted 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 of the 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 NH4CI. The organic layer was washed with IM aq NaOH twice and brine respectively,
-212- dried (Na2SO4) and concentrated. Rash chromatography of the residue on siUca gel with 5- 15% ethyl acetate/hexane provided 18 mg (17%) of the title compound. MS (DCI/NH3) m/e 348 (M+H)+
1H NMR (300 MHz, DMSO-d6) δ 8.01(d, IH), 7.04(t, IH), 6.67(d, IH), 6.60(d, IH), 6.57(d, IH), 6J6(s, IH), 5.44(s, IH), 5.42(d, IH), 3.85(s, 3H), 2J2(s, 3H), 1.26(s, 3H), 1.05(s, 3H), 0.28(m, 4H), 0.08(m, IH).
Example 32Q
2.5-dihvdro-10-methoxv-5-ethenvl-2.2.4-trimethvl-lH-πihenzopvranor3.4-f|quinoline 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 aUowed 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 of the residue on siUca gel with 5- 15% ethyl acetate/hexane provided 27 mg (81%) of the titie compound. MS (DCI NH3) m/e 334 (M+H)+
IH NMR (300 MHz, DMSO-d6) δ 7.93(d, IH), 7.02(t, IH), 6.63(dd, 2H), 6.54(d, IH), 6J9(d, IH), 6J0(s, IH), 5.93(m, IH), 5.42(s, IH), 5J6(dt, IH), 4.91(dt, IH), 3.83(s, 3H), 2J l(s, 3H), 1.21(s, 3H), 1.13(s, 3H).
Example 321 trans 2.5-dihydro-10-methoxy-5-(2-phenylethenyl)-2.2.4-trirnethyl-lH- πjbenzopyrano 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, 0J2 mmol) in CH3CN (1 ml) was heated to 80 °C for 4 hr in a sealed tube. After solvent removal, flash chromatography of the residue on siUca gel with 5-15% ethyl acetate/hexane provided 7 mg (44%) of the title compound. MS (DCI/NH3) m/e 410 (M+H)+ IH NMR (300 MHz, DMSO-d6) δ 7.99(d, IH), 7.22(m, 4H), 7J9(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), 6J4(s, IH), 5.43(s, IH), 3.82(s, IH), 2J2(s, 3H), 1.22(s, 3H), lJ3(s, 3H).
-213- Example 322 2.5-dihvdro-10-methoxv-5J2-phenvlethvnvl)-2.2.4- trimethvl- lH-r llhenzopyranor3.4- flquinoline 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) δ 7.92(d, IH), 7.29(m, 3H), 7J6(m, 2H), 7J0(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 ci 2.5-dihvdro-10-methoxy-5-r2-phenylethenyl)-2.2.4-trimethyl-lH-rilhenzopyranoI3.4- flquinoline A mixture of Example 322 (20 mg, 0.049 mmol), paUadium/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 of the residue on siUca gel with 5-15% ethyl acetate/hexane provided 13 mg (75%) of the titie compound. MS (DCI/NH3) m/e 410 (M+H)+ lH NMR (300 MHz, DMSO-d6) δ 7.97(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), 6J2(d, IH), 6J0(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-lH-fUbenzopyranor3.4- 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) δ 7.92(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), 5J8(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
-214- Example 325 trans 2.5-dihvdro-10-methoxy-5-π -cvclohexenyl)-2.2.4-trimethyl-lH-πihenzopyranor3.4- fJqqinQline Eχ.ample 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) δ 7.9 l(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), 2J8(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 C26H29NO2J.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-lH-["lJbenzopyranor3.4- fjquinoline A magnetically stirred mixture of triflate 3C [from the original patent appUcation] (196 mg, 0.421 mmol) and 2-(tributylstannyl)furan (0.250 mL, 0.79 mmol) and [1,1'- 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 aUowed to cool to room temperature, was dUuted 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 siUca 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 syrup: H NMR δ 7.67 (d, IH, J=1.0Hz), 7.18 (t, IH, J=7.8Hz), 7.08 (m, IH), 6.91 (dd, IH, J=8JHz, 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), 2J9 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H); mass spectrum (DCI) m/z 384 (M + 1). Anal. Calcd for C26H25NO2: C, 81.43; H, 6.57; N, 3.65. Found: C, 81.24; H, 6.62; N, 3.66.
-215- Example 327 2.5-dihvdro- 10-cvano-5-f 3-propenvl)-2.2.4-trimethvl- 1H-H lhenzopyranor3.4-flquinoline A magnetically stirred mixture of triflate 3C (195 mg, 0.419 mmol), 36 mg (0.031 mmol) of tetrakis(triphenylphosphine)paUadium(0) and zinc cyanide (36 mg, 0.31 mmol) in dry dicxane (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 dUuted 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, a . nd concentrated. The crude material was chromatographed on sUica gel (20 g) using ethyl acetate-hexane (10:90) to give product contaminated with starting triflate. The partiaUy pure nitrile was appUed 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: JH NMR δ 7.87 (d, IH, J=8.5Hz), 7.46 (dd, IH, J=7.5Hz, J=1.5Hz), 7.27 (t, IH, J=7.8Hz), 7J9 (dd, IH, J=8JHz, 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), 2J9 (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-riJbenzopyranor3.4- fjquinoline A magnetically stirred mixture of the 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 syrup: lH NMR δ 7.16 (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=1.5Hz), 2.30 (m, 2H), 2.18 (s, 3H), 1.20 (s, 3H), 1J6 (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.
-216- Example 329 2.5-dihvdro-10-(2-hvdroxymethyl)-5-r3-propenyl)-2.2.4-trimethyl-lH-
T 1 lbenzQpyranQ[3.4-flqwinoline To a magneticaUy stiired solution of ex.ample 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 of the reaction was allowed to rise to 0°C. After 3.5h, the reaction was quenched by addition to aqueous RocheUe'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 syrup: iH NMR δ 7.47 (d, IH, J=8.5Hz), 7J4 (m, 2H), 6.80 (dd, IH, J=7.3Hz, J=1.8Hz), 6.64 (d, IH, J=8.5Hz), 6J7 (m, IH), 5.81 (ddm, IH, J=10.5Hz, J=17JHz), 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=17JHz), 4.62 (m, 2H), 2.30 (m, 2H), 2J7 (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-dihvdro-10-formyl-5-r3-propenyl)-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinoline
A magneticaUy stirred mixture of the Example 329 (185 mg, 0.532 mmol) .and tetrapropylammonium perruthenate (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 crude material was chromatographed on sUica gel (20 g) using EtOAc-hexane (10:90) to furnish 144 mg (0.417 mmol, 78%) of desired aldehyde: iH NMR δ 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.
-217- Example 331 2.5-dihvdro-10-aminomethvl-5-C3-propenvl)-2.2.4-trimethvl-lH-rnhenzopyranor3.4- fjquinoline To a magneticaUy 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 crude material was applied to two 10 x 20 cm, 0.25 mm thick siUca 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: !H NMR δ 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=17JHz), 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-djhydro-10-methoxymethyl-5-(3-propenyl)-2.2.4-trimethyl-lH-πjbenzopyranor3.4- fjquinoline To a magnetically stiiτed solution of Example 329 (26 mg, 0.075 mmol) in dry THF (2.0 mL), cooled in an ice bath, was added 0J4 mL of IM potassium hexamethyldisilazide in hexane under argon. Methyl iodide (13.8 mg, 0.097 mmol) was added and the reaction was aUowed 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 crude 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: iH NMR δ 7.34 (d, IH, J=8.5Hz), 7.11 (m, 2H), 6.85 (dd, IH, J=7JHz, 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.
-218- Example 333 2.5-dihvdro-10-ethenyl-5-phenyl-2.2.4-trimethyl-1H-rilbenzopyranor3.4-πquinoline
Example 333A 2.5-dihvdro- 10-ethenvl-5-nhenvl-2.2.4-trimethvl- 1 H-r 1 lbenzopvranor3.4-flguinoline 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-dihvdro-10-ethenyl-5-phenyl-2.2.4-trimethyl-lH-[llbenzopyranor3.4-flquinoline Example 333A and vinyl tributylstannane were processed as in Example 5 to provide the desired compound. MS (DCIZNH3) m/z 380 (M+H)+; iH NMR (300 MHz, CDCI3) δ 7.30-7.11 (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) δ 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-[lJbenzopyranor3.4-f1quinoline
Example 333A and (trimethylsilyl)acetylene were processed as in Example 6A and
Example 6 to provide the desired compound.
MS (OCVNH3) m z 378 (M+H)+; H NMR (300 MHz, DMSO) δ 8.32 (d, 7=8.8 Hz, 1 H), 7.27-7J6 (m, 5 H), 7.01 (dd, 7=8.7, 1.8 Hz, 1 H), 6.83 (t, 7=8.6 Hz, 1 H), 6.84-6.79 (m, 1 H), 6.81 (br s, 1 H), 6.74
(d, 7=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) δ 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.
-219- Example 335 methyl 2.5-dihvdro-5-phenyl-2.2.4-trimethyl-lH-rilhenzopyranor3.4-flquinoline-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)+;
IH NMR (300 MHz, DMSO) δ 7.36-7.30 (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, 7=8.7 Hz, 1 H), 6.70 (d, 7=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);
1 C NMR (125 MHz, DMSO) δ 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 Jbenzopyranor3.4- flquinoline 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 of the solution from orange to tight yeUow) 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 RocheUe'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 (N 2SO4). 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, DMSO) δ 7.58 (d, 7=8.9 Hz, 1 H), 7.23-7. H (m, 5 H), 6.98 (dd, 7=8.7, 1.7 Hz, 1 H), 6.84 (t, 7=8.7 Hz, 1 H), 6.76 (br s, 1 H), 6.75 (d, 7=8.6 Hz, 1 H), 6.69 (dd, 7=8.7, 1.8 Hz, 1 H), 6.26 (br s, 1 H), 5.40 (br s, 1 H), 5.37 (dd, 7=6.0, 4.0
-220- 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);
1 C NMR (125 MHz, DMSO) δ 151.0, 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-flJbenzopyranor3.4-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 perruthenate (60 mg, 0J6 mmol) in CH2CI2 (14 mL). After 15 min, the reaction mixture was filtered through a smaU plug of siUca gel, rinsing with CH2CI2 followed by 1:1 EtOAc-hexanes. The filtrate was concentrated to give a gold syrup which was purified by preparative thin layer chromatography (elution with 3%
EtOAc/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) δ 10.13 (s, 1 H), 7.31 (dd, 7=8.8, 1.9 Hz, 1 H), 7.28-7.16 (m, 5 H), 7.12 (d, 7=8.7 Hz, 1 H), 7.05 (dd, 7=8.7, 2.0 Hz, 1 H), 6.95 (d, 7=8.8 Hz, 1
H), 6.92 (br s, 1 H), 6.81 (d, 7=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) δ 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-trimethyI-lH-[lJbenzopyranor3.4- 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 additionaUy 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
-221- 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) δ 7.40 (d, 7=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, DMSO) δ 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-dihvdro-10-ethenyl-5-oxo-2.2.4-trimethyl-lH-riJbenzopyranof3.4-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) δ 7.88 (d, 7=8.8 Hz, 1 H), 7.38 (dd, 7=8.8, 6.6 Hz, 1 H), 7.29 (s, 1 H), 7.28 (d, 7=8.6 Hz, 1 H), 7.19 (dd, 7=17.3, 11.1 Hz, 1 H), 7.13 (d, 7=8.7 Hz, 1 H), 7.03 (br s, 1 H), 5.75 (dd, 7=17.3, 1.2 Hz, 1 H), 5.52-5.47 (m, 2 H), 1.97 (s, 3 H), 1.24 (s, 6 H);
1 C NMR (125 MHz, CDCI3) δ 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- 1 HJ 1 Jhenzopyranor3.4- flquinoline To a magnetically stirred solution of Example 339 (100 mg, 0.300 mmol) and 3- (trimethylsUyl)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
-222- period of 1 h. The reaction mixture was poured into 10% NaHCOj 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, 0J86 mmol, 62%). MS (DCI/NH3) m/z 384 (M+H)+; iH NMR (300 MHz, DMSO) (data for major syn diastereomer) δ 7.30 (d, 7=8.0 Hz, 1 H), 7.16-6.97 (m, 3 H), 6.95-6.88 (m, 1 H), 6.67 (d, 7=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, 7=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) δ 138.8, 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-dihvdro-10-ethenyl-5-ri-methyl-3-cvc1ohexenyll-2.2.4-trimethyl-lH- r 11 benzopyrano[3.4- fjquinoline
Example 339 and 3-(dimethylphenylsUyl)-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) δ 7.30 (d, 7=7.9 Hz, 1 H), 7.16-7.00 (m, 3 H), 6.92 (dd, 7=7.1, 2.6 Hz, 1 H), 6.66 (d, 7=8.0 Hz, 1 H), 6.39 (br s, 1 H), 5.73 (d, 7=12.4 Hz, 1 H), 5.52-5.41 (m, 3 H), 5.32 (d, 7=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-methyIthio-2.2.4- trimethyl- lH-[nbenzopyranor3.4- fjquinoline
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
-223- rni.ne.ral oU, 0.430 mmol). The mixture was stirred under an atmosphere of nitrogen until evolution of hydrogen had ceased (1 h). SoUd 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, 0J09 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%_E40% EtOAc/hexanes) to provide the thermally rearranged thiocarbamate product (67 mg, 0J65 mmol, 59%) as a yellow solid. MS (DCI/NH3) m/z 348 (M+H)+.
To a solution of the 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 of the 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 RocheUe'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 and /?-TsOH»H20 (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 (N 2SO4). Filtration and concentration provided a yellow residue which was purified by flash chromatography (elution with 5% EtOAc/CH2Cl2) to
-224- provide the product methylacetal (157 mg, 0.416 mmol, 33% over two steps) as a yeUow foam.
MS (DCI/NH3) m/z 379 (M-OCH3)+.
The lactol prepared above and aUyltrimethylsUane were processed as in Example 2 to give a C-5 allyl compound.
MS (DCIZNH3) m/z 421 (M+H)+.
Example 343 2.5-dihvdro-5-(3-Dropenvl)-10-methylthio-2.2.4-trimethyl-lH-rilbenzopyranof3.4- flquinoline
A suspension of the 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% E-OAC/CH2O2) to provide nearly homogeneous thiophenol adduct (183 mg) as an off- yellow soUd that was used immediately: Η NMR (300 MHz, OMSO-dβ) δ 7.72 (d, 7=8.0 Hz, 1 H), 7.08 (dd, 7=7.6, 1.1 Hz, 1 H), 6.96 (t, 7=7.5 Hz, 1 H), 6.67 (d, 7=8.1 Hz, 1 H), 6.63 (dd, 7=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, lH),-5.03 (dd, 7=13.2, 1.3 Hz, 1 H), 4.98 (dd, 7=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) e 350 (M+H)+.
A solution of the crude thiophenol (183 mg) in DMF (10 mL) at 0 °C was treated with cesium carbonate (50 mg, 0J53 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: Η NMR (300 MHz, OMSO-d6) δ 7.82 (d, 7=8.1 Hz, 1 H), 7.11 (t, 7=7.6 Hz, 1 H), 6.98 (br d, 7=7.7 Hz, 1 H), 6.72 (br d, 7=7.6 Hz, 1 H), 6.62 (d, 7=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)+.
-225- Example 344 (r+/-) 2.5-dihvdro-9-r4-ace-amidohutanoyloxy)-10-methoxy-2.2.4-trimethyl-5-allyl-1H- r 1 Jbenzopyranor3.4-flquinoline MS (APCI) m/z 491 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 7.94 (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), 2J6 (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-riJbenzopyranor3.4- f] quinoline Example 7 and bromodifluoromethane were processed as in Example 8A to provide the desired compound.
MS (CI/NH3) m/z 420 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, J=8.8 Hz, 1 H), 7.26-7.15 (m, 5 H), 7.16-7.13 (ra, 1 H), 6.97 (t, J=8J 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- lH-ri1benzopyranof3.4-flquinoline MS (ESI) m/z 498 (M+H) +.
1H NMR (300 MHz, DMSO-d6) δ 7.68 (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) δ 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 C26H2281BrF2NO2: 499.0782 (M+H)+. Found: 499.0793.
-226- Example 347
10-rhromodifluoromethoxv)-5-phenvl-2.2-dimethv1-4-methylene-2.3.4.5-tetrahvdro-1H- chromenor3.4-flquinoline MS (ESI) m/z 498 (M+H) +.
1H NMR (300 MHz, CDC1 ) δ 7.88 (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=8J 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), 2J9 (d, J=12.4 Hz, 1 H), 1.35 (s, 3 H), 1.14 (s, 3 H); HRMS (FAB) calcd m/z for C26H2279BrF2NO2: 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-dihvdro-9-hvdroxy-10-me-hoxy-2.2.4-trimethyl-5-(r2-fluorophenyl)methyl) -lH- r 11benzopyranor3.4-flquinoline
Example 349 10-methoxy-5-f5-methylisoxazoI-3-yl)methyidene-2.5-dihydro-5-phenyl-2.2.4-trimethyl- lH-πjbenzopyranor3.4-f|quinoline Example IF and the lithium anion of 3,5-dimethyUsoxazole were processed as in
Example IB to provide the desired compound. MS (DCI NH3) m/z 401 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.33 (d, IH, J=8.83 Hz), 7.7-7.5 (m, IH), 7.22 (t, IH, j=8.09), 7.05 (d, IH, J=1J 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-methoxv-5-(3-methylisoxazol-5-yl)methyidene-2.5-dihydro-5-phenyl-2.2.4-trimethvl- lH-fll benzopyranoI3.4- 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)+;
1H NMR (300 MHz, DMSO-d6), isomer 1: δ 8.38 (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: δ 8.16 (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
-227- (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-methoxv-5-('4.5-dimethvl-1.3-oxa7 l-2-v1)methyidene-2.5-dihvdro-5-phenyl-2.2.4- trimethvl-lH-rilhenzopyrano[3.4-flquinoUne 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)+; 1H NMR (300 MHz, DMSO-d6), isomer 1: δ 8.36 (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 isomer δ 8.09 (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-f6-chloropyridin-2-yl)methyidene-2.5-dihydro-5-phenyl-2.2.4-trimethyl-lH-
[ 11 benzopyranor3.4- fjquinoline Example IF and the Uthium 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)+;
1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, IH, J=4.7 Hz), 8.25 (d, IH, J=8J 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, 1H, J=8J 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-
[lJbenzopyranor3.4-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)+;
1H NMR (300 MHz, DMSO-d6), isomer 1: δ 8.52 (d, 2H, J=6J 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: δ 8.32 (d, 2H, J=6J Hz), 8.19 (d, IH, j=8.8 Hz), 7J7 (t, IH, j=8.2 Hz), 6.99 (s, IH), 6.77 (m, 3H),
-228- 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-methoxv-5-(but-3-envlidene)-2.5-dihvdro-5-phenvl-2.2.4-trimethyl-1H- rilhenzopyranor3.4- fjquinoline 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)+; 1H NMR (300 MHz, DMSO-d6) δ 8.16 (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-lH- r 1 lbenzopyranor3.4- fjquinoline Example IF .and the jec-butyllithium were processed as in Example IB to provide the desired compound. MS (DCI NH3) m/z 362 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.01 (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=1J 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-( 1 -butylidene)-2.5-dihydro-5-phenyl-2.2.4-trimethyl- 1 H- πjbenzopyrano 3.4- fjquinoline Example IF and the /i-butyllithium were processed as in Example IB to provide the desired compound. MS (DCI/NH3) m/z 362 (M+H)+;
1H NMR (300 MHz, DMSO-d6) δ 8.14 (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).
-229- Example 357 2.5-dihvdro- 10-methoxy-2.2.4-trimethyl-3-oxide-5-phenyl- 1 H~r 1 lhenzopyranor3.4- fjquinazoline
Example 357A 8-amino-7-bromo- 1 -methoxv-6H-henzorclchromen-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-phenvI-6H-benzorclchromen-8-ylamine Example 357A (2.0 g, 6.25 mmol) and phenylUthium were processed as in
Examples IG and 1 to provide the desired compound.
Example 357C l-(7-bromo-l-methoxy-6-phenyl-6H-benzorcJchromen-8-yl)ethan-l-one Example 357B (1.23 g, 3.22 mmol), tributyl(l-ethoxyvinyl)tin, (1.4 g, .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 CeUte. 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 l-(7-bromo-l-methoxy-6-phenyl-6H-benzorcJchromen-8-yl)ethan-l-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 (N 2SO4) and concentrated to provide the desired compound without purifiction.
-230- 99/41256
Example 357 2.5-dihvdro-10-methoxy-2.2.4-trimethyl-3-oxide-5-phenyl-lH-rilhenzopyranof3.4- flgqinazQline 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 w.as 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 yeUow soUd was coUected by filtration to provide the desired compound.
MS (DCI/NH3) m/z 401 (M+H)+;
IH NMR (300 MHz, DMSO-d6) δ 8.21 (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- IH-fl lbenzopyranor3.4-fJquinazoline 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 w.as filtered through CeUte, concentrated and the resulting residue was flash chromatographed on sitica 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) δ 8.22 (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-dihvdro-10-methoxy-2.2-rspiro ('tetrahvdro-4-pyranyl)l-4-methyl-5-allvl-lH- I" lJbenzopyranor3.4- fjquinoline
Example 359A Example 357A (1.3 g, 4.08 mmol), isopropenyltrimethyltin (3.3 g, 16.3 mmol) a . nd 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)
-231- a . nd concentrated. Flash chromatography on silica eluting with 3:1 hexane/EtOAc provided the desired product.
Example 359 A mixture of the 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 Na2S2U3. The EtOAc layer was washed with water, brine, dried (Na2SO4) and concentrated. Flash chromatography on sUica eluting with 3:2 hexane/EtOAc provided the desired coumarin as a bright yeUow 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) δ 7.92 (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-dihvdro- 10-methoxv-2.2-rspirof hexyl)1-5-allyl- lH-fl lhenzopyranor3.4-flquinoline Example 357A 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) δ 7.95 (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-meth yl-5-allyl- 1 H-[ 1 Jbenzopyranor3.4-f.quinoline Example 357A 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) δ 7.92 (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),
-232- 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 C25H29NO2: C, 79.96; H, 7.78; N, 3.73. Found: C, 79.74; H, 7.89; N, 3.54.
Example 362 2,5-dihydrQ-lQ-methoχy-2,2,3,4-tetramethyl-5-allyl-lH-ri1benTOp.vranor3,4-flqyinQline Example 357A was treated sequentiaUy 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) δ 7.97 (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- 10-methoxy-2.2-dimethyl-4-ethyl-5-allyl- 1 H-f 1 Jbenzopyranor3.4-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) δ 7.98 (d, IH), 7.07 (t, IH), 6.70 (dd, IH), 6.63 (d, IH), 6.53 (dd, IH), 6J2 (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-rilbenzopyranor3.4-flquinoline 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 N . MR (300 MHz, DMSO-d6) δ 7.89 (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.
-233- Example 365 Z-5-(henzvlidenvl)-9-hvdroxv- 10-methoxy-2.2.4-trimethyl- 1 H-2.5-dihvdro- MS (DCI/NH3) 412 (M+H)+; IH NMR (300 MHz, DMSO-d6), δ 8.93 (s, 1 H), 8.13 (d, 7=8.8 Hz, 1 H), 7.63 (d, 7=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 J 834. Found 411.1821.
Example 366
Z-5-f 2.5-difluorobenzvlidenvl)-9-hvdroxy- 10-methoxy-2.2.4-trimethy1- 1 H-2.5-dihydro- rilbenzopyranor3.4-flquinoline MS (DCI/NH3) m/e (M+H)+ 448.
IH NMR (300 MHz, DMSO-d6) δ 9.06 (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-f3-fluorohenzvlidenyl)-10-chloro-9-hydroxy-2.2.4-trimethyl-2.5-dihydro-lH- riJbenzQpyranς>r3.4-f]quinQlipe MS (DCIZNH3) m/z 434 (M+H)+; 1H NMR (300 MHz, DMSO) δ 9.86 (br s, 1 H), 8.40 (d, 7=8.5 Hz, 1 H), 7.61 (dt, 7=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, 7=8.4 Hz, 1 H), 6.85 (d, 7=8.6 Hz, 1 H), 6.84 (s, 1 H), 6.78 (d, 7=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) δ 163.8, 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-hvdroxy-5-(2-picolinylidenyl)-2.2.4-trimethyl-2.5-dihydro-lH- rnbenzopyranof3.4- fjquinoline MS (DCI/NH3) m/z 417 (M+H)+;
-234- 1H NMR (300 MHz, DMSO) δ 9.79 (br s, 1 H), 8.51 (ddd, 7=5.9, 1.6, 1.0 Hz, 1 H),
8.43 (d, 7=8.6 Hz, 1 H), 8.24 (dt, 7=7.8, 1.0 Hz, 1 H), 7.53 (td, 7=7.8, 1.7 Hz, 1 H),
7.22 (ddd, 7=7.7, 5.8, 1.2 Hz, 1 H), 7.00 (d, 7=8.5 Hz, 1 H), 6.88 (d, 7=8.6 Hz, 1 H),
6.81 (d, 7=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) δ 153.5, 149.7, 146.4, 145.7, 136.5, 136J, 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,
114J, 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-C2-picolinylidenyl)-2.2.4-trimethyl-2.5-dihvdro-lH-
T 1 lbenzopyranor3.4- fjquinoline MS (DCI/NH3) m/z 413 (M+H)+; 1H NMR (300 MHz, DMSO) δ 9.08 (br s, 1 H), 8.55 (ddd, 7=5.3, 1.4, 1.0 Hz, 1 H), 8.32 (d, 7=8.6 Hz, 1 H), 8.30 (br t, 7=7.7 Hz, 1 H), 7.83 (td, 7=7.8, 1.4 Hz, 1 H), 7.21 (ddd, 7=7.6, 5.3, 1.2 Hz, 1 H), 6.97 (d, 7=8.6 Hz, 1 H), 6.86 (d, 7=8.5 Hz, 1 H), 6.81 (d, 7=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) δ 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 C26H24 2O3: 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- lH-fl Jbenzopyranor3.4-fJquinoline IH NMR (300 MHz, DMSO-d6) δ 9.05 (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) δ 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, 1 17.8, 1 15.2, 115.0, 114.8, 112.1, 110.9, 1 10.8, 110.5, 101.9, 101.6, 101.2, 29.3, 49.5, 21.1 (2xC); MS (DCI/NH3) /e (M+H)+ 448.
-235- Example 371
9-hvdroxv-10-methoxv-5-r3.4-difluorophenyl)methylidene-2.5-dihvdro-5-phenyl-2.2.4- trimethvl-1H-πibenzopyranor3.4-flquinoline iH NMR (300 MHz, DMSO-d6) δ 9.03 (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 fZ) 9-hvdroxy-10-methoxy-5-rr4-fluorophenyl)methylene)-2.2.4-trimethyl-lH-2.5- dihvdro- \\ lhenzopvranor3.4-flquinoline iH NMR (300 MHz, DMSO-d6) δ 9.01 (s, IH), 8J9 (d, 7=9 Hz, IH), 7.77 ( d, 7=9 Hz, IH), 7.76 (d, 7 =9 Hz, IH), 7.22 (d, 7=9 Hz, IH), 7.18 (d, 7=9 Hz, IH), 6.84 (d, 7=8 Hz, IH), 6.75 (d, 7=9 Hz, IH), 6.72 (d, 7=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); Ϊ3C NMR (75 MHz, DMSO-d6) δ 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 CZ'.-9-hydroxy-10-methoxy-5-(r2.3-difluorophenyllmethylene)-2.2.4-trimethyl-lH-2.5- dihydro-f lJbenzopyranof3.4-flquinoline iH NMR (300 MHz, DMSO-d6) δ 9.09 (s, IH), 8.27 (d, 7=9 Hz, IH), 8.04 ( d, 7=9 Hz, IH), 7.33-7.20 (m, 2H), 6.87 (d, 7=9 Hz, IH), 6.82 (d, 7=9 Hz, IH), 6.76 (s, IH), 6.75 (d, 7=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-
[11benzopyranor3.4- fjquinoline iH NMR (300 MHz, DMSO-d6) δ 9.04 (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)+;
-236- 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.
Exampl 375 rg/-f5S.3'R)-9-hvdroxv-5-ri-methoxvmethvl-3-cvclohexenv11-10-methoxy-2.2.4-trimethyl-
2.5-dihydro- 1 H-H JbenzQpyranor3,4-flquinoIine MS (DCI NH3) m/z 452 (M + H)+; lH NMR (300 MHz, DMSO) δ 8.02 (d, 7 = 8.6 Hz, 1 H), 6.93 (app s, 2 H), 6.68 (d, 7 =
8.3 Hz, 1 H), 6.48 (br s, 1 H), 5.52 (d, 7 = 10.3 Hz, 1 H), 5.42 (br s, 1 H), 5J0 (br s, 1 H), 4.46 (t, 7 = 5.5 Hz, 1 H), 3.81 (s, 3 H), 3.65 (br d, 7 = 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) δ 150.4, 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-riJbenzopyranof3.4- fjquinoline
IH NMR (200 MHz, DMSO-d6) δ 8.70 (s, IH), 7.90 (d, J=8 Hz, IH), 6.61 (m, 2H), 6.51 (d, J=8 Hz, IH), 6.16 (br s, 1H), 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) δ 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) /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-lH- f 1 Jbenzopyranor3.4-flquinoline
IH NMR (200 MHz, DMSO-d6) δ 7.92 (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).
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Example 378 2.5-dihydro-9-r4-N.N-diethylamino-4-oxo-butanoyloxy)-10-methoxy-2.2.4-trimethyl-5-('2- propenyl)-lH-rilbenzopyranor3.4-flquinoline IH NMR (400 MHz, DMSO-d6) δ 7.78 (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), 2J9 (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) δ 171.5, 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 C3iH38N2O5: 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- propenyP-lH-Plbenzopyranor, 3.4- fjquinoline
IH .NMR (200 MHz, DMSO-d6) δ 7.78 (d, J=8.4, 1H), 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), 2J0 (s, 2H), 1.51-1.16 (m, 6H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 171.7, 168.9, 148.5, 148.2, 146.5, 128.7, 124.2, 122.8, 122.2rJ27.5, 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-mo holino-4-oxo-butanoyloxy)-10-methoxy-2.2.4-trimethyl-5-(2- propenyl)- 1 HJ 1 Jbenzopyranor3.4-fJquinoIine IH NMR (400 MHz, DMSO-d6) δ 7.78 (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) δ 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.
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Example 381
2.5-dihvdro-9-r4-N.N-dimethvlamino-4-oxo-hutanovloxv)-10-methoxy-2.2.4-trimethyl-5- r3.4.5-trifluorophenvl)-lH-rnbenzopvranor3.4-flquinoline
IH NMR (400 MHz, DMSO-dό) δ 7.90 (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); πC NMR (100 MHz, DMSO-de) δ 171.4, 170.4, 150J (d, J=248), 148.4,
147.9, 146.4, 128.7, 128.2 (dd, J=251, 49), 126.5, 122.2, 128.2, 127J, 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/NHs) m/e 581(M+H)+, 602(M+Na)+; Anal. Calcd for
C32H31F3N2O5: 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-h ydroxy- 10-methoxy-2.2.4-trimethyl-5-(3-5-difluorophenylmethyl)- 1 H-
PJbenzopyranof 3.4- fjquinoline iH NMR (300 MHz, DMSO-d6) δ 8.81 (s, IH), 7.95 (d, 7 = 8 Hz, IH), 7.10-7.03 (m,
IH), 6.78 (d, 7 = 9 Hz, 2H), 6.63 (dd, 7 = 9, 9 Hz, 2H), 6.41 (d, 7 = 9 Hz, IH), 6.22 (s,
IH), 5.91 (dd, 7 = 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); i3C NMR (75 MHz, DMSO-d6) δ
163.8, 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-flJbenzopyranor3.4- fjquinoline
IH NMR δ 9.51 (s, IH), 7.95 (d, IH, J=8.5Hz), 7.40 (dd, IH, J=5JHz, 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 C22H20CINO2S: 409.0902. Found: 409.0902.
Example 384
2.5-dihydro-9-hydroxy- 10-methoxy-2.2.4-trimethyl-5-cvclopentyl-lH- rπhenzoρyrano|"3.4-f1quinoline iH NMR (300 MHz, DMSO-d6) δ 8.70 (s, IH), 7.99 (d, 7 = 8 Hz, IH), 6.63 (d, 7 = 9 Hz, IH), 6.61 (d, 7 = 9 Hz, IH), 6.48 (d, 7 = 8 Hz, IH), 6.27 (br s, IH), 5.45 (br s, IH),
5.35 (d, 7 = 10 Hz, IH), 3.65 (s, 3H), 2.15 (s, 3H), 2.11 - 1.97 (m, IH), 1.62 - 1.43 (m,
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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-dihvdro-9-hvdroxv-10-methoxy-2.2.4-trimethyl-5-r(2-fluorophenyl)methyl) -lH- riJbenzopyranor3.4- fjquinoline
MS (DCI/NH3) m/z 418 (M+H)+.
Example 386 .
2.5-dihvdro-9-hvdroxvmethvl-10-methoxv-2.2.4-trimethvl-5-allvl-lH-πihenzopyranor3.4- fjqginoline MS (DCI/NH3) m/z 378 (M+H)+;
1H .NMR (500 MHz, DMSO) δ 7.93 (d, 7 = 8.2 Hz, 1 H), 7.16 (d, 7 = 8.3 Hz, 1 H), 6.67 (d, 7 = 8.1 Hz, 1 H), 6.63 (d, 7 = 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, 7 = 10.3 Hz, 1 H), 4.98 (br d, 7 = 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);
,3C NMR (125 MHz, DMSO) δ 154.0, 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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trirι-;thyl-5-ri-penteny1)-lH- π Jbenzopyrano("3.4- fjquinoline iH NMR (300 MHz, DMSO-d6) δ 8.67 (s, IH), 7.88 (d, 7 = 9 Hz, IH), 6.59 (d, 7 = 9 Hz, 2H), 6.48 (d, 7 = 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) δ 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- 1 H- rπhenzopyranor3.4-flquinoline MS (DCIZNH3) m/z 406 (M+H)+; 1H NMR (125 MHz, DMSO) δ 7.92 (d, 7 = 8.1 Hz, 1 H), 6.48 (d, 7 = 8.3 Hz, 1 H), 6.75 (d, 7 = 8.2 Hz, 1 H), 6.65 (d, 7 = 8.2 Hz, 1 H), 6.33 (br s, 1 H), 5.90-5.75 (m, 2 H),
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5.46 (br s, 1 H), 5.04 (dd, 7 = 10.5, 1.0 Hz, 1 H), 4.98 (dd, 7 = 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), 1J6 (s, 3 H);
13C NMR (300 MHz, DMSO) δ 166.1. 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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-allenyl-lH-rilhenzopyranor3.4- fjquinoline
IH NMR (300 MHz, DMSO-d6) δ 8.67 (s, IH), 7.93 (d, 7 = 9 Hz, IH), 6.57 (dd, 7 = 10, 9 Hz, 2H), 6.48 (d, 7 = 9 Hz, IH), 6.15-6.12 (m, 2H), 5.41 (s, IH), 5.31 (q, 7 = 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-rcvclopenten-3-yl)-lH-
P!benzopyranof3.4- fjquinoline lH NMR (300 MHz, DMSO-d6) δ 8.05 (d, 7 = 9 Hz, IH), 7.09 (t, 7 = 8 Hz, IH), 6.72 (d, 7 = 8 Hz, IH), 6.66 (d, 7 = 9 Hz, IH), 6.58 (d, 7 = 8 Hz, IH), 6.19 (s, IH), 5.77 (dd, 7 = 6,3 Hz, IH), 5.50 (d, 7 = 10 Hz, IH), 5.43 (s, IH), 5.19 (dd, 7 = 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) δ 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 (-) f5S. 3'S) 2.5-dihvdro-10-methoxy-2.2.4-trimethyl-5-(cvclohexen-3-yl)-lH- πibenzopyranof 3.4- fjquinoline *H NMR (300 MHz, DMSO-d6) δ 8.03 (d, 7 = 9 Hz, IH), 7.07 (t, 7 = 8 Hz, IH), 6.68 (d, 7 = 8 Hz, IH), 6.63 (d, 7 = 9 Hz, IH), 6.57 (d, 7 = 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); 1 C NMR (75 MHz, DMSO-d6) δ 156.2, 151.0, 145.0, 133.7, 130.4, 129.1, 128.1,
-241- 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. [aJ23 D = -138° (c 0.114, CHCI3). Example 392
(-) (5S. 3'R) 2.5-dihvdro-1 -methoxy-2.2.4-trimethyl-5-fcvclohexen-3-yl)-lH- rnhenzopvranor3.4-f1quinoline H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 7 = 9 Hz, IH), 7.06 (t, 7 = 8 Hz, IH), 6.67 (d, 7 = 8 Hz, IH), 6.64 (d, 7 = 9 Hz, IH), 6.59 (d, 7 = 8 Hz, IH), 6.19 (s, IH), 5.82 (m, IH), 5.72 (m, IH), 5.41 (s, IH), 5.40 (d, 7 = 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) δ 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. [α]23 D = -147° (c 0.080, CHCI3).
Example 393 (-) f5S. 3'R) 2.5-dihvdro-10-methoxy-2.2.4-trimethyl-5-(cvclopenten-3-yl)-lH-
[ljbenzoρ.vranor3,4-fJquinoline lH NMR (300 MHz, DMSO-d6) δ 8.07 (d, 7 = 9 Hz, IH), 7.08 (t, 7 = 8 Hz, IH), 6.70 (d, 7 = 8 Hz, IH), 6.66 (d, 7 = 9 Hz, IH), 6.61 (d, 7 = 8 Hz, IH), 6.22 (s, IH), 5.82- 5.70 (m, 2H), 5.48 (d, 7 = 13 Hz, IH), 5.41 (d, 7 = 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) δ 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-(3rZ)-pentenyl) -lH- f 1 Jbenzopyranor3.4- jquinoline
IH NMR (300 MHz, DMSO-d6) δ 8.71 (s, IH), 7.92 (d, 7 = 8 Hz, 1 H), 6.62 (d, 7 = 9 Hz, IH), 6.60 (d, 7 = 9 Hz, IH), 6.47 (d, 7 = 9 Hz, IH), 6.18 (br s, IH), 5.63 (dd, 7 = 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, 7 = 8 Hz, 3H); MS (DCI/NH3) (M+H)+ 392.
-242- Example 395
2.5-dihvdro-9-hvdroxv- 10-mfithoxv-2.2.4-trimethvl-5J3-acetoxvphflnvl) - 1 H- rilhenzopvranor3.4-flquinoline 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), 7J2(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), 2J8(s, 2H), 1.8 l(s, 2H), 1.25(s, 2H), 1.12(s, 2H).
Example 396 10-difluQrQmethQxy-5-rr3-(methylthifi)methQxy]phenyn-2,2.4-trimethyl-lH-2.5-dihydro- πihenzopvranor3.4-flquinoline
MS (DCI/NH3) 496 (M+H)+;
IH NMR (200 MHz, DMSO-d6), δ 7.80 (d, J=8.5 Hz, 1 H), 7.21 (t, JH-F= 56 Hz, 1 H),
7.20-7J2 (m, 2 H), 6.99 (t, IH), 6.82-6.68 (m, 7 H), 6.29 (d, J=1J Hz, 1 H), 5.40 (s,
1 H), 5J4 (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-chIoro-2.2.4-trimethyl-5-aIlyl-lH- [ 1 Jbenzopyranor3.4- fjquinoline
MS (DCI NH3) m/z 448 (M+H)+; 1H NMR (300 MHz, DMSO) δ 10.03 (s, 1 H), 7.90 (d, 7 = 8.5 Hz, 1 H), 7.00 (app s, 2
H), 6.63 (d, 7 = 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.H-4.97 (m, 1 H), 2.44-2.26 (m, 2 H), 2J9 (s, 3 H), 1.22 (s, 3 H), 1.18 (s, 3 H);
13C NMR (125 MHz, DMSO-d6) δ 156.7, 150.2, 148.6, 144.0, 139J, 136.3, 135.5,
130.8, 129.2, 124.4, 117.6, 1 15.9, 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 C22H21 77BrClNO2: 445.0444 (M)+. Found: 445.0436.
HRMS (FAB) calcd m/z for C22H21 79BrClNO2: 447.0424 (M)+. Found: 447.0413.
Anal. Calcd for C22H2IBrClNO2: C, 59.15; H, 4.74; N, 3J4. 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)-lH- flJbenzopyranor3.4- fjquinoline
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), lJ2(s, 2H).
-243- Example 399 2.5-dihvdro-9-methvlthiomethoxv-10-methoxv-2.2.4-trimethyl-5-C3- fmethvlthio)methoxvphenv1)-lH-rilhenzopyranor3.4-flquinoline MS (DCI NH3) m/z 526(M+H)+ IH NMR (400 MHz, DMSO-d6) 7.94(d, IH), 7J4(t, IH), 6.82-6.70(m, 6H), 6.50(d, IH), 6.24(s, IH), 5.29(s, IH), 5J6(s, 2H), 5J4(s, 2H), 2.6 l(s, 2H), 2J4(s, 2H), 2.08(s, 2H), 1.82(s, 2H), 1.24(s, 2H), 1.16(s, 2H).
Example 400 2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethvl-5-r3-rmethvlthiomethoxv)phenyl)-lH- rilhenzopyranor3.4-flquinoline
MS (DCI/NH3) m/z 476(M+H)+;
IH NMR (400 MHz, DMSO-d6) 8.58(s, IH), 7.92(d, IH), 7J2(t, IH), 6.82-6.6.7 l(m, 4H), 6.62(s, IH), 6.42(d, IH), 6.26(d, IH), 6.25(s, IH), 5.28(s, IH), 5J2(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- r 1 lbenzopyranor3.4- fjquinoline IH NMR δ 9.48 (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), 5J2 (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-dihvdro-9-hvdroxy- 10-methox v-2.2.4-trimethyl-5-f r2-N.N- dimethylcarbamoyloxy1phenyl)-lH-πibenzopyranor3.4- fjquinoline 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-(r2-N.N- dimethylcarbamoyloxylphenyl)- 1 H-f" 1 Jhenzopyranor3.4-fJquinoline MS (DCI/NH3) 575(M+MH4)+; lH NMR (400 MHz, DMSO-d6) 7.90(d, IH), 7.25(t, IH), 7J l(d, IH), 6.95(dd, IH), 6.85(s, IH), 6.79(s, IH), 6.75(d, IH), 6.7 l(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).
-244- Example 404 2.5-dihvdro-9-hvdroxv-10-chloro-2.2.4-trimethyl-5-ethyl-lH-rilhen7npyranor3.4- flquinoline IH NMR (300 MHz, DMSO-d6) δ 9.59 (s, IH), 7.91 (d, 7 = 8 Hz, IH), 6.75 (s, 2H), 6.62 (d, 7 = 8 Hz, IH), 6.29 (d, 7 = 2 Hz, IH), 5.46 (m, 2H), 2.14 (s, 3H), 1.57 (m, 2H), 1J9 (s, 3H), 1.15 (s, 3H), 0.89 (t, 7 = 7 Hz, 3H); Hi Res MS (APCI) m/e calc'd for C21H22NO2CI: 355.1339, found 355.1353.
Example 4Q5
2.5-dihydro-9-hvdroxv-10-chloro-2.2.4-trimethvl-5-isopropvl-lH-rilhenzopyranor3.4- jqyinoline iH NMR (300 MHz, DMSO-d6) δ 9.57 (s, IH), 8.02 (d, 7 = 8 Hz, IH), 6.76 (s, 2H), 6.65 (d, 7 = 9 Hz, IH), 6.45 (s, IH), 5.45 (s, IH), 5.32 (d, 7 = 9 Hz, IH), 2.17 (s, 3H), 1.70 (m, IH), 1.30 (s, 3H), 1.02 (s, 3H), 0.92 (d, 7 = 6 Hz, 3H), 0.67 (d, 7 = 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- r 1 Jbenzopyranor3.4-flquinoline MS (DCI/NH3) 412 (M+H)+;
IH NMR (200 MHz, DMSO-d6), δ 8.92 (s, 1 H), 8.12 (d, 7=8.8 Hz, 1 H), 7.62 (d, 7=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-lH-riJbenzopyranor3.4- fjquinoline
IH NMR (300 MHz, DMSO-d6) δ 9.55 (br s, IH), 7.91 (d, 7 = 9 Hz, IH), 6.74 (s, 2H), 6.61 (d, 7 = 8 Hz, IH), 6.26 (d, 7 = 1 Hz, IH), 5.56 (dd, 7 = 11, 2 Hz, IH), 5.45 (br s, IH), 2.15 (m, 3H), 1.64 (m, IH), 1.46 (m, IH), 1.31 (m, 4H), 1.19 (s, 3H), 1.15 (s, 3H), 0.78 (t, 7 = 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)-lH- r 11 benzopyranor3.4-flquinoIine IH NMR (300 MHz, DMSO-d6) δ 8.72 (s, IH), 8.02 (d, 7 = 8 Hz, IH), 6.88 (s, IH), 6.70 (d, 7 = 8 Hz, IH), 6.68 (d, 7 = 8 Hz, IH), 6.61 (d, 7 = 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) δ 182.9, 182.5, 181.3, 179.8, 169.8, 167.9,
-245- 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-dihvdro-9-hvdroxv- 10-chloro-2.2.4-trimethvl-5J2-methvlprnpvl)- 1 H- r JbeηzQpyraιπor3,4-flqqiηoUpe
IH NMR (300 MHz, DMSO-d6) δ 9.59 (br s, IH), 7.91 (d, 7 = 9 Hz, IH), 6.75 (d, 7 = 8
Hz, IH), 6.73 (d, 7 = 8 Hz, IH), 6.62 (d, 7 = 8 Hz, IH), 6.28 (d, 7 = 2 Hz, IH), 5.70
(dd, 7 = 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), 1J5 (s, 3H), 0.98 (d, 7 = 6 Hz, 3H), 0.75 (d, 7 = 7 Hz, 3H); MS (DCJ/NH3) m/e (M+H)+ 384.
Example 410
2.5-dihvdro-9-hvdroxvmethvl-10-chloro-2.2.4-trimethvl-5-allvl-lH-rilhenzopyranor3.4- flquinoline MS (DCI NH3) m/z 381 (M)+; 1H NMR (500 MHz, DMSO) δ 7.91 (d, 7 = 8.4 Hz, 1 H), 7.30 (d, 7 = 8.5 Hz, 1 H), 6.90 (d, 7 = 8.4 Hz, 1 H), 6.64 (d, 7 = 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, 7 = 5.1 Hz, 1 H), 5.04 (dd, 7 = 10.2, 1.1 Hz, 1 H), 4.97 (dd, 7 = 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 C23H24ClNO2: 381.1496 (M)+. Found: 381.1495._
Example 411 2.5-dihvdro-9-hydroxy-10-chloro-2.2.4-trimethyl-5-propyl-lH-I11benzopyranor3.4- fjquinoline IH NMR (300 MHz, DMSO-d6) δ 9.55 (s, IH), 7.90 (d, 7 = 9 Hz, IH), 6.74 (s, 2H), 6.60 (d, 7 = 9 Hz, IH), 6.26 (s, IH), 5.59 (d, 7 = 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, 7 = 7 Hz, 3H); 3C NMR (75 MHz, DMSO-d6) δ 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-(rr3-fluorophenynmethylene)-2.2.4-trimethyl-lH-2.5-dihydro- rπbenzopyranof3.4-f1quinoline IH NMR (200 MHz, DMSO-d6) δ 9.04 (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)+;
-246- Anal, calcd for C27H24NO2F- 0.25 H2O: C, 75.51; H, 5.62; N, 2.26. Found: C, 74.84; H, 6J7; N.2.91.
Example 413 9-hvdroxv-10-chloro-5-(T2-pvridvnmethvleneV2.2.4- trimethvl- 1 H-2.5-dihvdro- r 1 lhenzopvranor3.4-flquinoline
MS (DCI/NH3) m/z 417 (M+H)+;
IH NMR (200 MHz, DMSO) δ 9.79 (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) δ 152.5, 149.7, 146.4, 145.7, 126.5, 126J, 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, 114J, 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-r("3S)-Cl-hydroxymethyl)cyclohexen-3-yll- 10-methoxy-2.2.4- trimethyl-2.5-dihydro-lH-riJhenzopyranor3.4-fJquinoline IH NMR (200 MHz, DMSO-d6), δ 8.49 (s, 1 H), 7.99 (d, 7=8.5 Hz, 1 H), 6.64 (d, 7=8.5 Hz, 1 H), 6.58 (d, 7=8.5 Hz, 1 H), 6.47 (d, 7=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-(5S)-9-hydroxy-5-f(3S)-(l-methoxycarhonyl)cyc-ohexen-3-yH- 10-methoxy-2.2.4- trimethyl-2.5-dihydro-lH-riJhenzopyranor3.4- fjquinoline MS (DCI/NH3) 462 (M+H)+; IH NMR (200 MHz, DMSO-d6), δ 8.72 (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.
-247- Example 416
2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethvl-5-G.5-dichlorophffnvl)-1H- r 1 lhenzopvranor3.4-flquinoline MS DCI m/z 468 (M+H)+; IH NMR (200 MHz, DMSO), δ 8.69 (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), δ 145.9, 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-dihvdro-9-hvdroxy-10-chloro-2.2.4-trimethyl-5-(l-methylcyclohexen-3- y 1 )- 1 H-π lbenzQpyranor3 Aflquinoliηe MS (DCI/NH3) m/z 422 (M + H)+;
1H NMR (300 MHz, DMSO) δ 9.55 (s, 1 H), 8.02 (d, 7 = 8.4 Hz, 1 H), 6.77 (app s, 2 H), 6.68 (d, 7 = 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) δ 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 C26H28ClNO2: 421.1809 (M)+. Found: 421.1810.
Example 418 (5S.3,R) 2.5-dihvdro-9-hvdroxy-10-chloro-2.2.4-trimethyl-5-(l-methylcvclohexen-3- yl)-lH-riJbenzopyranor3.4-fJquinoline MS (DCI NH3) m/z 422 (M + H)+;
1H NMR (300 MHz, DMSO) δ 9.58 (s, 1 H), 8.05 (d, 7 = 8.4 Hz, 1 H), 6.79 (ABq, 7 = 8.0 Hz, ΔnAB = 14.4 Hz, 2 H), 6.67 (d, 7 = 8.3 Hz, 1 H), 6.47 (br s, 1 H), 5.49-5.46 (m, 2 H), 5.35 (d, 7 = 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) δ 148.7, 145.8, 144.2, 135.1, 134.0, 132.1, 127.9, 126.7, 123.7, 121.4, 118.0, 1 16.0 (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 C26H2gClNO2: 421.1809 (M)+. Found: 421.1816.
-248- Example 419 (+) (5R.3 ' S) 2.5-dihvdro-9-hvdroxy- 10-chloro-2.2.4-trimeth yl-5-f 1 -methylcvclohexen-3- v 1 )- 1 H-π Jhenzopyranor3.4-flquinoline [αfo25 +237.8 ° (c = 0.5, CHC13); MS (DCI NH3) m/z 422 (M + H)+;
1H NMR (300 MHz, DMSO) δ 9.58 (s, 1 H), 8.05 (d, 7 = 8.4 Hz, 1 H), 6.79 (ABq, 7 = 8.0 Hz, ΔnAB = 14.4 Hz, 2 H), 6.67 (d, 7 = 8.3 Hz, 1 H), 6.47 (br s, 1 H), 5.49-5.46 (m, 2 H), 5.35 (d, 7 = 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) δ 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 C26H28ClNO2: 421.1809 (M)+. Found: 421.1806. Example 420 r+) f5R.3,R) 2.5-dihvdro-9-hvdroxy-10-chloro-2.2.4-trimethyl-5-π-methylcvcIohexen-3- y 1 )- 1 H-11 Jbenzopyranor3.4-flquinoline
[α 25 +147.5 ° (c = 0.2, CHC13);
MS (DC1 NH3) m/z 422 (M + H)+; 1H NMR (300 MHz, DMSO) δ 9.55 (s, 1 H), 8.02 (d, 7 = 8.4 Hz, 1 H), 6.77 (app s, 2
H), 6.68 (d, 7 = 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) δ 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 C26H28ClNO2: 421.1809 (M)+. Found: 421.1794.
Example 421
(+/-) 2.5-dihydro-9-(4-N.N-dimethylamino-4-oxo-butanoyloxy)-10-chloro-2.2.4-trimethyl- 5-allyI- 1 H-11 Jbenzopyranor3.4- fjquinoline
MS (ESI) m/z 495 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 7.90 (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).
-249- Example 422 ("-) 2.5-dihvdro-9-hydroxy- 10-chloro-2.2.4-trimethyl-5-cyclθDentyl- 1 H- rilbenzopyranor3.4- fjquinoline MS (DCI NH3) m/z 296(M+H)+; IH NMR (400 MHz, DMSO-d6) IH NMR (200 MHz, DMSO-d6) δ 9.50 (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-dihvdro-9-f4-N.N-dimethvlamino-4-oxo-butanovloxv)-10-methoxv-2.2.4-trimethyl-5- ( 1 -methvlethvl)- 1 HJ 1 lbenzopvranor3.4-flquinoline
*H NMR (400 MHz, DMSO-d6) δ 7.92 (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), 2J7 (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) δ 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-f4-N.N-dimethvlamino-4-oxo-hutanovloxv)-10-methoxv-5-(phenvlmethvl)-
2.2.4-trimethvl-lH-rilhenzopvranor3.4-flquinoline IH NMR (500 MHz, DMSO-d6) δ 7.90 (d, J=8.8, IH), 7.29-7.26 (m, 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=10J, 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) δ 171.5, 170.4, 148.2, 148J, 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, 60J, 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-riJbenzopyranof3.4-fJquinoline H NMR (500 MHz, DMSO-d6) δ 7.90 (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=1J, 3H), 1.23 (s, 3H), 1.15 (s, 3H); 13C NMR (125
-250- MHz, DMSO-d6) δ 171.1, 170.2, 148.6, 147.5, 146.0, 142.8, 138.4, 132.8, 130J, 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-dihvdro-9-(4-N.N-dimethvlaminohutanovloxv)-10-methoxv-2.2.4-trimethyl-5-f2- propenvl)-1H-πihenzopvranor3.4-flquino1ine IH NMR (500 MHz, DMSO-d6) δ 7.85 (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=7J, 2H), 2.47 (m, IH), 2.22 (t, j=7.0, 2H), 2.25 (m, IH), 2J8 (s, 2H), 2.16 (s, 6H), 1.80 (m, 2H), 1.18 (s, 2H), 1.17 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 171.8, 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 C29H36N- 204: C 72.08, H 7.61, N 5.88. Found: C 72.77, H 7.74, N 5.64.
Example 427 9-f2-ethoxv-2-oxo-ethvlaminocarhonvl)-oxv-10-methoxv-5- -propenvl)-2.2.4-trimethvl- lH-2.5-dihydro- rilbenzopyrano[3.4-f1quinoline MS (DCI NH3) 510 (M+NH4)+, 492 (M+H)+, 264;
IH NMR (200 MHz, DMSO-d6), δ 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=1J 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=1J 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- G-acetamido-propanoyloxy)- 10-methoxy-2.2.4-trimethyl-5-allyl- 1 H- πjbenzopyranor3.4-f1quinoline MS (APCI) m/z 477 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 8.04 (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), 3.04 (dd, IH), 4.98 (dd, IH), 2.61 (s, 2H), 2.40 (q, 2H), 2.76 (t, 2H), 2.52-2.44 (m, IH), 2.20-2.24 (m, IH), 2J8 (s, 2H), 1.84 (s, 2H), 1.18 (s, 2H), 1.17 (s, 2H).
-251- Example 4 f+/-) 2.5-dihvdro-9-hvdroxv-10-ch1oro-2.2.4-trimethvl-5-henzvl-lH-πihenznpyrannr3.4- flquinoline MS (DCI/NH3) m/z 418(M+H)+;
IH NMR (400 MHz, DMSO-d6) IH NMR (200 MHz, DMSO-d6) δ 9.70 (bs, IH), 7.99
(s, IH), 7.20-7.08 (m, 5H), 6.79 (d, IH), 6.67 (d, IH), 6.62 (d, IH), 6J9 (d, IH), 5.86
(dd, IH), 5.44 (s, IH) 2.98-2.84 (m, 2H), 2.22 (s, 2H), 1J9 (s, 2H), 1.17 (s, 2H).
Example 430 9-hvdroxv- 10-methoxv-5-tphenvlmethvlene)-2.2.4-trimethvl- 1 H-2.5-dihvdro- rilbenzopvranor3.4-flquinoline (DCI NH3) 412 (M + H)+; H NMR (300 MHz, DMSO-d6), δ 8.93 (s, 1 H), 8.13 (d, 7 = 8.8 Hz, 1 H), 7.63 (d, 7 = 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-fdimethylaminothiocarhonyl)-oxy-10-methoxy-5-f3-propenyl)-2.2.4-trimethyl-lH-2.5- dihydro- riJbenzopyranor3.4-flquinoline MS (DCI NH3) 451 (M+H)+;
IH NMR (200 MHz, DMSO-d6), δ 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), 1J8 (s, 2 H), 1.16 (s, 2 H);
Anal, calcd for C26H20N2O2S.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-carhamoyI-2-aminoacetoxy)-10-methoxy-2.2.4-trimethyl-5-allyl- lH-ri1benzopyranor3.4- fjquinoline
MS (APCI) m/z 464 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 7.78 (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), 2J0 (s, 2H), 1.11 (s, 2H), 1.10 (s, 2H).
-252- Example 433 f +/-) 2.5-dihvdro-9- f4-e. hoxv-4-oxo-hutoxv)- 10-methoxy-2.2.4-trimethyl-5-a11v1- 1 H- riJben?;c>pyran 'r3,4-flquinoline IH NMR (200 MHz, DMSO-d6) δ 7.92 (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), 1J9 (t, 2H, J=5Hz), 1.17 (s, 6H).
Example 4 4 C+/-) 2.5-dihvdro-9-(4-oxo-pentanovloxv)-10-methoxv-2.2.4-trimethvl-5-al1y1-lH- 1 lhenzopvranor3.4-flquinoline MS (APCI) m/z 462 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 7.78 (d, IH), 6.77 (d, IH), 6.59 (d, IH), 6.57 (d, IH), 6J8 (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-dihvdro-9-hvdroxy-10-chloro-2.2.4-trimethyl-5-G.4.5-trifluorophenyl)-lH-
[ 1 j henzopyrano[3.4- fjquinoline IH NMR δ 9.20 (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-alIyl-lH- rilbenzopyranoβ.4- fjquinoline 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), 5.8 l(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), 2J8(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)-lH-[lJhenzopyranor3.4-flquinoline iH NMR (400 MHz, DMSO-d6) δ 7.84 (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,
-253- J=7.2, 3H); 13C NMR (100 MHz, DMSO-d6) δ 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 C22H40N2O5: C 72.15, H 7.57, N 5.26. Found: C 72.16, H 7.76, N 5.06.
Example 438
2.5-dihvdro-9-r4-N.N-dimethvlamino-4-oxo-pentanoyloxy)-10-methoxy-2.2.4-trimethyl-5-
(2-propenyl)-lH-[11benzc)pyrappr3,4-fJqumpline IH NMR (400 MHz, DMSO-d6) δ 7.77 (d, J=8.5, IH), 6.81 (d, J=8.9, IH), 6.61-6.56 (m, 2H), 6J9 (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) δ 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 C3oH36N2O5: C 71.40, H 7J9, N 5.55. Found: C 71.20, H 7.19, N 5.29.
Example 439 2.5-dihydro-9-C4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2.2.4-trimethyl-5-(2- propenyl)-lH-rilbenzopyranoI3.4- fjquinoline IH NMR (400 MHz, DMSO-d6) δ 7.78 (d, J=8.9, IH), 6.81 (d, J=8.5, IH), 6.61- 6.55 (m, 2H), 6J9 (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), 1J0 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.7, 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 (ES17NH3) 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)-lH-fJlbenzopyranor3.4-flquinoline IH NMR (400 MHz, DMSO-d6) δ 7.77 (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),
-254- 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), 2J0 (s, 2H), 1.82 (m, 2H), 1.11 (s, 2H), 1.10 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.6, 170.2, 148.4, 147.9, 146.2, 128.4, 124.0, 122.5, 122J, 127.2, 126J, 120.7, 118.2, 117.2, 116.2, 114.9, 112.8, 112.6, 72.6, 66J, 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-dihvdro-9-f4-N.N-dimethvlamino-4-oxo-butanovloxv)-10-methoxv-2.2.4-trimethyl- 5fS)-r3rS)-l-cvclopenten-3-yl)-lH-πihenzopyranor3.4-flquinoline
MS (APCI) m z 517 (M+H)+;
IH NMR (200 MHz, DMSO-d6) δ 7.94 (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-methoxv-9-.rallvlaminocarhonvl)oxv-5-f3-propenv1)-2.2.4-trimethvl-lH-2.5-dihvdro- rilhenzopvranor3.4-flquinoline MS (DCI/NH3) 464 (M+NH4)+, 447 (M+H)+, 264.
IH NMR (200 MHz, DMSO-d6), δ 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-('cvclohexylaminocarhonyl)-oxy-5-(3-propenyl)-2.2.4-trimethvl-lH-2.5- dihydro-πibenzopyrano|"3.4-fJquinoline MS (DCI/NH3) 506 (M+NH4)+, 489 (M+H)+, 264.
IH NMR (200 MHz, DMSO-d6), δ 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=1.0 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.
-255- Example 444 2.5-dihvdro-9-hvdroxv-10-methoxv-2.2.4-trimethv1-5-('3-thienvl)-lH-rilhenzopvrannr3.4- flquinoliπe H NMR (300 MHz, DMSO-d6) δ 8.57 (s, IH), 7.91 (d, 7 = 9 Hz, IH), 7.35 (dd, 7 = 5, 5
Hz, IH), 6.99 (d, 7 = 5 Hz, IH), 6.92 (s, IH), 6.68 (d, 7 = 9 Hz, IH), 6.64 (s, IH), 6.44 (d, 7 = 9 Hz, IH), 6.34 (d, 7 = 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); i3C NMR (125 MHz, DMSO-dβ) δ 183.2, 182.4, 181.4, 181J, 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-dihvdro-9-hvdroxy-10-methoxy-2.2.4-trimethyl-5-r4-rfluorophenvl)methv1)-lH- rilbenzopyranor3.4-flquinoline iH NMR (300 MHz, DMSO-d6) δ 8.47 (s, IH), 7.94 (d, 7 = 8 Hz, IH), 7.33-7.31 (m, IH), 7.13-7.04 (m, 3H), 6.62 (dd, 7 = 9, 8 Hz, 2H), 6.41 (d, 7 = 9 Hz, IH), 6.41 (s, IH), 5.82 (dd, 7 = 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); i3C NMR (75 MHz, DMSO-d6) δ 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 C27H26O3lSrF 0.30 H2O: C, 74.23; H, 6.14; N, 3.21; found: C, 74.16; H, 6.44; N, 2.96.
-256-

Claims

WHAT IS CLAIMED IS:
1. A compound having Formula I
Figure imgf000259_0001
I, or a pharmaceuticaUy 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, l, 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) -NRδC(X)NR9- where X is O or S and Rs and R9 are independently selected from
-257- (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, (0 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) -CO2R20 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,
-258- (11) -NR7R7 where R7 is defined previously and Rγ 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
(n) 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 Rπ 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,
-259- (b) -OH, provided that no two -OH groups are attached to the same carbon,
(c) -SH,
110 (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, 115 (h) -NO2,
(i) haloalkoxy of one to twelve carbons, (j) perfluoroalkoxy of one to twelve carbons, (k) -NR7R7, (1) =NNR7R7', 120 (m) -NR7aNR7'R7" where R7 and R7- are defined previously and
R7" is selected from (i) hydrogen, (ii) aryl,
(iii) cycloalkyl of three to twelve carbons, 125 (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, 130 (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, 135 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, 140 (n) -CO2R10 where Rio is selected from
(i) aryl,
(ii) aryl substituted with 1 , 2, or 3 alkyl of one to twelve carbon substituents,
-260- (u) cycloalkyl of three to twelve carbons, 145 (iϋ) 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, 150 (q) =NRιo,
(r) -S(O)tRιo, (s) -X'C(X)Rιo, (t) (=X), and (u) -OSO2R11, 155 (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 Li is other than a covalent bond, where (17) and (18) can be optionally substituted with 1, 2, 3, or 4 substituents 160 independently selected from
(a) alkyl of one to twelve carbons,
(b) aryl,
(c) alkoxy of one to twelve carbons,
(d) halo,
165 (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 170 (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, 175 (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, 180 (g) thioalkoxy of one to twelve carbons,
-261- (h) perfluoroalkyl of one to twelve carbons,
(i) -NR7R7',
(j) -CO2R10,
(k) -OSO2R11, and
185
Figure imgf000264_0001
(1) (=X);
R2, R3, and R4 are independently hydrogen or Ri; or
Rl and R2 together are -X*-Y*-Z*- where X* is -O- or -CH2-, Y* is -C(O)- or 190 -(C(Ri2)(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 195 (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,
200 (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,
205 (4) alkynylene of two to twelve carbons,
(5) -NR7-,
(6) -C(X)-,
(7) -O-, and
(8) -S(O)r; and 210
R5 is selected from
(1) halo,
(2) hydrogen,
(3) -C(=NR7)ORιo, 215 (4) -CN, provided that when R5 is (1), (2), or (3), L2 is a covalent bond, (5) alkyl of one to twelve carbons,
-262- (6) .alkynyl two to twelve carbons, provided that a carbon of a carbon-carbon triple bond is not attached directiy 220 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 225 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, 230 (c) -CN,
(d) halo,
(e) -CHO,
(f) -NO2,
(g) haloalkoxy of one to twelve carbons,
235 (h) perfluoroalkoxy of one to twelve carbons,
(i) -NR8'R9' where Rs' and R91 are selected from (i) hydrogen,
(n) allsanoyl where the alkyl part is one to twelve carbons, (iii) alkoxycarbonyl where the alkyl part is one to twelve carbons, 240 (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 3 245 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 250 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,
-263- 255 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, 260 (xn) 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, 265 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 270 carbon, thioalkoxy of one to twelve carbons, perfluoroalkyl of one to twelve carbons, -NR7R7, -CO2R10, 275 -OSCfcRii. and
(=X), or R8" and R^ together with the nitrogen atom to which they are attached form a ring selected from
(i) aziridine,
280 (ii) azetidine,
(in) pyrrolidine,
(iv) piperidine,
(v) pyrazine,
(vi) moφholine,
285 (vii) phthalimide,
(viii) thiomorpholine, and
(ix) thiomoφholine sulfone where (i)-(ix) can be optionally substituted with 1, 2, or 3 alkyl of one to twelve carbon substituents,
290 (j) =NNR8'R9',
Figure imgf000266_0001
(k) -NR7NR8'R9',
-264- (1) -CO2R8,
(m) -C(X)NR8-R9', (n) =N-OR8, 295 (o) =NRs,
(p) -S(O)tRι0, (q) -X'C(X)R8, (r) (=X),
(s) -O-(CH2)q-Z-Rιo where Rio is defined previously, q is 1, 2, or 3, 300 and Z is O or -S(O)t-,
(t) -OC(X)NR8-R9s (u) -OSO2R11,
(v) alkanoyloxy where the alkyl group is one to twelve carbons, (w) -LBR30 where Lβ is selected from 305 (i) a covalent bond,
(n) -O-, (tii) -S(O)r, and (iv) -C(X)- and R30 is selected from 310 (i) alkyl of one to twelve carbons,
(u) alkenyl of one to twelve carbons, provided that a carbon of a carbon-carbon double bond is not attached directiy to Lβ when Lβ is other than a covalent bond, (in) alkynyl of one to twelve carbons, 315 provided that a carbon of a carbon-carbon triple bond is not attached directly to Lβ when Lβ is otiier than a covalent bond, where (i), (ii), and (iii) can be optionally substituted with cycloalkyl of three to twelve carbons, -OH, 320 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, 325 -NRs'R9'.
-O-(CH2)q-Z-Rιo, alkoxycarbonyl where the alkyl group is one to twelve carbons,
-265- alkanoyloxy where the alkyl group is one to twelve
330 carbons,
-NR7SO2-(alkyl of one to twelve carbons),
-OSO2-(alkyl of one to twelve carbons), aryl, and heterocycle,
335 (iv) aryl,
(v) aryl substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo,
340 -NO2, and
-OH, provided that no two -OH groups are attached to the same carbon,
(vi) heterocycle, and
345 (vn) heterocycle substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl of one to twelve carbons, halo,
-NO2, and
350 -OH, provided that no two -OH groups are attached to the same carbon,
(x) -X'C(X)X"Rιo,
(y) -NHC(O)NHNH2,
355 (z) alkenyl of two carbons,
(aa) -C(=NR7)ORιo, and
(bb) -NR7(X)NR8-R9', ^20
(10) R19 provided that when R5 is (9), L3 is other than -NR7- or -O-, 360 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,
-266- (c) alkoxycarbonyl where the alkyl group is of one to twelve carbons,
365 (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
370 carbon,
(iii) -SH, provided that no two -SH groups are attached to the same carbon,
(iv) -CN,
375 (v) halo,
(vi) -CHO,
(vii) -NO2,
(vui) haloalkoxy of one to twelve carbons,
(ix) perfluoroalkoxy of one to twelve carbons,
380 (x) -NR8-R9.
(xi) =NNR8'R9',
(xϋ) -NR7NR8'R9',
(xiii) -CO2R10,
(xiv) -C(X)NR8-R9-,
385 (XV) =N-ORιo,
(xvi) =NRιo,
(xvii) -S(O)tRιo.
(xvin) -X'C(X)RlO,
(xix) (=X),
390 (xx) -O-(CH2)q-Z-Rιo,
(xxi) -OC(X)NR8-R9\
(xxii) -LβR30.
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiv) -OSO2R11- and
395 (xxv) -NR7(X)NR8'R9', or
R20 and R21 together are selected from
(a) cycloalkyl of three to twelve carbon atoms,
Figure imgf000269_0001
(b) cycloalkenyl of four to twelve carbon atoms, and
-267- ,R22
(c) 23 (allene) where R22 and R23 are independently
400 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 405 (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, 410 (d) -CN,
(e) halo,
(f) -CHO,
(g) -NO2,
(h) haloalkoxy of one to twelve carbons,
415 (i) perfluoroalkoxy of one to twelve carbons,
(j) -NR8-R9-
(k) =NNR8'R9-,
(1) -NR7NR8'R9-,
(m) -CO2R10.
420 (n) -C(X)NR8'R9-,
(o) =N-ORιo,
(P) =NRιo,
(q) -S(O)tRιo-
(r) -X'C(X)Rιo,
425 (S) (=X),
(t) -O-(CH2)q-Z-Rιo,
(u) -OC(X)NR8'R9',
(v) -LBR30,
(w) alkanoyloxy where the alkyl group is one to twelve carbons,
430 (x) -OSO2R11, and
(y) -NR7(X)NR8'R9';
R<j is hydrogen or alkyl of one to twelve carbon atoms; or
-268- 435 -L2-R5 and Re together are selected from
(1) =0,
(2) £ ^*)« where δ is 1, 2, 3, or 4 and A is selected from
(a) -CH2-,
(b) -O-,
440 (c) -S(O)t, and
(d) -NR7-, and
y 26
(3) 26 where the carbon-carbon double bond can be in the E or Z configuration and R26 and R26' are independently selected from 445 (a) hydrogen,
(b) alkenyl of three to twelve carbons,
(c) aryl,
(d) heterocycle,
(e) alkyl of one to twelve carbons,
450 (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 455 (i) alkoxy of one to twelve carbons,
(ii) -OH, provided that no two -OH groups are attached to the same carbon, (iii) -SH, 460 provided that no two -SH groups are attached to the same carbon, (iv) -CN, (v) halo, (vi) -CHO, 465 (vii) -NO2,
(viii) haloalkoxy of one to twelve carbons, (ix) perfluoroalkoxy of one to twelve carbons,
-269- (x) -NR8-R9'
(xi) =NNR8'R9\ 470 (xu) -NR7NR8'R9',
(xiϋ) -CO2Rιo,
(xiv) -C(X)NR8-R9',
(xv) =N-ORιo,
(xvi) =NRιo, 475 (xvii) -S(O)tRιo,
(xviii) -X'C(X)Rιo,
(xix) (=X),
(xx) -O-(CH2)q-Z-Rιo,
(xxi) -OC(X)NR8 1R9% 480 (xxii) -LBR30,
(xxiii) alkanoyloxy where the alkyl group is one to twelve carbons,
(xxiii) -OSO2R11, and
(xxiv) -NR7(X)NR8'R9';
485 Ri6 and Ri6' are independently hydrogen or alkyl of one to six carbons; or
Rl6 and Ri6* together are alkenyl of two carbons;
a broken line represents the optional presence of a double bond, provided that when Ri6 and RKJ- together are alkenyl of two carbons, the double 490 bond is not present;
Y is selected from carbon, nitrogen, and N+(=O");
R17 is absent or hydrogen or alkyl of one to six carbons, 495 provided that when the double bond is present, and Y is nitrogen or N+(=O"),
R17 is absent; and
Rjg and Ris* are independently hydrogen or alkyl of one to six carbons; or Rl8 and Ri8' together are a cycloheteroalkyl ring or a cycloalkyl ring of three to 500 eight carbons.
2. A compound according to Claim 1 of Formula H
-270-
Figure imgf000273_0001
II, or a pharmaceuticaUy acceptable salt or prodrug thereof, where
Rl. R2» R3. R4- Rs. Rθ- and L2, are defined above.
3. A compound according to Claim 2 where Ri is -LI-RA, LI is -O- or -S-, .and RA is alkyl of one to twelve carbons that can be optionally substituted, or Rj and R2 together are -X*- Y*-Z*-.
4. A compound according to Claim 3 selected from 2,5-dihydro-10-methoxy-2,2,4-trimeιhyl-5-phenyl-lH-[l]benzopyrano[3,4- f . jquinoline 1 H- [ 1 ] benzopyrano [3 ,4- fjquinoline, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fjquinohne,
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-lH-[l]benzopyrano[3,4- fjquinoline, 5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano [ 3 ,4-fJquinoline ,
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-fJquinolin-5- yl)phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(methylthio)methoxyJphenylJ-lH-
[lJbenzopyrano[3,4-fJquinoline,
[3-(2,5-dihydro-10-methoxy-2,2, 4- trimethyl- lH-[lJbenzopyrano[3,4-f]quinolin-5- yl)phenyl] dimethylcarbamate, 5-[3-(2-furanyl)-5-methylphenylJ-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-methyl-5-(l-moφholinyl)phenyl]- lH-[lJbenzopyrano[3,4-fJquinoline,
-271- 2,5-d ιydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)-lH- [l]benzopyrano[3,4-fJquinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
5-butyl-2,5-dihydro- 10-methoxy-2,2,4- trimethyl- 1 H- [ 1 J benzopyrano[3,4- fJquinoUne, 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenyl]-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-(4-methoxyphenyl)-2,2,4- trimethyl- 1 H-
[ 1 ] benzopyrano [3 ,4- fjquinoline,
5-(3-chlorophenyl)-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-methylphenyl)-lH-
[l]benzopyrano[3,4-f]quinoline,
(± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fJquinoUne, (± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fJquinoUne,
5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, -
5-(4-chlorophenyl)-2,5-dihydiO-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4-fJquinoline,
5-(3,4-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano[3 ,4- fjquinoline, 5-[3,5-bis(trifluoromethyl)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
(-)-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- [l]benzopyrano[3,4-f]quinoline,
5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 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-
-272- ,-,.,„« PCT/US99/03127 9/41256
[ 1 ] benzopyrano[3 ,4-fJquinoline,
(+)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1H-
[ 1 ]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 ] benzopyrano[3 ,4-f]quinoline, 4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-5- yl)-N,N-dimethylbenzenamine,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)- 1 H-
[ 1 ] benzopyrano[3 ,4-fJquinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)- 1 H- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[4-( 1 -moφholinyl)phenylJ- 1 H-
[l]benzopyrano[3,4-f]quinoline, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
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-yl)-2-propanone, methyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinoUne-5-acetate,
2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-
5-yl)- 1-phenylethanone,
5-[2-(chloromethyl)-2-propenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[lJbenzopyrano[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] benzopyrano[3 ,4- fjquinoline,
5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4-f]quinoline,
5-(3-bromophenyl)-2,5-dihydro-10-methoxy-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(phenylmethyl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-propyl- 1 H-[ 1 Jbenzopyrano[3,4- fjquinoline,
-273- IΛ ..., PCT/US99/03127
WO 99/41256
5-(4-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4-fJquinoline,
5-(3-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1H- 100 [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4,5-tetramethyl-lH-[l]benzopyrano[3,4-f]qui-noline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(l-methylethyl)- 1 H-
[ l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H- 105 [l]benzopyrano[3,4-f]quinoline,
5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinoUne,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyr^o[3,4-f]quinoline-5- carboximidic acid ethyl ester, 110 2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene lH-[lJbenzopyrano[3,4- fjquinoline-5-propanol,
2,5-dihydro-10-methoxy-2,2,4,N,N-pent.amethyl-lH-[l]benzopyrano[3,4- fjquinoUne-5-acetamide,
2,5-dihydro- 10-methoxy-2,2 ,4,N,N-pentamethyl- 1 H- [ 1 J benzopyrano[3,4- 115 fJquinoline-5-ethanamine,
N-cyclopropyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinoUne-5-acetamide,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-propynyl)-lH-[l]benzopyrano[3,4- fJquinoUne, 120 5-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-5- yl)-2(5H)-furanone,
5-(3-butenyl)-2,5-dihdyro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinoUne,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline-5- 125 propanol,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4-f]quinoline,
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[l]benzopyrano[3,4-f]quinoline, 130 [3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoUn-5- yl)phenylj methylcarbonate,
2,5-dihydro- 10-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl- 1 H-
[lJbenzopyrano[3,4-fJquinoline,
-274- 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenyl]- 1 H- 135 [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenyl]-lH-
[ 1 ] benzopyrano [3, 4-fJquinoline,
5-[3-(cyclopropylmethoxy)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline, 140 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[2-(l-piperidinyl)ethoxy]pheny]-
1 H-[ 1 Jbenzopyrano[3,4- fjquinoline,
5-(3-hexyloxyphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano [3 ,4-fJquinoline,
5-[3-(2,4-dinitrophenoxy)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 145 1 H- [ 1 Jbenzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propynyloxy)phenyl]-lH-
[ 1 ] fc>enzopyr.ano [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), 150 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-[lJbenzopyrano[3,4-f]quinolin-
5-yl)phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[4-(methylthio)methoxyJphenylJ- 155 lH-[lJbenzopyrano[3,4-f]quinoline,
[4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoUn-
5-yl)phenylJ dimethylcarbamate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenylJ-lH-
[ 1 ] be nzopyrano[3 ,4- fjquinoline, 160 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenylJ-lH-
[lJbenzopyrano[3,4- fjquinoline,
[(2,5-dihydro-10-methoxy-2,2,4- trimethyl- lH-[lJbenzopyrano[3,4-f]quinolin-5- yl)phenylj 1 -moφholinecarboxylate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[(methylsulfinyl)methoxyJphenylJ- 165 lH-[lJbenzopyrano[3,4-fJquinoline,
O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinolin-5-yl)phenylJ ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenylJ-lH-
[l]benzopyrano[3,4-f]quinoline, 170 O-[3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 J benzopyrano[3,4-
-275- f]quinolin-5-yl)phenyl] methylcarbonothioate,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethylJ-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)phenylJ trifluoromethanesulfonate,
5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenylJ-2,5-dihydro-10-methoxy- 175 2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline, 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-[lJbenzopyrano[3,4-fJquinolin-5- yl)benzoic acid, 180 2,5-dihydro-10-methoxy-2,2,4-uimethyl-5-[3-methyl-5-(2-propenyl)phenylJ- lH-[lJbenzopyrano[3,4-f]quinoline, l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
5-yl)-5-methylphenyl]ethanone,
3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H- [ 1 J benzopyrano[3,4-f]quinolin-5- 185 yl)-5-trimethylbenzenemethanol,
5-[3-(2-furanyl)phenylJ-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-methyl-5-(lH-pyrrolidin-l- yl)phenylJ-lH-[lJbenzopyrano[3,4-f]quinoline, 190 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-
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-dihydro-10-methoxy-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinolin- 195 5-yl)-N-(2-methoxyethyl)-5-methylbenzenamine,
3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinolin-
5-yl)-N-(2-propenyl)benzenamine,
N'-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fJquinolin-5-yl)-5-methylphenyl]-N,N-dimethylurea, 200 N-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinolin-5-yl)phenylJbenzenemethanamine,
5-[(3,5-dichlorphenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4- jquinoline,
5-[(4-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- 205 [ 1 J benzopyrano[3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-
(trifluoromethyl)phenyl]methylene]-lH-[lJ-benzopyrano[3,4-fJquinoline,
-276- 5-[(2,6-difluorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]benzopyrano[3,4- fjquinoline,
210 5-[(2-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
5-[(2,6-dichlorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [lJbenzopyrano[3,4- fjquinoline,
5-[(2-fluorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- 215 [lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[(4,5-dihydro-4,4-dimethyl-2- oxazolyl)methy lenej- 1 H- [ 1 ] benzopyrano [3 ,4-fJquinoUne, 2,5-dUιydro- 10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)- 1H- [lJbenzopyrano[3,4-f]quinoline,
220 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-[l]benzopyrano[3,4- fJquinoUne,
2,5-dihydro-9J0-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)-lH- [lJbenzopyrano[3 ,4- fjquinoline,
5-(2-cyclohexen-l-yl)-2,5-dihydro-9J0-dimethoxy-2,2,4-trimethyl-lH- 225 [lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoUne,
2,5-dihydro-10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 jbenzopyrano [3 ,4-f] quinoUne, 230 rel (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl- 1 H-[ 1 ]benzopyrano[3 ,4-^quinoline, anti(5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl- 1 H-[ 1 Jbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4- trimethyl- 1H- 235 [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-(3-cyclohexenyl)-2,2,4- trimethyl- 1H-
[lJbenzopyri o[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-butenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, 240 2,5-dihydro- 10-methoxy-5-( 1 -ethenyl- 1 -cyclohexyl)-2,2,4-trimethyl- 1 H-
[1 jbenzopyrano [3, 4- fjquinoline,
2,5-dihydro-10-methoxy-5-(4,4-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
-277- 2,5-dihydro- 10-methoxy-5-( l-methylene-2-cyclohexyl)-2,2,4-trimethyl- 1H- 245 [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-meιhoxy-5-(l-oxo-2-cyclohexyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinotine,
2,5-dihydro- 10-methoxy-5-(3-cyclooctenyl)-2,2,4- trimethyl- 1H-
[ 1 ] benzopyrano [3 ,4-f] quinoUne, 250 2,5-dihydro-10-methoxy-5-(3-cycloheptenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinotine,
2,5-dihydro- 10-methoxy-5-( 1 -cyclohexenylmethyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-10-methoxy-5-(3,3-dimethyl-6-cyclohexenyl)-2,2,4-trimethyl-lH- 255 [ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinohne, re/(5R,3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ 1 ]benzopyrano[3 ,4-f]quinoline, 260 re/(5R,3'S) 2,5-dihydro- 10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxymethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [3,4-fJ quinoUne,
2,5-dihydro-10-methoxy-5-(3-indolyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 265 fjquinoline, rel (5S,3' S) 2,5-dihydro- 10-methoxy-5-( 1 -methyl-3-cyclohexenyl)-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline, rel (5R,3'S) 2,5-dihydro- 10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl-
1 H- [ 1 J benzopyrano [3 ,4-f] quinoline, 270 (-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethylr
1 H- [ 1 J 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-fJquinoline,
(+) (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- 275 trimethyl- 1 H-[ 1 ]benzopyrano[3,4-f]quinoline,
(-)-(5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ 1 Jbenzopyrano[3 ,4-f]quinoline,
(+)-(5R, 3 ' S) 2,5-dihydro- 10-methoxy-5-( 1 -methyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ 1 ]benzopyrano[3,4-f]quinoline,
-278- 280 2,5-dihydro- 10-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-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-methylthiomethyl-3-cyclohexenyl)- 285 2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'S) 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-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-fJquinoline, 290 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-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,N-dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-methylthiomethyl-3-cyclohexenyl)- 295 2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-moφholino)methyl-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-methyl-N- methylsulfonylamino)methyl-3-cyclohexenyl)-2,2,4-trime-hyl-lH- 300 [l]benzopyrano[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-lH-[lJbenzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline, 305 2,5-dihydro- 10-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(l,3-butadien-2-yl)-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-carbomethoxy-3-propenyl)-2,2,4-trimethyl-lH- 310 [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-
[l]benzopyrano[3,4-f]quinoline, 315 2,5-dihydro- 10-methoxy-5-( 1 -(N-phthalimido)-3-propyl)-2,2,4-trimethyl- 1H-
[ 1 ]benzopyrano[3 ,4- jquinoline,
-279- 2,5-dihydro-10-methoxy-5-(l-amino-3-propyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fJquinoUne,
2,5-dihydro-10-methoxy-5-(l-(hydrazinocarbonylamino)-3-propyl)-2,2,4-trimethyl- 320 1 H- [ 1 ] benzopyrano [3 ,4-fJ quinoline,
(^ 2,5-dihydro-10-methoxy-5-(2-carbomethoxy-l-ethenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne,
(Z)-2,5-dihydro-10-methoxy-5-(l-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, 325 (E) 2,5-dihydro-10-methoxy-5-(3-hydroxy-l-propenyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinoUne,
(E) 2,5-dihydro- 10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)- 1-propenyl)-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3-methoxymethoxy- 1 -propenyl)-2,2,4-trimethyl- 330 lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinolin-5-yl) acetyl hydroxamate, 335 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin-5- yl) acetaldehyde, _
2,5-dihydro-10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl-lH- 340 [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline, 345 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- 1 -yl)-2,2,4-trimethyl- 1H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
2,5-dihydro- 10-methoxy-5-( 1 ,1-difluoro- l-propen-3-yl)-2,2,4-trimethyl- 1H- 350 [ 1 ]benzopyrano[3 ,4-fJquinoline,
(E) methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-
^quinolin-5-yl) 2-butenoate,
-280- (E) 2,5-dihydro-10-memoxy-5-(4-hydroxy-2-buten-l-yl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, 355 (E) 2,5-dihydro- 10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten- 1 -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 J benzopyrano[3 ,4- fjquinoline, rø 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 360 fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl- 1 H-
[lJbenzopyr.ano[3,4-f]quinoUne,
2,5-dihydro-10-metiιoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinoUne, 365 2,5-dihydro-10-methoxy-5-(2-(N-moφhoUnoc-ιrbonyloxy)e-hyl)-2,2,4-trimethyl-
1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline ,
2,5-dihydro-10-methoxy-5-(2-(N-(2-methoxyethyl)aminocarbonyloxy)ethyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-methyaminocarbonyloxyoxy)ethyl)-2,2,4- 370 trimethyl- 1 H-[ 1 Jbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, 375 2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4- trimethyl- 1 H-[ l]benzopyrano[3,4-r]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- 380 [l]benzopyrano[3,4-r]quinoline,
2,5-dihydro-10-methoxy-5-(carboethoxy)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 385 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-
[l]benzopyrano[3,4-fjquinoline,
-281- 2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 390 f]quinoline,
2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyr-mo[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 395 2,5-dihydro-10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
9- 10-methylenedioxy-5-phenyl-2,2,4-trimethyl- lH-2,5-dihydro-
[l]benzopyrano[3,4-f]quinotine,
5-(3-propenyl)-9-chloro-10-ethenyl-2,2,4-trimethyl-2,5-dihydro-lH- 400 [l]benzopyrano[3,4-f]quinoUne,
9-chloro- 10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 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-fJquinoUne, 405 9-chloro-10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 ] benzopyrano [3 ,4- f] quinoUne,
8-fluoro- 10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1H-
[ l]benzopyr£mo[3,4-f]quinoUne,
5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dUιydro-lH- 410 [l]benzopyrano[3,4-f]quinoline,
(10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline,
10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4- trimethyl- lH-2,5-dihydro-
[l]benzopyrjmo[3,4-f]quinoline, 415 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-cyclohexenyl)-lH-
[ 1 Jbenzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-methylcyclohexen-3- yl)-lH-[l]benzopyrano[3,4- fjquinoline,
(-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl- 420 2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline,
(+) (5R,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro- 1 H-[ 1 ] benzopyrano[3,4-f]quinoline,
(+) (5R,3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro-lH-[l]benzopyrano[3,4-fJquinoline,
-282- 425 (-) (5S,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro- 1 H- [ 1 J benzopyrano [3 ,4-fJquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenyl]-10-methoxy-2,2,4- trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline, (+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-
430 methylcyclohexen-3-y 1)- 1 H-[ l]benzopyrano[3,4-f]quinoline, re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenylJ- lO-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H- [ 1 J benzopyrano[3,4-f]quinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-5-propyl-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano [3,4- fJquinoUne,
435 (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohepteny 1 )- 1 H- [ 1 J 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 J benzopyrano [3 ,4-f] quinoline, 2,5-dihydro-9-hydroxy- 10-methoxy -2,2,4-trimethyl-5-phenyl- 1 H-
440 [l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-difluorophenyl)-lH- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH- [l]benzopyrano[3,4- fjquinoline,
445 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)-lH-[lJbenzopyrano[3,4-f]quinoline, (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-
450 cyclopentenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
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)-lH- [l]benzopyrano[3,4- fjquinoline,
455 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethylphenyl)- lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5- bistrifluoromethylphenyl)-lH-[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4-
460 chlorophenyl)-lH-[l Jbenzopyrano [3, 4-fJquinoline,
-283- 2,5-dUιydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 Jbenzopyrano [3, 4-fJ quinoUne,
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-
[ l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy- 10-methoxy-5-(phenylmethyl)-2,2,4- trimethyl- 1 H-
[ l]benzopyrano[3,4-f]quinoUne,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenyl]- lH-[l]benzopyrano[3,4-f]quinoline,
(-) (S) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano[3,4-f]quinoUne,
(+) (R) 5-cyclopentyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, 2,5-dihydro-9-hydroxy-10-methoxy-5-(3-propynyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-propyl)-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-tiιienyl)-lH- [l]benzopyrano[3,4-f]quinoline, _
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,
6- pentafluorophenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- hydroxymethylcyclopenten-3-yl)-lH-[l]benzopyrano[3,4- fjquinoline, (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methylcarboxylatecyclopenten-3-yl)-lH-[lJbenzopyrano[3,4-f]quinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexenyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ 1 ]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-
[ 1 ]benzopyrano[3 ,4-fJquinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) -1H-
[lJbenzopyrano[3,4-f|quinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3- propenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
-284- (+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenyl]-lH-[l]benzopyrano[3,4-f|quinoline, 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-uimethyl-5-cyclohexyl- 1 H- 500 [l]benzopyrano[3,4-f]quinoUne,
2,5,5-trihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-metiιoxy-2,2,4-trimethyl-5-(2-hydroxymethyl-3- propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline, 505 methyl 2-[2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-f]-5-quinoUnyl] acetate,
(Z) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-butenyl)- 1H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH- 510 [lJbenzopyrano[3,4-fJquinoline,
(+) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ 1 Jbenzopyrano [3,4-fjquinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- lH-[ 1 Jbenzopyrano[3,4-f]quinoline, 515 (+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopentenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopentenyl)-lH-[l]benzopyrano[3,4-f]quinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l-methoxycarbonyl)cyclohexen-3-ylJ- 10-methoxy- 520 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(2-methyl-3-propenyl)- 1 H-
[l]benzopyrano[3,4-f]quinoline,
9, 10-Dimethoxy-5- (3-propenyl)-2,2,4- trimethyl- 1 H-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline, 525 9J0-Dimethoxy-5-[3-cyclohexenylJ-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4-fJquinoline,
10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline,
10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 530 [l]benzopyrano[3,4-f]quinoline,
10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4-f]quinoline,
-285- 2,5-dihydro-9-acetoxy-10-methoxy-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ l]benzopyrano[3,4-f]quinoUne, 535 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-f]quinoUne,
7-bromo -5-[3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4-f]quinoUne,
10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- .540 [l]benzopyrano[3,4-f]quinoUne,
7-bromo-5-[l-methyl-3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-
1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline ,
10-methoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ lJbenzopyrano[3,4- fjquinoline, 545 7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4- fjquinoline,
7,9-Dibromo-5-[cyclohexen-3-yl]- 10-methoxy-2,2,4-trimethyl-2,5-dihydro- 1H-
[l]benzopyrano[3,4-f]quinoUne,
7,9-Dibromo-5-[l-methyl-3-cyclohexenyl]-10-methoxy-2,2,4-trimethyl-2,5- 550 dihydro-lH-[l]benzopyrano[3,4-f]quinoUne,
10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4-f]quinoUne,
10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Jbenzopyrano [3 ,4-fJquinoline, 555 10-methoxy-7-acetyl-5-(3-propenyl)-2,2,4-trimethyl-lH-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]benzopyrano[3,4- fjquinoline,
10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 560 [ 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-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- 565 methylcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
-286- 2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH- 570 [l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(3-(2-metiιanesulfonyloxyethyl)phenyl)-2,2,4-trimethyl- lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano [ 3 ,4-fJquinoUne, 575 2,5-dihydro- 10-methoxy-5-(3-(2-(N,N-dimethylaminocarbonyloxy)ethyl)phenyl)-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-cyclopropyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 580 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- 1H-
[l]benzopyrano[3,4-f]quinotine, 585 2,5-dihydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH-
[l]benzopyr^o[3,4-f]quinoline, cis 2,5-dihydro- 10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4- trimethyl- 1H- 590 [l]benzopyrano[3,4-f]quinoliner trans 2,5-dihydro- 10-methoxy-5-(l-cyclohexenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 595 2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl- lH-[l]benzopyrano[3,4-fJquinoline,
10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- 600 [l]benzopyrano[3,4-f]quinoline,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano[3,4-.f}quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
-lH-[lJbenzopyrano[3,4-f]quinoline,
-287- 605 10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
10-methoxy-5-(3-methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyi- 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- 610 2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
10-methoxy-5-(6-chloropyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline,
10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, 615 10-methoxy-5-(but-3-enyUdene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4- fjquinoline,
10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
10-methoxy-5-(l-butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- 620 [l]benzopyrano[3,4-f]quinoline,
Z-5-(benzylidenyl)-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-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- dihydro-[lJbenzopyrano[3,4-fJquinoUne, _
625 Z-9-hydroxy- 10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro- 1H-
[l]benzopyrano[3,4- fjquinoline,
9-hydroxy-10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-
2,2,4- trimethyl- lH-[l]benzopyrano[3,4- fjquinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5-phenyl- 630 2,2,4-trimethyl- 1 H-[ 1 J benzopyrano[3,4-f]quinoline,
(Z) 9-hydroxy- 10-methoxy-5-((4-fluorophenyl)methylene)-2,2,4-trimethyl- 1 H-2,5- dihydro- [l]benzopyrano[3,4-f]quinoline,
(Z)-9-hydroxy-10-methoxy-5-([2,3-difluorophenylJmethylene)-2,2,4-trimethyl-lH-
2,5-dihydro-[l]benzopyrano[3,4- fjquinoline, 635 Z-5-(3-fluorobenzylidenyl)-10-methoxy-9-hydroxy-2,2,4-trimethyl-2,5-dihydro- lH-[lJbenzopyrano[3,4-f]quinoline,
9-hydroxy-10-methoxy-5-ethyl-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-cyanomethoxy- 10-methoxy-2,2,4-trimethyl-5-allyl- 1H- 640 [lJbenzopyrano[3,4-f]quinoline,
-288- 2,5-dihydro-9-(4-N,N-diethyl--mino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-(4-N-piperidmo-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoUne, 645 2,5-dihydro-9-(4-N-moφholino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl-
5- (2-propeny 1)- 1 H- [ 1 ] benzopyrano [3 ,4-fJ quinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(3,4,5-trifluorophenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-difluorophenylmethyl)- 650 1 H-[ 1 J benzopyrano [3 ,4-f] quinoline ,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclopentyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
-lH-[l]benzopyrano[3,4-fJquinoline, 655 2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2,4-trimethyl-5-aUyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-pentenyl)-lH-
[ 1 Jbenzopyrano [3, 4- fjquinoline,
2,5-dihydro-9-methylcarboxylate-10-methoxy-2,2,4-trimethyl-5-aUyl-lH- 660 [l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-aUenyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 665 (-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[l]benzopyrano[3,4- fjquinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclohexen-3-yl)-lH-
[l]benzopyrano[3,4- fjquinoline,
(-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH- 670 [lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3(Z)-pentenyl) -lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl) -lH-
[l]benzopyrano[3,4- fjquinoline, 675 10-difluoromethoxy-5-[[3-(methylthio)methoxy]phenylJ-2,2,4-trimethyl-lH-2,5- dihydro- [lJbenzopyrano[3,4-f]quinoline,
-289- 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)- 1 H-
[ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3- 680 (methylthio)methoxyphenyl)- lH-[l]benzopyrano[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,
2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-uimethyl-5-([2-N,N- dimethylcarbamoyloxyJphenyl)-lH-[l]benzopyrano[3,4- fjquinoline, 685 9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[l]benzopyrano[3,4-f]quinoUne,
9-hydroxy-10-methoxy-5-([3-fluorophenyl]methylene)-2,2,4-trimethyl-lH-2,5- dihydro- [l]benzopyrano[3,4-f]quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-methoxycarbonyl)cyclohexen-3-yl]- 10-methoxy- 690 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3,5-dichlorophenyl)- 1H-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(l-methylethyl)-lH-[lJbenzopyrano[3,4-fJquinoline, 695 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-methoxy-5-
(phenylmethyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoUne,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-thienyl)- IH- [ 1 ]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5- 700 (2-propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4- trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)-10-methoxy-2,2,4-trimethyl-5- allyl- 1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline, 705 9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4- trimethyl- 1 H-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline,
9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl- lH-2,5-dihydro- [lJbenzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)-10-methoxy-2,2,4-trimethyl-5- 710 allyl- lH-[l]benzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)-10-methoxy-2,2,4-trimethyl-5-aUyl- lH-[lJbenzopyrano[3,4-fJquinoline,
-290- (+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H-
[ l]benzopyrano[3,4-f]quinoUne, 715 2,5-dihydro-9-methylthiomethoxy- 10-methoxy-2,2,4-trimethyl-5-allyI- 1H-
[l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)- 1 H- [ 1 ] benzopyrano [3 ,4-f]quinotine,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- 720 trimethyl-5-(2-propenyl)- lH-[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)- 1 H-[ 1 ] benzopyrano [3 ,4-f] quinoUne,
2,5-dihydro-9-(4-N-morphoUno-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-
5-(2-propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline, 725 (-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- lO-methoxy-2,2,4- trimethyl-5(S)-(3(S)-l-cyclopenten-3-yl)-lH-[l]benzopyrano[3,4-flquinoline,
10-methoxy-9-(^lylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [l]benzopyrano[3,4-f]quinoline,
10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5-(3-propenyl)-2,2,4-trimethyl-lH- 730 2,5-dihydro-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH-
[l]benzopyrano[3,4-f]quinoline, .and
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- lH-[l]benzopyrano[3,4-f]quinoline.
735
A compound according to Claim 2 where Ri is -LI-RA, LI is a covalent bond and RA is -NR7R7-.
A compound according to Claim 5 selected from
2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fJquinoUn- 10-amine,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl-lH-[l]benzopyrano[3,4- fJquinoUn- 10-amine,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH- [l]benzopyrano[3,4-f]quinolin-10-amine, and 2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[lJbenzopyrano[3,4- fJquinoline-10-carboxylic acid.
10
-291-
7. A compound according to Claim 2 where Ri is -LI-RA, LI 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- fJquinotine-10-carboxylate and methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline- 10-carboxylate.
9. A compound according to Claim 2 where Ri is -LI-RA, LI 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-lH-[lJbenzopyrano[3,4-f]quinoUne-10-ol acetate (ester).
11. A compound according to Claim 2 where Ri is -LI-RA, LI is a covalent bond and RA 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-trimetiιyl-5-phenyl- 1 H-[ 1 ]benzopyrano[3 ,4-fJquinoline,
2,5-dihydro-2,2,4J0-tetrametnyl-5-phenyl-lH-[l]benzopyrano[3,4- fjquinoline,
5-(3,5-dichlorophenyl)- 10-ethyl-2,5-dihydro-2,2,4-trimethyl- 1 H- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoline-
10-methanol,
2,5-dihydro-10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline, 2,5-dihydro- 10-aminomethyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxymethyl-5-(3-propenyl)-2,2,4- trimethyl- 1H-
[1 Jbenzopyrano [3, 4- fjquinoline,
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-[lJbenzopyrano[3,4- fjquinoline.
-292-
13. A compound according to Claim 2 where Ri 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-trimetnyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fJquinoUne.
2,5-dihydro- 10-ethenyl-5-phenyl-2,2,4-trimethyl- lH-[ 1] benzopyrano [3,4- .fjquinoline,
2,5-dihydro-10-ethenyl-5-oxo-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, 5-(3-cyclohexenyl)-2,5-dihydro- 10-ethenyl-2,2,4- trimethyl- 1 H- [l]benzopyrano[3,4-f]quinoline, and
2,5-dihydro- 10-ethenyl-5-[ l-methyl-3-cyclohexenyl]-2,2,4-trimethyl- 1H- [l]benzopyrano[3,4-f]quinoUne.
15. A compound according to Claim 2 where Ri is -LI-RA, LI 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-f]quinoline and
2,5-dihydro- 10-ethynyl-5-phenyl-2,2,4- trimethyl- 1 H- [ l]benzopyrano[3,4- fjquinoline.
17. A compound according to Claim 2 where Ri is -LI-RA, LI 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-dihydro-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4-f]quinoUn-10-ol, 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fJquinolin-10-ol, 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4-fJquin olin-10-ol,
( 10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl- 1 H-2,5-dihydro-
[ 1 Jbenzopyrano[3,4-f]quinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro- [l]benzopyrano[3,4-f]quinoline,
-293- 10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4- fjquinoline,
10-chloro-9-hydroxy-5-(3,5-dimethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4-fJquinoUne, rel-(5S, 3'R)-9-hydroxy- 10-methoxy-5-[l-hydroxymethyl-3-cyclohexenyl]-2,2,4- trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline,
(-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3S-cyclopentenyl)-lH-
[l]benzopyrano[3,4-f]quinotine,
(-) 2,5(S)-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3R-cyclopenteny 1 )- 1 H- [l]benzopyrano[3,4-f]quinotine,
10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4-f]quinoUne,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 ] benzopyrano[3,4-f]quinoline, (+)-(5R, 3'R)2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1)- 1 H- [ 1 ] benzopyrano[3,4-f]quinoline,
10-chloro-9-hydroxy-5-(3,4-difluorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4-f]quinoUne,
10-chloro-5-(3-propenyl)-2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4- fjquinoline,
(+/-) 2,5-dUιydro-10-chloro-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyr^o[3,4- fjquinoline,
2,5-dihydro-10-(2-furanyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, 2,5-dihydro-10-cyano-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-carboxy-5-(3-propenyl)-2,2,4- trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-formyl-5-(3-propenyl)-2,2,4- trimethyl- lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-formyl-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
Z-5-(3-fluorobenzylidenyl)-10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 ] benzopyrano[3 ,4-f]quinoline, Z-10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[ l]benzopyrano[3,4-f]quinoline.
-294- re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenyl]-10-chloro-2,2,4- trimethyl-2,5-dihydro- 1 H-[ 1 ] benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-thienyl)-lH- [l]benzopyrano[3,4-fJquinoUne,
9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4- trimethyl- lH-2,5-dihydro-
[l]benzopyrano[3,4-f]quinoline, and
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinotine. 2,5-dihydro-7-bromo-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-allyl- 1 H-
[ l]benzopyrano [3 ,4-f]quinoUne,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyJphenyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-ethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-isopropyl-lH-
[l]benzopyrano[3,4-.f]quinotine,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-butyl-lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-thiazol-2-yl)-lH-
[ l]benzopyrano[3 ,4- .fjquinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[ 1 Jbenzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-hydroxymethyl- 10-chloro-2,2,4-trimethyl-5-allyl- 1 H- [l]benzopyr- o[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-propyl- 1 H-
[l]benzopyrano[3,4- fjquinoline,
9-hydroxy-10-chloro-5-([2-pyridyl]methylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyr∑uιo[3,4-^quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-hydroxymethyl)cyclohexen-3-yl]- 10-chloro-2,2,4- trimethyl-2,5-dihydro- 1 H-[ 1 J 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-[l]benzopyrano[3,4- fjquinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-yl)-lH-[l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-yl)-lH-[l]benzopyrano[3,4- jquinoline,
-295- (+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-y 1)- 1 H-[ l]benzopyrano[3,4-f]quinoline,
85 (+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)- 10-chloro-2,2,4- trimethyl-5-allyl- lH-[ l]benzopyrano[3,4- fjquinoline, (-) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-cyclopentyl-lH- [l]benzopyrano[3,4-f]quinoline, and (+/-) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-benzyl- 1H-
90 [l]benzopyrano[3,4-fJquinotine.
19. A compound according to Claim 2 where Ri is -LI-RA, LI is O and RA is alkenyl of three to twelve carbons that can be optionaUy 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- fJquinoUne.
21. A compound according to Claim 2 where Ri is -LI-RA, LI is O and RA is alkynyl of three to twelve carbons that can be optionaUy 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-f]quinoline.
23. A compound according to Claim 2 where Ri is -LI-RA, LI 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-[l]benzopyrano[3,4- fJquinoUn- 10-yl] methy -carbonate.
25. A compound according to Claim 1 of Formula in
-296-
Figure imgf000299_0001
in, or a pharmaceuticaUy acceptable salt or prodrug thereof, where Rl, R2, R3, R4, R5, R6, and L2, are defined above.
26. A compound according to Claim 25 where Ri is -LI-RA, LI 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-fJ quinoline.
28. A compound according to Claim 1 of Formula IN
Figure imgf000299_0002
IV, or a pharmaceutically acceptable salt or prodrug thereof, where
Y is nitrogen or Ν+(=O"), and
Rl, R2, R3, R4, R5, Rό, and L2, are defined above.
29. A compound according to Claim 28 where Ri is -LI-RA, LI 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
-297- 2,5-dihydro-10-methoxy-2,2,4-trimethyl-3-oxide-5-phenyl-lH-[l]benzopyrano[3,4- fjquinazoline and
2,5-dihydro- 10-me thoxy-2,2,4-trimethyl-5-phenyl- 1 H- [ 1 ]benzopyrano[3,4- fjquinazohne.
31. A compound according to Claim 1 of Formula V
Figure imgf000300_0001
H Riβ'
V, or a pharmaceuticaUy acceptable salt or prodrug thereof, where
Rl, R2, R3, R4, R5, Re, and L2, are defined above.
Rl6 and R17 are independently hydrogen or alkyl of one to six carbons; and
Rl8 and Riβ' are independently hydrogen or alkyl of one to six carbons; or Rl8 and Ri8« together are a cycloheteroalkyl ring or a cycloalkyl ring of three to eight carbons;
32. A compound according to Claim 31 where Ri is -LI-RA, Li 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-methy 1-5-ally 1-1 H- [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2-[spiro(hexyl)J-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2-diethyl-4-methyl-5-allyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
-298- 2,5-dihydro-10-methoxy-2,2-dimethyl-4-ethyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline, and
2,5-dihydro-10-methoxy-2,2,3-trimethyl-5-.allyl-lH-[l]benzopyrano[3,4- fjquinoline.
34. A compound selected from
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- f]quinolinelH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-[ 1 ]benzopyrano[3,4- fjquinotine,
2,5-dihydro-2,2,4,N-tetramethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4- fJquinoUn- 10-amine, methyl 2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fjquinoline- 10-carboxylate, 10-ethenyl-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fJquinoUne,
10-ethynyl-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[l]benzopyrano[3,4-^quinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrMθ[3,4-f]quinoUn-10-ol, 10-(difluoromethoxy)-2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Jbenzopyrano [3 ,4-f]quinoline,
10-ethoxy-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fjquinohne,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4-fJquinoline-10-ol acetate (ester),
5-(3-bromo-5-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyr-mo[3,4- fjquinoline,
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-f]quinolin-5- yl)phenol,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[[3-(methylthio)methoxyJphenylJ-lH-
[l]benzopyrano[3,4- fjquinoline,
[3-(2,5-dihydro-10-methoxy-2,2,4- trimethyl- lH-[l]benzopyrano[3,4-f]quinolin-5- yl)phenylj dimethylcarbamate,
5-[3-(2-furanyl)-5-methylphenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline,
-299- 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(l-moφholinyl)phenyl]- lH-[lJbenzopyrano[3,4- fjquinoline, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(phenylmethylene)-lH-
[l]benzopyrano[3,4-f]quinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
5-butyl-2,5-dihydro- 10-methoxy-2,2,4- trimethyl- 1 H-[ 1 ] benzopyrano[3,4- fJquinoUne,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(trifluoromethyl)phenylJ-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(4-methoxyphenyl)-2,2,4-trimethyl-lH-
[ lJbenzopyrano[3,4- fjquinoline, 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-
[lJbenzopyrano[3,4- fjquinoline,
(± )-2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrMo[3,4- jfjquinotine,
(± )-2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-phenyl- lH-[lJbenzopyrano[3,4- fjquinotine, -
5-(3,5-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline, 5-(4-chlorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
5-(3,4-dimethylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-fjquinoline,
5-(4-fluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH- [l]t>enzopyrano[3,4-f]quinoline,
5-[3,5-bis(trifluoromethyl)phenylJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-fjquinoline,
(-)-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- 1 H-
[ 1 J benzopyrano [3 ,4- fjquinoline,
5-(3,5-difluorophenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
-300- 2,5-dihydro- 10-methoxy-2,2,4,N-tetramethyl-N-phenyl- 1 H-[ 1 J 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)-lH-
[ 1 Jbenzopyrano [3, 4- fjquinoline, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 ] benzopyrano[3,4-f]quinoline,
4-(2,5-dihydro- 10-mefhoxy-2,2,4-trimethyl- 1 H-[ 1 ] 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 ] benzopyrano [3 ,4-f] quinoline, 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(5-propyl-2-thienyl)-
1 H- [ 1 ]benzopyrano[3 ,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(l-moφholinyl)phenylJ- lH-[lJbenzopyrano[3,4-f]quinoline, l-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinolin- 5-yl)-3,3-dimethyl-2-butanone,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[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-[lJbenzopyrano[3,4- f]quinoUne-5-acetate,
2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[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-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-
[l]benzopyrano[3,4- fjquinoline, 5-(3-fluoro-4-methylphenyl)-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[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)-lH- [l]benzopyrano[3,4-f]quinoline.
-301- 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-propyl- 1 H- [ 1 ] benzopyrano[3,4- fJquinoUne,
5-(4-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4-f]quinoline, 110 5-(3-fluorophenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1H-
[l]benzopyrano[3,4- fjquinoline,
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-( 1 -methylethyl)- 1 H-
[ 1 ] benzopyrano [3 ,4-f]quinoline, 115 2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H-
[l]benzopyr.ano[3,4-f]quinoline,
5-ethyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinoUne,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline-5- 120 carboximidic acid ethyl ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-(-methylene lH-[l]benzopyrano[3,4- f]quinoline-5-propanol,
2,5-dihy dro- 10-methoxy-2,2 ,4,N,N-pentamethyl- 1 H- [ 1 ] benzopyrano[3,4- f]quinoUne-5-acetamide, 125 2,5-dihydro-10-methoxy-2,2,4,N,N-pentamethyl-lH-[l]benzopyrano[3,4- fJquinoline-5-ethanamine,
N-cyclopropyl-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- πquinoUne-5-acetamide,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-propynyl)-lH-[lJbenzopyrano[3,4- 130 fJquinoUne,
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- lH-[l]benzopyrano[3,4- fjquinoline, 135 2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoline-5- propanol,
10-ethyl-2,5-dihydro-2,2,4-trimethyl-5-phenyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-2,2,4J0-tetrametnyl-5-phenyl-lH-[l]benzopyrano[3,4-f]quinoline,
5-(3,5-dichlorophenyl)- 10-ethyl-2,5-dihydro-2,2,4-trimethyl-lH-[l jbenzopyrano 140 [3,4-f]quinoline,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4,N-tetramethyl- 1 H-[ 1 Jbenzopyrano[3,4- fjquinolin-l 0-amine,
-302- 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-N-(2-propenyl)-lH-
[l]benzopyrano[3,4-f]quinolin-10-amine, 145 2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-proρynyloxy)-lH-[l]benzo pyrano[3,4- fjquinoline,
2,5-dihydro-2,2,4-trimethyl-5-phenyl-10-(2-propenyloxy)-lH-[l]benzopyrano[3,4- fJquinoUne,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoline- 150 10-methanol,
2,5-dihydro-2,2,4-trimethyl-5-(2propenyl)-lH-[lJbenzopyrano[3,4- fJquinoUne-10-carboxyUc acid,
5-(3,5-dichlorophenyl)-10-ethoxy-2,5-dihydro-2,2,4-trimethyl-lH-
[ 1 J benzopyrano[3 ,4- .fjquinoline, 155 5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinolin-10-ol,
5-(3,5-dichlorophenyl)-2,5-dihydro-2,2,4-trimethyl-lH-[lJbenzopyr^o[3,4- fjquinohn- 10-ylJmethy -carbonate,
2,5-dihydro-2,2,4-trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4-fJquin 160 olin-10-ol,
10-(bromodifluoromethoxy)-2,5-dihyro-2,2,4-trimethyl-5-(2-propenyl)-lH-
[ 1 Jbenzopyrano[3,4- fjquinoline,
[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-f]quinoUn-5- yl)phenylj methylcarbonate, 165 2,5-dihydro-10-methoxy-5-(3-methoxyphenyl)-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(2-propenyloxy)phenylJ-
1 H- [ 1 Jbenzopyrano[3 ,4- fj quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(phenylmethoxy)phenylJ- 170 lH-[lJbenzopyrano[3,4-f]quinoline,
5-[3-(cyclopropylmethoxy)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[2-(l-piperidinyl)ethoxy]pheny]- lH-[lJbenzopyrano[3,4-f]quinoline, 175 5-(3-hexyloxyphenyl)-2,5-dihydro- 10-methoxy-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline,
5-[3-(2,4-dinitrophenoxy)phenyl]-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-(2-propynyloxy)phenylJ-
-303- 180 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)phenol 4-methylbenzenesuhconate (ester),
4-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-
5-yl)phenolacetate (ester), 185 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)methoxyJphenylJ- lH-[l]benzopyrano[3,4- fjquinoline,
[4-(2,5-dihydro- 10-methoxy-2,2,4- trimethyl- lH-[lJbenzopyrano[3,4-f]quinoUn- 190 5-yl)phenyl] dimethylcarbamate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[4-(phenylmethoxy)phenylJ- lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methoxymethoxy)phenyl]-lH-
[ l]benzopyrano[3,4-f]quinoline, 195 [ (2,5-dihydro- 10-methoxy-2,2,4-trimethyl- 1 H-[ 1 ] benzopyrano[3 ,4-f]quinolin-5- yl)phenylj 1 -moφholinecarboxylate,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-[(methylsuUinyl)methoxyJphenylJ-
1 H-[ 1 ]benzopyrano[3,4-f]quinoline,
O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 200 f]quinolin-5-yl)phenylJ ester,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-(methylthio)phenyl]-lH-
[l]benzopyrano[3,4-f]quinoline,
O-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinoUn-5-yl)phenyl] methylcarbonothioate, 205 [3-(2,5-dihydro- 10-methoxy-2,2,4-trimethylJ-lH-[l]benzopyrano[3,4-fJquinolin-
5-yl)phenylJ trifluoromethanesulfonate,
5-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]-2,5-dihydro-10-methoxy-
2, 2,4- trimethyl- lH-[l]benzopyrano[3,4-f]quinoline, ethyl 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- 210 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]- lH-[l]benzopyrano[3,4-f]quinoline, 15 l-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-fJquinolin-
5-yl)-5-methylphenyl]ethanone,
-304- 3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinolin-5- yl)-5-trimethylbenzenemethanol,
5-[3-(2-furanyl)phenyl]-2,5-dihydro-10-methoxy-2,2,4-trimethyl- 220 lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[3-methyl-5-(lH-pyrrolidin-l- yl)phenyl]-lH-[l]benzopyrano[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, 225 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-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-fjquinolin- 230 5-yl)-N-(2-propenyl)benzenamine,
N'-[3-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fJquinotin-5-yl)-5-methylphenyl]-N,N-dimethylurea,
N-[3-(2,5-dihydro- 10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- f]quinolin-5-yl)phenyl]benzenemethanamine, 235 5-[(3,5-dichlθφhenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
5-[(4-chlorophenyl)methylene]-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- 240 (trifluoromethyl)phenyl]methyleneJ-lH-[lJ-benzopyrano[3,4-fJquinoline,
5-[(2,6-difluorophenyl)methylene]-2,5-dihydro- 10-methoxy-2,2,4- trimethyl- 1 H-
[ l]benzopyrano[3,4-f]quinoline,
5-[(2-chlorophenyl)methylene]-2,5-dihydro-10-methoxy-2,2,4-trimetiιyl-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinoline, 245 5-[(2,6-dichlorophenyl)methyleneJ-2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-
[ 1 ] benzopyrano [3 ,4-fJquinoline,
5-[(2-fluorophenyl)methyleneJ-2,5-dihydro-10-meιhoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-[(4,5-dihydro-4,4-dimethyl-2- 2.50 oxazolyl)methy lenej- 1 H- [ 1 ]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(2-pyridinylmethylene)-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-[lJbenzopyrano[3,4-
-305- fJquinoUne, 255 2,5-dihydro-9, 10-dimethoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[l]benzopyrano[3,4-f]quinoline,
5-(2-cyclohexen-l-yl)-2,5-dihydro-9J0-dimethoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-(3-methyl-3-butenyl)-2,2,4-trimethyl- 1H- 260 [l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-10-methoxy-5-(5,5-dimethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne, re/ (5R,2'R) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline, 265 anti(5R, 2'S) 2,5-dihydro-10-methoxy-5-(2-oxo-3-tetrahydropyranyl)-2,2,4- trimethyl- lH-[ l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-cyclopentenyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro- 10-methoxy-5-(3-cyclohexenyl)-2,2,4-trimethyl- 1 H- 270 [l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-butenyl)-2,2,4-trimethyl-lH-[l]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, 275 2,5-dihydro-10-meιhoxy-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-
[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-( 1 -oxo-2-cyclohexyl)-2,2,4-trimethyl- 1 H- 280 [l]benzopyr-mo[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(3-cyclooctenyl)-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3-cycloheptenyl)-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4-f]quinoline, 285 2,5-dihydro- 10-methoxy-5-( 1 -cyclohexenylmethyl)-2,2,4-trimethyl- 1 H-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(3,3-dimethyl-6-cyclohexenyl)-2,2,4- trimethyl- 1H-
[ 1 ]benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(2-bromo-3-propenyl)-2,2,4-trimethyl-lH- 290 [l]benzopyrano[3,4-f]quinoline,
-306- re/(5R,3 ' R) 2,5-dihydro- 10-methoxy-5-( 1 -hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ 1 ]benzopyrano[3,4-fjquinoline, re/(5R,3'S) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-fJquinoline, 295 2,5-dihydro-10-methoxy-5-(3-hydroxymethyl-3-cyclohexenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(3-indolyl)-2,2,4-uimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, re/ (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl- 300 1 H- [ 1 J benzopyrano [3 ,4-fJ quinoline , re/ (5R,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline,
(-) (5S,3'S) 2,5-dihydro-10-methoxy-5-(l-methyl-3-cyclohexenyl)-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline, 305 (-) (5S, 3'R) 2,5-dihydro-10-methoxy-5-(l-hydroxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[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-f]quinoline,
(-)-(5S, 3'R) 2,5-dihydro- 10-methoxy-5-( 1 -methyl-3-cyclohexenyl)-2,2,4- 310 trimethyl- 1 H-[ 1 J benzopyrano[3 ,4-f]quinoline,
(+)-(5R, 3'S) 2,5-dihydro- 10-methoxy-5-( 1 -methyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4-fjquinoline,
2,5-dihydro-10-methoxy-5-(l-chloromethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1H-
[l]benzopyrano[3,4-f]quinoline, 315 rel (5R, 3'R) 2,5-dihydro- 10-methoxy-5-(l-methoxymethyl-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-methylthiomethyl-3-cyclohexenyl)-
2,2,4- trimethyl- 1 H- [ 1 J benzopyrano [3 ,4- fjquinoline, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- 320 trimethyl-lH-[l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-acetoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl- 1 H-[ l]benzopyrano[3,4- fjquinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-methoxymethyl-3-cyclohexenyl)-2,2,4- trimethyl-lH-[lJbenzopyrano[3,4-f]quinoline, 325 rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N,N-dimethylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
-307- rel (5R, 3'S) 2,5-dihydro-10-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-moφholino)methyl-3- 330 cyclohexenyl)-2,2,4-trimethyl- lH-[ 1 Jbenzopyrano[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-f]quinoUne, rel (5R, 3'S) 2,5-dihydro-10-methoxy-5-(l-(N,N dimethylamino)methyl-3- 335 cyclohexenyl)-2,2,4-trimethyl- lH-[ l]benzopyrano[3,4-f]quinoline, rel (5R, 3'R) 2,5-dihydro-10-methoxy-5-(l-(N-methylamino)methyl-3- cyclohexenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-methyl-3-propenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fjquinoUne, 340 2,5-dihydro-10-methoxy-5-(l,3-butadien-2-yl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(2-C -rbomethoxy-3-propenyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(l,2-dihydroxy-3-propyl)-2,2,4-trimethyl-lH- 345 [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(l,2-epoxy-3-propenyl)-2,2,4- trimethyl- lH-_
[l]benzopyrano[3,4-.f]quinoline,
2,5-dihydro-10-methoxy-5-(l-(N-phth∑ιlimido)-3-propyl)-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinoline, 350 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-( 1 -(hydrazinocarbonylamino)-3-propyl)-2,2,4-trimethyl-
1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline ,
(E) 2,5-dihydro- 10-methoxy-5-(2-carbomethoxy- l-ethenyl)-2,2,4-trimethyl- 1H- 355 [ 1 Jbenzopyrano[3,4-f]quinoline,
(^-2,5-dihydro- 10-methoxy-5-( 1 -propenyl)-2,2,4-trimethyl- 1H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(E) 2,5-dihydro- 10-methoxy-5-(3-hydroxy- 1 -propenyl)-2,2,4-trimethyl- 1 H-
[lJbenzopyrano[3,4-f]quinoline, 360 (E) 2,5-dihydro-10-methoxy-5-(3-(N,N-dimethylaminocarbonyloxy)-l-propenyl)-
2,2,4- trimethyl- 1 H- [ 1 ]benzopyrano[3,4-f]quinoline,
(E) 2,5-dihydro-10-methoxy-5-(3-methoxymethoxy-l-propenyl)-2,2,4-trimethyl-
1H-[1 Jbenzopyrano [3, 4- fjquinoline,
-308- 2,5-dihydro-10-methoxy-5-(3-hydroxy-3-propenyl)-2,2,4-trimethyl-lH- 365 [l]benzopyrano[3,4-f]quinoUne, 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-[ 1 ]benzopyrano[3,4-f]quinolin-5- yl) acetaldehyde, 370 2,5-dihydro- 10-methoxy-5-(2-cyclohexylidenylethyl)-2,2,4- trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinotine,
2,5-dihydro-10-methoxy-5-(2-cyclopentylidenylethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro- 10-methoxy-5-(2-cycloheptylidenylethyl)-2,2,4- trimethyl- 1 H- 375 [l]benzopyrano[3,4-.f]quinotine,
2,5-dihydro- 10-methoxy-5-(3-methyl-2-butenyl)-2,2,4-trimethyl- 1 H-
[l]benzopyr.ano[3,4-f]quinotine, ti-ans 2,5-dihydro- 10-methoxy-5-(2-butenyl)-2,2,4-trimethyl- 1H-
[ 1 Jbenzopyrano [3 ,4- fjquinoline, 380 trans 2,5-dihydro- 10-methoxy-5-(2-penten- 1 -yl)-2,2,4- trimethyl- 1 H-
[l]benzopyr.ano[3,4-f]quinoUne,
2,5-dihydro- 10-methoxy-5- ( 1 , 1 -difluoro- 1 -propen-3-yl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoline,
(E) methyl 2-(2,5-dihydro-10-methoxy-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 385 f]quinolin-5-yl) 2-butenoate,
(^ 2,5-dihydro-10-methoxy-5-(4-hydroxy-2-buten-l-yl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
(E) 2,5-dihydro- 10-methoxy-5-(4-(N,N-dimethylaminocarbonyloxy)-2-buten- 1 -yl)-
2,2,4- trimethyl- lH-[l]benzopyrano[3,4- fjquinoline, 390 (E) 2,5-dihydro- 10-methoxy-5-(4-(N-methylaminocarbonyloxy)-2-buten- 1-yl)-
2,2,4- trimethyl- lH-[lJbenzopyrano[3,4- .fjquinoline,
(^ 2,5-dihydro-10-methoxy-5-(2-butenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-
.fjquinoline,
2,5-dihydro- 10-methoxy-5-(2-hydroxyethyl)-2,2,4-trimethyl- 1H- 395 [lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-(N-benzylcarbonyloxy)ethyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(2-(N-moφholinocarbonyloxy)ethyl)-2,2,4-trimethyl- lH-[lJbenzopyrano[3,4- jquinoline,
-309- 400 2,5-dihydro-10-methoxy-5-(2-(N-(2-metiιoxyethyl)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- trimethy 1- 1 H-[ 1 ]benzopyrano[3 ,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-(N,N-dimethylaminocarbonyloxy)ethyl)-2,2,4- 405 trimethyl- 1 H-[ 1 Jbenzopyrano[3 ,4-fJquinoline,
2,5-dihydro- 10-methoxy-5-(2-methoxymethoxyethyl)-2,2,4- trimethyl- 1 H-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(2,2-dimethylethoxycarbonylamino)methyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-fJquinoline, 410 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-
[lJbenzopyrano[3,4-f]quinotine,
2,5-dihydro-10-methoxy-5-(carboethoxy)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- 415 fjquinoline,
2,5-dihydro-10-methoxy-5-(cyclopentyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxy-5-( 1 -methylpropa- 1 ,2-dienyl)-2,2,4-trimethyl- 1H-
[ 1 Jbenzopyrano [3 ,4-f] quinoUne, 420 2,5-dihydro-10-methoxy-5-(3,4,5-trifluorophenyl)-2,2,4-trimethyl-lH-
[ 1 ]benzopyrano[3 ,4-f] quinoline,
2,5-dihydro-10-methoxy-5-(cyclohexyl)-2,2,4- trimethyl- lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(2-pyridyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 425 fjquinoline,
2,5-dihydro-10-methoxy-5-(3-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-5-(4-pyridyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 430 (10-chloro-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4-fJquinoline,
10-chloro-9-hydroxy-5-phenyl-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline,
10-chloro-9-hydroxy-5-(3-trifluoromethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 435 [ 1 Jbenzopyrano[3,4-f]quinoline,
-310- 10-chloro-9-hydroxy-5-(3,5-dimethylphenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline, rel-(5S, 3'R)-9-hydroxy-10-methoxy-5-[l-hydroxymethyl-3-cyclohexenylJ-2,2,4- trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline, 440 (-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3S-cyclopentenyl)-lH-
[ l]benzopyrano[3,4-f]quinotine,
(-) 2,5(S)-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3R-cyclopentenyl)-lH-
[ 1 ] benzopyrano [3 ,4-f] quinoUne,
10-chloro-9-hydroxy-5-(3,5-dichlorophenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 445 [l]benzopyrano[3,4-f]quinoUne,
(+)-(5R, 3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 ] benzopyrano [3 ,4-f] quinoline,
(+)-(5R, 3'R)2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3- cyclopentenyl)-lH-[l]benzopyrano[3,4-f]quinoline, 450 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-f]quinoline,
5-(3-propenyl)-9-chloro- 10-ethenyl-2,2,4-trimethyl-2,5-dihydro- 1 H- 455 [lJbenzopyrano[3,4-f]quinoline,
9-chloro-10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyr- o[3,4-l^]quinoline,
5-(3-propenyl)-9-chloro-10-difluoromethoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[ 1 Jbenzopyrano [3 ,4-fJquinoline, 460 9-chloro-10-difluoromethoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4-f]quinoUne,
8-fluoro- 10-methoxy-5-phenyl-2,2,4-trimethyl-2,5-dihydro- 1H-
[l]benzopyrano[3,4-f]quinoline,
5-(3-propenyl)-8-fluoro-10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH- 465 [l]benzopyrano[3,4-f]quinoline,
(10-methoxy-9-fluoro-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4- fjquinoline,
10-methoxy-9-hydroxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[lJbenzopyrano[3,4-f]quinoline, 470 (+/-) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-cyclohexeny 1 )- 1 H-
[l]benzopyrano[3,4-fJquinoline,
-311- (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l-methylcyclohexen-3- y 1 )- 1 H- [ 1 Jbenzopyrano[3,4- fjquinoline,
(-) (5S, 3'S)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl- 475 2,5-dihydro- 1 H-[ 1 J benzopyrano[3,4-f]quinoline,
(+) (5R,3 ' R)-9-hydroxy-5- [ 1 -methyl-3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro-lH-[l]benzopyrano[3,4- fjquinoline,
(+) (5R,3 ' S)-9-hydroxy-5-[ 1 -methyl-3-cyclohexenyl]- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro- 1 H- [ 1 ] benzopyrano [3 ,4- fjquinoline, 480 (-) (5S,3'R)-9-hydroxy-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-
2,5-dihydro-lH-[l]benzopyrano[3,4- fjquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-hydroxymethyl-3-cyclohexenylJ-10-methoxy-2,2,4- trimethyl-2,5-dihydro- 1 H-[ 1 ] benzopyrano[3,4-f]quinoline,
(+/-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(l- 485 methylcyclohexen-3-yl)-lH-[lJbenzopyrano[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-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-5-propyl-2,2,4-trimethyl- 1 H-
[lJbenzopyrano[3,4- fjquinoline, 490 (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohepteny 1 )- 1 H- [ 1 J benzopyrju o [3,4-fJquinoline, -
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cycloheptenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy -2,2,4-trimethyl-5-phenyl- 1 H- 495 [ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3,5-difluorophenyl)- 1 H-
[ l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 500 5-butyl-2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4- fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopentenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- 505 cyclopentenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3,4-difluorophenyl)-lH-
[lJbenzopyrano[3,4-f]quinoline,
-312- 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-fluorophenyl)-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinoline, 510 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethylphenyl)- lH-[lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-5- bistrifluoromethylphenyl)-lH-[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3-trifluoromethyl-4- 515 chlorophenyl)- 1 H-[ 1 Jbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylpropyl)-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-fluoro-4-chlorophenyl)- lH-[l]benzopyrano[3,4-f]quinoline, 520 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-butenyl)-lH-
[l]benzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy- 10-methoxy-5-(phenyιmethyl)-2,2,4- trimethyl- 1 H-
[ 1 Jbenzopyrano[3,4-fJquinotine,
(-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- 525 cyclohexenylJ-lH-[lJbenzopyrano[3,4-f]quinoline,
(-) (S) 5-cyclopentyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano[3,4-fJquinoUne,
(+) (R) 5-cyclopentyl-2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-lH-
[ lJbenzopyrano[3,4- fjquinoline, 530 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-
[lJbenzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(5-methoxy-2-thienyl)- 1 H- 535 [lJbenzopyr^o[3,4-f]quinoline,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2,3,4,5,6- pentafluorophenyl)-lH-[l]benzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- hydroxymethylcyclopenten-3-yl)-lH-[lJbenzopyrano[3,4-f]quinoUne, 540 (+/-) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5(S)-(3(S)-l- methylcarboxylatecyclopenten-3-yl)-lH-[l]benzopyrano[3,4- fjquinoline,
(-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ 1 ]benzopyrano[3,4- fjquinoline,
-313- (-) (5S,3'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- 545 cyclohexenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-thienyl)-lH-
[l]benzopyrano[3,4-f|quinotine,
(±) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methylphenyl) -lH-
[ 1 J benzopyrano [3 ,4-fJ quinoUne, 550 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-acetoxymethyl-3- propenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
(+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-[l-ethyl-3- cyclohexenylj- 1 H- [ 1 J benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-cyclohexyl-lH- 555 [lJbenzopyrano[3,4-fJquinoline,
2,5,5-trihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-[lJbenzopyrano[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, 560 methyl 2-[2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-fJ-5-quinolinylJ acetate,
(Z) 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-butenyl)-lH-
[ 1 J benzopyrano [3 ,4-fJ quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-methyl-2-butenyl)-lH- 565 [lJbenzopyrano[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-fJquinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-(3- cyclohexeny 1 )- 1 H-[ l]benzopyrano[3,4-fJquinoline, 570 (+) (5R,3'S) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopentenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
(+) (5R,3'R) 2,5(R)-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- cyclopenteny 1 )- 1 H- [ 1 ] benzopyrano [3,4-fJquinoline, rel-(5S)-9-hydroxy-5-[(3R)-(l-methoxycarbonyl)cyclohexen-3-yl]- 10-methoxy- 575 2,2,4-trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(2-methyl-3-propenyl)-lH-
[l]benzopyrano[3,4-f]quinoline,
9J0-Dimethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline,
-314- 580 9J0-Dimethoxy-5-[3-cyclohexenyl]-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4-fJquinoUne,
10-methoxy-9-ethoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- [lJbenzopyrjmo[3,4-f]quinoline-
10-methoxy-9-(3-propenyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 585 [lJbenzopyrano[3,4-fJquinoUne,
10-methoxy-9-(3-propynyloxy)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4-fJquinotine,
2,5-dihydro-9-acetoxy- 10-methoxy-2,2,4-trimethyl-5-(2-propenyl)- 1 H-
[l]benzopyrano[3,4-f]quinoUne, 590 2,5-dihydro-9-(4-N,N-dimethyl--mino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fJquinoUne,
7-bromo -5-[3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-lH-
[lJl)enzopyr.ano[3,4-fJquinoUne,
10-methoxy-7-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 595 [lJbenzopyrano[3,4-f]quinoUne,
7-bromo-5-[l-methyl-3-cyclohexenylJ- 10-methoxy-2,2,4-trimethyl-2,5-dihydro-
1 H- [ 1 J benzopyrano [3 ,4-f] quinoline ,
10-metiιoxy-9-bromo-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano[3,4- fjquinoline, 600 7,9-Dibromo-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ] benzopyrano [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-fJ quinoline,
7,9-Dibromo-5-[l-methyl-3-cyclohexenylJ-10-methoxy-2,2,4-trimethyl-2,5- 605 dihydro- 1 H- [ 1 ] benzopyrano [3,4- fjquinoline,
10-methoxy-7-(2-ethenyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-fJ quinoline,
10-methoxy-7-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro-
[l]benzopyrano[3,4- fjquinoline, 610 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 ]benzopyrano[3 ,4- fjquinoline,
10-methoxy-7-methyl-9-methyl-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5-dihydro- 615 [l]benzopyrano[3,4-f]quinoline,
-315- 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- 1 H- [ 1 ]benzopyrano[3,4- fjquinoline, 620 2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-
(carbomethoxymethyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-f] quinoUne,
2,5-dihydro-10-methoxy-5-(3-(N-methyl-N-(N- methylcarbonyl)aminocarbonyloxy)phenyl)-2,2,4-trimethyl-lH- 625 [lJbenzopyrano[3,4-f]quinoUne,
2,5-dihydro-10-methoxy-5-(3-(N-methylaminocarbonyloxy)phenyl)-2,2,4- trimethyl- 1 H-[ 1 Jbenzopyrano[3,4-fJquinoline,
2,5-dihydro-10-methoxy-5-(3-(2-hydroxyethyl)phenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-fJquinoUne, 630 2,5-dihydro-10-methoxy-5-(3-(2-methanesulfonyloxyethyl)phenyl)-2,2,4-trimethyl-
1 H- [ 1 ] benzopyrano [3 ,4-fj quinoline ,
2,5-dihydro-10-methoxy-5-(3-(2-methythioethyl)phenyl)-2,2,4-trimethyl-lH-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro- 10-methoxy-5-(3-(2-(N,N-dimethylaminocarbonyloxy)ethyl)phenyl)- 635 2,2,4-trimethyl- 1 H- [ 1 ] benzopyrano[3 ,4-f]quinoline, _
2,5-dihydro-10-methoxy-5-(3-(2-(N,N-dimethylamino)ethyl)phenyl)-2,2,4- trimethyl-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-cyclopropyl-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- fjquinoline, 640 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- 1H-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dUιydro-10-methoxy-5-(2-phenylethynyl)-2,2,4-trimethyl-lH- 645 [lJbenzopyrano[3,4-fJquinoline, cis 2,5-dihydro- 10-methoxy-5-(2-phenylethenyl)-2,2,4-trimethyl- 1 H-
[ 1 Jbenzopyrano[3,4-f]quinoline,
2,5-dihydro-10-methoxy-5-(2-methylpropenyl)-2,2,4-trimethyl-lH-
[1 Jbenzopyrano [3, 4- fjquinoline, 6.50 trans 2,5-dihydro- 10-methoxy-5-(l-cyclohexenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4-fJquinoline,
-316- 2,5-dihydro-10-(2-furanyl)-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-cy.ano-5-(3-propenyl)-2,2,4-trimethyl-lH-[l]benzopyrano[3,4- 655 fjquinoline,
2,5-dihydro-10-c--xboxy-5-(3-propenyl)-2,2,4-trimethyl-lH-[lJbenzopyr-ιno[3,4- fjquinoline,
2,5-dihydro- 10-(2-hydroxymethyl)-5-(3-propenyl)-2,2,4-trimethyl- 1 H-
[lJbenzopyrano[3,4-fJquinoUne, 660 2,5-dihydro- 10-f ormyl-5-(3-propenyl)-2,2,4-trimethyl- 1 H- [ 1 Jbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-aminomethyI-5-(3-propenyl)-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro- 10-methoxymethyl-5-(3-propenyl)-2,2,4- trimethyl- 1 H- 665 [l]benzopyrano[3,4-f]quinoUne,
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- fjquinoline, 670 methyl 2,5-dihydro-5-phenyl-2,2,4-trimethyl- lH-[ l]benzopyrano[3,4-fJquinoUne-
10-carboxylate,
2,5-dihydro-10-(hydroxymethyl)- 5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3,4- fJquinoUne,
2,5-dihydro-10-formyl-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- 675 fjquinoline,
2,5-dihydro-10-(methoxymethyl)-5-phenyl-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-
Hquinoline,
2,5-dihydro-10-ethenyl-5-oxo-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4-fJquinoline,
5-(3-cyclohexenyl)-2,5-dihydro-10-ethenyl-2,2,4-trimethyl-lH- 680 [lJbenzopyrano[3,4-fjquinoline,
2,5-dihydro-10-ethenyl-5-[l-methyl-3-cyclohexenylJ-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline, 685 2,5-dihydro-5-(3-propenyl)-10-methylthio-2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-(4-acetamidobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl- lH-[l]benzopyrano[3,4- fjquinoline,
-317- 10-(difluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl- 1 H- 690 [lJbenzopyrano[3,4-f]quinoUne,
10-(bromodifluoromethoxy)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4- fjquinohne,
10-(bromodifluoromethoxy)-5-phenyl-2,2-dimethyl-4-methylene-2,3,4,5- tetrahydro- 1 H-chromeno [3 ,4-fJ quinoline, 695 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl)
-lH-[lJbenzopyrano[3,4-f]quinoline,
10-methoxy-5-(5-methylisoxazol-3-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- trimethyl- 1 H-[ 1 Jbenzopyrano[3 ,4-f]quinoline,
10-methoxy-5-(3-methylisoxazol-5-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4- 700 trimethyl- 1 H-[ 1 Jbenzopyrano[3 ,4-fJquinoline,
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-f. ]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, 705 10-methoxy-5-(pyridin-2-yl)methyidene-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ 1 Jbenzopyrano [3 ,4-fJquinoUne,
10-methoxy-5-(but-3-enylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[ l]benzopyrano[3,4-f]quinoline,
10-methoxy-5-(l-methylpropylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH- 710 [lJbenzopyrano[3,4-fJquinoline,
10-methoxy-5-(l-butylidene)-2,5-dihydro-5-phenyl-2,2,4-trimethyl-lH-
[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,4-trimethyl-3-oxide-5-phenyl-lH-[l]benzopyrano[3,4- fJquinazoUne, 715 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-phenyl-lH-[lJbenzopyrano[3,4- fJquinazoUne,
2,5-dihydro-10-methoxy-2,2-[spiro(tetrahydro-4-pyranyl)]-4-methyl-5-allyl-lH-
[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2-[spiro(hexyl)J-5-allyl-lH-[lJbenzopyrano[3,4- 720 fjquinoline,
2,5-dihydro-10-methoxy-2,2-diethyl-4-methyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,3,4-tetramethyl-5-allyl-lH-[lJbenzopyrano[3,4- fjquinoline,
-318- 725 2,5-dihydro-10-methoxy-2,2-dimethyl-4-ethyl-5-allyl-lH-[l]benzopyrano[3,4- fjquinoline,
2,5-dihydro-10-methoxy-2,2,3-trimethyl-5-allyl-lH-[lJbenzoρyrano[3,4- fjquinoline,
Z-5-(benzylidenyl)-9-hydroxy-10-methoxy-2,2,4-trimethyl-lH-2,5-dihydro- 730 [lJbenzopyrano[3,4-f]quinotine,
Z-5-(2,5-difluorobenzylidenyl)-9-hydroxy- 10-methoxy-2,2,4-trimethyl- 1 H-2,5- dihydro-[lJbenzopyrano[3,4-f]quinoUne,
Z-5-(3-fluorobenzyUdenyl)- 10-chloro-9-hydroxy-2,2,4-trimethyl-2,5-dihydro- 1 H-
[ 1 Jbenzopyrano[3,4-f]quinoUne, 735 Z-10-chloro-9-hydroxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[l]benzopyrano[3,4-fjquinotine,
Z-9-hydroxy-10-methoxy-5-(2-picolinylidenyl)-2,2,4-trimethyl-2,5-dihydro-lH-
[lJbenzopyrano[3,4-f]quinoUne,
9-hydroxy-10-methoxy-5-(3,5-difluorophenyl)methylidene-2,5-dihydro-5-phenyl- 740 2,2,4-trimethyl- lH-[lJbenzopyrano[3,4-f]quinoline,
9-hydroxy-10-methoxy-5-(3,4-difluorophenyl)methylidene-2,5-dihydro-5-phenyl-
2,2,4-trimethyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(Z) 9-hydroxy-10-methoxy-5-((4-fluorophenyl)methylene)-2,2,4-trimethyl-lH-2,5- dihydro- [lJbenzopyrano[3,4-f]quinoline, 745 (Z)-9-hydroxy-10-methoxy-5-([2,3-difluorophenylJmethylene)-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- lH-[l]benzopyrano[3,4-fJquinoline, re/-(5S,3'R)-9-hydroxy-5-[l-methoxymethyl-3-cyclohexenyl]-10-chloro-2,2,4- 750 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- fJquinoUne,
(+/-) 2,5-dihydro-9-cyanomethoxy-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[lJbenzopyrano[3,4-f]quinoline, 755 2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-(4-N-piperidino-4-oxo-but£ oyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)-lH-[lJbenzopyrano[3,4-f]quinoline,
2,5-dihydro-9-(4-N-moφholino-4-oxo-butanoyloxy)-10-methoxy-2,2,4-trimethyl- 760 5-(2-propenyl)-lH-[l]benzopyrano[3,4-f]quinoline,
-319- 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-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-5-difluorophenylmethyl)- lH-[lJbenzopyrano[3,4- fjquinoline, 765 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(2-thienyl)- 1 H-
[lJbenzopyrano[3,4-fJquinoUne,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-cyclopentyl- 1 H-
[lJbenzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-((2-fluorophenyl)methyl) 770 - lH-[l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-9-hydroxymethyl-10-methoxy-2,2, trimethyl-5-aUyl-lH-
[l]benzopyrano[3,4-.f]quinotine,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-( 1 -pentenyl)- 1 H-
[ 1 Jbenzopyrano[3,4- fjquinoline, 775 2,5-dihydro-9-methylcarboxylate- 10-methoxy-2,2,4-trimethyl-5-aUyl- 1H-
[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy- 10-methoxy-2,2,4-trimethyl-5-aUenyl- 1H-
[ 1 Jbenzopyrano [3 ,4-fJquinoline,
(-) (5S, 3'S) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH- 780 [lJbenzopyrano[3,4-f]quinoUne, -
(-) (5S, 3'S) 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-(cyclohexen-3-yl)-lH-
[lJbenzopyrano[3,4- fjquinoline, 785 (-) (5S, 3'R) 2,5-dihydro-10-methoxy-2,2,4-trimethyl-5-(cyclopenten-3-yl)-lH-
[l]benzopyrano[3,4-fJquinoline,
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- 10-methoxy-2,2,4-trimethyl-5-(3-acetoxyphenyl) - 1H- 790 [lJbenzopyrano[3,4-f]quinoline,
10-difluoromethoxy-5-[[3-(methylthio)methoxyJphenyl]-2,2,4-trimethyl-lH-2,5- dihydro- [lJbenzopyrano[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, 795 2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-hydroxyphenyl)-lH-
[ 1 ]benzopyrano[3 ,4- fjquinoline,
-320- 2,5-dihydro-9-methylthiomethoxy-10-methoxy-2,2,4-trimethyl-5-(3-
(methylthio)methoxyphenyl)- 1 H- [ 1 Jbenzopyrano [3 ,4-fJquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3- 800 (methylthiomethoxy)phenyl)- lH-[lJbenzopyrano[3,4-f|quinoline,
9-hydroxy-10-chloro-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 Jbenzopyrano [3,4-fJquinoUne,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-([2-N,N- dimethylcarbamoyloxyjphenyl)- 1 H-[ 1 Jbenzopyrano[3,4-fJquinoline, 805 2,5-dihydro-9-N,N-dimethylcarbamoyloxy-10-methoxy-2,2,4-trime-hyl-5-([2-N,N- dimethylcarbamoyloxy]phenyl)-lH-[lJbenzopyrano[3,4- fjquinoline,
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-trϊmethyl-5-isopropyl- 1 H- 810 [l]benzopyrano[3,4-f]quinoUne,
9-hydroxy-10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ 1 ] benzopyrano [3 ,4-f] quinoline,
2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-butyl-lH-[l]benzopyrano[3,4- fjquinoline, 815 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-( 1 -thiazol-2-yl)- 1 H-
[ lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-(2-methylpropyl)- 1 H-
[l]benzopyr^o[3,4-fJquinoline,
2,5-dihydro-9-hydroxymethyl-10-chloro-2,2,4-trimethyl-5-allyl-lH- 820 [lJbenzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-propyl- 1 H-
[ l]benzopyrano[3,4-fJquinoline,
9-hydroxy-10-methoxy-5-([3-fluorophenylJmethylene)-2,2,4-trimethyl-lH-2,5- dihydro- [lJbenzopyrano[3,4-fJquinoline, 825 9-hydroxy-10-chloro-5-([2-pyridylJmethylene)-2,2,4-trimethyl-lH-2,5-dihydro-
[ l]benzopyrano[3,4- fjquinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-hydroxymethyl)cyclohexen-3-yl]-10-chloro-2,2,4- trimethyl-2,5-dihydro-lH-[lJbenzopyrano[3,4-f]quinoline, rel-(5S)-9-hydroxy-5-[(3S)-(l-methoxycarbonyl)cyclohexen-3-yl]- 10-methoxy- 830 2,2,4-trimethyl-2,5-dihydro-lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3,5-dichlorophenyl)-lH-
[l]benzopyrano[3,4- fjquinoline,
-321- (-) (5S,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-yl)-lH-[l]benzopyrano[3,4-fJquinoline, 835 (-) (5S,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-yl)-lH-[l]benzopyrano[3,4- fjquinoline,
(+) (5R,3'S) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- methylcyclohexen-3-y 1)- 1 H-[ 1 ]benzopyrano[3,4- fjquinoline,
(+) (5R,3'R) 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(l- 840 methylcyclohexen-3-yl)-lH-[l]benzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-chloro-2,2,4- trimethyl-5-allyl-lH-[lJbenzopyrano[3,4-fJquinoline,
(-) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-cyclopentyl- 1 H-
[ 1 Jbenzopyrano [3 ,4-fJquinoUne, 845 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(l-methylethyl)-lH-[lJbenzopyrano[3,4-fJquinoline,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-5-
(phenylmethy 1) -2 ,2 ,4- trimethyl- 1 H-[ 1 ] benzopyrano[3 ,4-f]quinoUne,
2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-butanoyloxy)-10-methoxy-2,2,4- 850 trimethyl-5-(2-thienyl)- lH-[l]benzopyrano[3,4-f]quinoline,
2,5-dihydro-9-(4-N,N-dimethylaminobutanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)- 1 H- [ 1 J benzopyrano [3 ,4-fJ quinoline,
9-(2-ethoxy-2-oxo-ethylaminocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4- trimethyl- 1 H-2,5-dihydro- [ 1 Jbenzopyrano[3,4- fjquinoline, 855 (+/-) 2,5-dihydro-9-(3-acetamido-propanoyloxy)- 10-methoxy-2,2,4-trimethyl-5- allyl-lH-[lJbenzopyrano[3,4- fjquinoline,
(+/-) 2,5-dihydro-9-hydroxy- 10-chloro-2,2,4-trimethyl-5-benzyl- 1H-
[lJbenzopyrano[3,4-f]quinoline,
9-hydroxy- 10-methoxy-5-(phenylmethylene)-2,2,4-trimethyl- 1 H-2,5-dihydro- 860 [1 Jbenzopyrano [3, 4- fjquinoline,
9-(dimethylaminothiocarbonyl)-oxy-10-methoxy-5-(3-propenyl)-2,2,4-trimethyl- lH-2,5-dihydro- [lJbenzopyrano[3,4-f]quinoline,
(+/-) 2,5-dihydro-9-(N-carbamoyl-2-aminoacetoxy)-10-methoxy-2,2,4-trimethyl-5- allyl-lH-[l]benzopyrano[3,4- fjquinoline, 865 (+/-) 2,5-dihydro-9-(4-ethoxy-4-oxo-butoxy)-10-methoxy-2,2,4-trimethyl-5-aUyl- lH-[lJbenzopyrano[3,4-fJquinoline,
(+/-) 2,5-dihydro-9-(4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-allyl-lH-
[l]benzopyrano[3,4- fjquinoline,
-322- 2,5-dihydro-9-hydroxy-10-chloro-2,2,4-trimethyl-5-(3,4,5-trifluorophenyl)-lH- 870 [l]benzopyrano[3,4-fJquinoline,
2,5-dihydro-9-methylthiomethoxy- 10-methoxy-2,2,4-trimethyl-5-allyl- 1 H-
[lJbenzopyrano[3,4-fJquinoUne,
2,5-dihydro-9-(4-N,N-diethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethy l-5-(2-propenyl)- 1 H- [ 1 J benzopyrano [3 ,4-fJ quinoUne, 875 2,5-dihydro-9-(4-N,N-dimethylamino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4- trimethyl-5-(2-propenyl)-lH-[l]benzopyrano[3,4-fJquinoUne,
2,5-dihydro-9-(4-N-piperidino-4-oxo-pentanoyloxy)-10-methoxy-2,2,4-trimethyl-5-
(2-propenyl)-lH-[lJbenzopyrano[3,4-f]quinoUne,
2,5-dihydro-9-(4-N-moφhoUno-4-oxo-pen-anoyloxy)-10-metiιoxy-2,2,4-trimethyl- 880 5-(2-propenyl)- 1 H- [ 1 J benzopyrano[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-f]quinoline,
10-methoxy-9-(allylaminocarbonyl)oxy-5-(3-propenyl)-2,2,4-trimethyl-lH-2,5- dihydro- [l]benzopyrano[3,4-f]quinoline, 885 10-methoxy-9-(cyclohexylaminocarbonyl)-oxy-5-(3-propenyl)-2,2,4--rimethyl-lH-
2,5-dihydro-[lJbenzopyrano[3,4- fjquinoline,
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(3-thienyl)-lH-
[l]benzopyrano[3,4-f]quinoline, and
2,5-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5-(4-(fluorophenyl)methyl)- 890 lH-[l]benzopyrano[3,4-f]quinoline.
35. A method of selectively modulating the activation, repression, agonism, and antagonism effects of the glucocorticoid receptor in a mammal comprising administering an effective amount of a compound of Claim 1.
-323-
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.
-324-
PCT/US1999/003127 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents WO1999041256A1 (en)

Priority Applications (18)

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NZ506013A NZ506013A (en) 1998-02-13 1999-02-12 1H-[1]benzopyrano[3,4-f]quinoline derivatives and their use as glucocorticoid-selective anti-inflammatory agents
AU26773/99A AU766441B2 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
PL343018A PL193323B1 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
DK99906996T DK1053239T3 (en) 1998-02-13 1999-02-12 Gluccocorticoid-selective, anti-inflammatory agents
AT99906996T ATE230749T1 (en) 1998-02-13 1999-02-12 GLUCOCORTICOID SELECTIVE ANTI-INFLAMMATORY AGENTS
EP99906996A EP1053239B1 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
SI9930243T SI1053239T1 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
BR9907788-4A BR9907788A (en) 1998-02-13 1999-02-12 Paraglycocorticoid selective anti-inflammatory agents
JP2000531449A JP2002503665A (en) 1998-02-13 1999-02-12 Glucocorticoid selective anti-inflammatory agent
SK1197-2000A SK284689B6 (en) 1998-02-13 1999-02-12 Benzopyrano[3,4-f]quinoline compound and medicament comprising thereof
DE69904804T DE69904804T2 (en) 1998-02-13 1999-02-12 GLUCOCORTICOID SELECTIVE ANTI-INFLAMMATORY AGENTS
HU0100460A HUP0100460A3 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
IL13750899A IL137508A0 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
KR1020007008850A KR20010040935A (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
CA002320943A CA2320943A1 (en) 1998-02-13 1999-02-12 Glucocorticoid-selective anti-inflammatory agents
NO20004053A NO20004053L (en) 1998-02-13 2000-08-11 Glucocorticoid-selective anti-inflammatory agents
BG104719A BG64317B1 (en) 1998-02-13 2000-08-28 Glucocorticoid-selective anti-inflammatory agents
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US6329534B1 (en) 1999-09-01 2001-12-11 Abbott Laboratories Glucocorticoid receptor antagonists for treatment of diabetes
WO2002002565A2 (en) * 2000-07-05 2002-01-10 Abbott Laboratories Glucocortiocoid-selective antiinflammatory agents
US6436986B1 (en) 1999-09-01 2002-08-20 Abbott Laboratories Glucocorticoid receptor antagonists for treatment of diabetes
WO2002070507A2 (en) * 2001-02-28 2002-09-12 Abbott Laboratories Glycorticoid receptor antagonists for treatment of diabetes
WO2003002548A1 (en) * 2001-06-29 2003-01-09 Abbott Laboratories A process for the preparation of chiral glucocorticoid receptor agents
US6518430B1 (en) 2001-09-21 2003-02-11 Abbott Laboratories Process for the preparation of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-F]quinolines and derivatives thereof
US6608216B2 (en) 2001-06-29 2003-08-19 Abbott Laboratories Process for the preparation of chiral glucocorticoid receptor agents
WO2004033461A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-SUBSTITUTED 7,9-DIFLUORO-5H-CHROMENO[3,4-f]QUINOLINE COMPOUNDS AS SELECTIVE PROGESTERONE RECEPTOR MODULATORS
WO2004033459A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-(1',1'-CYCLOALKYL/ALKENYL)METHYLIDENE 1,2-DIHYDRO-5H-CHROMENO[3,4-f]QUINOLINES AS SELECTIVE PROGESTERONE RECEPTOR MODULATOR COMPOUNDS
WO2004033460A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-cycloalkenyl 5h-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
US6852719B2 (en) 2000-10-30 2005-02-08 Pfizer Inc. Glucocorticoid receptor modulators
US6858627B2 (en) 2002-08-21 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2005030213A1 (en) 2003-09-24 2005-04-07 Boehringer Ingelheim Pharmaceuticals, Inc. 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1h-pyrrolo
US6903215B2 (en) 2002-03-26 2005-06-07 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6960581B2 (en) 2002-01-14 2005-11-01 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7235662B2 (en) 2003-06-11 2007-06-26 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US7268152B2 (en) 2002-03-26 2007-09-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7282591B2 (en) 2002-04-11 2007-10-16 Merck & Co., Inc. 1h-benzo{f}indazol-5-yl derivatives as selective glucocorticoid receptor modulators
US7507843B2 (en) 2003-10-16 2009-03-24 Boehringer Ingelheim Pharmaceuticals, Inc. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
US7579469B2 (en) 2003-01-03 2009-08-25 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7625920B2 (en) 2003-03-07 2009-12-01 Merck & Co., Inc. Fluorinated 4-azasteroid derivatives as androgen receptor modulators
US7635711B2 (en) 2004-12-27 2009-12-22 Boehringer-Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2010147947A2 (en) 2009-06-16 2010-12-23 Schering Corporation NOVEL [3,2-c] HETEROARYL STEROIDS AS GLUCOCORTICOID RECEPTOR AGONISTS, COMPOSITIONS AND USES THEREOF
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US6951942B2 (en) 1998-02-13 2005-10-04 Abbott Laboratories Glucocorticoid-selective anti-inflammatory agents
US6436986B1 (en) 1999-09-01 2002-08-20 Abbott Laboratories Glucocorticoid receptor antagonists for treatment of diabetes
US6593480B2 (en) 1999-09-01 2003-07-15 Abbott Laboratories Glucocorticoid receptor antagonists for treatment of diabetes
US6329534B1 (en) 1999-09-01 2001-12-11 Abbott Laboratories Glucocorticoid receptor antagonists for treatment of diabetes
WO2001016128A1 (en) * 1999-09-01 2001-03-08 Abbott Laboratories Dibenzopyrans as glucocorticoid receptor antagonists for treatment of diabetes
WO2002002565A2 (en) * 2000-07-05 2002-01-10 Abbott Laboratories Glucocortiocoid-selective antiinflammatory agents
WO2002002565A3 (en) * 2000-07-05 2002-05-30 Abbott Lab Glucocortiocoid-selective antiinflammatory agents
US6852719B2 (en) 2000-10-30 2005-02-08 Pfizer Inc. Glucocorticoid receptor modulators
WO2002070507A2 (en) * 2001-02-28 2002-09-12 Abbott Laboratories Glycorticoid receptor antagonists for treatment of diabetes
WO2002070507A3 (en) * 2001-02-28 2002-11-21 Abbott Lab Glycorticoid receptor antagonists for treatment of diabetes
US6608216B2 (en) 2001-06-29 2003-08-19 Abbott Laboratories Process for the preparation of chiral glucocorticoid receptor agents
WO2003002548A1 (en) * 2001-06-29 2003-01-09 Abbott Laboratories A process for the preparation of chiral glucocorticoid receptor agents
WO2003027117A1 (en) * 2001-09-21 2003-04-03 Abbott Laboratories A process for the preparation of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1h-chromeno[3,4-f]quinolines and derivatives thereof
US6673930B2 (en) * 2001-09-21 2004-01-06 Yi-Yin Ku Process for the preparation of 5-(substituted)-10 methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno [3,4-F] quinolines and derivatives thereof
US6518430B1 (en) 2001-09-21 2003-02-11 Abbott Laboratories Process for the preparation of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-F]quinolines and derivatives thereof
US6960581B2 (en) 2002-01-14 2005-11-01 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US7189758B2 (en) 2002-01-14 2007-03-13 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical formulations, and uses thereof
US8212040B2 (en) 2002-03-26 2012-07-03 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and thereof
US7932392B2 (en) 2002-03-26 2011-04-26 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6903215B2 (en) 2002-03-26 2005-06-07 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7553966B2 (en) 2002-03-26 2009-06-30 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7268152B2 (en) 2002-03-26 2007-09-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7625937B2 (en) 2002-04-11 2009-12-01 Merck & Co., Inc. 1H-benzo[F]indazol-5-YL derivatives as selective glucocorticoid receptor modulators
US7282591B2 (en) 2002-04-11 2007-10-16 Merck & Co., Inc. 1h-benzo{f}indazol-5-yl derivatives as selective glucocorticoid receptor modulators
US7186864B2 (en) 2002-05-29 2007-03-06 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US6858627B2 (en) 2002-08-21 2005-02-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2004033459A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-(1',1'-CYCLOALKYL/ALKENYL)METHYLIDENE 1,2-DIHYDRO-5H-CHROMENO[3,4-f]QUINOLINES AS SELECTIVE PROGESTERONE RECEPTOR MODULATOR COMPOUNDS
US7071205B2 (en) 2002-10-11 2006-07-04 Ligand Pharmaceuticals Incorporated 5-cycloalkenyl 5H-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
US7084151B2 (en) 2002-10-11 2006-08-01 Ligand Pharmaceuticals Incorporated 5-(1',1'-cycloalkyl/alkenyl)methylidene 1,2-dihydro-5H-chromeno[3,4-ƒ]quinolines as selective progesterone receptor modulator compounds
WO2004033461A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-SUBSTITUTED 7,9-DIFLUORO-5H-CHROMENO[3,4-f]QUINOLINE COMPOUNDS AS SELECTIVE PROGESTERONE RECEPTOR MODULATORS
WO2004033460A1 (en) * 2002-10-11 2004-04-22 Ligand Pharmaceuticals Incorporated 5-cycloalkenyl 5h-chromeno[3,4-f]quinoline derivatives as selective progesterone receptor modulator compounds
US7163946B2 (en) 2002-10-11 2007-01-16 Ligand Pharmaceuticals Incorporated 5-substituted 7,9-difluoro-5H-chromeno[3,4-f]quinoline compounds as selective progesterone receptor modulator compounds
US7579469B2 (en) 2003-01-03 2009-08-25 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7625920B2 (en) 2003-03-07 2009-12-01 Merck & Co., Inc. Fluorinated 4-azasteroid derivatives as androgen receptor modulators
US7235662B2 (en) 2003-06-11 2007-06-26 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor and method
US8097606B2 (en) 2003-07-23 2012-01-17 Corcept Therapeutics, Inc. Antiglucocorticoids for the treatment of catatonia
WO2005030213A1 (en) 2003-09-24 2005-04-07 Boehringer Ingelheim Pharmaceuticals, Inc. 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1h-pyrrolo
US7507843B2 (en) 2003-10-16 2009-03-24 Boehringer Ingelheim Pharmaceuticals, Inc. Stereoselective synthesis of certain trifluoromethyl-substituted alcohols
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US7741361B2 (en) 2004-12-27 2010-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7635711B2 (en) 2004-12-27 2009-12-22 Boehringer-Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
WO2010147947A2 (en) 2009-06-16 2010-12-23 Schering Corporation NOVEL [3,2-c] HETEROARYL STEROIDS AS GLUCOCORTICOID RECEPTOR AGONISTS, COMPOSITIONS AND USES THEREOF
WO2011016050A2 (en) 2009-07-31 2011-02-10 Cadila Healthcare Limited Novel compounds as modulators of glucocorticoid receptors

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